Processes for making cyclic lipid implants for intraocular use

Abstract

Biocompatible implants comprising a cyclic lipid therapeutic agent are made using a low temperature melt extrusion process. The implants are suitable for intraocular use to treat an ocular condition.

We claim: 
     
         1 . A low temperature process for making an intraocular implant, the process comprising the steps of:
 (a) combining a cyclic lipid therapeutic agent and a polymer to form a mixture;   (b) heating the mixture to a temperature between about 50° C. and about 80° C., and;   (c) extruding the heated mixture, thereby making an implant suitable for intraocular use.   
     
     
         2 . The process of  claim 1 , wherein the cyclic lipid therapeutic agent is selected from the group consisting of prostaglandins, prostaglandin analogs, and mixtures thereof. 
     
     
         3 . The process of  claim 1  wherein the cyclic lipid therapeutic agent is selected from the group consisting of bimatoprost, bimatoprost analogs, latanoprost, latanoprost analogs, travoprost, travoprost analogs, unoprostone, unoprostone analogs, prostaglandin E1 and prostaglandin E1 analogs, prostaglandin E2 and prostaglandin E2 analogs, and mixtures thereof. 
     
     
         4 . The process of  claim 3  wherein the cyclic lipid therapeutic agent is selected from the group consisting of bimatoprost, bimatoprost analogs, and mixtures thereof. 
     
     
         5 . The process of  claim 1  wherein the polymer is a biodegradable polymer. 
     
     
         6 . The process of  claim 5  wherein the biodegradable polymer is selected from the group consisting of polylactic acid, polyglycolic acid, polylactide-co-glycolide, and copolymers thereof. 
     
     
         7 . The process of  claim 1  wherein the polymer comprises from about 30% to about 95% by weight of the implant. 
     
     
         8 . The process of  claim 1  wherein the cyclic lipid therapeutic agent comprises from about 5% to about 70% by weight of the implant. 
     
     
         9 . The process of  claim 1 , wherein a potency of the cyclic lipid therapeutic agent released from the implant is at least about 50% of its maximum potency. 
     
     
         10 . A low temperature process for making an intraocular implant, the process comprising the steps of:
 (a) combining a prostaglandin analog and a biodegradable polymer to form a mixture;   (b) heating the mixture to a temperature between about 50° C. and about 80° C., and;   (c) extruding the heated mixture, thereby making an implant suitable for intraocular use.   
     
     
         11 . The implant made by the process of  claim 1 . 
     
     
         12 . A process for making an intraocular implant, the process comprising the steps of:
 (a) combining:
 (i) a cyclic lipid therapeutic agent; 
 (ii) a first biodegradable polymer, and; 
 (ii) a second biodegradable polymer to form a mixture, wherein;
 (α) the first biodegradable polymer and the second biodegradable polymer are different polymers; 
 (β) the solubilities of the cyclic lipid therapeutic agent, the first biodegradable polymer, and the second biodegradable polymer are substantially similar, and; 
 (γ) the melt temperature of the second biodegradable polymer is lower than the melt transition temperature of the first biodegradable polymer, 
 
   (b) heating the mixture to the lower melt temperature of the second biodegradable polymer, so that the second biodegradable polymer can function as a solvent for the cyclic lipid therapeutic agent and for the first biodegradable polymer, wherein the melt temperature of the second biodegradable polymer is lower than the temperature at which the cyclic lipid therapeutic agent exhibits a substantial loss of potency, and;   (c) extruding the heated mixture, thereby making an implant suitable for intraocular use.   
     
     
         13 . The process of  claim 12 , wherein the cyclic lipid therapeutic agent component is selected from the group consisting of prostaglandins, prostaglandin analogs, and mixtures thereof. 
     
     
         14 . The process of  claim 12  wherein the cyclic lipid therapeutic agent is selected from the group consisting of bimatoprost, bimatoprost analogs, and mixtures thereof. 
     
     
         15 . The process of  claim 12  wherein the first biodegradable polymer is selected from the group consisting of polylactic acid, polyglycolic acid, polylactide-co-glycolide, and copolymers thereof. 
     
     
         16 . The process of  claim 12  wherein the second biodegradable polymer is selected from the group consisting of decafluorobutane, poly(isobutylene), poly(hexemethylene adipamide), poly propylene, poly ethylene and polyethylne glycol. 
     
     
         17 . The process of  claim 12  wherein the solubilities of the cyclic lipid therapeutic agent, the first biodegradable polymer, and the second biodegradable polymer are all within about 10 Mpa 1/2  of each other. 
     
     
         18 . The process of  claim 12  wherein the solubilities of the cyclic lipid therapeutic agent, the first biodegradable polymer, and the second biodegradable polymer are all within about 15 to 30 Mpa 1/2 . 
     
     
         19 . The process of  claim 12  wherein the first polymer comprises from about 30% to about 90% by weight of the implant. 
     
     
         20 . The process of  claim 12  wherein the second polymer comprises from about 50% to about 30% by weight of the implant. 
     
     
         21 . The process of  claim 12  wherein the cyclic lipid therapeutic agent comprises from about 5% to about 30% by weight of the implant. 
     
     
         22 . A process for making an intraocular implant, the process comprising the steps of:
 (a) combining:
 (i) a prostaglandin analog, wherein the prostaglandin analog comprises from about 5% to about 30% by weight of the implant; 
 (ii) a poly(lactide-co-glycolide) copolymer, wherein the poly(lactide-co-glycolide) comprises from about 30% to about 90% by weight of the implant. and; 
 (ii) a second biodegradable polymer to form a mixture, wherein the second biodegradable polymer comprises from about 5% to about 40% by weight of the implant, and wherein;
 (α) the a poly(lactide-co-glycolide) copolymer and the second biodegradable polymer are different polymers; 
 (β) the solubilities of the prostaglandin analog, the poly(lactide-co-glycolide) copolymer, and the second biodegradable polymer are all within about 10 Mpa 112  of each other, and; 
 (γ) the melt temperature of the second biodegradable polymer is lower than the melting point of the a poly(lactide-co-glycolide) copolymer, 
 
   (b) heating the mixture to the lower melt temperature of the second biodegradable polymer, so that the second biodegradable polymer can function as a solvent for the prostaglandin analog and for the a poly(lactide-co-glycolide) copolymer, and; (c) extruding the heated mixture, thereby making an implant suitable for intraocular use, wherein the prostaglandin analog released from the implant has a potency of at least about 50%.   
     
     
         23 . A method for treating an ocular condition, the method comprising the step of intraocular administration of the implant made by the process of  claim 1 . 
     
     
         24 . The method of  claim 23 , wherein the intraocular administration is selected from a location selected from the group consisting of the anterior chamber, the posterior chamber, the vitreous cavity, the choroid, the suprachoroidal space, the subretinal space, the conjunctiva, the subconjunctival space, the episcleral space, the intracorneal space, the epicorneal space, the sclera, the pars plana, surgically-induced avascular regions, the macula, the retina and sub-tenon locations.