Polymeric delivery formulations of leuprolide with improved efficacy

Abstract

The present invention is directed to a flowable composition that is suitable for use as a controlled release implant. The flowable composition includes a biodegradable thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid. The flowable composition also includes a biocompatible polar aprotic solvent. The biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid. The flowable composition also includes leuprolide acetate.

1 . (canceled) 
     
     
         2 - 46 . (canceled) 
     
     
         47 . A method of treating precocious puberty in a patient comprising administering to the patient in need of such treatment or prevention an effective amount of a flowable composition suitable for use as a controlled release implant, the composition comprising:
 (a) a biodegradable thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid;   (b) a biocompatible polar aprotic solvent selected from the group consisting of an amide, an ester, a carbonate, a ketone, an ether, and a sulfonyl; wherein the biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid; and   (c) leuprolide acetate.   
     
     
         48 . The method of  claim 47  wherein the biodegradable thermoplastic polyester is a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, or any combination thereof. 
     
     
         49 . The method of  claim 47  wherein the biodegradable thermoplastic polyester is a polylactide, a polyglycolide, a copolymer thereof, a terpolymer thereof, or a combination thereof. 
     
     
         50 . The method of  claim 49  wherein the biodegradable thermoplastic polyester includes a diol and has only hydroxyl terminal groups. 
     
     
         51 . The method of  claim 47  wherein the biodegradable thermoplastic polyester is 50/50 poly (DL-lactide-co-glycolide) having a carboxy terminal group. 
     
     
         52 . The method of  claim 47  wherein the biodegradable thermoplastic polyester is 75/25 poly (DL-lactide-co-glycolide) without a carboxy terminal group. 
     
     
         53 . The method of  claim 47  wherein the biodegradable thermoplastic polyester has an average molecular weight of about 23,000 to about 45,000 or about 15,000 to about 24,000. 
     
     
         54 . The method of  claim 47  wherein the biocompatible polar aprotic solvent is N-methyl-2-pyrrolidone, 2-pyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin, or any combination thereof. 
     
     
         55 . The method of  claim 47  wherein the biocompatible polar aprotic solvent is N-methyl-2-pyrrolidone. 
     
     
         56 . The method of  claim 47  wherein the biocompatible polar aprotic solvent is present in about 60 wt. % to about 70 wt. % of the composition. 
     
     
         57 . The method of  claim 47  wherein the biocompatible polar aprotic solvent is present in about 50 wt. % to about 60 wt. % of the composition. 
     
     
         58 . The method of  claim 47  wherein the leuprolide acetate is present in about 2 wt. % to about 4 wt. % of the composition. 
     
     
         59 . The method of  claim 47  wherein the leuprolide acetate is present in about 4 wt. % to about 8 wt. % of the composition. 
     
     
         60 . The method of  claim 47  wherein the composition is formulated as an injectable subcutaneous delivery system. 
     
     
         61 . The method of  claim 60  wherein the composition has a volume of about 0.20 mL to about 0.40 mL. 
     
     
         62 . The method of  claim 60  wherein the composition has a volume of about 0.30 mL to about 0.50 mL. 
     
     
         63 . The method of  claim 60  wherein the composition is formulated for administration about once per month. 
     
     
         64 . The method of  claim 60  wherein the composition is formulated for administration about once per three months. 
     
     
         65 . The method of  claim 60  wherein the composition is formulated for administration about once per four months to about once per six months. 
     
     
         66 . The method of  claim 47  wherein the patient is a human. 
     
     
         67 . A method of reducing LHRH levels in a patient exhibiting precocious puberty comprising administering to the patient in need of such LHRH reduction an effective amount of a flowable composition of a flowable composition suitable for use as a controlled release implant, the composition comprising:
 (a) a biodegradable thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid;   (b) a biocompatible polar aprotic solvent selected from the group consisting of an amide, an ester, a carbonate, a ketone, an ether, and a sulfonyl; wherein the biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid; and   (c) leuprolide acetate.   
     
     
         68 . A biodegradable implant formed in situ, in a patient exhibiting precocious puberty, by the steps comprising:
 (a) injecting a composition within the body of the patient; and   (b) allowing the biocompatible polar aprotic solvent to dissipate to produce a solid biodegradable implant, wherein the composition comprises an effective amount of a biodegradable thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid; an effective amount of a biocompatible polar aprotic solvent selected from the group consisting of an amide, an ester, a carbonate, a ketone, an ether, and a sulfonyl, wherein the biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid; and an effective amount of leuprolide acetate;   
       the implant retarding, ameliorating or preventing precocious puberty. 
     
     
         69 . The biodegradable implant of  claim 68  wherein the patient is a human. 
     
     
         70 . The biodegradable implant of  claim 68  wherein the solid implant releases the effective amount of leuprolide as the solid implant biodegrades in the patient. 
     
     
         71 . The biodegradable implant of  claim 68  wherein the solid biodegradable implant adheres to tissue within the body of the patient. 
     
     
         72 . A kit for the treatment of precocious puberty comprising:
 (a) a first container comprising a composition comprising a biodegradable thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid and a biocompatible polar aprotic solvent selected from the group consisting of an amide, an ester, a carbonate, a ketone, an ether, and a sulfonyl; wherein the biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid; and   (b) a second container comprising leuprolide acetate.   
     
     
         73 . The kit of  claim 72  wherein the first container is a syringe. 
     
     
         74 . The kit of  claim 72  wherein the second container is a syringe. 
     
     
         75 . The kit of  claim 72  wherein the leuprolide acetate is lyophilised. 
     
     
         76 . The kit of  claim 72  further comprising instructions. 
     
     
         77 . The kit of  claim 72  wherein the first container can be connected to the second container. 
     
     
         78 . The kit of  claim 72  wherein the first container and the second container are each configured to be directly connected to each other. 
     
     
         79 . A solid implant for treatment of precocious puberty comprising:
 (a) a biocompatible thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid; and   (b) leuprolide acetate; wherein   
       the solid implant has a solid or gelatinous microporous matrix, the matrix being a core surrounded by a skin and the solid implant is present in a patient exhibiting precocious puberty; 
       the implant retarding, ameliorating or preventing precocious puberty. 
     
     
         80 . The solid implant of  claim 79  further comprising a biocompatible organic solvent that is miscible to dispersible in aqueous or body fluid and dissolves the thermoplastic polyester. 
     
     
         81 . The solid implant of  claim 80  wherein the amount of biocompatible organic solvent is minimal. 
     
     
         82 . The solid implant of  claim 80  wherein the amount of biocompatible organic solvent decreases over time. 
     
     
         83 . The solid implant of  claim 79  wherein the core contains pores of diameters from about 1 to about 1000 microns. 
     
     
         84 . The solid implant of  claim 79  wherein the skin contains pores of smaller diameters than those of the core pores. 
     
     
         85 . The solid implant of  claim 79  wherein the skin pores are of a size such that the skin is functionally non-porous in comparison with the core.