WO2002094216A2 - Administration de stimulants par voie d'inhalation - Google Patents

Administration de stimulants par voie d'inhalation Download PDF

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Publication number
WO2002094216A2
WO2002094216A2 PCT/US2002/015562 US0215562W WO02094216A2 WO 2002094216 A2 WO2002094216 A2 WO 2002094216A2 US 0215562 W US0215562 W US 0215562W WO 02094216 A2 WO02094216 A2 WO 02094216A2
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WO
WIPO (PCT)
Prior art keywords
aerosol
fenfluramine
ephedrine
percent
particles
Prior art date
Application number
PCT/US2002/015562
Other languages
English (en)
Other versions
WO2002094216A3 (fr
Inventor
Joshua D. Rabinowitz
Alejandro C. Zaffaroni
Original Assignee
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 Molecular Delivery Corporation filed Critical Alexza Molecular Delivery Corporation
Priority to AU2002314784A priority Critical patent/AU2002314784A1/en
Priority to PCT/US2002/015562 priority patent/WO2002094216A2/fr
Publication of WO2002094216A2 publication Critical patent/WO2002094216A2/fr
Publication of WO2002094216A3 publication Critical patent/WO2002094216A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/42—Oxazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
    • F24V—COLLECTION, PRODUCTION OR USE OF HEAT NOT OTHERWISE PROVIDED FOR
    • F24V30/00—Apparatus or devices using heat produced by exothermal chemical reactions other than combustion

Definitions

  • the present invention relates to the delivery of stimulants through an inhalation route. Specifically, it relates to aerosols containing ephedrine or fenfluramine that are used in inhalation therapy.
  • compositions currently marketed as stimulants contain at least one active ingredient that provides for observed therapeutic effects.
  • active ingredients given in stimulant compositions are ephedrine and fenfluramine.
  • the present invention relates to the delivery of stimulants through an inhalation route. Specifically, it relates to aerosols containing ephedrine or fenfluramine that are used in inhalation therapy.
  • the aerosol comprises particles comprising at least 5 percent by weight of ephedrine or fenfluramine.
  • the particles comprise at least 10 percent by weight of ephedrine or fenfluramine. 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 ephedrine or fenfluramine.
  • the aerosol has a mass of at least 10 ⁇ g.
  • the aerosol has a mass of at least 100 ⁇ g.
  • the aerosol has a mass of at least 200 ⁇ g.
  • the particles comprise less than 10 percent by weight of ephedrine or fenfluramine degradation products.
  • the particles comprise less than 5 percent by weight of ephedrine or fenfluramine degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of ephedrine or fenfluramine degradation products.
  • the particles comprise less than 90 percent by weight of water.
  • 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.
  • 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.
  • 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 in amorphous form.
  • the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 20 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 15 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 12.5 mg/L.
  • the aerosol comprises fenfluramine
  • the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 30 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 25 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 22.5 mg/L.
  • the aerosol has an inhalable aerosol particle density greater than 10 6 particles/mL.
  • the aerosol has an inhalable aerosol particle density greater than 10 7 particles/mL or 10 8 particles/mL.
  • the aerosol particles have a mass median aerodynamic diameter of less than 5 microns.
  • 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).
  • the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0.
  • the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.1.
  • the aerosol is formed by heating a composition containing ephedrine or fenfluramine to form a vapor and subsequently allowing the vapor to condense into an aerosol.
  • either ephedrine or fenfluramine 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 ephedrine or fenfluramine, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal.
  • the composition that is heated comprises at least 10 percent by weight of ephedrine or fenfluramine. More preferably, the composition comprises at least 20 percent, 30 percent,
  • the particles comprise at least 5 percent by weight of ephedrine or fenfluramine.
  • the particles comprise at least 10 percent by weight of ephedrine or fenfluramine. 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,
  • the aerosol has a mass of at least 10 ⁇ g.
  • the aerosol has a mass of at least 100 ⁇ g. More preferably, the aerosol has a mass of at least 200 ⁇ g.
  • the particles comprise less than 10 percent by weight of ephedrine or fenfluramine degradation products.
  • the particles comprise less than 5 percent by weight of ephedrine or fenfluramine degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of ephedrine or fenfluramine degradation products.
  • the particles comprise less than 90 percent by weight of water.
  • 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,
  • the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less th ⁇ an 5 microns.
  • the particles 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).
  • the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0.
  • the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.1.
  • the delivered aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 20 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 15 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and
  • the delivered aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 30 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 25 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and
  • the delivered aerosol has an inhalable aerosol particle density greater than 10 6 particles/mL.
  • the aerosol has an inhalable aerosol particle density greater than 10 particles/mL or 10 particles/mL.
  • the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 10 particles per second.
  • the aerosol is formed at a rate greater than 10 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 10 10 inhalable particles per second.
  • the delivered condensation aerosol is formed at a rate greater than 0.5 mg/second.
  • the aerosol is formed at a rate greater than 0.75 mg/second. More preferably, the aerosol is formed at a rate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.
  • the condensation aerosol comprises ephedrine
  • between 2 mg and 20 mg of ephedrine are delivered to the mammal in a single inspiration.
  • ephedrine More preferably, between 2 mg and 12.5 mg of ephedrine are delivered in a single inspiration.
  • condensation aerosol comprises fenfluramine
  • between 4 mg and 30 mg of fenfluramine are delivered to the mammal in a single inspiration.
  • fenfluramine Preferably, between 4 mg and 25 mg of fenfluramine are delivered to the mammal in a single inspiration. More preferably, between 4 mg and 22.5 mg of fenfluramine are delivered to the mammal in a single inspiration.
  • the delivered condensation aerosol results in a peak plasma concentration of ephedrine or fenfluramine in the mammal in less than 1 h.
  • 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 or 0.01 h.
  • kits for delivering ephedrine or fenfluramine through an inhalation route to a mammal comprises: a) a composition comprising at least 5 percent by weight of ephedrine or fenfluramine; and, b) a device that forms an ephedrine or fenfluramine aerosol from the composition, for inhalation by the mammal.
  • 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,
  • the device contained in the kit comprises: a) an element for heating the ephedrine or fenfluramine composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.
  • Fig. 1 shows a cross-sectional view of a device used to deliver ephedrine or fenfluramine aerosols to a mammal through an inhalation route.
  • 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.
  • Aerosol refers to a suspension of solid or liquid particles in a gas.
  • Aerosol drug mass density refers to the mass of ephedrine or fenfluramine per unit volume of aerosol.
  • Aerosol mass density refers to the mass of particulate matter per unit volume of aerosol.
  • Aerosol particle density refers to the number of particles per unit volume of aerosol.
  • 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 of a crystalline form.
  • Condensation aerosol refers to an aerosol formed by vaporization of a substance followed by condensation of the substance into an aerosol.
  • Ephedrine refers to 2-methylamino- 1 -phenyl- 1 -propanol.
  • Ephedrine degradation product refers to a compound resulting from a chemical modification of ephedrine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
  • Fenfluramine refers to 2-ethylamino- 1 -(3 -trifluoromethylphenyl)propane.
  • Frafluramine degradation product refers to a compound resulting from a chemical modification of fenfluramine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
  • 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.
  • Inhalable aerosol mass density refers to the aerosol mass density produced by an inhalation device and delivered into a typical patient tidal volume.
  • 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.
  • Mass median aerodynamic diameter or "MMAD” of an aerosol refers to the aerodynamic diameter for which half the paniculate 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 MMAD.
  • Rate of aerosol formation refers to the mass of aerosolized particulate matter produced by an inhalation device per unit time.
  • 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.
  • Rate of drug aerosol formation refers to the mass of aerosolized ephedrine or fenfluramine produced by an inhalation device per unit time.
  • Settling velocity refers to the terminal velocity of an aerosol particle undergoing gravitational settling in air.
  • Typical patient tidal volume refers to 1 L for an adult patient and 15 mL/kg for a pediatric patient.
  • Vapor refers to a gas
  • vapor phase refers to a gas phase
  • thermal vapor refers to a vapor phase, aerosol, or mixture of aerosol-vapor phases, formed preferably by heating.
  • any suitable method is used to form the aerosols of the present invention.
  • a preferred method involves heating a composition comprising ephedrine or fenfluramine to form a vapor, followed by cooling of the vapor such that it condenses to provide an ephedrine or fenfluramine comprising aerosol (condensation aerosol).
  • the composition is heated in one of four forms: as pure active compound (i.e., pure ephedrine or fenfluramine); as a mixture of active compound and a pharmaceutically acceptable excipient; as a salt form of the pure active compound; and, as a mixture of active compound salt form and a pharmaceutically acceptable excipient.
  • Salt forms of ephedrine or fenfluramine are either commercially available or are obtained from the corresponding free base using well known methods in the art.
  • a variety of pharmaceutically acceptable salts are suitable for aerosolization. Such salts include, without limitation, the following: hydrochloric acid, hydrobromic acid, acetic acid, maleic acid, formic acid, and fumaric acid salts.
  • compositions may be volatile or nonvolatile. Volatile excipients, when heated, are concurrently volatilized, aerosolized and inhaled with ephedrine or fenfluramine. Classes of such excipients are known in the art and include, without limitation, gaseous, supercritical fluid, liquid and solid solvents. The following is a list of exemplary carriers within the classes: water; terpenes, such as menthol; alcohols, such as ethanol, propylene glycol, glycerol and other similar alcohols; dimethylformamide; dimethylacetamide; wax; supercritical carbon dioxide; dry ice; and mixtures thereof.
  • Solid supports on which the composition is heated are of a variety of shapes. Examples of such shapes include, without limitation, cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness and virtually any shape permeated by small (e.g., less than 1.0 mm-sized) pores. Preferably, solid supports provide a large surface to volume ratio (e.g., greater than 100 per meter) and a large surface to mass ratio (e.g., greater than 1 cm per gram).
  • a solid support of one shape can also be transformed into another shape with different properties.
  • a flat sheet of 0.25 mm thickness has a surface to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder of 1 cm diameter produces a support that retains the high surface to mass ratio of the original sheet but has a lower surface to volume ratio (about 400 per meter).
  • a number of different materials are used to construct the solid supports. Classes of such materials include, without limitation, metals, inorganic materials, carbonaceous materials and polymers. The following are examples of the material classes: aluminum, silver, gold, stainless steel, copper and tungsten; silica, glass, silicon and alumina; graphite, porous carbons, carbon yarns and carbon felts; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are used as well. [0062] 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.
  • the heating of the ephedrine or fenfluramine compositions is performed using any suitable method.
  • methods by which heat can be generated include the following: passage of current through an electrical resistance element; absorption of electromagnetic radiation, such as microwave or laser light; and, exothermic chemical reactions, such as exothermic solvation, hydration of pyrophoric materials and oxidation of combustible materials.
  • Ephedrine or fenfluramine containing aerosols of the present invention are delivered to a mammal using an inhalation device.
  • the aerosol is a condensation aerosol
  • the device has at least three elements: an element for heating an ephedrine or fenfluramine 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.
  • 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 ephedrine or fenfluramine composition is deposited on a surface 112 of heating module 106.
  • power source 108 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 ephedrine or fenfluramine 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.
  • Devices if desired, contain a variety of components to facilitate the delivery of ephedrine or fenfluramine containing aerosols.
  • the device may include any component known in the art to control the timing of drug aerosolization relative to inhalation (e.g., breath-actuation), to provide feedback to patients on the rate and/or volume of inhalation, to prevent excessive use (i.e., "lock-out” feature), to prevent use by unauthorized individuals, and/or to record dosing histories.
  • Dosage of Ephedrine or Fenfluramine Containing Aerosols [0067] Ephedrine and fenfluramine are given at strengths of 10 mg and 20 mg respectively for appetite suppression.
  • ephendrine As aerosols, 2 mg to 20 mg of ephendrine, and 4 mg to 30 mg of fenfluramine are generally provided per inspiration for the same indication.
  • a typical dosage of an ephedrine or fenfluramine aerosol is either administered as a single inhalation or as a series of inhalations taken within an hour or less (dosage equals sum of inhaled amounts). Where the drug is administered as a series of inhalations, a different amount may be delivered in each inhalation.
  • the dosage amount of ephedrine or fenfluramine in aerosol form is generally no greater than twice the standard dose of the drug given orally.
  • One animal experiment involves measuring plasma concentrations of drug in an animal after its exposure to the aerosol. Mammals such as dogs or primates are typically used in such studies, since their respiratory systems are similar to that of a human.
  • Initial dose levels for testing in humans is generally less than or equal to the dose in the mammal model that resulted in plasma drug levels associated with a therapeutic effect in humans. Dose escalation in humans is then performed, until either an optimal therapeutic response is obtained or a dose-limiting toxicity is encountered.
  • ephedrine or fenfluramine 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 of Analytic Toxicology 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.
  • the aerosol is subjected to an analytical technique, such as gas or liquid chromatography, that permits a determination of composition purity.
  • 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.
  • a solid such as glass wool
  • 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.
  • the container is similarly extracted with a solvent.
  • the gas or liquid chromatograph discussed above contains a detection system (i.e., detector).
  • 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 ephedrine or fenfluramine degradation products.
  • Particle size distribution of an ephedrine or fenfluramine 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, Smyrna, GA) linked to a furnace tube by a mock throat (USP throat, Andersen Instruments, Smyrna, GA) is one system used for cascade impaction studies.
  • 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.
  • 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.
  • 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.
  • 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.
  • the amount of active drug compound collected in the chamber is determined by extracting the chamber, conducting chromatographic analysis of the extract and comparing the results of the chromatographic .analysis to those of a standard containing known amounts of drug.
  • 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.
  • Number of particles in a given size range Mass in the size range/Mass of a typical particle in the size range.
  • 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.
  • 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.
  • 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.
  • the mass of particulate matter may be equated with the mass lost from the device or component during the delivery of the aerosol.
  • 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.
  • Rate of drug aerosol formation is determined, for example, by delivering an ephedrine or fenfluramine 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 ephedrine or fenfluramine, the amount of drug collected in the chamber is measured as described above. The rate of drug aerosol formation is equal to the amount of ephedrine or fenfluramine collected in the chamber divided by the duration of the collection time.
  • ephedrine or fenfluramine containing aerosol comprises a pharmaceutically acceptable excipient
  • multiplying the rate of aerosol formation by the percentage of ephedrine or fenfluramine in the aerosol provides the rate of drug aerosol formation.
  • the ephedrine or fenfluramine containing aerosols of the present invention are typically used for appetite suppression, for increasing one's energy level, or for a positive inotropic effect.
  • Ephedrine and fenfluramine hydrochloride are commercially available from Sigma (www. si ma-aldrich. com) .
  • EXAMPLE 1 General Procedure for Obtaining Free Base of a Compound Salt
  • salt e.g., mono hydrochloride
  • deionized water -30 mL
  • sodium hydroxide 1 N NaOH aq
  • the aqueous solution is extracted four times with dichloromethane (-50 mL), and the extracts are combined, dried (Na 2 SO 4 ) and filtered.
  • the filtered organic solution is concentrated using a rotary evaporator to provide the desired free base. If necessary, purification of the free base is performed using standard methods such as chromatography or recrystallization.
  • a solution of drug in approximately 120 ⁇ L dichloromethane is coated on a 3.5 cm x 7.5 cm piece of aluminum foil (precleaned with acetone). The dichloromethane is allowed to evaporate. The coated foil is wrapped around a 300 watt halogen tube (Feit Electric Company, Pico Rivera, CA), which is inserted into a glass tube sealed at one end with a rubber stopper. Running 60 V of alternating current (driven by line power controlled by a variac) through the bulb for 6 s or 90 V for 3.5 s affords thermal vapor (including aerosol), which is collected on the glass tube walls. Reverse-phase HPLC analysis with detection by abso ⁇ tion of 225 nm light is used to determine the purity of the aerosol.
  • a 300 watt halogen tube Feit Electric Company, Pico Rivera, CA
  • Ephedrine aerosol (7.26 mg) was obtained in approximately 99% purity using this procedure, while fenfluramine aerosol (-10 mg) was obtained in approximately 100% purity.

Abstract

L'invention concerne l'administration de stimulants par voie d'inhalation. Plus spécifiquement, l'invention concerne des aérosols contenant de l'éphédrine ou de la fenfluramine, utilisés en thérapie respiratoire. Dans un mode de réalisation de cette invention, l'aérosol comprend des particules contenant au moins 5 % en poids d'éphédrine ou de fenfluramine. Dans un autre mode de réalisation de cette invention, qui concerne un procédé, un élément choisi dans le groupe comprenant éphédrine et fenfluramine est administré à un mammifère par voie d'inhalation. Ce procédé consiste a) à chauffer une composition qui comprend au moins 5 % en poids d'éphédrine ou de fenfluramine pour former une vapeur, et b) à permettre à cette vapeur de refroidir, pour former ainsi un aérosol de condensation comprenant des particules, lequel est inhalé par le mammifère. Dans un autre mode de réalisation encore de cette invention, un kit permettant d'administrer de l'éphédrine ou de la fenfluramine à un mammifère par voie d'inhalation comprend a) une composition comprenant au moins 5 % en poids d'éphédrine ou de fenfluramine, et b) un dispositif qui forme un aérosol contenant de l'éphédrine ou de la fenfluramine à partir de la composition, lequel aérosol est destiné à être inhalé par le mammifère.
PCT/US2002/015562 2001-05-24 2002-05-15 Administration de stimulants par voie d'inhalation WO2002094216A2 (fr)

Priority Applications (2)

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AU2002314784A AU2002314784A1 (en) 2001-05-24 2002-05-15 Delivery of stimulants through an inhalation route
PCT/US2002/015562 WO2002094216A2 (fr) 2001-05-24 2002-05-15 Administration de stimulants par voie d'inhalation

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US29420301P 2001-05-24 2001-05-24
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US31747901P 2001-09-05 2001-09-05
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EP3868364A1 (fr) * 2020-02-24 2021-08-25 GH Research Limited Aérosol comrpenant 5-methoxy-n,n-dimethyltryptamine
EP4159192A1 (fr) 2021-09-30 2023-04-05 Biomind Labs Inc Spray nasal à base de diméthyltriptamine pour le traitement personnalisé des troubles neurologiques et psychiatriques
WO2023114341A1 (fr) * 2021-12-14 2023-06-22 Alexza Pharmaceuticals, Inc. Dispositifs portatifs et procédés pour produire des aérosols à condensation d'apomorphine de haute pureté

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WO1992005781A1 (fr) * 1990-09-28 1992-04-16 The Procter & Gamble Company Composition contenant de l'ephedrine base et de l'alkyle salicylate pour la diffusion d'ephedrine base sous forme de vapeurs
WO1996031198A1 (fr) * 1995-04-07 1996-10-10 Edward Mendell Co., Inc. Excipient pour insufflation, a liberation progressive, destine a des medicaments

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US3169095A (en) * 1962-10-30 1965-02-09 Rexall Drug Chemical Self-propelling powder-dispensing compositions
US3560607A (en) * 1962-11-30 1971-02-02 Fisons Pharmaceuticals Ltd Aerosol formulations of finely divided solid medicaments with anionic surface-active agents
WO1992005781A1 (fr) * 1990-09-28 1992-04-16 The Procter & Gamble Company Composition contenant de l'ephedrine base et de l'alkyle salicylate pour la diffusion d'ephedrine base sous forme de vapeurs
WO1996031198A1 (fr) * 1995-04-07 1996-10-10 Edward Mendell Co., Inc. Excipient pour insufflation, a liberation progressive, destine a des medicaments

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3868364A1 (fr) * 2020-02-24 2021-08-25 GH Research Limited Aérosol comrpenant 5-methoxy-n,n-dimethyltryptamine
WO2021170614A1 (fr) * 2020-02-24 2021-09-02 Gh Research Limited Aérosol comprenant de la 5-méthoxy-n,n-diméthyltryptamine
CN115427019A (zh) * 2020-02-24 2022-12-02 Gh研究爱尔兰有限公司 包含5-甲氧基-n,n-二甲基色胺的气雾剂
EP4159192A1 (fr) 2021-09-30 2023-04-05 Biomind Labs Inc Spray nasal à base de diméthyltriptamine pour le traitement personnalisé des troubles neurologiques et psychiatriques
WO2023114341A1 (fr) * 2021-12-14 2023-06-22 Alexza Pharmaceuticals, Inc. Dispositifs portatifs et procédés pour produire des aérosols à condensation d'apomorphine de haute pureté

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