The present invention relates to the delivery of migraine headache drugs through an inhalation route. Specifically, it relates to aerosols containing migraine headache drugs that are used in inhalation therapy.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention relates to the delivery of migraine headache drugs through an inhalation route. Specifically, it relates to aerosols containing migraine headache drugs that are used in inhalation therapy.

New routes of administration for the compounds may increase the rate at which their peak plasma concentrations are reached. Such routes are provided herein.

In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of a migraine headache drug. Preferably, the particles comprise at least 10 percent by weight of a migraine headache drug. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of a migraine headache drug.

Typically, the aerosol has a mass of at least 10 .mu.g. Preferably, the aerosol has a mass of at least 100 .mu.g. More preferably, the aerosol has a mass of at least 200 .mu.g.

Typically, the particles comprise less than 10 percent by weight of migraine headache drug degradation products. Preferably, the particles comprise less than 5 percent by weight of migraine headache drug degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of migraine headache drug degradation products.

Typically, where the particles comprise rizatriptan, the particles comprise less than 5 percent by weight of rizatriptan N-oxide (C.sub.15H.sub.19N.sub.5O, MW of 285.34). Preferably, the particles comprise less than 2.5 percent by weight of rizatriptan N-oxide. More preferably, the particles comprise less than 1, 0.5, 0.1 or 0.03 percent by weight of rizatriptan N-oxide.

Typically, where the particles comprise rizatriptan, the particles comprise less than 5 percent by weight of didehydro rizatriptan (removal of H.sub.2, C.sub.15H.sub.17N.sub.5, MW of 267.33). Preferably, the particles comprise less than 2.5 percent by weight of didehydro rizatriptan. More preferably, the particles comprise less than 1, 0.5, 0.1 or 0.03 percent by weight of didehydro rizatriptan.

Typically, where the particles comprise zolmitriptan, the particles comprise less than 5 percent by weight of zolmitriptan N-oxide. Preferably, the particles comprise less than 2.5 percent by weight of zolmitriptan N-oxide. More preferably, the particles comprise less than 1, 0.5, 0.1 or 0.03 percent by weight of zolmitriptan N-oxide.

Typically, where the particles comprise zolmitriptan, the particles comprise less than 5 percent by weight of didehydro zolmitriptan. Preferably, the particles comprise less than 2.5 percent by weight of didehydro zolmitriptan. More preferably, the particles comprise less than 1, 0.5, 0.1 or 0.03 percent by weight of didehydro zolmitriptan.

Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.

Typically, the aerosol has an inhalable aerosol drug mass density of between 0.25 mg/L and 40 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 20 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 10 mg/L.

Typically, where the aerosol comprises sumatriptan, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 40 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 35 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 15 mg/L and 30 mg/L.

Typically, where the aerosol comprises frovatriptan, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 4 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 3.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 1.5 mg/L and 3.0 mg/L.

Typically, where the aerosol comprises naratriptan, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 2 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.3 mg/L and 1.75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.4 mg/L and 1.5 mg/L.

Typically, the aerosol has an inhalable aerosol particle density greater than 10.sup.6 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 10.sup.7 particles/mL or 10.sup.8 particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns, e.g., 0.2 to 3 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0 or 3.5. Preferably, the geometric standard deviation is less than 2.5 or 3.0. More preferably, the geometric standard deviation is less than 2.2, 2.5 or 2.0.

Typically, the aerosol is formed by heating a composition containing a migraine headache drug to form a vapor and subsequently allowing the vapor to condense into an aerosol.

In another composition aspect of the present invention, a dose form of a migraine headache drug is provided for the treatment of migraine, wherein the dose form comprises less than the typical oral dose of the drug. Preferably, the dose form comprises less than 80 percent by weight of the typical oral dose of the drug. More preferably, the dose form comprises less than 60 percent, 40 percent, or 20 percent by weight of the typical oral dose of the drug.

Typically, where the migraine headache drug is sumatriptan, the dose form comprises less than 20 mg of sumatriptan. Preferably, the dose form comprises less than 15 mg of sumatriptan. More preferably, the dose form comprises less than 10 mg or 5 mg of sumatriptan.

Typically, where the migraine headache drug is frovatriptan, the dose form comprises less than 2 mg of frovatriptan. Preferably, the dose form comprises less than 1.75 mg of frovatriptan. More preferably, the dose form comprises less than 1.5 mg, 1.25 mg or 1 mg of frovatriptan.

Typically, where the migraine headache drug is naratriptan, the dose form comprises less than 0.8 mg of naratriptan. Preferably, the dose form comprises less than 0.6 mg of naratriptan. More preferably, the dose for comprises less than 0.4 mg of naratriptan.

Typically, where the migraine headache drug is rizatriptan, the dose form comprises less than 4 mg of rizatriptan. Preferably, the dose form comprises less than 3.5 mg of rizatriptan. More preferably, the dose form comprises less than 3.0 or 2.5 mg of rizatriptan.

Typically, where the migraine headache drug is zolmitriptan, the dose form comprises less than 1 mg of zolmitriptan. Preferably, the dose form comprises less than 0.75 mg of zolmitriptan. More preferably, the dose form comprises less than 0.5 mg of zolmitriptan.

Typically, the dose form further comprises less than 90 percent by weight of water. Preferably, the dose form further comprises less than 80 percent by weight of water. More preferably, the dose form further comprises less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, or 10 percent by weight of water.

Typically, the dose form further comprises less than 90 percent by weight of a pharmaceutically acceptable excipient. Preferably, the dose form further comprises less than 80 percent by weight of a pharmaceutically acceptable excipient. More preferably, the dose form further comprises less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, or 10 percent by weight of a pharmaceutically acceptable excipient.

In a method aspect of the present invention, a migraine headache drug is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of a migraine headache drug to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. Preferably, the composition that is heated comprises at least 10 percent by weight of a migraine headache drug. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of a migraine headache drug.

Typically, the particles comprise at least 5 percent by weight of a migraine headache drug. Preferably, the particles comprise at least 10 percent by weight of a migraine headache drug. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of a migraine headache drug.

Typically, the aerosol has a mass of at least 10 .mu.g. Preferably, the aerosol has a mass of at least 100 .mu.g. More preferably, the aerosol has a mass of at least 200 .mu.g.

Typically, the particles comprise less than 10 percent by weight of migraine headache drug degradation products. Preferably, the particles comprise less than 5 percent by weight of migraine headache drug degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of migraine headache drug degradation products.

Typically, where the particles comprise rizatriptan, the particles comprise less than 5 percent by weight of rizatriptan N-oxide (C.sub.15H.sub.19N.sub.5O, MW of 285.34). Preferably, the particles comprise less than 2.5 percent by weight of rizatriptan N-oxide. More preferably, the particles comprise less than 1, 0.5, 0.1 or 0.03 percent by weight of rizatriptan N-oxide.

Typically, where the particles comprise rizatriptan, the particles comprise less than 5 percent by weight of didehydro rizatriptan (removal of H.sub.2, C.sub.15H.sub.17N.sub.5, MW of 267.33). Preferably, the particles comprise less than 2.5 percent by weight of didehydro rizatriptan. More preferably, the particles comprise less than 1, 0.5, 0.1 or 0.03 percent by weight of didehydro rizatriptan.

Typically, where the particles comprise zolmitriptan, the particles comprise less than 5 percent by weight of zolmitriptan N-oxide. Preferably, the particles comprise less than 2.5 percent by weight of zolmitriptan N-oxide. More preferably, the particles comprise less than 1, 0.5, 0.1 or 0.03 percent by weight of zolmitriptan N-oxide.

Typically, where the particles comprise zolmitriptan, the particles comprise less than 5 percent by weight of didehydro zolmitriptan. Preferably, the particles comprise less than 2.5 percent by weight of didehydro zolmitriptan. More preferably, the particles comprise less than 1, 0.5, 0.1 or 0.03 percent by weight of didehydro zolmitriptan.

Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.

Typically, the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns, e.g., 0.2 to 3 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0 or 3.5. Preferably, the geometric standard deviation is less than 2.5 or 3.0. More preferably, the geometric standard deviation is less than 2.2, 2.5 or 2.0.

Typically, the delivered aerosol has an inhaleable aerosol drug mass density of between 0.25 mg/L and 40 mg/L. Preferably, the aerosol has an inhaleable drug mass density of between 0.5 mg/L and 20 mg/L. More preferably, the aerosol has an inhalable drug mass density of between 0.5 mg/L and 10 mg/L.

Typically, where the aerosol comprises sumatriptan, the delivered aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 40 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 35 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 15 mg/L and 30 mg/L.

Typically, where the aerosol comprises frovatriptan, the delivered aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 4 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 3.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 1.5 mg/L and 3.0 mg/L.

Typically, where the aerosol comprises naratriptan, the delivered aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 2 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.3 mg/L and 1.75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.4 mg/L and 1.5 mg/L.

Typically, the delivered aerosol has an inhalable aerosol particle density greater than 10.sup.6 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 10.sup.7 particles/mL or 10.sup.8 particles/mL.

Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 10.sup.8 particles per second. Preferably, the aerosol is formed at a rate greater than 10.sup.9 inhaleable particles per second. More preferably, the aerosol is formed at a rate greater than 10.sup.10 inhaleable particles per second.

Typically, the delivered condensation aerosol is formed at a rate greater than 0.5 mg/second. Preferably, the aerosol is formed at a rate greater than 0.75 mg/second. More preferably, the aerosol is formed at a rate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, where the condensation aerosol comprises sumatriptan, between 5 mg and 40 mg of sumatriptan are delivered to the mammal in a single inspiration. Preferably, between 10 mg and 35 mg of sumatriptan are delivered to the mammal in a single inspiration. More preferably, between 15 mg and 30 mg of sumatriptan are delivered in a single inspiration.

Typically, where the condensation aerosol comprises frovatriptan, between 0.5 mg and 4 mg of frovatriptan are delivered to the mammal in a single inspiration. Preferably, between 1 mg and 3.5 mg of frovatriptan are delivered to the mammal in a single inspiration. More preferably, between 1.5 mg and 3.0 mg of frovatriptan are delivered in a single inspiration.

Typically, where the condensation aerosol comprises naratriptan, between 0.2 mg and 2 mg of naratriptan are delivered to the mammal in a single inspiration. Preferably, between 0.3 mg and 1.75 mg of naratriptan are delivered to the mammal in a single inspiration. More preferably, between 0.4 mg and 1.5 mg of naratriptan are delivered in a single inspiration.

Typically, where the condensation aerosol comprises rizatriptan, between 1 mg and 20 mg of rizatriptan are delivered to the mammal in a single inspiration. Preferably, between 1.5 mg and 15 mg of rizatriptan are delivered to the mammal in a single inspiration. More preferably, between 2 mg and 10 mg of rizatriptan are delivered to the mammal in a single inspiration.

Typically, where the condensation aerosol comprises zolmitriptan, between 0.5 mg and 10 mg of zolmitriptan are delivered to the mammal in a single inspiration. Preferably, between 1.5 mg and 7.5 mg of zolmitriptan are delivered to the mammal in a single inspiration. More preferably, between 2 mg and 5 mg of zolmitriptan are delivered to the mammal in a single inspiration.

Typically, the delivered condensation aerosol results in a peak plasma concentration of a migraine headache drug in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

Typically, less than 80 percent by weight of typical oral dose of a migraine headache drug is inhaled by the mammal in a 2 hour period. Preferably, less than 60 percent by weight of a typical oral dose of a migraine headache drug is inhaled by the mammal in a 2 hour period. More preferably, less than 40 percent or 20 percent of a typical oral dose of a migraine headache drug is inhaled in any 2 hour period.

Typically, the delivered condensation aerosol is used to treat migraine.

Typically, where the condensation aerosol comprises sumatriptan, less than 20 mg of sumatriptan is inhaled by the mammal in any 2 hour period. Preferably, less than 15 mg of sumatriptan is inhaled by the mammal in any 2 hour period. More preferably, less than 10 mg or 5 mg of sumatriptan is inhaled by the mammal in any 2 hour period.

Typically, where the condensation aerosol comprises frovatriptan, less than 2 mg of frovatriptan is inhaled by the mammal in any 2 hour period. Preferably, less than 1.75 mg of frovatriptan is inhaled by the mammal in any 2 hour period. More preferably, less than 1.5 mg of frovatriptan is inhaled by the mammal in any 2 hour period.

Typically, where the condensation aerosol comprises naratriptan, less than 0.8 mg of naratriptan is inhaled by the mammal in any 2 hour period. Preferably, less than 0.6 mg of naratriptan is inhaled by the mammal in any 2 hour period. More preferably, less than 0.4 mg of naratriptan is inhaled by the mammal in any 2 hour period.

Typically, where the condensation aerosol comprises rizatriptan, less than 4 mg of rizatriptan is inhaled by the mammal in a 2 hour period. Preferably, less than 3.5 mg of rizatriptan is inhaled by the mammal in a 2 hour period. More preferably, less than 3.0 or 2.5 mg of rizatriptan is inhaled by the mammal in a 2 hour period.

Typically, where the condensation aerosol comprises zolmitriptan, less than 1 mg of zolmitriptan is inhaled by the mammal in a 2 hour period. Preferably, less than 0.75 mg of zolmitriptan is inhaled by the mammal in a 2 hour period. More preferably, less than 0.5 mg of zolmitriptan is inhaled by the mammal in a 2 hour period.

In another method aspect of the present invention, a method of treating migraine is provided which comprises administering a dose of a migraine headache drug to a mammal that is less than the typical oral dose. Preferably, less than 80 percent by weight of the typical oral dose of a migraine drug is administered to the mammal in any 2 hour period. More preferably, less than 60 percent, 40 percent or 20 percent of the typical dose of a migraine drug is administered to the mammal in any 2 hour period.

In another method aspect of the present invention, a method of treating migraine is provided which comprises administering a dose of a migraine headache drug to a mammal that is less than the typical oral dose.

Typically, where the migraine headache drug is sumatriptan, less than 20 mg of sumatriptan is administered to the mammal in any 2 hour period. Preferably, less than 15 mg of sumatriptan is administered to the mammal in any 2 hour period. More preferably, less than 10 mg or 5 mg of sumatriptan is administered to the mammal in any 2 hour period.

Typically, where the migraine headache drug is frovatriptan, less than 2 mg of frovatriptan is administered to the mammal in any 2 hour period. Preferably, less than 1.75 mg of frovatriptan is administered to the mammal in any 2 hour period. More preferably, less than 1.5 mg, 1.25 mg, or 1 mg of frovatriptan is administered to the mammal in any 2 hour period.

Typically, where the migraine headache drug is naratriptan, less than 0.8 mg of naratriptan is administered to the mammal in any 2 hour period. Preferably, less than 0.6 mg of naratriptan is administered to the mammal in any 2 hour period. More preferably, less than 0.4 mg of naratriptan is inhaled by the mammal in any 2 hour period.

Typically, where the migraine headache drug is rizatriptan, less than 4 mg of rizatriptan is administered to the mammal in any 2 hour period. Preferably, less than 3.5 mg of rizatriptan is administered to the mammal in any 2 hour period. More preferably, less than 3.0 mg or 2.5 mg of rizatriptan is administered to the mammal in any 2 hour period.

Typically, where the migraine headache drug is zolmitriptan, less than 1 mg of zolmitriptan is administered to the mammal in any 2 hour period. Preferably, less than 0.75 mg of zolmitriptan is administered to the mammal in any 2 hour period. More preferably, less than 0.5 mg of zolmitriptan is administered to the mammal in any 2 hour period.

In a kit aspect of the present invention, a kit for delivering a migraine headache drug through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of a migraine headache drug; and, b) a device that forms a a migraine headache drug aerosol from the composition, for inhalation by the mammal. Preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of a migraine headache drug.

Typically, the device contained in the kit comprises: a) an element for heating the migraine headache drug composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.

Typically, the kit comprises a migraine headache drug less than the typical oral dose of a migraine headache drug. Preferably, the kit comprises less than 80 percent by weight of the typical dose of a migraine headache drug. More preferably, the kit comprises less than 60 percent, 40 percent, or 20 percent by weight of a migraine headache drug.

Typically, where the kit comprises sumatriptan, it comprises less than 20 mg of sumatriptan. Preferably, the kit comprises less than 15 mg of sumatriptan. More preferably, it comprises less than 10 mg or 5 mg of sumatriptan.

Typically, where the kit comprises frovatriptan, it comprises less than 2 mg of frovatriptan. Preferably, the kit comprises less than 1.75 mg of frovatriptan. More preferably, it comprises less than 1.5 mg, 1.25 mg, or 1 mg of frovatriptan.

Typically, where the kit comprises naratriptan, it comprises less than 0.8 mg of naratriptan. Preferably, the kit comprises less than 0.6 mg of naratriptan. More preferably, the kit comprises less than 0.4 mg of naratriptan.

Typically, where the kit comprises rizatriptan, it comprises less than 4 mg of rizatriptan. Preferably, the kit comprises less than 3.5 mg of rizatriptan. More preferably, it comprises less than 3 mg or 2.5 mg of rizatriptan.

Typically, where the kit comprises zolmitriptan, it comprises less than 1 mg of zolmitriptan. Preferably, the kit comprises less than 0.75 mg of zolmitriptan. More preferably, it comprises less than 0.5 mg of zolmitriptan.

DETAILED DESCRIPTION OF THE INVENTION

Formation of a Migraine Headache Drug Containing Aerosols

Any suitable method is used to form the aerosols of the present invention. A preferred method, however, involves heating a composition comprising a migraine headache drug to form a vapor, followed by cooling of the vapor such that it condenses to provide a migraine headache drug comprising aerosol (condensation aerosol). The composition is heated in one of four forms: as pure active compound (e.g., pure lidocaine, verapamil, diltiazem, isometheptene, lisuride, sumatriptan, frovatriptan, naratriptan, rizatriptan or zolmitriptan); as a mixture of active compound and a pharmaceutically acceptable excipient; as a salt form of the pure active compound; and, as a mixture of active compound salt form and a pharmaceutically acceptable excipient.

Salt forms of migraine headache drugs (e.g., lidocaine, verapamil, diltiazem, isometheptene and lisuride) are either commercially available or are obtained from the corresponding free base using well known methods in the art. A variety of pharmaceutically acceptable salts are suitable for aerosolization. Such salts include, without limitation, the following: hydrochloric acid, hydrobromic acid, acetic acid, maleic acid, formic acid, and fumaric acid salts.

Pharmaceutically acceptable excipients may be volatile or nonvolatile. Volatile excipients, when heated, are concurrently volatilized, aerosolized and inhaled with the migraine headache drugs. Classes of such excipients are known in the art and include, without limitation, gaseous, supercritical fluid, liquid and solid solvents. The following is a list of exemplary carriers within the classes: water; terpenes, such as menthol; alcohols, such as ethanol, propylene glycol, glycerol and other similar alcohols; dimethylformamide; dimethylacetamide; wax; supercritical carbon dioxide; dry ice; and mixtures thereof.

Solid supports on which the composition is heated are of a variety of shapes. Examples of such shapes include, without limitation, cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness and virtually any shape permeated by small (e.g., less than 1.0 mm-sized) pores. Preferably, solid supports provide a large surface to volume ratio (e.g., greater than 100 per meter) and a large surface to mass ratio (e.g., greater than 1 cm.sup.2 per gram).

A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet of 0.25 mm thickness has a surface to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder of 1 cm diameter produces a support that retains the high surface to mass ratio of the original sheet but has a lower surface to volume ratio (about 400 per meter).

A number of different materials are used to construct the solid supports. Classes of such materials include, without limitation, metals, inorganic materials, carbonaceous materials and polymers. The following are examples of the material classes: aluminum, silver, gold, stainless steel, copper and tungsten; silica, glass, silicon and alumina; graphite, porous carbons, carbon yarns and carbon felts; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are used as well.

Where aluminum is used as a solid support, aluminum foil is a suitable material. Examples of silica, alumina and silicon based materials include amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (an alumina of defined surface area greater than 2 m.sup.2/g from Aldrich, St. Louis, Mo.) and a silicon wafer as used in the semiconductor industry. Carbon yarns and felts are available from American Kynol, Inc., New York, N.Y. Chromatography resins such as octadecycl silane chemically bonded to porous silica are exemplary coated variants of silica.

The heating of the migraine headache drug compositions is performed using any suitable method. Examples of methods by which heat can be generated include the following: passage of current through an electrical resistance element; absorption of electromagnetic radiation, such as microwave or laser light; and, exothermic chemical reactions, such as exothermic salvation, hydration of pyrophoric materials and oxidation of combustible materials.

Delivery of Migraine Headache Drug Containing Aerosols

Migraine headache drug containing aerosols of the present invention are delivered to a mammal using an inhalation device. Where the aerosol is a condensation aerosol, the device has at least three elements: an element for heating a migraine headache drug containing composition to form a vapor; an element allowing the vapor to cool, thereby providing a condensation aerosol; and, an element permitting the mammal to inhale the aerosol. Various suitable heating methods are described above. The element that allows cooling is, in it simplest form, an inert passageway linking the heating means to the inhalation means. The element permitting inhalation is an aerosol exit portal that forms a connection between the cooling element and the mammal's respiratory system.

One device used to deliver the migraine headache drug containing aerosol is described in reference to FIG. 1 (see Original Patent). Delivery device 100 has a proximal end 102 and a distal end 104, a heating module 106, a power source 108, and a mouthpiece 110. A migraine headache drug composition is deposited on a surface 112 of heating module 106. Upon activation of a user activated switch 114, power source 108 initiates heating of heating module 106 (e.g, through ignition of combustible fuel or passage of current through a resistive heating element). The migraine headache drug composition volatilizes due to the heating of heating module 106 and condenses to form a condensation aerosol prior to reaching the mouthpiece 110 at the proximal end of the device 102. Air flow travelling from the device distal end 104 to the mouthpiece 110 carries the condensation aerosol to the mouthpiece 110, where it is inhaled by the mammal.

Devices, if desired, contain a variety of components to facilitate the delivery of migraine headache drug containing aerosols. For instance, the device may include any component known in the art to control the timing of drug aerosolization relative to inhalation (e.g., breath-actuation), to provide feedback to patients on the rate and/or volume of inhalation, to prevent excessive use (i.e., "lock-out" feature), to prevent use by unauthorized individuals, and/or to record dosing histories.

Dosage of Migraine Headache Drug Containing Aerosols

The dosage amount of a migraine headache drug in aerosol form is generally no greater than twice the standard dose of the drug given orally. A typical dosage of a migraine headache drug aerosol is either administered as a single inhalation or as a series of inhalations taken within an hour or less (dosage equals sum of inhaled amounts). Where the drug is administered as a series of inhalations, a different amount may be delivered in each inhalation.

Sumatriptan, frovatriptan and naratriptan are given at strengths of 25 mg, 2.5 mg, and 1 mg respectively for the treatment of migraine headaches. As aerosols, 5 mg to 40 mg of sumatriptan, 0.5 mg to 4 mg of frovatriptan, and 0.2 mg to 2 mg naratriptan are generally provided for the same indication. A typical dosage of a sumatriptan, frovatriptan, or naratriptan aerosol is either administered as a single inhalation or as a series of inhalations taken within an hour or less (dosage equals sum of inhaled amounts). Where the drug is administered as a series of inhalations, a different amount may be delivered in each inhalation. The dosage amount of sumatriptan, frovatriptan, or naratriptan in aerosol form is generally no greater than twice the standard dose of the drug given orally.

Rizatriptan and zolmitriptan are given orally at strengths of 5 mg or 10 mg and 2.5 mg or 5 mg respectively for the treatment of migraine. As aerosols, 0.5 mg to 15 mg of rizatriptan and 0.25 mg to 7.5 mg of zolmitriptan are generally provided per inspiration for the same indication. A typical dosage of a rizatriptan or zolmitriptan aerosol is either administered as a single inhalation or as a series of inhalations taken within an hour or less (dosage equals sum of inhaled amounts). Where the drug is administered as a series of inhalations, a different amount may be delivered in each inhalation. The dosage amount of rizatriptan or zolmitriptan in aerosol form is generally no greater than twice the standard dose of the drug given orally.

One can determine the appropriate dose of migraine headache drug containing aerosols to treat a particular condition using methods such as animal experiments and a dose-finding (Phase I/II) clinical trial. One animal experiment involves measuring plasma concentrations of drug in an animal after its exposure to the aerosol. Mammals such as dogs or primates are typically used in such studies, since their respiratory systems are similar to that of a human. Initial dose levels for testing in humans is generally less than or equal to the dose in the mammal model that resulted in plasma drug levels associated with a therapeutic effect in humans. Dose escalation in humans is then performed, until either an optimal therapeutic response is obtained or a dose-limiting toxicity is encountered.
 

Claim 1 of 54 Claims

1. A condensation aerosol for delivery of rizatriptan formed by heating a composition containing rizatriptan coated on a solid support to form a vapor and condensing the vapor to form a condensation aerosol comprising particles, wherein the particles comprise at least 10 percent by weight of rizatriptan and less than 5 percent by weight of rizatriptan degradation products, and the condensation aerosol has an MMAD of less than 5 microns.

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