Intranasal naloxone compositions and methods of making and using same

Abstract

Disclosed herein are compositions containing an opioid antagonist such as naloxone and one or more pharmaceutically acceptable excipients. The compositions may be used for intranasal delivery of Naloxone for the treatment of, for example, opioid overdose in an individual in need thereof. Also disclosed are methods of making compositions containing Naloxone, and devices for nasal delivery of naloxone compositions.

What is claimed is: 
     
         1 . A method for treating an opioid overdose in an individual in need thereof, the method comprising spraying about 100 μL of an aqueous solution into a nostril of the individual, wherein the aqueous solution comprises:
 about 15 mg/mL to about 30 mg/mL of naloxone or a pharmaceutically acceptable salt thereof, and 
 (ii) about 5 mM and about 15 mM of ethylene diamine tetraacetic acid or a pharmaceutically acceptable salt thereof, 
 wherein the aqueous solution is capable of remaining substantially free of a naloxone related substance for at least 6 months when stored in a sealed package, and wherein the naloxone related substance comprises 10-α-hydroxynaloxone, oxymorphone, noroxymorphone, 10-β-hydroxynaloxone, 7,8-didehydronaloxone, 2,2′-bisnaloxone, 3-O-allynlnaloxone, or a combination of two or more thereof. 
 
     
     
         2 . The method of  claim 1 , wherein the aqueous solution comprises about 0.1 wt % or less of the naloxone related substance. 
     
     
         3 . The method of  claim 1 , wherein the naloxone related substance is 2,2′-bisnaloxone. 
     
     
         4 . The method of  claim 1 , wherein the naloxone related substance comprises 10-α-hydroxynaloxone, oxymorphone, noroxymorphone, 10-β-hydroxynaloxone, 7,8-didehydronaloxone, 2,2′-bisnaloxone, and 3-O-allynlnaloxone. 
     
     
         5 . The method of  claim 1 , comprising spraying the aqueous solution into the nostril of the individual via a ready-to-use device. 
     
     
         6 . The method of  claim 1 , comprising spraying the aqueous solution into the nostril of the individual via a primeless device. 
     
     
         7 . The method of  claim 1 , wherein the aqueous solution further comprises about 5 mM to about 50 mM of a buffer. 
     
     
         8 . The method of  claim 1 , wherein the aqueous solution further comprises sodium chloride in an amount sufficient to achieve an osmolality of from about 350 mOsm to about 450 mOsm. 
     
     
         9 . The method of  claim 1 , wherein the aqueous solution further comprises an amount of hydrochloric acid sufficient to achieve a pH from about 3 to about 5.5. 
     
     
         10 . The method of  claim 1 , wherein the aqueous solution further comprises: (i) about 0.1 to about 1.0 wt % benzyl alcohol; (ii) about 5 to about 50 mM citric acid, or (iii) about 0.1 to about 1.0 wt % benzyl alcohol and about 5 to about 50 mM citric acid. 
     
     
         11 . The method of  claim 1 , wherein the aqueous solution further comprises about 0.1 wt % hypromellose, about 5 wt % sorbitol, and from about 0.1 wt % to about 2 wt % benzyl alcohol. 
     
     
         12 . The method of  claim 1 , wherein the aqueous solution further comprises hypromellose, sorbitol, polyethylene glycol 400, ascorbic acid, glycerine, propylene glycol, benzalkonium chloride, polysorbate 20, or a combination of two or more thereof. 
     
     
         13 . The method of  claim 1 , wherein the aqueous solution does not comprise an antimicrobial agent. 
     
     
         14 . The method of  claim 1 , wherein the aqueous solution is substantially free of methylparaben, ethylparaben, propylparaben, butylparaben, heptylparaben, isobutyparaben, isopropylparaben, benzylparaben, a sodium salts of any one of the foregoing, and or a combination of two or more thereof. 
     
     
         15 . The method of  claim 1 , wherein the aqueous solution is substantially free of dissolved oxygen. 
     
     
         16 . The method of  claim 1 , wherein the aqueous solution is capable of remaining substantially free of a naloxone related substance when stored in a sealed package for at least 6 months at about 25° C. and about 60% humidity. 
     
     
         17 . The method of  claim 16 , wherein the aqueous solution is capable of remaining substantially free of a naloxone related substance when stored in a sealed package for at least 12 months. 
     
     
         18 . The method of  claim 17 , wherein the aqueous solution is capable of remaining substantially free of a naloxone related substance when stored in a sealed package for at least 18 months. 
     
     
         19 . The method of  claim 18 , wherein the aqueous solution is capable of remaining substantially free of a naloxone related substance when stored in a sealed package for at least 24 months. 
     
     
         20 . The method of  claim 1 , wherein the aqueous solution is capable of remaining substantially free of a naloxone related substance when stored in a sealed package for at least 6 months at about 40° C. and about 75% humidity. 
     
     
         21 . The method of  claim 20 , wherein the aqueous solution is capable of remaining substantially free of a naloxone related substance when stored in a sealed package for at least 12 months. 
     
     
         22 . The method of  claim 21 , wherein the aqueous solution is capable of remaining substantially free of a naloxone related substance when stored in a sealed package for at least 18 months. 
     
     
         23 . The method of  claim 22 , wherein the aqueous solution is capable of remaining substantially free of a naloxone related substance when stored in a sealed package for at least 24 months. 
     
     
         24 . The method of  claim 1 , comprising (a) storing the aqueous solution for at least 6 months, and then (b) spraying the aqueous solution into the nostril of the individual. 
     
     
         25 . The method of  claim 1 , wherein the method provides a naloxone T max  from about 5 minutes to about 30 minutes after spraying into the nostril of the individual. 
     
     
         26 . The method of  claim 1 , wherein the method provides a naloxone peak plasma concentration (C max ) from about 1 ng/ml to about 4 ng/ml. 
     
     
         27 . The method of  claim 1 , wherein the method provides a naloxone AUC 0-inf  from about 2.5 ng·hr/ml to about 4.5 ng·hr/ml. 
     
     
         28 . The method of  claim 1 , wherein the method provides a naloxone plasma concentration of about 1 ng/ml within about 5 to 15 minutes after intranasal administration; a naloxone T max  of about 0.1 hours to about 0.5 hours; a naloxone AUC 0-inf  from about 2.5 to about 4.5 ng·hr/ml; a naloxone peaks plasma concentration (C max ) from about 1 to about 3 ng/ml; or a combination of two or more thereof. 
     
     
         29 . A method for treating an opioid overdose in an individual in need thereof, the method comprising spraying about 100 μL of an aqueous solution into a nostril of the individual, wherein the aqueous solution comprises
 (i) about 15 mg/mL and about 30 mg/mL of naloxone or a pharmaceutically acceptable salt thereof, wherein the naloxone is primarily in an ionized state, and 
 (ii) about 2 mM and about 15 mM of ethylene diamine tetraacetic acid or a pharmaceutically acceptable salt thereof, 
 wherein the aqueous solution is capable of remaining substantially free of a naloxone related substance when stored in a sealed package for at least 6 months, and wherein the naloxone related substance comprises 10-α-hydroxynaloxone, oxymorphone, noroxymorphone, 10-β-hydroxynaloxone, 7,8-didehydronaloxone, 2,2′-bisnaloxone, 3-O-allynlnaloxone, or a combination of two or more thereof. 
 
     
     
         30 . The method of  claim 29 , wherein the naloxone or the pharmaceutically acceptable salt thereof is naloxone hydrochloride.