Methods and compositions for enhancing the bioadhesive properties of polymers using organic excipients

Abstract

Methods and compositions are provided for enhancing the bioadhesive properties of polymers used in drug delivery systems. The bioadhesive properties of a polymer are enhanced by incorporating an anhydride oligomer into the polymer to enhance the ability of the polymer to adhere to a tissue surface such as a mucosal membrane. Anhydride oligomers which enhance the bioadhesive properties of a polymer include oligomers synthesized from dicarboxylic acid monomers, preferably those found in Krebs glycolysis cycle, especially fumaric acid. The oligomers can be incorporated within a wide range of polymers including proteins, polysaccharides and synthetic biocompatible polymers. In one embodiment, anhydride oligomers can be incorporated within polymers used to form or coat drug delivery systems, such as microspheres, which contain a drug or diagnostic agent. The oligomers can either be solubilized and blended with the polymer before manufacture or else used as a coating with polymers over existing systems. The polymers, for example in the form of microspheres, have improved ability to adhere to mucosal membranes, and thus can be used to deliver a drug or diagnostic agent via any of a range of mucosal membrane surfaces including those of the gastrointestinal, respiratory, excretory and reproductive tracts.

We claim:  
     
         1 . A method for improving the bioadhesiveness of a polymer, the method comprising incorporating an anhydride oligomer in the polymer in an amount effective to enhance the ability of the polymer to adhere to a mucosal membrane.  
     
     
         2 . The method of    claim 1    wherein the anhydride oligomer is associated with the polymer by ionic or covalent bonds.  
     
     
         3 . The method of    claim 1    wherein the anhydride oligomer comprises dicarboxylic acid monomers selected from the group consisting of fumaric, maleic, succinic, adipic, sebacic and carboxyphenolic acids.  
     
     
         4 . The method of    claim 1    wherein the anhydride oligomer comprises dicarboxylic acid monomers selected from the group consisting of bis(p-carboxyphenoxy)methane, bis(p-carboxyphenoxy)propane, and bis(p-carboxyphenoxy)hexane, phthalic acid, isophthalic acid, terephthalic acid, azeleic acid, pimelic acid, itaconic acid, cyclohexane dicarboxylic acid, 1,4  phenylene dipropionic acid and 1,10-dodecanedioic acid.  
     
     
         5 . The method of    claim 1    wherein the anhydride oligomer includes twenty or fewer diacid units linked by anhydride linkages.  
     
     
         6 . The method of    claim 1    wherein the polymer is in the form of a microsphere, and wherein the method comprises improving the bioadhesiveness of the microsphere by incorporating the anhydride oligomer in the polymer during formation of the microsphere, thereby to enhance the ability of the microsphere to adhere to a mucosal membrane.  
     
     
         7 . The method of    claim 6    wherein the anhydride oligomer is in the form of a fine dispersion of particles on at least the surface of the microsphere.  
     
     
         8 . The method of    claim 7    wherein the anhydride oligomer has a molecular weight of about 5000 Daltons or less.  
     
     
         9 . The method of    claim 6    wherein the polymer incorporating the anhydride oligomer is coated onto the surface of a microsphere formed of a different material.  
     
     
         10 . The method of    claim 1    wherein the polymer is selected from the group consisting of proteins and polysaccharides.  
     
     
         11 . The method of    claim 1    wherein the polymer is selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polyaryalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl polymers, polyphosphazenes, polyacrylamides, polysiloxanes, polyurethanes, polymers of acrylic and methacrylic acid, celluloses, polyanhydrides, polyesters, poly(hydroxy acids), and blends and copolymers thereof.  
     
     
         12 . The method of    claim 6    wherein the microsphere further comprises a therapeutic or diagnostic agent.  
     
     
         13 . The method of    claim 12    wherein the diagnostic agent is selected from the group consisting of gases, gas evolving agents and radio-opaque compounds.  
     
     
         14 . The method of    claim 1    wherein the polymer defines or coats a drug delivery device containing a therapeutic agent.  
     
     
         15 . The method of    claim 1    wherein the polymer defines or coats a surgical implant device.  
     
     
         16 . The method of    claim 1    wherein the microsphere has a diameter greater than or equal to about 10 microns.  
     
     
         17 . The method of    claim 1    wherein the microsphere has a diameter between about 2 and 5 microns.  
     
     
         18 . The method of    claim 1    wherein the microsphere has a diameter of less than about 2 microns.  
     
     
         19 . The method of    claim 1    wherein the microsphere has a diameter less than about 1 micron.  
     
     
         20 . A method for delivering a therapeutic or diagnostic agent to a patient comprising administering to a mucosal membrane of the patient in a pharmaceutically acceptable carrier the therapeutic or diagnostic agent within a microsphere, wherein the surface of the microsphere comprises a polymer having an anhydride oligomer incorporated therein which improves the adhesion of the polymer to the mucosal membrane.  
     
     
         21 . The method of    claim 20    wherein the microsphere is administered by a route selected from the group consisting of nasal, vaginal, rectal and oral administration.  
     
     
         22 . The method of    claim 20    comprising administering the agent within the microsphere to a mucosal membrane selected from the group consisting of gastrointestinal, respiratory, excretory and reproductive mucous membranes.  
     
     
         23 . The method of    claim 20    wherein the microsphere has a diameter greater than or equal to about 10 microns.  
     
     
         24 . The method of    claim 20    wherein the microsphere has a diameter of between about 2 and 5 microns.  
     
     
         25 . The method of    claim 20    wherein the microsphere has a diameter less than about 2 microns.   
     
     
         26 . The method of    claim 20    wherein the microsphere has a diameter less than about 1 micron.  
     
     
         27 . A composition comprising a polymer incorporating an anhydride oligomer in an amount effective to improve adhesion of the polymer to a mucosal membrane.  
     
     
         28 . The composition of    claim 27    wherein the anhydride oligomer is associated with the polymer by ionic interactions or covalent bonds.  
     
     
         29 . The composition of    claim 27    wherein the anhydride oligomer comprises dicarboxylic acid monomers selected from the group consisting of fumaric, maleic, succinic, adipic, sebacic and carboxyphenolic acids.  
     
     
         30 . The composition of    claim 27    wherein the anhydride oligomer includes twenty or fewer diacid units linked by anhydride linkages.  
     
     
         31 . The composition of    claim 27    wherein the polymer is in the form of a microsphere.  
     
     
         32 . The composition of    claim 31    wherein the anhydride oligomer is in the form of a fine dispersion of particles on at least the surface of the microsphere.  
     
     
         33 . The composition of    claim 32    wherein the anhydride oligomer has a molecular weight of about 5000 Daltons or less.  
     
     
         34 . The composition of    claim 31    wherein the polymer incorporating the anhydride oligomer is coated onto the surface of a microsphere formed of a different material.  
     
     
         35 . The composition of    claim 27    wherein the polymer is selected from the group consisting of proteins and polysaccharides.  
     
     
         36 . The composition of    claim 27    wherein the polymer is selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polyaryalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl polymers, polyphosphazenes, polyacrylamides, polysiloxanes, polyurethanes, polymers of acrylic and methacrylic acid, celluloses, polyanhydrides, polyesters, poly(hydroxy acids), and blends and copolymers thereof.  
     
     
         37 . The composition of    claim 31    wherein the microsphere further comprises a therapeutic or diagnostic agent.  
     
     
         38 . The composition of    claim 37    wherein the diagnostic agent is selected from the group consisting of gases, gas evolving agents and radio-opaque compounds.  
     
     
         39 . The composition of    claim 27    wherein the polymer defines or coats a drug delivery device containing a therapeutic agent.  
     
     
         40 . The composition of    claim 31    wherein the microsphere has a diameter greater than or equal to about 10 microns.  
     
     
         41 . The composition of    claim 31    wherein the microsphere has a diameter of between about 2 to 5 microns.  
     
     
         42 . The composition of    claim 31    wherein the microsphere has a diameter less than about 2 microns.  
     
     
         43 . The composition of    claim 31    wherein the microsphere has a diameter less than about 1 micron.  
     
     
         44 . A method of forming a bioadhesive microsphere, the method comprising forming the microsphere of anhydride oligomers having a molecular weight of 5000 Daltons or less.  
     
     
         45 . The method of    claim 44    wherein the microsphere further comprises a therapeutic or diagnostic agent.