CA 02637524 2008-07-14
DRUG DELIVERY DEVICE
TECHNICAL FIELD
[0002] The present disclosure relates generally to biocompatible crosslinked
polymers,
methods for preparing and using same, and the use of these polymers to release
drugs in
vivo.
BACKGROUND
[0003] Biocompatible crosslinked polymers may be used in drug and surgical
treatments
of various disease states found in animals, including humans. Biocompatible
crosslinked
polymers may be formed by various methods. For example, U.S. Patent No.
5,410,016
discloses the use of free radical photopolymerizable monomers to form
biocompatible
crosslinked polymers. Other biocompatible crosslinked polymers used for
medical
applications include polymers formed using electrophilic-nucleophilic
polymerization,
including those disclosed in U.S. Patent Nos. 5,296,518, 5,104,909, 5,514,379,
5,874,500, and 5,527,856.
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[0004] The systemic administration of drugs is known. Suitable routes of
administration
include, for example, oral, parenteral, buccal, peroral, nasal, rectal,
intravenous,
intramuscular, subcutaneous, intracisternal, intravaginal, intraperitonal,
intravesical,
intraventricular, intracranial, intrathecal, topical and/or transdermal,
combinations
thereof, and the like. In some cases, administration may require a high
systemic
concentration, which may be accompanied by adverse side effects. Similarly,
the use of
extended release fowls of medicaments, while desirable to prolong the time
period during
which the effects of a particular drug may be observed, may require the use of
mechanisms or systems that are inefficient in the release of the medicament in
a desired
amount.
[0005] There remains a need for improved biocompatible crosslinked polymers
and their
use as drug delivery devices.
SUMMARY
[0006] The present disclosure provides compositions suitable for use as drug
delivery
devices. In embodiments, a drug delivery device of the present disclosure may
include a
biocompatible crosslinked polymer hydrogel, and at least one drug. The
biocompatible
crosslinked polymer hydrogel may have at least three drug release profiles
including a
first drug release profile of from about 0 days to about 10 days, a second
drug release
profile of from about 0 days to about 30 days, and a third release profile of
from about 0
days to about 180 days.
[0007] In embodiments, suitable hydrogels utilized in the drug delivery
devices of the
present disclosure may include at least one biocompatible crosslinker region
including a
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crosslinked synthetic crosslinker molecule with a pre-crosslinked molecular
weight of
less than about 2000, and at least one biocompatible functional polymer region
including
a crosslinked synthetic polymer molecule with a pre-crosslinked molecular
weight of
more than about 7 times the molecular weight of the pre-crosslinked
crosslinker
molecule. The biocompatible crosslinked polymer may possess links, in
embodiments at
least three links, between the crosslinker region and the functional polymer
region, which
links may be the reaction product of at least one electrophilic functional
group with at
least one nucleophilic functional group.
[0008] Drug delivery devices of the present disclosure may be utilized to
release a single
drug at varying times, different drugs at varying times, or combinations of
the same or
different drugs at varying times.
DETAILED DESCRIPTION
[0009] The drug delivery devices of the present disclosure may have differing
release
profiles for the same, or different, bioactive agents. In embodiments, the
drug delivery
devices may be formed from biocompatible crosslinked polymers formed from the
reaction of precursors having electrophilic and nucleophilic functional
groups. The
precursors may be water soluble, non-toxic and biologically acceptable.
Suitable
polymers for forming such compositions include, for example, those disclosed
in U.S.
Patent No. 6,566,406.
[0010] In embodiments, at least one of the precursors may be a small molecule,
and may
be referred to herein, in embodiments, as a "crosslinker". Suitable
crosslinkers may,
prior to reacting with other precursors to form a composition of the present
disclosure,
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have a solubility of at least about 1 g/100 mL in an aqueous solution, in
embodiments
water. Crosslinkers may have a molecular weight of less than about 2000, in
embodiments from about 100 to about 2000, in other embodiments from about 450
to
about 650. One of the other precursors utilized to form a composition of the
present
disclosure may be a macromolecule, and may be referred to herein, in
embodiments, as a
"functional polymer". In embodiments, the functional polymer may include a
synthetic
polymer molecule, in embodiments a water soluble synthetic polymer, having a
pre-
crosslinked molecular weight of more than about 7 times the molecular weight
of the
crosslinker, in embodiments from about 7 times to about 50 times greater than
the
molecular weight of the crosslinker, in other embodiments from about 12 times
to about
35 times greater than the molecular weight of the crosslinker.
[0011] In some embodiments, each precursor may be multifunctional, meaning
that they
may include two or more electrophilic or nucleophilic functional groups, such
that a
nucleophilic functional group on one precursor may react with an electrophilic
functional
group on another precursor to form a covalent bond. At least one of the
precursors may
possess more than two functional groups, so that the precursors may combine to
form
crosslinked polymeric products as a result of the electrophilic-nucleophilic
reaction. In
embodiments, such reactions may be referred to as "crosslinking reactions".
[0012] In embodiments, each precursor may possess only nucleophilic or only
electrophilic functional groups, so long as both nucleophilic and
electrophilic precursors
are used in the crosslinking reaction. Thus, for example, if a crosslinker has
nucleophilic
functional groups such as amines, the functional polymer may have
electrophilic
functional groups such as N-hydroxysuccinimides. On the other hand, if a
crosslinker
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has electrophilic functional groups such as sulfosuccinimides, then the
functional
polymer may have nucleophilic functional groups such as amines. Thus,
functional
polymers such as proteins, poly(ally1 amines), or amine-terminated di-or
multifunctional
poly(ethylene glycols) ("PEG") can be used in some embodiments.
[0013] In other embodiments, the precursors may possess biologically inert and
water
soluble cores. When the core is a polymeric region that is water soluble,
suitable
polymers that may be used include, but are not limited to, polyethers, for
example
polyalkylene oxides such as polyethylene glycol ("PEG"), polyethylene oxide
("PEO"),
polyethylene oxide-co-polypropylene oxide ("PPO"), co-polyethylene oxide block
or
random copolymers; polyvinyl alcohol ("PVA"); poly(vinyl pyrrolidinone)
("PVP");
poly(amino acids); dextran; combinations of the foregoing, and the like.
Polyethers such
as poly(oxyalkylenes) or poly(ethylene oxide) may be useful in some
embodiments.
When the core is small, any of a variety of hydrophilic functionalities can be
used to
make the precursor water soluble. For example, functional groups like
hydroxyl, amine,
sulfonate and carboxylate, may be used to make the precursor water soluble. In
addition,
the N-hydroxysuccinimide ("NHS") ester of subaric acid is insoluble in water,
but by
adding a sulfonate group to the succinimide ring, the NHS ester of subaric
acid may be
made water soluble, without affecting its reactivity towards amine groups.
[0014] The crosslinking reactions may occur in aqueous solution under
physiological
conditions. In embodiments, the crosslinking reactions occur "in situ",
meaning they
occur at local sites such as on organs or tissues in a living animal or human
body. In
some embodiments, the crosslinking reactions do not release heat during
polymerization.
The crosslinking reaction leading to gelation may occur within about 10
minutes, in
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embodiments within about 2 minutes, in other embodiments within about one
minute, in
yet other embodiments within about 30 seconds, in other embodiments within
about 4
seconds. Gel time may be determined by a gel time measurement obtained by
methods
within the purview of those skilled in the art.
[0015] Certain functional groups, such as alcohols or carboxylic acids, do not
normally
react with other functional groups, such as amines, under physiological
conditions (e.g.,
pH from about 7.2 to about 11, at a temperature of about 37 C). However, such
functional groups can be made more reactive by using an activating group such
as N-
hydroxysuccinimide. Methods for activating such functional groups are within
the
purview of those skilled in the art. Suitable activating groups include, but
are not limited
to, carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidyl
esters, N-
hydroxysuccinimidyl esters, succinimidyl esters, epoxides, aldehydes,
maleimides,
imidoesters and the like. The N-hydroxysuccinimide esters or N-
hydroxysulfosuccinimide groups may be utilized, in embodiments, for
crosslinking of
proteins or amine functionalized polymers such as amino terminated
polyethylene glycol
("APEG").
[0016] In embodiments, suitable polymers include functional polymers such as
linear
water soluble and biodegradable functional polymers, which may be end-capped
with two
functional groups (e.g., N-hydroxysuccinimide ester (NHS), epoxide or similar
reactive
groups). The water soluble core may be a polyalkylene oxide, such as a
polyethylene
glycol block copolymer, which may be extended with at least one biodegradable
linkage
between it and each terminal functional group. The biodegradable linkage may
be a
single linkage or copolymers or homopolymers of absorbable polymers and
copolymers
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of poly(hydroxy acid)s, poly(orthocarbonate)s, poly(anhydride)s,
poly(lactone)s,
poly(aminoacid)s, poly(carbonate)s, poly(phosphonate)s, combinations thereof,
and the
like.
[0017] Other suitable water-soluble linear polymers include polyethylene
glycols
teiminated with reactive end group such as primary amines and/or thiols. Such
polymers
include those commercially available from Sigma (Milwaukee, Wis.) and
Shearwater
Polymers (Huntsville, Ala.). Some other suitable difunctional polymers are PPO-
PEO-
TM
PPO block copolymers such as PLURONIC F68 terminated with amine groups.
TM
PLURONIC or TETRONIC polymers are available with terminal hydroxyl groups.
The
hydroxyl groups may be converted into amine groups utilizing methods within
the
purview of those skilled in the art.
[0018] Other functional polymers may be branched or star shaped biodegradable
functional polymers which have an inert, water soluble polymer at the center.
The inert
and water soluble core may be terminated with oligomeric biodegradable
extensions
which, in turn, may be terminated with reactive functional groups.
[0019] Some suitable polymers may include multifunctional 4 arm biodegradable
functional polymers. These polymers may have a water-soluble core at the
center, such
as a 4 arm, tetrafunctional polyethylene glycol or a block copolymer of PEO-
PPO-PEO,
which may be extended with small oligomeric extensions of biodegradable
polymers to
maintain water solubility and terminated with reactive functional end-groups
such as
Carbodiimide (CDT) or NHS. Other multifunctional polymers with multiple arms
may be
utilized having about 6 arms, 8 arms, 10 arms, 12, arms, and the like.
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[0020] Other suitable functional polymers include multifunctional star or
graft type
biodegradable polymers such as polyethylene oxide, polyvinyl alcohol, or
poly(vinyl
pyrrolidinone) at the core, which may be completely or partially extended with
biodegradable polymers. The biodegradable polymers may, in embodiments, be
terminated with reactive end groups.
[0021] Small molecule crosslinkers may also be used, where the core includes a
small
molecule like ethoxylated glycerol, inositol, trimethylolpropane, and the like
to form the
resulting crosslinker. In addition, biodegradable extensions may include small
molecules
like succinate or glutarate or combinations of 2 or more esters, such as
glycolate/2-
hydroxybutyrate or glycolate/4-hydroxyproline, and the like. A dimer or trimer
of 4-
hydroxyproline may be used to not only add degradability, but also to add
nucleophilic
reactive sites via the pendant primary amines which are part of the
hydroxyproline
moiety.
[0022] Other variations of the core, the biodegradable linkages, and the
terminal
functional groups may be constructed so long as the resulting functional
polymer has the
properties of low tissue toxicity, water solubility, and reactivity with other
functional
groups, i.e., in embodiments electrophilic groups on the functional polymer
which may
react with nucleophilic functional groups on the crosslinker, or nucleophilic
groups on
the functional polymer which may react with electrophilic functional groups on
the
crosslinker.
[0023] Cores may also be terminated with a reactive functional group that is
also water
solubilizing, such a N-hydroxysulfosuccinimide ester ("SNHS") or N-
hydroxyethoxylated succinimide ester ("ENHS"). For example, suitable oligomers
and
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polymers may be made of a poly(hydroxy acid) such as poly(lactic acid), which
is
insoluble in water. However, the terminal carboxylic acid group of these
oligomers or
polymers can be activated with N-hydroxysulfosuccinimide ester ("SNHS") or N-
hydroxyethoxylated succinimide ester ("ENHS") groups. An ionic group, like a
metal
salt (for example, sodium salt) of sulfonic acid, or a nonionic group, like a
polyethylene
oxide on the succinimide ring, may provide water solubility while the NHS
ester provides
chemical reactivity towards amines. The sulfonate groups (sodium salts) or
ethoxylated
groups on the succinimide ring may solubilize the oligomer or polymer without
appreciably inhibiting reactivity towards amine groups.
[0024] Other precursors which may be utilized in forming the drug delivery
devices
herein include multifunctional graft or branch type water-soluble copolymers
with
terminal amine groups. For example, small molecule crosslinkers may be
utilized
including a small molecule like ethoxylated glycerol, ethoxylated
pentaerythritol,
inositol, trimethylolpropane, dilysine, trilysine, tetralysine, and the like,
to form the
resulting crosslinker.
[0025] If it is desired that the biocompatible crosslinked polymer be
biodegradable or
absorbable, one or more precursors having biodegradable linkages may be used.
The
biodegradable linkage may be between the functional groups and may optionally
also
serve as the water soluble core of one or more of the precursors. In the
alternative, or in
addition, the functional groups of the precursors may be chosen such that the
product of
the reaction between them results in a biodegradable linkage. For each
approach,
biodegradable linkages may be chosen such that the resulting biodegradable
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biocompatible crosslinked polymer may degrade under physiological conditions
into non-
toxic products or be absorbed over a desired period of time.
[0026] The biodegradable linkage may be chemically or enzymatically
hydrolyzable or
absorbable. Illustrative chemically hydrolyzable biodegradable linkages
include
polymers, copolymers and oligomers of glycolide, dl-lactide, I-lactide,
caprolactone,
dioxanone, trimethylene carbonate, combinations thereof, and the like.
Illustrative
enzymatically hydrolyzable biodegradable linkages include peptidic linkages
cleavable
by metalloproteinases and collagenases. Additional illustrative biodegradable
linkages
include polymers and copolymers of poly(hydroxy acid)s, poly(orthocarbonate)s,
poly(anhydride)s, poly(lactone)s, poly(aminoacid)s, poly(carbonate)s,
poly(phosphonate)s, combinations thereof, and the like.
[0027] In yet other embodiments, suitable biodegradable linkages that are
hydrolytically
degradable which may be utilized in the compositions of the present disclosure
include,
but are not limited to, esters, anhydrides, phosphoesters, combinations
thereof, and the
like. Other suitable biodegradable linkages which may be enzymatically
degradable and
included in the compositions of the present disclosure include, but are not
limited to: an
amino acid residue such as -Arg-, -Ala-, -Ala(D)-, -Val-, -Leu-, -Lys-,
-Pro-, -Phe-, -Tyr-, -Glu-, and the like; 2-mer to 6-mer oligopeptides such as
-Ile-Glu-Gly-Arg-, -Ala-Gly-Pro-Arg-,-Arg-Val-(Arg)2-, -Val-Pro-Arg-, -Gln-Ala-
Arg-,
-Gln-Gly-Arg-, -Asp-Pro-Axg-,-Gln(Arg)2 Phe-Arg-, -(Ala)3-, -(Ala)2-, -Ala-
Ala(D)-,
-(Ala)2-Pro-Val-, -(Val)2-,-(Ala)2-Leu-, -Gly-Leu-, -Phe-Leu-, -Val-Leu-Lys-,
-Gly-Pro-Leu-Gly-Pro-, -(Ala)2-Phe-, -(Ala)2-Tyr-, -(Ala)2-His-, -(Ala)2-Pro-
Phe-,
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-Ala-Gly-Phe-, -Asp-Glu-, -(Glu)2 -Ala-Glu-, -Ile-Glu-, -Gly-Phe-Leu-Gly-, -
(Arg)2-;
D-glucose, N-acetylgalactosamine, N-acetylneuraminic acid, N-
acetylglucosamine,
N-acetylmannnosamine or the oligosaccharides thereof; oligodeoxyribonucleic
acids such
as oligodeoxyadenine, oligodeoxyguanine, oligodeoxycytosine, and
oligodeoxythymidine; oligoribonucleic acids such as oligoadenine,
oligoguanine,
oligocytosine, oligouridine, combinations of any of the foregoing, and the
like. Those
skilled in the art will readily envision reaction schemes for incorporating
enzymatically
degradable linkages into the crosslinked polymers of the present disclosure.
[0028] Methods for forming these polymers and their precursors are within the
purview
of those skilled in the art and include, for example, those disclosed in U.S.
Patent No.
6,566,406.
[0029] In embodiments, suitable reactive groups which may be utilized to form
the
compositions of the present disclosure include N-hydroxysuccinimide esters,
which may
be synthesized by any of several methods. For example, hydroxyl groups may be
converted to carboxylic groups by reacting them with anhydrides such as
succinic
anhydride in the presence of tertiary amines such as pyridine or triethylamine
or
dimethylaminopyridine ("DMAP"). Other anhydrides such as glutaric anhydride,
phthalic anhydride, maleic anhydride and the like may also be used. The
resulting
terminal carboxyl groups may then be reacted with N-hydroxysuccinimide in the
presence of dicyclohexylcarbodiimide ("DCC") to produce an N-
hydroxysuccinimide
ester (referred to, in embodiments, as NHS activation).
[0030] The synthetic crosslinked gels described above may degrade due to
hydrolysis of
the biodegradable region. The degradation of gels containing synthetic peptide
sequences
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may depend on the action of a specific enzyme and its concentration. In some
cases, a
specific enzyme may be added during the crosslinking reaction to accelerate
the
degradation process. Suitable enzymes include, for example, peptide hydrolases
such as
elastase, cathepsin G, cathepsin E, cathepsin B, cathepsin H, cathepsin L,
trypsin, pepsin,
chymotrypsin, y-glutamyltransferase (y-GTP) and the like; sugar chain
hydrolases such as
phosphorylase, neuraminidase, dextranase, amylase, lysozyme, oligosaccharase
and the
like; oligonucleotide hydrolases such as alkaline phosphatase,
endoribonuclease,
endodeoxyribonuclease and the like. In some embodiments, where an enzyme is
added,
the enzyme may be included in a liposome or microsphere to control the rate of
its
release, thereby controlling the rate of degradation of the crosslinked
polymer of the
present disclosure. Methods for incorporating enzymes into liposomes and/or
microspheres are within the purview of those skilled in the art.
[0031] When the crosslinker and functional polymers are synthetic (for
example, when
they are based on polyalkylene oxide), it may be desirable to use molar
equivalent
quantities of the reactants. In some cases, excess molar crosslinker may be
added to
compensate for side reactions, such as reactions due to hydrolysis of the
functional group.
[0032] When choosing the crosslinker and crosslinkable polymer, at least one
of the
polymers may have more than 2 functional groups per molecule and at least one
degradable region, if it is desired that the resulting biocompatible
crosslinked polymer be
biodegradable. Generally, each biocompatible crosslinked polymer precursor may
have
more than 2 and, in some embodiments, more than 4 functional groups.
[0033] As noted above, in embodiments the polymer compositions suitable for
forming
the drug delivery devices herein may be formed from the reaction of
electrophilic groups
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on one precursor with nucleophilic groups on a second precursor. Suitable
electrophilic
groups include NHS, SNHS and ENHS. Suitable nucleophilic groups include
primary
amines. The NHS-amine reaction may possess reaction kinetics which leads to
quick
gelation, usually within 10 minutes, in embodiments within 1 minute, in other
embodiments within 10 seconds. This fast gelation may be desirable for in situ
reactions
on live tissue.
[0034] The NHS-amine crosslinking reaction leads to formation of N-
hydroxysuccinimide as a side product. The sulfonated or ethoxylated forms of N-
hydroxysuccinimide may be useful due to their increased solubility in water
and hence
their rapid clearance from the body. The sulfonic acid salt on the succinimide
ring does
not alter the reactivity of the NHS group with the primary amines.
[0035] The NHS-amine crosslinking reaction may be carried out in aqueous
solutions
and in the presence of buffers. Suitable buffers include phosphate buffer (pH
from about
to about 7.5), triethanolamine buffer (pH from about 7.5 to about 9), borate
buffer (pH
from about 9 to about 12), and sodium bicarbonate buffer (pH from about 9 to
about 10).
[0036] Aqueous solutions of NHS based crosslinkers and functional polymers may
be
made just before the crosslinking reaction due to reaction of NHS groups with
water.
Longer "pot life" may be obtained by keeping these solutions at a lower pH
(for example,
a pH from about 4 to about 5).
[0037] The crosslinking density of the resulting biocompatible crosslinked
polymer may
be controlled by the overall molecular weight of the crosslinker and
functional polymer
and the number of functional groups available per molecule. A lower molecular
weight
between crosslinks, such as 600 Da, may result in higher crosslinking density
as
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compared to a higher molecular weight, such as 10,000 Da. Higher molecular
weight
functional polymers may be useful, in embodiments having a molecular weight of
more
than about 3000 Da, so as to obtain elastic gels.
[0038] The crosslinking density may also be controlled by the overall percent
solids of
the crosslinker and functional polymer solutions. Increasing the number of
reactive
groups increases the number of degradable crosslinks in the resulting
hydrogel.
Increasing the percent solids may also increase the probability that an
electrophilic group
will combine with a nucleophilic group prior to inactivation by hydrolysis.
Yet another
method to control crosslink density is by adjusting the stoichiometry of
nucleophilic
groups to electrophilic groups. A one to one ratio may result in a higher
crosslink
density.
[0039] Where proteins are utilized to form the polymer, the resulting
crosslinked
hydrogel may be a semisynthetic hydrogel whose degradation depends on the
degradable
segment in the crosslinker as well as degradation of the protein, for example
albumin, by
enzymes. In the absence of any degradable enzymes, the crosslinked polymer may
degrade solely by the hydrolysis of the biodegradable segment. If
polyglycolate is used
as the biodegradable segment, the crosslinked polymer may degrade over a
period of time
of from about 1 day to about 30 days, depending on the crosslinking density of
the
network. Similarly, a polycaprolactone based crosslinked network may degrade
over a
period of time of from about 1 month to about 8 months. The degradation time
may vary
according to the type of degradable segment used, in the following order:
polyglycolate<polylactate<polytrimethylene carbonate<polycaprolactone.
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Thus, it is possible to construct a hydrogel with a desired degradation
profile, from a few
days to months, using a proper degradable segment. The degradation rate may
also vary
by the anhydride chosen to create the degradable linkage for a single ester,
in the
following order:
succinate<glutarate<methyl glutarate.
[0040] The hydrophobicity generated by biodegradable blocks such as
oligohydroxy acid
blocks or the hydrophobicity of PPO blocks in PLURONIC TM or TETRONIC polymers
may be helpful in dissolving small organic drug molecules. Other properties
which may
be affected by incorporation of biodegradable or hydrophobic blocks include:
water
absorption, mechanical properties and thermosensitivity.
[0041] In embodiments, the resulting crosslinked polymer may include at least
one ester
linkage between the crosslinker regions and the functional polymer regions, in
embodiments from about 1 ester link to about 20 ester links between the
crosslinker
regions and the functional polymer regions, in other embodiments from about 3
ester
links to about 12 ester links between the crosslinker regions and the
functional polymer
regions. As noted above, in embodiments the links may be the reaction product
of at
least one electrophilic group with at least one nucleophilic group. In
embodiments these
links may be biodegradable and/or enzymatically degradable.
[0042] In accordance with the present disclosure, the crosslinked polymers may
be
utilized as drug delivery devices. As used herein, the terms "drug",
"bioactive agent",
and "biologically active agent", are used interchangeably. Depending upon the
polymers
and crosslinkers utilized in forming the compositions herein, a drug may be
merely
incorporated into the polymeric matrix, without binding to the matrix.
Alternatively, or
CA 02637524 2008-07-14
in addition, a drug may be covalently bound to the polymeric matrix through a
pendant
linkage or incorporated into the polymer backbone during the crosslinking
reaction, either
separately or as part of either precursor. Utilizing multiple means for
attachment or
incorporation of a drug into a crosslinked polymer of the present disclosure
may allow for
one to form a drug delivery device possessing multiple release profiles. For
example, a
drug merely incorporated into a polymeric matrix, which is not covalently
bound thereto,
may be released from said matrix more rapidly than a drug covalently bound to
the same
matrix. Similarly, a drug attached to the polymeric matrix through a pendant
linkage, i.e.,
which projects from the backbone of the crosslinked polymer, may be released
more
rapidly than a drug that is incorporated into the backbone of the crosslinked
polymer.
[0043] In embodiments, the drug release profile of a drug from the crosslinked
polymeric
compositions of the present disclosure may thus be determined by different
mechanisms,
including the water solubility of the drug, the hydrolysis of the hydrogel,
and the mass
loss of the hydro gel.
[0044] In accordance with the present disclosure, the crosslinked polymer may
be
utilized to release the same, or a different drug, at different points in time
after formation
of the crosslinked polymer in situ. For example, in some embodiments, a first
drug may
be both incorporated into the matrix formed by the crosslinked polymer, with
additional
drug covalently bound to the crosslinked polymer. As noted above, in some
embodiments the drug covalently bound to the crosslinked polymer may be bound
by
pendant linkages, incorporated into the backbone of the crosslinked polymer,
or both.
Thus, for the same drug, there may exist at least two different release
profiles of the drug
from the crosslinked polymer: an initial release of drug that is not bound by,
but merely
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=
incorporated within, the polymeric matrix formed by the crosslinked polymer of
the
present disclosure (which, in embodiments will be dependent on the water
solubility of
the drug); and a second release of drug that is covalently bound to the
crosslinked
polymer (which, in embodiments will be dependent on the hydrolysis of the
hydrogel
and/or the mass loss of the hydrogel). As noted above, covalent linkage of a
drug to the
crosslinked polymer may be by pendant linkages or by incorporation into the
backbone of
the polymer.
[0045] In embodiments, drugs attached by pendant linkages may have multiple
release
profiles. A drug attached through a degradable linkage, for example an ester
on the
crosslinked polymer (which, in embodiments, would link an amine on the drug)
would be
released when the ester hydrolyzed. A drug attached through a non-degradable
linkage,
for example an amine on the crosslinked polymer (which, in embodiments, would
link an
ester such as NHS on the drug), would be released through mass loss of the
crosslinked
polymer of the present disclosure.
[0046] In other embodiments, there may exist at least three different release
profiles of
the drug from the crosslinked polymer: an initial release of drug that is not
bound, but
merely incorporated within, the polymeric matrix formed by the crosslinked
polymer of
the present disclosure; a second release of drug that is covalently bound to
the crosslinked
polymer through degradable pendant linkages; and a third release of drug that
is
covalently bound to the crosslinked polymer by being incorporated into the
backbone of
the polymer or is covalently bound to the crosslinked polymer through non-
degradable
pendant linkages. In embodiments, the first release profile may depend upon
the water
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solubility of the drug, the second release profile may depend upon the
hydrolysis of the
hydrogel, and the third release profile may depend upon the mass loss of the
hydrogel.
[0047] In yet other embodiments, instead of only a single drug being released
from the
crosslinked polymer at different times, multiple drugs may be released from
the
crosslinked polymer of the present disclosure at different times. Thus, a
first drug merely
incorporated into the polymeric matrix but not bound thereto may be released
either
immediately or shortly after formation of the crosslinked polymer in situ,
while a second
drug covalently bound to the crosslinked polymer through pendant linkages or
incorporated into the polymer backbone may be released later. Similarly, where
three
drugs are included in the crosslinked polymer of the present disclosure, a
first drug
incorporated into the polymeric matrix but not bound thereto may be released
either
immediately or shortly after formation of the crosslinked polymer in situ; a
second drug
covalently bound to the crosslinked polymer through a degradable linkage such
as a
pendant ester linkage may be released later by hydrolysis; and a third drug
covalently
bound to the crosslinked polymer by a pendant nondegradable linkage (such as
an amine
linkage) or incorporated into the polymeric backbone may be released last.
[0048] As noted above, combinations of drugs may be released from compositions
of the
present disclosure at varying times. For example, more than one drug may be
released
during a first release profile, a second release profile, a third release
profile, and the like.
[0049] Examples of suitable drugs which may be delivered by a crosslinked
polymer of
the present disclosure include, but are not limited to, antimicrobial agents,
protein and
peptide preparations, antipyretic, antiphlogistic and analgesic agents, anti-
inflammatory
agents, vasodilators, antihypertensive and antiarrhythmic agents, hypotensive
agents,
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CA 02637524 2008-07-14
antitussive agents, antineoplastic agents, local anesthetics, hormone
preparations, =
antiasthmatic and antiallergic agents, antihistaminics, anticoagulants,
antispasmodics,
cerebral circulation and metabolism improvers, antidepressant and antianxiety
agents,
vitamin D preparations, hypoglycemic agents, antiulcer agents, hypnotics,
antibiotics,
antifungal agents, sedative agents, bronchodilator agents, antiviral agents,
dysuric agents,
glycosaminoglycans, carbohydrates, nucleic acids, inorganic and organic
biologically
active compounds, combinations thereof, and the like. Specific biologically
active agents
include, but are not limited to, enzymes, angiogenic agents, anti-angiogenic
agents,
growth factors, antibodies, neurotransmitters, psychoactive drugs, anticancer
drugs,
antimicrobial agents including antibiotics such as rifampin, chemotherapeutic
drugs,
drugs affecting reproductive organs, genes, oligonucleotides, combinations
thereof, and
the like.
[0050] In embodiments, these bioactive agents may also possess functional
groups
capable of reacting with the crosslinker, the functional polymer, or both.
When these
biologically active agents also contain functional groups, the functional
groups of the
bioactive agent can react with the components of the crosslinked polymer
compositions
of the present disclosure, thereby becoming either attached thereto through a
pendant
linkage or incorporated in the backbone of the resulting crosslinked polymer.
[0051] As noted above, in embodiments a first drug may have one release
profile, with a
second and/or optional third drug having a different release profile.
Nonlimiting
examples of drugs which may be administered utilizing the crosslinked polymer
compositions of the present disclosure and the varying release profiles which
may be
desirable for such drugs, in embodiments, are summarized below in Table 1.
19
CA 02637524 2008-07-14
TABLE 1
0-3 days 0-30 days 0-90 days
Hemostatic agents Analgesics Anti-cancer agents
Topical anesthetics anti-inflammatories anti-scarring agents
Anti-adhesion agents Anti-adhesion agents proteins: BMP's, VGF,
TGF-beta
Antibiotics antibiotics
[0052] Thus, in embodiments, the time of release of a first agent may be from
about 0
days to about 10 days, the time of release of a second agent may be from about
0 days to
about 30 days, and the time of release of a third agent may be from about 0
days to about
180 days. In other embodiments, the time of release of a first agent may be
form about 2
days to about 8 days, the release of a second agent may be from about 9 days
to about 29
days and the release of a third drug may be from about 30 days to about 120
days.
[0053] Various combinations of the above drugs and different release profiles
may be
utilized. Thus, depending upon the condition to be treated, one could select
the desired
drug, deteiiiiine the desired release rate of such drug, and then incorporate
the drug in a
crosslinked polymer of the present disclosure as described above through
physical or
chemical incorporation, thereby achieving the desired rate of release from the
crosslinked
polymer of the present disclosure. For example, for wound healing, it may be
desirable
to have a drug delivery device including a crosslinked polymer of the present
disclosure
initially release a hemostatic agent, anti-adhesion agent, or combinations
thereof,
followed by the release of an anti-inflammatory agent, followed by the release
of an anti-
CA 02637524 2008-07-14
scarring agent. For cardiac surgery, it may be desirable for a drug delivery
device
including a crosslinked polymer of the present disclosure to initially release
an anti-
adhesion agent, followed by a long-term release of an anti-arrhythmic agent.
[0054] Moreover, the crosslinked polymer itself, in embodiments, possesses
anti-
adhesion properties which may be utilized in conjunction with additional drugs
as
described above. Thus, in embodiments, the crosslinked polymer itself may be
used as
an anti-adhesion agent, an adhesive, or a sealant, with additional drugs
incorporated
therein or bound thereto for other indications.
[0055] In embodiments, imaging agents such as iodine or barium sulfate, or
fluorine, can
also be combined with the compositions of the present disclosure to allow
visualization
of the polymer at the time of application or thereafter through the use of
imaging
equipment, including X-ray, MRI, and CAT scan equipment. Other imaging agents
which may be included are within the purview of those skilled in the art and
include, but
are not limited to, substances suitable for use in medical implantable medical
devices,
such as 1-1.)&C dyes 3 and 6, eosin, methylene blue, indocyanine green, or
colored dyes
normally found in synthetic surgical sutures. Suitable colors include green
and/or blue
because such colors may have better visibility in the presence of blood or on
a pink or
white tissue background.
[0056] The imaging agents may be added in small amounts, in embodiments less
than
about 1% weight/volume, in other embodiments less than about 0.01%
weight/volume,
and in yet other embodiments less than about 0.001% weight/volume
concentration.
[0057] In embodiments, the drug delivery devices including the above
biocompatible
crosslinked polymers may be formed "in situ" at a surgical site in the body.
In other
21
CA 02637524 2014-11-24
embodiments, the components and drugs may be combined prior to application,
thus
pendant attachment of a drug or incorporation of a drug into the backbone of a
precursor
may first occur ex vivo, with the rest of drug incorporation and polymer
formation
occurring in situ.
[0058] In using the crosslinked composition for drug delivery as mentioned
above, the
amount of functional polymer, crosslinker and the bioactive agent introduced
in the host
may depend upon the particular drug and the condition to be treated.
Administration may
be by any convenient means such as syringe, cannula, trocar, catheter and the
like.
Methodologies and devices for performing "in situ" gelation, developed for
other
adhesive or sealant systems such as fibrin glue or sealant applications, may
be used
herein. In embodiments, one may use specialized devices to apply the precursor
solutions, such as those described in U.S. Patent Numbers 4,874,368,
4,631,055,
4,735,616, 4,359,049, 4,978,336, 5,116,315, 4,902,281, 4,932,942, and
International
Application No. WO 91/09641.
[0059] To prepare drug delivery devices herein, the bioactive agents described
above
may be mixed with the crosslinkable polymer precursors prior to crosslinking
the
polymer or during the aseptic manufacturing of the functional polymer, the
crosslinker, or
TM
both. In embodiments, functional polymers made from inert polymers like
PLURONIC,
TNI
TETRONICS or TWEEN components may be suitablel in releasing small molecule
hydrophobic drugs. As described above, the bioactive agent may be merely
physically
incorporated in the resulting polymeric matrix, covalently bound thereto, or
both.
22
CA 02637524 2008-07-14
=
[0060] In embodiments, the active agent or agents may also be present in a
separate
phase when a crosslinker and crosslinkable functional polymers are reacted to
produce a
crosslinked polymer network or gel. This phase separation may prevent
participation of
the bioactive substance in the chemical crosslinking reaction such as the
reaction between
NHS esters and amine groups, which may be desirable in some embodiments. The
separate phase may also help to modulate the release kinetics of the active
agent from the
crosslinked material or gel, where the "separate phase" could be an oil (oil-
in water
emulsion), biodegradable vehicle, and the like. Biodegradable vehicles in
which the
active agent may be present include: encapsulation vehicles, such as
microparticles,
microspheres, microbeads, micropellets, and the like, where the active agent
is
encapsulated in a bioerodable or biodegradable polymers such as polymers and
copolymers of: poly(anhydride)s, poly(hydroxy acid)s, poly(lactone)s,
poly(trimethylene
carbonate), poly(glycolic acid), poly(lactic acid), poly(glycolic acid)-co-
poly(glycolic
acid), poly(orthocarbonate), poly(caprolactone), crosslinked biodegradable
hydrogel
networks like fibrin glues or fibrin sealants, caging and entrapping
molecules, like
cyclodextrin, molecular sieves, and the like. Microspheres made from polymers
and
copolymers of poly(lactone)s and poly(hydroxy acid)s may be useful as
biodegradable
encapsulation vehicles.
[0061] In embodiments, the functional polymer along with bioactive agent, with
or
without an encapsulating vehicle, may be administered to the host along with
an
equivalent amount of crosslinker and aqueous buffers. The chemical reaction
between
crosslinker and the functional polymer solution readily takes place to form a
crosslinked
gel and acts as a depot for release of the active agent to the patient. As
noted above, in
23
CA 02637524 2008-07-14
other embodiments the bioactive agent may become linked to the polymer through
a
pendant linkage or, in other embodiments, incorporated into the polymer
backbone
during crosslinking. Such methods of drug delivery may be useful in both
systemic and
local administration of an active agent.
[0062] Controlled rates of drug delivery also may be obtained with the system
of the
present disclosure by the degradable, covalent attachment of the bioactive
molecules to
the crosslinked hydrogel network. The nature of the covalent attachment can be
controlled to enable control of the release rate from hours to weeks or
longer. By using a
composite made from linkages with a range of hydrolysis times, a controlled
release
profile may be extended for longer durations.
[0063] It will be appreciated that various of the above-disclosed and other
features and
functions, or alternatives thereof, may be desirably combined with many other
systems or
applications. Also that various presently unforeseen or unanticipated
alternatives,
modifications, variations or improvements therein may be subsequently made by
those
skilled in the art which are also intended to be encompassed by the following
claims.
Unless specifically recited in a claim, steps or components of claims should
not be
implied or imported from the specification or any other claims as to any
particular order,
number, position, size, shape, angle, color, or material.
24
