Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines

• US 9,918,932 B2
• Filed: 02/21/2017
• Issued: 03/20/2018
• Est. Priority Date: 02/19/2016
• Status: Active Grant

• Current Assignee: Emergex USA Corp. (Emergex Vaccines Holding Ltd.)
• Original Assignee: Zosano Pharma Corporation
• Inventors: Ameri, Mahmoud, Kellerman, Donald, Daddona, Peter E., Ao, Yi
• Primary Examiner(s): Puttlitz, Karl J
• Application Number:
  US15/438,455
• Publication Number:
  US 20170239174A1
• Time in Patent Office: 392 Days
• Field of Search: None
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0021 Intradermal administration, e.g. through microneedle arrays, needleless injectors mechanical aspects A61M

Abstract

Compositions, devices and methods employing therapeutic concentrations of a triptan for treatment of migraine are described. Also described are methods and apparatuses for delivery of zolmitriptan for achieving a T_max as quick as 2 minutes and not later than 30 minutes in the majority of subjects.

Claims

1. A method for treating migraine in a human patient, comprising the steps of:

a. Providing an intracutaneous delivery system, comprising;

i. a disposable patch assembly having a plurality of microprojections disposed in an array of about 3 cm² to about 6 cm², the array having a density of about 200 to about 2000 microprojections/cm², the microprojections adapted to penetrate or pierce the stratum corneum of a human patient,

ii. the microprojections having a solid formulation coating disposed thereon, wherein the coating comprises zolmitriptan or a pharmaceutically acceptable salt thereof in an amount greater than about 0.6 mg/cm² to less than about 1 mg/cm²,

iii. the microprojections having a width of about 10 μ

m to about 500 μ

m and a tip angle of about 30 to about 70 degrees, and

iv. wherein at least 95% of the zolmitriptan is released from the system within about 5 minutes when measured by USP Paddle Over Disk Method (Apparatus

     5); and

b. applying the microprojections to a selected area of skin of the patient,

wherein the patient has pain freedom at about 2 hours post-application, and

wherein the T_max of a therapeutically effective blood plasma concentration of zolmitriptan occurs within about 30 minutes of the application, the C_max is about 5 to about 25 ng/ml and the AUC_{0-2 hr} is about 5 to about 20 ng/ml*hour.

2. The method of claim 1 wherein the patient is free of one or more of:

nausea, phonophobia, or photophobia at about 2 hours post-application.

3. The method of claim 1 wherein the patient has pain freedom at about 1 hour post-application.

4. The method of claim 1 wherein the coating has a thickness from about 20 μ

m to about 80 μ

m.

13. The method of claim 12 wherein the system is bioequivalent to the intracutaneous delivery system of claim 1 wherein bioequivalence is established by (a) a 90% Confidence Interval (CI) for AUC which is between 0.80 and 1.25;

and (b) a 90% CI for C_max which is between 0.80 and 1.25.

22. The method of claim 1, wherein the at least 95% of the zolmitriptan is released within about 1 minute.

23. The method of claim 22, wherein about 100% of the zolmitriptan is released within about 1 minute.

24. The method of claim 1, wherein the T_max of a therapeutically effective serum concentration occurs within about 20 minutes of the application.

25. The method of claim 24, wherein the T_max of a therapeutically effective serum concentration occurs within about 2 minutes of the application.

27. The method of claim 1, wherein the intracutaneous delivery system is comprised of one or more patches comprising the plurality of microprojections in the form of one or more arrays having a total area of about 5 cm² to about 6 cm², which system is capable of delivering about 3.8 mg zolmitriptan or a salt thereof to the skin of the patient.

28. The method of claim 1, further comprising preparing the solid formulation coating by drying an aqueous coating formulation which comprises about 20% to about 50% w/w zolmitriptan or salt thereof and about 5% to about 20% w/w of an acid selected from the group consisting of malic acid, ascorbic acid, lactic acid, tartaric acid, citric acid, maleic acid, succinic acid and hydrochloric acid, and wherein the composition is substantially free of a penetration enhancer.

29. The method of claim 1, wherein the patient is free of his or her most bothersome symptom at about 2 hours post-application.

30. The method of claim 1, wherein the solid formulation coating retains at least 95% of its zolmitriptan purity for at least 12 months.

31. The method of claim 1, wherein the plurality of microprojections is disposed in an array of about 3 cm² and the amount of zolmitriptan or pharmaceutically acceptable salt thereof is about 2 mg.

34. The method of claim 1, wherein the plurality of microprojections is disposed in an array of about 3 cm² and the amount of zolmitriptan or pharmaceutically acceptable salt thereof is about 1.9 mg.

37. The method of claim 1, wherein the plurality of microprojections is disposed in an array of about 5.5 cm² and the amount of zolmitriptan or pharmaceutically acceptable salt thereof is about 3.8 mg.

40. The method of claim 1, wherein the plurality of microprojections is disposed in an array of about 5.5 cm² and the amount of zolmitriptan or pharmaceutically acceptable salt thereof is about 4 mg.

5. A method of treating migraine in a population of human patients in need thereof, comprising the steps of:

a. Providing an intracutaneous delivery system, comprising;

i. a disposable patch assembly having a plurality of microprojections disposed in an array of about 3 cm² to about 6 cm², the array having a density of about 200 to about 800 microprojections/cm², the microprojections adapted to penetrate or pierce the stratum corneum of a human patient and having a length of about 300 μ

m to about 400 μ

m, a thickness of about 5 μ

m to about 50 μ

m, a width of about 100 μ

m to about 200 μ

m, and are configured at a tip angle of about 30 to about 70 degrees,

ii. the microprojections having a solid formulation coating disposed thereon, wherein the coating comprises zolmitriptan or a pharmaceutically acceptable salt thereof in an amount greater than about 0.6 mg/cm² to less than about 1 mg/cm², and

iii. wherein at least 95% of the zolmitriptan is released from the system within about 5 minutes when measured by USP Paddle Over Disk Method (Apparatus

     5); and

b. applying the microprojections to a selected area of skin of each patient, wherein more than about 15% of the patients experience pain freedom at about 1 hour post-application, and wherein the T_max of a therapeutically effective blood plasma concentration of zolmitriptan occurs within about 30 minutes of the application.

6. The method of claim 5 wherein more than about 20% of the patients experience pain freedom at about 1 hour post-application.

7. The method of claim 5 wherein those patients experiencing pain freedom are significantly more by comparison to a second population of human patients who receive either conventional oral tablets of zolmitriptan or orally disintegrating tablets of zolmitriptan for treatment of migraine.

8. The method of claim 5 wherein the population of patients numbers at least 8 and wherein the mean AUC_0-inf of N-desmethyl zolmitriptan is about 1 to about 8 ng·

H/mL.

9. The method of claim 8 wherein the formation of N-desmethyl zolmitriptan is less than about 50% as compared to the administration of an equivalent oral dose of zolmitriptan.

10. The method of claim 8 wherein the formation of N-desmethyl zolmitriptan is less than about 30% as compared to the administration of an equivalent oral dose of zolmitriptan.

11. The method of claim 5 wherein the patients'"'"' mean plasma concentration of zolmitriptan is at least 10 ng/mL within 15 minutes of application.

32. The method of claim 5, wherein the plurality of microprojections is disposed in an array of about 3 cm² and the amount of zolmitriptan or pharmaceutically acceptable salt thereof is about 2 mg.

35. The method of claim 5, wherein the plurality of microprojections is disposed in an array of about 3 cm² and the amount of zolmitriptan or pharmaceutically acceptable salt thereof is about 1.9 mg.

38. The method of claim 5, wherein the plurality of microprojections is disposed in an array of about 5.5 cm² and the amount of zolmitriptan or pharmaceutically acceptable salt thereof is about 3.8 mg.

41. The method of claim 5, wherein the plurality of microprojections is disposed in an array of about 5.5 cm² and the amount of zolmitriptan or pharmaceutically acceptable salt thereof is about 4 mg.

12. A method for treatment or alleviation of migraine or cluster headache in a human patient in need thereof, comprising the steps of:

a. Providing an intracutaneous delivery system, comprising;

i. a disposable patch assembly having an array of a plurality of microprojections disposed in an array of about 2 cm² to about 6 cm² at a density of about 200 to about 800 microprojections/cm², the microprojections adapted to penetrate or pierce the stratum corneum of the patient,

ii. the microprojections having a solid formulation coating disposed thereon, wherein the coating comprises zolmitriptan or a pharmaceutically acceptable salt thereof in an amount greater than about 0.6 mg/cm² to less than about 1 mg/cm²,

iii. the microprojections having a width of about 10 μ

m to about 500 μ

m, a thickness of about 5 μ

m to about 50 μ

m, and at a tip angle of about 30 to about 70 degrees,

iv. wherein at least 95% of the zolmitriptan is released from the system within about 5 minutes when measured by USP Paddle Over Disk Method (Apparatus

     5), and

vi. an impact applicator; and

b. applying the patch assembly to a selected area of skin of the patient with the applicator at an energy density of at least 0.05 joules per cm² in 10 milliseconds or less;

wherein the plasma zolmitriptan AUC for the first 2 hours is greater than the plasma zolmitriptan AUC following oral administration of an equivalent dose of zolmitriptan, but the plasma zolmitriptan AUC_0-inf following the intracutaneous administration is less than the plasma zolmitriptan AUC_0-inf observed after the oral administration of an equivalent dose of zolmitriptan; and

wherein the system is configured to deliver a plasma concentration of zolmitriptan of at least 2.0 ng/mL within 15 minutes after application.

14. The method of claim 12 wherein the system is configured to result in a therapeutic effect for a period of at least 5 hours.

15. The method of claim 12 wherein the system is configured to result in a therapeutic effect for a period of at least 2 hours.

16. The method of claim 12 wherein the coating has a thickness of about 20 μ

m to 80 μ

m.

17. The method of claim 12 wherein the system is configured to deliver a plasma concentration of zolmitriptan of at least 5.0 ng/mL within 15 minutes after application.

18. The method of claim 12, wherein the T_max of a therapeutically effective blood plasma concentration occurs within about 30 minutes of the application.

19. The method of claim 18, wherein the T_max of a therapeutically effective blood plasma concentration occurs within about 20 minutes of the application.

20. The method of claim 12, wherein the T_max of a therapeutically effective blood plasma concentration is at least about 0.6 hours earlier than the T_max following the oral administration of an equivalent dose of zolmitriptan.

21. The method of claim 20, wherein the T_max of a therapeutically effective blood plasma concentration is at least about 1.4 hours earlier than the T_max following the oral administration of an equivalent dose of zolmitriptan.

26. The method of claim 12, wherein the intracutaneous delivery system is comprised of a patch comprising the plurality of microprojections in the form of an array having an area of about 2 cm² to about 3 cm² that is capable of delivering about 1.9 mg zolmitriptan or a salt thereof to the skin of the patient.

33. The method of claim 12, wherein the plurality of microprojections is disposed in an array of about 3 cm² and the amount of zolmitriptan or pharmaceutically acceptable salt thereof is about 2 mg.

36. The method of claim 12, wherein the plurality of microprojections is disposed in an array of about 3 cm² and the amount of zolmitriptan or pharmaceutically acceptable salt thereof is about 1.9 mg.

39. The method of claim 12, wherein the plurality of microprojections is disposed in an array of about 5.5 cm² and the amount of zolmitriptan or pharmaceutically acceptable salt thereof is about 3.8 mg.

42. The method of claim 12, wherein the plurality of microprojections is disposed in an array of about 5.5 cm² and the amount of zolmitriptan or pharmaceutically acceptable salt thereof is about 4 mg.