Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile

• US 7,994,197 B2
• Filed: 08/26/2009
• Issued: 08/09/2011
• Est. Priority Date: 02/11/2007
• Status: Active Grant

• Current Assignee: MAP Pharmaceuticals, Inc. (Abbvie Incorporated)
• Original Assignee: MAP Pharmaceuticals, Inc. (Abbvie Incorporated)
• Inventors: Ramadan, Nabih N., Cook, Robert O., Shrewsbury, Stephen B., Armer, Thomas A.
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US12/548,292
• Publication Number:
  US 20100081663A1
• Time in Patent Office: 713 Days
• Field of Search: 514/322
• US Class Current: 514/322
• CPC Class Codes: A61K 31/10 Sulfides; Sulfoxides; Sulfones
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Pharmaceutical compositions containing dihydroergotamine (DHE) and methods in which DHE is administered to patients for treatment of migraine without side effects or adverse effects are disclosed. Methods for rapid treatment of migraine with DHE are disclosed comprising: dampening the peak plasma concentration (C_max) and slightly delaying the peak such as to avoid activating the dopaminergic and adrenergic receptors, while achieving sufficient active binding to the serotonin receptors to provide relief from migraine symptoms within a timeframe that permits rapid resolution of migraine symptoms. Inhaler devices suitable for the methods are disclosed. Kits for practicing the methods of invention are disclosed.

Claims

1. A method comprising:

administering dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof to a human suffering from migraine, cluster migraine, pediatric migraine, status migranosis or chronic daily headache;

wherein the dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof is administered at a rate such that a mean peak plasma concentration (C_max) of 8-hydroxy dihydroergotamine is less than 10,000 pg/ml, and a mean time to C_max (T_max) of 8-hydroxy dihydroergotamine is less than 45 minutes, thereby achieving low adrenergic receptor binding and low side effects of one or more of nausea, chest tightness or pain, blood pressure excursions, or emesis.

2. The method of claim 1, wherein the dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof is administered via intravenous, intraarterial, oral, intraperitoneal, intrapulmonary, sublingual, buccal, intranasal, oral inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, iontophoretic, or transdermal delivery.

3. The method of claim 2, wherein the dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof is administered via intrapulmonary delivery by oral inhalation.

4. The method of claim 1, wherein the dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof is administered by oral inhalation by a device comprising a dry powder inhaler, nebulizer, vaporizer, pressurized metered dose inhaler, or breath activated pressurized metered dose inhaler.

5. The method of claim 4, wherein the dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof is administered by a device comprising a breath activated pressurized metered dose inhaler.

6. The method of claim 5, wherein the breath activated pressurized metered dose inhaler comprises a plume control feature.

7. The method of claim 5, wherein the breath activated pressurized metered dose inhaler comprises a vortexing chamber.

8. The method of claim 4, wherein the dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof is administered by a device comprising a dry powder inhaler.

9. The method of claim 1, wherein the mean peak plasma concentration (C_max) of 8-hydroxy dihydroergotamine thereof is less than 5,000 pg/ml.

10. The method of claim 9, wherein the mean peak plasma concentration (C_max) of 8-hydroxy dihydroergotamine thereof is less than 1,000 pg/ml.

11. The method of claim 10, wherein the mean peak plasma concentration (C_max) of 8-hydroxy dihydroergotamine thereof is less than 500 pg/ml.

12. The method of claim 1, wherein the mean T_max of 8-hydroxy diydroergotamine is less than 30 minutes after administration.

13. The method of claim 1, wherein a total dose of the dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof that is administered ranges from 0.1 mg to 10.0 mg.

14. The method of claim 13, wherein the total dose ranges from 0.5 mg to 5.0 mg.

15. The method of claim 14, wherein the total dose ranges from 1.0 mg to 2.0 mg.

16. The method of claim 1, wherein the dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof comprises dihydroergotamine mesylate.

17. A method comprising:

administering dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof to a human suffering from migraine, cluster migraine, pediatric migraine, status migranosis or chronic daily headache;

wherein the dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof is administered at a rate such that a mean peak plasma concentration (C_max) of 8-hydroxy dihydroergotamine is less than 10,000 pg/ml, and a mean time to C_max (T_max) of 8-hydroxy dihydroergotamine is less than 45 minutes; and

wherein a total dose of the dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof that is administered ranges from 0.1 mg to 10.0 mg, and thereby achieving low adrenergic receptor binding and low side effects of one or more of nausea, chest tightness or pain, blood pressure excursions, or emesis.

18. The method of claim 17, wherein the dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof comprises dihydroergotamine mesylate.

19. A device comprising:

an inhaler; and

one or more unit doses of a formulation comprising dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof to a human;

wherein the inhaler is configured to administer each unit dose at a rate such that a mean peak plasma concentration (C_max) of 8-hydroxy dihydroergotamine is less than 10,000 pg/ml, and a mean time to C_max (T_max) of 8-hydroxy dihydroergotamine is less than 45 minutes.

20. The device of claim 19, wherein the dose of dihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof ranges from 0.1 to 10 mg.

21. The device of claim 20, wherein the dose ranges from 0.5 mg to 5.0 mg.

22. The device of claim 21, wherein the total dose ranges from 1.0 mg to 2.0 mg.

23. The device of claim 19, wherein the inhaler comprises a dry powder inhaler, nebulizer, vaporizer, pressurized metered dose inhaler, or breath activated pressurized metered dose inhaler.

24. The device of claim 23, wherein the inhaler comprises a dry powder inhaler.

25. The device of claim 23, wherein the inhaler comprises a breath activated pressurized metered dose inhaler.

26. The device of claim 25, wherein the breath activated pressurized metered dose inhaler comprises a plume control feature.

27. The device of claim 25, wherein the breath activated pressurized metered dose inhaler comprises a vortexing chamber.

28. The device of claim 19, wherein the inhaler is configured to deliver the formulation by an intranasal route of administration.

29. The device of claim 19, wherein the inhaler is configured to administer each unit dose at a rate such that a mean peak plasma concentration (C_max) of 8-hydroxy dihydroergotamine is less than 5,000 pg/ml.

30. The device of claim 29, wherein the inhaler is configured to administer each unit dose at a rate such that a mean peak plasma concentration (C_max) of 8-hydroxy dihydroergotamine is less than 1,000 pg/ml.

31. The device of claim 30, wherein the inhaler is configured to administer each unit dose at a rate such that a mean peak plasma concentration (C_max) of dihydroergotamine is less than 500 pg/ml.

32. The device of claim 19, wherein the inhaler is configured to administer each unit dose at a rate such that a mean time to C_max (T_max) of 8-hydroxy dihydroergotamine is less than 30 minutes after administration.