FORMULATIONS AND METHODS FOR THE PREVENTION OF OPIOID OVERDOSE
Formulations and methods for the preventative treatment of incidental opioid overdose comprising the intranasal (IN) administration of a pharmaceutical formulation containing the opioid antagonist nalmefene as a prophylactic measure.
1 . A method for the prevention (prophylaxis) of opioid overdose or a symptom thereof caused by incidental exposure of a subject to an opioid agonist, comprising nasally administering to a subject in need thereof a pharmaceutical formulation comprising a therapeutically effective amount of nalmefene hydrochloride, a hydrate thereof, or another pharmaceutically acceptable salt of nalmefene.
2 . The method of claim 1 , wherein the formulation comprises an isotonicity agent.
3 . A method for the prevention (prophylaxis) of opioid overdose or a symptom thereof caused by incidental exposure of a subject to an opioid agonist, comprising nasally administering to a subject in need thereof a pharmaceutical formulation comprising:
about 3.3 to about 26.6 mg nalmefene hydrochloride, a hydrate thereof, or another pharmaceutically acceptable salt;
of about 0.1 to about 6.0 mg of an isotonicity agent; and
optionally, an absorption enhancer.
4 . A method for the prophylaxis of opioid overdose or a symptom thereof caused by incidental exposure of a subject to opioid agonist, comprising nasally administering to a subject in need thereof, via a device adapted for nasal delivery of a pharmaceutical formulation to a subject by actuation of said device into at least one nostril of said subject, a nasal spray pharmaceutical formulation comprising:
from about 3.3 to about 26.6 mg nalmefene hydrochloride or a hydrate thereof;
from about 0.1 mg to about 6.0 mg of an isotonicity agent; and
optionally, an absorption enhancer.
5 . The method of any one of claims 1 - 4 , wherein the pharmaceutical formulation comprises an aqueous solution of about 50 to about 250 μL.
6 . The method of any one of claims 1 - 5 , wherein the pharmaceutical formulation comprises about 3.3 to about 16.6 mg nalmefene hydrochloride or a hydrate thereof and about 0.1 to about 6.0 mg of an isotonicity agent.
7 . The method of any one of claims 1 - 6 , wherein the pharmaceutical formulation comprises an absorption enhancer.
8 . The method of claim 7 , wherein the absorption enhancer is benzalkonium chloride.
9 . The method of claim 8 , comprising about 0.005% to about 0.015% (v/w) benzalkonium chloride.
10 . The method of claim 7 , wherein said absorption enhancer is an alkylsaccharide.
11 . The method of claim 10 , wherein said absorption enhancer is dodecyl maltoside or tetradecyl maltoside.
12 . The method of claim 11 , wherein said absorption enhancer is Intravail® (dodecyl maltoside).
13 . The method of claim 12 , comprising about 0.05% to about 2.5% Intravail® (dodecyl maltoside).
14 . The method of claim 13 , comprising about 0.1% to about 0.5% Intravail® (dodecyl maltoside).
15 . The method of any one of claims 1 - 14 , wherein the pharmaceutical formulation further comprises about 0.1 to about 0.5 mg of a stabilizing agent.
16 . The method of claim 15 , wherein the stabilizing agent is disodium edetate.
17 . The method of any one of claims 1 - 16 , wherein the pharmaceutical formulation further comprises an amount of an acid or base sufficient to achieve a pH of between about 3.5 and about 5.5.
18 . The method of claim 17 , wherein the pharmaceutical formulation further comprises an amount of an acid or base sufficient to achieve a pH of between about 3.5 and about 4.5.
19 . The method of claim 18 , wherein the acid is hydrochloric acid and the base is sodium hydroxide.
20 . The method of any one of claims 1 - 19 , wherein the isotonicity agent is NaCl.
21 . The method of any one of claim 1 - 7 or 16 - 20 , wherein the pharmaceutical formulation does not contain an absorption enhancer.
22 . The method of any one of claim 1 - 3 or 5 - 21 , wherein the pharmaceutical formulation is delivered via a device adapted for nasal delivery of a pharmaceutical formulation to a subject by actuation of said device into at least one nostril of said subject.
23 . The method of claim 22 , wherein said device is actuatable with one hand.
24 . The method of claim 23 , wherein the device can contain no more than about 280 μL of the formulation.
25 . The method of claim 23 , wherein the device can contain no more than about 140 μL of the formulation.
26 . The method of claim 24 wherein about 100 μL of formulation is delivered to the subject in one actuation.
27 . The method of any one of claims 1 - 26 , wherein the plasma concentration versus time curve of said nalmefene hydrochloride in said subject has a T max of between about 10 and about 30 minutes when the formulation comprises an absorption enhancer.
28 . The method of any one of claims 1 - 26 , wherein the plasma concentration versus time curve of said nalmefene hydrochloride in said subject has a T max of between about 1 and about 3 hours when the formulation does not comprise an absorption enhance.
29 . The method of any of claims 1 - 28 , wherein the incidental exposure to opioid agonist is selected from:
incidental inhalation via exposure by aerosolized opioid agonist; and
incidental transdermal or transmucosal exposure by either an aerosolized or powdered form of an opioid agonist.
30 . The method of any one of claims 1 - 29 , wherein the subject is a member of military, law enforcement, professional security personnel, or personnel providing emergency medical services.
31 . The method of any one of claims 1 - 30 wherein the subject is involved in the investigation or clean-up of an opioid agonist production or distribution site.
32 . The method of any one of claim 1 - 29 or 31 , wherein said subject is a law enforcement officer.
33 . The method of any one of claims 1 - 32 , wherein the pharmaceutical formulation will prevent a symptom of opioid overdose selected from the group consisting of: 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.
34 . The method of any one of claims 1 - 33 , wherein the opioid overdose or a symptom thereof occurs during a drug raid.
35 . The method of any one of claims 34 , wherein the nasal formulation is administered prior to incidental exposure to an opioid agonist.
36 . The method of claim 35 , wherein the formulation is administered from about 10 min to about 2 hours prior to incidental exposure to opioid.
37 . The method of any one of claims 1 - 34 , wherein the nasal formulation is administered concurrent with incidental exposure to an opioid agonist.
38 . The method of any one of claims 1 - 34 , wherein the nasal formulation is administered promptly after incidental exposure to an opioid agonist.
39 . The method of any one of claims 1 - 38 , wherein said subject is free from opioid overdose or a symptom thereof for at least about 4 hours following administration of the said therapeutically effective amount of nalmefene hydrochloride or a hydrate thereof.
40 . The method of any one of claims 1 - 38 , wherein said subject is free from opioid overdose or a symptom thereof for at least about 8 hours following administration of the said therapeutically effective amount of nalmefene hydrochloride or a hydrate thereof.