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.

1 .- 22 . (canceled) 
     
     
         23 . A method of preventing the use of naloxone to titrate opioid receptor occupancy, the method comprising:
 delivering a spray from a pre-primed device into a nostril of a patient   wherein the spray delivers a 25-200 μL spray of a pharmaceutical solution comprising between about 4 mg and about 10 mg naloxone hydrochloride of a hydrate thereof, an isotonicity agent, and between about 0.005% and about 0.15% (w/v) of benzalkonium chloride.   
     
     
         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 isotonicity agent is present in an amount between about 0.2% and about 1.2% (w/v). 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 26 , 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; and   the acid is hydrochloric acid.   
     
     
         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 spray delivers about 4 mg naloxone. 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 26 , 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 (AUC 0-∞ ) 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.   
     
     
         39 . 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 0.1% (w/v) disodium edetate.   
     
     
         40 . The method of  claim 25 , wherein the ovality ratio is less than about 1.3 when measured at 3 cm. 
     
     
         41 . The method of  claim 40 , wherein the ovality ratio is less than about 1.2 when measured at 3 cm. 
     
     
         42 . The method of  claim 41 , wherein the ovality ratio is less than about 1.1 when measured at 3 cm. 
     
     
         43 . The method of  claim 23 , wherein delivery time is less than about 25 seconds. 
     
     
         44 . The method of  claim 43 , wherein delivery time is less than about 20 seconds. 
     
     
         45 . The method of  claim 23 , wherein the spray delivers about 4 mg naloxone. 
     
     
         46 . The method of claim  1 , wherein the spray delivers about 5 mg naloxone. 
     
     
         47 . The method of claim  1 , wherein the spray delivers about 6 mg naloxone. 
     
     
         48 . The method of claim  1 , wherein the spray delivers about 7 mg naloxone. 
     
     
         49 . The method of claim  1 , wherein the spray delivers about 8 mg naloxone. 
     
     
         50 . The method of  claim 23 , wherein the spray delivers about 9 mg naloxone. 
     
     
         51 . The method of  claim 23 , wherein the spray delivers about 10 mg naloxone. 
     
     
         52 . The method of  claim 31 , wherein approximately 100 μL of the pharmaceutical solution is delivered by one actuation of the device. 
     
     
         53 . The method of  claim 52 , wherein the device comprises a reservoir, a piston, and a swirl chamber. 
     
     
         54 . The method of  claim 23 , wherein the spray has a droplet size median distribution of 30-70 μm. 
     
     
         55 . The method of  claim 23 , wherein a droplets in the spray with a diameter of less than 10 μm comprise less than 10% of the total volume of the spray. 
     
     
         55 . The method of  claim 54 , wherein a droplets in the spray with a diameter of less than 10 μm comprise less than 5% of the total volume of the spray. 
     
     
         56 . The method of  claim 55 , wherein a droplets in the spray with a diameter of less than 10 μm comprise less than 2% of the total volume of the spray. 
     
     
         55 . The method of  claim 56 , wherein a droplets in the spray with a diameter of less than 10 μm comprise less than 1% of the total volume of the spray. 
     
     
         56 . The method of  claim 36 , wherein the plasma concentration versus time curve of said naloxone hydrochloride in said patient has a T max  of between about 20 and about 30 minutes.