Polymer formulation for prevention of surgical adhesions

#Adhesions are fibrous bands of tissue connecting one or more organ sites within the body. Typically, adhesions are formed in connection with tissue injury. Injury to, or ischemia of, serosal tissue results in an increased immune response at the site, with a subsequent release of serosanguinous exudate resulting in fibrin deposition at the injured site. Adhesions form as a result of the induced inflammatory response in combination with an impaired ability to lyse such fibrin deposits.

#Normal tissue surfaces produce tissue plasminogen activator (t-PA) which converts inactive plasminogen to plasmin. In normal tissue, the localized proteolytic activity of plasmin dissolves fibrin deposits and thus prevents adhesion formation. However, ischemic injury to serosal surfaces retards t-PA production. Reduced t-PA production results in excessive fibrin accumulation at the injured site. Such fibrin deposits serve as a matrix for fibroblastic infiltration and proliferation. Eventually, collagenous bands form at the site of the fibrin deposit. The collagenous bands contract as healing proceeds and thereby limit movement of the affected organ or organs.

#Consequently, adhesions impair movement and can obstruct proper organ function. Such mechanical impairment is responsible for a majority of chest, back, abdominal, and pelvic pain experienced by patients recovering from thoracic, abdominal, lumbar and/or gynecological surgeries. Additionally, adhesions may complicate proper healing of the surgical site and lead to loss of function, infertility, bowel obstruction and even morbidity.

#FIG. 1 is a bar graph showing the average tenacity of adhesions for various formulations;

#FIG. 2 is a bar graph showing the average extent of adhesion formation for various formulations;

#FIG. 3 is a bar graph showing the average total score for various formulations; and

#The invention is directed to a polymer formulation for preventing formation of adhesions, particularly after cardiac, thoracic, abdominal, pelvic or gynecological surgery. The polymer formulation includes a pharmaceutically acceptable, biodegradable thermoplastic polymer that is substantially insoluble in water or human or animal body fluids. The thermoplastic polymer is dissolved in .epsilon.-caprolactone, a biocompatible organic solvent which is moderately soluble in water or human or animal body fluids. According to the invention, .epsilon.-caprolactone dissipates slowly into surrounding tissue fluids when the polymer formulation is applied to a tissue defect. As the .epsilon.-caprolactone dissipates, the water-insoluble thermoplastic polymer slowly coagulates to form a pliable matrix. Preferably, the thermoplastic polymer is a copolymer of caprolactone or trimethylene carbonate monomers and lactide or glycolide monomers. More preferably, the thermoplastic polymer is poly(DL-lactide-co-caprolactone).

#The resulting matrix provides a flexible, biodegradable barrier which prevents formation of tissue adhesions between the tissue defect and neighboring tissues. Because the resulting matrix is biodegradable, bioabsorbable, and/or bioerodible, it is gradually absorbed into surrounding tissue fluids, for example, blood serum, lymph, cerebral spinal fluid (CSF), or periodontal fluid and/or becomes disintegrated through enzymatic, chemical or cellular hydrolytic action. The amount of time required to degrade the matrix can be varied, for example, by altering the molecular weight of the thermoplastic polymer or the composition of the copolymer. Generally, the matrix is absorbed over a period of about 1 week to about 12 months, preferably within about 1 week to about 2 weeks.

#Although systems in which thermoplastic polymers are dissolved in a biocompatible, water soluble organic solvent and form a solid implant upon contact with body fluids have been described (See, for example, Dunn et al., U.S. Pat. No. 5,324,519), the inventors have found, surprisingly, that dissolving a thermoplastic polymer, such as poly(DL-lactide-co-caprolactone), in .epsilon.-caprolactone results in an in-situ barrier film that is more effective at preventing adhesion formation than formulations prepared with other solvents. While not intending to be bound by theory, the inventors believe that the surprising efficacy is due either to the slow coagulation of the elastomeric copolymer (due to the moderate solubility of .epsilon.-caprolactone in aqueous media) or the inherent properties of the caprolactone solvent. Additionally, the thermoplastic polymer used in the formulation may impact the efficacy of the formulation. Preferably, the thermoplastic polymer or copolymer is elastomeric such that the resulting matrix is pliable and able to conform to the underlying tissue, even when the tissue is moved, for example when the tissue is manipulated by medical personnel.