Protecting oral overdose with abuse deterrent immediate release formulations

Abstract

The invention relates to a pharmaceutical dosage form which is particularly useful for the prevention of an overdose of the pharmacologically active ingredient contained therein after accidental or intentional simultaneous administration of a plurality of the dosage forms containing an overall supratherapeutic dose of the pharmacologically active ingredient.

1 . A pharmaceutical dosage form comprising a pharmacologically active ingredient a, said pharmacologically active ingredient a being selected from the group consisting of amphetamine and physiologically acceptable salts thereof, at least a portion of the pharmacologically active ingredient a being contained in one or more particles A, each of said one or more particles A comprising a homogeneous mixture of the pharmacologically active ingredient a, one or more disintegrants and a polymer matrix, the one or more disintegrants being present in an amount of 10-30 wt % based on a total weight of the one or more particles A, the polymer matrix comprising a polyethylene oxide having an average molecular weight of at least 200,000 g/mol, the polyethylene oxide being present in an amount of at least 40 wt %, based on a total weight of the one or more particles A, the one or more particles A not comprising hydroxypropylmethyl cellulose, the one or more particles A not comprising a wax, and the one or more particles A having a breaking strength of at least 300 N;
 said dosage form being adapted to prevent an overdose of the pharmacologically active ingredient a after accidental or intentional simultaneous administration of a plurality of the dosage forms containing an overall supratherapeutic dose of the pharmacologically active ingredient a.   
     
     
         2 . The pharmaceutical dosage form according to  claim 1 , wherein the one or more disintegrants are selected from the group consisting of starches, starch derivatives, cellulose derivatives, and gas releasing substances. 
     
     
         3 . The pharmaceutical dosage form according to  claim 2 , wherein the one or more disintegrants are selected from the group consisting of maize starch, pregelatinized starch, sodium starch glycolate, croscarmellose sodium, and sodium bicarbonate. 
     
     
         4 . The pharmaceutical dosage form according to  claim 3 , wherein the disintegrant is pregelatinized starch. 
     
     
         5 . The pharmaceutical dosage form according to  claim 1 , wherein the polyalkylene oxide has an average molecular weight of at least 500,000 g/mol. 
     
     
         6 . The pharmaceutical dosage form according to  claim 5 , wherein the polyalkylene oxide has an average molecular weight in the range of 1,000,000 g/mol to 15,000,000 g/mol. 
     
     
         7 . The pharmaceutical dosage form according to  claim 1 , wherein the content of the polyalkylene oxide in the dosage form amounts to at least 25 mg. 
     
     
         8 . The pharmaceutical dosage form according to  claim 7 , wherein the content of the polyalkylene oxide in the dosage form amounts to at least 50 mg. 
     
     
         9 . The pharmaceutical dosage form according to  claim 1 , wherein the one or more particles A amount to a total number within the range of from 20 to 600. 
     
     
         10 . The pharmaceutical dosage form according to  claim 1 , wherein the one or more particles A amount to a total content of at least 25 wt.-%, based on the total weight of the dosage form. 
     
     
         11 . The pharmaceutical dosage form according to  claim 1 , wherein the one or more particles A are tamper-resistant as such so that they also provide tamper-resistance after they have been separated from the remaining constituents of the dosage form. 
     
     
         12 . The pharmaceutical dosage form according to  claim 1 , wherein the one or more particles A contain the total amount of the pharmacologically active ingredient a that is contained in the dosage form. 
     
     
         13 . The pharmaceutical dosage form according to  claim 1 , wherein the one or more particles A are thermoformed by hot-melt extrusion. 
     
     
         14 . The pharmaceutical dosage form according to  claim 1 , wherein each of said intact dosage forms additionally contains a pharmacologically active ingredient b which differs from the pharmacologically active ingredient a. 
     
     
         15 . The pharmaceutical dosage form according to  claim 14 , wherein the pharmacologically active ingredient b 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, acetaminophen (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, bucillamine, their physiologically acceptable salts, and mixtures thereof. 
     
     
         16 . The pharmaceutical dosage form according to  claim 1 , wherein the one or more particles A comprise an antioxidant. 
     
     
         17 . The pharmaceutical dosage form according to  claim 16 , wherein the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), salts of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and the derivatives thereof, coniferyl benzoate, nordihydroguajaretic acid, gallus acid esters, and sodium bisulfite. 
     
     
         18 . The pharmaceutical dosage form according to  claim 1 , wherein the one or more particles A comprise an antioxidant. 
     
     
         19 . The pharmaceutical dosage form according to  claim 1 , wherein the one or more particles A cannot be comminuted with a hammer or with a mortar and pestle. 
     
     
         20 . The pharmaceutical dosage from according to  claim 1 , which is a capsule. 
     
     
         21 . The pharmaceutical dosage form according to  claim 1 , which is a tablet. 
     
     
         22 . A method for reducing the risk that a human subject will suffer an overdose of pharmacologically active ingredient a after accidental or intentional simultaneous administration of a plurality of intact dosage forms containing in combination an overall supratherapeutic dose of the pharmacologically active ingredient a, said pharmacologically active ingredient a being selected from the group consisting of amphetamine and physiologically acceptable salts thereof, at least a portion of the pharmacologically active ingredient a being contained in one or more particles A, each of said one or more particles A comprising a homogeneous mixture of the pharmacologically active ingredient a, one or more disintegrants and a polymer matrix, the one or more disintegrants being present in an amount of 10-30 wt % based on a total weight of the one or more particles A, the polymer matrix comprising a polyethylene oxide having an average molecular weight of at least 200,000 g/mol, the polyethylene oxide being present in an amount of at least 40 wt %, based on a total weight of the one or more particles A, the one or more particles A not comprising hydroxypropylmethyl cellulose, the one or more particles A not comprising a wax, and the one or more particles A having a breaking strength of at least 300 N, and said method comprising (a) administering to said human subject said plurality of intact dosage forms containing in combination an overall supratherapeutic dose of the pharmacologically active ingredient a and (b) achieving as a result said administering of said plurality of intact dosage forms to said human subject does not cause said human subject to suffer an overdose of the pharmacologically active ingredient a. 
     
     
         23 . The method according to  claim 22 , wherein each of said intact dosage forms is a capsule. 
     
     
         24 . The method according to  claim 22 , wherein each of said intact dosage forms is a tablet.