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 pharmaceutical formulation for intranasal administration comprising, in an aqueous solution of not more than about 140 μL:
 about 2 mg naloxone hydrochloride; 
 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. 
 
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein the aqueous solution has a volume of 100 μL. 
     
     
         3 . The pharmaceutical formulation of  claim 1 , which yields, when intranasally administered to a patient, a mean naloxone plasma concentration of ≧0.2 ng/mL within 2.5 minutes in said patient. 
     
     
         4 . The pharmaceutical formulation of  claim 1 , which yields, when intranasally administered to a patient, a mean naloxone plasma concentration of ≧1 ng/mL within 5 minutes in said patient. 
     
     
         5 . The pharmaceutical formulation of  claim 1 , which yields, when intranasally administered to a patient, a mean naloxone plasma concentration of ≧3 ng/mL within 10 minutes in said patient. 
     
     
         6 . The pharmaceutical formulation of  claim 1 , which yields, when intranasally administered to a patient, a naloxone T max  of less than 30 minutes. 
     
     
         7 . The pharmaceutical formulation of  claim 1 , which yields, when intranasally administered to a patient, a naloxone T max  of less than 25 minutes. 
     
     
         8 . The pharmaceutical formulation of  claim 1 , which yields, when intranasally administered to a patient, a naloxone T max  of less than 20 minutes. 
     
     
         9 . A single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, having a single reservoir comprising a pharmaceutical composition which comprises per 100 μL of aqueous solution:
 about 2 mg naloxone hydrochloride; 
 between about 0.2 mg and about 1.2 mg of an isotonicity agent; 
 between about 0.005 mg and about 0.015 mg of a preservative; 
 between about 0.1 mg and about 0.5 mg of a stabilizing agent; and 
 an amount of an acid sufficient to achieve a pH of 3.5-5.5. 
 
     
     
         10 . The device as recited in  claim 9 , wherein:
 the isotonicity agent is NaCl;   the preservative is benzalkonium chloride;   the stabilizing agent is disodium edetate; and   the acid is hydrochloric acid.   
     
     
         11 . The device of  claim 10 , wherein the aqueous solution comprises per 100 μL:
 about 2 mg naloxone hydrochloride; 
 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. 
 
     
     
         12 . The device of  claim 9 , wherein said device is actuatable with one hand. 
     
     
         13 . The device of  claim 9 , wherein the volume of said reservoir is not more than about 140 μL. 
     
     
         14 . The device of  claim 9 , wherein about 100 μL of said aqueous solution in said reservoir is delivered to said patient in one actuation. 
     
     
         15 . The device of  claim 9 , wherein the pharmaceutical composition which is an aqueous solution comprises about 2 mg naloxone hydrochloride. 
     
     
         16 . The device of  claim 9 , wherein the device is configured such that the 90% confidence interval for dose delivered per actuation is about ±2%. 
     
     
         17 . The device of  claim 9 , wherein the device is configured such that the 95% confidence interval for dose delivered per actuation is about ±2.5%. 
     
     
         18 . The device of  claim 9 , wherein the device is configured such that the delivery time is less than about 25 seconds. 
     
     
         19 . The device of  claim 9 , wherein the device is configured such that the delivery time is less than about 20 seconds. 
     
     
         20 . A method of treatment of opioid overdose or a symptom thereof, comprising nasally administering to a patient in need thereof a dose of naloxone hydrochloride from the device of  claim 9 . 
     
     
         21 . The method of  claim 20  wherein:
 the isotonicity agent is NaCl; 
 the compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer is benzalkonium chloride; 
 the stabilizing agent is disodium edetate; and 
 the acid is hydrochloric acid. 
 
     
     
         22 . The method of  claim 21 , wherein the aqueous solution comprises:
 about 2 mg naloxone hydrochloride;   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 . The method of  claim 20 , wherein said device is actuatable with one hand. 
     
     
         24 . The method of  claim 20 , wherein the volume of said reservoir is not more than about 140 μL. 
     
     
         25 . The method of  claim 24 , wherein about 100 μL of said aqueous solution in said reservoir is delivered to said patient in one actuation. 
     
     
         26 . The method of  claim 25 , wherein the pharmaceutical composition which is an aqueous solution comprises 2 mg naloxone hydrochloride. 
     
     
         27 . The method of  claim 26 , wherein the 90% confidence interval for dose delivered per actuation is about ±2%. 
     
     
         28 . The method of  claim 26 , wherein the 95% confidence interval for dose delivered per actuation is about ±2.5%. 
     
     
         29 . The method of  claim 26 , wherein the delivery time is less than about 25 seconds. 
     
     
         30 . The method of  claim 26 , wherein the delivery time is less than about 20 seconds. 
     
     
         31 . The method of  claim 22 , wherein upon nasal delivery of said pharmaceutical composition to said patient, less than about 20% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         32 . The method of  claim 31 , wherein upon nasal delivery of said pharmaceutical composition to said patient, less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         33 . The method of  claim 32 , wherein upon nasal delivery of said pharmaceutical composition to said patient, less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         34 . The method of  claim 20 , 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. 
     
     
         35 . The method of  claim 20 , wherein said patient is an opioid overdose patient or a suspected opioid overdose patient. 
     
     
         36 . The method of  claim 35 , 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. 
     
     
         37 . The method of  claim 36 , wherein the patient exhibits respiratory depression. 
     
     
         38 . The method of  claim 37 , wherein said respiratory depression is caused by the illicit use of opioids, or by an accidental misuse of opioids during medical opioid therapy. 
     
     
         39 . The method of  claim 37 , wherein said patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. 
     
     
         40 . The method of  claim 39 , wherein said patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. 
     
     
         41 . The method of  claim 40 , wherein said patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. 
     
     
         42 . The method of  claim 41 , wherein said patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. 
     
     
         43 . The method of  claim 39 , wherein said patient is in a lying, supine, or recovery position. 
     
     
         44 . A method of complete or partial reversal of narcotic depression or respiratory depression induced by opioids in a patient, comprising nasally administering to a patient in need thereof a dose of naloxone hydrochloride from the device of  claim 9 . 
     
     
         45 . The method of  claim 44 , wherein:
 the isotonicity agent is NaCl;   the compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer is benzalkonium chloride;   the stabilizing agent is disodium edetate; and   the acid is hydrochloric acid.   
     
     
         46 . The method of  claim 43 , wherein the aqueous solution comprises:
 about 2 mg naloxone hydrochloride;   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.   
     
     
         47 . The method of  claim 43 , wherein said method is actuatable with one hand. 
     
     
         48 . The method of  claim 47 , wherein the volume of said reservoir is not more than about 140 μL. 
     
     
         49 . The method of  claim 48 , wherein about 100 μL of said aqueous solution in said reservoir is delivered to said patient in one actuation. 
     
     
         50 . The method of  claim 49 , wherein the pharmaceutical composition which is an aqueous solution comprises 2 mg naloxone hydrochloride. 
     
     
         51 . The method of  claim 49 , wherein the 90% confidence interval for dose delivered per actuation is about ±2%. 
     
     
         52 . The method of  claim 49 , wherein the 95% confidence interval for dose delivered per actuation is about ±2.5%. 
     
     
         53 . The method of  claim 50 , wherein the delivery time is less than about 25 seconds. 
     
     
         54 . The method of  claim 53 , wherein the delivery time is less than about 20 seconds. 
     
     
         55 . The method of  claim 46 , wherein upon nasal delivery of said pharmaceutical composition to said patient, less than about 20% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         56 . The method of  claim 55 , wherein upon nasal delivery of said pharmaceutical composition to said patient, less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         57 . The method of  claim 56 , wherein upon nasal delivery of said pharmaceutical composition to said patient, less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         58 . The method of  claim 44 , 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. 
     
     
         59 . The method of  claim 44 , wherein said patient is an opioid overdose patient or a suspected opioid overdose patient. 
     
     
         60 . The method of  claim 59 , 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. 
     
     
         61 . The method of  claim 60 , wherein the patient exhibits respiratory depression. 
     
     
         62 . The method of  claim 61 , wherein said respiratory depression is caused by the illicit use of opioids, or by an accidental misuse of opioids during medical opioid therapy. 
     
     
         63 . The method of  claim 61 , wherein said patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. 
     
     
         64 . The method of  claim 63 , wherein said patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. 
     
     
         65 . The method of  claim 64 , wherein said patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. 
     
     
         66 . The method of  claim 65 , wherein said patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist. 
     
     
         67 . The method of  claim 59 , wherein said patient is in a lying, supine, or recovery position.