U.S. patent application number 10/293464 was filed with the patent office on 2003-07-10 for method and non-gelling composition for inhibiting post-surgical adhesions.
Invention is credited to Flore, Stephen G., Foley, Frederick J., Henry, Raymond L., Reeve, Lorraine E..
Application Number | 20030129240 10/293464 |
Document ID | / |
Family ID | 27578249 |
Filed Date | 2003-07-10 |
United States Patent
Application |
20030129240 |
Kind Code |
A1 |
Reeve, Lorraine E. ; et
al. |
July 10, 2003 |
Method and non-gelling composition for inhibiting post-surgical
adhesions
Abstract
Non-gelling polyoxyalkylene compositions, and methods of their
use for inhibiting surgical adhesion formation/reformation in
mammals are disclosed. The useful non-gelling compositions
preferably comprise polyoxyalkylene block copolymer at desired
concentrations with or without a therapeutic agent. When used with
an incorporated drug, the non-gelling compositions serve as a
carrier providing sustained or prolonged release of the therapeutic
agent.
Inventors: |
Reeve, Lorraine E.; (Dexter,
MI) ; Flore, Stephen G.; (San Diego, CA) ;
Foley, Frederick J.; (Bedford, NH) ; Henry, Raymond
L.; (St. Clair Shores, MI) |
Correspondence
Address: |
ATTN: John Wurst
Alliance Pharmaceutical Corp
6175 Lusk Blvd
San Diego
CA
92121
US
|
Family ID: |
27578249 |
Appl. No.: |
10/293464 |
Filed: |
November 12, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10293464 |
Nov 12, 2002 |
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09524174 |
Mar 13, 2000 |
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09524174 |
Mar 13, 2000 |
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09059716 |
Apr 13, 1998 |
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09059716 |
Apr 13, 1998 |
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08540287 |
Oct 6, 1995 |
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08954630 |
Oct 20, 1997 |
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08599116 |
Feb 9, 1996 |
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5681576 |
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08599116 |
Feb 9, 1996 |
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08208418 |
Mar 8, 1994 |
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08208418 |
Mar 8, 1994 |
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07977483 |
Nov 17, 1992 |
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5366735 |
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07977483 |
Nov 17, 1992 |
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07517283 |
May 1, 1990 |
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07517283 |
May 1, 1990 |
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07449215 |
Dec 12, 1989 |
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5135751 |
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07449215 |
Dec 12, 1989 |
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07272199 |
Nov 16, 1988 |
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4911926 |
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Current U.S.
Class: |
424/486 |
Current CPC
Class: |
A61K 31/522 20130101;
A61K 31/77 20130101; A61L 31/06 20130101; A61P 41/00 20180101; C08L
71/02 20130101; A61K 9/1075 20130101; A61K 9/0014 20130101; A61K
47/18 20130101; A61L 31/06 20130101; A61K 31/785 20130101; A61K
47/10 20130101; A61K 31/765 20130101 |
Class at
Publication: |
424/486 |
International
Class: |
A61K 009/14 |
Claims
What is claimed is:
1. A method of delivering one or more drugs to a subject in need of
treatment comprising administering a non-gelling aqueous
composition comprising: (1) about 70% to about 99% by weight of
water; (2) about 1% to about 30% by weight of a polyoxyalkylene
block copolymer of the formula: Y[(A).sub.n-E-H].sub.x (I) wherein
A is a polyoxyalkylene moiety having an oxygen/carbon atom ratio of
less than 0.5, x is at least 1, 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 minimum
molecular weight of A is between about 500 and about 900, as
determined by the hydroxyl number of an intermediate of the
formula: Y[(A)-H].sub.x (II) and the total average molecular weight
of the polyoxyalkylene block copolymer is at least about 5000; and,
(3) a therapeutically effective amount of the drug.
2. The method of claim 1, wherein Y is derived from a water soluble
organic compound having 1 to about 6 carbon atoms.
3. The method of claim 1, wherein said polyoxyalkylene block
copolymer is selected from the group consisting of a
polyoxyethylene-polyoxybutylene block copolymer, a
polyoxyethylene-polyoxypropylene block copolymer and mixtures
thereof, wherein the polyoxyethylene moiety constitutes at least
about 70% by weight of the polyoxyalkylene block copolymer.
4. The method of claim 1, wherein the pH of the aqueous composition
is maintained at about 7.4.+-.0.4.
5. The method of claim 1, wherein said polyoxyalkylene block
polymer is selected from block copolymers which form aqueous
solutions at a concentration of about 1% to about 16% by weight of
the total weight of said composition.
6. The method of claim 5, wherein said polyoxyalkylene block
polymer is selected from block copolymers which form aqueous
solutions at a concentration of about 7% to about 14% by weight of
the total weight of said composition.
7. The method of claim 6, wherein Y is selected from the group
consisting of propylene glycol, glycerin, pentaerythritol,
trimethylolpropane, ethylenediamine, and mixtures thereof.
8. The method of claim 1, wherein Y is derived from propylene
glycol, A is a propylene oxide residue, and the intermediate of
formula II has an average molecular weight of a least about
900.
9. The method of claim 1, wherein Y is derived from butylene
glycol, A is a butylene oxide residue, and the intermediate of
formula II has an average molecular weight of at least about
500.
10. The method of claim 1, wherein said polyoxyalkylene block
copolymer is of the formula:
HO(C.sub.2H.sub.4O).sub.b(C.sub.4H.sub.8O).sub.a(C.sub.2H-
.sub.4O).sub.bH (III) wherein a and b are integers such that the
hydrophobe base represented by (C.sub.4H.sub.8O) has an average
molecular weight of at least about 1000, as determined by hydroxyl
number, and the polyoxyethylene chain constitutes at least about
60% by weight of the polyoxyalkylene block copolymer; or of the
formula:
HO(C.sub.2H.sub.4O).sub.b(C.sub.3H.sub.6O).sub.a(C.sub.2H.sub.4O).sub.bH
(IV) wherein a and b are integers such the hydrophobe base
represented by (C.sub.3H.sub.6O) has an average molecular weight of
at least about 1500, as determined by hydroxyl number, the
polyoxyalkylene chain constitutes at least about 60% by weight of
the polyoxyalkylene block copolymer, and the block copolymer has a
total average molecular weight of at least about 5,000; or of the
formula: [H(OC.sub.2H.sub.4).sub.b(OC.sub.3H.sub.6-
).sub.a].sub.2--N--CH.sub.2--CH.sub.2--N--[(C.sub.3H.sub.6O).sub.a(C.sub.2-
H.sub.4O).sub.bH].sub.2 (V) wherein a and b are integers such that
the polyoxyalkylene block copolymer has an average hydrophobe
molecular weight of at least 2000, a hydrophile content of at least
about 60%, and a total average molecular weight of at least about
5,000.
11. The method of claim 10, wherein the total average molecular
weight of the block copolymer is at least about 15,000.
12. The method of claim 10, wherein the copolymer is:
H(OC.sub.2H.sub.4).sub.101
(OCH(CH.sub.3)CH.sub.2).sub.56(OC.sub.2H.sub.4- ).sub.101OH.
13. The method of claim 1 wherein the composition is hyper-, iso-,
or hypoosmotic to mammalian body tissues.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S. Ser.
No. 09/524,174, filed Mar. 13, 2000, which is a continuation of
U.S. Ser. No. 09/059,716, filed Apr. 13, 1998, now abandoned, which
is a continuation of U.S. Ser. No. 08/540,287, filed Oct. 6, 1995,
now abandoned, said U.S. Ser. No. 09/524,174 is also a
continuation-in-part of U.S. Ser. No. 08/954,630, filed Oct. 20,
1997, which is a continuation of U.S. Ser. No. 08/599,116, filed
Feb. 9, 1996, now U.S. Pat. No. 5,681,576, which is a continuation
of U.S. Ser. No. 08/208,418, filed Mar. 8, 1994, now abandoned,
which is a continuation of U.S. Ser. No. 07/977,483, filed Nov. 17,
1992, now U.S. Pat. No. 5,366,735, which is a division of U.S. Ser.
No. 07/517,283, filed May 1, 1990, now abandoned, which is a
continuation-in-part of U.S. Ser. No. 07/449,215, filed Dec. 12,
1989, now U.S. Pat. No. 5,135,751, which is a division of U.S. Ser.
No. 07/272,199, filed Nov. 16, 1988, now U.S. Pat. No.
4,911,926.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to methods and compositions for
inhibiting adhesions in the mammalian abdominal or thoracic cavity
or other body spaces, whether accidentally or surgically
created.
[0004] 2. Description of the Related Art
[0005] There is a need for improved methods and compositions for
inhibiting adhesion formation/reformation in body spaces of
mammals, whether accidentally or surgically created. According to
Ellis in a review entitled, "The Cause and Prevention of
Post-operative Intraperitoneal Adhesions," in Surgery, Gynecology
and Obstetrics for September 1971, volume 133, pages 497-509, at
pages 502-503, the prevention of adhesions has been the subject of
an enormous amount of work since the beginning of this century.
According to Ellis, these attempts have included means of
preventing the fibrin-coated walls of the intestine from reaching
each other by distending the abdomen with oxygen or filling the
abdomen with saline solution, paraffin, olive oil, lanolin,
concentrated dextrose solution, macromolecular solutions of all
sorts, and silicones.
[0006] Menzies and Ellis in a review entitled, "Intestinal
Obstruction from Adhesions--How Big is the Problem?" Annals of the
Royal College of Surgeons of England, vol. 72, pages 60-63, 1990,
reported finding adhesions in 10.4% of 115 patients with first-time
laparotomies while 93% of 210 patients had intra-abdominal
adhesions due to previous surgery. Admission for intestinal
obstruction was made for 0.9% of 28,297 general surgery patients
while 3.3% of 4,502 laparotomy patients were admitted for
intestinal obstruction due to adhesions. These data emphasize the
magnitude of readhesions after adhesiolysis or from subsequent
surgical procedures. The authors state on p. 62, that there is
currently no effective treatment that prevents their
recurrence.
[0007] High molecular weight dextran either alone or in combination
with dextrose has been used to prevent peritoneal adhesions
subsequent to surgery. Dextran is clinically standardized to a low
molecular weight of about 75,000 by partial hydrolysis and
fractional precipitation of the high molecular weight particles
which normally have molecular weights up to 200,000. Dextran is a
polymer of glucose which has a chain-like structure and is produced
from sucrose by Lenconostoc bacteria. In articles appearing in
Fertility and Sterility, volume 33, number 6, June 1980, pages
660-662, Holtz, Baker, and Tsai and volume 34, number 4, October,
1980, pages 394-395, by Holtz and Baker, results are reported of
the adhesion reducing effects of a 32% (aqueous) solution of
Dextran 70 containing 10% dextrose (sold under the trade name
HYSKON by Pharmacia, of Piscataway, N.J.). Holtz et al. postulate
several mechanisms of action in the prevention of peritoneal
adhesions utilizing HYSKON.RTM. including a simple mechanical
separation of adjacent surfaces, termed a hydroflotation
effect.
[0008] Project coordinator diZerega and several contributors have
reported the results of a large study in an article entitled,
"Reduction of Post-operative Pelvic Adhesions with Intraperitoneal
32% Dextron 70: A Prospective, Randomized Clinical Trial," in
Fertility and Sterility, volume 40, number 5, for November 1983,
pages 612-619. The authors, on page 618, indicate that the use of
Dextran intraperitoneally has limitations such as the reported
tendency of HYSKON to support bacterial proliferation and concern
over the anaphylactoid potential of dextran. In addition, the
benefit of Dextran 70 in preventing post-operative adhesions was
shown to be limited to the more lower regions of the pelvis.
[0009] Borten, Seibert, and Taymor in Obstetrics and Gynecology,
vol. 61, number 6, June, 1983, pages 755-757 report in an article
entitled, "Recurrent Anaphylactic Reaction to Intraperitoneal
Dextran 75 Used for Prevention of Postsurgical Adhesions." These
authors indicate that anaphylactic reaction to Dextran administered
intravenously is well documented and report such a reaction after
intraperitoneal administration of Dextran.
[0010] The use of ethylene oxide/propylene oxide block copolymers
as surfactants in surgical scrub solutions and the topical
application of 10% solutions of these copolymers to wounds is
described in Edlich et al. in the Journal of Surgical Research,
volume 14, number 4, April 1973, pages 277-284. The test results
indicate that copolymers having an ethylene oxide:propylene oxide
ratio of 4:1 provide less inflammatory response in a wound to which
the copolymer is applied in comparison with a copolymer having an
ethylene oxide:propylene oxide ratio of 1:4. There is no indication
by Edlich et al. or any cited prior art that such copolymers are
useful in reducing post-operative adhesions or that isotonic,
aqueous solutions of such copolymers are useful in reducing
post-operative adhesions.
[0011] Over the years, methods have been developed to achieve the
efficient delivery of a therapeutic drug to a mammalian body part
requiring pharmaceutical treatment. Use of an aqueous composition
which can be applied at room temperature as a liquid but which
forms a semi-solid gel when warmed to body temperature has been
utilized as a vehicle for drug delivery. Such a system combines
ease of application with greater retention at the site requiring
treatment than would be the case if the aqueous composition were
not converted to a gel as it is warmed to mammalian body
temperature. In U.S. Pat. No. 4,188,373, PLURONIC.RTM. polyols are
used in aqueous compositions to provide thermally gelling aqueous
systems. Adjusting the concentration of the polymer provides the
desired sol-gel transition, that is, the lower the concentration of
polymer, the higher the sol-gel transition temperature.
[0012] In U.S. Pat. Nos. 4,474,751; 4,474,752; 4,474,753; and
4,478,822, drug delivery systems are described which utilize
thermosetting polyoxyalkylene gels; the unique feature of these
systems is that both the gel transition temperature and/or the
rigidity of the gel can be modified by adjustment of the ionic
strength, as well as by the concentration of the polymer.
[0013] Other patents disclosing pharmaceutical compositions which
rely upon an aqueous gel composition as a vehicle for the
application of the drug or cosmetic preparation are U.S. Pat. Nos.
4,883,660; 4,861,760; 4,810,503; 4,767,619; and 4,511,563. U.S.
patent application Ser. No. 09/524,174 filed Mar. 13, 2000 is
hereby incorporated by reference.
[0014] Steinleitner et al. in an article entitled, "Poloxamer 407
as an Intraperitoneal Barrier Material for the Prevention of
Post-Surgical Adhesion Formation and Reformation in Rodent Models
for Reproductive Surgery, Obstetrics and Gynecology, Volume 1,
pages 48-52, 1991, discloses the anti-adhesion properties of
poloxamer 407. Poloxamer 407 is a biocompatible polymer, the
viscosity of which is dependent upon temperature and concentration
in aqueous solutions. The material is a liquid at room temperature
and is a solid at body temperature. In one experiment, poloxamer
solutions in concentrations ranging from 15-35% were applied to the
lesions on the uterine horn of hamsters. Significant reduction in
post-traumatic adhesion formation was observed following treatment
with the poloxamer solutions. In a second experiment, the polymer
was used in a paradigm for a typical situation encountered in
fertility surgery, that is, the prevention of adhesion reformation
after lysis of established adhesions. The effects of applying
poloxamer 407 after adhesiotomy in rabbits was compared to controls
that had received no treatments. The adhesion reformation was
reduced by a poloxamer 407 treatment.
[0015] Steinleitner in an article entitled, "New Modalities Under
Development for Adhesion Prevention; "Immunomodulatory Agents and
Poloxamer Barrier Materials," Gynecologic Surgery and Adhesion
Prevention, pages 235-251, 1993 discloses a review of the
pathophysiology of peritoneal wound repair that summarizes studies
evaluating immunomodulatory agents designed to favorably influence
aspects of post-surgical healing. Besides describing the physiology
of peritoneal repairs, the authors of the studies list a number of
immunomodulatory agents used in adhesion prevention such as calcium
channel blocking agents and other agents such as pentoxifylline.
The authors emphasize the application of barrier materials to
effect physical separation of injured viscera stating that it may
be the most effective therapy currently available to surgeons. The
ideal barrier material should be biocompatible, be absorbable and
have a neutral or beneficial effect on the events of peritoneal
healing. Further, the barrier material should serve as a local
delivery system for pharmacologic anti-adhesion treatments.
Poloxamer 407 has been identified as particularly well suited for
use in preventing adhesion formation or reformation as a barrier
material in infertility surgery.
[0016] The Steinleitner review discloses the use of pentoxifylline
in preventing the formation of post-surgical adhesions.
Pentoxifylline is a methylxanthine derivative which improves the
flow properties of blood by decreasing its viscosity. In patients
with chronic peripheral arterial disease, pentoxifylline increases
blood flow to the affected microcirculation and enhances tissue
oxygenation. Steinleitner et al. used the hamster uterine horn
primary injury model and administered doses of 0.1 to 10 mg/kg
subcutaneously at 12-hour intervals. This regimen was found to
provide protection against post-traumatic adhesion formation.
[0017] While the prior art discloses the use of pentoxifylline and
poloxamer 407 separately as agents that may be useful in inhibiting
or reducing the formation/reformation of adhesions in the
peritoneal cavity for mammals, there is a need for an improved
non-gelling composition that can be applied directly to the body
cavity and a process for reducing post-surgical adhesion
formation/reformation.
SUMMARY OF THE INVENTION
[0018] Non-gelling polyoxyalkylene compositions, therapeutic
agents, and a method are disclosed for inhibiting post-surgical
adhesion formation/reformation in mammals following injury to the
organs of a body cavity. The compositions of the invention are also
useful in reducing adhesion formation/reformation in body cavities.
The useful compositions comprise a surfactant and a non-gelling
polyoxyalkylene block copolymer at desired concentrations with or
without a therapeutic agent. The non-gelling polyakylene block
copolymer serves as a carrier with a sustained or prolonged release
of the therapeutic agent.
[0019] Single phase systems are also useful and may contain aqueous
solutes, aqueous solvents, and other aqueous additives.
Homogeneous, single phase systems can contain such additives as
alginate, cellulosics, polysaccharides, glycerol, polyethers, and
collagen altering the functionality of the system. The
concentration of the block copolymer in the compositions of the
present invention to take advantage of the non-gelation properties
of certain polyoxyalkylene block copolymers. Typically,
formulations of the present invention may contain up to about 16%
(w/w) of the polyoxyalkylene block copolymer of the present
invention.
[0020] The aqueous solutions of block copolymers can be provided as
isomotically and pH balanced compositions which match the pH and
osmotic pressure of mammalian bodily fluids. Subsequent to
deposition of the compositions of the invention on the tissues of
the peritoneal, pelvic, or pleural cavity of a mammal, or other
body spaces, the polyoxyalkylene block copolymer is absorbed into
the circulatory system and is eventually excreted, mainly in the
urine. In addition to functioning as a means of reducing
post-operative adhesion formation/reformation in mammals following
surgical or accidental injury or inflammation to the peritoneal,
pelvic or pleural cavity or other body spaces, a therapeutic agent
and polyoxyalkylene compositions provide an osmotically balanced
environment surrounding the surgical injury which reduces adhesion
formation/reformation. For instance, the polyoxyalkylene block
copolymer and therapeutic agent can be instilled within the uterine
cavity as a distending medium during diagnostic or operative
intrauterine endoscopic procedures. This procedure has two
advantages. First, since certain aqueous concentrations of the
preferred polyoxyalkylene block copolymers form a clear gel, their
use is well suited for visualization of the tissues within the
uterine cavity. Second, since these aqueous solutions are liquids
at room temperature and below and form a clear gel at body
temperature, the use of said solutions to separate the uterine
cavity walls will diminish or prevent post-surgical adhesion
formation. Similarly, the application of the aqueous,
polyoxyalkylene, capped polyether-surfactant pentoxifylline
combination as gels provide a similar adhesion reducing effect.
DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 is a chromogram of a poloxamer 407 analysis by gel
permeation choromography.
[0022] FIG. 2 illustrates pentoxifylline release from formulations
of carboxymethylcellulose, hydroxyethylcellulose, sodium alginate,
xanthan gum, and phosphate buffer (vehicle control).
[0023] FIG. 3 illustrates pentoxifylline release from formulations
of low MW hyaluronic acid, high MW hyaluronic acid, collagen, and
phosphate buffer (vehicle control).
[0024] FIG. 4 illustrates pentoxifylline release formulations from
PEG 8000, 14% poloxamer 407 with 20 mg/ml pentoxifylline, PEG 8000,
14% poloxamer 407 with 20 mg/ml pentoxifylline, 14% poloxamer 407
with 24 mg/ml pentoxifylline, and 16% poloxamer 188 with 12 mg/ml
pentoxifylline, and phosphate buffer (vehicle control).
[0025] FIG. 5 illustrates pentoxifylline release from formulations
of 28% poloxamer 407 with 12 mg/ml pentoxifylline, 14% poloxamer
407 with 36 mg/ml pentoxifylline and 14% poloxamer 407 with 12
mg/ml pentoxifylline.
DETAILED DESCRIPTION OF THE INVENTION
[0026] A process and composition are disclosed for inhibiting
post-operative adhesion formation/reformation in mammals following
surgical or accidental injury or inflammation to the organs of the
peritoneal or pleural cavity or other body spaces. In this
specification and claims, the terms "peritoneal" and "abdominal"
cavity are used as synonyms, as are the terms "pleural" and
"thoracic" cavity. By the term "body spaces," we mean cavities or
areas of the body where there is an environment for allowing the
composition of the present invention to be in contact with body
tissues. "Body spaces" may be further defined as peritoneal,
abdominal, and thoracic cavities as well as joints and areas of the
body containing synovial fluid. The compositions include
pentoxifylline, which is a methylxanthine derivative, and indicated
for the treatment of patients with intermittent claudication on the
basis of chronic occlusive arterial disease of the limbs.
[0027] The present invention discloses a novel use for
pentoxifylline, in effective amounts, in combination with the
polyoxyalkylene compositions disclosed herein, by providing for the
inhibition of post-surgical adhesion formation/reformation when
applied directly onto a body tissue following injury.
[0028] In one embodiment of the invention, the preferred aqueous,
polyoxyalkylene block copolymer compositions are prepared at a pH
and osmotic pressure which match that of bodily fluids (pH 7.4 and
290 mOsm/kg). When certain of the polyoxyalkylene block copolymers
of the invention are present in aqueous solutions at concentrations
preferably of about 1% to about 16%, preferably about 7 to about
14% by weight such compositions.
[0029] Alternatively, useful compositions of the invention include
aqueous compositions comprising at least one polyoxyalkylene block
copolymer which do not form gels at mammalian body temperature as
well as aqueous, isotonic, polyoxyalkylene gel polymers comprising
an alpha-olefin epoxide capped polyether and a surfactant. It is
believed that the aqueous compositions of the invention which do
not form gels upon contact with living mammalian tissue as well as
those which are applied to mammalian tissue in the gel state, also
function to prevent the formation/reformation of adhesions
subsequent to surgical procedures incurred by a mechanism of action
which has been termed in the prior art "hydroflotation."Thus, the
injured tissues are prevented from contacting adjacent tissues by
the means of the inclusion of a foreign fluid or gel in the
peritoneal, pelvic, or pleural cavity or other body spaces. It is
believed that the mechanism of action to prevent the
formation/reformation of adhesions is, in addition to
hydroflotation, properly characterized as the result of separating
the adjacent mammalian tissues by an adherent coating.
[0030] The polyoxyalkylene block copolymer compositions of one
embodiment of the invention include at least one block copolymer as
defined below, in combination with pentoxifylline. The copolymer is
applied to injured tissue in combination with pentoxifylline, both
in effective amounts. The block copolymer compositions of the
invention comprise at least one polyoxyalkylene block copolymer of
the formula:
Y[(A).sub.n-E-H].sub.x (I)
[0031] wherein A is a polyoxyalkylene moiety having an
oxygen/carbon atom ration of less than 0.5, x is at least 1, Y is
derived from water or an organic compound containing x reactive
hydrogen atoms, E is a polyoxyalkylene moiety constituting at least
about 60% by weight of the copolymer, n has a value such that the
average molecular weight of A is at least about 500 to about 900,
as determined by the hydroxyl number of a hydrophobe base
intermediate:
Y[(A).sub.n-H].sub.x (II)
[0032] and the total average molecular weight of the copolymer is
at least about 5000.
[0033] In addition to those polyoxyalkylene polymers described
above, which are suitable in combination with effective amounts of
pentoxifylline in the formation of the compositions of the
invention, other polyoxyalkylene polymers which form gels at low
concentrations in water are suitable. These 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 alpha-olefin 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. Detailed methods of preparing
these aqueous gels are disclosed in U.S. Pat. No. 4,810,503.
Preparation of said aqueous gels is generally described below.
Preferred surfactants for use in preparing these gels are also
disclosed in said patent.
[0034] A conventional copolymer polyether polyol is 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
to prepare the polymers of this invention. Ethylene oxide
homopolymers capped with said alpha-olefin oxides are also useful
as intermediates.
[0035] 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.
[0036] A block copolymer intermediate is prepared by reacting
either the ethylene oxide or said alkylene oxide having 3 to 4
carbon atoms with said active hydrogen-containing compound followed
by reaction with the other alkylene oxide. The ethylene oxide and
the alkylene oxides having from 3 to 4 carbon atoms are used in
said intermediates in amounts so that the resulting polyether
product will contain at least 10 percent by weight, preferably
about 60 percent to about 80 percent by weight, ethylene oxide
residue. The ethylene oxide homopolymer intermediate is prepared by
reacting ethylene oxide with said 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.
[0037] The alpha-olefin oxides which are utilized to modify the
conventional polyether intermediate of the prior art are those
oxides and the 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 of the invention.
[0038] Since the preparation of heteric and block copolymers of
alkylene oxides and ethylene oxide homopolymers are well known in
the art, further description of the preparation of said polymers is
unnecessary. Further details of the preparation of heteric
copolymers of lower alkylene oxides can be obtained in U.S. Pat.
No. 3,829,506, incorporated herein by reference. Further
information on the preparation of block copolymers of lower
alkylene oxides can be obtained in U.S. Pat. Nos. 3,535,307;
3,036,118; 2,979,578; 2,677,700; and 2,675,619 incorporated herein
by reference.
[0039] The surfactants may be ionic or non-ionic and many
surfactants and types of surfactants may be employed. While all
surfactants may not be effective in the preparation of osmotically
balanced gels of the instant invention, the fact that many are
effective makes it a simple matter for one skilled in the art to
select such surfactant with a minimum of trial and error.
[0040] The amounts of capped polyether polymer and surfactant may
be as little as 1.0 percent by weight or less of each depending on
the type and amount of the other components. There appears to be no
maximum amount of either component than that dictated by solubility
and osmolality in an aqueous solution. However, the total amount of
capped polymer and surfactant would generally not exceed 10 percent
by weight.
[0041] Preferably, the block copolymers which are useful are
selected from those defined above in formula I which contain at
least about 60% by weight, preferably at least about 70%, by weight
of the residue of ethylene oxide (polyoxyethylene moiety). Said
copolymers have a total average molecular weight of at least about
5000, and form a gel at mammalian body temperature, when in an
aqueous solution at a concentration generally, of about 10 to about
40%, and preferably, about 15 to about 30% by weight.
[0042] The proportion of water used is about 60% to about 90%, by
weight, preferably, about 70% to about 85%, by weight based upon
the total weight of the composition of the invention. Useful
polyoxyalkylene block copolymers which will form gels in such
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.
[0043] 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 hereby
incorporated by reference.
[0044] Useful polyoxybutylene based block copolymers conform to the
following generic formula:
HO(C.sub.2H.sub.4O).sub.b(C.sub.4H.sub.8O).sub.a(C.sub.2H.sub.4O).sub.bH
(III)
[0045] wherein a is an integer such that the hydrophobe base
represented by (C.sub.4H.sub.8O).sub.a has a molecular weight of at
least about 500, preferably at least about 1000 and most preferably
at least about 3000, as determined by hydroxyl number, the
polyoxyethylene chain constituting at least about 60%, preferably
at least about 70% by weight of the copolymer, and the copolymer
having a total average molecular weight of at least about 5000,
preferably at least about 10,000, and, most preferably, at least
about 15,000.
[0046] The copolymer is characterized in that all the hydrophobic
oxybutylene groups are present in chains bonded to an organic
radical at the former site of a reactive hydrogen atom thereby
constituting a polyoxybutylene base copolymer. The hydrophilic
oxyethylene groups are used to cap the polyoxybutylene base
polymer.
[0047] Polyoxyethylene-polyoxypropylene block copolymers which can
be used to form aqueous gels can be represented by the following
formula:
HO(C.sub.2H.sub.4O).sub.b(C.sub.3H.sub.6O).sub.a(C.sub.2H.sub.4O).sub.bH
(IV)
[0048] wherein a is an integer such that the hydrophobe base
represented by (C.sub.3H.sub.6O) has a molecular weight of at least
about 900, preferably at least about 2500 average molecular weight,
as determined by hydroxyl number; the polyoxyethylene chain
constituting at least about 60%, preferably at least about 70% by
weight of the copolymer, and the copolymer having a total average
molecular weight of at least about 5000, preferably at least about
10,000.
[0049] Polyoxyethylene-polyoxypropylene block copolymer adducts of
ethylenediamine which can be used may be represented by the
following formula: 1
[0050] wherein a and b are integers such that the copolymer may
have (1) a hydrophobe base molecular weight of at least about 2000,
preferably at least about 3000, and most preferably at least about
4500, (2) a hydrophile content of at least about 60%, preferably at
least about 70% by weight, and (3) a total average molecular weight
of at least about 5000, preferably at least about 10,000, and most
preferably at least about 15,000.
[0051] The hydrophobe base of the copolymer of formula V 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. These hydrophile polyoxyethylene groups are
controlled so as to constitute about 60% to about 80% by weight of
the copolymer.
[0052] 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. C. to about
10.degree. C. in water.
[0053] The organic compound initiator which is utilized in the
process for 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. Y is derived from water soluble
organic compounds having at least two reactive hydrogen atoms.
Falling within the scope of the compounds of the present invention
are water soluble organic compounds such as propylene glycol,
glycerin, pentaerythritol, trimethylolpropane, ethylenediamine, and
mixtures thereof and the like.
[0054] 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. Useful
polyoxyalkylene block copolymers generally have a total average
molecular weight of about 5000 to about 50,000, preferably about
5,000 to about 35,000 and most preferably about 5,000 to about
15,000.
[0055] Preferably the polyoxyalkylene block copolymer is applied to
surgically injured tissue as an aqueous solution which upon contact
with living mammalian tissue forms an adherent coating. Where a
polyoxyalkylene block copolymer is a viscous liquid or paste, the
compositions can be applied without dilution to areas of surgical
injury in the abdominal or thoracic cavities. The aqueous solution
or viscous liquid or paste may be applied to form an adherent
coating with the body tissues in the body cavity to aid in the
inhibition of the formation or reformation of adhesions. Serving as
a barrier, the composition of the present invention prevents the
close proximity or contact of tissues between surfaces of which
adhesions would form.
[0056] Another function of the non-gelling composition is to
deliver drugs to the site of treatment. In a preferred embodiment
of the invention, the non-gelling composition is used to deliver
pentoxifylline to the site of treatment. The amount of
pentoxifylline used is an amount effective to inhibit adhesion
formation/reformation in combination with the block copolymers of
this invention when applied as a liquid or gel to a body cavity
following surgery. Typically, the amount may be about 0.05% to
about 5.0% by weight, preferably about 0.1% to about 2.0% by
weight, based upon the total weight of the compositions of the
invention.
[0057] The poloxamers are a series of copolymers composed of two
polyoxyethylene blocks separated by a polyoxypropylene block.
(Lundsted, L. G., U.S. Pat. No. 2,674,619, 1954; Schmolka, I. R.
"Poloxamers in the Pharmaceutical Industry", in Polymers for
Controlled Drug Delivery, Tracha, P. J. (ed), CRC Press, Boca
Raton, Fla., 1991; Lundsted, L. G. and Schmolka, I. R. "The
Synthesis and Properties of Block Copolymer Polyol Surfactants", in
Block and Graft Copolymerization, vol 2, Ceresa, R. J. (ed). John
Wiley and Sons, New York, N.Y. 1976). Although composed of the same
two monomers, they vary in total molecular weight, polyoxypropylene
to polyoxyethylene ratio, and surfactant properties. The poloxamers
all have the general structure:
HO(C.sub.2H.sub.4O).sub.a(C.sub.3H.sub.6O).sub.b(C.sub.2H.sub.4O).sub.cH
(VI)
[0058] in which a and c are approximately equal, and b is at least
15.
[0059] The hydrophobic center block is synthesized in a base
catalyzed ether condensation using propylene glycol as the
initiator and sequentially adding propylene oxide under an inert,
anhydrous atmosphere, at elevated temperature and pressure. Upon
reaching the desired molecular weight, the reaction is terminated
by neutralization of the catalyst with acid. Using similar reaction
conditions, the polymer is then extended by the addition of
ethylene oxide to form a hydrophilic segment of polyoxyethylene at
each end of the polyoxypropylene block. More than thirty different
poloxamers have been synthesized which range in molecular weight
from 1,000 to 15,000. The polyoxyethylene content of the molecule
may vary from 10 to 90% of the weight of the molecule. The
poloxamers are freely soluble in water, and are soluble in polar
solvents. They are liquids, pastes or solids, depending largely on
their polyoxyethylene to polyoxypropylene ratio, and secondarily on
their total molecular weight. In general, poloxamers having an
average molecular weight of 3,000 or less are liquids if their
polyoxyethylene content is not more than 50%. Poloxamers with
molecular weights between 3,000 and 5,000 are liquids only if their
polyoxyethylene content is 20% or less. Pastes range in molecular
weight from 3300 to 6600 with a polyoxyethylene content between 30
and 50%. Solid poloxamers are the largest, having molecular weights
of 5,000 to 15,000 and a polyoxyethylene content of 70% or
greater.
[0060] A nomenclature system has been developed in which each
poloxamer has been assigned a number composed of three digits. This
number indicates the molecular weight of the hydrophobe and the
polyoxyethylene content of the respective poloxamer. The
approximate molecular weight of the hydrophobic polyoxypropylene
block is obtained by multiplying the first two digits by 100. The
approximate weight percent of polyoxyethylene is obtained is
multiplying the third digit by 10. For example, poloxamer 188 is
composed of a center block of polyoxypropylene having an
approximate molecular weight of 1,800, and an ethylene oxide
content of approximately 80% of the total molecular weight. Since
in Structure VI, a and c are statistically equal, poloxamer 188
should consist of a polyoxypropylene block having a molecular
weight of about 1,800, flanked on either end by polyoxyethylene
segments with molecular weights of about 3,600. In fact, nominal
molecular weights and polyoxyethylene to polyoxypropylene ratios
vary among manufacturing lots and among suppliers.
[0061] Because poloxamers are the products of a sequential series
of reactions, the molecular weights of individual poloxamer
molecules are statistical distributions about the average molecular
weight. When poloxamer 407 was analyzed by gel permeation
chromotography, a bimodal molecular weight distribution was
observed (FIG. 1). The larger peak accounted for approximately 85%
of the mass and was composed of molecules having molecular weights
between 9,000 and 20,000. A second peak ranging in molecular weight
from approximately 4,000 to 8,000 accounted for the remaining 15%
of the poloxamer mass. A similar bimodal distribution and broad
molecular weight range was observed for poloxamer 188. However, it
has been reported that poloxamer 407 obtained from various
suppliers have significantly different molecular weight
distributions. (Porter, C. J. H., Moghimi, S. M., Davies, M. C.,
Davis, S. S., and Illum, L., Int. J. Pharm. 83, (1972)
273-276).
[0062] The poloxamers are unsaturated to the extent of about 0.02
to 0.07 mEq/g as determined by titration with iodine or mercuric
acetate. This unsaturation results from the abstraction of a proton
and the formation of an allylic double bond during polyether
synthesis. This double bond causes termination of the
polymerization process. The unsaturated poloxamer molecules
partition overwhelmingly into the lower molecular weight fraction
during gel permeation chromatography. This suggests that the broad
molecular weight range observed for the commercially available
poloxamers is at least in part due to early chain termination. It
has been claimed that this termination process can be minimized by
using cesium hydroxide catalyst in place of sodium or potassium
hydroxide during polyether synthesis. (Ott, R. A., U.S. Pat. No.
4,764,567, 1988).
[0063] Because they contain both hydrophilic and hydrophobic
regions, poloxamer molecules form micelles in aqueous solution if
their polyoxypropylene region is large enough. Their aggregation
behavior, however, is quite complex, and cannot be described by
simply determining the critical micelle concentration for each
polymer. Studies measuring changes in surface-tension with
poloxamer concentration indicated two inflection points (Prasad, K.
N., Luong T. T., Florence, A. t., Paris, J., Vaution, C. Seiller,
M., and Puisieux, F., J. Colloid Interface Sci., 69, 2, 225-232,
1979). The first inflection point may be due to conformational
changes of the individual poloxamer molecules or intermolecular
interactions involving a small number of molecules. The second
inflection point, at a higher poloxomer concentration, is thought
to result from multimolecular aggregation. Zhou, Z., and Chu, B.,
J. Colloid Interface Sci., 126, 1, 171-180, 1988 observed that as
the concentration of poloxamer 188 in an aqueous solution
increased, a plot of temperature versus hydrodynamic radius was
shifted to the left, indicating an inverse relationship between
temperature and critical micelle concentration. Between 40 and
80.degree. C. the aggregation number of micelles rose sharply.
Rassing, J., and Attwood, D., Inter. J. Pharm. 13, 47-55, 1983
studied the aggregation behavior of poloxamer 407 over a
temperature range of 10 to 40.degree. C. They concluded from
measurements of the radius of gyration, that below 10.degree. C.
the polymer exists largely as loosely associated aggregates of
extended molecules, and, at least in this temperature range,
questioned the presence of coiled monomers as had been previously
proposed (Prasad, K. N., Luong, T. T., Florence, A. T., Paris, J.,
Vaution, C. Seiller, M., and Puisieux, F., J. Colloid Interface
Sci., 69, 2, 225-232, 1979). Above 10.degree. C. light scattering
measurements indicate that the aggregates become larger and more
highly organized, and above approximately 25.degree. C., they are
spherical entities whose aggregation number increases with
increasing temperature. Similar behavior has been reported for
poloxamers 184 and 237. It is thus apparent that there are no
single values for critical micelle concentration, critical micelle
temperature, or aggregation number for the poloxamers.
[0064] Table 1 (below) provides viscosities in centipoise of
aqueous solutions of poloxamer 407. The abrupt increase in
viscosity indicates gelation at a characteristic temperature for
each concentration of poloxamer.
1TABLE 1 Temperature Concentration of poloxamer 407 in water (w/w
%) .degree. C. 18 20 25 28 30 5 <1000 <1000 <1000 <1000
<1000 10 <1000 <1000 <1000 <1000 <1000 15
<1000 <1000 <1000 158000 254000 20 <1000 <1000
214000 248000 306000 25 76000 118000 250000 268000 320000 30 107000
138000 254000 272000 334000 35 120000 140000 258000 276000
338000
[0065] Concentrated aqueous solutions of many of the poloxamers
form gels in a fully reversible, temperature dependent process. A
20% solution of poloxamer 407 forms a solid gel at 25.degree. C.
(Table 1), but other poloxamers act similarly, at higher
concentrations. The gelation behavior of the poloxamers is
explained by their complex aggregation behavior. Although the
polyoxypropylene segment of the poloxamer molecule is hydrophobic,
its ether oxygens form hydrogen bonds with water molecules. For
this reason, the transfer of energy of a propyleneoxide unit from
the aqueous to the micellar phase is a fairly low 0.3 kT at
25.degree. C., which results in a loose association of molecules.
However, at higher temperatures, the polyoxypropylene segments are
dehydrated. This has been shown to occur over a fairly broad
temperature range, below the temperature at which gelation occurs.
In addition, the aggregation number of the micelles increases with
increasing temperature. These two phenomena, loss of water and
aggregation of more poloxamer molecules per micelle compensate for
each other and the hydrodynamic radius remains approximately
constant over a broad temperature range. At higher temperatures,
the polyoxyethylene chains begin to dehydrate as well. Upon the
loss of water, the polyoxyethylene chains of different micelles
interact with each other, if the poloxamer concentration is high
enough, and gelation occurs. This process is fully reversible, and
if the temperature of the poloxamer gel is reduced, rehydration
occurs and the solution returns to the liquid phase.
[0066] In practicing this invention, the concentration of
poloxamers employed in the formulations are such that the
formulation viscosities about 1000 CPS or less. At this viscosity,
the formulations remain liquid and exhibit anti-adhesion formation
activity when applied to tissues.
[0067] The poloxamers are widely used in topical and oral consumer
products as solubilizers, emulsifiers, stabilizers, dispersing,
suspending and coating agents. An extensive amount of research has
been done on similar uses of the poloxamers for drug delivery. A
monograph setting specifications and analytical methods for
poloxamers 124, 188, 237, 338 and 407 has been included in the
United States National Formularly since 1990. Poloxamer 188 is
included in the British Pharmacopea.
[0068] Because their backbone is composed of ether linkages, none
of the poloxamers is known to be metabolized in the body. They are
generally nonirritating and do not cause sensitization when applied
topically. The oral LD.sub.50 values for the liquid poloxamers are
generally greater than 1 gm/km of body weight, and for solids and
pastes greater than 10 gm/km. Two of the poloxamers, 188 and 407,
have been studied extensively for internal medical use.
[0069] 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
[0070] An aqueous solution was made of a
polyoxyethylene-polyoxypropylene block copolymer having the
structure generically shown as formula IV and having a
polyoxypropylene hydrophobe base average molecular weight of about
4000, a total average molecular weight of about 11,500, and
containing oxyethylene groups in the amount of at least about 70%
by weight of the total weight of copolymer. This copolymer is sold
under the trademark PLURONIC.RTM. F-127 by the BASF Corporation,
Parsippany, N.J. (also known as Poloxamer 407). A solution was made
by dissolving said polymer in cold (4.degree. C.) distilled water
to give a concentration of 30% by weight in accordance with the
cold process described above for forming aqueous solutions. More
specific solution procedures are described in "Artificial Skin I
Preparation and Properties of Pluronic F-127 Gels for Treatment of
Burns", J. Biomed. Mater. Res. 6, 527, 1972, incorporated herein by
reference. The block copolymer has the formula: 2
[0071] This solution is a liquid at 4.degree. C. and is non-gelling
but is adherent to living tissue upon contact. It is mixed with the
following formula:
2 1A INGREDIENT PERCENT BY WEIGHT Poloxamer 407, NF 14.00
Tromethamine (TRIS), USP 0.1091 Maleic Acid 0.1045 Sodium Hydroxide
pellets, USP 0.0420 Sodium chloride, USP 0.160 Sterile Water for
Irrigation, USP 85.584
[0072] First, the water was weighed in a tared vessel. Second, the
tromethamine, maleic acid and sodium hydroxide were added to the
water and mixed for twenty minutes. The pH and osmolality of the
solution were tested. The solution was cooled to 10.degree. C. and
the poloxamer was added to the solution over a two hour period with
constant stirring. The solution was stored under a nitrogen
atmosphere at 4.degree. C. for fifteen hours to effect a reduction
in the foam content of the solution. The solution was tested for
pH, osmolality, and viscosity and the results were 7.0-7.8, 280-320
mOsm/kg and 1,000 centipoise at temperature range of 2 to
35.degree. C., respectively. The solution was packaged into 30 cc
serum vials, capped with rubber stoppers and sterilized with steam
at 121.degree. C. and 15 psi for twenty minutes. Each vial was
cooled to 4.degree. C. and mixed for ten minutes to ensure uniform
solution.
EXAMPLE 2
[0073] The following formulation was prepared by following the
steps defined in Example 1:
3 2A Description % (w/w) Unit Example Poloxamer 188, NF 16.00 gm
16.00 Tromethamine (TRIS), USP 0.1091 gm 0.11 Maleic Acid 0.1045 gm
0.10 Sodium Hydroxide pellets, USP 0.0420 gm 0.04 Sterile Water for
Irrigation, USP 83.744 gm 83.74
[0074] First, the water was weighed in a tared vessel. Second, the
tromethamine, maleic acid and sodium hydroxide were added to the
water and mixed for twenty minutes. The pH and osmolality of the
solution were tested. The solution was cooled to 10.degree. C. and
the poloxamer was added to the solution over a two hour period with
constant stirring. The solution was stored under a nitrogen
atmosphere at 4.degree. C. for fifteen hours to effect a reduction
in the foam content of the solution. The solution was tested for
pH, osmolality, and viscosity and the results were 320 mOsm/kg and
>1000 centipoise at temperature range of 25.degree. C. to
35.degree. C., respectively. The solution was packaged into 30 cc
serum vials, capped with rubber stoppers and sterilized with steam
at 121.degree. C. and 15 psi for twenty minutes. Each vial was
cooled to 4.degree. C. and mixed for ten minutes to ensure uniform
solution.
EXAMPLE 3
Analytical Method
Measurement of Pentoxifylline Release from Various Formulations
[0075] Approximately 15 cm of SpectraPor regenerated cellulose
dialysis tubing (6000-8000 molecular weight cut off, cat. #132650,
Source: Spectrum Medical Industries, Inc.) is rinsed in distilled
water to remove preservatives. One end is sealed with the
appropriate sized closure.
[0076] 5 ml of the formulation to be tested was placed in the
tubing and the other end sealed as close as possible to the sample.
The tubing is placed in a beaker containing 95 ml of phosphate
buffer (0.05 M KH.sub.2PO.sub.4+0.0391 M NaOH, pH 7.4) and a
magnetic stirring bar. The solution was mixed on low speed at room
temperature. One ml samples were withdrawn (via pipet) at each time
point and diluted to an appropriate volume (either 10 or 25 ml)
with water for UV absorbance measurements.
[0077] UV absorbance of the test solution is determined at 273 nm
versus a water blank. A 100% release standard is prepared by
diluting 5 ml of the formulation to be tested to 100 ml with
phosphate buffer. 1 ml of this solution is then diluted to 25 ml
with water for absorbance measurement.
[0078] Percent released is calculated by ratioing the absorbance of
the test solution at each time point against the 100% release
standard, taking into account any differences in dilution, the
small decrease in volume of the test solution at each time point
caused by earlier sample withdrawals and the amount of
pentoxifylline already removed due to previous samplings.
[0079] The results are summarized in FIGS. 1-5. FIG. 1 is a
chromogram of a poloxamer 407 analysis by gel permeation
choromography. FIG. 2 illustrates pentoxifylline release from
formulations of carboxymethylcellulose, hydroxyethylcellulose,
sodium alginate, xanthan gum, and phosphate buffer (vehicle
control). FIG. 3 illustrates pentoxifylline release from
formulations of low MW hyaluronic acid, high MW hyaluronic acid,
collagen, and phosphate buffer (vehicle control). FIG. 4
illustrates pentoxifylline release formulations from PEG 8000, 14%
poloxamer 407 with 20 mg/ml pentoxifylline, PEG 8000, 14% poloxamer
407 with 20 mg/ml pentoxifylline, 14% poloxamer 407 with 24 mg/ml
pentoxifylline, and 16% poloxamer 188 with 12 mg/ml pentoxifylline,
and phosphate buffer (vehicle control). FIG. 5 illustrates
pentoxifylline release from formulations of 28% poloxamer 407 with
12 mg/ml pentoxifylline, 14% poloxamer 407 with 36 mg/ml
pentoxifylline and 14% poloxamer 407 with 12 mg/ml
pentoxifylline.
4 Representative Formulations Ingredient Source Weight %
Formulation: Sodium Alginate Gel with Pentoxifylline Sodium
Alginate TIC Gums 2.000 Pentoxifylline ICN 1.200 Tromethamine, USP
Spectrum 0.109 Maleic Acid Spectrum 0.105 Sodium Hydroxide, USP
Spectrum 0.042 Purified Water Bamsted 96.544 Formulation: Collagen
Gel with Pentoxifylline Hydracol Soluble Collagen Gattefasse 1.000
Pentoxifylline ICN 1.200 Tromethamine, USP Spectrum 0.109 Maleic
Acid Spectrum 0.105 Sodium Hydroxide, USP Spectrum 0.042 Purified
Water Bamsted 97.540 Formulation: Vehicle Control with
Pentoxifylline Pentoxifylline ICN 1.200 Tromethamine, USP Spectrum
0.109 Maleic Acid Spectrum 0.105 Sodium Hydroxide, USP Spectrum
0.042 Sodium Chloride Spectrum 0.750 Purified Water Bamsted 97.794
Formula: PEG 8000 with Pentoxifylline PEG 8000 Union Carbide 10.000
Pentoxifylline ICN 1.200 Tromethamine, USP Spectrum 0.109 Maleic
Acid Spectrum 0.105 Sodium Hydroxide, USP Spectrum 0.042 Purified
Water Bamsted 88.544 Formula: 14% Poloxamer 407 with 20 mg/ml
Pentoxifylline Poloxamer 407 BASF 14.000 Pentoxifylline ICN 2.000
Tromethamine, USP Spectrum 0.109 Maleic Acid Spectrum 0.105 Sodium
Hydroxide, USP Spectrum 0.042 Sodium Chloride Spectrum 0.040
Purified Water Bamsted 83.700 Formula: 14% Poloxamer 407 with 24
mg/ml Pentoxifylline Poloxamer 407 BASF 14.000 Penloxifylline ICN
2.400 Tromethamine, USP Spectrum 0.109 Maleic Acid Spectrum 0.105
Sodium Hydroxide, USP Spectrum 0.042 Sodium Chloride Spectrum 0.020
Purified Water Bamsted 83.324 Formula: 16% Poloxamer 188 with 12
mg/ml Pentoxifylline Poloxamer 188 BASF 16.000 Pentoxifylline ICN
1.200 Tromethamine, USP Spectrum 0.109 Maleic Acid Spectrum 0.105
Sodium Hydroxide, USP Spectrum 0.042 Purified Water Bamsted 82.544
Formula: 28% Poloxamer 407 with 12 mg/ml Pentoxifylline Poloxamer
407 BASF 28.00 Pentoxifylline ICN 1.20 Tromethamine, USP Spectrum
0.109 Maleic Acid Spectrum 0.105 Sodium Hydroxide, USP Spectrum
0.042 Purified Water Bamsted 70.544 Formula: 14% Poloxamer 407 with
36 mg/ml Pentoxifylline Poloxamer 407 BASF 14.00 Pentoxifylline ICN
3.60 Tromethamine, USP Spectrum 0.109 Maleic Acid Spectrum 0.105
Sodium Hydroxide, USP Spectrum 0.042 Purified Water Bamsted 82.144
Formula: 14% Poloxamer 407 with 12 mg/ml Pentoxifylline Poloxamer
407 BASF 14.00 Pentoxifylline ICN 1.20 Tromethamine, USP Spectrum
0.109 Maleic Acid Spectrum 0.105 Sodium Hydroxide, USP Spectrum
0.042 Sodium Chloride Spectrum 0.040 Purified Water Bamsted
84.504
EXAMPLE 4
Surgical Trial on Prospective Study on Adhesions in the Rabbit
Model
[0080] To assess the potential of poloxamer 407 with pentoxifylline
to prevent or reduce adhesions, the following experiment was
performed.
[0081] Preparation of 14% poloxamer 407 with 1.2% pentoxifylline
solution.
5 Ingredient Percent by Weight Poloxamer 407, NF 14.00
Pentoxifylline 1.20 Tromethamine (TRIS), USP 0.1091 Maleic Acid
0.1045 Sodium Hydroxide pellets, USP 0.0420 Sodium Chloride, USP
0.04 Sterile Water for Irrigation, USP 82.54
[0082] Water was weighed into a tared vessel. Pentoxifylline,
tromethamine, maleic acid and sodium hydroxide were added to the
water and mixed for twenty minutes. The pH and osmolality of the
solution were tested and found to be 7.6 and 109 mOsm/Kg,
respectively. The solution was cooled to 6.degree. C. and the
poloxamer was added to the solution over a two-hour period with
constant stirring. The solution was stored under a nitrogen
atmosphere at 4.degree. C. for fifteen hours to effect a reduction
in the foam content of the solution. The solution was tested for pH
and osmolality and the results were 7.4 and 290 mOsm/Kg,
respectively. The solution was packaged into 30 cc serum vials,
capped with rubber stoppers and sterilized with steam at
121.degree. C. and 15 psi for twenty minutes. The vials were cooled
to 4.degree. C. and swirled for ten minutes to ensure uniform
distribution.
[0083] The equipment utilized eighteen, healthy, female, New
Zealand White rabbits. The uterine horn was exteriorized, then
abraded by scraping 20-30 times with a no. 10 scalpel blade until a
wound was produced that had punctate bleeding. Nine of the rabbits
received 3.0 ml of 14% poloxamer 407 with 1.2% pentoxifylline
delivered at 0.degree. C. Five rabbits received a physiologic
buffer also delivered at 0.degree. C. Four rabbits received no
treatment. The opposite uterine horn was untreated. The uterine
horns were returned to the peritoneal cavity and the incision was
closed. On the 12th day after the initial surgery, the animals were
necropsied and the adhesions were scored. The adhesions were scored
as follows: 0=no adhesions, 1=adhesions up to 25% of area,
2=adhesions from 25% to 50% of area, 3=greater than 50% of area,
4=100% adhesions.
6 Treatment Adhesion Score (Mean) 14% poloxamer 407 with 12%
pentoxifylline 0.67 physiologic buffer 2.4 no treatment 2.35
Preparation of poloxamer 188 solution. Ingredient Percent by Weight
Poloxamer 188, NF 16.00 Pentoxifylline 1.20 Tromethamine (TRIS),
USP 0.1091 Maleic Acid 0.1045 Sodium Hydroxide pellets, USP 0.0420
Sterile Water for Irrigation, USP 82.54
[0084] Water was weighed into a tared vessel. Pentoxifylline,
tromethamine, maleic acid and sodium hydroxide were added to the
water and mixed for twenty minutes. The pH and osmolality of the
solution were tested and found to be 7.7 and 50 mOsm/Kg,
respectively. The solution was cooled to 6.degree. C. and the
poloxamer was added to the solution over a two-hour period with
constant stirring. The solution was stored under a nitrogen
atmosphere at 4.degree. C. for fifteen hours to effect a reduction
in the foam content of the solution. The solution was tested for pH
and osmolality and the rabbits were 7.4 and 140 mOsm/Kg,
respectively. The solution was packaged into 30 cc serum vials,
capped with rubber stoppers and sterilized with steam at
121.degree. C. and 15 psi for twenty minutes. The vials were cooled
to 4.degree. C. and swirled for ten minutes to ensure uniform
distribution of pentoxifylline in the vial.
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