Abuse-deterrent pharmaceutical compositions

Abstract

Disclosed are pharmaceutical compositions comprising oxycodone and an oxycodone-processing enzyme, wherein oxycodone is contained in the pharmaceutical composition in a storage stable, enzyme-reactive state and under conditions wherein no enzymatic activity acts on oxycodone.

1 . A pharmaceutical composition comprising oxycodone or a pharmaceutically acceptable salt thereof and an oxycodone-processing enzyme, wherein oxycodone is contained in the pharmaceutical composition in a storage stable, enzyme-reactive state and under conditions wherein no enzymatic activity acts on oxycodone. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the enzyme is selected from the group of oxidoreductases and/or transferases and/or hydrolases, especially a monooxygenase, a peroxidase, a peroxygenase and/or a sulfotransferase. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the enzyme catalyses O-demethylation, N-demethylation, keto-reduction, N-oxidation, epoxy-hydroxylation of oxycodone or addition of molecules, especially glucuronidation, sulfation and acetylation, to oxycodone. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein oxycodone is a salt, hydrate, solvate or prodrug of oxycodone, preferably a salt selected from the group of hydrochloride, bitartrate, tartrate, camphorsulphonate, phenylpriopionate, sulphate, pectinate, phosphate, methyiodide, hydroiodide and terephthalate or a prodrug form. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is selected from a tablet, a mini-tablet, a coat-core tablet (coated tablet), a bi-layer tablet, a multi-layer tablet, a capsule, a pellet, a MUPS (multiple unit pellet system), a granulate, a powder, especially coated, sugar-coated and/or functionally coated (e.g. enteric coated) forms thereof. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the composition comprises a coated oxycodone-processing enzyme. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein oxycodone is contained in an amount of 0.1 to 5.000 mg, preferably 0.5 to 1.000 mg, especially 1 to 500 mg, per dosage unit. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein the composition comprises co-factors of the oxycodone-processing enzyme, preferably H and/or electron donors and acceptors, especially NAD(P)H, FMN, FAD, ferredoxin, 2-oxoglutarate, and/or hemes; or donors for the groups to be added to oxycodone, especially acetyl-Coenzyme A (ac-CoA) or UDP-glucuronate. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein the composition is storage stable, preferably by comprising less than 5%, especially less than 1%, enzyme-processed oxycodone after 6 month storage at 25° C. under dry conditions. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the enzyme is selected from the group of 3-alpha-hydroxysteroid 3-dehydrogenase (EC 1.1.1.213), cytochrome P450 (EC 1.14), especially non-heme iron-dependent monooxygenase (EC 1.14.16), copper-dependent monooxygenases (EC 1.14.17 and EC 1.14.18), the CYP2C subfamily; CYP2D6; unspecific monooxygenase (EC 1.14.14.1), Codeine 3-O-demethylase (CODM; EC 1.14.11.32), CYP1-(EC 1.14.14.1), preferably CYP3A, CYP1A, CYP2B, CYP2C and CYP2D, especially CYP3A4, CYP3A5, CYP3A7, CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6; peroxidases (EC 1.11.1 and EC 1.11.2), preferably horseradish peroxidase (EC 1.11.1.7) and fungal unspecific peroxygenase (EC 1.11.2.1); carbonyl reductase (NADPH) (EC 1.1.1.184), preferably dihydromorphinine ketone reductase (DMKR; types I to V), dihydrocodeinone ketone reductase (DCKR, types I and II) or morphine 6-dehydrogenase (EC 1.1.1.218); flavin-dependent monooxygenases (EC 1.13.12 and EC 1.14.13), especially flavin-containing monooxygenase (EC 1.14.13.8); microsomal epoxide hydrolase (EC 3.3.2.9), cofactor-independent monooxygenase; epoxide hydratase (EC 3.3.2.3 and 4.2.1.63), and soluble epoxide hydrolase (EC 3.3.2.10); UDP-glucuronosyltransferase (EC 2.4.1.17), preferably UGT1 and UGT2 enzymes, especially UGT1.1 and UGT2B7; bilirubin-glucuronoside glucuronosyltransferase (EC 2.4.1.95); ac(et)yltransferase (EC 2.3), sulfotransferases (EC 2.8.2), CoA-transferase (EC 2.8.3), especially N-acetyltransferase (NAT, EC 2.3.1) and O-acetyltransferase (OAT; EC 2.3.1). 
     
     
         11 . The pharmaceutical composition according to  claim 1 , comprising a further enzyme, preferably a further oxycodone-processing enzyme or an enzyme further processing the processed oxycodone forms, especially laccase (EC 1.10.3.2). 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the composition comprises oxycodone alone or in combination with a non-opioid analgesic, preferably with ibuprofen, diclofenac, naproxen, paracetamol and acetyl-salicylic acid. 
     
     
         13 . The pharmaceutical composition according to  claim 1  for use in the treatment of pain and/or drug addiction. 
     
     
         14 . A method for manufacturing the pharmaceutical composition according to  claim 1  comprising the steps of mixing oxycodone or a pharmaceutically acceptable salt, hydrate, solvate, ester or prodrug thereof with the oxycodone-processing enzyme and finishing the mixture to a pharmaceutical composition. 
     
     
         15 . A method for manufacturing a pharmaceutical composition according to  claim 1  comprising the steps of providing oxycodone or a pharmaceutically acceptable salt, hydrate, solvate, ester or prodrug thereof and the oxycodone-processing enzyme in separated form and finishing the separated oxycodone or a pharmaceutically acceptable salt, hydrate, solvate, ester or prodrug thereof and oxycodone-processing enzyme to a pharmaceutical composition.