Pharmaceutical Composition Of S-Ketamine Hydrochloride

Abstract

The present invention is directed to an aqueous formulation of S-ketamine hydrochloride, preferably for nasal administration, wherein the formulation does not contain an antimicrobial preservative.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising:
 (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride and water;   wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about eq. 120 mg/mL to about eq. 250 mg/mL, based on the total volume of the pharmaceutical composition.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is formulated for nasal administration. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition exhibits a shelf life of at least three months under accelerated storage conditions comprising 40° C. and 75% relative humidity. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about eq. 120 mg/mL to about eq. 175 mg/mL, based on the total volume of the pharmaceutical composition. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about eq. 125 mg/mL to about eq. 180 mg/mL, based on the total volume of the pharmaceutical composition. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about eq. 125 mg/mL to about eq. 150 mg/mL, based on the total volume of the pharmaceutical composition. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about eq. 140 mg/mL to about eq. 160 mg/mL, based on the total volume of the pharmaceutical composition. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration of about eq. 140 mg/mL, based on the total volume of the pharmaceutical composition. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the water content of the pharmaceutical composition is in the range of from 75 to 99.99 wt %, based on the total weight of the pharmaceutical composition. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition
 (i) additionally comprises one or more buffers; or   (ii) has a pH value in the range of from about 3.5 to about 6.5.   
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutical composition comprises the one or more buffers and has a pH value in the range of from about 4.0 to about 6.0. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the one or more buffers is selected from the group consisting of citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, malic acid, lactic acid, furmaric acid, and sodium hydroxide. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the one or more buffers is selected from the group consisting of sodium hydroxide, citric acid, sodium dihydrogen phosphate, and disodium hydrogen phosphate. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the buffer comprises citric acid or sodium hydroxide. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the buffer comprises sodium hydroxide. 
     
     
         16 . The pharmaceutical composition of  claim 14 , wherein the pH of the pharmaceutical composition is in the range of from about 4.0 to about 5.5. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the pH of the pharmaceutical composition is in the range of from about 4.5 to about 5.0. 
     
     
         18 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition further comprises a preservative. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the preservative is selected from the group consisting of benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorbutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid, and potassium sorbate. 
     
     
         20 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition does not contain a preservative. 
     
     
         21 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition further comprises a penetrating agent. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the penetrating agent is selected from the group consisting of tetradecyl maltoside, sodium glycocholate, tauroursodeoxycholic acid (TUDCA), lecithines, chitosan, benzalkonium chloride, sodium dodecyl sulfate, sodium docusate, polysorbates, laureth-9, oxtoxynol, sodium deoxycholate, and polyarginine. 
     
     
         23 . The pharmaceutical composition of  claim 12 , wherein the pharmaceutical composition further comprises one or more additional excipients selected from the group consisting of a wetting agent, a surfactant, a solubilizing agent, a thickening agent, an isotonizing agent, a suspending agent, a colorant agent, and an antioxidant. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the additional excipient is an antioxidant selected from the group consisting of a sulfite; ascorbic acid; an ascorbate; fumaric acid; ethylene diamine tetraacetic acid (EDTA) or its sodium or calcium salt; tocopherol; a gallate; vitamin E; and mixtures thereof. 
     
     
         25 . The pharmaceutical composition of  claim 23 , wherein the additional excipient is a solubilizing agent selected from the group consisting of polyethylene glycol, glycerin, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof. 
     
     
         26 . The pharmaceutical composition of  claim 23 , wherein the additional excipient is an isotonizing agent selected from the group consisting of sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and mixtures thereof. 
     
     
         27 . The pharmaceutical composition of  claim 23 , wherein the additional excipient is a suspending agent selected from the group consisting of hydroxypropyl methylcellulose, sodium carmellose, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salts, gellan gum, poloxamer, polyvinyl pyrrolidone, xanthan gum, and mixtures thereof. 
     
     
         28 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition further comprises an emulsifying agent selected from the group consisting of gelatin, cholesterol, acacia, tragacanth, pectin, methyl cellulose, carbomer, and mixtures thereof. 
     
     
         29 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition further comprises a chelating agent. 
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the chelating agent is EDTA, or its sodium or calcium salt. 
     
     
         31 . The pharmaceutical composition of  claim 1 , wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about eq. 140 mg/mL to about eq. 160 mg/mL, based on the total volume of the pharmaceutical composition, and the pharmaceutical composition further comprises citric acid, EDTA, and sodium hydroxide, wherein the pH of the pharmaceutical composition is in the range of from about 4.0 to about 5.5. 
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration of about eq. 140 mg/mL. 
     
     
         33 . The pharmaceutical composition of  claim 31 , wherein the pH of the pharmaceutical composition is about 4.5. 
     
     
         34 . The pharmaceutical composition of  claim 32 , wherein the pH of the pharmaceutical composition is about 4.5. 
     
     
         35 . A pharmaceutical dosage form comprising the pharmaceutical composition of  claim 1 . 
     
     
         36 . A pharmaceutical dosage form comprising the pharmaceutical composition of  claim 31 . 
     
     
         37 . A pharmaceutical dosage form comprising the pharmaceutical composition of  claim 34 . 
     
     
         38 . A pharmaceutical composition comprising:
 (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride and water; wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about 126 mg/mL to about 250 mg/mL, based on the total volume of the pharmaceutical composition.   
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the pharmaceutical composition is formulated for nasal administration. 
     
     
         40 . The pharmaceutical composition of  claim 38 , wherein the pharmaceutical composition exhibits a shelf life of at least three months under accelerated storage conditions comprising 40° C. and 75% relative humidity. 
     
     
         41 . The pharmaceutical composition of  claim 38 , wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about 126 mg/mL to about 162 mg/mL, based on the total volume of the pharmaceutical composition. 
     
     
         42 . The pharmaceutical composition of  claim 38 , wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about 150 mg/mL to about 200 mg/mL, based on the total volume of the pharmaceutical composition. 
     
     
         43 . The pharmaceutical composition of  claim 38 , wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about 150 mg/mL to about 175 mg/mL, based on the total volume of the pharmaceutical composition. 
     
     
         44 . The pharmaceutical composition of  claim 38 , wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about 160 mg/mL to about 163 mg/mL, based on the total volume of the pharmaceutical composition. 
     
     
         45 . The pharmaceutical composition of  claim 38 , wherein the water content of the pharmaceutical composition is in the range of from 75 to 99.99 wt %, based on the total weight of the pharmaceutical composition. 
     
     
         46 . The pharmaceutical composition of  claim 38 , wherein the pharmaceutical composition
 (i) additionally comprises one or more buffers; or   (ii) has a pH value in the range of from about 3.5 to about 6.5.   
     
     
         47 . The pharmaceutical composition of  claim 46 , wherein the pharmaceutical composition comprises the one or more buffers and has a pH value in the range of from about 4.0 to about 6.0. 
     
     
         48 . The pharmaceutical composition of  claim 47 , wherein the one or more buffers is selected from the group consisting of citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, malic acid, lactic acid, furmaric acid, and sodium hydroxide. 
     
     
         49 . The pharmaceutical composition of  claim 48 , wherein the one or more buffers is selected from the group consisting of sodium hydroxide, citric acid, sodium dihydrogen phosphate, and disodium hydrogen phosphate. 
     
     
         50 . The pharmaceutical composition of  claim 49 , wherein the buffer comprises citric acid or sodium hydroxide. 
     
     
         51 . The pharmaceutical composition of  claim 50 , wherein the buffer comprises sodium hydroxide. 
     
     
         52 . The pharmaceutical composition of  claim 50 , wherein the pH of the pharmaceutical composition is in the range of from about 4.0 to about 5.5. 
     
     
         53 . The pharmaceutical composition of  claim 50 , wherein the pH of the pharmaceutical composition is in the range of from about 4.5 to about 5.0. 
     
     
         54 . The pharmaceutical composition of  claim 38 , wherein the pharmaceutical composition further comprises a preservative. 
     
     
         55 . The pharmaceutical composition of  claim 54 , wherein the preservative is selected from the group consisting of benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorbutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid, and potassium sorbate. 
     
     
         56 . The pharmaceutical composition of  claim 38 , wherein the pharmaceutical composition does not contain a preservative. 
     
     
         57 . The pharmaceutical composition of  claim 38 , wherein the pharmaceutical composition further comprises a penetrating agent. 
     
     
         58 . The pharmaceutical composition of  claim 57 , wherein the penetrating agent is selected from the group consisting of tetradecyl maltoside, sodium glycocholate, tauroursodeoxycholic acid (TUDCA), lecithines, chitosan, benzalkonium chloride, sodium dodecyl sulfate, sodium docusate, polysorbates, laureth-9, oxtoxynol, sodium deoxycholate, and polyarginine. 
     
     
         59 . The pharmaceutical composition of  claim 48 , wherein the pharmaceutical composition further comprises one or more additional excipients selected from the group consisting of a wetting agent, a surfactant, a solubilizing agent, a thickening agent, an isotonizing agent, a suspending agent, a colorant agent, and an antioxidant. 
     
     
         60 . The pharmaceutical composition of  claim 59 , wherein the additional excipient is an antioxidant selected from the group consisting of a sulfite; ascorbic acid; an ascorbate; fumaric acid; ethylene diamine tetraacetic acid (EDTA) or its sodium or calcium salt; tocopherol; a gallate; vitamin E; and mixtures thereof. 
     
     
         61 . The pharmaceutical composition of  claim 59 , wherein the additional excipient is a solubilizing agent selected from the group consisting of polyethylene glycol, glycerin, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof. 
     
     
         62 . The pharmaceutical composition of  claim 59 , wherein the additional excipient is an isotonizing agent selected from the group consisting of sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and mixtures thereof. 
     
     
         63 . The pharmaceutical composition of  claim 59 , wherein the additional excipient is a suspending agent selected from the group consisting of hydroxypropyl methylcellulose, sodium carmellose, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salts, gellan gum, poloxamer, polyvinyl pyrrolidone, xanthan gum, and mixtures thereof. 
     
     
         64 . The pharmaceutical composition of  claim 38 , wherein the pharmaceutical composition further comprises an emulsifying agent selected from the group consisting of gelatin, cholesterol, acacia, tragacanth, pectin, methyl cellulose, carbomer, and mixtures thereof. 
     
     
         65 . The pharmaceutical composition of  claim 38 , wherein the pharmaceutical composition further comprises a chelating agent. 
     
     
         66 . The pharmaceutical composition of  claim 65 , wherein the chelating agent is EDTA, or its sodium or calcium salt. 
     
     
         67 . The pharmaceutical composition of  claim 38 , wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about 160 mg/mL to about 163 mg/mL, based on the total volume of the pharmaceutical composition, and the pharmaceutical composition further comprises citric acid, EDTA, and sodium hydroxide, wherein the pH of the pharmaceutical composition is in the range of from about 4.0 to about 5.5. 
     
     
         68 . The pharmaceutical composition of  claim 67 , wherein the pH of the pharmaceutical composition is about 4.5. 
     
     
         69 . A pharmaceutical dosage form comprising the pharmaceutical composition of  claim 38 . 
     
     
         70 . A pharmaceutical dosage form comprising the pharmaceutical composition of  claim 67 . 
     
     
         71 . A pharmaceutical dosage form comprising the pharmaceutical composition of  claim 68 .