CO-CRYSTALS OF TRAMADOL AND NSAIDs

Abstract

The present invention relates to co-crystals of tramadol and co-crystal formers selected from NSAIDs, processes for preparation of the same, their uses in pharmaceutical formulations, and for the treatment of various disorders, including pain.

1 . A co-crystal comprising tramadol either as a free base or as a physiologically acceptable salt and at least one NSAID. 
     
     
         2 . A co-crystal according to  claim 1  comprising tramadol either as a free base or as a physiologically acceptable salt and at least one NSAID, wherein the NSAID or at least one of the NSAIDs has at least one functional group from the group consisting of ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, s-heterocyclic ring, thiophene, n-heterocyclic ring, pyrrole, o-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, and pyridine. 
     
     
         3 . A co-crystal according to  claim 1 , wherein the NSAID is chosen in such a way that if compared to either tramadol alone, or to a mixture of tramadol and the corresponding NSAID, as active agent/s:
 the solubility of the co-crystal is increased; and/or   the dose response of the co-crystal is increased; and/or   the efficacy of the co-crystal is increased; and/or   the dissolution of the co-crystal is increased; and/or   the bioavailability of the co-crystal is increased; and/or   the stability of the co-crystal is increased; and/or   the hygroscopicity of the co-crystal is decreased; and/or   the form diversity of the co-crystal is decreased; and/or   the morphology of the co-crystal is modulated.   
     
     
         4 . The co-crystal according to  claim 1 , wherein the NSAID is selected from:
 Acetylsalicylic Acid;   Triflusal;   HTB (2-hydroxy-4-trifluoromethyl benzoic acid);   Diflunisal;   Meclofenamic acid;   Mefenamic acid;   Niflumic acid;   Flufenamic acid.   Diclofenac;   Lonazolac;   Acemetacin;   Indomethacin;   Tolmetin;   Sulindac   Etodolac;   Keterolac;   Flurbiprofen;   (RS)-Flurbiprofen;   Esflurbiprofen;   Ibuprofen;   (RS)-Ibuprofen;   S-(+)-Ibuprofen;   Ketoprofen;   (rac)-Ketoprofen   R-(−)-Ketoprofen   Bermoprofen;   Pelubiprofen;   Tenosal;   Aceneuramic acid;   Pirazolac;   Xinoprofen;   Flobufen;   Anirolac;   Zoliprofen;   Bromfenac;   Pemedolac;   Dexpemedolac;   Bindarit;   Romazarit;   Naproxen;   (S)—Naproxen;   (R)—Naproxen;   Tiaprofenic acid;   Ketorolac;   Fenbufen;   Fenoprofen;   Flobufen;   Oxaprozin;   Celecoxib,   Etoricoxib,   Lumiracoxib,   Parecoxib,   Rofecoxib,   Valdecoxib, and   Cimicoxib.   
     
     
         5 . The co-crystal according to  claim 1 , wherein the NSAID is naproxen, its enantiomers or salts thereof. 
     
     
         6 . The co-crystal according to  claim 1 , wherein the NSAID is (S)-naproxen or (R)-naproxen. 
     
     
         7 . The co-crystal according to  claim 1 , wherein the tramadol is (−)-tramadol or (+)-tramadol. 
     
     
         8 . A co-crystal according to  claim 1 , selected from:
 a co-crystal comprising (−)-tramadol either as a free base or as a physiologically acceptable salt and (S)-naproxen;   a co-crystal comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen;   an enantiomeric mixture of co-crystals comprising (−)-tramadol either as a free base or as a physiologically acceptable salt and (S)-naproxen and co-crystals comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen;   a solvate co-crystal comprising (−)-tramadol either as a free base or as a physiologically acceptable salt and (S)-naproxen;   a solvate co-crystal comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen; and   an enantiomeric mixture of solvate co-crystals comprising (−)-tramadol either as a free base or as a physiologically acceptable salt and (S)-naproxen and co-crystals comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen.   
     
     
         9 . A co-crystal according to  claim 5 , wherein the molecular ratio between the tramadol and naproxen is 1:2. 
     
     
         10 . A co-crystal according to  claim 9  comprising (−)-tramadol either as a free base or as a physiologically acceptable salt and (S)-naproxen or comprising (+) tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen, or enantiomeric mixtures of these co-crystals, characterized in that it shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 4.3, 8.7, 9.5, 10.2, 10.6, 11.3, 12.1, 12.7, 13.2, 13.7, 14.3, 14.6, 14.8, 15.5, 15.7, 16.0, 16.2, 17.0, 17.4, 17.9, 18.1, 18.7, 19.1, 19.4, 19.7, 20.1, 20.5, 20.8, 21.1, 21.4, 21.6 and 21.8 [°], with the 2θ values being obtained using copper radiation (Cu Kα 1.54060 Å). 
     
     
         11 . A co-crystal according to  claim 9  comprising (−)-tramadol either as a free base or as a physiologically acceptable salt and (S)-naproxen or comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen, or mixture of enantiomers of these co-crystals, characterized in that it has a monoclinic unit cell with the following dimensions:
 a=9.512(2) Å 
 b=40.5736(11) Å 
 c=10.323(4) Å 
 α=90° 
 β 32  96.29(1)° 
 γ=90°. 
 
     
     
         12 . A co-crystal according to  claim 9  comprising (−)-tramadol either as a free base or as a physiologically acceptable salt and (S)-naproxen or comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen, or enantiomeric mixtures of these co-crystals, characterized in that the endothermic sharp peak corresponding to the melting point has an onset at 82° C. to 84° C. 
     
     
         13 . A co-crystal according to  claim 9  in the form of a methanol solvate comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen, characterized in that it shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 4.1, 6.6, 9.0, 9.2, 10.4, 11.0, 11.5, 12.3, 12.5, 12.7, 13.0, 13.2, 13.8, 14.9, 15.4, 16.2, 17.2, 17.6, 18.1, 18.5, 19.1, 19.3, 19.6, 19.9, 20.1, 20.4, 20.9, 21.0, 21.5, 22.0, 22.3 and 22.6 [°], with the 2θ values being obtained using copper radiation (Cu Kα  1.54060 Å). 
     
     
         14 . The co-crystal according to  claim 1 , wherein the NSAID is celecoxib or a salt thereof. 
     
     
         15 . A co-crystal according to  claim 14 , selected from:
 a co-crystal comprising (rac)-tramadol either as a free base or as a physiologically acceptable salt and celecoxib;   a co-crystal comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and celecoxib; and   a co-crystal comprising (−)-tramadol either as a free base or as a physiologically acceptable salt and celecoxib.   
     
     
         16 . Process for the production of a co-crystal according to  claim 1  comprising the steps of:
 (a) dissolving or suspending tramadol either as a free base or as a salt and an NSAID in a solvent; and optionally heating the solution or dispersion to a temperature above ambient temperature and below the boiling point of the solution or dispersion; 
 (d) optionally adding a solvent to the solution/dispersion of (a) and mixing them; 
 (e) cooling the mixed solution/dispersion of step (a) or (d) to ambient temperature or below; 
 (f) optionally evaporating part or all of the solvent; and 
 (g) filtering-off the resulting co-crystals. 
 
     
     
         17 . Pharmaceutical composition wherein said composition comprises a therapeutically effective amount of the co-crystal according to  claim 1  in a physiologically acceptable medium. 
     
     
         18 . A method for the treatment of pain comprising administering to a subject in need thereof a therapeutically effective amount of at least one co-crystal according to  claim 1 . 
     
     
         19 . A co-crystal according to  claim 2  comprising tramadol either as a free base or as a physiologically acceptable salt and at least one NSAID, wherein the NSAID or at least one of the NSAIDs has at least one functional group chosen from the group consisting of alcohol, thiol, ester, carboxylic acid, primary amine, secondary amine, tertiary amine. 
     
     
         20 . A co-crystal according to  claim 8 , wherein said solvate co-crystals are alcohol solvate co-crystals. 
     
     
         21 . A co-crystal according to  claim 20 , wherein said solvate co-crystals are methanol solvate co-crystals. 
     
     
         22 . A co-crystal according to  claim 15 , selected from a co-crystal comprising (rac)-tramadol.HCl and celecoxib. 
     
     
         23 . A method according to  claim 18 , wherein said pain is selected from acute pain, chronic pain, neuropathic pain, severe to moderate pain, hyperalgesia, allodynia, cancer pain, diabetic neuropathy, diabetic peripheral neuropathy, osteoarthritis, fibromyalgia, rheumatoid arthritis, ankylosing spondylitis, frozen shoulder and sciatica. 
     
     
         24 . Process for the production of a co-crystal according to  claim 1  comprising the steps of:
 (a) dissolving or suspending an NSAID in a solvent and optionally heating the solution or dispersion to a temperature above ambient temperature and below the boiling point of the solution or dispersion; 
 (b) dissolving tramadol either as a free base or as a salt in a solvent at the same time as, after, or before step (a); 
 (c) combining the solution of (b) with the solution/dispersion of (a) and mixing them; 
 (d) optionally adding a solvent to the solution of (c) and mixing them; 
 (e) cooling the mixed solution/dispersion of step (c) or (d) to ambient temperature or below; 
 (f) optionally evaporating part or all of the solvent; and 
 (g) filtering-off the resulting co-crystals.