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 composition comprising
 a. from about 5 mg/mL to about 50 mg/mL of an opioid antagonist;   b. from about 5 mM to about 50 mM citric acid;   c. from about 2 to about 20 mM disodium ethylene diamine tetraacetic acid (EDTA);   d. from about 0.1 to about 2 weight % benzyl alcohol; and   e. a carrier.   
     
     
         2 . The composition of  claim 1 , wherein administration of said composition intranasally results in a parameter selected from a T max  of about 0.1 hours to about 0.5 hours in a subject; a peak plasma concentration of from about 1.0 to about 4.0 ng/mL at a time period of from about 5 to about 30 minutes after administration; and combinations thereof. 
     
     
         3 . The composition of  claim 1 , wherein administration of about 200 μL of said composition administers about 2 mg of said opioid antagonist intranasally, and results in an AUC 0-inf  of from about 2.5 to about 4.5 ng-hr/mL, or about 2.5 to about 2.7 ng-hr/mL, or about 2.6 ng-hr/mL. 
     
     
         4 . The composition of  claim 1 , wherein administration of about 200 μL of said composition administers about 2 mg of said opioid antagonist intranasally, and results in a Cmax of from about 1 to about 3 or about 1.5 to about 2.5 or about 1.8 ng/mL. 
     
     
         5 . The composition of  claim 1 , wherein said composition has an osmolality of from about 300 to about 500 mOsm. 
     
     
         6 . The composition of  claim 1 , wherein said composition has a pH of from about 3.5 to about 5.0. 
     
     
         7 . The composition of  claim 1 , wherein said composition is substantially free of a material selected from a viscoelastic polymer, hydroxypropyl methylcellulose (hypromellose), glycerine, propylene glycol, sorbitol, ascorbic acid, a paraben preservative, or a combination thereof. 
     
     
         8 . The composition of  claim 1 , wherein said composition is substantially free of a paraben preservative selected from methylparaben, ethylparaben, propylparaben, butylparaben, heptylparaben, isobutyparaben, isopropylparaben, benzylparaben, sodium salts thereof, and combinations thereof, preferably methyl paraben, propylparaben, and combinations thereof. 
     
     
         9 . The composition of  claim 1 , wherein said composition comprises less than 0.1% of any individual Naloxone Related Substance. 
     
     
         10 . The composition of  claim 1 , wherein said composition is stable at room temperature for at least 6 months. 
     
     
         11 . The composition of  claim 1  comprising
 a. about 10 mg/mL naloxone HCl dihydrate; 
 b. about 25 mM citric acid; 
 c. about 10 mM EDTA; 
 d. about 0.5 weight % benzyl alcohol; and 
 e. a pharmaceutically acceptable carrier; 
 wherein intransal administration of about 200 μL of said composition achieves one or more parameters selected from a plasma concentration of about 1 ng/mL within about 5 to 15 minutes after intranasal administration; a T max  of about 0.1 hours to about 0.5 hours, or about 0.3 hours; an AUC 0-inf  of from about 2.5 to about 4.5 ng-hr/mL, or about 2.5 to about 2.7 ng-hr/mL, or about 2.6 ng-hr/mL; and a Cmax of from about 1 to about 3 or about 1.5 to about 2.5 or about 1.8 ng/mL. 
 
     
     
         12 . The composition according to  claim 1 , wherein said composition is a nasal spray comprising:
 (i) about 7 mg/mL to about 11 mg/mL naloxone or a pharmaceutically acceptable salt thereof;   (ii) about 20 mM to about 30 mM citric acid;   (iii) about 5 mM to about 15 mM ethylenediaminetetraacetic acid; and   (iv) about 0.2% to about 1.0 weight % benzyl alcohol;   wherein the nasal spray has a pH from about 3 to about 5.5.   
     
     
         13 . The composition of  claim 12 , wherein the naloxone or pharmaceutically acceptable salt thereof is naloxone hydrochloride dihydrate. 
     
     
         14 . The composition of  claim 13 , which comprises:
 (i) about 10 mg/mL naloxone hydrochloride dihydrate;   (ii) about 25 mM citric acid;   (iii) about 10 mM ethylenediaminetetraacetic acid; and   (iv) about 0.5 weight % benzyl alcohol;   wherein the nasal spray has a pH from about 3.5 to 5.0.   
     
     
         15 . A method of treating a known or suspected opioid overdose comprising the step of intranasally administering a composition according to  claim 1  to an individual in need thereof,
 wherein said composition is administered via the nasal membranes to said individual; 
 wherein said individual is administered a dose, per naris, of from about 0.1 to about 2 mg. 
 
     
     
         16 . The method of  claim 15 , wherein said known or suspected opioid overdose is manifested by respiratory and/or central nervous system depression. 
     
     
         17 . The method of  claim 15 , wherein said intransal administration results in a T max  of about 5 to about 30 minutes. 
     
     
         18 . The method of  claim 15 , wherein said method utilizes a device having a property selected from needle-free, ready-to-use, disposable, or a combination thereof. 
     
     
         19 . The method of  claim 15 , wherein said administration step comprises intranasal administration of a single spray per naris, wherein said spray may be repeated as necessary. 
     
     
         20 . The method of  claim 15  wherein said composition is administered in a volume of from 50 μL to 250 μL. 
     
     
         21 . The method of  claim 15 , wherein the method of treating the opioid overdose is a method for the complete or partial reversal of opioid intoxication. 
     
     
         22 . A method for reversing the effects of an opioid overdose in an individual in need thereof, comprising the step of administering intranasally a dose of a naloxone composition, wherein said naloxone composition comprises about 10 mg/mL naloxone HCl dihydrate, about 25 mM citric acid, about 10 mM EDTA, and about 0.5 weight % benzyl alcohol;
 wherein said dose comprises about 200 μL of said naloxone composition; and   wherein said dose is divided into two half doses;   wherein each said half dose comprises about 100 μL of said composition; and   wherein each said half dose may be administered intranasally to a subject in need thereof.   
     
     
         23 . A device for nasal administration of naloxone, containing a composition according to  claim 1 , wherein said device has a feature selected from single-use, needle-free, ready-to-use, disposable, and combinations thereof. 
     
     
         24 . The device according to  claim 23 , wherein said device contains a composition comprising about 10 mg/mL naloxone HCl dihydrate, about 25 mM citric acid, about 10 mM EDTA, and about 0.5 weight % benzyl alcohol;
 wherein said composition is provided in a dose for nasal administration to a subject in need thereof;   wherein said dose comprises about 200 μL of said composition;   wherein said dose is divided into two half doses;   wherein each said half dose comprises about 100 μL of said composition; and   wherein each said half dose may be administered intranasally to a subject in need thereof.   
     
     
         25 . The device according to  claim 23 , further comprising instructions for use, wherein said device and said instructions for use are combined as a kit. 
     
     
         26 . The device according to  claim 25 , wherein said instructions comprise instruction for an administrator of said device having the steps of
 a. placing said individual on their back;   b. inserting a first sprayer of said device into said individuals nostril;   c. aiming the nozzle towards the side of said individual's nose and away from the center of said nose;   d. pressing a plunger of said device firmly with a thumb of said administrator;   e. repeating steps b and d with a second sprayer in a second nostril of said individual's nose;   f. monitoring said individual and the breaths of said individual, wherein if said individual does not improve or if signs of opioid overdose reappear 3-5 minutes after administering, repeating the steps of b through e with a second device.