1. Field of the Invention
This invention relates to methods and compositions for reducing post-surgical adhesions in the mammalian abdominal or thoracic cavity or other body spaces, whether accidentally or surgically created.
2. Description of the Prior Art
There is a need for a method and composition suitable for use in preventing adhesion formation/reformation in mammals following injury to the organs of the peritoneal, pelvic or pleural cavity, or other body spaces, such as subdural, extraocular, intraocular, otic, synovial, tendon sheath, 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.
Menzies and Ellis in an article entitled "Intestinal Obstruction from Adhesions--How Big is the Problem?" Annals of the Royal College of Surgeons of England, volume 72, pages 60-63, 1990 reported adhesions findings 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 adhesive obstruction. These data emphasize the magnitude of readhesion after adhesiolysis or from subsequent surgical procedures. The authors state on p. 62, that there is currently no effective treatment that prevents their recurrence.
Caspi, Halperin, and Bukovsky in an article entitled "The Importance of Periadnexal Adhesions in Reconstructive Surgery for Infertility" appearing in Fertility and Sterility for Mar. 1982, volume 31, number 3, pages 296-300, at page 299 indicate that despite experimental and clinical efforts in the prevention of adhesion formation following surgery, no major advances have thus far been achieved. The authors discuss the use of post-operative intraperitoneal instillation of a mixture of hydrocortisone acetate (a glucocorticoid), promethazine, and ampicillin. As an alternative method of treatment, a low molecular weight dextran (a branched polysaccharide composed of glucose units) was also instilled intraperitoneally in another group of patients. The authors conclude that the intraperitoneal instillation of high doses of glucocorticoids combined with early hydrotubations seems to be a worthwhile method.
Musich and Behrman in an article entitled "Infertility Laparoscopy In Perspective: Review of 500 Cases" appearing in The American Journal of Obstetrics and Gynecology for Jun. 1, 1982, pages 293-303, at page 300 in the discussion section of the article disclose that there is a need to prevent adhesions subsequent to surgery in view of a study of 35 patients which indicated that 30 of these patients having previous tuboplasties had severe adhesions, one-third of which were judged to be inoperable.
High molecular weight dextran either alone or in combination with dextrose has been used in the prevention of 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 of up to 200,000. Dextran is a polymer of glucose which has a chain-like structure and is produced from sucrose by Leuconostoc 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 including a simple mechanical separation of adjacent surfaces, termed a hydroflotation effect.
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% Dextran 70: A Prospective, Randomized Clinical Trial" in Fertility and Sterility, volume 40, number 5, for November 1983, pages 612-619. The authors, at 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 dependent regions of the pelvis.
Borten, Seibert, and Taymor in Obstetrics and Gynecology, volume 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.
Linsky in The Journal of Reproductive Medicine for Jan. 1987, pages 17-20 in an article entitled "Adhesion Reduction in the Rabbit Uterine Horn Model Using an Absorbable Barrier, TC-7". These authors report that the use of a resorbable fabric barrier provides a significant reduction in post-operative adhesion formation and that no gross remnants of the fabric barrier material were noted, subsequent to initial placement, after a two week period.
Oelsner et al in The Journal of Reproductive Medicine for November 1987, volume 32, number 11, pages 812-814, report results of a comparison of sodium carboxymethyl cellulose, 32% dextran 70, and chondroitin sulfate to prevent the formation of postoperative adhesions in the rabbit uterus. The authors report superior results with chondroitin sulfate which is described as a member of a family of biochemical compounds referred to as glycosaminoglycans (formerly termed mucopolysaccharides), to which hyaluronic acid, heparitin sulfate and heparin also belong.
Peterson et al in The Journal of Hand Surgery for Jan. 1990, volume 15A, number 1, pages 48-56 state on page 48 that despite refinements in surgical technique and improved postoperative rehabilitation programs, results (of repair of lacerated flexor tendons) are often unsatisfactory because of the formation of adhesions around the repair site which restrict tendon gliding and prevent flexion of the digit. The authors on page 49 refer to use of biological barriers including paratenon, endothelial vein grafts, arterial grafts, fascial sheath grafts, and synthetic materials such as, metal tubes, cellophane, celloidin, polytef (Teflon), polyethylene, millipore cellulose tubes, and silcone sheeting. Complications from use of these materials included severe inflammatory response, ingrowth of adhesions around the edges of the material, and prevention of nutrient diffusion leading to tendon necrosis. They conclude that a suitable biologic or synthetic flexor sheath patch has not yet gained widespread clinical acceptance. The authors tested primary tendon sheath repair, autogenous fascia lata patches, and a synthetic patch of expanded polytetraflorethylene surgical membranes. They concluded on p. 55 that restoration of the sheath integrity was beneficial in reducing adhesion formation, but it is not possible to advocate one particular method.
The use of ethylene oxide/propylene oxide block copolymers as surfactants for use 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 the 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 in 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.
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 liquid which can be applied at room temperature as a liquid but which forms a semisolid gel when warmed to body temperature has been utilized as a vehicle for drug delivery since 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 temperature, that is, the lower the concentration of polymer, the higher the sol-gel transition temperature.
In U.S. Pat. Nos. 4,474,751; '752; '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 pH and/or the ionic strength, as well as by the concentration of the polymer.
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.
While the prior art is silent with respect to the use of aqueous drug delivery vehicles which are isotonic to mammalian bodily fluids, osmotic drug delivery systems are disclosed in U.S. Pat. No. 4,439,196 which utilize a multi-chamber compartment for holding osmotic agents, adjuvants, enzymes, drugs, pro-drugs, pesticides, and the like. These materials are enclosed by semipermeable membranes so as to allow the fluids within the chambers to diffuse into the environment into which the osmotic drug delivery system is in contact. The drug delivery device can be sized for oral ingestion, implantation, rectal, vaginal, or ocular insertion for delivery of a drug or other beneficial substance. Since this drug delivery device relies on the permeability of the semipermeable membranes to control the rate of delivery of the drug, the drugs or other pharmaceutical preparations, by definition, are not isotonic with mammalian blood.