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 - 46 . (canceled)  
     
     
         47 . A method of reducing serum testosterone level in a male mammal below the serum testosterone level achievable by physical castration of the mammal, comprising: 
 forming a flowable composition; the composition comprising a biodegradable thermoplastic polyester that is substantially insoluble in aqueous medium or body fluids; 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 or dispersible in aqueous medium or body fluid; and leuprolide acetate; and    emplacing the flowable composition within a body tissue of the mammal such that the solvent mixes or disperses in the body fluid to cause precipitation of the polyester containing the leuprolide acetate to form an in situ solid implant.    
     
     
         48 . The method of  claim 47  wherein the solid implant undergoes biodegradation over a time period of about 1 month to about 6 months such that the leuprolide acetate is released in sufficient serum concentration to produce the reduced serum testosterone level.  
     
     
         49 . The method of  claim 47  wherein the flowable composition is emplaced within the body tissue with a syringe needle.  
     
     
         50 . The method of  claim 47  wherein the male mammal is a male human being.  
     
     
         51 . The method of  claim 47  wherein the biodegradable thermoplastic polyester comprises a homopolymer of lactide, glycolide, or caprolactone, or a copolymer of any combination of any of lactide, glycolide or caprolactone.  
     
     
         52 . The method of  claim 51  wherein the homopolymer or copolymer includes a monofunctional alcohol or a diol residue and is without a carboxylic acid terminus  
     
     
         53 . The method of  claim 52  wherein the diol residue is polyethylene glycol or hexane-1,6-diol.  
     
     
         54 . The method of  claim 52  wherein the biodegradable thermoplastic polyester is about 75/25 poly(DL-lactide-co-glycolide).  
     
     
         55 . The method of  claim 51  wherein the homopolymer or copolymer comprises a carboxylic acid terminus.  
     
     
         56 . The method of  claim 55  wherein the biodegradable thermoplastic polyester is about 50/50 poly(DL-lactide-co-glycolide).  
     
     
         57 . 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.  
     
     
         58 . The method of  claim 55  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.  
     
     
         59 . 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.  
     
     
         60 . The method of  claim 47  wherein the biocompatible polar aprotic solvent is present in about 50 wt % to about 60 wt % of the flowable composition.  
     
     
         61 . The method of  claim 47  wherein the biocompatible polar aprotic solvent is present in about 60 wt % to about 70 wt % of the flowable composition.  
     
     
         62 . The method of  claim 47  wherein the leuprolide acetate is present in about 2 wt % to about 4 wt % of the flowable composition.  
     
     
         63 . The method of  claim 47  wherein the leuprolide acetate is present in about 4 wt % to about 8 wt % of the flowable composition.  
     
     
         64 . The method of  claim 47  wherein the flowable composition is emplaced within the body tissue about once a month.  
     
     
         65 . The method of  claim 47  wherein the flowable composition is emplaced within the body tissue about once every three months.  
     
     
         66 . The method of  claim 47  wherein the flowable composition is emplaced within the body tissue about once every four months to about once every six months.  
     
     
         67 . A method of treatment of prostate cancer comprising use of the method of  claim 47  wherein the male mammal is a male human being afflicted with prostate cancer in need of treatment thereof within whose body tissue the flowable composition is emplaced.