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WO2002094231A1 - Administration d'analgesiques par voie d'inhalation - Google Patents

Administration d'analgesiques par voie d'inhalation Download PDF

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Publication number
WO2002094231A1
WO2002094231A1 PCT/US2002/015757 US0215757W WO02094231A1 WO 2002094231 A1 WO2002094231 A1 WO 2002094231A1 US 0215757 W US0215757 W US 0215757W WO 02094231 A1 WO02094231 A1 WO 02094231A1
Authority
WO
WIPO (PCT)
Prior art keywords
aerosol
tramadol
acetaminophen
percent
oφhenadrine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2002/015757
Other languages
English (en)
Inventor
Joshua D. Rabinowitz
Alejandro C. Zaffaroni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alexza Pharmaceuticals Inc
Original Assignee
Alexza Molecular Delivery Corp
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 Corp filed Critical Alexza Molecular Delivery Corp
Priority to PCT/US2002/015757 priority Critical patent/WO2002094231A1/fr
Publication of WO2002094231A1 publication Critical patent/WO2002094231A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/007—Pulmonary tract; Aromatherapy
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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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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    • A61K31/435—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
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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    • 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 analgesics through an inhalation route. Specifically, it relates to aerosols containing acetaminophen, orphenadrine or tramadol that are used in inhalation therapy.
  • compositions currently marketed as analgesics contain at least one active ingredient that provides for the observed therapeutic effects.
  • active ingredients given in analgesic compositions are acetaminophen, orphenadrine and tramadol.
  • the present invention relates to the delivery of analgesics through an inhalation route. Specifically, it relates to aerosols containing acetaminophen, o ⁇ henadrine or tramadol that are used in inhalation therapy.
  • the aerosol comprises particles comprising at least 5 percent by weight of acetaminophen, orphenadrine or tramadol.
  • the particles comprise at least 10 percent by weight of acetaminophen, orphenadrine or tramadol. 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 acetaminophen, orphenadrine or tramadol.
  • 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 acetaminophen, orphenadrine or tramadol degradation products.
  • the particles comprise less than 5 percent by weight of acetaminophen, orphenadrine or tramadol degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of acetaminophen, orphenadrine or tramadol 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 amorphous in form.
  • the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 1000 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 750 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 30 mg/L and 500 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 100 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 85 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 30 mg/L and 70 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 100 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 50 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.
  • 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 acetaminophen, orphenadrine or tramadol to form a vapor and subsequently allowing the vapor to condense into an aerosol.
  • one of acetaminophen, orphenadrine or tramadol 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 acetaminophen, orphenadrine or tramadol, 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 acetaminophen, orphenadrine or tramadol.
  • 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 acetaminophen, orphenadrine or tramadol.
  • the particles comprise at least 5 percent by weight of acetaminophen, orphenadrine or tramadol.
  • the particles comprise at least 10 percent by weight of acetaminophen, orphenadrine or tramadol. 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 acetaminophen, orphenadrine or tramadol.
  • 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 acetaminophen, orphenadrine or tramadol degradation products.
  • the particles comprise less than 5 percent by weight of acetaminophen, orphenadrine or tramadol degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of acetaminophen, orphenadrine or tramadol 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 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.
  • 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 10 mg/L and 1000 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 750 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 30 mg/L and 500 mg/L.
  • the aerosol comprises orphenadrine
  • the delivered aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 100 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 85 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 30 mg/L and 70 mg/L.
  • the delivered aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 100 mg/L.
  • the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 10 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 9 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.
  • condensation aerosol comprises acetaminophen
  • acetaminophen are delivered to the mammal in a single inspiration. More preferably, between 30 mg and 500 mg of acetaminophen are delivered in a single inspiration.
  • condensation aerosol comprises orphenadrine
  • 10 mg and 100 mg of orphenadrine are delivered to the mammal in a single inspiration.
  • the condensation aerosol comprises tramadol
  • between 2 mg and 100 mg of tramadol are delivered to the mammal in a single inspiration.
  • the delivered condensation aerosol results in a peak plasma concentration of acetaminophen, orphenadrine or tramadol 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).
  • kits for delivering acetaminophen, orphenadrine or tramadol through an inhalation route to a mammal which comprises: a) a composition comprising at least 5 percent by weight of acetaminophen, orphenadrine or tramadol; and, b) a device that forms an acetaminophen, orphenadrine or tramadol 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, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of acetaminophen, orphenadrine or tramadol.
  • the device contained in the kit comprises: a) an element for heating the acetaminophen, orphenadrine or tramadol 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 acetaminophen, o ⁇ henadrine or tramadol aerosols to a mammal through an inhalation route.
  • Alcohol refers to N-(4-hydroxyphenyl)acetamide.
  • Alcohol degradation product refers to a compound resulting from a chemical modification of acetaminophen. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
  • 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.
  • Alcohol refers to a suspension of solid or liquid particles in a gas.
  • Aerosol drug mass density refers to the mass of acetaminophen, o ⁇ henadrine or tramadol 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.
  • 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 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.
  • O ⁇ henadrine refers to N,N-dm ⁇ ethyl-2-[(2-methylphenyl)phenylmethoxy]- ethanamine.
  • O ⁇ henadrine degradation product refers to a compound resulting from a chemical modification of o ⁇ henadrine.
  • the modification for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
  • 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 acetaminophen, o ⁇ henadrine or tramadol produced by an inhalation device per unit time.
  • Settling velocity refers to the terminal velocity of an aerosol particle undergoing gravitational settling in air.
  • Tramadol refers to ( ⁇ )cis-2-[(dimethylamino)methyl]-l-(3-methoxyphenyl)- cyclohexanol.
  • Tramadol degradation product refers to a compound resulting from a chemical modification of tramadol.
  • 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 acetaminophen, o ⁇ henadrine or tramadol to form a vapor, followed by cooling of the vapor such that it condenses to provide an acetaminophen, o ⁇ henadrine or tramadol comprising aerosol
  • composition is heated in one of four forms: as pure active compound (i.e., pure acetaminophen, o ⁇ henadrine or tramadol); 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 acetaminophen, o ⁇ henadrine or tramadol 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 acetaminophen, o ⁇ henadrine or tramadol. 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. 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.
  • aluminum foil is a suitable material.
  • silica, alumina and silicon based materials include amphorous silica S-5631 (Sigma, St. Louis, MO), BCR171 (an alumina of defined surface area greater than 2 m 2 /g from Aldrich, St. Louis, MO) and a silicon wafer as used in the semiconductor industry. Carbon yarns and felts are available from American Kynol, Inc., New York, NY. Chromatography resins such as octadecycl silane chemically bonded to porous silica are exemplary coated variants of silica.
  • the heating of the acetaminophen, o ⁇ henadrine or tramadol 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.
  • Acetaminophen, O ⁇ henadrine or tramadol 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 acetaminophen, o ⁇ henadrine or tramadol 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 acetaminophen, o ⁇ henadrine or tramadol composition is deposited on a surface 108 initiates heating of heating module 106 (e.g, through ignition of combustible fuel or passage of current through a resistive heating element).
  • the acetaminophen, o ⁇ henadrine or tramadol 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 acetaminophen, o ⁇ henadrine or tramadol 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.
  • Acetaminophen, Orphenadrine or Tramadol Containing Aerosols are given at strengths of 650 mg, 60 mg, and 50 mg respectively for the treatment of pain.
  • aerosols 10 mg to 1000 mg or acetaminophen, 10 mg to 100 mg of o ⁇ henadrine, and 2 mg to 100 mg of tramadol are generally provided per inspiration for the same indication.
  • a typical dosage of an acetaminophen, o ⁇ henadrine or tramadol 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 acetaminophen, o ⁇ henadrine or tramadol 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.
  • acetaminophen, Orphenadrine or Tramadol Containing Aerosols Purity of an acetaminophen, o ⁇ henadrine or tramadol 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 acetaminophen, o ⁇ henadrine or tramadol degradation products.
  • Particle size distribution of an acetaminophen, o ⁇ henadrine or tramadol containing aerosol is determined using any suitable method in the art (e.g., cascade impaction).
  • 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 an acetaminophen, o ⁇ henadrine or tramadol 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 acetaminophen, o ⁇ henadrine or tramadol, 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 acetaminophen, o ⁇ henadrine or tramadol collected in the chamber divided by the duration of the collection time.
  • acetaminophen, o ⁇ henadrine or tramadol containing aerosol comprises a pharmaceutically acceptable excipient
  • multiplying the rate of aerosol formation by the percentage of acetaminophen, o ⁇ henadrine or tramadol in the aerosol provides the rate of drug aerosol formation.
  • acetaminophen, o ⁇ henadrine or tramadol containing aerosols of the present invention are typically used for the treatment of pain.
  • Acetaminophen and o ⁇ henadrine hydrochloride are commercially available from Sigma (www.sigma-aldrich.com). Tramadol hydrochloride is available in tablets (ULTRAM®) and can be isolated using standard methods in the art.
  • 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 (acetaminophen) or 90 V for 3.5 s (o ⁇ henadrine or O ⁇ henadrine hydrochloride) 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. (When desired, the system is flushed through with argon prior to volatilization.)
  • Acetaminophen aerosol and o ⁇ henadrine aerosol were obtained in 100% purity using this procedure.
  • Tramadol (17.5 mg) was spread out in a thin layer on a 8 cm x 5 cm sheet of aluminum foil.
  • the coated aluminum foil sheet was inserted into a glass tube in a furnace (tube furnace).
  • a glass wool plug was placed in the tube adjacent to the foil sheet, and an air flow of 2 L/min was applied.
  • the furnace was heated to 250 °C for 120 s to volatilize the coated tramadol and then was allowed to cool.
  • the glass wool was extracted, and HPLC analysis of the collected material showed it to be at least 97.3% pure tramadol.

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Abstract

L'invention concerne l'administration d'analgésiques par voie d'inhalation. Plus spécifiquement, l'invention concerne des aérosols contenant de l'acétaminophène, de l'orphénadrine ou du tramadol, utilisés en thérapie respiratoire. Dans un mode de réalisation de cette invention, l'aérosol comprend des particules comprenant au moins 5 % en poids d'acétaminophène, d'orphénadrine ou de tramadol. Dans un autre mode de réalisation de cette invention, qui concerne un procédé, un élément choisi dans le groupe comprenant acétaminophène, orphénadrine ou tramadol est administré à un mammifère par voie d'inhalation. Ce procédé consiste a) à chauffer une composition comprenant au moins 5 % en poids d'acétaminophène, d'orphénadrine ou de tramadol, pour former une vapeur, et b) à permettre à cette vapeur de se refroidir, formant ainsi un aérosol de condensation comprenant des particules, lequel est inhalé par un mammifère. Dans un autre mode de réalisation encore de cette invention, un kit permet d'administrer de l'acétaminophène, de l'orphénadrine ou du tramadol par voie d'inhalation à un mammifère. Ce kit comprend a) une composition comprenant au moins 5 % en poids d'acétaminophène, d'orphénadrine ou de tramadol, et b) un dispositif qui forme un aérosol contenant de l'acétaminophène, de l'orphénadrine ou du tramadol à partir de la composition, lequel aérosol est destiné à être inhalé par le mammifère.
PCT/US2002/015757 2001-05-24 2002-05-16 Administration d'analgesiques par voie d'inhalation Ceased WO2002094231A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003094900A1 (fr) * 2002-05-13 2003-11-20 Alexza Molecular Delivery Corporation Distribution de medicament a base d'amines par voie d'inhalation
CN104208044A (zh) * 2013-05-29 2014-12-17 天津金耀集团有限公司 盐酸曲马多吸入制剂

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997017948A1 (fr) * 1995-11-14 1997-05-22 Euro-Celtique, S.A. Formulation pour administration par les voies respiratoires
US6095134A (en) * 1992-03-06 2000-08-01 The Board Of Regents Of The University Of Co Methods and apparatus for fine particle formation
WO2000072827A2 (fr) * 1999-05-27 2000-12-07 Acusphere, Inc. Matrices medicamenteuses poreuses et procedes de fabrication associes
EP1177793A1 (fr) * 2000-08-03 2002-02-06 Air Liquide Santé (International) Aérosol médicamenteux inhalable dans le traitement ou la prévention de la douleur

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6095134A (en) * 1992-03-06 2000-08-01 The Board Of Regents Of The University Of Co Methods and apparatus for fine particle formation
WO1997017948A1 (fr) * 1995-11-14 1997-05-22 Euro-Celtique, S.A. Formulation pour administration par les voies respiratoires
WO2000072827A2 (fr) * 1999-05-27 2000-12-07 Acusphere, Inc. Matrices medicamenteuses poreuses et procedes de fabrication associes
EP1177793A1 (fr) * 2000-08-03 2002-02-06 Air Liquide Santé (International) Aérosol médicamenteux inhalable dans le traitement ou la prévention de la douleur

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003094900A1 (fr) * 2002-05-13 2003-11-20 Alexza Molecular Delivery Corporation Distribution de medicament a base d'amines par voie d'inhalation
CN104208044A (zh) * 2013-05-29 2014-12-17 天津金耀集团有限公司 盐酸曲马多吸入制剂

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