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Last Updated: December 1, 2020

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Claims for Patent: 10,085,937

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Summary for Patent: 10,085,937
Title:Nasal drug products and methods of their use
Abstract: 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.
Inventor(s): Keegan; Fintan (Dublin, IE), Bell; Robert Gerard (Clearwater, FL), Crystal; Roger (Santa Monica, CA), Weiss; Michael Brenner (New York, NY)
Assignee: ADAPT PHARMA LIMITED (Dublin, IE) OPIANT PHARMACEUTICALS (Santa Monica, CA)
Application Number:15/268,066
Patent Litigation and PTAB cases: See patent lawsuits and PTAB cases for patent 10,085,937
Patent Claims: 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), ##STR00048## wherein A is aryl or heteroaryl optionally substituted with halo, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 alkoxy, wherein X is C.sub.1-C.sub.3 alkyl or hydroxyethyl, optionally substituted with --COOCH.sub.3, aryl, or heteroaryl optionally substituted with both C.sub.1-C.sub.3 alkyl and .dbd.O, wherein Y is C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkoxyalkyl, cycloalkyl, or heteroaryl, wherein R.sub.1 and R.sub.2 are each independently selected from the group consisting of hydrogen (--H), phenyl, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.1-C.sub.3 alkoxyalkyl, or C.sub.1-C.sub.3 alkoxy, and --COOCH.sub.3, wherein n is 1, 2, or 3, wherein the device is adapted for nasal delivery, and wherein the spray delivers a 25-200 .mu.L spray of a pharmaceutical solution comprising between about 4 mg and about 10 mg naloxone hydrochloride or a hydrate thereof, an isotonicity agent, and between about 0.005% and about 0.015% (w/v) of benzalkonium chloride.

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, .alpha.-methylacetylfentanyl, .alpha.-methylbutyrfentanyl, .alpha.-methylfentanyl, .alpha.-methylthiofentanyl, acetylfentanyl, alfentanyl, benzylfentanyl, .beta.-hydroxyfentanyl, .beta.-hydroxythiofentanyl, 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 isotonicity agent is present in an amount between about 0.2% and about 1.2% (w/v).

5. The method of claim 4, 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.

6. The method of claim 5, wherein: the isotonicity agent is sodium chloride; the stabilizing agent is disodium edetate; and the acid is hydrochloric acid.

7. The method of claim 6, 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.

8. The method of claim 7, wherein the device has a single reservoir containing approximately 125 .mu.L of the pharmaceutical solution.

9. The method of claim 8, wherein approximately 100 .mu.L of the pharmaceutical solution is delivered by one actuation of the device.

10. The method of claim 9, wherein the device comprises a reservoir, a piston, and a swirl chamber.

11. The method of claim 4, further comprising storing the device for about twelve months or less at 25.degree. 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.

12. The method of claim 1, wherein the patient experiences a geometric mean naloxone C.sub.max not less than about 3 ng/mL following a single spray.

13. The method of claim 12, wherein the patient experiences a plasma naloxone concentration such that the geometric mean of area under a plasma concentration versus time curve (AUC.sub.0-.infin.) is not less than about 8 hr*ng/mL when time is extrapolated to infinity.

14. The method of claim 12, wherein the plasma concentration versus time curve of said naloxone hydrochloride in said patient has a T.sub.max of between about 20 and about 30 minutes.

15. 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.

16. 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.

17. The method of claim 16, wherein less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.

18. 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.

19. The method of claim 1, wherein the patient whose bloodstream simultaneously contains a second opioid drug in addition to the opioid of formula (I).

20. The method of claim 19, wherein the second opioid drug is heroin.

21. 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.

22. The method of claim 3, wherein the ovality ratio is less than about 1.3 when measured at 3 cm.

23. The method of claim 3, wherein the ovality ratio is less than about 1.2 when measured at 3 cm.

24. The method of claim 3, wherein the ovality ratio is less than about 1.1 when measured at 3 cm.

25. The method of claim 1, wherein the spray delivers about 4 mg naloxone.

26. The method of claim 25, wherein the spray delivers about 100 .mu.L of the pharmaceutical solution comprising: about 4% (w/v) naloxone hydrochloride; about 0.74% (w/v) sodium chloride; about 0.01% (w/v) benzalkonium chloride; and about 0.1% (w/v) disodium edetate.

27. The method of claim 1, wherein the spray delivers about 5 mg naloxone.

28. The method of claim 1, wherein the spray delivers about 6 mg naloxone.

29. The method of claim 1, wherein the spray delivers about 7 mg naloxone.

30. The method of claim 1, wherein the spray delivers about 8 mg naloxone.

31. The method of claim 1, wherein the spray delivers about 9 mg naloxone.

32. The method of claim 1, wherein the spray delivers about 10 mg naloxone.

33. The method of claim 1, wherein delivery time is less than about 25 seconds.

34. The method of claim 33, wherein delivery time is less than about 20 seconds.

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