Source: https://patents.google.com/patent/US20040105819A1/en
Timestamp: 2019-04-23 06:49:18+00:00

Document:
2003-11-20 Assigned to ALEXZA MOLECULAR DELIVERY CORPORATION reassignment ALEXZA MOLECULAR DELIVERY CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HALE, RON L., LLOYD, PETER M., LU, AMY T., RABINOWITZ, JOSHUA D., WENSLEY, MARTIN J.
Described herein are respiratory drug condensation aerosols and methods of making and using them. Kits for delivering condensation aerosols are also described. The respiratory drug aerosols typically comprise respiratory drug condensation aerosol particles. In some variations the respiratory drug compound is selected from the group consisting of β-adrenergics, methylxanthines, anticholinergics, corticosteroids, mediator-release inhibitors, anti-leukotriene drugs, asthma inhibitors, asthma antagonists, anti-endothelin drugs, prostacyclin drugs, ion channel or pump inhibitors, enhancers, or modulators and pharmaceutically acceptable analogs, derivatives, and mixtures thereof. Methods of treating a respiratory ailment using the described aerosols are also described. In general, the methods typically comprise the step of administering a therapeutically effective amount of respiratory drug condensation aerosol to a person with a respiratory ailment. Methods of forming a respiratory drug condensation aerosol are also described. The methods comprise the steps of vaporizing and condensing a respiratory drug composition.
This application claims priority to U.S. Provisional Application Serial No. 60/429,364 entitled, “Delivery of Asthma Drugs through an Inhalation Route,” which was filed on Nov. 26, 2002 and is hereby incorporated by reference in its entirety.
There are two primary types of medicines used to treat asthma: the “relievers” and the “controllers” (sometimes also referred to as the “preventers”). Reliever medicines are typically bronchodilators. They are used to provide immediate relief of asthma symptoms (e.g., wheezing, coughing, tightness in the chest, shortness of breath, etc.). Bronchodilators function by dilating, or opening up, the bronchi (i.e., the larger airways delivering air inside the lungs). Most commonly prescribed are the β 2-adrenoceptor agonists, also referred to as the β-adrenergics (e.g., epinephrine, isoproterenol, albuterol, salmeterol, salbutamol, terbutaline, isoprenaline, isoetharine, metaproterenol, etc.) and the xanthines (e.g., caffeine, theophylline, etc.).
The composition typically comprises one or more respiratory drug selected from the group consisting of β-adrenergics, methylxanthines, anticholinergics, corticosteroids, mediator-release inhibitors, anti-leukotriene drugs, asthma inhibitors, asthma antagonists, anti-endothelin drugs, prostacyclin drugs, ion channel or pump inhibitors, enhancers, or modulators and pharmaceutically acceptable analogs, derivatives, and mixtures thereof. In other variations, the asthma drug is selected from the group consisting of albuterol, epinephrine, metaproterenol, terbutaline, pseudoephedrine hydrochloride, bambuterol, bitolterol, carbuterol, clenbuterol, clorprenalin, dioxethedrine, eprozinol, etefedrine, ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, isoetharine, isoproterenol, mabuterol, methoxyphenamine, pirbuterol, procaterol, protokylol, rimiterol, salmeterol, soterenol, tretoquinol, tulobuterol, caffeine, theophylline, aminophylline, acefylline, bamifylline, doxofylline, dyphylline, etamiphyllin, etofylline, proxyphylline, reproterol, theobromine-1-acetic acid, atropine, ipratropium bromide, flutropium bromide, oxitropium bromide, tiotropium bromide, budesonide, beclomethasone, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, prednisolone, methylprednisolone, hydrocortisone, cromolyn sodium, nedocromil sodium, montelukast, zafirlukast, pirfenidone, CPX, IBMX, cilomilast, roflumilast, pumafentrine, domitroban, israpafant, ramatroban, seratrodast, tiaramide, zileuton, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan, iloprost, treprostinil, and pharmaceutically acceptable analogs, derivatives, and mixtures thereof.
FIG. 5 is a plot depicting the effects of film thickness on aerosol purity for ciclesonide.
Typically, the respiratory drug composition is coated on a solid support and the solid support is heated to vaporize the asthma drug composition. The support may be of any geometry and a variety of different sizes. It is often desirable that the solid support 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).
When it is desirable to use aluminum as a solid support, aluminum foil is a suitable material. Examples of alumina and silicon based materials include 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. Chromatography resins such as octadecycl silane chemically bonded to porous silica are exemplary coated variants of silica.
The aerosol particles for administration can typically be formed using any of the described methods at a rate of greater than 10 8 inhalable particles per second. In some variations, the aerosol particles for administration are formed at a rate of greater than 109 or 1010 inhalable particles per second. With respect to the rate of aerosol formation (i.e., the mass of aerosolized particulate matter produced by a delivery device per unit time) the aerosol may be formed at a rate greater than 0.25 mg/second, greater than 0.5 mg/second, or greater than 1 or 2 mg/second. Similarly, with respect to the rate of drug aerosol formation (i.e., the mass of aerosolized drug produced by a delivery device per unit time) the drug aerosol may be formed at a rate in the range of from about 0.03 mg/second to about 2 mg/second. Alternatively or in addition, the rate of drug aerosol formation may be greater than 0.01 mg/s, 0.03 mg/s, 0.05 mg/s, 0.09 mg/s, 0.15 mg/s, 0.25 mg/s, 0.4 mg/s, 0.6 mg/s, 0.9 mg/s, 1.3 mg/s, 1.9 mg/s, or 2.5 mg/s.
Typically, the delivered aerosol has an inhalable aerosol particle density greater than 10 6 particles/mL. More typically, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL, and most typically, the aerosol has an inhalable aerosol particle density greater than 108 particles/mL.
One suitable device is illustrated in FIG. 1. Delivery device  100 has a proximal end 102 and a distal end 104, a solid support 106, a power source 108, and a mouthpiece 110. In this depiction, solid support 106 also comprises a heating module. An asthma drug composition is deposited on solid support 106. Upon activation of a user activated switch 114, power source 108 initiates heating of heating module (e.g, through ignition of combustible fuel or passage of current through a resistive heating element, etc.).
The respiratory drug composition vaporizes 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 a user.
Other suitable devices for use with the aerosols described herein are shown in FIGS. 2A and 2B. As shown in FIG. 2A, there is a device  200 comprising an element for heating an asthma drug composition to form a vapor, an element allowing the vapor to cool, thereby forming a condensation aerosol, and an element permitting a user to inhale the aerosol. Device 200 also comprises a housing 202 with a tapered end 204 for insertion into the mouth of a user. On the end opposite tapered end 204, the housing has one or more openings, such as slots 206, for air intake when a user places the device in the mouth and inhales a breath. Within housing 202 is a solid support 208, visible in the cut-away portion of the figure. At least a portion of the solid support is coated on a surface 210 with a film 212 of an asthma drug composition.
Typically, the solid support  208 is heated to a temperature sufficient to vaporize all or a portion of the film 212, so that the respiratory drug composition forms a vapor that becomes entrained in a stream of air during inhalation. As noted above, heating of the solid support 208 may be accomplished using, for example, an electrically-resistive wire embedded or inserted into the substrate and connected to a battery disposed in the housing. The heating can be actuated, for example, with a button on the housing or via breath actuation, as is known in the art.
FIG. 2B shows another device that may be used to form and deliver the aerosols described herein. The device,  214 comprises an element for heating a respiratory drug composition to form a vapor, an element allowing the vapor to cool, thereby forming a condensation aerosol, and an element permitting a user to inhale the aerosol. The device also comprises an upper external housing member 216 and a lower external housing member 218 that fit together.
Shown in the depiction of FIG. 2B, the downstream end of each housing member is gently tapered for insertion into a user's mouth, as best seen on upper housing member  216 at downstream end 220. The upstream end of the upper and lower housing members are slotted, as seen best in the figure in the upper housing member at 222, to provide for air intake when a user inhales. The upper and lower housing members when fitted together define a chamber 224. Positioned within chamber 224 is a solid support 226, shown in a partial cut-away view.
As shown in FIG. 2B, the solid support shown there is of a substantially cylindrical configuration having a slight taper. However, as described above the solid support may be of any desirable configuration. At least a portion of the solid support surface  228 is coated with a respiratory drug composition film 230. Visible in the cutaway portion of the solid support is an interior region 232, which comprises a substance suitable to generate heat. The substance may be, for example, a solid chemical fuel, chemical reagents that mix exothermically, an electrically resistive wire, or the like. A power supply source, if needed for heating, and any necessary valving for the inhalation device may be contained in end piece 234.
FIGS. 3A and 3B provide exploded views of solid supports that may be used in combination with the devices described herein. As shown in FIG. 3A, there is a solid support  300 having a respiratory drug composition coating 302 at least a portion of the upper surface 304. While the coating 302 is shown on upper surface 304 in FIG. 3A, it should be understood that it need not be so. Indeed, the coating may be placed on any suitable surface, such as surfaces 306 and 308.
FIG. 3B provides a perspective, cut-away view of another solid support  310 that may be used with the methods and devices herein described. As shown there, the solid support 310 comprises a cylindrically-shaped substrate 312. This substrate may be formed from a heat-conductive material, for example. The exterior surface 314 of substrate 312 is coated with an asthma drug composition. As shown in the cut-away portion, there is a heating element 316 disposed in the substrate. The substrate can be hollow with a heating element inserted into the hollow space or solid with a heating element incorporated into the substrate.
Purity of a respiratory drug aerosol may be determined using a number of different methods. Examples of suitable methods for determining aerosol purity are described in Sekine et al.,  Journal of Forensic Science 32:1271-1280 (1987) and in Martin et al., Journal of Analytic Toxicology 13:158-162 (1989).
Particle size distribution of a respiratory drug aerosol may be 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. For most pharmaceutical aerosol testing the Anderson Cascade Impactor (ACI) is a gold standard instrument. The ACI inertially separates the aerosol into 7 stages with progressively smaller cutoff diameters from 9.0 μm to 0.4 μm. However, when testing particle size distribution of aerosols that have a substantial fraction less than 1 μm aerodynamic diameter, or aerosols with a MMAD less than 1 micrometer, the ACI is does not provide optimal resolution at that size range. The ACI has only one stage with a cutoff diameter less than 1 μm, at 0.4 mm and thus cannot provide much information about the size distribution of an aerosol below 1 μm. A better alternative is the Micro Orifice Uniform Deposit Impactor (MOUDI) designed and distributed by MSP Corporation in Shoreview, Minn. The MOUDI model  110 has eleven stages, five with cutoff diameters less than 1.0 μm. The stage 0 cut diameter is 18 μm and below 1 μm the cutoffs are 0.56, 0.32, 0.18, 0.1, and 0.056 μm. If additional resolution is required below 0.056 μm, the nano-MOUDI model 115 provides cutoffs of 0.032, 0.018 and 0.010 μm. The performance of these devices has been documented by Virgil Marple, Kenneth Rubow, and Steven Behm (see Marple et al., Aerosol Science and Technology 14:434-446, 1991).
Inhalable aerosol particle density may be 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. Alternatively, the number of particles of a given size may be determined by measuring the mass of particles within the given size range and calculating the number of particles based on the mass as follows: Total number of particles=Sum (from size range 1 to size range N) of number of particles in each size range. 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=π*D 3*φ/6, where D is a typical particle diameter in the size range (generally, the mean boundary MMADs defining the size range) in microns, φ is the particle density (in g/mL) and mass is given in units of picograms (g−12).
Drug is dissolved or suspended in a solvent (e.g., dichloromethane or methanol). The solution or suspension is coated to about a 4 micron thickness on a stainless steel substrate of about 8 cm 2 surface area. The substrate may either be a standard stainless steel foil or a heat-passivated stainless steel foil. The substrate is heated to a temperature sufficient to generate a thermal vapor (generally ˜350° C.) but at least to a temperature of 200 ° C. with an air flow typically of 20 L/min (1 m/s) passing over the film during heating. The heating is done in a volatilization chamber fitted with a trap (such as described in the Examples above). After vaporization is complete, airflow is discontinued and the resultant aerosol is analyzed for purity using the methods disclosed herein. If the resultant aerosol contains less than 10% drug degradation product, i.e., the TSR≧9, then the drug is a heat stable drug. If, however, at about 4 micron thickness, greater than 10% degradation is determined, the experiment is repeated at the same conditions, except that film thicknesses of about 1.5 microns, and of about 0.5 micron, respectively, are used. If a decrease in degradation products relative to the 4 micron thickness is seen at either of these thinner film thicknesses, a plot of film thickness versus purity is graphed and extrapolated out to a film thickness of 0.05 microns. The graph is used to determine if there exists a film thickness where the purity of the aerosol would be such that it contains less than 10% drug degradation products. If such a point exists on the graph, then the drug is defined as a heat stable drug.
Strips of clean  304 stainless steel foil (0.0125 cm thick, Thin Metal Sales) having dimensions 1.3 cm by 7.0 cm were dip-coated approximately 4.5 to 5 cm on the strip with an asthma drug solution prepared as described above. The foil was then partially dipped three times into solvent to rinse drug off of the last 2-3 cm of the dipped end of the foil. Alternatively, the drug-coating from this bottom 2-3 cm area was carefully taken off with a razor blade. The final coated area was between 2.0-2.5 cm by 1.3 cm on both sides of the foil, for a total area of between 5.2-6.5 cm2. Foils were prepared as stated above and then some were extracted with methanol or acetonitrile as standards. The amount of drug was determined from quantitative HPLC analysis. Using the known drug-coated surface area, the thickness was then calculated.
A hollow stainless steel cylinder with thin walls, typically 0.12 mm wall thickness, a diameter of 13 mm, and a length of 34 mm was cleaned in dichloromethane, methanol, and acetone, then dried, and fired at least once to remove any residual volatile material and to thermally passivate the stainless steel surface. The substrate was then dip-coated with a drug coating solution (prepared as described above). The dip-coating was done using a computerized dipcoating machine to produce a thin layer of drug on the outside of the substrate surface. The substrate was lowered into the drug solution and then removed from the solvent at a rate of typically 5-25 cm/sec. (To coat larger amounts of material on the substrate, the substrate was removed more rapidly from the solvent or the solution used was more concentrated.) The substrate was then allowed to dry for 30 minutes inside a fume hood. If either dimethylformamide (DMF) or a water mixture was used as a dip-coating solvent, the substrate was vacuum dried inside a desiccator for a minimum of one hour. The drug-coated portion of the cylinder generally has a surface area of 8 cm 2. By assuming a unit density for the drug, the initial drug coating thickness was calculated. The amount of drug coated onto the substrates was determined in the same manner as that described above: the substrates were coated, then extracted with methanol or acetonitrile and analyzed with quantitative HPLC methods, to determine the mass of drug coated onto the substrate.
Albuterol (MW 239, melting point 158° C., MDI inhalation dose 0.18 mg), a bronchodilator, was coated onto six stainless steel foil substrates (5 cm 2) according to the method “Volatilization Using Stainless Steel Foil” described above. The calculated thickness of the drug film on each substrate ranged from about 0.4 μm to about 1.6 μm. The substrates were heated as described above by charging the capacitors to 15 V. Purity of the drug aerosol particles from each substrate was determined and the results are shown in FIG. 4.
About 0.204 mg ciclesonide (MW 541, melting point 206.5-207° C., MDI inhalation dose 0.2 mg) was coated onto a stainless steel foil substrate (5 cm 2) according to the method “Volatilization Using Stainless Steel Foil” described above. The calculated thickness of the drug film was about 0.4 μm. The substrate was heated as described above by charging the capacitor to 15 V. Purity analysis indicated that the aerosol was 99.03% ciclesonide. A total mass of 0.2 mg was recovered from the test apparatus and substrate, for a total recovery of 100%.
Ciclesonide (MW 541, melting point 206.5-207° C., oral dose 0.2 mg) was coated on stainless steel foil substrates (6 cm 2) according to the method “Volatilization Using Stainless Steel Foil” described above. Eight substrates were prepared, with the drug film thickness ranging from about 0.4 μm to about 2.4 μm. The substrates were heated as described above, with the capacitors charged with 15.0 or 15.5 V. Purity of the drug-aerosol particles from each substrate was determined and the results are shown in FIG. 5.
About 0.3 mg flunisolide (MW 435, MDI inhalation dose 0.25 mg) was coated onto a stainless steel foil substrate (5 cm 2) according to the method “Volatilization Using Stainless Steel Foil” described above. The calculated thickness of the drug film was about 0.6 μm. The substrate was heated as described above by charging the capacitor to 15 V. Purity analysis indicated that the aerosol was 94.9% flunisolide. A total mass of 0.3 mg was recovered from the test apparatus and substrate, for a total recovery of 100%.
About 0.3 mg fluticasone propionate (MW 501, MDI inhalation dose 0.044 mg) was coated onto a stainless steel foil substrate (5 cm 2) according to the method “Volatilization Using Stainless Steel Foil” described above. The calculated thickness of the drug film was about 0.6 μm. The substrate was heated as described above by charging the capacitor to 15 V. Purity analysis indicated that the aerosol was 91.6% fluticasone propionate. A total mass of about 0.2 mg was recovered from the test apparatus and substrate, for a total recovery of about 71.4%.
About 0.64 mg CPX (MW 304) was coated onto a stainless steel foil substrate (5 cm 2) according to the method “Volatilization Using Stainless Steel Foil” described above. The calculated thickness of the drug film was about 1.1 μm. The substrate was heated as described above by charging the capacitor to 15 V. Purity analysis indicated that the aerosol was 99.8% CPX. A total mass of about 0.6 mg was recovered from the test apparatus and substrate, for a total recovery of about 98.0%.
About 0.66 mg IBMX (MW 222) was coated onto a stainless steel foil substrate (5 cm 2) according to the method “Volatilization Using Stainless Steel Foil” described above. The calculated thickness of the drug film was about 1.2 μm. The substrate was heated as described above by charging the capacitor to 15 V. Purity analysis indicated that the aerosol was 99.9% IBMX. A total mass of about 0.66 mg was recovered from the test apparatus and substrate, for a total recovery of about 100%.
A solution of about 0.20 mg flunisolide (MW 435, oral dose 0.25 mg) and about 0.16 mg albuterol (MW 239, melting point 158° C., oral dose 0.18 mg) was coated onto a stainless steel foil substrate (5 cm 2) according to the method “Volatilization Using Stainless Steel Foil” described above. The calculated thickness of the drug film was about 0.64 μm. The substrate was heated as described above by charging the capacitor to 15.5 V. Purity analysis indicated that the aerosol was composed of albuterol (97.2% purity) and flunisolide (94.5%) along with their associated impurities. A total mass of 0.36 mg was recovered from the test apparatus and substrate, for a total recovery of 100%.
administering a therapeutically effective amount of a respiratory drug condensation aerosol to a person with the respiratory ailment, wherein the step of administering comprises the step of administering an orally inhalable respiratory drug condensation aerosol to the person with the respiratory ailment, and wherein the aerosol comprises at least 50% by weight of a respiratory drug.
2. The method of claim 1 wherein the respiratory drug is selected from the group consisting of β-adrenergics, methylxanthines, anticholinergics, corticosteroids, mediator-release inhibitors, anti-leukotriene drugs, asthma inhibitors, asthma antagonists, anti-endothelin drugs, prostacyclin drugs, ion channel or pump inhibitors, enhancers, or modulators and pharmaceutically acceptable analogs, derivatives, and mixtures thereof.
3. The method of claim 2 wherein the respiratory drug is selected from the group consisting of albuterol, epinephrine, metaproterenol, terbutaline, pseudoephedrine hydrochloride, bambuterol, bitolterol, carbuterol, clenbuterol, clorprenalin, dioxethedrine, eprozinol, etefedrine, ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, isoetharine, isoproterenol, mabuterol, methoxyphenamine, pirbuterol, procaterol, protokylol, rimiterol, salmeterol, soterenol, tretoquinol, tulobuterol, caffeine, theophylline, aminophylline, acefylline, bamifylline, doxofylline, dyphylline, etamiphyllin, etofylline, proxyphylline, reproterol, theobromine-1-acetic acid, atropine, ipratropium bromide, flutropium bromide, oxitropium bromide, tiotropium bromide, budesonide, beclomethasone, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, prednisolone, methylprednisolone, hydrocortisone, cromolyn sodium, nedocromil sodium, montelukast, zafirlukast, pirfenidone, CPX, IBMX, cilomilast, roflumilast, pumafentrine, domitroban, israpafant, ramatroban, seratrodast, tiaramide, zileuton, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan, iloprost, treprostinil, and pharmaceutically acceptable analogs, derivatives, and mixtures thereof.
4. The method of claim 1 wherein the respiratory drug condensation aerosol has a MMAD in the range of about 1.5-4 μm.
5. The method of claim 1 wherein the respiratory drug condensation aerosol has a MMAD in the range of about 10-100 nm.
6. The method of claim 1 wherein the step of administering the respiratory drug condensation aerosol comprises the step of administering the respiratory drug condensation aerosol in a single inhalation.
7. The method of claim 1 wherein the step of administering the respiratory drug condensation aerosol comprises the step of administering the respiratory drug condensation aerosol in more than one inhalation.
vaporizing the respiratory drug composition, wherein the step of vaporizing the respiratory drug composition comprises the step of heating the composition to form a vapor.
9. The method of claim 8 wherein the respiratory drug composition comprises a respiratory drug selected from the group consisting of β-adrenergics, methylxanthines, anticholinergics, corticosteroids, mediator-release inhibitors, anti-leukotriene drugs, asthma inhibitors, asthma antagonists, anti-endothelin drugs, prostacyclin drugs, ion channel or pump inhibitors, enhancers, or modulators, and pharmaceutically acceptable analogs, derivatives, and mixtures thereof.
10. The respiratory drug condensation aerosol of claim 9 wherein the respiratory drug is selected from the group consisting of albuterol, epinephrine, metaproterenol, terbutaline, pseudoephedrine hydrochloride, bambuterol, bitolterol, carbuterol, clenbuterol, clorprenalin, dioxethedrine, eprozinol, etefedrine, ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, isoetharine, isoproterenol, mabuterol, methoxyphenamine, pirbuterol, procaterol, protokylol, rimiterol, salmeterol, soterenol, tretoquinol, tulobuterol, caffeine, theophylline, aminophylline, acefylline, bamifylline, doxofylline, dyphylline, etamiphyllin, etofylline, proxyphylline, reproterol, theobromine-1-acetic acid, atropine, ipratropium bromide, flutropium bromide, oxitropium bromide, tiotropium bromide, budesonide, beclomethasone, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, prednisolone, methylprednisolone, hydrocortisone, cromolyn sodium, nedocromil sodium, montelukast, zafirlukast, pirfenidone, CPX, IBMX, cilomilast, roflumilast, pumafentrine, domitroban, israpafant, ramatroban, seratrodast, tiaramide, zileuton, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan, iloprost, treprostinil, and pharmaceutically acceptable analogs, derivatives, and mixtures thereof.
11. The method of claim 8 wherein the respiratory drug composition further comprises a pharmaceutically acceptable excipient.
12. The method of claim 8 wherein the respiratory drug condensation aerosol comprises at least 50% by weight of a respiratory drug.
respiratory drug condensation aerosol particles, wherein the respiratory drug aerosol particles comprise a respiratory drug selected from the group consisting of β-adrenergics, methylxanthines, anticholinergics, corticosteroids, mediator-release inhibitors, anti-leukotriene drugs, asthma inhibitors, asthma antagonists, anti-endothelin drugs, prostacyclin drugs, ion channel or pump inhibitors, enhancers, or modulators, and pharmaceutically acceptable analogs, derivatives, and mixtures thereof, and wherein the respiratory drug condensation aerosol has a MMAD in the range of about 2-4 μm.
14. The respiratory drug condensation aerosol of claim 13 wherein the respiratory drug is selected from the group consisting of albuterol, epinephrine, metaproterenol, terbutaline, pseudoephedrine hydrochloride, bambuterol, bitolterol, carbuterol, clenbuterol, clorprenalin, dioxethedrine, eprozinol, etefedrine, ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, isoetharine, isoproterenol, mabuterol, methoxyphenamine, pirbuterol, procaterol, protokylol, rimiterol, salmeterol, soterenol, tretoquinol, tulobuterol, caffeine, theophylline, aminophylline, acefylline, bamifylline, doxofylline, dyphylline, etamiphyllin, etofylline, proxyphylline, reproterol, theobromine-1-acetic acid, atropine, ipratropium bromide, flutropium bromide, oxitropium bromide, tiotropium bromide, budesonide, beclomethasone, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, prednisolone, methylprednisolone, hydrocortisone, cromolyn sodium, nedocromil sodium, montelukast, zafirlukast, pirfenidone, CPX, IBMX, cilomilast, roflumilast, pumafentrine, domitroban, israpafant, ramatroban, seratrodast, tiaramide, zileuton, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan, iloprost, treprostinil, and pharmaceutically acceptable analogs, derivatives, and mixtures thereof.
15. The respiratory drug condensation aerosol of claim 13 wherein the aerosol comprises at least 50% by weight of a respiratory drug.
16. The respiratory drug condensation aerosol of claim 13 wherein the aerosol is substantially free of thermal degradation products.
a device for forming a respiratory drug aerosol, wherein the device for forming the respiratory drug aerosol comprises an element configured to heat the composition to form a vapor, an element allowing the vapor to condense to form a condensation aerosol, and an element permitting a user to inhale the condensation aerosol.
18. The kit of claim 17 wherein the composition further comprises a pharmaceutically acceptable excipient.
19. The kit of claim 17 wherein the respiratory drug condensation aerosol comprises at least 50% by weight of a respiratory drug.
20. The kit of claim 17 wherein the respiratory drug is selected from the group consisting of β-adrenergics, methylxanthines, anticholinergics, corticosteroids, mediator-release inhibitors, anti-leukotriene drugs, asthma inhibitors, asthma antagonists, anti-endothelin drugs, prostacyclin drugs, ion channel or pump inhibitors, enhancers, or modulators, and pharmaceutically acceptable analogs, derivatives, and mixtures thereof.
21. The kit of claim 20 wherein the respiratory drug is selected from the group consisting of albuterol, epinephrine, metaproterenol, terbutaline, pseudoephedrine hydrochloride, bambuterol, bitolterol, carbuterol, clenbuterol, clorprenalin, dioxethedrine, eprozinol, etefedrine, ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, isoetharine, isoproterenol, mabuterol, methoxyphenamine, pirbuterol, procaterol, protokylol, rimiterol, salmeterol, soterenol, tretoquinol, tulobuterol, caffeine, theophylline, aminophylline, acefylline, bamifylline, doxofylline, dyphylline, etamiphyllin, etofylline, proxyphylline, reproterol, theobromine-1-acetic acid, atropine, ipratropium bromide, flutropium bromide, oxitropium bromide, tiotropium bromide, budesonide, beclomethasone, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, prednisolone, methylprednisolone, hydrocortisone, cromolyn sodium, nedocromil sodium, montelukast, zafirlukast, pirfenidone, CPX, IBMX, cilomilast, roflumilast, pumafentrine, domitroban, israpafant, ramatroban, seratrodast, tiaramide, zileuton, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan, iloprost, treprostinil, and pharmaceutically acceptable analogs, derivatives, and mixtures thereof.
wherein the step of administering comprises the step of administering an orally inhalable respiratory drug aerosol to the person with the respiratory ailment.
23. The method of claim 22 wherein the respiratory drug is selected from the group consisting of β-adrenergics, methylxanthines, anticholinergics, corticosteroids, mediator-release inhibitors, anti-leukotriene drugs, asthma inhibitors, asthma antagonists, endothelin antagonists, prostacylins, and pharmaceutically acceptable analogs, derivatives, and mixtures thereof.
24. The method of claim 23 wherein the respiratory drug is selected from the group consisting of albuterol, epinephrine, metaproterenol, terbutaline, pseudoephedrine hydrochloride, bambuterol, bitolterol, carbuterol, clenbuterol, clorprenalin, dioxethedrine, eprozinol, etefedrine, ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, isoetharine, isoproterenol, mabuterol, methoxyphenamine, pirbuterol, procaterol, protokylol, rimiterol, salmeterol, soterenol, tretoquinol, tulobuterol, caffeine, theophylline, aminophylline, acefylline, bamifylline, doxofylline, dyphylline, etamiphyllin, etofylline, proxyphylline, reproterol, theobromine-1-acetic acid, atropine, ipratropium bromide, flutropium bromide, oxitropium bromide, tiotropium bromide, budesonide, beclomethasone, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, prednisolone, methylprednisolone, hydrocortisone, cromolyn sodium, nedocromil sodium, montelukast, zafirlukast, pirfenidone, CPX, IBMX, cilomilast, roflumilast, pumafentrine, domitroban, israpafant, ramatroban, seratrodast, tiaramide, zileuton, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan, iloprost, treprostinil, and pharmaceutically acceptable analogs, derivatives, and mixtures thereof.
a) formed by volatilizing a heat stable drug composition comprising a respiratory drug selected from the group consisting of β-adrenergics, methylxanthines, anticholinergics, corticosteroids, mediator-release inhibitors, anti-leukotriene drugs, asthma inhibitors, asthma antagonists, anti-endothelin drugs, prostacyclin drugs, ion channel or pump inhibitors, enhancers, or modulators under conditions effective to produce a heated vapor of said drug composition and condensing the heated vapor of the drug composition to form condensation aerosol particles and wherein the respiratory drug condensation aerosol has a MMAD in the range of about 2-4 μm.
26. The composition of claim 25, wherein the heat stable drug is selected from the group consisting albuterol, epinephrine, metaproterenol, terbutaline, pseudoephedrine hydrochloride, bambuterol, bitolterol, carbuterol, clenbuterol, clorprenalin, dioxethedrine, eprozinol, etefedrine, ethylnorepinephrine, fenoterol, fenspiride, hexoprenaline, isoetharine, isoproterenol, mabuterol, methoxyphenamine, pirbuterol, procaterol, protokylol, rimiterol, salmeterol, soterenol, tretoquinol, tulobuterol, caffeine, theophylline, aminophylline, acefylline, bamifylline, doxofylline, dyphylline, etamiphyllin, etofylline, proxyphylline, reproterol, theobromine-1-acetic acid, atropine, ipratropium bromide, flutropium bromide, oxitropium bromide, tiotropium bromide, budesonide, beclomethasone, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, prednisolone, methylprednisolone, hydrocortisone, cromolyn sodium, nedocromil sodium, montelukast, zafirlukast, pirfenidone, CPX, IBMX, cilomilast, roflumilast, pumafentrine, domitroban, israpafant, ramatroban, seratrodast, tiaramide, zileuton, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan, iloprost, treprostinil, and pharmaceutically acceptable analogs, derivatives, and mixtures thereof.
28. The composition of claim 25, wherein said drug composition comprises at least two drugs.
29. The composition of claim 28, wherein at least one drug of the drug composition is a reliever and another drug of the drug composition is a controller.
30. The composition of claim 29, wherein the reliever is a β-adrenergic.
31. The composition of claim 30, wherein the controller is a corticosteriod.
32. The composition of claim 29, wherein the controller is a corticosteriod.
administering a therapeutically effective amount of a respiratory drug condensation aerosol comprising a heat stable respiratory drug to a person with the respiratory ailment, wherein the step of administering comprises administering an orally inhalable respiratory drug condensation aerosol to the person with the respiratory ailment, and wherein the aerosol comprises at least 50% by weight of a respiratory drug.
b) during said volatilizing, passing through the heated vapor to produce aerosol particles of the drug and an aerosol having an MMAD in the range of 1.5-4.
35. The method of claim 34, wherein the aerosol particles comprise less than 5% compound degradation products.
36. The method of claim 34, wherein said volatilizing includes heating a coating of the respiratory drug, which is formed on a solid support having the surface texture of a metal foil, to a temperature sufficient to volatized the compound from the coating.
37. The method of claim 36, wherein said coating comprises at least two respiratory drugs.
38. The method of claim 37, wherein at least one drug is a reliever and another drug is a controller.
US802256A (en) * 1904-07-13 1905-10-17 Max Bamberger Heating composition.
Newman et al. 1983 Therapeutic aerosols 1--physical and practical considerations.
ES2311607T3 (en) 2009-02-16 Antipsychotic Liberacion inhaled.

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