Nasal drug products and methods of their use

Abstract

Drug products adapted for nasal delivery, comprising a pre-primed device filled with a pharmaceutical composition comprising an opioid receptor antagonist, are provided. Methods of treating opioid overdose or its symptoms with the inventive drug products are also provided.

What is claimed is: 
     
         1 . A method of treating opioid overdose in a subject in need thereof, the method comprising:
 delivering a spray from a pre-primed device into a nostril of a patient whose bloodstream contains an opioid of Formula (I),   
       
         
           
           
               
               
           
         
         wherein A is aryl or heteroaryl optionally substituted with halo, C 1 -C 3  alkyl, or C 1 -C 3  alkoxy, 
         wherein X is C 1 -C 3  alkyl or hydroxyethyl, optionally substituted with —COOCH 3 , aryl, or heteroaryl optionally substituted with both C 1 -C 3  alkyl and ═O, 
         wherein Y is C 1 -C 4  alkyl, C 2 -C 3  alkenyl, C 1 -C 3  alkoxy, C 1 -C 3  alkoxyalkyl, cycloalkyl, or heteroaryl, 
         wherein R 1  and R 2  are each independently selected from the group consisting of —H, phenyl, C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 1 -C 3  alkoxyalkyl, or C 1 -C 3  alkoxy, and —COOCH 3 , 
         wherein n is 1, 2, or 3, 
         wherein the device is adapted for nasal delivery, and 
         wherein the spray delivers a pharmaceutical solution comprising about 4 mg naloxone hydrochloride or a hydrate thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the opioid of Formula (I) is selected from the group consisting of fentanyl, 2,5-dimethylfentanyl, 3-allylfentanyl, 3-methylbutyrfentanyl, 3-methylfentanyl, 3-methylthiofentanyl, 4-fluorobutyrfentanyl, p-chloroisobutyrfentanyl, p-fluoroisobutyrfentanyl, 4-fluorofentanyl, 4-phenylfentanyl, 4-methoxybutyrfentanyl, acrylfentanyl, α-methylacetylfentanyl, α-methylbutyrfentanyl, α-methylfentanyl, α-methylthiofentanyl, acetylfentanyl, alfentanyl, benzylfentanyl, β-hydroxyfentanyl, β-hydroxythiofentanyl, β-methylfentanyl, butyrfentanyl, brifentanyl, carfentanyl, cyclopentylfentanyl, isobutyrfentanyl, furanylfentanyl, furanylethylfentanyl, lofentanyl, N-methylcarfentanyl, methoxyacetylfentanyl, mirfentanyl, ocfentanyl, ohmefentanyl, R-30490, remifentanil, sufentanyl, thenylfentanyl, thiofentanyl, trefentanyl, and valerylfentanyl. 
     
     
         3 . The method of  claim 1 , wherein the spray is delivered as a round plume with an ovality ratio less than about 1.5 when measured at 3 cm. 
     
     
         4 . The method of  claim 3 , wherein the pharmaceutical solution further comprises between about 0.2% and about 1.2% (w/v) of an isotonicity agent. 
     
     
         5 . The method of  claim 4 , wherein the pharmaceutical solution further comprises between about 0.005% and about 0.015% (w/v) of a preservative. 
     
     
         6 . The method of  claim 5 , wherein the pharmaceutical solution further comprises between about 0.1% and about 0.5% (w/v) of a stabilizing agent and an amount of an acid sufficient to achieve a pH between about 3.5 and about 5.5. 
     
     
         7 . The method of  claim 6 , wherein:
 the isotonicity agent is sodium chloride;   the stabilizing agent is disodium edetate;   the acid is hydrochloric acid; and   the preservative is benzalkonium chloride.   
     
     
         8 . The method of  claim 7 , wherein the pharmaceutical solution comprises:
 about 4.4% (w/v) naloxone hydrochloride dihydrate;   about 0.74% (w/v) sodium chloride;   about 0.01% (w/v) benzalkonium chloride; and   about 0.2% (w/v) disodium edetate.   
     
     
         9 . The method of  claim 8 , wherein the device has a single reservoir containing approximately 125 μL of the pharmaceutical solution. 
     
     
         10 . The method of  claim 9 , wherein approximately 100 μL of the pharmaceutical solution is delivered by one actuation of the device. 
     
     
         11 . The method of  claim 10 , wherein the device comprises a reservoir, a piston, and a swirl chamber. 
     
     
         12 . The method of  claim 5 , further comprising storing the device for about twelve months or less at 25° C. and 60% relative humidity prior to actuating the device, wherein the device retains at least about 100% of initial naloxone hydrochloride content at actuation. 
     
     
         13 . The method of  claim 1 , wherein the patient experiences a geometric mean naloxone C max  not less than about 3 ng/mL following a single spray. 
     
     
         14 . The method of  claim 13 , wherein the patient experiences a plasma naloxone concentration such that the geometric mean of area under a plasma concentration versus time curve (AUC0-∞) is not less than about 8 hr*ng/mL when time is extrapolated to infinity. 
     
     
         15 . The method of  claim 13 , wherein the plasma concentration versus time curve of said naloxone hydrochloride in said patient has a Tmax of between about 20 and about 30 minutes. 
     
     
         16 . The method of  claim 1 , wherein the patient has consumed the fentanyl by touching the fentanyl with an unprotected area of the patient's skin. 
     
     
         17 . The method of  claim 1 , wherein less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         18 . The method of  claim 17 , wherein less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         19 . The method of  claim 1 , wherein the patient exhibits one or more symptoms chosen from: respiratory depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury, aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing; erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, and vomiting. 
     
     
         20 . The method of  claim 1 , wherein the patient whose bloodstream simultaneously contains a second opioid drug in addition to the opioid of formula (1). 
     
     
         21 . The method of  claim 20 , wherein the second opioid drug is heroin. 
     
     
         22 . The method of  claim 3 , wherein pharmaceutical solution comprises:
 about 4.4 mg naloxone hydrochloride dihydrate;   about 0.74 mg NaCl;   about 0.01 mg benzalkonium chloride;   about 0.2 mg disodium edetate; and   an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5.   
     
     
         23 . A method of preventing the use of naloxone to titrate opioid receptor occupancy, the method comprising:
 actuating a pre-primed, single use device to deliver a spray into a nostril of a patient,   wherein the device contains a pharmaceutical solution comprising at least 2% (w/v) naloxone hydrochloride or a hydrate thereof, and   wherein the device is configured to deliver no less than about 2 mg of naloxone per actuation.   
     
     
         24 . The method of  claim 23 , wherein the spray consists of a mist in which no more than about 10% of the droplets have a diameter less than 10 μm. 
     
     
         25 . The method of  claim 24 , wherein the pharmaceutical solution is delivered in a round spray plume with an ovality ratio less than about 2.0 when measured at 3 cm. 
     
     
         26 . The method of  claim 25 , wherein the pharmaceutical solution further comprises between about 0.2% and about 1.2% (w/v) of an isotonicity agent. 
     
     
         27 . The method of  claim 26 , wherein the pharmaceutical solution further comprises between about 0.005% and about 0.015% (w/v) of a preservative. 
     
     
         28 . The method of  claim 27 , wherein the pharmaceutical solution further comprises between about 0.1% and about 0.5% (w/v) of a stabilizing agent and an amount of an acid sufficient to achieve a pH between about 3.5 and about 5.5. 
     
     
         29 . The method of  claim 28 , wherein:
 the isotonicity agent is sodium chloride;   the stabilizing agent is disodium edetate;   the acid is hydrochloric acid; and   the preservative is benzalkonium chloride.   
     
     
         30 . The method of  claim 29 , wherein the pharmaceutical solution comprises:
 about 4.4% (w/v) naloxone hydrochloride dihydrate;   about 0.74% (w/v) sodium chloride;   about 0.01% (w/v) benzalkonium chloride; and   about 0.2% (w/v) disodium edetate.   
     
     
         31 . The method of  claim 30 , wherein the device has a single reservoir containing approximately 125 μL of the pharmaceutical solution. 
     
     
         32 . The method of  claim 23 , wherein the pharmaceutical solution comprises about 4% (w/v) naloxone hydrochloride or a hydrate thereof. 
     
     
         33 . The method of  claim 32 , the device is configured to deliver no less than about 4 mg of naloxone per actuation. 
     
     
         34 . The method of  claim 33 , the device is configured to deliver no less than about 8 mg of naloxone per actuation. 
     
     
         35 . The method of  claim 30 , further comprising storing the device for about twelve months or less at 25° C. and 60% relative humidity prior to actuating the device, wherein the device retains at least about 100% of initial naloxone hydrochloride content at actuation. 
     
     
         36 . The method of  claim 23 , wherein the patient experiences a geometric mean naloxone C max  not less than about 3 ng/mL following a single spray. 
     
     
         37 . The method of  claim 36 , wherein the patient experiences a plasma naloxone concentration such that the geometric mean of area under a plasma concentration versus time curve (AUC0-∞) is not less than about 8 hr*ng/mL when time is extrapolated to infinity. 
     
     
         38 . The method of  claim 23 , wherein pharmaceutical solution comprises:
 about 4.4 mg naloxone hydrochloride dihydrate;   about 0.74 mg NaCl;   about 0.01 mg benzalkonium chloride;   about 0.2 mg disodium edetate; and   an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5.