Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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METHODS AND COMPOSITIONS FOR THE DELIVERY QF
PHARMACEUTICAL AGENTS AND/OR THE PREVENTION OF ADHESIONS
FIELD OF THE INVENTION
The present invention generally relates to pharmaceutical preparations and
methods of
their use. More particularly, the present invention relates to preparations
suitable for the
reduction of adhesion formation in mammals or the delivery of pharmaceutically
active
compounds.
BACKGROUND OF THE INVENTION
Over the years, methods have been developed to achieve the efficient delivery
of
therapeutic or diagnostic agents to a mammal requiring such treatment. Aqueous
liquids
which can be applied at room temperature in a free flowing state but which
forms a semi-
solid geI when warmed to body temperature have been used in such capacities
for some time.
Such systems combine ease of application with greater retention at the site of
application than
the use of exclusively free flowing vehicles. For example, in U.S. Pat. No.
4,188,373,
incorporated herein by reference, Pluronic~ polyols are used in aqueous
compositions to
provide thermally gelling aqueous systems. Adjusting the concentration
provides the desired
sol-gel transition temperature. More particularly, the lower the concentration
of the
2o incorporated polymer the higher the sol-gel transition temperature. At a
critical polymer
concentration minimum, the system reaches a point where a gel will not form at
any
physiologically compatible temperature. While such vehicles are a substantial
improvement
over prior art systems, it is hard to precisely adjust the sol-gel temperature
to the desired
value.
In U.S. Pat. Nos. 4,474,751; '752; '753; and 4,478,822, each incorporated
herein by
reference, drug delivery systems are described which utilize thermosetting
gels. In these
systems both the gel transition temperature and/or rigidity of the gel may be
modified by
adjustment of the pH andlor the ionic strength as well as by the concentration
of the polymer.
Although such vehicles may be efficiently used for the delivery of bioactive
agents,
3o establishment and maintenance of the desired sol-gel temperature and/ or
persistence of the
gel may be complicated by several variables including the Eocalized physiology
of the
mammalian subject. Accordingly, a need still exists for pharmaceutical
preparations or drug
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delivery compositions that allow for the establishment of a precise soi-gel
transition
temperature and accurate control of the gel dissolution rate in vivo.
Control of such characteristics is also desirable when similar polymeric gels
are used
for the prevention of adhesion formations in mammals. Adhesions are thought to
form
following a trauma or injury to the peritoneum. This results in increased
vascular
permeability, which produces an inflammatory exudate and results in the
formation of a fibrin
matrix. In normal wound healing, the fibrin matrix is removed by fibrinolysis,
and
subsequent fibroblast proliferation results in remesotheiialization. However
under the
ischemic conditions present following surgical trauma the fibrinolytic process
is suppressed
lU and the fibrin matrix may persist. If it persists until about day three,
significant collagen
deposition within the fibrin matrix, can lead to adhesion formation.
As will be appreciated by those skilled in the art, prevention of adhesions
has been
the subject of various efforts since the beginning of this century (see, for
example, Surgery,
Gynecology and Obstetrics, 13 3:497-509, 502-503 ( 1971 )). These efforts have
included
means of preventing the f brin-coated walls of the intestine from contacting
one another by
distending the abdomen with oxygen or filling the abdomen with various liquids
such as
saline solution, paraffin, olive oil, lanolin, concentrated dextrose solution,
various
macromolecular solutions and silicones.
High molecular weight dextran either alone or in combination with dextrose has
also
2o been used (Holtz, et al., Fertility and Sterility, 33:660-662 (1980);
34:394-395 (1980)). One
such formulation, HYSKON~ (Pharmacia, Piscataway, N.J.), which comprises 32%
aqueous
solution of dextran 70 containing 10% dextrose, was effective in reducing
peritoneal
adhesions subsequent to surgery. However, it has been reported that HYSKON has
a
tendency to support bacterial proliferation. Further concern has been
expressed over the
anaphylactoid potential of dextran~ (DiZerega et al., Fertility and Sterility,
40:612-619
(1983)). In addition, the benefit of dextran 70 in preventing post-operative
adhesions was
shown to be limited to the more dependent regions of the pelvis.
The use of resorbable fibrous barriers to separate injured tissues has also
been
described (Linsky, J. Reprod. Med., 17-20 (1987)). For example, TC-7 (Johnson
and Johnson
3o Products, Inc., New Brunswick, N.J.), an oxidized cellulose fabric barrier,
has been used as a
treatment to prevent organ adhesion to the peritoneum. Other solid sheet
devices include
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polytetrafluoroethylene (Gore-Tex~, W. L. Gore) and crosslinked hyaluronic
acid
(Seprafilm~Genzyme Corp.).
Chondroitin sulfate and sodium carboxymethyl cellulose have also been used to
prevent the formation of postoperative adhesions in the rabbit uterus (Oelsner
et al., J.
s Reprod Med 32:812-814 (1987)). Chondroitin sulfate solutions have also been
proposed for
intraperitoneal use in the prevention of adhesions in rabbits
More recently, aqueous gel compositions comprising polyalkylene polymers have
been shown to successfully reduce adhesions (U.S. Pat. No., 5,366,735,
incorporated herein
by reference). These compositions can be applied below room temperature as a
liquid and
to form semi-solid gels when warmed to body temperature. However, as with the
aforementioned drug delivery compositions, precise control of the sol-gel
transition
temperature and dissolution rate of the gel within the physiological
environment still present
problems in many cases. Accordingly, despite these previous efforts, a need
exists for
improved means to treating and/or preventing post-surgical adhesions.
1s As such, it is an object of the present invention to provide polymeric gel
compositions
which allow for precise control of the sol-gel transition temperatiue and/or
dissolution rate of
the gel once formed.
It is a further objective of the present invention to provide gelling drug
delivery
preparations, and methods for their use, comprising at least one bioactive
agent and exhibiting
2o desired sol-gel transition tempe~ratmes andlor gel dissolution rates.
It is yet another objective of the present invention to provide gelling
compositions, and
methods of their use in preventing or reducing adhesions, which exhibit
desired sol-gel
transition temperatures and/or gel dissolution rates.
2s SUMMARY OF THE INVENTION
The present invention accomplishes these and other objectives by providing
polymeric
compositions that exhibit well defined sol-gel transition temperatures (or
defined ranges of
temperatures) and/or established dissolution rates. In one embodiment, the
disclosed
compositions generally comprise at least one constitutive polymer and at least
one modifier
3o polymer that may be used to modify or control the dissolution rate of gel
once it has been
formed. In another preferred embodiment, the compositions of the present
invention
comprise at least one constitutive polymer and at least one hydrophilic co-
surfactant whereby
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the gelation temperature (or sol-gel transition temperature) of the
composition may be
controlled or modified. Of course, it will be appreciated that the
compositions may comprise
at least one constitutive polymer in combination with both at least one
modifier polymer and
at least one hydrophilic co-surfactant to provide preparations having both
selected gelation
temperatures and superior dissolution times. Yet other preferred embodiments
of the
invention will comprise the aforementioned preparations and at least one
bioactive agent. In
any event, the polyphase preparations of the present invention may be used to
retard or
prevent the formation of scar tissue or adhesions in a mammal, for the
prolonged delivery of a
bioactive agent or both.
io Accordingly, in selected embodiments the present invention comprises
methods for
the reduction of adhesion or scar tissue formation comprising the
administration of the
disclosed preparations to a mammal in need thereof. Yet other selected
embodiments
comprise methods of delivering a bioactive agent to a mammal comprising
administering the
disclosed polyphase compositions incorporating a pharmaceutically effective
amount of at
least one bioactive agent to a mammal in need thereof. With respect to each of
the
aforementioned embodiments the compositions of the present invention will be
administered
as a relatively free flowing liquid that gels upon contact with the mammalian
tissue to provide
a viscoelastic senu-solid barrier or mask that may remain in place for an
extended period.
In preferred embodiments of the instant invention the constitutive polymer
will be a
2o polyoxyalkylene copolymer. More particularly, in selected embodiments the
constitutive
polymer will be selected from the group consisting of polyoxyalkylene block
copolymers,
polyoxyalkylene polyethers and combinations thereof. In especially preferred
embodiments
of the invention, the constitutive polymer will comprise Poloxamer 407. The
constitutive
polymer or polymers may be present at any concentration that provides the
desired gel
viscosity and/or viscoelastic properties. Preferably, the constitutive
polymers are present in a
concentration which, when combined with the other components of the
preparation, allows
for the administration of the composition as a relatively free flowing liquid
which gels upon
contact with mammalian tissue.
Besides the constitutive polymer discussed above, selected embodiments of the
3o invention will comprise at least one modifier polymer that may be used to
modify the
dissolution rate of the composition. Essentially, modifier polymers compatible
with the
present invention comprise any polymeric entity capable of slowing or
retarding the
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dissolution rate of the constitutive polymer once it has gelled. That is, the
modifier polymers
of the present invention comprise any polymer that, when added to the
constitutive
polymer(s), provides for a slower dissolving or diffusing gel when compared
with a gel
formed from pure constitutive polymers) under equivalent conditions. Preferred
modifier
polymers typically have a relatively high average molecular weight on the
order of tens or
hundreds of thousands. While a large number of polymeric compounds are
suitable for use as
modifier polymers, particularly preferred compounds comprise cellulose ethers
(carboxymethyl cellulose) and Carbopols (e.g. Carbopol 940-NF). The absolute
incorporated
concentration of the modifier polymers in the compositions of the present
invention is not
critical and may be adjusted to provide the desired dissolution rates and/or
retention times.
In addition to the aforementioned elements, selected embodiments of the
compositions disclosed herein may further comprise one or more hydrophilic co-
surfactants
which may be used to modify the gelation temperature (sol-gel transition
temperature) of the
resulting preparation. More particularly, selected hydrophilic co-
surfactant(s) may be added
to compositions comprising a constitutive copolymers) or compositions
comprising
constitutive copolymers) and modifier polymers) to alter or modify the
gelation temperature
of the resulting composition when compared to similar compositions not
comprising the
hydrophilic co-surfactant. In especially preferred embodiments the hydrophilic
may be added
at an effective concentration to lower the gelation temperature of the
composition so as to
2o provide for more rapid and complete gelation upon contact with the
relatively high
temperature mammalian tissue. While a number of compounds may be used as
hydrophilic
co-surfactants in accordance with the teachings herein, particularly preferred
embodiments of
the present invention incorporate fatty acid soaps such as sodium laureate,
sodium caprate or
sodium caprylate. Of course it will be appreciated that combinations of
hydrophilic co-
surfactants may be incorporated in the compositions of the present invention
to provide the
desired transition temperature or transition temperature range.
As previously alluded to the preparations of the present invention may further
include
one or more selected bioactive agents. More specifically, pharmaceutically
effective amounts of
both hydrophilic and lipophilic bioactive agents may be advantageously
delivered using the
3o preparations of the present invention. Thus, in accordance with the
aforementioned
embodiments, bioactive agents compatible with the present invention include,
but are not
limited to, antibiotics, antivirals, mydriatics, antiglaucomas, anti-
inflammatories,
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antihistaminics, antineoplastics, anesthetics, ophthalmic agents, enzymes,
cardiovascular agents,
polynucleotides, genetic material, viral vectors, immunoactive agents, imaging
agents,
immunosuppressive agents, peptides, proteins, physiological gases,
gastrointestinal agents and
combinations thereof. Particularly preferred compositions may comprise one or
more
s humectants, bactericides, bacteriostatic agents, fibrinolytic agents or
agents effective in
preventing leukocyte migration into the area of surgical injury.
Pharmaceutically effective
amounts of the selected bioaetive agents may be determined using techniques
well known in the
art. It will further be appreciated that the bioactive agents may be
incorporated in the form of
relatively insoluble solid particulates or associated with insoluble polymeric
particulates.
1o It will be appreciated that, in accordance with the teachings herein, the
preparations of
the present invention, with or without an incorporated bioactive agent, may be
administered to a
patient using a route of administration selected from the group consisting of
topical,
subcutaneous, pulmonary, synovial, intramuscular, intraperitoneal, nasal,
vaginal, rectal, aural,
oral and ocular routes. The administered composition preferably gels upon
contact with the
15 relatively warm mammalian tissue and may act as a depot for the prolonged
delivery of one or
more incorporated bioactive agents. In other embodiments the gelled
compositions may act as a
barrier or film which prevents or retards the formation of adhesion or scar
tissue. Since the
present invention provides particularly effective methods for the prevention
of post-surgical and
other adhesion fornation, administration of pharmaceutically effective amounts
to the
2o peritoneal, pelvic or pleural cavity is especially preferred. As such
adhesions are often
associated with injury to mammalian organs, those skilled in the art will
appreciate that the
compositions are particularly useful when applied to the selected area during
or immediately
following surgery.
Besides the components mentioned above, the compositions of the present
invention
25 may further comprise pharmaceutically acceptable stabilizers, preservatives
and buffers,
preferably in an amount sufficient to maintain the pH of the composition at
about pH 7.410.2.
Other objects, features and advantages of the present invention will be
apparent to those
skilled in the art from a consideration of the following detailed description
of preferred
exemplary embodiments thereof taken in conjunction with the associated Figures
which will
3o first be described briefly.
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BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graphical representation of an exemplary phase diagram for a
prior art
composition comprising a constitutive polymer;
Figure 2 illustrates an equilibrium phase diagram of 20% w/w poloxamer 407
(407F)
s in tromethamine/maleate buffer with added sodium caprate with arrows
indicating that the
cloud point temperature is greater than the highest temperature measured, i.e.
140 °C;
Figure 3 is a graphical representation of a gelation profile of 1%, 3% and 5%
(w/w)
sodium caprylate in 20% w/w poloxamer 407 (407F) in hypotonic
tromethaminelmaleic acid
buffer;
t o Figure 4 is a graphical representation illustrating the effect of fatty
acid soap
concentration on the lower gelation temperature (LGT) of 20% w/w poloxamer
407F
solutions for soaps of varying alkyl chain lengths and degrees of saturation.
DETAILED DESCRIPTION OF THE INVENTION
t 5 Compositions and methods are disclosed herein for delivering bioactive
agents and/or
reducing post-surgical adhesion fonmation/reformation in mammals following
injury to the
organs or tissues, particularly those of the peritoneal, pelvic or pleural
cavity. The
compositions of the invention are also useful in reducing adhesion
formation/reformation in
other body spaces such as the subdural, extraocular, intraocular, otic,
synovial, tendon sheath,
20 or those body spaces created either surgically or accidentally. In selected
embodiments of the
invention, the concentration of the constitutive polymer in the disclosed
compositions may be
adjusted to take advantage of the gelation properties of certain
polyoxyalkylene polymers.
For instance, at certain concentrations aqueous solutions of said polymers
form clear gels at
mammalian body temperatures but are liquids at ambient temperatures or below.
Of course,
25 it is a major advantage of the present invention that selected hydrophilic
co-surfactants may
also be used to modify the gelation temperature of the disclosed compositions.
This
advantageously allows the selected compositions of the present invention to be
administered
as a relatively free flowing liquid which gels or thickens at the body
temperature of the
mammalian subject. However, it should be appreciated that compositions may be
formed in
3o accordance with the teachings herein that do not gel or thicken following
application to the
selected area or tissue.
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Preferably, the osmolality and pH of the compositions are adjusted to match
the pH
and osmotic pressure of mammalian bodily fluids, i.e. approximately pH 7.4.
Subsequent to
deposition of the compositions of the invention in the peritoneal, pelvic, or
pleural cavity of a
mammal, or other body spaces the constitutive polymer (i.e., a polyoxyalkylene
block
copolymer) is eventually excreted in a non-metabolized form, mainly through
the kidney.
The present compositions may also be used as a distending medium during
diagnostic
or operative endoscopic procedures, such as, for example, for intrauterine
procedures. In
addition to the anti-adhesive properties, since certain aqueous concentrations
of the preferred
polyoxyalkylene block copolymers form a clear gel, their use is well suited
for visualization
to of interior cavities.
In a further advantage, the disclosed formulations provide a barrier between
tissues for
hours or days. Because they are applied as liquids, they are easier to use,
particularly for
laparoscopic surgical procedures. That is, the compositions of the instant
invention may be
administered though a relatively small incision using a cannula or catheter
assembly.
is Those skilled in the art will appreciate that the disclosed compositions of
the present
invention are preferably aqueous based preparations. Thus, the compositions
typically
comprise water in an amount of from about 60% to about 90%, by weight,
preferably, about
70% to about 85%, by weight, and most preferably, about 75% to about 82% by
weight,
based upon the total weight of the composition.
2o As used herein, the terms "peritoneal" and "abdominal" cavity are used as
synonyms, as are the terms "pleural" and "thoracic" cavity.
As used herein, the term "polyaikylene block polymers" include those polymers
which form clear gels at mammalian body temperatures but are liquids at
ambient
temperatures or below.
25 As used herein, the term "gel" is defined as a solid or semisolid colloid
containing a
certain quantity of water. The colloidal solution with water is often called a
"hydrosol".
A. Constitutive Polymers:
As set forth above, the present invention comprises at least one constitutive
polymer
3o dispersed in a aqueous medium. In preferred embodiments of the instant
invention the
constitutive polymer will be a polyoxyalkylene polymer. More particularly, in
selected
embodiments the constitutive polymer will be selected from the group
consisting of
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polyoxyalkylene block copolymers, polyoxyalkylene polyethers and combinations
thereof. In
especially preferred embodiments of the invention, the constitutive polymer
will comprise
poloxamer 407. The constitutive polymer or polymers may be present at any
concentration
that provides the desired gel viscosity and/or viscoelastic properties.
Preferably, the
s constitutive polymers are present in a concentration which, when combined
with the other
components of the preparation, allows for the administration of the
composition as a
relatively free flowing liquid which gels upon contact with mammalian tissue.
Thus, according to a preferred embodiment, the compositions comprise one or
more
polyoxyalkylene block copolymers of the formula
to
YI(A)n E-Hlx (I)
wherein A is a polyoxyalkylene moiety;
x is at least 2;
1s Y is derived from water or an organic compound containing x reactive
hydrogen
atoms;
E is a polyoxyethylene moiety;
n has a value such that the average molecular weight of A is at least about
500; and
the total average molecular weight of the copolymer is at Ieast about 5000.
2o Preferably, the polyoxyalkylene moiety A has an oxygen/carbon atom ratio of
less
than 0.5. According to one embodiment of the invention, A is derived from an
alkylene oxide
selected from the group consisting of butylene oxide, propylene oxide or a
mixture thereof.
Preferably, A is a polyoxypropylene moiety, and preferably has an average
molecular weight
of from about 3,000 to about 4,000 g mof'.
25 The polyoxyethylene moiety E preferably constitutes from about 60 to about
85% by
weight of the copolymer, more preferably at least about 70%.
In one embodiment, Y is derived from a water soluble organic compound having 1
to
about 6 carbon atoms. In another embodiment, Y is derived from an organic
compound
selected from the group consisting of propylene glycol, glycerin,
pentaerythritol
3o trimethylolpropane, ethylenediamine and mixtures thereof.
According to one embodiment, the copolymer has the formula:
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HO(C~H40)b(C4H80)a(CZH40)bH (II)
wherein a and b are integers such that (C4H80)a has a molecular weight of at
least about 500.
Useful polyoxyalkylene block copolymers which will form gels in aqueous
solutions
can be prepared using a hydrophobe base (such as A in Formulas (I) and (II))
derived from
propylene oxide, butylene oxide or mixtures thereof. These block copolymers
and
representative methods of preparation are further generally described in U.S.
Pat. Nos.
2,677,700; 2,674,619; and U.S. Pat. No. 2,979,528, incorporated herein by
reference.
Generally, the polyoxybutylene-based block copolymers useful in the
compositions of
1o the invention are prepared by first condensing 1,2 butylene oxide with a
water soluble organic
compound initiator containing 1 to about 6 carbon atoms such as 1,4 butylene
glycol or
propylene glycol and at least 2 reactive hydrogen atoms to prepare a
polyoxyalkylene
polymer hydrophobe of at least about 500, preferably at least about 1000, most
preferably at
least about 1500 average molecular weight. Subsequently, the hydrophobe is
capped with an
ethylene oxide residue. Specific methods for preparing these compounds are
described in U.S.
Pat. No. 2,828,345 and British Patent No. 722,746, both of which are herein
incorporated by
reference.
In a further preferred embodiment, the compositions comprise polyoxyethylene-
polyoxypropylene block copolymers of the formula (III):
HO(C2H4O)b(CsHsO).(CzHaO)bH (III)
wherein a is an integer such that the hydrophobe base represented by (C3H60),
has a
molecular weight of at least about 900, preferably at least about 2500, most
preferably at least
about 4000 average molecular weight, as determined by hydroxyl number. In a
particularly
preferred embodiment, the compositions comprise a polyxyethylene-
polyoxyproplyene block
copolymer of formula (III), having a polyoxyproplyene hydmphobe base average
molecular
weight of about 4000, a total average molecular weight of about 12,000 and
containing
oxyethylene groups in the amount of about 70% by weight of the total weight of
the
3o copolymer. This copolymer is sold under the trademark PLURONIC~ F-127 (also
known as
poloxamer 407)(BASF Corp, Parsippany, N.J.).
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More specifically, poloxamer 407 is a tri-block copolymer containing two
polyoxyethylene blocks flanking a central polyoxypropylene block. The USP
material has an
average molecular formula of (EO),°,-(PO)~-(E~),°,, and average
molecular weight of ca.
12,000 g mo1-'. When placed in an aqueous solution in accordance with the
present
invention, poloxamer 407 self assembles so as to remove contact h~~n
polyoxypropylene groups and water (i.e. self assembly is driven by the
hydrophobic effect).
The self assembled units are termed micelles. The structure of the micelles
and the
interactions between them is strongly dependent on temperature. Interestingly,
a Large
increase in solution viscosity (i.e. gel-phase formation) is noted with
increasing temperature.
to Gel phase formation occurs as a result of organization of the micelles into
a three-
dimensional cubic array.
In another embodiment, the copolymer has the formula:
~)xN-(CHZ)2-N(R)z
wherein R is H(OCzH4)b(OC3H6),-; and a and b are integers such that the
hydrophobe base
represented by (C3H60)a has a sum average molecular weight of at least about
2000, about 3
to about 5%. The hydrophobe base is prepared by adding propylene oxide for
reaction at the
site of the four reactive hydrogen atoms on the amine groups of
ethylenediamine. An
2o ethylene oxide residue is used to cap the hydrophobe base.
In all permutations of copolymers of formula (I), it is preferred that the
polyoxyethylene chain constitute frora about 60 to about 85% by weight of the
colpolymer,
preferably at least about 70%. It is further preferred that the copolymer have
a total average
molecular weight of at least about 5000, preferably from about 9,000 to about
15,000 as
2s specified in the USP).
The procedure used to prepare aqueous solutions which form gels of the
polyoxyalkylene block copolymers is well known. Either a hot or cold process
for forming
the solutions can be used. A cold techniaue invnlvet the dens of riieenl«;".r
fl,e
polyoxyalkylene block copolymer at a temperature of about 5° to about
10° C in water. When
3o solution is complete the system is brought to room temperature whereupon it
forms a gel. If
the hot process of forming the gel is used the polymer is added to water
heated to a
temperature of about 75 °C to about 85 °C, with slow stirring
until a clear homogeneous
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solution is obtained. Upon cooling, a clear gel is formed. Block co~lymer gels
containing
polyoxybutylene hydrophobes must be prepared by the above hot process, since
these will not
liquefy at low temperatures.
The organic compound initiator which is utilized in the preparation of the
polyoxyaikylene block copolymers generally is water or an organic compound,
and can
contain a plurality of reactive hydrogen atoms. Preferably, Y in formulas (I)
and (II) above is
defined as derived from a water soluble organic compound having 1 to about 6
carbon atoms
and containing x reactive hydrogen atoms where x has a value generally, of at
least 1,
preferably, a value of at least 2. Failing within the scope of the compounds
from which Y is
1 o derived from water soluble organic compounds having at least two reactive
hydrogen atoms
are water soluble organic compounds such as propylene glycol, glycerin,
pentaerythritol,
trimethylolpmpane, ethylenediamine, and mixtures thereof and the like.
The oxypropylene chains can optionally contain small amounts of at least one
of
oxyethylene or oxybutylene groups. Oxyethylene chains can optionally contain
small
amounts of at least one of oxypropylene or oxybutylene groups. Oxybutylene
chains can
optionally contain small amounts of at least one of oxyethylene or
oxypropylene groups. The
physical form of the polyoxyalkylene block copolymers can be a viscous liquid,
a paste or a
solid granular material depending upon the molecular weight of the polymer.
In addition to those polyoxyalkylene polymers described above, the present
2o compositions may comprise other polyoxyalkylene polymers which form gels at
low
concentrations in water. Examples of such polymers are described in U.S. Pat.
No.
4,810,503, incorporated herein by reference. These polymers are prepared by
capping
conventional polyoxyalkylene polyether polyols with an alphaolefin epoxide
having an
average of about 20 to about 45 carbon atoms, or mixtures thereof. Aqueous
solutions of
these polymers gel in combination with surfactants, which can be ionic or
nonionic. The
combination of the capped polyether polymers and the surfactants provide
aqueous gels at
low concentrations of the capped polymer and surfactant which generally do not
exceed 10%
by weight total.
Conventional copolymer polyether polyols are prepared by preparing block or
heteric
3o intermediate polymers of ethylene oxide and at least one lower alkylene
oxide having 3 to 4
carbon atoms as intermediates. These are then capped with the alpha-olefin
epoxide.
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Ethylene oxide homopolymers capped with the alpha-olefin oxides are also
useful as
intermediates.
The heteric copolymer intermediate is prepared by mixing ethylene oxide and at
least
one lower alkylene oxide having 3 to 4 carbon atoms with a low molecular
weight ~ active
s hydrogen-containing compound initiator having at least two active hydrogens
and preferably,
2 to 6 active hydrogen atoms such as a polyhydric alcohol, containing from 2
to 10 carbon
atoms and from 2 to 6 hydroxyl groups, heating said mixture to a temperature
in the range of
about 50° C to 150° C, preferably, from 80° C to
130°, under an inert gas pressure, preferably,
from about 30 psig to 90 psig.
1 o A block copolymer intermediate is prepared by reacting either the ethylene
oxide or
the alkylene oxide having 3 to 4 carbon atoms with the active hydrogen-
containing compound
followed by reaction with the other aikylene oxide.
The ethylene oxide and the alkylene oxides having from 3 to 4 carbon atoms are
used
in the intermediates in amounts so that the resulting polyether product will
contain at least 10
15 percent by weight, preferably about 70 percent to about 90 percent by
weight, ethylene oxide
residue. The ethylene oxide homopolymer intermediate is prepared by reacting
ethylene
oxide with the active hydrogen-containing compound. The reaction conditions
for preparing
the block copolymer and ethylene oxide homopolymer intermediates are similar
to those for
the heteric copolymer intermediate. The temperature and pressure are
maintained in the
2o above ranges for a period of about one hour to ten hours, preferably one to
three hours.
The alpha-olefin oxides which are utilized to modify the conventional
polyether
intermediates are those oxides, and commercially available mixtures thereof,
generally
containing an average of about 20 to 45, preferably about 20 to 30, carbon
atoms. The
amount of alpha-olefin required to obtain the more efficient capped polyethers
is generally
2s about 0.3 to 10 percent, preferably about 4 to 8 percent, of the total
weight of the polyethers.
Further description regarding the preparation of heteric and block copolymers
of
alkylene oxides and ethylene oxide homopolymers is described in the art (LJ.S.
Pat. Nos.
3,829,506, 3,535,307; 3,036,118; 2,979,578; 2,677,700; and 2,675,619,
incorporated herein
by reference.)
3o Whatever constitutive polymer is selected the absolute concentration
present in the
compositions of the present invention is determined by the gelation
characteristics desired.
One major advantage of the present invention is that the desired gelation
temperatures and
t3
CA 02316248 2000-06-22
WO 99132151 PCT/US97I23865
viscosity of the resulting gels may be adjusted through the addition of
modifier polymers and
hydrophilic co-surfactants. This allows the use of lower concentrations of
constitutive
polymer without markedly reducing the ultimate gel characteristics of the
composition.
However, for the purposes of the present invention, exemplary concentrations
of constitutive
polymer may iange from approximately 2% w/w to SO% w/w and more preferably
from 4%
to 30% w/w and even more preferably from 16% to 28% w/w.
B. Modifier Polymers:
As set forth above any biocompatible polymeric entity that modifies the
dissolution
1o time of the gel resulting from the administration of the compositions of
the present invention
may be used in accordance with the teachings herein. In general terms,
preferred modifier
polymers to alter the dissolution time should preferably have the following
characteristics: (a)
high molecular weight; (b) effective swelling in water but poor dissolution:
(c) compatibility
with the constitutive polymer and, in particular, poloxamers; and (d)
stability to extremes in
IS heat and pH. Those skilled in the art will appreciate that the phrase
"alter the dissolution
time" is held to mean the alteration of the gel dissolution time in vitro or
in vivo with respect
to a gel comprising constitutive polymer without the modifier polymer under
similar
conditions. It will further be appreciated that the alteration of dissolution
times or release
rates of the constitutive polymer from the gel matrix may be used to optimize
formulations
20 for antiadhesion applications as well as for other applications including
controlled drug
delivery.
Without wishing to be bound by any one particular theory, it is believed that
release
(and subsequent gel dissolution) is a function of several physicochemical
characteristics
within the gel, and can be modified by the addition of high molecular weight
polymers such
2s as sodium carboxymethyl cellulose,,polyacrylates (i.e. Carbopols) or other
polyester based
polymers. It appears that the dissolution rate is modified by the formation of
a strong
polymeric matrix (i.e. the modifier polymeric matrix) that controls the
release of the
constitutive polymer via diffusion through the formed modifier polymer
interstices. One
possible reason for this effect may be that the constitutive polymer has to
diffuse around the
30 long linear molecules of the incorporated modifier polymer. In general,
this effect appears to
be most pronounced when the selected modifier polymers) have a molecular
weight greater
than or equal to approximately 500,000 although modifier polymers of much
lower molecular
14
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WO 99/32151 PC1'/US97IZ3865
weight (i.e. on the order of 50,000). In particularly preferred embodiments
the selected
modifier polymers will combine a relatively high molecular weight with a
biodegradable
moiety in their structure to speed excretion. High molecular weight polylactic-
glycolide
copolymers which are broken down by hydrolytic decomposition are one example
of such a
s polymer. It should be emphasized that these modifier polymers may also be
used to slow the
dissolution (and hence prolong delivery time) of any incorporated bioactive
agent.
While any polymeric entity possessing the appropriate characteristics may be
incorporated in the compositions of the present invention, exemplary polymers
compatible
with the teachings herein include, but are not limited to: poly(acrylic acid),
polystyrene
Io sulfonate), carboxymethylcellulose, polyvinyl alcohol), polyethylene
oxide),
poly(vinylpyrrolidone), shellac, cellulose acetate phthalate, cellulose
acetate succinate,
polyvinyl acetate phthalate, hydroxypropylmethylcellulose acetate,
poly(methacrylic acid-co-
methylmethacrylate), poly(methyl acrylate), poly(methyl methacrylate),
poly(glutamic acid),
poly(lactic acid), poly(lactic-glycolide), poly(glycolic acid), poly(s-
capmlactone), poly((3-
15 hydroxybutyric acid), poly((3-hydroxyvaleric acid), polydioxanone,
polyethylene
terephthalate), poly (malic acid), poly(tartronic acid), poly(ortho esters),
polyanhydrides,
polycyanoacrylate, poly(phosphoesters), polyphosphazenes, poly(lysine),
polysaccharides,
chitosan, polyelectrolytes, gelatin, gum arabic, poly(anzino acids), agar,
furcelleran, alginate,
carageenan, starch, pectin, celluloses, exudate gums, tragacanth, karaya,
ghatti seed gums,
2o guar gum, locust bean gum, xanthan, pullulan, scleroglucan, curdlan;
dextran, gellan, chitin,
chondroitin sulfate, water soluble collagen, dermantan sulfate, heparin,
keratan sulfate,
hyaluronic acid and combinations thereof. It will further be appreciated that
any
pharmaceutically acceptable salt of the foregoing compounds may be used in the
disclosed
compositions with compromising the effectiveness thereof.
25 As will be seen in the Examples below the modifier polymers of the present
invention
may be used in suprisingly low concentrations to provide extended dissolution
times or
release times. In this regard, the selected modifier polymers are preferably
incorporated in a
range between about 0.05% and about 25% by weight and more preferably in a
range of from
approximately 0.5% to approximately 5% by weight. Of course the absolute
amount of
3o modifier polymer included in the composition will depend on factors such as
the constitutive
polymer selected, the molecular weight of the modifier polymer and the
physiochemical
IS
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WO 99/32151 PCT/US97l23865
properties of the various composition components. These determinations are
well within the
purview of the skilled artisan and may easily be determined without undue
experimentation.
C. HYC~rOphilic Co-Surfactants:
Yet another aspect of the present invention comprises the addition of a
hydrophilic co-
surfactant to the disclosed compositions (i.e. constitutive polymer
preparations and
constitutive polymer + modifier polymer preparations) to alter the
physiochemical properties
thereof. That is, the incorporation of a hydrophilic co-surfactant in
accordance with the
teachings herein may provide several advantages over prior art formulations.
These
to advantages are most easily understood in conjunction with a graphical
representation of a
polyphase system of the instant invention and examples set forth below.
Accordingly, turning to Fig. 1 a phase diagram for a constitutive polymer
solution
(poloxamer 407) is shown. The lower gelation temperature (LGT) refers to the
temperature at
which the poloxamer micelles (sol phase) self assemble into the cubic array
(i.e. the gel
phase). At temperatures above the upper gelation temperature (UGT) the
micelles change
their shape from spheres to prolates, thereby negating their ability to
assemble in a cubic
packing. This leads to the reformation of the low viscosity sol phase. Above
another critical
temperature, termed the cloud point (CP), the micelles separate into their own
coacervate
phase in excess water. The solution clouds due to mixing of the two insoluble
phases.
2o The lower gelation temperature (LGT) of the constitutive polymer solutions
in water
is largely dependent upon the total constitutive polymer concentration, such
that increases in
concentration lead to decreases in the LGT. Fractionation of the constitutive
polymer
(fractionated using organic phase separation or other means known in the art,
such as
described, for example, in Textbook of Polvmer Science F. Billmeyer, Wiley-
Interscience,
pp. 45-56 (197I)) and the addition of high viscosity carboxymethylcellulose
(CMC) does
little to alter the LGT. FloGel 28 (28% w/w poloxamer 407) has an LGT of 13
°C, and is
currently applied surgically at a temperature of 0°C. Therefore,
application of the product will
have to be done in a timely fashion to avoid gelation in the application
catheter.
Additionally, it has been hypothesized that increases in the LGT to a
temperature close to or
3o above room temperature may be advantageous.
As previously discussed, the equilibrium phase behavior of solutions
comprising a
constitutive polymer can be dramatically altered by the addition of
hydrophilic co-surfactants.
16
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WO 99/32151 PCTIUS97I23865
The changes in phase behavior are typically manifested by significant
increases in the lower
gelation temperature and cloud point temperature. While any hydrophilic co-
surfactant may
be used to modify the equilibrium phase behavior of the disclosed compositions
in
accordance with the teachings herein, hydrophilic co-surfactants comprising
fatty acid soaps
are particularly compatible with the present invention. In this regard long
chain, saturated
soaps appear to be particularly efficient at altering the phase behavior to
provide the desired
composition characteristics. Significantly, the rheological properties of the
gelled
compositions of the present invention are unaltered by the presence of the
fatty acid soaps,
indicating that, as long as the critical packing volume of the cubic phase is
exceeded, the
1 o rheology will remain virtually unchanged. Thus, in accordance with the
instant invention, the
addition of hydrophilic co-surfactants to the disclosed polyphase systems
provides an
efficient method for modifying the gelation temperature and cloud point
temperature. These
changes in phase behavior are particularly advantageous for a drug delivery
vehicle or
antiadhesion product as they allow for storage and application at temperatures
near room
temperature. Moreover, these characteristics reduce the potential for
significant syneresis
during terminal sterilization.
Accordingly, preferred embodiments of the present invention may comprise
effective
amounts of at least one hydrophilic co-surfactant. In particularly preferred
embodiments the
incorporated hydrophilic co-surfactant will comprise a fatty acid soap. Those
skilled in the
2o art will appreciate that fatty acid soaps are GRAS (generally regarded as
safe) materials,
present naturally in the human body, and included in many pharmaceutical
products including
large volume parenterals (e.g. Fluosol~. Their toxicological profile is well
understood and, at
the concentrations compatible with the present invention, they pose no
toxicological risk.
While several compounds comprising fatty acids are useful in the present
invention,
especially compatible fatty acid soaps comprise sodium oleate, sodium laurate,
sodium
caprate, sodium caprylate and combinations thereof.
In any event, as illustrated by the Examples below, the hydrophilic co-
surfactants of
the present invention may be incorporated in relatively low concentrations to
provide the
desired gelation properties. It will be appreciated that the selected
hydrophilic co-surfactant
or surfactants may comprise any concentration that provides for the preferred
gelation
temperatures. However, exemplary concentrations of hydrophilic co-surfactants
compatible
with the instant invention are typically in a range between about 0.05% and
about 25% by
17
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WO 99/32151 PCT/US97/23865
weight and more preferably in a range of from approximately 0.5% to
approximately 5% by
weight.
D. Bioactive Agents:
In addition to the antiadhesion characteristics of the compositions of the
present
invention the preparations also provide for the efficient delivery of
bioactive agents. Along
with the prolonged deposition time supplied by the disclosed compositions,
they may increase
the solubilization and bioavailability of incorporated pharmaceutical
compounds. More
particularly, the micelle core of the gelled compositions of the present
invention may serve as
to a reservoir for solubilizing nonpolar solutes such as hydrophobic drugs.
Interestingly the
micelles may also self assemble to form stiff gels above a critical
temperature. As previously
discussed, gel formation appears to occur when the micelles behave as hard
spheres in a
close-packed simple cubic array. This thermal gelation property provides
interesting
formulation alternatives for pharmaceuflcal applications, whereby the
poloxamer micelles are
applied in the fluid sol state and allowed to geI in place on tissue surfaces.
Thus, in addition
to their ability to act as a barrier to prevent surgical adhesions, poloxamer
gels may also be an
ideal drug delivery vehicle, owing to their low toxicity and ability to impede
drug diffusion.
Accordingly, the compositions disclosed herein may further optionally comprise
one
or more pharmaceutically acceptable adjuvants such as a humectant, a
bactericide, a
2o bacteriostatic agent, an antihistamine, or a decongestant, an agent to
prevent leucocyte
migration into the area of surgical injury, or a fibrinolytic agent. Useful
humectants include,
but are not limited to, glycerin, propylene glycol and sorbitol. Useful
bactericides include, by
way of example, antibacterial substances such as (3-lactam antibiotics, such
as cefoxitin, n-
formamidoyl thienamycin and other thienamycin derivatives, tetracyclines,
chloramphenicol,
neomycin, gramicidin, bacitracin, . sulfonamides; aminoglycoside antibiotics
such as
gentamycin, kanamycin, amikacin, sisomicin and tobramycin; nalidixic acids and
analogs
such as norfloxacin and the antimicrobial combination of
fluoroalanine/pentizidone;
nitrofurazones, and the like. Antihistamines and decongestants such as
pyrilamine,
chlorpheniramine, tetrahydrozoline, antazoline, and the like, can also be used
in admixtures
3o as well as anti-inflammatories such as cortisone, hydrocortisone, beta-
methasone,
dexamethasone, fluocortolone, prednisolone, triamcinolone, indomethacin,
sulindac, its salts
and its corresponding sulfide, and the like. Both steroidal and nonsteroidal
compounds are
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WO 99/32151 PCT/US97/23865
particularly compatible with the compositions and methods of the present
invention. With
regard to the latter, ketoprofen, indomethacin and tolmetin sodium are
particularly preferred.
Nitric oxide donors such as nononates and nitrosylated compounds may also be
incorporated.
Useful leucocyte migration preventing agents which can be used in admixtures
include but
are not limited to silver sulfadiazine, acetylsalicylic acid, indomethacin and
Nafazatrom.
Useful fibrinolytic agents include urokinase, streptokinase, tissue
piasminogen activator
(TPA) and acylated plasmin.
In a more general sense, compatible bioactive agents comprise both hydrophilic
and
lipophilic compounds including antibiotics, antivirals, mydriatics,
antiglaucomas, anti-
1 o inflammatories, antihistaminics, antineoplastics, anesthetics, ophthalmic
agents including anti-
glaucomics, enzymes, cardiovascular agents, polynucleotides; genetic material,
viral vectors,
immunoactive agents, imaging agents, immunosuppressive agents, peptides,
proteins,
physiological gases, gastrointestinal agents and combinations thereof.
Because the preparations of the present invention are uniquely suited for
various
administrative techniques such as ocular, oral, pulmonary, rectal, synovial,
subcutaneous,
intramuscular, intraperitoneal, nasal, vaginal, or aural administration of
medicaments or
diagnostic compounds, they are compatible for use with a wide variety of
bioacdve agents. For
example, ophthalmic applications involving topical administration of the
disclosed preparations
are particularly preferred. Accordingly, the foregoing list of compounds is
exemplary only and
2o not intended to be limiting. It will also be appreciated by those skilled
in the art that the proper
amount of bioactive agent and the timing of the dosages may be determined for
the formulations
in accordance with ali~eady-existing information and without undue
experimentation.
Preferably, the compositions are applied to surgically injured tissue as an
aqueous
solution which upon contact with living mammalian tissue forms a firm,
adherent gel. Where
the composition is a viscous liquid. or paste, these compositions can be
applied without
dilution to areas of surgical injury in the abdominal or thoracic cavities.
The formulations
adhere to the site of tissue injury and reduce or prevent the formation of
postsurgical
adhesions during the healing process.
In addition to the aforementioned applications, the preparations of the
invention may
also be used to deliver therapeutic and diagnostic agents to the
gastrointestinal tract by, for
example, the oral or direct routes of administration. A contemplated example
would be the
delivery of antibiotics to the lining of the gastrointestinal tract in the
treatment of Heliobacter
19
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WO 99132151 PCTNS97/23865
pylori infections. H. pylori has been implicated in the cause of gastric
ulcers and stomach
cancer. Antibiotics effective in the treatment of H. pylori infections could
be administered in
the form of a free flowing liquid that gels and adheres to the sites of
infection.
It will be appreciated that the compositions of the present invention may
further
contain preservatives, cosolvents, suspending agents, viscosity enhancing
agents, ionic-
strength and osmolality adjustors and other excipients in addition to
buffering agents.
Suitable water soluble preservatives which may be employed are sodium
bisulfite, sodium
thiosulfate, ascorbate, benzalkonium chloride, chlorabutanol, thimerosal,
phenylmercuric
borate, parabens, benzylalcohol phenylethanol and others. These agents may be
present,
1 o generally, in amounts of about 0.001 % to about 5% by weight and,
preferably, in the amount
of about 0.01 to about 2% by weight.
Suitable buffering agents or salts useful in maintaining pH include alkali or
alkaline
earth metal carbonates, chlorides, sulfates, phosphates, bicarbonates,
citrates, borates, acetates
and succinates such as sodium phosphate, citrate, borate, acetate,
bicarbonate, carbonate and
tromethamine (TRIS). Preferably, these agents are present in amounts
sufficient to maintain
the pH of the system at 7.4~ 0.2 and preferably, 7.4. As such, the buffering
agent can be as
much as 5% by weight.
It will also be appreciated by those skilled in the art that the preparations
of the present
invention may be sterilized, for example, by heat, irradiation,
ultrafiltration or combinations of
any of these .or equivalent techniques. Specifically, the preparations of the
invention may be
sterilized, for example, by autoclaving at 121 °C for 15 minutes or by
filtration through a 0.22
mm filter.
The high bioavailability bioactive preparations of the present invention may
advantageously be supplied to the physician in a sterile prepackaged form.
More particularly,
the formulations may be supplied as stable, preformed preparations, ready for
administration or
as separate, ready to mix components. When supplied as components the final
preparation of
the polyphase material could easily be performed in the pharmacy just prior to
administration.
The following examples illustrate the various aspects of the invention but are
not
intended to limit its scope. Where not otherwise specified throughout this
specification and
clams, temperatures are given in degrees centigrade, and parts, percentages,
and proportions
are by weight.
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WO 99/32151 PCTIUS97lZ3865
EXAMPLE 1
Synthesis of Compositions Comprising Modifier Polymers
s Compositions comprising a constitutive polymer (poloxamer 407) and a
modifier
polymer (sodium carboxymethylcellulose) were prepared by dissolving the
poloxamer in
distilled water (4°C) to give a concentration of 28% by weight in
accordance with the cold
process described above for forming aqueous solutions.
to Formulation 1: FloGe128B (Control)
Ingredients Source Lot %w/w
_itrams
Poloxamer 407, NF, Prill BASF WPDP-586B 28.0000
15 280.00
Tromethatnine (TRIS), USP Spectrum ID 289 0.1091
1.09
Malefic Acid Spectrum IK 051 0.1045
1.05
2o Sodium Hydroxide Pellets,Spectrum IG 043 0.0420
USP
0.42
Sterile Water for Irrigation,Baxter 6876094 71,7444
USP
717.44
Total
25 1000
Formulation 2 : FloGel 25B/0.5
Dents Source Lot %w/w
30 g~
Poloxamer 407, NF, Prill BASF WPDP-586B 25.0000
250.00
21
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WO 99/32151 PCTNS97/23865
Sodium CarboxymethylcelluloseSpectrum JA 156 0.5000
5.00
Tromethamine {TRIS), USP Spectrum ID 289 0.1091
1.09
Malefic Acid Spectrum IK 051 0.1045
1.05
Sodium Hydroxide Pellets, Spectrum IG 043 0.0420
USP
0.42
Sterile Water for Irrigation,Baxter 6876094 74.2444
USP
742.44
Total
1000
Formulation 3 : FloGe120F/0.8
Ineredients Source Lot %w/w
,roams
Poloxamer 407, Fractionated MDV 1145-107 20.0000
2o 200.00
Sodium CarboxymethylcelluloseSpectrum JA 156 0.8000
8.00
Tromethamine (TRIS), USP Spectrum ID 289 0.1091
1.09
Malefic Acid ,Spectrum IK 051 0.1045
1.05
Sodium Hydroxide Pellets, Spectrum IG 043 0.0420
USP
0.42
Sterile Water for Irrigation,Baxter 6876094 78.9444
USP
789.44
Total
1000
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WO 99I3Z151 PCTNS97/23865
Formulation 4 : FloGel 16B/1.5
Ingredients Source Lot %w/w
s crams
Poloxamer 407, NF, Prill BASF WPDP-586B 16.0000
160.00
Sodium CarboxymethylcelluloseSpectrum JA 156 1.5000
15.00
to Tromethamine (TRIS), USP Spectrum ID 289 0.1091
1.09
Malefic Acid Spectrum IK 051 0.1045
1.05
Sodium Hydroxide Pellets, Spectrum IG 043 0.0420
USP
15 0.42
Sterile Water for Irngation,Baxter 6876094 82.2444
USP
822.44
Total
1000
EXAMPLE 2
Anti-adhesion Characteristics of Compositions Comprising Modifier Polymers
The following test procedure .was utilized to determine the effect of the
formulations
of Example 1 on surgically injured rats. Female Sprague-Dawley rats having a
300-400 gram
body weight were anesthetized with pentobarbital sodium (30 milligrams per
kilogram of
body weight) by application intrapertoneally through the left lumbar region of
the ventral
abdominal wall. Surgical defects (2) were created in directly opposed
proximity by excising
3o the peritoneal membrane and thereby exposing sidewall muscle tissue
(2xlcm). The outer
membrane of the cecum was removed by surgical peeling, thus exposing blood
vessel loops
(2xlcm). Both exposed defects were abraded to cause petechial bleeding, and
then exposed
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WO 99/32151 PCT/US97I23865
to direct radiant heat source for 15 minutes to accelerate desiccation. One ml
of the
compositions of Example 1 (application temperature of 0 °C) was applied
to one injured site.
The other injured site was left untreated.
Results of this experiment indicate that a formulation containing only
poloxamer 407
(Formulation 1 ) reduced adhesions by approximately 50%, while formulations
containing
poloxamer 407 and carboxymethylcellulose (Formulations 2-4) reduced adhesions
by 70 to
99%. The increased efficacy of formulations containing both polymers may be
due to a
reduced rate of erosion in vivo analogous to that observed in vitro. All of
the formulations
exhibited maximal eiflcacy when applied to the injured tissue at approximately
0 °C.
EXAMPLE 3
Dissolution Rates of Compositions Comprising Modifier Polymers
The following example is directed to the determination of dissolution rates
for various
1s formulations prepared in accordance with the teachings herein. Several of
the formulations
incorporate at least one modifier polymer.
Materials:
Chemicals utilized in the study and their sources are listed below, All
chemicals were used
2o without further purification.
Sodium phosphate dibasic, NazHP04, ~7H20 (Sigma Chemical Co.. St. Louis, MO)
Malefic acid sodium salt (Sigma Chemical Co., St. Louis, MO)
1 N hydrochloric acid solution (Fisher Scientific, Fair Lawn, NJ)
Potassium nitrate (Fisher Scientific. Fair Lawn. NJ)
2s 0.1 N potassium hydroxide solution (fisher Scientific, Fair Lawn, NJ)
Methylene Chloride stabilized with amylene (Fisher Scientific. Fair Lawn, NJ)
Picric Acid with 35% water (Aldrich Chemical Co., St. Louis. MO)
Tris(hydroxymethyI~aminomethane (EM Science, Wakefield, RI)
Poloxamer 407 (BASF. Mount Olive, NJ)
3o Fractionated Poloxamer 407 (APC Lot #9630201)
Carbopol 940 NF (BF-Goodrich. Cleveland, OH)
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WO 99132151 PfTNS97/23865
Hydroxypropylmethylcellulose K100M, HPMC-K100M, (Dow Chemical Company,
Midland, MI)
Carboxymethylcellulose high viscosity, CMC (Spectrum Chemical Co., Gardens,
CA)
Carboxymethylcellulose medium viscosity CMC-MV (Penta Manufacturing Co.,
Livingston,
s Nn
Preparation. Polymer solutions were prepared by first dispersing the modifier
polymer (i.e., CMC, hydmpropylmethylcellulose (HPMC) or Carbopol) in the
Trislmaleate
buffer solution (0.1515 g of tris(hydroxymethyl)-aminomethane and 0.1726 g of
sodium
maleate were dissolved and brought up to 100 g with DI water) until fully
hydrated.
Poloxamer 407 (the constitutive polymer) was then added to the sample in an
ice bath (T = 3-
5°C), and mixed until the poloxamer dissolved. The sample was kept
under refrigeration
until usage.
In-vitro dissolution rate of poloxamer gels. The in-vitro dissolution rates of
poloxamer-based gels were determined using a modified USP dissolution
apparatus (Hanson
Research model SR6,) equipped with enhancer cells. Each of the dissolution
vessels were
filled with 25 mL of 0.1 M phosphate buffer (pH 7.4) (26.78 g of sodium
phosphate dibasic
(Na2HP0,~7H20) was brought to a volume of 1L with DI water) and left to
equilibrate for
about 20 minutes to 36.8°C. Membranes (1.2 ~m cellulose ester
membranes, 25 mm
diameter, type RAWP) were presoaked in phosphate buffer and placed on the
cell.
Approximately 0.6 mL of sample in the fluid sol phase was then loaded into
each of
the enhancer cells. The cells were subsequently closed and the fluid sol phase
allowed to gel
at room temperature prior to introduction into the dissolution vessels. The
dissolution
paddles were rotated at a speed of 100 rpm (approximating the hydrodynamic
stress found in
the peritoneal cavity) and were adjusted to remain at approximately 1 cm from
the top of the
cells throughout all experiments. The in-vitro release of poloxamer from the
gels was
monitored over a period of 4 hr, with 1 mL samples collected every 0.5 hr. The
vessel was
replaced with fresh buffer each time a sample aliquot was removed. Each sample
was run in
triplicate. The average standard error of the measurements was of 0.013.
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WO 99/32151 PCT/US97/23865
Quantitation of poloxamer. The determination of poloxamer concentration in the
aqueous phase was carried out using the potassium picrate spectrophotometric
method. This
method is based on the extraction of picrate ion from water into an organic
solvent in
association with potassium ion complexes of polyoxyethylene chains.
s The procedure consists of mixing 250 ~,L of potassium picrate solution
(0.23g of
picric acid (wet-based) dissolved in 10 mL of potassium hydroxide solution and
brought to a
volume of SO mL with DI water) with 1 mL of 2.5 M potassium nitrate solution
(SO.SSg of
potassium nitrate was bmught up to a volume of 200 mL with DI water; the pH
was then
adjusted to 12 with 0.1 N KOH) and 0.1 mL of the sample containing the
poloxamer solution
to in a 16x250 mm test tube. The mixture is then vortexed and extracted with 3
mL of CHZC12.
The absorbance of the organic phase was measured at 378 nm vs. a reagent
blank, with the
concentration determined from a calibration curve (Table 1 ) prepared by
adding aliquots of
surfactant standard solution (1024 ug/mL). A Beckman UV/Vis spectrophotometer
model
DU-65 was used to measure poloxamer concentration. The pH was adjusted to 7.4
with 1N
15 HCl using a Sentron pH meter.
Poloxamer 407 Standard Solutions
Table I
Std ID Poloxamer 407 (fig) Absorbance (378 nm)
1 ~ 0.245
2 128 0.497
3 256 0.982
Release Rates of Test Formulations: The results obtained for various poloxamer-
based formulations, including those comprising modifier polymers are detailed
in Table II.
The nomenclature of the various compositions is detailed below. FloGel 25
refers to a 25%
w/w formulation of poloxamer 407 ~ in the Tris/maleate buffer system. Should
the letter F
follow the number, the poloxamer 407 has been fractionated to remove low
molecular weight
impurities. For the purposes of this example, poloxamer 407 is the
constitutive polymer.
Should the formulation contain a modifier polymer, it follows after a slash.
Thus, FloGel
20F/O.SC, contains 20% w/w fractionated poloxamer 407 and 0.5% w/w high
viscosity grade
CMC. The acronyms for the modifier polymers are denoted in Table II
immediately below.
Table II
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WO 99/32151 PCT/US97r13865
In-Vitro Release Profiles of FloGels:
Sample k (hr~) n b MDT (hr)
Floge125 0.15 0.66 0.011
Floge128 0.15 0.66 0.0026 7
Flogel28' 0.97 1.0 0,009 1
Floge128F 0.22 0.5 0,099 7
Flogel 25/0.5 C' 0.78 0.8 -0.041 1
Flogel 0.22 0.5 -0.040
25/O.SCMV
Flogel25/1CMV 0.23 0.5 -0.032 6
Floge125/0.5 0.17 0.5 -0.023 11
HPMC .
Floge125/O.SC 0.14 0.5 -0.0064 17
Flogel 25/0.5 0.12 0.5 -0.028 22
940
Floge120F/O.SC 0.10 0.5 0.001 33
Floge120F/0.8C 0.074 0.5 0.0053 60
Floge116/1.SC 0.044 0.6 0.018 67
Flogel 14F/1 C 0.037 0.6 0.019 90
a No membrane used in dissolution study
F Fractionated Poloxamer 407
940 Carbopo1940-NF
C High Viscosity CMC
CMV Medium Viscosity CMC
HPMC Hydroxypropylmethylcellulose
Discussion: The data reported in Table II are fits to the Korsmeyer-Peppas
equation
V viz.
Q=k~~+b (
Qa
where Q is the amount released at the time t, Qa is the overall released
amount, k is a release
rate constant of the n~' order, n is a dimensionless number related to the
dissolution
mechanism and b is the y axis intercept, characterizing the initial burst
effect. A value of
n=0.5 characterizes a release mechanism controlled by polymer diffusion, while
a value of
n=1.0 characterizes an erosion controlled mechanism. Erosion and diffusion
control the
2o process in equal parts if n~.66. Since the release rate constant k has the
dimension hr'',
values for different mechanisms cannot be compared directly. To overcome this
problem it is
possible to define another quantity termed the mean dissolution time (MDT).
The MDT is
the sum of the different periods of time the poloxamer molecules stay in the
matrix before
release, divided by the total number of molecules, and is calculated according
to equation VI:
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WO 99/32151 PCTNS97IZ3865
MDT=r~ k''~° (VI)
n
Poloxamer 407 gels. in the absence of a membrane in the dissolution apparatus,
exhibit erosion controlled kinetics (n=1.0) with an MDT of 1 hr. Placement of
the cellulose
ester membrane introduces a diffisional barrier to the release, and is
characterized by equal
contributions of erosion and diffusion control (n=0.66), with an MDT of 7 hr.
Changes in gel
viscosity (i.e. comparison of FloGe1 25 vs. FloGel 28) and poloxamer
fractionation do not
appreciably alter the dissolution mechanism or the MDT.
The addition of a modifier polymer, especially one of high molecular weight,
can
have profound effects on poloxamer dissolution. Cellulose ethers (e.g. CMC and
HPMC) are
long chain polymers. The solution characteristics appear to depend on the
average chain
length as well as the degree of substitution. As molecular weight increases,
the viscosity will
increase rapidly.
Addition of 0.5% w/w of the high viscosity CMC to a 25% w/w poloxamer 407
solution dramatically increases the MDT to 17 hr. It also changes the
mechanism of release
to one of pure diffusion control (i.e. n~.50). Alternatively, the medium
viscosity grade of
CMC does not appear to have a dramatic effect on the MDT at the concentrations
of modifier
2o polymer employed. Other high molecular weight polymers (e.g. Carbopol 940-
NF) also alter
the dissolution mechanism and dramatically increase the MDT. In short it was
suprisingly
found that increases in the MDT by nearly an order of magnitude can be
achieved by the
addition of a modifier polymer. It is believed that the magnitude of the
dissolution times
measured in this in-vitro test are indicative of release rates found in-vivo
in the peritoneal
2s cavity.
EXAMPLE 4
Modification of the Geladon Temperature of Poloxamer Preparations
Through the Incorporation of Hydrophilic Co-Surfactants
In order to demonstrate the advantages associated with the addition of a
hydrophilic
co-surfactant to polymeric compositions in accordance with the present
invention, several
different preparations were formulated.
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WO 99/32151 PCT/US97/23865
Methods: Fractionated poloxamer 407 (i.e. poloxamer 407F) was prepared from NF
grade Pluronic F-127 (BASF Corporation, Mount Olive, NJ) as described herein.
Hydrophilic
co-surfactants in the form of fatty acid soaps (i.e. sodium oleate, sodium
laurate, sodium
caprate, and sodium caprylate) were obtained from Nu-Chek Prep. (Elysian, MN).
The buffer
s materials, tromethamine (EM Sciences Inc., Gibbstown, NJ) and malefic acid
{Sigma
Chemical Co., St. Louis, MO), were used as received, and a hypoosmotic buffer
containing
O.I515% w/w tromethamine and 0.1451% w/w malefic acid was prepared. Final
formulations
contained a constant 20% w/w percentage of poloxamer 407F, and varying levels
of fatty acid
soaps.
Far phase behavior studies, samples were loaded into 5 ml Wheaton vacuoles
(Fisher
Scientific, Pittsburgh, PA), and flame-sealed. The vacuoles were then immersed
in a constant
temperature bath. For temperatures less than 60 °C, phase behavior was
determined in a water
bath (Koehler, Bohemia, NY). At higher temperatures an oil bath (Haake, model
DC3,
Germany) was utilized. Temperature was raised in two degree increments from
ca. 1 °C to
120 °C. Samples were allowed to equilibrate for at least I hour at
constant temperature prior
to examination. Since the cubic liquid crystalline phase is isotropic (i.e.
not birefringent), the
determination of the gel boundary is somewhat subjective. Once equilibrium was
reached, the
vials were simply inverted and gravity was allowed to determine if the sample
was in the sol
or gel state.
2o Rheological studies were performed on a Rheometric Scientific Inc.
(Piscataway,
N.J.) model SR 5000 constant stress rheometer. A 25 mm parallel plate geometry
with a gap
of 1.0 mm was employed. In dynamic temperature ramp studies, a sinusoidal
stress (w = 1 s''}
was applied at a stress less than the yield stress of the material (ca. 1-10
Pa). This ensured that
the sample was in the linear viscoelastic region. Temperature was ramped at a
rate of 2 °C
2s miri '. Rapid temperature equilibration was ensured with a peltier/water
bath system. Samples
were loaded at 0-5 °C (i.e. in the sol phase), and allowed to gel on
the plate. This was done to
avoid applying an unknown shear history to the sample. Plots of the complex
viscosity (r~*)
vs. temperature were recorded.
Discussion: Details regarding the equilibrium phase behavior of 20% poloxamer
30 407F solutions with added fatty acid soaps are shown in Table III below. As
may be seen
from the data, fatty acid soaps have a substantial effect on the phase
behavior of the
poloxamer 407F solutions. The LGT for a 20% poloxamer 407F solution in the
absence of
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WO 99!32151 PCT/US97/23865
added fatty acid soaps is 19 °C. With added fatty acid soaps, the LGT
can be increased to
temperatures as high as 87 °C (observed with 4.86% added sodium
caprate). In addition, the
cloud point temperature, which is 108 °C for the 20% poloxamer 407F
solution, may be
easily increased to temperatures above 140 °C, i.e. significantly above
the typical
temperatures used during terminal steam sterilization.
CA 02316248 2000-06-22
WO 99132151 PCT/US97I23865
Table III
Phase behavior of 20% poloxamer 407F solutions in hypoosmotic
tromethamine/maleate
buffer with added fatty acid soaps.
~i : ''00- .:. .
. ..... ~ . ~ ~o~ ; :' : : : :: .: : : -..:.
:....1 (.._ . ... ~ . .:.. .. :: ~ .j,j ,("~~~.',.; : ::::
.. :. . ~~ , ~.~. o"'.,:.:
... :
0% Fatty Acid Soap ~ 81 108'
a xr
~- ~ :,:~..
..~.:..
. :
19
1.0% Oleate ( 18:1 ) 17 78 106
3.01 % Oleate 41 77 117
1% Laurate (12:0) 22 78 110
I .5% Laurate 31 84 ~ 114
2.0% Laurels 49.5 84 121
2.2% Laurate 54.5 83 > 140
2.4% Lat~rate 57 77 >140
2.5% Laurate no gel no gel > 140
1% Caprate (10:0) 19.5 80 1 I2
1.5% Caprate 25 85 120
2.0% Caprate 33 89 128
2.5% Caprate 39.5 93 130
3% Caprate 52 94 >140
3.3% Capratt 55 98 >140
4.0% CapTate 69.5 102 > 140
4.5% Caprate 85 102 >140
4.86% Caprate 87 92 >140
5% Caprate no gel no gel >140
1 % Caprylate (8:0) 17.4 82 113
3% Caprylate 19.5 94 131
4% Ceprylate 24.8 102 >140
5% Caprylate 34 109 >140
5.5% Caprylate 36 113 >140
6.2% Caprylate 43 120 > 140
8% Caprylete 57.9 >140 >140
10% Caprylate 74 > 140 > 140
10.57% Caprylate 75 ~__ >140
11.05% Caprylate 75 150 >150
1 I .48% Caprylate no gel no gel > 150
In accordance with the results reported above a typical phase diagram obtained
for
poloxamer 407F/fatty acid soap mixtures is shown in Figure 2. This diagram
illustrates the
to effect of increasing sodium caprate concentrations on the phase behavior of
20% w/w
poloxamer 407F solutions in the hypo-osmotic tromethamine/maleate buffer
system.
Above a sodium caprate concentration of ca. 1% w/w, the LGT is observed to
increase
systematically from 19 °C to 87 °C. At concentrations between
ca. 1.5 and 2.0% caprate, the
LGT is in the temperature range between room and body temperature. Having a
LGT in this
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WO 99/32151 PCT/US97/23865
temperature range might have some importance for the formulation of
antiadhesion products,
possibly improving the ease of use by obviating the need to maintain product
temperature
near 0 °C, and allowing the surgeon greater time to apply compositions
in accordance with
the methods herein. Above ca. 5% caprate, the gel phase is completely
suppressed. Also of
note in Figure 2 is the fact that above ca. 2% sodium caparate, the cloud
point temperature is
above typical steam sterilization temperatures. Being able to maintain a
single phase above
terminal sterilization temperatures may play a role in reducing post-
sterilization syneresis.
Dynamic temperature ramp studies for formulations ,with varying levels of
added
sodium caprylate are shown in Figure 3. At low temperatures (below gel phase
formation),
l0 the dynamic rheological method is not an efficient method for measuring low
viscosities.
This leads to a significant degree of noise in the data. Once the sol-gel
phase transition is
encountered, a sharp increase by ca. 4 orders of magnitude in the complex
viscosity is noted.
Above the phase transition, the dynamic rheological method is very sensitive
and little noise
is apparent in the data. Interestingly, the complex viscosity of the gel phase
remains virtually
constant as the LGT is varied by the addition of the hydrophilic co-
surfactants. This is
consistent with the model that the gel phase formation is due to the formation
of a cubic array
of micelles above their critical packing volume fraction. Accordingly, as long
as the critical
volume fraction is exceeded, the rheological properties of the gel do not
appear to be
significantly altered. Thus, the addition of fatty acid soaps represents a
very efficient way of
altering the LGT and cloud point of constitutive polymer gels without varying
the rheological
characteristics of the gel. This is, of course, in contrast to changing the
LGT by varying
poloxamer concentration, or the nature of the poloxamer (e.g. poloxamer 338).
The chainlength and degree of unsaturation of the hydrophilic co-surfactant
may also
be used to selectively alter the characteristics of the constitutive polymer
gels. These effects
are graphically illustrated in Figure 4 where the LGT is plotted as a function
of soap
concentration for different fatty acid soaps. The value next to the curve
refers to the fatty acid
portion of the soap. Thus, 8:0 represents an eight carbon fatty acid soap with
no double bonds
in the alkyl chain. 18:1, on the other hand, represents an alkyl chain
containing eighteen
carbons and a single double bond. It is apparent from Figure 4 that longer
chainlength
3o saturated soaps provide more substantial alterations of the gel
characteristics than shorter
chainlength analogues which appear to be less efficient at disrupting gel
phase formation.
Thus, while 2.5% of 12:0 soap is required to melt the 20% poloxamer 407F gel,
nearly 11.5%
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WO 99I3Z151 PCT/US97I23865
of the 8:0 soap is used to provide the same characteristics. Unsaturated soaps
also appear to
be less active than their saturated analogues at increasing both the LGT and
cloud point of
poloxamer 407 gels. In any case, with a 20% w/w concentration of poloxamer
407F, it is
possible to achieve gelation between room and body temperature, and a cloud
point greater
s than 121 °C for the caprate (10:0) and caprylate (8:0) soaps.
Moreover, as the total poloxamer
concentration is increased, higher concentrations of hydrophilic co-surfactant
may be used to
achieve the same degree of shift in the LGT. Thus, the laurate soap (12:0) may
be preferred
under these conditions.
1 o EXAMPLE 5
Drug Solubility and in-vitro Drug Release Rates
in Poloxamer 407-Based Thermoreversible Gels
In order to demonstrate the advantages of the present invention with respect
to drug delivery,
is selected compounds were incorporated in various preparations formed in
conjunction with the
present invention.
Materials
2o The chemicals utilized in this study and their sources are listed below.
All chemicals were
used without further purification.
Ketoprofen (Sigma Chemical Co., St. Louis, MO)
Prednisone (Sigma Chemical Co., St. Louis, MO)
lndomethacin (Sigma Chemical Co., St. Louis, MO)
2s Tolmetin Sodium (Sigma Chemical Co., St. Louis, MO)
Hydrocortisone (Sigma Chemical Co., St. Louis, MO)
Poloxamer 407 (BASF, Mount Olive, NJ)
Ethyl Alcohol 200 proof (Spectrum Chemical Co.. Gardens, CA)
FloGe128 (MDV Technologies Inc., Dearborn MI)
3o FIoGeI 25B/O.SC (MDV Technologies Inc., Dearborn MI)
FIoGeI 25 B/ 1 C (Alliance Pharmaceutical lot # 587-29b).
FIoGe125 (Alliance Pharmaceutical lot #587-29a).
FloGe128F (Alliance Pharmaceutical lot #534-73).
Gentamicin Sulfate (Amresco, Solon, OH)
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Methods
Preparation of Drug solutions in Poloxamer 407-water systems. Poloxamer 407
was added
to deionized (DI) water in an ice bath (T = 3-5°C), and mixed until the
poloxamer dissolved.
Excess amounts of drug were then added to the aqueous poloxamer solutions and
allowed to
equilibrate overnight (T = 3-5°C). The next day the sample was warmed
momentarily to 40°
C to hasten solubilization. This process was repeated two or three times to
ensure saturation.
Io Samples containing less than 20% poloxamer 407 were then equilibrated
overnight at room
temperature while the other samples were equilibrated at 5°. Prior to
analysis, the samples
were filtered through a 0.2N.m nylon filter syringe to remove unsolubilized
drug. Samples
were assayed for solubilized drug concentrations by absorbance spectroscopy
(see below).
Preparation of drug solutions in FIoGeI. Two mg of drug was added to 1 mL of
the FloGel
material and equilibrated overnight (T = 3-5°C). As before, the sample
was warned two to
three times to 40°to hasten solubilization. Samples were stored at
5°C until use.
Drug Concentration Determinations: The samples were diluted to a suitable
concentration
2o with ethanol (for water insoluble drugs) or DI water. Drug concentrations
were measured at
the appropriate wavelength for each drug (see Table I) using a UV/Vis
spectrophotometer
(Beckman model DU-65). Concentrations were determined using Beer's law from
the
appropriate calibration curve (Table II). Gentamicin sulfate determination was
performed by
the UCSD Medical Center laboratory.
In-vitro release rate of drugs in poloxamer gels. The in-vitro release rates
of drugs in
poloxamer-based gels were determined using a modified USP dissolution
apparatus (Hanson
Research model SR6) equipped with enhancer cells. Each of the dissolution
vessels was
filled with 25 mL of .O1 M phosphate buffer (pH 7.4)' and left to equilibrate
for about 20
3o minutes to 36.8°C. Membranes (1.2 Erm cellulose ester membranes, 25
mm diameter, type
26.78 g of sodium phosphate dibasic (NaZHPO, 7Hz0) was brought to a volume of
1 L with DI water. The pH
was adjusted to a pH of 7.4 with IN HC1 using a Sentron pH meter.
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WO 99/32151 PCT/US97/23865
1ZAWP) were presoaked in phosphate buffer and placed on the cell.
Approximately 0.6 mL
of sample in the fluid sol phase was then loaded into each of the enhancer
cells. The cells
were subsequently closed and the gel phase was allowed to form at room
temperature prior to
introduction into the dissolution vessels. The dissolution paddles were
rotated at a speed of
100 rpm (approximating the hydrodynamic stress found at the peritoneal cavity)
and were
positioned approximately 1 cm from the top of the cells for all experiments.
The in-vitro
release of drug from the gels was monitored over a period of 4 hr. One mL
samples were
collected every 0.5 hr. The vessel was refilled with fresh buffer every time a
sample aliquot
was removed, and each sample was run in duplicate. For additional details
regarding the
dissolution apparatus the reader is referred to: (Dellamary L:In-vitro
dissolution rates of
poloaamer-based thermoreversible gels. Research & Development Technical Report
No.
EPR-32-97 4).
Table IV
Calibration Curve Equations 'for the Different Drugs Selected
Calibration Curve Equation R2
ltetoproten Conc,ng~,=22.9(Abs~0.2 0.9996
Prednisone Concmg~,=33.3(Abs)-0.06 0.9999
Indomethacin Concmg/I,=232.4(Abs~2 0.991
Tolmetin Sodium Concmg~,=22.9(Abs~0.7 0.9919
Hydrocortisone Concmg~=27.8(Abs~O.1 0.9956
solubilization was, for most of the cases, enhanced in the gel state.
Solubilization for hydrocortisone
was higher in the liquid state. Two reasons could be responsible for the
observed reduction in
solubilization: 1) hydrocortisone has a relatively higher water solubility
than the rest of the
hydrophobic drugs tested: 2) samples below the gel transition temperature were
equilibrated at room
temperature, instead of the lower temperature used for the gels.
Apparent distribution coefficients (Km) of the hydrophobic drugs between a
micellar phase
and an aqueous phase were determined according to equation VII.
S=KmC+1 (VII)
So
Where S and So are the concentration of solubilized drug in the presence and
absence of
poloxamer, respectively. C is the concentration of poloxamer (weight
fraction).
CA 02316248 2000-06-22
WO 99/32151 PCT/US97I23865
Table V, shows the apparent distribution coefficients. The higher the value of
K, the greater
the amount of drug that can be incorporated into the system.
Table V
Distribution Coeffcients of Hydrophobic Drugs Between a Micellar Phase and an
Aqueous Phase
Drug Evaluation Distribution Coeffiecient r~.,a rr__~
t~yarocortlsone 1
0.55
Prednisone 1.1 ~ 1.5
Ketoprofen 2.9 3.1
Indomethacin 3 3.4
Positive distribution coefficients (log Km) indicate that the drug preferably
partitions
into the micelle rather than into the water phase. Sodium tolmetin, in
contrast, would rather
partition into the water phase. It is not possible to calculate a partition
coefficient for
tolmetin using equation VII. The decreasing solubility with increasing
poloxamer
concentration gives a negative slope and an undefined value of log Ku,. It is
clear that tolmetin
partitions almost entirely into the bulk aqueous phase and very little is
solubilized in the
poloxamer micelle. The above results confirm that hydrophobic drugs are
actually
solubilizing into the core of poloxamer 407 micelles.
There were no appreciable differences in diffusion coefficients or mean
dissolution
times (MDT) between different drugs within the same poloxamer formulations.
Thus, no
differences were observed between sodium tolmetin and ketoprofen despite the
fact that the
2o tolmetin is simply dissolved in the continuous aqueous phase of the gel
while the ketoprofen
is solubilized in the micelle core. These results imply that the micelles
present little
impediment to diffusion (i.e. there is no diffusional resistance). Significant
reductions in the
rate of diffusion are observed, however. when a modifier polymer (i.e.
carboxymethylcellulose, CMC) is added to the poloxamer.
The slow diffusion observed in poloxamer gets results (at least in part) from
the
longer diffusion path that a drug must take in order to pass around the
micelles. In the case of
polymer mixtures, the modifier polymer is preferably of sufficient molecular
weight that it
too alters the diffusion path of the solute. The fact that the size of the
drug molecules did not
seem to affect release rate also supports this hypothesis.
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WO 99/32151 PCT/US97I23865
While this invention has been described with reference to certain specific
embodiments, it will be recognized by those skilled in the art that many
variations are
possible without departing from the scope and spirit of the invention, and it
will be
understood that it is intended to cover all changes and modif cations of the
invention,
s disclosed herein for the purposes of illustration, which do not constitute
departures from the
spirit and scope of the invention.
l0
37
