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 and wherein under physiological conditions the release of the physiologically active substance (A) from the dosage form is at least partially delayed. 
     
     
         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 1 , wherein polymer (C) is selected from the group consisting of polyalkylene oxide, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, the copolymers thereof and mixtures thereof. 
     
     
         7 . The dosage form according to  claim 1 , wherein polymer (C) is an polyalkylene oxide selected from the group consisting of polymethylene oxide, polyethylene oxide, polypropylene oxide, the copolymers thereof, the block-copolymers thereof, and the mixtures of any of the foregoing. 
     
     
         8 . The dosage form according to  claim 6 , wherein polymer (C) has a molecular weight of at least 0.5 million according to rheological measurements. 
     
     
         9 . 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. 
     
     
         10 . The dosage form according to  claim 9 , wherein the material forming the tubular domain ( 82 ) and the material forming the core ( 83 ) have different optical properties. 
     
     
         11 . The dosage form according to  claim 9 , wherein the thickness of the tubular domain ( 82 ) is within the range of 0.1 to 4 mm. 
     
     
         12 . 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%. 
     
     
         13 . 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. 
     
     
         14 . The dosage form according to  claim 13 , wherein wax (D) is carnauba wax or beeswax. 
     
     
         15 . The dosage form according to  claim 1 , wherein substance (A) is present in a delayed-release matrix. 
     
     
         16 . The dosage form according to  claim 15 , wherein the delayed-release matrix comprises polymer (C) and/or the optionally present wax (D). 
     
     
         17 . The dosage form according to  claim 1 , wherein after 5 hours under physiological conditions it has released not more than 99% of substance (A). 
     
     
         18 . The dosage form according to  claim 1 , wherein substance (A) is a nutritional supplement or a pharmaceutical substance. 
     
     
         19 . The dosage form according to  claim 18 , wherein substance (A) is selected from the group consisting of agents for the treatment and prevention of diseases of the alimentary system and metabolism; agents for the treatment and prevention of diseases of the blood and the blood forming organs; agents for the treatment and prevention of diseases of the cardiovascular system; dermatologicals; agents for the treatment and prevention of diseases of the genitourinary system and sex hormones; systemic hormone preparations excluding sex hormones and insulins; antiinfectives for systemic use; antineoplastic and immunomodulating agents; agents for the treatment and prevention of diseases of the musculo-skeletal system; agents for the treatment and prevention of diseases of the nervous system; antiparasitic products, insecticides and repellents; agents for the treatment and prevention of diseases of the respiratory system; agents for the treatment and prevention of diseases of the sensory organs; general diet products and therapeutic radiopharmaceuticals. 
     
     
         20 . 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. 
 
     
     
         21 . The process according to  claim 20 , wherein step (c) is performed by means of a twin-screw-extruder or a planetary-gear extruder. 
     
     
         22 . The process according to  claim 21 , wherein step (e) is performed in the plasticized state of the mixture of components (A), (C), optionally (B) and optionally (D). 
     
     
         23 . The process according to  claim 20 , wherein step (c) is performed by the effect of ultrasound and force. 
     
     
         24 . The product of the process of  claim 20 . 
     
     
         25 . The product of the process of  claim 21 . 
     
     
         26 . The product of the process of  claim 22 . 
     
     
         27 . The product of the process of  claim 23 . 
     
     
         28 . 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 . 
     
     
         29 . The use according to  claim 25  or the method according to  claim 26 , 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. 
     
     
         30 . 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. 
     
     
         31 . 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 . 
     
     
         32 . 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 . 
     
     
         33 . 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 .