US 2003OO12738A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0012738A1 Rabinowitz et al. (43) Pub. Date: Jan. 16, 2003

(54) DELIVERY OF ALPRAZOLAM, (52) U.S. Cl...... 424/45 ESTAZOLAM, MIDAZOLAM OR TRAZOLAM THROUGH AN INHALATION ROUTE (57) ABSTRACT (76) Inventors: Joshua D. Rabinowitz, Mountain View, The present invention relates to the delivery of alprazolam, CA (US); Alejandro C. Zaffaroni, estazolam, midazolam or triazolam through an inhalation Atherton, CA (US) route. Specifically, it relates to aerosols containing alpra Zolam, estazolam, midazolam or triazolam that are used in Correspondence Address: inhalation therapy. In a composition aspect of the present Richard R. Eckman invention, the aerosol comprises particles comprising at Morrison & Foerster LLP least 5 percent by weight of alprazolam, estazolam, mida 755 Page Mill Road Zolam or triazolam. In a method aspect of the present Palo Alto, CA 94.304-1018 (US) invention, alprazolam, estazolam, midazolam or triazolam is delivered to a mammal through an inhalation route. The (21) Appl. No.: 10/155,373 method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of (22) Filed: May 22, 2002 alprazolam, estazolam, midazolam or triazolam, to form a Related U.S. Application Data vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is (60) Provisional application No. 60/294,203, filed on May inhaled by the mammal. In a kit aspect of the present 24, 2001. Provisional application No. 60/317,479, invention, a kit for delivering alprazolam, estazolam, mida filed on Sep. 5, 2001. Provisional application No. Zolam or triazolam through an inhalation route to a mammal 60/345,876, filed on Nov. 9, 2001. is provided which comprises: a) a composition comprising at least 5 percent by weight of alprazolam, estazolam, mida Publication Classification Zolam or triazolam; and, b) a device that forms an alpra Zolam, estazolam, midazolam or triazolam containing aero (51) Int. Cl." ...... A61L 9/04 Sol from the composition, for inhalation by the mammal. Patent Application Publication Jan. 16, 2003 US 2003/0012738A1 - -

-- r --

S

Q

C

S. US 2003/0012738A1 Jan. 16, 2003

DELIVERY OF ALPRAZOLAM, ESTAZOLAM, comprise less than 5 percent by weight of alprazolam, MIDAZOLAM OR TRAZOLAM THROUGH AN estazolam, midazolam or triazolam degradation products. INHALATION ROUTE More preferably, the particles comprise less than 2.5, 1, 0.5, 0001. This application claims priority to U.S. provisional 0.1 or 0.03 percent by weight of alprazolam, estazolam, application Serial No. 60/294,203 entitled “Thermal Vapor midazolam or triazolam degradation products. Delivery of Drugs, filed May 24, 2001, Rabinowitz and 0009 Typically, the aerosol particles comprise less than Zaffaroni, the entire disclosure of which is hereby incorpo 90 percent by weight of water. Preferably, the particles rated by reference. This application further claims priority to comprise less than 80 percent by weight of water. More U.S. provisional application Serial No. 60/317,479 entitled preferably, the particles comprise less than 70 percent, 60 “Aerosol Drug Delivery,” filed Sep. 5, 2001, Rabinowitz and percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 Zaffaroni, the entire disclosure of which is hereby incorpo percent, or 5 percent by weight of water. rated by reference. This application further claims priority to 0010 Typically, at least 50 percent by weight of the U.S. provisional application Serial No. 60/345,876 entitled aeroSol is amorphous in form, wherein crystalline forms “Delivery of Alprazolam, Estazolam, Midazolam, and Tria make up leSS than 50 percent by weight of the total aeroSol Zolam Through an Inhalation Route,” filed Nov. 9, 2001, weight, regardless of the nature of individual particles. Rabinowitz and Hale, the entire disclosure of which is Preferably, at least 75 percent by weight of the aerosol is hereby incorporated by reference. amorphous in form. More preferably, at least 90 percent by FIELD OF THE INVENTION weight of the aeroSol is amorphous in form. 0011 Typically, the aerosol has an inhalable aerosol drug 0002 The present invention relates to the delivery of mass density of between 0.02 mg/L and 10 mg/L. Preferably, alprazolam, estaZolam, midazolam or triazolam through an the aerosol has an inhalable aerosol drug mass density of inhalation route. Specifically, it relates to aerosols contain between 0.05 mg/L and 5 mg/L. More preferably, the aerosol ing alprazolam, estazolam, midazolam or triazolam that are has an inhalable aerosol drug mass density of between 0.1 used in inhalation therapy. mg/L and 2 mg/L. 0012 Typically, the aerosol has an inhalable aerosol BACKGROUND OF THE INVENTION particle density greater than 10° particles/mL. Preferably, the 0003. There are a number of compositions currently aeroSol has an inhalable aeroSol particle density greater than marketed for the treatment of anxiety or insomnia. The 107 particles/mL. More preferably, the aerosol has an inhal compositions contain at least one active ingredient that able aerosol particle density greater than 10 particles/mL. provides for observed therapeutic effects. Among the active ingredients in Such compositions are alprazolam, estaZolam, 0013 Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns. Preferably, the midazolam, and triazolam. particles have a mass median aerodynamic diameter of leSS 0004. It is desirable to provide a new route of adminis than 3 microns. More preferably, the particles have a mass tration for alprazolam, estaZolam, midazolam, and triazolam median aerodynamic diameter of less than 2 or 1 micron(s). that rapidly produces peak plasma concentrations of the compound. The provision of Such a route is an object of the 0014 Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol par present invention. ticles is less than 3.0. Preferably, the geometric standard SUMMARY OF THE INVENTION deviation is less than 2.5. More preferably, the geometric Standard deviation is less than 2.1. 0005 The present invention relates to the delivery of 0015 Typically, the aerosol is formed by heating a com alprazolam, estaZolam, midazolam or triazolam through an position containing alprazolam, estazolam, midazolam or inhalation route. Specifically, it relates to aerosols contain triazolam to form a vapor and Subsequently allowing the ing alprazolam, estazolam, midazolam or triazolam that are used in inhalation therapy. Vapor to condense into an aerosol. 0016. In a method aspect of the present invention, either 0006. In a composition aspect of the present invention, alprazolam, estazolam, midazolam or triazolam is delivered the aeroSol comprises particles comprising at least 5 percent to a mammal through an inhalation route. The method by weight of alprazolam, estazolam, midazolam or triaz comprises: a) heating a composition, wherein the composi olam. Preferably, the particles comprise at least 10 percent tion comprises at least 5 percent by weight of alprazolam, by weight of alprazolam, estazolam, midazolam or triaz estazolam, midazolam or triazolam; and, b) allowing the olam. More preferably, the particles comprise at least 20 Vapor to cool, thereby forming a condensation aeroSol percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 comprising particles, which is inhaled by the mammal. percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 Preferably, the composition that is heated comprises at least percent, 99.5 percent or 99.97 percent by weight of alpra 10 percent by weight of alprazolam, estaZolam, midazolam Zolam, estaZolam, midazolam or triazolam. or triazolam. More preferably, the composition comprises 20 0007 Typically, the aerosol has a mass of at least 1 lug. percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 Preferably, the aerosol has a mass of at least 10 ug. More percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 preferably, the aerosol has a mass of at least 20 ug. percent, 99.5 percent, 99.9 percent or 99.97 percent by 0008 Typically, the aerosol particles comprise less than weight of alprazolam, estazolam, midazolam or triazolam. 10 percent by weight of alprazolam, estaZolam, midazolam 0017. Typically, the delivered aerosol particles comprise or triazolam degradation products. Preferably, the particles at least 5 percent by weight of alprazolam, estazolam, US 2003/0012738A1 Jan. 16, 2003

midazolam or triazolam. Preferably, the particles comprise Second. More preferably, the aerosol is formed at a rate at least 10 percent by weight of alprazolam, estazolam, greater than 10" inhalable particles per second. midazolam or triazolam. More preferably, the particles com prise at least 20 percent, 30 percent, 40 percent, 50 percent, 0027 Typically, the delivered aerosol is formed at a rate 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 greater than 0.1 mg/second. Preferably, the aerosol is formed percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 at a rate greater than 0.25 mg/second. More preferably, the percent by weight of alprazolam, estaZolam, midazolam or aeroSol is formed at a rate greater than 0.5, 1 or 2 mg/second. triazolam. 0028. Typically, where the condensation aerosol com 0.018 Typically, the aerosol has a mass of at least 1 lug. prises alprazolam, between 0.05 mg and 4 mg of alprazolam Preferably, the aerosol has a mass of at least 10 ug. More are delivered to the mammal in a single inspiration. Prefer preferably, the aerosol has a mass of at least 20 ug. ably, between 0.1 mg and 2 mg of alprazolam are delivered to the mammal in a Single inspiration. More preferably, 0.019 Typically, the delivered aerosol particles comprise between 0.2 mg and 1 mg of alprazolam are delivered to the less than 10 percent by weight of alprazolam, estaZolam, mammal in a single inspiration. midazolam or triazolam degradation products. Preferably, the particles comprise less than 5 percent by weight of 0029. Typically, where the condensation aerosol com alprazolam, estazolam, midazolam or triazolam degradation prises estaZolam, between 0.05 mg and 4 mg of estazolam products. More preferably, the particles comprise less than are delivered to the mammal in a single inspiration. Prefer 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of alprazolam, ably, between 0.1 mg and 2 mg of estazolam are delivered estazolam, midazolam or triazolam degradation products. to the mammal in a Single inspiration. More preferably, between 0.2 mg and 1 mg of estaZolam are delivered to the 0020 Typically, the aerosol particles comprise less than mammal in a single inspiration. 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More 0030 Typically, where the condensation aerosol com preferably, the particles comprise less than 70 percent, 60 prises midazolam, between 0.05 mg and 4 mg of midazolam percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 are delivered to the mammal in a single inspiration. Prefer percent, or 5 percent by weight of water. ably, between 0.1 mg and 2 mg of midazolam are delivered to the mammal in a Single inspiration. More preferably, 0021 Typically, at least 50 percent by weight of the between 0.2 mg and 1 mg of midazolam are delivered in a aeroSol is amorphous in form, wherein crystalline forms Single inspiration. make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. 0031 Typically, where the condensation aerosol com Preferably, at least 75 percent by weight of the aerosol is prises triazolam, between 0.006 mg and 0.5 mg of triazolam amorphous in form. More preferably, at least 90 percent by are delivered to the mammal in a single inspiration. Prefer weight of the aerosol is amorphous in form. ably, between 0.0125 mg and 0.25 mg of triazolam are 0022 Typically, the particles of the delivered condensa delivered to the mammal in a single inspiration. More tion aerosol have a mass median aerodynamic diameter of preferably, between 0.025 mg and 0.125 mg of triazolam are less than 5 microns. Preferably, the particles have a mass delivered to the mammal in a Single inspiration. median aerodynamic diameter of less than 3 microns. More 0032 Typically, the delivered condensation aerosol preferably, the particles have a mass median aerodynamic results in a peak plasma concentration of alprazolam, esta diameter of less than 2 or 1 micron(s). Zolam, midazolam or triazolam in the mammal in less than 0023 Typically, the geometric standard deviation around 1 h. Preferably, the peak plasma concentration is reached in the mass median aerodynamic diameter of the aerosol par less than 0.5 h. More preferably, the peak plasma concen ticles is less than 3.0. Preferably, the geometric standard tration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or deviation is less than 2.5. More preferably, the geometric 0.005 h (arterial measurement). Standard deviation is less than 2.1. 0033. In a kit aspect of the present invention, a kit for 0024 Typically, the delivered aerosol has an inhalable delivering alprazolam, estaZolam, midazolam or triazolam aerosol drug mass density of between 0.02 mg/L and 10 through an inhalation route to a mammal is provided which mg/L. Preferably, the aerosol has an inhalable aeroSol drug comprises: a) a composition comprising at least 5 percent by mass density of between 0.05 mg/L and 5 mg/L. More weight of alprazolam, estazolam, midazolam or triazolam; preferably, the aerosol has an inhalable aerosol drug mass and, b) a device that forms an alprazolam, estazolam, midazolam or triazolam containing aerosol from the com density of between 0.1 mg/L and 2 mg/L. position, for inhalation by the mammal. Preferably, the 0.025 Typically, the delivered aerosol has an inhalable composition comprises at least 10 percent by weight of aerosol particle density greater than 10° particles/mL. Pref alprazolam, estazolam, midazolam or triazolam. More pref erably, the aerosol has an inhalable aerosol particle density erably, the composition comprises at least 20 percent, 30 greater than 107 particles/mL. More preferably, the aerosol percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 has an inhalable aerosol particle density greater than 10 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 particles/mL. percent, 99.9 percent or 99.97 percent by weight of alpra Zolam, estazolam, midazolam or triazolam. 0026. Typically, the rate of inhalable aerosol particle formation of the delivered condensation aeroSol is greater 0034) Typically, the device contained in the kit com than 10 particles per second. Preferably, the aerosol is prises: a) an element for heating the alprazolam, estazolam, formed at a rate greater than 10 inhalable particles per midazolam or triazolam composition to form a vapor; b) an US 2003/0012738A1 Jan. 16, 2003 element allowing the vapor to cool to form an aeroSol; and, 0048 "Inhalable aerosol mass density” refers to the aero c) an element permitting the mammal to inhale the aerosol. Sol mass density produced by an inhalation device and delivered into a typical patient tidal Volume. BRIEF DESCRIPTION OF THE FIGURE 0049) “Inhalable aerosol particle density” refers to the 0.035 FIG. 1 shows a device used to deliver alprazolam, aerosol particle density of particles of size between 100 nm estazolam, midazolam or triazolam containing aerosols to a and 5 microns produced by an inhalation device and deliv mammal through an inhalation route. ered into a typical patient tidal Volume. 0050 “Mass median aerodynamic diameter” or DETAILED DESCRIPTION OF THE “MMAD” of an aerosol refers to the aerodynamic diameter INVENTION for which half the particulate mass of the aerosol is con tributed by particles with an aerodynamic diameter larger Definitions than the MMAD and half by particles with an aerodynamic diameter Smaller than the MMAD. 0.036 “Aerodynamic diameter of a given particle refers to the diameter of a spherical droplet with a density of 1 0051) “Midazolam” refers to 8-chloro-6-(2-fluorophe g/mL (the density of water) that has the same Settling nyl)- 1-methyl-4H-imidazol,5-C1,4)benzodiazepine, Velocity as the given particle. which has an empirical formula of CHCIFN. 0037 “Aerosol” refers to a suspension of solid or liquid 0052 “Midazolam degradation product” refers to a com particles in a gas. pound resulting from a chemical modification of midazolam. The modification, for example, can be the result of a 0.038 “Aerosol drug mass density” refers to the mass of thermally or photochemically induced reaction. Such reac alprazolam, estaZolam, midazolam or triazolam per unit tions include, without limitation, oxidation (e.g., of the Volume of aeroSol. methyl or methylene unit) and hydrolysis (e.g., of the imine 0039) “Aerosol mass density' refers to the mass of par portion). ticulate matter per unit Volume of aeroSol. 0053 “Rate of aerosol formation” refers to the mass of 0040 “Aerosol particle density” refers to the number of aeroSolized particulate matter produced by an inhalation particles per unit volume of aeroSol. device per unit time. 0054) “Rate of inhalable aerosol particle formation” 0041) “Alprazolam” refers to 8-chloro-1-methyl-6-phe refers to the number of particles of size between 100 nm and nyl-4H-S-triazolo-4,3-CI1,4)benzodiazepine, which has an 5 microns produced by an inhalation device per unit time. empirical formula of CHCIN. 0055 “Rate of drug aerosol formation” refers to the mass 0.042 “Alprazolam degradation product” refers to a com of aeroSolized alprazolam, estazolam, midazolam or triaz pound resulting from a chemical modification of alprazolam. olam produced by an inhalation device per unit time. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reac 0056 “Settling velocity” refers to the terminal velocity of tions include, without limitation, oxidation (e.g., of the an aerosol particle undergoing gravitational Settling in air. methyl or methylene unit) and hydrolysis (e.g., of the imine 0057. “Triazolam” refers to 8-chloro-6-(-o-chlorophe portion). nyl)-1-methyl-4H-S-triazolo-4,3-CI1,4)benzodiazepine, 0.043 “Amorphous particle” refers to a particle that does which has an empirical formula of CH-ClN. not contain more than 50 percent by weight of a crystalline 0058 “Triazolam degradation product” refers to a com form. Preferably, the particle does not contain more than 25 pound resulting from a chemical modification of triazolam. percent by weight of a crystalline form. More preferably, the The modification, for example, can be the result of a particle does not contain more than 10 percent by weight of thermally or photochemically induced reaction. Such reac a crystalline form. tions include, without limitation, oxidation (e.g., of the methyl or methylene unit) and hydrolysis (e.g., of the imine 0044) “Condensation aerosol refers to an aerosol formed portion). by vaporization of a Substance followed by condensation of the Substance into an aerosol. 0059) “Typical patient tidal volume” refers to 1 L for an adult patient and 15 mL/kg for a pediatric patient. 0.045 “Estazolam” refers to 8-chloro-6-phenyl-4H-s-tria Zolo4.3-CI1,4)benzodiazepine, which has an empirical for 0060) “Vapor” refers to a gas, and “vapor phase” refers to a gas phase. The term “thermal vapor refers to a vapor mula of CHCIN. phase, aerosol, or mixture of aeroSol-Vapor phases, formed 0046) “Estazolam degradation product” refers to a com preferably by heating. pound resulting from a chemical modification of estazolam. The modification, for example, can be the result of a Formation of Alprazolam, EstaZolam, Midazolam thermally or photochemically induced reaction. Such reac or Triazolam Containing AeroSols tions include, without limitation, oxidation (e.g., of the methylene unit) and hydrolysis (e.g., of the imine portion). 0061 Any suitable method is used to form the aerosols of the present invention. A preferred method, however, 0047. “Inhalable aerosol drug mass density” refers to the involves heating a composition comprising alprazolam, esta aeroSol drug mass density produced by an inhalation device Zolam, midazolam or triazolam to produce a vapor, followed and delivered into a typical patient tidal Volume. by cooling of the vapor Such that it condenses to provide an US 2003/0012738A1 Jan. 16, 2003 alprazolam, estazolam, midazolam or triazolam comprising Delivery of Alprazolam, Estazolam, Midazolam or aerosol (condensation aerosol). The composition is heated in Triazolam Containing AeroSols one of two forms: as pure active compound (i.e., pure alprazolam, estazolam, midazolam or triazolam); or, as a 0068 Alprazolam, estazolam, midazolam and triazolam mixture of active compound and a pharmaceutically accept containing aerosols of the present invention are delivered to able excipient. Typically, the composition is heated on a a mammal using an inhalation device. Where the aeroSol is a condensation aerosol, the device has at least three ele Solid Support. ments: an element for heating an alprazolam, estazolam, 0.062 Pharmaceutically acceptable excipients are either midazolam or triazolam containing composition to form a Volatile or nonvolatile. Volatile excipients, when heated, are Vapor, an element allowing the vapor to cool, thereby concurrently volatilized, aeroSolized and inhaled with alpra providing a condensation aeroSol; and, an element permit Zolam, estazolam, midazolam or triazolam. Classes of Such ting the mammal to inhale the aerosol. Various Suitable excipients are known in the art and include, without limi heating methods are described above. The element that tation, gaseous, Supercritical fluid, liquid and Solid Solvents. allows cooling is, in it Simplest form, an inert passageway The following is a list of exemplary carriers within the linking the heating means to the inhalation means. The classes: water, terpenes, Such as menthol; alcohols, Such as element permitting inhalation is an aerosol exit portal that ethanol, propylene glycol, glycerol and other similar alco forms a connection between the cooling element and the hols, dimethylformamide, dimethylacetamide, wax; Super mammal’s respiratory System. critical carbon dioxide; dry ice; and mixtures thereof. 0069. One device used to deliver alprazolam, estazolam, 0.063 Solid supports on which the composition is heated midazolam or triazolam containing aerosol is described in are of a variety of shapes. Examples of Such shapes include, reference to FIG.1. Delivery device 100 has a proximal end without limitation, cylinders of less than 1.0 mm in diameter, 102 and a distal end 104, a heating module 106, a power boxes of less than 1.0 mm thickneSS and Virtually any shape Source 108, and a mouthpiece 110. An alprazolam, esta permeated by Small (e.g., less than 1.0 mm-sized) pores. Zolam, midazolam or triazolam composition is deposited on Preferably, Solid Supports provide a large Surface to Volume a surface 112 of heating module 106. Upon activation of a ratio (e.g., greater than 100 per meter) and a large Surface to user activated Switch 114, power source 108 initiates heating mass ratio (e.g., greater than 1 cm per gram). of heating module 106 (e.g., through ignition of combustible 0064. A solid support of one shape can also be trans fuel or passage of current through a resistive heating ele formed into another shape with different properties. For ment). The alprazolam, estazolam, midazolam or triazolam example, a box of 0.25 mm thickness has a Surface to composition volatilizes due to the heating of heating module volume ratio of approximately 8,000 per meter. Rolling the 106 and condenses to form a condensation aerosol prior to box into a hollow cylinder of 1 cm diameter produces a reaching the mouthpiece 110 at the proximal end of the Support that retains the high Surface to mass ratio of the device 102. Air flow traveling from the device distal end 104 original box but has a lower Surface to volume ratio (about to the mouthpiece 110 carries the condensation aerosol to the 400 per meter). mouthpiece 110, where it is inhaled by the mammal. 0065. A number of different materials are used to con Struct the Solid Supports. Classes of Such materials include, 0070 Devices, if desired, contain a variety of compo without limitation, metals, inorganic materials, carbon nents to facilitate the delivery of alprazolam, estazolam, aceous materials and polymers. The following are examples midazolam or triazolam containing aerosols. For instance, of the material classes: aluminum, Silver, gold, StainleSS the device may include any component known in the art to Steel, copper and tungsten; Silica, glass, Silicon and alumina; control the timing of drug aeroSolization relative to inhala graphite, porous carbons, carbon yarns and carbon felts, tion (e.g., breath-actuation), to provide feedback to patients polytetrafluoroethylene and polyethylene glycol. Combina on the rate and/or Volume of inhalation, to prevent excessive tions of materials and coated variants of materials are used use (i.e., "lock-out” feature), to prevent use by unauthorized as well. individuals, and/or to record dosing histories. 0.066 Where aluminum is used as a solid support, alu Dosage of Alprazolam, EstaZolam, Midazolam or minum foil is a Suitable material. Examples of Silica, alu Triazolam Containing AeroSols mina and Silicon based materials include amphorous Silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (an alumina of 0071 For the short-term management of insomnia, esta defined Surface area greater than 2 m/g from Aldrich, St. Zolam is given orally at Strengths of 1 mg or 2 mg Louis, Mo.) and a silicon wafer as used in the Semiconductor (PROSOMTM Tablets). Alprazolam is used for the treatment industry. Carbon yams and felts are available from American of anxiety disorders and is provided for oral administration Kynol, Inc., New York, N.Y. Chromatography resins such at strengths of 0.25 mg, 0.5 mg, 1 mg or 2 mg (XANAX(R) as octadecycl Silane chemically bonded to porous Silica are Tablets). Midazolam is given (injection or Syrup) either as an exemplary coated variants of Silica. anesthetic or anxiolytic in a typical dose of 0.5 mg to 4 mg 0067. The heating of the alprazolam, estazolam, mida (VERSED(R). Triazolam is used to treat insomnia as an oral Zolam or triazolam compositions is performed using any formulation in strengths of 0.125 mg and 0.25 mg (HAL suitable method. Examples of methods by which heat can be CION(R) Tablets). generated include the following: passage of current through 0072 AS aerosols, 0.05 mg to 4 mg of estazolam, 0.05 mg an electrical resistance element, absorption of electromag to 4 mg alprazolam, 0.05 mg to 4 mg midazolam and 0.006 netic radiation, Such as microwave or laser light; and, mg to 0.5 mg triazolam are generally provided per inspira exothermic chemical reactions, Such as exothermic Solva tion for the Same indications. A typical dosage of an alpra tion, hydration of pyrophoric materials and oxidation of Zolam, estazolam, midazolam or triazolam aerosol is either combustible materials. administered as a Single inhalation or as a Series of inhala US 2003/0012738A1 Jan. 16, 2003 tions taken within an hour or less (dosage equals Sum of furnace tube by a mock throat (USP throat, Andersen Instru inhaled amounts). Where the drug is administered as a Series ments, Smyrna, Ga.) is one system used for cascade impac of inhalations, a different amount may be delivered in each tion Studies. inhalation. The dosage amount of alprazolam, estaZolam, midazolam or triazolam in aeroSol form is generally no 0078 Inhalable aerosol mass density is determined, for greater than twice the Standard dose of the drug given orally example, by delivering a drug-containing aeroSol into a or by injection. confined chamber via an inhalation device and measuring the mass collected in the chamber. Typically, the aerosol is 0073. One can determine the appropriate dose of alpra drawn into the chamber by having a pressure gradient Zolam, estaZolam, midazolam or triazolam containing aero between the device and the chamber, wherein the chamber Sols to treat a particular condition using methods Such as is at lower pressure than the device. The volume of the animal experiments and a dose-finding (Phase I/II) clinical chamber should approximate the tidal Volume of an inhaling trial. One animal experiment involves measuring plasma patient. concentrations of an animal after its exposure to the aeroSol. 0079 Inhalable aerosol drug mass density is determined, Mammals. Such as dogs or primates are typically used in Such for example, by delivering a drug-containing aerosol into a Studies, Since their respiratory Systems are similar to that of confined chamber via an inhalation device and measuring a human. Initial dose levels for testing in humans are the amount of active drug compound collected in the cham generally less than or equal to the dose in the mammal model ber. Typically, the aerosol is drawn into the chamber by that resulted in plasma drug levels associated with a thera having a preSSure gradient between the device and the peutic effect in humans. Dose escalation in humans is then chamber, wherein the chamber is at lower preSSure than the performed, until either an optimal therapeutic response is device. The volume of the chamber should approximate the obtained or a dose-limiting toxicity is encountered. tidal Volume of an inhaling patient. The amount of active drug compound collected in the chamber is determined by Analysis of AlproZolam, EstaZolam, Midazolam or extracting the chamber, conducting chromatographic analy Triazolam Containing AeroSols sis of the extract and comparing the results of the chromato 0.074 Purity of an alprazolam, estazolam, midazolam or graphic analysis to those of a Standard containing known triazolam containing aeroSol is determined using a number amounts of drug. of methods, examples of which are described in Sekine et 0080 Inhalable aerosol particle density is determined, for al., Journal of Forensic Science 32:1271-1280 (1987) and example, by delivering aerosol phase drug into a confined Martin et al., Journal of Analytic Toxicology 13:158-162 chamber via an inhalation device and measuring the number (1989). One method involves forming the aerosol in a device of particles of given size collected in the chamber. The through which a gas flow (e.g., air flow) is maintained, number of particles of a given size may be directly measured generally at a rate between 0.4 and 60 L/min. The gas flow based on the light-Scattering properties of the particles. carries the aeroSol into one or more traps. After isolation Alternatively, the number of particles of a given size may be from the trap, the aerosol is Subjected to an analytical determined by measuring the mass of particles within the technique, Such as gas or liquid chromatography, that per given size range and calculating the number of particles mits a determination of composition purity. based on the mass as follows: Total number of particles Sum (from size range 1 to size range N) of number of 0075) A variety of different traps are used for aerosol particles in each size range. Number of particles in a given collection. The following list contains examples of Such Size range=Mass in the Size range/Mass of a typical particle traps: filters, glass wool; impingers, Solvent traps, Such as in the size range. Mass of a typical particle in a given size dry ice-cooled ethanol, methanol, acetone and dichlo range=TL*D"' where D is a typical particle diameter in the romethane traps at various pH values, Syringes that Sample size range (generally, the mean boundary of the MMADs the aerosol, empty, low-pressure (e.g., vacuum) containers defining the size range) in microns, p is the particle density into which the aerosol is drawn; and, empty containers that (in g/mL) and mass is given in units of picograms (g'). fully Surround and enclose the aeroSol generating device. Where a Solid Such as glass wool is used, it is typically 0081. Rate of inhalable aerosol particle formation is extracted with a Solvent Such as ethanol. The Solvent extract determined, for example, by delivering aerosol phase drug is Subjected to analysis rather than the Solid (i.e., glass wool) into a confined chamber via an inhalation device. The itself. Where a Syringe or container is used, the container is delivery is for a set period of time (e.g., 3 s), and the number Similarly extracted with a Solvent. of particles of a given size collected in the chamber is determined as outlined above. The rate of particle formation 0.076 The gas or liquid chromatograph discussed above is equal to the number of 100 nm to 5 micron particles contains a detection System (i.e., detector). Such detection collected divided by the duration of the collection time. Systems are well known in the art and include, for example, flame ionization, photon absorption and mass spectrometry 0082) Rate of aerosol formation is determined, for detectors. An advantage of a mass spectrometry detector is example, by delivering aerosol phase drug into a confined that it can be used to determine the Structure of alprazolam, chamber via an inhalation device. The delivery is for a set estazolam, midazolam or triazolam degradation products. period of time (e.g., 3 s), and the mass of particulate matter-collected is determined by weighing the confined 0.077 Particle size distribution of an alprazolam, esta chamber before and after the delivery of the particulate Zolam, midazolam or triazolam containing aerosol is deter matter. The rate of aerosol formation is equal to the increase mined using any Suitable method in the art (e.g., cascade in mass in the chamber divided by the duration of the impaction). An Andersen Eight Stage Non-viable Cascade collection time. Alternatively, where a change in mass of the Impactor (Andersen Instruments, Smyrna, Ga.) linked to a delivery device or component thereof can only occur US 2003/0012738A1 Jan. 16, 2003 through release of the aerosol phase particulate matter, the aeroSol), which collected on the glass tube walls. Reverse mass of particulate matter may be equated with the mass lost phase HPLC analysis with detection by absorption of 225 from the device or component during the delivery of the nm light showed the collected material to be at least 99.9% aeroSol. In this case, the rate of aeroSol formation is equal to pure alprazolam. To obtain higher purity aeroSols, one can the decrease in mass of the device or component during the coat a lesser amount of drug, yielding a thinner film to heat. delivery event divided by the duration of the delivery event. Alinear decrease in film thickneSS is associated with a linear 0.083 Rate of drug aerosol formation is determined, for decrease in impurities. example, by delivering an alprazolam, estaZolam, mida Zolam or triazolam containing aerosol into a confined cham EXAMPLE 2 ber via an inhalation device over a set period of time (e.g., 3 S). Where the aerosol is pure alprazolam, estazolam, Volatilization of Estazolam midazolam or triazolam, the amount of drug collected in the 0088 A Solution of 2.0 mg estazolam in 120 u, dichlo chamber is measured as described above. The rate of drug romethane was coated on a 3.6 cmx8 cm piece of aluminum aeroSol formation is equal to the amount of alprazolam, foil. The dichloromethane was allowed to evaporate. The estazolam, midazolam or triazolam collected in the chamber coated foil was wrapped around a 300 watt halogen tube divided by the duration of the collection time. Where the (Feit Electric Company, Pico Rivera, Calif.), which was alprazolam, estazolam, midazolam or triazolam containing inserted into a glass tube Sealed at one end with a rubber aeroSol comprises a pharmaceutically acceptable excipient, Stopper. Running 60 V of alternating current (driven by line multiplying the rate of aerosol formation by the percentage power controlled by a variac) through the bulb for 3 s, of alprazolam, estaZolam, midazolam or triazolam in the followed by 45 V for 11s, afforded estazolam thermal vapor aeroSol provides the rate of drug aerosol formation. (including estazolam aerosol), which collected on the glass tube walls. Reverse-phase HPLC analysis with detection by Utility of Alprazolam, Estazolam, Midazolam and absorption of 225 nm light showed the collected material to Triazolam Containing AeroSols be at least 99.9% pure estazolam. 0084 Typical uses for alprazolam, estazolam, mida Zolam, and triazolam-containing aerosols include without EXAMPLE 3 limitation the following: relief of the symptoms of situ Volatilization of Midazolam ational anxiety, relief of acute panic attacks, relaxation of skeletal muscle, treatment of nausea and Vomiting, induction 0089. A solution of 5.0 mg midazolam in 120 till dichlo of Sleep, and sedation for medical or dental procedures. romethane was coated on a 3.6 cmx8 cm piece of aluminum Alprazolam and estazolam containing-aerosols are distin foil. The dichloromethane was allowed to evaporate. The guished from midazolam and triazolam-containing aerosols coated foil was wrapped around a 300 watt halogen tube primarily by their durations of action, with alprazolam and (Feit Electric Company, Pico Rivera, Calif.), which was estazolam having half-lives of approximately 12 hours and inserted into a glass tube Sealed at one end with a rubber midazolam and triazolam having half-lives of approximately Stopper. Running 60V of alternating current (driven by line 3 hours. Thus triazolam or midazolam-containing aerosols power controlled by a variac) through the bulb for 6 s are typically used in instances where a rapid offset of action afforded midazolam thermal vapor (including midazolam is desired (e.g. in Sedation for medical or dental procedures). aeroSol), which collected on the glass tube walls. Reverse In contrast, alprazolam or estazolam-containing aerosols are phase HPLC analysis with detection by absorption of 225 typically used in instances where a Sustained action is nm light showed the collected material to be at least 99.9% desired (e.g. in the case of a panic attack, where a rapid pure midazolam. offset of action might predispose to another episode of panic). EXAMPLE 4 0085. The following examples are meant to illustrate, Particle Size, Particle Density, and Rate of rather than limit, the present invention. Inhalable Particle Formation of Midazolam Aerosol 0.086 Alprazolam, estazolam and triazolam were pur chased from Sigma (www.sigma-aldrich.com). Midazolam 0090 Asolution of 17.1 mg midazolam in 200 till dichlo was obtained from Gyma Laboratories of America, Inc. romethane was spread out in a thin layer on the central (Westbury, N.Y.). portion of a 4 cmx9 cm sheet of aluminum foil. The dichloromethane was allowed to evaporate. The aluminum foil was wrapped around a 300 watt halogen tube, which was EXAMPLE 1. inserted into a T-shaped glass tube. One of the openings of Volatilization of Alprazolam the tube was Sealed with a rubber Stopper, another was loosely covered with the end of the halogen tube, and the 0087. A solution of 2.6 mgalprazolam in 120 till dichlo third was connected to a 1 liter, 3-neck glass flask. The glass romethane was coated on a 3.6 cmx8 cm piece of aluminum flask was further connected to a large piston capable of foil. The dichloromethane was allowed to evaporate. The drawing 1.1 liters of air through the flask. Alternating coated foil was wrapped around a 300 watt halogen tube current was run through the halogen bulb by application of (Feit Electric Company, Pico Rivera, Calif.), which was 90 V using a variac connected to 110 V line power. Within inserted into a glass tube Sealed at one end with a rubber 1S, an aerosol appeared and was drawn into the 1 L flask by stopper. Running 75 V of alternating current (driven by line use of the piston, with collection of the aerosol terminated power controlled by a variac) through the bulb for 6 s after 6 S. The aerosol was analyzed by connecting the 1 L afforded alprazolam thermal vapor (including alprazolam flask to an eight-stage Andersen non-viable cascade impac US 2003/0012738A1 Jan. 16, 2003

tor. Results are shown in table 1. MMAD of the collected nally coated on the aluminum, all of the material was found aeroSol was 2.8 microns with a geometric Standard deviation to have aeroSolized in the 6S time period, implying a rate of of 1.9. Also shown in table 1 is the number of particles drug aeroSol formation of 2.7 mg/S. 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 EXAMPLE 6 Single particle of diameter D is given by the Volume of the particle, cD/6, multiplied by the density of the drug (taken Volatilization of Triazolam to be 1 g/cm). The inhalable aerosol particle density is the Sum of the numbers of particles collected on impactor Stages 0092. A solution of 2.0 mg triazolam in 120 u, dichlo 3 to 8 divided by the collection volume of 1 L, giving an romethane was coated on a 3.6 cmx8 cm piece of aluminum inhalable aerosol particle density of 5.5x10" particles/mL. foil. The dichloromethane was allowed to evaporate. The The rate of inhalable aerosol particle formation is the sum of coated foil was wrapped around a 300 watt halogen tube the numbers of particles collected on impactor Stages 3 (Feit Electric Company, Pico Rivera, Calif.), which was through 8 divided by the formation time of 6 S, giving a rate inserted into a glass tube Sealed at one end with a rubber of inhalable aerosol particle formation of 9.1x10° particles/ stopper. Running 75 V of alternating current (driven by line Second. power controlled by a variac) through the bulb for 2 s, followed by 45 V for 8 s, afforded triazolam thermal vapor TABLE 1. (including triazolam aerosol), which collected on the glass Determination of the characteristics of a midazolam tube walls. Reverse-phase HPLC analysis with detection by condensation aerosol by cascade impaction using an Andersen 8-stage absorption of 225 nm light showed the collected material to non-viable cascade impactor run at 1 cubic foot per minute air flow. be at least 99.85% pure triazolam. Particle size Average particle Mass Number of Stage range (microns) size (microns) collected (mg) particles EXAMPLE 7 O 9.0-10.O 9.5 O.1 2.2 x 10 1 5.8-9.0 7.4 O.6 2.8 x 10 Particle Size, Particle Density, and Rate of 2 4.7-5.8 5.25 O.7 9.2 x 10 Inhalable Particle Formation of Triazolam Aerosol 3 3.3-47 4.0 1.1 3.3 x 107 4 2.1-3.3 2.7 1.1 1.1 x 10 5 1.1-2.1 1.6 1.1 5.1 x 10 0093. A solution of 16.4 mg. triazolam in 200 it dichlo 6 0.7-1.1 O.9 O.7 1.8 x 10 romethane was spread out in a thin layer on the central 7 O.4-O-7 0.55 O.3 4.6 x 10 portion of a 4 cmx9 cm sheet of aluminum foil. The 8 0-0.4 O.2 O.2 4.8 x 100 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 EXAMPLE 5 the tube was Sealed with a rubber Stopper, another was loosely covered with the end of the halogen tube, and the Drug Mass Density and Rate of Drug Aerosol third was connected to a 1 liter, 3-neck glass flask. The glass Formation of Midazolam Aerosol flask was further connected to a large piston capable of 0.091 Asolution of 16.7 mg midazolam in 200 till dichlo drawing 1.1 liters of air through the flask. Alternating romethane was spread out in a thin layer on the central current was run through the halogen bulb by application of portion of a 4 cmx9 cm sheet of aluminum foil. The 90 V using a variac connected to 110 V line power. Within dichloromethane was allowed to evaporate. The aluminum 1S, an aerosol appeared and was drawn into the 1 L flask by foil was wrapped around a 300 watt halogen tube, which was use of the piston, with collection of the aerosol terminated inserted into a T-shaped glass tube. One of the openings of after 6 S. The aerosol was analyzed by connecting the 1 L the tube was Sealed with a rubber Stopper, another was flask to an eight-stage Andersen non-viable cascade impac loosely covered with the end of the halogen tube, and the tor. Results are shown in table 1. MMAD of the collected third was connected to a 1 liter, 3-neck glass flask. The glass aeroSol was 2.2 microns with a geometric Standard deviation flask was further connected to a large piston capable of of 2. Also shown in table 1 is the number of particles drawing 1.1 liters of air through the flask. Alternating current was run through the halogen bulb by application of collected on the various Stages of the cascade impactor, 90 V using a variac connected to 110 V line power. Within given by the mass collected on the Stage divided by the mass Seconds, an aerosol appeared and was drawn into the 1 L of a typical particle trapped on that Stage. The mass of a flask by use of the piston, with formation of the aerosol Single particle of diameter D is given by the Volume of the terminated after 6 s. The aerosol was allowed to sediment particle, cD/6, multiplied by the density of the drug (taken onto the walls of the 1 L flask for approximately 30 minutes. to be 1 g/cm). The inhalable aerosol particle density is the The flask was then extracted with dichloromethane and the Sum of the numbers of particles collected on impactor Stages extract analyzed by HPLC with detection by light absorption 3 to 8 divided by the collection volume of 1 L, giving an at 225 nm. Comparison with Standards containing known inhalable aerosol particle density of 3.8x10° particles/mL. amounts of midazolam revealed that 8.12 mg of >99% pure The rate of inhalable aerosol particle formation is the sum of midazolam had been collected in the flask, resulting in an the numbers of particles collected on impactor Stages 3 aeroSol drug mass density of 8.12 mg/L. The aluminum foil through 8 divided by the formation time of 6 S, giving a rate upon which the midazolam had previously been coated was of inhalable aerosol particle formation of 6x10 particles/ weighed following the experiment. Of the 16.7 mg origi Second. US 2003/0012738A1 Jan. 16, 2003

min, 1 min, 1.5 min, 2 min, 10 min, and 30 min. HPLC TABLE 1. analysis of the blood samples indicated that the Tmax for triazolam was about 0.25 minutes, with a concentration of Determination of the characteristics of a triazolam greater than 100 ng/mL reached. condensation aerosol by cascade impaction using an Andersen 8-stage non-viable cascade impactor run at 1 cubic foot per minute air flow. 1. An aerosol for inhalation therapy, wherein the aeroSol comprises particles comprising at least 10 percent by weight Particle size Average particle Mass Number of of alprazolam, estaZolam, midazolam or triazolam. Stage range (microns) size (microns) collected (mg) particles 2. The aerosol according to claim 1, wherein the aeroSol O 9.0-10.O 9.5 O.O O particles have a mass median aerodynamic diameter of leSS 1 5.8-9.0 7.4 O.3 1.4 x 10 than 3 microns. 2 4.7-5.8 5.25 O.3 4.0 x 10 3 3.3-47 4.0 O.7 2.1 x 107 3. The aerosol according to claim 1, wherein the particles 4 2.1-3.3 2.7 1.2 1.2 x 10 comprise less than 5 percent by weight of alprazolam, 5 1.1-2.1 1.6 1.5 7.0 x 10 estazolam, midazolam or triazolam degradation products. 6 0.7-1.1 O.9 O.7 1.8 x 10 4. The aeroSol according to claim 3, wherein the aeroSol 7 O.4-O-7 0.55 O.1 1.2 x 10 comprises particles comprising at least 90 percent by weight 8 0-0.4 O.2 O.O O of alprazolam, estaZolam, midazolam or triazolam. 5. The aeroSol according to claim 4, wherein the aeroSol comprises particles comprising at least 95 percent by weight EXAMPLE 8 of alprazolam, estaZolam, midazolam or triazolam. 6. A method of delivering alprazolam, estazolam, mida Drug Mass Density and Rate of Drug Aerosol Zolam or triazolam to a mammal through an inhalation route, Formation of Triazolam Aerosol wherein the route comprises: 0094. A solution of 0.6 mg triazolam in 200 lull dichlo a) heating a composition, wherein the composition com romethane was spread out in a thin layer on the central prises at least 5 percent by weight of alprazolam, portion of a 4 cmx9 cm sheet of aluminum foil. The estaZolam, midazolam or triazolam, to form a vapor; dichloromethane was allowed to evaporate. The aluminum and, foil was wrapped around a 300 watt halogen tube, which was inserted into a T-shaped glass tube. One of the openings of b) allowing the vapor to cool, thereby forming a conden the tube was Sealed with a rubber Stopper, another was sation aerosol comprising particles, loosely covered with the end of the halogen tube, and the which is inhaled by the mammal. third was connected to a 1 liter, 3-neck glass flask. The glass 7. The method according to claim 6, wherein the particles flask was further connected to a large piston capable of comprise at least 10 percent by weight of alprazolam, drawing 1.1 liters of air through the flask. Glass wool was estazolam, midazolam or triazolam. placed in the tube connecting the flask to the piston. Alter 8. The method according to claim 6, wherein the aerosol nating current was run through the halogen bulb by appli particles have a mass median aerodynamic diameter of leSS cation of 90 V using a variac connected to 110 V line power. than 3 microns. Within Seconds, an aerosol appeared and was drawn into the 9. The method according to claim 6, wherein the particles 1 L flask by use of the piston, with formation of the aerosol comprise less than 5 percent by weight of alprazolam, terminated after 6 s. The aerosol was allowed to sediment estazolam, midazolam or triazolam degradation products. onto the walls of the 1 L flask for approximately 30 minutes. 10. The method according to claim 9, wherein the aerosol The flask and glass wool were then extracted with dichlo comprises particles comprising at least 90 percent by weight romethane and the extract analyzed by HPLC with detection of alprazolam, estaZolam, midazolam or triazolam. by light absorption at 225 nm. Comparison with Standards 11. The method according to claim 10, wherein the containing known amounts of triazolam revealed that 0.17 aeroSol comprises particles comprising at least 95 percent by mg of >99% pure triazolam had been collected in the flask, weight of alprazolam, estazolam, midazolam or triazolam. resulting in an aeroSol drug mass density of 0.17 mg/L. The 12. Akit for delivering alprazolam, estazolam, midazolam aluminum foil upon which the triazolam had previously or triazolam through an inhalation route to a mammal, been coated was weighed following the experiment. Of the wherein the kit comprises: 0.6 mg originally coated on the aluminum, all of the material was found to have aeroSolized in the 6 S time period, a) a composition comprising at least 5 percent by weight implying a rate of drug aeroSol formation of 0.1 mg/S. of alprazolam, estaZolam, midazolam or triazolam; and, b) a device that forms a alprazolam, estazolam, mida EXAMPLE 9 Zolam or triazolam aerosol from the composition, for Delivery of Triazolam to a Dog inhalation by the mammal 0.095 Apnea was induced in a dog, which was subse and wherein the device comprises: quently exposed to a 15 SLPM flow of air containing 140 ug a) an element for heating the alprazolam, estazolam, of triazolam (condensation aerosol formed by volatilizing midazolam or triazolam composition to form a triazolam off of a heated, metal substrate; MMAD ~1.1) Vapor, through an endotracheal tube. This corresponded to approxi mately a 625 cc volume of inhalation air delivered to the b) an element allowing the vapor to cool to form an dog. Once the dog had received the triazolam aerosol, an air aeroSol; and, supply valve was shut off for 5 s, which simulated a 5 s c) an element permitting the mammal to inhale the breath hold. Following the hold, the dog was allowed to aerosol. exhale through an exhalation filter. Arterial blood Samples were taken at the following intervals: 0 min, 0.25 min, 0.5