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 .- 22 . (canceled)
23 . A method of preventing the use of naloxone to titrate opioid receptor occupancy, the method comprising:
delivering a spray from a pre-primed device into a nostril of a patient
wherein the spray delivers a 25-200 μL spray of a pharmaceutical solution comprising between about 4 mg and about 10 mg naloxone hydrochloride of a hydrate thereof, an isotonicity agent, and between about 0.005% and about 0.15% (w/v) of benzalkonium chloride.
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 isotonicity agent is present in an amount between about 0.2% and about 1.2% (w/v).
27 . (canceled)
28 . The method of claim 26 , 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; and
the acid is hydrochloric acid.
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 spray delivers about 4 mg naloxone.
33 . (canceled)
34 . (canceled)
35 . The method of claim 26 , 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.
39 . 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 0.1% (w/v) disodium edetate.
40 . The method of claim 25 , wherein the ovality ratio is less than about 1.3 when measured at 3 cm.
41 . The method of claim 40 , wherein the ovality ratio is less than about 1.2 when measured at 3 cm.
42 . The method of claim 41 , wherein the ovality ratio is less than about 1.1 when measured at 3 cm.
43 . The method of claim 23 , wherein delivery time is less than about 25 seconds.
44 . The method of claim 43 , wherein delivery time is less than about 20 seconds.
45 . The method of claim 23 , wherein the spray delivers about 4 mg naloxone.
46 . The method of claim 1 , wherein the spray delivers about 5 mg naloxone.
47 . The method of claim 1 , wherein the spray delivers about 6 mg naloxone.
48 . The method of claim 1 , wherein the spray delivers about 7 mg naloxone.
49 . The method of claim 1 , wherein the spray delivers about 8 mg naloxone.
50 . The method of claim 23 , wherein the spray delivers about 9 mg naloxone.
51 . The method of claim 23 , wherein the spray delivers about 10 mg naloxone.
52 . The method of claim 31 , wherein approximately 100 μL of the pharmaceutical solution is delivered by one actuation of the device.
53 . The method of claim 52 , wherein the device comprises a reservoir, a piston, and a swirl chamber.
54 . The method of claim 23 , wherein the spray has a droplet size median distribution of 30-70 μm.
55 . The method of claim 23 , wherein a droplets in the spray with a diameter of less than 10 μm comprise less than 10% of the total volume of the spray.
55 . The method of claim 54 , wherein a droplets in the spray with a diameter of less than 10 μm comprise less than 5% of the total volume of the spray.
56 . The method of claim 55 , wherein a droplets in the spray with a diameter of less than 10 μm comprise less than 2% of the total volume of the spray.
55 . The method of claim 56 , wherein a droplets in the spray with a diameter of less than 10 μm comprise less than 1% of the total volume of the spray.
56 . The method of claim 36 , 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.