Poly(glycerol sebacate)-interleukin inhibitor copolymers and methods of making and use

Abstract

A method includes combining an alcohol-pharmaceutical conjugate, a polyol, and an aqueous liquid in a vessel. The alcohol-pharmaceutical conjugate includes a pharmaceutical compound having at least one carboxyl group attached to the polyol by an ester bond. The method also includes adding an acid monomer to the vessel and heating and removing water from the vessel to produce the polymeric material. The polymeric material includes a polyester copolymer of the acid monomer and the polyol and the pharmaceutical compound.

What is claimed is: 
     
         1 . A method of preparing a polymeric material, comprising the steps of:
 providing an alcohol-pharmaceutical conjugate of a pharmaceutical compound covalently attached by an ester bond to a polyol by a carboxyl group of the pharmaceutical compound;   combining the alcohol-pharmaceutical conjugate, additional polyol, and an aqueous liquid in a vessel;   adding an acid monomer to the vessel; and   heating and removing water from the vessel to produce the polymeric material;   wherein the polymeric material comprises a polyester copolymer of the acid monomer, the polyol and the pharmaceutical compound, and the additional polyol.   
     
     
         2 . The method of  claim 1  further comprising:
 combining the polyol and additional aqueous liquid; 
 adding the pharmaceutical compound to the polyol and additional aqueous liquid; 
 heating and removing water to produce the alcohol-pharmaceutical conjugate. 
 
     
     
         3 . The method of  claim 1 , wherein the heating and removing water from the vessel comprises refluxing the alcohol-pharmaceutical conjugate, the additional polyol, the aqueous liquid, and the acid monomer. 
     
     
         4 . The method of  claim 1 , wherein the heating and removing water from the vessel further comprises reducing a pressure in the vessel to the range of 5 Ton to 20 Torr. 
     
     
         5 . The method of  claim 1 , wherein the polyol and the additional polyol comprise glycerol. 
     
     
         6 . The method of  claim 1 , wherein the aqueous liquid is water. 
     
     
         7 . The method of  claim 1 , wherein the acid monomer comprises a diacid. 
     
     
         8 . The method of  claim 7 , wherein the diacid comprises a compound of the formula [HOOC(CH 2 ) n COOH], wherein n=1-30. 
     
     
         9 . The method of  claim 8 , wherein the diacid comprises malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, or a combination thereof. 
     
     
         10 . The method of  claim 8 , wherein the diacid is sebacic acid. 
     
     
         11 . The method of  claim 1 , wherein the heating and removing water comprises heating to about 50-200° C. 
     
     
         12 . The method of  claim 1 , wherein the heating and removing water includes applying an inert atmosphere at atmospheric pressure for about 1 hour to about 48 hours. 
     
     
         13 . The method of  claim 12 , wherein the heating and removing water further includes applying a sub-atmospheric pressure for about 1 hour to about 76 hours after the applying an inert atmosphere at atmospheric pressure for about 1 hour to about 48 hours. 
     
     
         14 . The method of  claim 1 , wherein the heating and removing water comprises applying a sub-atmospheric pressure for about 1 hour to about 76 hours. 
     
     
         15 . The method of  claim 1  further comprising adding a co-monomer or a polymer to the vessel to form the polymeric material as a co-polymer. 
     
     
         16 . The method of  claim 15 , wherein the co-monomer comprises a diacid, lactic acid, caprolactone, or a combination thereof. 
     
     
         17 . The method of  claim 1 , wherein the polymeric material includes 20% to 25% of the pharmaceutical compound, by weight, based on the total weight of the polymeric material. 
     
     
         18 . The polymeric material prepared by the method of  claim 1 . 
     
     
         19 . A method of preparing a polymeric material, comprising the steps of:
 providing a glycerol-pharmaceutical conjugate of a pharmaceutical compound covalently attached by an ester bond to glycerol by a carboxyl group of the pharmaceutical compound; then   combining additional glycerol, the glycerol-pharmaceutical conjugate, and water in a vessel; then   adding sebacic acid to the vessel; then   removing water from the vessel; then   reacting the additional glycerol, glycerol-pharmaceutical conjugate, and sebacic acid in the vessel at atmospheric pressure and a temperature in the range of 50−200° C. in the presence of an inert gas for a period of about 1 hour to about 48 hours; and then   applying a sub-atmospheric pressure to the vessel for about 1 hour to about 76 hours after the step of reacting in the presence of an inert gas at atmospheric pressure, with a temperature in the vessel in the range of 50−200° C., thereby forming the polymeric material in the vessel, the polymeric material comprising a polyester copolymer of the acid monomer and the polyol and the pharmaceutical compound.   
     
     
         20 . The method of  claim 19 , wherein the sub-atmospheric pressure is in the range of 5 Torr to 20 Torr. 
     
     
         21 . The method of  claim 19 , wherein the sub-atmospheric pressure is applied for about 24 hours to about 36 hours.