WO2002094219A2 - Delivery of erectile dysfunction drugs through an inhalation route - Google Patents
Delivery of erectile dysfunction drugs through an inhalation route Download PDFInfo
- Publication number
- WO2002094219A2 WO2002094219A2 PCT/US2002/016398 US0216398W WO02094219A2 WO 2002094219 A2 WO2002094219 A2 WO 2002094219A2 US 0216398 W US0216398 W US 0216398W WO 02094219 A2 WO02094219 A2 WO 02094219A2
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- WIPO (PCT)
- Prior art keywords
- aerosol
- percent
- particles
- weight
- sildenafil
- Prior art date
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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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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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A61K31/19—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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- A61K31/403—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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- A61K31/4353—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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- 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 erectile dysfunction drugs through an inhalation route. Specifically, it relates to aerosols containing erectile dysfunction drugs that are used in inhalation therapy.
- compositions currently marketed for the treatment of erectile dysfunction contain at least one active ingredient that provides for observed therapeutic effects.
- active ingredients given in such erectile dysfunction compositions are sildenafil, tadalafil and vardenafil.
- the present invention relates to the delivery of erectile dysfunction drugs through an inhalation route. Specifically, it relates to aerosols containing erectile dysfunction drugs that are used in inhalation therapy. [0006]
- the aerosol comprises particles comprising at least 5 percent by weight of an erectile dysfunction drug.
- the particles comprise at least 10 percent by weight of an erectile dysfunction drug. 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 an erectile dysfunction drug.
- the erectile dysfunction drug is not sildenafil citrate.
- 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 erectile dysfunction drug degradation products.
- the particles comprise less than 5 percent by weight of erectile dysfunction drug degradation products.
- the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of erectile dysfunction drug degradation products.
- the particles comprise less than 90 percent by weight of water.
- the particles comprise less than 80 percent by weight of water.
- 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 particle density greater than 10 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 3.5.
- the geometric standard deviation is less than 3.0. More preferably, the geometric standard deviation is less than 2.5 or 2.2.
- the aerosol is formed by heating a composition containing an erectile dysfunction drug to form a vapor and subsequently allowing the vapor to condense into an aerosol.
- the aerosol comprises particles comprising at least 5 percent by weight of sildenafil, tadalafil or vardenafil.
- the particles comprise at least 10 percent by weight of sildenafil, tadalafil or vardenafil. More preferably, the particles comprise at least
- sildenafil 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of sildenafil, tadalafil or vardenafil.
- 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 sildenafil, tadalafil or vardenafil degradation products.
- the particles comprise less than 5 percent by weight of sildenafil, tadalafil or vardenafil degradation products. More preferably, the particles comprise less than 2.5, 1,
- sildenafil, tadalafil or vardenafil degradation products 0.5, 0.1 or 0.03 percent by weight of sildenafil, tadalafil or vardenafil degradation products.
- the particles comprise less than 90 percent by weight of water.
- the particles comprise less than 80 percent by weight of water.
- 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 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 tadalafil
- the aerosol has an inhalable aerosol drug mass density of between 2.5 mg/L and 20 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 3.5 mg/L and 17.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 15 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 20 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 1.5 mg/L and
- the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 15 mg/L.
- the aerosol has an inhalable aerosol particle density greater than 10 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 3.5.
- the geometric standard deviation is less than 3.0. More preferably, the geometric standard deviation is less than 2.5 or 2.2.
- the aerosol is formed by heating a composition containing sildenafil, tadalafil or vardenafil to form a vapor and subsequently allowing the vapor to condense into an aerosol.
- an erectile dysfunction drug 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 an erectile dysfunction drug, 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 an erectile dysfunction drug.
- 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 an erectile dysfunction drug.
- the particles comprise at least 5 percent by weight of an erectile dysfunction drug.
- the particles comprise at least 10 percent by weight of an erectile dysfunction drug. 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 an erectile dysfunction drug.
- 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 erectile dysfunction drug degradation products.
- the particles comprise less than 5 percent by weight of erectile dysfunction drug degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of erectile dysfunction drug 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 3.5.
- the geometric standard deviation is less than 3.0. More preferably, the geometric standard deviation is less than 2.5 or 2.2.
- 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 8 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
- the delivered condensation aerosol results in a peak plasma concentration of an erectile dysfunction drug 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).
- sildenafil, tadalafil or vardenafil 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 sildenafil, tadalafil or vardenafil, 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 sildenafil, . tadalafil or vardenafil.
- 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 sildenafil, tadalafil or vardenafil.
- the particles comprise at least 5 percent by weight of sildenafil, tadalafil or vardenafil.
- the particles comprise at least 10 percent by weight of sildenafil, tadalafil or vardenafil.
- 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 sildenafil, tadalafil or vardenafil.
- 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 sildenafil, tadalafil or vardenafil degradation products.
- the particles comprise less than 5 percent by weight of sildenafil, tadalafil or vardenafil degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of sildenafil, tadalafil or vardenafil 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 3.5.
- the geometric standard deviation is less than 3.0. More preferably, the geometric standard deviation is less than 2.5 or 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. More preferably, 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 2.5 mg/L and 20 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 3.5 mg/L and 17.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 15 mg/L.
- the delivered aerosol has an inhalable aerosol drag mass density of between 1 mg/L and 20 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 1.5 mg/L and 17.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 15 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 7 particles/mL or 10 8 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.
- the condensation aerosol comprises sildenafil
- between 5 mg and 40 mg of sildenafil are delivered to the mammal in a single inspiration.
- the condensation aerosol comprises tadalafil
- tadalafil between 2.5 mg and 20 mg of tadalafil are delivered to the mammal in a single inspiration.
- tadalafil preferably, between 3.5 mg and 17.5 mg of tadalafil are delivered to the mammal in a single inspiration. More preferably, between 5 mg and 15 mg of tadalafil are delivered in a single inspiration.
- the condensation aerosol comprises vardenafil
- between 1 mg and 20 mg of vardenafil are delivered to the mammal in a single inspiration.
- the delivered condensation aerosol results in a peak plasma concentration of sildenafil, tadalafil or vardenafil 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 an erectile dysfunction drug through an inhalation route to a mammal which comprises: a) a composition comprising at least 5 percent by weight of an erectile dysfunction drug; and, b) a device that forms an erectile dysfunction drug 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 an erectile dysfunction drug.
- the device contained in the kit comprises: a) an element for heating the erectile dysfunction drug 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.
- kits for delivering sildenafil, tadalafil or vardenafil through an inhalation route to a mammal which comprises: a) a composition comprising at least 5 percent by weight of sildenafil, tadalafil or vardenafil; and, b) a device that forms a sildenafil, tadalafil or vardenafil 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 sildenafil, tadalafil or vardenafil.
- the device contained in the kit comprises: a) an element for heating the sildenafil, tadalafil or vardenafil 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 erectile dysfunction drug 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.
- Alcohol refers to a suspension of solid or liquid particles in a gas.
- Aerosol drug mass density refers to the mass of sildenafil or tadalafil 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 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.
- Erectile dysfunction drug degradation product refers to a compound resulting from a chemical modification of an erectile dysfunction drug.
- 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 particulate mass of the aerosol is contributed by particles with an aerodynamic diameter larger than the
- 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 sildenafil or tadalafil produced by an inhalation device per unit time.
- Settling velocity refers to the terminal velocity of an aerosol particle undergoing gravitational settling in air.
- “Sildenafil” refers to 5- [2-ethoxy-5-(4-methylpiperazin- 1 - ylsulfonyl)phenyl] - 1 - methyl-3 -propyl- 1 ,6-dihy dro-7H-pyrazolo [4,3 -djpyrimidin-
- Silicondenafil degradation product refers to a compound resulting from a chemical modification of sildenafil.
- the modification for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
- Tadalafil refers to (6R, 12aR)-2,3, 6,7, 12,12a-hexal ydro-2-methyl-6-
- Tadalafil degradation product refers to a compound resulting from a chemical modification of tadalafil.
- 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.
- Vardenafil refers to l-[[3-(l,4-dihydro-5-methyl-4-oxo-7- propylimidazo[5, 1 -fj [1 ,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl- piperazine (C 23 H 32 N 6 O 4 S).
- Vardenafil degradation product refers to a compound resulting from a chemical modification of vardenafil.
- the modification for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
- any suitable method is used to form the aerosols of the present invention.
- a preferred method involves heating a composition comprising an erectile dysfunction drug to form a vapor, followed by cooling of the vapor such that it condenses to provide an erectile dysfunction drug comprising aerosol (condensation aerosol).
- the composition is heated in one of four forms: as pure active compound (e.g., pure sildenafil, tadalafil or vardenafil); 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 erectile dysfunction drugs 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.
- Pharmaceutically acceptable excipients may be volatile or nonvolatile. Volatile excipients, when heated, are concurrently volatilized, aerosolized and inhaled with the erectile dysfunction drug.
- Classes of such excipients 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.
- 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. For example, 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. [0093] 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 erectile drug 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.
- Erectile dysfunction drug 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 erectile dysfunction drag 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 erectile dysfunction drug 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 erectile dysfunction drug 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 erectile dysfunction drag 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.
- breath-actuation e.g., breath-actuation
- lock-out i.e., "lock-out” feature
- the dosage amount of an erectile dysfunction drug in aerosol form is generally no greater than twice the standard dose of the drug given orally.
- sildenafil, tadalafil and vardenafil are given at strengths of 25 mg, 10 mg, and 5 mg respectively for the treatment of erectile dysfunction.
- 5 mg to 40 mg of sildenafil, 2.5 mg to 20 mg of tadalafil, and 1 to 20 mg of vardenafil are generally provided for the same indication.
- a typical dosage of an erectile dysfunction drag 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.
- 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 drag 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.
- erectile dysfunction drag 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 erectile dysfunction drag degradation products.
- Particle size distribution of an erectile dysfunction drug 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 drag-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 drag-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 drag.
- Inhalable aerosol particle density is determined, for example, by delivering aerosol phase drag 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.
- Mass of a typical particle in a given size range ⁇ *D 3 * ⁇ /6, where D is a typical particle diameter in the size range (generally, the mean boundary MMADs defining the size range) in microns, ⁇ is the particle density (in g/mL) and mass is given in units of picograms (g "12 ).
- Rate of inhalable aerosol particle formation is determined, for example, by delivering aerosol phase drag 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. [0108] 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 erectile dysfunction drug 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 erectile dysfunction drag, the amount of drag collected in the chamber is measured as described above. The rate of -drug aerosol formation is equal to the amount of erectile dysfunction drug collected in the chamber divided by the duration of the collection time. Where the erectile dysfunction drug containing aerosol comprises a pharmaceutically acceptable excipient, multiplying the rate of aerosol formation by the percentage of erectile dysfunction drug in the aerosol provides the rate of drug aerosol formation.
- the erectile dysfunction drug containing aerosols of the present invention are typically used for the treatment of erectile dysfunction.
- Tadalafil can be synthesized using the methods described in U.S. Pat. No. 6,143,746 (issued
- Vardenafil can be synthesized using the methods described in WO/99/24433 (published May 20,
- salt e.g., mono hydrochloride
- deionized water ⁇ 30 mL
- three equivalents of sodium hydroxide I N NaOH aq
- the aqueous solution is extracted four times with dichloromethane ( ⁇ 50 mL), and the extracts are combined, dried (Na 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 drag 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 90 V of alternating current (driven by line power controlled by a variac) through the bulb for 2.5 s affords thermal vapor (including aerosol), which is collected on the glass tube walls. Reverse-phase HPLC analysis with detection by absorption of 225 nm light is used to determine the purity of the aerosol.
- Tadalafil aerosol (0.29 mg) was obtained in 98.5% purity using this procedure. To obtain higher purity aerosols, one can coat a lesser amount of drug, yielding a thinner film to heat. A linear decrease in film thickness is associated with a linear decrease in impurities.
- a flash assembly consisting of a stainless steel outer cylinder and an inner brass electrode was dipped into an organic solution containing a drug and quickly removed. Evaporation of residual solvent from the assembly was performed by air drying. This left a film of drag coated on the exterior surface of the stainless steel cylinder.
- the assembly was electrically connected to a capacitor network (e.g., 1.5 F) and a mechanical relay using brass connectors and then placed into a glass sleeve.
- a filter assembly was placed between the glass sleeve and a vacuum system. Flow ( ⁇ 15 L/min) was instigated through the glass sleeve using the vacuum system.
- Heating of the flash assembly was performed for about 0.25 s by momentarily turning on the relay between the flash assembly and the capacitors (connected to DC power supply and charged to 20.5 V) to volatilize (form an aerosol of) the coated drug.
- the assembly was allowed to cool.
- Analysis of the formed aerosol involved rinsing the filter with 5 mL of acetonitrile and injecting a sample of the organic solution into an HPLC.
- Sildenafil aerosol was obtained in 98.9% purity (0.075 mg) using this procedure.
- Vardenafil aerosol was obtained in 81.4% purity (0.7 mg) using this procedure.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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EP02737132A EP1392259B1 (en) | 2001-05-24 | 2002-05-22 | Delivery of erectile dysfunction drugs through an inhalation route |
AU2002310086A AU2002310086B2 (en) | 2001-05-24 | 2002-05-22 | Delivery of erectile dysfunction drugs through an inhalation route |
PCT/US2002/016398 WO2002094219A2 (en) | 2001-05-24 | 2002-05-22 | Delivery of erectile dysfunction drugs through an inhalation route |
JP2002590938A JP2004531556A (en) | 2001-05-24 | 2002-05-22 | Delivery of erectile dysfunction drugs by prescribed inhalation route |
NZ529418A NZ529418A (en) | 2001-05-24 | 2002-05-22 | Delivery of erectile dysfunction drugs through an inhalation route |
CA002447166A CA2447166C (en) | 2001-05-24 | 2002-05-22 | Delivery of erectile dysfunction drugs through an inhalation route |
DE60220909T DE60220909T2 (en) | 2001-05-24 | 2002-05-22 | ADMINISTRATION OF MEDICINAL PRODUCTS FOR THE TREATMENT OF EFFECTS OF INHALATION |
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US60/317,479 | 2001-09-05 | ||
PCT/US2002/016398 WO2002094219A2 (en) | 2001-05-24 | 2002-05-22 | Delivery of erectile dysfunction drugs through an inhalation route |
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WO2002094219A2 true WO2002094219A2 (en) | 2002-11-28 |
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PCT/US2002/016398 WO2002094219A2 (en) | 2001-05-24 | 2002-05-22 | Delivery of erectile dysfunction drugs through an inhalation route |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2006528176A (en) * | 2003-07-23 | 2006-12-14 | エラン ファーマ インターナショナル リミテッド | Novel sildenafil free base composition |
WO2007027612A2 (en) * | 2005-08-29 | 2007-03-08 | Teva Pharmaceutical Industries Ltd. | Solid particulate tadalafil having a bimodal particle size distribution |
WO2009115235A1 (en) * | 2008-03-20 | 2009-09-24 | Bayer Schering Pharma Aktiengesellschaft | Pde inhibitors for the treatment of pulmonary hypertension |
US11806314B2 (en) | 2013-12-09 | 2023-11-07 | Respira Therapeutics, Inc. | PDE5 inhibitor powder formulations and methods relating thereto |
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EP0967214A1 (en) * | 1998-06-22 | 1999-12-29 | Pfizer Limited | Intranasal formulations for treating sexual disorders |
WO2000066084A1 (en) * | 1999-05-04 | 2000-11-09 | Aradigm Corporation | Aerosol formulations and devices for increasing libido in women via acute testosterone administration |
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AU5358694A (en) * | 1992-10-28 | 1994-05-24 | Charles A. Rosen | Method and devices for delivering drugs by inhalation |
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EP0967214A1 (en) * | 1998-06-22 | 1999-12-29 | Pfizer Limited | Intranasal formulations for treating sexual disorders |
WO2000066084A1 (en) * | 1999-05-04 | 2000-11-09 | Aradigm Corporation | Aerosol formulations and devices for increasing libido in women via acute testosterone administration |
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JP2006528176A (en) * | 2003-07-23 | 2006-12-14 | エラン ファーマ インターナショナル リミテッド | Novel sildenafil free base composition |
JP4860469B2 (en) * | 2003-07-23 | 2012-01-25 | エラン ファーマ インターナショナル,リミティド | Novel sildenafil free base composition |
WO2007027612A2 (en) * | 2005-08-29 | 2007-03-08 | Teva Pharmaceutical Industries Ltd. | Solid particulate tadalafil having a bimodal particle size distribution |
WO2007027612A3 (en) * | 2005-08-29 | 2007-08-02 | Teva Pharma | Solid particulate tadalafil having a bimodal particle size distribution |
WO2009115235A1 (en) * | 2008-03-20 | 2009-09-24 | Bayer Schering Pharma Aktiengesellschaft | Pde inhibitors for the treatment of pulmonary hypertension |
US11806314B2 (en) | 2013-12-09 | 2023-11-07 | Respira Therapeutics, Inc. | PDE5 inhibitor powder formulations and methods relating thereto |
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WO2002094219A3 (en) | 2003-03-06 |
AU2002310086B2 (en) | 2008-09-04 |
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