Crush resistant delayed-release dosage forms

Abstract

The invention relates to a dosage form comprising a physiologically effective amount of a physiologically active substance (A), a synthetic, semi-synthetic or natural polymer (C), optionally one or more physiologically acceptable auxiliary substances (B) and optionally a synthetic, semi-synthetic or natural wax (D), wherein the dosage form exhibits a resistance to crushing of at least 400 N and wherein under physiological conditions the release of the physiologically active substance (A) from the dosage form is at least partially delayed.

1 . A dosage form comprising a physiologically effective amount of a physiologically active substance (A), a synthetic, semi-synthetic or natural polymer (C), optionally one or more physiologically acceptable auxiliary substances (B) and optionally a synthetic, semi-synthetic or natural wax (D), wherein the dosage form exhibits a resistance to crushing of at least 400 N, wherein under physiological conditions the release of the physiologically active substance (A) from the dosage form is at least partially delayed, wherein the physiologically active substance (A) consists of oxycodone, a physiologically acceptable derivative thereof, and wherein the polymer (C) is polyethylene oxide (PEO). 
     
     
         2 . The dosage form according to  claim 1 , which exhibits a resistance to crushing of at least 500 N. 
     
     
         3 . The dosage form according to  claim 1 , which is in the form of a tablet. 
     
     
         4 . The dosage form according to  claim 1  which is in multiparticulate form, the individual particles exhibiting a resistance to crushing of at least 400 N. 
     
     
         5 . The dosage form according to  claim 4 , wherein the particles are pressed into tablets or packaged in capsules. 
     
     
         6 . The dosage form according to  claim 6 , wherein polymer (C) has a molecular weight of at least 0.5 million according to rheological measurements. 
     
     
         7 . The dosage form according to  claim 1 , which comprises a tubular domain ( 82 ) and a core ( 83 ) located therein, wherein the tubular domain ( 82 ) is connected with the core ( 83 ) in a seamless manner and the material forming the tubular domain ( 82 ) and the material forming the core ( 83 ) have substantially the same chemical composition but different morphology. 
     
     
         8 . The dosage form according to  claim 7 , wherein the material forming the tubular domain ( 82 ) and the material forming the core ( 83 ) have different optical properties. 
     
     
         9 . The dosage form according to  claim 7 , wherein the thickness of the tubular domain ( 82 ) is within the range of 0.1 to 4 mm. 
     
     
         10 . The dosage form according to  claim 1 , wherein upon storage for at least 12 hour at a temperature of 20° C. below the melting range of the mixture of components (A), (C), optionally (B) and optionally (D) the volume of the dosage form increases by not more than 20%. 
     
     
         11 . The dosage form according to  claim 1 , wherein wax (D) is at least one synthetic, semi-synthetic or natural wax with a softening point of at least 50° C. 
     
     
         12 . The dosage form according to  claim 11 , wherein wax (D) is carnauba wax or beeswax. 
     
     
         13 . The dosage form according to  claim 1 , wherein substance (A) is present in a delayed-release matrix. 
     
     
         14 . The dosage form according to  claim 13 , wherein the delayed-release matrix comprises polymer (C) and/or the optionally present wax (D). 
     
     
         15 . The dosage form according to  claim 1 , wherein after 5 hours under physiological conditions it has released not more than 99% of substance (A). 
     
     
         16 . A process for the production of a dosage form according to  claim 1  comprising the following steps:
 (a) mixing of component (A), (C), optionally (B) and optionally (D); 
 (b) optionally preforming the mixture obtained from step (a), preferably by applying heat and/or force to the mixture obtained from step (a), the quantity of heat supplied preferably not being sufficient to heat component (C) up to its softening point; 
 (c) hardening the mixture by applying heat and force, where the heat is supplied during and/or before the application of force and the quantity of heat supplied is sufficient to heat component (C) at least up to its softening point; 
 (d) optionally singulating the hardened mixture; 
 (e) optionally shaping the dosage form; and 
 (f) optionally providing a film coating. 
 
     
     
         17 . The process according to  claim 16 , wherein step (c) is performed by means of a twin-screw-extruder or a planetary-gear extruder. 
     
     
         18 . The process according to  claim 19 , wherein step (e) is performed in the plasticized state of the mixture of components (A), (C), optionally (B) and optionally (D). 
     
     
         19 . The process according to  claim 16 , wherein step (c) is performed by the effect of ultrasound and force. 
     
     
         20 . The product of the process of  claim 16 . 
     
     
         21 . The product of the process of  claim 17 . 
     
     
         22 . The product of the process of  claim 18 . 
     
     
         23 . The product of the process of  claim 19 . 
     
     
         24 . A method of preventing the misuse or abuse of a dosage form containing a physiologically active substance (A), due to comminution of the dosage form by mechanical action comprising administering the active substance to a patient in need thereof in a dosage form in accordance with  claim 1 . 25 . The method according to  claim 24 , wherein the mechanical action is selected from the group consisting of chewing, grinding in a mortar, pounding, and using apparatuses for pulverising conventional dosage forms. 
     
     
         25 . A method for the prophylaxis and/or the treatment of a disorder treatable by the administration of a therapeutically effective amount of an agent capable of treating such disorder comprising administering a dosage form according to  claim 1  to prevent the unintentional disruption of the controlled release mechanism of the physiologically active substance (A) which can result from crushing or chewing the dosage form. 
     
     
         26 . A method of preventing an accidental overdose of a physiologically active substance comprising administering the active substance to a patient in need thereof in a dosage form in accordance with  claim 1 . 
     
     
         27 . A method of preventing the misuse or abuse of a physiologically active substance comprising administering the active substance to a patient in need thereof in a dosage form in accordance with  claim 1 . 
     
     
         28 . A method of preventing the disruption of a controlled release mechanism in a dosage form comprising a physiologically active substance intended for controlled release of such active substance comprising administering the active substance in a dosage form according to  claim 1 .