Delivery of rizatriptan or zolmitriptan through an inhalation route

• US 20040170572A1
• Filed: 03/03/2004
• Published: 09/02/2004
• Est. Priority Date: 05/24/2001
• Status: Active Grant

• Current Assignee: Alexza Pharmaceuticals Inc. (Grupo Ferrer Internacional SA)
• Original Assignee: Alexza Molecular Delivery Corporation (Grupo Ferrer Internacional SA)
• Inventors: Hale, Ron L., Rabinowitz, Joshua D., Solas, Dennis W., Zaffaroni, Alejandro C.
• Granted Patent: US 7,011,819 B2
• Time in Patent Office: Days
• US Class Current: 424/46
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/423 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/49 Cinchonan derivatives, e.g. quinine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/501 : not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 : ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/53 : having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/551 : having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/5517 : condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• CPC Class Codes: A61K 47/54 : the modifying agent being an organic compound
• CPC Class Codes: A61K 9/007 : Pulmonary tract; Aromatherapy
• 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 9/12 : Aerosols; Foams A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015
• CPC Class Codes: F24V 30/00 : Apparatus or devices using heat produced by exothermal chemical reactions other than combustion

Abstract

The present invention relates to the delivery of headache and anti-migraine compounds through an inhalation route. Specifically, it relates to aerosols containing that are used in inhalation therapy. In a method aspect of the present invention, rizatriptan or zolmitriptan is administered to a patient through an inhalation route. The method comprises: a) heating a composition, comprising rizatriptan or zolmitriptan to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol with less than 5% of the drug degradation products. In a kit aspect of the present invention, a kit for delivering rizatriptan or zolmitriptan through an inhalation route is provided which comprises: a) a thin coating of a rizatriptan or zolmitriptan composition; and, b) a device for dispending said thin coating as a condensation aerosol.

Claims

1. A method of treating headache or migraine comprising administering a therapeutic amount of a rizatriptan or zolmitriptan condensation aerosol, having an MMAD less than 3 μ

m and less than 5% rizatriptan or zolmitriptan degradation products, to a patient by inhalation, upon activation by the patient of the formation of, and delivery of, the condensation aerosol.

2. The method of claim 1, wherein said condensation aerosol is formed by

a. volatilizing rizatriptan or zolmitriptan under conditions effective to produce a heated vapor of the rizatriptan or zolmitriptan;

and

b. condensing the heated vapor of the rizatriptan or zolmitriptan to form condensation aerosol particles.

3. The method according to claim 1, wherein the condensation aerosol is formed at a rate greater than 0.5 mg/second.

4. The method according to claim 1, wherein said therapeutic amount of rizatriptan condensation aerosol comprises between 1 mg and 20 mg of rizatriptan delivered in a single inspiration.

5. The method according to claim 1, wherein said therapeutic amount of zolmitriptan condensation aerosol comprises between 0.5 mg and 10 mg of zolmitriptan delivered in a single inspiration.

6. The method according to claim 2, wherein said administration results in a peak plasma concentration of said rizatriptan or zolmitriptan in less than 0.1 hours.

7. The method according to claim 1, wherein at least 50% by weight of the condensation aerosol is amorphous in form.

8. A method of administering rizatriptan or zolmitriptan to a patient to achieve a peak plasma drug concentration rapidly, comprising administering to the patient by inhalation an aerosol of rizatriptan or zolmitriptan having less than 5% rizatriptan or zolmitriptan products and an MMAD less than 3 microns wherein the peak plasma drug concentration is achieved in less than 0.1 hours.

9. A kit for delivering a drug aerosol comprising:

a) a thin coating of a rizatriptan or zolmitriptan composition, and

b) a device for dispensing said thin coating as a condensation aerosol.

10. The kit of claim 9, wherein the device for dispensing said coating as a condensation aerosol comprises:

(a) a flow through enclosure,

(b) contained within the enclosure, a metal substrate with a foil-like surface and having a thin coating of a rizatriptan or zolmitriptan composition formed on the substrate surface,

(c) a power source that can be activated to heat the substrate to a temperature effective to volatilize the rizatriptan or zolmitriptan composition contained in said coating, and

(d) inlet and exit portals through which air can be drawn through said device by inhalation,

wherein heating the substrate by activation of the power source is effective to form a rizatriptan or zolmitriptan vapor containing less than 5% rizatriptan or zolmitriptan degradation products, and drawing air through said chamber is effective to condense the rizatriptan or zolmitriptan vapor to form aerosol particles wherein the aerosol has an MMAD of less than 3 microns.

11. The kit according to claim 10, wherein the heat for heating the substrate is generated by an exothermic chemical reaction.

12. The kit according to claim 11, wherein said exothermic chemical reaction is oxidation of combustible materials.

13. The kit according to claim 10, wherein the heat for heating the substrate is generated by passage of current through an electrical resistance element.

14. The kit according to claim 10, wherein said substrate has a surface area dimensioned to accommodate a therapeutic dose of rizatriptan or zolmitriptan composition in said coating.

15. The kit according to claim 9, wherein a peak plasma concentration of rizatriptan or zolmitriptan is obtained in less than 0.1 hours after delivery of condensation aerosol to the pulmonary system.

16. The kit of claim 9, further including instructions for use.