Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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~~HIGH MOLECULAR WEIGHT POLYMERS, DEVICES
AND METHOD FOR MAKING AND USING SAME
FIELD OF THE INVENTION
[0002] This invention relates to novel polymers that release active or
activatable compounds having
desirable properties, such as high molecular weight (MW), rigidity, stability,
flexibility, adhesiveness,
temperature range, etc. These polymers are useful for delivering compounds in
situ, preventing and
treating diseases, coating and protecting surfaces and articles, and for
multiple other applications.
BACKGROUND
[0003] The safe and effective delivery of an active agents) to a specific
location enables a site-specific
delivery that generally is associated with lesser side effects than more
widespread delivery. Site-
specific delivery is particularly desirable for the treatment of localized
health conditions such as
cancer, cardiovascular disease, orthopedic conditions, dental conditions,
wounds and auto-immune
diseases such as arthritis or gastrointestinal (G.L) conditions. Such site-
specific delivery is also
desirable for the protection of inanimate products including marine,
construction, and articles that are
exposed to water and biological contamination, among others. The use of
polymers for drug delivery
began in the 1960s as controlled-release oral formulations of an agent coated
with a non-therapeutic
polymer. Many such formulations, however, induce inflammation or host
responses at the delivery
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site, or have low and/or unpredictable potency, breakdown products, non-zero-
order release rates, burst
effects (drug delivery spikes), or other untoward effects.
[0004] Devices such as stems, grafts, implants, and surgical and wound healing
devices frequently
induce, or are associated with, undesirable side effects that include pain,
inflammation, swelling,
infection, adjacent tissue hyperproliferation, capsule, and foreign body
response, such as granuloma or
~,~ fibroma formation surrounding an implant. Although more biocompatible
polymer coatings and other
surface technologies were developed in order to reduce these effects, the
polymers employed are either
not biodegradable, or are inherently highly inflammatory and unpredictable in
nature. Non-
biodegradable coatings are disadvantageous, in addition, because they suffer
from fatigue over time
and i~hey delaminate in situ.
[0005] Polymers containing therapeutic and other agents incorporated into a
polymer backbone have
been described for use in formulations and devices for use in medical and
other applications. Many
polymers, however, have limitations associated with, for example, adhesion (or
lack thereof), and
temperature dependency that detract from their performance. Most of the
problems stem from lack of
control over polymer structure and growth during the synthetic process. Up to
now, the polymeric
backbone had been formed by standard reaction mechanisms, such as the
formation of a phenolic di-
ester, and conversion to free aromatic diacids reacted to form a polymeric
anhydride; known methods
being represented by three main synthetic routes. In the first method, a mixed
anhydride is prepared
by reaction of a diacid with a low molecular weight aliphatic acid anhydride,
e.g. acetic or propionic
acid, and the mixed anhydride is heated under reduced pressure to form a
polyanhydride in the molten
state. Because of its low molecular weight, the acid anhydride may be
discarded as a volatile by-
product.
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[0006] A second method involves reacting stochiometric amounts of an acid
chloride of a diacid with a
free diacid in the presence of an acid-acceptor, e.g. triethylamine, to
generate a polyanhydride.
[0007] A third method relies on the polymerization-dehydration of a diacid
with a dehydrating agent
such as phosgene, diphosgene, triphosgene, or organophosphorus derivative, to
obtain a pre-
~polyanhydride that is then polymerized.
[0008] Each of these methods, however, has disadvantages. The synthesis of
polyanhydride-esters by
melt condensation polymerization using a pre-polymer intermediate is generally
conducted at high
temperature, e.g. about 180 C, under vacuum. The increasing viscosity of the
polymer melt as the
reaction proceeds slows polymerization considerably and results in polymers of
low molecular weight.
Moreover, portions of the polymer melt undergo local decomposition due to the
occurrence of
localized high temperatures and incomplete mixing, and produce undesirable
brownish polymers.
[0009] Certain applications require the use of resilient materials and
tenacious films that require
polymers of substantial molecular weight (MW), many times in excess of 100,000
Dalton. As is known
in the art, the physical characteristics of a polymer depend on its molecular
structure; discreet
monomer units of regular structure tend to form crystalline or semi-
crystalline materials, whereas
polymers of irregular structure such as random copolymers tend to be
amorphous. For other
applications, polymers need to be solvent-cast into tough films or coatings,
or molded under pressure
into shaped articles, and then subjected to~ sterilization by ionizing
radiation or electron . beam
bombardment, which seriously affect the polymer's molecular weight. It has
heretofore been
problematic to increase a polymer's molecular weight while retaining other
desirable qualities. These
polymers either fail to achieve a desired molecular weight, or form insoluble
gels requiring extensive
heating in the melt, or develop a high polydispersity index (MW/Mn), or both,
due to the occuwence of
side reactions. In the case of step-growth polymers, the polydispersity index
(MW/Mn) often greatly
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exceeds a theoretical value of 2.0, possibly due to chain branching andlor
interference from large ring
macrocyclic oligomers.
[0010] Thus, there is a need for polymers, and for drug and other formulations
and medical devices
employing them, that exhibit a range of improved characteristics such as
flexibility (or rigidity),
adhesiveness, hardness, biocompatibility, processability temperature range,
loading capacity, duration
of'delivery, and others, while al the same time limiting or avoiding one or
mare of the above described
disadvantages. Many of these characteristics are achieved by producing high
molecular weight
polymers, and by careful control of the polymer structure and characteristics.
In order to attain this
goal, there is a need for novel synthetic processes that produces polymers of
desired characteristics, in
high yield, and with high purity.
SUMMARY OF THE INVENTION
[0011 ] This invention relates to the development of new processes for the
preparation of high
molecular weight polymers and there uses. A more complete appreciation of the
invention and other
intended advantages may be readily obtained by reference to the following
detailed description of
embodiments of the invention.
DETAILED DESCRIPTION
I. Introduction
[0012] This invention relates to polymers, formulations, and medical devices
employing them, all of
which release, under appropriate conditions, one or more agents that are
active upon delivery, or are
activated in situ by hydrolysis or other processes. The polymers,
compositions, and devices of the
invention contain high loads of one or more agents, and can release active or
activatable agents in high
amounts, e.g. about 70wt% to about 90wt% agent(s). This makes them highly
potent; and provides an
excellent means for controlled or sustained delivery of an agent. These
polymers and compositions
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may be used to form, or as coatings for, medical devices, or may be provided
as a delivery formulation
comprising nano- or micro-particles in the form of spheres or other desired
shapes. The polymers,
compositions, and devices may also be used as carriers for other agents to be
released as the polymer
degrades.
~~'' [0013] For historical reasons many of the polymers, their chemical
structures, physical characteristics,
~,, and synthetic routes will be described in this patent with reference to
certain anti-inflammatory drugs,
e.g. salicylic acid and diflunisal, some of their characteristics being shown
in Table 1a below. The
overall concepts and description, however, are intended broadly to encompass
all types of agents,
for]'nulations, and devices, and their applications.
Table la: Anti-Inflammatory Properties of Salicylic Acid and Diflunisal
Property Salicylic Acid Diflunisal
OOH F OOH
H F / ~ ~ / H,
Molecular Weight 138 250
Water Solubility high Very Low
Plasma half life (hours) 2.5 8 to 12
Clinical Use
Single ~ral Dose (mg) 650 500
Repeated Dosing 650 mg (4xDay) 250 to 500 mg (2xDay)
Plasma Levels* (~g/ml) 150 to 300 50 to 190
439
LDso (~g/kg) 1,300
Metabolism
No. Metabolites ~ 0 2
Where Metabolized Liver, Intestine Liver, Intestine
Other Tissues
*Anti-Inflammator Effectiveness
Y
[0014] Exemplary polymers provided throughout this patent are tabulated in the
following Table lb.
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Table lb: Exemplary polymers throughout the Patent
Compound Compound Name
No.
125PL poly (ester-anhydride) made from monomer of (salicylic acid-C12-
salicylic
acid)" by a
melt polymerization rocess.
261PL poly (ester-anhydride) made from monomer of (salicylic acid-C8-
salicylic
acid)" by a
melt polymerization rocess.
510PL poly (ester-anhydride) made from monomer of (salicylic acid-C6-
salicylic
acid)" by a
melt polymerization process.
657PL poly (ester-anhydride) made from monomer of (diflunisal-C
14-diflunisal)" by a melt
polymerization process.
749PL poly (ester-anhydride) made from monomer of (salicylic acid-C
10-salicylic acid)" by a
melt olymerization rocess.
Note: n is a positive integer showing the degree of polymerization.
II. Glossary
[0015] The following definitions are used throughout this patent, unless
otherwise indicated.
[0016] The article "a" and "an" as used herein refers to one or to more than
one, i.e. at least one, of the
grammatical object of the article. By way of example, "an element" means one
element or more than
one element.
[0017] As used herein, an "agent" is a chemical compound that is suitable for
incorporation into the
polymer, formulation, or device of this patent, and includes "active" and
"activatable" agents; an
"active agent" refers to a substance that has a physiological effect when
present in a living system; and
an "activatable agent" refers to an agent or its precursor that may be
activated either upon or after its
release by any mechanism.
[0018] An agent may be a compound that has a use. For, example, an agent may
be a marker, a
compound that has an effect for a certain application, be it. for use to
ascertain, diagnose, foster or
impede biological life, or otherwise. An agent may be a compound suitable for
use in construction,
land and marine applications. It may be a drug or therapeutic compound or
precursor of a compound
115ed to treat a specific disease or medical condition. The active agent may
be "biologically active,"
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meaning that the active agent is active and/or exhibits some effect on a
biological system, whether
plant, animal, when applied to a living system or to the inanimate world.
[0019] The active agent may also be "therapeutically active," meaning that the
active agent has
therapeutic properties in a living system, such as aiding in the prevention or
treatment of an undesired
f'' 'occurrence or condition in the living system.
[0020] A "physiological effect" may be, for example, any effect on the
functioning of an organism,
such as, e.g., alteration of normal function, alteration of abnormal function,
andlor restoration to
normal function. A physiological effect may include, but is not limited to,
binding to a biomolecule,
i.e.~ DNA, protein, carbohydrate, lipid, inhibition of enzyme activity, and
sequestration of small
molecule cofactors, i.e. metal ions, amino acids. Biologically active
compounds that may be
incorporated into the polymers of the invention either possess, or are
chemically or biologically added,
at least two functional groups capable of forming a breakable bond or linkage,
e.g. an ester, thioester,
amide, thioamide, carbonate, and the like, within the polymer. Such bonds or
linkages, upon erosion,
breakage, or hydrolysis of the polymer in situ, will release the agent(s).
Examples of functional groups
for the agent or compound comprise, e.g. hydroxy (-OH), mercapto (-SR), amine
(-NR2, or -NR3+) or
carboxylic acid (-COOH), where R may be H or a (C~-C2o) substituent that may
be substituted with O,
N, P, or halogen), among others.
[0021] The term ester linkage refers to -OC(=O)- or -C(=O)O-; the term
thioester linkage refers to -
SC(=O)-, -OC(=S)-, -C(=O)S-, or -C(=O)S-; the term amide linkage refers to -
N(RZ)C(=O)- or -
C(=O)N(RZ)-, the term urethane or carbamate linkage refers to -OC(=O)N(R)- or -
N(R2)C(=O)O-,
wherein each RZ is a suitable organic radical, such as, for example, hydrogen,
(C~-C2o)alkyl, (C3-
Cao)cycloalkyl, (C3-CZO)cycloalkyl(C~-CZO)alkyl, aryl, heteroaryl, aryl(C~-
CZO)alkyl, or heteroaryl(C~-
C~o)alkyl; and the teen carbonate linlcage refers to -OC(=O)O-.
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[0022] "Heteroaryl" refers to a radical attached via a ring carbon or
heteroatom, or via an appended
chain of an aromatic ring containing 3 to 20 ring atoms consisting of carbon
and heteroatoms
comprising O, S, P, or N, which may be substituted by R, wherein R may be
absent or H, O, halogen,
(C~-C2o)alkyl, (C3-Cao)cycloalkyl, (C3-C2o)aryl, including phenyl, benzyl, and
bicyclic structures, all of
which may be further substituted by a heteroatom, e.g. a (C3-C2o)heterocyclic
group, particularly a
benzyl derivative or. one derived by fusing a propylene, trimethylene, or
tetramethylene diradical
~;n ,
thereto
[0023] As used herein, "administering an active agent near the site" means
applying the agent at, or
proximal to, a given site to produce a desired or stated therapeutic effect in
a localized manner, e.g. to
red~ce bone resorption, stop bleeding, or foster bone growth at the site.
[0024] "Alkyl", "alkoxyl", etc. may denote both straight and branched groups;
a reference to an
individual radical such as "propyl" may denote a straight chain radical; a
branched chain isomer such
as "isopropyl" being specifically referred to.
[0025] The term "amino acid" refers to residues of the natural amino acids,
e.g. the D or L forms of
alanine (Ala), arginine (Arg), asparragine (Asn), aspartic acid (Asp),
cysteine (Cys), glutamic acid
(Glu), glutamine (Gln), glycine (Gly), histamine (His), isoleucine (Ile),
leucine (Leu), lysine (Lys),
methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine
(Thr), triptophan (Trp),
tyrosine (Tyr), and valine (Val), and non-natural amino acids, e.g.
phosphoserine, phosphothreonine,
phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid,
octahydroindole-2-
carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
penicillamine, ornithine,
citruline, a-methyl-alanine, para-benzoylphenylalanine, phenylglycine,
propargylglycine, sarcosine,
and tert-butylglycine, among many others. The term "amino acid" also comprises
natural and non-
natural amino acids bearing a conventional amino protecting group, e.g. acetyl
or benzyloxycarbonyl,
~n:r~n;;w: r,_:.~~,~,-~:_: ~::-; r~~_:,.-:
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as well as natural and non-natural amino acids protected at the carboxy
terminus, e.g. as a (C1-C6)
alkyl, phenyl or benzyl ester or amide; or as an a-methylbenzyl amide. Other
suitable amino and
carboxy protecting groups are known to those skilled in the art, and are
included within the context of
this invention. See, for example, Greene, T.W. and Wutz, P.G.M. "Protecting
Groups In Organic
Synthesis", Second Edition, New York, John Wiley & Sons, Inc., 1991, and
references cited therein.
~n ,
[0026] As used herein, an agent is "appended" to a polymer when the agent is
bonded or complexed to
the polymer as a side chain or side group, but is not part of the polymer
backbone. The agent is
bonded to the polymer preferably through a breakable linkage that will release
it when applied or
adr~.ninistered according to the methods of the invention. For example, an
agent or compound may be
linked to a polymer through a hydrolyzable linkage such as an anhydride or
ester linkage. Others,
however, are also suitable.
[0027] "Aryl" denotes any' aromatic residue, including phenyl and ortho-fused
bi- or tri-cyclic carbo-
or hetero-cyclic residue having about 4 to 20 ring atoms in which at least one
ring may be aromatic.
[002] As used herein, an agent or functional group may be "associated" with
the polymer by one of
many forms, including by direct, linear integration (i.e. chemical bonding)
into the polymer backbone,
as a side chain or side residue chemically bonded to the polymer backbone not
part of the backbone,
electrostatic bonding to the polymer backbone, linkage to the polymer backbone
through a linking
group, pendent (i.e. an off shoot of the backbone) neither oligomeric nor
polymeric, attachment to the
polymer backbone, or bonding to one or more endings of the backbone. The
association used will
depend on the functional characteristics (e.g. . number and type of reactive
groups) of the functional
group.
[0029] A substance is said to be "bioabsorbable", but not necessarily
biocompatible or biodegradable,
when it may be absorbed by, whether integrated or not into, a living system in
which it is placed.
~;p:(tl''?'.-I it-i-.Inn-n-t p_;~ n~~")=:~"
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tVVJVJ t1 JlAUJ6Gl111:G 15 SQllt W ~~ ~~~~~~a~~y "compatible", e.g.
"biocompatible", when it has the
properties of being compatible with a system, e.g. a living system, and is not
detrimental to the general
existence and functioning of the system, e.g. neither toxic to, nor causes a
detrimental reaction (e.g.
immunological reaction) in a living system, so that it would make it
undesirable to continue its use. A
substance is said to be "degradable", e.g. "biodegradable", when it is broken
down into components
smaller than its original size when present in the target system, e.g. a
living system.
;n
[0031 ] A "diagnostic agent or compound" refers to a substance that may be
employed to assess a
certain status or presence by a known means.
[0032] A "tracer" or "marker" refers tb an agent or compound that, although it
may or may not have its
owm activity, may be located when placed in a pre-determined position, or it
may be followed to
ascertain where it lodges, therefore providing information on the path it
followed and its current
location.
[0033] "Therapeutically active compounds", or "detectable diagnostically,
veterinarily or
therapeutically active compounds" include diagnostic and therapeutic agents
that provide a diagnostic,
preventative or therapeutic effect when administered to a subject, e.g. an
animal such as a mammal
including a human.
[0034] A "functional group" refers to a chemical residue or moiety that may be
incorporated into a
polymer, e.g., into an ester, thioester, or amide linkage of a polymer as
discussed in detail below, such
that it releases the agent or its precursor upon erosion or breakage of the
polymer, e.g. hydrolisis,
enzymatic breakage for example by esterases. These groups may independently be
a hydroxy group (-
OH), a mercapto group (-SH), an amine group (-NHR), a carboxylic acid (-COOH),
a . halo that
comprises fluoro, chloro, bromo, or iodo, and others known in the art.
I;p~~WV.~ o-i-)m,_n~ I_:?I n-I~~y:~~ '
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[0035] The term "peptide".reters.to sequences of about 2, 3, or 5 to about 15,
20, or 35 and more
amino acids as defined above, or peptidyl residues that may be linear or
cyclic, such as those that may
be prepared or result from the formation of disulfide bridges between two
cysteine residues. Peptide
derivatives may be prepared as disclosed in U.S. Patent Nos. 4,612,302;
4,853,371; 4,684,620, or as
described in the Examples provided below. Peptide sequences specifically
provided in this patent are
:y, ,
written with the amino terminus on the left and the carboxy terminus on the
right.
[0036] As used herein, "physiological conditions" are the conditions in a
physiological system or
environment, such as a mammal, e.g.' a human, and may be "normal physiological
conditions" such as
those encountered in a normal, healthy subject or patient, or "abnormal
physiological conditions" such
as those in an unhealthy, sick, or injured subject or patient. Physiological
conditions may be found, for
example, inside a mammal, or on the surface of a mammal, such as in skin or
hair.
[0037] An agent is considered to be "physiologically irrelevant" when it does
not perform a
physiological or biological function, such as for example when incorporated
into a polymer backbone.
The fact that the agent is chemically coupled in the polymeric structure
renders it unavailable to
interact 'with a target.
[0038] An agent may be considered "physiologically inactive" when it is in a
form in which it may not
perform a biological function, even when it is freely available in the
biological milieu.
[0039] An agent is considered "physiologically relevant" when in a chemical
form in which it may
perform its desired biological function, e.g. interacting with a biological
molecule, or sequestering of a
relevant substance.
[0040] Even though it is present in a physiologically relevant form, an agent
may not be "active" in a
physiological environment. The agent may be, for example dispersed in, or
sequestered inside empty
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JjJCt4GJ Vl 111G ~lVlyiliGl, lGliuClili~' m unavaiiaDie to the surrounding
biological milieu. .As a result, even
though it is present in a biologically active form, the biological activity of
that active agent is hill until
released from the polymer. A physiologically relevant active agent is said to
be "physiologically
active" when it is available to the surrounding biological milieu and actively
involved in its biological
role.
[0041] As used herein,. the term "healing" means the repair of a defect or non-
normal condition or
state, and it may be applied to a living or non-living entity. When applied to
a living entity healing
refers to the restoration of health or the process of a return to health. When
applied to a non-living
entity, "healing" refers to the return to a normal or acceptable state, or to
the fixing of a condition so
that the entity is operational.
[0042] The inventive polymers form biodegradable bonds within the backbone of
the polymer that
may be broken by regular hydrolysis, proteolysis, or other biological or
biochemical processes when
placed in contact with an aqueous environment, microorganisms, body tissues,
fluids, and the like.
[0043] A substance is said to be "resorbable", e.g. "bioresorbable", when its
material is a naturally
occurring material, e.g. in a living system, and is capable of being absorbed
by, and integrated into, a
system, e.g. the living system, when placed into it or when created and
subsequently placed in the
system.
[0044] As used herein, the term "dispersed through the polymer matrix" means
that an agent or
compound is located within a matrix, for example a polymer by mixing,
spreading, sprinkling,
thoroughly mixing, physically admixing, or dispersing in the polymer matrix,
among others, so that it
may be released in a controlled manner over a period of time when placed in a
system, e.g. within a
living host.
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[0045] As used herein, the term "dissociate" indicates that an agent,
compound, or substance is
separated or broken into smaller parts that may be chemically similar to the
undissociated whole or
they may be chemically dissimilar to the undissociated whole. Chemically
dissimilar dissociation
products may be heterogeneous or homogeneous with respect to either chemical
properties or size, or
,f~ both. Dissociation products may also be able to recombine to recreate the
original undissociated
whole, or they may remain permanently dissociated. Dissociation may occur
spontaneously, as an
;n ,
inherent property of the undissociated whole, or as a result of a physical or
chemical process, such as
hydrolysis of the undissociated whole.
[Of~46] The term "formed into" includes a polymer, compound, composition, or
formulation of the
invention that may be physically placed into various shapes, geometries,
structures and configurations
including, but not limited to a film(s), coating(s), fiber, rod, coil, suture,
closure, sealer, sphere, pin,
corkscrew, hook, cone, pellet, tablet, tube (smooth or fluted), disc,
membrane, formulations comprising
microparticles, nanoparticles, and/or "biobullets" (i.e., bullet shaped), seed
(i.e., bullet shaped, or
targeted seeds), sleeve, cuff, free standing film, sheath, wrap, tube, cuff,
stitches, formed gel, etc.
[0047] A "sleeve" is a physical conformation of a compound, agent or article
that is placed adjacent to
and fits around or covers a second compound, agent or article, for example a
medical or therapeutic
device. A plastic coating surrounding a metal rod may be considered to be a
sleeve for the rod: A
sleeve may also be placed adjacent to a separate compound, agent or article
without completely
enclosing the latter. A sleeve may describe a compound, agent or article that
is formed into, for
example, a coating, a film, a sheath, a wrap, a tube, a cuff, or a formed gel
partially or wholly
'surrounding a second compound, agent or article, such as a medical device or
implant.
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[004] As used herein, a substance is said to be solid when it has three
dimensions and has the
properties of a solid; namely it is not in liquid or gaseous form. For
example, a piece of paper, a metal
rod, a steel needle are all considered to be solids in the context of this
patent.
[0049] A substance is said to be "semi-solid" when it has some properties of a
solid, and some of a
liquid; for example it is easily deformable by physical or chemical action.
For example, gel and clay
are "semi-solids" in accordance with this definition.
[0050] As used herein formulated for "controlled release" refers to an agent
formulated to be released
over an extended period of time when administered according to this invention.
For example, the
agent may be formulated for release over a period of at least about l, 2, 5,
or 10 hour(s), about 1, 2, 5,
10, 20, 40, or 90 days, about 1, 2, 4, 6, 9, or 12 months, or 1 or more years.
The agent is formulated
for release over about 1-10 days. For the treatment of hard tissue, the agent
is formulated for release
over about 8, 15, or 30 to about 45, 60, or 90 days, and for the treatment of
soft tissue over about 1, 2,
or 3 to about 5, 10, or 30 days.
[0051 ] As used herein, the term "hard tissue" includes tissue that has become
mineralized, such as, for
example, bone, cartilage, or both.
[0052] The term "host" includes animals and plants, such as, e.g., a mammal,
including a human. A
host may also be a "human patient" or an "non-living environment" to which the
polymer is applied.
[0053] For purposes of the present invention a "low molecular weight agent"
includes any compound
with, but not limited to, one carboxylic acid group and at least one amine,
thiol, carboxyl, amide,
alcohol or phenol group within its structure, wherein the compound has a
specific activity, e.g.
pharmaceutical activity, and up to about 1000 molecular weight.
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[0054] By "device" it is meant a structure that is formed of, or covered by, a
polymer of the invention.
Devices may be used for different applications on inanimate and living
systems.
[0055] A "medical device" or "medical implant" refers to a therapeutic device
or a therapeutic implant,
respectively, that is used specifically for a medically-related purpose. For
example, a bone "screw",
"'cuff', or "pin" are both medical devices and medical implants. A device,
whether therapeutic or
otherwise may comprise more than one component. A therapeutic device that is
either temporarily or
permanently placed either partially or wholly inside a living system may also
be referred to as a
"therapeutic implant", and may be~ active when implanted, or activated after
implantation. The
adihinistration or application of an agent "to" or "near a tissue" refers to
the delivery of agent to a
loc~,ation proximal to, or in direct contact with, the tissue to produce the
desired localized therapeutic
effect. A "veterinary device" refers to a device that is adapted specifically
for use in an animal,
whether wild, domesticated, marine, zoological animals, and the like.
III. Structure of the Inventive Polymers
A. Introduction
[0056] The polymers of the invention are suitable for delivering an agents) or
compounds) to a pre-
selected site, such as a biocompatible and biodegradable polymer that is
capable of releasing at least
one agents) upon degradation and/or hydrolysis of the polymer under
appropriate conditions, e.g.
physiological conditions, for monitoring, diagnostic, prophylactic and
therapeutic applications.
Suitable polymers include backbones comprising an agents) and are suitable as
delivery systems.
Such polymers may incorporate an agents) as a repeating unit of the backbone,
which units are linked
~by labile bonds such as esters, thioesters, amides, .thioamides, urethanes,
carbamates, carbonates,
,ethers, azo links, and carbonates, among others.
CA 02527495 2005-11-28
WO 2005/042600 ~6 PCT/US2004/017916
[0057] When delivered into a host, such as a mammal, and more specifically a
human, the polymer
will break down over a period of time and release the agent(s). In one
embodiment, a suitable polymer
degrades over a period of time to produce relatively high, localized levels of
an agents) to deliver an
enhanced therapeutic effect while minimizing side effects associated with the
systemic delivery of
drugs. In one embodiment, a suitable polymer is biocompatible. In another
embodiment, the polymer
is biodegradable and demonstrates favorable solubility and processability, as
well as degradation
properties suitable for the desired use: In yet another embodiment, the active
agent is released over a
period of time as the polymer hydrolyzes under physiological conditions,
providing for an extended-
release formulation that provides a consistent and continuous source of the
therapeutic substance for an
extended period of time. Suitable polymers for use in the present invention
include polyesters, such as
polyester-esters) and polyester-carbonates), polyamides, polycarbonates, and
polyanhydrides such as
poly(anhydride-esters), and poly(azo-anhydrides), among others. Examples may
found in U.S. Patents
6,328,988; 6,365,146; 6,468,519; 6,486;214; 6,497,895; 6,602,915; 6,613,807;
4,916,204; and
4,868,265; U.S. Published Patent Applications 2002/0071822 A1; 2002/0106345
A1; 2003/0035787
Al; 2003/0059469 Al; 2003/0104614A1; 2003/0170202A1; U.S.S.N.s 091508,217;
10/368,288;
101622,072; 10/646,336; 10/647,701; WO 99/12990; WO 01/28492; WO 01/41753; WO
01/58502;
WO 02109767; WO 02/09768; WO 02/09769; WO 03/005959; WO 03/046034; WO
03/065928; and
WO 03/072020; and Erdmann, L., LThrich,. K.E., Biomaterials, 21: 1941-1946
(2000), the relevant
portions of all of which being incorporated herein by reference. The polymer
of the invention may be
a polyanhydride, preferably having a backbone comprising one or more groups
that will release a
compound upon hydrolysis or enzymatic degradation of the polymer.
[0058] The polymers of this invention have valuable physical and chemical
properties that are useful
for a broad number of applications, such as the delivery of biologically
active compounds, the
preparation of formulations, tamponades, films, coatings, devices, implants,
and coated devices. The
CA 02527495 2005-11-28
WO 2005/042600 ~7 PCT/US2004/017916
polymers of the invention may be readily processed into pastes, films,
coatings, nanoparticles,
microparticles, gels, powders, sprays, creams, ointments, tablets, capsules,
emulsions, solutions;
suspensions, granules, fillers, covers, linings, grids, meshes, gramps, and
fibers for use in the design of
articles, e.g. devices and implants, of different geometric shapes using
techniques known in the art,
such as solvent casting, solution or suspension spraying, compression molding
or extrusion.
Applications of these products may be found in every aspect of modem life,
from coatings for articles
of use in the home, such as to protect bathroom, laundry room, and kitchen
facilities and their
polymeric, metal and ceramic surfaces, pictures, furniture, and other articles
from mildew, dust
deposition, microbial contamination, and the like, to marine, construction,
medical, veterinary,
agricultural, dental, surgical, orthopedic, laundry, household, and hair and
cosmetic uses. Some
applications will benefit from incorporating short half life polymers that
will disappear after a pre-
determined initial stage. Examples of these are laundry products, cosmetics
and hair products, arid the
like that only need be active until the next application. Coloring products,
however, may be made for
short or long lasting effects as is known in the art. The color of short
acting polymers will wear out
after a few washes whereas the longer half life polymers will permanently
alter the color of hair and
other materials. Other applications are more suited for the use of polymers of
longer half lives that
will preserve the activity of the incorporated agent for extended periods of
time: Examples of the latter
are household applications such as coating of surfaces with a prolonged half
life polymer that will
deliver a desired agent for periods of months or years, or for the duration of
the life of the article if the
polymer is incorporated into the article itself or mixed therein with other
polymers or natural
substances such as wood derivatives and the like.
B. General Formulas
[0059] The present invention provides a compound of formula H-Y-C(=Y)-R'-A-R'-
C(=Y)-Y-H
("Formula Ia"), wherein each R' comprises, independently from one another, a
residues) of a
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WO 2005/042600 i8 PCT/US2004/017916
diagnostically, traceably, biologically or therapeutically active or
activatable agents) or compounds)
that is(are) released upon polymer degradation; each Y comprises independently
O, S, NRZ, where Ra
comprises H, alkyl, alkenyl, alkynyl, all of which may be substituted with O,
N, S, P or halogen; each .
A, independently from one another, comprises ester, amide, thioester, azo, or
thioamide, or their
combination.
~;n [0060] In another embodiment, the compound, and the polymer comprising
units) of this compound,
comprise the chemical formula H-Y-C(=Y)-R'-A-L-A-Rl-C(=Y)-Y-H ("Formula Ib"),
wherein all
variables are def ned as above; and L comprises a linking group. In one
embodiment, A comprises an
amide, an ester, or both, and in another embodiment, A comprises a thioamide,
a thioester, or
combinations thereof. Typically, the Rl may comprise monomers, dimmers,
trimmers, tetramers, and
higher meric units of the agent's residue. These individual residues may be
bound directly to one
another, or through a linking group(s). Suitable linking groups are those
described in this patent and
include all other suitable functional groups and residues known in the art.
[0061] The polymers of the present invention comprise an agents) or
compound(s), and an optional
linker groups) bonded through a labile linkage such as an ester, thioester,
amide, thioamide, azo,
anhydride, carbonate, ether, thioether, or a combination thereof. Due to the
presence of the ester,
thioester, amide, andlor thioamide linkages, the polymers may be hydrolyzed,
enzymatically, or
otherwise degraded under physiological conditions to provide the biologically
active compounds.
Thus, the polymers of the present invention are particularly useful as for
controlled release of agents,
whether for biological or other types of applications, and as a means for
localized delivery of agents to
a selected site or target. The polymers of the invention may be used, for
example; for the localized
.delivery of an agent to a targeted site within the human body, e.g. within or
near a tumor, where the
polymer provides a localized, controlled release of the agent. The polymers
prepared using the
processes of the invention may have an avera~~e molecular weight (M~~h~~,i:)
of about 1,500; 3,000;
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WO 2005/042600 19 PCT/US2004/017916
10,000; 30,000; 50,000; 100,000; 250,000; 500,000; or 1,000,000 Dalton to
about 20,000; 50,000;
100,000; 200,000; 350,000; 500,000; 750,000; 1,000,000; 1,200,000; 1,350,000;
or 1,500,000 Dalton;
and even higher, as determined by Gel Permeation Chromatography (GPC) relative
to narrow
molecular weight polystyrene standards as is known in the art. The present
polymers exhibit a
backbone linking one or more agents or compounds into polymeric delivery
systems. The polymers '
are typically biocompatible and biodegradable, and preferably demonstrate
excellent solubility and''
processability, as well as suitable degradation properties, such as
erodability, due to the presence of
bonds such as anhydride, ester, amide, urethane, carbamate, azo, and
carbonate, among many others,
that are breakable under specified conditions. Suitable polymer bonds for use
in the present invention
include, for example, polyesters, polyamides and polyanhydrides of the type
described in WO
99/12990; U.S. Patent Applications No. 09/917,231; 09/917,194; 09/508,217;
09/422,294; 09/732,516;
60/220,707; 60/261,337; 60/058,328; and 60/220,998. '
[0062] The invention provides a compound of the formula
-(M)m (IIa)
B-[(M)n,]Y (IIb)
[0063] Where M is a moiety suitable for polymerization and B is a moiety with
multiple functional groups. M
represents the number of repeating units, e.g., M may be about 2, 5, 10, 15,
20, 30, 50 to about 100 or any higher
number as needed to reach a desired average molecular weight of about 1,500;
3,000; 5,000; 7,00; 10,000;
20,000; 50,000; or 100,000 Dalton to about 50,000, 75,000; 100,000; 250,000;
500,000; 1,000,000, and higher
Dalton; and y is a positive integer between 2-8. B can be a moiety with
multiple functional groups suitable to
(start polymerization such as, e.g., COOH, NHz, SH, and others. Examples of
compounds which could be used
as B are, 1,3,5-benzene tricarboxylic acid, 1,2,3,4-butane tetracarboxylic
acid, cis-aconitic acid, and trans-
aconitic acid.
CA 02527495 2005-11-28
WO 2005/042600 20 PCT/US2004/017916
[0064] In one embodiment, M comprises one or more units of the chemical
formulas
-R'-A-R'- (IIIa) and
-R'-A-L-A-R'- (IIIb)
[0065] wherein R' independently comprises one or more residues comprising an
agents) that is released upon
polymer degradation; A independently comprises a labile group such as amide,
thioamide, ester, thioester,
carbonate, azo, or thiocarbonate, among others; and L, which may or may not be
present in the polymer
backbone, independently from one another, comprises one or more units of a
linking residue(s). Such a polymer
is particularly useful for the administration of a combination of more than
one agent. In one embodiment, R'
comprises a monomer, dimer, trimer, tetramer, pentamer, and higher mers such
as a decamer, dodecamer,
hea~~.decamer, etc., of the same or different agent(s).
[0066] The polyanhydride made of formulas (IIIa) and/or (IIIb) or combinations
thereof serves as the backbone
of a delivery system that provides a controlled delivery of an agents) or
compounds) to any targeted site, e.g.,
of a host such as a human, animal, plant, or article of manufacture. In one
embodiment, the polymer of formula
(III) comprises a low molecular weight agents) with functional groups such as
carboxylic acid, thioacid, amine,
amide, thiol, thioamide, carbonate, azo, alcohol or phenol, among many that
form labile bonds, including those
comprising heteroatoms such as P, S, N, and the like. In another embodiment,
the polymer comprises a units)
comprising formula (IIIa) and/or (IIIb), wherein each R', independently from
one another, comprises and is
capable of releasing an aromatic agent(s), such as an NSAID, or any other
agents) to be delivered by the
polymer, some of which are listed below. Examples of suitable salicylates
include, but are not limited to,
diflunisal, diflucan, thymotic acid, 4,4-sulfinyldinailine, 4-
sulfanilamidosalicylic acid, sulfanilic acid,
sulfanilylbenzylamine, sulfaloxic acid, succisulfone, salicylsulfuric acid,
salsallate, salicylic alcohol, salicylic
acid, orthocaine, mesalamine, gentisic acid, enfenamic acid, cresotic acid,
aminosalicylic acid,
~aminophenylacetic acid, acetylsalicylic acid, and the like. The
identification of a suitable R' and A to release an
aromatic agent(s), e.g., a salicylate, may be readily determined by those of
ordinary skill in the art without
undue experimentation. In one e.»>bodiment, the active a~~ent is salicylic
acid or one oi~ its derivatives that are:
CA 02527495 2005-11-28
WO 2005/042600 21 PCT/US2004/017916
well known in the art. In another embodiment suitable azo monomers are
polymerized to provide polyazo
compounds and then polyazo anhydrides. In a preferred embodiment the polymer
may be a polyester or a
polyamide, and it comprises units containing at least two free hydroxyl,
phenols, amines, or combinations
thereof available for co-polymerization with carboxylic acids or bis(acyl)
chlorides. Another preferred polymer
may comprise one or more units of formula
-R'-A-L-A-(IV)
[0067] wherein all variables are as defined above. Another exemplary polymer
of the invention is a co-
polymer that comprises one or more units of formula
I
-R,-A-L-A-R,-A- (~)
[0068] wherein all variables are as defined above. In one embodiment, the
polymer comprises one or more
units of formula.
-RZ-A-L-A-R3-A-L-A- (V)
[0069] wherein RZ and R3, independently from one another, comprise a residue
that will yield a compounds)
upon polymer hydrolysis or enzymatic degradation; and other variables are as
defined above. Polymers where
RZ and R3 comprise residues' that will yield different compounds upon polymer
degradation are particularly
useful for the administration of combination therapy. Another preferred
embodiment comprises a co-polymer of
one or more units of formula
-R'-A-LZ-A-R'-A-L3-A- (VI)
(0070] wherein LZ and L3, independently from one another, comprise a linking
group; each A, independently
from one another, comprises amide, thioamide, carbonate, azo, ether,
thioester, or ester, among labile bonds; and
each R is independently a group that will yield a active compound upon
hydrolysis or enzymatic degradation of
the polymer. In this embodiment L' and L~ are linking groups that impart
different physical properties to the
polymer thai malees them particularly useful for cusiomizin~ the physical
characierisiics of the polymer for a
CA 02527495 2005-11-28
WO 2005/042600 22 PCT/US2004/017916
specific application. In one embodiment, the active agent is salicylic acid,
and the polymer comprises a
polyester-ester).
[OD71 ] In one embodiment, the polymer comprises one or more units of formula
-A-R'-N=N-R'-(A-L)n_ (VIIa) and/or units of formula
-A-R'-N=N-R'-(A-L)"- (VIIb)
[0072] wherein each R'-N, independently from one another, comprises a group
that will provide a biologically
active compound upon polymer degradation; each A, independently from one
another, comprises anhydride,
amide, thioamide, thioester, carbonate, enter, or ester; L comprises a linking
group as already described; n is 0 to
10. Suitable monomers are polymerized to provide the polyazo compounds. In one
embodiment, the polyazo
compound comprises at least one free amine group to form the azo group and at
least one free, carboxylic acid,
alcohol or amine available for self polymerization, or co-polymerization with
other carboxylic acids or bis(acyl)
chlorides. In one embodiment, the polymer comprises more than one agents)
incorporated into a poly(azo-
anhydride) that serves as a polymeric drug delivery system for oral delivery
of a cancer drug. The polymer may
have two, three, or more different R groups, each of which will provide a
different agents) upon polymer
degradation, and each R group may have one or more repeats of the same or
different agent(s), e.g. monomer,
dimer, etc. In one preferred embodiment, the polymer comprises a non-steroidal
anti-inflammatory agent
(NSAID), such as, e.g., salicylic acid and/or diflunisal. Such polymers may
comprising repeating units of
chemical formula II, III, VII and/or X, or combinations thereof.
[0073] The polymers of the invention may be prepared by any suitable method
known in the art. Examples are
those described in WO 99/12990; U.S.S.Nos. 09/917,231; 09/917,194; 09/508,217;
091422,294; 09/732,516;
60/220,707; 60/261,337; 60/058,328; and 60/220,998; and Conix,, Macromol.
Synth. 2: 95-99 (1966). When
specific characteristics are desired, the polymers may be prepared using
processes described herein.
[0074] In another embodiment the polymer comprises polyester-anhydride) bonds.
One preferred polymer
comprises units of the chemical formula
CA 02527495 2005-11-28
WO 2005/042600 23 PCT/US2004/017916
O O
R~-O~ Lr _O-R~ O~
O ~ (II)
[0075] wherein all variables are as defined above.
'~~ '[0076] In another embodiment the polymer comprises polyester-ester)
bonds. One preferred polymer
~~i comprises units of the chemical formula
O O
R~-O~ L' 'O-R~ O~
[0077] wherein all variables are as defined above.
[0078] In another embodiment the polymer comprises polyester-carbonate) bonds.
One preferred
polymer comprises units of the chemical formula
O O
\ 'O, R~ ~O~ L ~O~ R~.O~
(xI)
[0079] wherein all variables are as defined above.
[0080] The polymer may have two, three, or more different R' groups, each of
which may provide a
different agents) upon polymer degradation. Such polymers are particularly
useful for the application
or administration of a combination of two or more agents to a host, such as an
animal or plant, or an
article of manufacture. In another embodiment the polymer comprises a
homopolymer, and in another
it comprises a co-polymer.
CA 02527495 2005-11-28
WO 2005/042600 24 PCT/US2004/017916
[0081 ] The polymers) described herein will release their agents) when placed
at a pH of about 3, 4, 5,
6, 7 to about 8, 9, 10, 11, 12, 13, and higher over a period of time of about
1, 2, 3, 5, 10 20, 50, 75 days
to about 2, 3, 5, 7, 9, 12, 24 months or longer. When the polymer is placed at
a pH below its pKa it
will degrade slowly, for example over a period of 6 months or longer. When Rl
comprises a drug
residue(s), the polymer may function as a drugs) delivery system that provides
a controlled effective
amount of the agents) as a function of polymer degradation at any pre-
determined site to which it is
applied, or delivered. Polyanhydride materials have been extensively
described. See, for example,
U.S. Patents 4,757,128; 4,997,904; 4,888,176; 4,857,311; 5,264,540; and WO
99/12990; WO
02/09769; WO 02/09767. In general, anhydride polymers of higher, average
molecular weights such
as, e.g., polymers described herein, possess unexpected and advantageous
properties, such as greater
mechanical strength and higher stability, that polymers of lower average
molecular weights do not
possess. Because of this higher molecular weight, these polyanhydrides may be
laid as harder and
thicker coatings. In one embodiment, the polymer of the invention may have an
average molecular
weight (MWAVE) of at least about 200,000, and preferably above about 250,000
Dalton, and up to
1,000,000 Dalton and higher.
[0082] The polymer of the invention typically have a glass transition
temperature (Tg) about -10, -5, 0,
10, 30, 50 to about 60, 70, 80, 100, 130, 160, 200C, with a most preferred Tg
is in the vicinity of or
below about SOC.
[0083] The polymer may comprise any number of agents, whether biologically,
diagnostically,
prophylactically, therapeutically or otherwise active or inactive, or whether
the agents have other
activities that make them suitable for applications other than to
microorganisms, plants, animas,
humans, or articles of manufacture. In fact any type of agent that may be
polymerized or appended, or
mixed, blended, dispersed or otherwise incorporated into a polymeric
formulations and released from
its structure is suitable for use in this application. S11c17 a'~ent(s) may be
loaded in amounts of about 0.
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WO 2005/042600 25 PCT/US2004/017916
5, 10, 15, 20 %w/w to about 25, 30, 35, 40, 45, 50 %w/w, although other
amounts are also
contemplated including up to 70wt%, and 90wt%, and even higher.
[004] In one embodiment, the polymer comprises a non-steroidal anti-
inflammatory agent (NSAID)
such as salicylic acid and/or diflunisal, and units of chemical formula I,
among others, or their
~H~ 'combinations, where each RI may be a monomer, dimer, trimer, tetramer, or
higher mer of an agent(s).
v;~i ~n another embodiment the polymer is combined with one or more agents in
any suitable manner, such
as by physically admixing, blending, embedding, appending, or dispersing the
additional agents) in
the polymeric matrix. The agents) may be also incorporated into the backbone,
chemically linked in
the' backbone directly or through a 'linker or spacer, directly or indirectly
chemically linked to a
che~~nical group attached to the backbone, or electrostatically or in any
other manner attached to the
polymer or its backbone. In one embodiment, the active agents may be attached
to repeating units of
the polymers of the present invention by covalent bonds linked to an aromatic
(Ar) ring or an linear,
branched, or cyclic aliphatic (R) organic residue, providing for sustained
release of the agent(s). In
another embodiment the agents) may merely reside in the unoccupied spaces
present in the polymer:
In another embodiment, the agents) forms) a salts) with the polymer or its
backbone. In still another
embodiment the agent is located in the unoccupied spaces of a polymer and is
present as a
homogeneous functional group, or is - incorporated into a salt(s), micelle(s),
liposome(s), or
heterogeneous aggregate(s). The polymer may comprise various segments
comprising one or more
similar or different residues of an agents) that will be released either
directly or indirectly by polymer
degradation. The polymer may also comprise a second or additional agents) that
is physically
admixed, embedded or dispersed in, or combined with the polymer as is known in
the art.
[0085] In another embodiment, the compound(s), and the polymer comprising
units) of the
compound(s), of chemical formula (Ia) or (Ib) shown above comprises a
diagnostically, traceably,
biolo;~ically or pharmaceutically active or activatable a'~ent(s) or
compounds) of the chemical formula
CA 02527495 2005-11-28
WO 2005/042600 26 PCT/US2004/017916
OH
4/ - 3
R R
(II)
wherein, R3, comprises hydroxy, amine, thiol, or an aliphatic or aromatic
organic residue that may
further comprise hydroxy, amine, or thiol; and R4 comprises H, halo, NHRS, a
cycloaliphatic residue,
or aryl, and may be further substituted with HO, halo or halo (C,-C4)alkyl;
wherein R5 is H, (C1-
C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl (C~-C6)alkyl, aryl, heteroaryl,
aryl (CI-C6)alkyl, or
heteroaryl (C1-C6)alkyl or (C~-C4)alkyl carbonyl. Preferred R4 groups include
but are not limited to -
NHZ, -NHAc, Cl, 2,4-diflurophenyl, chloromethyl, difluoromethyl, -CF3 and the
like. The diacids of
chemical formulas (Ia) and (Ib), including those comprising monomers, dimers,
trimers; tetramers, and
higher numbers of units of the agents) or ~compound(s), may be incorporated
into the polymer
backbone of this invention, and may be employed also by appending, dispersing,
blending, or
admixing them, in the polymer. Biocompatible, hydrophobic polyanhydride
matrices of this invention
are suitable for use in many applications, including surgical, wound healing,
hemostatic, orthopedic
and dental applications, such as prosthesis and implants. The biodegradable
polymer networks of the
invention for use in these ~ and other applications may be formed by
polymerizing anhydride pre-
polymers and employing the methods) of this patent. Controlled or sustained
release polyanhydrides
prepared as described in this patent release biologically or pharmaceutically
'active agents, e.g.
salicylate or difluorophenyl derivatives, or their precursors, e.g.
pharmacophores, by in vivo ,
biodegradation, as well as other agents that are incorporated either into the
polymer backbone, or
appended thereto, or added into a formulation of the polymer.
[0086] Some other suitable polymers are shown below:
CA 02527495 2005-11-28
WO 2005/042600 a7 PCT/US2004/017916
O
n
O O x
p OII
R~~O~O.R~~O
~O \ / O~ x
';~I
O OII
R? O~R~~O~O.R~~p~R~O
p ~O( \ / ~O( O x
p R~~O~R:o~R~~O~O.R~~O,R~O.R~~O
IOI IOI ' ' IOI I IO
o R~~OO.R~~O~R~~O~R~Rip~O.R~O.R~~O
O~ ~ ~ rr~O IO' O IIO
x
O O 0If 0 O
O O R:O~O~R~~O O R~ p~p'R~ O
x
O O O OII' 'OII
p O R~p~0~R2~0 ~ R:O~p~R~0
x
p O O O O
II II II 1 1
O~O~O~O~R~.O~O.R~~p~R~ ~O~R.o~p. R
'" p ~p \ , ~p IOI ' , O
x
pII OII OII OII OII
O~O~O~O~R~i0~0. R~~O~R~rO~ R:O~O. R~
\ /n I
O n O O O 0 O.!
x
CA 02527495 2005-11-28
WO 2005/042600 28 PCT/US2004/017916
OII OII
O.R~~O~O~R~~O
O x
OI~ OII
O.R~~O~O~R~~O
n
O O x
O OII
'~,I ~ RWO~O.R~~~~O~O~O
O~ ~ ~ ,,~0 O
x
O OII
R~~O~O.R~~O~O~O~O
JO[ ' ' ~O ~O m IOf
x
O Z
O O'I OII O
Z - R~~O~O.R~~O or~ R~ O~R~~O~O.R~~O~R~O or
Z / Z 0 0O x O ~O ~ ~ ~O IOI x
O O
O O
R1~O~R:O~R~~O~O.R~~O~R~O.R~~O
'OI ~O( ~ ~ ~O( IO x
Z 00
O O1I OI OII
Z Z Z- R~~O~O.R~~O or R:O~R~~O~O.R~~O~R~O~ or
00 Z 0~~~~0( x ~O~~O~ IOI Jx
O R~~O~R:O~R~~O~O.R~~O~R~O.R~~O
O O O O x
O Z
Z O O O OII
0 Z- R~~O~O.R~~O or R:O~R~~O~O.Ri~O~R~O or
O Z O~ ~ ~ ~O( x O ~O ~ ~ ~O( IOI x
~ pII OII OI'
RWO~R'O~R1~O~O.R~~O.R~O.R~~O
~O~ ~0 0O IOI x
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WO 2005/042600 29 PCT/US2004/017916
0 0II 0II ~II
R~~O~O~R~~O or R:~~R~~OO.R~~O~R~O or
O O JO( \ / ~O( x O ~O( ~ ~ ~O I0I x
O O O 0II
R~~O~R~ O~R~~O~O.R~~O~R~O.R~~O
jO( ~ ~ O~ IOI x
:ivl
O O OII 0'I 0 O OII O
* O~Z~O~ ~O~Z~O
polymer A
polymer B
x
Z = Ra-L-R~
x
Z = R~-L-R~
O O O
O O ,
O n0 I / ~ ,
/ F F I / F m.
n
CA 02527495 2005-11-28
WO 2005/042600 30 PCT/US2004/017916
O
~O O O O
m
wherein R, R1 and RZ comprise, independently from one another, an agents) as
defined above; and n
and M are, independently from one another, 0 or a positive integer showing the
degrees of
polymerization.
;n
C. Linking Groups
[0087] The mechanical and degradation properties, e.g. hydrolytic properties,
of polymers comprising
an agents) or compounds) may be determined by incorporating and/or modifying a
linking group into
th ~ polymer backbone. Among other properties, selecting molecular weight and
chemical composition
of a linking group will critically affect the polymer's glass transition
temperature (Tg) and,
accordingly, the mechanical properties of the polymers) and coatings they form
at various
temperatures. In general, the higher the molecular weight, the greater the
toughness of the material in
terms of elasticity and tear strength. The polymers of the invention may
comprise backbones wherein
an agents) or compounds) and a linking groups) are bonded together through
breakable linkages,
such as ester, thioester, amide, carbonate, and many others known in the art
as well as combinations
thereof. These linkages form biodegradable bonds that are hydrolyzed, broken
by proteolysis, or
broken by other biological of biochemical processes when placed in contact
with the appropriate
medium, e.g. body tissues or fluids, to release an active agents) or
compound(s).
[0088] In some embodiments, the linking groups) may be selected in
coordination with the actual
agents) to impart desirable physical, chemical, and biological properties,
such as adhesion to smooth
and porous surfaces, e.g. metallic, polymeric, asphaltic, ceramic, or glass
surfaces. Such surfaces may
be located in diverse environments, including marine surfaces, constructions
sites including cement
structures, plastic and other polymeric artifacts, alloys, stainless steel,
and other metals, or on
CA 02527495 2005-11-28
WO 2005/042600 31 PCT/US2004/017916
implantable dental, medical and veterinary devices to allow formation of a
coating that may withstand
handling, coating, implantation, and exposure to inclement weather, water
contact, body tissues and/or
fluids, and the like. Other desirable characteristics that are critically
influenced by the linker type are
mechanical strength, flexibility, and ability to withstand application of
mechanical stress without
failure, low sticking to a surface so that~adhesion to delivery vehicles and
neighboring surfaces may be
minimized, e.g. when implanted in an animal or human. Also important is
resistance to sterilization
conditions by different methods, e.g. gamma irradiation, electron beam (E
beam), treatment with
ethylene oxide, or other chemical or physical treatments providing
sterilization. Suitable linking
gr ups typically comprise a divalent organic residue of molecular weight about
25, 40, 75, 100, 130
Dalton to about 100, 170, 250, 330, 400, 520 Dalton. In one embodiment, L
comprises a divalent,
branched or unbranched, saturated or unsaturated (C,-CZS) hydrocarbon chain,
where one or more
carbon atoms may be further substituted by -O-, -NR2-, an amino acid, a
peptide, (C~-C6) alkoxy; (C3-
C6) cycloalkyl, (C~-C6) alkanoyl, (C~-C6) alkanoyloxy, (C~-C6) alkoxycarbonyl,
(C~-C6) alkylthio,
azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl,
or heteroaryloxy. In one
embodiment, the polymer is employed to coat the surface of an article or
device, e.g. a stmt, such that
it will allow for its expansion, contraction or torsion during the application
and useful life of the
article. In such case a linking groups) may be a (C3-C35) dicarboxlyic acid
hydrocarbon residue.
[009] In one embodiment, the polymer of the invention may comprise a linking
groups) that may be
present in the polymer backbone along with the agents) through bonds that
release the agents) under
certain environmental conditions. Examples of bonds are esters, thioesters,
amides, thioamides,
urethanes, carbamates, thiocarbamates, carbonates, thiocarbonates, and any
others than fulfill a similar
function. This includes combinations and mixtures thereof. The linking bonds
may comprise other
1 ou s and atoms includin P C O S halo ens metals and other inor anic and or
anic atoms
~' p> > g > > > > g > > g g
provided that they form labile bonds that may release under appropriate
circumstances the agents)
CA 02527495 2005-11-28
WO 2005/042600 32 PCT/US2004/017916
within the backbone, and the agents) mixed into the polymer. The linking
groups) may be selected as
well to impart to the polymer desirable physical, chemical, and/or biological
properties. Examples of
these are adhesion to metallic, polymeric, ceramic or glassy surfaces on
implantable medical and
veterinary devices to allow formation of a coating that may withstand
handling, implantation, and
exposure to body tissues and/or fluids post-implantation; sufficient
mechanical strength, flexibility,
and ability to withstand without failure application of mechanical stress
without failure; minimal
stickiness on the surface of the resulting coating to minimize adhesion to
vehicles used in the delivery
or implantation of the medical or veterinary device in the body of a human or
animal; and the ability to
sterilize the coating and the associated medical or veterinary device by the
application of gamma
irradiation, electron beam (E beam), treatment with ethylene oxide, or other
chemical or physical
treatments providing sterilization. Suitable linking groups are widely known
in the art, and need not be
fully detailed here. Examples are described in U.S. Patent Nos. 6,613,807;
6,328,988; 6,365,146;
6,468,519; 6,486,214; 6,497,895; 6,602,915; 6,613,807; U.S. Published Patent
Applns. 2002/0071822
Al; 2002/0106345 A1; 2003/0035787 A1; 2003/0059469 A1; 2003/0104614 A1;
2003/0170202 A1;
U.S.S.Ns. 09/508,217; 10/368,288; 10/622,072; 10/646,336; 10/647,701; and
International Patent
Applications WO 99/12990; WO 01/28492; WO 01/41753; WO 01/58502; WO 02/09767;
WO
02/09768; WO 02/09769; WO 03/005959; WO 03/046034; WO 03/065928; and WO
03/072020. The
nature of the linking group (L) in a polymer of the invention may be employed
to provide the polymer
of the invention with one or more desirable physical, chemical, and/or
biological 'properties, such as
mechanical and thermal properties; adhesiveness; wetability; hardness; drug
generation, and release
kinetics and solubility; and tissue compatibility and response for the
selected therapeutic application.
The linking group L is typically a divalent organic radical having a molecular
weight (MW) about 25,
or 40 daltons to about 200, or 400 daltons. The mechanical and degradative
properties, e.g. hydrolytic
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WO 2005/042600 33 PCT/US2004/017916
properties, of the polymer of the invention may be controlled by incorporating
and/or modifying a
specific linking group (L) into the polymer backbone.
[0090] The mechanical and degradative properties, e.g. hydrolytic properties,
of the polymer of the
invention may be controlled by incorporating and/or modifying a specific
linking group (L) into the
polymer backbone. L may be any substituted and unsubstituted hydrocarbon
unit,. such as, for
yn example, propane, butane, pentane, etc. A suitable number of carbon atoms
includes any number of
carbon atoms that will result in a functional polymer, e.g., about 2 to about
20 carbon atoms, about 2 to
about 113 carbon atoms, about 4 to about 16 carbon atoms, about 4 to about 14
carbon atoms, about 6 to
about 16 carbon atoms, about 8 to about 12 carbon atoms, or about 6 to about
10 carbon atoms.
Further, the nature of the linking group L in a polymer of the invention is
not critical provided the
polymer of the invention possesses acceptable mechanical properties and
release kinetics for the
selected therapeutic application. The linking group L is typically a divalent
organic radical having a
molecular weight of from about 5, 10, 15, 20, 25, or 40 to about 100, 200,
300, or 400 Dalton, and a
length of from about 5, 10, 30, or 40 to about 50, 75, or 100 Angstrom using
standard bond lengths and
angles. . The linking group may be biologically inactive, or may itself
possess biological or other
activity.
[0091 ] One preferred polymer comprises L representing a residue of a linking
groups) that,
independently from one another, comprises linear or branched (C3-C30)
aliphatic, alicyclic or aromatic
residue that may be further substituted; n, independently from one another,
may be 0 to 28; and m
represents the number of units and is correlated to the polymer molecular
weight. Although any
'agent(s) may be polymerized in this manner, particularly suited are
aliphatic, alicyclic, aromatic small
.and large organic molecules that have at least two functional groups, and
optionally additional groups
such as OH, SH, COOH, COOK, phosphate, amine, amide, thioester, thiamide, S,
P, N, halogen, ether,
aldehyde. I<etone, and many others; such molecules being ltnown as suitable
for re~~ulaiion of
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WO 2005/042600 34 PCT/US2004/017916
properties such as hydrophilicity, solubility, and the like. In one
embodiment, the active agent is
salicylic acid, and the linker is a dicarboxylic acid hydrocarbon chain with
an even number of carbon
atoms. The nature and presence of the linking group L in the polymer is not
critical as long as it does
not negatively impact the polymer's acceptable mechanical properties and
release kinetics for the
selected therapeutic application.
[0092] In one embodiment, the linking group L typically comprises a divalent
organic residue of
molecular weight about 2.5, 40, 60, 100, 130, or 150 Daltons to about 80, 110,
125, 140, 170, 250, 370,
or 400 Daltons, and any combination thereof. In another embodiment the linking
groups) L typically
comprises a length of about 5, 10, 15, 20, or 25 Angstrom to about 30, 35, 45,
50, 75, or 100 Angstrom
using standard bond lengths and angles.
[0093] In one embodiment, the linking group may be biologically inactive, and
in another it may
possess biological activity. The linking group may also comprise other
functional groups including
hydroxy, mercapto, amine, halo, SH, -~-, -C=O, -N=, -P=, or carboxylic acid,
as well as others that
may be used to modify the properties of the polymer. These may be employed for
example for polymer
branching, cross-linking, appending other molecules, e. g. another
compound(s), to the polymer,
changing the polymer solubility, or affecting the biodistribution of the
polymer, among others.
[0094] In one embodiment, the linking group may incorporate other
biodegradable groups such as
alpha-ester (lactate, glycolate), e-caprolactone, ortho-ester, or
enzymatically biodegradable groups
such as amino acids. In another embodiment, the linking group may be a water-
soluble, non-
biodegradable segment such as a polyethylene glycol (PEG), polyvinyl alcohol
(PVA) or polyvinyl
pyrrolidone (PVP). In yet another embodiment, the linking group may be a water-
insoluble, non-
biodegradable segment such as polypropylene glycol (PPG), polyetherurethane
(PEU), or poly(n-alkyl
ether). In still another embodiment, the linker may be an amorphous or
semicrystalline biodegradable
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WO 2005/042600 35 PCT/US2004/017916
polymer, such as poly(d, 1-lactide), poly(trimethylene carbonate),
poly(dioxanone),
polyanhydridepoly(orthoester) poly(glycolide), poly(1-lactide) poly(e-
caprolactone) and co-polymers
of e-caprolactone, glycolide, trimethylene carbonate, dioxanone, d,l-lactide,
1-lactide and d-lactide. In
another embodiment, the linking group may have surfactant properties, such as
a Pluronic block
copolymer with polyethylene glycol and polypropylene glycol blocks, and in
another it may have polar
or charged moieties, including carboxylic acid groups from poly(acrylic acid)
and poly(alginates),
sulfonic acid groups from poly(2-acrylamido-2-methyl-propanesulfonicacid)
(AMPS), hydroxy groups
from polyvinyl alcohol), polysaccharides and poly(alginates), and amino groups
from poly(L-lysine),
poly(2, 2-dimethylaminoethyl methacrylate) and poly(amino acids).
[0095] In addition, the linking group may be a segment that undergoes
thermoreversible gellation,
such as Pluronic F127 and poly (N-isopropyl acrylamide). It may incorporate
structurally-reinforcing
segments, such as polyetherurethane, polyesterurethane, etc. In yet another
embodiment, the linking
group may be a divalent, branched or unbranched, saturated or unsaturated,
hydrocarbon chain, having
from 1 to 25 carbon atoms, wherein one or more, e.g. l, 2, 3, or 4, of the
carbon atoms .is optionally
replaced by (--O--), (-S-), (--P--), or (--NR--), and wherein the chain is
optionally substituted with one
or more, e.g. l, 2, 3, or ,4, substituents comprising (C1-C6) alkoxy, (C3-C6)
cycloalkyl, (C1-C6)
alkanoyl, (C 1-C6) alkanoyloxy, (C 1-C6) alkoxycarbonyl, (C 1-C6) alkylthio,
azido, cyano, nitro, halo,
hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, or heteroaryloxy, among
others. The linking group
may be a divalent (C2-C32) branched or unbranched, saturated or unsaturated
hydrocarbon chain
optionally further substituted with one or more, e.g. 1, 2, 3, or 4,
substituents comprising (C1-C6)
alkoxy, (C3-C6) cycloalkyl, (C1-C6) alkanoyl, (C1-C6) alkanoyloxy, (C1-C6)
alkoxycarbonyl, (Cl-
C6) alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl,
aryloxy, heteroaryl, or
heteroaryloxy, among many others.
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WO 2005/042600 36 PCT/US2004/017916
[0096] The linking group may be also a biological molecule such as a
carbohydrate, saccharide;
polysaccharide, fatty acid, lipid, nucleic acid, peptide, amino acid, or
combinations thereof.
[0097] The linking group may be a divalent, branched or unbranched, saturated
or unsaturated (C3-
C31) hydrocarbon chain, preferably of uneven number of carbons, with one or
more optionally
substituted by -O- or -NR-; or a divalent, branched or unbranched, saturated
or unsaturated,
.y, hydrocarbon chain, having from about 3, 6, 9 to about 12, 15 carbon atoms,
wherein one or more, e.g.
1, 2, 3, or 4, of the carbon atoms is optionally replaced by -O- or -NR- or -S-
, and wherein the chain is
optionally substituted on carbon with one or more, e. g. 1, 2, 3, or 4,
substituents selected from the
group consisting of (C1-C6) alkoxy; (C3-C6) cycloalkyl, (C1-C6) alkanoyl, (C1-
C6) alkanoyloxy,
(C ~,-C6) alkoxycarbonyl, (C 1-C6) alkylthio, azido, cyano, nitro, halo,
hydroxy, oxo, carboxy, aryl,
aryloxy, heteroaryl, and heteroaryloxy. The linking group may be a divalent,
branched or unbranched,
saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms,
wherein one or more
(e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (--O--), (-
S-), (--P--), or (--NR-); ~or a
divalent branched or unbranched, saturated or unsaturated, hydrocarbon chain,
having from 3 to i 5
carbon atoms; or a divalent, branched or unbranched, hydrocarbon chain, having
from 3 to 15 carbon
atoms; or a divalent, branched or unbranched, (C6-C 10) hydrocarbon chain; or
a divalent (C7-C9)
hydrocarbon chain, or a divalent C8 hydrocarbon chain.
[0098] The linking group may be biologically inactive, or may itself possess
biological or other
activity, and may comprise other functional groups. Examples of functional
groups that the linker may
have are hydroxy, mercapto, amine, carboxylic acid, halogen, aliphatic and
aromatic hydrocarbons
with and without heteroatoms, and many others useful for modifying the
properties of the polymer, e.g.
,for branching, cross linking, increasing hydrophillicity or hydrophobicity,
solubility, degradation rate,
hardness, flexibility, elasticity, ability to append another agents) to the
polymer, or biodistribution of
the polymer. amon~~ many others. In one embodiment, the linlcer may have tv~o
or more functional
CA 02527495 2005-11-28
WO 2005/042600 37 PCT/US2004/017916
groups that, among others, may be hydroxy -OH, mercapto -SH or SR, amine NH-
or NR-,
carboxylic acid -COOH, and many others that form degradable bonds with the
agents) to be
polymerized, e.g. hydrolyzed, or cleaved by proteolytic, or other biological
of biochemical processes
when placed in contact with body tissues or fluids. L may be an amino acid, a
peptide, a nucleic acid,
,I ,a carbohydrate or polysaccharide, or any other type of chemical structure.
L generally comprises a '
,i
divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain,
having about 3, 6, 8,
10, 12, or 14 to about 16, 18, 20, 22, or 25 carbon atoms, and at times more
carbon atoms, wherein one
or more, e.g. l, 2, 3, or 4, carbon atoms is optionally replaced by (-O-) or (-
NR-). L may be a divalent,
br~nched or unbranched, saturated or unsaturated, hydrocarbon chain, having
from 1 to 25 carbon
II
atoms, wherein the chain is optionally substituted on carbon with one or more,
e.g. 1, 2, 3, or 4,
substituents comprising (C~-C6)alkoxy, (C~-C6)cycloalkyl, (C~-C6)alkanoyl, (C~-
C6)alkanoyloxy, (CI-
C6)alkoxycarbonyl, (C~-C6)alkylthio, azido, cyano, nitro; halo, hydroxy, oxo,
carboxy, aryl, aryloxy,
heteroaryl, and heteroaryloxy, or other functional groups. In one embodiment,
L comprises a
dicarboxylic acid hydrocarbon chain with about 3, 4, 6, 8, or 10 to about 12,
14, 16, 18, 22, 24, or 26
carbon atoms, preferably an even number of carbon atoms that may be the same
or different. This
linker may be used with any suitable active agent, such as, e.g., salicylic
acid, diflunisal and/or a
derivative thereof.
[0099] In another embodiment the polymer may be employed to coat a rigid
article; e.g. an implantable
orthopedic device, including a hip, knee, shoulder, or elbow replacement, a
fixation devices) for other
orthopedic applications, and many others. In such case, the linking groups)
may be a (C3-C35)
dicarboxylic acid hydrocarbon residues) The linking group contributes to the
control of a polymer's
characteristics, mechanical properties and release kinetics for selected
applications. The linking
groups) typically is(are) about 5, 10, I 5, 25, 50, 80, or 120 Angstroms to
about 75, I 00, 140, 180, 230,
or 300 Angstroms employing standard bond lengths and angles. The linking group
may be
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WO 2005/042600 38 PCT/US2004/017916
biologically inactive, or may itself possess biological activity, and may
further comprise O, N, P,
halogen, etc. Suitable functional groups that may be attached to the linking
groups) is(are) hydroxy,
keto, aldehyde, lactame, mercapto, amide, acryl, vynil, amine, carboxyl,
halogen, and many others that
may be used to modify the properties of the polymer for example by branching,
cross linking, for
appending other molecules, e.g. other biologically active of activatable
compound(s), to the polymer,
for changing the solubility of the polymer, or for affecting the
biodistribution of the polymer, etc.
[0100] Thus, different embodiments may be prepared changing the chemical
structure of the linker that
will evidence a direct or reverse correlation with the Tg of the specific type
of polymers. This
invention provides an improved process for the preparation of the present
polymers which permits the
synthetic design of polymers with pre-designed properties and, moreover, of
properties never before
attained with prior synthetic processes. For example, in one embodiment of the
process of this
invention the polymer may be prepared from an agents) or compounds) of
chemical formula Z~-R'-Z2
and a linker precursor of formula X1-L-XZ, wherein Z~, Z2, X~, and X2,
independently from one
another, comprise functional groups that are able to form degradable bonds in
situ. Examples of these
functional grouped are shov~rn in Table 2 below.
[0101 ] Essentially across this range, the polymers of the invention e:g. poly-
NSAIDs are highly
flexible at room and body temperature. Soaking the polymers for an hour in PBS
at about 37 C caused
no observable change in flexibility as shown in Table 2 below.
Table 2: Functional Groups & Polymer Bonds
Agent Linker Polymer Bond
Functional Group Functional Group (A)
(Z~ or Z2) (X~ or X2)
-COOH -OH Ester
-COOH -NHR Amide
-COOH -SH Thioester
-OI-3 -COON Ester
-SN -CO01-1 Thioester
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Agent Linker Polymer Bond
Functional Group Functional Group ~ (A)
(ZI or Z2) (X~ or X~)
-NHR ~ -COOH ~ Amide
Z2 + x~_~_xZ -. _~c~=p)_R _A_ R _c~=ol_oh_ (IV)
wherein n is a positive integer showing the degree of
polymerization
~fi,i ,[0102] An agents) or compounds) and a linker precursor may be
polymerized, for example, by
condensation, to provide a polymer of the invention such as, for example, that
of chemical formula
yn
(IV), wherein each A, independently from one another, comprises a bond that is
degradable in situ, e.g.
in vivo when administered to a living organism. Examples of breakable bonds
comprise an ester,
thigester, thioamide, azo, carbonate, or amide. Depending on the reactive
functional groups ZI and Z2
present in the agents) or compound(s), a corresponding functional group X' or
X2 may be selected for
the linking group or second functional group of the agents) or compounds) to
provide one or more of
the breakable bonds described above in the formation of the polymeric
backbone. The polymers the
present invention may be prepared in at least two general manners or
embodiments, which ,
embodiments are expanded by the addition, and various permutations, of the
optional steps that each ~f
the illustrative methods shown in the Schemes Stated below. In one embodiment,
the polymerization
step occurs in a non-aqueous dispersion medium. Once a pre-polymers) or a
diacid monomers) is
synthesized as described above, and activated as a mixed anhydride, it may be
heated above its melting
point in the presence of a solvent for the pre-polymer(s), e.g. an inert, high
boiling point pre-polymer
solvent, to allow polymerization to occur while the thus produced polymer
remains out of solution as it
is generated. This process is capable of yielding polymers of high molecular
weights, e.g. in excess of
40,000 Dalton. Vigorous mechanical mixing or stirring may be favorably
employed with an optional
,addition of a minor amount of, or even without, a non-aqueous dispersing
agent or surfactant that will
foster the formation of a suitable emulsion of molten droplets of the
polymerization phase.
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D. Agents and Compounds
[0103] Any diagnostic agents) may be incorporated into the backbone of the
polymers of the
invention, or be dispersed into, or earned by them. Examples are
phosphorescent agents, fluorescent
agents, radioactive agents, enzymatic agents, among others.
[0104] Any therapeutic agents) is suitable for use in the polymer backbone, or
dispersed into, or
earned by the polymer. Examples of therapeutic agents include antibacterial,
antiviral,
antiproliferative, anticancer, anti-inflammatory analgesic, anesthetic,
antipyretic, antiseptic, and
antimicrobial compounds. Examples of such compounds include salicylic acid, 4-
aminosalicylic acid,
5-aminosalicylic acid, 4-(acetylamino)salicylic acid, 5-(acetylamino)salicylic
acid, 5-chlorosalicylic
acid, salicylsalicylic acid (salsalate), 4-thiosalicylic acid, 5-thiosalicylic
acid, 5-(2,4-difluorophenyl)-
salicylic acid (diflunisal), 4-trifluoromethylsalicylic, sulfasalazine,
diclofenac, penicillamine,
balsalazide, olsalazine, mefenamic acid, carbidopa, levodopa, etodolac,
cefaclor, captopril, and the
like. Any traceable agents) or compounds) is suitable for use in this
invention.
[0105] The synthetic process of this invention enables the preparation of
different embodiments by
modifying the chemical structure of a linker taking into consideration that
such change will evidence a
direct or reverse correlation with the Tg of the specific polymers. The
present process enables the
preparation of polyanhydrides that release a broad scope of families of agents
and drugs, such as those
disclosed in U.S. Patent No. 6,46,214. Compounds suitable for incorporation
into the polymer of this
invention preferably have relatively low molecular weights, e.g. up to 1,000
dalton: The compounds
generally contain within their molecular structure at least one functional
group, and preferably two
functional groups, more preferably one of the functional groups comprises
carboxylic acid. The
functional groups of the compounds) are preferably hydroxy (-OH), thiol (-SH),
amine (-NHR), amide
(-CNR), azo, carbonate (-COO-), carboxy (-COR), and similarly breakable
groups. These functional
;groups form breakable, e.g. biodegradable, bonds within the polymer and are
able to release the
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WO 2005/042600 4~ PCT/US2004/017916
compound in its active form or as a precursor. The polymeric bonds may be
broken by hydrolysis, such
as proteolysis, or by other biological or biochemical processes when placed in
contact with the target
environment, e.g. body tissues or fluids.
[0106] The compounds may also comprise other functional groups, including
hydroxy, phenol, ketone,
~~~ 'algehyde, double and triple bond C-C substituents, amide, mercapto,
amine, halide, carboxylic acid,
;~,i and many others known in the art, all of which may be used to modify the
properties of the polymer,
such as for branching, cross-linking, appending,other molecules to the
polymer, changing polymer
characteristics such as solubility, consistency, adhesiveness, or rigidity,
among others, or for affecting
po~'ymer distribution in a specific system, e.g. biodistribution. One skilled
in the art will be able to
readily select from the listed compounds those that possess, or may be
modified by methods known in
the art to possess, the necessary functional groups for polymerization in
accordance with the method of
the invention. Suitable therapeutic and diagnostic compounds may be found, for
example, in the
Physician's Desk Reference, 55 Ed., Medical Economics Company, Inc., Montvale,
New Jersey
(2001); USPN Dictionary of USAN and International Drug Names, The United
States Pharmacopeial
Convention, Inc., Rockville, Maryland (2000); The Merck Index, 12 Ed., Merck &
Co., Inc.,
Whitehouse Station, New Jersey (1996). Any suitable agent may be employed in
the polymers of the
invention. In one embodiment, the active agents that may be incorporated into
the polymers of the
invention possess at least two functional groups that may each be incorporated
into an ester, thioester,
urethane, carbamate, carbonate or amide linkage of a polymer, such that, upon
hydrolysis or enzymatic
degradation of the polymer, the active agent is obtained. The functional
groups may independently be
a hydroxy group (-OH), a mercapto group (-SH), an amine group (-NHR), or a
carboxylic acid (-
COOH). These functionalities form biodegradable bonds with the drug to be
polymerized that are
hydrolyzed, broken by proteolytic process, or broken by other biological of
biochemical processes
when placed in contact with body tissues or fluids. An active agent may also
comprise other functional
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groups (including hydxoxy groups, mercapto groups, amine groups, and
carboxylic acids, as well as
others) that may be used to modify the properties of the polymer, e.g. for
branching, for cross linking,
for appending other molecules, e.g. another active compound, to the polymer,
for changing the
solubility of the polymer, or for effecting the biodistribution of the
polymer. One skilled in the art may
readily select active agents that possess the necessary functional groups for
incorporation into the
polymers of the invention from these lists. The agent may comprise a
biological,.diagnostic,
therapeutic, or other type of agent such as suitably functionalized
analgesics, anesthetics, anti-acne
agents, antibiotics, anti-cholinergics, anti-coagulants, anti-convulsants,
anti-diabetic agents, anti-
dyskinetics, antifibrotic agents, antifungal agents, anti-glaucoma agents,
anti-infectives, anti-
inflammatory compounds, antimicrobial compounds, anti-neoplastics, anti-
Parkinson's agents,
antiosteoporotics, antiseptics, antisporatics, antithrombotics, antiviral
compounds, bacteriostatic
compounds, bone resorption inhibitors, calcium regulators, cardioprotective
agents, cardiovascular
agents, central nervous system stimulants, cholinesterase inhibitors,
contraceptives, deodorants,
disinfectants, dopamine receptor agonists, erectile dysfunction agents,
fertility agents, gastrointestinal
agents, gout agents, hormones, hypnotics, immunomodulators,
immunosuppressives, keratolytics,
migraine agents, motion sickness agents, muscle relaxants, nucleoside analogs,
obesity agents,
opthalmic agents, bone healing, osteoporosis 'agents, parasympatholytics,
parasympathomimetics,
prostaglandins, psychotherapeutic agents, respiratory agents, sclerosing and
anti-sclerosing agents,
sedatives, skin and mucous membrane agents, smoking cessation agents,
sympatholytics, ultraviolet
screening agents, urinary tract agents, vaginal agents, contraceptives,
hormones, sexual function aid
agents, and vasodilators: See, Physicians' Desk Reference, 55 Ed., Medical
Economics Company,
Inc., Montvale, New Jersey, pages 201-202 (2001 ). Suitable active agents may
be found, for example,
in: Physician's Desk Reference, 55 ed., 2001, Medical Economics Company, Inc.,
Montvale, New
Jersey; USPN Dictionary of USAN and International Drug Names, 2000, The United
States
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Pharmacopeial Convention; Inc., Rockville, Maryland; and The Merck Index, 12
ed., 1996, Merck &
Co., Inc., Whitehouse Station, New Jersey.
[0107] Other therapeutically active families of compounds that may be
incorporated into the polymers
of the invention include, but not limited to, analgesics, anesthetics, skin
treating agents such as
'~~ exfoliating agents, anti-acne agents, pore refining agents, skin sloughing
agents, cleansers, pore closing
agents, skin toning agents, skin revitalizing agents, anti-infectives
including disinfectants, antiseptics,
antibiotics, anti-fungal agents, anti-viral agents, anti-microbial agents,
antisporatic agents, or
bacteriostatic agents, among others, anti-cholinergics, anti-coagulants, anti-
convulsants, anti-diabetic
agents, anti-dyskinetics, anti-fibrotic agents, anti-inflammatory agents, anti-
neoplastic agents, anti-
glaucoma agents, anti-Parkinson's agents, anti-osteoporotic agents, anti-
thrombotic agents, bone
resorption inhibitors, bone growth inducing agents, calcium regulators,
cardioprotective agents,
cardiovascular agents, central nervous system (CNS) acting agents such as
sedatives, hypnotics, anti-
depressants, stimulants, anti-bipolar agents, anti-schizophrenic agents,
psychotherapeutic agents in
general, CNS receptor agonists and antagonists such as serotonin, dopamine,
epinephrine,
norepinephrine, gamma amino butyric acid (GABA), receptor agonists and
antagonists, among others,
syrnpathomimetic agents, sympatholytic agents, cholinergic and anti-
cholinergic agents, cholinesterase
inhibitors, parasympatholytic agents, parasympathomimetic agents,
contraceptive agents, fertility
inducing agents, deodorants, hormones, immunomodulating agents such as
immunosuppressive and
immunostimulating agents, keratolytic agents; hair follicle treating agents,
muscle relaxants, anti-
cancer agents such as antibodies and their fragments, radioactive materials,
anti-angiogenic agents,
carcinolytic agents, nucleoside analogs, anti-sense agents, anti-oxidant
agents, metabolic and anti-
metabolic agents, among others known in the art, anti-sense agents, nail
treating agents, opthalmic and
otical agents, vasodilators, prostaglandins, smoking cessation agents,
ultraviolet screening agents,
agents for the treatment of erectile dysfunction, migraine, motion sickness,
osteoporosis, alzheimer's
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disease, sclerosis, obesity, anorexia, bulimia, and gastrointestinal (G.L),
skin, muscous membrane,
aesophagal, respiratory, gout, mouth, nasal, throat, glandular, lymphatic,
urinary tract, vaginal and
colonic conditions and ailments, among many others. See, for example,
Physicians' Desk Reference,
55 Ed., pp. 201-202 (2001). Examples of specific therapeutic, screening and
diagnostic agents or
compounds that may be incorporated into the polymers of the invention are
bupivacaine; mepivacaine,
atorvastatin; enalapril; ranitidine; ciprofloxacin; pravastatin;
clarithromycin; cyclosporin; diflunisal;
famotidine; leuprolide; acyclovir; paclitaxel; azithromycin;
lamivudinebudesonide; albuterol;
indinavir; metformin; alendronate; nizatidine; zidovudine; carboplatin;
metoprolol; amoxicillin;
diclofenac; lisinopril; ceftriaxone; captopril; salmeterolxinafoate; imipenem;
cilastatin; benazepril;
cefaclor; ceftazidime; morphine; dopamine; bialamicol; fluvastatin;
phenamidine; podophyllinic acid
2-ethylhydrazine; acriflavine; chloroazodin; arsphenamine; amicarbilide;
aminoquinuride; quinapril;
oxymorphone; buprenorphine; butorphanol; nalbuphine. streptozocin;
doxorubicin; daunorubicin;
plicamycin; idarubicin; mitomycin C; pentostatin; mitoxantrone; cytarabine;
fludarabine phosphate;
floxuridine; cladribine; 6-mercaptopurine; thioguanine; capecitabine;
docetaxel; podophyllotoxin;
etoposide; gemcitabine; camptothecin; topotecan; irinotecan; vinorelbine;
vincristine; vinblastine;
teniposide; tamoxifen; melphalan; methotrexate; 2-p- sulfanilyanilinoethanol;
4,4'-sulfinyldianiline; 4-
sulfanilamidosalicylic acid; acediasulfone; acetosulfone; amikacin;
amphotericin B; ampicillin;
apalcillin; apicycline; apramycin; arbekacin; aspoxicillin; azidamfenicol;
aztreonam; bacitracin;
bambermycin(s); biapenem; brodimoprim; butirosin; capreomycin; carbenicillin;
carbomycin;
carumonam; cefadroxil; cefamandole; cefatrizine; cefbuperazone; cefclidin;
cefdinir; cefditoren;
cefepime; cefetamet; cefixime; cefmenoxime; cefminox; cefodizime; cefonicid;
cefoperazone;
ceforanide; cefotaxime; cefotetan; cefotiam; cefozopran; cefpimizole;
cefpiramide; cefpirome;
cefprozil; cefroxadine; cefteram; ceftibuten; cefuzonam; cephalexin;
cephaloglycin; cephalosporin C;
cephradine; chloramphenicol; chlortetracycline; clinafloxacin; clindamycin;
clomocycline; colistin;
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cyclacillin; dapsone; demeclocycline; diathymosulfone; dibekacin;
dihydrostreptomycin;
dirithromycin; doxycycline; enoxacin; enviomycin; epicillin; erythromycin;
flomoxef; fortimicin(s);
gentamicin(s); glucosulfone solasulfone; gramicidin S; gramicidin(s);
grepafloxacin; guamecycline;
hetacillin; isepamicin; josamycin; kanamycin(s); leucomycin(s); lincomycin;
lomefloxacin;
lucensomycin; lymecycline; meclocycline; meropenem; methacycline;
methsalamine; micronomicin;
:in
midecamycin(s); minocycline; moxalactam; mupirocin; nadifloxacin; natamycin;
neomycin;
vf4i
netilmicin; norfloxacin; oleandomycin; oxytetracycline; p-
sulfanilylbenzylamine; panipenem;
paromomycin; pazufloxacin; penicillin N; pipacycline; pipemidic acid;
polymyxin; primycin;
qui~nacillin; ribostamycin; rifamide; rifampin; rifamycin SV; rifapentine;
rifaximin; ristocetin;
ritipenem; rokitamycin; rolitetracycline; rosaramycin; roxithromycin;
salazosulfadimidine; salicylic
acid, sancycline; sisomicin; sparfloxacin; spectinomycin; spiramycin;
streptomycin; succisulfone;
sulfachrysoidine; sulfaloxic acid; sulfamidochrysoidine; sulfanilic acid;
sulfoxone; teicoplanin;
temafloxacin; temocillin; tetroxoprim; thiamphenicol; thiazolsulfone;
thiostrepton; ticarcillin;
tigemonam; tobramycin; tosufloxacin; trimethoprim; trospectomycin;
trovafloxacin; tuberactinomycin;
vancomycin; azaserine; candicidin(s); chlorphenesin; dermostatin(s); filipin;
fungichromin;
mepartricin; nystatin; oligomycin(s); perimycin A; tubercidiri;6-azauridine; 6-
diazo-5-oxo-L-
norleucine; aclacinomycin(s); ancitabine; anthramycin; azacitadine; azaserine;
bleomycin(s); carubicin;
carzinophillin A; chlorozotocin; chromomycin(s); denopterin; doxifluridine;
edatrexate; eflornithine;
elliptinium; enocitabine; epirubicin; mannomustine; menogaril; mitobronitol;
mitolactol; mopidamol;
mycophenolic acid; nogalamycin; olivomycin(s); peplomycin; pirarubicin;
piritrexim; prednimustine;
procarbazine; pteropterin; puromycin; ranimustine; streptonigrin; thiamiprine;
tamoxifen; Tomudex
(N-[[5-[[(1,4-Dihydro-2-methyl-4-oxo-6- quinazolinyl)methyl]methylamino]-2-
thienyl]carbonyl]-L-
~glutamic acid), trimetrexate, tubercidin, ubenimex, vindesine, zorubicin;
argatroban; coumetarol;
dicoumarol; ethyl biscoumacetate; ethylidene dicoumarol; iloprost; lamifiban;
taprostene; tioclomarol;
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tirofiban; amiprilose; bucillamine; gusperimus; mycophenolic acid;
procodazole; romurtide; sirolimus
(rapamycin); tacrolimus; butethamine; fenalcomine; hydroxytetracaine;
naepaine; orthocaine;
piridocaine; salicyl alcohol; 3-amino-4-hydroxybutyric acid; aceclofenac;
alminoprofen; amfenac;
bromfenac; bromosaligenin; bumadizon; carprofen; diclofenac; diflunisal;
ditazol; enfenamic acid;
etodolac; etofenamate; fendosal; fepradinol; flufenamic acid; gentisic acid;
glucamethacin; glycol
salicylate; meclofenamic acid; mefenamic acid; mesalamine; niflumic acid;
olsalazine; oxaceprol; S-
adenosylinethionine; salicylic acid; salsalate; sulfasalazine; and tolfenamic
acid, among many other
suitable.
[010] Examples of suitable agents are 2-p- sulfanilyanilinoethanol; 3-amino-4-
hydroxybutyric acid;
4,4'-sulfinyldianiline; 4-sulfanilamidosalicylic acid; 6-azauridine; 6-diazo-5-
oxo-L-norleucine; 6-
mercaptopurine; aceclofenac; acediasulfone; acetosulfone; aclacinomycin(s);
acriflavine; acyclovir;
albuterol; alendronate; alminoprofen; amfenac; amicarbilide; amikacin;
aminoquinuride; amiprilose;
amoxicillin; amphotericin B; ampicillin; ancitabine; anthramycin; apalcillin;
apicycline; apramycin;
arbekacin; argatroban; arsphenamine; aspoxicillin; atorvastatin; azacitadine;
azaserine; azidamfenicol;
azithromycin; aztreonam; bacitracin; bambermycin(s); benazepril; bialamicol;
biapenem;
bleomycin(s); brodimoprim; bromfenac; bromosaligenin; bucillamine; budesonide;
bumadizon;
buprenorphine; butethamine; butirosin; butorphanol; candicidin(s);
capecitabine; capreomycin;
captopril; carbenicillin; carbomycin; carboplatin; carprofen; carubicin;
carumonam; carzinophillin A;
cefaclor; cefadroxil; cefamandole; cefatrizine; cefbuperazone; cefclidin;
cefdinir; cefditoren; cefepime;
cefetamet; cefixime; cefmenoxime; cefminox; cefodizime; cefonicid;
cefoperazone; ceforariide;
cefotaxime; cefotetan; cefotiam; cefozopran; cefpimizole; cefpiramide;
cefpirome; cefprozil;
cefroxadine; ceftazidime; cefteram; ceftibuten; ceftriaxone; cefuzonam;
cephalexin; cephaloglycin;
cephalosporin C; cephradine; chloramphenicol; chloroazodin; chloroazodin;
chlorozotocin;
chlo~phenesin; chlortetracycline; chromomycin(s); cilastatin; ciprofloxacin;
cladribine; clarithromycin;
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clinafloxacin; clindamycin;~clomocycline; colistin; coumetarol; cyclacillin;
cyclosporin; cytarabine;
dapsone; daunorubicin; demeclocycline; denopterin; dermostatin(s);
diathymosulfone; dibekacin;
diclofenac; dicoumarol; diflunisal; dihydrostreptomycin; dirithromycin;
ditazol; docetaxel; dopamine;
doxifluridine; doxorubicin; doxycycline; edatrexate; eflornithine;
elliptinium; enalapril; enfenamic
'i acid; enocitabine; enoxacin; enviomycin; epicillin; epirubicin;
erythromycin; ethyl biscoumacetate;
ethylidene; etodolac; etofenamate; etoposide; famotidine; fenalcomine;
fendosal; fepradinol; filipin;
flomoxef; floxuridine; fludarabine phosphate; flufenamic acid; fluvastatin;
fortimicin(s); fungichromin;
gemcitabine; gentamicin(s); gentisic acid; glucamethacin; glucosulfone; glycol
salicylate; gramicidin
S; gramicidin(s); grepafloxacin; guamecycline; gusperimus; hetacillin;
hydroxytetracaine; idarubicin;
iloprost; imipenem; indinavir; isepamicin; josamycin; kanamycin(s); lamifiban;
lamivudine;
leucomycin(s); leuprolide; lincomycin; lisinopril; lisinpril; lomefloxacin;
lucensomycin; lymecycline;
mannomustine; meclocycline; meclofenamic acid; mefenamic acid; melphalan;
menogaril;
mepartricin; meropenem; mesalamine; metformin; methacycline; methotrexate;
methsalamine;
metoprolol; micronomicin; midecamycin(s); minocycline; mitobronitol;
mitolactol; mitomycin C;
mitoxantrone; mopidamol; morphine; moxalactam; mupirocin; mycophenolic acid;
nadifloxacin;
naepaine; nalbuphine; natamycin; neomycin; netilmicin; niflumic acid;
nizatidine; nogalamycin;
norfloxacin; nystatin; oleandomycin; oligomycin(s); olivomycin(s); olsalazine;
orthocaine; oxaceprol;
oxymorphone; oxytetracycline; paclitaxel; panipenem; paromomycin;
pazufloxacin; penicillin N;
pentostatin; peplomycin; perimycin A; phenamidine; pipacycline; pipemidic
acid; pirarubicin;
piridocaine; piritrexim; plicamycin; podophyllinic acid 2-ethylhydrazine;
polymyxin; pravastatin;
prednimustine; primycin; procarbazine; procodazole; p-sulfanilylbenzylamine;
pteropterin; puromycin;
~quinacillin; quinapril; ranimustine; ranitidine; ribostamycin; rifamide;
rifampin; rifamycin SV;
~rifapentine; rifaximin; ristocetin; ritipenem; rokitamycin; rolitetracycline;
romurtide; rosaramycin;
roxithromycin; S-adenosylmethionine; salazosulfadimidine; salicyl alcohol;
salicylic acid; salmeterol;
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salsalate; sancycline; sirolimus (rapamycin); sisomicin; solasulfone;
sparfloxacin; spectinomycin;
spiramycin; streptomycin; streptonigrin; streptozocin; succisulfone;
sulfachrysoidine; sulfaloxic acid;
sulfamidochrysoidine; sulfanilic acid; sulfasalazine; sulfoxone; tacrolimus;
taprostene; teicoplanin;
temafloxacin; temocillin; teniposide; tetracycline; tetroxoprim; thiamiprine;
thiamphenicol;
thiazolsulfone; thioguanine; thiostrepton; ticarcillin; tigemonam;
tioclomarol; tirofiban; tobramycin;
tolfenamic acid; Tomudex7 (N - [[5 -[ [ (1, 4-Dihydro-2-methyl-4-oxo-6-
quinazolinyl) methyl]
methylamino] -2-thienyl] carbonyl] -L-glutamic acid), topotecan; tosufloxacin;
trimethoprim;
trimetrexate; trospectomycin; trovafloxacin; tuberactinomycin; tubercidin;
ubenimex; vancomycin;
vinblastine; vincristine; vindesine; vinorelbine; xinafoate; zidovudine;
zorubicin; and any enantiomers,
derivatives, bases, salts or mixtures thereof.
[0109] In one embodiment, the active agent comprises a non-steroidal anti-
inflammatory drugs)
(NSAID(s)) such as those described in U.S.S.N. 09/732,516, filed 07 December
2000; 3-amino-4-
hydroxybutyric acid, aceclofenac, alminoprofen, amfenac, bromfenac,
bromosaligenin, bumadizon,
carprofen, diclofenac, diflunisal, ditazol, enfenamic acid, etodolac,
etofenamate, fendosal, fepradinol;
flufenamic acid, gentisic acid, glucamethacin, glycol salicylate, meclofenamic
acid, mefenamic acid,
mesalamine, niflumic acid, olsalazine, oxaceprol, S-adenosylmethionine,
salicylic acid, salsalate,
sulfasalazine, tolfenamic acid and the like. In another embodiment, the active
agent is an anti-
bacterial, for example, 2-p- sulfanilyanilinoethanol, 4,4'-sulfinyldianiline,
4-sulfanilamidosalicylic
acid, acediasulfone, acetosulfone, amikacin, amoxicillin, amphotericin B,
ampicillin, apalcillin,
apicycline, apramycin, arbekacin, aspoxicillin, azidamfenicol, azithromycin,
aztreonam, bacitracin,
bambermycin(s), biapenem, brodimoprim, butirosin, capreomycin, carbenicillin,
carbomycin,
carumonam, cefadroxil, cefamandole, cefatrizine, cefbuperazone, cefclidin,
cefdinir, cefditoren,
cefepime, cefetamet, cefixime, cefinenoxime, cefminox, cefodizime, cefonicid,
cefoperazone,
ceforanide, cefotaxime, cefotetan, cefotiam, cefozopran, cefpimizole,
cefpiramide, cefpirome,
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cefprozil, cefroxadine, ceftazidime, cefteram, ceftibuten, ceftriaxone,
cefuzonam, cephalexin,
cephaloglycin, cephalosporin C, cephradine, chloramphenicol,
chlortetracycline, ciprofloxacin,
clarithromycin, clinafloxacin, clindamycin, clomocycline, colistin,
cyclacillin, dapsone,
demeclocycline, diathymosulfone, dibekacin, dihydrostreptomycin,
dirithromycin, doxycycline,
enoxacin, enviomycin, epicillin, erythromycin, flomoxef, fortimicin(s),
gentamicin(s), glucosulfone
v, i
solasulfone , gramicidin S, gramicidin(s), grepafloxacin, guamecycline,
hetacillin, imipenem,
,~u
isepamicin, josamycin, kanamycin(s), leucomycin(s), lincomycin, lomefloxacin,
lucensomycin,
lymecycline, meclocycline, meropenem, methacycline, micronomicin,
midecamycin(s), minocycline,
mo~xalactam, mupirocin, nadifloxacin, natamycin, neomycin, netilmicin,
norfloxacin, oleandomycin,
oxytetracycline, p- sulfanilylbenzylamine, panipenem, paromomycin,
pazufloxacin, penicillin N,
pipacycline, pipemidic acid, polymyxin, primycin, quinacillin, ribostamycin,
rifamide, rifampin,
rifamycin SV, rifapentine, rifaximin, ristocetin, ritipenem, rokitamycin,
rolitetracycline, rosaramycin,
roxithromycin, salazosulfadimidine, sancycline, sisomicin, sparfloxacin,
spectinomycin, spiramycin,
streptomycin, succisulfone, sulfachrysoidine, sulfaloxic acid,
sulfamidochrysoidine, sulfanilic acid,
sulfoxone, teicoplanin, temafloxacin, temocillin, tetracycline, tetroxoprim,
thiamphenicol,
thiazolsulfone, thiostrepton, ticarcillin, tigemonam, tobramycin,
tosufloxacin, trimethoprim,
trospectomycin, trovafloxacin, tuberactinomycin, vancomycin and the like.
[Ol 10] In still another embodiment, the active agent comprises an anti-fungal
agent such as
amphotericin B, azaserine, candicidin(s), chlorphenesin, dermostatin(s),
filipin, fungichromin,
lucensomycin, mepartricin, natamycin, nystatin, oligomycin(s), perimycin A,
tubercidin, and the like.
In another embodiment the active agent comprises an anti-cancer, e.g.,
carcinomas, sarcomas,
leukemias and cancers.derived from cells of the nervous system), including
anti-neoplastic, for
example, 6-azauridine, 6-diazo-5-oxo-L-norleucine, 6-mercaptopurine,
aclacinomycin(s), ancitabine,
anthramycin, azacitadine, azaserine, bleomycin(s), capecitabine, carubicin,
carzinophillin A,
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chlorozotocin, chromomycin(s), cladribine; cytarabine, daunorubicin,
denopterin, docetaxel,
doxifluridine, doxorubicin, edatrexate, eflornithine, elliptinium,
enocitabine, epirubicin, etoposide,
floxuridine, fludarabine, gemcitabine, idarubicin, mannomustine, melphalan,
menogaril, methotrexate,
mitobronitol, mitolactol, mitomycin C, mitoxantrone, mopidamol, mycophenolic
acid, nogalamycin,
olivomycin(s), paclitaxel, pentostatin, peplomycin, pirarubicin, piritrexim,
plicamycin, podophyllinic
acid 2- ethylhydrazine, prednimustine, procarbazine, pteropterin, puromycin,
ranimustine,
streptonigrin, streptozocin, teniposide, thiamiprine, thioguanine, Tomudex0 (N-
[[5- [[(1, 4-Dihydro-
2-methyl- 4-oxo- 6-quinazolinyl) methyl] methylamino]- 2-thienyl] carbonyl]- L-
glutamic acid),
toptecan, trimetrexate, tubercidin, ubenimex, vinblastine, vindesine,
vinorelbine, zorubicin and the
like. In yet another embodiment, the active agent comprises an anti-
thrombotic, for example,
argatroban, coumetarol, dicoumarol, ethyl biscoumacetate, ethylidene
dicoumarol, iloprcist, lamifiban,
taprostene, tioclomarol, tirofiban and the like. The agent may also comprise
an immunosuppressive,
for example, 6- mercaptopurine, amiprilose, bucillamine, gusperimus,
mycophenolic acid,
procodazole, romurtide, sirolimus (rapamycin), tacrolimus, ubenimex and the
like; a general or local
anesthetic such as butethamine, fenalcomine, hydroxytetracaine, naepaine,
orthocaine, piridocaine,
salicyl alcohol and the like, and many others whose list is too extensive to
incorporate into the text of
this patent.
[0111] In still another embodiment the active agent is a low molecular weight
drug suitable for linkage
into degradable copolymers via a polyanhydride. Such low molecular weight
drugs typically have a
relatively low molecular weights of approximately 1,000 daltons or less, and
may comprise~one or
more of a carboxylic acid (-COOH), amine (-NH-, -NR-), thiol (-SH, -SR-),
alcohol (-OH), phenol (-
Ph-OH), ester (-COO-), carbonate (OCOO-), or others that are suitable as well.
Suitable examples of
low molecular weight drugs with the required functional groups within their
structure may be found in
almost all classes of drugs including, but not limited to, analgesics,
anesthetics, antiacne agents,
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antibiotics,.synthetic antibacterial agents, anticholinergics, anticoagulants,
antidyskinetics,
antifibrotics, antifungal agents, antiglaucoma agents, anti- inflammatory
agents, antineoplastics,
antiosteoporotics, antipagetics, anti-Parkinson's agents, antisporatics,
antipyretics,
antiseptics/disinfectants, antithrombotics, bone resorption inhibitors,
calcium regulators, keratolytics,
,sclerosing agents and ultraviolet screening agents. Particularly important
classes of agents are
analgesics, anesthetics, antiacne agents, antibiotics, anticancer agents,
anticholinergics, anticoagulants,
~In
anticonvulsants; antidiabetic agents, antidyskinetics, antifibrotic agents,
antifungal agents,
antiglaucoma agents, anti-infectives, anti-inflammatory compounds,
antimicrobial compounds,
antineoplastics, anti-Parkinson's agents, antiosteoporotics, antiseptics,
antisporatics, antithrombotics,
I
antiviral compounds, bacteriostatic compounds, bone resorption inhibitors,
calcium regulators,
cardioprotective agents, cardiovascular agents, central nervous system
stimulants, cholinesterase
inhibitors, contraceptives, deodorants, disinfectants, dopamine receptor
agonists, agents for the
treatment of erectile dysfunction, fertility agents, agents for the treatment
of gastrointestinal ailments,
agents for the treatment of gout, hormones, hypnotics, immunomodulators,
immunosuppressives,
keratolytics, agents for the treatment of migraine, agents for the treatment
of motion sickness, muscle
relaxants, nucleoside analogs, agents for the treatment of obesity, opthalmic
agents, osteoporosis
agents, parasympatholytics, parasympathomimetics; prostaglandins,
psychotherapeutic agents, agents
for the treatment of respiratory ailments, agents for the treatment of
sclerosis, sedatives, agents for the
treatment of skin and muscous membrane ailments, smoking cessation agents,
sympatholytics,.
ultraviolet screening agents, agents for the treatment of urinary ailments,
agents for the treatment of
vaginal ailments, and vasodilators.
[0112] One highly preferred embodiment includes, but is not limited to, agents
and compounds such as
analgesics, anesthetics, anti-acne agents, antibiotics, synthetic
antibacterial agents, anti-cholinergic
agents, anti-coagulants, anti-dyskinetics, anti-fibrotics, anti-fungal agents,
anti-glaucoma agents, anti-
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inflammatory agents, anti-neoplastic agents, anti-osteoporotic agents,
antipagetic agents, anti-
Parkinson's disease agents, anti-sporatics, anti-pyretics,
antiseptics/disinfectants, anti-thrombotic
agents, bone growth stimulating agents, hemostatic agents, bone resorption
inhibitors, calcium, sodium
and potassium ion regulating agents, keratolytics, anti-sclerosing agents and
detectable and signal
producing agents for screening and diagnostic purposes such as ultraviolet
(U.V.), fluorescent,
phosphorescent, radioactive, enzymatic, antibodies, and other known screening
agents, among many
others. ~ne highly preferred embodiment of the polymer of this invention
includes NSAIDs such as 4-
aminosalicylic acid, 5-aminosalicylic acid, 4-(acetylamino) salicylic acid, 5-
(acetylamino) salicylic
acid, sallsallate, 5-chlorosalicylic acid, 5-(2,4-difluorophenyl) salicylic
acid (diflunisal), by themselves
or in combination with one another, or in combination with other types of
agents such as anti-fibrotic
agents, antiseptic agents, anti-microbial agents, hemostatic agents, analgesic
agents, anti-pyretic
agents, or anti-coagulating agents, among many others. Yet another preferred
polymer includes agents
or compounds such as CNS acting agents of the type described above, which may
be in the form of a
monomer, or in combination with one another, or in combination with non-
centrally acting agents such
as muscle relaxants, local anesthetics, and the like, all of which would be
known to an artisan. Still
another highly preferred embodiment includes agents by themselves or in
combination with other
agents, as an artisan would know to select. Moreover, any combination of
agents, whether or not
specifically described in this patent are included within the four corners of
this invention.
[0113] Preferred agents included in the manufacture of the polymer of the
invention for applications
other than in the pharmaceutical, biological and veterinary fields, include
anti-infectives such as
disinfectants, antiseptics, antibiotics, anti-fungal agents, anti-viral
agents, anti-microbial agents,
antisporatic agents, or bacteriostatic agents, among others, hydrophobicity
increasing agents, insulating
agents, acustic promoting and shielding agents, adhesives, sealants or
coatings, among others, suitable
for use in the polymers of this invention. The present polymers may be
combined in the form of a co-
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polymer with segments of tacky polymers, among many others known in the art.
The polymers of the
invention may also be admixed with adhesives, coatings and/or coatings used in
different industries,
including the paint, cement, nautical, boating, vehicle, construction
materials, electrical, electronics,
furniture, household article manufacturing, industries, among many others.
~'~~ ' [0114] In another embodiment, each Rl, independently from one another,
comprises at least one
residues) of the chemical formula
OH
4A - R3
R
(II)
wherein R3 comprises amine, thiol, carbonate, amide, halo, or hydroxy; R4
comprises hydrogen, halo, .
NHR2, or aryl, which may be substituted with hydroxy, halo or halo (C~-
C4)alkyl; and RZ comprises
hydrogen, (C~-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl (C~-C6)alkyl,
aryl, heteroaryl, aryl (C~-
C6)alkyl, heteroaryl (C~-C6)alkyl, or (C~-C4)alkylcarbonyl, all of which may
be further substituted. In
another embodiment Rl comprises an aryl comprising residue that will yield the
agents) in an active or
activatable form upon hydrolysis of the polymer. In another embodiment each
agent comprises,
independently from one another, an anti-inflammatory, analgesic, anesthetic,
or anti-pyretic compound
comprising carboxylic acid and at least one amine, thiol, amide, carbonate, or
hydroxy. All specific
and preferred values for residues, substituents, linking groups, and ranges in
this patent are provided
for illustration only, and should serve as mere guidance to an invention that
is not limited by the
specific information listed. More specifically, lower alkyl may be straight or
branched (C~-C6)alkyl
'such as methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, sec-butyl,
pentyl, 3-pentyl, or hexyl, among
others; (C3-C6)cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl; (C_;-
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C6)cycloalkyl (CI-C6)alkyl may .be cyclopropylmethyl, cyclobutylinethyl,
cyclopentylmethyl,
cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl,
or 2-cyclohexylethyl,
among others; (CI_ C6)alkoxy such as methoxy, ethoxy, propoxy, isopropoxy,
butoxy, iso-butoxy, sec-
butoxy, pentoxy, 3-pentoxy, or hexyloxy, among others; (C1-C6)alkanoyl such as
acetyl; propanoyl or
butanoyl, among others; (C~-C6)alkoxycarbonyl such as methoxycarbonyl,
ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyla or
hexyloxycarbonyl, among
others; (C~-C6)alkylthio such as methylthio, ethylthio, propylthio,
isopropylthio, butylthio,
isobutylthio, pentylthio, or hexylthio, among others; (CZ-C6)alkanoyloxy such
as acetoxy,
propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy, among
others; aryl such
as phenyl, indenyl, or naphthyl, among others; and heteroaryl may be furyl,
imidazolyl, triazolyl,
triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl,
pyrazinyl, tetrazolyl, pyridyl,
(or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl
(or its N-oxide) or quinolyl
(or its N-oxide), among others.
[0115] One preferred linking group comprises a divalent, branched or
unbranched, saturated or
unsaturated (CI-Cao) hydrocarbon, which is optionally substituted with, e. g.
1, 2, 3, 4, or more,
substituents comprising (C1-C6)alkoxy, (C3_ C6)cycloalkyl, (C1-C6)alkanoyl,
(C~-C6)alkanoyloxy, (C~-
C6)alkoxycarbonyl, (C~_ C6)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo,
carboxy, aryl, aryloxy,
heteroaryl, and heteroaryloxy. Other specific substituents comprise -(CHRS)4-,
where each RS
comprises hydrogen, -C(=O)-(CHZ)ioCHs, or -O-P(=O)-O(CHZ)~oCH3, among others.
Other preferred
linking groups comprise an amino acid(s), peptide(s), protein(s), divalent,
branched or unbranched, ,
saturated or unsaturated (C ~-C ~ o) hydrocarbon residue(s), wherein one or
more carbon comprises) or
is(are) substituted by -O-, or NR -. Still other preferred linking groups
comprise divalent, branched
or unbranched, saturated or unsaturated (C3-CZO) hydrocarbon residue(s),
wherein one or more, e. g. l,
2, 3, 4, or more, carbon atoms is(are) optionally replaced by -O-, or -NR-,
and may be further
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substituted by (C~-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (CI-
C6)alkanoyloxy, (C~-
C6)alkoxycarbonyl, (C1-C6)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo,
carboxy, aryl, aryloxy,
heteroaryl, and/or heteroaryloxy, among others. Still other preferred linking
groups comprise divalent,
branched or unbranched, saturated or unsaturated (C3-C2o) hydrocarbon, wherein
one or more, e.g. 1, 2,
3, 4, or more, atoms is(are) substituted by -O-, -C(=O)O-, -C(=S)O-, -C(=O)S-,
-C(=O)NR7-, -
C(=S)NR7-, or -NR7-, wherein R7 comprises hydrogen, or (CI-C6) aliphatic
residue.
~In
[0116] Another group of polymers comprise a linking agents) that comprises) a
divalent, branched or
unbranched, saturated or unsaturated (C3-Czo)hydrocarbon, more preferably a
(C4-C~5)hydrocarbon,
ands even more preferably n-butyl, n-hexyl, n-octyl, n-decyl, n-dodecyl or n-
tetradecyl. Yet another
gropp of polymers includes an agents) or compounds) where R3, independently
from one another,
comprises) HO(CI-C6)alkylene; HS(C1-C6)alkylene, R6HN(C1-C6)alkylene, -OH, -
SH, -NHa, -HNR6,
wherein R6 comprises alkyl, alkenyl, alkynyl, alkoxy, carboxy, cycloaliphatic
residue, aryl, among
others, which may be further substituted with halogeil, O, N, S, or P; R4,
independently from one
another, comprises halo, NHRS, cycloaliphatic residue, or aryl, which may be
substituted with
hydroxy, halo or halo(CI-C4)alkyl, wherein RS comprises hydrogen or (C~-C4)
alkyl carbonyl, -NH2, -
NHAc, -Cl, 2,4-difluorophenyl, chloromethyl, difluoromethyl, -CF3, with -Cl,
and 2,4-difluoro-phenyl
being highly preferred. Another preferred group of polymers comprises a
residue where R5 comprises
H or (C~-C6)alkyl, more preferably methyl, ethyl or propyl. Another highly
group of polymers
comprises a residue where R6, independently from one another, comprises H, (C~-
C6)alkyl, (C3-
C6)cycloalkyl, (C3-C6)cycloalkyl(C~-C6)alkyl, aryl or aryl(C~-C6)alkyl; R7,
independently from one
another, comprises H, methyl, ethyl or propyl; and R$, independently from one
another, comprises -
C(=O)CH3. A group of compounds and polymers is that where Y comprises O.
Another group of
polymers releases an active or activatable agents) or compounds) comprising a
biologically active
hydroxy-carboxylic acid(s), or that may be converted to such agents) upon
relase by the polymer in
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situ. The hydroxy-carboxylic agents) may be aliphatic or aromatic agents.
Preferred among these are
agents such as a -(C1-C2o) aliphatic carboxylic acids) comprising 1 to 40
hydroxyl residues, including
alpha-hydroxy carboxylic and beta-hydroxy carboxylic acids, where preferred
are -(CHa)$-, -(CHa)14-.
Another preferred group of agents are hydroxy-aryl carboxylic acids, such as
ortho-hydroxy aryl
carboxylic acids, particularly those having anti-inflammatory activities. In
another embodiment, the
polymer of the invention is such where each agent included in Rl,
independently from one another,
comprises residues of different agents or compounds. This embodiment is
particularly suitable for the
administration of a mbination of, or complementary agents, such as in the case
of adjunt therapy
administered to a subject e.g. in medical, veterinary and agricultural
applications, among others. Such
polymers are also useful for applications other than screening, diagnosis and
therapy where, for
example, an additive such as an anti-infective is combined with a coating
agent in the polymer
backbone to seal an inanimate surface. These applications are particularly
suited for the paint, coating,
and many other industries, and may applied to surfaces and porous bodies in
maritime, engineering,
construction, building, oil, mining, and other industries, among many others.
[0117] Examples of suitable agents are 2-p- sulfanilyanilinoethanol; 3-amino-4-
hydroxybutyric acid;
4,4'-sulfinyldianiline; 4-sulfanilamidosalicylic acid; 6-azauridine; 6-diazo-5-
oxo-L-norleucine; 6-
mercaptopurine; aceclofenac; acediasulfone; acetosulfone; aclacinomycin(s);
acriflavine; acyclovir;
albuterol; alendronate; alminoprofen; amfenac; amicarbilide; amikacin;
aminoquinuride; amiprilose;
amoxicillin; amphotericin B; ampicillin; ancitabine; anthramycin; apalcillin;
apicycline; apramycin;
arbekacin; argatroban; arsphenamine; aspoxicillin; atorvastatin; azacitadine;
azaserine.; azidamfenicol;
azithromycin; aztreonam; bacitracin; bambermycin(s); benazepril; bialamicol;
biapenem;
bleomycin(s); brodimoprim; bromfenac; bromosaligenin; bucillamine; budesonide;
bumadizon;
buprenorphine; butethamine; butirosin; butorphanol; candicidin(s);
capecitabine; capreomycin;
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captopril; carbenicillin; carbomycin; carboplatin; carprofen; carubicin;
carumonam; carzinophillin A;
cefaclor; cefadroxil; cefamandole; cefatrizine; cefbuperazone; cefclidin;
cefdinir; cefditoren; cefepime;
cefetamet; cefixime; cefmenoxime; cefininox; cefodizime; cefonicid;
cefoperazone; ceforanide;
cefotaxime; cefotetan; cefotiam; cefozopran; cefpimizole; cefpiramide;
cefpirome; cefprozil;
cefroxadine; ceftazidime; cefteram; ceftibuten; ceftriaxone; cefuzonam;
cephalexin; cephaloglycin;
cephalosporin C; cephradine; chloramphenicol; chloroazodin; chloroazodin;
chlorozotocin;
'' .
chlorphenesin; chlortetracycline; chromomycin(s); cilastatin; ciprofloxacin;
cladribine; clarithromycin;
clinafloxacin; clindamycin; clomocycline; colistin; coumetarol; cyclacillin;
cyclosporin; cytarabine;
dapsone; daunorubicin; demeclocycline; denopterin; dermostatin(s);
diathymosulfone; dibekacin;
diclofenac; dicoumarol; diflunisal; dihydrostreptomycin; dirithromycin;
ditazol; docetaxel; dopamine;
doXifluridine; doxorubicin; doxycycline; edatrexate; eflornithine;
elliptinium; enalapril; enfenamic
acid; enocitabine; enoxacin; enviomycin; epicillin; epirubicin; erythromycin;
ethyl biscoumacetate;
ethylidene; etodolac; etofenamate; etoposide; famotidine; fenalcomine;
fendosal; fepradinol; filipin;
flomoxef; floxuridine; fludarabine phosphate; flufenamic acid; fluvastatin;
fortimicin(s); fungichrornin;
gemcitabine; gentamicin(s); gentisic acid; glucamethacin; glucosulfone; glycol
salicylate; gramicidin
S; gramicidin(s); grepafloxacin; guamecycline; gusperimus; hetacillin;
hydroxytetracaine; idarubicin;
iloprostimipenem; indinavir; isepamicin; josamycin; kanamycin(s); lamifiban;
lamivudine;
leucomycin(s); leuprolide; lincomycin; lisinopril; lisinpril; lomefloxacin;
lucensomycin; lymecycline;
mannomustine; meclocycline; meclofenamic acid; mefenamic acid; melphalan;
menogaril;
mepartricin; meropenem; mesalamine; metformin; methacycline; methotrexate;
methsalamine;
metoprolol; micronomicin; midecamyciri(s); minocycline; mitobronitol;
mitolactol; mitomycin C;
mitoxantrone; mopidamol; morphine; moxalactam; mupirocin; mycophenolic acid;
nadifloxacin;
~naepaine; nalbuphine; natamycin; neomycin; netilmicin; niflumic acid;
nizatidine; nogalamycin;
norfloxacin; nystatin; oleandomycin; oligomycin(s); olivomycin(s); olsalazine;
orthocaine; oxaceprol;
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oxymorphone; oxytetracycline; paclitaxel; panipenem; paromomycin;
pazufloxacin; penicillin N;
pentostatin; peplomycin; perimycin A; phenamidine; pipacycline; pipemidic
acid; pirarubicin;
piridocaine; piritrexim; plicamycin; podophyllinic acid 2-ethylhydrazine;
polymyxin; pravastatin;
prednimustine; primycin; procarbazine; procodazole; p-sulfanilylbenzylamine;
pteropterin; puromycin;
quinacillin; quinapril; ranimustine; ranitidine; ribostamycin; rifamide;
rifampin; rifamycin SV;
rifapentine; rifaximin; ristocetin; ritipenem; rokitamycin; rolitetracycline;
romurtide; rosaramycin;
roxithromycin; S-adenosylmethionine; salazosulfadimidine; salicyl alcohol;
salicylic acid; salmeterol;
salsalate; sancycline; sirolimus (rapamycin); sisomicin; solasulfone;
sparfloxacin; spectinomycin;
spiramycin; streptomycin; streptonigrin; streptozocin; succisulfone;
sulfachrysoidine; sulfaloxic acid;
sulfamidochrysoidine; sulfanilic acid; sulfasalazine; sulfoxone; tacrolimus;
taprostene; teicoplanin;
temafloxacin; temocillin; teniposide; tetracycline; tetroxoprim; thiamiprine;
thiamphenicol;
thiazolsulfone; thioguanine; thiostrepton; ticarcillin; tigemonam;
tioclomarol; tirofiban; tobramycin;
tolfenamic acid; Tomudex (N - [[5 -[ [ (1, 4.-Dihydro-2-methyl-4-oxo-6-
quinazolinyl) methyl]
methylamino] -2-thienyl] carbonyl] -L-glutamic acid), topotecan; tosufloxacin;
trimethoprim;
trimetrexate; trospectomycin; trovafloxacin; tuberactinomycin; tubercidin;
ubenimex; vancomycin;
vinblastine; vincristine; vindesine; vinorelbine; xinafoate; zidovudine;
zorubicin; and any enantiomers,
derivatives, bases, salts or mixtures thereof.
[0118] In one embodiment the agents) comprises) a non-steroidal anti-
inflammatory drugs)
(NSAID(s)) such as those described in U.S.S.N. 09/732,516, filed 07 December
2000; 3-amino-4-
hydroxybutyric acid, aceclofenac, alminoprofen, amfenac, bromfenac,
bromosaligenin, bumadizon,
carprofen, diclofenac, diflunisal, ditazol, enfenamic acid, etodolac,
etofenamate, fendosal, fepradinol,
flufenamic acid, gentisic acid, glucamethacin, glycol salicylate, meclofenamic
acid, mefenamic acid,
mesalamine, niflumic acid, olsalazine, oxaceprol, S-adenosylmethionine,
salicylic acid, salsalate,
sulfasalazine, tolfenamic acid and the like. In another embodiment, the active
agent is an anti-
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bacterial, for example, 2-p- sulfanilyanilinoethanol, 4,4'-sulfinyldianiline,
4-sulfanilamidosalicylic
acid, acediasulfone, acetosulfone, amikacin, amoxicillin, amphotericin B,
ampicillin, apalcillin,
apicycline, apramycin, arbekacin, aspoxicillin, azidamfenicol, azithromycin,
aztreonam, bacitracin,
bambermycin(s), biapenem, brodimoprim, butirosin, capreomycin, carbenicillin,
carbomycin,
carumonam, cefadroxil, cefamandole, cefatrizine, cefbuperazone, cefclidin,
cefdinir, cefditoren,
cefepime, cefetamet, cefixime, cefinenoxime, cefminox, cefodizime, cefonicid,
cefoperazone,
~ceforanide, cefotaxime, cefotetan, cefotiam, cefozopran, cefpimizole,
cefpiramide, cefpirome,
cefprozil, cefroxadine, ceftazidime, cefteram, ceftibuten, ceftriaxone,
cefuzonam, cephalexin,
cephaloglycin, cephalosporin G, cephradine;
chloramphenicol,.chlortetracycline, ciprofloxacin,
clarithromycin, clinafloxacin, clindamycin, clomocycline, colistin,
cyclacillin, dapsone,
demeclocycline, diathymosulfone, dibekacin, dihydrostreptomycin,
dirithromycin, doxycycline;
enoxacin, enviomycin, epicillin, erythromycin, flomoxef, fortimicin(s),
gentamicin(s), glucosulfone
solasulfone , gramicidin S, gramicidin(s), grepafloxacin, guamecycline,
hetacillin, imipenem,
isepamicin, josamycin, kanamycin(s), leucomycin(s), lincomycin, lomefloxacin,
lucensomycin,
lymecycline, meclocycline, meropenem, methacycline, micronomicin,
midecamycin(s), minocycline,
moxalactam, mupirocin, nadifloxacin, natamycin, neomycin, netilmicin,
norfloxacin, oleandomycin,
oxytetracycline, p- sulfanilylbenzylamine, panipenem, paromomycin,
pazufloxacin, penicillin N,
pipacycline, pipemidic acid, polymyxin, primycin, quinacillin, ribostamycin,
rifamide, rifampin,
rifamycin SV; rifapentine, rifaximin, ristocetin, ritipenem, rokitamycin,
rolitetracycline, rosaramycin,
roxithromycin, salazosulfadimidine, sancycline, sisomicin, sparfloxacin,
spectinomycin, spiramycin,
streptomycin, succisulfone, sulfachrysoidine, sulfaloxic acid,
sulfamidochrysoidine, sulfanilic acid,
sulfoxone, teicoplanin, temafloxacin, temocillin, tetracycline, tetroxoprim,
thiamphenicol,
~thiazolsulfone, thiostrepton, ticarcillin, tigemonam, tobramycin,
tosufloxacin, trimethoprim,
trospectomycin, trovafloxacin, tuberactinomycin, vancomycin and the like.
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[0119] In still another embodiment, the active agent comprises an anti-fungal
agent such as
amphotericin B, azaserine, candicidin(s), chlorphenesin, dermostatin(s),
filipin, fungichromin,
lucensomycin, mepartricin, natamycin, nystatin, oligomycin(s), perimycin A,
tubercidin, and the like.
In another embodiment the active agent comprises an anti-cancer, e.g.,
carcinomas, sarcomas,
leukemias and cancers derived from cells of the nervous system), including
anti-neoplastic, for
example, 6-azauridine, 6-diazo-5-oxo-L-norleucine, 6-mercaptopurine,
aclacinomycin(s), ancitabine,
anthramycin, azacitadine, azaserine, bleomycin(s), capecitabine, carubicin,
carzinophillin A,
chlorozotocin, chromomycin(s), cladribine, cytarabine, daunorubicin,
denopterin, docetaxel,
doxifluridine, doxorubicin, edatrexate, eflornithine, elliptinium,
enocitabine, epirubicin, etoposide,
floxuridine, fludarabine, gemcitabine, idarubicin, mannomustine, melphalan,
menogaril, methotrexate,
mitobronitol, mitolactol, mitomycin C, mitoxantrone, mopidamol, mycophenolic
acid, nogalamycin,
olivomycin(s), paclitaxel, pentostatin, peplomycin, pirarubicin, piritrexim,
plicamycin, podophyllinic
acid 2- ethylhydrazine, prednimustine, procarbazine, pteropterin, puxomycin,
ranimustine,
streptonigrin, streptozocin, teniposide, thiamiprine, thioguanine, Tomudex0 (N-
[[5- [[(1,4-Dihydro-2-
methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2- thienyl]carbonyl]-L-
glutamic acid), toptecan,
trimetrexate; tubercidin, ubenimex, vinblastine, vindesine, vinorelbine,
zorubicin and the like. In yet
another embodiment, the active agent comprises an anti-thrombotic, for
example, argatroban,
coumetarol, dicoumarol, ethyl biscoumacetate, ethylidene dicoumarol, iloprost,
lamifiban, taprostene,
tioclomarol, tirofiban and the like. The agent may also comprise an
immunosuppressive, for example,
6- mercaptopurine, amiprilose, bucillamine, gusperimus, mycophenolic acid,
procodazole, romurtide,
sirolimus (rapamycin), tacrolimus, ubenimex and the like; a general or local
anesthetic such as
butethamine, fenalcomine, hydroxytetracaine, naepaine, orthocaine,
piridocaine, salicyl alcohol and the
like, and many others whose list is too extensive to incorporate into the text
of this patent.
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[0120] In still another embodiment the agents) is(are) a low molecular weight
drug suitable for
linkage into degradable copolymers via a polyanhydride. Such low molecular
weight drugs typically
have a relatively low molecular weights up to about 1,000 Dalton, and may
comprise one or more of a
carboxylic acid (-COOH), amine (-NH-, -NR-), thiol (-SH, -SR-), alcohol (-OH),
phenol (-Ph-OH),
ester (-COO-), carbonate (OCOO-), or others that are suitable as well.
Suitable examples of low
molecular weight drugs with the required functional groups within their
structure may be found in
;~i
almost all classes of,drugs including, but not limited to, analgesics,
anesthetics, antiacne agents,
antibiotics; synthetic antibacterial agents, anticholinergics, anticoagulants,
antidyskinetics,
an~ifibrotics, antifungal agents, antiglaucoma agents, anti- inflammatory
agents, antineoplastics,
antiosteoporotics, antipagetics, anti-Parkinson's agents, antisporatics,
antipyretics,
an~isepticsldisinfectants, antithrombotics, bone resorption inhibitors,
calcium regulators, keratolytics,
sclerosing agents and ultraviolet screening agents. Particularly important
classes of agents are '
analgesics, anesthetics, antiacne agents, antibiotics, anticancer agents,
anticholinergics, anticoagulants,
anticonvulsants, antidiabetic agents, antidyskinetics, antifibrotic agents,
antifungal agents,
antiglaucoma agents, anti-infectives, anti-inflammatory compounds,
antimicrobial compounds,
antineoplastics, anti-Parkinson's agents, antiosteoporotics, antiseptics,
antisporatics, antithrombotics,
antiviral compounds, bacteriostatic compounds, bone resorption inhibitors,
calcium regulators,
cardioprotective agents, cardiovascular agents, central nervous system
stimulants, cholinesterase
inhibitors, contraceptives, deodorants, disinfectants, dopamine receptor
agonists, agents for the
w treatment of erectile dysfunction, fertility agents, agents for the
treatment of gastrointestinal ailments,
agents for the treatment of gout, hormones, hypnotics, immunomodulators,
immunosuppressives,
keratolytics, agents for the treatment of migraine, agents for the treatment
of motion sickness, muscle
,relaxants, nucleoside analogs, agents for the treatment of obesity, opthalmic
agents, osteoporosis
agents, parasympatholytics, parasympathomimetics, prostaglandins,
psychotherapeutic agents, agents
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for the treatment of respiratory ailments, agents for the treatment of
sclerosis, sedatives, agents for the
treatment of skin and muscous membrane ailments, smoking cessation agents,
sympatholytics,
ultraviolet screening agents, agents for the treatment of urinary ailments,
agents for the treatment of
vaginal ailments, and vasodilators.
IV. Polymer Preparation
A. Introduction
[0121 ] The following Table 3 provides a schematic description of the features
of the different
embodiments of the process of the invention.
Table 3: Features of Embodiments of Invention Pre arative Process
Process Embodiment Result of Structure or
Process
Solution Polymerization Ability to produce wide
range of
polymeric forms e.g.
elastomers,
semi-crystalline polymers,
controlled cross-linked
polymers, etc.
Pro erties Medical Device Structures
Exact control over structureApplies to all medicalSee below thermoplastic
and devices:
molecular weights. elastomer, multiblock
polymers,
Exact control of end groups semi-crystalline polymers,
of
polymer thermoset polymers, various
Control enables creation molecular weights
of
ethylene oxide and radiation
resistant polyanhydrides
- new
properties.
Release behavior is unaffected
by
sterilization
Shelf life and solvent
stability is
extended significantly
with new
chemistry
Exact control over release
profile
(duration, rate & induction
period)
Vary structure's solubility
to
control incorporation
of agents
(match solubility parameters
of
polymer with agent)
Exact Structure control,
molecular
weight control, ability
to create
unique bond sequences.
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Process Embodiment How Obtained Result of Structure or
Process
Block Copolymer of controlledThe solution polymerizationMultiple therapeutics
from one
sequence & length route proposed allows polymer.
one to
create blocks of any Multiple release profiles
molecular from
weight and structure one polymer
desirable.
These blocks are then Crystallizable segments
end- in the
linked as described same polymer
in the
examples to create Phase separated segments
a single in one
polymer with multiple polymer:
blocks
where each block can Reactive segments in
be a one
' different drug based polymer (blocks that
sequence can be
or different sequencescross-linked for example
of the with
same therapeutic agentblocks that cannot.
but
with different release
characteristics.
Uni ue Pro erties Medical Device Structures
Can create thermoplastic,All medical devices. Blocks of different chemical
Devices
elastomers (based on crystallinewould include flexiblecompositions; for
example
se~ments or associated biodegradable items different therapeutics,
segments (sutures,
- see examples below). mesh, coatings onto Blocks of different physical
elastic
Can create unique block surfaces, etc.). applicationsproperties; for example
different
sequences. that require multiple Tg's, different solubilities,
Multiple properties withintherapeutics from one different dielectric
one constant,
polymer. device/coating/. microspheredifferent rate of
degradation;
or
Thermal temperature differencesnanosphere different wettability,
etc.
between the blocks (Tgl-Tg2,
Tm-Tg)
Differences in any physical
property (release rate,
compatibility, solubility,
solubility for a specific
agent,
refractive index, etc.)
Differences in. any chemical
roperty.
Process Embodiment How Obtained Result of What Structure
or
Process
Altering linker chain Change the linker lengthChange in linker length
length used
to create the polymer.Change in linker bond
type
Mixtures of various Change in linker type.
linker
lengths in one polymer
randomly can produce
similar
effects as well.
Pro erties ~ Medical Device
Direct control of physicalAll
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properties (Tg, % crystallinity,
modulus, adhesion for example)
Carbon length of linker and
flexibility of linker (can be
quantified as persistence length).
Process Embodiment How Obtained Result of What Structure
or
Process .
Non-Aqueous Dispersion Dispersion provides uniformDispersion process
as
Process temperatures and temperaturedescribed
control
No surfactant avoids poisoning.
Particular mix of solvents
creates
a ratio of viscosities
and surface
tension that stabilizes
the dispersion
during polymerization.
Medical Device
All
Process Embodiment How Obtained Result of What Prepare by Previous
Structure or ProcessMethod
End capping & End Solution chemistrySolution ChemistryNo
linking method described
above. '
Pro erties Medical Device Structure
- see solution All Blocks, muti-agent
polymerization, TPE ~ polymers very
and high
Block Polymers; end molecular weights.
groups, end group
chemistry
Process Embodiment How Obtained Result of What Structure
or
Process
Branching at Well-definedFor example, random branchesThe solution chemistry
and
Branch Points can be placed by using end-linking methods
muti-acids enable
as part of the normal this practice.
solution
synthesis.
Star-like branches can
be created
by polymerizing from
an initial
branch point and growing
the
chain my solution
polymerization.
Branching at various
lengths
(molecular weights) can
be
created by forming polymers
of
1<nov~ Mw's, creating
the
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Process Embodiment How Obtained Result of What Structure
or
Process
appropriate end groups,
and then
end linking to create
the final
olymer.
Pro erties Medical Device Structure
Control elasticity Applies to all devices Branched.
Control of melt elasticityApplies to processes for
and coating
melt elongation or making devices.
Control of Fatigue ResistanceTo increase the melt elasticity
for
' Control of toughness making blow-molded devices,
,Control of adhesion branching has to be incorporate.
~
Ability to create branchesThis allows for the production
that are of
chemically different biodegradable bottle-like
than the
main chain structures.
Ability to create branchesTo modify coating application
that
ha a different physical(higher viscosity without
and changes
~
ch iri molecular weight),
mical properties than branching
the main
chain. ' is used to alter solution
viscosity.
Surfactant-like molecules
that
may serve as blend (or '
phase)
compatibilizers and
stabilizers
The ability to have
targeting
structures (branches)
on a
polymer chain.
Chain & branch composition
Molecular weight .
Molecular weight between
branches
Distribution of the
two pervious
items
Physical & chemical
properties
'of branches and chain
End group or branch
point
chemistry (anhydride
vs.
carbonate for exam le.)
Process Embodiment How Obtained Result of What Structure
or
Process
Thermoplastic Elastomer Polymers based on two Result of the block
structure
incompatible units are enabled by the solution
created so
that they phase separatechemistry method and
when end-
processed. Incompatibilitylinking chemistry.
means
difference in solubility
as defined
by the Van Krevlin (for
example)
solubility parameter,
or
differences based on
crvstallizability. One
component
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Process Embodiment How Obtained Result of What Structure
or
Process
is selected with a glass
transition
temperature or crystalline
melt
temperature above the
targeted use
temperature. The second
component is selected
to have a
Tg below the targeted
use
temperature. On processing,
these
materials phase separate
and form
anchored phases that create
a
rubber-like material that
can be re-
processed by heating about
the Tg
or Tm of the higher temperature
polymer.
As a compatibilizer, the
solubility
of a particular block
is selected to
be similar,to one of the
phases of
a blend that needs to
be
compatibilized (homogeneous
polymers that are not
compatible
with each other). Similar
approach
is taken to match the
additional
blocks) with the additional
phase(s). The compatibilizer
(usually in the range
of 5% w/w or
less) is blended with
the two
homopolyers to create
a
compatibilized system.
Pro erties Medical Device Structure
Elastomeric behavior All devices with specificAs described.
over a wide
temperature range. opportunity to coat devices
that
Multi therapeutic (at require elastomeric flexibility
least two in
the preferred embodiment)(artificial hart valves,
bone pin
Mufti-release profile sheaths, ocular devises,
(at least two dermal
in preferred embodiment)applications, bandages,
wound
Control phase or domain closure devices, coatings
on
morphology by varying organs, coatings on dimensionally
the
degree of compatibility.changing medical devices,
etc.)
Can server as a mechanical
reinforcing agent when
incorporated into homopolymers
or homopolymer blends.
Glass transition, Tg
Melt Temp" Tm
Relative Solubility (solubility
parameter)
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Process Embodiment How Obtained Result of What Structure
or
Process
MW Molecular Weight
Distribution
Tg, l - Tg,2 Temperature
range
for phase separated amorphous
TPE
Tm-Tg2, temperature range
for
,~licrystalline separated
TPE.
(
In both cases, Tg,2 is
the lower
temperature and Tm &
Tg, l are
;n.the higher temperatures.
[0122] The polymers of this invention, such as the polySA and polyDF being
described for exemplary
purpose only, may be produced by a number of methods. In each case, the
polymers are produced by
I I
chemically connecting repeating monomers ("-mers"). Each repeating unit
contains two drug
molecules connected via ester bonds to one linker molecule; the drug molecules
are connected via
anhydride bonds. In the standard "melt condensation" approach used to prepare
the polymers of this
invention, e.g. polyAspirin, the monomers were dissolved in a solvent and
stirred for several hours at
relatively high temperatures. The inventors produced polymers such as polySA
and polyDF polymers
by this method, with molecular weights ranging from about 30,000 to about
90,000 and poly-
dispersities, a measure of polymer homogeneity, of about 1.5 to about 3Ø
Other methods permit the
preparation of polymers in higher yields, as well as of higher MWs and greater
uniformity than prior
methods permitted.
[0123] By.definition, all biodegradable polymers are designed to degrade and
release its agents) over
a period of time. Unlike other poly(anhydride-ester) polymers reported in the
literature, the present
polymers are highly soluble in common industrial solvents, and are relatively
stable (as measured by
I
loss of molecular weight) both in bulk and in solution. The desirable "bulk
stability", or molecular
(weight stability of the polymers at room temperature is generally about 1
week, 1 month, 6 months to
about 8 months, 1 year, 2 years, although longer periods of stability may be
attained as well. As with
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most other drugs the stability of the polymers of this invention is enhanced
by storage under dry
conditions and at low temperatures e.g. -20°C. However, even under
unprotected ambient conditions,
polymers such as polyNSAIDs are stable for weeks, and storage-related changes
in molecular weight
do not significantly affect polymer performance for drug delivery.
B. Non-Aqueous Dispersion Process
[0124] This embodiment provides a process for polyanhydride polymerization to
attain a high
molecular weight, e.g. in excess of 40,000 Dalton, polymer with negligible or
no gel formation. This
is a novel process for the preparation of a polyanhydride starting from a
mixed anhydride of a
dicarboxylic acid, also called here a pre-polymer, by non-aqueous dispersion
polymerization. The
method comprises heating a pre-polymer above its melting point in the presence
of a solvent for the
pre-polymer, e.g. an inert high boiling point solvent, that will not be a
solvent for the polymer, under
conditions effective for removing a mixed anhydride evolved upon
polymerization. The mild
conditions of this novel process permit the extension of a polyanhydride to a
higher molecular weight
than attainable by existing processes that form gelatinous or insoluble
polymer fractions that slow the
polymerization reaction and impede the extension of the polymer.
[0125] The inventors discovered that the melt-polymerization of polyanhydrides
from selected diacids
formed as mixed anhydrides with lower molecular weight acids e.g. acetic or
propionic acids permits
the extension of the polymer backbone to molecular weights exceeding 40,000
Dalton without
formation of a gel. This is achieved by carrying out the reaction as a non-
aqueous dispersion of molten
droplets suspended in a stable high boiling heat-transfer fluid that is
generally chemically unreactive
with respect to the polymer. In practicing this method, the formation of a
stable non-aqueous
dispersion (NAD) may be carried out by any known method, such as by vigorous
mechanical mixing
or stin-ing, for example with a variety of agitator designs or proprietary
mixing devices, or by
incorporating a minor amount of a dispersing a;~ent or surfactant, e.~~. a non-
aqueous agent or
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surfactant, to encourage the formation of a stable emulsion of molten droplets
of the polymerization
phase as a dispersion in the continuous phase of the inert fluid. In one
embodiment, the dispersing
agent should not react chemically with the polyanhydride, its chemical nature
being free from any
functional groups that would react with the anhydride moieties in the polymer.
~''~ '[0126] In another embodiment, the reaction is carried out in the absence
of any surfactant. The
~~~i particle size of the suspended droplets is preferably about 0.5, 1.0,
2.5, or 5.0 to about 7.5, 10, 25, 35,
or 50 micron in diameter, and any combination thereof, although values for the
droplet diameter
outside of this range are also contemplated. A small particle size encourages
rapid removal of volatile
materials, for instance under vacuum, 'and provides uniform, constant heating
to the system. Local
ov~xheating phenomena, or localized "hot spots" that are prone to occur in the
monolithic melt
procedures of the prior art led to undesirable side-reactions that may result,
for example, in gel-
formation and the like. Moreover, the viscous heating effects produced by
stirring a high melt
viscosity molten polymer employed by the prior art also caused local
overheating.
[0127] In the present method, the dispersion is almost always fluid, and this
avoids all the undesirable
effects mentioned above. The heat transfer fluid itself (the pre-polymer
solvent) is preferably not
volatile, and a poor solvent or a non-solvent for the molten polymer. The pre-
polymer solvent, in
addition, should have a sufficiently high boiling point so that it will not
distill extensively from the
system under high vacuum during the course of polymerization. Examples of heat
transfer liquids or
pre-polymer solvents comprise, although not being limited to, mineral oils,
vegetable oils, silicone oils,
napthalenes, biphenyls, decalines, and substituted benzenes, among others. The
inventors have found
'that hydrocarbon oils such as "white mineral oils" are eminently suitable.
[0128] Although generally conducted at ambient pressure, the polymerization
reaction in accordance
with this invention may be conducted at a pressure as low as about 0.002 mmNg
with little loss of oil
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by distillation, and clearly at any pressure therebetween. The polymerization
may also be conducted at
higher pressures, up to about 0.0002 mmHg, and even higher. As the reaction
progresses the reaction's
volatile materials may be removed from the system, e.g. condensed separately
in a trap cooled to -78°C
with a solid carbon dioxide/isopropanol mixture. Other methods for removal of
volatile substances
known in the art may also be employed. The polymerization is preferably
conducted at a temperature
of about 100, 120, 140, or 160°C to about 160, 180, or 200°C,
with a preferred temperature for certain
polyanhydride esters being about 160 C~20°C. When polymerization is
completed the reaction
mixture may be allowed to cool with agitation, under e.g. constant and
vigorous agitation, until the
molten drops solidify and form a suspension of solid spherical particles in
the matrix fluid. Upon
cooling the particles may be separated from the reaction medium, e.g. by
filtration, and washed with a
substance that dissolves the mineral oil but not the particles. Although other
substances may be
employed, light petroleum fractions with an about 40°C to about
60°C boiling point were found
particularly suitable for this purpose. The particles may be subjected to
continuous extraction in a
suitable apparatus, such as a Soxhlet apparatus, if desired. The temperature
of the solvent during the
extraction step should preferably not exceed the glass transition temperature
(Tg) of the polymer to
avoid causing sintering of the polymer particles. To this end, the use of a
modified Soxhlet apparatus
is preferred such that the extraction is performed with cooling of the
solvent.
C. Solution Polymerization Process
[0129] This embodiment comprises a process for synthesizing polymers in
solution by controlling the
polymer structure and molecular weight (MW) to attain polymers of enhanced
properties such as
mechanical properties, stability, and hydrolytic stability, among others. The
invention entails the
selection of monomer structure and amount, feed ratio, and activation strategy
to obtain polymers of
molecular weight greater, and of enhanced performance, than previously
attained by the prior art. This
embodiment enables the choice and amount of monomer, solvent, and use of
activation chemistry in a
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selection that impacts the performance characteristics of the resulting
polymer. The present process
teaches the selection of these parameters for the preparation of different
types of polymers of selected
characteristics such as polyesters, polycarbonates, polyanhydrides, and
polyamides, among others.
This patent teaches how to produce a polymer possessing desired performance
properties by choosing
specific monomers, solvents, reaction conditions, and optional steps as
described below. This process
enables the selection of a plurality of monomers, and reaction conditions to
produce a polymer
~f n
possessing a random. array of conjoined monomer units imparting to the product
desirable properties.
[0130] One embodiment of this process employs an acylating or dehydrating
agent, e.g. phosgene or
phosgene analogue, equivalent or substitute e.g. triphosgene, preferably in
stoichiometric combination
with an aliphatic or aromatic diacid salts) in the presence of a solvent for
the diacid salts) e.g. volatile
organic solvent, comprising halogenated hydrocarbons e.g. chlorinated
hydrocarbons, ethers, esters,
amides, and sulfoxides having boiling points less than 200°C, among
others. Preferred solvents
include halo mated solvents e. . chlorinated solvents with boilin
g g g points less than about 100°C, an
example being dichloromethane. In a preferred embodiment, the aliphatic or
aromatic diacid salts)
may be monomeric, oligomeric or polymeric in nature. In another preferred
embodiment, the
monomeric, oligomeric, or polymeric diacid chloride may be replaced by
phosgene and the
corresponding diacid. In another embodiment, various diacid ammonium and
alkali metal salts may be
utilized as well.
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[0131 ] Still another embodiment of the solution polymerization process for
preparation of the
polymers of this invention comprises employing the synthetic routes described
below with or without
different optional steps. Various permutations of the different steps shown in
the overall schemes
illustrated below provide the flexibility of designing polymers of desired
characteristics such as
molecular weight, flexibility, hardness, adhesiveness, and the like by
modulating different parameters
associated with their manufacture, such as linker length, substituents,
combining stretches of different
(1) -(D-L-D]X- H02C-Linker-CO2H 1
(CICO)2
O O
CIC-Linker-CCI HO-Drug-C02H + Pyridine
3
O O
H02C-Drug-O~Linker~0-Drug-CO2H
4
1 ) Triethylamine
2) Triphosgene
O O O
OII II
* C-Drug-O~Linker~0-Drug-C-O
x
polymers of different physical and chemical properties, end-capping, combining
aromatic with
aliphatic moieties in the linkers and co-polymer segments, and the like, as
described below. Schemes
1 ( 1 ) and 1 (2) provided below show two embodiments of the process of this
invention involving
solution polymerization.
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WO 2005/042600 PCT/US2004/017916
(1) -[D-L-D]x- H02C-Linker-C02H 1
(CICO)2
O O
2 CIC-Linker-~CCI HO-Drug-C02H + Pyridine
O O
H02C-Drug-O~ Linker~0-Drug-C02H
1 ) Triethylamine
2) Triphosgene
* O-Dru -O~Linker~0-Dru -O-O
9 9
x
Scheme 1(1)
[0132] In the embodiment shown in Scheme 1 ( 1 ) above, the hydroxyl group of
each of two molecules
of an agents) or compounds) of interest is(are) reacted with a bi-functional
linkers) that has been
activated by acylation to obtain the corresponding acid chlorides) (2) in the
presence of a solvent and
allowed to form a diacid intermediate (4) comprising two end agent units, in
the example 2 drug
molecules, with one linker between them. The diacid intermediate (4) is then
placed in the presence of
an amine, e.g. a tertiary amine, such as triethyl amine, pyridine and/or di-
isopropylethylamine to obtain
a quaternary ammonium salt, which in the presence of an effective amount of
triphosgene or similar
agent dissolved in a solvent, e.g. an anhydrous solvent such as
dichloromethane or chloroform, that is
preferably added slowly to the quaternary ammonium salt of the diacid mixture
to form a .desired
~polyanhydride (5). In this embodiment, the molecular weight may be determined
by the amount of
triphosgene as well as the period of time the reaction is allowed to proceed.
The growth of the
molecular weight may be monitored as the polymer is extended, for example by
GPC as is known in
the art. The reaction may be conducted across a vide ran~~e of temperatures,
e.~~. about -?0, -l 5, -l 0., -
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WO 2005/042600 PCT/US2004/017916
5, 0, or 5°C to about 5, 7, 10, 15, or 20, ambient temperature,
provided that the temperature does not
facilitate the occurrence of side reactions that might impede the linear
growth of the polymer, e.g.
<25°C. If practiced in the manner described, this process produces a
polymer comprising alternating
units of the agents) or compounds) and the linking group(s).
-Cp-L-pox- H02C-Linker-COzH '~
(CICO>Z.
0 0
3 CIC-Linker-CCI HO-Drug-C02H + PyrIUina
3
HOzC-Drug-O~Linkar~0-prug-COZH
4
~ ) Triathylamina
2) Triplnosgana
O 1' O
'-~C-Crug-O~LInkar~0-Drug-C-O~%
(2D -Cp'-p-L-p-p'7x-
(CICO)a O ~.I~ ~ ~O
CI-C-Drug-O Linker O-Drug-C-CI HO-drug'-COZH -~ PyriUlna
6 1
O 1' O
HOzC-Drug'-O-C-Drug-O~LInkar~0-Orug-C-O-Orug'-COaH
7
'1 ~ Triatt~ylamina
2 Triptiosgana
a ,O O 1' I' O O '1~
C-prug'-O-C-pru g-O~ Lin ka r~0-Drug-~-O-Orug'-C-O-FX
8
Scheme 1(2)
[0133) In another embodiment shown in Scheme l (2) above the diacid
intermediate (4) may be
activated by acylation to attain a diacid halide (6) comprising two molecules
of agents) and one linker,
which is then reacted with the hydroxyl of two molecules of agents) or
compounds) to form a diacid
comprising four agents) units, and so on. This diacid may then be subjected to
the remaining steps of
the process described above to form its triethylammonium salt, and then
placing the salt in the
presence of triphosgene to form a polymer in accordance with this invention
comprising alternating
units of one linker and four drug moieties. In the same manner the process may
be adapted to design
polymers of varying numbers of agents) units bonded to one another and then
linked through one
linker, or by employing the same or other linkers and other agents to vary the
chemical sequence of the
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WO 2005/042600 75 PCT/US2004/017916
resulting polymer. Yet another embodiment of the process of the invention is
shown in Scheme 2
below.
O O O 0
CI-C-Drug-Linker-Drug-C-CI +~ CI-C-Linker-C-CI
6
'fin
1 ) HO-Drug-C02H + TEA
.l,i ~ 2) Triphosgene
O
* C-Drug-Linker-Drug-A-Drug-A-Linker-A-Drug-C-O
n
A =ester or anhydride bond
Scheme 2
[0134] This embodiment of the process of the invention comprises generating a
pre-polymer with a
relatively low molecular weight, e.g. about <20,000, by reacting two different
diacids that may be
activated as acid chlorides (6) and (9) with, e.g. a triethyl ammonium salt of
an agents) or
compounds) in an anhydrous solvent. The thus formed pre-polymer may be
isolated and linked
together by addition of, for example triphosgene, to the quaternary ammonium
salt of the pre-polymer
to achieve a higher molecular weight, e.g. about <50,000, by end-linkage.
Depending on the
composition and the order of addition of the different components, the
arrangement around the agenf(s)
or compounds) units may be modified by using this procedure to attain
sequences such as -L-D-L-, -
L-D-D-L-, -L-D-D-D-L-, or -L-D-D-D-D-L-, wherein D comprises an agent(s), and
L comprises a
linking group(s), among many others. The thus produced bonds between linker
and agents) or
compound(s), agent(s)-agent(s), or linker(s)-linkers) may comprise ester or
anhydride depending on
the combination of process. It will be appreciated by those skilled in the art
that the compounds of the
invention may comprise a chiral centers) and, therefore, may exist in and be
isolated in optically
active and racemic forms. Some compounds may exhibit polymorphism. The present
polymers
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comprise any racemic, optically-active, polymorphic, or stereoisomeric form,
and their mixtures,
including those of an agents) or compounds) possessing the useful properties
described herein. Based
on the description of the process of the invention, an artisan will know how
to prepare optically active
forms, for example by resolution of the racemic form by recrystallization
techniques, by synthesis from
optically-active starting materials, by chiral synthesis, and by
chromatographic separation using a
chiral stationary phase, among.others, and how to determine cADPR agonist or
antagonist activity of
the polymers and agents or compounds using standard tests that are either
described here or are well
known in the pertinent art.
[0135] Intermediates useful for preparing compounds of formula (I) are also
provided as further
embodiments of the invention. In cases where compounds are sufficiently basic
or acidic to form acid.
or base salts, use of the compounds as salts may be appropriate. Examples of
acceptable.salts are
organic acid addition salts formed with acids that form a physiological
acceptable anion, for example,
tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate,
benzoate, ascorbate, oc-
ketoglutarate, and a-glycerophosphate, among others. Suitable inorganic salts
may also be formed,
including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts,
among many others.
Acceptable salts may be obtained using standard procedures well known in the
art such as by reacting
a sufficiently basic compound such as an amine with a suitable acid affording
a physiologically
acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or
alkaline earth metal (for
example, calcium) salts of carboxylic acids may also be made. The ability of a
compound of the
invention to be polymerized may be determined using polymer formation
techniques that are well
known to the art. The activity of the polymers may be determined using assays
that are well known to
the art or described herein.
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D. Solution Process - Structure & Molecular Weight Control
[0136] This embodiment of the solution polymerization process of the invention
comprises novel
polymer workup steps, and produces polymers hat exhibit marked improvements
over prior art
polymers in overall performance as it applies to various structural and
performance polymer properties.
The process of the present invention produces polymers that greatly improves.
on the desirable '
,In
characteristics of prior art polymers, particularly in attaining higher
molecular weights e.g. up to about
in ,
100,000; 200,000; 350,000; 500,000; 750,000; 1,000,000 Dalton, and higher. The
process of the
invention results in polymers that exhibit specific unexpected properties that
are described below.
1 ) Enhanced , structural control is employed to achieve targeted polymer
assembly
ch~~acteristics by polymerization of pre-designed co-monomers and/or linking
chemistries. The
present polymers attain configurations representing a broad spectrum ranging
from purely alternating,
to random, to tapered block, to multiblock polymeric structures. An
illustrative, non-limiting example
includes hybrid ester-anhydride polymers based on salicylic acid derivatives.
These compounds
contain relatively labile phenolate esters that are readily amenable to
concerted trans-esterification and
anhydride exchange. This feature is controlled by the method of the invention
to attain a targeted,
controlled structure during the solution polymerization process.
2) Enhanced yield and purity are achieved through inhibition or suppression of
deleterious
oxidative, cross-linking, and other side-reactions by employing mild
polymerization temperatures, e.g.
ambient and lower solution-polymerization temperatures that are milder by
comparison with the prior
art melt-condensation temperatures typically well in excess of 100°C.
3) Enhanced capability to control polymer molecular weight, and in particular
a
demonstrated capability to achieve high polymer molecular weights, both in one-
pot, and in post-end-
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linking syntheses. These molecular weights are higher that were ever reported
by the prior art using
melt-condensation, and solution polymerization.
4) Greatly enhanced storage stability (shelf life) and "pot-life" stability,
particularly in
terms of hydrolytic stability in organic solvents and in the solid state,
achievable with a wide range of
alternating, randomized and block polymer structures. This is generally
imparted during an acidic
work-up and isolation of the polymer following the solution-polymerization
step.
5) Ability to control the performance properties of a polymer e.g. degradation
rate and
mechanical strength, for instance by selection of appropriate co-monomer and
linking chemistry
configurations. This may be implemented by the following means.
a. Inhibition of, or decreased, pitting that is mostly due to crystallization
of a less
randomized polymeric structure (a more regular crystalline structure) as it
degrades. Bulk and
surface integrity and mechanical strength may be maintained by preventing
unwanted
crystallization. This facilitates sustained polymer surface erosion, inhibits
transition to bulk
erosion, and enhances long-term adhesion to surfaces and
predictable/controllable active
compound generation rates from polymer films and other forms and shapes, even
when wet.
b. Prevention of formation of long block structures of phenolate-ester-linked
diflunisal units that typically arise during melt polycondensation and are
very slow to degrade.
This prolongs the time to achieve complete elution of diflunisal.
c. Prevention of formation of long block units that arise during melt-
polycondensation and increase instability in organic solvents, and in the
solid state due to
enhanced hydrolytic lability of non-aromatic anhydride linkages:
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6) Ability to obtain high polymer molecular weights of up to about 600,000
Dalton, and
even higher, by solution polymerization. These molecular weights are
substantially higher than those
attained by melt-polycondensation by the prior art. Such high molecular
weights enhance the
mechanical strength, flexibility, and toughness, among other properties, of
the polymer.
'I~ '[0137] The unexpected ability to control a polymer's structure,
performance and stability provided by
In the process of the invention relative to the prior art melt-
polycondensation processes arises largely
from the interplay of various factors, two of which being described below,
1) The use of a solution medium in the polymerization process of this
invention eliminates
I '
the occurrence of "melt incompatibility" that is prevalent in melt-
polycondensation methods of the
prior art. The net effect is seen most readily when co-monomer units highly
incompatible in the melt,
such as fluorinated aromatic-fatty aliphatic co-monomer units, e.g. diflunisal-
C14 diacids; are
polymerized by these two distinct methods. In the melt-polymerization process
of the prior art"this
melt incompatibility may drive the ultimate formation of segregated, tapered
block co-monomer
arrangements. In melt polycondensation, melt segregation may also contribute
to the formation of
insoluble domains, or chemically- or physically-cross-linked gels. This
significantly lowers the yield
of useful polymer, and requires the extraction of soluble polymer portions
upon completion of the
synthesis. In the specific case of the mentioned C 14 diflunisal polymer, for
example, the occurrence of
block sequences of bis-C 14 anhydride may compromise the polymer's hydrolytic
stability in organic
solution and in the solid state whereas block sequences of phenolate-ester-
linked diflunisal units
degrade very slowly and, thereby extend the time for complete polymer
degradation and diflunisal
'release.
2) The solution process of the invention utilizes highly-reactive linking
chemistries in
combination with low temperatures that facilitate the design and attainment of
desired end-structures
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and disfavors unwanted side reactions that are prevalent under the high
temperatures required by melt-
polycondensation. The nature of the polymer end-groups, e.g. aromatic and
aliphatic carboxylic acids,
produced by solution polymerization in combination with an acidic aqueous
workup procedure
facilitates the conversion of anionic salts to carboxylic acids, and produces
a marked improvement in
both storage and "pot-life" hydrolytic stability. In the specific case of
polymer-drugs such as the C 14-
diflunisal ester-anhydride polymer the end group factor adds to the improved
control of the polymer
structure the formation of lesser sequences of bis-C 14 anhydrides, all of
which contribute to improving
hydrolytic stability in organic solvents and in the solid state.
E. Process Employing End-Capping/End-Linking
[0138] This is another embodiment of the solution polymerization process that
was suitably designed
to attain high molecular weight polymers, e.g. polyanhydrides and hybrid
polyester-anhydrides), by
addition of controlled end-group structures through solution end-linking
chemistry. In one
embodiment, end-linking or end-capping involves the use of an acylating or
dehydrating agent e.g.
phosgene, preferably in stoichiometric combination, with an aliphatic or
aromatic diacid ammonium
alt(s), preferably alkylammonium or alkali metal salt(s), in the presence of a
solvent e.g. an organic
solvent. For polymeric extension by coupling or polymer end-capping preferred
diacid salts comprise
oligomeric or polymeric aliphatic or aromatic diacid salts. An oligomeric or
polymeric diacid halide,
e.g. diacid chloride, may be substituted for phosgene, and the corresponding
diacids and/or diacid
ammonium and alkali metal salts utilized. The choice of end-linking chemistry
for polymer extension
to increase the polymer's molecular weight vs: reactive propagation of co-
monomer functional groups
impacts the type of structural arrangement produced, in terms of both linking
bonds and co-monomer
arrangement, the resulting configurations ranging from purely alternating to
random to tapered block to
mufti-block structures. The following are non-limiting examples intended to
illustrate the numerous
conceivable synthetic permutations encompassed by this process.
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1) Polymerization of two different diacid alkylammonium salts with phosgene
produces a
randomized co-monomer.
2) Polymerization of two different diacids, one present as an acid halide,
e.g. chloride, and
the other present as an alkylammonium salt, yields a strictly alternating co-
monomer.
3) Polymerization of two different' diacids forming part of an acid halide,
and
In ,
alkylammonium salt produces a randomized co-monomer.
4) Utilization of a co-monomer with a phenol group, e.g., salicylate drugs, in
the form of
an ~alkylammonium salt imparts an enhanced capability for concerted
transesterification and anhydride
exchange during the synthesis of ester-anhydride polymers based on them. The
frequency may be
modulated by starving the pot of free phenol groups to varying degrees. This
method achieves a wide
range of polymer structures incorporating varying degrees of randomization
and/or blocking of~both
co-monomer units and linking structures.
[0139] In one embodiment, the choice of chemistry for polymer end-capping
differs primarily from
chain extension in that the end-cap comprises a mono-functional rather than di-
functional entity. Non-
limiting examples of possible. compounds for end-linking include acetyl
chloride with an
alkylammonium carboxylate-terminated polymer to produce a mixed acetic
anhydride end-group.
Conversely, alkylammonium acetate with a carboxylic acid chloride-terminated
polyrrier may be
employed to produce a mixed acetic anhydride end-group. Fatty acid halides,
e.g. chlorides, or fatty
alkylammonium or metal salts, such as palmitoyl halides, e.g. chloride, may be
similarly employed to
produce fatty acid end-groups. Clearly, other structural end-groups may be
used if suitably pre-
~unctionalized to allow end-capping with the polymer of interest. The chemical
reactions or steps of
the process involved in end-linking may be implemented in-situ as the last
step of a polymer synthesis.
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[0140] In another embodiment this effect may be attained by end-capping a pre-
synthesized polymer.
In this embodiment where a pre-synthesized polymer is employed, it is
preferable to use cross-linked
acid-acceptor beads instead of tri-ethylamine or other tertary amine to make
an alkylammonium
carboxylate salt. This preferred modification greatly facilitates the
manipulation of the polymer
subsequent to end-capping. A choice of linking chemistry may be implemented by
selection of the
propagating co-monomer functional groups. This selection will impact the type
of structural
arrangement produced, e.g. linking bonds and co-monomer arrangement, resulting
in structure .
configurations ranging from purely alternating to random to tapered-block to
mufti-block structures.
Non-limiting examples intended to illustrate the numerous conceivable
synthetic permutations are
described below.
[0141] This process conducts the polymerization with all acylating agents at
temperatures e.g. ambient
to about 0°C, and even lower temperatures. Such temperature range will
generally suffice for the facile
acylating propagation reactions, and polymerization may typically be achieved
in times ranging from
as little as about 1/2 hour to about 6 hours. Imone embodiment low
polymerization temperatures are
more amenable to temperature sensitive co-monomer units than the prior art
melt polycondensation
process that requires long intervals of sustained high temperatures e.g. in
excess of 100°C, typically in
excess of 140°C, for more than 12 to 24 hours.
[0142] In yet another embodiment. when phosgene or phosgene-generating
substitutes like triphosgene
are employed it is preferred to utilize a temperature below phosgene's boiling
point (8°C) to prevent its
loss during the reaction. This embodiment extends the range of molecular
weight and end-capping
capabilities achievable with the above described solution method for synthesis
of polyanhydrides and
polyester-anhydrides), among other polymers. The advantages of the above
described process extend
to this embodiment as well. Although end-capping has been used in the art, the
use of polymer
extension by end-linking, e.!~. with phos~~ene in particular, is novel and
unobvious.
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F. Process with Controlled Sequence Domains
[0143] This embodiment of the process of the invention may employ either melt-
condensation or
solution-polymerization to produce new polymers comprising two or more
different monomeric units
covalently joined in defined molar ratios. This embodiment results in a
polymer of predictable
domains that is constructed by careful selection of the nature and quantity of
the input monomer feeds,
and by an appropriate choice of reaction conditions. Each of the polymer
domains results from the
structural characteristics of the individual monomers and imparts to the
overall polymer useful
chemical and physical properties such as hardness, adhesion, hydrophobicity,
permeability,
crystallinity, flexibility, hydrolytic stability, intrinsic thermogravimetric
profile, among many other
pr ~perties that may be also enhanced and are contemplated in this invention.
These properties may be
altered in a predictable pattern by controlling the input molar % of monomer
to obtain polymers of
unexpectedly superior chemical and other characteristics, and a freely tunable
rate of degradation and,
thereby, agents) or compounds) released in situ. The process of this invention
provides a means of
designing a desired polymer by correlation of the nature and mole ratio of
constituent monomers with .
specific polymer performance characteristics. The present inventors realized
that individual polymer .
characteristics may be qualitative or quantitative measured as is their
contribution to the overall co-
polymer characteristics. This permits them to select a defined ratio of two or
more constituent
monomers or alter the mole ratio of reactant monomers to design specific co-
polymers of predictable
polymer performance parameters.
[0144] The following is an example provided for illustrative purposes only,
and it relates to the -
formation of a co-polymer comprising A and B monomer units, where monomer A is
Diflunisal-
Diflunisal-C14 Linker=Diflunisal-Diflunisal (DFL-DFL-C14-DFL-DFL), and monomer
B is diflunisal-
C14 Linker-Diflunisal (DFL-C14-DFL). An increase in the content of monomer A
from 0% to 50
mol% in a mixture of monomers A and B, with monomer B going from l 00% to 50%,
resulted in
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polyanhydrides with regularly increasing hydrolytic stability and Glass
Transition Temperatures (Tgs).
Prior to the present invention it had not been recognized that the performance
characteristics of a
resultant polymer may be controlled by modifications of the structure and mole
fraction of the
participating monomers. Given the relationship between individual monomer mole
fraction and
particular polymer parameters, the process of this invention provides an
unexpected advantage of
allowing the design of polymers of pre-determined performance characteristics
by proper choice of
mole% monomer ratio(s). In the above example it was observed that a step-wise
increase in the mole
fraction of monomer A in a solution-based process led to polymers with
increasingly different
performance parameters, e.g. Tg, flexibility, and hydrolytic stability, among
others. Thus, the
inventors found unexpectedly that they could manufacture a polymer that
possesses a desired Tg and
hydrolytic stability profile by choosing the appropriate mole % fraction of
one monomer over the
other, e.g. monomer A over monomer B. The polymers of the present invention
possess refined
performance characteristics, and may be employed, for example, as coatings,
films, laminates,
adhesives, formed implantable structures, e.g. drug-containing nano- and micro-
spheres, medical
devices, orthopedic and dental implants, and pharmaceutical formulations,
among others.
G. Branching Process at Well-defined Branch Points
[0145] This embodiment of the process of this invention incorporates well-
defined branch points into
polymeric materials to permit the modification by branching of their
performance characteristics. The
process relies on the structure, synthesis, and deployment of branching agents
as a preferred
embodiment of either melt dispersion or solution phase polymerization
processes of the invention.
Suitable branching agents may comprise tri-, tetra-, penta-, hexa-, or higher-
order functional functional
groups. The functional group for a branching agent may be selected to impart
the polymer properties
such as increased elasticity, increased melt elasticity, change in toughness
and fatigue resistance,
among many others. The performance of each specific brapched polymer will be
determined by
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factors such as the amount of each branched segment and the molecular weight
of the segments
between branching points. In one embodiment a branching agents) may be
incorporated into the
process at the beginning of polymerization to produce star-like polymeric
structures. In another
embodiment the branching agents) may be incorporated late in the
polymerization process to yield
,i ~ 'highly networked structures.
y~~ C0146] Another embodiment of this process provides for combinations of
these two extreme modes by
varying the ratio and time of incorporation into the polymerization step of
the process. The molecular
weight of the polymeric segments present between branch points may range from
one unit to any
nu rrilber of repeating units..
[0147] In one embodiment of the process molecular weights above those
necessary for chain
entanglement aie produced and are preferred. Any percentage of branching
agents is effective with a
demonstrated and preferred embodiment of about 1%, 2%, 3%, 5%, or 10%, and
higher, but less than .
the amount necessary to cause significant gelation during polymerization. The
prior art required
branching to be incorporated as a random adjunct to polymerization in
polyanhydrides.
[0148] In still another embodiment of the process of the invention the
specific chemistries employed
by this process enables a significant control of the polymer structure where
the molecular weight of
segments between branching points, branch point distribution, and branch point
type may be selected
to yield controlled structures of pre-determined erosion kinetics. In yet
another embodiment this
process permits control of mechanical properties such as fatigue resistance,
elasticity, and others that
had heretofore not been engineered to the extent provided by this invention.
H. Process of Preparation of Thermoplastic Elastomers
[0149] A further embodiment of the invention provides a process for the
synthesis of a biodegradable
polymer with increased elasticity at its application temperature. The thus
desi~~ned polymer may be
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formed by heat-based synthesis, and cast using known coating technologies. The
ability to increase the
elasticity of a polymer provides advantages in terms of, for example, better
flexibility, malleability,
resilience, and flow behavior, among many others. The present inventors
discovered that their.specific
solution chemistry process would help create the block structures needed to
synthesize these materials.
Applications where flexibility is necessary, e.g. in medical and other
devices, require a polymer of
rubber-like behavior for enhanced or maintained performance. Examples of this
type of applications
are all types of stems, coatings on tubing and other flexible surfaces,
coating of Nitinol and other
similar nickel-based alloy devices, ophthalmblogical applications requiring
flexible erodable polymers
to assist in non-inflammatory support or substance delivery, and many others.
[0150] In one embodiment the solution polymerization process of this invention
permits the design of
materials that will lead to phase separation. Block co-polymers may be created
from a repeating
structure based on a linker and incorporating an agents) of one solubility, as
determined by any
acceptable solubility calculation, and a linker and incorporating an agents)
of different solubility.
This will generally result in phase separation of the two blocks observed as
two distinct glass transition
temperatures, as measured by any acceptable technique. The co-polymer blocks
may be selected such
that the glass transition temperature (Tg) of the two phases bracket the
application temperature of
interest. That is, the Tg of one phase is lower while the Tg for the other
phase is higher than the target
temperature.
[0151] Various polymers, such as polyester, polycarbonate, polyamide,
polyurethane, polyanhydride,
may be prepared in this manner by proper choice of condensation conditions. As
the block phases
separate they form an extended network that results in increased elasticity.
The new polymer is more
rubber-like at the designed application temperature. Yet, when the polymer is
heated above the glass
transition temperature of the higher Tg block, it may be processed into a
variety of shapes by standard
polymer processin~~ technidues. This embodiment of the process may be carried
out by means of a
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solution based coupling process known to those skilled in the art. A non-
limiting example comprises
coupling of two pre-polymers having different Tgs in a volatile solvent for
the pre-polymer employing
a condensing agents) such as phosgene, diphosgene, triphosgene, oxalyl
chloride, thionyl chloride,
alkanedioic dichlorides, phosphochloridates, and carbodiimides, among many
others known in the art.
Suitable volatile solvents include, but are not limited to, chlorinated
hydrocarbons, chlorinated
hydrocarbons, ethers, esters, amides; and sulfoxides having boiling points
less than about 200°C,
among others known in the art. A group of preferred solvents includes
chlorinated solvents with
boiling points less than about 100°C. , In another embodiment the
thermoplastic elastomeric block co-
polymer may be synthesized by other polymerization techniques such as a melt
process.
I,
I. General Processes for the Synthesis of Inventive Polymers,
[0152] The following Schemes are illustrative of the synthetic process for the
preparation of various
inventive compounds described in the examples. The numbers assigned to each of
the monomers and
polymers will be referred to later on in the actual description of the
compound's synthesis or its use for
the preparation of another compound. Scheme 3 below shows the preparation of a
diacid monomer
employing two di-ortho hydroxy-carboxylic acid residues bound by a (CHZ)"
linking group. By means
of example, the starting material represents a dicarboxylic acid 11 that has a
linking group of either.12
(Compound l la), or 14 (Compound l lb) carbon atoms. Similarly, the
intermediate compound 15
represents a diacid halide of an ortho hydroxy carboxylic acid, where the
substituent R and the number
of carbons in the linking group may be H/6 (Compound 15a), H/8 (Compound 15b),
o, p-
difluorophenyl/10 (Compound 15c), o, p-difluorophenyl/12 (Compound 1 Sd), o, p-
difluorophenyl/14
(Compound 15e), o, p-difluorophenyl/6 (Compound l5fj, or o, p-difluorophenyl/8
(Compound 15g).
The resulting monomer (Compound 16) is a diacid of an aromatic ester dimer
bridged by an aliphatic
linking group, where the substituent R and the number of carbons in the
linking group may be H/6
(Compound l 6a)~ or o, p-difluorophenyl/l 2 (Compow~d 1 Sd).
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OH O
i off Pyridine,
O O
O O oxalyl chloride, CI~~~CI R THF
HO'~OH
CHC13 13
11 12 13a: R = H (SA)
11a: n = 12 11a: n = 12 13b: n = o,p-difluorophenyl (DF)
11b: n=14 11b: n=14
O O
oxalyl chloride,
CHCI3 CI
14 15
14a:n=6, R=H 15a: n=6, R=H
14b:n=8, R=H 15b: n=8, R=H
14c:n = 10, R = o,p-difluorophenyl15c: n = 10; R = o,p-difluorophenyl
14d:n = 12, R = o,p-difluorophenyl15d: n = 12, R = o,p-difluorophenyl
14e:n = 14, R = o,p-difluorophenyl15e: n = 14, R = o,p-difluorophenyl
'
15f: n = 6, R = o,p-difluorophenyl
15g: n = 8, R = o,p-difluorophenyl
13, Pyridine,THF
16a: n=6, R=H
16d: n = 12, R = o,p-difluorophenyl
Scheme 3 ,
[0153] Scheme 4 bellow shows the synthesis of a linking group starting from a
salt of an hydroxy
carboxylic acid (Compound 17) where the cation is sodium (Compound 17a), or
tetra n-butiryl-amino
(Compound 17b), and a dihalide of the desired linking group (Compound 18)
where the halide and
number of carbons are Br/6 (Compound 18a), I/10 (Compound 18b), or Br/8
(Compound 18c) to
obtain a di-hydroxy di-anhydride of the linking group (Compound 19) where the
number of carbons is
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6 (Compound 19a), 10 (Compound 19b), or 8 (Compound 19c). The second reaction
shown in Scheme
4 represents the synthesis of a specific product (Compound 21) of this group
where the substituent R
and the number of carbons in the linking group are H/8 (Compound 21 a) that
results from reacting an
aliphatic hydroxy carboxylic acid (Compound 20) with a di-halide of the
linking group (Compound
18c) in a solvent at about 60oC.
;n
;fn , o
~ ~O OH + X_(CH HO~O~O~OH
-X ----~
)
M ~
n
O O
17 18 19
17a: M = Na ~ _18a: X 19a: n = 6 (L)
= Br, n
= 6
17b: M = (n-Bu)4-N 18b: 19b: n = 10 (L)
X = I, n = 10
17c: M = Li 18c: X = 19c: n = 8 (L)
Br, n =
8
1 9d: n = 6 (D,L)
R R R
HO~OH 18c' E13N/DMF,HO~O~O~OH
60 C I ~ J
'
I I
O n
O
O
_20 _21
20a : 21a: R=H,n=8
R=H
Scheme 4
[0154 Scheme 5 below shows the polymerization by non-aqueous dispersion method
where polymers
with anhydride bonds between diacid monomer units bonded by an aliphatic
linking group (Compound
14), that is formed via a di-anhydride (Compound 22) where R and the number of
carbons in the
linking group are H/6 (Compound 22a), or o,p-difluorophenyl/12 (Compound 22b).
The resulting
polymer (Compound 23) has repeating units of the diacid linked through an
anhydride bond where R
and the number of carbons in the linking group are H/6 (Compound 23a), or o,p-
difluoropheny1l12
(Compound 23b).
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0 0
O O
0 0~0 0
HO ~ ~ ~ I off AC20 O~~ O O~O O O
i w ~ /'O \ / O
R R / \
_14
R R
22
22a: n = 6, R = H
22b: n = 12, R = o,p-difluorophenyl
[0155] Scheme 6 below shows the polymerization of a di-carboxylic acid
(Compound 11) to form an
anhydride polymer 24 by solution polymerization that results in a high
molecular weight polymer,
(Compound 24a), when the number of carbons in the linking group is 8.
0 0 0 0
TEA, Triphosgene
HO~OH n O
x
11 24
24a: n = 8
Scheme 6
[0156] Scheme 7 below shows the polymerization of an aromatic diacid (Compound
14) to form ari
anhydride polymer (Compound 25) by solution polymerization where R and the
number of carbons in
the linking group are o, p-difluorophenyl/12 (Compound 25a), H/6 (Compound
25b), or H/8
(Compound 25c).
_23
23a: n = 6, R = H
23b: n =.12, R = o,p-difluorophenyl
Scheme 5
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o O 1 ) TEA
2) Triphosgene
0 0~0 0
HO I \ ~ I ~OH
i \
R R
14 w
- 25
25a: n = 12, R = o,p-difluorophenyl
25b: n=6,R=H
25c: n = 8, R = H
Scheme 7
[0157] Scheme 8 below shows the syntheses of three mixed random polymers
(Compound 26) in
different compositions where the units are a di-aromatic diacid (Compound 14)
and a tetra-aromatic
diacid (Compound 16), both bridged by aliphatic linkers via esters.
0 0
0 o Y o o~0 0
1 ) TEA
X o o~0 0 0 0 \ i o 0 2) Triphosgene
HO ' I \ i I OH + HO ~ ~ \ I i OH 3) H+
\ \ ~ R R \ I
R R
[0158] Scheme 9 below shows the syntheses of a mixed random polymers (Compound
27) in different
compositions where the units are di-aromatic diacid chloride(Compound 15),
linker diacid chloride
(Compound 12), and triethyl ammonium salt of aromatic hydroxyacid (Compound
13, and other active
agents) by solution polymerization.
26a: m=8,n=8,X=3,Y=1,R=R'=H
26b: m = 14, n = 14, X = 3, Y = 1, R = R' = o,p-difluorophenyl
26c: m = 16, n = 14, X = 85, Y = 15, R = R' = o,p-difluorophenyl
Scheme 8
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0 0
O O~O O OH O
1)TEA, CHCI3
ci I ~ ~ I ci + X o o + Y \ ~ off 2) TEA, Triphosgene
i ~ cl~Ci
R R R
27a: n = 14, m = 14, X = 1, Y = 2, R = o,p-difluorophenyl
27b: n=8,m=8,X=1,Y=2,R=H
27c: n = 14, X = 0, Y = 1, R = o,p-difluorophenyl
K
27d 1
r
27e
Scheme 9 .
[0159] Scheme 10 below shows the syntheses of a mixed random polymers
(Compound 28) with a-
hydroxyester linker where the units are di-aromatic diacid chloride(Compound
15), a-hydroxyester
linker (Compound 12), and triethylammonium salt of aromatic o-hydroxyacid
(Compound 13) by
solution polymerization.
15 12 13
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0 0 0 off
o o \ 1) Chloroform
H0~ ~'m ~OH O O~O O HO 2) TEA / TP
n Y
O O y \ / O~ /
19 + ~ / \ ~ + 13 R
X.
+ TEA R R + TEA
;n , 'I~,.J~,O,~ Lo, ~_J~ ~ ° ,l 1L 11 .l ~ ,] ~, I~ ~ ~ ,
m
,1n , I 1' Y Y " " I . ,
x
28
28a: m = 10, n = 10, R = o,p-difluorophenyl
28b: m = 10, n = 12, R = o,p-difluorophenyl
28c: m = 8, n = 12, R = o,p-difluorophenyl
Scheme 10
[01~~60] Scheme l l below shows the syntheses of polyer (ester-carbonate)
where di-aromatic diol
(Compound 29a) was polymerized by solution method using triphosgene.
OH O O OH ,
OH O
OH + Br-(CHZ),; Br TES \ I O~O I j
18
13 R 29 R
29a: n = 6, R = H
1 ) TEA
2) Triphosgene
[0l 61 ] Scheme 12 below shows the syntheses of polyer (ester-ester) where di-
aromatic diol
(Compound 29) and linker diacid chloride (Compound 12) were polymerized by
solution method using
triphosgene.
JU
30a: n = 3, R = H
Scheme 11
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O O
OH O O . OH
w
0 0 0 o TEA O O O O « m
+ CI~CI - / ~ p'1 ''O ~ \
\'n /
R R 1a \
as -
R 31 R
Scheme 12
[Ol 62] Scheme 13 below shows the syntheses of polyer (ester-ester-ester) with
a-hydroxy ester
linkers, where di-aromatic di-acid chloride (Compound 15) and a-hydroxy ester
linker diol chloride
(Compound 19 or Compound 21) were polymerized by solution method using
triphosgene.
HO~O~O~OH
O m O
1 ) TEA
19 or 21 2) Triphosgene
0 0
0 0~0 0
c
of I w ~ ~ of , 32
32a: m = 8, n = 6, R = o,p-difluorophenyl, R' = H
R R 32b: m = 6, n = 8, R = o,p-difluorophenyi, R' = CH3
Scheme 13
[0163] Scheme 14 below shows the syntheses of the branched polymer with a
defined branch point
and controlled degree of polymerization by solution method from 1,3,5-benzene
tricarboxylic acid
(Compound 33) and di-aromatic linker di-acid (Compound 14).
0 0 ,
0 0~0 0 O X o 0
HO ~ ~ OH O O~O O
~i w~ \ x. ~w i~ o,
R R 1 ) TEA X I / X
14 2) triphosgene
O O R R v
+ .
COOH 34
34a: n = 14, R = o,p-difluorophenyl
HOOC ~ COOH
_33
Scheme 14
31a: n=3,m=8,R=H
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[0164] Scheme 15 below shows the syntheses of the branched polymer with a
defined branch point
and controlled degree of polymerization by solution method from 1,2,3,4-butane
tetracarboxylic acid
(Compound 35) and di-aromatic linker di-acid (Compound 14).
0 0
0 0~0 0 ,
I w i I OH X O O O
1 ) TEA O O O~O O
14 R 1 2) triphosgene X X X * I / \ I ~
O
COZH ~ X R R
COzH 36
H02C
C02H , 36a: n = 12, R = o,p-difluorophenyl
y ' Scheme 15
[015] Scheme 16 below shows the syntheses of the branched polymer with a
defined branch point
and controlled degree of polymerization by solution method from traps-
acotnitic acid (Compound 37)
and di-aromatic linker di-acid (Compound 14).
0 0
0 0~0 0
HO ~ i OH O O
O X
1 ) TEA X O O~O O
2) triphosgene ~O X - * I ~ i I p
Y
R R
H02C~CO~H 38
~-.-~C02H 38a: n = 12, R = o,p-difluorophenyl
37
Scheme 16
[0166] Scheme 17 below shows the synthesis of random block copolymer using
polymer A
(Compound 26b) and polymer B (Compound 25c) by solution polymerization method.
1 ) TEA Random
2) triphosgene block
HOC polymer A~--C02H + HOZC polymer B C02H copolymer
26b 25c 39
Scheme 17
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[0167] Scheme 18 below shows the synthesis of alternate block thermoplastic
elastomeric polymer
(Compound 40) using a high Tg block, polymer A (Compound 26b) and low Tg
block, polymer B
(Compound 25c) by solution polymerization method.
HOZC polymer A -C02H
26b
1 ) TEA
0 0
2) 2CI~x~CI 15d
3) H02C- polymer B C02H + TEA
25c
O O O OII O O OI' OII
O~X~O~ ~O~X~O * Alternate
polymer A , polymer B Block TPE
x
Scheme 18
[0168] Scheme 19 below shows the synthesis of tri-block thermoplastic
elastomeric polymer
(Compound 42) using a high Tg block, polymer A (Compound 26b) and low Tg
block, polymer B
(Compound 25c) by solution polymerization method where the inside block was
activated with di-
aromatic di-acid chloride to achieve the definite connecting point for the
blocks.
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H02C polymer A~--COZH
26b
1 ) TEA
0II 0
2) 2CI~Z~CI
O O O 2
O O O H02C polymer B CO~H
CI-C-~-C-O-C polymer A C-O-C-Z-C-CI
41.
'f t I . 25c + TEA
i
0 0 OII O O O 0II O
polymerA O~~~O~ ~O~~~O
polymer B polymer A
42 TriBlock TPE
Scheme 19
J. Sterilization
[0169] All implantable and percutaneous medical devices should be sterilized
before utilization, e.g.,
before or after packaging. Commonly employed sterilization methods are gamma
ray irradiation,
electron beam ("E-beam"), and ethylene oxide treatment. Gamma ray irradiation
penetrates objects
deeply, and is used for sterilizing foodstuffs and many medical device
products. This method,
however, requires relatively prolonged exposure times. E-beam sterilization
requires shorter exposure
times but has poor object penetration making the procedure useful mainly for
surfaces. Ethylene oxide
sterilization is more complex and more aggressive on organic materials than
the other two methods,
and is being replaced by them whereever possible because it is an
environmental hazardous agent. The
relatively high temperatures and humidity conditions required by many ethylene
oxide sterilization
protocols make it not to be highly compatible with many poly(anhydride-
ester)polymers. The
sterilization methods of choice for the polymers of this invention, therefore,
comprise gamma radiation
or E-beam sterilization. Experimental results show that E-beam (3.5 mRad) and
gamma radiation (25-
35 K~;~ys1 sterilization have no, effert on the pattern of diflunisal release
from polydiflunisal (polyT~F)
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coated stainless steel samples incubated,in serum at 37°C.
Notwithstanding its lack of effect on
polymer degradation, gamma ray and e-beam irradiation sterilization do produce
some changes in the
molecular weight and mechanical properties of polymers. The tensile modulus of
melt-polymerized
polySalicylic Acid (polySA), for example, was seen to decrease at room
temperature by about a third
after gamma sterilization (25-35 Kgys). There was no change in either
variable, however, at~37°C.
Gamma radiation had no effect on the molecular weight, flexibility, or
adhesiveness of the polymers of
the invention, such as polySA and poly DF, and only minor effects on their
hardness.
K. Layering Coatings of Polymers
[0170] The polymers of the invention may be layered onto devices with other
polymers of the
invention, or other polymers in general, to form coatings with desirable
properties. The therapeutic
polymers may be structured and/or layered as a coating with one or more
additional coatings that may
or may not be biodegradable (i.e., degradable by hydrolysis or
enzymatic/proteolytic activity when
placed in contact or exposed to body tissues or fluids). The additional
coatings may contain the same
polymerized active compound, a different polymerized active compound, no
polymerized active
compound, or one or more admixed drugs or agents. This structuring may be in
the form of a layer of a
coating on the exposed surface of the coating of the therapeutic polymer such
that this coating lies
between the polymerized active compound, and the body tissues and/or fluids
following implantation.
Alternatively, a second polymer or smaller molecular-weight species may be
physically blended with
the therapeutic polymer, and a series of layered coatings of therapeutic
polymer compositions that have
different chemical compositions and/or physical, e.g. mechanical, properties.
[0171 ] In some embodiments of the invention, layering permits refinement of
the rate or duration of
generation, release, or elution of active agents over time, including the
possibility of having one or
more outer coatings with higher or lower permeability to modulate the
breakdown of one or more inner
coatings and thereby result in a more constant release of active agent over
particular periods of time. In
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embodiments in which one or more outer coatings are biodegradable, the
breakdown and resulting
increase in permeability of these outer coatings may compensate for a rate of
generation (by
breakdown of the polymer) or release of an active agent that varies with time
by increasing the rate of
permeation of the active agent from the inner coating through the outer
coatings. Such embodiments
,~ ~ may be used to create a rate of delivery of drug from the coatings on the
device that vary less
temporally (i.e., are more closely more zero-order) and that may be adjusted
based on the preferred
shape and, therefore; surface area of the device and changes in surface area
that occur as the coatings
erode. Multiple layers of polymers generating, eluting, or releasing inert and
active products upon
br ~akdown may be designed for specific applications, including those
applications in which one class
or ember of a class of agents is to be generated, eluted, or released from the
coating before a second
class or a second member of the first class of agents is generated, eluted, or
released from the coating.
Possible structuring of layers of coatings, in which one or more of these
layers contains a polymerized
agents) or compound(s), e.g. drug, for implantable medical and veterinary
devices are contemplated
within this invention. Examples of these are a single layered coating, a
multiple layered coating in
which the layers may have different compositions and physical properties,
including thickness,
molecular weight, and others, and in which the top layers) comprises) or
dodoes) not comprises) the
polymerized agents) or compounds) and the bottom layers) comprises) or dodoes)
not comprises)
a polymerized agents) or compound(s), a bilayered or multilayered coating in
which the top and
bottom layers comprises) a polymer of the invention of different
composition(s). An example of such
a layered coating releases an anti-inflammatory agent, e.g. an NSAID(s)
substantially before an anti-
proliferative agent is generated, eluted, or released from the coating. Such
types of layered coatings
enable tuning of the rate of generation, elution, or release of drugs from the
coating over time, such
that' a near constant, gradually increasing, gradually decreasing, or a
combination thereof amount of
dn~g most appropriate for treatment of tissues in the vicinity of the device
may be delivered to these
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tissues. In one embodiment of the invention, an inert polymer coatings) may
applied as a top coats)
on one or more polymer coatings, even those that have drugs or other agents
admixed therein. A top
coatings) may be applied to increase the hardness and/or lubricity of an outer
coatings) to facilitate
use and insertion of a device. A top coating may be applied also to vary, e.g.
increase or decrease, the
rate of hydration or enzyme penetration to vary, e.g. increase or decrease,
the rate of backbone or
admixed drug release, or the release of other agents) from underlying
coating(s). A top coatings)
may be applied as well to increase the.shelf life of the final product by
limiting water and/or oxygen
contact with the underlying therapeutic polymer coating. In one preferred
embodiment the top coatings
comprises a biodegradable polymer. The polymers of this invention achieve
degrees of hardness
suitable for a variety of applications. Typically, the polymer of the
invention may attain a hardness of
about 24, 26, 28, 35, 45, 55 to about 60, 70, 80, 95, 101, based on a Shore
hardness range. Different
applications Polymers of the inventionhave different degrees of hardness that
are suitable for different
applications, such as for use in the devices of the invention.
L. Admixing Component Materials
[0172] The formation of a composite of two or more materials results in a new
material that may have
physical properties and performance characteristics substantially different
from any of the individual
component materials comprising the new material. In the case of polymers,
these altered physical
properties may include an increase or decrease in glass transition
temperature, tensile or shear moduli,
effective viscosity, yield strength and elongation, elongation at failure,
tackiness or adhesiveness,
hardness, color, rate of thermal or biological breakdown, surface texture, or
wettability by water or
other fluid. For example, the mechanical properties of bone, a composite of
inorganic calcium
phosphates and organic collagen molecules, are distinct from the mechanical
properties of either
calcium phosphates or collagen alone. In one embodiment, a polymer of the
invention is admixed with
an anti-proliferative agent, such sirolimus, everolimus or paclitaxel, or
other material or agent, such as
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specific RNA and DNA sequences and their chemical mimics or derivatives,
calcium phosphate,
hydroxyapatite, an antibiotic, an immunosuppressive agent, or another agent.
These added compounds
may alter the mechanical properties of the polymer (e.g., by modifying the
degradation rate, the tensile
modulus, the yield strength, and/or the elongation at which failure of the
material occurs). Coatings
,~i ,made from the therapeutic polymer will also exhibit the altered
mechanical properties. The extent to
which the admixture of.one or more drugs or other therapeutic agents changes
the physical properties
and performance characteristics of the coating will depend on the amount or
concentration of each of
the drugs or agents, with a trend that increasing the amount or concentration
of a drug or agent is
erected to increase, if at any changed occurs at all, one or more of these
properties or characteristics.
In practice, coatings with about 0.1, 1, 3, 5, 10 wt% or more to aboutl5, 20,
30, 35, 40, 45wt%
S
admixed drug or agent may be achieved by blending the admixed compound into
the polymer prior to
coating or by first applying the polymer as a coating and then absorbing the
compound to be admixed
into the coating by exposing the coating to a solution with the compound. In
an exemplary '
embodiment, a coating of a polymer with an admixed drug, applied on an
expandable stent, comprises
a dicarboxylic acid with more than six carbon atoms in the linear alkyl chain,
or a co-polymer or
physical blend of polymers or co-polymers that approximate the physical
properties and performance
characteristics of the polymer with a linker with more than six carbon atoms
in the linear alkyl chain,
such that these polymers approximate the physical properties and performance
characteristics of a
polymer with a linker of suberic acid (C~). In another exemplary embodiment, a
coating of a polymer
with an admixed drug, applied on an orthopedic implant, comprises a
dicarboxylic acid with more than
four carbon atoms in the linear alkyl chain, or a co-polymer or physical blend
of polymers or co-
polymers that approximate the physical properties and performance
characteristics of the polymer with
a linker with more than four carbon atoms in the linear alkyl chain, such
these polymers approximate
the physical properties and performance characteristics of a polymer with a
linker of succinic (C4) or
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adipic (6C) acid. In some embodiments, compositions comprising polymers may
have optimum
physical and chemical properties derived by blending compounds into the
polymer that decrease or
increase the rate of penetration of water and/or enzymes into the polymer
matrix and, thereby, decrease
or increase the rate of breakdown of the polymer, thereby modulating the
duration of generation of
drug from the components of the polymer backbone and/or the release of admixed
drug or agent. In
addition, qualities such as shelf life, e.g. stability in the presence of
elevated temperatures, humilities,
or electromagnetic radiation, rates of depolyrnerization, e.g. by hydrolysis
or proteolytic activity, or
oxidation, and rates of hydration may be varied by adding antioxidants or
lipophilic molecules to
reduce oxidation or hydration of the polymer blend, respectively. In some
cases, the qualities of the
admixed drug or agent may influence the physical or chemical properties,
including shelf life,
tolerance to sterilization methods, or degradation rate of the final product.
For example, the admixed
drug or agent may extend the shelf life, increase the types and/or dosages of
sterilant that may be
applied without changing other properties of the material; or decrease or
increase the degradation rate
of the final product.
V. General Overview of the Uses of the Inventive Polymers
[0173] The present invention also relates to methods of using compositions
comprising at least one
agents) linked to the polymer backbone in any application wherein delivery of
the active agent or
agents is desired. A route of delivery may be selected in accordance with the
drug being administered
and the condition being treated. In one embodiment, the polymers decompose
harmlessly while
delivering a selected low molecular weight drug at the site of implantation
within a known 'time period.
Another embodiment provides a method for site-specific or systemic drug
delivery by implanting in
the body of a patient in need thereof an implantable drug delivery device
containing a therapeutically
effective amount of a biologically or pharmaceutically active compound in
combination with the
polymer. In one embodiment, the polymers of the invention may be particularly
useful for the
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controlled delivery of an agent(s), or as a medium for the localized delivery
of an agents) to a selected
site. For example, the polymers of the invention may be used for the localized
delivery of a
therapeutic agent to a selected site within the body of a human patient, i.e.
within or near a tumor,
where the polymer degradation provides a localized, controlled release of the
therapeutic agent(s). In
another embodiment a method for delivering an active agent to a patient
comprises providing a
n
,medical device having at least one surface, comprising a first polymer on all
or a portion of the surface,
wherein the polymer is capable of breaking down, e.g. including but not
limited to hydrolyzing, in the
physiologic milieu to form a first active agent(s), and administering the
device to the patient so that the
fir ~t agent(s) is(are) delivered to the patient. The device may comprise
additional polymers and/or
additional active agents such as a second agent, third agent, and so on, where
the additional active
agents are, e.g. incorporated, blended, attached, appended or dispersed within
the polymer as described
herein, or otherwise annexed to or associated with the polymer such that the
additional agents)
dissociate from the polymer upon hydrolysis and are delivered to the patient.
The device may '
comprise active agents that combine in vivo to form a new active agent or
agents that is delivered to
the patient. The active agents) may be delivered to any suitable sites) in a
patient, such as the
circulatory system e.g. a vein or artery, a tissue, an organ e.g. lung, liver,
spleen, kidneys, brain, eye,
heart, muscle, and the like, a bone, cartilage, connective tissue, epithelium,
endothelium, nerves, a
tumor, or other site suitable for delivery of an active agent(s). Suitable
sites will typically be sites that
are or will .be in need of treatment with an active agent or agents, such as,
e.g., an injured site or a site
that may become injured, for example, due to a disease, a medical condition,
or during or after a
medical procedure, e.g. a balloon angioplasty and/or implantation of a medical
device. In one
embodiment, a method for delivering an active agent to an interior surface of
a vein or artery is
provided. The method comprises providing a medical device having at least one
surface, comprising a
first polymer on all or a portion of the surface, wherein the polymer is
capable of breaking down e.g.
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hydrolyzing, in the physiologic milieu to form a first active agent, and
positioning the medical device
at or near the interior surface of the vein or artery such that the first
active agent dissociates upon
hydrolysis and is delivered to the interior surface of the vein or artery. The
device may comprise
additional polymers andlor additional active agents, e.g. an additional active
agent(s), where the
additional active agents may be incorporated, attached, appended or dispersed
within the polymer, as
described herein, or otherwise annexed to or associated with the polymer such
that the additional active
agents dissociate from the polymer upon hydrolysis and are delivered to the
interior surface of the vein
or artery. The device may comprise active agents that combine in vivo to form
a new active agent or
agents that are delivered to the interior surface of the vein or artery. In
one embodiment, the method
prevents, reduces, and/or inhibits the development of restenosis in the blood
vessel. Restenosis may be
defined as, for example, the narrowing of the vessel to about ~0%, about 70%,
about 60%, about 50%,
about 40%, about 30%, about 20%, about 1~0% ~or less, of the diameter of the
vessel after removal of
any blockages from the vessel and the placement of the device into the vessel.
The compositions,
devices and methods of the present invention are useful for treating a wide
array of diseases and
conditions, including, for example, those set forth below and/or otherwise
described herein. In
cardiology, such compositions, devices and methods may be used, for example,
to develop coatings for
stems, sutures and pacemakers, or other devices used in cardiology as
otherwise referenced herein. In
ophthalmology, such compositions, devices and methods may be used, e.g., to
develop a lens
replacement for cataracts with a translucent polymer; for a direct injection
of microspheres into the eye
to provide a depot of anti-inflammatory therapy; or for the treatment of
glaucoma. In otolaryngology,
such compositions, devices and methods may be used, e.g., to develop
antibiotics for otic
administration, e.g. amoxicillin microspheres or nanospheres; for
reconstructive surgery, e.g. bone
restructuring; as a treatment for tuberomandibular joint (TMJ) pain by direct
injection; as a treatment
of chronic sinusitis by injection of microspheres; or for compositions
delivered via inhalers, e.g. dry
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powders or admixed with non-CFC propellants. In bone and orthopedic
applications, such
compositions, devices and methods may be used, e.g., to develop orthopedic
injections of inventive
compositions; for bone implants; for the prevention of bone erosion; for wound
healing by inhibiting
osteoclasts and preventing spurious bone growth; as bone putty; for spinal
cage bone pins e.g. mixture
of inventive polymers with hydroxyapatite fillers and other fillers; as a
coating for orthopedic implants
~;n ,
to decrease pain, inflammation, bone erosion and infections; as combinations
of poly-NSAIDs= plus
poly-antibiotics to treat osteomyelitis or other bone infections by direct
injection into the marrow; for
the treatment of bone cancer with ant~proliferatives; for the treatment of
trauma; as prosthetic devices
and coatings therefore; or other devices used in bone and orthopedic
applications as otherwise
referenced herein.
[0174] In neurology, such compositions, devices and methods may be used, for
instance to develop
microspheres injections for injection into the cerebral spinal fluid. In
oncology, such compositions,
devices and methods may be used for treating cancers, such as liver, ovarian,
prostate, breast, or colon,
cancer, among many others; for delivery to any surgical site where cancer is
removed and there exists a
concern that not all cancer cells were removed; or to develop compositions of
poly-antiproliferatives
sprinkled into the peritoneum, which slowly erode and circulate through the
lymphatic system where
the primary metastases congregate. In dentistry, such compositions, devices
and methods may be used
to develop alveolar bridges, tooth implants, patches for treating long-term
pain, microspheres to treat
or prevent dry socket, chips and wafers, chewing gum, dental floss and
microspheres coatings on
toothbrushes; and for the prevention of bone erosion. In gastroenterology,
such compositions, devices
and methods may be used for oral administration of inventive polymers with
antacids to treat ulcers,
heartburn and other acid-related diseases; for the treatment of irritable
bowel syndrome with inventive
compositions having a particular particle size; or for use of the
compositions, e.g. a poly-NSAID, to
prevent or treat inflammation at a colostomy sinus. In obstetrics and
gynecology, such compositions,
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devices and methods may be used for the prevention of toxic shock syndrome by
using the inventive .
compositions in fibers of tampons; for the treatment of yeast infections; for
the treatment of chlamydia
infections; as suppositories; as a cervical ring to treat or prevent cramps or
premenstrual syndrome,
among others; and as surgical meshes and coatings to treat hernias and the
like. Surgical applications
of the compositions, devices and methods include coatings for bladder
catheters and others; coatings
for indwelling catheters; as coatings for biosensors, particularly the leads,
to prevent scarring and
granulomas and to avoid signal interference and increase battery life; as
compositions as surgical
adhesives; as microspheres sprinkled into any surgical field to prevent
adhesions; and for subdural
barriers or films to prevent swelling and inflammation. The compositions,
devices and methods may
also be used in wound healing applications, including as sutures, surgical
meshes, bandages, and other
mechanical wound closure products, coatings, and the like. The compositions
may be also be in the
form of microparticles e.g. microspheres, microplatelets or other
microstructures, as a powder or
pellets to be applied locally e.g. sprinkling, to the affected area, and many
others. In dermatology,
such compositions, devices and methods may be used for instance to develop
sunscreens and the like;
insect repellants of admixed or polymerized compounds such as DEFT, Merck IR
3535, citronella, and
other safe ones; bandages; as microspheres in patches to deliver systemically
active drugs; for the
treatment of psoriasis e.g. poly-methotrexate optionally combined with a poly-
NSAID(s) and/or other
agents; for the treatment of seborrhea, dandruff, and other skin and hair
conditions. The polymers of
the invention may also be incorporated into oral formulations and into
products such as skin
moisturizers, deodorant, cleansers, pads, plasters, lotions, creams, gels,
ointments, solutions,
shampoos, tanning products and lipsticks for topical application.
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VI. Polymer Formulations
A. Introduction
[0175] The polymers of the invention may be formulated as pharmaceutical
compositions and
administered to a mammalian host, such as a human patient in a variety of
forms adapted to the chosen
route of administration, i.e., orally, rectally, or parenterally, by
intravenous, intramuscular,
intraperitoneal, intraspinal, intracranial, topical, ocular, pulmonary or
subcutaneous routes. For some
routes of administration, the polymer may conveniently be formulated as
microni~ed particles. Thus,
the present compounds may be systemically administered orally, in combination
with a
pharmaceutically acceptable vehicle such as an inert diluent or an
assimilatable edible carrier. They
may be enclosed in hard or soft shell gelatin capsules, may be compressed into
tablets, or may be
incorporated directly with the food of the patient's diet. For oral
therapeutic administration, the active
compound may be combined with one or more excipients and used in the form.of
ingestible tablets,
buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and
the like. Such compositions
and preparations preferably contain at least 0.1 % of polymer by weight. The
percentage of agent or .
polymer in the compositions and preparations may, of course, be varied and may
conveniently be
about 0.1, 1, 25, 10, 30, 45 to about 50, 60, 75, 80wt%, and any ranges
defined by their combination,
and of a given unit dosage form. The amount of polymer in such therapeutically
useful compositions
is such that an effective dosage level will be obtained. The tablets, troches,
pills, capsules, and the like
may also comprise binders such as gum tragacanth, acacia, corn starch, gelatin
or others; excipients
such as dicalcium phosphate; a disintegrating agent such as corn starch,
potato starch, alginic acid and
the like; a lubricant such as magnesium stearate; and a sweetening agent such
as sucrose, fructose,
' lactose or aspartame or a flavoring agent such as peppermint, oil of
wintergreen, or cherry flavoring
may be added. When the unit dosage form is a capsule, it may contain, in
addition to materials of the
above type, a liquid can-ier, such as a vegetable oil or a polyethylene
glycol. Various other materials
may be present as coatings or to otherwise modify the physical form of the
solid unit dosage form. For
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instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac
or sugar and the like. A
syrup or elixir may contain the active compound, sucrose or fructose as a
sweetening agent, methyl and
propylparabens as preservatives, a dye and flavoring such as cherry or orange
flavor. Of course, any
material used in preparing any unit dosage form should be pharmaceutically
acceptable and
substantially non-toxic in the amounts employed. In addition, the active
compound may be
incorporated into sustained-release preparations and devices.
[0176] The polymer may also be administered subcutaneously, intramuscularly,
intravenously,
intraspinally, intracranially, intrauterally, rectally, intraperitoneally, and
into and mound any applicable
body cavity, wound and surgical site by infusion or injection. Solutions of
the polymer.may be
prepared with a suitable solvent such as an alcohol, optionally mixed with a
nontoxic surfactant.
Dispersions, may also be prepared in glycerol, liquid polyethylene glycols,
triacetin, and mixtures
thereof and in oils. Under ordinary conditions of storage and use, these
preparations contain a
preservative to prevent the growth of microorganisms. The pharmaceutical
dosage forms suitable for
injection or infusion may include sterile solutions or dispersions or sterile
powders comprising the
polymer containing the active ingredient which are adapted for the
extemporaneous preparation of
sterile injectable or infusible solutions or dispersions, optionally
encapsulated in liposomes. In all
cases, the ultimate dosage form should be sterile, fluid and stable under the
conditions of manufacture
and storage.
[0177] The liquid carrier or vehicle may be a solvent or liquid dispersion
medium comprising, for
example, ethanol, a polyol (for example, glycerol, propylene glycol, liquid
polyethylene glycols, and
the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures
thereof. The proper fluidity
may be maintained, for example, by the formation of liposomes, by the
maintenance of the required
particle size in the case of dispersions or by the use of surfactants. The
prevention of the action of
1171CI'001'~a171S11'15 177a1r be brou;~ht about by various antibacterial and
antifiu~gal a'ents. for example.
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paranens, cmoronutanol, phenol, sorbic acid, thimerosal, and the like. In many
cases, it will be
preferable to include isotonic agents, for example, sugars, buffers or sodium
chloride.
[0178] Prolonged absorption of the injectable compositions may be brought
about by the use in the
compositions of agents delaying absorption, for example, aluminum monostearate
and gelatin. Sterile
'~~ 'injectable solutions are prepared by incorporating the polymer in the
required amount in the
'~'~ appropriate solvent with various of the other ingredients enumerated
above, as required, followed by
filter sterilization. In the case of sterile powders for the preparation of
sterile injectable solutions, the
preferred methods of preparation are vacuum drying and the freeze drying
techniques, which yield a
powder of the active ingredient plus any additional desired ingredient present
in the previously sterile-
filtered solutions.
[0179] For topical administration, the present polymers may be applied in pure
form. However, it~ will
generally be desirable to administer them as compositions or formulations, in
combination with a
dermatologically acceptable carrier, which may be a solid or a liquid.
Examples of useful
dermatological compositions which may be used to deliver the polymers of the
invention to the skin
are known to the art. See, for example U.S. Patent Nos. 4,608,392; 4,992,478;
4,559,157; 4,820,508.
[0180] Useful solid Garners include finely divided solids such as talc, clay,
microcrystalline cellulose,
silica, alumina and the like. Useful liquid Garners include alcohols or
glycols or alcohol/glycol blends,
in which the present compounds may be dissolved or dispersed at effective
levels, optionally with the
aid of non-toxic surfactants. Adjuvants such as fragrances and additional
antimicrobial agents may be
added to optimize the properties for a given use. The resultant liquid
compositions may be applied
from absorbent pads, used to impregnate bandages and other dressings, or
sprayed onto the affected
area using pump-type or aerosol sprayers.
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[0181] Thickeners such as synthetic polymers, fatty acids, fatty acid salts
and esters, fatty alcohols,
modified celluloses or modified mineral materials may also be employed with
liquid carriers to form
spreadable pastes, gels, ointments, soaps, and the like, for application
directly to the skin of the user.
The polymer may be formulated so that it will be released over an extended
period of time when
administered in accordance with the invention, e.g: over at least about 2, 5,
7, 10, 20, 40, 60, 80, 100,
120, 140, 160, or 180 to about 200, 220, 240, 260, 280, 300, 320, 340, or 360
days, and even over
longer periods of time. For example, when applied for treatment of hard tissue
the polymer maybe
formulated for release over a period of about 30 to about 90 days; for
treatment of soft tissue about 1,
2, 5, or 10 to about 12, 15, 20, or 30 days, or over about 1 to 2 years. A
polymer of this invention may
have for example properties compatible with dosage of drug delivered,
pharmacokinetics, rate of
generation, elution or release, duration of release, elution or generation of
the drug, agent solubility
and binding characteristics to other agents and substances in the environment,
another agent
interaction, e.g. drug interaction. The polymer may have properties compatible
with the physical,
chemical, and/or biological requirements for matching the environment for
which it is intended, e.g.
coating with the surface and bulk of a medical or veterinary device, such as
the coating's adherence to
the surface of the implanted medical device during processing/coating as well
as during implantation,
coating stability on the device, coating reproducibility and reliability, non-
planar coating ability,
porous, and textured geometries, the void filling ability for providing agent
reservoirs, and the ability
of the coating to withstand mechanical e.g. tensile, compressive, torsional,
and shear, and frictional
forces generated during coating processing/application, implantation and
subsequent use.
[0182] One example is the behavior of a coating during subsequent tissue
response of an implanted
medical or veterinary device. The polymers of the present invention may also
be incorporated into
systemic and topical formulations and among these, preferred are formulations
that are suitable for
inhalation, oral, rectal, vaginal, nasal, ophthalmic, otical, intracavitary,
intraorgan, topical (including
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buccal, sublingual, dermal and intraocular), parenteral (including
subcutaneous, intradermal,
intramuscular, intravenous and intraarticular), intracavitary, CNS
penetrating, and transdermal
administration, among others. The compositions may conveniently be presented
in single or multiple
unit dosage forms as well as in bulk, and may. be prepared by any methods well
known in the art of
.,j i ,pharmacy.
l~ '[0183] The composition of the invention may also be provided in the form
of a kit containing
instructions for its use, whether already formulated or with instructions for
its formulation and
administration regime. The kit may also contain other agents, such as those
which were described in
this patent, and for example when for parenteral administration, also a
carrier in a separate container,
car~ridge, pack or pouch, which may be sterile. The present composition may
also be provided in a
sterile contained for addition of a liquid carrier prior to administration.
See, e.g. US Patent 4,956,355;
UI~ Patent 2,240,472; EPA 429,187; PCT 91/04030; Mortensen, S. A., et al.,
Int. J. Tiss. Reac. XII(3):
155-162 (1990); Greenberg, S., et al., J. Clin. Pharm. 30: 596-608 (1990);
Folkers, I~., et al., Proc.
Nat'1. Acad. Sci. 87: 8931-8934 (1990), the relevant preparatory and
compounding portions of all of
which being incorporated herein by reference.
[0184] Formulations suitable for topical, oral, colonic, inhalable, and
parenteral administration are
preferred. All methods include the step of bringing the polymer carrying an
agents) or compounds)
into association with a Garner and one or more accessory ingredients. In
general, the formulations are
prepared by uniformly and intimately bringing the polymer into contact or
association with any agents
that will be dispersed therein, and optionally with a liquid carrier, a solid
carrier, or both, and then, if
'necessary, shaping the product into desired formulations described elsewhere
in this patent.
[0185] Compositions suitable for oral administration may be presented in
discrete units, such as
capsules, cachets, lozenges, or tablets, each containing a predetermined
amount of the active
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compound; as a powder or granules; as a solution, or suspension in an aqueous
or non-aqueous liquid;
or as an oil-in-water or water-in-oil emulsion. Such compositions may be
prepared by any suitable
method of pharmacy that includes the step of bringing into association the
polymer with any agent to
be carried by the polymer, and an optional suitable Garner.
[0186] In general, the compositions of the invention are prepared by uniformly
and intimately
admixing the active compound with a liquid or finely divided solid carrier, or
both, and then, if
necessary, shaping the resulting mixture. For example, a tablet may be
prepared by compressing or
molding a power or granules containing the active compound, optionally with
one or more accessory
ingredients. Compressed tablets may be prepared by compressing, in a suitable
machine, the compound
in a free-lowing form, such as a powder or granules optionally mixed with a
binder, lubricant, inert
diluent, and/or surface active/dispensing agent(s), among other formulation
ingredients known in the
art. Tablets may be made by molding in a suitable machine, the powdered
polymer moistened with an
inert liquid binder.
[0187] Compositions for oral administration may optionally include enteric
coatings known in the art
to prevent degradation of the compositions in the stomach and provide release
of the drug in the small
intestine. Compositions suitable for buccal (sub-lingual) administration
include lozenges comprising
the active compound in a flavored base, usually sucrose and acacia or
tragacanth; and pastilles
comprising the compound in an inert base such as gelation and glycerin or
sucrose and acacia.
Compositions suitable for parenteral administration comprise sterile aqueous
and non-aqueous
injection solutions of the polymer, and are preferably isotonic with the blood
of the intended recipient,
and may contain in addition to other agents antioxidants, buffers,
bacteriostats and solutes which
render the compositions isotonic with the blood of the intended recipient.
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[0188] Aqueous and non-aqueous sterile suspensions may include suspending
agents and thickening
agents. The compositions may be presented in unit-dose or mufti-dose
containers, for example sealed
ampoules and vials, and may be stored in a freeze-dried (lyophilized)
condition requiring only the
addition of the sterile liquid carrier, for example, saline or water-for-
injection immediately prior to use.
,~ ~ 'Extemporaneous injection solutions and suspensions may be prepared from
sterile powders, granules
and tablets of the kind previously described.
;n
[Ol 89J Compositions suitable for topical application to the skin preferably
take the form of an
ointment, cream, lotion, paste, gel, spray, aerosol, or oil, and the carriers
that may be used include
va~'eline, lanoline, polyethylene glycols, alcohols, transdermal enhancers,
and many others known in
the dart, as well as combinations of two or more of them. Compositions
suitable for transdermal
administration may be presented as discrete patches adapted to remain in
intimate contact with the
epidermis of the recipient for a prolonged period of time, and may be
delivered by iontophoresis and ,
typically take the form of an optionally buffered aqueous solution of the
active compound. See, e.g.
Pharmaceutical Research 3: 318 (1986), the brelevant portion of which is
incorporated herein by
reference.
[0190] The agent is loaded in the polymer of this invention within broad
amounts of the composition.
For example, the agents) may be contained in the composition in amounts of
about 0.001 %, about 1 %,
about 2%, about 5% to about 5%, about 10%, about 20%, about 40%, about 90%,
about 98%, about
99%, or about 99.999 % of the composition. These amounts may be adjusted when
and if additional
agents with overlapping activities are included as discussed above. Dosage
will vary depending on the
'agent(s), age, weight, and condition of the subject, and the treatment may be
initiated with small
dosages less than optimal doses of the polymer of the invention, and increased
until a desired or even
an optimal effect under the circumstances, is reached. In general, the dosage
comprises about l, 5, 10,
or 20m~r polymerll<;~ body weight to about 100, 200, 500 or l 000 m~~
polvmer/1<~T body vrei'~ht. Ni;~her
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or lower doses, however, are also contemplated depending on the actual loading
of the agents) in the
polymer and are, therefor, within the confines of this patent. In general, the
content of the agent in the
amount of polymer delivered is preferably such that when administered it will
provide a concentration
at the desired site that will afford effective results without causing unduly
harmful or deleterious side
effects, and may be administered either as a single unit dose, or if desired
in convenient subunits
administered at suitable times throughout the day. The additional agents) are
administered iri amounts
that are known in the art to be effective for the intended application. In
cases where the additional
agent in the composition has overlapping activities with the principal agent,
i.e. an additional NSAID
and its salts, the dose of one, the other or both agents may be adjusted to
attain a desirable effect
without exceeding a dose range which avoids untoward side effects. Thus, when
other analgesic and
anti-inflammatory agents are added to the composition, they may be added in
amounts known in the art
for their intended application or in doses somewhat lower that when
administered by themselves.
[0191 ] In general, the present composition is provided as various systemic
and topical formulations,
which include, but are not limited to, oral, intrabuccal, intrapulmonary,
rectal, intrauterine, intradermal,
topical, dermal, parenteral, intratumor, intracranial, buccal, colonic,
sublingual, nasal, injectable such
as intramuscular, subcutaneous, intraglandular; intraorgan, intralymphatic,
intraarticular, intravascular,
intravenous, or intrathecal, inhalable, transdermal, intraarticular,
intracavitary, implantable,
transdermal, iontophoretic, intraocular, ophthalmic, vaginal, otical,
implantable, slow release and
enteric coating formulations. The actual preparation and compounding of these
different formulations
is known in the art and need not be detailed here. The poler of the invention
may be administered once
or several, times per day, per week, per month, or per year, depending on its
half life. The polymers
disclosed herein may be administered to the inhalation system, e. g. to the
lungs or nasally by any
suitable means, but are preferably administered by generation of an aerosol
comprised of respirable
particles that the subject inhales. Respirable particles may be liquid or
solid, and are of- respirable size;
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that is particles of a size sufficiently small to pass through the mouth and
larynx upon inhalation and
into the bronchi and alveoli of the lungs. In general, particles ranging from
about 0.5, 1, 2, or 5 micron
to about 5, 7, 10, or 20 micron in size are respirable, whereas those larger
than respirable size tend to
deposit in the throat and be swallowed. Thus, the quantity of non-respirable
particles in the aerosol is
,~ i preferably minimized. For nasal administration, a particle size in the
range of about 10, 15, 20, 30, or
50 ~.m to about 20, 75, 100, 200, 350, or 500 ~m is preferred to ensure
retention in the nasal cavity.
Liquid pharmaceutical compositions of polymer for producing an aerosol may be
prepared by
combining the polymer alone or in admixture or dispersion with other polymers
or agents with a stable
vehicle, such as sterile pyrogen free water, or other known carriers.
[O1 ~2] Solid particulate compositions containing dry respirable particles of
micronized active
compound may be prepared by grinding dry polymers) with/without dispersed
agents with a mortar
and pestle, and then passing the micronized composition through a 400 mesh
screen to break up or
separate out large agglomerates. A solid particulate composition comprised of
the polymer may
optionally comprise a dispersant that facilitates aerosol formation. A
suitable dispersant is lactose,
which may be blended with the active compound in any suitable ratio, e.g. a 1
to 1 ratio by weight.
Other dispersants, however, are also suitable and their identities and
formulation characteristics may be
learned from their use in the art. Aerosols of liquid particles comprising the
polymer of the invention
may be produced by any suitable means, such as with a Nebulizer. See, e.g. US
Patent No. 4,501, 729:
[0193] Nebulizers are commercially available devices that transform solutions
or suspensions of the
active ingredient into a therapeutic aerosol mist either by means of
acceleration of a compressed gas,
'typically air or oxygen, through a narrow venturi orifice, or by ultrasonic
agitation. Suitable
Compositions for use in a nebulizer consist of the polymer in a liquid
carrier, the polymer comprising
about 0.01, l, 5, 10 w/w% to,about 20, 30, 40 w/w% of the formulation, and
some times even higher
amounts. The cameo is typically v~ater, or a dilute adueous alcoholic
solution. preferaL~ly made isotonic
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mth body timds by the addition of, for example sodium chloride. Optional
additives include
preservatives if the compositions is not prepared sterile, for example, methyl
hydroxybenzoate,
antioxidants, flavoring agents, volatile oils, buffering agents and
surfactants. Likewise, aerosols of
solid particles comprising the polymer with/without other polymers and/or
agents may be produced
with any sold particulate aerosol generator. Suitable aerosol generators for
administering solid
particulate medicaments to a subject produce respirable particles, and
generate a volume of aerosol
containing a predetermined metered dose of a medicament at a rate suitable for
human administration.
[0194] Examples of such aerosol generators include metered dose inhalers and
insizfflators. The
dispersed agents) may be administered concurrently with the polymer(s), and
may be an agent suitable
for preventing and treating sleeplessness, mood disorders, anxiety,
irritability, wasting, bulimia,
anorexia nervosa, cancer, viral and microbial infections, heart conditions,
ischemia, menopause, pain,
inflammation, wounds and burns, muscle tension, low bone calcification,
inflammatory diseases such
as auto-immune diseases, COPD, and inflammatory bowel disease, and many more,
and to treat and
prevent steroid intake secondary effects and to improve body weight and
increase muscle mass,
preferably in the same composition, as described above.
[0195] The phrase "concurrently administering" as used herein refers to the
polymers) and the
dispersed or appended agents) being administered either (a) simultaneously in
time, and preferably by
formulating the two together in a common pharmaceutical carrier, or (b) at
different times during the
course of a common treatment schedule. In the latter case, the two may be
administered at times
effective to complement their half lives and, thereby offset a reduction in
peak level of one with an
increasing level of the other and, thereby, counter balance any decrease in
activity of one with an
increase in activity of the other as a result of their alternate
administration schedule: Thus, the polymer
may or may not be administered for a time sufficient to bring endogenous
levels of an active agents)
back to prior levels in the subject. if the present composition or
formulations are administered for a
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time sufficient to replenish endogenous levels of an agents) (if lowered with
respect to prior levels in
the same subject), then the active agents) or its(their) precursors) present
in the polymer, or their
dispersions or mixtures with other polymers and/or agents are administered in
amounts effective to
increase levels to a desired level. Thereafter, the doses of the two or more
polymers and agents may be
reduced so as to maintain desired levels, whether the dispersed, appended or
admixed polymers) or
li agent(s) has(have) overlapping activity(ies) with the active agents) or
compounds) released by the
polymer or, if of different activity, the dose of the admixed, appended or
dispersed polymers) and/or
agents) may be reduced along with that of the active compound released by the
polymers) in cases of
reduced risk of relapse. If the polyrner(s) is(are) administered for a time
sufficient to replenish
end genous levels, and this is attained, the continuation of treatment will
depend on whether levels are
maintain in the absence of treatment or not. Moreover, whether the admixed,
appended or dispersed
agent(s)' dose is reduced or not will depend on whether or not it is necessary
to continue its
administration or the subject remains stable in its absence. If the
practitioner perceives a need to offset
a future relapse, be it as a decrease in agents) levels or even its depletion
and/or a need or benefit from
a continued administration of the dispersed, appended or admixed polymers)
and/or agent(s), the
treatment may be continued under close monitoring.
[0196] The admixed, appended or dispersed polymers and agents, examples of
which are listed above,
may be administered per se or in the form of their biologically,
physiologically, pharmacologically,
pharmaceutically or veterinarily acceptable salts. When used in medicine, the
salts of these agents
should be pharmacologically and pharmaceutically acceptable, but non-
pharmaceutically acceptable
salts may be used to prepare the free active compound or pharmaceutically
acceptable salts thereof and
are appropriately included within the scope of this invention. Such
pharmacologically and
pharmaceutically acceptable salts include, but are not limited to, those
prepared from the hydrochloric,
hydrobromic, sulphuric, nitric, phosphoric, malefic, acetic, salicylic, p-
toluenesulfonic, tartaric, citric,
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methanesulphonic, formic, malonic, succinic, naphthalene-2-sulphonic and
benzenesulphonic acids,
among others. Pharmaceutically acceptable salts also may be prepared as
alkaline metal or alkaline
earth salts, such as sodium, potassium or calcium salts of the carboxylic acid
group. The present
pharmaceutical formulations, whether for veterinary or human use, may
comprise, in addition to the
polymers) and one or more appended, admixed or dispersed polymers and/or
agents, one or more
pharmaceutically acceptable carriers, and other markers, diagnostic,
prophylactic and/or therapeutic
ingredients suitable for specific applications. The carner(s) should be
biologically, physiologically,
pharmacologically, pharmaceutically or veterinarily acceptable in the sense of
being compatible with
the other ingredients of the formulation and not unduly deleterious to the
recipient thereof.
[0197] Formulations of the present invention suitable for oral administration
may be presented in
discrete units such as powders, granules, dragees, capsules, cachets, tablets
or lozenges, each
containing a pre-determined amount of the polymer that will release a desired
dose of the active;,
agents) in the form of a powder or granules; or a suspension in an aqueous
liquor or non-aqueous
liquid such as a syrup, elixir, emulsion or draught. Tablets may be made by
compression or molding
of the polyrner(s), optionally with one or more agents and accessory
ingredients. Compressed tablets
may be prepared by compressing in a suitable machine, with the active compound
being in a free-
flowing form such as a powder or granules that may be mixed with a binder,
disintegrant, lubricant,
inert diluent, surface active agent or dispersing agent, among other
ingredients. Molded tablets
comprised of a mixture of the powdered active compound with a suitable carrier
may be made by a
suitable molding machine. Syrups may be made by adding the polymer to a
concentrated aqueous
solution of a sugar, for example sucrose, and then adding any desired admixed,
or dispersed polymers
and agents and accessory ingredients) such as flavorings, preservatives,
crystallization retardation
agent(s), and solubility increasing agents such as a polyhydric alcohol,
glycerol or sorbitol, among
others. Formulations suitable for parenteral administration may be prepared as
a sterile adueous
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formulation of the polymers) and agent(s), preferably isotonic with the blood
of the recipient. Nasal
spray formulations may be prepared as purified aqueous solutions of the active
compound with
preservative agents and isotonic agents, although others are also suitable.
Such formulations are
preferably adjusted to a pH and isotonic state compatible with the nasal
mucous membranes.
''~ '[0198] Formulations for colonic, rectal or vaginal administration may be
solid or liquid form, typically
l~~ ' being presented as a suppository with a suitable carrier such as cocoa
butter, or hydrogenated fats or
hydrogenated fatty carboxylic acids, or a solution, suspension or emulsion in
a liquid carrier suitable
for colonic, vaginal or rectal administration.
[0199] Ophthalmic formulations may be prepared by methods similar to those for
nasal sprays, except
that the pH and' isotonic factors are preferably adjusted to match that of the
eye. Otical formulations are
generally prepared in viscous carriers, such as oils and the like, as is known
in the art, so that they may
be easily administered into the ear without spilling.
[0200] Topical formulations comprise the polymers) of this invention in
amounts effective to release
the agents) or compounds) dissolved or suspended in one or more media such as
mineral oil,
petroleum, polyhydroxy alcohols or other bases used for topical pharmaceutical
formulations, and are
provided in the form of products for the skin and hair such as skin
moisturizers, deodorant, cleansers,
pads, plasters, lotions, creams, gels, ointments, solutions, shampoos,
conditioners, hair straighteners,
hair revitalizing treatments, sun-blocking and tanning products, make-up and
lipsticks for topical
application.
[0201 ] Coating or filler formulations for applications other than those
mentioned above are suitably
'prepared by methods known in the art, by mixing the polymers) of the
invention and other desired
ingredients in a manner suitable for the intended purpose. For example, if
intended for coating marine
or construction surfaces, or for filling porous articles, the polymers) of the
invention may be applied
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by itself or with formulation ingredients as a primer or undercoating, with or
without prior sanding and
cleaning of the target surfaces, or it may be incorporated into a varnish,
paint, or other type or coating
normally employed on such surfaces. Other polymers and agents may be appended
to, mixed with, or
dispersed within the polymers) as desired. The addition of other admixed or
dispersed polymers,
agents and accessory ingredients may be desirable: In addition to the
aforementioned ingredients, the
formulations of this invention may further include one or more accessory
ingredients) such as
diluents, buffers, flavoring agents, binders, disintegrant, surface active
agents, thickeners, lubricants,
preservatives (including antioxidants), colorants, perfumes, sun-blockers, sun-
tanning agents,
preservatives, and the like. Other ingredients may also be utilized as is
known in the art.
[0202] Useful doses of the polymers may be determined using techniques known
in the art, such as,
e.g., by comparing their in vitro activity with the in vivo activity of the
therapeutic agent.in animal
models. Methods for the extrapolation of effective doses in mice, and other
animals, to humans are
known to the art; for example, see U.S. Patent 4,938,949. Additionally, useful
doses may be
determined by measuring the rate of hydrolysis or enzymatic degradation for a
given polymer under
various physiological conditions. The amount of a polymer required for use in
treatment will vary not
only with the particular polymer selected but also with the route of
administration, the nature of the
condition being treated and the age and condition of the patient and will be
ultimately at the discretion
of the attendant physician or clinician, and is easily determinable by one of
ordinary skill in the art.
The quantity of polymeric drug to be administered to a host that is effective
for the selected use may be
readily determined by those of ordinary skill in the art without undue
experimentation. The quantity
essentially corresponds stoichiometrically to the amount of drug which is
known to produce an
effective treatment for the selected use. The desired dose may conveniently be
presented in a single
dose or as divided doses administered at appropriate intervals, for example,
as two, three, four or more
sub-doses per day. The sub-dose itself may be further divided, e.g., into a
number of discrete loosely
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spaced administrations. The total amount of an agents) released will vary
depending on the particular
agents) and treatment protocol involved, as is easily determined by one
ordinarily skilled in the art.
The amount of active agent released will typically be from about 0.1 ~,g to
about 10 g, preferably from
about 1 ~g to about 100 mg, more preferably from about 10 ~,g to about 10 mg,
more preferably from
about 50 ~,g to about 1 mg. Preferably, the polymers are formulated to provide
local release of an
effective amount of an active agent or agent over a period of at least about
2, about 5, about 10, about
l~i
20, or about 40 days. The compositions may also preferably be formulated to
provide local release' of
an effective amount of the agent over,a period of up to about 3 months, about
6 months, about 1 year,
or bout 2 years. The agents) may be released from the polymer at any rate
suitable for appropriate
delivery of the active agent to the patient. In one embodiment, the active
agent is released at a rate
from about 0.01 ~,g per day to about 100 mg per day, from about 1 ~g per day
to about 10 mg per day,
or from about 10 ~,g per day to about 1 mg per day. It will be appreciated
that the greater the potency
of the coating, the better with regard to minimizing the space required for
the administered product; the
potential cost of the product, the ease of manufacturing the product, and the
potential impact on other
desired properties of the medical implant. The polymers of the present
invention may be characterized
by techniques known in the art. Degradation and drug release profiles of the
polymer drug delivery
systems of the present invention may also be determined routinely. The range
of therapeutically
effective dosages, that is, the dosage levels necessary to achieve the desired
result, of a microparticle of
the invention will be influenced by the route of administration, the
therapeutic objectives, and the
condition of the patient. As such, a polymer of the invention may be
administered as a single daily
dose, several times daily, every other day, weekly, etc. depending on the
dosage requirements.
Individual determinations will need to be made to identify the optimal dosage
required.
[0203] As is known in the art a polymer dosage may be determined by comparing
their in vitro
activity, and in viva activity of an agent(s), compounds) or polymers) in an
animal model. Methods
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for the extrapolation of effective dosages in mice, and higher animals, to
humans are known to the art
as well. See, for example, U.S. Patent 4,938,949. Useful dosages may be
determined also by
measuring the rate of hydrolysis or enzymatic degradation for a given polymer
under various
physiological conditions. The amount of a polymer required for use in
treatment will vary not only
with the particular polymer selected but also with the route of
administration, the nature of the
condition being treated and the age and condition of the patient and will be
ultimately at the discretion
of the attendant physician or clinician. The desired dose may conveniently be
presented as a single
daily dose, or as divided doses administered at appropriate intervals, for
example, as multiple daily
sub-doses. Each sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced
administrations. The polymers of the invention are also useful for the
application, administration and
release of a combination of agents typically by 1) dispersing a second agents)
or compounds) within
a polymeric matrix of the invention comprising a first agents) or compound(s);
both the first and
second agents will be released upon polymer degradation; 2) appending a second
therapeutic agent to a
polymer of the invention, i.e. not incorporated into the polymer backbone,
through hydrolyzable
bonds; 3) incorporating into the polymer backbone more than a single agents
e.g. a polymer comprising
different agent units; and/or 4) administering more than a single polymer,
each comprising a different
therapeutic agents) either as a blend, a mixture or as separate entities
administered together or within a
short period of time.
[0204] The invention thus provides a composition comprising a polymer of the
invention incorporating
a first agents) in its backbone, and a second agents) that is blended or
admixed with, or dispersed
within the,polymer matrix. The invention also provides a pharmaceutical
composition comprising a
polymer of the invention of a first agents) in its backbone, and a second
agents) appended to the
polymer e.g. through hydrolyzable bonds that will release the second agents)
under appropriate
conditions. The polymers of the invention may also be employed, applied, or
administered in
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combination with other agents that are effective to prevent, contain, or treat
a given condition, such as
is the case in combination therapy, and applications in the field of coating,
paints, and many others.
The present invention thus provides a method for delivering an agents) or
compounds) to a targeted
site by applying, delivering, administering and the like an effective amount
of the polymers) of the
,~~ invention by itself(themselves, or in combination with other agent(s). In
the veterinary and medical
1,~ ,fields, the method will take the form of the prevention, containment, or
treatment of a disease or
condition comprising application, delivery, or administering of an effective
amount of a polymers) of
the invention by itself(themselves) along another prophylactic, containment,
therapeutic and/or
tra~eable agent(s). The polymer maybe administered or applied as a composition
comprising a
pharmaceutically acceptable carrier or diluent, and optionally another
agent(s).
B. Co-Polymers and Blends of Polymers
[0205] The therapeutic polymers and compositions thereof used in some
applications, such as for '
coating implantable medical and veterinary .devices, including stems and
orthopedic implants, may
require greater elasticity or flexibility while retaining sufficient hardness
and adhesiveness to remain
intact on the device as the device is handled or otherwise manipulated by the
clinician or surgeon or
within the body of the patient, such as, e.g., when the device interacts, e.g.
mechanically and
chemically, with the surrounding tissue or fluid or luminal wall, or, in the
case of a stmt, with the
intraluminal wall of a vessel in which the vessel and stmt experience
pulsatile motion due to the
pulsatile nature of blood flow and the contraction of the vessel wall by the
associated smooth muscle.
To provide desired physical properties, including mechanical strength,
modulus, and elongation
without failure, it is possible to create coating comprised of a eo-polymer of
two or more monomers
used to create the two or more polymers that have physical properties and
other performance
characteristics bracketing those properties and characteristics desired. In
one embodiment, copolymers
of similarly sized or "seduential" linkers, i.e. adipic acid (C6) and suberic
acid (C8) are made in order
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to "fine tune" the physical properties of the polymer to a state between the
two available linkers.
However, "non-sequential" co-polymers are also contemplated, for example a co-
polymer containing
adipic acid (C6) and sebacic acid (C 10) linkers. Additionally, co-polymers
comprising three or more
linker group moieties are also contemplated. In one embodiment, the co-polymer
is formed of
monomers of salicylic acid and adipic acid, and salicylic acid and suberic
acid, at about 50% or more
mole percent of the co-polymer is the monomer salicylic acid and adipic acid
respectively. However,
proportions of any of the agent monomers may be employed in the polymers of
the invention, such as
about 5, 10, 20, 30, 40, or 50 to about 60, 70, 80, 90, 95, or 99 wt%.
Alternatively or in combination
with one or more of the co-polymers described above, it is possible to create
a physical blend of two or
more polymers or co-polymers in which the individual polymers or co-polymers
blended each have a
set of physical properties and performance characteristics that meet or exceed
requirements for a
coating for the specified implantable medical or veterinary device and its
application but may have one
or more physical properties and performance characteristics that are
insufficient for that device and its
application, such that the combination of properties and characteristics
provided by the blend meet or
exceed the required properties and characteristics needed for the device and
its application.
[0206) These blends may be of polymers that are miscible or immiscible in each
other. For example, it
is possible to make a co-polymer or blend of polymers or co-polymers in which
one monomer in the
co-polymer or one polymer or co-polymer in the blend has a hardness that
exceeds the requirements
for the coating for the device and its 'application but a flexibility
insufficient and another monomer in
the co-polymer or another polymer or co-polymer in the blend that has a
flexibility sufficient but a
hardness insufficient for the device and its application. The physical
properties and performance
characteristics of the copolymer may be fine tuned further by selecting the
percentage of each
monomer in the copolymer or the percentage of each polymer or co-polymer in
the blend towards the
combination of monomers or polymers or co-polymers that produce a coating that
has physical
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properties and performance characteristics closer to the desired set. In an
exemplary embodiment, a
polymer comprising salicylic acid or a derivative of salicylic acid, such as
diflunisal, and linkers of
dicarboxylic acids in which the pair of carboxylic acids within the diacid are
separated by a linear alkyl
chain, is coated on a stmt or other device experiencing expansion,
contraction, or torsion in application
or use. A coating comprising a polymer in which the alkyl chain comprises six
atoms of carbon
i , (known as adipic acid) .may crack or craze upon change in dimensions, e.g.
expansion for a stmt,
whereas a coating comprising a polymer in which the alkyl chain comprises
eight atoms of carbon
(known as suberic acid) may be excessively tacky or otherwise adhere to the
materials used in handling
and implantation, e.g, the balloon used for expansion of the stmt. For such
applications, in the absence
of fan admixed drug or other additive that alters the physical properties and
performance characteristics
in a predictable and repeatable manner, a suitable coating may comprise, for
example, a polymer of
salicylic acid and suberic acid or a copolymer of monomers of salicylic acid
and dicarboxylic acid'or a
physical blend of polymers or co-polymers of salicylic acid and dicarboxylic
acid that approximate the
tradeoffs in physical properties and performance characteristics, including
hardness, tackiness, and
flexibility, of polymers created with a linker of suberic acid. In another
exemplary embodiment, a
polymer comprising salicylic acid or a derivative of salicylic acid, such as
diflunisal, and linkers of
dicarboxylic acids with linear alkyl chains, and is coated on an orthopedic
implant for use as a hip,
knee, shoulder, elbow replacement, a fixation device, or another orthopedic
application. In the absence
of an admixed drug or other additive that alters the physical properties and
performance characteristics
in a predictable and repeatable manner, a suitable coating may comprise, e.g.,
a polymer of salicylic
acid and a dicarboxylic acid linker with four, six, eight or ten carbon atoms
in the linear alkyl chain
(known as succinic and adipic acids, respectively) or a copolymer of monomers
of salicylic acid and
~dicarboxylic acid or a physical blend of polymers or co-polymers of salicylic
acid and dicarboxylic
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dmu w~ a~yr~x~maie me tracteotts in physical properties and performance
characteristics, including
hardness, tackiness, and flexibility, of polymers created with a linker of
succinic or adipic acids.
C. Combination Therapies
[0207] The polymers of the invention are also useful for administering a
combination of therapeutic
agents to an animal. Such a combination therapy may be carried out in the
following ways: 1) a
~fn ~ second therapeutic agent may be dispersed within the polymer matrix of a
polymer of the invention,
and may be released upon degradation of the polymer; 2) a second therapeutic
agent may be appended
to a polymer of the invention (i.e. not in the backbone of the polymer) with
bonds that hydrolyze to
release the second therapeutic agent under physiological conditions; 3) the
polymer of the invention
may incorporate two therapeutic agents into the polymer backbone; or 4) two
polymers of the
invention, each with a different therapeutic. agent may be administered
together (or within a short
period of time). Of course, more than one therapeutic agent may be used in
each of the above cases.
Thus, the invention also provides a medical device comprising a polymer that
hydrolyzes to form a
first active agent and a second active agent that is dispersed within the
polymer matrix of a polymer of
he invention. The invention also provides a medical device comprising a
polymer that hydrolyzes to
form a first active agent having a.second active agent appended to the polymer
(e.g. with bonds that
will hydrolyze to release the second therapeutic agent under physiological
conditions).
[020] The polymers of the invention may also be administered in combination
with other active
agents that are effective to treat a given condition to provide a combination
therapy. Thus, the
invention also provides a method for treating a disease in a mammal comprising
administering an
effective amount of a combination of a polymer of the invention and another
therapeutic agent. The
.invention also provides a pharmaceutical composition comprising a polymer of
the invention; another
therapeutic agent, and a pharmaceutically acceptable carrier. Suitable drug
combinations for
incorporation into the polymers or the compositions of the invention include
for example, a first active
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agent that is classified as a non-steroidal anti-inflammatory drug (NSAID),
such as, e.g., salicylic acid
or diflunisal, combined with a second active agent classified as an anti-
cancer and/or anti-neoplastic
agent, e.g. paclitaxel or methotrexate, or as an immunosuppressive, e.g.
rapamycin. Preferred drug
combinations for incorporation into the polymers or the compositions of the
invention include
,i~ ,amoxicillin/clavulanic acid; and imipenem vilastatin, among others.
D. Injectable Polymers SR for Immune Disease Treatment
[0209] Immune diseases such as rheumatoid arthritis (1RA), lupus, and the
like, are debilitating diseases
affecting millions. Although RA will be discussed as an example of a group of
immune diseases, it is
intended to cover immune and particularly all auto-immune diseases in this
description. By far the
most troubling symptoms of RA are severe pain and swelling of the joints of
the wrists, hands, ankles
and feet, which occur when the~body's immune system mistakenly attacks the
synovium (the cells
lining the joints), causing intense inflammation. The therapeutic mainstay of
RA is oral NSAIDs,
including non-selective COX inhibitors like aspirin and diflunisal, as well as
the newer COX 2-specific
NSAIDs, rofecoxib and celecoxib. As disease severity progresses, disease-
modifying anti-rheumatic
drugs (DMAIZDs) such as methotrexate, azothioprine, gold salts and
immunosuppressive agents are
used, despite their serious side effects. More recently, injectable biological
response modifiers that
block the action of tumor necrosis factor (etanercept and infliximab) have
shown great promise,
despite their high cost and associated risk of tuberculosis and cancer.
Another injectable protein
(anakinra) blocks the effects of IL-1 ~ an inflammatory protein over-expressed
in RA patients.
Notwithstanding the effectiveness of these newer treatments, RA remains a
chronic disease, the
severity of which fluctuates over time. When pain and swelling flare, a
standard treatment is to inject
steroids directly into the affected joint, sometimes in combination with a
local anesthetic. Such intra-
articular injections provide rapid and long-lasting relief of pain and
swelling, but only a few steroid
injections may be administered safely at any one time, and repeated injections
into the same joint may
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destroy cartilage. These drawbacks have spurred the development of "steroid-
sparing" treatments for
flared joints. A PLGA microsphere-based infra-articular product is being
currently tested to provide
slow-release of betamethasone, with the goal of minimizing tissue damage
whereas infra-articular
hyaluronic acid products are used mostly for osteoarthritis
[0210] In one embodiment, the present invention is an injectable polymer, e.g.
a polyNSAID product,
'~" bomprising microparticles designed to provide sustained relief of swollen
and painful joints after intra-
articular injection and other uses. On example is a micro formulation of
polyDF. In cases where
polyDF alone may be insufficient, other drugs, including analgesics such as
morphine, may be added
during preparation of the microparticle formulation, or as a coating or core
of the formulation. Long
cony~idered to produce analgesia by the activation of receptors located only
within the central nervous
system, new evidence demonstrates that narcotic analgesics have a potent local
analgesic effect when
injected into chronically-inflamed tissue. Clinical studies demonstrated
profound pain relief from lmg
morphine injected into chronically-inflamed (but not acutely-inflamed) gum
tissue, and pain relief
similar to that of 4 mg dexamethasone by the infra-articular injection of 3 mg
morphine in RA patients.
[0211] The addition of strong analgesics, such a~ narcotic analgesics, e.g.
morphine, to the polymer of
the invention presents little or no abuse potential because only low
concentrations of morphine are
required, generally less than about 5 to l Owt% as is known in the art, and
morphine release from
polyDF will be retarded generally by an about 15- to about 18-hr induction
period before the onset of
polymer biodegradation. For more extended effects, e.g. analgesia, antibiotic
and antiseptic action,
and the like, drugs such as narcotic analgesics, antibiotics, and other drugs,
may also be incorporated
into the backbone of the polymer.
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E. Nanoparticle and Microparticle Formulations
[0212] All of the foregoing pharmaceutical applications may employ nano-
and/or micro-particular
formulations. Nanospheres and microspheres have been made form polydiflunisal
having a mean
diameter of about 10 to about 100 nm and about 10 to about 100 ~.m, with an
average of 45-50 nm, and
45-50 p,m, respectively, the latter being slightly smaller than the size
commonly used for drug delivery.
yn ,
A process for preparing microencapsulated polymers of this invention, e. g. of
chemical formula I, or
for preparing intermediates useful for preparing compounds of formula I are
provided in Table 4
below, and also as further embodiments of the invention.
Table 4: Microencapsulation Process
Advantages Microencapsulated
Agent
IJS Patent 5,407,609 Proteins
Fast Encapsulation Time (msec.)Peptides
Minimal Exposure to Polymer Small Molecules
Solvent ,
High Encapsulation EfficiencyWater-Soluble Drugs
Good Yield Hydrophobic Drugs
Yields Small Microparticles Drugs Encapsulated in
(<100~,; <10~,) Lactide/Glycolide Polymers
[0213] Processes for making nanoparticle formulations are also known in the
art, and need not be fully
described in this patent. The surface eroding property of polymers such as
polydiflunisal makes for
solid, non-porous particles, e.g. nano- and micro-spheres, useful for
sustained drug delivery, and their
release duration rnay be controlled by varying particle diameter, e.g. larger
microparticles biodegrade
more slowly than smaller ones. Nano- and microparticles for pharmaceutical
formulations may be
designed to deliver an agents) or compounds) incorporated into the polymer
backbone and optionally
an agents) blended, appended to, or dispersed in the polymer. When rats were
administered a single
subcutaneous injection of 250mg polydiflunisal microspheres containing about
192mg diflunisal
formulated in a standard agueous veliicle a peak plasma diflunisal of 35~g1m1
was achieved within two
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days, and thereafter the drug level declined slowly over about two weeks
whereas a single oral dose of
diflunisal produced a drug level that declined rapidly. Microparticle
formulations of about l, 2, 5, 7.5,
10, 25, 50 to about 10, 15, 30, 50, 75, 100, 250 ~,m are suitable for use in a
pharmaceutical, veterinary
or other type of formulations. Similarly, nanoparticle formulations may be
administered for various
applications, having a particle size about 1, 2, 5, 10 to about 15, 20, 30,
50, 100, 250, 500 nm, or
various ranges between any two of these values. These polymers may also be
employed as carriers for
other agents) as has been demonstrated with polymers of the invention carrying
paclitaxel and
sirolimus. The. anti-inflammatory properties of polyNSAIDs as delivery
vehicles for an admixed
pharmaceutical agents) and biological agents) is expected to significantly
diminish the foreign body
re ~ponse associated ovith polymers commonly used for injectable depot
products, such as PLGA.
While the injection of a drug or biological agent carried by a polymer of the
invention, e.g. a
polyNSAID, may be expected to generate significant drug, e.g. NSAID,
concentrations in tissues near
the injection site, their systemic levels in most cases will remain less than
about 0.1~,, which are far .
below therapeutic levels. The microparticles of the invention may be formed
into various shapes and
geometries e:g. spheres, and regular or irregular spheroid shapes. They may
also be incorporated into
various formulations or compositions, e.g. gelatin capsule, liquid
formulation, spray dry formulations,
formulations for use with dry powder or aerosol inhalers, compressed tablet,
topical gels, topical
ointments, topical powder. As would be understood by one of skill in the art,
the desired size of a
microparticle of the invention will depend on the desired application and mode
of delivery. Modes of
administration or delivery of a microparticle and nanoparticle formulations of
the invention include
those set forth herein, including orally, by inhalation, by injection, and
topically. The present
invention contemplates the administration of microparticle and nanoparticle
formulations that upon
degradation or bioerosion may be delivered as is, or yield a smaller particle
and/or active agent for the
effective treatment of a targeted organ or tissue. The present invention also
contemplates
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administration of one or more of the same or different microparticle or
nanoparticle formulations of the
invention having either all the same size or a mixture of two or more
different sizes. By varying the
size of the microparticle, the rate of bioerosion and/or the rate of
generation of active drug and/or the
location of active drug generation may be controlled. As a result, timed e.g.
delayed and/or sustained
generation of active drug may be achieved. For example, treatment of the
inflamed wall of the colon,
e.g. the treatment of inflammatory bowel disease, infections, and the like,
may be achieved by oral
administration of a microparticle of the invention containing as the active
agent an anti-inflammatory
drug. Such a microparticle of about 1, to aboutl0 ~,m in size may be
administered such that upon
rea~ hing the ileum region of the small intestine, the microparticle is about
0.1-1.0 ~,m in size, and
about 0.01 to about 0.1 ~,m in size upon reaching the colon. See, for example
Lamprecht et al.,
Abstracts/Journal of Controlled Release 72: 235-237 (2001). Once in the
intestine, the microparticle
may be physically entrapped by the villi and/or microvilli of the intestinal
wall andlor by the mucous
lining of the intestinal wall, thereby retarding expulsion, and prolonging
gastrointestinal residence time
and enabling timed sustained,generation of the active agent in the proximity
of the intestinal wall upon
bioerosion of the polymer. The microparticles of the invention may be of about
0.1, 1, 10, 20, SO to
about 60, 70, 80, 90 -100 Vim, preferably about 0.1 to about 10 Vim, and any
ranges therewithin. The
microparticle of the invention may be administered orally such that blood
levels of the microparticle
enable perfusion of the active agent into the surrounding tissue upon
bioerosion. In yet another
example, oral administration of a microparticles of the invention of about 0.6
~,m, preferably about 0.3
~,m, more preferably about 0.1 Vim, or any sizes therebetween, may be used to
deliver an active drug
through the intestine and eventually to the liver via the lymph system. See,
for example Jani et al.,
Pharm. Pharmacol. 42: 821-826 (1990); Desai et al., Pharmaceutical Research 13
(12): 1838-1845
(1996). Microparticles of the invention of about 1 to about 50 ~m may be
applied topically or
ocularly. Preferably, the microparticle is about 5 to about 20 Vim. For
subcutaneous or intramuscular
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injection, about 1-70 wm microparticle of the invention may be used. In one
preferred embodiment,
about 10 to about 70 pm microparticle of the invention is used for
subcutaneous or intramuscular
injection. In another preferred embodiment, an about <_10 wm microparticle of
the invention is used to
create a product that feels smooth when applied to human skin. In another
preferred embodiment,
about 1 to about 3 ~.m microparticles of the invention are used for skin
penetration. However, many
3,i other ranges of microparticle sizes may be used as well, as exemplified by
Smart ParticleTM and others
(PowderJect Pharmaceuticals, U.K.); U.S. Patents 6,328,714, 6,053,889 and
6,013,050), in tissue e.g.
skin, mucosa penetration applications that appear to rely more on shape and
strength of the
microparticle rather than size. The microparticles of the invention may also
be used in an inhaled
delivery, e.g. direct inhalation at a certain velocity, or by aerosol spray,
to the lungs, including deep
lungs, or pulmonary region. For example, a microparticle of the invention of
about 0.5 to about '10
~,m, preferably about 1-5 ~,m, more preferably about 1-3 ~,m, even more
preferably about 1-2 ~m may
be formulated into an aerosol. For direct inhalation, about 0.5-6 ~,m, more
preferably about 1-3 Vim,
microparticle may be used. See, for example AERx~ System (Aradigm Corporation,
Hayward, CA.)
as well as those described in U.S. Patents 6,263,872, 6,131,570, 6,012,450,
5,957;124, 5,934,272,
5,910,301, 5,735,263, 5,694,919, 5,522,385, 5,509,404, and 5,507,277, and
MicroDose DPI Inhaler
(MicroDose Technologies Inc., Monmouth Junction, NJ) as well as those
described in U.S. Patents
6,152,130, 6,142,146, 6,026,809, and 5,960,609. Microparticles of the
invention of about <_10~m may
be used for intraarticular injections in the treatment of, for example,
arthritis. A microparticle of the
invention of about 0.1 to about 100 Vim, preferably about 0.1 to about 10 ~,m,
more preferably about
0.1-1 ~.m, may be admixed with a suppository, e.g. glycerin suppository.
Nanoparticle formulations of
this invention have diameters (average or range of size) about 2, 5, 10, 20,
50, 100 nm to about 150,
1250, 350, 500, 700, 850 nm may be applied to therapeutic and prophylactic
applications, such as
healing of wounds and the like.
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133
[0214] A polymer, compound and/or composition of the invention may also be
formed into pellets,
"biobullets", i.e. bullet shaped, or seeds, e.g. bullet-shaped seeds, for
inclusion in an implantable
and/or injectable bioerodable, hollow carrier e.g. barrel, bullet, capsule,
syringe or needle that are
known in the art. Both animal and human applications are contemplated. Hollow
needle-type carriers
axe also contemplated for use in the invention. In one embodiment, a hollow
can~ier may have a
diameter ranging from about 0:5 to about 10 mm, although other gauges are also
suitable. Pallets,
"biobullets", andlor seeds of the invention may be placed inside the hollow
cavity or chamber of a
bioerodable needle-type carrier. According to the invention, one or more of
the same or different
pe~let(s), "biobullet(s)" or seeds) of the invention may be placed inside a
hollow earner or delivery
device. The pellet, "biobullet" or seed may be any size that will enable
placement inside the hollow
carrier. The oral, injectable, implantable and topical formulations of the
invention are suitable for uses
in sub-cutaneous, intra-muscular, intradermal, and many other types of
injections, site-specific
injection by themselves or at site of other implant placement e.g. by other
medical devices, in
conjunction with other implanted materials such as bone cement and other
adhesives, xenographs,
collagen and other fillers, resorbable biomaterials, biodegradable and non-
degradable biomaterials, in
conjunction with excipients,for oral and tablet formulation, in creams,
ointments and topical
formulations and solutions, suspensions and emulsions intended for application
on external and
internal surfaces of the body. Particularly preferred particle diameters
include nanoparticle and
microparticle ranges of about 10-9, 10-8, 10-7 to about 10-x, 10-5 m, among
others. Useful formulations
of the present polymers comprise particles similar to those described for
other uses as well as for
topical applications, e..g. creams, ointments, suspension, and the like,
including encapsulation of
particles (coated particles) and particles coated with the polymers of this
invention. The pellets,
"biobullets", and seeds of the invention, all of which are forms known in the
art, release upon
bioerosion one or more agents. These products may be stored in hollow can -
iers that may itself
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comprise a polymer, compound and/or composition of the invention such that,
when the hollow carrier
is eroded it releases the pellets, "biobullets" and/or seeds of the invention.
In one preferred
embodiment, the pellets, "biobullets", and seeds comprise or are made from a
polymer of the invention
containing salicylic acid admixed with follicle stimulating hormone (FSH)
and/or leuteinizing
hormone (LH) which are then placed in the hollow cavity or chamber of a
bioerodable hollow carrier
~i or as part of a depot formulation, e.g. Lupron Depot~, for a timed release
delivery of the hormones up
to about 96 hours in order to stimulate ovulation. According to the invention,
a pellet, "biobullet" or
seed of the invention and/or one or more hollow carriers containing a pellet,
"biobullet," or seed of the
invention may be placed in a delivery device, e.g. injector, gas-driven
applicator. In one embodiment,
the ~ elivery device may be further equipped with an axially slideable sleeve
e.g. plunger, protrusions
to prevent movement of the delivery device upon application e.g. chamfered
protrusions, and
handgrips. Examples of suitable Garners and/or delivery devices include, but
are not limited to, those
described in U.S. Patents 6,001,385, 5,989,214, 5,549,560; WO 96/13300, WO
96/09070, WO '
93/23110, and EPA 068053, each of which is herein incorporated by reference in
its entirety. U.S.
Patent 5,989,214 and WO 96/13300, for example, describe an apparatus for
injecting the body of
humans or animals with a pharmaceutical preparation, wherein the preparation
is arranged in a rigid
carrier, wherein the apparatus includes: a chamber into which the carrier may
be transported; and a
channel connecting onto the chamber for transporting the carrier into the body
including fixation
means for fixing the end of the channel relative to the skin of the body for
injecting in order to prevent
a movement of the channel in the direction perpendicularly of the axis of the
barrel and where
according to one embodiment the fixation means are formed by chamfered
protrusions formed on the
part adapted for contact with the skin of the body and extending substantially
in the direction of the
axis of the channel. U.S. Patents 5,549,560, WO 93/23110, and EPA 068053
describe a device for
injecting humans and animals with a pharmaceutical preparation, wherein the
preparation is held in a
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rigid carrier and the carrier is.carried through the skin into the body by
means of gas pressure, and
wherein during carrying of a rigid carrier into the body by means of gas
pressure the device with which
the carrier is carried into the body is held against the body. U.S. Patent
5,549,560, W~ 93/23110, and
EPA 068053 also describe a device for injecting animals or humans with a
pharmaceutical preparation,
wherein a chamber is present in which a carrier containing the pharmaceutical
preparation may be
i
placed, a barrel connecting onto this chamber and means for carrying the
carrier by means of gas
pressure through the barrel into the body for injecting, wherein means are
present for blocking the use
of the device when it is not pressed against a body. U.S. Patent 6,001,385 and
WO 96/09070, for
ex ~mple, describe "bullets" that are at. least partly manufactured from
substantially fully destructurized
starch, particularly implants, suitable as vehicles for introducing active
agents into the human or
animal body in a transdermal manner.
F. Polymer Microparticles and Nanoparticles for Pharmaceutical Products
[0215] Microspheres have been made from a diflunisal polymer (polyDF) having a
mean diameter of,
for example about 45~,m; slightly smaller than the size commonly used for drug
delivery. Polymers
having surface eroding properties, e.g. polyDF are extremely suitable for
making solid, non-porous
microparticles, e.g. microspheres and nanospheres, useful for sustained drug
delivery, particularly
suitable for injectable formulations of particle size smaller than red blood
cells (RBCs). The duration
release for any agents) or compounds) may be controlled by varying the
particle diameter, e.g. larger
particles biodegrade more slowly than smaller ones. Microparticles for
pharmaceutical products may
be designed to deliver a drugs) incorporated into the polymer backbone as well
as an agents) admixed
or dispersed into the polymer. When rats were subcutaneous injected 250mg
polydiflunisal (polyDF)
microspheres containing about 192mg diflunisal formulated in a standard
aqueous vehicle (figure 20) a
peak plasma diflunisal of about 35~.g/ml was achieved within 2 days,
thereafter the drug level declined
slowly for about 2 v~eelcs. Incontrast a single oral dose of diflunisal
produced a level of the drug that
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uecimea rapiaiy. aimuariy, nanoparticte formulations may be administered for
various applications,
having a particle size about 0.5, 1, 2, 5, 10, 20, 35, 50, 75 to about 15, 20,
30, 50, 100, 250, 500 rim, or
various ranges between any two of these values. One very preferred embodiment
comprises a
nanoparticular formulation comprising a particle size range smaller than red
blood cells in a form
suitable for infra venous (LV.) injection. These polymers may also be employed
as earners for other
drugs, as has been demonstrated with paclitaxel and sirolimus. The anti-
inflammatory property of
PoIyNSAIDs as a delivery vehicle for admixed drugs and biologicals is expected
to significantly
diminish the foreign body response associated with polymers commonly used for
injectable depot
products, such as PLGA. The injection of an agents) or corripound(s) or a
biological agents) carried
in ~ polymer of this invention, e.g. a polyNSAID, will generate a significant
agents) concentration,
e.g. NSAID(s) concentrations, in tissues near the injection site. The systemic
level of the agent(s),
however, in most cases will remain less than about 0.1 p,; that is far below
therapeutic levels.
G. Polymer Microparticle and ~Nanoparticle Formulations for Injectable
Biological
Products
[0216] In the pharmaceutical arena, the major marketed products in this axea,
LUPRON DEPOT~
(leuprolide for prostate cancer and endometriosis), NUTROPIN DEPOT~ (human
growth hormone),
TRELSTAR DEPOT~ (triptorelin for prostate cancer), and SANDOSTAT1N LAR~
(octreotide for
acromegaly), account for a market that is increasing very rapidly. Key drivers
for growth are branded
drug and biological products requiring product line extension, and new drug
and biological products
requiring delivery systems that improve patient compliance. Several leading
products are summarized
in Table 5 below.
Table 5: Injectable Drug
and Biological Depot
Products
Chiron DEPOCYTE~ Cytarabine DepofoamTM liposome
SkyePhanna DepoMorphineT~ Morphine DepofoainT"'~ liposome*
TAP Pharma LUPRON DEPOTO Leuprolide MedisorbTM (PLGA)
Genentech NUTROPIN DEPOT n HGH MedisorbT"'~ (PLGA)
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Pharmacia TRELSTAR DEPOT~ Triptorelin MedisorbTM (PLGA)
Novartis SANDOSTAT1N LAR~ Octreotide PLGA
J & J Risperdal ConstaTM Resperidone MedisorbTM (PLGA)*
* Currently in Development
[0217] Many new products contain proteins formulated with aqueous suspensions
of PGLA
microspheres. While generally considered to have acceptable biodegradation
kinetics, safety and
biocompatibility, PLGA elicits localized inflammation and foreign body
response, which may be
severe depending on the tissues involved. This is evidenced by clinical
studies involving 138 pediatric
patients who received subcutaneous injections of NUTROPIN DEPOT~, a
recombinant human growth
hormone formulated with PLGA microspheres. Almost every patient reported two
or three "injection
site reactions" per injection, most of which represent hallmark foreign-body
reactions, as shown in
Table 6 below whereas patients receiving aqueous formulations of NUTROPIN
reported infrequent
foreign-body reactions.
Table 6: Reported Injection Site Reaction with NUTROPIN Products
NUTROPIN DEPOTS INCIDENCE
Granuloma (nodules) 61
erythema (redness) 53%
pain after injection ~ 47%
pain during injection 43%
bruising 20%
itching 13%
swelling/puffiness 8%
NUTROPIN AQ~
injection site discomfort "reported"
NUTROPIN~
injection site pl
[0218] The poly~rners of the invention, such as e.g., polyNSAID
microparticles, provide safe injectable
depot formulations for proteins, monoclonal antibodies, polysaccharide, and
nucleic acid prophylactic
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and therapeutic products with improved tolerability, enhanced bioavailability,
and lower production
costs compared to PLGA-based products.
VII. Devices
A. Introduction
[0219] Medical implant and device applications include the use of the polymers
of this invention to.
'~~ 'form sha ed articles such as
p grafts and stems, e.g., vascular and tissue regeneration grafts.and stents;
plates, e.g., bone plates and teeth; cuffs; pins; sutures; stitches;
implantable sensors and drug delivery
devices, and other articles that erode or decompose to release a desired
agents) and non-toxic, non-
inflammatory components within a period of time. The present polymers may be
used also to form
coatings and layers for similar articles that are made of other materials,
including vascular grafts and
stems, bone plates, sutures, implantable sensors, implantable drug delivery
devices, stents for tissue
regeneration, and other articles, which may require the release of an active
compound. In one
embodiment, the polymers described herein may be used to form, coat or
otherwise treat medical
devices. The medical device of the invention may be an implantable device. The
polymers of the
invention may be employed for forming or coating shaped articles such as stems
and grafts, e.g.,
vascular grafts and stems; plates, e.g., bone, dental,. and orthodontic
plates; sutures; wound closing
staples; stitches; surgical meshes; dental and bone implants; implantable
sensors; cuffs; pins; sutures;
implantable drug delivery and sensory or diagnostic devices; stems for tissue
regeneration; and other v
articles suitable for implantation into a patient. Suitable medical devices
include, for example, stents,
e.g., coronary vascular stems and peripheral vascular stems; free standing
films of about 0.08, 0:1, 0.2,
0.4 or 0.6 mm to about 0.5, 0.75, 0.9, 1, 1.5, or 2 mm, and in some cases even
thicker, suitable for.
surgical coverings to prevent surgical adhesion and other uses; solutions,
suspensions, emulsions,
powders, gels, sprays, coats, creams, gels, in situ solidifying formulations,
and semi-liquid and liquid
formulations for "painting" surgically treated areas; urethral stems; biliary
stems; stems used for
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supporting the lumen of other anatomical tubes; and stems used for other
medical treatments; catheters,
e.g., surgical catheters and urinary catheters; grafts; and orthopedic
implants including, e.g., hip, knee
and shoulder implants, internal and external fixation devices and spinal cages
and dental tooth
implants; dry sockets; biosensor implants, e.g., for preventing fibrosis,
ophthalmic implants and
,;n ,replacements; prolene mesh or thread; eye drops, e.g., non crystalline
formulation; marine coatings;
cervical rings, e.g., for contraception or sexual enhancement; other women's
health applications; anti-
infective coating on health aids such as bandages of the sort shown in U.S.
patent No. S,S 14,031;
dental applications, e.g., fibrous and coated floss; cosmetic surgery fillers,
e.g., botox, collagen,
hy~ luronic acid, etc.; fiber; strand form for sutures; dermabrasion
treatments; wrinkle reduction; acne,
I
e.g., with retinoic acid; breast implants; adhesions; capsular contracture;
for employing products such
as pivucane (e.g. APP Pharma), injectable formulations (e.g. Injectile
Technologies), all of the relevant
information relating to these products from publically available sources being
incorporated herein by
reference.
[0220] In one embodiment, the present devices comprise a polymers) that will
break down to release
an agent(s), either active or that may be activated in situ, for example, at
physiological conditions. In
one embodiment, the medical device comprises a polymer comprising at least one
active' agents) or a
pro-agents) that is (are) incorporated into the polymer backbone. In another
embodiment, the polymer
further comprises at least one agents) that is not incorporated into the
polymer backbone. The
agents) present in the backbone, appended to it, or otherwise admixed may be
the same or different.
The medical devices of the invention can compromise at least one polymers) on
all or a part of their
surface, and may be used, for example, to deliver the agent to a pre-
determined site for effecting a
I
specified action, such as to reduce or eliminate an adverse condition
associated with the use of the
device.
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[0221 ] In one embodiment, the medical device is entirely formed of a
polymers) that break down in
situ, e.g. by hydrolysis or enzymatic activity of an agent(s). The medical
devices may be formed in
their entirety of the polymer, or comprise layers thereof, or be coated by a
polymer(s), or many other
possible. configurations that will permit, for example, the release of an
agent or different agents at
different rates or times. One or more polymers may be arranged in accordance
with this invention in
alternating layers or coatings either in the formation of the device or
formulation, or by subsequent
coating of a device or formulation. The present device may be in the form of a
stmt, mesh, suture, pin,
cuff, catheter, contraceptive device, reconstructive dental structure and
tooth, orthopedic structure,
drug delivery device, sensor, stitches,,meshes, wound closure, implant, and
the like. These devices
may be formed of one or more polymers, and in addition may comprise an agents)
mixed therein.
[0222] In another embodiment, these devices may be made of another material,
such as metal, and the
like, and may have one or more of their surfaces or a portion thereof covered
with the polymer(s). The
stmt and other devices may comprise a polymers) comprising at least one
agent(s), and the same '
agents) may also be mixed into the polymer matrix. The device, such as, e.g.,
a stmt, may also
comprise several layers of polymers) in accordance with the invention, which
may comprise one or
more agents within the backbone, and mixed in the polymer matrix. The devices
of the invention may
be employed for delivering an agents) to a specific site, such as is the case
with the stmt where the
delivery may be to an interior surface of a vein or an artery.
[0223] The polymers, medical devices, pharmaceutical compositions and methods
of treatment
provided herein may be designed to reflect advantages such as, e.g., the
ability to deliver a high
potency or concentration of drug by weight if desired; a near "zero-order"
drug release over short or .
'long periods if desired; ease of fabrication into coatings fibers,
microspheres, pellets, etc.; little or no
evidence of a "burst effect" or initial spike of drug; predictable breakdown
products; multiple routes of
administration: and localized delivery for improved efficacy and reduced side-
effects. Furthermore. the
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polymers, medical devices, pharmaceutical compositions and methods of
treatment provided herein
may be designed such that they do not induce an inflammatory response when
administered to or
implanted within a host. In one embodiment, the present invention comprises
the control of the onset
and progression of adverse physiological conditions at a targeted site by
means of a medical device or
method of treatment in accordance with this invention. A directed application
of pharmaceutical
treatment circumvents the need for a general or systemic, i.e. "whole-body",
or oral administration of
the necessary therapeutic agent(s). Accordingly, such directed application of
therapeutics provides
faster, more targeted relief of the adverse conditions while minimizing side
effects of the
ad ~ inistration of the therapeutics.
[0224] Medical devices employed, for example, as implants, typically elicit
foreign body responses
characterized by thrombosis, inflammation, and infection, among others.
Polymers of this invention,
such as polyNSAIDs and others having anti-inflammatory and antiseptic
properties, are extremely well
suited for these applications. Other types of polymers described herein are
well suited to impart
properties such as biological, pharmaceutical, therapeutic or diagnostic
properties.
[0225] The polymers of this patent have a broad range of fracture toughness,
as measured in ksi (or
1000 psi), or times the square root of an inch. Generally, the fracture
toughness values for the
polymers of the invention fall in the range of about 0.2, 0.4, 0.5 ksi to
about 0.6, 0.8, 0.9, 1.0, '1.2 ksi.
Higher and lower ksi values, are also attainable. The polymers of the
invention are suitable for
releasing the contained agents) for a broad period of time, including, but not
limited to, 1-2 hours, 12
hours, 24 hours, 2 days, 8 days, 2 weeks, 4 weeks, 3 months, 6 months to about
8 months, 12 months,
15 months, 18 months, 2 years, and even longer periods of time in specific
applications that are
specifically tailored for such a purpose.
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[0226] In another embodiment, a medical device may be coated with a co-polymer
comprising two or
more monomers, each of them independently comprising a different linker
groups) and a different
agents) or compound(s). In another embodiment, the medical device may be
coated with a therapeutic
polymer composition comprising at least two independent polymers that rnay be
mixed after
polymerization. In yet another embodiment a device, e.g. an implantable stmt,
is formed of or coated
with one or more polymers in accordance with the invention. The device or stmt
may be made of any
suitable material, including, e.g., many materials well known in the art,
including electropolished 316L
stainless steel, other metallic alloys, and/or polymeric materials. In one
embodiment, the polymer
coating exhibits 1) adequate wetability and adhesiveness to the surface of the
stent to be coated, 2)
ad~quate flexibility when crimped onto a balloon catheter, maneuvered into
position, and then
expanded in position in the body, 3) adequate hardness to avoid premature
removal of the coating or its
portions, pitting, or damage to the coating during implantation and thereafter
such as may occur from
handling, flow of body fluids such as blood, or organ, or recipient's,body
movement, and/or 4) '
appropriate rates of degradation that enable maintenance of the agents) or
compounds) levels for
predictable lengths of time without causing local or systemic toxicity. Such a
device may be used as a
coronary, renal, or biliary stmt, among other applications, and it may
comprise a coatings) of a
thickness of about 100 nm, 1 ~m to about 30 ~.m, 100 ~,m, and values
therebetween and outside of this
range as needed. Typically, devices, e.g., stems, for use in other medical or
veterinary applications,
coatings or sets of coatings preferably have a thickness less than about 100
Vim.
[0227] One preferred rate of drug delivery may be achieved by using multiple
layers of polymer. In
some cases different concentrations of the same admixed drug may be used in
each layer or different
copolymers having different rates of drug generation and/or polymers with
different breakdown rates
for release of admixed drugs or agents may be used in each layer, thereby
achieving a predictable and
repeatable timin' of delivery of one or more bioactive agents. Such layering
effects may be enhanced
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143 _. ..-__ .
by a combination of layers of inert polymer and/or layers with inert polymer
with admixed drug or
agents and/or layers with therapeutic polymers and admixed drugs or agents
and/or layers with only
therapeutic polymers. In an exemplary embodiment, an outer coating that would
provide an initially
high dose of anti-inflammatory agent that is followed by the release or
generation of an anti-
proliferative agent from underlying layers. In one embodiment, a medical
device is coated with more
than one layer of polymer, where at least one layer is the therapeutic polymer
of the invention. The
polymers include but are not limited to "inert" polymers that do not breakdown
or breakdown into non-
therapeutic agents. One or more coatings or layers of an inert or therapeutic
polymers may be used to
ad ~ antage with the therapeutic polymers of the invention to regulate the
release of active agents
released from or generated by therapeutic polymer underlying the coating or
layer of polymer. In more
preferred embodiments, the active agents) is predictably and repeated released
over time. For
example, the active agent may be released from the set of coatings at a
steadily increasing or
decreasing rate, or at a nearly constant rate over time. In other more
preferred embodiments, the outer
layers) of polymer slow or prevent the penetration of water and/or enzymes to
the inner layers) of
therapeutic polymer. These embodiments are useful to lengthen the shelf life
of the medical device,
and/or to regulate the release or generation of the active agent in underlying
layers. In most preferred
embodiments, the layers) of therapeutic polymer on the medical device are
further coated with a layer
of polymer which is polylactic acid, a polymerized form of amino acids, a
polymerized form of fatty
acid metabolites, and derivatives and/or combinations of any of these. Both
types of polymers have
been made with several different linker molecules that modulate their physical
properties and NSAID
generation profiles. Table 7 and Table 8 below provide various examples.
Table 7: Coating Hardness of Salicylic Acid Polymer on Stainless Steel
Pol mer
Conditions 51 OPL 261 PL 749PL 125PL 51 OPL
+ l4% Paclitaxel
Nardness~~
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Ambient F B 3B 4B F
65min 37C F B 9B <9B F
Saline,pH
7.4~
* Hardness
measured
in the ASTM
test for
pencil hardness.
Rating 2H,
-H, -F,
-HB, -B,
-2B, -3B,
-4B, -SB,
-6B, -7B,
-8B, -9B
Harder <________________________________________________>
Softer
Table 8: Straight-Chain Dicarboxylic Acid Linkers
Linker Chemical Formula Comments
fn~ Succinic Acid HO2C(CHa)2CO2H Rat Oral LDso = 8,530
mg/kg
Adipic Acid H02C(CHa)4COaH Rat Oral LDso = 5,050
mg/kg
Suberic Acid H02C(CHZ)6COiH
Sebacic Acid H02C(CH2)gCOaH Rat Oral LDso =14,4'0
mg/kg
Dodecanoic Acid H02C(CHa)~oCO~H Marketed as dietary supplement
Tetradecanoic Acid HO~C(CH2)i2C02H In Foods (e.g., butter)
Hexanedecanoic Acid HOaC(CH2)iaCOaH -
[0228] All of these molecules are produced enzymatically by fatty acid
synthase and are routinely
present in the body (and in foods) in varying amounts. Available data indicate
that they are highly
non-toxic after oral administration. In fact, one form is currently being
marketed in the U.S: as a
dietary supplement. While many effects of these molecules administered
directly to tissues are not
fully known, they are likely to be innocuous. As noted abov a one of these
molecules, sebacic acid, was
approved by the FDA as a linker in a wafer for insertion into brain tissue
(GLIADEL~, Guilford
Pharmaceuticals).
[0229] In another preferred embodiment, the medical device comprises an
orthopedic implant such as
a hip, knee, and shoulder implant, and internal and external fixation devices
and spinal implants.
These orthopedic devices may be made of many kinds of materials well known in
the art such as
electropolished 316L stainless steel, other metallic alloys, inorganic
ceramics such as calcium
phosphate and/or hydroxyapatite, human and animal cadaveric bone, naturally-
occurring and synthetic
bone analogs, degradable and non-degradable polymers such as glycolic acid,
lactic acid and/or
caprolactone polymers and their co-polymers with other agents and/or their
blends. The orthopedic
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implants may be coated with a polymer of the invention that preferably
exhibits the characteristics
listed above for implantable devices such as stems. In one embodiment, a
polymer coating or film
comprises an about 1 ~.m to about 1 mm thickness. Some entirely porous
implants may benefit from a
longer lasting effect that is enabled by a coating that fills the device's
interstices with a thin coating on
areas proximal to a target bone or,tissue. In some cases it may be preferable
to employ a nano- and/or
micro-sphere formulation of a diameter typically less than about 10 ~,m for in
situ administration or
application, or for application to the surface of a device before placement. A
sterile liquid may be used
to coat the device to foster adherence ,of the nano- or microspheres for
minutes to weeks to enable
un ~oated devices to act as coated devices do.
(i) Polymer Adhesion to Metal and Non-Metal Surfaces
[0230] The metallic components of many implantable orthopedic devices can be
made of various
alloys, such as nickel-titanium and cobalt-chromium. The adhesion load
displacement profile of
polymers in accordance to this invention, e.g., polyDF, on these metals at
ambient temperature, were
measured by testing polymers that were melt-coated directly onto clean, dry
1.25 metal butt joints.
[0231 ] On one type of satin-finish titanium alloy, polyDF exhibited a load
failure of 2,030 PSI.
Testing of the polymer on a cobalt-chromium alloy was interrupted at 1,630 PSI
when the metal grip
pins used to hold the meal test cylinder broke. These results demonstrate that
polyDF adheres to these
metals as tightly as commonly used epoxies and glues. ASTM test methods were
used to demonstrate
the strong adhesion of polymers of the invention such as polySA and polyDF to
electro-polished 316L
stainless steel, i.e., the metal used for coronary vascular stems. This
property is in sharp contrast to
'other polymers, many of which adhere to metals only after special treatment
of the metal surfaces.
[0232] In general, the polymers of the invention exhibit excellent adhesion to
non-metallic surfaces,
including polymers such as b'iopolymers, polyanhydrides and other
biocompatible and non-
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biocbmpatible polymers, nickel alloys, PMMA based materials, and the like. The
polymers of this
patent may be employed in conjunction and for covering and adhering to any
material suitable for use
in the applications mentioned here. The polymers of this invention achieve a
broad range of cohesive
failure values as measured by a 1.1" Butt Weld test. Generally, cohesive
values of about 100, 200,
300, 400, 600, 700, 1000 to about 1500, 2000, 2500, 3000 psi are easily
attained. The lower value
,,fl (represents minimal adhesion whereas the higher value represents cohesive
failure of the polymer.
Much broader range values are consistently achieved on surfaces such as
titanium alloys, stainless
steel, cobalt alloys, and chromium alloys.]
(ii) Polymer Biodegradation
[033] The degradation of polymers of the invention, such as polySA and polyDF,
was tested with
polymers coated onto samples of electro-polished 316L stainless steel. The
polymers were dissolved
in anhydrous chloroform and spread into thin films onto dry metal surfaces
that had been cleaned with
acetone, after which the solvent was removed overnight in a 40°C vacuum
oven. A 5 ~,m layer of
polySA incubated in pH 7.4 PBS at 37°C generated salicylic acid for
about one week as shown in
Table 9a below.
Table 9a: Erosion of PoIySA (261PL) and PoIyDF (657PL): Generation of 1'~TSAID
into 37°C
pI37.4 PBS from 'S um-thick Coatings on 316 SS Plates
Cumulative drug
Time (Days)release I)
_
Salicylic Acid Ditlunisal -
- 261PL 657PL
0 - 0.0
1 0.0 0.0
2 16.0 0.8
3 40.0 3.2
69.4 11.7
8 73.3 25.4
11 77.9 39.2
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Cumulative drug
Time (Days) release ~
Salicylic Acid Diflunisal
- 261PL - 657PL
14 78,7 47.9
17 54.7
20 58.5
25 71.4
32 _ - 71.9
62 97.8 ,
74 ~ 103.1
[0234] While not apparent from the Table, it should be noted that polySA did
not begin to degrade
until ~-10 hours after exposure to buffer or serum. This "induction period" is
characteristic of
poly(anhydride-ester) polymers; in general, the higher the molecular weight
the longer the induction
time. In contrast, a similar 5 wm layer of polyDF generated diflunisal for a
period of time of over 2
months. The results are shown in Table 9b below.
Table 9b: Effect of MW. on Erosion: Generation of Diflunisal from 657PL into
37°C Serum
from Coatings on 316L SS Plates
Cumulative Diflunisal
Time (days) Generated (~,g/cmz)
33K - 9 ~,m thick 100K - 22 ~,m thick
coating coating
0.17 ' 0.00 0.00
0.33 3.90 0.00
1 41.73 7.14
3 471.55 101.55
S 751.92 267.76
7 753.74 346.20
13 959.21 658.26
19 814..59 756.35
25 731.07 796.82
34 835.77 945.26
[0235] Kinetic analysis of the results shown in Table 9b above evidence that
the generation of salicylic
acid from polySA proceeded in a sharply bi-phasic, non-linear rate, v~hile the
''eneration of diflunisal
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rrom poiy~r was mono-pnas>c anct hear. This high molecular-weight polymer has
an induction time
of 15-18 hours. These different kinetic profiles may be partly explained by
the different degradation
mechanisms of polySA versus polyDF. So-called "bulk eroding" polymers degrade
throughout their
structure, like a limp of sugar in water. Because essentially the whole
polymer mass is available for
degradation, the greater the amount of a bulk eroding polymer, the more
breakdown product generated
over time. This is exactly the case with polySA; when solid disks of this
polymer were incubated in
37°C PBS, the thicker disks generated more salicylic acid, as shown in
Table 9c below.
Table 9c: Elution of 261PL, melt polymer on wafer of 6.7 mm diameter with
different
thickness of coating, in PBS at 37 °C.
Elapsed Time Cumulative
SA Generated
(pg/cm )
(days) 0.1 mm coating0.2 mm coating0.8 mm coating
0 0.00 0.00 0.00
1 644.83 0.00 1563.63
4 2644.67 3415.78 14349.41
7 3338.06 5989.35 18160.02
11 3721.91 8698.98 20373.20
15 3646.73 9222.90 20968.46
20 3655.84 9041.59 19183.40
22 3632.68 8892.61 19024.90
[0236] "Surface-eroding" polymers, on the other hand, degrade only from their
surface, like a bar of
soap. Since only the polymer surface is available for degradation, the
generation or~breakdown
products over time generally does not vary with polymer mass. This is the case
with polyDF; when
disks of this polymer were incubated in 37°C PBS, the same amount of
diflunisal was generated
regardless of disk thickness. The surface eroding property of polyDF makes it
ideal for use as coatings
in settings where a constant, controlled rate of drug delivery is desired.
This property of polyDF
enabled.an evaluation of the effect of polymer molecular weight on the
generation of diflunisal. Two
preparations of polyDr (molecular weights 33K and 1 OOK) produced by the melt-
condensation method
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were solvent coated onto electro-polished stainless steel samples and
incubated in 37°C serum, which
contains esterase enzymes that might be expected to contribute to polymer
degradation in the body. As
shown in Table 9c, the 33,000 Dalton polymer degraded much more rapidly than
the 100,000 Dalton
polymer, which, in PBS, generated diflunisal for about two months.
~t~~ '[0237] The molecular profile of the products of polymer degradation that
may be generated over a
period of time is another important characteristic of biodegradable polymers.
Polymers that
biodegrade consistently into a small number of breakdown products generally
have good
biocompatibility, and will encounter fewer regulatory hurdles.
[0238) In the case of polySA, the HPLC chromatograms showed only breakdown
products that
contained salicylic acid with the linker itself not being observed. After two
days, the main breakdown
product in serum was salicylic acid, which exhibited a 2-minute elution time.
Also observed were
minor amounts of the monomer and several oligomers. By day three, the elution
profile indicated
increasing amounts of salicylic acid, with smaller amounts of monomer and
oligomers. After seven .
days, only salicylic acid and one other compound were apparent, and by day 13,
only salicylic acid was
observed. The pattern of soluble breakdown products generated during the
degradation of polyDF in
37°C serum was less complex. consisting of diflunisal itself with a 7-
minute elution time, with no other
breakdown products observed in serum up to two days, and at every point
thereafter.
B. Biodegradation of Polymers Containing Admixed Drugs
[0239] For many medical device applications it may be desirable to use
polymers in accordance with
this invention, e.g. polyNSAIDs, in combination with other drugs added to the
polymers to produce
additional therapeutic effects. Such "solid solution" preparations may be
created by simply mixing a
polymer dissolved in a solvent with a solution of another drug dissolved in
the same solvent, or by any
other method known in the art. Evaporation of the solvent results in a
homogeneous solid solution of
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drug in polymer. The usefulness of the invention's polymers in medical
devices, such as drug-eluting
coronary stems and others, led the inventors to prepare and evaluate solid
solutions of, for example
polyDF containing 20 wt% paclitaxel or sirolimus, i.e., 1 mg of polymer/drug
admixture contained 0.~
mg polymer and 0.2 mg drug. Table 11 below shows the concurrent release of
paclitaxel from a
polyDF/paclitaxel admixture coated onto electropolished stainless steel
samples and incubated in 37°C
serum. Paclitaxel was released at the same rate at which the polymer
biodegraded to generate
diflunisal (the relatively small percentage of paclitaxel released reflects
the inability of serum to hold
this very poorly water-soluble drug). The incorporation of paclitaxel into the
polymer did not affect
the generation of diflunisal, which proceeded at the same rate as from polyDF
without paclitaxel.
Similar results were obtained with a polyDF/sirolimus admixture.
C. Effect of Sterilization by Various Methods
[0240] All implantable and percutaneous medical devices must be sterilized
before or after packaging.
Sterilization methods commonly employed are gamma irradiation, electron beam
("E-beam"), and
ethylene oxide. Sterilization by gamma radiation penetrates obj ects deeply,
and is used for food and
many medical device products, but the method requires relatively prolonged
exposure times. E-beam
sterilization allows shorter exposure times, but the electrons penetrate
objects poorly, making the
procedure useful mainly for surfaces. Ethylene oxide sterilization is more
complex and more
aggressive on organic materials than the other methods and is being replaced
where possible due to
environmental hazards. The relatively high temperatures and humidity employed
in many ethylene
oxide sterilization protocols is not very compatible with poly(anhydride-
ester) polymers. Accordingly,
gamma radiation and E-beam sterilization methods are preferred for use with
such compositions. The
sterilization with E-beam (3.5 mRad) and gamma radiation (25-35 Kgys) had no
effect on the pattern
of diflunisal generated from polyDF coated stainless steel samples incubated
in 37°C serum.
Notwithstanding the lack of effect on polymer degradation, sterilization does
produce some changes in
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molecular weight and mechanical properties. For example, the tensile modulus
of melt-polymerized
polySA at room temperature decreased by about a third after gamma
sterilization (25-35 I~gys), but
there was no change at 37°C. Gamma radiation had no effect on the
molecular weight, flexibility, or
adhesiveness of the polymers of the invention, such as polySA and poly DF, and
only minor effects on
hardness.
D. Polymer Coatings for Stents and Grafts
[0241] The example provided by the remarkable effectiveness of drug-coated
stems in reducing the
incidence of coronary arterial restenosis represents at the same time a
breakthrough in the treatment of
vascular disease, and provides a model for other applications of the present
invention. Most leading
stems under development are based on the sustained delivery of anti-
proliferative and/or
immunosuppressive drugs like paclitaxel and sirolimus. These drugs were
selected because of their
ability to reduce the over-growth of smooth muscle cells that occurs after
insertion of stems into the
axterial wall.
[0242] Stents are inserted, and then over-expanded into the arterial wall so
that they will remain
lodged in place. This produces a "wound" that rapidly leads to fibrin clot
formation that walls off the
damaged area, a process called thrombus deposition. At the same time,
inflammation induces immune
system cells to migrate into the area in order to engulf and destroy damaged
cells in a classic response
to a foreign body. This causes smooth muscle cells to overproliferate in the
damaged area, which leads
to abnormal tissue remodeling, also called restenosis. While the use of anti-
proliferative drugs is a
rational strategy to reduce restenosis, the overproliferation of arterial
smooth muscle cells is thought to
be a direct consequence of inflammation. The sustained delivery of drugs as
disclosed herein, e.g.
anti-inflammatory and other drugs, into the damaged area does itself prevent
or substantially reduce
the development of restenosis.
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Table 10: Salicylic (261PL) ~ Diflunisal (657PL) Polymers Polymer
261PL 657PL
Hardness
Ambient B F 3H
Smn PBS 37 °C B 2B B
lhr PBS 37 °C - 8B 4B
Flexibility
Ambient <3 mm <3 mm
min PBS 37°C <3 mm <3 mm
1 hr PBS 37°C - <3 mm
Adhesion
Ambient SB SB SB
[0243] Table 10 above shows the properties of the stems that were coated with
a 55 ~,m thick salicylic
acid polymer coating (lmg polySA), were subjected to E-beam sterilization,
expanded via a balloon
catheter, and soaked in serum 37°C for 2 hours. Similar results were
obtained with a diflunisal
polymer (polyDF). Polymer-coated stems, such as these polyNSAID-coated stems,
were implanted
into the iliac arteries of rabbits employing uncoated stents as controls. The
characteristics of the
coatings employed are shown in Table 11 below.
Table 11: Coating Hardness, Flexibility & Adhesion of Diflunisal (261PL)
Polymer
Alone & Admixed with Paclitaxel
Diflunisal Polymer (657PL)
Polymer Polymer + %PAC
Alone
Hardness
Ambient F F
5 Min in PBS, 37C 2B F
1 Hr in PBS, 37C+ 8B 6B
Flexibility
Ambient <3 mm <3 mm
5 Min in PBS, 37C <3 mm <3 mm
1 Hr in PBS, 37C <3 nun <3 mm
Adhesion
Ambient Temp. SB SB
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[0244] Histological arterial sections collected seven days post-implantation
of Salicylic Acid polymer-
(polySA-) coated stems revealed no evidence of thrombosis or inflammation when
compared to
controls. he vitro poly-SA bulk eroded within about one week.
[0245] As in the case of polysalicylic acid, rabbit iliac arterial sections
collected seven days after
implantation of polydiflunisal- (polyDF-) coated stems revealed no thrombosis
or inflammation as
demonstrated in Table 12a.
Table 12a: Paclitaxel Release from Polymer Alone & Admixed with Paclitaxel
Cumulative Dru Released
Time Elapsed 20 /o PAC in Coatin
D 0 /o PAC in Coatin
( DF* DF* PAC+
ays)
0 0.00 0.00 0.00
3 40.22 17.28 0.72
45.00 48.72 2.48
7 49.41 58.35 3.87
61.88 58.76 4.09
12 79.51 78.94 4.31
14 68.88 - 68.87 5
.42
___
76.13 74.82 _
6.24
26 ~ 69.04 -. I 67.11 ~ 5.69
* Diflunisal Release from DF Polymer into 37°C Serum from 5 ~,m-
thick Coatings on 316 SS Plates.
+ Paclitaxel Release from Admixture with DF Polymer into 37°C
Serum from S~.m-thick Coatings on 316 SS Plates.
Table 12b: Cumulative Diflunisal Released by Untreated & Sterilized Polymer
Cumulative Diflunisal*
Time ElapsedReleased from
657PL Polymer
(%)
(days) Not Irradiated Gamma Irradiated E-Beam Irradiated
1 0.39 0.57 1.12
2 - 4.02 4.81
3 5.47 - -
5 14.47 - -
7 18.50 28.25 27.87
9 - 30.05 28.02
13 34.87 34.74 32.84
17 - 29.23 36.58
19 39.85 - -
20 - 44.06 41.84
42.00 - -
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Cumulative Diflunisal*
Time ElapsedReleased from
657PL Polymer
(%)
(days) Not Irradiated Gamma Irradiated E-Beam Irradiated
26 - 50.38 44.07
34 49.89 - -
* Released by S~,m Diflunisal Polymer Coated on 316LSS Plates &
Placed in Serum at 37 C.
[0246] In contrast to the results obtained with polySA, these arterial
sections clearly reveal the
presence of the polyDF coating. In vitro tests evidenced that the latter will
last at least one month.
The effect of polySA-coated stems also were evaluated at 28 days post
implantation, and were found to
be indistinguishable from uncoated controls, most likely due to prior polymer
depletion. Arterial
sections from polyDF-coated stems revealed that the polymer was still present
after 28 days, but
evidenced only very mild inflammation (figure not shown). In a follow-up
study, pig coronary arteries
were implanted with stems coated with 1 mg polyDF alone, with polyDF
containing 200 ~,g paclitaxel
and with polyDF containing 200 ~,g sirolimus. After 28 days, the arteries
receiving stems coated with
polyDF alone showed considerably less fibrin deposition, hemorrhage, and
inflammation than those
treated with polyDF plus sirolimus or paclitaxel. These results axe applicable
also to polyNSAID
coatings for self expanding nitinol stems and grafts for non-coronaxy
applications, e.g., endovascular
applications, and are in marked contrast to the non-degradable, inflammation-
generating polymers
currently used for drug-coated stems. Results from 28-day and 90-day pig
studies demonstrate that
polyNSAIDs are biocompatible, biodegradable, anti-inflammatory materials
effective for coronaxy
stems, and to deliver drugs of interest.
[0247] Comparative studies were conducted on the characteristics of salicylic
acid and diflunisal
polymers before and after sterilization by various methods commonly employed
in the art. A
comparison of the results obtained is provided in Table 12c and Table 12d
below.
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Table 12c: Changes Produced by y-Irradiation of Salicylic Acid (261PL) &
Diflunisal (657PL1 Polymer
Property 261PL 657PL
Molecular Weight about 20,000 about 100,000
(Non Irradiated)
Molecular Weight about 20,000 (N.C.) about 50,000
(Irradiated)
Haxdness -2 Units -3 Units
Flexibility N. C. -
Adhesion N.C. -
N.C. No Change.
Table l2d:Changes E-Beam-Irradiation*
Produced by of Salicylic
Acid
(261PL) & Diflunisal
(657PL) Polymer
Polymer
261PL 657PL
Property 261PL 657PL
Molecular Weight
(Non Irradiated)about 20,000about 33,000about 80,000
Molecular Weight
(Irradiated) - 26% +5% -30%
Hardness -1 Unit +2 Units N.C.
Flexibility N.C. - N.C.
Adhesion -1 Unit - -
* 3-4.5 MRad E-Beam Radiation.
N.C. No Change.
[0248 Some characteristics of polyNSAIDs and prior art polymer coatings
currently used on drug-
eluting stems are provided in Table 13 below.
Table 13: PoIyNSAIDs vs. Current Polymer Stent Coatings
Property PoIyNSAID Coatings Current Polymer Coatings
Biodegradable Yes No
Pharmacological Yes ~ No
Activity
Inflammation Little/None Significant
Additional Agent OK NOT OK
Application to metal Easy Complex
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[0249] The ability of the polymers of this invention, e.g. polyNSAIDs and
others, to adhere strongly to
metal, e.g. stainless steel, without need for glues or other surface
treatments provides an important
advantage over other available stems, and eliminates the need for treating the
metal surface prior to
affixing a drug-eluting polymer, and/or for an additional layer with another
polymer coating to prolong
drug release and prevent a "burst effect".
E. Polymer Coatings for Implanted Orthopedic Joint-Replacement/ Aid Devices
[0250] Joint-replacement implants and bone aid devices are widely used to
restore quality of life for
million of patients with irreparably damaged shoulders, knees, and hips as
well as for repairing broken
and splintered bones. These devices are generally made of titanium/nickel or
cobalt/chromium alloys,
with metal stems that are inserted into the hollow portion of the arm or leg
bones. Some of these stems
have smooth surfaces that require the use of bone cement to ensure strong
connection, while others
have highly engineered, honeycomb-textured surfaces that become partially
filled with bone and
marrow cells during insertion, thereby seeding the stem for in growth of new
bone and reducing the
need for cement. Orthopedic surgeons are eager to incorporate agents into
these surfaces that may
accelerate bond growth. A number of recombinant bone morphogenic proteins
(BMPs) and other
"osteogenic" proteins are in development for this purpose, notwithstanding
their high manufacturing
costs and product development challenges.
[0251 ] The dynamics of bone formation, resorption, and repair are complex,
and appear to vary for
different types of bone. Dental studies showed that the inhibition of
prostaglandin production by
NSAIDs decreases bone resorption in the trabecular bone of the palate and
alveolar bone of the jaw,
causing a net increase in bond mass and density. This phenomenon was
demonstrated in the mouse for
"PolyAspirin" implants). In addition, polySA prevented bone erosion in a rat
femur transaction model.
Other animal studies suggest that the repair of long-bone fractures may be
inhibited by long-term
exposure to high levels of NSAIDs.
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[0252] Different forms of the present polymers may be prepared that are
suitable for these and other
applications in the orthopedics and dental fields, among others. Polymers of
this invention, such as
polyNSAIDs and others, may be employed as coatings to reduce pain and
inflation associated
with device implantation and adjustment of dental and orthopedic aids, to
reduce the incidence of
infection, which is a major problem associated with joint replacement devices,
and to prevent and treat
other conditions by delivering appropriate agents to the site. While infection
at the implant/bone
interface reportedly occurs in less than 1 % of cases, the limited blood
supply to the region makes these
infections particularly hard to treat with systemic antibiotics. The
antiseptic properties of a polymer of
the invention, such as a polyNSAID, a polyantibiotic, a combination or mixture
thereof, in a coating
prevents or greatly reduces infection without the potential for bacterial
resistance. Together with the
properties of polymers such as polyNSAIDs sarized in Table 4, this
characteristic makes
PoIyNSAIDs attractive for use on orthopedic, dental, ocular, and many other
implanted medical
devices.
[0253] Medical devices useful with coverings of the present invention include,
but are not limited to, a
fixation device, catheters, drain tubes, intravenous tubes, tampon
applicators, ventilator tubes,
endoscopes, syringes, arthroscopes, IUDs and other drug-based contraceptive
implants and patches of
all sorts for drug delivery, e.g. hormones, nicotine, and other patches,
needles, condoms, barrier
devices, monitoring and diagnostic devices such as a speculum, dental
appliances, and surgical
appliances. The polymers, compounds and/or compositions of the invention may
be formed into a
medical implant such as a medical, dental, orthopedic and surgical implant, or
applied or coated onto
such implant. In addition to the implants described above, other examples are
implants for vascular,
cardiovascular, coronary, peripheral vascular, orthopedic, dental, oro-
maxillary, gastrointestinal,
urogenital, ophthalmic, gynecological, pulmonary, surgical, physiological,
metabolic, neurological,
diagnostic and therapeutic uses, may be fornled from or applied or coated with
the above identified
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polymers, compounds and/or compositions. Such implants include, but are not
limited to, stems,
catheters, balloons, guidewires, grafts, sutures, meshes, joint prostheses,
breast prostheses, fracture
management devices, drug dosing devices, pacemakers, mechanical pumps, dental
implants (e.g.,
dental, oro-maxillary, and alveolax), defibrillators, and filters.
[0254] Suitable medical implants also include, but are not limited to the ones
described here. 1 )
Boston Scientific (Boston Scientific Corporation, Natick, MA) products
PolarisTM, NIR~ Elite OTW
Stent System, NIR~ Elite Monorail(TM) Stent System, Magic WALLSTENT~ Stent
System, Radius~
Self Expanding Stent, NIR~ Biliary Stent System, NIROYAL(TM) Biliary Stent
System,
WALLGRAFT~ Endoprosthesis, WALLSTENT~ Endoprosthesis, RX Plastic Biliary
Stents, UroMax
Ultra (TM) High Pressure Balloon Catheter, Passport (TM) Balloon on a Wire
Catheter, Excelsior(TM)
1018(TM) Microcatheter, Spinnaker~ Elite(TM) Flow-Directed Microcatheter,
Guider Softip(TM) XF
Guide Catheters, Sentry(TM) Balloon Catheters, Flexima(TM) APD(TM) Drainage
Catheters with Twist
Loc(TM) Hub, Vaxcel(TM) Chronic Dialysis Catheter, PASV~ PICC Peripherally
Inserted Central
Catheters, Chilli~ Cooled Ablation Catheters, and Constellation~ Catheters. 2)
Cordis (Cordis, a
Johnson ~ Johnson Company, Piscataway NJ) products: BX Velocity(TM) Coronary
Stents, Ninja
FX(TM) Balloon Catheters, Raptor (TM) Balloon Catheters, NC Raptor(TM) Balloon
Catheters,
Predator(TM) Balloon Catheters, Titan Mega(TM) Balloon Catheters,
Checkmate(TM) Brachytherapy
Catheters, Infiniti(TM) Diagnostic Catheters, Cinemayre(TM) Diagnostic
Catheters, SuperTorque
Plus(TM) Diagnostic Catheters, and High Flow(TM) Diagnostic Catheters. 3)
Medtronics (Medtronics,
Inc., Minneapolis, MN) products: Aneurx Stentgraft, S7 Coronary Stents, 5670
Coronary Stents, 5660
Coronary Stents, BeStent 2 Coronary Stents, D1 Balloon Catheters, and D2
Balloon Catheters. 4)
Avantec Vascular (Avantec Vascular, San Jose, CA) products: Duraflex(TM)
Coronary Stent System,
and Apollo (TM) Coronary Dilatation Catheter. 5) B. Braun (B.Braun Medical
Ltd., Sheffield,
England) products: Coroflex(TM) Coronary Stent, Cystofix(TM) Urogenital
Catheters, and Urecath(TM)
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Urogenital Catheters. 6) Cook (Cook Group Inc., Bloomington, IN.) products: V-
Flex Plus(TM)
Coronary Stent, and CR II~ Coronary Stent. 7) Guidant (Guidant Corporation,
Indianapolis, IN)
products: Multilink Penta(TM) Coronary Stents, Multilinle Pixel(TM) Coronary
Stents, Multilink
Ultra(TM) Coronary Stents, Multilink Tetra(TM) Coronary Stents, Multilink
Tristar (TM) Coronary
Stems, Ancure (TM) Stentgraft, Dynalink (TM) Biliary Stents, Rx Herculink(TM)
Biliary Stents,
Omnilink(TM) Biliary Stents, Megalink(TM) Biliary Stents, Rx Crosssail(TM)
Balloon Dilatation
Catheters, Rx Pauersail(TM) Balloon Dilatation Catheters, OTW Opensail(TM)
Balloon Dilatation
Catheters, OTW Highsail(TM) Balloon Dilatation Catheters, Rx Esprit (TM)
Balloon Dilatation
Catheters, Rx Viatrac(TM) Peripheral Catheters, and OTW Viatrac(TM) Peripheral
Catheters. 8) Ethicon
(Ethicon, a Johnson & Johnson Company, Piscataway, N.J.) products: VicrylTM
(resorbable braided
coated), PronovaTM, and PanacrylTM. 9) USS/DG Sutures (U.S. Surgical, a
division of Tyco Healthcare
Group LP, Norwalk, CT) products: Decon IITM (coated, braided synthetic,
absorbable), PolySorbTM
(coated, braided synthetic, absorbable), Dexon STM (Uncoated, braided
synthetic, absorbable), Gut
sutures (absorbable), BiosynTM (synthetic monofilament, absorbable), MaxonTM
(synthetic
monofilament, absorbable), SurgilonTM (braided nylon, non-absorbable), Ti-
CronTM (coated, braided
polyester, non-absorbable), SurgidacTM (coated, braided polyester, non-
absorbable), SofSilkTM (coated,
braided silk, non-absorbable), DermalonTM(nylon monofilament, non-absorbable),
MonosofrM (nylon
monofilament, non-absorbable), NovafilTM (polybutester monofilament, non-
absorbable), VascufilTM
(coated polybutester monofilament, non-absorbable), SurgileneTM (polypropylene
monofilament, non-
absorbable), SurgiproTM (polypropylene monofilament, non-absorbable), FlexonTM
(stainless steel
monofilament, non-absorbable), SURGALLOYTM needle, and SURGALLOYTM OptiVisTM
needle.
10) Surgical Dynamics (Surgical Dynamics, Inc., North Haven, Connecticut,)
products: S*D*SorbTM
(suture anchor, AnchorSewTM (suture anchor), S*D*Sorb E-Z TacTM (bio-
resorbable implant w/o
sutures), S*D*Sorb Meniscal StaplerTM (delivers bio-absorbable repair
implant), Ray Threaded Fusion
CA 02527495 2005-11-28
WO 2005/042600 16o PCT/US2004/017916
CageTM (spine), AlineTM (cervical plating system), SecureStrandTM (spinal
reconstruction cable), and
Spiral Radius 90DTM (spinal rod system). 11) Zimmer (Zimmer, Warsaw, Indiana)
products:
VerSysTM cemented stem hip system, VerSys HeritageTM Hip cemented stem hip
system, VerSysTM
LD/Fx cemented stem hip system, CPTTM Hip cemented stem hip system, VerSysTM
Cemented
Revision/Calcar cemented stem hip system, MayoTM Hip porous stem hip system,
VerSysTM Beaded
MidCoat porous stem hip system, VerSysTM Beaded FullCoat Plus porous stem hip
system, VerSysTM
Fiber Metal MidCoat porous stem hip system, and VerSysTM Fiber Metal Taper
porous stem hip
system, VerSysTM LD/Fx press-fit hip system, VerSysTM Cemented Revision/Calcar
revision stem hip
system, ZMRTM hip revision stem hip system, TrilogyTM Cup acetabular cup hip
system, ZCATM cup
acetabular cup hip system, LongevityTM polyethylene hip system, CalcicoatTM
coating hip system,
NexGenTM Implant knee system, NexGenTM Instruments knee system, NexGenTM
Revision Instruments
knee system, IMTM Instruments knee system, MICRO-MILLTM 5-in-1 Instruments
knee system, Multi-
ReferenceTM 4-in-1 knee system, V-STATTM Instruments knee system,
Coonrad/MorreyTM elbow,
Bigliani/FlatowTM shoulder, Cable ReadyTM Cable Grip System, CollagraftTM Bone
Graft Matrix,
HerbertTM Bone Screw, M/DNTM Intramedullary Fixation, Mini Magna-FxTM Screw
Fixation, Magna-
FxTM Screw Fixation, PeriarticularTM Plating System, Versa-Fx TMFemoral
Fixation system, Versa-Fix
IITM Femoral Fixation System, and TrabecularTM Metal. 12) Alza technologies
(ALZA Corporation,
Mountain View, CA) products: DUROS~ Implant, OROSTM osmotic, D-TRANSTM
transdermal,
STEALTHTM liposomal, E-TRANSTM electrotransport, MacrofluxTM, and ALZAMER
depot. 13)
described in Stuart, M., "Technology Strategies, Stent and Deliver," Start-Up,
Windhover's Review of
Emer,gin~ Medical Ventures, pp. 34-3~, June 2000); van der Giessen, Willem J.,
et al. "Marked
Inflammatory Sequelae to Implantation of Biodegradable and Nonbiodegradable
Polymers in Porcine
Coronary Arteries," Circulation, Vol. 94, No. 7, pp. 1690-1697 (October l,
1996); Gunn, J. et al.,
"Stent coatings and local drug delivery," European Heart Journal 20: 1693-1700
(1999); EP
CA 02527495 2005-11-28
WO 2005/042600 161 PCT/US2004/017916
Applications 01301671, 00127666, 99302918, 95308988, 95306529, 95302858,
94115691, 99933575,
94922724, 97933150, 95308988, 91309923, 91906591, and 112119841; WO 00/187372,
WO
00/170295, WO 00/145862, WO 00/143743, WO 00/044357, WO 00/009672, WO
99/03517, WO
99/00071, WO 98/58680, WO 98/34669, WO 98/23244, and WO 97/49434; U.S.S.Nos.
061568,
346263, 346975, 325198, 797743, 815104, 538301, 430028, 306785, and 429459;
and U.S. Patents
6,325,825, 6,325,790, 6,322,534, 6,315,708, 6,293,959, 6,289,568, 6,273,913,
6,270,525, 6,270,521,
6,267,783, 6,267,777, 6,264,687, 6,258,116, 6,254,612, 6,245,100, 6,241,746,
6,238,409, 6,214,036,
6,210,407, 6,210,406, 6,210,362, 6,203,507, 6,198,974, 6,190,403, 6,190,393,
6,171,277, 6,171,275,
6,165,164, 6,162,243, 6,140,127, 6,134,463, 6,126,650, 6,123,699, 6,120,476,
6,120,457, 6,102,891,
6,096,012, 6,090,104, 6,068,644, 6,066,125, 6,064,905, 6,063,111, 6,063,080,
6,039,721, 6,039,699,
6,036,670, 6,033,393, 6,033,380, 6,027,473, 6,019,778, 6,017,363, 6,001,078,
5,997,570, 5,980,553,
5,971,955, 5,968,070, 5,964,757, 5,948,489, 5,948,191, 5,944,735, 5,944,691,
5,938,682, 5,938,603,
5,928,186, 5,925,301, 5,916,158, 5,911,732, 5,908,403, 5,902,282, 5,897,536,
5,897,529, 5,897,497,
5,895,406, 5,893,885, 5,891,108, 5,891,082, 5,882,347, 5,882,335, 5,879,282,
RE36,104, 5,863,285,
5,853,393, 5,853,389, 5,851,464, 5,846,246, 5,846,199, 5,843,356, 5,843,076,
5,836,952, 5,836,875,
5,833,659, 5,830,189, 5,827,278, 5,824,173, 5,823,996, 5,820,613, 5,820,594,
5,811,814, 5,810,874,
5,810,785, 5,807,391, 5,807,350, 5,807,331, 5,803,083, 5,800,399, 5,797,948,
5,797,868, 5,795,322,
5,792,415, 5,792,300, 5,785,678, 5,783,227, 5,782,817, 5,782,239, 5,779,731,
5,779,730, 5,776,140,
5,772,590, 5,769,829, 5,759,179, 5,759,172, 5,746,764, 5,741,326, 5,741,324,
5,738,667, 5,736,094,
5,736,085, 5,735,831, 5,733,400, 5,733,299, 5,728,104, 5,728,079, 5,728,068,
5,720,775, 5,716,572,
5,713,876, 5,713,851, 5,713,849, 5,711,909, 5,709,653, 5,702,410, 5,700,242,
5,693,021, 5,690,645,
5,688,249, 5,683,368, 5,681,343, 5,674,198, 5,674,197, 5,669,880, 5,662,622,
5,658,263, 5,658,262,
5,653,736, 5,645,562, 5,643,279, 5,634,902, 5,632,763, 5,632,760, 5,628,313,
5,626,604, 5,626,136,
5,624,450, 5,620,649, 5,613,979, 5,613,948, 5,611,812, 5,607,422, 5,607,406,
5,601,539, 5,599,319,
CA 02527495 2005-11-28
WO 2005/042600 162 PCT/US2004/017916
5,599,310, 5,598,844, 5,593,412, 5,591,142, 5,588,961, 5,571,073, 5,569,220,
5,569,202, 5,569,199,
5,562,632, 5,562,631, 5,549,580, 5,549,119, 5,542,938, 5,538,510, 5,538,505,
5,533,969, 5,531,690,
5,520,655, 5,514,236, 5,514,108, 5,507,731, 5,507,726, 5,505,700, 5,501,341,
5,497,785, 5,497,601,
5,490,838, 5,489,270, 5,487,729, 5,480,392, 6,325,800, 6,312,404, 6,264,624,
6,238,402, 6,174,328,
6,165,127, 6,152,910, 6,146,389, 6,136,006, 6,120,454, 6,110,192, 6,096,009,
6,083,222, 6,071,308,
6,048,356, 6,042,577, 6,033,381, 6,032,061, 6,013,055, 6,010,480, 6,007,522,
5,968,092, 5,967,984,
5,957,941, 5,957,863, 5,954,740, 5,954,693, 5,938,645, 5,931,812, 5,928,247,
5,928,208, 5,921,971,
5,921,952, 5,919,164, 5,919,145, 5,868,719, 5,865,800, 5,860,974, 5,857,998,
5,843,089, 5,842,994,
5,836,951, 5,833,688, 5,827,313, 5,827,229, 5,800,391, 5,792,105, 5,766,237,
5,766,201, 5,759,175,
5,755,722, 5,755,685, 5,746,745, 5,715,832, 5,715,825, 5,704,913, 5,702,418,
5,697,906, 5,693,086,
5,693,014, 5,685,847, 5,683,448, 5,681,274, 5,665,115, 5,656,030, 5,637,086,
5,607,394, 5,599,324,
5,599,298, 5,597,377, 5,578,018, 5,562,619, 5,545,135, 5,544,660, 5,514,112,
5,512,051, 5,501,668,
5,489,271, 6,319,287, 6,287,278, 6,221,064, 6,113,613 5,984,903, 5,910,132,
5,800,515, 5,797,878,
5,769,786, 5,630,802, 5,492,532, 5,322,518, 5,279,563, 5,213,115, 5,156,597,
5,135,525, 5,007,902,
4,994,036, 4,981,475, 4,951,686, 4,929,243, 4,917,668, 4,871,356, 6,322,582,
6,319,445, 6,309,202,
6,293,961, 6,254,616, 6,206,677, 6,205,748, 6,178,622, 6,156,056, 6,128,816,
6,120,527, 6,105,339,
6,081,981, 6,076,659, 6,058,821, 6,045,573, 6,035,916, 6,035,751, 6,029,805,
6,024,757, 6,022,360,
6,019,768, 6,015,042, 6,001,121, 5,987,855, 5,975,876, 5,970,686, 5,956,927,
5,951,587, RE36,289,
5,924,561, 5,906,273, 5,894,921, 5,891,166, 5,887,706, 5,871,502, 5,871,490,
5,855,'156, 5,853,423,
5,843,574, 5,843,087, 5,833,055, 5,814,069, 5,813,303, 5,792,181, 5,788,063,
5,788,062, 5,776,150,
5,749,898, 5,732,816, 5,728,135, 5,709,067, 5,704,469, 5,695,138, 5,692,602,
5,683,416, 5,681,351,
5,675,961, 5,669,935, 5,667,155, 5,655,652, 5,628,395, 5,623,810, 5,601,185,
5,571,469, 5,555,976,
5,545,180, 5,529,175, 5,500,991, 5,495,420, 5,491,955, 5,491,954, 5,487,216,
5,487,212, 5,486,197,
5,485,668, 5,477,609, 5,473,810, 5,409,499, 5,364,410, 5,358,624, 5,344,005,
5,341,922, 5,306,280,
CA 02527495 2005-11-28
WO 2005/042600 i63 PCT/US2004/017916
5,284,240, 5,271,495, 5,254,126, 5,242,458, 5,236,083, 5,234,449, 5,230,424,
5,226,535, 5,224,948,
5,213,210, 5,199,561, 5,188,636, 5,179,818, 5,178,629, 5,171,251, 5,165,217,
5,160,339, 5,147,383,
5,102,420, 5,100,433, 5,099,994, 5,089,013, 5,089,012, 5,080,667, 5,056,658,
5,052,551, 5,007,922,
4,994,074, 4,967,902, 4,961,498, 4,896,767, 4,572,363, 4,555,016, 4,549,649,
4,533,041, 4,491,218,
4,483,437, 4,424,898, 4,412,614, D260,955, 4,253,563, 4,249,656, 4,127,133,
D245,069, 3,972,418,
3,963,031, 3,951,261, 3,949,756, 3,943,933, 3,942,532, 3,939,969, 6,270,518,
6,213,940, 6,203,564,
6,191,236, 6,138,440, 6,135,385, 6,074,409, 6,053,086, 6,016,905, 6,015,427,
6,011,121, 5,988,367,
5,961,538, 5,954,748, 5,948,001, 5,948,000, 5,944,739, 5,944,724, 5,939,191,
5,925,065, 5,910,148,
5,906,624, 5,904,704, 5,904,692, 5,903,966, 5,891,247, 5,891,167, 5,889,075,
5,865,836, 5,860,517,
5,851,219, 5,814,051, 5,810,852, 5,800,447, 5,782,864, 5,755,729, 5,746,311,
5,741,278, 5,725,557,
5,722,991, 5,709,694, 5,709,692, 5,707,391, 5,701,664, 5,695,879, 5,683,418,
5,669,490, 5,667,528,
5,662,682, 5,662,663, 5,649,962, 5,645,553, 5,643,628, 5,639,506, 5,615,766,
5,608,962, 5,584,860,
5,584,857, 5,573,542, 5,569,302, 5,568,746, 5,566,822, 5,566,821, 5,562,685,
5,560,477, 5,554,171,
5,549,907, 5,540,717, 5,531,763, 5,527,323, 5,520,702, 5,520,084, 5,514,159,
5,507,798, 5,507,777,
5,503,266, 5,494,620, 5,480,411, 5,480,403, 5,462,558, 5,462,543, 5,460,263,
5,456,697, 5,456,696,
5,442,896, 5,435,438, 5,425,746, 5,425,445, 5,423,859, 5,417,036, 5,411,523,
5,405,358, 5,403,345,
5,403,331, 5,394,971, 5,391,176, 5,386,908, 5,383,905, 5,383,902, 5,383,387,
5,376,101, D353,672,
5,368,599, D353,002, 5,359,831, 5,358,511, 5,354,298, 5,353,922, 5,350,373,
5,349,044, 5,335,783,
5,335,775, 5,330,442, 5,325,975, 5,318,577, 5,318,575, 5,314,433, 5,312,437,
5,310,348, 5,306,290,
5,306,289, 5,306,288, 5,294,389, 5,282,832, 5,282,533, 5,280,674, 5,279,783,
5,275,618, 5,269,807,
5,261,886, 5,261,210, 5,259,846, 5,259,845, 5,249,672, 5,246,104, 5,226,912,
5,225,485, 5,217,772,
5,217,486, 5,217,485, 5,207,679, D334,860, 5,197,597, 5,192,303, D333,401,
D333,400, 5,181,923,
5,178,277, 5,174,087, 5,168,619, 5,163,946, 5,156,615, 5,154,283, 5,139,514,
5,133,738, 5,133,723,
5,131,534, 5,131,131, 5,129,511, 5,123,911, 5,121,836, 5,116,358, 5,102,418,
5,099,676, 5,092,455,
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5,089,011, 5,089,010, 5,087,263, 5,084,063, 5,084,058, 5,078,730, 5,067,959,
5,059,213, 5,059,212,
5,051,107, 5,046,513, 5,046,350, 5,037,429, 5,024,322, 5,019,093, 5,002,550,
4,984,941, 4,968,315,
4,946,468, 4,932,963, 4,899,743, and 4,898,156; among many others available in
the public domain,
the relevant portions of all of the above listed being hereby incorporated by
reference in their
entireties.
[0255] Polymeric drug delivery systems comprising the polymers of the
invention may be readily
processed into pastes or solvent cast to yield films, coatings, nanoparticles
e.g. nanospheres,
micropaxticles e.g. microspheres and fibers with different geometric shapes
for design of vaxious
medical devices, and may also be processed by compression molding and
extrusion. In one
embodiment, a polymer or polymers may be coated onto or applied onto a medical
device, such as,
e.g., by forming the polymer or polymers into a covering. In another
embodiment, the polymer or
polymers may be formed into a medical device, such as, e.g., an implant. In
one embodiment of the
present invention, a polymer comprising a functional group or active agent may
used to form a
covering, such as, e.g., a coating or a sheath, that partially or completely
covers and/or surrounds a
medical device. Such a covering may cover a portion of the medical device or
it may completely cover
a medical device. The covering may be divided into separate portions or
several smaller coverings
may be present on the medical device. In another embodiment of the invention,
a polymer may
surround the medical device, or a portion thereof, and may have the form of a
coating, a layer, a film,
and combinations thereof. The polymer may be in the form of a solid or a semi-
solid, such as a gel,
sheath, a wrap, a tube or a cuff covering all or a portion of the medical
device. The polymer may be
rigid, semi-rigid, or non-rigid. The coating of polymer may comprise about 100
nm, 1 ~m to about
lmm, 1 cm thiclc, although some porous implants may benefit from longer
lasting effects enabled by a
coating that completely fills the interstices of the device with, in some
cases, a thin coating on those
surfaces proximal to bone or other tissue upon placement in the body. In one
embodiment, the
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WO 2005/042600 165 PCT/US2004/017916
polymer coating is comprised of microparticles, such as microspheres that may
typically but not
necessarily be less than 10 microns in diameter. These microparticles may be
applied to the surface of
a medical device before placement in the body. A sterile liquid may be used to
coat the device to
adhere such microspheres for minutes to weeks to enable uncoated medical
devices to benefit from the
same or similar therapeutic benefits as coated devices.
[0256] A polymer, compound and/or composition of the invention may be applied
or coated onto a
medical implant by any means known in the art including, but not limited to,
solvent methods such as,
for example, dipping and spray-drying, and non-solvent methods such as
chemical vapor deposition,
extrusion coating, covalently grafting or dipping in molten polymer, compound
and/or composition of
the invention. The method of preparation may vary depending on the polymer,
compound and
composition and/or the medical implant. The medical implant may be formed from
or coated with one
or more layers of the same or different polymer, compound and/or composition
of the invention. In
another example, a polymer, compound and/or composition of the invention may
be coated onto a
medical implant in the shape of a membrane or tube for use in the treatment of
injury or damage to the
peripheral nervous system or a block of solid or foamed composition containing
pathways drilled or
otherwise formed to encouraged nerve growth or bone growth. In the above
instances, bioerosion of
the disc, membrane, tube or block would yield or generate an active agent
included within the polymer
or composition. The polymer may be formed into a device by any means known in
the art including,
but not limited to, molding e.g. compression or blow molding, and extrusion.
The medical device may
be formed from one or more of the same or different polymer, compound and/or
composition of the
invention.
[0257] A polymer, compound and/or composition of the invention may be formed,
that is, physically
configured, into various shapes, geometries, structures and configurations
including, but not limited to,
a film, fiber, rod, coil, corkscrew, hook, cone, pellet, tablet, tube e.g.
smooth or fluted, disc, membrane,
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microparticle, nanoparticle, "biobullet" i.e. bullet shaped, seed i.e. bullet
shaped or targeted seeds, as
well as those described in the above identified products, patents and
articles, including in some cases
forming medical implants that have the same, similar or completely different
functional characteristics
compaxed to those functional characteristics of the medical devices described
in the above identified
products, patents and articles. The above-mentioned shapes, geometries,
structures and configurations
may contain additional features that will further enhance the desired
application or use. For example, a
polymer, compound and/or composition of the invention in the form of a rod,
coil, or cone may have
barbs that spring out upon insertion from a needle or cannula or when waxmed
to body temperature to
reduce movement and/or expulsion.
[0258] The shape, geometry, structure or configuration of a device, such as a
medical implant, will
vary depending upon the use of the device. For example, for treatment of a
spinal cord injury or
concussion to the brain, a polymer, compound and/or composition of the
invention may be formed into
a medical implant in the shape of a disc for placement under the dura or dura
mater, or a solution,
suspension, emulsion, cream, gel, ointment, or other adhesive formulation form
for covering the spine,
dura or other surgically exposed areas, film, sprayed or coated formulation.
In another example, a
polymer, compound and/or composition of the invention may be formed into a
medical implant in the
shape of a membrane or tube for use in the treatment of injury or damage to
the peripheral nervous
system or a block of solid or foamed composition containing pathways drilled
or otherwise formed to
encourage nerve growth or bone growth. In another example, in the treatment of
cancer, a polymer,
compound and/or composition of the invention may be formed into a medical
implant in the shape of a
pellet, microparticle e.g. microsphere, nanoparticle e.g. nanosphere, rod,
membrane, pin, cuff, disc,
bullet, hook, rod or cone, with or without barbs, for insertion in a bone,
joint, tumor excision site or
other structures, or for insertion within the same and other structures. In
the above instances,
bioerosion of the medical implant would yield or generate an active agent.
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WO 2005/042600 167 PCT/US2004/017916
[0259] The invention also contemplates that the shape, geometry, structure or
configuration of a
medical implant of the invention may change depending on the mode of delivery
or administration and
may enhance the therapeutic effect of the medical implant. For example, a
medical device of the
invention may be in the form of a linear rod when inserted in needles and
stored but may become coil-
like or form a multiplicity of coils or corkscrew shapes as the medical
implant is pushed out of the
needle by a trochar. As a result of the change of the shape, geometry,
structure or configuration of the
medical implant, expulsion from the tumor or tumor excision site by hydraulic
pressures or body
movements may be prevented and as much mass of active ingredient may be
delivered to a small
region with as small a diameter needle as possible.
[0260] The polymers of the present invention may take the form of a shape
memory polymer, which is
a stimulus responsive material that may change its shape in response to
outside stimuli. Usually this is
a temperature-related effect. It depends on the morphology of the material in
combination with various
processing parameters. Thus, many materials of widely different polymeric
chemistry may behave as
shape memory. See, e.g. Lendlein and Kelch, on Shape Memory Polymers,
Encyclopedia of Polymer
Science and Technology, Ed III, Publ. J Wiley & Sons, New York (2003). The
material may be
programmed initially by deforming the sample, usually at an elevated
transition temperature, and then
cooled in a distorted form so that it remains in this temporary state. It will
remain there a long time but
on reheating to above the programming transition temperature it will revert to
its natural undeformed
state.
[0261] Shape memory materials are all elastomers. They have a molecular
structure consisting of
network linked at certain net points either by physical or chemical cross-
linking processes. The
elastomer contains two types of polymer blocks whose phases are immiscible and
have differing T"' or
Tg values. Shape memory effects are usually recognized by tensile tests in a
hot chamber over a range
of transitions and seeing how the dimensions alter. The upper limit is the
melting point of the highest
CA 02527495 2005-11-28
WO 2005/042600 168 PCT/US2004/017916
Tm block. A cyclical regimen will show how well the polymer recovers its
original shape. Examples
of shape memory polymers are polyester-urethanes with hard and soft segments.
A typical hard
switching one is made from butane-1,4- diol and MDI with low Tg but
crystalline polycaprolactone
blocks. The Tm of the hard 4G-MDI block is the upper temperature limit.
Another segmented
polyether-urethane is the one from polyTHF and butane dial with MDI. Here, the
molecular weight of
the soft poly (THF) segment is important - if it is too high the recovery may
suffer.
[0262] Biodegradable shape memory polymers axe possible based upon
polycaprolactone diols capped
with methacrylate groups and copolymerized with a low Tg amorphous vinyl
component such as
polybutyl acrylate. Other compositions may include block copolyester-ethers
with hard segments such
as polylactide, glycolide and soft segments such as polyTHF diol or
caprolactone-diol. Polyanhydride
linkers could be incorporated and, if a phosgene route were used to make the
polyanhydride, it could
also generate carbamoyl chlorides and urethane links at the same time form
suitable amine precursors.
The polymers of this invention achieve a broad range of tensile modulus
anywhere between about 500,
1000, 5000, 10000, 50000, 100000, or 300000 psi to about 500000, 600000,
850000, 1000000,
1200000, or 1500000 psi, among others, as well as any combination of ranges
therebetween.
[0263] The mode of delivery, application, or administration of a device or
implant of the invention
may vary depending upon the use and may include those known in the art as well
as those set forth
herein. The thickness of the polymer, compound and/or composition as either
the medical implant
itself or as applied or coated onto a medical implant will vary depending upon
one or more factors such
as the physical and/or chemical characteristics of the polymer, compound
and/or composition, the
medical implant and/or the application or use. For example, a coronary artery
stent may be formed
from or applied or coated with a polymer, compound and/or composition of the
invention to a
thickness of about <_30-50 pm while a vascular stmt may be applied or coated
with a polymer,
compound and/or composition of the invention to a thickness of about <_100 ~,m
and a drug delivery
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device may be applied or coated with a polymer, compound and/or composition of
the invention to a
thickness of about <_5 mm. In another example, round films/membranes for
buccal (sublingual)
administration, e.g. placement in lining of cheek, under the tongue, will have
diameters of up to about
mm (1 cm) and a thickness of about 0.5-2.0 mm.
[0264] In the present invention, a covering may be affixed to a medical device
in several ways. In one
embodiment, the covering may be placed on the outside of the medical device,
and through the natural
properties of the polymer (i.e., stickiness or adhesiveness), adhere to the
device. In one embodiment,
the covering may fit snugly, form-fitting, or loosely around the medical
device, such that no adhesive
is required to affix the covering to the medical device. In another
embodiment, a covering of the
invention may be affixed to the medical device by means of a biocompatible
adhesive, the
characteristics of which would be understood by one skilled in the art. In
another embodiment of the
invention, a covering may be affixed to a medical device by means of a device
external to both the
covering and the medical device. For example, the covering may be affixed to
the medical device by
means of an external clamp, retaining pin, or other such device commonly known
in the art. External
retaining devices used to affix a covering to a medical device may also be
used to retain the shape of
the covering. External retaining devices may retain the covering adjacent to
the medical device by
existing on the outside of the covering, on the inside of the covering (i.e.,
in between the covering and
the medical device), or as a combination both outside and inside of the
covering. In yet another
embodiment, the covering may be affixed to the medical device by means of a
fastener. Non-limiting
examples of materials that may be used to make an external fixing device for a
covering of the present
invention include surgical steel, nylon, polyethylene, and combinations
thereof.
[0265] As a non-limiting example of the present invention, a medical device
may be covered by a first
covering in the form of a polymeric sheath, which is in turn covered by an
external retaining device in
the form of a semi-rigid or rigid sleeve. Such an external retaining device
may be made of metal,
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plastic, a polymeric substance, or a combination thereof. Such an external
retaining device may also
be formed of, covered by, or impregnated with a polymer according to the
present invention as
described herein, or may be covered by or impregnated with an active agent
that may be the same as or
different than an active agent present in the first therapeutic device
according to the present invention.
,i~ ,An external retaining device may also contain a polymer that contains a
functional group as described
,i,i above. In another embodiment of the invention, an external retaining
device, that is formed from a
polymer according to the present invention may contain at least one functional
group and/or active
agent in any of the forms as described above for a first covering.
[066] In one embodiment, a cuff or sleeve comprising a polymer that generates
an active agent, such
as, ~.g., an anti-inflammatory,, an anti-infective, an antiseptic agent, or an
anti-proliferative agent, is
provided. Such a cuff may be made of the polymer entirely or made of an inert
substance that is
coated with the polymer. The cuff may adjoin or penetrate tissue layers to
ensure delivery to the most
likely sites of infection. The simplest version of the embodiment would be to
coat the surfaces of a
suitable device with the polymer and thereby enable a slow release of active
agent along its length
within the moist and enzyme rich milieu of body tissue. In preferred
embodiment, the medical device
is coated with a polymer composition comprising a active agent including, but
not limited to, an anti-
inflammatory agent, an anti-infective agent, an antiseptic, and an anti-
proliferative agent or drug.
[0267] Polymers and compositions thereof with specific physical properties may
be developed by one
of skill in the art using the guidance given herein. In some preferred
embodiments, a vascular device
maybe further coated with a polymer that has lubricating qualities.
[0268] A polymer, compound and/or composition of the invention may be combined
or admixed with
other ingredients prior to or while being formed into or coated onto a medical
device or into a
particular coating for a medical device. Examples of suitable additives
include, but are not limited to,
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stabilizers, mechanical stabilizers, plasticizers, hardeners, emulsifiers,
other polymers including other
biocompatible and biodegradable polymers, e.g. biocompatible and biodegradable
polyanhydrides as
set forth in U.S.S.N. 09/917,231 and PCT US/O1/23740, biocompatible and
biodegradable polyazo
compounds as set forth in U.S.S.N. 09/917,595 and PCT US/Ol/2374~,
biocompatible and
biodegradable polyesters, polythioesters, and polyamides as set forth in
U.S.S.N. 09/917,194 and PCT
US/Ol/23747, the relevant portions of which are incorporated herein by
reference in their entireties,
radioopaque and/or radioisotopic materials, e.g., boron, iodine, etc.,
suppositories, and other diagnostic
or therapeutic agents or drugs.
[0269] An added ingredient may enhance stability of the polymer, compound
and/or composition
itself, the medical implant itself and/or may enhance the diagnostic or
therapeutic effect and/or may
enhance or enable diagnostic activity. For example, if the added ingredient is
a diagnostic or
therapeutic agent or drug, bioerosion would not only release the agents) but
also the diagnostic or
therapeutic agent(s). In another example, by adding a radioopaque material,
visualization of both the
targeted area e.g. tumor site, tumor, and the medical implant e.g. catheter
would be enabled during
and/or after, e.g. angioplasty, dental applications, joint injections, etc.,
insertion of the medical implant.
In another example, the radioopaque material may also be used to control
and/or enhance bioerosion of
the medical implant and thereby control and/or enhance generation of the
active agent by the
generation of heat resulting from neutron capture.
[0270] An added ingredient may also enhance the overall mechanical stability
of the medical implant,
e.g. carbon fibers. The type of additive used would vary and depend upon the
desired property and
application. In one embodiment, a medical device is coated with a therapeutic
co-polymer of two or
more monomers or more monomers that each independently have different linker
groups. In other
preferred embodiments, the medical device is coated with a therapeutic polymer
composition that is
comprised of at lease two therapeutic polymers that are mixed after
polymerization.
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[0271 ] The first and second active agents may be the same or different, and
in one embodiment, the
first and second agents may both be incorporated into the polymer backbone or
attached directly to it,
for example, through a linker or spacer, or by direct or indirect chemical
linkage to a chemical group
attached to the polymer backbone; or the second active agent may be dispersed
within the polymer
matrix or appended to the polymer, while the first active agent is
incorporated into the backbone of the
yn
l~i polymer or attached directly to the backbone, for example, through a
linker or spacer, or by direct or
indirect chemical linkage to a chemical group attached to the polymer
backbone; or the first and
second active agent may be dispersed, within the polymer matrix of the polymer
or appended to the
po ~ymer. The polymer may also comprise additional agents, such as a third
agent, a fourth agent, a
fift~ agent, and so on, where the additional agents are released by
degradation of the polymer. For
example, the additional agents) may be incorporated into the backbone of the
polymer or attached
directly to it, for example through a linker or spacer, or attached to the
backbone by direct or indirect
chemical linkage to the polymer backbone; or dispersed within the polymer
matrix of the polymer or
appended to the polymer as described herein, or otherwise annexed to or
associated with the polymer
such that the additional active agents dissociate from the polymer upon
hydrolysis:
[0272] Another preferred embodiment comprises a device having at least one
surface, the device
comprising more than one polymer on all or a part of the surface, such as
having first and second
polymers that may be the same or different. For example, in one embodiment the
polymer is coated on
a device such as a stmt or graft that experiences expansion, contraction or
torsion during the
application or its use. In the case of vascular stems, the polymer coating
might be used to reduce the
incidence of inflammation and resulting hyperproliferation of cells that
results in occlusion of the
vessel (restenosis). In one embodiment, the linking group is a dicarboxlyic
acid hydrocarbon chain
with eight carbon atoms. In another embodiment the medical device is a stent.
The stmt may be any
suitable stmt, such as those described herein. Suitable stems include, for
example, coronary vascular
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stems, peripheral vascular stents, urethral stems, biliary stems, stents used
for supporting the lumen of
other anatomical tubes, and stems used for other medical and veterinary
treatments. In one
embodiment, the medical device comprises a polymer comprising at least one
active agent, wherein the
active agent or agents are incorporated into the polymer backbone The stmt may
comprise additional
polymers and/or additional active agents, such as, e.g., a second active
agent, a third active agent, and
so on, where the additional active agents are, e.g., incorporated, attached,
appended or dispersed within
the polymer, as described herein, or otherwise annexed to or associated with
the polymer such that the
additional active agents dissociate from the polymer upon hydrolysis. The
stent may comprise active
agents that combine in vivo to form a new active agent or agents.
[0273] In one embodiment, an implantable stmt is coated with the therapeutic
polymer(s). The
implantable stmt may be made of many materials well known to those in the art,
including but not
limited to, electropolished 316L stainless steel and other metallic alloys as
well as polymeric materials.
In one embodiment, the polymer coating exhibits: 1 ) adequate wettability and
adhesiveness to the
surface of the stmt to be coated, 2) adequate flexibility when crimped onto a
balloon catheter,
maneuvered into position, and then expanded in position in the body, 3)
adequate hardness to avoid
premature removal of the coating or portions thereof or pitting or other
damage to the coating during
implantation of the stmt and thereafter (e.g., from handling, flow of blood or
other body fluids, or
movement of organs or the recipient's body), and 4) appropriate rates of
degradation, enabling
therapeutic drug levels to be maintained for predictable lengths of time
without causing toxicity locally
or systemically. For such a device used as a coronary, renal, or biliary stmt,
the preferred coating, or
set of coatings, applied to the stmt preferably has a thickness~from about 100
nm to about 100 ~,m; and
most preferably has a thickness of about 1, about 2, about 3.5, about 5, about
7.5, about 10 ~,m to about
12.5, about 15, about 20, about 24, about 26, about 28.5, about 30 Vim. For
stems used in other
medical or veterinary applications, coatings or sets of coatings preferably
have a thickness less than
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about 100 Vim. In another embodiment, the therapeutic polymer is used as a
coatings) for an
implantable orthopedic device, including hip, knee, shoulder, or elbow
replacements, fixation devices,
or devices for other orthopedic application.
[0274] In the case of orthopedic and dental implants such a coating could be
used to maintain bone
'° 'strength or induce bone penetration of the device to stabilize it
and/or to reduce pain and inflammation
ifs and/or to reduce infections. In one embodiment, the linking group is
preferably a dicarboxylic acid
hydrocarbon chain with four six, eight or ten carbon atoms. In one embodiment,
the medical devices
are orthopedic implants, including hip, knee; and shoulder implants, and
internal and external fixation
deices and spinal implants. These orthopedic devices may be made of many kinds
of materials well
kn~~wn to those in the art, including but not limited to, electropolished 316L
stainless steel and other
metallic alloys, inorganic ceramics including calcium phosphate and
hydroxyapatite, cadaveric bone
from humans and other animals, naturally-occurring and synthetic analogs of
bone, biodegradable and
non-degradable polymers (such as polymers of glycolic acid, lactic acid, and
caprolactone, and
copolymers thereof), and blends of the above materials.
[0275] In one embodiment, the orthopedic implants are coated with a
therapeutic polymer of the
invention such that the polymer coating that exhibits: 1 ) adequate
wettability and adhesiveness to the
surfaces of the implant to be coated, such that the coating wets and
penetrates into porous spaces
percolating to the exposed surfaces of the device, 2) adequate flexibility
when handled by the clinician,
maneuvered into position, and then interfaced to tissue in the body, 3)
adequate hardness to avoid
premature removal of the coating or portions thereof or pitting or other
damage to the coating during
' implantation and thereafter e.g. from handling, flow of blood or other body
fluids, or movement of
organs or the recipient's body, and 4) appropriate rates of degradation,
enabling therapeutic drug levels
to be maintained for predictable lengths of time without causing toxicity
locally or systemically.
C0lTll)OS1t10115 C0117171'1S111~ a polymer may be used to coat orthopedic
devices for fixation of bone
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fractures such as pins or screws, thereby decreasing the local inflammation
and bone resorption
associated with these devices.
[0276] Films comprising an aromatic polyanhydride are also believed to be
useful as orthopedic
devices to enhance the healing process of bone fractures. A polymer may be
coated or applied onto or
formed into sutures, wound closures, stitches, staples and other related
devices. In the case of sutures,
staples and other devices such a coating could be used to reduce infections,
pain and/or inflammation
in the vicinity of the suture or staple. Fibers made of the present
polyrner(s) are useful as suture
materials, and may be used in oral surgery to suture cleft palates. Use of a
polymer that degrades to an
active agent, such as a therapeutic salicylate, would enhance the regeneration
of the tissue via the
sutures while decreasing the pain and inflammation associated with the surgery
via the degradation
products. Films, membranes, pastes, gels, chips and microspheres comprising
the polymer may also be
used to decrease dental pain and promote healing within a tooth, in the pulp
chamber and root canal.
Films or membranes comprising a polymer may also be used in guided bone or
tissue regeneration.
[0277] In one embodiment, the polymers, compounds and/or compositions of the
invention may be
formed into micronized particles or micxoparticles, or nanoparticles e.g.
microspheres~ nanospheres,
nanocapsules and/or microcapsules. Microparticles of a polymer, compound
and/or composition of
the invention may be prepared by any means known in the art and may include
one or more of the
same or different polymer, compound and/or composition of the invention. For
example, the
microparticles may be prepared using an oil-in-water emulsion method whereby a
polymer of the
invention is dissolved in an organic solvent. The polymer solution may be then
added to a stirring
solution of water and polyvinyl alcohol (PVA) as a stabilizer to obtain the
precipitation of the desired
microparticles. Optionally, a homogenizer may be used. The solution may be
then allowed to settle,
the solvent decanted off the solution, and the microparticles dried. The
microparticles, such as, e.g.,
microspheres may be applied to the surface of a medical device before
placement in the body. A
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sterile liquid may be used to coat the device to adhere such microspheres for
minutes to weeks to
enable uncoated medical devices to benefit from the same or similar
therapeutic benefits as coated
devices. In one embodiment, the nanoparticles or microparticles are
typically.but not necessarily less
than about 10 nm or microns in diameter. In another oil-in-water emulsion
method, the polymer
solution is added to a solution of water and a surfactant such as PVA, which
is stirred rapidly at high
i~i
shear rates with, for example, a homogenizer or dispersator. After the
addition of the polymer
solution, the solvent is allowed to evaporate while stirring is continued. The
resulting microparticles
are recovered by decantation, filtration or centrifugation and dried.
[0~7~] Microparticles of the invention may also be prepared by known
microencapsulation processes,
e.g~ the process described by U.S. Patent 5,407,609, the relevant text of
which is incorporated herein
by reference. The patent describes a continuous microencapsulation process
whereby a polymer,
protein, peptide, small molecule, water-soluble, hydrophobic drug, and drugs
within a polymer may be
added to a mechanically agitated water/surfactant mixture to form a
microdroplet emulsion. Water is
then employed to extract or remove the solvent, and form hardened
microcapsules or microspheres that
are collected by centrifugation, filtration or the like. In accordance with
this continuous
microencapsulation processmolecules such as nucleic acids, saccharides,lipids,
proteins, peptides,
small molecules, water-soluble drugs, hydrophobic drugs, and drugs may be
encapsulated in
lactide/glycolide polymers to sizes of about l, 2, 5, 10, 15 to up to about
10, 50, 75, 100, 150, 200, 250
~.m, with minimal exposure to polymer solvent and with high encapsulation
efficiency and good
yields.
[0279] Having now generally described this invention, the same will be better
understood by reference
~to certain specific examples, which are included herein for purposes of
illustration only and are not
intended to be limiting of the invention or any embodiment thereof, unless so
specified. While the
present invention may he emt~odied in many different forms. several specific
embodiments are
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discussed herein with the understanding that the present disclosure is to be
considered only as an
exemplification of the principles of the invention, and it is not intended to
limit the invention to the
embodiments illustrated.
EXAMPLES
[0280] The following abbreviations are employed throughout the examples: BPC
(bupivacaine), D
(drug), L (linker), DCM (dichloromethane), DF. (diflunisal), MPA (mycophenolic
acid), MTX
(methotrexate), PAC (paclitaxel), SA (salicylic acid), TEA (triethylamine),
TFA (trifluoroacetic acid),
THF (tetrahydrofuran), TP (triphosgene).
[0281 ] All solvents and reagents employed in the following examples were
purchased and used as
received. Proton nuclear magnetic resonance ('H NMR) spectra were recorded on
a Varian 300 MHz
Mercury VX-300 spectrometer using an appropriate deuterated solvent. Chemical
shifts (8) are
reported in parts per million (ppm) downfield from tetramethylsilane (TMS) and
coupling. constants (J
values) are given in hertz (Hz). Molecular weights (MW) and polydispersity
indices (PDI) were
determined by gel permeation chromatography (GPC) on a Viscotek TDA 301 system
consisting of a
refractive index detector and a Viscotek VE1122 pump using Omnisec software
for data collection and
processing. Molecular weights were calibrated relative to a narrow molecular
weight polystyrene
standard (Viscotek, Houston, TX). The HPLC impurity profile is performed on an
Agilent Rapid
Phase Cl 8 column 4.6 X 70 mm column with a flow rate of 1.8 mllmin and a
gradient of 6%/min of
mobile phase B (0.1 % (v/v) TFA in acetonitrile) in mobile phase A (0.1 %
(v/v) TFA in water). The
gradient runs on an ambient column with a VWD at 225 nm.
Example 1: General Procedure for Preparation of.Linker-Diacid Chloride (12)
[0282] 0.48 mol oxalyl chloride was added to a mixture of 0.16 mol diacid
(Compound 11 ) in 320 ml
anhydrous chloroform, and the mixture stirred overnight at room temperature,
gently refluxed for 1
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hour, and cooled to room temperature. The solvent was then removed in vacuo,
and the residue dried in
vacuo at 45°C to obtain the product.
Example 2: Preparation of C14 Diacid Chloride (Compound 12a )
[0283] 1,12-Dodecanedicarboxylic acid (Compound 1 la) was subjected to the
conditions described in
'~~~ 'Example 1.
Results:
[0284] Yield C 14 Diacid Chloride: 99%
[0?~85] The structure of the product was confirmed by IH NMR.
Example 3: Preparation of C16 Diacid Chloride (Compound 12b)
[0286] 1,16-Hexadecanedioic acid (Compound l lb) was subjected to the
conditions shown in
Example 1:
Results:
[0287] Yield C 16 Diacid Chloride: 99%.
[0288] The structure of the product was confirmed by'H NMR.
Examule 4: General Procedure for Preparation of D-L-D Aromatic Diacids
(Compound 14)
[0289] 1.0 mol pyridine was added to a solution of 0.325 mol of compound 13 in
800 ml anhydrous
THF, and then 125 ml solution of 0.16 mol linker diacid chloride in anhydrous
THF was added
dropwise. The reaction mixture was stirred for 45 minutes, and poured into an
80 ml solution of HCl
(cone) maintained in 2.4 ice-cold water. The mixture was stirred for 1 hr, and
the solid produced was
isolated by decanting then supernate, and washing the solid with 1 cold water.
The crude solid
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product was washed with cold water, filtered, and dried in a vacuum oven at
45°C overnight, and the
dried solid was purified twice from 3:1 (v:v) hexane-ethyl acetate.
Example 5: Preparation of Salicylic Acid-C8-Salicylic Acid (SA-C8-SA; Compound
14a)
[0290] The diacid was prepared from SA and suberoyl chloride using the general
procedure given in
Example 4. The structure of the product was confirmed by 1H NMR.
Example 6: Preparation of Salicylic Acid-C10-Salicylic Acid (SA-C10-SA;
Compound 14b)
[0291 ] The diacid was prepared from SA and sebacoyl chloride employing the
procedure described in
example 4 above.
Results:
[0292] Yield SA-C10-SA: 97%.
[0293] The structure of the product was confirmed by'H NMR.
Example 7:. Preparation of Diflunisal-C12-Dillunisal (DF-C12-DF; Compound 14c)
[0294] The diacid was prepared from DF and 1,10-decane dicarboxylic acid
chloride using the general
procedure provided in Example 4 above. The structure of the product was
confirmed by'H NMR.
Example 8: Preparation of Diflunisal-C14-Diflunisal Diacid (DF-C14-DF;
Compound 14d)
[0295] The diacid was prepared from diflunisal (DF) and 1,12-dodecane
dicarboxylic acid dichloride
(Compound 12a) at 99% yield using the general procedure given in Example 4.
Results:
[0296] Yield DF-C14-DF: 99%.
[0297] The structure of the product was confirmed by'H NMR.
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PMX-0229 180 6!4/2004
Example 9: Preparation of Diflunisal-C16-Diflunisal Diacid (DF-C16-DF;
Compound 14e)
[0298] The diacid was prepared from DF and 1,16-hexadecanedioic acid
dichloride (Compound 12b)
using the general procedure given in Example 4. The structure of the product
was confirmed by IH
NMR.
~'" 'Example 10: General Procedure for Preparation of D-L-D Diacid Chloride
(Compound 15)
[0299] 106.6 mol oxalyl chloride were added to a solution of 34.59 mol D-L-D
diacid in 200 ml
anhydrous chloroform, and the reaction mixture was refluxed gently for three
hours. The clear
reaction solution was concentrated in~vacuo, and the residue recrystallized in
1:1 (v:v) anhydrous
DAM-heptane to obtain a white solid. The solid was filtered and washed with
heptane to obtain the
product.
Example 11: Preparation of Salicylic Acid-C8-Salicylic Acid Diacid Chloride
(SA-C8-SA Diacid
Chloride; Compound 15a)
[0300] The diacid chloride was prepared from SA-C8-SA diacid using the general
procedure shown in
Example 10 above.
[0301] The structure of the product was confirmed by IH NMR.
Example 12: Preparation of Salicylic Acid-C10-Salicylic Acid Diacid Chloride
(SA-C10-SA
Diacid Chloride; Compound 15b)
[0302] The diacid chloride was prepared from SA-C10-SA diacid using the
general procedure given in '
Example 10 above.
' [0303] The structure of the product was confirmed by'H NMR.
Example 13: Preparation of Diflunisal-C12-Diflunisal Diacid Chloride (DF-C12-
DF Diacid
Chloride; Compound l5c)
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181
[0304] The diacid chloride was prepared from DF-C12-DF diacid employing the
procedure provided
in Example 10 above.
[0305] The structure of the product was confirmed by 1H NMR.
Example 14: Preparation of Diflunisal-C14-Diflunisal Diacid Chloride (DF-C14-
DF Diacid
Chloride; Compound 15d)
[0306] The diacid chloride was prepared from DF-C14-DF diacid in 99% yield
using the general
procedure given in Example 10.
[0307] The structure of the product was confirmed by ~H NMR.
Ex~mple 15: General Procedure for Preparation of D-D-L-D-D Diacid (Compound
16)
[0308] 0.189 mol anhydrous pyridine was added to a solution of 0.077 mol
Compound 13 in 150 ml
anhydrous THF, the mixture was stirred for 5 minutes, and a solution of 0.035
mol D-L-D diacid
chloride in 150 ml anhydrous THF was added drop-wise. The reaction mixture was
stirred for 30
minutes at room temperature, and was poured into a mixture of 180 ml cold
water and 20 ml HCl
(cone). The mixture was extracted three times with 150 ml ethyl acetate, and
the combined organic
layer was washed twice with 100 ml water and 100 ml brine, and was dried over
anhydrous sodium
sulfate. The solvent was removed in vacuo, and the residue was purified twice
from 1:1 (v:v) ethyl
ether-pentane to obtain the product.
Examule 16: Preparation of Salicylic Acid-Salicylic Acid-C8-Salicylic Acid-
Salicylic Acid Diacid (SA-SA-C8-SA-SA Diacid; Compound 16a)
[0309] The diacid was prepared from SA and SA-C8-SA diacid chloride (Compound
1 Sa) employing
the general procedure given in Example 15.
~0:~ 10] Yield: ~5%
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[0311] The structure of the product was confirmed by ~H NMR.
Example 17: Preparation of Diflunisal-Diflunisal-C14-Diflunisal-Diflunisal
Diacid
(DF-DF-C14-DF-DF Diacid; Compound 16d)
[0312] The diacid was prepared from DF and DF-C14-DF diacid chloride (Compound
15d) employing
yn ,
the procedure described in Example 15 above.
Results:
[0313] Yield: 95%
[0314] The structure of the product was confirmed by 1H NMR.
Example 18: Preparation of C6 bis-L-Lactate Diol (Compound 19a)
[0315] 33.60 g 1,6-dibromo hexane (Compound 18a; 0.15 mol) was added to a
solution of 33.62 g
sodium L-lactate (Compound 17a; 0.3 mol) in 60 ml anhydrous DMF, and the
mixture was heated at
60°C for 3 days. The reaction mixture was cooled to room temperature
and poured into 500 ml cold
water, acidified to about pH 4 with 1N HCI, and extracted 4 times with 75 ml
ethyl acetate. The
organic layers were combined and washed with water, dried over anhydrous
sodium sulfate, and the
solvent removed in vacuo to obtain a slightly brownish oily product. The
product was filtered over
silica gel with 1:1 (v:v) ethyl acetate-hexane. Thirty-two g of pure product
were obtained.
[0316] The structure of the product was confirmed by'H NMR.
Example 19: Preparation of C10-bis-L-Lactate.Diol (Compound 19b)
[0317] 25.0 g 1,10-diiododecane (Compound 18b) was dissolved in 7 ml DCM, and
the solution added
to 120 g tetrabutylammonium-L-lactate (Compound 17b). The reaction mixture was
placed in a 40°C
rotary evaporator bath, and rotated at top speed for 20 hours. The solution
was then diluted with
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1 uuml dichloromethane, anct washeet mth 100 ml water. 750 ml diethyl ether
were placed into a 2-liter
Erlenmeyer flask and stirred magnetically. The lower organic phase from the
separatory funnel was
dripped into the diethyl ether with stirring until a precipitate appeared. The
precipitated salt
(tetrabutylammonium iodide) was vacuum-filtered through a medium porosity
frit, and the filtrate was
collected in a 1-liter round-bottom flask and washed once with 400 ml 1.25%
sodium thiosulfate in
water, and twice with 400 ml water. The ether layer was dried over anhydrous
magnesium sulfate and
'" the solvent was removed in vacuo to produce 15.5 g of the product.
[0318] The structure of the product was confirmed by ~H.NMR.
Example 20: Preparation of C8 bis-L-Lactate Diol (Compound 19c)
[0319] The diol was prepared from 1,8-dibromoooctane (Compound 18c) and
Compound 17a,
employing the same conditions given in Example 18.
[0320] The structure of the product was confirmed by ~ H NMR.
Examule 21: Preparation of C6 bis-D,L-Lactate.Diol (Compound 19d)
[0321 ] The diol was prepared from Compound 18a and lithium D,L-lactate
(Compound 17c)
employing the same conditions given in Example 18.
[0322] The structure of the product was confirmed by'H NMR.
Example 22: Preparation of C8-bis-Glycolate Diol (Compound 21a)
[0323] 4.2 ml triethyl amine (30 mmol) were added to a solution of 2.28 g
glycolic acid (Compound
20a; 30 mmol) in 10 ml anhydrous DMF. The mixture was stirred for 5 minutes at
60°C, 4.08 g 1,8-
dibromoocatane (Compound 18b; 15 mmol) was added, and the reaction mixture was
stirred at 60°C
for 24 hours and then cooled to room temperature, poured into 75 ml cold
water, and acidified to about
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pH 4 with 1N HCI. A white precipate that appeared was filtered and dried to
obtain 2.8 g of the
product.
[0324] The structure of the product was confirmed by 1H NMR.
Example 23: Preparation of C8 Salicylic Acid Polymer (Compound 23a)
;n
by Non-aqueous Dispersion Method with Dispersing Agent
[0325] A 50 ml reaction vessel fitted with a 3-neck flanged lid; carrying a
sealed Teflon paddle stirrer,
a rubber septum over one side neck, and a short Vigreux distillation column
and receiver flask, was
cooled in a dry ice bath. Fifty ml light white mineral oil, 8.60 g suberoyl
bis-salicylic acid-acetic acid
I
mixed anhydride (Compound 22), and 0.26 g polyvinylpyrrolidone/eicosane co-
polymer (ISP Corp.,
Antaron 220) as dispersing agent were added to the reaction vessel, and the
mixture was briskly mixed.
A slow stream of Argon gas was passed through the stirred mixture as a sparge,
and the mixture was
heated to 120°C in an oil bath and maintained in these conditions under
Argon for 30 minutes. The
vessel was then slowly placed under vacuum at 120-140°C with constant
vigorous stirring to a final
vacuum of 2.0 mTorr, and the oil was refluxed halfway in a Vigreux column. The
reaction was
allowed to proceed for 6 hours, then allowed to cool to 70°C under
vacuum with stirring while the
volatile products, e.g., acetic anhydride, were collected in a chilled
receiver flask. The vacuum was
then released with Argon, and the vessel cooled to room temperature. The
reaction mixture was
diluted with anhydrous petroleum ether, and centrifuged for 30 minutes to
collect the product. The
supernate was removed, and the residual solid was washed 3 times with dry
petroleum ether, and dried
a
at 40 C in a vacuum oven for several hours to obtain 4.38 g of the product.
Results:
[0326] Yield: 64%
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[0327] MW=51,000 Dalton, as determined by GPC as compared with a limiting
14,000 Dalton MW
obtained by standard bulk-melt polymerization.
[0328] Polymer particles were amorphous, clear, and formed perfectly spherical
S to 50~, diameter
particles as determined in a low power optical microscope.
Example 24: Preparation of C14 Diflunisal Polyanhydrides (Compound 23b)
' by Non-aqueous Dispersion Method without Dispersing Agent
[0329] A SO ml reaction vessel fitted with. a 3-neck flanged lid, in turn
carrying a sealed Teflon paddle
stirrer, a rubber septum over one side neck and a short Vigreux distillation
column and receiver flask,
was cooled in a dry ice bath, and was charged with SO mL of light white
mineral oil, 8.54 g of bis (2-
car ~b' oxy-4-(2,4-difluorophenyl) tetradecane dicarboxylate=acetic acid mixed
anhydride (22b). The
reactor was evacuated to 40 mTorr, and heated'to 110°C for 1 hour with
constant vigorous stirring.
The temperature was increased to 160°C and held for the duration of the
reaction. A final vacuum of
30 mTorr was achieved, and the oil was refluxed part of the way up ~ Vigreux
column. The volatile
reaction products, e.g. acetic anhydride, were collected in a chilled receiver
flask. The reaction was
allowed to proceed overnight and was cooled to room temperature under vacuum
with stirring. The
solution consisted of a polymer mass on the bottom of the reactor, and oil
above the solids. The oil
was decanted off and the residue was washed with petroleum ether twice. The
residue was dissolved
in anhydrous DCM, and a white precipitate was obtained by precipitation into
anhydrous ethyl ether.
The white precipitate was dried at 40 °C under vacuum to give the
product as a solid (S.6 g).
Results:
[0330] Yield: 7S%
[0331 ] M,N 405,000
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[0332] PDI=1.75
Examule 25: Preparation of High Molecular Weight Poly (Sebacic Anhydride)
(Compound 24a)
[0333] 27.8 ml anhydrous TEA were added to a solution of 20.226 g sebacic acid
in 100 ml anhydrous
''~~ 'chloroform, and the mixture was cooled to 0°C in an ice bath. A
solution of 9.892 g triphosgene in 25
ml anhydrous chloroform was added very slowly to the reaction mixture at
0°C with vigorous stirring.
The reaction mixture was then warmed up to room temperature and mildly
refluxed for 3 hours. The
ice-water bath was removed and replaced with a heating mantle while a flow of
Argon gas and stirring
w~~ maintained, and the flask contents were heated to boiling point until the
contents became
homogeneous and viscous. To reduce the viscosity of the thin layer of
undissolved polymer that
remained at the bottom of the flask, 250 ml anhydrous chloroform were added,
and the system was .
heated to near the solvent's boiling point with stirring under Argon gas until
the flask's contents
completely dissolved. A sample of the polyiner~solution was removed from the
flask, and a
conventional calibration was performed with GPC using narrow polydispersity
polystyrene standards.
Results:
[0334] MW=626,000
[0335] PDI=1.79 .
Example 26: Preparation of Poly Diflunisal-C14-Diflunisal Ester Anhydride
(DF-C14-DF Ester Anhydride; Compound 25a)
[0336] 7.70 ml anhydrous TEA were added to a solution of 20.000 g DF-C14-DF
diacid (Compound
14d) in 80 ml anhydrous chloroform at 0°C, the solution was stirred for
30 minutes, and a solution of
2.750 g triphosgene in 20 ml anhydrous chloroform was added drop-wise. The
reaction mixture was
stirred at 0°C for 30 minutes, diluted with 40 ml chloroform, and
washed once with 100 ml 1N NCI,
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and once with 100 ml distilled water. The organic layer was dried over
anhydrous magnesium sulfate,
and the solvent was removed in vacuo. The residue was dissolved in DCM and
poured into diethyl
ether in a Teflon beaker with stirring to precipitate the product. The
supernate was decanted, and the
residue washed with additional ether before drying in a vacuum oven at
45°C overnight to obtain 10.7
g of the product.
Results:
:,,i
''
[0337] Mw 176,000
[0338] PDI=1.85
Examule 27: Preparation of Poly Salicylic Acid-C8-Salicylic Acid Ester
Anhydride
(SA-C8-SA Ester Anhydride (Compound 25b)
[0339] This polymer was prepared from SA-C8-SA diacid (14a) using the same
conditions given in
Example 24 above. ,
Results:
[0340] MW=121,000
[0341] PDI=1.73
Example 28: Preparation of Poly Salicylic Acid-C8-Salicylic Acid Ester
Anhydride
(SA-C8-SA ester Anhydride; Compound 25c)
[0342] The polymer was prepared from SA-C 10-SA diacid (14b) using the same
conditions given in
Example 24 above.
,Results:
[0343] MW=I 10,000
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[0344] PDI=1.61
[0345] The structure of the product was confirmed by 1H NMR.
Example 29: Preparation of Mixed Random Poly Anhydride of
SA-C8-SA and SA-SA-C8-SA-SA (Compound 26a)
[0346] 8.7 ml anhydrous TEA (61.6 mmol) were added to a solution of 8.7 g SA-
C8-SA diacid
(Compound 14a; 21 mmol) and 4.58 g SA-SA-C8-SA-SA diacid (Compound 16a) (7
mmol) in 70 ml
anhydrous DCM at 0°C, and the solution was stirred for 30 minutes. A
solution of 2.8 g triphosgene
(9.34 mmol) in 20 ml anhydrous DCM was added drop-wise to the mixture at
0°C, stirred for 1 hour at
0°C, diluted with 25 ml DCM, washed once with 25 ml 1N HCl and twice
with 100 ml distilled water,
and dried over anhydrous magnesium sulfate. The solution was concentrated in
vacuo to about 75 ml,
and the was product precipitated by pouring the solution into anhydrous
diethyl ether in a Teflon
cylinder while stirnng. The thus obtained solid was washed with diethyl ether
and dried in a vacuum
oven at 40°C overnight to obtain 10.0 g of the product.
Results:
[0347] MW=110,000
[0348] PDI=1.24
Examule 30: Preparation of Mixed Random Poly Anhydride of
DF-C14-DF and DF-DF-C14-DF-DF (Compound 26b)
[0349] 21 mmol DF-C 14-DF diacid (Compound 14d) and 7 mmol DF-DF-C 14-DF-DF
diacid
(Compound 16d) were employed as described in Example 27 to obtain 25.2 g of
the product.
Results:
[0350] MW=163,000
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WO 2005/042600 PCT/US2004/017916
~u~~y rlJi=i.3~
[0352] The structure of the product was confirmed by'H NMR.
[0353] Example 31: Preparation of Mixed Random Poly Anhydride of DF-C16-DF and
DF-DF-C14-
DF-DF (Compound 26c)
[0354] 42.5 mmol DF-C16-DF diacid (Compound 14e) and 7.5 mmol DF-DF-C14-DF-DF
(DF-DF-
C14-DF-DF diacid; compound 16d) were subjected to the conditions described in
Example 27 above to
obtain 30 g of product.
[0355] Results:
[03r56] MW=168,000
[0357] PDI=3.1
[0358] Example 32: Preparation of Random Poly Diflunisal-C 14-Diflunisal-coDF
Anhydride (DF-
C 14-DF-coDF Anhydride; Compound 27a)
[0359] A solution of 6.579 g DF and 7.35 ml TEA in 20.0 ml anhydrous
chloroform was slowly added
to a solution of 10.000 g compound 15d and 3.895 g compound 12b in 80 ml
anhydrous chloroform at
0°C ~ 4°C. The reaction mixture was stirred for 1 hour at
0~4°C, and washed with 100 ml 1N HCI,
and 100 ml distilled water. The organic layer was dried over anhydrous
magnesium sulfate, the
solvent was removed in vacuo, and then the solid was dried in a vacuum oven at
40°C overnight.
Fifteen g of the dried polymer were redissolved in 70 ml anhydrous chloroform
and 0.625 ml TEA was
added to the solution at 0°C. The reaction solution was stirred for 1
hour, and a solution of 87.2 mg
triphosgene in 2.0 ml anhydrous chloroform at 0°C was slowly added. The
reaction mixture was
stirred for l hour at 0~4°C, and was washed with 100 ml 1N NCl and l 00
ml distilled water. The
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organic layer was dried-over'ai~Yiydrou's "s'oc'lium sulfate, and the solvent
was removed in vacuo at 40°C.
The crude polymer was dissolved in 120 ml DCM, and then slowly added to 1.21
anhydrous diethyl
ether that was placed in a Teflon cylinder while stirnng vigorously. The
supernate was decanted, and
the residue was washed with anhydrous ethyl ether. The thus obtained gummy
polymer was
;ii transferred into a Teflon dish and dried in a vacuum oven at 40°C
for 24 hours to obtain 11.4 g of
product.
[0360] Results:
[0361] MW=149,000
[0362] PDI=2.36
[0363] Example 33: Preparation of Random Poly Salicylic Acid-C8-Salicylic Acid-
coSalicylic Acid
Anhydride (SA-C8-SA-co-SA Anhydride; Compound 27b)
[0364] The polymer was prepared from SA-C8-SA diacid (Compound 14a), suberoyl
chloride, and SA
using the same conditions shown in Example 30 above.
[0365] Results:
[0366] MW=79,000
[0367] PDI=2.66
[0368] Example 34: Preparation of Random Poly (DF-C14-DF-coDF) Anhydride
(Compound 27c)
[0369] A mixture of 3.971 g DF and 4.64 ml TEA in 18 ml anhydrous DCM was
added dropwise to a
solution of 10.000 g of DF-C 14-DF diacid chloride (Compound I Sd) in 30 ml
anhydrous DCM at 5
°C, and the reaction mixture vas stirred for 30 minutes at 5°C.
The mixture was then diluted with 40
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ml DCM, washed with 100 ml 1N HCl and 100 ml distilled water, and dried over
anhydrous
magnesium sulfate. The solution was concentrated to about 50 ml in vacuo, and
was poured into
anhydrous diethyl ether in a Teflon cylinder with stirnng to precipitate the
product. The supernate was
decanted, and the solid was washed with ethyl ether, and dried in a vacuum
oven at 40°C overnight to
obtain 9.3 g of the product.
[0370] Results:
[0371] MW=106,000
[0372] PDI=1.88
[0313] Example 35: Preparation of Random Poly (DF-C14-DF co-Mycophenolic acid)
Anhydride
(Compound 27d)
[0374] Compound 27c was prepared from DF-C14-DF diacid (Compound 15d) and MPA
using the,
conditions shown in Example 32 above.
Example 36: Preparation of Random Poly (DF-C14-DF c0-Methotrexate) Anhydride
(Compound 27e)
[0375] Compound 27e was prepared from DF-C14-DF diacid and MTX using the same
conditions
given in Example 32.
Example 37: Preparation of Random Poly (DF-C12-DF co-Diflunisal) Anhydride
(Compound
28a)
[0376] A solution of 2.755 g C10-bis-L-lactate diol (Compound 19b) and 3.623
ml anhydrous TEA in
25 ml anhydrous THF was added to 19.00 g of a solution of DF-C 12-DF diacid
chloride (Compound
15c) in 125 ml anhydrous THF. The reaction mixture was stirred for 12 hours at
30°C, concentrated in
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vacuo, co-evaporated twice~with 200 ml additional chloroform, and dried in a
vacuum oven at 30°C
overnight. The dried intermediate (prepolymer) was re-dissolved in 100 ml
anhydrous chloroform, and
was cooled to 0°C in an ice bath. A mixture of 3.466 g DF and 4.058 ml
anhydrous TEA was made in
100 ml anhydrous chlofororm, and was slowly added to the pre-polymer solution
at 0°C. The reaction
mixture was stirred for 1 hour at 0°C, washed with 200 ml 1N HCl and
200 ml distilled water, dried
over anhydrous magnesium sulfate, concentrated in vacuo, and dried in a vacuum
oven at 40°C
overnight. 0.317 ml anhydrous TEA were added to a solution of 21.6 g
intermediate prepolyrner in
140 ml DCM, and a solution of 111 mg triphosgene in 5.0 ml anhydrous
chlofororm was added
dropwise at 0°C. The reaction mixture was stirred at 0°C for 1
hour, diluted with 40 ml chloroform,
washed with 100 ml 1N HCl and twice with 500 ml distilled water, and dried
over anhydrous MgS04.
The solution was concentrated in vacuo to about 50 ml, and poured into
anhydrous diethyl ether in a
Teflon cylinder with stirring to precipitate the product. The supernate was
decanted, and the solid 'was
washed with ethyl ether, and dried in a vacuum .oven at 40°C overnight
to yield 13.3 g of product.
Results:
[0377] MW=120,000
[0378] PDI=1.35
Example 3~: Preparation of Random Poly (Tetradecanedioic Acid-bis-Diflunisal
Phenolate.DF-
C14-DF-co-C10-bis-Lactate-co-DF) Anhydride
(Compound 28b)
[0379] A random tetradecanedioic acid-bis-diflunisal phenolate ester-co-
decanediol-bis-L-lactate-co-
diflunisal anhydride polymer (Compound 28b) was prepared from (DF), DF-C14-DF
diacid chloride
(Compound 15d), and C10-bis-lactate diol (Compound 19b) employing the
conditions given in
Example 35 above. '
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Results:
[0380] MW=89,000
[0381] PDI=1.29
Example 39: Preparation of Random Poly (DF-C14-DF-co-C8-bis-Lactate-co-DF)
Anhydride
(Compound 28c)
v;4i
[0382] A random tetradecanedioic acid-bis-diflunisal phenolate ester-co-
octanediol-bis-L-lactate-co-
diflunisal anhydride polymer (Compound 28c) was prepared from DF-DF-C14-DF
diacid chloride
(Compound 15d), and C8-dilactate diol (Compound 19c) using the conditions
shown in Example 35
above.
Results:
[0383] MW=63,000
[0384] PDI=1.46
Examule 40: Preparation of 1,3-Propanediyl Bissalicylate (Compound 29a)
[0385] 13.94 ml TEA (100 mmol) were added to a solution of 13.81 g salicylic
acid (SA; 100 mmol)
in 40 ml DMF at 60°C, the reaction mixture was stiired for 20 minutes
at 60°C, and 12.2 g 1,3-
dibromo propane (Compound 18d; 50 mmol) were added. The reaction mixture was
stirred at 60°C for
24 hours, cooled to room temperature, poured into 250 ml cold water, and
acidified to about pH 4 with
1N HCI. A white precipitate separated. The precipitate was filtered, washed
with water, and dried in a
vacuum oven at 40°C overnight. The thus obtained crude product was
recrystallized from n-heptane to
obtain a pure product.
Results:
[0386] Yield: 85 %
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Example 41: Preparatiomof a Poly (SA-C6-SA) Carbonate (Compound 30a)
[0387] 2.09 ml TEA (15 mmol) and 0.18 g DMAP were added to a solution of 1.89
g Compound 29a
(6 mmol) in 30 ml anhydrous DCM at 0°C. The reaction mixture was
stirred for 10 minutes and
20wt% toluene solution containing 3.18 ml phosgene (6 mmol) in.5m1 anhydrous
DCM was added
drop-wise. The mixture was warmed to room temperature, stirred for 3 hours,
and diluted with 30 ml
.;n
DCM. The solution was washed with 20 ml 1N HCI, washed three times with 25 ml
water, and was
dried over anhydrous sodium sulfate, and concentrated in vacuo. The polymer
residue was redissolved
in 10 ml anhydrous DCM, and was added to 150 ml anhydrous ether with stirring
until an insoluble
polycarbonate separated. The polymer was washed with ethyl ether and dried in
a vacuum oven at
40°C to obtain 1.3 g of the product.
Results:
[0388] MW=73,643
[0389] PDI=1.85
Example 42: Preparation of a Poly (SA-C6-SA-co-diacid) Ester (Compound 31a)
[0390] 0.42 ml TEA (3 mmol) and 10 mg DMAP were added to a solution of 0.316 g
Compound 29a
(1 mmol) in 5 ml anhydrous DCM at 0°C. The reaction mixture was stirred
for 10 minutes, and 0.23.9
g sebacoyl chloride (1 mmol) in 2 ml anhydrous DCM was added thereto. The
mixture was then
warmed to room temperature, stirred for 3 hours, and diluted with 20 ml DCM.
The solution was then
washed with 20 ml 1N HCI, three times with 25 ml water, dried over anhydrous
sodium sulfate, and
concentrated in vacuo to produce 0.4g of the product.
Results:
[0391] MW=25,293
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[0392] PDI=1.6
Examine 43: Preparation of a Poly (DF-C8-DF co-C8-bis-Glycolate) Ester
(Compound 32a)
[0393] 0.7 ml anhydrous TEA (5 mmol) were added to a solution of 0.53 g bis-
glycolate diol
(Compound 21a; 2 mmol) in 10 ml anhydrous DCM at 0°C. A solution of
2.70 g DF-C8-DF diacid
chloride (Compound 15f; 4 mmol) in 15 ml anhydrous DCM was prepared, and added
drop-wise to the
'~n
reaction mixture. The mixture was allowed to warm to room temperature, and
maintained at this
temperature with stirring for 4 hours. The reaction solution was diluted with
25 ml DCM, washed
once with 20 ml 1N HCI, twice with 20 ml distilled water, and was then dried
over anhydrous
m ~gnesium sulfate, filtered, and concentrated in vacuo to about 5 ml. The
polymer solution was
poured into 40 ml anhydrous diethyl ether in a 1 liter Teflon cylinder while
stirring with a magnetic stir
bar to precipitate the product. The supernate was decanted and the remaining
was solid rinsed with
anhydrous diethyl ether and dried in a vacuum oven at 40°C overnight to
yield 1.8 g of the product'.
Results:
[0394] MW=8,349
[0395] PDI=1.33
Examule 44: Preparation of a Poly (DF-C10-DF co-C8-bis-D,L-Lactate Ester)
(Compound
32b)
[0396] Compound 32b was prepared from Compound 19c and Compound 15e employing
the
procedures described in Example 43.
Results:
[0397] MW=42,785
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[0398] PDI=1.68
[0399] The structure of the product was confirmed by 1H NMR.
Example 45: Preparation of a Branched Poly (DF-C14-DF) Anhydride with 1, 3, 5-
Benzene
Tricarboxylic Acid (Compound 34a)
[0400] 3.2 ml anhydrous TEA were added slowly to a mixture of 6.86 g (9.5
mmol) DF-C 14-DF
diacid (14d) and 0.106 g (0.5 mmol) 1,3,5-benzenetricarboxylic acid (Compound
33) in 40 ml
anhydrous DCM at 0°C. A solution of 0.99 g triphosgene in 25.0 ml
anhydrous DCM was then added
into the reaction flask in a slow drop-wise manner at 0°C, and the
reaction was stirred for 1.5 hours at
0~4°C under Argon. The reaction mixture was diluted with anhydrous 50
ml DCM, and washed once
with 50 ml 1N HCl and twice with 50 ml distilled water, dried over anhydrous
magnesium sulfate,
filtered, and concentrated in vacuo to about 20 ml. The polymer solution was
then poured into
anhydrous 500 ml diethyl ether contained in a 1 Teflon cylinder while stirnng
with a magnetic stir bar
to precipitate the product. The supernate was decanted, and the solid was
rinsed with anhydrous
diethyl ether, and dried in a vacuum oven at 40°C overnight to obtain
4.0 g of the product as a solid.
Results:
[0401] MW=223,000
[0402] PDI=4.2
Examine 46: Preparation of a Branched Poly (DF-C14-DF) Anhydride with 1, 2, 3,
4-Butane
Tetracarboxylic Acid (Compound 36a)
' [0403] Compound 36a was prepared from DF-C14-DF diacid (Compound 14d) and
1,2,3,4-
butanetetracarboxylic acid (Compound 35) using the conditions described in
Example 42 above.
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Example 47: Preparation of a Branched Polymer using trans-Aconitic Acid
(Compound 38a)
[0404] Compound 38a was prepared from DF-C14-DF diacid (Compound 14d), and
trans-aconitic acid
(Compound 37) employing the conditions shown in Example 42 above.
Example 48: Preparation of a Random Block Polyanhydride (Compound 39)
[0405] 0.256 ml anhydrous TEA was added drop-wise to a solution of 10.83 g
Compound 26b
;~, ,(Mn 51,000; 0.21 mmol)) and 5.00 g of Compound 25c (Mn 22,000; 0.23 mmol)
in 70 ml anhydrous
DCM at 0°C. The reaction mixture was stirred for 30 minutes, and a
solution of 76.4 mg triphosgene
(0.26 mmol) in 10 ml DCM was added drop-wise in an ice water bath. The
resulting reaction mixture
was stirred for 30 minutes at 0°C~ and diluted with 70 ml DCM. The
solution was washed once with
15~ ml 1N HCI, and twice with 50 ml of water, and dried over anhydrous MgS04.
The solution was
concentrated in vacuo to about 50 ml, and poured into anhydrous ethyl ether
placed in a Teflon
cylinder to precipitate the product. The solid was washed with anhydrous ethyl
ether and dried in a
vacuum oven at 40°C overnight to obtain 12.2 g of the product.
Results:
[0406] MW=112,000
[0407] PDI=1.53
Example 49: Preparation of Alternating Block Thermoplastic Elastomeric
Polyanhydride
(Compound 40)
[0408] A solution of 0.921 g of Compound 25c (Mp 96,000) and 3.2 ~,1 TEA in 19
ml anhydrous
chloroform was slowly added to a solution of 7.29 mg Compound 1 Sd in 20 ml
anhydrous chloroform.
The mixture was stirred for 30 minutes, and then was slowly added to
a.solution of 1.2 g of Compound
26b and 6.4 ~,1 anhydrous TEA in 20 nil anhydrous chloroform. The reaction
mixture.was stirred at
room temperature for 17 hours, diluted v~ith 20 ml chloroform. washed v~ith 25
ml IN HC1 and then
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with 25 ml distilled water, and was dried over anhydrous magnesium sulfate.
The dried solution was
concentrated in vacuo to about 10 ml, and poured into anhydrous ethyl ether in
Teflon cylinder to
precipitate the polymer. The solid was washed with ethyl ether and dried in
the vacuum oven at 40°C
overnight to obtain 1.8 g of the product.
'~~~ 'Results:
[0409] MW=167,000
[0410] PDI=1.27
Example 50: Preparation of a Triblock Thermoplastic Elastomeric Polyanhydride
(Compound 42)
[0411] A solution of 2.849 g Compound 25c (Mn 30,000; 0.095 mmol) and 0.0477
ml anhydrous TEA
(0.34 mmol) in 30 ml anhydrous chloroform was added drop-wise to a solution of
219.3 mg
Compound 15g (0.31 mmol) in 15 ml anhydrous chloroform. The reaction solution
was stirred at 18°C
overnight, and then concentrated in vacuo. The residue was dissolved in 1 ml
DCM, and anhydrous .
ethyl ether was added to precipitate a crude diacid chloride (Compound 41).
The supernatant was
decanted, the dissolution/precipitation process was repeated three times, and
the solid was finally
washed with ethyl ether, and dried in a vacuum oven at 40 °C for 5
hours to obtain Compound 41. A
solution of the dried solid (Compound 4'1) in 25 ml anhydrous chloroform was
added drop-wise to a
solution of 12.008 g Compound 26b (Mn = 67,000; 0.18 mmol) in 45 ml anhydrous
chloroform at
18°C, and the solution was stirred overnight at room temperature. The
reaction mixture was then
washed once with 75 ml 1N HCl and twice with 50 ml water twice, and was dried
over anhydrous
sodium sulfate. The solution was concentrated to 30 ml, and dripped into 880
ml anhydrous ethyl
ether placed in a Teflon beaker to precipitate the crude product. The crude
product was washed with
ether and dried in a vacuum oven at 40°C overnight to produce 12.5 g of
the product.
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Results:
[0412] Yield: 84%
[0413] MW=129,000
[0414] PDI=1.693
[0415] The structure was confirmed by NMR.
~n
Example 51: Preparation of Polymer Microspheres
[0416] One g polymer was dissolved in 5 ml DCM, and 0-500 mg of a drug was
added to the solution.
The mixture was mixed thoroughly arid poured into 1.0-2.5% aqueous solution of
PVA while agitating
at 3;000-5,000 rpm. The mixture was agitated for 1 hour, magnetically stirred
for 2 hours, centrifuged,
washed with water several times, and lyophilized to obtain microspheres.
Example 52: Content Uniformity Determination of Drug (Methotrexate) Admixed
with
Polymer in Microspheres
[0417] The weight per weight percent (wt/wt%) loading of methotrexate with
various polymer
polyanhydrides was determined by a liquid-liquid extraction procedure. 5-10 mg
polymer were
weighed and dissolved with 3 ml ethyl acetate. The methotrexate was then
extracted from the ethyl
acetate layer into 5 ml of an aqueous phosphate buffer saline (PBS) layer. A
0.3 ml aliquot was
removed and was filtered with a 0.45 ~m filter into an HPLC vial with a 300
~,1 insert. The
methotrexate response and extraction efficiency were tested by extracting
methotrexate-free
microspheres and adding between 50 ~,g and 200 ~,g of methotrexate into the
polymer extract and
filtering as above. The HPLC procedure used a Rapid Resolution RP-1, 0.1 v/v%
TFA in aqueous as
mobile phase A and 0.1 v/v% TFA in acetonitrile as mobile phase B at a 1.0
ml/minute flow rate. The
compositions of the microspheres prepared are presented in Table 14 below.
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Table 14: Microspheric Cnpnnnsitions
Compound Polymer No. Drug Dr og Content
( /owt/wt)
43 26b N/a n/a
44 26b BPC 26.5"
45 26b BPC 14.8a
46 26b MTX 10
47 26b MTX 16
48 26a MTX 13
49 32a MTX 10''
50 25a MTX 16
aMeasured by H NMR
(3Measured by the method of Example 49
Example 53: Determination of Elution Profile of Methotrexate-Loaded
Microspheres
[0418] The in vitj~o release of drug (methotrexate) present in microspheres
was determined by kinetic
elution. The calculated level of w/w% loading described in Example 51 above
was used to calculate
the expected % release for about 10 mg methotrexate-loaded microspheres.
Aliquots of approximately
mg microspheres prepared as in Example 51 above were weighed and placed in 50
ml conical tubes
provided with screw cap closures. A 40 ml aliquot of release media, either PBS
or serum, was added
to each tube with a pipet, and the tubes were capped and placed in a
37°C incubator chamber for
periodic sampling. The test tubes were removed for sampling, centrifuged for 5
minutes and 1 ml
samples of either PBS or serum were withdrawn for analysis. The samples were
initially withdrawn at
1 hour intervals, then daily until changes were noted in either the presence
of polymer microspheres or
color of the medium. The samples were removed from the PBS, filtered, and
typically injected directly
or diluted 10 times (100 ~,1 to 900 ~,1) with PBS. Any samples removed from
serum were extracted with
a common solid phase extraction (SPE) procedure, and analyzed by high pressure
liquid
chromatography (HPLC). The HPLC method was also used for determining content
uniformity. The
'results obtained are shown in Table 15 below.
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Table 15: MTX-DF Microspheres' Elution Profile
Elapsed Time Cumulative %MTX Cumulative %MTX Cumulative %MTX
(Days) Compound 48 Compound 49 Compound 50
0 0.00 0.00 0
1.00 18.80 34.40 13.09
2.0 48.26 52.45 37.83
3.0 52.14 85.88 40.59
7.0 52.68 85.81 46.77
10.0 ND ND 45.89
14.0 ND ND 55.50
ND not determined.
Example 54: Biodegradation of Polymer-Coated Coupons
[0419] Metal coupons were labeled, cleaned, and air-dried for about 15
minutes. 100 mg polymer were
prepared in 400 mg anhydrous DGM and vortexed, and the coupons were coated
with 150 (uM gap
width, air dried for 2 hours, and placed in a vacuum oven at 50°C for 4
hours. The thickness and mass
of the coatings were measured, and the following results were obtained. The
results obtained are
shown in Table 16 below.
Table 16: Coated Polymer Degradation Curve
Coupon Total Mass Coating Mass
Thickness
(mg) (mg) ~,m ~ ~,m
A 4851.0 36.8 24.8 ~ 17.2
B 4932.1 23.6 18.8 ~ 4.2
[0420] All coupons were immersed in a phosphate buffered saline medium
(pH=7.4) and incubated at
37°C. The release of the drug (diflunisal) was evaluated by periodic
sampling of the medium and
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quantitation by high pressure liquid chromatography (HPLC) as described above.
The data are shown
in Table 17 below.
Table 17: Polymer Flntinn*lProfiles
Time Elapsed Cumulative %SA Cumulative %DF
(Days) Compound 26a Compound 26c
0 0.00 0.00
' 1.0 0.00 0.00
2.0 0.94 2.02
3.0 2.96 5.00
5.0 33.40 11.68
8.0 56.74 44.07
13.0 ~ 99.31 68.60
15.0 99.73 73.50
21.0 100.15 74.30
27.0 101.69 76.94
31.0 1 01.69 79.31
36.0 100.51 81.75
* Eluted from Unstenhzed Coupons of Yolyrners 26a and Z6c m YtiS at 3~/"L
Example SS: Effect of Sterilization Method and Measurement of Polymer
Degradation
[0421 ] The degradation of polymers from coupons, with and without E-beam
sterilization, with a 3 Nxn
thick coating was measured in PBS (pH = 7.4) at 37°C. The results are
shown in Table 18 below.
Table 18: Polymer Elution Profile with/without E-Beam Sterilization
Compound Compound Compound
26a (1.7 26c (3.4 28a (3.6
mg) mg) mg)
Time Cum.%SA Cum.%SA Cum.%DF Cum.%DF Cum.%DF Cum.%DF
Elapsed No E-BeamE-Beam No E-Beam E-Beam No E-BeamE-Beam
(days)
0 0.00 0.00 0.00 0.00 0.00 0.00
1.0 0.00 0.00 0.00 0.00 0.21 0.00
2.0 0.85 3.88 2.19 2.94 0.21_ 0.00
3.0 4.61 12.60 13.59 15.46 0.31 0.45
4.0 17.10 23.74 21.85 25.19 1.08 2.93
5.0 27.39 32.27 32.29 35.83 3.41 8.10
6.0 45.73 46.10 54.72 53.92 9.39 18.28
9.0 65.51 64.90 79.20 81.37 67.26 87.98
18.0 69.88 65.59 88.99 92.72 97.49 87.98
21.0 74.38 .72.09 92.84 98.20 98.16 76.60
30.0 ND ND 97.13 98.20 99.95 77.27
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Compound Compound Compound
26a (1.7 26c (3.4 28a (3.6
mg) mg) mg)
Time
Elapsed Cum.%SA Cum.%SA Cum.%DF Cum.%DF Cum.%DF Cum.%DF
(days) No E-BeamE-Beam No E-Beam E-Beam No E-BeamE-Beam
44.0 ND ND 98.49 98.41 102.33 75.76
ND not determined.
[0422] As shown in Table 18 above, E-Beam sterilization (3.5 mRad) had
substantially no effect on
the pattern of diflunisal released from the polymer-(polyDF- or poly SA)
coated stainless steel samples
incubated in serum at 37°C. Notwithstanding the lack of effect on
polymer degradation, sterilization
may produce some changes in the molecular weight and mechanical properties of
a polymer. For
example, the tensile modulus of a melt-polymerized salicylic acid polymer
(polySA) decreased by
about 1/3 after gamma sterilization (25-35 Kgys) at room temperature although
no change occurred
wh~ n irradiated at 37°C. Gamma radiation had no effect on the
molecular weight, flexibility, or
adhesiveness of polySA, and only a very minor effect on its hardness. The
effects of gamma radiation
and E-beam sterilization on polyDF were similar to those observed with polySA.
Example 56: Biodegradation of Polymers Containing Admixed Drug (Paclitaxel)
[0423] Paclitaxel (PAC) was admixed in a solution of polymer at a
concentration of 0 to about 40
wt%, i.e., 1 mg of polymer-drug admixture contained 0.8 mg polymer and 0.2 mg
drug. Paclitaxel was
released.at the same rate at which the polymer biodegraded to generate
diflunisal (the relatively small
amount of paclitaxel released reflects the inability of serum to hold this
relatively insoluble drug).
Tables 20a, 20b, 20c and 20d below show the concurrent release of paclitaxel
from a polydiflunisal
(polyDF)-paclitaxel admixture coated onto electro-polished stainless steel
samples and incubated in
serum or PBS at 37°C.
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Table 19: ~ Elution of PAC admixed into Diflunisal (DF) Polymer
0% PAC 5% PAC 40% PAC
Time Elapsed Cumulative %DF Cumulative %DF Cumulative %DF
(days) Generated Generated Generated
0 0.0 0.0 0.0
1.0 13.1 8.7 11.6
2.0 38.3 42.1 38.3
3.0 40.5 50.1 47.3
4.0 44.4 53.6 57.7
5.0 48.4 58.0 61.7
6.0 50.4 61.0 69.0
7.0 52.8 64.0 74.0
10.0 57.4 69.4 80.8
12.0 60.6 78.8 95.1
14.0 67.8 82.2 99.6
17.0 76.6 93.4 110.1
19.0 79.5 96.9 112.2
21.0 82.0 100.6 115.0
28.0 88.9 110.0 122.0
*Elution of <S~,m Coating of Compound 27a on 1 cma Coupons in Serum with 0%,
5% and 40% PAC
loading.
Table 20a: Elution* of PAC admixed into Polymer
Compound 26b ~ Compound 27a
with 10%.PAC with 5% PAC
Time ElapsedPAC Released PAC Released
(days) (Cumulative ~, ) (Cumulative ~ )
0 0.0 0.0
1:0 13.8 6.3
2.0 9.7 8.2
3.0 13:6 8.2
4.0 11.2 9.1
5.0 12.8 9.7
6.0 14.2 13.1
7.0 20.5 17.3
10.0 21.2 21.7
12.0 31.5 21.9
14.0 33.4 25.2
17.0 41.7 27.4
19.0 41.6 27.4
' 21.0 50.9 34.4
28.0 42.0 40.4
*Elution of Paclitaxel from <S~,m Coating of Compound 26b and Compound 27a on
1 cm1 Coupons in
Serum
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Table 20b: Elution of Paclitax~l
Time Elapsed PAC Released (Cumulative
%)
(days) Compound 27a Compound 27a
with 0% PAC with 40% PAC
0 0.00 -~ 0.00
1.0 5.79 12.16
2.0 7.56 11.22
3.0 7.56 10.56
4.0 8.38 9.67
5.0 8.96 17.02
6.0 12.11 17.24
7.0 16.05 19.19
10.0 20.05 19.69
12.0 20.23 22.59
14.0 23.34 23.05
17.0 25.37 27.84
19.0 ' 25.37 28.19
*Elution of Paclitaxel from <5 ~,m Compound 27a Coating on 1 cmZ Coupons in
Serum
Table 20c: Elution of PAC Admixed into Polymer*
' PAC Released (Cumulative
Ti ~,g)
El
d
me Compound 26b Compound 26b
apse With 0% PAC with 10% PAC
(days)
0 ~ 0 0
1.0 59.75 38.5
2.0 140.39 76.42
3.0 199.18 136.22
4.0 ' 307.39 174.94
5.0 268.49 282.67
6.0 410.89 333.27
7.0 485.14 ~ 407.52
10.0 617.14 539.52
12.0 661.33 752.02
14.0 671.89 779.52
17.0 785.64 955.77
19.0 807.97 965.04
21.0 842.47 1001.29
28.0 ~- - 837.73 985.2
*Elution from <S~,m Coating of Comp~und 26b with 0% and 10% PAC Loadings on 1
cmZ Coupons
in PBS
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Example 57: Determination of Polymer Glass Transition Temperature (Tg) in a
Differential
Scanning 'Calorimeter
[0424] Approximately 10 mg polymer were accurately weighed, and the mass was
recorded in a pre-
tared aluminum pan (no-hermetic seal). The pan was crimped to complete a seal
and to facilitate good
heat transfer. The pan was placed in the calorimeter opposite an empty
reference pan of mass similar to
;n ,
the sample pan. The calorimeter was closed and sealed in a nitrogen sweep gas
atmosphere. The
sample temperature was controlled at a program rate of 10 °C/min from
room temperature to -20°C,
followed by heating to 110 °C. The sample was then cooled to -
20°C, and was heated at the same rate
a s~ cond time to 110°C. The Tg was observed as the mid-point in the
heat capacity inflection. The
measurements were made using Thermal Analytical Instruments Q-100 with a
circulation bath chiller.
The data obtained from each of ten polymers are shown below in Table 21.
Table 21: Glass Transition Temperatures
Com ound , T (C)
23b 40
25a 35.7
25b 31.1
25c 17.5
26a 41.0
26b 49.0
26c 42.3
27a 38.4
27b 33.9
28a 45.1
Examule 58: NMR Analyses of Different Bond Types
[0425] The polymerization of a Diflunisal-Linker-Diflunisal was conducted to
demonstrate the ability
of the process of the invention to control bond types and bond type
distribution. The bond type was
determined by NMR. Melt polymerization produced a distribution labeled as
"Dispersion" in the
polymer type axes. This polymer released 70% of the contained Diflunisal in
approximately 28 days
with a more gradual release for another 14+ days. By applying the synthetic
methods presented here, a
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polymer was created with the same % of ingredients but with only one bond type
("Controlled
Sequence"). By creating a strictly alternating repeat structure, only one bond
type predominates. This
polymer will release more rapidly, and will form crystals in the later stage
of elution. By altering the
rate of addition of phosgene or by changing the pre-polymer, other precise
distributions and sequences
can be created which result in changes in crystallinity, release kinetics
(hours to months from a 5
micron thick coating) and other physical attributes such as compatibility &
solubility. "Random"
'~~ iepresents a polymer in which the polymerization reaction is allowed to
take place in once step. By
slowing down the addition rate of phosgene, additional distributions of bond
types were achieved
("Random -1 hour Addition" and "Random.- 6 hour Addition"). As the % of weaker
bonds was
altered, the breakdown rate, stability, sterilization breakdown, etc. was
altered as well but in a
controlled manners Thus, the design capabilities of these polymers are far
beyond those of typical melt
polymerization or solution polymerization prior to this art.
Scheme 20 Sond type distribution
Example 59: Glass Transition Temperature
[0426] A polymer's glass transition temperature (T~) is a key parameter that
significantly influences its
mechanical, physical chemical and handling properties. The molecular wei ~~ht
and chemical
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composition of the linking group may affect the polymer's glass transition
temperature (Tg), and
accordingly, the mechanical properties of the therapeutic polymers and
coatings of the therapeutic
polymers at body temperatures. The higher the molecular weight, the greater
the toughness of the
material in terms of elasticity and tear strength. A polymer's tensile modulus
may be taken as an index
,~~ ,of the polymer's rigidity. The glass transition temperatures and tensile
moduli for several polymers are
listed in Table 22 below.
Table 22: Aliphatic Linker - Effect of Chain Length and Tensile Modulus
Number of Carbons Temp. 6 6:8 8 10
(Linker)
Gl ss Transition Temp. (C) 44 38 29 16
(Tg)
Tensile Modulus (kPa) 25C 3300 2100 140 7
37C 480 45 4 NO
NO Not observed
Polymer prepared by Solution Process
[0427] Table 22 shows a salicylic acid polymer with a C6 linker molecule as
having a Tg=44°C, and
that the polymer is relatively hard at room temperature. Increasing the carbon-
chain length will
generally lower the glass transition temperature (Tg) of the resulting polymer
in a somewhat linear
manner, so that a polymer of salicylic acid (polySA) produced with a C12
linker molecule has a Tg 8°C
and is a rubbery, elastic material at room temperature. A similar profile is
seen with polymers of
diflunisal (polyDF), a potent derivative of salicylic acid. For a specific
linker chain length, a
polydiflunisal will generally exhibit a much higher Tg when compared to the
same linker in the
corresponding polysalicylic acid. Thus, the data provided in Table 22 show a
that in one embodiment
of the invention, the tensile modulus (polymer rigidity) and glass transition
temperature are inversely
proportional to linker chain length. In addition for each specific linker, the
polymer's rigidity
decreased with increased temperature from 25°C to body temperature
(37°C). Table 23 below shows
data for another embodiment of the invention.
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Table 23: Aliphatic Linker in PolySalicylic Acid (Anhydride Ester)
Pol mers* / Linkers MW PDI T (C) Tm C T'd C
Glutaric acid 3,206 1.1 58 175 424
Adi is acid 2,221 1.7 76 N.C. 391
Dodecanedioic acid 18,427 1.8 53 178 434
Di-glycolic acid 3,051 1.0 ' 68 N.C. 408
N.C. Not observed
*Synthesized at 180°C for 2.5 hr under vacuum
[0428] In this embodiment, the polymer's Tg increases with increasing chain
carbon number, e.g.,
,~,i glutaric acid vs. adipic acid. A linker of a very short carbon chain, for
instance, less than about C5,
provides a lesser chance for cross-linking by generally known synthetic
methods, e.g., melt
polymerization variations, probably due to steric hindrance, and the polymer
products may have a
lower Tg, e.g., about 58°C, than with a~longer chain linker that may
favor more extensive cross-linking
ands therefore, higher Tg, e.g. about 76°C. This potential cross-
linking reactivity generally decreases
as the molecular weight of the polymer increases and as the linker chain
length increases sufficiently:
Dodecanedioic acid, for example, has a Tg of about 53°C. In another
embodiment of this invention,
the linkers are aromatic molecules that have different structural rigidity
(Table 24).
Table 24: Aromatic Linker in Salicylic Acid (Anhydride Ester) Polymer
Pol mers / Linkers MW PDI T (C) Tm (C) Td (C)
Terephthalic 2,101 1.3 111 N.O. 436
1-4'- Phenyldiacetic 1,584 1.0 89 N.O. 386
4-4'-Biphelyldicarboxylic ~ 5,531 1.1 150 N.O. 463
4-4'-Oxybisphenyldicarboxylic 9,064 1.1 103 N.O. 387
4-4'-(Hexafluoroisoporpylidene) 9,436 1.2 149 315 464
dicarboxylic
N.O. Not observed
Synthesized at 180°C for 2.5 hr under Vacuum
[0429] Table 24 provides information that corresponds to a salicylic acid
polymer having an aromatic
linker, where the introduction in the polymer chain of aromatic linkers of
different characteristics, such
as structural rigidity, results in different Tg values. The data provided in
the previous tables show that
the transition temperature T~ may vary with the number of carbons of a
straight aliphatic chain linker
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as well as with other parameters of the linker molecule such as, but not
limited to; hydrophobicity,
structural rigidity, presence'of heteroatoms, etc. The polymers of the
invention evidence an
extraordinary range of properties that may be varied as required by any one
specific application, as
exemplified in Tables 4a, 4b and 4c. v These data also show that a great
variety of polymers, e.g. poly-
NSAIDs as well as polymers of other types of molecules, may be created from
combinations of a
~,i
monomers) and different linkers that may have varied chain lengths and
chemical structures, to attain
a polymer of pre-determined physical properties, e.g. in-between those of the
respective homologous
polymers. In addition, the process of,the invention also allows the formation
of polymers of desired
ch ~racteristics by combination of molecules with certain linkers in pre-
selected proportions to obtain
desired values for the polymer characteristics. For example, a co-polymer made
from equal amounts
of a monomer attached to C6 and C$ linkers should have an intermediate Tg and
tensile modulus with
respect to those of the C6 and C8 polymers. In addition, different molecules
may be introduced into the
polymer to obtain a compound of combined activities. For example, NSAIDs of
the type of salicylic
acid, diflunisal, salsalate (a di-salicylic acid), analgesics, hemostatics,
antibiotics, etc., and in general
any polymerizable molecule may be employed examples of which are given herein.
This flexibility in
the design of a polymer extends to the synthesis of all polymers of the
invention, e.g. polymers of
salicylic acid, diflunisal, salsalate, etc., and thereby allows the control of
polymer properties by
varying monomer ratio, e.g. 20:80, 50:50, 80:20, linker combinations, linker
structure, molecules in the
form of monomers, dimers, trimers, tetramers, etc. combinations of molecules,
and others.
[0430] Varying the linker chain length may have an inverse influence on the
polymer's hardness.
When measured by ASTM methods, the relative hardness of the polymer of the
invention, e.g., with
polyNSAIDs such as poly-salicylic acid and poly-diflunisal, was seen to
decrease with increasing
linker chain length. That is, shorter linkers produced harder polymers
compared to longer linkers. As
the carbon number in the linker chain was increased, the polymers also became
slightly softer when
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hydrated. When the data are normalized to the intended use temperature (T-Tg),
a roughly linear
relationship for all polymers is observed, thereby providing a powerful tool
for designing polymers of
pre-selected characteristics.
Example 60: Effect of Linker Chain Length on Glass Transition Temperature &
Mechanical
Properties
[0431 ] Glass transition temperature (Tg) is a key parameter of polymers that
significantly influences
their mechanical, physical chemical and handling properties. Polymers of
salicylic acid carrying
different linkers were tested for their Tgs, which are shown in Table 25
below.
Table 25: Tg Versus Linker of polySA and polyDF
Number of Carbon AtomsTg (C)
in
Linker PolyAspirin PolyAspirin II
I
6 46 76
8 30 -
19 54
12 6 48
14 - 38
-
16 - la
[0432] As shown in Table 25 above, a polySA polymer with a six-carbon linker
molecule has a
Tg 44°C, and is relatively hard at room temperature. Increasing the
carbon-chain length lowers Tg in a
linear manners so that polySA produced with a 12-carbon linker molecule has a
Tg 8°C, which results
in a rubbery, elastic material at room temperature. A similar profile is seen
with polyDF polymers,
noting that for a specific linker chain length, a much higher Tg is measured
relative to the same linker
in the polySA polymers. As summarized in Table 22 shown above, tensile modulus
(another index of
rigidity) also increased with decreasing linker chain length, while for a
specific linker, rigidity
decreased as temperature was increased from 25°C to body temperature
(37°C). As shown above, in
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one of the embodiments of the invention, the Tg of the polymer was seen to
increase with increased
length of the carbon chain. In another embodiment shown in Table 25 above, the
Tg may increase until
certain number of carbons in the chain is obtained, e.g., glutaric acid vs.
adipic acid. A linker of a very
short carbon chain, e.g., C of about <5, provides less of a chance for cross-
linking in any of the
generally known synthetic methods, e.g., melt polymerization variations,
probably due to steric
hindrance, and the polymer produced may have a lower Tg, e.g., about
58°C, than when the linker has a
longer chain that lends itself to more extensive cross-linking. The latter
produced a polymer with
higher Tg, e.g., about 76°C. This cross-linking reactivity generally
decreases as the molecular weight
of the polymer increases and as the linker chain length increases
sufficiently, e.g., dodecanedioic acid
has a Tg °fabout 53°C. Similar data are provided in Table 25
above, which shows that different
aromatic linkers of different structural rigidity resulted in different Tg
values. All these data show that
- the transition temperature Tg not only varies with the number of carbons of
a straight aliphatic chain
linker but also might vary based on other properties of the linker molecule
such as, but not limited to,
hydrophobicity, structural rigidity, heteroatoms present, etc. It is evidenced
by the results shown in
Tables 4a, 4b, and 4c that the polymers of the invention evidence an
extraordinary range of properties
that may be varied as required by any one specific application. These data
also show that poly-NSAIDs
may be created from combinations of monomers containing different linker chain
lengths, with
physical properties in between those of the respective homologous polymers.
For example, a co-
polymer made from equal amounts of monomers prepared with 6 and 8 carbon atoms
had intermediate
Tg and tensile modulus values. This flexibility applies to both polySA and
polyDF, allowing control of
polymer properties by varying the monomer ratio, e.g. 20:80, 50:50, 80:20,
etc.
[0433] Varying the linker chain length influences polymer hardness as well. In
this case, the relative
hardness of polymers of the invention, e.g. polySA and polyDF, when measured
by ASTM methods,
decreased as the linker chain~length increased, and the polymers became
slightly softer when hydrated.
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WO 2005/042600 213 PCT/US2004/017916
Normalizing the data to the intended use temperature (T-Tg) showed a roughly
linear relationship for
all polymers, thereby creating a convenient application design tool.
Essentially across this range,
polyNSAIDs were highly flexible at room temperature and body temperature, as
flexible as could be
measured by standard ASTM methods. Soaking the polymers for an hour in
37°C PBS caused no
observable change in flexibility. This is shown in Table 26 below.
;n
Polymer
S l OPL 261PL 749PL 125PL S l OPL
+14% Paclitaxel
Adhesion ClassSB ( SB ~ SB ~ 4B ~ SB
~
*Adhesion as measured in the ASTM test for adhesion under ambient conditions
Class Rating 5B= 0%
of coating removed from substrate 4B= <5% of coating removed from substrate
[0'34] Essentially across this range, the polymers of the invention, e.g.,
poly-NSAIDs, are highly
flexible at room and body temperature. Soaking the polymers for an hour in PBS
at about 37°C caused
no observable change in flexibility
[0435] All patents, publications and patent applications listed herein are
incorporated by reference in
their entirety, as though individually incorporated by reference. The
invention has been described with
reference to various embodiments and techniques. However, it should be
understood that many
variations arid modifications may be made while remaining within the spirit
and scope of the invention.
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