Tamper resistant dosage form with bimodal release profile

Abstract

The invention relates to a pharmaceutical dosage form comprising (i) at least one formed segment (S 1 ), which contains a first pharmacologically active ingredient (A 1 ) and provides prolonged release thereof, and (ii) at least one further segment (S 2 ), which contains a second pharmacologically active ingredient (A 2 ) and provides immediate release thereof, wherein the at least one formed segment (S 1 ) exhibits a higher breaking strength than the at least one further segment (S 2 ) and the at least one formed segment (S 1 ) exhibits a breaking strength of more than 500 N.

1 . A pharmaceutical dosage form comprising:
 (i) at least one formed segment (S 1 ), which contains a first pharmacologically active ingredient (A 1 ) and provides prolonged release thereof; and   (ii) at least one further segment (S 2 ), which contains a second pharmacologically active ingredient (A 2 ) and provides immediate release thereof;   wherein the at least one formed segment (S 1 ) exhibits a higher breaking strength than the at least one further segment (S 2 ) and the at least one formed segment (S 1 ) exhibits a breaking strength of more than 500 N.   
     
     
         2 . The pharmaceutical dosage form according to  claim 1 , wherein the at least one further segment (S 2 ) exhibits a breaking strength of at most 500 N. 
     
     
         3 . The pharmaceutical dosage form according to  claim 1 , wherein the second pharmacologically active ingredient (A 2 ) is different from the first pharmacologically active ingredient (A 1 ). 
     
     
         4 . The pharmaceutical dosage form according to  claim 1 , wherein
 (i) the first pharmacologically active ingredient (A 1 ) has a psychotropic effect; and/or   (ii) the second pharmacologically active ingredient (A 2 ) is selected from ATC classes [M01A], [M01C], [N02B] and [N02C] according to the WHO.   
     
     
         5 . The pharmaceutical dosage form according to  claim 1 , wherein the first pharmacologically active ingredient (A 1 ) is an opioid or a physiologically acceptable salt thereof. 
     
     
         6 . The pharmaceutical dosage form according to  claim 1 , wherein the second pharmacologically active ingredient (A 2 ) is selected from the group consisting of acetylsalicylic acid, aloxiprin, choline salicylate, sodium salicylate, salicylamide, salsalate, ethenzamide, morpholine salicylate, dipyrocetyl, benorilate, diflunisal, potassium salicylate, guacetisal, carbasalate calcium, imidazole salicylate, phenazone, metamizole sodium, aminophenazone, propyphenazone, nifenazone, paracetamol, phenacetin, bucetin, propacetamol, rimazolium, glafenine, floctafenine, viminol, nefopam, flupirtine, ziconotide, methoxyflurane, nabiximols, dihydroergotamine, ergotamine, methysergide, lisuride, flumedroxone, sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, frovatriptan, pizotifen, clonidine, iprazochrome, dimetotiazine, oxetorone, phenylbutazone, mofebutazone, oxyphenbutazone, clofezone, kebuzone, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac, bumadizone, etodolac, lonazolac, fentiazac, acemetacin, difenpiramide, oxametacin, proglumetacin, ketorolac, aceclofenac, bufexamac, piroxicam, tenoxicam, droxicam, lornoxicam, meloxicam, ibuprofen, naproxen, ketoprofen, fenoprofen, fenbufen, benoxaprofen, suprofen, pirprofen, flurbiprofen, indoprofen, tiaprofenic acid, oxaprozin, ibuproxam, dexibuprofen, flunoxaprofen, alminoprofen, dexketoprofen, naproxcinod, mefenamic acid, tolfenamic acid, flufenamic acid, meclofenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, nabumetone, niflumic acid, azapropazone, glucosamine, benzydamine, glucosaminoglycan polysulfate, proquazone, orgotein, nimesulide, feprazone, diacerein, morniflumate, tenidap, oxaceprol, chondroitin sulfate, oxycinchophen, sodium aurothiomalate, sodium aurotiosulfate, auranofin, aurothioglucose, aurotioprol, penicillamine and bucillamine. 
     
     
         7 . The pharmaceutical dosage form according to  claim 1 , wherein the first pharmacologically active ingredient (A 1 ) is hydrocodone or a physiologically acceptable salt thereof and the second pharmacologically active ingredient (A 2 ) is paracetamol. 
     
     
         8 . The pharmaceutical dosage form according to  claim 1 , wherein the first pharmacologically active ingredient (A 1 ) is embedded in a prolonged release matrix comprising a synthetic or natural polymer (C). 
     
     
         9 . The pharmaceutical dosage form according to  claim 8 , wherein
 (i) the content of the synthetic or natural polymer (C) is at least 30 wt.-% relative to the total weight of the formed segment(s) (S 1 ); and/or   (ii) the synthetic or natural polymer (C) is selected from acrylic polymers and polyalkylene oxides.   
     
     
         10 . The pharmaceutical dosage form according to  claim 1 , which under in vitro conditions in 600 mL 0.1 N HCl using the basket method according to Ph. Eur. at 75 rpm, after 1 h under physiological conditions has released at most 50% of the first pharmacologically active ingredient (A 1 ) relative to the total amount of A 1  originally contained in the pharmaceutical dosage form. 
     
     
         11 . The pharmaceutical dosage form according to  claim 1 , which under in vitro conditions in 600 mL 0.1 N HCl using the basket method according to Ph. Eur. at 75 rpm, after 1 h under physiological conditions has released at least 60% of the second pharmacologically active ingredient (A 2 ) relative to the total amount of the second pharmacologically active ingredient (A 2 ) originally contained in the pharmaceutical dosage form. 
     
     
         12 . The pharmaceutical dosage form according to  claim 1 , wherein the at least one formed segment (S 1 ) is tamper resistant and provides resistance against grinding and/or resistance against solvent extraction and/or resistance against dose-dumping in aqueous ethanol. 
     
     
         13 . The pharmaceutical dosage form according to  claim 1 , which is selected from the group consisting of capsules, sugar-coated tablets, dry-coated tablets, mantle tablets, and layered tablets. 
     
     
         14 . The pharmaceutical dosage form according to  claim 1 , wherein the at least one formed segment (S 1 ) is thermoformed. 
     
     
         15 . The pharmaceutical dosage form according to  claim 1 , which contains a single, monolithic formed segment (S 1 ), or a multitude of particulate formed segments (S 1 ). 
     
     
         16 . The pharmaceutical dosage form according to  claim 15 , wherein the formed segment/s (S 1 ) has/have an extension in any direction of at least 2.0 mm. 
     
     
         17 . The pharmaceutical dosage form according to  claim 1 , which is to be administered orally. 
     
     
         18 . The pharmaceutical dosage form according to  claim 1 , which is to be administered as a whole. 
     
     
         19 . A process for the production of a pharmaceutical dosage form according to  claim 1  comprising the steps of:
 (i) thermoforming at least one formed segment (S 1 ) comprising a first pharmacologically active ingredient (A 1 ) and a natural or synthetic polymer (C); 
 (ii) providing at least one further segment (S 2 ) comprising a second pharmacologically active ingredient (A 2 ); and 
 (iii) combining the at least one formed segment (S 1 ), the at least one further segment (S 2 ) and optionally further excipients. 
 
     
     
         20 . A method of treating pain in a patient in need of such treating, said method comprising orally administering to said patient a pharmaceutical dosage form according to  claim 1 , wherein the dosage form is swallowed by said patient as a whole.