Use of antistatic materials in airways for thermal aerosol condensation processes.

Abstract

To provide the use of antistatic materials in devices for producing aerosol containing active drugs that are used in inhalation therapy.SOLUTION: Antistatic materials are used in an airway for thermal aerosol generation devices. Antistatic materials for drug delivery are used in any drug that may be susceptible to charging during aerosol generation.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001]

[0001] The present invention relates to materials for use in devices for delivering aerosols by the inhalation route. In particular, the present invention relates to the use of antistatic materials in devices for generating aerosols containing active drugs for use in inhalation therapy. [Background technology]

[0002]

[0002] Currently, there are a number of approved devices for inhalation delivery of drugs, including dry powder inhalers, nebulizers, and pressurized metered dose inhalers. These devices include metered dose inhalers, but the aerosols produced by these devices generally contain excipients.

[0003]

[0003] Rapid vaporization of thin films of drugs into an air stream within 500 milliseconds at temperatures up to 600°C produces high-yield, high-purity drug aerosols with minimal drug degradation. Condensed drug aerosols can be used for effective pulmonary delivery of drugs using inhalation medical devices. A device and method for vaporizing thin films of drugs deposited on a metal substrate by electrical resistive heating have been presented. Chemical-based heat packages capable of containing fuels capable of undergoing exothermic metal oxidation-reduction reactions in a sealed container can also be used to generate rapid heat impulses capable of vaporizing thin films to produce high-purity aerosols; see, for example, U.S. Application No. 10 / 850,895, entitled "Self-Contained Heating Unit and Drug-Supply Unit Employing Same," filed May 20, 2004, and U.S. Application No. 10 / 851,883, entitled "Percussively Ignited or Electrically Ignited Self-Contained Heating Unit and Drug Supply Unit Employing Same," filed May 20, 2004; both of which are incorporated herein by reference in their entireties. These devices and methods are suitable for use with compounds that can be deposited as physically and chemically stable solids.

[0004]

[0004] Aerosols from MDIs and DPIs are often highly charged, which can result in inconsistent aerosol discharge and affect therapeutic efficacy. For example, Pierart et al. reported that MDI spacers lose approximately 14% of their aerosol particles due to charging. One factor that may affect drug output from an inhaler is the electrostatic interaction between charged drug aerosol particles and device components surrounding the aerosol. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] US Application No. 10 / 850,895, “Self-Contained Heating Unit and Drug-Supply Unit Employing Same,” filed May 20, 2004 [Patent Document 2] US Application No. 10 / 851,883, “Percussively Ignited or Electrically Ignited Self-Contained Heating Unit and Drug Supply Unit Employing Same,” filed May 20, 2004 Summary of the Invention [Problem to be solved by the invention]

[0006]

[0005] The embodiments disclosed herein are directed to overcoming one or more of the problems discussed above. [Means for solving the problem]

[0007]

[0006] The present disclosure teaches the use of antistatic materials in airways for thermal aerosol generating devices. The present disclosure teaches the use of antistatic materials for drug delivery in any drug, such as alprazolam, that may be susceptible to charging during aerosol generation. Many possible embodiments of the present disclosure include both antistatic airway materials and coatings for airways. The present disclosure teaches metallized airways (manufactured by coating the inner walls of the airway with a conductive metal, such as stainless steel / copper / copper / stainless steel, or by applying metal tape (e.g., copper) to the inner and outer walls of the airway), the use of antistatic sprays (e.g., Staticide brand) in default airways, and the use of antistatic plastics (e.g., Permastat or Permastat plus brand) as airway materials.

[0008]

[0007] The present disclosure teaches drug aerosols formed using thermal aerosol condensation. One aspect of this technology involves a drug-coated substrate placed inside an airway. For certain drugs, such as alprazolam, the formed aerosols tend to deposit erratically on the airway, resulting in reduced and inconsistent delivery. Some drugs form charged aerosols when vaporized under certain conditions. Charged aerosols can deposit on the airway due to electrostatic attraction. The present disclosure teaches the use of antistatic treatments to reduce aerosol charging and airway deposition.

[0009]

[0008] The present disclosure teaches methods and devices for providing inhalation delivery of a drug, wherein the emitted dose of drug aerosol formed by thermal aerosol condensation with an antistatic material in the airway results in a more consistent dose than the emitted dose of drug aerosol formed by thermal aerosol condensation without an antistatic material in the airway. The use of an antistatic material significantly reduces the amount of drug aerosol that deposits in the airway. The use of an antistatic material reduces the charge on the aerosol. The method and device achieve drug delivery of a drug characterized by the drug forming a charged aerosol upon vaporization. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 shows a Staccato single dose device. [Figure 2] FIG. 2 is a graph showing airway deposition and aerosol charging for Permastat, Permastat Plus, and standard airway materials. [Figure 3]

[0011] FIG. 3 is a graph showing aerosol characteristics using a Permastat airway. [Figure 4]

[0012] FIG. 4 is a schematic diagram of a drug delivery device. DETAILED DESCRIPTION OF THE INVENTION

[0011]

[0013] As defined herein, the following terms shall have the following meanings when referred to throughout this specification:

[0014] The "aerodynamic diameter" of a particular particle refers to the diameter of a spherical droplet of 1 g / mL density (the density of water) that has the same settling velocity as the particular particle.

[0012]

[0015] "Aerosol" refers to a collection of solid or liquid particles suspended in a gas.

[0016] "Mass concentration of aerosol" refers to the mass of particulate matter per unit volume of aerosol.

[0013]

[0017] Antistatic materials include airway materials and and coatings for the airway. These antistatic materials include metallized airways (manufactured by coating the interior walls of the airway with a conductive metal, e.g., stainless steel / copper / copper / stainless steel, and / or by applying metal tape (e.g., copper) to the interior and exterior walls of the airway), the use of antistatic sprays (e.g., Staticide brands) in the default airway, and / or the use of antistatic plastics (e.g., Permastat or Permastat plus brands) as the airway material. Materials with antistatic properties are included in this disclosure.

[0014]

[0018] "Condensation aerosol" refers to an aerosol formed by vaporizing a composition and subsequently cooling the vapor, thereby causing the vapor to condense and form particles.

[0019] "Decomposition Index" refers to a number derived from the assay, which is determined by subtracting the purity of the generated aerosol (expressed as a decimal) from 1.

[0015]

[0020] "Drug" means any substance used in the prevention, diagnosis, mitigation, treatment, or cure of a condition. The drug is preferably in a form suitable for thermal vapor delivery, such as an ester, free acid, or free base. The terms "drug," "compound," and "medicine" are used interchangeably herein. The term drug as used throughout this specification includes nicotine and nicotine meta-salicylate.

[0016]

[0021] A "drug composition" refers to a composition containing a pure drug alone, a combination of two or more drugs, or one or more drugs in combination with additional components, which may include, for example, pharmaceutically acceptable excipients, carriers, and surfactants.

[0017]

[0022] "Drug degradation product" or "thermal degradation product" are used interchangeably and mean any by-product produced by heating a drug(s) that does not contribute to producing a therapeutic effect.

[0018]

[0023] The terms "drug delivery article" or "drug delivery unit" are used interchangeably and refer to a substrate having at least a portion of its surface coated with one or more drug compositions. The drug delivery articles of the present invention may also include additional elements, such as, but not limited to, a heating element.

[0019]

[0024] "Drug degradation product fraction" refers to the amount of drug degradation product present in an aerosol particle divided by the amount of drug plus drug degradation product present in the aerosol, i.e., (the sum of the amounts of all drug degradation products present in the aerosol) / ((the amount of drug(s) present in the aerosol)+(the sum of the amounts of all drug degradation products present in the aerosol)). As used herein, the term "percent drug degradation product" refers to the drug degradation product fraction multiplied by 100%, while the "purity" of an aerosol refers to 100% minus the percent drug degradation product.

[0020]

[0025] "Thermostable drug" refers to a drug that has a TSR ≥ 9 when vaporized from a film of a certain thickness, between 0.05 μm and 20 μm.

[0026] The "mass median aerodynamic diameter" or "MMAD" of an aerosol refers to the aerodynamic diameter where half of the particle mass of the aerosol is contributed by particles with an aerodynamic diameter greater than the MMAD and half is contributed by particles with an aerodynamic diameter less than the MMAD.

[0021]

[0027] "Number concentration" is the number of particles per unit volume of aerosol. Represents a number.

[0028] As used herein with respect to aerosol purity, "purity" refers to the drug composition fraction in the aerosol / the drug composition fraction in the aerosol plus drug degradation products. Thus, purity is relative, taking into account the purity of the starting material. For example, if the starting drug or starting drug composition used to coat the substrate contained detectable impurities, the reported aerosol purity does not include impurities present in the starting material that are also found in the aerosol; for example, in a particular case, if the starting material contains 1% impurity and the aerosol is found to contain the same 1% impurity, the purity of the aerosol can nevertheless be reported as >99% pure, reflecting the fact that the detectable 1% impurity was not generated during the evaporation-condensation aerosol generation process.

[0022]

[0029] "Settling velocity" refers to the terminal velocity of an aerosol particle settling gravitationally in air.

[0030] A "support" is a material on which a composition is applied, generally as a coating or film. The terms "support" and "substrate" are used herein to refer to a material to be attached. Used interchangeably

[0031] "Substantially free of" means that the described substance, compound, aerosol, etc. is at least 95% free from other components that are substantially free.

[0023]

[0032] "Typical patient tidal volume" refers to 1 L for adults and 15 mL / kg for pediatric patients.

[0033] A "therapeutically effective amount" means an amount necessary to achieve a therapeutic effect, which may be any therapeutic effect ranging from prevention, symptom amelioration, symptom treatment, to disease termination or cure.

[0024]

[0034] "Thermal stability ratio" or "TSR" is the ratio of a purity <99% 0.9% means %Purity / (100%-%Purity), and 1000 if the %Purity is ≥ 99.9%. For example, a vaporized respiratory drug with 90% purity would have a TSR of 9.

[0025]

[0035] "4 μm Thermal Stability Ratio" or "4TSR" means the TSR of a drug as determined by heating an approximately 4 micron drug-containing film under conditions sufficient to vaporize at least 50% of the drug in the film, collecting the resulting aerosol, determining the purity of the aerosol, and using that purity to calculate the TSR. Such vaporization typically involves heating an approximately 4 micron thick drug film to about 350°C (but not less than 200°C) for about 1 second to vaporize at least 50% of the drug in the film.

[0026]

[0036] "1.5 μm thermal stability ratio" or "1.5 TSR" means the TSR of a drug as determined by heating an approximately 1.5 micron drug-containing film under conditions sufficient to vaporize at least 50% of the drug in the film, collecting the resulting aerosol, determining the purity of the aerosol, and calculating the TSR using that purity. Such vaporization typically involves heating an approximately 1.5 micron thick drug film to about 350°C (but not less than 200°C) for about 1 second to vaporize at least 50% of the drug in the film.

[0027]

[0037] "0.5 μm thermal stability ratio" or "0.5 TSR" means the TSR of a drug as determined by heating an about 0.5 micron drug-containing film under conditions sufficient to vaporize at least 50% of the drug in the film, collecting the resulting aerosol, determining the purity of the aerosol, and calculating the TSR using that purity. Such vaporization typically involves heating an about 0.5 micron thick drug film to about 350°C (but not less than 200°C) for about 1 second to vaporize at least 50% of the drug in the film.

[0028]

[0038] "Vapor" refers to a gas, and "vapor phase" refers to a gas phase. The term "thermal vapor" refers to a vapor phase, an aerosol, or an aerosol-vapor phase mixture, preferably formed by heating.

[0029]

[0039] When condensation aerosols form in the airflow, a percentage of the aerosol may deposit on downstream physical features, such as the sidewalls of the airway that define the airflow, the device mouthpiece, or other structures, thereby reducing the amount of active compound released by the device for administration. For many treatment regimens, the ability to deliver doses containing accurate, consistent, and reproducible amounts of bioactive compounds impacts the therapeutic efficacy of the treatment regimen, and in some cases, such an ability may enable new therapies. Thus, there is a need for inhalation devices and methods that generate condensation aerosols that can deliver accurate, reproducible, and / or controlled amounts of bioactive substances. The present disclosure teaches the use of antistatic materials in airways for thermal aerosol generating devices. The present disclosure teaches the use of antistatic materials for drug delivery of any drug that may be prone to electrostatic charge generation during aerosol generation, such as alprazolam. Many possible embodiments of the present disclosure include both airway materials and coatings for the airway that are antistatic. The present disclosure teaches metallized airways (manufactured by coating the interior walls of the airway with a conductive metal, e.g., stainless steel / copper / copper / stainless steel, or by applying metal tape (e.g., copper) to the interior and exterior walls of the airway), the use of antistatic sprays (e.g., Staticide brand) in the default airway, and the use of antistatic plastics (e.g., Permastat or Permastat plus brand) as the airway material.

[0030] Aerosol Composition

[0040] The compositions described herein generally comprise a pharmaceutical compound. The compositions can also comprise other compounds. For example, the compositions can comprise a mixture of a pharmaceutical compound and a pharmaceutically acceptable excipient, or a mixture of a pharmaceutical compound and other compounds with useful or desirable properties. The compositions can also comprise a pure pharmaceutical compound. In one embodiment, the composition consists essentially of pure drug and does not contain a propellant or solvent.

[0031]

[0041] Additionally, pharmaceutically acceptable carriers, surfactants, enhancers, and inorganic compounds may be included in the composition. Examples of such materials are known in the art.

[0042] In some variations, the aerosol is substantially free of organic solvents and propellants. Furthermore, no water is added as a solvent for nicotine meta-salicylate, although water from the atmosphere may be incorporated into the forming aerosol, particularly during the airflow over the membrane and during the cooling process. In other variations, the aerosol is completely free of organic solvents and propellants. In yet other variations, the aerosol is completely free of organic solvents, propellants, and any excipients. These aerosols contain only the pure drug, less than 10% of drug degradation products, and a carrier gas (typically air).

[0032]

[0043] Generally, the drug has a degradation index of less than 0.15. Preferably, the drug has a degradation index of less than 0.10. More preferably, the drug has a degradation index of less than 0.05. Most preferably, the drug has a degradation index of less than 0.025.

[0033]

[0044] In some variations, the condensation aerosol contains at least 5% by weight of condensation drug aerosol particles. In other variations, the aerosol contains at least 10%, 20%, 30%, 40%, 50%, 60%, or 75% by weight of condensation drug aerosol particles. In yet other variations, the aerosol contains at least 95%, 99%, or , or 99.5% by weight of condensed drug aerosol particles.

[0034]

[0045] In some variations, the condensation aerosol particles contain less than 10% by weight of thermal decomposition products, hi other variations, the condensation drug aerosol particles contain less than 5%, 1%, 0.5%, 0.1%, or 0.03% by weight of thermal decomposition products.

[0035]

[0046] In certain embodiments of the disclosure, the drug aerosol has a purity of 90%-99.8%, or 93%-99.7%, or 95%-99.5%, or 96.5%-99.2%. In certain embodiments of the disclosure, the drug aerosol has a percent free base nicotine in the aerosol of 90%-99.8%, or 93%-99.7%, or 95%-99.5%, or 96.5%-99.2%.

[0036]

[0047] Generally, aerosols are particles of 10 6 In other variations, the aerosol has a particle concentration greater than 10 7 In yet another variation, the aerosol has a particle concentration greater than 10 8 greater than 10 cells / mL 9 greater than 10 cells / mL 10 cells / mL or greater than 10 11 have a particle concentration greater than particles / mL.

[0037]

[0048] The gas in the aerosol is typically air. However, other gases, particularly inert gases such as argon, nitrogen, and helium, can be used. The gas can also include vapors of the composition that have not yet condensed to form particles. Generally, the gas does not contain propellants or vaporized organic solvents. In some variations, the condensation aerosol contains at least 5% by weight of condensation drug aerosol particles. In other variations, the aerosol contains at least 10%, 20%, 30%, 40%, 50%, 60%, or 75% by weight of condensation drug aerosol particles. In still other variations, the aerosol contains at least 95%, 99%, or 99.5% by weight of condensation aerosol particles.

[0038]

[0049] In some variations, the condensation drug aerosol has an MMAD in the range of about 0.01 to 3 μm. In some variations, the condensation drug aerosol has an MMAD in the range of about 0.1 to 3 μm. In some variations, the geometric standard deviation of the condensation drug aerosol particles about the MMAD is less than 3.0. In other variations, the geometric standard deviation of the condensation drug aerosol particles about the MMAD is less than 2.5, or less than 2.0.

[0039]

[0050] In some embodiments of the invention, the drug aerosol contains one or more drugs with a 4TSR of at least 5 or 10, a 1.5TSR of at least 7 or 14, or a 0.5TSR of at least 9 or 18. In other embodiments of the invention, the drug aerosol contains one or more drugs with a 4TSR of 5-100 or 10-50, a 1.5TSR of 7-200 or 14-100, or a 0.5TSR of 9-900 or 18-300.

[0040] Condensation aerosol formation

[0051] Any suitable method can be used to form the condensation aerosols described herein. One such method involves heating the composition to form a vapor, and then cooling the vapor so that it forms an aerosol (i.e., a condensation aerosol). This method is previously described in U.S. Patent No. 7,090,830, which reference is incorporated herein in its entirety.

[0052] Generally, the composition is coated onto a substrate, and then the substrate is heated to vaporize the composition. The substrate can be of any geometric shape and can be of a wide variety of sizes. If the substrate has a large surface area to volume ratio (e.g., greater than 100 per meter), and a large surface-to-mass ratio (e.g., 1 cm per gram) 2 It is often desirable to have a larger surface. A substrate can have more than one surface.

[0041]

[0053] Substrates of one shape can also be transformed into other shapes with different properties. For example, a flat sheet 0.25 mm thick has a surface area-to-volume ratio of approximately 8,000 per meter. Rolling this sheet into a hollow cylinder 1 cm in diameter produces a substrate with a higher surface area-to-mass ratio than the original sheet, but a lower surface area-to-volume ratio (about 400 per meter).

[0042]

[0054] A wide variety of materials can be used to construct the substrate. Generally, the substrate is thermally conductive and includes metals, such as aluminum, iron, copper, stainless steel, alloys, ceramics, and filled polymers. In one variation, the substrate is stainless steel. Material combinations and coated forms of materials can also be used.

[0043]

[0055] If aluminum is desired as the substrate, aluminum foil is a suitable material. BCR171 (2m), an example of an alumina and silicon based material, is also suitable. 2 Alumina with a specified surface area greater than 1 / g (from Aldrich, St. Louis, MO) and silicon wafers used in the semiconductor industry.

[0044]

[0056] Generally, it is desirable for the substrate to have relatively few or substantially no surface irregularities. While a variety of substrates can be used, substrates having an impermeable surface or an impermeable surface coating are generally desirable. Examples of such substrates include metal foils, smooth metal surfaces, non-porous ceramics, and the like. Alternatively, or in addition, preferred substrates have an impermeable surface, and the substrate surface area is about 20 mm 2 Alternatively, or in addition, preferred substrates have an impermeable surface, and the substrate surface area is about 1 mm 2 Larger, preferably 10mm 2 , more preferably 50 mm 2 , and even more preferably 100 mm 2They are characterized by a large continuous surface area and a material density greater than 0.5 g / cc. In contrast, undesired substrates generally have a substrate density less than 0.5 g / cc (e.g., yarn, felt, and foam) or a density of less than 1 mm 2 / particles with sub-particle surface areas (e.g., small alumina particles and other inorganic particles); it is difficult to generate therapeutic amounts of drug aerosol by vaporization with less than 10% drug degradation on these types of surfaces.

[0045]

[0057] In one variation, the present disclosure teaches a stainless steel foil substrate. A hollow stainless steel tube can be used as the drug film substrate. In another variation, aluminum foil can be used as the substrate for the test drug.

[0046]

[0058] The composition is generally coated onto a solid support in the form of a film. Any suitable method can be used to coat the film onto the solid support. The appropriate method for coating often depends on the physical properties of the compound and the desired film thickness. One example of how to coat the composition onto a solid support is by preparing a solution of the compound (alone or in combination with other desired compounds) in a suitable solvent, applying the solution to the exterior surface of the solid support, and then removing the solvent (e.g., by evaporation), thereby leaving a film on the surface of the support.

[0047]

[0059] Common solvents include methanol, dichloromethane, methyl ethyl ketone, diethyl ether, acetone, ethanol, isopropyl alcohol, a 3:1 chloroform:methanol mixture, a 1:1 dichloromethane:methyl ethyl ketone mixture, dimethylformamide, and deionized water. In some cases (e.g., when using triamterene), it may be desirable to use a solvent such as formic acid. Sonication can also be used to dissolve the compound.

[0048]

[0060] The composition can also be coated onto a solid support by dipping the support into a solution of the composition, or by spraying, brushing, or otherwise applying the solution to the support. Alternatively, a melt of the drug can be prepared and applied to the support. For drugs that are liquid at room temperature, a thickening agent can be mixed with the drug to allow for the application of a solid drug film.

[0049]

[0061] The film can vary in thickness depending on the compound and the maximum amount of thermal decomposition desired. In one method, heating the composition involves heating a thin film of the composition having a thickness of about 0.1 μm to 30 μm to form a vapor. In yet another variation, the composition has a film thickness of about 0.5 μm to 21 μm. Most commonly, the vaporized film thickness is 0.5 μm to 25 μm.

[0050]

[0062] The substrate coated with the film of the composition can be heated by various means to Materials can be vaporized. Exemplary heating methods include passing current through an electrical resistance element, absorbing electromagnetic radiation (e.g., microwave or laser light), and exothermic chemical reactions (e.g., exothermic solvation, hydration of pyrophoric substances, and oxidation of combustible substances). Heating a substrate by conductive heating is also suitable. One exemplary heat source is described in U.S. patent application, SELF-CONTAINED HEATING UNIT AND DRUG-SUPPLY UNIT EMPLOYING SAME, U.S. Ser. No. 60 / 472,697, filed May 21, 2003. The description of the exemplary heat source disclosed therein is incorporated herein by reference.

[0051]

[0063] The heat source generally supplies heat to the substrate at a rate sufficient to achieve a substrate temperature of at least 200°C, preferably at least 250°C, or more preferably at least 300°C or 350°C, and to substantially completely volatilize the drug composition from the substrate within 2 seconds, preferably within 1 second, or more preferably within 0.5 seconds. Suitable heat sources include resistive heating devices to which electrical current is supplied at a rate sufficient to achieve rapid heating, e.g., to a substrate temperature of at least 200°C, 250°C, 300°C, or 350°C, preferably within 50-500 milliseconds, more preferably within 50-200 milliseconds. Also suitable are heat sources or devices containing a chemically reactive substance that undergoes an exothermic reaction when activated, e.g., by a spark or heating element, such as flash bulb-type heaters of the type described in some examples, and heat sources described in the above-cited U.S. patent application, SELF-CONTAINED HEATING UNIT AND DRUG-SUPPLY UNIT EMPLOYING SAME. In particular, heat sources that generate heat by exothermic reactions in which the chemical "charge" of the heat source is consumed in a period of 50-500 milliseconds or less are generally suitable, assuming good thermal coupling between the heat source and the substrate.

[0052]

[0064] When heating a thin film of a composition, it is desirable for vaporized compounds to migrate rapidly from the heated surface or surrounding heated gas to a cooler environment to avoid decomposition. This can be achieved not only by rapid heating of the substrate, but also by using a gas flow across the surface of the substrate. While vaporized vapor from the surface can migrate by Brownian motion or diffusion, the time for this migration can be affected by the gas velocity gradient over the surface and the extent of the elevated surface temperature zone established by the physical geometry of the surface. Typical gas flow rates used to minimize such decomposition and generate the desired particle size are 1 to 10 L / min.

[0053]

[0065] Aerosol particles for administration are generally prepared using any of the methods described above to produce inhalable particles 108 In some variations, the aerosol particles for administration can be formed at a rate of greater than 10 particles / second. 9 or 10 10 Similarly, in terms of aerosol formation (i.e., the mass of aerosolized particles produced by the delivery device per unit time), a rate of greater than 0.25 mg / sec, 0.5 m Further, with respect to aerosol formation, when looking at the drug aerosol formation rate (i.e., the rate of pharmaceutical compound released in aerosol form by the delivery device per unit time), the drug can be aerosolized at a rate of greater than 0.05 mg drug / sec, greater than 0.1 mg drug / sec, greater than 0.5 mg drug / sec, or greater than 1 or 2 mg drug / sec.

[0054]

[0066] In some variations, the drug condensation aerosol is formed from a composition that provides at least 5% by weight of drug condensation aerosol particles. In other variations, the aerosol is formed from a composition that provides at least 10%, 20%, 30%, 40%, 50%, 60%, or 75% by weight of drug condensation aerosol particles. In still other variations, the aerosol is formed from a composition that provides at least 95%, 99%, or 99.5% by weight of drug condensation aerosol particles.

[0055]

[0067] In some variations, the drug condensation aerosol particles contain less than 10% by weight of thermal decomposition products when formed, hi other variations, the drug condensation aerosol particles contain less than 5%, 1%, 0.5%, 0.1%, or 0.03% by weight of thermal decomposition products when formed.

[0056]

[0068] In some variations, the drug condensation aerosol is generated in the gas stream at a velocity such that the resulting aerosol has an MMAD in the range of about 0.1 to 3 μm. In some variations, the geometric standard deviation of the drug condensation aerosol particles about the MMAD is less than 3.0. In other variations, the geometric standard deviation of the drug condensation aerosol particles about the MMAD is less than 2.5, or less than 2.0.

[0057] Delivery Device

[0069] The delivery devices described herein for administering condensation drug aerosols generally include an element for heating the composition to form a vapor and an element for cooling the vapor, thereby forming a condensation aerosol. These aerosols are generally delivered by inhalation to a patient's lungs for local or systemic treatment. However, the drug-aerosol particles can also be applied to a target site, or the condensation aerosols of the present invention can be generated in an airstream. For example, an airstream carrying the drug-aerosol particles can be applied to treat acute or chronic skin conditions, to an incision site during a surgical procedure, or to an open wound. The delivery device can be combined with a drug-containing composition in unit dosage form for use as a kit.

[0058]

[0070] The devices described herein can further include various components to facilitate aerosol delivery. For example, the devices can include any component known in the art for controlling the timing of drug aerosolization relative to inhalation (e.g., inspiration actuation). Similarly, the devices can include components for providing feedback to the patient on the rate and / or volume of inhalation or components for preventing overuse (i.e., "lockout" features). The devices can further include features such as metering / logging or tapering schemes. Additionally, the devices can further include components for preventing use by unauthorized individuals and components for recording administration history. These components can be used alone or in combination with other components.

[0059]

[0071] The cooling element may be of any structure, for example it may be an inert passageway connecting the heating means to the inhalation means. Similarly, the element allowing the user to inhale may be of any structure, for example it may be a passageway connecting the cooling element to the user. It may also be an exit portal that forms a connection with the respiratory system of the patient.

[0060]

[0072] The present disclosure teaches a Staccato device, shown in FIG. 4, that uses antistatic material in the airway.

[0073] Antistatic materials include, but are not limited to, both airway materials and coatings for airways that are antistatic. The present disclosure teaches metallized airways (manufactured by coating the interior walls of the airway with a conductive metal, e.g., stainless steel / copper / copper / stainless steel, or by applying metal tape (e.g., copper) to the interior and exterior walls of the airway), the use of antistatic sprays (e.g., Staticide brand) in default airways, and the use of antistatic plastics (e.g., Permastat or Permastat plus brand) as airway materials.

[0061]

[0074] Generally, the drug delivery article is heated to a temperature sufficient to vaporize all or a portion of the membrane, causing the composition to form a vapor that is entrained in the airstream upon inhalation. As noted above, heating of the drug delivery article can be achieved, for example, using an electrical resistance wire embedded or inserted in the substrate and connected to a battery located in the housing. Heating can be activated, for example, by a button on the housing or by inhalation actuation, as is known in the art.

[0062]

[0075] Another device that can be used to form and deliver the aerosols described herein is the following. The device includes an element for heating the composition to form a vapor, an element for cooling the vapor, thereby forming a condensed aerosol, and an element that allows a user to inhale the aerosol. The device also includes upper and lower outer housing members that fit together.

[0063]

[0076] The downstream end of each housing member is gently tapered for insertion into a user's mouth. The upstream ends of the upper and lower housing members have slots (one or both have slots) for capturing air when the user inhales. The upper and lower housing members, when mated together, define a chamber. A drug supply unit is disposed within the chamber.

[0064]

[0077] The solid support may have any desired structure. At least a portion of the surface of the substrate is coated with a film of the composition. An example of a thermite-type heat source is In this case, the inner region of the substrate contains a material suitable for generating heat. The material may be a solid chemical fuel, a chemical that generates heat when mixed, an electrical resistance wire, etc. The end piece may house a power source, if needed for heating, and any valve arrangement required for the inhalation device. The power source may be a piece that mates with the drug delivery unit.

[0065]

[0078] In one variation of the device used, the device includes a drug composition delivery article comprised of: a substrate, a film of the selected drug composition on the surface of the substrate, and a heat source for supplying heat to the substrate at a rate effective to heat the substrate to a temperature greater than 200°C, or in other embodiments, greater than 250°C, 300°C, or 350°C, to substantially completely volatilize the drug composition within a period of not more than 2 seconds.

[0066]

[0079] Other drug delivery articles that can be used in combination with the device are described herein.A variety of coating methods are known in the art and / or described above.

[0067]

[0080] 4 is a schematic diagram of a drug delivery device 40. The drug delivery device 40 The drug delivery device includes a housing 42 that encloses the supply unit 10 and defines an airway 44. In use, air can be drawn into the housing 42 through the airway 44 by drawing air through the inlet 46 in the direction of arrow 48 to the outlet 50. In use, the drug layer 38 vaporizes, and the vaporized drug is entrained in the air and then condenses in the condensation space 52 to form an aerosol, which can then be delivered through the outlet 50. The drug delivery device can be constructed and dimensioned to provide the air flow rate required to form aerosol particles of selected sizes from a variety of drugs.

[0068]

[0081] The airway housing material can be made of an antistatic material. Many possible embodiments of the present disclosure include both airway materials and coatings for airways that are antistatic. The present disclosure teaches metallized airways (manufactured by coating the interior walls of the airway with a conductive metal, e.g., stainless steel / copper / copper / stainless steel, or by applying metal tape (e.g., copper) to the interior and exterior walls of the airway), the use of antistatic sprays (e.g., Staticide brand) in default airways, and the use of antistatic plastics (e.g., Permastat or Permastat plus brand) as airway materials.

[0069]

[0082] While the heating element is exemplified as an electrical resistance wire that generates heat when an electric current is passed through it, as noted above, a wide variety of heating methods and corresponding devices are acceptable. For example, an acceptable heat source can supply heat to the drug delivery article at a rate sufficient to rapidly reach a temperature sufficient to completely vaporize the composition from the substrate surface. For example, heat sources that achieve temperatures of 200°C to 500°C or higher within a 2-second period are common; it should be recognized that the temperature selected will depend on the vaporization characteristics of the composition, but they are generally heated to temperatures of at least about 200°C, preferably at least about 250°C, and more preferably at least about 300°C or 350°C. Heating the substrate produces a drug composition vapor, which, in the presence of a flowing gas, generates aerosol particles of a desired size range. The presence of a gas flow generally occurs before, simultaneously with, or after heating the substrate. In one embodiment, the substrate is heated for a period of less than about 1 second, more preferably less than about 500 milliseconds, and even more preferably less than about 200 milliseconds. The drug-aerosol particles are inhaled by the subject for delivery to the lungs.

[0070]

[0083] The device can also include a gas flow control valve positioned upstream of the solid support to limit the gas flow rate through the condensation region. The gas flow valve can include, for example, an inlet communicating with the chamber and a deformable flap adapted to gradually divert or restrict air flow away from the inlet as pressure across the valve gradually increases. Similarly, the gas flow valve can include an actuation switch. In this variation, the movement of the valve could be responsive to an air pressure differential across the valve, which could function, for example, to close a switch. The gas flow valve can also include an opening designed to limit the air flow rate into the chamber.

[0071]

[0084] The device may also include a bypass valve in communication with the downstream chamber of the unit to offset the airflow reduction caused by the gas flow control valve as the user draws air into the chamber. Thus, the bypass valve, in cooperation with the gas control valve, can control the flow through the condensation region of the chamber and the total amount of air drawn into the device. Thus, in this variation, the total volume of airflow through the device will be the sum of the volumetric air flow rate through the gas control valve and the volumetric air flow rate through the bypass valve.

[0072]

[0085] The gas control valve can function, for example, to limit the air drawn into the device to a preselected level, e.g., 15 L / min. In this way, the air flow can be preselected and generated to produce particles of a desired size. For example, this selection Once the selected airflow level is reached, additional air drawn into the device will create a pressure drop across the bypass valve, which in turn will accommodate airflow through the bypass valve and into the downstream end of the device adjacent the user's mouth. Thus, the user will feel all of the inhaled air being drawn in as the two valves divide the total airflow between the desired airflow rate and the bypass airflow rate.

[0073]

[0086] These valves can be used to control the gas velocity through the condensation region of the chamber, and therefore the particle size of the aerosol particles produced. Generally, the faster the air flow, the smaller the particles. Therefore, to obtain smaller or larger particles, the gas velocity through the condensation region of the chamber can be changed by modifying the gas flow control valve to increase or decrease the volumetric air flow rate. For example, to produce condensation particles in the size range of approximately 1 to 3.5 μm MMAD, a chamber with substantially smooth walls would have a selected gas flow rate in the range of 1 to 10 L / min.

[0074]

[0087] Additionally, one skilled in the art will appreciate that particle size can be altered by modifying the cross-section of the chamber condensation region to increase or decrease the linear gas velocity for a particular volumetric flow rate, and / or by the presence or absence of structures that create turbulence within the chamber. Thus, for example, to produce condensation particles in the 10-100 nm MMAD size range, the chamber can include gas flow barriers to create turbulent air flow within the condensation chamber. These barriers are typically located within a few thousandths of an inch of the substrate surface.

[0075] Drug composition film thickness

[0088] Typically, the drug composition film coated on the solid support has a thickness of about 0.05 to 30 μm, typically 0.1 to 30 μm. More typically, the thickness is about 0.2 to 30 μm; even more typically, the thickness is about 0.5 to 30 μm, and most typically, the thickness is about 0.5 to 25 μm. The desired film thickness for any particular drug composition is typically determined by iterative methods, where the desired yield and purity of the condensation aerosol composition is selected or known.

[0076]

[0089] For example, if the particle purity is lower than desired or the yield is lower than desired, the drug film thickness is adjusted to a thickness different from the initial film thickness. The purity and yield are then determined at the prepared film thickness, and the process is repeated until the desired purity and yield are achieved. After selecting the appropriate film thickness, the substrate area required to deliver a therapeutically effective amount is determined.

[0077]

[0090] Generally, the film thickness for a particular drug composition is such that the drug-aerosol particles formed by vaporizing the drug composition by heating the substrate and entraining the vapor in a gas stream contain (i) no more than 10% by weight, more preferably no more than 5% by weight, and most preferably no more than 2.5% by weight of drug degradation products, and (ii) at least 50% of the total amount of drug composition contained in the film. The area of ​​the substrate onto which the drug composition film is formed is selected to achieve an effective amount of drug aerosol for human therapy, as further described below.

[0078]

[0091] One method that can be used to determine the thickness of the drug film is to determine the area of ​​the substrate and calculate the thickness of the drug film using the following relationship: Film thickness (cm) = drug mass (g) / [drug density (g / cm 3 ) x base material area (cm 2 )]

[0092] The drug mass can be determined by weighing the substrate before and after drug film formation, or by extracting the drug and analytically measuring the amount. Drug density can be determined experimentally by a variety of techniques, known to those skilled in the art, or found in the literature or reference texts. , can be found, for example, in CRC. If the actual drug density is not known, an estimate of the unit density is acceptable.

[0079]

[0093] A substrate with a drug film of known thickness was heated to a temperature sufficient to generate a thermal vapor. All or a portion of the thermal vapor was collected and analyzed for the presence of drug degradation products to determine the purity of the aerosol particles in the thermal vapor. There is a clear relationship between film thickness and aerosol particle purity, with purity increasing as film thickness decreases.

[0080]

[0094] In addition to selecting a drug film thickness that provides aerosol particles containing 10% or less drug degradation products (i.e., aerosol particles that are 90% or more pure), the film thickness is selected so that at least about 50% of the total amount of drug composition contained in the film is vaporized when the substrate is heated to a temperature sufficient to vaporize the film.

[0081]

[0095] To obtain a higher purity aerosol, one can coat a smaller amount of drug and heat a thinner film, or use the same amount of drug but a larger surface area. Generally, as discussed above, impurities decrease linearly with a linear decrease in film thickness, except for extremely thin drug films.

[0082]

[0096] Thus, for drug compositions whose aerosols exhibit increasing levels of drug degradation products with increasing film thickness, particularly at thicknesses greater than 0.05-30 microns, film thicknesses on a substrate capable of forming a particle aerosol with less than 5% drug degradation will generally be between 0.05 and 30 microns, e.g., at or near the maximum of this range.

[0083]

[0097] Another method allows for the generation of drug-aerosol particles with a desired level of drug composition purity by forming a thermal vapor under a controlled atmosphere of an inert gas, such as argon, nitrogen, or helium.

[0084]

[0098] Once the desired purity and yield is achieved, or the corresponding film thickness can be determined by extrapolation from an aerosol purity versus film thickness graph, the substrate area required to deliver a therapeutically effective dose is determined.

[0085] Base material area

[0099] As noted above, the surface area of ​​the substrate surface region is selected to be sufficient to provide a therapeutically effective amount. The amount of drug that provides a therapeutic amount is generally known in the art and is discussed further below. The required amount discussed above and the selected film thickness govern the minimum required substrate area according to the following relationship: Film thickness (cm) × drug density (g / cm 3 ) x base material area (cm 2 )=dose(g) That is, Base material area (cm 2 ) = Dose (g) / [film thickness (cm) × drug density (g / cm 3 )]

[0100] The drug mass can be determined by weighing the substrate before and after drug film formation or by measuring the drug content. The density of a drug can be determined by extracting the substance and analytically measuring the amount. Drug density can be determined experimentally by a variety of well-known techniques or can be found in the literature or in reference texts, such as the CRC. If the actual drug density is unknown, an estimate of the unit density is acceptable.

[0086]

[0101] Drugs capable of being administered in therapeutically effective amounts to humans, comprising a drug film on a thermally conductive substrate To manufacture the delivery article, the minimum substrate surface area is determined using the relationship set forth above for determining the substrate area that will yield a therapeutic amount of drug aerosol for a selected film thickness.

[0087]

[0102] In one variation, the selected substrate surface area is approximately 0.05 to 500 cm m 2 In other cases, the surface area is approximately 0.05 to 300 cm 2 In one embodiment, the substrate surface area is 0.05 to 0.5 cm 2 In one embodiment, the substrate surface area is 0.1 to 0 .2cm 2The actual amount of drug delivered from the drug delivery article, i.e., the yield or release rate, will depend, among other factors, on the percentage of the drug film that vaporizes when the substrate is heated. Thus, for a drug film that results in a 100% drug film and aerosol particles with 100% drug purity when heated, the dose, thickness, and area relationships listed above directly correlate to the dose delivered to the user. As the yield and / or particle purity decrease, adjustments to the substrate area can be made as needed to deliver the desired dose. As one of ordinary skill in the art will recognize, a substrate area greater than the maximum area calculated for a particular film thickness can be used to deliver a therapeutically effective amount of drug. Furthermore, as one of ordinary skill in the art will recognize, the film need not coat the entire surface area if the selected surface area exceeds the minimum required to deliver a therapeutic dose from the selected film thickness.

[0088] Drug-containing aerosol dosage

[0103] The amount of drug delivered in the aerosol is determined by heating the drug under specified conditions and The term "unit amount" refers to the amount of drug obtained by cooling the resulting vapor and delivering the resulting aerosol. A "unit amount" is the total amount of drug in a specific volume of inhalation aerosol. A unit amount can be determined by collecting the aerosol, analyzing its composition as described herein, and comparing the aerosol analysis results to a series of standards containing known amounts of drug. The amount of drug or drugs required in the starting composition for delivery as an aerosol depends on the amount of drug or drugs that enters the thermal vapor phase upon heating (i.e., the amount produced by the starting drug or drugs), the bioavailability of the aerosol drug or drugs, the patient's inhalation volume, and the potency of the aerosol drug or drugs as a function of plasma drug concentration.

[0089]

[0104] The appropriate dose of drug-containing aerosol to treat a particular condition can be determined through animal experiments and The toxicity of aerosols can be determined using methods such as dose-finding (Phase I / II) clinical trials. These experiments can also be used to evaluate the potential for pulmonary toxicity of aerosols. Some animal studies involve measuring plasma drug concentrations in animals after exposure to aerosols. Mammals, such as dogs or primates, are commonly used for such studies because their respiratory systems are similar to those of humans and test results generally can be accurately extrapolated to humans. The initial dose level for testing in humans is generally less than or equal to the dose in the mammalian model that produced plasma drug levels associated with therapeutic efficacy in humans. Dose escalation is then performed in humans until an optimal therapeutic response is obtained or dose-limiting toxicity is observed. The actual effective drug amount for a particular patient may vary according to the specific drug or combination used, the specific composition formulated, the mode of administration, and the age, weight, and condition of the patient and the severity of the episode being treated.

[0090] Particle size

[0105] Effective aerosol delivery to the lung requires particles to undergo some degree of penetration and settling or diffusion. It is necessary for particles to have the properties of effective dispersion. Deposition in the deep lung occurs by gravitational settling, which requires that particles have an effective settling size, defined as the mass median aerodynamic diameter (MMAD), typically between 1 and 3.5 μm. For smaller particles, deposition in the deep lung occurs by a diffusion process, which requires a particle size in the range of 10 to 100 nm, typically between 20 and 100 nm. Inhalation drug delivery devices for deep lung delivery should produce aerosols containing particles in one of these two size ranges, preferably about 0.1 to 3 μm MMAD. Generally, to generate particles with the desired MMAD, gas or air is passed over a solid support at a specific flow rate.

[0091]

[0106] During the condensation stage, the MMAD of the aerosol increases over time. In a variation of MMAD, the vapor is in the size range of 0.01 to 3 microns. increases as the aerosol particles cool and condense upon contact with the carrier gas, and then further increases as the aerosol particles collide with each other and coalesce into larger particles. Most commonly, the MMAD grows from <0.5 microns to >1 micron within one second. Thus, generally, immediately after condensation into particles, the MMAD of the condensing aerosol doubles at least once per second, and often at least 2, 4, 8, or 20 times per second. In other variations, the MMAD grows within the 0.1-3 micron size range.

[0092]

[0107] Generally, the higher the flow rate, the smaller the particles formed. The flow rate through the condensation region of the delivery device can be varied to obtain smaller or larger particles. The desired particle size is determined when the number concentration of the mixture is approximately 10 particles. 9 This is achieved by mixing the compound in the vapor state into a volume of carrier gas at a ratio such that the desired particle size is achieved when the number concentration reaches 1000 particles / mL. Particle growth at this number concentration is then slow enough that the particle size can be considered "stable" for a single deep inhalation. This can be achieved, for example, by modifying the gas flow control valve to increase or decrease the air volumetric flow rate. Specifically, by selecting a gas flow rate over the vaporizing drug in the range of 1 to 10 L / min, preferably 2 to 8 L / min, condensation particles in the size range of 0.1 to 3 μm MMAD can be produced.

[0093]

[0108] Furthermore, as one skilled in the art will recognize, for a particular volumetric flow rate, the linear velocity of the gas Particle size can also be altered by modifying the cross-section of the chamber condensation region to increase or decrease the flow rate. Additionally, particle size can be altered by the presence or absence of structures that create turbulence within the chamber. Thus, for example, to produce condensed particles in the size range of 10-100 nm MMAD, the chamber can be equipped with gas flow barriers to create turbulent air flow within the condensation chamber. These barriers are typically located within a few thousandths of an inch of the substrate surface.

[0094] Analysis of drug-containing aerosols

[0109] The purity of a drug-containing aerosol can be determined using a variety of methods. It should be noted that when "purity" is used, it refers to the percent of the aerosol minus the percent of by-products produced during its formation. By-products are undesired products produced, for example, during vaporization. For example, by-products include thermal decomposition products and undesired metabolites of the active compound or compound class. Examples of suitable methods for determining aerosol purity 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). There are.

[0095]

[0110] One suitable method involves the use of traps. In this method, the percentage of by-products Alternatively, the aerosol may be collected in a trap to determine the fraction. Any suitable trap may be used. Suitable traps include filters, glass wool, impingers, solvent traps, cold traps, and the like. Filters are often most desirable. The trap is then typically extracted with a solvent, such as acetonitrile, and the extract is analyzed by any of a variety of analytical techniques known in the art, with gas, liquid, and high performance liquid chromatography being particularly useful.

[0096]

[0111] Gas or liquid chromatography methods generally involve a detection system, e.g. The detection system includes a mass spectrometer or ultraviolet absorbance detector. Ideally, the detection system will be capable of determining the weight of the components and by-products of the drug composition. This is accomplished in practice by measuring the signal obtained upon analysis of one or more known masses of components (standards) of the drug composition or by-products, and then comparing the signal obtained upon analysis of the aerosol with the signal obtained upon analysis of the standard(s), a method well known in the art.

[0097]

[0112] In many cases, the structure of the by-product is unknown or no standard for it is available. It may not be available. In such cases, the weight fraction of the by-product may be calculated by assuming that it has the same response factor (e.g., the same extinction coefficient for ultraviolet absorption detection) as the drug component or components in the drug composition. When performing such analyses, by-products present at less than a very small fraction of the drug compound, e.g., less than 0.1% or 0.03% of the drug compound, are generally excluded. Because it is often necessary to assume that the drug and by-product responses are identical when calculating the weight percent of the by-product, it is often more desirable to use an analytical method in which such an assumption has a high probability of validity. In this regard, high performance liquid chromatography with detection by ultraviolet absorbance at 225 nm is generally preferred. If the compound absorbs more strongly at 250 nm, or if for other reasons one skilled in the art believes that detection at 250 nm is the best means for estimating purity (by weight) using HPLC analysis, UV absorbance at 250 nm can be used to detect the compound. In certain cases where UV drug analysis is not available, other analytical tools, such as GC / MS or LC / MS, can be used to determine purity.

[0098]

[0113] Changing the gas under which the composition vaporizes may affect purity. be. Other analytical methods

[0114] The particle size distribution of the drug-containing aerosol can be determined by any suitable method in the art. (e.g., cascade impaction). A Next Generation Cascade Impactor (MSP Corporation, Shoreview, MN) connected to a vaporizer by an induction port (USP Induction Port, MSP Corporation, Shoreview, MN) is one system used for cascade impaction testing.

[0099]

[0115] Inhalable aerosol mass density can be determined, for example, by dissolving a drug-containing aerosol in a limited volume. It can be determined by delivering aerosol through an inhalation device into a chamber and measuring the mass collected in the chamber. Typically, the aerosol is drawn into the chamber by a pressure gradient between the device and the chamber, where the chamber is at a lower pressure than the device. The volume of the chamber should approximate the inhalation volume of the inhaling patient, typically about 2-4 liters.

[0100]

[0116] Inhalable aerosol drug mass density may be limited to, for example, a drug-containing aerosol. The amount of active pharmaceutical compound collected in the chamber can be determined by delivering the aerosol via an inhalation device into a chamber containing the active pharmaceutical compound and measuring the amount of active pharmaceutical compound collected in the chamber. Typically, the aerosol is drawn into the chamber by a pressure gradient between the device and the chamber, which is at a lower pressure than the device. The volume of the chamber should approximate the inhaled volume of the inhaling patient, typically about 2-4 liters. The amount of active pharmaceutical compound collected in the chamber can be determined by extracting the chamber, performing chromatographic analysis of the extract, and comparing the results of the chromatographic analysis to those of a standard containing a known amount of drug.

[0101]

[0117] Inhalable aerosol particle concentrations can be determined, for example, by administering aerosol-phase drugs to a limited number of people. The number of particles of a particular size can be determined by delivering particles of a particular size into a chamber via an inhalation device and measuring the number of particles collected in the chamber. The number of particles of a particular size can be measured directly based on the light scattering properties of the particles. Alternatively, the number of particles of a particular size can be determined by measuring the mass of particles within a particular size range and calculating the number of particles based on that mass as follows: Total number of particles = sum of the number of particles in each size range (from size range 1 to size range N). Number of particles of a particular size = mass of that size range / mass of a typical particle in that size range. Mass of a typical particle in the size range = π * D 3* φ / 6; where D is the diameter (microns) of a typical particle in that size range (typically, the mean boundary MMAD defines the size range), φ is the particle density (g / mL), and mass is in picograms (g -12 ) units.

[0102]

[0118] The rate of inhalable aerosol particle formation can be limited, for example, by the aerosol phase drug. The particle formation rate can be determined by delivering particles via an inhalation device into a chamber containing a suction pump. The delivery is for a set period (e.g., 3 seconds), and the number of particles of a particular size collected in the chamber is determined as outlined above. The particle formation rate is equal to the number of particles between 10 nm and 5 microns collected divided by the collection period.

[0103]

[0119] The rate of aerosol formation can be controlled by, for example, dispensing the aerosol-phase drug into a confined chamber. The mass of particulate matter can be determined by delivery via an inhalation device into a confined chamber. Delivery is for a set period (e.g., 3 seconds), and the mass of particulate matter collected is determined by weighing the confined chamber before and after delivery of the particulate matter. The aerosol formation rate is equal to the increase in mass of the chamber divided by the collection period. Alternatively, if a change in mass of the delivery device or its components can occur only upon release of aerosol-phase particulate matter, the mass of particulate matter can be equal to the mass lost from the device or components during delivery of the aerosol. In this case, the aerosol formation rate is equal to the mass loss of the device or components during the delivery event divided by the duration of the delivery event.

[0104]

[0120] The rate of drug aerosol formation can be determined, for example, by administering a drug-containing aerosol to a limited number of people. The rate of drug aerosol formation can be determined by delivering the drug to the chamber via an inhalation device over a set period (e.g., 3 seconds). If the aerosol is pure drug, the amount collected in the chamber is measured as described above. The rate of drug aerosol formation is equal to the amount of drug collected in the chamber divided by the collection period. If the drug-containing aerosol contains pharmaceutically acceptable excipients, the rate of drug aerosol formation is obtained by multiplying the rate of aerosol formation by the percent of drug in the aerosol.

[0105] kit

[0121] In some embodiments of the present invention, a medical provider, or more preferably, a patient, may use Kits for delivering condensation aerosol compositions are provided. Kits for delivering condensation aerosol compositions generally include a drug-containing composition and a device for forming a condensation aerosol. The composition generally does not include solvents or excipients and generally includes a heat-stable drug. The device for forming a condensation aerosol generally includes an element configured to heat the composition to form a vapor, an element capable of condensing the vapor to form a condensation aerosol, and an element that allows a user to inhale the condensation aerosol. The device in the kit may further include features such as a breath-actuation element or a lockout element, or a metering / logging device or a tapering device. A typical kit will include a portable aerosol delivery device and at least one dose.

[0106]

[0122] In another embodiment, a thin film of the drug composition and the film is formed as a condensation aerosol. A kit for drug aerosol delivery is provided, comprising a device for dispensing a thin film of a drug composition as a condensation aerosol. The composition may contain pharmaceutical excipients. The device for dispensing a thin film of a drug composition as a condensation aerosol includes an element configured to heat the film to form a vapor, and an element for condensing the vapor to form a condensation aerosol.

[0107]

[0123] In the kit of the present invention, the composition is generally formed as a thin film, generally about 0.5 to 3 The coating is applied to a substrate at a thickness of 0 microns and heated by a heat source. The heat source generally achieves a substrate temperature of at least 200°C, preferably at least 250°C, or more preferably at least 300°C or 350°C, within 2 seconds, preferably within 1 second. Heat is supplied to the substrate at a rate that substantially completely volatilizes the drug composition from the substrate within 0.5 seconds, or more preferably within 0.5 seconds. To prevent drug degradation, the heat source preferably does not heat the substrate to a temperature greater than 600°C with the drug film on the substrate. More preferably, the heat source does not heat the substrate to a temperature greater than 500°C.

[0108]

[0124] The kits of the present invention may comprise various combinations of drugs and drug delivery devices. In some embodiments, the device can also deliver more than one drug. Other drugs can be administered orally or topically. Instructions for use are generally included with the kit.

[0109]

[0125] As used herein, the term "drug" refers to a substance that is used to prevent or treat a disease in humans or animals. "Pharmaceutical compounds" refers to any compound used in the diagnosis, treatment or cure, pain relief, or control or amelioration of any physiological or pathological disorder. Any suitable pharmaceutical compound can be used. Drugs that can be used include, for example, but are not limited to, drugs from one of the following classes: anesthetics, anticonvulsants, antidepressants, antidiabetics, antidotes, antiemetics, antihistamines, anti-infectives, antineoplastics, antiparkinsonians, antirheumatics, antipsychotics, anxiolytics, appetite stimulants and suppressants, hemoregulators, cardiovascular drugs, central nervous system stimulants, drugs for the management of Alzheimer's disease, drugs for the management of cystic fibrosis, diagnostic agents, dietary supplements, drugs for erectile dysfunction, and the like. drugs for the treatment of alcoholism, drugs for the treatment of addiction, immunosuppressants, mast cell stabilizers, migraine preparations, motion sickness preparations, drugs for managing multiple sclerosis, muscle relaxants, nonsteroidal anti-inflammatory drugs, opioids, other analgesics and stimulants, ophthalmic preparations, osteoporosis preparations, prostaglandins, respiratory system medications, sedatives and hypnotics, skin and mucous membrane medications, smoking cessation aids, Tourette's syndrome medications, urinary tract medications, and vertigo medications.

[0110]

[0126] Generally, if the drug is an anesthetic, it may consist of one of the following compounds: Selected: ketamine and lidocaine.

[0127] Generally, if a drug is an anticonvulsant, it is one of the following compounds: Selected from: GABA analogs, tiagabine, vigabatrin; barbiturates, e.g., pentobarbital; benzodiazepines, e.g., alprazolam, clonazepam hydantoins, such as phenytoin; phenyltriazines, such as lamotriazine various anticonvulsants, such as carbamazepine, topiramate, valproic acid, and zonisamide.

[0111]

[0128] Generally, if a drug is an antidepressant, it is one of the following compounds: Selected from: amitriptyline, amoxapine, benmoxine, butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, xantanserin, lofepramine, medifoxamine, mianserin, maprothrine, mitrazapine, nortriptyline, protriptyline, trimipramine, venlafaxine, viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine, milnacipran, nisoxetine, paroxetine, reboxetine, sertaline, tineptine, acetafenadine, binedaline, brofaromine , cericlamine, clovoxamine, iproniazid, isocarboxazid, moclobemide, phenylhydrazine, phenelzine, selegiline, sibutramine, tranylcypromine, ademethionine, adrafinil, amesergide, amisulpride, amperozide, benactyzine, bupropion, caroxazone, gepirone, idazoxan, metralindole, milnacipran, minaprine, nefazodone, nomifensine, ritanserin, loxindol, S-adenosylmethionine, escitalopram, tofenacin, trazodone, tryptophan, and zalospirone.

[0112]

[0129] Generally, if the drug is an antidiabetic drug, it is one of the following compounds: Selected from: pioglitazone, rosiglitazone, and troglitazone.

[0130] Generally, if a drug is an antidote, it consists of one of the following compounds: Selected: edrophonium chloride, flumazenil, deferoxamine, nalmefene, naloxone, and naltrexone.

[0113]

[0131] Generally, if a drug is an antiemetic, it may consist of one of the following compounds: Selected: alizapride, azasetron, benzquinamide, bromopride, buclizine, chlorpromazine, cinnarizine, clebopride, cyclizine, diphenhydramine, diphenidol, dolasetron, droperidol, granisetron, hyoscine, lorazepam, dronabinol, metoclopramide, metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine, scopolamine, triethylperazine, trifluoperazine, triflupromazine, trimethobenzamide, tropisetron, domperidone, and palonosetron.

[0114]

[0132] Generally, if the drug is an antihistamine, it may be one of the following compounds: Select from: astemizole, azatadine, brompheniramine, carbinoxamine, cetrizine, chlorpheniramine, cinnarizine, clemastine, cyproheptadine, dexmedetomidine, diphenhydramine, doxylamine, phenytoin ... xofenadine, hydroxyzine, loratidine, promethazine, pyrilamine, and terfenidin.

[0115]

[0133] Generally, if the drug is an anti-infective, it will be one of the following compounds: Antivirals such as efavirenz; AIDS adjunct agents such as dapsone; aminoglycosides such as tobramycin; antifungals such as fluconazole; antimalarials such as quinine; antituberculosis agents such as ethambutol; β-lactams such as cefmetazole, cefazolin, cephalexin, cefoperazone, cefoxitin, cephacetrile, cephaloglycin, cephaloridine; cephalosporins such as cephalosporin C, cephalothin; cephamycins such as cephamycin A, cephamycin B, and cephamycin C, cephapirin, cephradine; antileprosy agents such as clofazimine; penicillins penicillins such as ampicillin, amoxicillin, hetacillin, carfecillin, carindacillin, carbenicillin, amylpenicillin, azidocillin, benzylpenicillin, clometocillin, cloxacillin, cyclacillin, methicillin, nafcillin, 2-pentenylpenicillin, penicillin N, penicillin O, penicillin S, penicillin V, dicloxacillin; diphenicillin; heptylpenicillin; and methampicillin; quinolones such as ciprofloxacin, clinafloxacin, difloxacin, grepafloxacin, norfloxacin, ofloxacin, temafloxacin; tetracyclines such as doxycycline and oxytetracycline; various anti-infectives such as linezolid, trimethoprim, and sulfamethoxazole.

[0116]

[0134] Generally, if the drug is an antineoplastic agent, it will be one of the following compounds: Selected from: droloxifene, tamoxifen, and toremifene.

[0135] Generally, if the drug is an anti-Parkinson's drug, it is one of the following compounds: Selected from one of: rotigotine, amantadine, baclofen, biperiden, benztropine, orphenadrine, procyclidine, trihexylphenidyl, levodopa, carbidopa, andropinirole, apomorphine, benserazide, bromocriptine, budipine, cabergoline, eliprodil, eptastigmine, ergoline, galantamine, lazabemide, lisuride, mazindol, memantine, mofegiline, pergolide, piribedil, pramipexole, propentofylline, rasagiline, Remacemide, ropinerole, selegiline, spheramine, terguride, entacapone, and tolcapone.

[0117]

[0136] Generally, if the drug is an antirheumatic drug, it is one of the following compounds: Selected from: diclofenac, hydroxychloroquine and methotrexate.

[0137] Generally, if a drug is an antipsychotic, it is one of the following compounds: Selected from: acetophenazine, alizapride, amisulpride, amoxapine, amperozide, aripirazole, benperidol, benzquinamide, bromperidol, bramate, butaclamol, butaperazine, carphenazine, carpipramine, chlorpromazine, chlorprothixene, clocapramine, clomacran, clopenthixol, clospyrazine, clothiapine, clozapine, cyamemazine, droperidol, flupenthixol, fluphenazine, fluspirilene, haloperidol, loxacin Sapine, melperone, mesoridazine, metofenazate, molindrone, olanzapine, penfluridol, pericyazine, perphenazine, pimozide, pipamelon, piperacetazine, pipotiazine, prochlorperazine, promazine, quetiapine, remoxipride, risperidone, sertindole, spiperone, sulpiride, thioridazine, thiothixene, trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine, and zuclopenthixol.

[0118]

[0138] Generally, if a drug is an anxiolytic, it is one of the following compounds: Selected from: alprazolam, bromazepam, diazepam, oxazepam, buspirone, hydroxyzine, mecloqualone, medetomidine, metomidate, adinazolam, chlordiazepoxide, clobenzepam, flurazepam, lorazepam, loprazolam, midazolam, alpidem, alseroxlon, amphenidone, azacyclonol, bromisovalum, captodiamine, capride, carbuchloral, carbromal, chloral betaine, enciprazine, flesinoxan, ipsapiraone, lesopitron, loxapine, methaqualone, mesprylon, propanolol, tandospirone, tolaza Don, Zopiclone, and Zolpidem.

[0119]

[0139] Generally, if the drug is an appetite stimulant, it is dronabinol is.

[0140] Generally, if a drug is an appetite suppressant, it is one of the following compounds: Selected from: fenfluramine, phentermine and sibutramine.

[0120]

[0141] Generally, if a drug is a hemoregulator, it is one of the following compounds: Selected from: cilostazol and dipyridamole.

[0142] Generally, if a drug is a cardiovascular drug, it may be one of the following compounds: Selected from: benazepril, captopril, enalapril, quinapril, ramipril, doxazosin, prazosin, clonidine, labetolol, candesartan, irbesartan, losartan, telmisartan, valsartan, disopyramide, flecanide, mexiletine, procainamide, propafenone, quinidine, tocainide, amiodarone Amiodarone, dofetilide, ibutilide, adenosine, gemfibrozil, lovastatin, acebutalol, atenolol, bisoprolol, esmolol, metoprolol, nadolol, pindolol, propranolol, sotalol, diltiazem, nifedipine, verapamil, spironolactone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, triamterene, and metolazone.

[0121]

[0143] Generally, if a drug is a central nervous system stimulant, it may be one of the following compounds: Choose from: amphetamine, brucine, caffeine, dexfenfluramine, dextroamphetamine, ephedrine, fenfluramine, mazindol, methyl Phenidate, pemoline, phentermine, sibutramine, and modafinil.

[0122]

[0144] Generally, if the drug is for the management of Alzheimer's disease, it is The compound is selected from one of the following compounds: donepezil, galantamine and tacrine.

[0145] Generally, if the drug is for the management of cystic fibrosis, it is one of the following chemicals: The compound is selected from one of: CPX, IBMX, XAC and analogs; 4-phenylbutyric acid; genistein and similar isoflavones; and milrinone.

[0123]

[0146] Generally, if the drug is a diagnostic agent, it may consist of one of the following compounds: Selected: adenosine and aminohippuric acid.

[0147] Generally, if a drug is a dietary supplement, it may be one of the following compounds: Choose from: melatonin and vitamin E.

[0124]

[0148] Generally, if the drug is a drug for erectile dysfunction, it is one of the following compounds: Select from one of: tadalafil, sildenafil, vardenafil, apomorphine, apomorphine diacetate, phentolamine, and yohimbine.

[0125]

[0149] Generally, if the drug is a gastrointestinal drug, it is one of the following compounds: Selected from: loperamide, atropine, hyoscyamine, famotidine, lansoprazole, omeprazole, and rebeprazole.

[0126]

[0150] Generally, if the drug is a hormone, it is one of the following compounds: Selected from: testosterone, estradiol, and cortisone.

[0151] Generally, if the drug is for the treatment of alcoholism, it is The compound is selected from one of the following: naloxone, naltrexone, and disulfiram.

[0127]

[0152] Generally, if a drug is for the treatment of addiction, it is buprenorphine. The drug is buprenorphine.

[0153] Generally, if a drug is an immunosuppressant, it is one of the following compounds: Selected from: mycophenolic acid, cyclosporine, azathioprine, tacrolimus, and rapamycin.

[0128]

[0154] Generally, when the drug is a mast cell stabilizer, it is one of the following compounds: Choose from one of: cromolyn, pemirolast, and nedocromil.

[0129]

[0155] Generally, if the drug is a drug for migraine, it is one of the following compounds: Selected from one of the following: almotriptan, alperopride, codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan, isometheptene, lidocaine, lisuride, metoclopramide, naratriptan, oxycodone, protriptan Lopoxyphene, rizatriptan, sumatriptan, tolfenamic acid, zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine, diltiazem, doxepin, fluoxetine, lisinopril, methysergide, metoprolol, nadolol, nortriptyline, paroxetine, pizotifen, pizotyline, propanolol, protriptyline, sertaline, timolol, and verapamil.

[0130]

[0156] Generally, when the drug is a motion sickness formulation, it is one of the following compounds: Choose from: diphenhydramine, promethazine, and scopolamine.

[0157] Generally, if the drug is a drug for the management of multiple sclerosis, it is one of the following chemical compounds: The compound is selected from one of the following: bencyclane, methylprednisolone, mitoxantrone, and prednisolone.

[0131]

[0158] Generally, if a drug is a muscle relaxant, it may be one of the following compounds: Selected from: baclofen, chlorzoxazone, cyclobenzaprine, methocarbamol, orphenadrine, quinine, and tizanidine.

[0132]

[0159] Generally, when the drug is a nonsteroidal anti-inflammatory drug, it is Select from one of: aceclofenac, acetaminophen, alminoprofen, amfenac, aminopropyl, amixetrin, aspirin, benoxaprofen, bromfenac, bufexamac, carprofen, celecoxib, Choline, salicylate, cinchophen, cinmetacin, clopriac, clometacin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, mazipredone, meclofenamate, nabumetone, naproxen, parecoxib, piroxicam, pirprofen, rofecoxib, sulindac, tolfenamate, tolmetin, and valdecoxib.

[0133]

[0160] Generally, if the drug is an opioid, it is one of the following compounds: Selected from: alfentanil, allylprozine, alphaprozine, anileridine, benzylmorphine, bezitramide, buprenorphine, butophanol, carbifene, cipramadol, clonitazene, codeine, dextromoramide, dextropropoxyphene, diamorphine, dihydrocodeine, diphenoxylate, dipipanone, fentanyl, hydromorphone, L-alpha acetylmethadol, lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon, morphine, nalbuphine, nalorphine, oxycodone, papaveretum, petidil pentazocine, phenazocine, remifentanil, sufentanil, and tramadol.

[0134]

[0161] Generally, if the drug is another analgesic, it may be one of the following compounds: Selected from: apazone, benzpiperylone, benzidramine, caffeine, clonixin, ethoheptadine, flupertine, nefopam, orphenadrine, propacetamol, and propoxyphene.

[0135]

[0162] Generally, when a drug is in an ophthalmic formulation, it is one of the following compounds: Selected from: ketotifen and betaxolol.

[0163] Generally, if the drug is an osteoporosis drug, it is one of the following compounds: Selected from: alendronate, estradiol, estropitate, risedronate and raloxifene.

[0136]

[0164] Generally, when the drug is a prostaglandin, it is one of the following compounds: The agent is selected from one of: epoprostanol, dinoprostone, misoprostol, and alprostadil.

[0137]

[0165] Generally, if the drug is a respiratory agent, it is one of the following compounds: Selected from: albuterol, ephedrine, epinephrine, fomoterol, metaproterenol, terbutaline, budesonide, ciclesonide, dexamethasone Fluticasone, flunisolide, fluticasone propionate, triamcinolone acetonide, ipratopium bromide, pseudoephedrine, theophylline, montelukast, zafirlukast, ambrisentan, bosentan, enrasentan, sitaxse entan, tezosentan, iloprost, treprostinil, and pirfenidone.

[0138]

[0166] Generally, if a drug is a sedative and hypnotic, it is one of the following compounds: Selected from one of: butalbital, chlordiazepoxide, diazepam, estazolam, flunitrazepam, flurazepam, lorazepam, midazolam, temazepam, triazolam, zaleplon, zolpidem, and zopiclone.

[0139]

[0167] Generally, if the drug is a skin and mucous membrane drug, it is a compound of the following: isotretinoin, bergapten and methoxamer Salen (methoxsalen).

[0140]

[0168] Generally, if a drug is a smoking cessation aid, it is one of the following compounds: Selected from: nicotine, nicotine meta-salicylate and varenicline.

[0141]

[0169] Generally, when the drug is a Tourette's syndrome drug, it is pimozide.

[0170] Generally, if a drug is a urinary tract drug, it may consist of one of the following compounds: Selected: tolteridine, darifenicin, propantheline bromide, and oxybutynin.

[0142]

[0171] Generally, if a drug is an antidote, it is one of the following compounds: Choose from: betahistine and meclizine.

[0172] In general, we believe that suitable drugs are those that are suitable for use in the devices described herein. and methods. For example, pharmaceutical compounds are generally volatile or can be made volatile. Generally, the drugs are heat-stable drugs. Representative drugs include: acebutolol, acetaminophen, alprazolam, amantadine, amitriptyline, apomorphine diacetate, apomorphine hydrochloride, atropine, azatadine, betahistine, brompheniramine, bumetanide, buprenorphine, bupropion hydrochloride, butalbital, butophanol, carbinoxamine maleate, celecoxib, chlordiazepoxide, chlorpheniramine, chlorzoxazone, ciclesonide, citalopram, clomipramine, clonazepam, clozapine, codeine, cyclobenzaprine, cyproheptadine, dapsone, diazepam, and diclofenac. Ethyl ester, diflunisal, disopyramide, doxepin, estradiol, ephedrine, estazolam, ethacrynic acid, fenfluramine, fenoprofen, flecainide, flunitrazepam, galantamine, granisetron, haloperidol, hydromorphone, hydroxychloroquine, ibuprofen, imipramine, indomethacin ethyl ester, indomethacin methyl ester, isocarboxazid, ketamine, ketoprofen Ethyl ester, ketoprofen methyl ester, ketorolac ethyl ester, ketorolac methyl ester, ketotifen, lamotrigine, lidocaine, loperamide, loratadine, loxapine, maprotiline, memantine, meperidine, metaproterenol, methoxsalen, metoprolol, mexiletine HCl, midazolam, mirtazapine, morphine, nalbuphine, naloxone, naproxen, naratriptan, nortriptyline, olanzapine, orphenadrine, oxycodone, paroxetine, pergolide, phenytoin , pindolol, piribedil, pramipexole, procainamide, procloperazine, propafenone, propranolol, pyrilamine, quetiapine, quinidine, rizatriptan, ropinirole, sertaline, selegiline, sildenafil, spironolactone, tacrine, tadalafil, terbutaline, testosterone, thalidomide, theophylline, tocainide, toremifene, trazodone, triazolam, trifluoperazine, valproate Protic acid, venlafaxine, vitamin E, zaleplon, zetepin, amoxapine, atenolol, benztropine, caffeine, doxylamine, estradiol 17-acetate, flurazepam, flurbiprofen, hydroxyzine, ibutilide, indomethacin norcholinester, ketorolac Norcholine ester, melatonin, metoclopramide, nabumetone, perphenazine, protriptyline HCl, quinine, triamterene, trimipramine, zonisamide, bergapten, chlorpromazine, colchicine, diltiazem, donepezil, eletriptan, estradiol-3,17-diacetate, efavirenz, esmolol, fentanyl, flunisolide, fluoxetine, hyoscyamine, indomethacin, isotretinoin, linezolid, meclizine, paracoxib, pioglitazone, Rofe Coxib, sumatriptan, tolterodine, tramadol, tranylcybromine, trimipramine maleate, valdecoxib, vardenafil, verapamil, zolmitriptan, zolpidem, zopiclone, bromazepam, buspirone, cinnarizine, dipyridamole, naltrexone, sotalol, telmisartan, temazepam, albuterol, apomorphine hydrochloride diacetate, carbinoxamine, clonidine, diphenhydramine, tambutol, fluticasone propionate, fluconazole, Lovastatin, N,O-diacetyllorazepam, methadone, nefazodone, oxybutynin, promazine, promethazine, sibutramine, tamoxifen, tolfenamic acid, aripirazole, astemizole, benazepril, clemastine, estradiol 17-heptanoate, fluphenazine, protriptyline, ethambutal, frovatriptan, pyrilamine maleate, scopolamine, and triamcinolone acetonide, and pharmaceutically acceptable analogs and equivalents thereof.

[0143]

[0173] The above list of drug categories may include other or new categories. It is clarified that the drug is not limited to one category for different uses in the literature.

[0144]

[0174] Pharmaceutically acceptable excipients may be volatile or non-volatile. When heated, the excipient simultaneously volatilizes with the drug to be delivered and is aerosolized and inhaled. Such excipient classes are known in the art and include, but are not limited to, gaseous, supercritical liquid, liquid, and solid solvents. The following is a list of representative carriers within these classes: water; terpenes, such as menthol; alcohols, such as ethanol, propylene glycol, glycerol, and other similar alcohols; dimethylformamide; dimethylacetamide; waxes; and mixtures thereof.

[0145]

[0175] The present disclosure relates to a thermal aerosol for drugs that are prone to charging during aerosol generation. This application teaches the use of antistatic materials in airways for air-generating devices. These include, but are not limited to, the drugs listed above.

[0146]

[0176] Various aspects of the disclosure are such that each dependent claim is a separate and distinct entity, each of which is a separate and distinct entity. The various elements set forth in the claims may be interchanged as if they were multiple dependent claims, including the limitations of the dependent claims, and such interchanges are clearly within the scope of the present disclosure.

[0147]

[0177] Although the present invention has been particularly shown and described with reference to numerous embodiments, the various embodiments disclosed It will be understood by those skilled in the art that changes in form and detail may be made therein without departing from the spirit and scope of the invention, and that the various embodiments disclosed herein are not intended to be used as limitations on the claims. All references cited herein are incorporated by reference in their entirety. [Example]

[0148] Example 1: Electrostatic phenomena in thermally condensed aerosols

[0178] Here, the thermal aggregation of multiple drugs in the Staccato® system We demonstrate the electrical properties of condensed aerosols.

[0149] method

[0179] Test Formulations and Devices

[0180] Some benzodiazepines (alprazolam, estradiol) estazolam, triazolam, diazepam, clobazam, loxapine, prochlorperazine, and xalepone Zaleplon was used on the Staccato single-dose platform. The Staccato single-dose platform is inspiration-activated and consists of a thin film of excipient-free drug coated on a stainless steel substrate inside a plastic airway housing. As the patient inhales through the device, the substrate is heated by an internal energy source. The drug film rapidly vaporizes, becomes entrained in the airflow inside the airway housing, and eventually condenses into an aerosol (Figure 1).

[0150]

[0181] The vapor phase drug cools almost instantly in the air stream, releasing the drug into aerosols of 1-3 μm diameter. See Figure 1.

[0182] Drug combination: Alprazolam, Estazolam, Triazolam, Diazepam, clobazam, loxapine, prochlorperazine, and zaleplon.

[0151]

[0183] The free base form of the drug dissolved in a suitable solvent is sprayed onto the substrate at a film thickness of 3-8 μm. It was coated.

[0184] Electrometer: The TSI Model 3068A aerosol electrometer measures the potential of aerosol drug particles. Measure the total net charge of

[0152]

[0185] ESD Simulator: Schaffner Model NSG 435 ESD Simulator; induces a specific polarization and amount of electrical potential into the plastic airway housing.

[0153]

[0186] Procedure: Experiment 1a: Measuring Net Charge

[0187] The total net charge of the aerosol particles was measured using an aerosol electrometer (TSI3068A). The sample flow rate was set at 10 LPM; this is the upper limit for aerosols. It was from.

[0154]

[0188] Electrometer. The device is manually activated to activate the device, heat the drug film, and The electrometer was connected to an oscilloscope to capture the current output of the aerosol. The current versus time curve from the oscilloscope was integrated and divided by the total drug mass released from the device to calculate the total net charge of the aerosol. At least two equivalent tests were performed for each drug.

[0155]

[0189] Experiment 1b: Effect of induced charging on airway housing deposition

[0190] A filter holder ( Aerosol deposition onto the airway housing was measured by connecting a Pall in-line filter holder to a vacuum pump. The airflow rate was set to 15 LPM for 5 seconds. Once set up, an ESD simulator was used to apply either +16 kV or -16 kV potential to the plastic airway housing. Airflow was initiated by switching on the solenoid valve to activate the device. After activation, the Staccato device was opened, and the airway housing was assayed by extraction and high-performance liquid chromatography analysis to determine aerosol deposition. Unless otherwise specified, at least three equivalent experiments were performed for each drug. Ta.

[0156] Experiment 2: Total Net Charge vs. Airway Housing Deposition: Total net charge (Part 1a) and housing deposition were measured simultaneously for Staccato alprazolam. Two Staccato alprazolam device versions were examined in this part of the study. The first version (used in Part 1) had a surface resistivity of -1 x 10 18 The airway housing was constructed from polycarbonate with a 0 / sq. The second version was constructed from polycarbonate with a lower resistivity (-1×10) to allow for charge dissipation. 11 An airway housing made of 0 / sq was used.

[0157]

[0191] Results and Discussion

[0192] Most heat-condensed drug aerosols did not exhibit high charge content. The total net charge of aerosol particles for certain structurally similar benzodiazepines (alprazolam, estazolam, and triazolam) was substantial (Table 1).

[0158]

[0193] The induced charge on the housing due to the applied electric field is generated by electrostatic interactions and the This amplifies the effect of aerosol deposition on the components. Table 1 shows the results of aerosol deposition on the airway housing for alprazolam, prochlorperazine, and loxapine. Overall, induced charging on the housing showed minimal effect for prochlorperazine or loxapine aerosols. Although not tested under an applied electric field, zaleplon also showed negligible airway housing deposition. For alprazolam aerosol, airway housing deposition significantly increased when the housing was positively charged, suggesting that alprazolam aerosol is negatively charged. This finding is consistent with the net charge results for alprazolam aerosol from Part 1. The charging process is likely due to triboelectric separation of the different materials (organic drug and steel substrate). This explains why certain benzodiazepines, e.g., Why this occurs for alprazolam, estazolam, and triazolam and not for other drugs is not known with certainty, but is likely a function of the molecular structures of alprazolam, estazolam, and triazolam and their stability when the additional free electron is delocalized.

[0159] Table 1 Net charge and aerosol deposition on the housing (values ​​are mean ± SD)

[0194]

[0160] [Table 1]

[0161]

[0195] Previous studies have shown that conductive surfactant coatings on the surface of device components can Antistatic polycarbonate, which has significantly lower electrical resistivity than standard polycarbonate, was used in Staccato alprazolam devices to reduce airway housing deposition and dose loss. The total net charge on alprazolam particles and airway housing deposition were measured for standard Staccato alprazolam devices and Staccato alprazolam devices using antistatic housing material. The results are shown in Table 2. The total net charge on alprazolam particles released from the antistatic housing was 100-fold less than that from the standard housing, while aerosol deposition on the airway housing was also significantly reduced with the antistatic housing.

[0162] [Table 2]

[0163]

[0196] Some benzodiazepines (alprazolam, estazolam, triazola methicillin, diazepam, clobazam), prochlorperazine, loxapine, and zaleplon Electrostatic phenomena in thermally condensed aerosols were investigated. Alprazolam aerosol exhibited a relatively large net negative charge, which resulted in a substantially higher aerosol charge on the airway housing. To overcome electrostatic interactions, a more conductive polycarbonate was used for the housing, which significantly reduced the total net charge of the alprazolam aerosol and airway housing deposition.

[0164] Example 2:

[0197] Aerosol charging test on heat packages and screening foils using an aerosol electrometer. Azole charging was small, positive, and unrelated to coating density. For Staccato heat packages, aerosol charging was large and negative without Staticide, whereas aerosol charging was small and negative with Staticide. Bumetanide and PCZ aerosols were approximately one order of magnitude less negatively charged than alprazolam.

[0165] Example 3:

[0198] A funnel was used as the heat package and access to the aerosol electrometer. Aerosol charging tests were performed. The heat package was operated without a housing. A galvanized steel funnel was used to generate a negative charge. A plastic funnel was used to generate a positive charge. Additional testing showed that a partially Staticide-coated airway generated a positively polarized alprazolam aerosol. Other testing showed that the zaleplon device had a low charge.

[0166] Example 4:

[0199] With Permastat and Permastat plus airways Aerosol Charging Testing. Airways made with Permastat and Permastat plus conductive polycarbonate alloys demonstrated a highly significant reduction in aerosol charging and airway deposition when compared to standard airway materials.

[0167] Example 5:

[0200] A modified screening foil was used to apply an electrostatic field to the screening foil during vaporization. Aerosol charging tests using a leaning foil device. This experiment showed that the aerosol charging increased monotonically with the strength of the applied potential difference. However, the potential difference used (0 V to 5 kV) resulted in saturation of the electrometer sensor.

[0168] Example 6:

[0201] A modified screening foil was used to apply an electrostatic field to the screening foil during vaporization. Tracking aerosol charging tests using a leaning foil apparatus. The applied voltage range in this experimental setup was 0V to 500V due to saturation at higher voltages. Again, a monotonic trend in increasing aerosol charging with increasing field strength was observed.

[0169] Example 7:

[0202] A metallized housing is used to apply an electrostatic field to the heat package during vaporization. Aerosol charging test using a jing.

[0170]

[0203] Phase 2A2 DCT2 Aerosol Characterization Test (P SD, ED, and EP, with 0.5 mg ALP). Electrostatic testing for ALP was performed with this DCT. Higher airway deposition (crystallization) was observed from devices tested after 4 days rather than the day of drug coating (amorphous). Drug crystals were observed in both the HP and airway after actuation of the 4-day coated device (the first time they were observed).

[0171] Example 8:

[0204] Testing HP type (one-sided vs. two-sided) and coating spray rate. Phase 2A2 DCT2 ED and EP at 28.3 LPM (1.5 mg). The original coating parameters were tested with both single-sided and double-sided HP, and drug crystals were found on the airway for both types of HP. A lower spray rate was applied, but drug crystals were still found on the airway. The presence of drug crystals on the airway was not caused by the single-sided or double-sided HP or the lower spray rate.

[0172] Example 9:

[0205] Coating spray rate. Phase 2A2 using lower spray rates DCT2 ED, 28.3 LPM (0.5 mg). Mean airway deposition was 10%. Drug crystals were present in all airways after actuation. Again, lower spray rates did not resolve the airway deposition problem.

[0173] Example 10:

[0206] High-temperature vs. low-temperature HP at lower spray rates. Phase 2A2 DCT2 , ED and EP, 28.3 LPM, 1.5 mg. The cold HP resulted in fewer drug crystals on the airway, both visually and quantitatively.

[0174] Example 11:

[0207] Airway with HP, PNF0027, 1 mg from lot M0167 Deposition studies: Airway deposition was low (no crystals) when the device was held ungloved, but high (drug crystals) when held with gloves.

[0175] Example 12:

[0208] Airway deposition testing for the following effects: 1) 1- and 2-pass coating 1) with the HP with gloves and without gloves for the HP with glove (1 and 2 passes coating), and 2) with the ESD gun (8 kV+, 8 kV-, 16 kV+). Airway deposition was higher with gloves and increased with increasing positive polarity of the ESD gun (highest at 16 kV+, lowest at 8 kV-). This also suggested that the ALP aerosol was net negatively charged.

[0176] Example 13:

[0209] The effects of 16kV+, 16kV-, and grounded conditions on clamshell and front / back airway deposition. Results showed that clamshell airways had the highest airway deposition at 16kV+, followed by grounded airways, and were lowest when 16kV- was applied. A similar trend was observed for front / back airways, but with smaller amounts of deposition.

[0177] Example 14:

[0210] The effects of 16kV+ and 16kV- on PCZ and loxapine. showed that there was no significant effect on airway deposition from + / - 16 kV.

[0178]

[0211] The effect of gloves on airway deposition of PCZ and loxapine, and The effect of + / - 16kV and grounding conditions on ALP airway deposition was investigated. Gloves had no effect on airway deposition of PCZ and loxapine. 16kV+ still produced the highest ALP airway deposition, while 16kV- and grounding conditions produced similar but less ALP airway deposition. This study also showed that the amorphous coating produced a greater amount of ALP airway deposition.

[0179] Example 15:

[0212] ALP Airway Submersion in Grounded and Ungrounded Conditions in High and Low Humidity Environments Comparison of airway deposition. This study showed that airway deposition was significantly higher at low humidity (20% RH) compared to 40% RH. However, this study did not show any significant differences between grounded and ungrounded conditions at both humidity settings.

[0180]

[0213] Tests were performed with a grounded person under two different humidity conditions (28 and 55% RH). A comparison of ALP airway deposition in grounded and ungrounded conditions was performed, and charge measurements were made using an electrometer at various stages from when the device was in the foil pouch to the moment of actuation. Results showed that airway deposition at 28% RH was generally higher than at 55% RH. Grounding the person holding the device reduced airway deposition in most cases. Electrometer testing showed that 1) some static charge already existed on the foil pouch, 2) the static charge on the airway increased in most cases after the pull tab was removed, and 3) grounding the person during actuation reduced the static charge on the airway.

[0181] Example 16:

[0214] ALP airway deposition test using antistatic spray and copper tape. Their testing showed that both antistatic spray and copper tape were able to reduce airway deposition, even with 16kV+ applied to the airway.

[0182]

[0215] AL using anti-static spray and copper tape at low humidity (27% RH) P Airway Deposition Test. This test showed that antistatic spray and copper tape helped reduce airway deposition, even in low humidity conditions.

[0183]

[0216] ALP airway deposition studies using antistatic sprays where the HP had normal reactant propagation times (previous studies 152p144-151 used HPs with slower propagation times). Results again showed that the antistatic spray reduced airway deposition regardless of reactant propagation times.

[0184] Example 17:

[0217] ALP Air comparing external actuation (with actuation box) and pull tab actuation Airway deposition testing was performed under the following conditions: 1) 16kV+ applied to the airway, 2) the airway was held without gloves, and 3) the airway was grounded. Results showed no difference in airway deposition between pull-tab activation and external activation under the three conditions tested. Deposition was not reduced.

[0185] Example 18:

[0218] ALP airway deposition test: 1) Pre-treat the airway with IPA before the test. 1) The airway was prepared and cleaned, and 2) the airway was constructed without a check valve. Results showed that neither method reduced airway deposition.

[0186] Example 19:

[0219] The device was built by the manufacturing group and tested with one-sided HP (front) without gloves. ALP airway deposition studies were performed using a unilateral HP (back airway) and a bilateral HP (clamshell airway). Results showed that unilateral HP had higher airway deposition (16%), while bilateral HP had lower airway deposition (2%).

[0187] Example 20

[0220] The device was constructed by the manufacturing group and 16kV+ was applied to the airway. ALP airway deposition study. Unilateral HP (front / back airway) and bilateral HP (clamshell airway) were tested. The results showed that unilateral HP (17%) had higher airway deposition than bilateral HP (1%).

[0188] Example 21

[0221] Device-to-device built by our manufacturing group and R&D (Jasmine) ALP airway deposition was compared between the two and a series of assembly differences were identified. 16kV+ was applied to the airway. Results showed that the device constructed by the manufacturing group had lower airway deposition.

[0189] Example 22

[0222] Pouched devices and devices removed from pouches (devices tested) Comparison of ALP airway deposition between the two conditions (removed from the foil pouch 20 hours before treatment). 16 kV+ was applied to the airway. Results showed no significant difference in airway deposition between these two conditions.

[0190] Example 24

[0223] Comparison of the effects of + / - 16kV on ALP airway deposition. The device was constructed by the manufacturing group. Results showed that both conditions had little effect on airway deposition.

[0191] Example 25

[0224] All devices are built and pouched by our manufacturing group, AL P Airway Deposition Test. The QC group tested both the control (normal) and staticide devices without 16kV+ applied. The R&D group tested both the control (normal) and staticide devices with 16kV+ applied to the airway. These were tested for 16 days. Results showed that there was more airway deposition on the control (normal) devices than on the staticide ones. All staticide devices from both the QC and R&D groups had very low airway deposition. The control (normal) devices, when tested by R&D, had more airway deposition compared to QC.

[0192] Example 26

[0225] When manufacturing the assembled device (first batch), +16 kV was applied. ALP airway deposition test with added steroids. Minimal airway deposition was observed.

[0193] Example 27

[0226] HP was used in place of the methanol / acetone 50 / 50 ALP solution in DCM A ALP airway deposition test coated with LP solution. Results showed that the DCM coating solution did not help reduce airway deposition.

[0194] Example 28

[0227] ALP airway deposition study using an ionizer. Results showed that the ionizer reduced airway deposition.

[0195] Example 29

[0228] Airway sedimentation for ALP, PCZ, and loxapine at 10 LPM For ALP, the results showed that the staticide device had low airway deposition and the conventional (control) device constructed by R&D had high airway deposition, while that constructed by the manufacturing group was slightly lower. There was very little airway deposition with acetaminophen, but loxapine resulted in significant airway deposition.

[0196] Example 30

[0229] The device was placed in a pouch for different days at different humidity levels. Airway Deposition Test. The results showed that although airway deposition generally did not vary significantly, there were some devices with higher airway deposition.

[0197] Example 31

[0230] HP Surface and Aerosol Charge Measurements: 1) Normal / Control Air with ALP 1) staticide airway with ALP, 2) staticide airway with ALP, 3) regular / control airway (placebo), and 4) staticide airway (placebo). Results showed that the regular airway with ALP had the highest aerosol charge, while the others had very low charges, all of negative polarity. HP surface charge was positive for all regular airways. For staticide airways, HP charge appeared to be more variable, with positive, zero, and negative charges measured. Deposition on staticide airways was also observed to be nearly 0%.

[0198] Example 32

[0231] Regular (control), metallized, and Permastat plus air Aerosol charging and airway deposition tests were performed using standard airways. For regular airways, both aerosol charging and airway deposition were high. For metallized airways, aerosol charging was mostly high, but airway deposition was low. For Permastat plus airways, both aerosol charging and airway deposition were low.

[0199] Example 33

[0232] Aerosol characterization using a Permastat airway at 28.3 LPM The ED, PSD, and EP were all good and within expected values. Nearly zero deposition was observed on the airway.

[0200] Example 34

[0233] Aerosol injection using Permastat airways with different surface resistances Charging and Airway Deposition. Airway deposition was negligible in all cases. Aerosol charging was low, but most of them had a positive rather than negative charge.

[0201] Example 35

[0234] Aerosol with Permastat airway and regular airway Charging and Airway Deposition (continuation of previous study A233p110-p115). This study further confirmed that airway deposition was negligible for the Permastat airways and that aerosol charging was low for both positive and negative charges measured. Conventional airways assembled by the manufacturing group had lower airway deposition and lower charging (positive and negative charge), while those assembled by R&D had higher airway deposition and much higher aerosol charging (negative charge).

[0202] Example 36

[0235] Regular airway glued with acetone and Perm glued with THF Comparison of EP with astat airway. Results showed no difference in EP.

[0203] Example 37

[0236] Permastat airway and assembly bonded with Loctite Leak and pull tests using regular (control) airways bonded with Permastat. Leak rates were good for both airways. Less force was required to pull the Permastat airway apart compared to the regular airway.

[0204] Example 38

[0237] I. Airway Deposition and Aerosol Charging for Permastat, Permastat Plus, and Standard Airway Materials (#3) the purpose: To characterize aerosol charging resulting from Permastat and Permastat Plus airways and compare it with a regular airway (control) Material / equipment Standard airway material: Makrolon polycarbonate ○ Permastat: Surface resistivity approximately 1E11 ohm / sq ○ Permastat Plus: Surface resistivity approximately 1E9 ohm / sq Drug: Alprazolam Experimental setup • A single-dose Staccato alprazolam device was placed in a mouthpiece connected to an aerosol electrometer; • The aerosol generated at 28.3 LPM was captured in an aerosol electrometer and measured for current (pA); • The measured current was recorded on a computer and the charge was calculated by integrating the current-time graph; • The housing was extracted with a solvent and the amount of drug was determined using HPLC.

[0205]

[0238] Table 3

[0206] [Table 3]

[0207]

[0239] Results: See Table 3 and Figure 2.

[0240] Conclusion: Permastat and Permastat Plus Airway Aerosol charging and airway deposition were significantly reduced for

[0208] Example 39 II. Alprazolam Airway Deposition with an ESD Simulator or Low Humidity Using Antistatic Spray and Copper Tape (#18 and 19) the purpose: To determine methods for reducing airway deposition Material / equipment General purpose staticide coated airway: General purpose staticide coated airway on the inside and outside of the airway. Sprayed with staticide Heavy duty staticide coated airway: Heavy duty staticide is sprayed on the inside and outside of the airway. Conductive / Copper Airway: Copper tape is attached to the inside and outside of the airway. Normal airway or control: Makrolon ESD simulator Drug: Alprazolam Experimental setup A. Airway deposition at ambient humidity (approximately 41% RH to 54% RH) ● Using an ESD simulator, +16 kV is applied to the airway, charging the drug-side airway. Aerosol generation at 15 LPM for devices with various airways: general purpose staticide coated airway, heavy duty staticide coated airway, and conductive / copper airway. • Extract the airway with a solvent to determine the amount of drug deposited in the airway. B. Airway deposition at low humidity (approximately 27% RH) Aerosol generation at 15 LPM for devices with various airways: general purpose static ide coated airway, conductive / copper airway, and regular airway. • Extract the airway with a solvent to determine the amount of drug deposited in the airway. result A. Airway deposition at ambient humidity (approximately 41% RH to 54% RH) B. Airway deposition at low humidity (approximately 27% RH)

[0209] [Table 4]

[0210]

[0241] Table 4

[0242] Both staticide and copper tape are suitable for ambient or low humidity environments. Under either condition, airway deposition can be substantially reduced.

[0211] Example 40 III. Airway Deposition and Aerosol Charging of Various Airways (#35) the purpose To compare airway charging and aerosol deposition of various airways: regular airway, metallized airway (SS) * / Cu / Cu / SS), and Permastat Plus Airway Material / equipment Standard airway material: Makrolon polycarbonate Metallized airway: Stainless steel / copper / copper / stainless steel layers coated on the inside of the housing ○ Permastat Plus: Surface resistivity approximately 1E9 ohm / sq Experimental setup • A single-dose Staccato device was placed in a mouthpiece connected to an aerosol electrometer; ● For tests with 16kV+ applied, use an electrostatic gun (ESD simulator) to charge the airway; • The aerosol generated at 28.3 LPM was captured in an aerosol electrometer and measured for current (pA); • The measured current was recorded by a Tektronix scope and transmitted to a computer; ● Charge was calculated by integrating the current-time graph; ● Airways and HPs were extracted for quantitative analysis (examined for deposition);

[0212] [Table 5]

[0213]

[0243] Metallized airways did not reduce aerosol charging, but airways The Permastat Plus airway reduced both aerosol charging and airway deposition.

[0214] Example 41 IV. Aerosol Characteristics Using Permastat Airway (#36) the purpose Evaluating aerosol characteristics using Permastat airways Material / equipment Staccato alprazolam device constructed with Permastat housing Staccato alprazolam device constructed with a standard Makrolon housing Experimental setup ● Flow rate=28.3LPM Emitted dose, particle size, and emitted purity were collected for Permastat and regular Makrolon housings.

[0215] [Table 6]

[0216]

[0244] See Figure 3.

[0245] Emission volume, particle size, and net emission using Permastat airways The results were good and within expected limits. There was almost no deposition on the Permastat airway.

[0217] Example 42 I. Net Charge and Aerosol Deposition on Airways for Various Drugs (Cited from Multiple Studies) Several benzodiazepines (alprazolam, estazolam, triazolam, diazepam, clobazam), loxapine, prochlorperazine, and zaleplon were used on the Staccato single-dose platform. An electrostatic gun (ESD simulator) was used to charge the airway and amplify the impact of electrostatic effects.

[0218] [Table 7]

[0219]

[0246] Remove the sealed vial and expose the housing that contains the assembly and electrical components. Those skilled in the art will appreciate that the experimental device detailed above can be converted into an inhalation delivery device by including a housing containing an air inlet and mouthpiece, such that upon volatilization of the drug, inspiration will carry the aerosol formed into the subject's lungs.

[0220] The present invention also includes the following aspects. Aspect 1 A device for delivering a condensation aerosol comprising a housing and an airway, the airway housing comprising an antistatic material. Aspect 2 10. The device of embodiment 1, wherein an antistatic material is coated on the interior wall of the airway. Aspect 3 3. The device of embodiment 2, wherein the antistatic material comprises a metallized airway, wherein an interior wall of the airway is coated with a conductive metal. Aspect 4 The device of embodiment 3, wherein the conductive metal comprises stainless steel / copper / copper / stainless steel. Aspect 5 2. The device of embodiment 1, wherein the antistatic material is comprised of metal tape applied to the interior and exterior walls of the airway. Aspect 6 2. The device of embodiment 1, wherein the antistatic material comprises an antistatic spray applied to the default airway. Aspect 7 2. The device of embodiment 1, wherein the antistatic material is comprised of an antistatic plastic applied as an airway material. Aspect 8 The device of embodiment 1, wherein the condensation aerosol comprises a drug that is susceptible to being charged upon aerosol generation. Aspect 9 The device of embodiment 8, wherein the drug is alprazolam. Aspect 10 A method for generating a drug condensation aerosol for a patient by inhalation in a drug delivery device, comprising heating a thin layer containing the drug on a solid support to generate a drug vapor, and condensing the vapor to form a condensation aerosol characterized by less than 10% by weight of drug degradation products and an MMAD of less than 5 microns; wherein the airway of the drug delivery device comprises an antistatic material. Aspect 11 11. The method of embodiment 10, wherein an antistatic material is coated on the interior wall of the airway. Aspect 12 11. The method of embodiment 10, wherein the antistatic material comprises a metallized airway, wherein an interior wall of the airway is coated with a conductive metal. Aspect 13 13. The method of embodiment 12, wherein the conductive metal comprises stainless steel / copper / copper / stainless steel. Aspect 14 11. The method of embodiment 10, wherein the antistatic material comprises metal tape applied to the interior and exterior walls of the airway. Aspect 15 11. The method of embodiment 10, wherein the antistatic material comprises an antistatic spray applied to the default airway. Aspect 16 11. The method of embodiment 10, wherein the antistatic material comprises an antistatic plastic applied as an airway material.

[0247] The foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed, it being understood that numerous modifications and variations are possible in light of the above teachings. The embodiments were chosen and described to best explain the principles of the invention and its practical application, and thereby to best enable others skilled in the art to utilize various modifications as suited to the particular uses contemplated for the invention and its various embodiments. Numerous other variations are also considered to be within the scope of the invention.

Claims

1. 1. A device for delivering a thermal condensation aerosol, comprising: (a) an airway comprising an antistatic polycarbonate; and (b) a substrate disposed within the airway, said substrate being coated with an alprazolam composition; Including, The thermal condensation aerosol is formed by heating the substrate to form an alprazolam vapor and then cooling the vapor such that the vapor condenses to form particles; The aerosol is free of organic solvents and propellants, The heat source supplies heat to the substrate at a rate that achieves a substrate temperature of at least 300°C or 350°C and completely volatilizes the alprazolam composition from the substrate within 2 seconds.

2. 10. The device of claim 1, wherein the vapor cools in the air stream, causing the drug to condense into aerosol particles having a mass median aerodynamic diameter in the range of 0.1 to 3 μm.

3. 3. The device of claim 1 or 2, wherein the alprazolam is coated onto the substrate in the form of a thin film having a thickness between 0.5 μm and 25 μm.

4. The device according to any one of claims 1 to 3, wherein an antistatic polycarbonate is coated on the inner wall of the airway.

5. 10. The device of claim 1, wherein the antistatic polycarbonate has a surface resistivity of 1E11 ohm / sq or 1E9 ohm / sq.

6. A device according to any one of claims 1 to 5, wherein the device is inspiration activated.

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