Solvent/polymer solutions as suspension vehicles

Abstract

A nonaqueous, single-phase vehicle that is capable of suspending an active agent. The nonaqueous, single-phase vehicle includes at least one solvent and at least one polymer and is formulated to exhibit phase separation upon contact with an aqueous environment. The at least one solvent may be selected from the group consisting of benzyl benzoate, decanol, ethyl hexyl lactate, and mixtures thereof and the at least one polymer may be selected from the group consisting of a polyester, pryyolidone, ester of an unsaturated alcohol, ether of an unsaturated alcohol, polyoxyethylenepolyoxypropylene block copolymer, and mixtures thereof. In one embodiment, the at least one solvent is benzyl benzoate and the at least one polymer is polyvinylpyrrolidone. A stable, nonaqueous suspension formulation that includes the nonaqueous, single-phase vehicle and an active agent, and a method of forming the same, are also disclosed.

What is claimed is: 
     
         1 . A nonaqueous, single-phase vehicle capable of suspending an active agent, the nonaqueous, single-phase vehicle comprising at least one solvent and at least one polymer, wherein the nonaqueous, single-phase vehicle exhibits phase separation upon contact with an aqueous environment. 
     
     
         2 . The nonaqueous, single-phase vehicle of  claim 1 , wherein the at least one solvent is immiscible with water and wherein the at least one polymer is soluble in the at least one solvent at a concentration of greater than approximately 30%. 
     
     
         3 . The nonaqueous, single-phase vehicle of  claim 1 , wherein the at least one solvent is selected from the group consisting of benzyl benzoate, decanol, ethyl hexyl lactate, and long chain (C8 to C24) aliphatic alcohols, esters, and mixtures thereof. 
     
     
         4 . The nonaqueous, single-phase vehicle of  claim 1 , wherein the nonaqueous, single-phase vehicle exhibits phase separation upon contact with an aqueous environment having less than approximately 10% water. 
     
     
         5 . The nonaqueous, single-phase vehicle of  claim 1 , wherein the at least one polymer is selected from the group consisting of a polyester, pyrrolidone, ester of an unsaturated alcohol, ether of an unsaturated alcohol, polyoxyethylenepolyoxypropylene block copolymer, and mixtures thereof. 
     
     
         6 . The nonaqueous, single-phase vehicle of  claim 1 , wherein the at least one solvent comprises benzyl benzoate and the at least one polymer comprises polyvinylpyrrolidone. 
     
     
         7 . The nonaqueous, single-phase vehicle of  claim 1 , wherein the nonaqueous, single-phase vehicle comprises from approximately 40% (w/w) to approximately 60% (w/w) of the at least one solvent and from approximately 10% (w/w) to approximately 90% (w/w) of the at least one polymer. 
     
     
         8 . A stable, nonaqueous suspension formulation, comprising:
 an active agent and a nonaqueous, single-phase vehicle, the nonaqueous, single-phase vehicle comprising at least one polymer and at least one solvent, wherein the nonaqueous, single-phase vehicle exhibits phase separation upon contact with an aqueous environment.   
     
     
         9 . The stable, nonaqueous suspension formulation of  claim 8 , wherein the at least one solvent is immiscible with water and wherein the at least one polymer is soluble in the at least one solvent at a concentration of greater than approximately 30%. 
     
     
         10 . The stable, nonaqueous suspension formulation of  claim 8 , wherein the active agent is selected from the group consisting of baclofen, glial-cell line-derived neurotrophic factor, a neurotrophic factor, conatonkin G, Ziconotide, clonidine, axokine, an antisense oligonucleotide, adrenocorticotropic hormone, angiotensin I, angiotensin II, atrial natriuretic peptide, B-natriuretic peptide, bombesin, bradykinin, calcitonin, cerebellin, dynorphin N, alpha endorphin, beta endorphin, endothelin, enkephalin, epidermal growth factor, fertirelin, follicular gonadotropin releasing peptide, galanin, glucagon, glucagon-like peptide-I, gonadorelin, gonadotropin, goserelin, growth hormone releasing peptide, histrelin, human growth hormone, insulin, an interferon, leuprolide, luteinizing hormone-releasing hormone, motilin, nafarerlin, neurotensin, oxytocin, relaxin, somatostatin, substance P, tumor necrosis factor, triptorelin, vasopressin, growth hormone, nerve growth factor, a blood clotting factor, and a ribozyme. 
     
     
         11 . The stable, nonaqueous suspension formulation of  claim 8 , wherein the at least one solvent is selected from the group consisting of benzyl benzoate, decanol, ethyl hexyl lactate, and long chain (C8 to C24) aliphatic alcohols, esters, and mixtures thereof. 
     
     
         12 . The stable, nonaqueous suspension formulation of  claim 11 , wherein the nonaqueous, single-phase vehicle exhibits phase separation upon contact with an aqueous environment having less than approximately 10% water. 
     
     
         13 . The stable, nonaqueous suspension formulation of  claim 8 , wherein the at least one polymer is selected from the group consisting of a polyester, a pyrrolidone, an ester of an unsaturated alcohol, an ether of an unsaturated alcohol, a polyoxyethylenepolyoxypropylene block copolymer, and mixtures thereof. 
     
     
         14 . The stable, nonaqueous suspension formulation of  claim 8 , wherein the at least one solvent comprises benzyl benzoate, the at least one polymer comprises polyvinylpryrrolidone, and the active agent comprises omega-interferon. 
     
     
         15 . The stable, nonaqueous suspension formulation of  claim 8 , wherein the nonaqueous, single-phase vehicle comprises from approximately 40% (w/w) to approximately 60% (w/w) of the at least one solvent and from approximately 10% (w/w) to approximately 90% (w/w) of the at least one polymer. 
     
     
         16 . The stable, nonaqueous suspension formulation of  claim 8 , wherein the active agent is present in the stable, nonaqueous suspension formulation in an amount ranging from approximately 0.1% (w/w) to approximately 50% (w/w). 
     
     
         17 . The stable, nonaqueous suspension formulation of  claim 8 , wherein the particle containing the active agent is present in the stable, nonaqueous suspension formulation in an amount of approximately 3-12% (w/w). 
     
     
         18 . A method of preparing a stable, nonaqueous suspension formulation comprising: providing a nonaqueous, single-phase vehicle comprising at least one polymer and at least one solvent, wherein the nonaqueous, single-phase vehicle exhibits phase separation upon contact with an aqueous environment;
 providing an active agent, wherein the active agent is substantially insoluble in the nonaqueous, single-phase vehicle; and   mixing the active agent and the nonaqueous, single-phase vehicle to form a stable, nonaqueous suspension formulation.   
     
     
         19 . The method of  claim 18 , wherein providing a nonaqueous, single-phase vehicle comprising at least one polymer and at least one solvent comprises selecting the at least one solvent to be immiscible with water and selecting the at least one polymer to be soluble in the at least one solvent at a concentration of greater than approximately 30%. 
     
     
         20 . The method of  claim 18 , wherein providing a nonaqueous, single-phase vehicle comprising at least one polymer and at least one solvent comprises using at least one solvent selected from the group consisting of benzyl benzoate, decanol, ethyl hexyl lactate, and mixtures thereof. 
     
     
         21 . The method of  claim 18 , wherein providing a nonaqueous, single-phase vehicle comprising at least one polymer and at least one solvent comprises using at least one polymer selected from the group consisting of a polyester, a pyrrolidone, an ester of an unsaturated alcohol, an ether of an unsaturated alcohol, a polyoxyethylenepolyoxypropylene block copolymer, and mixtures thereof. 
     
     
         22 . The method of  claim 18 , wherein providing a nonaqueous, single-phase vehicle comprising at least one polymer and at least one solvent comprises using benzyl benzoate as the at least one solvent and polyvinylpyrrolidone as the at least one polymer. 
     
     
         23 . The method of  claim 18 , wherein providing an active agent comprises providing an active agent selected from the group consisting of baclofen, glial-cell line-derived neurotrophic factor, a neurotrophic factor, conatonkin G, Ziconotide, clonidine, axokine, an antisense oligonucleotide, adrenocorticotropic hormone, angiotensin I, angiotensin II, atrial natriuretic peptide, B-natriuretic peptide, bombesin, bradykinin, calcitonin, cerebellin, dynorphin N, alpha endorphin, beta endorphin, endothelin, enkephalin, epidermal growth factor, fertirelin, follicular gonadotropin releasing peptide, galanin, glucagon, glucagon-like peptide-I, gonadorelin, gonadotropin, goserelin, growth hormone releasing peptide, histrelin, human growth hormone, insulin, an interferon, leuprolide, luteinizing hormone-releasing hormone, motilin, nafarerlin, neurotensin, oxytocin, relaxin, somatostatin, substance P, tumor necrosis factor, triptorelin, vasopressin, growth hormone, nerve growth factor, a blood clotting factor, and a ribozyme. 
     
     
         24 . The method of  claim 18 , wherein providing an active agent comprises using omega-interferon as the active agent. 
     
     
         25 . The method of  claim 18 , wherein providing a nonaqueous, single-phase vehicle comprises providing a nonaqueous, single-phase vehicle that exhibits phase separation upon contact with an aqueous environment having less than approximately 10% water.