CA2641760A1 - Delivery of alprazolam, estazolam, midazolam or triazolam through an inhalation route - Google Patents

Delivery of alprazolam, estazolam, midazolam or triazolam through an inhalation route Download PDF

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Publication number
CA2641760A1
CA2641760A1 CA002641760A CA2641760A CA2641760A1 CA 2641760 A1 CA2641760 A1 CA 2641760A1 CA 002641760 A CA002641760 A CA 002641760A CA 2641760 A CA2641760 A CA 2641760A CA 2641760 A1 CA2641760 A1 CA 2641760A1
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CA
Canada
Prior art keywords
aerosol
percent
therapeutic compound
triazolam
midazolam
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002641760A
Other languages
French (fr)
Inventor
Joshua D. Rabinowitz
Alejandro C. Zaffaroni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alexza Pharmaceuticals Inc
Original Assignee
Alexza Pharmaceuticals, Inc.
Joshua D. Rabinowitz
Alejandro C. Zaffaroni
Alexza Molecular Delivery Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alexza Pharmaceuticals, Inc., Joshua D. Rabinowitz, Alejandro C. Zaffaroni, Alexza Molecular Delivery Corporation filed Critical Alexza Pharmaceuticals, Inc.
Publication of CA2641760A1 publication Critical patent/CA2641760A1/en
Abandoned legal-status Critical Current

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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
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Abstract

The present invention relates to aerosols containing alprazolam, estazolam, midazolam or triazolam that are used in inhalation therapy. In a method aspect of the present invention, alprazolam, estazolam, midazolam or triazolam is administered to a patient through an inhalation route. The method comprises: a) heating a thin layer of alprazolam, estazolam, midazolam or triazolam, on a solid support to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles having less than 5% drug degradation products. In a kit aspect of the present invention, a kit for delivering alprazolam, estazolam, midazolam or triazolam through an inhalation route is provided which comprises: a) a thin coating of an alprazolam, estazolam, midazolam, or triazolam composition and b) a device for dispensing said thin coating as a condensation aerosol.

Description

DELIVERY OF ALPRAZOLAM, ESTAZOLAM, MIDAZOLAM OR
TRIAZOLAM THROUGH AN INHALATION ROUTE

Field of the Invention [0002] The present invention relates to the delivery of alprazolam, estazolam, mid'Lazolam or triazolam through an inhalation route. Specifically, it relates to aerosols containing alprazolam, estazolam, midazolam or triazolam that are used in inhalation therapy.

Background of the Invention [0003] There are a number of compositions currently marketed for the treatment of anxiety or insomnia. The compositions contain at least one active ingredient that provides for observed therapeutic effects. Among the active ingredients in such conipositions are alprazolam, estazolam, midazolam, and triazolam.
[0004] It is desirable to provide a new route of administration for alprazolam, estazolam, midazolam, and triazolam that rapidly produces peak plasma concentrations of the compound.
Summary of the Invention [0005] The present invention relates to the delivery of alprazolam, estazolam, midazolam or triazolam through an inhalation route. Specifically, it relates to aerosols containing alprazolam, estazolam, midazolam or triazolam that are used in inhalation therapy.
[0005.1] In one aspect, the invention provides a composition for delivery of a therapeutic compound comprising a condensation aerosol a) formed by volatilizing a therapeutic compound selected from the group consisting of alprazolam, estazolam, midazolam and triazolam under conditions effective to produce a heated vapor of the compound, and condensing the heated vapor of the compound to form condensation aerosol particles, and b) characterized by less than 5% compound degradation products, and c) an aerosol having an MMAD less than 3 .m.

[0005.2] In a further aspect, the invention provides a method of producing the ther=apeutic compound alprazolam, estazolam, midazolam or triazolam in an aerosol form comprising a) volatilizing a therapeutic compound selected from the group consisting of alprazolam, estazolam, midazolam and triazolam under conditions effective to produce a heated vapor of the compound, and during said volatilizing, passing air through the heated vapor to produce aerosol particles of the compound comprising less than 5%
conipound degradation products and an aerosol having an MMAD of less than 3 m.
[0005.3] In a still further aspect, the invention provides a kit for delivering alprazolam, estazolam, midazolam or triazolam aerosol, wherein the kit comprises: a) a composition of alprazolam, estazolam, midazolam or triazolam; and, b) a device that fonns the alprazolam, estazolam, midazolam or triazolam aerosol from the composition, and wherein the device comprises: c) an element for heating the alprazolam, estazolam, midlazolam or triazolam composition to form a vapor; d) an element allowing the vapor to cool to form an aerosol; and e) an element permitting inhalation of the aerosol.

la [0006] In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of alprazolam, estazolam, midazolam or triazolam.
Preferably, the particles comprise at least 10 percent by weight of alprazolam, estazolam, midazolam or triazolam. 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 alprazolam, estazolam, midazolam or triazolam.
[0007] Typically, the aerosol has a mass of at least 1 g. Preferably, the aerosol has a mass of at least 10 g. More preferably, the aerosol has a mass of at least 20 gg.
[0008] Typically, the aerosol particles comprise less than 10 percent by weight of alprazolam, estazolam, midazolam or triazolam degradation products.
Preferably, the particles comprise less than 5 percent by weight of alprazolam, estazolam, midazolam or triazolam degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of alprazolam, estazolam, midazolam or triazolam degradation products.
[0009] Typically, the aerosol 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.
[0010] 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 weig:ht of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.
[00111 Typically, the aerosol has an inhalable aerosol drug mass density of between 0.02 mg/L and 10 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 2 mg/L.
[0012] Typically, the aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL. More preferably, the aerosol has an inhalable aerosol particle density greater than 108 particles/mL.

[0013] Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 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).
[0014] Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3Ø Preferably, the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.1.
[0015] Typically, the aerosol is formed by heating a composition containing alprazolam, estazolam, midazolam or triazolam to form a vapor and subsequently allowing the vapor to condense into an aerosol.
[0016] In a method aspect of the present invention, either alprazolam, estazolam, midazolam or triazolam 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 alprazolam, estazolam, midazolam or triazolam; 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 alprazolam, estazolam, midazolam or triazolam. More preferably, the composition comprises 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 alprazolam, estazolam, midazolam or triazolam.
[0017] Typically, the delivered aerosol particles comprise at least 5 percent by weight of alprazolam, estazolam, midazolam or triazolam. Preferably, the particles comprise at least 10 percent by weight of alprazolam, estazolam, midazolam or triazolam.
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 alprazolam, estazolam, midazolam or triazolam.
[0018] Typically, the aerosol has a mass of at least 1 g. Preferably, the aerosol has a mass of at least 10 g. More preferably, the aerosol has a mass of at least 20 g.
[0019] Typically, the delivered aerosol particles comprise less than 10 percent by weight of alprazolam, estazolam, midazolam or triazolam degradation products.

Prefe;rably, the particles comprise less than 5 percent by weight of alprazolam, estazolam, midazolam or triazolam degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of alprazolam, estazolam, midazolam or triazolam degradation products.
[0020] Typically, the aerosol 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.
[0021] 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.
[0022] Typically, the particles of the delivered condensation aerosol have a mass mediian aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass mediian 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).
[0023] Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3Ø Preferably, the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.1.
[0024] Typically, the delivered aerosol has an inhalable aerosol drug mass density of between 0.02 mg/L and 10 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 5 mg/L. More preferably, the aerosol has an inhal[able aerosol drug mass density of between 0.1 mg/L and 2 mg/L.
[0025] Typically, the delivered aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL. More preferably, the aerosol has an inhalable aerosol particle density greater than 108 particles/mL.
[0026] Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 108 particles per second. Preferably, the aerosol is formed at a rate greater than 109 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 1010 inhalable particles per second.
[002 1-] Typically, the delivered aerosol is formed at a rate greater than 0.1 mg/second.
Preferably, the aerosol is formed at a rate greater than 0.25 mg/second. More preferably, the aerosol is formed at a rate greater than 0.5, 1 or 2 mg/second.
j0028] Typically, where the condensation aerosol comprises alprazolam, between 0.05 mg and 4 mg of alprazolam are delivered to the mammal in a single inspiration.
Preferably, between 0.1 mg and 2 mg of alprazolam are delivered to the mammal in a single inspiration. More preferably, between 0.2 mg and 1 mg of alprazolam are delivered to the mammal in a single inspiration.
[0029] Typically, where the condensation aerosol comprises estazolam, between 0.05 mg a:nd 4 mg of estazolam are delivered to the mammal in a single inspiration.
Preferably, between 0.1 mg and 2 mg of estazolam are delivered to the mammal in a single inspiration.
More preferably, between 0.2 mg and 1 mg of estazolam are delivered to the mammal in a single inspiration.
[0030] Typically, where the condensation aerosol comprises midazolam, between 0.05 mg and 4 mg of midazolam are delivered to the mammal in a single inspiration.
Preferably, between 0.1 mg and 2 mg of midazolam are delivered to the mammal in a single inspiration. More preferably, between 0.2 mg and 1 mg of midazolam are delivered in a single inspiration.
[0031] Typically, where the condensation aerosol comprises triazolam, between 0.006 mg and 0.5 mg of triazolam are delivered to the mammal in a single inspiration.
Preferably, between 0.0125 mg and 0.25 mg of triazolam are delivered to the mammal in a single inspiration. More preferably, between 0.025 mg and 0.125 mg of triazolam are delivered to the mammal in a single inspiration.
[0032] Typically, the delivered condensation aerosol results in a peak plasma concentration of alprazolam, estazolam, midazolam or triazolam 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).
[0033] In a kit aspect of the present invention, a kit for delivering alprazolam, estazolam, midazolam or triazolam through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of alprazolam, estazolam, midazolarn or triazolam; and, b) a device that forms an alprazolam, estazolam, midazolam or triazolam containing aerosol from the composition, for inhalation by the mammal. Preferably, the composition comprises at least 10 percent by weight of alprazolam, estazolam, midazolam or triazolam. 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 alprazolam, estazolam, midazolam or triazolam.
[0034] Typically, the device contained in the kit comprises: a) an element for heating the alprazolam, estazolam, midazolam or triazolam composition to form a vapor;
b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mamunal to inhale the aerosol.

Brief Description of the Figure [0035] Fig. 1 shows a device used to deliver alprazolam, estazolam, midazolam or triazolam containing aerosols to a mammal through an inhalation route.

Detailed Description of the Invention Defi.'nitions [0036] "Aerodynamic diameter" of a given particle refers to the diameter of a spherical droplet with a density of 1 g/mL (the density of water) that has the same settling velocity as the given particle.
[0037] "Aerosol" refers to a suspension of solid or liquid particles in a gas.
[0038] "Aerosol drug mass density" refers to the mass of alprazolam, estazolam, midazolam or triazolam per unit volume of aerosol.
[003:9] "Aerosol mass density" refers to the mass of particulate matter per unit volume of aerosol.
[0040] "Aerosol particle density" refers to the number of particles per unit volume of aerosol.
[0041] "Alprazolam" refers to 8-chloro-l-methyl-6-phenyl-4H-s-triazolo-[4,3-a]
[1,4]benzodiazepine, which has an empirical formula of C17H13CIN4.
[004:Z] "Alprazolam degradation product" refers to a compound resulting from a cherriical modification of alprazolam. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation (e.g., of the methyl or methylene unit) and hydrolysis (e.g., of the imine portion).
[0043] "Amorphous particle" refers to a particle that does not contain more than 50 percent by weight of a crystalline form. Preferably, the particle does not contain more than 25 percent by weight of a crystalline form. More preferably, the particle does not contain more than 10 percent by weight of a crystalline form.
[0044] "Condensation aerosol" refers to an aerosol formed by vaporization of a substance followed by condensation of the substance into an aerosol.

[0045] "Estazolam" refers to 8-chloro-6-phenyl-4H-s-triazolo[4,3-a]
[1,4]!benzodiazepine, which has an empirical formula of C16H11C1N4.
[0046] "Estazolam degradation product" refers to a compound resulting from a chemical modification of estazolam. The modification, for example, can be the result of a thertnally or photochemically induced reaction. Such reactions include, without limitation, oxidation (e.g., of the methylene unit) and hydrolysis (e.g:; of the imine portion).
[0047] "Inhalable aerosol drug mass density" refers to the aerosol drug mass density produced by an inhalation device and delivered into a typical patient tidal volume.
[0048] "Inhalable aerosol mass density" refers to the aerosol mass density produced by an inhalation device and delivered into a typical patient tidal volume.
[0049] "Inhalable aerosol particle density" refers to the aerosol particle density of particles of size between 100 nm and 5 microns produced by an inhalation device and delivered into a typical patient tidal volume.
[0050] "Mass median aerodynamic diameter" or "MMAD" of an aerosol refers to the aerodynamic diameter for which'half the particulate mass of the aerosol is contributed by particles with an aerodynamic diameter larger than the MMAD and half by particles with an aerodynamic diameter smaller than the MNIAD.
[0051] "Midazolam" refers to 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[1,5-a] [1,4]benzodiazepine, which has an empirical formula of C1sH13C1FN3.
[0052] "Midazolam degradation product" refers to a compound resulting from a chernical modification of midazolam. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation (e.g., of the methyl or methylene unit) and hydrolysis (e.g., of the imine portion).

[0053] "Rate of aerosol formation" refers to the mass of aerosolized particulate matter produced by an inhalation device per unit time.
[0054] "Rate of inhalable aerosol particle formation" refers to the number of particles of size between 100 nm and 5 microns produced by an inhalation device per unit time.
[0055] "Rate of drug aerosol formation" refers to the mass of aerosolized alprazolam, estazolam, midazolam or triazolam produced by an inhalation device per unit time.
[0056] "Settling velocity" refers to the terminal velocity of an aerosol particle undergoing gravitational settling in air.
[005~7] "Triazolam" refers to 8-chloro-6-(-o-chlorophenyl)-1-methyl-4H-s-triazolo-[4,3--a] [1,4]benzodiazepine, which has an empirical formula of C17Hr2C12N4.
[0058] "Triazolam degradation product" refers to a compound resulting from a chenaical modification of triazolam. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation (e.g., of the methyl or methylene unit) and hydrolysis (e.g., of the imine portion).
[0059] "Typical patient tidal volume" refers to 1 L for an adult patient and 15 mL/kg for a pediatric patient.
[0060] "Vapor" refers to a gas, and "vapor phase" refers to a gas phase. The term "thermal vapor" refers to a vapor phase, aerosol, or mixture of aerosol-vapor phases, fornted preferably by heating.
Formation of Alprazolam, Estazolam, Midazolam or Triazolam Containing Aerosols [0061] Any suitable method is used to form the aerosols of the present invention. A
prefi-Irred method, however, involves heating a composition comprising alprazolam, estazolam, midazolam or triazolam to produce a vapor, followed by cooling of the vapor such. that it condenses to provide an alprazolam, estazolam, midazolam or triazolam comprising aerosol (condensation aerosol). The composition is heated in one of two forms:
as pure active compound (i.e., pure alprazolam, estazolam, midazolam or triazolam); or, as a mixture of active compound and a pharmaceutically acceptable excipient.
Typically, the composition is heated on a solid support.
[0062] Pharmaceutically acceptable excipients are either volatile 'or nonvolatile.
Volatile excipients, when heated, are concurrently volatilized, aerosolized and inhaled with alprazolam, estazolam, midazolam or triazolam. 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 alcoliols; dimethylformamide; dimetliylacetamide; wax; supercritical carbon dioxide; dry ice; and mixtures thereof.
[0063] Solid supports on which the composition is heated are of a variety of shapes.
Exarnples of such shapes include, without limitation, cylinders of less than 1.0 mm in diarr.ieter, 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 cm2 per gram).
[0064] A solid support of one shape can also be transformed into another shape with different properties. For example, a box of 0.25 mm thickness has a surface to volume ratio of approximately 8,000 per meter. Rolling the box into a hollow cylinder of 1 cm dianieter produces a support that retains the high surface to mass ratio of the original box but lias a lower surface to volume ratio (about 400 per meter).
[0065] 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.
[00661 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 m2/g from Aldrich, St. Louis, MO) and a silicon wafer as used in the semiconductor industry.
Carbon yams and felts are available from American Kynol, Inc., New York, NY.
Chromatography resins such as octadecycl silane chemically bonded to porous silica are exer.nplary coated variants of silica.
[0067] The heating of the alprazolam, estazolam, midazolam or triazolam 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 elerr.ient; absorption of electromagnetic radiation, such as microwave or laser light; and, exothermic chemical reactions, such as exothermic solvation, hydration of pyrophoric .materials and oxidation of combustible materials.
Delivery of Aiprazolam, Estazolam, Midazolam or Triazolam Containing Aerosols [0068] Alprazolam, estazolam, midazolam and triazolam 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 an alprazolam, estazolam, midazolam or triazolain 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.
[0069] One device used to deliver alprazolam, estazolam, midazolam or triazolam containing aerosol is described in reference to Fig. 1. 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. An alprazolam, estazolam, midazolam or triazolam 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 alprazolam, estazolam, midazolam or triazolam 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 traveling 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.
[0070] Devices, if desired, contain a variety of components to facilitate the delivery of alprazolam, estazolam, midazolam or triazolam containing aerosols. For instance, the device may include any component known in the art to control the t.imi.ng 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 (Le., "lock-out" feature), to prevent use by unauthorized individuals, and/or to record dosing histories.

Dosage of A.lprazolam, Estazolam, Midazolam or Triazolam Containing Aerosols [0071] For the short-term management of insomnia, estazolam is given orally at strengths of 1 mg or 2 mg (PROSOMTM Tablets). Alprazolam is used for the treatment of anxiety disorders and is provided for oral administration at strengths of 0.25 mg, 0.5 mg, I
mg or 2 mg (XANAX Tablets). Midazolam is given (injection or syrup) either as an anesthetic or anxiolytic in a typical dose of 0.5 mg to 4 mg (VERSED ).
Triazolam is used to treat insomnia as an oral formulation in strengths of 0.125 mg and 0.25 mg (HALCION Tablets).
[0072] As aerosols, 0.05 mg to 4 mg of estazolam, 0.05 mg to 4 mg alprazolam, 0.05 mg to 4 mg midazolam and 0.006 mg to 0.5 mg triazolam are generally provided per inspiration for the same indications. A typical dosage of an alprazolam, estazolam, midazolam or triazolam 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 chug is administered as a series of inhalations, a different amount may be delivered in each inhalation. The dosage amount of alprazolam, estazolam, midazolam or triazolam in aerosol form is generally no greater than twice the standard dose of the drug given orally or by injection.
[0073] One can determine the appropriate dose of alprazolam, estazolam, midazolam or triazolam containing aerosols to treat a particular condition using methods such as animal experiments and a dose-fmding (Phase I/IT) clinical trial. One animal experiment involves measuring plasma concentrations of 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 are 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.
Analysis of Alprozolam, Estazolam, Midazolam or Triazolam Containing Aerosols [0074] Purity of an alprazolam, estazolam, midazolam or triazolam containing aerosol is determined using a number of methods, examples of which are described in Sekine et al., Journal of Forensic Science 32:1271-1280 (1987) and Martin et al., Journal ofAnalytic Toxlicology 13:158-162 (1989). One method involves forming the aerosol in a device through which a gas flow (e.g., air flow) is maintained, generally at a rate between 0.4 and 60 L/min. The gas flow carries the aerosol into one or more traps. After isolation from the trap, the aerosol is subjected to an analytical technique, such as gas or liquid chromatography, that permits a determination of composition purity.
[0075] A variety of different traps are used for aerosol collection. The following list contains examples of such traps: filters; glass wool; impingers; solvent traps, such as dry ice-cooled ethanol, methanol, acetone and dichloromethane traps at various pH
values;
syringes that sample the aerosol; empty, low-pressure (e.g., vacuum) containers into which the aerosol is drawn; and, empty containers that fully surround and enclose the aerosol generating device. Where a solid such as glass wool is used, it is typically extracted with a solvent such as ethanol. The solvent extract is subjected to analysis rather than the solid (i.e., glass wool) itself. Where a syringe or container is used, the container is similarly extracted with a solvent.
[0076] The gas or liquid chromatograph discussed above contains a detection system (i.e.,, detector). Such detection systems are well known in the art and include, for example, flame ionization, photon absorption and mass spectrometry detectors. An advantage of a mass spectrometry detector is that it can be used to determine the structure of alprazolam, estazolam, midazolam or triazolam degradation products.
[0077] Particle size distribution of an alprazolam, estazolam, midazolam or triazolam containing aerosol is determined using any suitable method in the art (e.g., cascade impaction). An Andersen Eight Stage Non-viable Cascade Impactor (Andersen Instruments, Smyma, GA) linked to a furnace tube by a mock throat (USP throat, Andersen Instruments, Smyrna, GA) is one system used for cascade impaction studies.
[0078] Inhalable aerosol mass density is determined, for example, by delivering a drug-containing aerosol into a confined chamber via an inhalation device and measuring the mass collected in the chamber. Typically, the aerosol is drawn into the chamber by having a pressure gradient between the device and the chamber, wherein the chamber is at lower pressure than the device. The volume of the chamber should approximate the tidal volume of an inhaling patient.
[0079] Inhalable aerosol drug mass density is determined, for example, by delivering a drug-containing aerosol into a confined chamber via an inhalation device and measuring the amount of active drug compound collected in the chamber. Typically, the aerosol is dra,Ani into the chamber by having a pressure gradient between the device and the chamber, wherein the chamber is at lower pressure than the device. The volume of the chamber should approximate the tidal volume of an inhaling patient. The amount of active drug compound collected in the chamber is determined by extracting the chamber, conducting chro.matographic analysis of the extract and comparing the results of the chromatographic analysis to those of a standard containing known amounts of drug.
[0080] Inhalable aerosol particle density is determined, for example, by delivering aerosol phase drug into a confined chamber via an inhalation device and measuring the number of particles of given size collected in the chamber. The number of particles of a given size may be directly measured based on the light-scattering properties of the particles. Alternatively, the number of particles of a given size may be determined by measuring the mass of particles within the given size range and calculating the number of parti:cles based on the mass as follows: Total number of particles = Sum (from size range 1 to size range N) of number of particles in each size range., Number of particles in a given size range = Mass in the size range/Mass of a typical particle in the size range. Mass of a typical particle in a given size range =z*D3*cp/6, where D is a typical particle diameter in the size range (generally, the mean boundary of the MMADs defining the size range) in microns, cp is the particle density (in g/mL) and mass is given in units of picograms (g'12) [0081] Rate of inhalable aerosol particle formation is determined, for example, by delivering aerosol phase drug into a confined chamber via an inhalation device. The delivery is for a set period of time (e.g., 3 s), and the number of particles of a given size collected in the chamber is determined as outlined above. The rate of particle formation is equal to the number of 100 nm to 5 micron particles collected divided by the duration of the collection time.
[0052] Rate of aerosol formation is determined, for example, by delivering aerosol phase drug into a confined chamber via an inhalation device. The delivery is for a set period of time (e.g., 3 s), and the mass of particulate matter collected is determined by weighing the confined chamber before and after the delivery of the particulate matter. The rate of aerosol formation is equal to the increase in mass in the chamber divided by the duration of the collection time. Alternatively, where a change in mass of the delivery device or component thereof can only occur through release of the aerosol phase particulate mati:er, the mass of particulate matter may be equated with the mass lost from the device or component during the delivery of the aerosol. In this case, the rate of aerosol formation is equal to the decrease in mass of the device or component during the delivery event divided by the duration of the delivery event.
[0083] Rate of drug aerosol formation is determined, for example, by delivering an alprazolam, estazolam, midazolam or triazolam containing aerosol into a confined chamber via an inhalation device over a set period of time (e.g., 3 s). Where the aerosol is pure alprazolam, estazolam, midazolam or triazolam, the amount of drug collected in the chaniber is measured as described above. The rate of drug aerosol formation is equal to the amoiant of alprazolam, estazolam, midazolam or triazolam collected in the chamber divided by the duration of the collection time. Where the alprazolam, estazolam, midazolam or triazolam containing aerosol comprises a pharmaceutically acceptable excipient, multiplying the rate of aerosol formation by the percentage of alprazolam, estazolam, midazolam or triazolam in the aerosol provides the rate of drug aerosol formation.
Utility of Alprazolam, Estazolam, Midazolam and Triazolam Containing Aerosols [0084] Typical uses for alprazolam, estazolam, midazolam, and triazolarn-containing aerosols include without limitation the following: relief of the symptoms of situational anxiety, relief of acute panic attacks, relaxation of skeletal muscle, treatment of nausea and vomiting, induction of sleep, and sedation for medical or dental procedures.
Alprazolam and estazolam containing-aerosols are distinguished from midazolam and triazolam-containing aerosols primarily by their durations of action, with alprazolam and estazolam having half-lives of approximately 12 hours and midazolam and triazolam having half-lives of approximately 3 hours. Thus triazolam or midazolam-containing aerosols are typically used in instances where a rapid offset of action is desired (e.g. in sedation for medical or dentiil procedures). In contrast, alprazolam or estazolam-containing aerosols are typically used in instances where a sustained action is desired (e.g. in the case of a panic attack, where a rapid offset of action might predispose to another episode of panic).
[0085] The following examples are meant to illustrate, rather than limit, the present inveintion.
[0086] Alprazolam, estazolam and triazolam were purchased from Sigma (www.sigrna-aldrich.com). Midazolam was obtained from Gyma Laboratories of America, Inc.
(Westbury, NY).
Volatilization of Alprazolam [0087] A solution of 2.6 mg alprazolam in 120 L dichloromethane was coated on a 3.6 cm x. 8 cm piece of aluminum foil. The dichloromethane was allowed to evaporate. The coated foil was wrapped around a 300 watt halogen tube (Feit Electric Company, Pico Rivera, CA), which was inserted into a glass tube sealed at one end with a rubber stopper.
Running 75 V of alternating current (driven by line power controlled by a variac) through the bulb for 6 s afforded alprazolam thermal vapor (including alprazolam aerosol), which collected on the glass tube walls. Reverse-phase HPLC analysis with detection by absorption of 225 nm light showed the collected material to be at least 99.9%
pure alprazolam. To obtain higher purity aerosols, one can coat a lesser amount of drug, yielding a thinner film to heat. A linear decrease in film thickness is associated with a linear decrease in impurities.
EXA,MPLE 2 Yolatilizakon ofEstazolam [0088] A solution of 2.0 mg estazolam in 120 L dichloromethane was coated on a 3.6 cm x 8 cm piece of aluminum foil. The dichloromethane was allowed to evaporate. The coated foil was wrapped around a 300 watt halogen tube (Feit Electric Company, Pico Rivera, CA), which was inserted into a glass tube sealed at one end with a rubber stopper.
Rurvaing 60 V of alternating current (driven by line power controlled by a variac) through the bulb for 3 s, followed by 45 V for 11 s, afforded estazolam thermal vapor (including estazolam aerosol), which collected on the glass tube walls. Reverse-phase HPLC analysis with detection by absorption of 225 nm light showed the collected material to be at least 99.9% pure estazolam.

T'olatilrzation ofMidazolam [0089] A solution of 5.0 mg midazolam in 120 L dichloromethane was coated on a 3.6 cm x 8 cm piece of aluminum foil. The dichloromethane was allowed to evaporate. The coated foil was wrapped around a 300 watt halogen tube (Feit Electric Company, Pico Rivera, CA), which was inserted into a glass tube sealed at one end with a rubber stopper.
Running 60V of alternating current (driven by line power controlled by a variac) through the bulb for 6 s afforded midazolam thermal vapor (including midazolam aerosol), which collected on the glass tube walls. Reverse-phase HPLC analysis with detection by absorption of 225 nm light showed the collected material to be at least 99.9%
pure midazolam.

Particle Size, Particle Density, and Rate oflnbalable Particle Formation of Midazolam Aerosol [0090] A solution of 17.1 mg midazolam in 200 L dichloromethane was spread out in a thin layer on the central portion of a 4 cm x 9 cm sheet of aluminum foil.
The dichl.oromethane was allowed to evaporate. The aluminum foil was wrapped around a 300 watt halogen tube, which was inserted into a T-shaped glass tube. One of the openings of the tube was sealed with a rubber stopper, another was loosely covered with the end of the halogen tube, and the third was connected to a 1 liter, 3-neck glass flask.
The glass flask was fiu-ther connected to a large piston capable of drawing 1.1 liters of air through the flask. Alternating current was run through the halogen bulb by application of 90 V using a variac connected to 110 V line power. Within I s, an aerosol appeared and was drawn into the 1 L flask by use of the piston, with collection of the aerosol terminated after 6 s. The aerosol was analyzed by connecting the 1 L flask to an eight-stage Andersen non-viable cascade impactor. Results are shown in table 1. MMAD of the collected aerosol was 2.8 microns with a geometric standard deviation of 1.9. Also shown in table I is the number of particles collected on the various stages of the cascade impactor, given by the mass collected on the stage divided by the mass of a typical particle trapped on that stage. The mass of a single particle of diameter D is given by the volume of the particle, 703/6, multiplied by the density of the drug (taken to be 1 g/cm3). The inhalable aerosol particle density is the sum of the numbers of particles collected on impactor stages 3 to 8 divided by the collection volume of 1 L, giving an inhalable aerosol particle density of 5.5 x 10' particles/.mL. The rate of inhalable aerosol particle formation is the sum of the numbers of particles collected on impactor stages 3 through 8 divided by the formation time of 6 s, giving a rate of inhalable aerosol particle formation of 9.1 x 109 particles/second.

[0091] Table 1: Determination of the characteristics of a midazolam condensation aerosol by cascade impaction using an Andersen 8-stage non-viable cascade impactor run at 1 cubic foot per minute air flow.

Stage Particle size Average particle Mass Number of range (microns) size (microns) collected particles (mg) 0 9.0-10.0 9.5 0.1 2.2 x 10 1 5.8-9.0 7.4 0.6 2.8 x 10 2 4.7-5.8 5.25 0.7 9.2 x 10 3 3.3-4.7 4.0 1.1 3.3x10 4 2.1-3.3 2.7 1.1 108 1.1-2.1 1.6 1.1 5.1 x 108 6 0.7-1.1 0.9 0.7 1.8x10 7 0.4-0.7 0.55 0.3 4.6 x 10 8 0-0.4 0.2 0.2 4.8 x 1010 Drug Mass Density and Rate ofDrug Aerosol Formatiov ofMidazolam Aerosol [0092] A solution of 16.7mg midazolam in 200 L dichloromethane was spread out in a thin layer on the central portion of a 4 cm x 9 cm sheet of aluminum foil.
The dichloromethane was allowed to evaporate. The aluminum foil was wrapped around a 300 watt halogen tube, which was inserted into a T-shaped glass tube. One of the openings of the tube was sealed with a rubber stopper, another was loosely covered with the end of the halogen tube, and the third was connected to a 1 liter, 3-neck glass flask.
The glass flask was further connected to a large piston capable of drawing 1.1 liters of air through the flask. Alterna.ting current was run through the halogen bulb by application of 90 V using a variac connected to 110 V line power. Within seconds, an aerosol appeared and was drawn into the 1 L flask by use of the piston, with formation of the aerosol terminated after 6 s.
The aerosol was allowed to sediment onto the walls of the 1 L flask for approximately 30 minutes. The flask was then extracted with dichloromethane and the extract analyzed by HPI.C with detection by light absorption at 225 nm. Comparison with standards containing known amounts of midazolam revealed that 8.12 mg of > 99% pure midazolam had been collected in the flask, resulting in an aerosol drug mass density of 8.12 mg/L. The aluminum foil upon which the midazolam had previously been coated was weighed following the experiment. Of the 16.7 mg originally coated on the aluminum, all of the material was found to have aerosolized in the 6 s time period, implying a rate of drug aerosol formation of 2.7 mg/s.

Volatilization of Triazolam [009:3] A solution of 2.0 mg triazolam in 120 gL dichloromethane was coated on a 3.6 cm x 8 cm piece of aluminum foil. The dichloromethane was allowed to evaporate. The coated foil was wrapped around a 300 watt halogen tube (Feit Electric Company, Pico Rivera, CA), which was inserted into a glass tube sealed at one end with a rubber stopper.
Running 75 V of alternating current (driven by line power controlled by a variac) through the bulb for 2 s, followed by 45 V for 8 s, afforded triazolam thermal vapor (including triazolam aerosol), which collected on the glass tube walls. Reverse-phase HPLC analysis with detection by absorption of 225 nm light showed the collected material to be at least 99.85% pure triazolam.

Particle Size, Particle Density, and Rate oflnbalable Partrcle Formation of Triazolam Aerosol [0094] A solution of 16.4 mg triazolam in 200 L dichloromethane was spread out in a thin layer on the central portion of a 4 cm x 9 cro sheet of aluminum foil.
The dichloromethane was allowed to evaporate. The aluminum foil was wrapped around a 300 watt halogen tube, which was inserted into a T-shaped glass tube. One of the openings of the tube was sealed with a rubber stopper, another was loosely covered with the end of the halogen tube, and the third was connected to a 1 liter, 3-neck glass flask.
The glass flask was further connected to a large piston capable of drawing 1.1 liters of air through the flask. Alternating current was run through the halogen bulb by application of 90 V using a variac connected to 110 V line power. Within 1 s, an aerosol appeared and was drawn into the 1 L flask by use of the piston, with collection of the aerosol terminated after 6 s. The aerosol was analyzed by connecting the 1 L flask to an eight-stage Andersen non-viable cascade impactor. Results are shown in table 1. MMAD of the collected aerosol was 2.2 microns with a geometric standard deviation of 2. Also shown in table 1 is the number of particles collected on the various stages of the cascade impactor, given by the mass collected on the stage divided by the mass of a typical particle trapped on that stage. The mass of a single particle of diameter D is given by the volume of the particle, 70 3/6, multiplied by the density of the drug (taken to be 1 g/cm3). The inhalable aerosol particle density is the sum of the numbers of particles collected on impactor stages 3 to 8 divided by the collection volume of 1 L, giving an inhalable aerosol particle density of 3.8 x 106 particles/mL. The rate of inhalable aerosol particle formation is the sum of the numbers of particles collected on impactor stages 3 through 8 divided by the formation time of 6 s, giving a rate of inhalable aerosol particle formation of 6 x 108 particles/second.
[0095] Table 1: Determination of the characteristics of a triazolam condensation aerosol by cascade impaction using an Andersen 8-stage non-viable cascade impactor run at 1 cubic foot per minute air flow.

Stage Particle size Average particle Mass Number of range (microns) size (microns) collected particles (mg) 0 9.0-10.0 9.5 0.0 0 1 5.8-9.0 7.4 0.3 1.4x10 2 4.7-5.8 5.25 0.3 4.0 x 10 3 3.3-4.7 4.0 0.7 2.1x10 4 2.1-3.3 2.7 1.2 1.2x10 1.1-2.1 1.6 1.5 7.0x10 6 0.7-1.1 0.9 0.7 1.8x 10 7 0.4-0.7 0.55 0.1 1.2 x 09 8 0-0.4 0.2 0.0 0 Drrrg Mass Density and Rate ofDrrrg Aerosol Forma tion of Triazolam Aerosol [0096] A solution of 0.6 mg triazolam in 200 L dichloromethane was spread out in a thin layer on the central portion of a 4 cm x 9 cm sheet of aluminum foil. The dichloromethane was allowed to evaporate. The aluminum foil was wrapped around a 300 watt halogen tube, which was inserted into a T-shaped glass tube. One of the openings of the tube was sealed with a rubber stopper, another was loosely covered with the end of the halogen tube, and the third was connected to a 1 liter, 3-neck glass flask.
The glass flask was further connected to a large piston capable of drawing 1.1 liters of air-through the flask. Glass wool was placed in the tube connecting the flask to the piston _Alternating current was run through the halogen bulb by application of 90 V using a variac connected to 110 V line power. Within seconds, an aerosol appeared and was drawn into the 1 L flask by use of the piston, with formation of the aerosol terminated after 6 s. The aerosol was allowed to sediment onto the walls of the 1 L flask for approximately 30 minutes. The flask and glass wool were then extracted with dichloromethane and the extract analyzed by HPLC with detection by light absorption at 225 nm. Comparison with standards containing knovvn amounts of triazolam revealed that 0.17 mg of > 99% pure triazolain had been collected in the flask, resulting in an aerosol drug mass density of 0.17 mg/L. The aluminum foil upon which the triazolam had previously been coated was weighed following the experiment. Of the 0.6 mg originally coated on the aluminum, all of the material was found to have aerosolized in the 6 s time period, implying a rate of drug aerosol formation of 0.1 mg/s.

Delivery of Triazolam to a Dog [0097] Apnea was induced in a dog, which was subsequently exposed to a 15 SLPM
flow of air containing 140 g of triazolam (condensation aerosol formed by volatilizing triazolam off of a heated, metal substrate; MMAD -1.1) through an endotracheal tube.
This corresponded to approximately a 625 cc volume of inhalation air delivered to the dog.
Once the dog had received the triazolam aerosol, an air supply valve was shut off for 5 s, which simulated a 5 s breath hold. Following the hold, the dog was allowed to exhale through an exhalation filter. Arterial blood samples were taken at the following intervals:
0 min, 0.25 min, 0.5 min, 1 min, 1.5 min, 2 min, 10 min, and 30 min. HPLC
analysis of the blood samples indicated that the Tmax for triazolam was about 0.25 minutes, with a concentration of greater than 100 ng/mL reached.

Claims (25)

1. A condensation aerosol containing a therapeutic compound selected from the group consisting of alprazolam, estazolam, midazolam and triazolam, wherein:
a) said condensation aerosol comprises particles comprising less than 10 percent by weight therapeutic compound degradation products; and b) said condensation aerosol has an MMAD of less than 5 µm.
2. A condensation aerosol according to Claim 1, formed by volatilizing the therapeutic compound under conditions effective to produce a vapor of the therapeutic compound and condensing the vapor to form said particles.
3. A condensation aerosol according to Claim 2, wherein said volatilizing includes heating a solid support coated with a composition comprising the therapeutic compound to volatilize the therapeutic compound from the coated composition.
4. A condensation aerosol according to Claim 2 or 3, wherein said condensing includes allowing the vapor to cool.
5. A condensation aerosol according to any one of Claims 1 to 4, wherein said particles comprise less than 5 percent by weight therapeutic compound degradation products.
6. A condensation aerosol according to any one of Claims 1 to 4, wherein said particles comprise less than 2.5 percent by weight therapeutic compound degradation products.
7. A condensation aerosol according to any one of Claims 1 to 6, wherein said condensation aerosol comprises at least 5 percent by weight of the therapeutic compound.
8. A condensation aerosol according to any one of Claims 1 to 6, wherein said condensation aerosol comprises at least 90 percent by weight of the therapeutic compound.
9. A condensation aerosol according to any one of Claims 1 to 8, wherein said condensation aerosol has an MMAD of less than 3 µm
10. A condensation aerosol according to any one of Claims 1 to 9 for use in inhalation therapy.
11. A composition for delivery of an therapeutic compound, the composition comprising a condensation aerosol according to any one of Claims 1 to 10.
12. A method of producing an therapeutic compound in an aerosol form comprising:
a) volatilizing an therapeutic compound selected from the group consisting of alprazolam, estazolam, midazolam and triazolam, under conditions effective to produce a vapor of the therapeutic compound, wherein said volatilizing comprises heating a composition comprising at least 5 percent by weight of the therapeutic compound; and b) condensing the vapor thereby providing a condensation aerosol comprising particles comprising less than 10 percent by weight therapeutic compound degradation products and having an MMAD of less than 5 µm.
13. A method according to Claim 12, wherein step a) comprises heating a solid support coated with a composition comprising the therapeutic compound to volatilize the therapeutic compound from the coated composition.
14. A method according to Claim 12, wherein step a) comprises heating a solid support on which a composition comprising the therapeutic compound is deposited to volatilize the therapeutic compound from the deposited composition.
15. A method according to any one of Claims 12 to 14, wherein step b) comprises allowing the vapor to cool thereby providing the condensation aerosol.
16. A method according to any one of Claims 12 to 15, wherein said particles comprise less than 5 percent by weight therapeutic compound degradation products.
17. A method according to any one of Claims 12 to 15, wherein said particles comprise less than 2.5 percent by weight therapeutic compound degradation products.
18. A method according to any one of Claims 12 to 17, wherein said condensation aerosol comprises at least 90 percent by weight of the therapeutic compound.
19. A method according to any one of Claims 12 to 18, wherein said particles are formed at a rate of greater than 0.5 mg/sec.
20. A method according to any one of Claims 12 to 18, wherein said particles are formed at a rate of greater than 1 mg/sec.
21. A method according to any one of Claims 12 to 20, wherein said condensation aerosol has an MMAD of less than 3 µm.
22. A method according to any one of Claims 12 to 21, wherein the condensation aerosol is for use in inhalation therapy.
23. A kit for delivering an therapeutic compound selected from the group consisting of alprazolam, estazolam, midazolam and triazolam, wherein the kit comprises:
a) a composition comprising the therapeutic compound; and b) a device that forms an therapeutic compound aerosol from the composition; wherein the device comprises:

1) an element for heating the therapeutic compound composition to form a vapour;

2) an element allowing the vapour to cool to form an aerosol; and 3) an element permitting inhalation of the aerosol.
24. A kit according to claim 23, wherein the condensation aerosol is for use in inhalation therapy.
25. A kit according to claim 23 or 24, wherein the condensation aerosol is as defined in any one of claims 1 to 10.
CA002641760A 2001-05-24 2002-05-22 Delivery of alprazolam, estazolam, midazolam or triazolam through an inhalation route Abandoned CA2641760A1 (en)

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Families Citing this family (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6805853B2 (en) * 2001-11-09 2004-10-19 Alexza Molecular Delivery Corporation Delivery of diazepam through an inhalation route
US7498019B2 (en) 2001-05-24 2009-03-03 Alexza Pharmaceuticals, Inc. Delivery of compounds for the treatment of headache through an inhalation route
US20030051728A1 (en) 2001-06-05 2003-03-20 Lloyd Peter M. Method and device for delivering a physiologically active compound
US20070122353A1 (en) 2001-05-24 2007-05-31 Hale Ron L Drug condensation aerosols and kits
JP2005503425A (en) * 2001-05-24 2005-02-03 アレックザ モレキュラー デリヴァリー コーポレイション Delivery of drug ester by the prescribed inhalation route
US7090830B2 (en) * 2001-05-24 2006-08-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US7645442B2 (en) 2001-05-24 2010-01-12 Alexza Pharmaceuticals, Inc. Rapid-heating drug delivery article and method of use
ATE415155T1 (en) * 2001-05-24 2008-12-15 Alexza Pharmaceuticals Inc ADMINISTRATION OF ALPRAZOLAM, ESTAZOLAM, MIDAZOLAM, OR TRIAZOLAM BY INHALATION
WO2002094242A1 (en) 2001-05-24 2002-11-28 Alexza Molecular Delivery Corporation Delivery of rizatriptan or zolmitriptan through an inhalation route
US7078016B2 (en) * 2001-11-21 2006-07-18 Alexza Pharmaceuticals, Inc. Delivery of caffeine through an inhalation route
US7458374B2 (en) 2002-05-13 2008-12-02 Alexza Pharmaceuticals, Inc. Method and apparatus for vaporizing a compound
EP1503744A1 (en) * 2002-05-13 2005-02-09 Alexza Molecular Delivery Corporation Delivery of drug amines through an inhalation route
US20060193788A1 (en) * 2002-11-26 2006-08-31 Hale Ron L Acute treatment of headache with phenothiazine antipsychotics
US7550133B2 (en) * 2002-11-26 2009-06-23 Alexza Pharmaceuticals, Inc. Respiratory drug condensation aerosols and methods of making and using them
US20040105818A1 (en) 2002-11-26 2004-06-03 Alexza Molecular Delivery Corporation Diuretic aerosols and methods of making and using them
CA2507158A1 (en) * 2002-11-26 2004-06-10 Alexza Molecular Delivery Corporation Treatment of headache with antipsychotics delivered by inhalation
JP2006514934A (en) * 2002-11-26 2006-05-18 アレックザ ファーマシューティカルズ， インコーポレイテッド Use of loxapine or amoxapine for the manufacture of drugs for the treatment of pain
US7913688B2 (en) 2002-11-27 2011-03-29 Alexza Pharmaceuticals, Inc. Inhalation device for producing a drug aerosol
AU2003297087B2 (en) * 2003-02-04 2009-06-11 Philip Morris Products S.A. Aerosol formulations and aerosol delivery of buspirone, buprenorphine, triazolam, cyclobenzaprine and zolpidem
ATE510174T1 (en) * 2003-05-21 2011-06-15 Alexza Pharmaceuticals Inc IMPACT LIT INDEPENDENT HEATING UNIT
US20050034723A1 (en) * 2003-08-04 2005-02-17 Bryson Bennett Substrates for drug delivery device and methods of preparing and use
US20050163843A1 (en) * 2003-12-31 2005-07-28 Garth Boehm Alprazolam formulations
GB0400804D0 (en) 2004-01-14 2004-02-18 Innoscience Technology Bv Pharmaceutical compositions
US7402777B2 (en) 2004-05-20 2008-07-22 Alexza Pharmaceuticals, Inc. Stable initiator compositions and igniters
US7540286B2 (en) 2004-06-03 2009-06-02 Alexza Pharmaceuticals, Inc. Multiple dose condensation aerosol devices and methods of forming condensation aerosols
CN101189001A (en) * 2005-02-15 2008-05-28 伊兰制药国际有限公司 Aerosol and injectable formulations of nanoparticulate benzodiazepine
US20070087055A1 (en) * 2005-10-14 2007-04-19 David Jan Directly compressible extended release alprazolam formulation
US8252328B2 (en) 2006-01-06 2012-08-28 Acelrx Pharmaceuticals, Inc. Bioadhesive drug formulations for oral transmucosal delivery
US8535714B2 (en) 2006-01-06 2013-09-17 Acelrx Pharmaceuticals, Inc. Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain
US9289583B2 (en) 2006-01-06 2016-03-22 Acelrx Pharmaceuticals, Inc. Methods for administering small volume oral transmucosal dosage forms using a dispensing device
US8202535B2 (en) * 2006-01-06 2012-06-19 Acelrx Pharmaceuticals, Inc. Small-volume oral transmucosal dosage forms
US9066847B2 (en) 2007-01-05 2015-06-30 Aceirx Pharmaceuticals, Inc. Storage and dispensing devices for administration of oral transmucosal dosage forms
US8753308B2 (en) 2006-01-06 2014-06-17 Acelrx Pharmaceuticals, Inc. Methods for administering small volume oral transmucosal dosage forms using a dispensing device
US8865743B2 (en) 2006-01-06 2014-10-21 Acelrx Pharmaceuticals, Inc. Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain
US8357114B2 (en) * 2006-01-06 2013-01-22 Acelrx Pharmaceuticals, Inc. Drug dispensing device with flexible push rod
US8252329B2 (en) 2007-01-05 2012-08-28 Acelrx Pharmaceuticals, Inc. Bioadhesive drug formulations for oral transmucosal delivery
US8915158B2 (en) * 2006-06-02 2014-12-23 MicroZeus, LLC Methods and systems for micro transmissions
US20070299687A1 (en) * 2006-06-23 2007-12-27 Pamela Palmer Inpatient system for patient-controlled delivery of oral transmucosal medications dosed as needed
US20080299048A1 (en) * 2006-12-22 2008-12-04 Alexza Pharmaceuticals, Inc. Mixed drug aerosol compositions
US20080275030A1 (en) * 2007-01-19 2008-11-06 Sveinbjorn Gizurarson Methods and Compositions for the Delivery of a Therapeutic Agent
WO2008112661A2 (en) 2007-03-09 2008-09-18 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
ES2403193T3 (en) 2008-02-05 2013-05-16 Laboratorios Bago S.A. Compositions comprising alprazolam for the treatment of primary insomnia and insomnia associated with anxiety states and procedures for their preparation
WO2009102976A2 (en) * 2008-02-15 2009-08-20 Timothy Sean Immel Aerosol therapy device with high frequency delivery
US7834295B2 (en) 2008-09-16 2010-11-16 Alexza Pharmaceuticals, Inc. Printable igniters
US20100065052A1 (en) * 2008-09-16 2010-03-18 Alexza Pharmaceuticals, Inc. Heating Units
US8945592B2 (en) 2008-11-21 2015-02-03 Acelrx Pharmaceuticals, Inc. Sufentanil solid dosage forms comprising oxygen scavengers and methods of using the same
US8548623B2 (en) 2009-03-18 2013-10-01 Acelrx Pharmaceuticals, Inc. Storage and dispensing devices for administration of oral transmucosal dosage forms
US20100300433A1 (en) * 2009-05-28 2010-12-02 Alexza Pharmaceuticals, Inc. Substrates for Enhancing Purity or Yield of Compounds Forming a Condensation Aerosol
US20100181387A1 (en) * 2009-12-01 2010-07-22 Zaffaroni Alejandro C Aerosol delivery system and uses thereof
US20120048963A1 (en) 2010-08-26 2012-03-01 Alexza Pharmaceuticals, Inc. Heat Units Using a Solid Fuel Capable of Undergoing an Exothermic Metal Oxidation-Reduction Reaction Propagated without an Igniter
US20140158129A1 (en) 2010-09-22 2014-06-12 Clovershield, Inc. Transversely-activated valve for a therapeutic vaporizer bag attachment system
US11577035B2 (en) 2010-09-22 2023-02-14 Robert Irving Pratt, JR. Therapeutic vaporizer
KR20130099112A (en) * 2010-09-22 2013-09-05 클로버쉴드, 인크. Therapeutic vaporizer
US10478505B2 (en) 2011-09-23 2019-11-19 The Regents Of The University Of California Edible oils to enhance delivery of orally administered steroids
RS59734B1 (en) 2012-01-23 2020-02-28 Sage Therapeutics Inc Neuroactive steroid formulations comprising a complex of allopregnanolone and sulfobutyl ether beta-cyclodextrin
US20140050789A1 (en) 2012-08-13 2014-02-20 The Regents Of The University Of California Mitigation of epileptic seizures by combination therapy using benzodiazepines and neurosteroids
EP4335505A2 (en) 2012-11-30 2024-03-13 The Regents of The University of California Anticonvulsant activity of steroids
USD752807S1 (en) 2013-02-19 2016-03-29 1Ready, Llc Therapeutic vaporizer
JP6397493B2 (en) 2013-07-11 2018-09-26 アレックザ ファーマシューティカルズ， インコーポレイテッド Nicotine salt with meta-salicylic acid
MY187877A (en) 2014-12-23 2021-10-26 Acelrx Pharmaceuticals Inc Systems, devices and methods for dispensing oral transmucosal dosage forms
CN114522307A (en) * 2015-03-11 2022-05-24 艾利斯达医药品公司 Use of antistatic materials in airways for hot aerosol condensation processes
CN111603643B (en) 2015-04-02 2023-05-23 希尔－罗姆服务私人有限公司 Pressure control of breathing apparatus
USD799691S1 (en) 2015-09-03 2017-10-10 1Ready, Llc Tray for a therapeutic vaporizer
CA3158448A1 (en) 2016-03-08 2017-09-14 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
RS65112B1 (en) * 2016-12-09 2024-02-29 Alexza Pharmaceuticals Inc Alprazolam for use in treating epilepsy

Family Cites Families (146)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE629985A (en) 1962-11-29
GB1063512A (en) 1962-11-30 1967-03-30 Benger Lab Ltd Aerosols
USRE30285E (en) 1972-05-22 1980-05-27 Spraying devices, in particular nebulizing devices
US3949743A (en) 1973-03-19 1976-04-13 Schick Incorporated Medicated vapor production method and apparatus
US3982095A (en) 1973-10-04 1976-09-21 Searle Cardio-Pulmonary Systems Inc. Respiratory humidifier
US4141369A (en) 1977-01-24 1979-02-27 Burruss Robert P Noncombustion system for the utilization of tobacco and other smoking materials
US4229447A (en) 1979-06-04 1980-10-21 American Home Products Corporation Intraoral methods of using benzodiazepines
US4303083A (en) 1980-10-10 1981-12-01 Burruss Jr Robert P Device for evaporation and inhalation of volatile compounds and medications
DE3116951C2 (en) 1981-04-29 1984-12-20 Drägerwerk AG, 2400 Lübeck Device for adding liquid anesthetics to the breathing gas to be supplied to the patient
DE3224849A1 (en) 1982-07-02 1984-01-05 Plantorgan Werk Heinrich G.E. Christensen, KG, 2903 Bad Zwischenahn STEAM INHALER
US4508726A (en) 1982-09-16 1985-04-02 The Upjohn Company Treatment of panic disorders with alprazolam
US4474191A (en) 1982-09-30 1984-10-02 Steiner Pierre G Tar-free smoking devices
US4588721A (en) 1983-09-12 1986-05-13 The Upjohn Company Treatment of negative symptoms of schizophrenia
US4683231A (en) 1984-03-02 1987-07-28 Research Foundation For Mental Hygiene, Inc. Method of preventing withdrawal symptoms associated with the cessation or reduction of tobacco smoking
US5042509A (en) 1984-09-14 1991-08-27 R. J. Reynolds Tobacco Company Method for making aerosol generating cartridge
JPS63500175A (en) 1985-05-22 1988-01-21 リポソ−ム　テクノロジ−，インコ−ポレイテツド Liposome inhalation method and inhalation system
ATE60226T1 (en) 1986-03-10 1991-02-15 Kurt Burghart PHARMACEUTICAL AND PROCESS FOR PRODUCTION.
US4708151A (en) 1986-03-14 1987-11-24 R. J. Reynolds Tobacco Company Pipe with replaceable cartridge
US4735217A (en) 1986-08-21 1988-04-05 The Procter & Gamble Company Dosing device to provide vaporized medicament to the lungs as a fine aerosol
US4734560A (en) 1987-01-20 1988-03-29 Medical Enterprises, Ltd. Vaporizing unit
US4819665A (en) 1987-01-23 1989-04-11 R. J. Reynolds Tobacco Company Aerosol delivery article
US4924883A (en) 1987-03-06 1990-05-15 R. J. Reynolds Tobacco Company Smoking article
GB8713645D0 (en) 1987-06-11 1987-07-15 Imp Tobacco Ltd Smoking device
US4906417A (en) 1988-02-08 1990-03-06 Associated Mills Inc. Humidifier
US4853517A (en) 1988-03-28 1989-08-01 John G. Bowen Vaporizing unit
US5345951A (en) 1988-07-22 1994-09-13 Philip Morris Incorporated Smoking article
EP0358114A3 (en) 1988-09-08 1990-11-14 R.J. Reynolds Tobacco Company Aerosol delivery articles utilizing electrical energy
USRE36744E (en) 1988-09-16 2000-06-20 Ribogene, Inc. Nasal administration of benzodiazepine hypnotics
US4950664A (en) 1988-09-16 1990-08-21 Rugby-Darby Group Companies, Inc. Nasal administration of benzodiazepine hypnotics
US4963289A (en) 1988-09-19 1990-10-16 The United States Of America As Represented By The United States Department Of Energy Method for producing monodisperse aerosols
US5511726A (en) 1988-09-23 1996-04-30 Battelle Memorial Institute Nebulizer device
US4917119A (en) 1988-11-30 1990-04-17 R. J. Reynolds Tobacco Company Drug delivery article
US4906476A (en) 1988-12-14 1990-03-06 Liposome Technology, Inc. Novel liposome composition for sustained release of steroidal drugs in lungs
DE3908161A1 (en) 1989-03-13 1990-09-27 Bat Cigarettenfab Gmbh Smokable article
EP0705614B1 (en) 1989-04-28 2002-09-25 Riker Laboratories, Inc. Dry powder inhalation device
HUT60631A (en) 1989-05-05 1992-10-28 North Sydney Area Health Serv Process for producing pharmaceutical compositions suitable for increasing fertility
US4941483A (en) 1989-09-18 1990-07-17 R. J. Reynolds Tobacco Company Aerosol delivery article
US6048857A (en) 1989-10-17 2000-04-11 Ellinwood, Jr.; Everett H. Dosing method of administering medicaments via inhalation administration
US5144962A (en) 1989-12-01 1992-09-08 Philip Morris Incorporated Flavor-delivery article
US5060671A (en) 1989-12-01 1991-10-29 Philip Morris Incorporated Flavor generating article
US5224498A (en) 1989-12-01 1993-07-06 Philip Morris Incorporated Electrically-powered heating element
GB2239807A (en) 1990-01-09 1991-07-17 Boc Group Plc Anaesthetic vaporiser
US5099861A (en) 1990-02-27 1992-03-31 R. J. Reynolds Tobacco Company Aerosol delivery article
US5366770A (en) 1990-04-17 1994-11-22 Xingwu Wang Aerosol-plasma deposition of films for electronic cells
DE69110785T3 (en) 1990-08-02 2002-05-23 Boc Group Plc Anesthetic vaporizers.
US5166202A (en) 1990-09-19 1992-11-24 Trustees Of The University Of Pennsylvania Method for the treatment of panic disorder
ATE179605T1 (en) 1991-02-09 1999-05-15 B S D Bio Science Dev Snc Di O ANTIREACTIVE ANTIASTHMATIC EFFECT OF ACETYL SALICYLIC ACID BY INHALATION
US5993805A (en) 1991-04-10 1999-11-30 Quadrant Healthcare (Uk) Limited Spray-dried microparticles and their use as therapeutic vehicles
US5457100A (en) 1991-12-02 1995-10-10 Daniel; David G. Method for treatment of recurrent paroxysmal neuropsychiatric
US5639441A (en) 1992-03-06 1997-06-17 Board Of Regents Of University Of Colorado Methods for fine particle formation
AU5358694A (en) * 1992-10-28 1994-05-24 Charles A. Rosen Method and devices for delivering drugs by inhalation
US5694919A (en) 1993-01-29 1997-12-09 Aradigm Corporation Lockout device for controlled release of drug from patient-activated dispenser
US5558085A (en) 1993-01-29 1996-09-24 Aradigm Corporation Intrapulmonary delivery of peptide drugs
US5672581A (en) 1993-01-29 1997-09-30 Aradigm Corporation Method of administration of insulin
US5915378A (en) 1993-01-29 1999-06-29 Aradigm Corporation Creating an aerosolized formulation of insulin
US5507277A (en) 1993-01-29 1996-04-16 Aradigm Corporation Lockout device for controlled release of drug from patient-activateddispenser
US5724957A (en) 1993-01-29 1998-03-10 Aradigm Corporation Intrapulmonary delivery of narcotics
US5934272A (en) 1993-01-29 1999-08-10 Aradigm Corporation Device and method of creating aerosolized mist of respiratory drug
US5497763A (en) 1993-05-21 1996-03-12 Aradigm Corporation Disposable package for intrapulmonary delivery of aerosolized formulations
US5666977A (en) 1993-06-10 1997-09-16 Philip Morris Incorporated Electrical smoking article using liquid tobacco flavor medium delivery system
ES2171455T3 (en) 1993-06-29 2002-09-16 Ponwell Entpr Ltd DISPENSER.
US5388574A (en) 1993-07-29 1995-02-14 Ingebrethsen; Bradley J. Aerosol delivery article
DE4328243C1 (en) 1993-08-19 1995-03-09 Sven Mielordt Smoke or inhalation device
US5456247A (en) 1993-08-26 1995-10-10 Iowa State University Research Foundation, Inc. Method for delivering drugs soluble in a vaporization vehicle
FI98270C (en) 1993-11-29 1997-05-26 Instrumentarium Oy Method and apparatus for evaporation of anesthetic agent
US5543434A (en) 1994-02-25 1996-08-06 Weg; Stuart L. Nasal administration of ketamine to manage pain
US6102036A (en) 1994-04-12 2000-08-15 Smoke-Stop Breath activated inhaler
CA2152684A1 (en) 1994-07-01 1996-01-02 Richard Anthony Henry Aerosol delivery of midazolam
US5522385A (en) 1994-09-27 1996-06-04 Aradigm Corporation Dynamic particle size control for aerosolized drug delivery
JP3748890B2 (en) 1994-10-28 2006-02-22 アラダイム コーポレーション Disposable container, disposable package, drug delivery device, and method for producing aerosol for use in aerosolized spray of respiratory medication
US5767117A (en) 1994-11-18 1998-06-16 The General Hospital Corporation Method for treating vascular headaches
CA2216443A1 (en) 1995-03-31 1996-10-03 Aradigm Corporation Intrapulmonary delivery of hematopoietic drug
US5758637A (en) 1995-08-31 1998-06-02 Aerogen, Inc. Liquid dispensing apparatus and methods
US5612053A (en) 1995-04-07 1997-03-18 Edward Mendell Co., Inc. Controlled release insufflation carrier for medicaments
US5874481A (en) 1995-06-07 1999-02-23 Alliance Pharmaceutical Corp. Fluorochemical solutions for the delivery of lipophilic pharmaceutical agents
US5649554A (en) 1995-10-16 1997-07-22 Philip Morris Incorporated Electrical lighter with a rotatable tobacco supply
US5564442A (en) 1995-11-22 1996-10-15 Angus Collingwood MacDonald Battery powered nicotine vaporizer
US6041777A (en) * 1995-12-01 2000-03-28 Alliance Pharmaceutical Corp. Methods and apparatus for closed-circuit ventilation therapy
NZ330679A (en) 1995-12-14 2000-03-27 Taisho Pharmaceutical Co Ltd an aerosol preparation containing an alcohol having 1 to 3 carbons, alcohol having 12 or more carbons and a liquefied gas propellant; use as a pain relief spray
SE9504580L (en) 1995-12-21 1997-06-22 Siemens Elema Ab Procedure for gasification of an anesthetic fluid and a carburetor
EP0955885A1 (en) 1996-02-05 1999-11-17 Aradigm Corporation Ventilation imaging using a fine particle aerosol generator
US5743251A (en) 1996-05-15 1998-04-28 Philip Morris Incorporated Aerosol and a method and apparatus for generating an aerosol
US5874064A (en) 1996-05-24 1999-02-23 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
US5855913A (en) 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
GB9613015D0 (en) 1996-06-21 1996-08-28 Reckitt & Colman Inc Device
US6694975B2 (en) 1996-11-21 2004-02-24 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US5906202A (en) 1996-11-21 1999-05-25 Aradigm Corporation Device and method for directing aerosolized mist to a specific area of the respiratory tract
US5829435A (en) 1997-02-24 1998-11-03 Aradigm Corporation Prefilter for prevention of clogging of a nozzle in the generation of an aerosol and prevention of administration of undesirable particles
KR100289448B1 (en) 1997-07-23 2001-05-02 미즈노 마사루 Flavor generator
US6090212A (en) 1997-08-15 2000-07-18 Micro C Technologies, Inc. Substrate platform for a semiconductor substrate during rapid high temperature processing and method of supporting a substrate
EP1019021B2 (en) 1997-09-29 2012-12-26 Novartis AG Stabilized preparations for use in metered dose inhalers
US6403597B1 (en) 1997-10-28 2002-06-11 Vivus, Inc. Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation
US6158431A (en) 1998-02-13 2000-12-12 Tsi Incorporated Portable systems and methods for delivery of therapeutic material to the pulmonary system
US20020086852A1 (en) 1998-05-14 2002-07-04 Cantor Jerome O. Method for treating respiratory disorders associated with pulmonary elastic fiber injury
EP1083951A4 (en) 1998-06-12 2004-07-07 Aradigm Corp Methods of delivering aerosolized polynucleotides to the respiratory tract
US6095153A (en) 1998-06-19 2000-08-01 Kessler; Stephen B. Vaporization of volatile materials
US6241969B1 (en) 1998-06-26 2001-06-05 Elan Corporation Plc Aqueous compositions containing corticosteroids for nasal and pulmonary delivery
WO2000000215A1 (en) 1998-06-29 2000-01-06 Inhale Therapeutic Systems, Inc. Particulate delivery systems and methods of use
GB9814172D0 (en) 1998-06-30 1998-08-26 Andaris Ltd Formulation for inhalation
US6234167B1 (en) 1998-10-14 2001-05-22 Chrysalis Technologies, Incorporated Aerosol generator and methods of making and using an aerosol generator
US6255334B1 (en) 1998-10-30 2001-07-03 Pfizer Inc 5HT 1 receptor agonists and metoclopramide for the treatment of migraine
US6070575A (en) 1998-11-16 2000-06-06 Aradigm Corporation Aerosol-forming porous membrane with certain pore structure
AU2879100A (en) 1999-02-12 2000-08-29 Miles A. Libbey Iii Formulation and system for intra-oral delivery of pharmaceutical agents
US6591839B2 (en) * 1999-02-17 2003-07-15 Dieter Meyer Filter material for reducing harmful substances in tobacco smoke
WO2000064940A1 (en) 1999-04-27 2000-11-02 Eli Lilly And Company Insulin crystals for pulmonary administration
ATE274955T1 (en) 1999-05-03 2004-09-15 Battelle Memorial Institute MEDICINAL COMPOSITIONS FOR AEROSOL FORMATION AND INHALATION PURPOSES
US6428769B1 (en) 1999-05-04 2002-08-06 Aradigm Corporation Acute testosterone administration
CA2374232C (en) 1999-06-11 2013-08-20 Aradigm Corporation Method for producing an aerosol
AU777326B2 (en) 1999-07-16 2004-10-14 Aradigm Corporation System for effecting smoke cessation
HUP0202636A3 (en) 1999-09-30 2004-06-28 Pfizer Certain alkylene diamine-substituted heterocycles
CA2401288A1 (en) 2000-02-28 2001-09-07 Vectura Limited Improvements in or relating to the delivery of oral drugs
US6632047B2 (en) 2000-04-14 2003-10-14 Board Of Regents, The University Of Texas System Heater element for use in an in situ thermal desorption soil remediation system
MY136453A (en) * 2000-04-27 2008-10-31 Philip Morris Usa Inc "improved method and apparatus for generating an aerosol"
US6514482B1 (en) * 2000-09-19 2003-02-04 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
US6613308B2 (en) 2000-09-19 2003-09-02 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
WO2002056932A2 (en) 2000-10-27 2002-07-25 Emlin Biosciences Thermal vaporizing device for drug delivery
WO2002074247A2 (en) 2001-03-19 2002-09-26 Praecis Pharmaceuticals Incorporated Pharmaceutical formulations for sustained release
US20030004142A1 (en) * 2001-04-18 2003-01-02 Prior Christopher P. Use of NSAIDs for prevention and treatment of cellular abnormalities of the lung or bronchial pathway
US7645442B2 (en) * 2001-05-24 2010-01-12 Alexza Pharmaceuticals, Inc. Rapid-heating drug delivery article and method of use
US20070122353A1 (en) * 2001-05-24 2007-05-31 Hale Ron L Drug condensation aerosols and kits
US20030118512A1 (en) * 2001-10-30 2003-06-26 Shen William W. Volatilization of a drug from an inclusion complex
ATE415155T1 (en) * 2001-05-24 2008-12-15 Alexza Pharmaceuticals Inc ADMINISTRATION OF ALPRAZOLAM, ESTAZOLAM, MIDAZOLAM, OR TRIAZOLAM BY INHALATION
US7090830B2 (en) * 2001-05-24 2006-08-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
WO2002094244A2 (en) * 2001-05-24 2002-11-28 Alexza Molecular Delivery Corporation Delivery of benzodiazepines through an inhalation route
WO2002094242A1 (en) * 2001-05-24 2002-11-28 Alexza Molecular Delivery Corporation Delivery of rizatriptan or zolmitriptan through an inhalation route
JP2005503425A (en) * 2001-05-24 2005-02-03 アレックザ モレキュラー デリヴァリー コーポレイション Delivery of drug ester by the prescribed inhalation route
US6805853B2 (en) * 2001-11-09 2004-10-19 Alexza Molecular Delivery Corporation Delivery of diazepam through an inhalation route
US7585493B2 (en) * 2001-05-24 2009-09-08 Alexza Pharmaceuticals, Inc. Thin-film drug delivery article and method of use
US20030051728A1 (en) * 2001-06-05 2003-03-20 Lloyd Peter M. Method and device for delivering a physiologically active compound
US6701922B2 (en) 2001-12-20 2004-03-09 Chrysalis Technologies Incorporated Mouthpiece entrainment airflow control for aerosol generators
US6772756B2 (en) 2002-02-09 2004-08-10 Advanced Inhalation Revolutions Inc. Method and system for vaporization of a substance
EP1503744A1 (en) * 2002-05-13 2005-02-09 Alexza Molecular Delivery Corporation Delivery of drug amines through an inhalation route
JP2006514934A (en) * 2002-11-26 2006-05-18 アレックザ ファーマシューティカルズ， インコーポレイテッド Use of loxapine or amoxapine for the manufacture of drugs for the treatment of pain
US7550133B2 (en) * 2002-11-26 2009-06-23 Alexza Pharmaceuticals, Inc. Respiratory drug condensation aerosols and methods of making and using them
US20040105818A1 (en) * 2002-11-26 2004-06-03 Alexza Molecular Delivery Corporation Diuretic aerosols and methods of making and using them
CA2507158A1 (en) * 2002-11-26 2004-06-10 Alexza Molecular Delivery Corporation Treatment of headache with antipsychotics delivered by inhalation
US7913688B2 (en) * 2002-11-27 2011-03-29 Alexza Pharmaceuticals, Inc. Inhalation device for producing a drug aerosol
ATE510174T1 (en) * 2003-05-21 2011-06-15 Alexza Pharmaceuticals Inc IMPACT LIT INDEPENDENT HEATING UNIT
US20050034723A1 (en) * 2003-08-04 2005-02-17 Bryson Bennett Substrates for drug delivery device and methods of preparing and use
WO2005014090A1 (en) * 2003-08-04 2005-02-17 Alexza Pharmaceuticals, Inc. Methods of determining film thicknesses for an aerosol delivery article
JP2007526796A (en) * 2003-12-15 2007-09-20 アレックザ ファーマシューティカルズ， インコーポレイテッド Treatment of breakthrough pain by drug aerosol inhalation
WO2005059804A2 (en) * 2003-12-16 2005-06-30 Alexza Pharmaceuticals, Inc. Methods for monitoring severity of panic attacks and other rapidly evolving medical events in real-time
EP1781360A1 (en) * 2004-08-12 2007-05-09 Alexza Pharmaceuticals, Inc. Aerosol drug delivery device incorporating percussively activated heat packages
US20060032496A1 (en) * 2004-08-12 2006-02-16 Alexza Molecular Delivery Corporation Inhalation actuated percussive ignition system
US20060120962A1 (en) * 2004-10-12 2006-06-08 Rabinowitz Joshua D Cardiac safe, rapid medication delivery

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