Nmda receptor antagonist formulation with reduced neurotoxicity

Abstract

The present invention is directed to pharmaceutical compositions of effective amounts of NMDA receptor antagonists and preservative 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 preferred preservative is benzalkonium chloride.

1 - 20 . (canceled) 
     
     
         21 . A pharmaceutical composition consisting of:
 about 10% ketamine hydrochloride, about 0.002% benzalkonium chloride, and a carrier selected from the group consisting of saline, aqueous sodium bicarbonate, and water;   wherein the formulation is adapted for once daily administration;   wherein the composition does not cause any significant neurotoxicity, and   wherein the level of neurotoxicity is comparable to sterile water when administered.   
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the composition contains 10% ketamine hydrochloride. 
     
     
         23 . The pharmaceutical composition of  claim 21 , wherein the composition contains 0.002% benzalkonium chloride. 
     
     
         24 . The pharmaceutical composition of  claim 21 , wherein the carrier is saline. 
     
     
         25 . The pharmaceutical composition of  claim 21 , wherein the carrier is aqueous sodium bicarbonate. 
     
     
         26 . The pharmaceutical composition of  claim 21 , wherein the carrier is water. 
     
     
         27 . A method of treating breakthrough pain, comprising administering a pharmaceutical composition consisting of a therapeutically effective amount of ketamine hydrochloride, about 0.002% benzalkonium chloride, and a carrier selected from the group consisting of saline, aqueous sodium bicarbonate, and water, to a subject;
 wherein the subject has been diagnosed with chronic malignant pain.   
     
     
         28 . The method of  claim 27 , wherein the subject has been diagnosed with cancer. 
     
     
         29 . The method of  claim 27 , wherein the pain intensity prior to administration of the pharmaceutical composition is at least 5 points on the Numeric Pain Intensity Scale (NPIS). 
     
     
         30 . The method of  claim 29 , wherein the pain intensity is reduced by 2-3 points at about 5 minutes to about 10 minutes after administration of the pharmaceutical composition. 
     
     
         31 . The method of  claim 29 , wherein the pain intensity is reduced by 3-4 points at about 5 minutes to about 10 minutes after administration of the pharmaceutical composition. 
     
     
         32 . The method of  claim 27 , wherein the therapeutically effective amount of ketamine hydrochloride is about 10% ketamine hydrochloride. 
     
     
         33 . The method of  claim 27 , wherein the composition contains 0.002% benzalkonium chloride. 
     
     
         34 . The method of  claim 27 , wherein the carrier is saline. 
     
     
         35 . The method of  claim 27 , wherein the carrier is aqueous sodium bicarbonate. 
     
     
         36 . The method of  claim 27 , wherein the carrier is water. 
     
     
         37 . A method of delivering ketamine through a nasal spray, comprising: administering to a nostril of a subject a number of sprays of a pharmaceutical composition; wherein the pharmaceutical composition consists of a therapeutically effective amount of ketamine hydrochloride, about 0.002% benzalkonium chloride, and a carrier selected from the group consisting of saline, aqueous sodium bicarbonate, and water;
 wherein the composition does not cause any significant neurotoxicity;   wherein the composition has a level of neurotoxicity is comparable to sterile water when administered.   
     
     
         38 . The method of  claim 27 , wherein administering to the nostril of the patient a number of sprays of a pharmaceutical composition comprises administering the ketamine hydrochloride at a dose of 0.01 milligrams per kilogram of body weight (mg/kg) to 1 mg/kg. 
     
     
         39 . The method of  claim 37 , wherein the dose is from 0.05 mg/kg to 0.7 mg/kg ketamine hydrochloride. 
     
     
         40 . The method of  claim 37 , wherein the therapeutically effective amount of ketamine hydrochloride is about 10% ketamine hydrochloride.