In Situ Film-Forming Bioactive Solutions of Absorbable Multiblock Copolymers

Abstract

An in situ film-forming methyl acetate-based solution of at least one absorbable, segmented block copolymer with amorphous and semi-crystalline segments contains at least one bioactive agent which exhibits antimicrobial, anti-inflammatory, antiviral, anesthetic, hemostatic, and/or antineoplastic activity. The absorbable polymers can be a polyaxial copolyester, polyether-ester and polyether-ester urethane. The solution can be applied (e.g., sprayed or swabbed) onto animal and human skin or accessible body cavities to prevent or treat one or more disorders preventable or treatable by the bioactive agent therein.

What is claimed is: 
     
         1 . An in situ film-forming solution comprising at least one absorbable, segmented block copolymer with amorphous and semi-crystalline segments in a methyl acetate solvent, the solution further comprising at least one bioactive agent selected from the group consisting of antimicrobial agents, anesthetic agents, antiviral agents, anti-inflammatory agents, hemostatic agents, and antineoplastic agents. 
     
     
         2 . The in situ film-forming solution as in  claim 1  wherein the solvent consists essentially of methyl acetate. 
     
     
         3 . The in situ film-forming solution as in  claim 2  wherein said solution can be sprayed or applied on animal or human skin and accessible body cavities to form an adherent, flexible, conformable, stretchable, dimensionally stable film having a tack-free outer surface, the film exhibiting an elongation of 100 to 600 percent, a tensile strength of 3-10 MPa and a tensile modulus of 5-20 MPa. 
     
     
         4 . The in situ film-forming solution as in  claim 2  wherein the segmented copolymer comprises from about 0.1 to about 20 weight/volume percent of the solution. 
     
     
         5 . The in situ film-forming solution as in  claim 2  wherein the at least one absorbable, segmented block copolymer with amorphous and semi-crystalline segments is selected from the group consisting of polyaxial copolyesters, polyether-esters and polyether-ester-urethanes and exhibits a heat of fusion (ΔH f ) of 1 to 20 J/g. 
     
     
         6 . The in situ film-forming solution as in  claim 2  wherein the at least one bioactive agent comprises from about 0.1 to about 15 weight percent of the absorbable copolymer and comprises a soluble entity or partially soluble microparticles or colloids. 
     
     
         7 . The in situ film-forming solution as in  claim 5  wherein the polymer is a polyaxial copolyester is derived from at least two cyclic monomers selected from the group consisting of p-dioxanone, 1,5-dioxapan-2-one, glycolide, 1-lactide, ε-caprolactone, trimethylene carbonate and a morpholinedione. 
     
     
         8 . The in situ film-forming solution as in  claim 6  wherein the at least one bioactive agent is selected from the group consisting of miconazole, ketoconazole, metronidazole, fluconazole, a silver salt, chlorhexidine and related salts?, curcumin, capsaicin, lidocaine, benzocaine, 8-hydroxyquinaline, triclosan, and paclitaxel. 
     
     
         9 . The in situ film-forming solution as in  claim 8  wherein the at least one bioactive agent is chlorhexidine. 
     
     
         10 . An in situ film-forming solution as in  claim 1  wherein the solvent consists essentially of methyl acetate and a ketone. 
     
     
         11 . The in situ film-forming solution as in  claim 10  wherein the segmented copolymer comprises from about 0.1 to about 20 weight percent of the solution. 
     
     
         12 . The in situ film-forming solution as in  claim 10  wherein the at least one absorbable, segmented block copolymer with amorphous and semi-crystalline segments is selected from the group consisting of polyaxial copolyesters, polyether-esters and polyether-ester-urethanes and exhibits a heat of fusion (ΔH f ) of 1 to 20 J/g. 
     
     
         13 . The in situ film-forming solution as in  claim 10  wherein the at least one bioactive agent comprises from about 0.1 to about 15 weight percent of the absorbable copolymer and comprises a soluble entity or partially soluble microparticles. 
     
     
         14 . The in situ film-forming solution as in  claim 13  wherein the polymer is a polyaxial copolyester derived from at least two cyclic monomers selected from the group consisting of p-dioxanone, 1,5-dioxapan-2-one, glycolide, 1-lactide, ε-caprolactone, trimethylene carbonate and a morpholinedione. 
     
     
         15 . The in situ film-forming solution as in  claim 14  wherein the at least one bioactive agent is selected from the group consisting of a silver salt, chlorhexidine, and combinations thereof. 
     
     
         16 . The in situ film-forming solution as in  claim 15  wherein the bioactive agent comprises silver nitrate and chlorhexidine. 
     
     
         17 . The in situ film-forming solution as in  claim 16  wherein the polyaxial copolyester is 35/14/34/17 (molar) ε-caprolactone/trimethylene carbonate/l-lactide/glycolide. 
     
     
         18 . The in situ film-forming solution as in  claim 17  wherein the ketone is acetone. 
     
     
         19 . A method of forming an in situ film-forming polymer solution that comprises the sequential steps of:
 a) preparing a solvent component comprising methyl acetate and a ketone;   b1) i) dissolving chlorhexidine base in the solvent component; and
 ii) dissolving a polymer component in the solution from step b1i), the polymer component comprising at least one absorbable, low crystallinity, segmented copolyester made from ε-caprolactone, trimethylene carbonate, l-lactide, and glycolide; 
 OR 
   b2) i) dissolving a polymer component in the solvent component, the polymer component comprising at least one absorbable, low crystallinity, segmented copolyester made from e-caprolactone, trimethylene carbonate, l-lactide, and glycolide; and
 ii) dissolving chlorhexidine base in the solution from step b2i); and 
   c) adding excess silver salt to the solution from step b1) or step b2) and allowing a saturated solution of the silver salt to form in the solution; and   d) removing the undissolved silver salt from the solution from step c).   
     
     
         20 . The method as in  claim 19  wherein the solvent component comprises from 0 to 50 weight percent ketone and from 50 to 100 weight percent methyl acetate. 
     
     
         21 . The method as in  claim 19  wherein the ketone is acetone. 
     
     
         22 . The method as in  claim 19  wherein the silver salt is silver nitrate or silver acetate. 
     
     
         23 . The method as in  claim 19  wherein the polymer component is 35/14/34/17 (molar) ε-caprolactone/trimethylene carbonate/l-lactide/glycolide.