U.S. patent application number 09/930760 was filed with the patent office on 2002-04-25 for methods and compositions for the delivery of pharmaceutical agents and/or the prevention of adhesions.
This patent application is currently assigned to Alliance Pharmaceutical Corp.. Invention is credited to Dellamary, Luis A., Flore, Stephen G., Reeve, Lorraine E., Weers, Jeffry G..
Application Number | 20020048602 09/930760 |
Document ID | / |
Family ID | 24329422 |
Filed Date | 2002-04-25 |
United States Patent
Application |
20020048602 |
Kind Code |
A1 |
Flore, Stephen G. ; et
al. |
April 25, 2002 |
Methods and compositions for the delivery of pharmaceutical agents
and/or the prevention of adhesions
Abstract
The present invention provides a composition comprising one or
more constitutive polymers and modifier polymers and/or hydrophilic
co-surfactants useful for reducing adhesions or delivering
bioactive agents. Methods for preventing and/or reducing
post-surgical adhesions or delivering bioactive agents are also
provided.
Inventors: |
Flore, Stephen G.; (San
Diego, CA) ; Dellamary, Luis A.; (San Marcos, CA)
; Reeve, Lorraine E.; (Dexter, MI) ; Weers, Jeffry
G.; (Half Moon Bay, CA) |
Correspondence
Address: |
Pillsbury Winthrop LLP
50 Fremont Street
San Francisco
CA
94105
US
|
Assignee: |
Alliance Pharmaceutical
Corp.
|
Family ID: |
24329422 |
Appl. No.: |
09/930760 |
Filed: |
August 15, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09930760 |
Aug 15, 2001 |
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09582508 |
Jun 22, 2000 |
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6280745 |
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09582508 |
Jun 22, 2000 |
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PCT/US97/23865 |
Dec 23, 1997 |
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Current U.S.
Class: |
424/486 ;
424/488 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 9/06 20130101; B82Y 5/00 20130101; A61K 31/77 20130101; A61K
47/38 20130101; A61K 31/785 20130101; A61K 31/522 20130101 |
Class at
Publication: |
424/486 ;
424/488 |
International
Class: |
A61K 009/14 |
Claims
1. A pharmaceutical aqueous-gel composition, said composition
comprising a constitutive polymer selected from the group
consisting of polyoxyalkylene block copolymers and polyoxyalkylene
polyethers and combinations thereof, further including a modifier
polymer selected from the group consisting of cellulose ethers,
sodium carboxymethylcelluolose and polyacrylates and further
including a co-surfactant comprising at least one fatty acid soap.
Description
FIELD OF THE INVENTION
[0001] 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
[0002] 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 gel 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.RTM.
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 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.
[0003] 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 and/or 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,
establishment and maintenance of the desired sol-gel temperature
and/or persistence of the gel may be complicated by several
variables including the localized physiology of the mammalian
subject. Accordingly, a need still exists for pharmaceutical
preparations or drug delivery compositions that allow for the
establishment of a precise sol-gel transition temperature and
accurate control of the gel dissolution rate in vivo.
[0004] 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
remesothelialization. However under the ischemic conditions present
following surgical trauma the fibrinolytic process is suppressed
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.
[0005] 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, 133:497-509, 502-503 (1971)). These
efforts have included means of preventing the fibrin-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.
[0006] High molecular weight dextran either alone or in combination
with dextrose has also been used (Holtz, et al., Fertility and
Sterility, 33:660-662 (1980); 34:394-395 (1980)). One such
formulation, HYSKON.RTM. (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.
[0007] 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 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 polytetrafluoroethylene
(Gore-Tex.RTM., W. L. Gore) and crosslinked hyaluronic acid
(Seprafilm.RTM.Genzyme Corp.).
[0008] 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. 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 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.
[0009] 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 temperature and/or dissolution rate of the gel
once formed.
[0010] 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 desired
sol-gel transition temperatures and/or gel dissolution rates.
[0011] 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.
SUMMARY OF THE INVENTION
[0012] 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 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 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.
[0013] 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 semi-solid barrier or mask that may remain
in place for an extended period.
[0014] In preferred embodiments of the instant invention the
constitutive polymer will be a 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.
[0015] Besides the constitutive polymer discussed above, selected
embodiments of the 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 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 polymer(s) 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.
[0016] 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 copolymer(s) or compositions comprising
constitutive copolymer(s) and modifier polymer(s) 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 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.
[0017] 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 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, 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 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 bioactive 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.
[0018] 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 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 formation, administration of pharmaceutically
effective amounts to the 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.
[0019] Besides the components mentioned above, the compositions of
the present invention may further comprise pharmaceutically
acceptable stabilizers, preservatives and buffers, preferably in an
amount sufficient to maintain the pH of the composition at about pH
7.4.+-.2.
[0020] 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 first be described briefly.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 is a graphical representation of an exemplary phase
diagram for a prior art composition comprising a constitutive
polymer;
[0022] FIG. 2 illustrates an equilibrium phase diagram of 20% w/w
poloxamer 407 (407F) 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.degree. C.;
[0023] FIG. 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 tromethamine/maleic acid buffer;
[0024] FIG. 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
[0025] Compositions and methods are disclosed herein for delivering
bioactive agents and/or reducing post-surgical adhesion
formation/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, 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, 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 accordance with the
teachings herein that do not gel or thicken following application
to the selected area or tissue.
[0026] Preferably, the osmolality and pH of the compositions are
adjusted to match the pH arid 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.
[0027] 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 of interior
cavities.
[0028] 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.
[0029] 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.
[0030] As used herein, the terms "peritoneal" and "abdominal"
cavity are used as synonyms, as are the terms "pleural" and
"thoracic" cavity.
[0031] As used herein, the term "polyalkylene block polymers"
include those polymers which form clear gels at mammalian body
temperatures but are liquids at ambient temperatures or below.
[0032] 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".
[0033] A. Constitutive Polymers:
[0034] As set forth above, the present invention comprises at least
one constitutive polymer 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 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.
[0035] Thus, according to a preferred embodiment, the compositions
comprise one or more polyoxyalkylene block copolymers of the
formula
Y[(A).sub.n-E-H].sub.x (I)
[0036] wherein A is a polyoxyalkylene moiety;
[0037] x is at least 2;
[0038] Y is derived from water or an organic compound containing x
reactive hydrogen atoms;
[0039] B is a polyoxyethylene moiety;
[0040] 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 least about 5000.
[0041] 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 mold.
[0042] The polyoxyethylene moiety E preferably constitutes from
about 60 to about 85% by weight of the copolymer, more preferably
at least about 70%.
[0043] 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
trimethylolpropane, ethylenediamine and mixtures thereof.
[0044] According to one embodiment, the copolymer has the
formula:
HO(C.sub.2H.sub.4O).sub.b(C.sub.4H.sub.8O).sub.a(C.sub.2H.sub.4O).sub.bH
(II)
[0045] wherein a and b are integers such that
(C.sub.4H.sub.8O).sub.a has a molecular weight of at least about
500.
[0046] 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.
[0047] Generally, the polyoxybutylene-based block copolymers useful
in the compositions of 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.
[0048] In a further preferred embodiment, the compositions comprise
polyoxyethyene-polyoxypropylene block copolymers of the formula
(III):
HO(C.sub.2H.sub.4O).sub.b(C.sub.3H.sub.6O).sub.a(C.sub.2H.sub.4O).sub.bH
(III)
[0049] wherein a is an integer such that the hydrophobe base
represented by (C.sub.3H.sub.6O).sub.a 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 hydrophobe
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
copolymer. This copolymer is sold under the trademark PLURONIC.RTM.
F-127 (also known as poloxamer 407)(BASF Corp. Parsippany,
N.J.).
[0050] 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).sub.101-(PO).sub.56-(EO).sub.101, and average
molecular weight of ca. 12,000 g mol.sup.-1. When placed in an
aqueous solution in accordance with the present invention,
poloxamer 407 self-assembles so as to remove contact between the
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. Gel phase formation occurs as a
result of organization of the micelles into a three-dimensional
cubic array.
[0051] In another embodiment, the copolymer has the formula:
(R).sub.2N--(CH.sub.2).sub.2-N(R).sub.2 (IV)
[0052] wherein R is
H(OC.sub.2H.sub.4).sub.b(OC.sub.3H.sub.6).sub.a-; and a and b are
integers such that the hydrophobe base represented by
(C.sub.3H.sub.6O).sub.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 ethylene oxide residue is used to cap the
hydrophobe base.
[0053] In all permutations of copolymers of formula (I), it is
preferred that the polyoxyethylene chain constitute from 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 specified in the USP).
[0054] 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
technique involves the steps of dissolving the polyoxyalkylene
block copolymer at a temperature of about 5.degree. to about
10.degree. C. in water. When 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.degree. C. to about 85.degree.
C., with slow stirring until a clear homogeneous solution is
obtained. Upon cooling, a clear gel is formed. Block copolymer gels
containing polyoxybutylene hydrophobes must be prepared by the
above hot process, since these will not liquefy at low
temperatures.
[0055] The organic compound initiator which is utilized in the
preparation of the polyoxyalkylene 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. Falling within the scope of the compounds from
which Y is derived from water soluble organic compounds having at
least two reactive hydrogen atoms are water soluble organic
compounds such as propylene glycol, glycerin, pentaerythritol,
trimethylolpropane, ethylenediamine, and mixtures thereof and the
like.
[0056] 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.
[0057] In addition to those polyoxyalkylene polymers described
above, the present 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.
[0058] Conventional copolymer polyether polyols are prepared by
preparing block or heteric 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.
Ethylene oxide homopolymers capped with the alpha-olefin oxides are
also useful as intermediates.
[0059] 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 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.degree. C. to 150.degree. C., preferably, from
80.degree. C. to 130.degree. C., under an inert gas pressure,
preferably, from about 30 psig to 90 psig.
[0060] 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 alkylene oxide.
[0061] 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 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 above ranges for a
period of about one hour to ten hours, preferably one to three
hours.
[0062] 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 about 0.3 to 10 percent, preferably
about 4 to 8 percent, of the total weight of the polyethers.
[0063] Further description regarding the preparation of heteric and
block copolymers of alkylene oxides and ethylene oxide homopolymers
is described in the art (U.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.)
[0064] 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 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 range from approximately 2% w/w to 50% w/w and more
preferably from 4% to 30% w/w and even more preferably from 16% to
28% w/w.
[0065] B. Modifier Polymers:
[0066] As set forth above any biocompatible polymeric entity that
modifies the dissolution 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 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 for antiadhesion applications as well as for other
applications including controlled drug delivery.
[0067] 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 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 long linear molecules of the incorporated modifier polymer. In
general, this effect appears to be most pronounced when the
selected modifier polymer(s) have a molecular weight greater than
or equal to approximately 500,000 although modifier polymers of
much lower molecular 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 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.
[0068] 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),
poly(styrene sulfonate), carboxymethylcellulose, poly(vinyl
alcohol), poly(ethylene 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(.epsilon.-caprolactone)- , poly(.beta.-hydroxybutyric acid),
poly(.beta.-hydroxyvaleric acid), polydioxanone, poly(ethylene
terephthalate), poly (malic acid), poly(tartronic acid), poly(ortho
esters), polyanhydrides, polycyanoacrylate, poly(phosphoesters),
polyphosphazenes, poly(lysine), polysaccharides, chitosan,
polyelectrolytes, gelatin, gum arabic, poly(amino acids), agar,
furcelleran, alginate, carageenan, starch, pectin, celluloses,
exudate gums, tragacanth, karaya, ghatti seed gums, 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.
[0069] As will be seen in the Examples below the modifier polymers
of the present invention may be used in surprisingly 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 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 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.
[0070] C. Hydrophilic Co-Surfactants:
[0071] 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
advantages are most easily understood in conjunction with a
graphical representation of a polyphase system of the instant
invention and examples set forth below.
[0072] 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.
[0073] 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 Polymer Science, F. Billmeyer, Wiley-Interscience, pp.
45-56 (1971)) 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.degree. C., and is
currently applied surgically at a temperature of 0.degree. 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 above room temperature may be
advantageous.
[0074] As previously discussed, the equilibrium phase behavior of
solutions comprising a constitutive polymer can be dramatically
altered by the addition of hydrophilic co-surfactants. 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 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.
[0075] 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 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.RTM.).
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.
[0076] 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 weight and more
preferably in a range of from approximately 0.5% to approximately
5% by weight.
[0077] D. Bioactive Agents:
[0078] 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 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 pharmaceutical applications, whereby
the poloxamer micelles are applied in the fluid sol state and
allowed to gel 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.
[0079] Accordingly, the compositions disclosed herein may further
optionally comprise one or more pharmaceutically acceptable
adjuvants such as a humectant, a bactericide, a 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
.beta.-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/pentizidon- e, nitrofurazones, and the like.
Antihistamines and decongestants such as pyrilamine,
chlorpheniramine, tetrahydrozoline, antazoline, and the like, can
also be used in admixtures 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 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
plasminogen activator (TPA) and acylated plasmin.
[0080] In a more general sense, compatible bioactive agents
comprise both hydrophilic and lipophilic compounds including
antibiotics, antivirals, mydriatics, antiglaucomas,
anti-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.
[0081] 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 bioactive 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
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 already-existing information and without undue
experimentation.
[0082] 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.
[0083] 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 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.
[0084] 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, 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.
[0085] 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.
[0086] 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.degree. C. for 15 minutes or by filtration
through a 0.22 mm filter.
[0087] 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.
[0088] 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 claims,
temperatures are given in degrees centigrade, and parts,
percentages, and proportions are by weight.
EXAMPLE 1
Synthesis of Compositions Comprising Modifier Polymers
[0089] Compositions comprising a constitutive polymer (poloxamer
407) and a modifier polymer (sodium carboxymethylcellulose) were
prepared by dissolving the poloxamer in distilled water (4.degree.
C.) to give a concentration of 28% by weight in accordance with the
cold process described above for forming aqueous solutions.
1 Ingredients Source Lot % w/w grams Formulation 1: FloGel 28B
(Control) Poloxamer 407, NF, Pril BASF WPDP-586B 28.0000 280.00
Tromethamine (TRIS), USP Spectrum ID 289 0.1091 1.09 Maleic Acid
Spectrum IK 051 0.1045 1.05 Sodium Hydroxide Pellets, Spectrum IG
043 0.0420 0.42 USP Sterile Water for Irrigation, Baxter G876094
71.7444 717.44 USP Total 1000 Formulation 2: FloGel 25B/0.5
Poloxamer 407, NF, Prill BASF WPDP-586B 25.0000 250.00 Sodium
Carboxy- Spectrum JA 156 0.5000 5.00 methylcellulose Tromethamine
(TRIS), USP Spectrum ID 289 0.1091 1.09 Maleic Acid Spectrum IK 051
0.1045 1.05 Sodium Hydroxide Pellets, Spectrum IG 043 0.0420 0.42
USP Sterile Water for Irrigation, Baxter G876094 74.2444 742.44 USP
Total 1000 Formulation 3: FloGel 20F/0.8 Poloxamer 407, MDV
1145-107 20.0000 200.00 Fractionated Sodium Carboxy- Spectrum JA
156 0.8000 8.00 methylcellulose Tromethamine (TRIS), USP Spectrum
ID 289 0.1091 1.09 Maleic Acid Spectrum IK 051 0.1045 1.05 Sodium
Hydroxide Pellets, Spectrum IG 043 0.0420 0.42 USP Sterile Water
for Irrigation, Baxter G876094 78.9444 789.44 USP Total 1000
Formulation 4: FloGel 16B/1.5 Poloxamer 407, NF, Prill BASF
WPDP-586B 16.0000 160.00 Sodium Carboxy- Spectrum JA 156 1.5000
15.00 methylcellulose Tromethamine (TRIS), USP Spectrum ID 289
0.1091 1.09 Maleic Acid Spectrum IK 051 0.1045 1.05 Sodium
Hydroxide Pellets, Spectrum IG 043 0.0420 0.42 USP Sterile Water
for Irrigation, Baxter G876094 82.2444 822.44 USP Total 1000
EXAMPLE 2
Anti-adhesion Characteristics of Compositions Comprising Modifier
Polymers
[0090] 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 the
peritoneal membrane and thereby exposing sidewall muscle tissue
(2.times.1 cm). The outer membrane of the cecum was removed by
surgical peeling, thus exposing blood vessel loops (2.times.1 cm).
Both exposed defects were abraded to cause petechial bleeding, and
then exposed to direct radiant heat source for 15 minutes to
accelerate desiccation. One ml of the compositions of Example 1
(application temperature of 0.degree. C.) was applied to one
injured site. The other injured site was left untreated.
[0091] 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 efficacy when applied to the injured tissue at
approximately 0.degree. C.
EXAMPLE 3
Dissolution Rates of Compositions Comprising Modifier Polymers
[0092] The following example is directed to the determination of
dissolution rates for various formulations prepared in accordance
with the teachings herein. Several of the formulations incorporate
at least one modifier polymer.
[0093] Materials:
[0094] Chemicals utilized in the study and their sources are listed
below, All chemicals were used without further purification.
[0095] Sodium phosphate dibasic, Na.sub.2HPO.sub.4, 7H.sub.2O
(Sigma Chemical Co., St. Louis, Mo.)
[0096] Maleic acid sodium salt (Sigma Chemical Co., St. Louis,
Mo.)
[0097] 1 N hydrochloric acid solution (Fisher Scientific, Fair
Lawn, N.J.)
[0098] Potassium nitrate (Fisher Scientific. Fair Lawn, N.J.)
[0099] 0.1 N potassium hydroxide solution (Fisher Scientific, Fair
Lawn, N.J.)
[0100] Methylene Chloride stabilized with amylene (Fisher
Scientific. Fair Lawn, N.J.)
[0101] Picric Acid with 35% water (Aldrich Chemical Co., St. Louis,
Mo.)
[0102] Tris(hydroxymethyl)-aminomethane (EM Science, Wakefield,
R.I.)
[0103] Poloxamer 407 (BASF. Mount Olive, N.J.)
[0104] Fractionated Poloxamer 407 (APC Lot #9630201)
[0105] Carbopol 940 NF (BF-Goodrich. Cleveland, Ohio)
[0106] Hydroxypropylmethylcellulose K100M, HPMC-K100M, (Dow
Chemical Company, Midland, Mich.)
[0107] Carboxymethylcellulose high viscosity, CMC (Spectrum
Chemical Co., Gardena, Calif.)
[0108] Carboxymethylcellulose medium viscosity CMC-MV (Penta
Manufacturing Co., Livingston, N.J.)
[0109] Preparation. Polymer solutions were prepared by first
dispersing the modifier polymer (i.e., CMC,
hydropropylmethylcellulose (HPMC) or Carbopol) in the Tris/maleate
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.degree. C.), and mixed until the poloxamer dissolved. The
sample was kept under refrigeration until usage.
[0110] 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 (Na.sub.2HPO.sub.47H.sub.2O) was brought
to a volume of 1L with DI water) and left to equilibrate for about
20 minutes to 36.8.degree. C. Membranes (1.2 gm cellulose ester
membranes, 25 mm diameter, type RAWP) were presoaked in phosphate
buffer and placed on the cell.
[0111] 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.
[0112] 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.
[0113] The procedure consists of mixing 250 .mu.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 50 mL
with DI water) with 1 mL of 2.5 M potassium nitrate solution
(50.55g of potassium nitrate was brought 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 in a
16.times.250 mm test tube. The mixture is then vortexed and
extracted with 3 mL of CH.sub.2Cl.sub.2. 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
HCI using a Sentron pH meter.
2TABLE I Poloxamer 407 Standard Solutions Std ID Poloxamer 407
(.mu.g) Absorbance (378 nm) 1 64 0.245 2 128 0.497 3 256 0.982
[0114] 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/0.5C, 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.
3Table II In-Vitro Release Profiles of FloGels: Sample k
(hr.sup.-n) n b MDT (hr) Flogel25 0.15 0.66 0.011 7 Flogel 28 0.15
0.66 0.0026 7 Flogel 28.sup.a 0.97 1.0 0.009 1 Flogel 28F 0.22 0.5
0.099 7 Flogel 25/0.5 C.sup.a 0.78 0.8 -0.041 1 Flogel 25/0.5CMV
0.22 0.5 -0.040 7 Flogel 25/1CMV 0.23 0.5 -0.032 6 Flogel 25/0.5
0.17 0.5 -0.023 11 HPMC Flogel 25/0.5C 0.14 0.5 -0.0064 17 Flogel
25/0.5 0.12 0.5 -0.028 22 940 Flogel 20F/0.5C 0.10 0.5 0.001 33
Flogel 20F/0.8C 0.074 0.5 0.0053 60 Flogel 16/1.5C 0.044 0.6 0.018
67 Flogel 14F/1C 0.037 0.6 0.019 90 .sup.a No membrane used in
dissolution study F Fractionated Poloxamer 407 940 Carbopol 940-NF
C High Viscosity CMC CMV Medium Viscosity CMC HPMC
Hydroxypropylmethylcellulose
[0115] Discussion: The data reported in Table II are fits to the
Korsmeyer-Peppas equation V viz. 1 Q Q = k t n + b ( V )
[0116] where Q is the amount released at the time t, Q.sub..alpha.
is the overall released amount, k is a release rate constant of the
n.sup.th 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 process in equal parts if n=0.66. Since the
release rate constant k has the dimension hr.sup.-n, 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: 2 MDT = nk - l / n n ( VI )
[0117] 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 FloGel 25 vs. FloGel 28) and poloxamer
fractionation do not appreciably alter the dissolution mechanism or
the MDT.
[0118] 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.
[0119] 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=0.50). Alternatively, the medium viscosity grade of
CMC does not appear to have a dramatic effect on the MDT at the
concentrations of modifier 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
surprisingly 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 cavity.
EXAMPLE 4
Modification of the Gelation Temperature of Poloxamer Preparations
Through the Incorporation of Hydrophilic Co-Surfactants
[0120] 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.
[0121] Methods: Fractionated poloxamer 407 (i.e. poloxamer 407F)
was prepared from NF grade Pluronic F-127 (BASF Corporation, Mount
Olive, N.J.) 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, Minn.). The buffer materials, tromethamine (EM
Sciences Inc., Gibbstown, N.J.) and maleic acid (Sigma Chemical
Co., St. Louis, Mo.), were used as received, and a hypoosmotic
buffer containing 0.1515% w/w tromethamine and 0.1451% w/w maleic
acid was prepared. Final formulations contained a constant 20% w/w
percentage of poloxamer 407F, and varying levels of fatty acid
soaps.
[0122] For 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.degree. C., phase
behavior was determined in a water bath (Koehler, Bohemia, N.Y.).
At higher temperatures an oil bath (Haake, model DC3, Germany) was
utilized. Temperature was raised in two degree increments from ca.
1.degree. C. to 120.degree. C. Samples were allowed to equilibrate
for at least 1 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.
[0123] 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
(.omega.=1 s.sup.-1) 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.degree. C. min.sup.-1. Rapid temperature equilibration
was ensured with a peltier/water bath system. Samples were loaded
at 0-5 .degree. 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 (.eta.*) vs.
temperature were recorded.
[0124] Discussion: Details regarding the equilibrium phase behavior
of 20% poloxamer 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 added fatty acid soaps is 19.degree. C. With
added fatty acid soaps, the LGT can be increased to temperatures as
high as 87.degree. C. (observed with 4.86% added sodium caprate).
In addition, the cloud point temperature, which is 108.degree. C.
for the 20% poloxamer 407F solution, may be easily increased to
temperatures above 140.degree. C., i.e. significantly above the
typical temperatures used during terminal steam sterilization.
4TABLE III Phase behavior of 20% poloxamer 407F solutions in
hypoosmotic tromethamine/maleate buffer with added fatty acid
soaps. Concentration of Cloud Co-Surfactant (% w/w) LGT (.degree.
C.) UGT (.degree. C.) Point (.degree. C.) 0% Fatty Acid Soap 19 81
108 1.0% Oleate (18:1) 17 78 106 3.01% Oleate 41 77 117 1% Laurate
(12:0) 22 78 110 1.5% Laurate 31 84 114 2.0% Laurate 49.5 84 121
2.2% Laurate 54.5 83 >140 2.4% Laurate 57 77 >140 2.5%
Laurate no gel no gel >140 1% Caprate (10:0) 19.5 80 112 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% Caprate 55 98 >140 4.0% Caprate
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% Caprylate 24.8 102 >140 5%
Caprylate 34 109 >140 5.5% Caprylate 36 113 >140 6.2%
Caprylate 43 120 >140 8% Caprylate 57.9 >140 >140 10%
Caprylate 74 >140 >140 10.57% Caprylate 75 -- >140 11.05%
Caprylate 75 150 >150 11.48% Caprylate no gel no gel >150
[0125] In accordance with the results reported above a typical
phase diagram obtained for poloxamer 407F/fatty acid soap mixtures
is shown in FIG. 2. This diagram illustrates the 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.
[0126] Above a sodium caprate concentration of ca. 1% w/w, the LGT
is observed to increase systematically from 19.degree. C. to
87.degree. 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 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.degree. 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 FIG. 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.
[0127] Dynamic temperature ramp studies for formulations with
varying levels of added sodium caprylate are shown in FIG. 3. At
low temperatures (below gel phase formation), the dynamic
Theological 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 Theological 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).
[0128] 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 FIG. 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 FIG. 4 that longer chainlength
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% 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 than
121.degree. 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.
EXAMPLE 5
Drug Solubility and in-vitro Drug Release Rates in Poloxamer
407-Based Thermoreversible Gels
[0129] In order to demonstrate the advantages of the present
invention with respect to drug delivery, selected compounds were
incorporated in various preparations formed in conjunction with the
present invention.
[0130] Materials
[0131] The chemicals utilized in this study and their sources are
listed below. All chemicals were used without further
purification.
[0132] Ketoprofen (Sigma Chemical Co., St. Louis, Mo.)
[0133] Prednisone (Sigma Chemical Co., St. Louis, Mo.)
[0134] lndomethacin (Sigma Chemical Co., St. Louis. Mo.)
[0135] Tolmetin Sodium (Sigma Chemical Co., St. Louis, Mo.)
[0136] Hydrocortisone (Sigma Chemical Co., St. Louis, Mo.)
[0137] Poloxamer 407 (BASF, Mount Olive, N.J.)
[0138] Ethyl Alcohol 200 proof (Spectrum Chemical Co., Gardena,
Calif.)
[0139] FloGel 28 (MDV Technologies Inc., Dearborn Mich.)
[0140] FloGel 25B/0.5C (MDV Technologies Inc., Dearborn Mich.)
[0141] FloGel 25 B/1 C (Alliance Pharmaceutical lot # 587-29b).
[0142] FloGel 25 (Alliance Pharmaceutical lot #587-29a).
[0143] FloGel 28F (Alliance Pharmaceutical lot p534-73).
[0144] Gentamicin Sulfate (Amresco, Solon, Ohio)
[0145] Methods
[0146] Preparation of Drug solutions in Poloxamer 407-water
systems. Poloxamer 407 was added to deionized (DI) water in an ice
bath (T=3-5.degree. 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.degree. C).
The next day the sample was warmed momentarily to 40.degree. C. to
hasten solubilization. This process was repeated two or three times
to ensure saturation. Samples containing less than 20% poloxamer
407 were then equilibrated overnight at room temperature while the
other samples were equilibrated at 5.degree.. Prior to analysis,
the samples were filtered through a 0.2.mu.m nylon filter syringe
to remove unsolubilized drug. Samples were assayed for solubilized
drug concentrations by absorbance spectroscopy (see below).
[0147] Preparation of drug solutions in FloGel. Two mg of drug was
added to 1 mL of the FloGel material and equilibrated overnight
(T=3-5.degree. C.). As before, the sample was warned two to three
times to 40.degree. to hasten solubilization. Samples were stored
at 5.degree. C. until use.
[0148] Drug Concentration Determinations: The samples were diluted
to a suitable concentration 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.
[0149] 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 0.01 M phosphate
buffer (pH 7.4)1 and left to equilibrate for about 20 minutes to
36.8.degree. C. Membranes (1.2 .mu.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 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 poloxamer-based thermoreversible gels. .sup.1
26.78 g of sodium phosphate dibasic (Na.sub.2HPO.sub.4 7H.sub.20)
was brought to a volume of 1L with DI water. The pH was adjusted to
a pH of 7.4 with 1N HCl using a Sentron pH meter.
[0150] Research & Development Technical Report No. EPR-32-9
7-4).
5TABLE IV Calibration Curve Equations for the Different Drugs
Selected Drug Calibration Curve Equation R.sup.2 Ketoprofen
Conc.sub.mg/L = 22.9(Abs) - 0.2 0.9996 Prednisone Conc.sub.mg/L =
33.3(Abs) - 0.06 0.9999 Indomethacin Conc.sub.mg/L = 232.4(Abs) - 2
0.991 Tolmetin Sodium Conc.sub.mg/L = 22.9(Abs) - 0.7 0.9919
Hydrocortisone Conc.sub.mg/L = 27.8(Abs) - 0.1 0.9956
[0151] 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.
[0152] Apparent distribution coefficients (Km) of the hydrophobic
drugs between a micellar phase and an aqueous phase were determined
according to equation VII. 3 S S o = K m C + 1 ( VII )
[0153] Where S and S.sub.o are the concentration of solubilized
drug in the presence and absence of poloxamer, respectively. C is
the concentration of poloxamer (weight fraction).
[0154] 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.
6TABLE V Distribution Coefficients of Hydrophobic Drugs Between a
Micellar Phase and an Aqueous Phase Distribution Coeffiecient (log
K.sub.m) Drug Evaluation Liquid State Gel State Hydrocortisone 1
0.55 Prednisone 1.1 1.5 Ketoprofen 2.9 3.1 Indomethacin 3 3.4
[0155] Positive distribution coefficients (log K.sub.m) 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 K.sub.m. 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.
[0156] 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 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.
[0157] 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.
[0158] 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
modifications of the invention, disclosed herein for the purposes
of illustration, which do not constitute departures from the spirit
and scope of the invention.
* * * * *