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 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.