Prolonged Release Pharmaceutical Composition Containing 3-(3-Dimethylamino-1-Ethyl-2-Methyl-Propyl)Phenol

Abstract

A pharmaceutical formulation for prolonged release of the active ingredient 3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol or a pharmaceutically acceptable salt thereof in a matrix containing between 1 and 80 wt. % of at least one pharmaceutically acceptable hydrophilic or hydrophobic polymer as a matrix forming agent and exhibiting in vivo the following release rate: 3 to 35% by weight (based on 100% by weight active ingredient) 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 0.5 hours; 5 to 50% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 1 hour; 10 to 75% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 2 hours; 15 to 82% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 3 hours; 30 to 97% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 6 hours; more than 50% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 12 hours; more than 70% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 18 hours, and more than 80% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 24 hours.

1 . A slow-release pharmaceutical formulation containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof as active ingredient in a matrix, wherein the formulation comprises from 3 to 70% of the active ingredient and from 1 to 80% by weight of one or more pharmaceutically acceptable hydrophilic or hydrophobic polymers as matrix forming agents and has the following release rate in vitro, measured by the Ph. Eur. Paddle Method at 75 rpm in a buffer (to Ph. Eur.) at a pH of 6.8 at 37° C. and detected using a UV spectrometer:
 15 to 28% by weight (based on 100% by weight active ingredient) 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 0.5 hours, 
 24 to 39% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 1 hour, 
 36 to 56% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 2 hours, 
 44 to 68% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 3 hours, 
 51 to 80% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 4 hours, 
 61 to 97% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 6 hours, 
 69 to 99% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 8 hours, 
 75 to 100% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 10 hours, 
 79 to 100% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 12 hours, and 
 more than 80% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 24 hours. 
 
     
     
         2 . A pharmaceutical composition according to  claim 1 , wherein the matrix forming agents comprise cellulose ethers, cellulose esters or a mixture thereof having a viscosity of 10,000 to 150,000 mPa·s in a 2% by weight solution at 20° C. 
     
     
         3 . A pharmaceutical composition according to  claim 1 , wherein the matrix forming agents comprise cellulose ethers, cellulose esters or a mixture thereof having a viscosity of 50,000 to 150,000 mPa·s in a 2% by weight solution at 20° C. 
     
     
         4 . A pharmaceutical composition according to  claim 1 , wherein the matrix forming agent comprises at least one substance selected from the group consisting of hydroxypropylmethyl celluloses (HPMC), hydroxyethyl celluloses, hydroxypropyl celluloses (HPC), methyl celluloses, ethyl celluloses and carboxymethyl celluloses. 
     
     
         5 . A pharmaceutical composition according to  claim 1 , wherein the matrix forming agent comprises at least one substance selected from the group consisting of hydroxypropylmethyl celluloses, hydroxyethyl celluloses, and hydroxypropyl celluloses. 
     
     
         6 . A pharmaceutical composition according to  claim 1 , wherein said composition contains from 0.5 to 85% by weight active ingredient and from 8 to 40% by weight matrix forming agents. 
     
     
         7 . A pharmaceutical composition according to  claim 1 , wherein said composition comprises from 3 to 70% by weight active ingredient and from 10 to 35% by weight matrix forming agents. 
     
     
         8 . A pharmaceutical composition according to  claim 1 , wherein said composition comprises from 8 to 66% by weight active ingredient and from 10 to 30% by weight matrix forming agents. 
     
     
         9 . A pharmaceutical composition according to  claim 1 , wherein the peak plasma level of the active ingredient is obtained in vivo 3.5 to 6 hours after administration of the composition. 
     
     
         10 . A pharmaceutical formulation according to  claim 1 , wherein the active ingredient comprises (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof. 
     
     
         11 . A pharmaceutical formulation according to  claim 1 , wherein the active ingredient comprises (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A tablet for twice daily oral administration of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, said tablet containing a pharmaceutical formulation according to  claim 1 . 
     
     
         13 . A pharmaceutical composition as claimed in  claim 1 , wherein 1 hour after administration the plasma level of the active ingredient is higher than 10 ng/ml and wherein a peak plasma level of the active ingredient is obtained in vivo 2 to 10 hours after administration of the composition. 
     
     
         14 . A pharmaceutical composition as claimed in  claim 1 , wherein the pharmaceutically acceptable polymer matrix forming agents are selected from the group consisting of cellulose ethers, cellulose esters and acrylic resins. 
     
     
         15 . A pharmaceutical composition as claimed in  claim 1 , wherein said polymers have a viscosity of 3,000 to 150,000 mPa·s in a 2% by weight aqueous solution at 20° C. 
     
     
         16 . A slow-release pharmaceutical formulation containing from 3 to 70% by weight of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof as active ingredient in a matrix coated with a material controlling the slow release of the active ingredient in an aqueous medium, the coating material comprising a water-insoluble wax, a polymethacrylate or a water-insoluble cellulose, wherein the active ingredient has the following release rate in vitro, measured by the Ph. Eur. Paddle Method at 75 rpm in a buffer (to Ph. Eur.) at a pH of 6.8 at 37° C. and detected using a UV spectrometer:
 15 to 28% by weight (based on 100% by weight active ingredient) 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 0.5 hours, 
 24 to 39% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 1 hour, 
 36 to 56% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 2 hours, 
 44 to 68% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 3 hours, 
 61 to 97% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 6 hours, 
 69 to 99% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 8 hours, 
 75 to 100% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 10 hours, 
 79 to 100% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 12 hours, and 
 more than 80% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 24 hours. 
 
     
     
         17 . The slow-release pharmaceutical formulation according to  claim 16 , wherein the coating material contains water-soluble polymers or hydrophilic pore-forming agents. 
     
     
         18 . A pharmaceutical formulation according to  claim 16 , wherein 1 hour after administration the plasma level of the active ingredient is higher than 10 ng/ml and wherein a peak plasma level of the active ingredient is obtained in vivo 2 to 10 hours after administration of the composition. 
     
     
         19 . A pharmaceutical composition according to  claim 18 , wherein the peak plasma level of the active ingredient is obtained in vivo 3.5 to 6 hours after administration of the composition. 
     
     
         20 . A pharmaceutical formulation according to  claim 16 , wherein the active ingredient comprises (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof. 
     
     
         21 . A pharmaceutical formulation according to  claim 16 , wherein the active ingredient comprises (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof.