Controlled release tramadol preparations with a storage-stable release profile and process for their production

Abstract

A process for producing an oral, controlled release preparation of tramadol or a physiologically compatible tramadol salt having a storage stable active substance release profile by coating the active substance preparation with an aqueous ethylcellulose dispersion which contains at least one physiologically compatible, lipophilic diester of a C 6 -C 40 aliphatic or aromatic dicarboxylic acid and a C 6 -C 8 aliphatic alcohol as plasticizer, and, during coating, drying the coating at conventional temperatures, with the result that a storage stable active substance release profile is obtained even without subsequent heat treatment. Optionally, in order to increase the active substance release profile without impairing the storage stability of the preparation, a heat treatment may be performed at temperatures of >35° C. until a desired, increased active substance release profile is achieved.

What is claimed is:  
     
         1 . A process for producing an oral, controlled release preparation of tramadol or a physiologically compatible salt of tramadol having a storage stable active substance release profile, said process comprising the step of coating a tramadol or physiologically compatible tramadol salt preparation with an aqueous ethylcellulose dispersion containing at least one physiologically compatible plasticizer comprising a lipophilic diester of a C 6 -C 40  aliphatic or aromatic dicarboxylic acid and a C 1 -C 8  aliphatic alcohol, and drying the coating, whereby a storage stable active substance release profile is obtained without subsequent heat treatment.  
     
     
         2 . A process according to  claim 1 , wherein said coating is dried during coating at conventional drying temperatures.  
     
     
         3 . A process according to  claim 1 , further comprising the step of heat treating the tramadol preparation at temperatures of >35° C. until a desired, increased active substance release profile is achieved without impairing the storage stability of the preparation.  
     
     
         4 . A process according to  claim 1 , wherein said plasticizer is a diester of an C 6 -C 30  aliphatic or aromatic dicarboxylic acid and a C 2 -C 6  aliphatic alcohol.  
     
     
         5 . A process according to  claim 4 , wherein said plasticizer is a diester of a C 10 -C 16  aliphatic or aromatic dicarboxylic acid and a C 2 -C 5  aliphatic alcohol.  
     
     
         6 . A process according to  claim 5 , wherein said plasticizer is selected from the group consisting of dibutyl phthalate, diethyl phthalate, dibutyl sebacate, and diethyl sebacate.  
     
     
         7 . A process according to  claim 5 , wherein said plasticizer is dibutyl sebacate.  
     
     
         8 . A process according to  claim 1 , wherein the plasticizer is used in an amount equal to 5 to 50 wt. % of the ethylcellulose.  
     
     
         9 . A process according to  claim 8 , wherein the plasticizer is used in an amount equal to 10 to 40 wt. % of the ethylcellulose.  
     
     
         10 . A process according to  claim 9 , wherein the plasticizer is used in an amount equal to 10 to 30 wt. % of the ethylcellulose.  
     
     
         11 . A process according to  claim 1 , wherein the ethylcellulose dispersion has an ethylcellulose concentration of from 3 wt. % to 35 wt. %.  
     
     
         12 . A process according to  claim 11 , wherein the ethylcellulose dispersion has an ethylcellulose concentration of from 10 wt. % to 30 wt. %.  
     
     
         13 . A process according to  claim 1 , wherein the controlled release coating is dried at a temperature of from 40 to 80° C.  
     
     
         14 . A process according to  claim 13 , wherein the controlled release coating is dried at a temperature of from 50 to 70° C.  
     
     
         15 . A process according to  claim 1 , further comprising the step of applying a protective coating of water-soluble polymer and talcum prior to coating with the controlled release coating.  
     
     
         16 . A process according to  claim 15 , wherein said water-soluble polymer is hydroxypropylmethylcellulose or hydroxypropylcellulose.  
     
     
         17 . A process according to  claim 15 , wherein the protective coating produces an increase in weight of 1 to 10 wt. %.  
     
     
         18 . A process according to  claim 17 , wherein the protective coating produces an increase in weight of 2.5 to 5 wt. %.  
     
     
         19 . A, process according to  claim 1 , wherein said preparation is a tramadol hydrochloride preparation.  
     
     
         20 . A process according to  claim 1 , wherein said tramadol or physiologically compatible tramadol salt preparation is a multiparticulate preparation.  
     
     
         21 . A process according to  claim 20 , wherein said multiparticulate preparation is comprised of microtablets, granules, pellets or crystals.  
     
     
         22 . A process according to  claim 20 , wherein the multiparticulate preparation is comprised of particles having an average particle size of 0.3 to 2.5 mm.  
     
     
         23 . An oral, controlled release active substance preparation having a storage stable active substance release profile, wherein said active substance is tramadol or a physiologically compatible salt of tramadol, said active substance preparation being coated with a coalesced ethylcellulose coating obtained by coating a substrate containing the active substance with an aqueous ethylcellulose dispersion containing a plasticizer comprised of a lipophilic diester of a C 6 -C 40  aliphatic or aromatic dicarboxylic acid and a C 1 -C 8  aliphatic alcohol, and only drying the coating at conventional temperature, whereby a storage stable active substance release profile is obtained.  
     
     
         24 . A controlled release preparation according to  claim 23 , wherein the active substance release profile is increased by subsequent heat treatment at temperatures of >35° C. without affecting storage stability of the preparation.  
     
     
         25 . A controlled release preparation according to  claim 23 , wherein said preparation is a multiparticulate preparation.  
     
     
         26 . A controlled release preparation according to  claim 25 , wherein said multiparticulate preparation is in the form of microtablets, granules, pellets or crystals.