Topical compositions and methods for treating pain

Abstract

Topical compositions and methods for treating pain. The invention provides oil-in-water emulsions comprising an antidepressant; an NMDA-receptor antagonists; a lipophilic component; water; and a surfactant. The compositions induce a local-anesthetic effect when topically administered to intact skin thereby treating or preventing pain, for example, neuropathic pain.

What is claimed is:  
     
         1 . A emulsion comprising: 
 (a) an antidepressant or a pharmaceutically acceptable salt thereof;    (b) an NMDA receptor antagonists or a pharmaceutically acceptable salt thereof;    (c) a lipophilic component;    (d) water; and    (e) a surfactant, wherein the emulsion is an oil in water emulsion.    
     
     
         2 . The emulsion of  claim 1 , wherein the mean oil droplet size is within the range of about 0.01 microns to about 100 microns.  
     
     
         3 . The emulsion of  claim 1 , wherein the mean oil droplet size is within the range of about 0.1 microns to about 10 microns.  
     
     
         4 . The emulsion of  claim 1 , wherein the antidepressant is a norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, a monoamine oxidase inhibitor, a serotonin and noradrenaline reuptake inhibitor, a corticotropin releasing factor antagonist, an α adrenoreceptor antagonist, an NK1 receptor antagonist, a 5 HT 1A  receptor agonist, a 5 HT 1A  receptor antagonist, a 5 HT 1A  receptor partial agonist, an atypical antidepressant, or an other antidepressant or a pharmaceutically acceptable salt thereof.  
     
     
         5 . The emulsion of  claim 4 , wherein the antidepressant is a norepinephrin reuptake inhibitor or a pharmaceutically salt thereof.  
     
     
         6 . The emulsion of  claim 1 , wherein the antidepressant is a tricyclic depressant or a pharmaceutically acceptable salt thereof.  
     
     
         7 . The emulsion of  claim 6 , wherein the tricyclic antidepressant is amitriptyline, desmethylamitriptyline, clomipramine, doxepin, imipramine, imipramine N oxide, trimipramine; adinazolam, amiltriptylinoxide, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, amineptine, butriptyline, demexiptiline, dibenzepin, dimetacrine, dothiepin, fluacizine, iprindole, lofepramine, melitracen, metapramine, norclolipramine, noxiptilin, opipramol, perlapine, pizotyline, propizepine, quinupramine, reboxetine, or tianeptine or a pharmaceutically acceptable salt thereof.  
     
     
         8 . The emulsion of  claim 1 , wherein the antidepressant is amitriptyline or a pharmaceutically acceptable salt thereof.  
     
     
         9 . The emulsion of  claim 1 , wherein an amount of the antidepressant is within the range of about 0. 1% by weight to about 10% by weight of a total weight of the emulsion.  
     
     
         10 . The emulsion of  claim 1 , wherein the NMDA receptor antagonist is one that binds to the NMDA receptor at the glycine binding site, the glutamate binding site, the PCP binding site, the polyamine binding site, or the zinc binding site or a pharmaceutically acceptable salt thereof.  
     
     
         11 . The emulsion of  claim 10 , wherein the NMDA receptor antagonist is one that binds to the NMDA receptor at the PCP binding site or a pharmaceutically acceptable salt thereof.  
     
     
         12 . The emulsion of  claim 1 , wherein the NMDA receptor antagonist is ketamine, phencyclidine, dextromethorphan, dextrorphan, dexoxadrol, dizocilpine, remacemide, thienylcyclohexylpiperidine, N-allylnormetazocine, cyclazocine, etoxadrol, (1,2,3,4,9,9a-hexahydro-fluoren-4a-yl)-methyl-amine, (1,3,4,9,10,10a-hexahydro-2H-phenanthren-4a-yl)-methyl-amine, PD 138558, tiletamine, kynurenic acid, 7-chloro-kynurenic acid, memantine, 6-cyano-7-nitroquinoxaline-2,3-dione, or 6,7-dinitro-quinoxaline-2,3-dione or a pharmaceutically acceptable salt thereof.  
     
     
         13 . The emulsion of  claim 1 , wherein the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt thereof.  
     
     
         14 . The emulsion of  claim 1 , wherein an amount of the NMDA receptor antagonist is within the range of about 0.1% by weight to about 10% by weight of a total weight of the emulsion.  
     
     
         15 . The emulsion of  claim 1 , wherein the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt thereof and the antidepressant is amitriptyline or a pharmaceutically acceptable salt thereof.  
     
     
         16 . The emulsion of  claim 1 , wherein the lipophilic component comprises petrolatum.  
     
     
         17 . The emulsion of  claim 1 , wherein the lipophilic component comprises a stiffening agent.  
     
     
         18 . The emulsion of  claim 17 , wherein the stiffening agent is cetyl alcohol.  
     
     
         19 . The emulsion of  claim 1 , further comprising a lipophilic Intradermal penetration enhancer.  
     
     
         20 . The emulsion of  claim 19 , wherein the lipophilic intradermal penetration enhancer is isopropyl myristate, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, isopropyl linoleate, isopropyl myristate/fatty acid monoglyceride combination, isopropyl myristate/ethanol/L-lactic acid combination, isopropyl palmitate, methyl acetate, methyl caprate, or methyl laurate.  
     
     
         21 . The emulsion of  claim 1  further comprising a humectant or an anti-foaming agent.  
     
     
         22 . A patch comprising: 
 (a) an antidepressant or a pharmaceutically acceptable salt thereof;    (b) an NMDA receptor antagonists or a pharmaceutically acceptable salt thereof;    (c) a lipophilic component;    (d) water; and    (e) a surfactant, wherein the emulsion is an oil in water emulsion.    
     
     
         23 . The patch of  claim 22 , wherein the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt thereof and the antidepressant is amitriptyline or a pharmaceutically acceptable salt thereof.  
     
     
         24 . A method of treating pain in a mammal comprising topically administering to the skin of a mammal in need thereof an emulsion comprising: 
 (a) a therapeutically effective amount of an antidepressant or a pharmaceutically acceptable salt thereof;    (b) a therapeutically effective amount of an NMDA receptor antagonists or a pharmaceutically acceptable salt thereof;    (c) a lipophilic component;    (d) water; and    (e) a surfactant,    wherein the emulsion is an oil in water emulsion.    
     
     
         25 . The method of  claim 24 , wherein the emulsion has a mean oil droplet size within the range of about 0.01 microns to about 100 microns.  
     
     
         26 . The method of  claim 24 , wherein the emulsion has a mean oil droplet size within the range of about 0.1 microns to about 10 microns.  
     
     
         27 . The method of  claim 24 , wherein the antidepressant is a norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, a monoamine oxidase inhibitor, a serotonin and noradrenaline reuptake inhibitor, a corticotropin releasing factor antagonist, an α adrenoreceptor antagonist, an NK1 receptor antagonist, a 5 HT 1A  receptor agonist, a 5 HT 1A  receptor antagonist, a 5 HT 1A  receptor partial agonist, an atypical antidepressant, or an other antidepressant or a pharmaceutically acceptable salt thereof.  
     
     
         28 . The method of  claim 27 , wherein the antidepressant is a norepinephrin reuptake inhibitor or a pharmaceutically salt thereof.  
     
     
         29 . The method of  claim 24 , wherein the antidepressant is a tricyclic depressant or a pharmaceutically acceptable salt thereof.  
     
     
         30 . The method of  claim 29 , wherein the tricyclic antidepressant is amitriptyline, desmethylamitriptyline, clomipramine, doxepin, imipramine, imipramine N-oxide, trimipramine; adinazolam, amiltriptylinoxide, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, amineptine, butriptyline, demexiptiline, dibenzepin, dimetacrine, dothiepin, fluacizine, iprindole, lofepramine, melitracen, metapramine, norclolipramine, noxiptilin, opipramol, perlapine, pizotyline, propizepine, quinupramine, reboxetine, or tianeptine or a pharmaceutically acceptable salt thereof.  
     
     
         31 . The method of  claim 24 , wherein the antidepressant is amitriptyline or a pharmaceutically acceptable salt thereof.  
     
     
         32 . The method of  claim 24 , wherein an amount of the antidepressant is within the range of about 0.1% by weight to about 10% by weight of a total weight of the emulsion.  
     
     
         33 . The method of  claim 24 , wherein the NMDA receptor antagonist is one that binds to the NMDA receptor at the glycine binding site, the glutamate binding site, the PCP binding site, the polyamine binding site, or the zinc binding site or a pharmaceutically acceptable salt thereof.  
     
     
         34 . The method of  claim 33 , wherein the NMDA receptor antagonist is one that binds to the NMDA receptor at the PCP binding site or a pharmaceutically acceptable salt thereof.  
     
     
         35 . The method of  claim 24 , wherein the NMDA receptor antagonist is ketamine, phencyclidine, dextromethorphan, dextrorphan, dexoxadrol, dizocilpine, remacemide, thienylcyclohexylpiperidine, N-allylnormetazocine, cyclazocine, etoxadrol, (1,2,3,4,9,9a -hexahydro-fluoren-4a-yl)-methyl-amine, (1,3,4,9,10,10a-hexahydro-2H-phenanthren-4a-yl)-methyl-amine, PD 138558, tiletamine, kynurenic acid, 7-chloro-kynurenic acid, memantine, 20 6-cyano-7-nitroquinoxaline-2,3-dione, or 6,7-dinitro-quinoxaline-2,3-dione or a pharmaceutically acceptable salt thereof.  
     
     
         36 . The method of  claim 24 , wherein the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt thereof.  
     
     
         37 . The method of  claim 24 , wherein an amount of the NMDA receptor antagonist is within the range of about 0.1% by weight to about 10% by weight of a total weight of the emulsion.  
     
     
         38 . The method of  claim 24 , wherein the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt thereof and the antidepressant is amitriptyline or a pharmaceutically acceptable salt thereof.  
     
     
         39 . The method of  claim 24 , wherein the emulsion further comprises a lipophilic intradermal penetration enhancer.  
     
     
         40 . The method of  claim 39 , wherein the lipophilic Intradermal penetration enhancer is isopropyl myristate, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, isopropyl linoleate, isopropyl myristate/fatty acid monoglyceride combination, isopropyl myristate/ethanol/L-lactic acid combination, isopropyl palmitate, methyl acetate, methyl caprate, or methyl laurate.  
     
     
         41 . A method of inducing local anesthesia in a mammal comprising topically administering to the skin of a mammal in need thereof an emulsion comprising: 
 (a) a therapeutically effective amount of an antidepressant or a pharmaceutically acceptable salt thereof;    (b) a therapeutically effective amount of an NMDA receptor antagonists or a pharmaceutically acceptable salt thereof;    (c) a lipophilic component;    (d) water; and    (e) a surfactant,    wherein the emulsion is an oil in water emulsion.    
     
     
         42 . The method of  claim 41 , wherein the emulsion has a mean oil droplet size within the range of about 0.01 microns to about 100 microns.  
     
     
         43 . The method of  claim 41 , wherein the emulsion has a mean oil droplet size within the range of about 0.1 microns to about 10 microns.  
     
     
         44 . The method of  claim 41 , wherein the antidepressant is a norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, a monoamine oxidase inhibitor, a serotonin and noradrenaline reuptake inhibitor, a corticotropin releasing factor antagonist, an α adrenoreceptor antagonist, an NK1 receptor antagonist, a 5 HT 1A  receptor agonist, a 5 HT 1A  receptor antagonist, a 5 HT 1A  receptor partial agonist, an atypical antidepressant, or an other antidepressant or a pharmaceutically acceptable salt thereof.  
     
     
         45 . The method of  claim 44 , wherein the antidepressant is a norepinephrin reuptake inhibitor or a pharmaceutically salt thereof.  
     
     
         46 . The method of  claim 41 , wherein the antidepressant is a tricyclic depressant or a pharmaceutically acceptable salt thereof.  
     
     
         47 . The method of  claim 46 , wherein the tricyclic antidepressant is amitriptyline, desmethylamitriptyline, clomipramine, doxepin, imipramine, imipramine N-oxide, trimipramine; adinazolam, amiltriptylinoxide, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, amineptine, butriptyline, demexiptiline, dibenzepin, dimetacrine, dothiepin, fluacizine, iprindole, lofepramine, melitracen, metapramine, norclolipramine, noxiptilin, opipramol, perlapine, pizotyline, propizepine, quinupramine, reboxetine, or tianeptine or a pharmaceutically acceptable salt thereof.  
     
     
         48 . The method of  claim 41 , wherein the antidepressant is amitriptyline or a pharmaceutically acceptable salt thereof.  
     
     
         49 . The method of  claim 41 , wherein an amount of the antidepressant is within the range of about 0.1% by weight to about 10% by weight of a total weight of the emulsion.  
     
     
         50 . The method of  claim 41 , wherein the NMDA receptor antagonist is one that binds to the NMDA receptor at the glycine binding site, the glutamate binding site, the PCP binding site, the polyamine binding site, or the zinc binding site or a pharmaceutically acceptable salt thereof.  
     
     
         51 . The method of  claim 50 , wherein the NMDA receptor antagonist is one that binds to the NMDA receptor at the PCP binding site or a pharmaceutically acceptable salt thereof.  
     
     
         52 . The method of  claim 41 , wherein the NMDA receptor antagonist is ketamine, phencyclidine, dextromethorphan, dextrorphan, dexoxadrol, dizocilpine, remacemide, thienylcyclohexylpiperidine, N-allylnormetazocine, cyclazocine, etoxadrol, (1,2,3,4,9,9a hexahydro-fluoren-4a-yl)-methyl-amine, (1,3,4,9,10,10a-hexahydro-2H-phenanthren-4a-yl)methyl-amine, PD 138558, tiletamine, kynurenic acid, 7-chloro-kynurenic acid, memantine, 6-cyano-7-nitroquinoxaline-2,3-dione, or 6,7-dinitro-quinoxaline-2,3-dione or a pharmaceutically acceptable salt thereof.  
     
     
         53 . The method of  claim 41 , wherein the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt thereof.  
     
     
         54 . The method of  claim 41 , wherein an amount of the NMDA receptor antagonist is within the range of about 0.1% by weight to about 10% by weight of a total weight of the emulsion.  
     
     
         55 . The method of  claim 41 , wherein the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt thereof and the antidepressant is amitriptyline or a pharmaceutically acceptable salt thereof.  
     
     
         56 . The method of  claim 41 , wherein the emulsion further comprises a lipophilic intradermal penetration enhancer.  
     
     
         57 . The method of  claim 56 , wherein the lipophilic intradermal penetration enhancer is isopropyl myristate, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, isopropyl linoleate, isopropyl myristate/fatty acid monoglyceride combination, isopropyl myristate/ethanol/L-lactic acid combination, isopropyl palmitate, methyl acetate, methyl caprate, or methyl laurate.