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 - 30 . (canceled) 
     
     
         31 . A method of treating opioid overdose, the method comprising:
 delivering a 25-200 μL spray of a pharmaceutical solution from a pre-primed device into a nostril of a patient,   wherein the device is adapted for nasal delivery,   wherein the pharmaceutical solution comprises about 4 mg naloxone hydrochloride or a hydrate thereof, an isotonicity agent, and between about 0.005% and about 0.015% (w/v) of benzalkonium chloride, and   wherein the patient is in a lying, supine, or recovery position.   
     
     
         32 . The method of  claim 31 , wherein the pre-primed device is actuatable with one hand. 
     
     
         33 . The method of  claim 31 , wherein the 90% confidence interval for dose delivered per actuation is about ±2%. 
     
     
         34 . The method of  claim 33 , wherein the 95% confidence interval for dose delivered per actuation is about ±2.5%. 
     
     
         35 . The method of  claim 31 , wherein delivery time is less than about 25 seconds. 
     
     
         36 . The method of  claim 35 , wherein delivery time is less than about 20 seconds. 
     
     
         37 . The method of  claim 31 , wherein less than about 20% of the pharmaceutical solution leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         38 . The method of  claim 37 , wherein less than about 10% of the pharmaceutical solution leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         39 . The method of  claim 38 , wherein less than about 5% of the pharmaceutical solution leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         40 . The method of  claim 31 , wherein the spray is delivered as a round spray plume with an ovality ratio less than about 2.0 when measured at 3 cm. 
     
     
         41 . The method of  claim 40 , wherein the ovality ratio is less than about 1.5 when measured at 3 cm. 
     
     
         42 . The method of  claim 41 , wherein the ovality ratio is less than about 1.3 when measured at 3 cm. 
     
     
         43 . The method of  claim 42 , wherein the ovality ratio is less than about 1.2 when measured at 3 cm. 
     
     
         44 . The method of  claim 43 , wherein the ovality ratio is less than about 1.1 when measured at 3 cm. 
     
     
         45 . The method of  claim 31 , wherein the patient is an opioid overdose patient or a suspected opioid overdose patient. 
     
     
         46 . The method of  claim 45 , 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. 
     
     
         47 . The method of  claim 46 , wherein the patient exhibits respiratory depression or cardiovascular depression. 
     
     
         48 . The method of  claim 47 , wherein the respiratory depression is caused by the illicit use of opioids, or by an accidental misuse of. 
     
     
         49 . The method of  claim 47 , wherein the patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of the therapeutically effective amount of the opioid antagonist. 
     
     
         50 . The method of  claim 47 , wherein the patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of the therapeutically effective amount of the opioid antagonist. 
     
     
         51 . The method of  claim 47 , wherein the patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of the therapeutically effective amount of the opioid antagonist. 
     
     
         52 . The method of  claim 47 , wherein the patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of the therapeutically effective amount of the opioid antagonist. 
     
     
         53 . The method of  claim 47 , wherein the device comprises a reservoir not more than about 140 μL in volume. 
     
     
         54 . The method of  claim 31 , wherein said single actuation yields a plasma concentration of ≧0.2 ng/mL within 2.5 minutes in said patient. 
     
     
         55 . The method of  claim 54 , wherein said single actuation yields a plasma concentration of ≧1 ng/mL within 5 minutes in said patient. 
     
     
         56 . The method of  claim 55 , wherein said single actuation yields a plasma concentration of ≧3 ng/mL within 10 minutes in said patient. 
     
     
         57 . The method of  claim 31 , wherein said single actuation yields a plasma concentration of ≧0.2 ng/mL within 2.5 minutes in said patient. 
     
     
         58 . The method of  claim 57 , wherein said single actuation yields a plasma concentration of ≧1 ng/mL within 5 minutes in said patient. 
     
     
         59 . A mist delivered from a pre-primed device, wherein the mist comprises droplets,
 wherein the droplets comprise in aggregate about 4 mg of naloxone hydrochloride, an isotonicity agent, a stabilizing agent, and between about 0.005% and about 1% (w/v) of benzalkonium chloride, and   wherein no more than about 10% of the droplets have a diameter less than 10 μm.   
     
     
         60 . The mist of  claim 59 , further comprising an acid. 
     
     
         61 . The mist of  claim 60 , wherein the stabilizing agent is disodium edetate and the acid is hydrochloric acid. 
     
     
         62 . The mist of  claim 61 , wherein the mist comprises per 100 μL of aqueous solution:
 about 4 mg naloxone hydrochloride; 
 about 0.74 mg NaCl; 
 about 0.01 mg benzalkonium chloride; 
 about 0.2 mg disodium edetate; and 
 hydrochloric acid sufficient to achieve a pH of 3.5-5.5. 
 
     
     
         63 . The mist of  claim 62 , wherein no more than approximately 5% of droplets have a diameter less than about 10 μm. 
     
     
         64 . The mist of  claim 59 , wherein no more than approximately 5% of droplets have a diameter less than about 10 μm. 
     
     
         65 . The mist of  claim 63 , wherein the ovality ratio is less than about 1.5 when measured at 3 cm. 
     
     
         66 . The mist of  claim 65 , wherein the ovality ratio is less than about 1.3 when measured at 3 cm. 
     
     
         67 . The mist of  claim 66 , wherein the ovality ratio is less than about 1.2 when measured at 3 cm. 
     
     
         68 . The mist of  claim 67 , wherein the ovality ratio is less than about 1.1 when measured at 3 cm. 
     
     
         69 . A method of treating narcotic-induced respiratory depression, the method comprising:
 delivering a 25-200 μL spray of a pharmaceutical solution from a pre-primed device into a nostril of a patient in need thereof in a manner that delivers the pharmaceutical solution in a round spray plume with an ovality ratio less than about 2.0 when measured at 3 cm,   wherein the device is adapted for nasal delivery,   wherein the spray comprises about 4 mg naloxone hydrochloride or a hydrate thereof, an isotonicity agent, and between about 0.005% and about 0.015% (w/v) of benzalkonium chloride,   wherein the patient is in a lying, supine, or recovery position, and   wherein the patient experiences a geometric mean naloxone C max  not less than about 3 ng/mL following a single spray.   
     
     
         70 . The method of  claim 69 , wherein said single actuation yields a plasma concentration of ≧3 ng/mL within 10 minutes in said patient. 
     
     
         71 . The method of  claim 70 , wherein said single actuation yields a plasma concentration of 0.2 ng/mL within 2.5 minutes in said patient. 
     
     
         72 . The method of  claim 71 , wherein said single actuation yields a plasma concentration of ≧1 ng/mL within 5 minutes in said patient. 
     
     
         73 . The method of  claim 69 , wherein the pre-primed device is actuatable with one hand. 
     
     
         74 . The method of  claim 73 , wherein the pre-primed device has a single reservoir containing approximately 125 μL of the pharmaceutical solution. 
     
     
         75 . The method of  claim 74 , wherein approximately 100 μL of the pharmaceutical solution is delivered by one actuation of the device. 
     
     
         76 . The method of  claim 74 , wherein the volume of the reservoir is not more than about 140 μL. 
     
     
         77 . The method of  claim 69 , wherein the 90% confidence interval for dose delivered per actuation is about ±2%. 
     
     
         78 . The method of  claim 77 , wherein the 95% confidence interval for dose delivered per actuation is about ±2.5%. 
     
     
         79 . The method of  claim 69 , wherein delivery time is less than about 25 seconds. 
     
     
         80 . The method of  claim 79 , wherein delivery time is less than about 20 seconds. 
     
     
         81 . The method of  claim 69 , wherein less than about 20% of the pharmaceutical solution leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         82 . The method of  claim 81 , wherein less than about 10% of the pharmaceutical solution leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         83 . The method of  claim 82 , wherein less than about 5% of the pharmaceutical solution leaves the nasal cavity via drainage into the nasopharynx or externally. 
     
     
         84 . The method of  claim 69 , wherein the ovality ratio is less than about 1.5 when measured at 3 cm. 
     
     
         85 . The method of  claim 84 , wherein the ovality ratio is less than about 1.3 when measured at 3 cm. 
     
     
         86 . The method of  claim 85 , wherein the ovality ratio is less than about 1.2 when measured at 3 cm. 
     
     
         87 . The method of  claim 86 , wherein the ovality ratio is less than about 1.1 when measured at 3 cm. 
     
     
         88 . The method of  claim 69 , wherein the patient is an opioid overdose patient or a suspected opioid overdose patient. 
     
     
         89 . The method of  claim 88 , 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. 
     
     
         90 . The method of  claim 89 , wherein the patient exhibits respiratory depression or cardiovascular depression. 
     
     
         91 . The method of  claim 90 , wherein the respiratory depression is caused by the illicit use of opioids, or by an accidental misuse of opioids. 
     
     
         92 . The method of  claim 90 , wherein the patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of the therapeutically effective amount of the opioid antagonist. 
     
     
         93 . The method of  claim 93 , wherein the patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of the therapeutically effective amount of the opioid antagonist. 
     
     
         94 . The method of  claim 94 , wherein the patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of the therapeutically effective amount of the opioid antagonist. 
     
     
         95 . The method of  claim 95 , wherein the patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of the therapeutically effective amount of the opioid antagonist. 
     
     
         96 . The method of  claim 91 , wherein the device comprises a reservoir not more than about 140 μL in volume. 
     
     
         97 . The method of  claim 69 , wherein said single actuation yields a plasma concentration of ≧0.2 ng/mL within 2.5 minutes in said patient. 
     
     
         98 . A method of treating opioid overdose, the method comprising:
 delivering a 25-200 μL spray of a pharmaceutical solution from a pre-primed device into a nostril of a patient,   wherein the device is adapted for nasal delivery, and   wherein the pharmaceutical solution comprises about 4 mg naloxone hydrochloride or a hydrate thereof, an isotonicity agent, and between about 0.005% and about 1% (w/v) of benzalkonium chloride.   
     
     
         99 . The method of  claim 98 , wherein the isotonicity agent is present in a concentration between about 0.2% and about 1.2% (w/v). 
     
     
         100 . The method of  claim 99 , 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. 
     
     
         101 . The method of  claim 100 , wherein
 the isotonicity agent is sodium chloride;   the stabilizing agent is disodium edetate; and   the acid is hydrochloric acid.   
     
     
         102 . The method of  claim 101 , wherein the device has a single reservoir containing approximately 125 μL of the pharmaceutical solution. 
     
     
         103 . The method of  claim 102 , wherein approximately 100 μL of the pharmaceutical solution is delivered by one actuation of the device. 
     
     
         104 . The method of  claim 103 , wherein the device comprises a reservoir, a piston, and a swirl chamber. 
     
     
         105 . The method of  claim 104 , 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 97.9% of initial naloxone hydrochloride content at actuation. 
     
     
         106 . The method of  claim 105 , wherein the patient experiences a geometric mean naloxone C max  not less than about 3 ng/mL following a single spray. 
     
     
         107 . The method of  claim 106 , 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.