Oxymorphone controlled release formulations

Abstract

The invention pertains to a method of relieving pain by administering a controlled release pharmaceutical tablet containing oxymorphone which produces a mean minimum blood plasma level 12 to 24 hours after dosing, as well as the tablet producing the sustained pain relief.

1 . A controlled release pharmaceutical composition comprising oxymorphone or a pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient, wherein upon placement of the composition in an in vitro dissolution test comprising USP paddle method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37° C., about 15% to about 50%, by weight, of the oxymorphone or salt thereof is released from the composition after about 1 hour in the test.  
     
     
         2 . The pharmaceutical composition of  claim 1  wherein about 45% to about 80%, by weight, of the oxymorphone or salt thereof is released from the composition after about 4 hours in the test.  
     
     
         3 . The pharmaceutical composition of  claim 1  wherein at least about 80%, by weight, of the oxymorphone or salt thereof is released from the composition after about 10 hours in the test.  
     
     
         4 . The pharmaceutical composition of  claim 1  wherein about 28% to about 32%, by weight, of the oxymorphone or salt thereof is released from the composition after about 1 hour in the test.  
     
     
         5 . The pharmaceutical composition of  claim 1  wherein about 58% to about 66%, by weight, of the oxymorphone or salt thereof is released from the composition after about 4 hours in the test.  
     
     
         6 . The pharmaceutical composition of  claim 1  wherein about 85% to about 96%, by weight, of the oxymorphone or salt thereof is released from the composition after about 10 hours in the test.  
     
     
         7 . The pharmaceutical composition of  claim 1  wherein the at least one pharmaceutical excipient comprises a controlled release delivery system.  
     
     
         8 . The pharmaceutical composition of  claim 7  wherein the controlled release delivery system comprises a hydrophilic material.  
     
     
         9 . The pharmaceutical composition of  claim 7  wherein the controlled release delivery system comprises a heteropolysaccharide and an agent capable of cross-linking the heteropolysaccharide in presence of gastrointestinal fluid.  
     
     
         10 . The pharmaceutical composition of  claim 9  wherein the heteropolysaccharide and the agent capable of cross-linking the heteropolysaccharide are present in a weight ratio of about 1:3 to about 3:1.  
     
     
         11 . The pharmaceutical composition of  claim 10  wherein the heteropolysaccharide and the agent capable of cross-linking the heteropolysaccharide are present in a weight ratio of about 1:1.  
     
     
         12 . The pharmaceutical composition of  claim 9  wherein the heteropolysaccharide comprises xanthan gum or deacylated xanthan gum.  
     
     
         13 . The pharmaceutical composition of  claim 9  wherein the agent capable of cross-linking the heteropolysaccharide comprises a homopolysaccharide gum.  
     
     
         14 . The pharmaceutical composition of  claim 13  wherein the homopolysaccharide gum, comprises locust bean gum.  
     
     
         15 . The pharmaceutical composition of  claim 14  wherein the controlled release delivery system further comprises a hydrophobic polymer.  
     
     
         16 . The pharmaceutical composition of  claim 15  wherein the hydrophobic polymer is selected from hydrophobic cellulosic materials, polymers or copolymers derived from acrylic or methacrylic acid esters, copolymers of acrylic and methacrylic acid esters, zein, waxes, shellac, and hydrogenated vegetable oils.  
     
     
         17 . The pharmaceutical composition of  claim 16  wherein the hydrophobic polymer comprises an alkylcellulose.  
     
     
         18 . The pharmaceutical composition of  claim 1  further comprising a filler selected from sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol and sorbitol.  
     
     
         19 . The pharmaceutical composition of  claim 1  further comprising a cationic cross-linking agent.  
     
     
         20 . The pharmaceutical composition of  claim 19  wherein the cationic cross-linking agent is an alkali metal sulfate, chloride, borate, bromide, citrate, acetate or lactate or an alkaline earth metal sulfate, chloride, borate, bromide, citrate, acetate or lactate.  
     
     
         21 . The pharmaceutical composition of  claim 20  wherein the cationic cross-linking agent is selected from calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate and sodium fluoride.  
     
     
         22 . The pharmaceutical composition of  claim 21  wherein the cationic cross-linking agent is present in an amount of about 0.5% to about 16%, by weight of the composition.  
     
     
         23 . The pharmaceutical composition of  claim 9  wherein the weight ratio of heteropolysaccharide to oxymorphone or pharmaceutically acceptable salt thereof is about 10: 1 to about 1:10.  
     
     
         24 . The pharmaceutical composition of  claim 1  wherein oxymorphone or pharmaceutically acceptable salt thereof is present in an amount of about 5 mg to about 80 mg.  
     
     
         25 . The pharmaceutical composition of  claim 24  wherein oxymorphone or pharmaceutically acceptable salt thereof is present in an amount of about 20 mg.  
     
     
         26 . The pharmaceutical composition of  claim 9  wherein the controlled release delivery system comprises about 10% to about 99% of a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum, about 1% to about 20% of a cationic crosslinking agent, and about 0% to about 89% of an inert pharmaceutical diluent, by total weight of the controlled release delivery system.  
     
     
         27 . A controlled release pharmaceutical composition comprising oxymorphone or pharmaceutically acceptable salt thereof and a controlled release delivery system, wherein upon placement of the composition in an in vitro dissolution test comprising USP paddle method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37, about 15% to about 50%, by weight, of the oxymorphone or salt thereof is released from the composition after about 1 hour in the test, about 45% to about 80%, by weight, of the oxymorphone or salt thereof is released from the composition after about 4 hours in the test, and at least about 80%, by weight, of the oxymorphone or salt thereof is released from the composition after about 10 hours in the test.  
     
     
         28 . The pharmaceutical composition of  claim 27  wherein about 28% to about 32%, by weight, of the oxymorphone or salt thereof is released from the composition after about 1 hour in the test  
     
     
         29 . The pharmaceutical composition of  claim 27  wherein about 58% to about 66%, by weight, of the oxymorphone or salt thereof is released from the composition after about 4 hours in the test.  
     
     
         30 . The pharmaceutical composition of  claim 27  wherein about 85% to about 96%, by weight, of the oxymorphone or salt thereof is released from the composition after about 10 hours in the test.  
     
     
         31 . The pharmaceutical composition of  claim 27  wherein the controlled release delivery system comprises a hydrophilic material.  
     
     
         32 . The pharmaceutical composition of  claim 27  wherein the controlled release delivery system comprises a heteropolysaccharide and an agent capable of cross-linking the heteropolysaccharide in presence of gastrointestinal fluid.  
     
     
         33 . The pharmaceutical composition of  claim 32  wherein the heteropolysaccharide and the agent capable of cross-linking the heteropolysaccharide are present in a weight ratio of about 1:3 to about 3:1.  
     
     
         34 . The pharmaceutical composition of  claim 32  wherein the heteropolysaccharide and the agent capable of cross-linking the heteropolysaccharide are present in a weight ratio of about 1:3 to about 1:1.  
     
     
         35 . The pharmaceutical composition of  claim 32  wherein the heteropolysaccharide comprises xanthan gum or deacylated xanthan gum.  
     
     
         36 . The pharmaceutical composition of  claim 32  wherein the agent capable of cross-linking the heteropolysaccharide comprises a homopolysaccharide gum.  
     
     
         37 . The pharmaceutical composition of  claim 36  wherein the homopolysaccharide gum comprises locust bean gum.  
     
     
         38 . The pharmaceutical composition of  claim 32  wherein the controlled release delivery system further comprises a hydrophobic polymer.  
     
     
         39 . The pharmaceutical composition of  claim 38  wherein the hydrophobic polymer is selected from hydrophobic cellulosic materials, polymers or copolymers derived from acrylic or methacrylic acid esters, copolymers of acrylic and methacrylic acid esters, zein, waxes, shellac, and hydrogenated vegetable oils.  
     
     
         40 . The pharmaceutical composition of  claim 39  wherein the hydrophobic polymer comprises an alkylcellulose.  
     
     
         41 . The pharmaceutical composition of  claim 27  further comprising a filler selected from sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol and sorbitol.  
     
     
         42 . The pharmaceutical composition of  claim 27  further comprising a cationic cross-linking, agent.  
     
     
         43 . The pharmaceutical composition of  claim 42  wherein the cationic cross-linking agent is an alkali metal sulfate, chloride, borate, bromide, citrate, acetate or lactate or an alkaline earth metal sulfate, chloride, borate,,bromide, citrate, acetate or lactate.  
     
     
         44 . The pharmaceutical composition of  claim 43  wherein the cationic cross-linking agent is selected from calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate and sodium fluoride.  
     
     
         45 . The pharmaceutical composition of  claim 44  wherein the cationic cross-linking agent is present in an amount of about 0.5% to about 16%, by weight of the composition.  
     
     
         46 . The pharmaceutical composition of  claim 32  wherein the weight ratio of heteropolysaccharide to oxymorphone or pharmaceutically acceptable salt thereof is about 10:1 to about 1:10.  
     
     
         47 . The pharmaceutical composition of  claim 27  wherein oxymorphone or pharmaceutically acceptable salt thereof is present in an amount of about 5 mg to about 80 mg.  
     
     
         48 . The pharmaceutical composition of  claim 47  wherein oxymorphone or pharmaceutically acceptable salt thereof is present in an amount of about 20 mg.  
     
     
         49 . The pharmaceutical composition of  claim 27  wherein the controlled release delivery system comprises about 10% to about 99% of a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum, about 1% to about 20% of a cationic crosslinking agent, and about 0% to about 89% of an inert pharmaceutical diluent, by total weight of the controlled release delivery system.  
     
     
         50 . A method of treating pain in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of  claim 1  in an amount sufficient to provide the subject with about 5 mg to about 80 mg of oxymorphone or salt thereof.  
     
     
         51 . A method of treating pain in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of  claim 27  in an amount sufficient to provide the subject with about 5 mg to about 80 mg of oxymorphone or salt thereof.  
     
     
         52 . A method of treating pain in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of  claim 49  in an amount sufficient to provide the subject with about 5 mg to about 80 mg of oxymorphone or salt thereof.