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 method of treating opioid overdose in a subject in need thereof, the method comprising:
delivering a spray from a pre-primed device into a nostril of a patient whose bloodstream contains an opioid of Formula (I),
wherein A is aryl or heteroaryl optionally substituted with halo, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy,
wherein X is C 1 -C 3 alkyl or hydroxyethyl, optionally substituted with —COOCH 3 , aryl, or heteroaryl optionally substituted with both C 1 -C 3 alkyl and ═O,
wherein Y is C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxyalkyl, cycloalkyl, or heteroaryl,
wherein R 1 and R 2 are each independently selected from the group consisting of —H, phenyl, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 1 -C 3 alkoxyalkyl, or C 1 -C 3 alkoxy, and —COOCH 3 ,
wherein n is 1, 2, or 3,
wherein the device is adapted for nasal delivery, and
wherein the spray delivers a pharmaceutical solution comprising about 4 mg naloxone hydrochloride or a hydrate thereof.
2 . The method of claim 1 , wherein the opioid of Formula (I) is selected from the group consisting of fentanyl, 2,5-dimethylfentanyl, 3-allylfentanyl, 3-methylbutyrfentanyl, 3-methylfentanyl, 3-methylthiofentanyl, 4-fluorobutyrfentanyl, p-chloroisobutyrfentanyl, p-fluoroisobutyrfentanyl, 4-fluorofentanyl, 4-phenylfentanyl, 4-methoxybutyrfentanyl, acrylfentanyl, α-methylacetylfentanyl, α-methylbutyrfentanyl, α-methylfentanyl, α-methylthiofentanyl, acetylfentanyl, alfentanyl, benzylfentanyl, β-hydroxyfentanyl, β-hydroxythiofentanyl, β-methylfentanyl, butyrfentanyl, brifentanyl, carfentanyl, cyclopentylfentanyl, isobutyrfentanyl, furanylfentanyl, furanylethylfentanyl, lofentanyl, N-methylcarfentanyl, methoxyacetylfentanyl, mirfentanyl, ocfentanyl, ohmefentanyl, R-30490, remifentanil, sufentanyl, thenylfentanyl, thiofentanyl, trefentanyl, and valerylfentanyl.
3 . The method of claim 1 , wherein the spray is delivered as a round plume with an ovality ratio less than about 1.5 when measured at 3 cm.
4 . The method of claim 3 , wherein the pharmaceutical solution further comprises between about 0.2% and about 1.2% (w/v) of an isotonicity agent.
5 . The method of claim 4 , wherein the pharmaceutical solution further comprises between about 0.005% and about 0.015% (w/v) of a preservative.
6 . The method of claim 5 , 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.
7 . The method of claim 6 , wherein:
the isotonicity agent is sodium chloride;
the stabilizing agent is disodium edetate;
the acid is hydrochloric acid; and
the preservative is benzalkonium chloride.
8 . The method of claim 7 , wherein the pharmaceutical solution comprises:
about 4.4% (w/v) naloxone hydrochloride dihydrate;
about 0.74% (w/v) sodium chloride;
about 0.01% (w/v) benzalkonium chloride; and
about 0.2% (w/v) disodium edetate.
9 . The method of claim 8 , wherein the device has a single reservoir containing approximately 125 μL of the pharmaceutical solution.
10 . The method of claim 9 , wherein approximately 100 μL of the pharmaceutical solution is delivered by one actuation of the device.
11 . The method of claim 10 , wherein the device comprises a reservoir, a piston, and a swirl chamber.
12 . The method of claim 5 , 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 about 100% of initial naloxone hydrochloride content at actuation.
13 . The method of claim 1 , wherein the patient experiences a geometric mean naloxone C max not less than about 3 ng/mL following a single spray.
14 . The method of claim 13 , 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.
15 . The method of claim 13 , wherein the plasma concentration versus time curve of said naloxone hydrochloride in said patient has a Tmax of between about 20 and about 30 minutes.
16 . The method of claim 1 , wherein the patient has consumed the fentanyl by touching the fentanyl with an unprotected area of the patient's skin.
17 . The method of claim 1 , wherein less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
18 . The method of claim 17 , wherein less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
19 . The method of claim 1 , 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.
20 . The method of claim 1 , wherein the patient whose bloodstream simultaneously contains a second opioid drug in addition to the opioid of formula (I).
21 . The method of claim 20 , wherein the second opioid drug is heroin.
22 . The method of claim 3 , wherein pharmaceutical solution comprises:
about 4.4 mg naloxone hydrochloride dihydrate;
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 . A method of preventing the use of naloxone to titrate opioid receptor occupancy, the method comprising:
actuating a pre-primed, single use device to deliver a spray into a nostril of a patient,
wherein the device contains a pharmaceutical solution comprising at least 2% (w/v) naloxone hydrochloride or a hydrate thereof, and
wherein the device is configured to deliver no less than about 2 mg of naloxone per actuation.
24 . The method of claim 23 , wherein the spray consists of a mist in which no more than about 10% of the droplets have a diameter less than 10 μm.
25 . The method of claim 24 , wherein the pharmaceutical solution is delivered in a round spray plume with an ovality ratio less than about 2.0 when measured at 3 cm.
26 . The method of claim 25 , wherein the pharmaceutical solution further comprises between about 0.2% and about 1.2% (w/v) of an isotonicity agent.
27 . The method of claim 26 , wherein the pharmaceutical solution further comprises between about 0.005% and about 0.015% (w/v) of a preservative.
28 . The method of claim 27 , 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.
29 . The method of claim 28 , wherein:
the isotonicity agent is sodium chloride;
the stabilizing agent is disodium edetate;
the acid is hydrochloric acid; and
the preservative is benzalkonium chloride.
30 . The method of claim 29 , wherein the pharmaceutical solution comprises:
about 4.4% (w/v) naloxone hydrochloride dihydrate;
about 0.74% (w/v) sodium chloride;
about 0.01% (w/v) benzalkonium chloride; and
about 0.2% (w/v) disodium edetate.
31 . The method of claim 30 , wherein the device has a single reservoir containing approximately 125 μL of the pharmaceutical solution.
32 . The method of claim 23 , wherein the pharmaceutical solution comprises about 4% (w/v) naloxone hydrochloride or a hydrate thereof.
33 . The method of claim 32 , the device is configured to deliver no less than about 4 mg of naloxone per actuation.
34 . The method of claim 33 , the device is configured to deliver no less than about 8 mg of naloxone per actuation.
35 . The method of claim 30 , 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 about 100% of initial naloxone hydrochloride content at actuation.
36 . The method of claim 23 , wherein the patient experiences a geometric mean naloxone C max not less than about 3 ng/mL following a single spray.
37 . The method of claim 36 , 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.
38 . The method of claim 23 , wherein pharmaceutical solution comprises:
about 4.4 mg naloxone hydrochloride dihydrate;
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.