NMDA receptor antagonist formulation with reduced neurotoxicity

Abstract

The present invention is directed to pharmaceutical compositions of effective amounts of NMDA receptor antagonists and non-neurotoxic compounds having preservative activity for the administration to a patient in need of effective analgesia and anesthesia. The compositions of the invention advantageously do not cause any significant neurotoxicity. The preferred NMDA receptor antagonist is ketamine. The non-neurotoxic compound is selected from one of the following groups including organic acids, esters thereof, and salts thereof; alcohols, polyols, and phenols; alkyl parabens; cresols; benzalkonium chloride quaternary ammonium salts; chlorhexidine, imidurea, alpha tocopherol, and EDTA. Preferably, the nonneurotoxic compound is benzalkonium chloride, benzyl alcohol or phenol.

What is claimed is:  
     
         1 . A pharmaceutical composition administered to a subject in need thereof comprising an effective amount of a NMDA receptor antagonist and an effective amount of a preservative in a suitable carrier, wherein the composition does not cause any significant neurotoxicity.  
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the preservative is selected from the group consisting of organic acids, esters thereof, and salts thereof.  
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the organic acid, ester thereof, or salt thereof is selected from the group consisting of ascorbic acid, fumaric acid, malic acid, benzoic acid, sorbic acid, phenolic acid, ascorbic acid palmitate, sodium ascorbate, sodium benzoate, sodium propionate, potassium sorbate, and propyl gallate.  
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the preservative is selected from the group consisting of alcohols, polyols, and phenols.  
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the alcohol, polyol, or phenol is selected from the group consisting of benzyl alcohol, isopropyl alcohol, phenylethyl alcohol, phenoxyethanol, chlorobutanol, propylene glycol, glycerol, phenol, butylated hydroxyanisole, and bronopol.  
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the preservative is an alkyl paraben.  
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the alkyl paraben is selected from the group consisting of methylparaben, ethylparaben, propylparaben, and butylparaben.  
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the preservative is a cresol.  
     
     
         9 . The pharmaceutical composition of  8 , wherein the cresol is selected from the group consisting of chlorcresol and cresol.  
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the preservative is selected from the group consisting of benzalkonium chloride, chlorhexidine, imidurea, alpha tocopherol, and EDTA.  
     
     
         11 . The pharmaceutical composition of  claim 1  wherein the NMDA receptor antagonist is ketamine.  
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the dosage range of ketamine for anesthesia is broadly from about 1 mg/kg to about 15 mg/kg per unit dose.  
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein the dosage range of ketamine for anesthesia is preferably from about 1.0 mg/kg to about 4.5 mg/kg per unit dose delivered I.V. and 6.5 mg/kg to about 13 mg/kg via intramuscular injection.  
     
     
         14 . The pharmaceutical composition of  claim 11 , wherein the dosage range of ketamine for analgesia is broadly from about 0.01 mg/kg to about 1 mg/kg per unit dose.  
     
     
         15 . The pharmaceutical composition of  claim 11 , wherein the dosage range of ketamine for analgesia is preferably from about 0.05 mg/kg to about 0.7 mg/kg per unit dose.  
     
     
         16 . The pharmaceutical composition of  claim 11 , wherein the dosage of ketamine is about 10 mg per unit 100 microliter dose.  
     
     
         17 . The pharmaceutical composition of  claim 1  wherein the preservative is benzalkonium chloride.  
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the amount of the benzalkonium chloride is from about 0.001% to about 0.2% per unit dose.  
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the amount of the benzalkonium chloride is from about 0.07% to about 0.14% per unit dose.  
     
     
         20 . The pharmaceutical composition of  claim 17 , wherein the amount of the benzalkonium chloride is about 0.002%.  
     
     
         21 . The pharmaceutical composition of  claim 1  wherein the suitable carrier is an aqueous solution selected from the group consisting of water, saline, bicarbonate, sucrose and any mixture of the above components.  
     
     
         22 . A pharmaceutical composition which comprises an aqueous solution containing about 10% ketamine hydrochloride and about 0.002% benzalkonium chloride.  
     
     
         23 . A pharmaceutical composition which comprises an aqueous solution containing about 10% ketamine hydrochloride and about 0.002% benzyl alcohol.  
     
     
         24 . A pharmaceutical composition which comprises an aqueous solution containing about 10% ketamine hydrochloride and about 0.002% phenol.  
     
     
         25 . A method of inducing analgesia in a subject, which method comprises: administering to the subject a pharmaceutical composition comprising an analgesically effective amount of ketamine and benzalkonium chloride in a suitable carrier.  
     
     
         26 . The method of  claim 25  wherein the mode of administration is parenteral.  
     
     
         27 . The method of  claim 26  wherein the parenteral administration is selected from the group comprising intravenous, intrathecal, intramuscular, and subcutaneous.  
     
     
         28 . The method of  claim 25  wherein the mode of administration is intranasal, oral, transmucosal, transdermal, rectal, or intraocular.  
     
     
         29 . The method of  claim 25 , wherein the composition is administered to a subject suffering from breakthrough episodes of moderate to severe pain.  
     
     
         30 . A method of inducing analgesia in a subject, which method comprises: administering to the subject a pharmaceutical composition comprising an analgesically effective amount of ketamine and benzyl alcohol in a suitable carrier.  
     
     
         31 . A method of inducing analgesia in a subject, which method comprises: administering to the subject a pharmaceutical composition comprising an analgesically effective amount of ketamine and phenol in a suitable carrier.  
     
     
         32 . A method of inducing analgesia in a subject, which method comprises: administering to the subject a pharmaceutical composition comprising an anesthetically effective amount of ketamine and benzalkonium chloride in a suitable carrier.  
     
     
         33 . The method of  claim 32  wherein the mode of administration is parenteral.  
     
     
         34 . The method of  claim 33  wherein the parenteral administration is selected from the group comprising intravenous, intrathecal, intramuscular, and subcutaneous.  
     
     
         35 . The method of  claim 32  wherein the mode of administration is intranasal, oral, transmucosal, transdermal, rectal, or intraocular.  
     
     
         36 . The method of  claim 32 , wherein the composition is administered to a subject suffering from moderate to severe pain.  
     
     
         37 . The method of  claim 32 , wherein the composition is administered to a subject suffering from acute episodic or breakthrough pain.  
     
     
         38 . A method of inducing analgesia in a subject, which method comprises: administering to the subject a pharmaceutical composition comprising an anesthetically effective amount of ketamine and benzyl alcohol in a suitable carrier.  
     
     
         39 . A method of inducing analgesia in a subject, which method comprises: administering to the subject a pharmaceutical composition comprising an anesthetically effective amount of ketamine and phenol in a suitable carrier  
     
     
         40 . The pharmaceutical composition of  claim 1 , wherein the subject is a mammal.  
     
     
         41 . The pharmaceutical composition of  claim 1 , wherein the subject is a human.