Pharmaceutical Combination

Abstract

A pharmaceutical combination comprising as components (a) at least one 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound, and (b) at least one NMDA-antagonist, a pharmaceutical formulation and a dosage form comprising such a combination, and a method of treating pain, e.g. inflammatory pain or neuropathic pain, in which components (a) and (b) are administered simultaneously or sequentially to a mammal, with component (a) being administered either before or after component (b), and with components (a) or (b) being administered to the mammal either via the same pathway of administration or via different pathways of administration.

1 . A pharmaceutical combination comprising as components:
 (a) at least one 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound of formula (I),   
       
         
           
           
               
               
           
         
          or a pharmaceutically acceptable acid addition salt thereof, and 
         (b) at least one NMDA-antagonist. 
       
     
     
         2 . The combination according to  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,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 thereof in any mixing ratio.   
     
     
         3 . The combination according to  claim 2 , 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, and   mixtures thereof in any mixing ratio.   
     
     
         4 . The combination according to  claim 3 , wherein the 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. 
     
     
         5 . The combination according to  claim 4 , wherein the compound of formula (I′) is the hydrochloride acid addition salt of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol. 
     
     
         6 . The combination according to  claim 1 , wherein the NMDA-antagonist is selected from the group consisting of norvaline (AP5), D-norvaline (D-AP5), 4-(3-phosphono-propyl)-piperazine-2-carboxylic acid (CPP), D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D-CPPene), cis-4-(phosphonomethyl)-2-piperidine carboxylic acid (Selfotel, CGS 19755), SDZ-220581, PD-134705, LY-274614, WAY-126090, kynurenic acid, 7-chloro-kynurenic acid, 7-chloro-thiokynurenic acid, 5,7-dichloro-knynurenic acid, 4-chlorokynurenine, 3-hydroxy-kynurenine, L-689,560, L-701,324, licostinel (ACEA-1021), CGP-68,730A, MDL-105,519, gavestinel (GV-150,526), GV-196,771A, ZD-9,379, MRZ-2/576, (+)-HA-966, dextromethorphan, dextrophan, BIII-277CL, dextropropoxyphene, ketobemidone, dextromethadone, D-morphine, amantadine, memantine, MRZ-2/579, ifenprodil, eliprodil, PD-196,860, nitroprusside, D-cycloserine, 1-aminocyclopropane-carboxylic acid, dizocilpine (MK 801), phencyclidine (PCP), ketamine, (R,S)-ketamine, (R)-ketamine, (S)-ketamine, remacemide, FPL-12,495, AR-R-15,896, methadone, sulfazocine, AN19/AVex-144, AN2/AVex-73, Besonprodil, CGX-1007, EAB-318, Felbamate and NPS-1407. 
     
     
         7 . The combination according to  claim 6 , wherein the NMDA-antagonist is selected from the group consisting of (R,S)-ketamine, (S)-ketamine and memantine. 
     
     
         8 . The combination according to  claim 1 , wherein components (a) and (b) are present in such a weight ratio that the composition will exert a synergistic effect upon administration to a patient. 
     
     
         9 . A pharmaceutical composition comprising a combination according to  claim 1  and at least one pharmaceutically acceptable auxiliary agent. 
     
     
         10 . A pharmaceutical dosage form comprising a combination according to  claim 1  and at least one pharmaceutically acceptable auxiliary agent. 
     
     
         11 . A dosage form according to  claim 10 , wherein said dosage form is suitable for oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathekal, intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration. 
     
     
         12 . A dosage form according to  claim 10 , wherein at least one of the components (a) and (b) is present in controlled-release form. 
     
     
         13 . A method of treating pain in a mammal in need thereof, said method comprising administering to said mammal a pharmacologically effective amount of a combination according to  claim 1 . 
     
     
         14 . The method according to  claim 13 , wherein the pain is selected from the group consisting of inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain. 
     
     
         15 . The method according to  claim 13 , wherein the pain is inflammatory pain. 
     
     
         16 . The method according to  claim 13 , wherein component (a) and component (b) of the combination are administered simultaneously to the mammal. 
     
     
         17 . The method according to  claim 13 , wherein component (a) and component (b) of the combination are administered or sequentially to the mammal in either order. 
     
     
         18 . The method according to  claim 13 , wherein component (a) and component (b) of the combination are administered via different pathways of administration. 
     
     
         19 . The method according to  claim 13 , wherein component (a) and component (b) of the combination are administered via the same pathway of administration.