Liquid polymeric compositions for controlled release of bioactive substances

Abstract

Controlled release of hydrophobic bioactive substances in vivo over an extended time period and without “bursts” of drug release is achieved using a liquid polymeric composition including a polymer such as poly(lactide-co-glycolide) copolymer in a mixture of hydrophilic and lipophilic solvents.

What is claimed is:  
     
         1 . A liquid polymeric composition for controlled release of hydrophobic bioactive substances comprising: 
 (a) 1 to 30% of a hydrophobic bioactive substance;    (b) 1 to 20% of a poly(lactide-co-glycolide) copolymer; wherein the weight ratio of the poly(lactide-co-glycolide) copolymer to the hydrophobic bioactive substance is 1:1 or less; and    (c) a mixture of hydrophilic and lipophilic solvents wherein the volume ratio of the hydrophilic and lipophilic solvents is from about 80:20 to about 5:95.    
     
     
         2 . A composition of  claim 1  wherein said bioactive substance is present in about 1 to 10%.  
     
     
         3 . A composition of  claim 1  wherein said poly(lactide-co-glycolide) copolymer is present in about 1 to 10%.  
     
     
         4 . A composition of  claim 1  wherein the ratio of said hydrophilic and lipophilic solvents is from about 65:35 to about 35:65.  
     
     
         5 . A composition of  claim 1  which comprises: 
 (a) 1 to 10% of a hydrophobic bioactive substance;  
 (b) 1 to 10% of a poly(lactide-co-glycolide) copolymer, wherein the weight ratio of the poly(lactide-co-glycolide) copolymer to the hydrophobic bioactive substance is 1:1 or less;  
 (c) a mixture of hydrophilic and lipophilic solvents wherein the volume ratio of the hydrophilic and lipophilic solvents is from about 65:35 to about 35:65.  
 
     
     
         6 . A composition of  claim 1  which comprises: 
 (a) 5 to 10% of a hydrophobic bioactive substance;  
 (b) 5 to 10% of a poly(lactide-co-glycolide) copolymer, wherein the weight ratio of the poly(lactide-co-glycolide) copolymer to the hydrophobic bioactive substance is 1:1 or less;  
 (c) a mixture of hydrophilic and lipophilic solvents wherein the volume ratio of the hydrophilic and lipophilic solvents is from about 65:35 to about 35:65.  
 
     
     
         7 . A composition of  claim 1  wherein said bioactive substance is selected from fipronil, the avermectins, ivermectins, eprinomectin, milbemycins, nodulisporic acid and derivatives thereof, estradiol benzoate, trenbolone acetate, progesterone, and norethisterone.  
     
     
         8 . A composition of  claim 1  wherein the ratio of lactide:glycolide of the poly(lactide-co-glycolide) copolymer is from about 95:5 to about 50:50.  
     
     
         9 . A composition of  claim 1  wherein the ratio of lactide:glycolide of the poly(lactide-co-glycolide) copolymer is from about 75:25 to about 65:35.  
     
     
         10 . A composition of  claim 1  wherein said hydrophilic solvent is selected from glycerol formal, glycofural, N-methyl pyrrolidone, 2-pyrrolidone, isopropylidene glycerol, di(propylene glycol) methyl ether, and mixtures thereof.  
     
     
         11 . A composition of  claim 1  which comprises: 
 (a) 5 to 10% of a hydrophobic bioactive substance;  
 (b) 5 to 10% of a poly(lactide-co-glycolide) copolymer, wherein the ratio of lactide:glycolide of the poly(lactide-co-glycolide) copolymer is from about 75:25 to about 65:35, and the weight ratio of the poly(lactide-co-glycolide) copolymer to the hydrophobic bioactive substance is 1:1 or less;  
 (c) a mixture of glycerol formal and triacetin wherein the volume ratio of glycerol formal and triacetin is from about 65:35 to about 35:65.  
 
     
     
         12 . A method for the controlled release of a hydrophobic bioactive substance in an animal, including human, which comprises injecting said animal with a liquid polymeric composition of  claim 1 .  
     
     
         13 . A liquid polymeric composition comprising: 
 (1) about 1-30% of at least one bioactive substance;    (2) about 1-20% of at least one biologically acceptable polymer, wherein the weight ratio of the polymer to the bioactive substance is 1:1 or less; and    (3) at least one lipophilic solvent or a mixture of at least one hydrophilic solvent and at least one lipophilic solvent, wherein the volume ratio of the hydrophilic and lipophilic solvents is from about about 80:20 to about 0:100, and/or wherein the lipophilic solvent is present in an amount of at least about 16.5% by weight.    
     
     
         14 . A method for the controlled release of a hydrophobic bioactive substance in an animal, including human, which comprises injecting said animal with a liquid polymeric composition of  claim 13.