Oxidation-stabilized tamper-resistant dosage form

Abstract

A thermoformed pharmaceutical dosage form having a breaking strength of at least 300 N, said dosage form comprising a pharmacologically active ingredient (A), a free physiologically acceptable acid (B) in an amount of from 0.001 wt.-% to 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form, and a polyalkylene oxide (C) having a weight average molecular weight M w of at least 200,000 g/mol.

1 . A tamper-resistant pharmaceutical dosage form in form of a tablet having a breaking strength of at least 300 N thermoformed by hot-melt extrusion of a mixture comprising
 a pharmacologically active ingredient (A),   a free physiologically acceptable multicarboxylic acid (B) in an amount of from 0.001 wt.-% to 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form,   an antioxidant selected from the group consisting of ascorbic acid or the salts thereof, ascorbylic palmitate, α-tocopherol, vitamin E-succinate, vitamin E-palmitate, butylhydroxyanisol, butylhydroxytoluene, monothioglycerine, coniferyl benzoate, nordihydroguaiaretic acid, gallus acid esters, phosphoric acid, and sodium bisulphite; in an amount of from 0.001 wt.-% to 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form; and   a polyalkylene oxide (C) having a weight average molecular weight M w  of at least 200,000 g/mol.   
     
     
         2 . The pharmaceutical dosage form according to  claim 1 , wherein the pharmacologically active ingredient (A) is an opioid. 
     
     
         3 . The pharmaceutical dosage form according to  claim 1 , wherein the multicarboxylic acid is selected from the group consisting of maleic acid, fumaric acid, glutaric acid, malonic acid and citric acid. 
     
     
         4 . The pharmaceutical dosage form according to  claim 1 , wherein the content of the acid (B) is within the range of from 0.005 to 2.5 wt.-%, based on the total weight of the pharmaceutical dosage form. 
     
     
         5 . The pharmaceutical dosage form according to  claim 1 , wherein the antioxidant is α-tocopherol. 
     
     
         6 . The pharmaceutical dosage form according to  claim 1 , wherein after storage for 4 weeks at 40° C. and 75% rel. humidity, the content of pharmacologically active ingredient (A) amounts to at least 98.0% of its original content before storage. 
     
     
         7 . The pharmaceutical dosage form according to  claim 1 , wherein after storage for 4 weeks at 40° C. and 75% rel. humidity, the content of the polyethylene oxide (C) amounts to at least 98.0% of its original content before storage. 
     
     
         8 . The pharmaceutical dosage form according to  claim 1 , wherein the pharmacologically active ingredient (A) is embedded in a matrix comprising the polyalkylene oxide (C), said matrix controlling the release of the pharmacologically active ingredient (A) from the pharmaceutical dosage form. 
     
     
         9 . The pharmaceutical dosage form according to  claim 1 , wherein the pharmacologically active ingredient (A) is selected from the group consisting of oxymorphone, oxycodone, hydromorphone, and the physiologically acceptable salts thereof. 
     
     
         10 . The pharmaceutical dosage form according to  claim 1 , wherein the relative weight ratio of the polyalkylene oxide (C) to the pharmacologically active ingredient (A) is at least 1:1. 
     
     
         11 . The pharmaceutical dosage form according to  claim 1 , which is adapted for administration once daily or twice daily. 
     
     
         12 . The pharmaceutical dosage form according to  claim 1 , which has a breaking strength of at least 500 N. 
     
     
         13 . A packaging containing a pharmaceutical dosage form according to  claim 1  and an oxygen scavenger. 
     
     
         14 . A process for the production of the pharmaceutical dosage form according to  claim 1  comprising the steps:
 a) mixing all components to form a resultant mixture; 
 b) heating the resultant mixture in an extruder at least up to the softening point of the polyalkylene oxide (C) and extruding extrudate through the outlet orifice of the extruder by application of force, 
 c) singulating the still plastic extrudate and forming into the pharmaceutical dosage form or 
 d) cooling and optionally reheating the singulated extrudate and forming it into the pharmaceutical dosage form. 
 
     
     
         15 . A method of treating pain in a patient in need of such treatment, said method comprising administering to said patient a pharmaceutical dosage form according to  claim 1 .