Oxymorphone controlled release compositions

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.

We claim: 
     
         1 . A solid oral controlled release dosage form, comprising:
 (a) about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient; and   (b) a controlled release matrix, comprising:
 (i) about 10% to about 75% (by total weight of the controlled release matrix) of a gelling agent which forms a gel upon exposure to gastrointestinal fluid; and 
 (ii) a filler; 
   
       wherein upon placement of the dosage form in an in vitro release rate test, about 27% to about 33%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 1 hour in the test, about 40% to about 48%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 2 hours in the test, about 50% to about 59%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 3 hours in the test, about 58% to about 67%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 4 hours in the test, about 64% to about 74%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 5 hours in the test, about 70% to about 84%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 6 hours in the test, about 79% to about 92%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 8 hours in the test, and at least 85%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 10 hours in the test; 
       wherein upon oral administration of the dosage form to a human subject in need of an analgesic effect, the blood plasma concentration of oxymorphone comprises a first peak at about 3 hours after administration and a second peak at about 6-7 hours after administration; and 
       wherein upon oral administration of the dosage form to the subject:
 (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 area under the curve (AUC (0 to 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. 
 
     
     
         2 . The dosage form according to  claim 1 , further comprising a third blood plasma concentration peak between about 10-14 hours after administration. 
     
     
         3 . The dosage form according to  claim 2 , wherein the third blood plasma concentration peak occurs at about 12 hours after administration. 
     
     
         4 . The dosage form according to  claim 1 , wherein the mean blood plasma concentration of oxymorphone 12 hours after administration is between about 36.8% and 95.8% that of the highest mean blood plasma concentration of oxymorphone. 
     
     
         5 . The dosage form according to  claim 1 , wherein the mean blood plasma concentration of oxymorphone 12 hours after administration is between about 59.3% and 95.8% that of the highest mean blood plasma concentration of oxymorphone. 
     
     
         6 . The dosage form according to  claim 1 , wherein the mean blood plasma concentration of oxymorphone 12 hours after administration is between about 74.8% and 95.8% that of the highest mean blood plasma concentration of oxymorphone. 
     
     
         7 . A solid oral controlled release dosage form, comprising:
 (a) about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient; and   (b) a controlled release matrix, comprising:
 (i) about 10% to about 75% (by total weight of the controlled release matrix) of a gelling agent which forms a gel upon exposure to gastrointestinal fluid; 
 (ii) about 2% to about 15% (by total weight of the controlled release matrix) of a cationic crosslinking agent; and 
 (iii) about 30% to about 75% (by total weight of the controlled release matrix) of a diluent; 
   
       wherein the dosage form has a dissolution rate in vitro, when measured by USP Paddle Method at 50 rpm in 500 ml media having a pH between 1.2 and 6.8 at 37° C., of about 15% to about 50% by weight oxymorphone released after 1 hour, about 45% to about 80% by weight oxymorphone released after 4 hours, and at least about 80% by weight oxymorphone released after 10 hours; and 
       wherein upon oral administration of the dosage form to a subject in need of an analgesic effect:
 (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 area under the curve (AUC (0 to 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. 
 
     
     
         8 . The dosage form according to  claim 7 , wherein the blood plasma concentration of oxymorphone 12 hours after administration is between about 30.5% and 81.9% that of the blood plasma concentration of oxymorphone at Cmax. 
     
     
         9 . The dosage form according to  claim 7 , wherein the blood plasma concentration of oxymorphone 12 hours after administration is between about 46.6% and 81.9% that of the blood plasma concentration of oxymorphone at Cmax. 
     
     
         10 . The dosage form according to  claim 7 , wherein the blood plasma concentration of oxymorphone 12 hours after administration is between about 65.6% and 81.9% that of the blood plasma concentration of oxymorphone at Cmax. 
     
     
         11 . A solid oral controlled release dosage form, comprising:
 (a) about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient; and   (b) a controlled release matrix, comprising:
 (i) about 10% to about 75% (by total weight of the controlled release matrix) of a gelling agent which forms a gel upon exposure to gastrointestinal fluid wherein the agent is selected from the group consisting of hydroxyalkyl cellulose, carboxyalkyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), carboxy methylcellulose (CMC), a polymer of acrylic acid, a copolymer of acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, xanthan gum, tragacanth, acacia, karaya, alginate, agar, guar, hydroxypropyl guar, carrageenan, locust bean gum, a protein-derived material and mixtures of any of the foregoing; and 
 (ii) a filler; 
   
       wherein upon placement of the dosage form in an in vitro release rate test, about 27% to about 33%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 1 hour in the test, about 40% to about 48%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 2 hours in the test, about 50% to about 59%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 3 hours in the test, and about 58% to about 67%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 4 hours in the test; 
       wherein upon oral administration of the dosage form to a human subject in need of an analgesic effect, the blood plasma concentration of oxymorphone comprises a first peak at about 3 hours after administration and a second peak at about 6-7 hours after administration; and 
       wherein upon oral administration of the dosage form to the subject:
 (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 area under the curve (AUC (0 to 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. 
 
     
     
         12 . The dosage form according to  claim 11  wherein about 64% to about 74%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 5 hours in the test, about 70% to about 84%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 6 hours in the test, about 79% to about 92%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 8 hours in the test, and at least 85%, by weight, of the oxymorphone or salt thereof is released from the dosage form at about 10 hours in the test. 
     
     
         13 . The dosage form according to  claim 11  wherein the controlled release matrix further comprises a hydrophobic polymer. 
     
     
         14 . The dosage form according to  claim 13  wherein the hydrophobic polymer comprises an alkylcellulose. 
     
     
         15 . The dosage form according to  claim 11  wherein the controlled release matrix further comprises a cationic cross-linking agent. 
     
     
         16 . The dosage form according to  claim 15  wherein the cationic cross-linking agent is selected from the group consisting of an alkali metal sulfate, chloride, borate, bromide, citrate, acetate or lactate or an alkaline earth metal sulfate, chloride, borate, bromide, citrate, acetate or lactate. 
     
     
         17 . The dosage form according to  claim 15  wherein the cationic cross-linking agent is selected from the group consisting of 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. 
     
     
         18 . The dosage form according to  claim 11  wherein the filler is selected from the group consisting of sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, sorbitol, and mixtures thereof. 
     
     
         19 . The dosage form according to  claim 11 , wherein the gelling agent which forms a gel upon exposure to gastrointestinal fluid is a mixture of xanthan gum and locust bean gum. 
     
     
         20 . The dosage form according to  claim 11 , wherein the filler is present in an amount of about 30% to about 75% of an inert diluent, by total weight of the controlled release matrix.