Tamper-resistant dosage form with immediate release and resistance against solvent extraction

Abstract

A tamper-resistant pharmaceutical dosage form comprising a multitude of particles which comprise a pharmacologically active compound, a polyalkylene oxide, and a disintegrant; wherein the pharmacologically active compound is dispersed in a matrix comprising the polyalkylene oxide and the disintegrant; wherein the content of the disintegrant is more than 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles; wherein the content of the polyalkylene oxide is at least 25 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles; and wherein the dosage form provides under in vitro conditions immediate release of the pharmacologically active compound in accordance with Ph. Eur.

1 . A tamper resistant pharmaceutical dosage form comprising
 a multitude of particles each of which particles comprises an extruded mixture of a pharmacologically active compound, a polyalkylene oxide, and a disintegrant;   wherein the pharmacologically active compound is selected from the group consisting of amphetamine, dexamphetamine, methylphenidate, and the physiologically acceptable salts thereof;   wherein the content of the disintegrant is about 5 wt. % to about 25 wt. % based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles;   wherein the content of the polyalkylene oxide is about 35 wt. % to about 65 wt. % based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles;   wherein the dosage form provides under in vitro conditions immediate release of the pharmacologically active compound in accordance with Ph. Eur.;   wherein the particles exhibit a breaking strength of at least 300 N; and   wherein the particles exhibit an increased resistance against solvent extraction compared to particles that are otherwise identical but for the lack of a disintegrant.   
     
     
         2 . The pharmaceutical dosage form according to  claim 1 , wherein the particles exhibit a breaking strength of at least 500 N. 
     
     
         3 . The pharmaceutical dosage form according to  claim 1 , which exhibits resistance against solvent extraction such that when
 (i) dispensing the pharmaceutical dosage form that is either intact or has been manually comminuted by means of two spoons in 5 ml of purified water,   (ii) heating the liquid up to its boiling point,   (iii) boiling the liquid in a covered vessel for 5 mm without the addition of further purified water,   (iv) drawing up the hot liquid into a syringe, and   (v) determining the amount of the pharmacologically active compound contained in the liquid within the syringe, the liquid part of the formulation that can be separated from the remainder by means of the syringe is not more than 10 wt.-% of the pharmacologically active compound originally contained in the dosage form.   
     
     
         4 . The pharmaceutical dosage form according to  claim 1 , wherein the disintegrant is selected from the group consisting of polysaccharides, starches, starch derivatives, cellulose derivatives, acrylates, polyvinylpyrrolidones, gas releasing substances, proteins and protein derivatives. 
     
     
         5 . The pharmaceutical dosage form according to  claim 4 , wherein the disintegrant is or comprises a starch; and/or the starch is standard starch or pregelatinized starch. 
     
     
         6 . The pharmaceutical dosage form according to  claim 4 , wherein the disintegrant is or comprises a starch derivative; and/or the starch derivative is sodium starch glycolate or sodium carboxymethyl starch. 
     
     
         7 . The pharmaceutical dosage form according to  claim 4 , wherein the disintegrant is or comprises a cellulose derivative; and/or the cellulose derivative is croscarmellose sodium. 
     
     
         8 . The pharmaceutical dosage form according to  claim 4 , wherein the disintegrant is or comprises an acrylate; and/or the acrylate is carbopol. 
     
     
         9 . The pharmaceutical dosage form according to  claim 4 , wherein the disintegrant is or comprises a gas releasing substance; and/or the gas releasing substance is sodium bicarbonate. 
     
     
         10 . The pharmaceutical dosage form according to  claim 1 , wherein the content of the disintegrant is at least 10 wt.-%, based on the total weight of the particles; or the content of the disintegrant is within the range of 15±5.0 wt.-%, based on the total weight of the particles; or the content of the disintegrant is within the range of 20±5.0 wt.-%, based on the total weight of the particles; or the content of the disintegrant is within the range of 25±5.0 wt.-%, based on the total weight of the particles. 
     
     
         11 . The pharmaceutical dosage form according to  claim 1 , wherein the polyalkylene oxide has a weight average molecular weight of at least 500,000 g/mol; or the content of the polyalkylene oxide is at least 40 wt.-%, based on the total weight of the particles; or the content of the polyalkylene oxide is at least 45 wt.-%, based on the total weight of the particles. 
     
     
         12 . The pharmaceutical dosage form according to  claim 1 , wherein the relative weight ratio of the polyalkylene oxide to the disintegrant is within the range of 5:1 to 1:2. 
     
     
         13 . The pharmaceutical dosage form according to  claim 1 , wherein the relative weight ratio of the pharmacologically active ingredient to the disintegrant is within the range of 2:1 to 1:8. 
     
     
         14 . The pharmaceutical dosage form according to  claim 1 , which provides a release profile such that under in vitro conditions in 600 ml 0.1 M HCl (pH 1) at 75 rpm after 30 min at least 90 wt.-% of the pharmacologically active ingredient that was originally contained in the dosage form have been released. 
     
     
         15 . The pharmaceutical dosage form according to  claim 1 , which additionally comprises a gelling agent. 
     
     
         16 . The pharmaceutical dosage form according to  claim 1 , wherein the particles are film coated. 
     
     
         17 . The pharmaceutical dosage form according to  claim 16 , wherein the film coating is water-soluble. 
     
     
         18 . The pharmaceutical dosage form according to  claim 16 , wherein the film coating is based on polyvinyl alcohol or hydroxypropylmethylcellulose. 
     
     
         19 . The pharmaceutical dosage form according to  claim 16 , wherein the particles additionally comprises citric acid. 
     
     
         20 . The pharmaceutical dosage form according to  claim 19 , the content of citric acid is about 0.1 wt. % to about 1.0 wt. %, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles. 
     
     
         21 . The pharmaceutical dosage form according to  claim 1 , which is a tablet or capsule. 
     
     
         22 . The pharmaceutical dosage form according to  claim 1 , wherein the particles are hot melt-extruded. 
     
     
         23 . A method for treating attention deficit hyperactivity disorder (ADHD) comprising administering to a person in need of ADHD treatment a tamper-resistant pharmaceutical dosage form, the pharmaceutical dosage form comprising:
 a pharmaceutically active compound selected from the group consisting of amphetamine, dex-amphetamine, methylphenidate, and their respective pharmaceutically acceptable salts;   a disintegrant in the amount of about 5 wt. % to about 25 wt. % based on the total weight of the pharmaceutical dosage form;   polyalkylene oxide in the amount of about 35 wt. % to about 65 wt. % based on the total weight of the pharmaceutical dosage form;   wherein the pharmaceutically active compound, the disintegrant and the polyalkylene oxide are homogenously mixed in a multitude of particles that exhibit a breaking strength of at least 300N;   wherein the pharmaceutical dosage form provides under in vitro conditions immediate release of the pharmacologically active compound in accordance with Ph. Eur.; and   wherein the pharmaceutical dosage form exhibits an increased resistance against solvent extraction compared to particles that are otherwise identical but for the lack of disintegrant.   
     
     
         24 . The method according to  claim 23 , wherein the pharmaceutical dosage form comprises amphetamine or its respective pharmaceutically acceptable salts as pharmaceutically active compound. 
     
     
         25 . The method according to  claim 23 , wherein the pharmaceutical dosage form comprises dex-amphetamine or its respective pharmaceutically acceptable salts as pharmaceutically active compound. 
     
     
         26 . The method according to  claim 25 , wherein the pharmaceutical dosage form comprises dex-amphetamine sulfate as pharmaceutically active compound. 
     
     
         27 . The method according to  claim 25 , wherein the T max  of dex-amphetamine is within the range of 3.0+/−1.3 hr. 
     
     
         28 . The method according to  claim 25 , wherein the t 1/2  of dex-amphetamine is within the range of 10+/−3.0 hr.