WO2002094243A1 - Administration de sumatriptan, de frovatriptan ou de naratriptan par voie d'inhalation - Google Patents

Administration de sumatriptan, de frovatriptan ou de naratriptan par voie d'inhalation Download PDF

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Publication number
WO2002094243A1
WO2002094243A1 PCT/US2002/016402 US0216402W WO02094243A1 WO 2002094243 A1 WO2002094243 A1 WO 2002094243A1 US 0216402 W US0216402 W US 0216402W WO 02094243 A1 WO02094243 A1 WO 02094243A1
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WIPO (PCT)
Prior art keywords
aerosol
naratriptan
frovatriptan
sumatriptan
percent
Prior art date
Application number
PCT/US2002/016402
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English (en)
Inventor
Ron L. Hale
Joshua D. Rabinowitz
Dennis W. Solas
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 PCT/US2002/016402 priority Critical patent/WO2002094243A1/fr
Publication of WO2002094243A1 publication Critical patent/WO2002094243A1/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
    • 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
    • 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
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/185—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 
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • 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
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • 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
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/40—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
    • 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
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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 anti -migraine compounds through an inhalation route. Specifically, it relates to aerosols containing sumatriptan, frovatriptan, or naratriptan that are used in inhalation therapy.
  • compositions currently marketed for the treatment of migraine headaches contain at least one active ingredient that provides for observed therapeutic effects.
  • active ingredients given in such anti-migraine compositions are sumatriptan, frovatriptan, and naratriptan.
  • the present invention relates to the delivery of anti-migraine compounds through an inhalation route. Specifically, it relates to aerosols containing sumatriptan, frovatriptan, or naratriptan that are used in inhalation therapy.
  • the aerosol comprises particles comprising at least 5 percent by weight of sumatriptan, frovatriptan, or naratriptan.
  • the particles comprise at least 10 percent by weight of sumatriptan, frovatriptan, or naratriptan. 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 sumatriptan, frovatriptan, or naratriptan.
  • 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 sumatriptan, frovatriptan, or naratriptan degradation products.
  • the particles comprise less than 5 percent by weight of sumatriptan, frovatriptan, or naratriptan degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of sumatriptan, frovatriptan, or naratriptan.
  • 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 amo ⁇ hous 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 amorphous in form.
  • the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 40 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 35 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 15 mg/L and 30 mg/L.
  • the aerosol comprises frovatriptan
  • the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 4 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 3.5 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 1.5 mg/L and 3.0 mg/L.
  • the aerosol comprises naratriptan
  • the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 2 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 0.3 mg/L and 1.75 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 0.4 mg/L and 1.5 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
  • 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 2.2.
  • the aerosol is formed by heating a composition containing sumatriptan, frovatriptan, or naratriptan to form a vapor and subsequently allowing the vapor to condense into an aerosol.
  • a dose form of an antimigraine compound for the treatment of migraine, wherein the dose form comprises less than the typical oral dose of the antimigraine compound.
  • the dose form comprises less than 20 mg of sumitriptan.
  • the dose form comprises less than 15 mg of sumitriptan. More preferably, the dose form comprises less than 10 mg or 5 mg of sumitriptan.
  • the dose form comprises less than 2 mg of frovatriptan.
  • the dose form comprises less than
  • the dose form comprises less than 1.5 mg, 1.25 mg or 1 mg of frovatriptan.
  • the dose form comprises less than 0.8 mg of naratriptan.
  • the dose form comprises less than
  • the dose for comprises less than 0.4 mg of naratriptan.
  • the dose form further comprises less than 90 percent by weight of water.
  • the dose form further comprises less than 80 percent by weight of water. More preferably, the dose form further comprises less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, or 10 percent by weight of water.
  • the dose form further comprises less than 90 percent by weight of a pharmaceutically acceptable excipient.
  • the dose form further comprises less than 80 percent by weight of a pharmaceutically acceptable excipient. More preferably, the dose form further comprises less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, or 10 percent by weight of a pharmaceutically acceptable excipient.
  • one of sumatriptan, frovatriptan, or naratriptan 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 sumatriptan, frovatriptan, or naratriptan, 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 sumatriptan, frovatriptan, or naratriptan.
  • 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 sumatriptan, frovatriptan, or naratriptan.
  • the particles comprise at least 5 percent by weight of sumatriptan, frovatriptan, or naratriptan.
  • the particles comprise at least 10 percent by weight of sumatriptan, frovatriptan, or naratriptan. 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 sumatriptan, frovatriptan, or naratriptan.
  • 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 sumatriptan, frovatriptan, or naratriptan degradation products.
  • the particles comprise less than 5 percent by weight of sumatriptan, frovatriptan, or naratriptan degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of sumatriptan, frovatriptan, or naratriptan 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,
  • 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 amorphous in form.
  • the particles of the delivered condensation aerosol 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 2.2.
  • the delivered aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 40 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 35 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 15 mg/L and 30 mg/L.
  • the delivered aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 4 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 3.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 1.5 mg/L and
  • the delivered aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 2 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 0.3 mg/L and 1.75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.4 mg/L and 1.5 mg/L.
  • 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 9 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 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.
  • condensation aerosol comprises sumatriptan
  • between 5 mg and 40 mg of sumatriptan are delivered to the mammal in a single inspiration.
  • sumatriptan are delivered to the mammal in a single inspiration. More preferably, between 15 mg and 30 mg of sumatriptan are delivered in a single inspiration.
  • the condensation aerosol comprises frovatriptan
  • between 0.5 mg and 4 mg of frovatriptan are delivered to the mammal in a single inspiration.
  • frovatriptan Preferably, between 1 mg and 3.5 mg of frovatriptan are delivered to the mammal in a single inspiration. More preferably, between 1.5 mg and 3.0 mg of frovatriptan are delivered in a single inspiration.
  • the condensation aerosol comprises naratriptan
  • naratriptan between 0.2 mg and 2 mg of naratriptan are delivered to the mammal in a single inspiration.
  • naratriptan preferably, between 0.3 mg and 1.75 mg of naratriptan are delivered to the mammal in a single inspiration.
  • the delivered condensation aerosol results in a peak plasma concentration of sumatriptan, frovatriptan, or naratriptan 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, 0.01, or 0.005 h (arterial measurement).
  • the condensation aerosol comprises sumatriptan
  • less than 20 mg of sumitriptan is inhaled by the mammal in any 2 hour period.
  • less than 15 mg of sumitriptan is inhaled by the mammal in any 2 hour period.
  • More preferably, less than 10 mg or 5 mg of sumitriptan is inhaled by the mammal in any 2 hour period.
  • the condensation aerosol comprises frovatriptan
  • less than 2 mg of frovatriptan is inhaled by the mammal in any 2 hour period.
  • Preferably, less than 1.75 mg of frovatriptan is inhaled by the mammal in any 2 hour period.
  • a method of treating migraine comprises administering a dose of an antimigraine compound to a mammal that is less than the typical oral dose.
  • the antimigraine compound is sumatriptan
  • less than 20 mg of sumitriptan is administered to the mammal in any 2 hour period.
  • less than 15 mg of sumitriptan is administered to the mammal in any 2 hour period.
  • More preferably, less than 10 mg or 5 mg of sumitriptan is administered to the mammal in any 2 hour period.
  • the antimigraine compound is frovatriptan
  • less than 2 mg of frovatriptan is administered to the mammal in any 2 hour period.
  • less than 1.75 mg of frovatriptan is administered to the mammal in any 2 hour period.
  • less than 1.5 mg, 1.25 mg, or 1 mg of frovatriptan is administered to the mammal in any 2 hour period.
  • the antimigraine compound is naratriptan
  • less than 0.8 mg of naratriptan is administered to the mammal in any 2 hour period.
  • less than 0.6 mg of naratriptan is administered to the mammal in any 2 hour period.
  • More preferably, less than 0.4 mg of naratriptan is inhaled by the mammal in any 2 hour period.
  • kits for delivering sumatriptan, frovatriptan, or naratriptan through an inhalation route to a mammal which comprises: a) a composition comprising at least 5 percent by weight of sumatriptan, frovatriptan, or naratriptan; and, b) a device that forms a sumatriptan, frovatriptan, or naratriptan aerosol from the composition, for inhalation by the mammal.
  • the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent,
  • the device contained in the kit comprises: a) an element for heating the sumatriptan, frovatriptan, or naratriptan 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.
  • the kit comprises sumitriptan, it comprises less than 20 mg of sumitriptan. Preferably, the kit comprises less than 15 mg of sumitriptan. More preferably, it comprises less than 10 mg or 5 mg of sumitriptan.
  • the kit comprises frovatriptan, it comprises less than 2 mg of frovatriptan. Preferably, the kit comprises less than 1.75 mg of frovatriptan. More preferably, it comprises less than 1.5 mg, 1.25 mg, or 1 mg of frovatriptan.
  • the kit comprises naratriptan, it comprises less than 0.8 mg of naratriptan. Preferably, the kit comprises less than 0.6 mg of naratriptan. More preferably, the kit comprises less than 0.4 mg of naratriptan.
  • FIG. 1 shows a cross-sectional view of a device used to deliver sumatriptan, frovatriptan, or naratriptan 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 sumatriptan, frovatriptan, or naratriptan 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.
  • Amo ⁇ hous 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
  • the particle does not contain more than 10 percent by weight 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.
  • Fibertriptan refers to 3-methylamino-6-carboxamido-l ,2,3,4- tetrahydrocarbazole.
  • Fratriptan degradation product refers to a compound resulting from a chemical modification of frovatriptan.
  • 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.
  • Naratriptan refers to N-methyl-3-(l-methyl-4-piperidinyl)-lH-indole-5- ethane-sulfonamide.
  • Naratriptan degradation product refers to a compound resulting from a chemical modification of naratriptan.
  • the modification for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
  • 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 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 sumatriptan, frovatriptan, or naratriptan produced by an inhalation device per unit time.
  • Settling velocity refers to the terminal velocity of an aerosol particle undergoing gravitational settling in air.
  • Sumatriptan refers to 3-[2-(dimethylamino)ethyl]-N-methyl-lH-indole-5- methanesulfonamide .
  • “Sumatriptan degradation product” refers to a compound resulting from a chemical modification of sumatriptan.
  • the modification for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
  • 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 sumatriptan, frovatriptan, or naratriptan to form a vapor, followed by cooling of the vapor such that it condenses to provide a sumatriptan, frovatriptan, or naratriptan comprising aerosol
  • composition is heated in one of four forms: as pure active compound (i.e., pure sumatriptan, frovatriptan, or naratriptan); 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.
  • pure active compound i.e., pure sumatriptan, frovatriptan, or naratriptan
  • Salt forms of sumatriptan, frovatriptan, or naratriptan 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 sumatriptan, frovatriptan, or naratriptan. 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; te ⁇ enes, 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.
  • 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 2 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. [0084] 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 sumatriptan, frovatriptan, or naratriptan 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; abso ⁇ tion 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.
  • Sumatriptan, frovatriptan, or naratriptan containing aerosols of the present invention are delivered to a mammal using an inhalation device.
  • the aerosol is a sumatriptan, frovatriptan, or naratriptan 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.
  • a sumatriptan, frovatriptan, or naratriptan composition is deposited on a surface 112 of heating module 106.
  • 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 sumatriptan, frovatriptan, or naratriptan 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 sumatriptan, frovatriptan, or naratriptan 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 Sumatriptan, Frovatriptan, or Naratriptan Containing Aerosols [0089] Sumatriptan, frovatriptan, and naratriptan are given at strengths of 25 mg, 2.5 mg, and 1 mg respectively for the treatment of migraine headaches.
  • a typical dosage of a sumatriptan, frovatriptan, or naratriptan aerosol is either administered as a single inhalation or as a series of inhalations taken within an hour or less (dosage equals sum of inhaled amounts). Where the drug is administered as a series of inhalations, a different amount may be delivered in each inhalation.
  • the dosage amount of sumatriptan, frovatriptan, or naratriptan in aerosol form is generally no greater than twice the standard dose of the drug given orally.
  • 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.
  • a sumatriptan, frovatriptan, or naratriptan 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.
  • a gas flow e.g., air flow
  • traps are used for aerosol collection.
  • filters such as 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.
  • 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.
  • solvent such as ethanol
  • the solvent extract is subjected to analysis rather than the solid (i.e., glass wool) itself.
  • a syringe or container is used, 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 abso ⁇ tion and mass spectrometry detectors.
  • An advantage of a mass spectrometry detector is that it can be used to determine the structure of sumatriptan, frovatriptan, or naratriptan degradation products.
  • Particle size distribution of a sumatriptan, frovatriptan, or naratriptan 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. 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.
  • 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 a sumatriptan, frovatriptan, or naratriptan 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 sumatriptan, frovatriptan, or naratriptan, 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 sumatriptan, frovatriptan, or naratriptan collected in the chamber divided by the duration of the collection time.
  • sumatriptan, frovatriptan, or naratriptan containing aerosol comprises a pharmaceutically acceptable excipient
  • multiplying the rate of aerosol formation by the percentage of sumatriptan, frovatriptan, or naratriptan in the aerosol provides the rate of drug aerosol formation.
  • the sumatriptan, frovatriptan, or naratriptan containing aerosols of the present invention are typically used for the treatment of migraine headaches.
  • 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.
  • Frovatriptan Aerosol A solution of 5.0 mg frovatriptan in 100 ⁇ L methanol was spread out in a thin layer on the central portion of a 3.5 cm x 7 cm sheet of aluminum foil. The methanol was allowed to evaporate. The aluminum foil was wrapped around a 300 watt halogen tube, which was inserted into a T-shaped glass tube. Both of the openings of the tube were left open and the third opening 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.
  • 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 7.3 x 10 5 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 1.2 x 10 8 particles/second.
  • Alternating current was run through the halogen bulb by application of 90 V using a variac connected to 110 V line power.
  • 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 acetonitrile and the extract analyzed by HPLC with detection by light abso ⁇ tion at 225 nm.
  • Comparison with standards containing known amounts of frovatriptan revealed that 0.85 mg of > 91% pure frovatriptan had been collected in the flask, resulting in an aerosol drug mass density of 0.85 mg/L.
  • the aluminum foil upon which the frovatriptan had previously been coated was weighed following the experiment. Of the 5.0 mg originally coated on the aluminum, 2.8 mg of the material was found to have aerosolized in the 6 s time period, implying a rate of drug aerosol formation of 0.5 mg/s.
  • a high-power flashcube (GE or Sylvania), which can produce 300-400 J of energy, was inserted into an anodized aluminum tube.
  • the flashcube/tube assembly was dipped into an organic solution containing a drug and quickly removed. Evaporation of residual solvent from the assembly was performed by placing it into a vacuum chamber for 30 min. This left a film of drug coated on the exterior surface of the aluminum tube.
  • the flashbulb assembly was electrically connected to two 1.5 V batteries and a switch using copper wires and then enclosed in a sealed, glass vial. Ignition of the flashbulb was performed by momentarily turning on the switch between the flashbulb and batteries.
  • the vial was kept closed for 30 minutes such that particles of volatilized drug coagulated and condensed on the inside surface of the vial.
  • Analysis of the aerosol involved rinsing the vial with 5 mL of acetonitrile and injecting a sample of the organic solution into an HPLC. Frovatriptan (0.45 mg) aerosol was obtained in approximately 92% purity using this procedure.

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Abstract

La présente invention concerne l'administration de composés antimigraineux par voie d'inhalation. L'invention concerne plus particulièrement des aérosols contenant du sumatriptan, du frovatriptan ou du naratriptan, utilisés en inhalothérapie. Dans une composition de la présente invention, l'aérosol renferme des particules comprenant au moins 5 % en masse de sumatriptan, de frovatriptan ou de naratriptan. Dans un procédé de la présente invention, du sumatriptan, du frovatriptan ou du naratriptan est administré à un mammifère par voie d'inhalation. Ce procédé consiste a) à chauffer une composition pour former de la vapeur, la composition comprenant au moins 5 % en masse de sumatriptan, de frovatriptan ou de naratriptan ; et b) à laisser la vapeur refroidir pour qu'elle forme un aérosol de condensation comprenant des particules destiné à être inhalé par le mammifère. La présente invention concerne également un nécessaire conçu pour l'administration de sumatriptan, de frovatriptan ou de naratriptan à un mammifère, par voie d'inhalation, comprenant a) une composition comprenant au moins 5 % en masse de sumatriptan, de frovatriptan ou de naratriptan ; et b) un dispositif permettant de former un aérosol à base de sumatriptan, de frovatriptan ou de naratriptan, à partir de ladite composition, destiné à être inhalé par le mammifère.
PCT/US2002/016402 2001-05-24 2002-05-22 Administration de sumatriptan, de frovatriptan ou de naratriptan par voie d'inhalation WO2002094243A1 (fr)

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WO2009095684A1 (fr) * 2008-02-01 2009-08-06 Vectura Limited Préparations pulmonaires de triptans
EP2526990A3 (fr) * 2005-10-12 2013-03-06 Innovata Biomed Limited Poudre sèche pour inhalation
EP3061453A1 (fr) * 2000-09-19 2016-08-31 Civitas Therapeutics, Inc. Administration pulmonaire de triptan
CN109528670A (zh) * 2018-12-28 2019-03-29 正大制药（青岛）有限公司 一种琥珀酸夫罗曲坦片及其制备方法

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US5388574A (en) * 1993-07-29 1995-02-14 Ingebrethsen; Bradley J. Aerosol delivery article
WO1998016205A2 (fr) * 1996-10-17 1998-04-23 Inhale Therapeutic Systems Compositions stables en poudre a l'etat vitreux
WO2002000198A1 (fr) * 2000-06-29 2002-01-03 Glaxo Group Limited Procede de preparation et de collecte de particules cristallines

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Publication number Priority date Publication date Assignee Title
US5388574A (en) * 1993-07-29 1995-02-14 Ingebrethsen; Bradley J. Aerosol delivery article
WO1998016205A2 (fr) * 1996-10-17 1998-04-23 Inhale Therapeutic Systems Compositions stables en poudre a l'etat vitreux
WO2002000198A1 (fr) * 2000-06-29 2002-01-03 Glaxo Group Limited Procede de preparation et de collecte de particules cristallines

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3061453A1 (fr) * 2000-09-19 2016-08-31 Civitas Therapeutics, Inc. Administration pulmonaire de triptan
EP2526990A3 (fr) * 2005-10-12 2013-03-06 Innovata Biomed Limited Poudre sèche pour inhalation
WO2009095684A1 (fr) * 2008-02-01 2009-08-06 Vectura Limited Préparations pulmonaires de triptans
US20110077272A1 (en) * 2008-02-01 2011-03-31 Vectura Limited Pulmonary formulations of triptans
CN109528670A (zh) * 2018-12-28 2019-03-29 正大制药（青岛）有限公司 一种琥珀酸夫罗曲坦片及其制备方法
CN109528670B (zh) * 2018-12-28 2021-05-07 正大制药（青岛）有限公司 一种琥珀酸夫罗曲坦片及其制备方法

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