Pharmaceutical Combination

Abstract

A composition of matter comprising in combination as component (a) at least one 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound, and as component (b) at least one antiepileptic, a pharmaceutical formulation and a dosage form comprising said composition of matter, and a method of treating pain, e.g. neuropathic pain, in which components (a) and (b) are administered simultaneously or sequentially to a mammal, whereby component (a) may be administered before or after component (b) and whereby components (a) or (b) are administered to the mammal either via the same or a different pathway of administration.

1 . A composition of matter comprising in combination:
 (a) a 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol compound corresponding to formula (I):   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and 
         (b) at least one antiepileptic. 
       
     
     
         2 . A composition of matter as claimed in  claim 1 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound is present in the form of an isolated stereoisomer. 
     
     
         3 . A composition of matter as claimed in  claim 1 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound is present in the form of a mixture of stereoisomers in any mixing ratio. 
     
     
         4 . A composition of matter as claimed in  claim 3 , wherein said mixture is a racemic mixture. 
     
     
         5 . A composition of matter as claimed in  claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
 (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,   (1S,25)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,   (1R,25)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,   (1S,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, and   mixtures of two or more of the foregoing.   
     
     
         6 . A composition of matter as claimed in  claim 5 , wherein said compound of formula (I) is selected from the group consisting of:
 (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,   (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and   mixtures thereof.   
     
     
         7 . A composition of matter as claimed in  claim 6 , wherein said compound of formula (I) is (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (I′), 
       
         
           
           
               
               
           
         
       
       or an acid addition salt thereof. 
     
     
         8 . A composition of matter as claimed in  claim 7 , wherein said compound of formula (I) is a hydrochloride salt of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol. 
     
     
         9 . A composition of matter as claimed in  claim 1 , wherein the antiepileptic is selected from the group consisting of methylphenobarbital, phenobarbital, primidone, barbexaclone, metharbital, ethotoin, phenyloin, amino(diphenylhydantoin) valeric acid, mephenyloin, fosphenyloin, paramethadione, trimethadione, ethadione, ethosuximide, phensuximide, mesuximide, clonazepam, carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide, tiagabine, sultiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, pheneturide, levetiracetam, brivaracetam, selectracetam, zonisamide, pregabalin, stiripentol, lacosamide, beclamide, mexiletin, retigabin and ralfinamide. 
     
     
         10 . A composition of matter as claimed in  claim 9 , wherein the antiepileptic is selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, carbamazepine, mexiletin, lacosamide, phenyloin, levetiracetam, retigabin, valproic acid and ralfinamide. 
     
     
         11 . A composition of matter as claimed in  claim 10 , wherein the antiepileptic is selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, lacosamide, levetiracetam and retigabine. 
     
     
         12 . A composition of matter as claimed in  claim 11 , wherein the antiepileptic is pregabalin. 
     
     
         13 . A composition of matter as claimed in  claim 11 , wherein the antiepileptic is gabapentin. 
     
     
         14 . A composition of matter as claimed in  claim 11 , wherein the antiepileptic is, topiramate. 
     
     
         15 . A composition of matter as claimed in  claim 11 , wherein the antiepileptic is lamotrigine. 
     
     
         16 . A composition of matter as claimed in  claim 11 , wherein the antiepileptic is lacosamide. 
     
     
         17 . A composition of matter as claimed in  claim 11 , wherein the antiepileptic is, levetiracetam. 
     
     
         18 . A composition of matter as claimed in  claim 11 , wherein the antiepileptic is retigabine. 
     
     
         19 . A composition of matter as claimed in  claim 1 , wherein the two components (a) and (b) are present in the form of a salt formed from said two components. 
     
     
         20 . A composition of matter as claimed in  claim 1 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound or salt thereof and said antiepileptic are present in a weight ratio such that the composition exerts a synergistic effect upon administration to a patient. 
     
     
         21 . A composition of matter as claimed in  claim 1 , further comprising at least one pharmaceutical carrier or auxiliary agent. 
     
     
         22 . A composition of matter as claimed in  claim 21 , wherein said composition is formed into a dosage form suitable for oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathekal, intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration. 
     
     
         23 . A composition of matter as claimed in  claim 22 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound or said antiepileptic, or both, is present in controlled-release form. 
     
     
         24 . A composition of matter as claimed in  claim 21 , wherein said composition comprises caffeine. 
     
     
         25 . A method of treating or inhibiting pain in a subject in need thereof, said method comprising administering to said subject a pharmacologically effective amount of a composition as claimed in  claim 1 . 
     
     
         26 . A method as claimed in  claim 25 , wherein said pain is selected from the group consisting of inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain. 
     
     
         27 . A method as claimed in  claim 25 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound and said antiepileptic are administered simultaneously either by the same or by different pathways of administration. 
     
     
         28 . A method as claimed in  claim 25 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound and said antiepileptic are administered sequentially either by the same or by different pathways of administration, with the 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound being administered before the antiepileptic. 
     
     
         29 . A method as claimed in  claim 25 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound and said antiepileptic are administered sequentially either by the same or by different pathways of administration, with the 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound being administered after the antiepileptic. 
     
     
         30 . A composition of matter comprising in combination:
 (a) a 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol compound corresponding to formula (I):   
       
         
           
           
               
               
           
         
          or a pharmaceutically acceptable salt thereof, and 
         (b) at least one antiepileptic and/or at least one compound selected from the group consisting of voltage dependent calcium channel blockers, voltage dependent t-type calcium channel blockers, voltage dependent sodium channel blockers, compounds that exhibit enhancement of fast or slow inactivation of voltage dependent sodium channels, KCNQ channel openers, SV2A ligands, modulators of collapsin response mediator protein-2, glutamate release inhibitors, AMPA receptor antagonists, NMDA antagonists, GABA receptor modulators, GABA aminotransferase inhibitors, GABA reuptake inhibitors and carbonic anhydrase inhibitors. 
       
     
     
         31 . A composition of matter as claimed in  claim 30 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound is present in the form of an isolated stereoisomer. 
     
     
         32 . A composition of matter as claimed in  claim 30 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound is present in the form of a mixture of stereoisomers in any mixing ratio. 
     
     
         33 . A composition of matter as claimed in  claim 32 , wherein said mixture is a racemic mixture. 
     
     
         34 . A composition of matter as claimed in  claim 30 , wherein the compound of formula (I) is selected from the group consisting of:
 (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,   (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,   (1R,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,   (1S,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and   mixtures of two or more of the foregoing.   
     
     
         35 . A composition of matter as claimed in  claim 34 , wherein said compound of formula (I) is (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (I′), 
       
         
           
           
               
               
           
         
       
       or an acid addition salt thereof. 
     
     
         36 . A composition of matter as claimed in  claim 30 , wherein the antiepileptic is selected from the group consisting of methylphenobarbital, phenobarbital, primidone, barbexaclone, metharbital, ethotoin, phenyloin, amino(diphenylhydantoin) valeric acid, mephenyloin, fosphenyloin, paramethadione, trimethadione, ethadione, ethosuximide, phensuximide, mesuximide, clonazepam, carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide, tiagabine, sultiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, pheneturide, levetiracetam, brivaracetam, selectracetam, zonisamide, pregabalin, stiripentol, lacosamide, beclamide, mexiletin, retigabin and ralfinamide. 
     
     
         37 . A composition of matter as claimed in  claim 30 , wherein the two components (a) and (b) are present in the form of a salt formed from said two components. 
     
     
         38 . A composition of matter as claimed in  claim 30 , wherein the two components (a) and (b) are present in a weight ratio such that the composition exerts a synergistic effect upon administration to a patient. 
     
     
         39 . A composition of matter as claimed in  claim 30 , further comprising at least one pharmaceutical carrier or auxiliary agent. 
     
     
         40 . A composition of matter as claimed in  claim 22 , wherein component (a) or component (b), or both, is/are present in controlled-release form. 
     
     
         41 . A method of treating or inhibiting pain in a subject in need thereof, said method comprising administering to said subject a pharmacologically effective amount of a composition as claimed in  claim 30 .