NASAL DRUG PRODUCTS AND METHODS OF THEIR USE
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 . 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, a mean naloxone plasma concentration of >1 ng/mL within 5 minutes, or a mean naloxone plasma concentration of >3 ng/mL within 10 minutes in said patient.
4 - 5 . (canceled)
6 . The pharmaceutical formulation of claim 1 , which yields, when intranasally administered to a patient, a naloxone T max selected from the group consisting of less than 30 minutes, less than 25 minutes and less than 20 minutes.
7 - 8 . (canceled)
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 device has at least one of the following features:
a. the isotonicity agent is NaCl, the preservative is benzalkonium chloride the stabilizing agent is disodium edetate, and the acid is hydrochloric acid;
b. 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;
c. the device is actuatable with one hand;
d. the volume of said reservoir is not more than about 140 μL;
e. about 100 μL of said aqueous solution in said reservoir is delivered to said patient in one actuation;
f. the pharmaceutical composition which is an aqueous solution comprises about 2 mg naloxone hydrochloride;
g. the device is configured such that 90% confidence interval for dose delivered per actuation is about ±2%;
h. the device is configured such that 95% confidence interval for dose delivered per actuation is about ±2.5%;
i. the device is configured such that delivery time is less than about 25 seconds;
j. the device is configured such that delivery time is less than about 20 seconds.
11 - 19 . (canceled)
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 method has at least one of the following features:
a. (i) the isotonicity agent is NaCl, (ii) the compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer is benzalkonium chloride, (iii) the stabilizing agent is disodium edetate, and (iv) the acid is hydrochloric acid;
b. 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;
c. the device is actuatable with one hand;
d. the volume of said reservoir is not more than about 140 μL;
e. 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.
22 - 24 . (canceled)
25 . The method of claim 21 , wherein when the volume of said reservoir is not more than about 140 μL, 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 method has at least one of the following features:
a. 90% confidence interval for dose delivered per actuation is about ±2%;
b. 95% confidence interval for dose delivered per actuation is about ±2.5%;
c. delivery time is less than about 25 seconds;
d. delivery time is less than about 20 seconds.
28 - 30 . (canceled)
31 . The method of claim 21 , wherein when the method has feature b, 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, less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally, or less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
32 - 34 . (canceled)
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 and wherein the method has at least one of the following features:
a. said respiratory depression is caused by the illicit use of opioids, or by an accidental misuse of opioids during medical opioid therapy;
b. 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;
c. 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;
d. 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;
e. 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;
f. said patient is in a lying, supine, or recovery position.
38 - 43 . (canceled)
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 method has at least one of the following features:
a. 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;
b. 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;
c. the method is actuatable with one hand;
d. volume of said reservoir is not more than about 140 μL;
e. plasma concentration versus time curve of said naloxone hydrochloride in said patient has a T max of between about 20 and about 30 minutes;
f. said patient is an opioid overdose patient or a suspected opioid overdose patient.
46 - 48 . (canceled)
49 . The method of claim 45 , wherein when the volume of said reservoir is not more than about 140 μL, 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 method has at least one of the following features:
a. the pharmaceutical composition which is an aqueous solution comprises 2 mg naloxone hydrochloride;
b. 90% confidence interval for dose delivered per actuation is about ±2%;
c. 95% confidence interval for dose delivered per actuation is about ±2.5%;
d. delivery time is less than about 25 seconds;
e. delivery time is less than about 20 seconds;
f. the pharmaceutical composition which is an aqueous solution comprises 2 mg naloxone hydrochloride and wherein the delivery time is less than about 25 seconds;
g. the pharmaceutical composition which is an aqueous solution comprises 2 mg naloxone hydrochloride and wherein the delivery time is less than about 20 seconds.
51 - 54 . (canceled)
55 . The method of claim 45 , wherein when the method has feature b, 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, less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally, or less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
56 - 59 . (canceled)
60 . The method of claim 45 , wherein when said patient is an opioid overdose patient or a suspected opioid overdose patient, 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 and wherein the method has at least one of the following features:
a. said respiratory depression is caused by the illicit use of opioids, or by an accidental misuse of opioids during medical opioid therapy;
b. 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;
c. 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;
d. 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;
e. 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;
f. said patient is in a lying, supine, or recovery position.
62 - 67 . (canceled)