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 method for treating pain in a human subject in need of acute or chronic pain relief, comprising the steps of: 
 (a) Providing a solid oral dosage form of a controlled release oxymorphone formulation, comprising about 20 mg to about 40 mg oxymorphone or a pharmaceutically acceptable salt thereof; and    (b) administering a single dose of the dosage form to the subject,    wherein there is no substantial difference between the oxymorphone area under the curve (AUC (0-inf) ) when the dosage form is administered to the subject under fed versus fasted conditions, and wherein the oxymorphone C max  is at least about 50% higher when the dosage form is administered to the subject under fed as compared to fasted conditions.    
     
     
         2 . The method of  claim 1  wherein the dosage form comprises about 40 mg oxymorphone or a pharmaceutically acceptable salt thereof, and wherein the oxymorphone C max  is about 58% higher when the dosage form is administered to the subject under fed as compared to fasted conditions.  
     
     
         3 . The method of  claim 1  wherein the dosage form comprises about 20 mg oxymorphone or a pharmaceutically acceptable salt thereof.  
     
     
         4 . The method of  claim 1  wherein the dosage form comprises about 20 mg to about 40 mg oxymorphone hydrochloride.  
     
     
         5 . The method of  claim 1  wherein the difference in AUC (0-inf)  between fed and fasted conditions is less than about 20%.  
     
     
         6 . The method of  claim 1  wherein the difference in AUC (0-inf)  between fed and fasted conditions is about 18%.  
     
     
         7 . The method of  claim 1  wherein the duration of the analgesic effect is through at least about 12 hours after administration.  
     
     
         8 . The method of  claim 1  wherein upon oral administration of the dosage form to the subject under fed or fasting conditions: 
 (i) the dosage form provides detectable blood plasma levels of 6-OH oxymorphone and oxymorphone;    (ii) the blood plasma levels of 6-OH oxymorphone and oxymorphone peak within about 1 hour to about 8 hours after administration;    (iii) the blood plasma levels of 6-OH oxymorphone and oxymorphone exhibit a ratio of AUC (0-inf)  of blood plasma level versus time for 6-OH oxymorphone compared to oxymorphone in a range of about 0.5 to about 1.5; and    (iv) the duration of the analgesic effect is through at least about 12 hours after administration.    
     
     
         9 . A method for treating pain in a human subject in need of acute or chronic pain relief, comprising the steps of: 
 (a) Providing a solid oral dosage form comprising about 5 mg to about 80 mg oxymorphone or a pharmaceutically acceptable salt thereof in a controlled release delivery system, the system comprising a filler and a hydrophilic material; and    (b) administering a single dose of the dosage form to the subject, wherein there is no substantial difference between the oxymorphone AUC (0-inf)  when the dosage form is administered to the subject under fed versus fasted conditions.    
     
     
         10 . The method of  claim 9  wherein the oxymorphone C max  is at least about 50% higher when the dosage form is administered to the subject under fed as compared to fasted conditions.  
     
     
         11 . The method of  claim 9  wherein wherein the difference in AUC (0-inf)  between fed and fasted conditions is less than about 20%.  
     
     
         12 . The method of  claim 9  wherein the difference in AUC (0-inf)  between fed and fasted conditions is about 18%.  
     
     
         13 . The method of  claim 9  wherein upon oral administration of the dosage form to the subject under fed or fasting conditions: 
 (i) the dosage form provides detectable blood plasma levels of 6-OH oxymorphone and oxymorphone;    (ii) the blood plasma levels of 6-OH oxymorphone and oxymorphone peak within about 1 hour to about 8 hours after administration;    (iii) the blood plasma levels of 6-OH oxymorphone and oxymorphone exhibit a ratio of AUC (0-inf)  of blood plasma level versus time for 6-OH oxymorphone compared to oxymorphone in a range of about 0.5 to about 1.5; and    (iv) the duration of the analgesic effect is through at least about 12 hours after administration.    
     
     
         14 . The method of  claim 9  wherein the hydrophilic material is selected from the group consisting of a gum, a cellulose ether, an acrylic resin, a protein-derived material, and mixtures thereof.  
     
     
         15 . The method of  claim 9  wherein the hydrophilic material is a gum selected from the group consisting of a heteropolysaccharide gum, a homopolysaccharide gum, and mixtures thereof.  
     
     
         16 . The method of  claim 15  wherein the gum is selected from the group consisting of xanthan, tragacanth, acacia, karaya, alginates, agar, guar, hydroxypropyl guar, carrageenan, locust bean, and mixtures thereof.  
     
     
         17 . The method of  claim 9  wherein the hydrophilic material is a cellulose ether selected from the group consisting of a hydroxyalkyl cellulose, a carboxyalkyl cellulose, and mixtures thereof.  
     
     
         18 . The method of  claim 9  wherein the hydrophilic material is selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, and mixtures thereof.  
     
     
         19 . The method of  claim 9  wherein the hydrophilic material comprises at least one of: 
 a. a heteropolysaccharide; or    b. a heteropolysaccharide and a cross-linking agent capable of cross-linking the heteropolysaccharide; or    c. a mixture of (a), (b) and a polysaccharide gum.    
     
     
         20 . The method of  claim 19  wherein the heteropolysaccharide is a water soluble polysaccharide containing two or more kinds of sugar units and having a branched or helical configuration.  
     
     
         21 . The method of  claim 19  wherein the heteropolysaccharide is selected from the group consisting of xanthan gum, deacylated xanthan gum, carboxymethyl ether xanthan gum, propylene glycol ester xanthan gum and mixtures thereof.  
     
     
         22 . The method of  claim 19  wherein the cross-linking agent is a homopolysaccharide gum.  
     
     
         23 . The method of  claim 19  wherein the homopolysaccharide gum is locust bean gum.  
     
     
         24 . The method of  claim 19  wherein the filler is selected from the group consisting of sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, sorbitol, and mixtures thereof.  
     
     
         25 . A controlled release oxymorphone oral tablet dosage form, comprising: 
 a. a controlled release delivery system; and    b. about 5 mg to about 80 mg of a pharmaceutically acceptable salt of oxymorphone,    wherein upon oral administration of a single dose of the tablet to a human subject, there is no substantial difference in the AUC (0-inf)  between the administration of the tablet in fed and fasting conditions.    
     
     
         26 . The dosage form of  claim 25  wherein upon oral administration thereof the oxymorphone C max  is at least about 50% higher when the dosage form is administered to the subject under fed as compared to fasted conditions.  
     
     
         27 . The dosage form of  claim 25  wherein the dosage form comprises about 40 mg oxymorphone, and wherein the oxymorphone C max  is about 58% higher when the dosage form is administered to the subject under fed as compared to fasted conditions.  
     
     
         28 . The dosage form of  claim 25  wherein the controlled release delivery system comprises a heteropolysaccharide and an agent capable of cross-linking the heteropolysaccharide in presence of gastrointestinal fluid.  
     
     
         29 . The dosage form of  claim 28  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.  
     
     
         30 . The dosage form of  claim 28  wherein the heteropolysaccharide and the agent capable of cross-linking the heteropolysaccharide are present in a weight ratio of about 1:1.  
     
     
         31 . The dosage form of  claim 28  wherein the heteropolysaccharide comprises xanthan gum or deacylated xanthan gum.  
     
     
         32 . The dosage form of  claim 28  wherein the agent capable of cross-linking the heteropolysaccharide comprises a homopolysaccharide gum.  
     
     
         33 . The dosage form of  claim 32  wherein the homopolysaccharide gum comprises locust bean gum.  
     
     
         34 . The dosage form of  claim 25  wherein the controlled release delivery system further comprises a hydrophobic polymer.  
     
     
         35 . The dosage form of  claim 34  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.  
     
     
         36 . The dosage form of  claim 34  wherein the hydrophobic polymer comprises an alkylcellulose.  
     
     
         37 . The dosage form of  claim 25  wherein the system comprises a filler selected from sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol and sorbitol.  
     
     
         38 . The dosage form of  claim 25  further comprising a cationic cross-linking agent.  
     
     
         39 . The dosage form of  claim 38  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.  
     
     
         40 . The dosage form of  claim 38  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.  
     
     
         41 . The dosage form of  claim 38  wherein the cationic cross-linking agent is present in an amount of about 0.5% to about 16%, by weight of the composition.  
     
     
         42 . The dosage form of  claim 28  wherein the weight ratio of heteropolysaccharide to oxymorphone is about 10:1 to about 1:10.  
     
     
         43 . The dosage form  claim 25  wherein oxymorphone is present in an amount of about 20 mg.  
     
     
         44 . The dosage form of  claim 25  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.