A device, method, and system for producing a condensation aerosol are disclosed. The device includes a chamber having an upstream opening and a downstream opening which allow gas to flow through the chamber, and a heat-conductive substrate located at a position between the upstream and downstream openings. Formed on the substrate is a drug composition film containing a therapeutically effective dose of a drug when the drug is administered in aerosol form. A heat source in the device is operable to supply heat to the substrate to produce a substrate temperature greater than 300.degree. C., and to substantially volatilize the drug composition film from the substrate in a period of 2 seconds or less. The device produces an aerosol containing less than about 10% by weight drug composition degradation products and at least 50% of the drug composition of said film.

Description of the Invention

Drug-Supply Article

In one aspect, the invention provides a drug-supply article for production of drug-aerosol particles. The article is particularly suited for use in a device for inhalation therapy for delivery of a therapeutic agent to the lungs of a patient, for local or systemic treatment. The article is also suited for use in a device that generates an air stream, for application of drug-aerosol particles to a target site. For example, a stream of air carrying drug-aerosol particles can be applied to treat an acute or chronic skin condition, can be applied during surgery at the incision site, or can be applied to an open wound. In Section A below, the drug-supply article and use of the drug-supply article in an inhalation device are described. In Section B, the relationship between drug-film thickness, substrate area, and purity of drug-aerosol particles are discussed.

The term "purity" as used herein, with respect to the aerosol purity, means the fraction of drug composition in the aerosol/the fraction of drug composition in the aerosol plus drug degradation products. Thus purity is relative with regard to the purity of the starting material. For example, when the starting drug or drug composition used for substrate coating contained detectable impurities, the reported purity of the aerosol does not include those impurities present in the starting material that were also found in the aerosol, e.g., in certain cases if the starting material contained a 1% impurity and the aerosol was found to contain the identical 1% impurity, the aerosol purity may nevertheless be reported as >99% pure, reflecting the fact that the detectable 1% purity was not produced during the vaporization-condensation aerosol generation process.

A. Thin-Film Coated Substrate

A drug-supply article according to one embodiment of the invention is shown in cross-sectional view in FIG. 1A (see Original Patent). Drug-supply article 10 is comprised of a heat-conductive substrate 12. Heat-conductive materials for use in forming the substrate are well known, and typically include metals, such as aluminum, iron, copper, stainless steel, and the like, alloys, ceramics, and filled polymers. The substrate can be of virtually any geometry, the square or rectangular configuration shown in FIG. 1A (see Original Patent) merely exemplary. Heat-conductive substrate 12 has an upper surface 14 and a lower surface 16.

Preferred substrates are those substrates that have surfaces with relatively few or substantially no surface irregularities so that a molecule of a compound vaporized from a film of the compound on the surface is unlikely to acquire sufficient energy through contact with either other hot vapor molecules, hot gases surrounding the area, or the substrate surface to result in cleavage of chemical bonds and hence compound decomposition. To avoid such decomposition, the vaporized compound should transition rapidly from the heated surface or surrounding heated gas to a cooler environment. While a vaporized compound from a surface may transition through Brownian motion or diffusion, the temporal duration of this transition may be impacted by the extent of the region of elevated temperature at the surface which is established by the velocity gradient of gases over the surface and the physical shape of surface. A high velocity gradient (a rapid increase in velocity gradient near the surface) results in minimization of the hot gas region above the heated surface and decreases the time of transition of the vaporized compound to a cooler environment. Likewise, a smoother surface facilitates this transition, as the hot gases and compound vapor are not precluded from rapid transition by being trapped in, for example, depressions, pockets or pores. Although a variety of substrates can be used, specifically preferred substrates are those that have impermeable surfaces or have an impermeable surface coating, such as, for example, metal foils, smooth metal surfaces, non-porous ceramics, etc. For the reasons stated above, non-preferred substrates for producing a therapeutic amount of a compound with less than 10% compound degradation via vaporization are those that have a substrate density of less than 0.5 g/cc, such as, for example, yarn, felts and foams, or those that have a surface area of less than 1 mm.sup.2/particle such as, for example small alumina particles, and other inorganic particles.

With continuing reference to FIG. 1A, deposited on all or a portion of the upper surface 14 of the substrate is a film 18 of drug. Preferably the film has a thickness of between about 0.05 .mu.m and 20 .mu.m. Film deposition is achieved by a variety of methods, depending in part on the physical properties of the drug and on the desired drug film thickness. Exemplary methods include, but are not limited to, preparing a solution of drug in solvent, applying the solution to the exterior surface and removing the solvent to leave a film of drug. The drug solution can be applied by dipping the substrate into the solution, spraying, brushing or otherwise applying the solution to the substrate. Alternatively, a melt of the drug can be prepared and applied to the substrate. For drugs that are liquids at room temperature, thickening agents can be admixed with the drug to permit application of a solid drug film. Examples of drug film deposition on a variety of substrates are given below.

FIG. 1B (see Original Patent) is a perspective, cut-away view of an alternative geometry of the drug-supply article. Article 20 is comprised of a cylindrically-shaped substrate 22 formed from a heat-conductive material. Substrate 22 has an exterior surface 24 that is preferably impermeable by virtue of material selection, surface treatment, or the like. Deposited on the exterior surface of the substrate is a film 26 of the drug composition. As will be described in more detail below, in use the substrate of the drug-supply article is heated to vaporize all or a portion of the drug film. Control of air flow across the substrate surface during vaporization produces the desired size of drug-aerosol particles. In FIG. 1B, the drug film and substrate surface is partially cut-away in the figure to expose a heating element 28 disposed in the substrate. The substrate can be hollow with a heating element inserted into the hollow space or solid with a heating element incorporated into the substrate. The heating element in the embodiment shown takes the form of an electrical resistive wire that produces heat when a current flows through the wire. Other heating elements are suitable, including but not limited to a solid chemical fuel, chemical components that undergo an exothermic reaction, inductive heat, etc. Heating of the substrate by conductive heating is also suitable. One exemplary heating source is described in U.S. patent application for SELF-CONTAINED, HEATING UNIT AND DRUG-SUPPLY UNIT EMPLOYING SAME, U.S. Ser. No. 60/472,697 filed May 21, 2003 which is incorporated herein by reference.

FIG. 2A (see Original Patent) is a perspective view of a drug-delivery device that incorporates a drug-supply article similar to that shown in FIG. 1B (see Original Patent). Device 30 includes a housing 32 with a tapered end 34 for insertion into the mouth of a user. On the end opposite tapered end 34, the housing has one or more openings, such as slot 36, for air intake when a user places the device in the mouth and inhales a breath. Disposed within housing 32 is a drug-supply article 38, visible in the cut-away portion of the figure. Drug-supply article includes a substrate 40 coated on its external surface with a film 42 of a therapeutic drug to be delivered to the user. The drug-supply article can be rapidly heated to a temperature sufficient to vaporize all or a portion of the film of drug to form a drug vapor that becomes entrained in the stream of air during inhalation, thus forming the drug-aerosol particles. Heating of the drug-supply article is accomplished by, for example, an electrically-resistive wire embedded or inserted into the substrate and connected to a battery disposed in the housing. Substrate heating can be actuated by a user-activated button on the housing or via breath actuation, as is known in the art.

FIG. 2B (see Original Patent) shows another drug-delivery device that incorporates a drug-supply article, where the device components are shown in unassembled form. Inhalation device 50 is comprised of an upper external housing member 52 and a lower external housing member 54 that fit together. The downstream end of each housing member is gently tapered for insertion into a user's mouth, best seen on upper housing member 52 at downstream end 56. The upstream end of the upper and lower housing members are slotted, as seen best in the figure in the upper housing member at 58, to provide for air intake when a user inhales. The upper and lower housing members when fitted together define a chamber 60. Positioned within chamber 60 is a drug-supply unit 62, shown in a partial cut-away view. The drug supply unit has a tapered, substantially cylindrical substrate 64 coated with a film 66 of drug on its external, smooth, impermeable surface 68. Visible in the cut-away portion of the drug-supply unit is an interior region 70 of the substrate containing a substance suitable to generate heat. The substance can be a solid chemical fuel, chemical reagents that mix exothermically, electrically resistive wire, etc. A power supply source, if needed for heating, and any necessary valving for the inhalation device are, contained in end piece 72.

In a typical embodiment, the device includes a gas-flow control valve disposed upstream of the drug-supply unit for limiting gas-flow rate through the condensation region to the selected gas-flow rate, for example, for limiting air flow through the chamber as air is drawn by the user's mouth into and through the chamber. In a specific embodiment, the gas-flow valve includes an inlet port communicating with the chamber, and a deformable flap adapted to divert or restrict air flow away from the port increasingly, with increasing pressure drop across the valve. In another embodiment, the gas-flow valve includes the actuation switch, with valve movement in response to an air pressure differential across the valve acting to close the switch. In still another embodiment, the gas-flow valve includes an orifice designed to limit airflow rate into the chamber.

The device may also include a bypass valve communicating with the chamber downstream of the unit for offsetting the decrease in airflow produced by the gas-flow control valve, as the user draws air into the chamber. The bypass valve cooperates with the gas-control valve to control the flow through the condensation region of the chamber as well as the total amount of air being drawn through the device. Thus the total volumetric airflow through the device, is the sum of the volumetric airflow rate through the gas-control valve, and the volumetric airflow rate through the bypass valve. The gas control valve acts to limit air drawn into the device to a preselected level, e.g., 15 L/minute, corresponding to the selected air-flow rate for producing aerosol particles of a selected size. Once this selected airflow level is reached, additional air drawn into the device creates a pressure drop across the bypass valve which then accommodates airflow through the bypass valve into the downstream end of the device adjacent the user's mouth. Thus, the user senses a full breath being drawn in, with the two valves distributing the total airflow between desired airflow rate and bypass airflow rate.

These valves may be used to control the gas velocity through the condensation region of the chamber and hence to control the particle size of the aerosol particles produced by vapor condensation. More rapid airflow dilutes the vapor such that it condenses into smaller particles. In other words, the particle size distribution of the aerosol is determined by the concentration of the compound vapor during condensation. This vapor concentration is, in turn, determined by the extent to which airflow over the surface of the heating substrate dilutes the evolved vapor. Thus, to achieve smaller or larger particles, the gas velocity through the condensation region of the chamber may be altered by modifying the gas-flow control valve to increase or decrease the volumetric airflow rate. For example, to produce condensation particles in the size range 1-3.5 .mu.m MMAD, the chamber may have substantially smooth-surfaced walls, and the selected gas-flow rate may be in the range of 4-50 L/minute.

Additionally, as will be appreciated by one of skill in the art, particle size may be also altered by modifying the cross-section of the chamber condensation region to increase or decrease linear gas velocity for a given volumetric flow rate, and/or the presence or absence of structures that produce turbulence within the chamber. Thus, for example to produce condensation particles in the size range 20-100 nm MMAD, the chamber may provide gas-flow barriers for creating air turbulence within the condensation chamber. These barriers are typically placed within a few thousands of an inch from the substrate surface.

The heat source in one general embodiment is effective to supply heat to the substrate at a rate that achieves a substrate temperature of at least 200.degree. C., preferably at least 250.degree. C., or more preferably at least 300.degree. C. or 350.degree. C., and produces substantially complete volatilization of the drug composition from the substrate within a period of 2 seconds, preferably, within 1 second, or more preferably within 0.5 seconds. Suitable heat sources include resistive heating devices which are supplied current at a rate sufficient to achieve rapid heating, e.g., to a substrate temperature of at least 200.degree. C., 250.degree. C., 300.degree. C., or 350.degree. C. preferably within 50-500 ms, more preferably in the range of 50-200 ms. Heat sources or devices that contain a chemically reactive material which undergoes an exothermic reaction upon actuation, e.g., by a spark or heat element, such as flashbulb type heaters of the type described in several examples, and the heating source described in the above-cited U.S. patent application for SELF-CONTAINED HEATING UNIT AND DRUG-SUPPLY UNIT EMPLOYING SAME, are also suitable. In particular, heat sources that generate heat by exothermic reaction, where the chemical "load" of the source is consumed in a period of between 50-500 msec or less are generally suitable, assuming good thermal coupling between the heat source and substrate.

FIGS. 3A-3E (see Original Patent) are high speed photographs showing the generation of aerosol particles from a drug-supply unit. FIG. 3A shows a heat-conductive substrate about 2 cm in length coated with a film of drug. The drug-coated substrate was placed in a chamber through which a stream of air was flowing in an upstream-to-downstream direction (indicated by the arrow in FIG. 3A) at rate, of about 15 L/min. The substrate was electrically heated and the progression of drug vaporization monitored by real-time photography. FIGS. 3B-3E (see Original Patent) show the sequence of drug vaporization and aerosol generation at time intervals of 50 milliseconds (msec), 100 msec, 200 msec, and 500, msec, respectively. The white cloud of drug-aerosol particles formed from the drug vapor entrained in the flowing air is visible in the photographs. Complete vaporization of the drug film was achieved by 500 msec.

The drug-supply unit generates a drug vapor that can readily be mixed with gas to produce an aerosol for inhalation or for delivery, typically by a spray nozzle, to a topical site for a variety of treatment regimens, including acute or chronic treatment of a skin condition, administration of a drug to an incision site during surgery or to an open wound. Rapid vaporization of the drug film occurs with minimal thermal decomposition of the drug, as will be further demonstrated in Section B.

B. Selection of Drug Film Thickness and Substrate Area

As discussed above, the drug supply article includes a film of drug formed on a substrate. In a preferred embodiment, the drug composition consists of two or more drugs. In a more preferred embodiment, the drug composition comprises pure drug. The drug film in one general embodiment of the invention has a thickness of between about 0.05-20 .mu.m, and preferably between 0.1-15 .mu.m, more preferably between 0.2-10 .mu.m and still more preferably 0.5-10 .mu.m, and most preferably 1-10 .mu.m. The film thickness for a given drug composition is such that drug-aerosol particles, formed by vaporizing the drug composition by heating the substrate and entraining the vapor in a gas stream, have (i) 10% by weight or less drug-degradation product, more preferably 5% by weight or less, most preferably 2.5% by weight or less and (ii) at least 50% of the total amount of drug composition contained in the film. The area of the substrate on which the drug composition film is formed is selected to achieve an effective human therapeutic dose of the drug aerosol. Each of these features of the drug article is described below.

1. Aerosol Particle Purity and Yield

In studies conducted in support of the invention, a variety of drugs were deposited on a heat-conductive, impermeable substrate and the substrate was heated to a temperature sufficient to generate a thermal vapor. Purity of drug-aerosol particles in the thermal vapor was determined by a suitable analytical method. Three different substrate materials were used in the studies: stainless steel foil, aluminum foil, and a stainless steel cylinder. Methods B-G below detail the procedures for forming a drug film on each substrate and the method of heating each substrate.

The stainless steel foil substrate-employed for drugs tested according to Method B was resistively heated by placing the substrate between a pair of electrodes connected to a capacitor. The capacitor was charged to between 14-17 Volts to resistively heat the substrate. FIG. 4A (see Original Patent) is of substrate temperature increase, measured in still air with a thin thermocouple (Omega, Model CO2-K), as a function of time, in seconds, for a stainless steel foil substrate resistively heated by charging the capacitor to 13.5 V (lower line), 15 V (middle line), and 16 V (upper line). When charged with 13.5 V, the substrate temperature increase was about 250.degree. C. within about 200-300 milliseconds. As the capacitor voltage increased, the peak temperature of the substrate also increased. Charging the capacitor to 16V heated the foil substrate temperature about 375.degree. C. in 200-300 milliseconds (to a maximum temperature of about 400.degree. C.).

FIG. 4B shows the time-temperature relationship for a stainless steel foil substrate having a thickness of 0.005 inches. The foil substrate was heated by charging a capacitor, connected to the substrate through electrodes, to 16 V. The substrate reached its peak temperature of 400.degree. C. in about 200 milliseconds, and maintained that temperature for the 1 second testing period.

In Methods D and E, a hollow, stainless steel tube was used as the drug-film substrate. The cylindrical tube in Method D had a diameter of 13 mm and a length of 34 mm. The cylindrical tube in Method E had a diameter of 7.6 mm and a length of 51 mm. In Method D, the substrate was connected to two 1 Farad capacitors wired in parallel, whereas in Method E, the substrate was connected to two capacitors (a 1 Farad and a 0.5 Farad) wired in parallel. FIGS. 5A-5B (see Original Patent) show substrate temperature as a function of time, for the cylindrical substrate of Method D. FIG. 5B shows a detail of the first 1 second of heating.

Aluminum foil was used as a substrate for testing other compounds, as described in Methods C, F, and G. The drug-coated substrate was heated either by wrapping it around a halogen tube and applying 60. V or 90 V alternating current through the bulb or by placing the substrate in a furnace.

For each substrate type, a drug film was formed by applying a solution containing the drug onto the substrate. As described in Method A, a solution of the drug in a solvent was prepared. A variety of solvents can be used and selection is based, in part, on the solubility properties of the drug and the desired solution concentration. Common solvent choices included methanol, chloroform, acetone, dichloromethane, other volatile organic solvents, dimethylformamide, water, and solvent mixtures. The drug solution was applied to the substrate by dip coating, yet other methods such as spray coating are contemplated as well. Alternatively, a melt of the drug can be applied to the substrate.

In Examples 1-236 below a substrate containing a drug film of a certain thickness was prepared. To determine the thickness of the drug film, one method that can be used is to determine the area of the substrate and calculate drug film thickness using the following relationship: film thickness (cm)=drug mass (g)/[drug density (g/cm.sup.3).times.substrate area (cm.sup.2)] The drug mass can be determined by weighing the substrate before and after formation of the drug film or by extracting the drug and measuring the amount analytically. Drug density can be experimentally determined by a variety of techniques, known by those of skill in the art or found in the literature or in reference texts, such as in the CRC. An assumption of unit density is acceptable if an actual drug density is not known.

In the studies reported in the Examples, the substrate having 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 recovered and analyzed for presence of drug-degradation products, to determine purity of the aerosol particles in the thermal vapor. Several drugs are discussed here as merely exemplary of the studies reported in Examples 1-236. Example 10 describes preparation of a drug-supply article containing atropine, a muscarinic antagonist. Substrates containing films of atropine ranging in thickness from between about 1.7 .mu.m to about 9.0 .mu.m were prepared. The stainless steel substrates were heated and the purity of the drug-aerosol particles in the thermal vapor generated from each substrate was determined. FIG. 6 (see Original Patent) shows the results, where drug aerosol purity as a function of drug film thickness is plotted. There is a clear relationship between film thickness and aerosol particle purity, where as the film thickness decreases, the purity increases. An atropine film having a thickness of 9.0 .mu.m produced a thermal vapor having a purity of 91%; an atropine film having a thickness of 1.7 .mu.m produced a thermal vapor having a purity of 98%.

Hydromorphone, an analgesic, was also tested, as describe in Example 66. Substrates having a drug film thickness of between about 0.7 .mu.m to about 2.7 .mu.m were prepared and heated to generate a thermal vapor. Purity of the aerosol particles improved as the thickness of the drug film on the substrate decreased.

FIG. 7 (see Original Patent) shows the relationship between drug film thickness and aerosol-purity for donepezil. As described in Example 44, donepezil was coated onto foil substrates to film thicknesses ranging from about 0.5 .mu.m to about 3.2 .mu.m. Purity of the aerosol particles from each of the films on the substrates was analyzed. At drug film thicknesses of 1.5 .mu.m to 3.2 .mu.m, purity of the aerosol particles improved as thickness of the drug film on the substrate decreased, similar to the trend found for atropine and hydromorphone. In contrast, at less than 1.5 .mu.m thickness, purity of the aerosol particles worsened as thickness of the drug film on the substrate decreased. A similar pattern was also observed for albuterol, as described in Example 3, with aerosol particles purity peaking for films of approximately 3 .mu.m, and decreasing for both thinner and thicker films as shown in FIG. 23 (see Original Patent).

FIGS. 9-23 (see Original Patent) present data for aerosol purity as a function of film thickness for the following compounds: buprenorphine (Example 16), clomipramine (Example 28), ciclesonide (Example 26), midazolam (Example 100), nalbuphine (Example 103), naratriptan (Example 106), olanzapine (Example 109), quetiapine (Example 127), tadalafil (Example 140), prochlorperazine (Example 122), zolpidem (Example 163), fentanyl (Example 57), alprazolam (Example 4), sildenafil (Example 134), and albuterol (Example 3).

In FIGS. 6-23 (see Original Patent), the general relationship between increasing aerosol purity with decreasing film thickness is apparent; however the extent to which aerosol purity varies with a change in film thickness varies for each drug composition. For example, aerosol purity of sildenafil (FIG. 22 (see Original Patent)) exhibited a strong dependence on film thickness, where films about 0.5 .mu.m in thickness had a purity of greater than 99% and films of about 1.6 .mu.m in thickness had a purity of between 94-95%. In contrast, for midazolam (FIG. 12 (see Original Patent)), increasing the film thickness from approximately 1.2 .mu.m to approximately 5.8 .mu.m resulted in a decrease in aerosol particle purity from greater than 99.9% to approximately 99.5%, a smaller change in particle purity despite a larger increase in film thickness compared with the sildenafil example. Moreover, as was discussed above, the inverse relationship between film thickness and purity of aerosolized drug observed for many compounds in the thickness range less than about 20 .mu.m does not necessarily apply at the thinnest film thicknesses that were tested. Some compounds, such as illustrated by donepezil (FIG. 7 (see Original Patent)) show a rather pronounced decrease in purity at film thicknesses both below and above an optimal film thickness, in this case, above and below about 2 .mu.m film thicknesses.

One way to express the dependence of aerosol purity on film thickness is by the slope of the line from a plot of aerosol purity against film thickness. For compounds such as donepezil (FIG. 7), the slope of the line is taken from the maximum point in the curve towards the higher film thickness. Table 1 (see Original Patent), discussed below, shows the slope of the line for the curves shown in FIGS. 6-23 (see Original Patent). Particularly preferred compounds for delivery by the various embodiments of the present invention are compounds with a substantial (i.e., highly negative) slope of the line on the aerosol purity versus thickness plot, e.g., a slope more negative than -0.1% purity per micron and more preferably -0.5% purity per micron.

In addition to selection of a drug film thickness that provides aerosol particles containing 10% or less drug-degradation product (i.e., an aerosol particle purity of 90% or more), the film thickness is selected such 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. In the studies described herein, the percentage of drug film vaporized was determined by quantifying (primarily by HPLC or weight) the mass of drug composition collected upon vaporization or alternatively by the amount of substrate mass decrease. The mass of drug composition collected after vaporization and condensation was compared with the starting mass of the drug composition film that was determined prior to vaporization to determine a percent yield, also referred to herein as a percent emitted. This value is indicated in many of the Examples set forth below. For example, in Example 1 a film having a thickness of 1.1 .mu.m was formed from the drug acebutolol, a beta adrenergic blocking agent. The mass coated on the substrate was 0.89 mg and the mass of drug collected in the thermal vapor was 0.53 mg, to give a 59.6 percent yield. After vaporization, the substrate and the testing chamber were washed to recover any remaining drug. The total drug recovered from the test apparatus, including the emitted thermal vapor, was 0.8 mg, to give a 91% total recovery. In another example, midazolam was coated onto a impermeable substrate, as described in Example 100. A drug film having a thickness of 9 .mu.m was formed. Heating of the substrate generated a thermal vapor containing drug aerosol particles having a purity of 99.5%. The fraction of drug film collected on the filter, i.e., the percent yield, was 57.9%. After vaporization, the substrate and the testing chamber were washed to recover any remaining drug. The total drug recovered from the test apparatus and the filter was 5.06 mg, to give a 94.2% total recovery.

2. Substrate Area

Another feature of the drug-supply article is that the selected substrate surface area is sufficient to yield a therapeutic dose of the drug aerosol when used by a subject. The amount of drug to provide a therapeutic dose is generally known in the art or can be determined as discussed above. The required dosage and selected film thickness, discussed above, dictate the minimum required substrate area in accord with the following relationship: film thickness (cm).times.drug density (g/cm.sup.3).times.substrate area (cm.sup.2)=dose (g) As noted above, drug density can be determined experimentally or from the literature, or if unknown, can be assumed to be 1 g/cc. To prepare a drug supply article comprised of a drug film on a heat-conductive substrate that is capable of administering an effective human therapeutic dose, the minimum substrate surface area is determined using the relationships described above to determine a substrate area for a selected film thickness that will yield a therapeutic dose of drug aerosol. Table 1 shows a calculated substrate surface area for a variety of drugs on which an aerosol purity-film thickness profile was constructed.

The actual dose of drug delivered, i.e., the percent yield or percent emitted, from the drug-supply article will depend on, along with other factors, the percent of drug film that is vaporized upon heating the substrate. Thus, for drug films that yield upon heating 100% of the drug film and aerosol particles that have a 100% drug purity, the relationship between dose, thickness, and area given above correlates directly to the dose provided to the user. As the percent yield and/or particle purity decrease, adjustments in the substrate area can be made as needed to provide the desired dose. Also, as one of skill in the art will recognize, larger substrate areas other than the minimum calculated area for a particular film thickness can be used to deliver a therapeutically effective dose of the drug. Moreover as can be appreciated by one of skill in art, the film need not coat the complete surface area if a selected surface area exceeds the minimum required for delivering a therapeutic dose from a selected film thickness.

3. Characteristics of the Drug-Supply Article

The drug-supply article of the invention is heated to generate a thermal vapor containing drug aerosol particles for therapeutic administration to a patient. In studies performed in support of the invention, high speed photography was used to monitor visually production of the thermal vapor. FIGS. 24A-24D are high speed photographs showing the generation of a thermal vapor of phenytoin from a film coated on a substrate, prepared as described in Example 116. FIG. 24A is a photograph showing the drug-coated substrate prior to heating (t=0 milliseconds (ms)). The photographs in FIGS. 24B-24D show formation of a thermal vapor as a function of time after initiation of substrate heating. The photograph in FIG. 24B, taken 50 milliseconds after initiation of substrate heating, shows formation of a thermal vapor over the substrate surface. The subsequent photographs show that the majority of the thermal vapor is formed prior to 100 milliseconds after initiation of substrate heating (FIG. 24C), with formation substantially completed by about 200 milliseconds after initiation of substrate heating (FIG. 24D).

FIGS. 25A-25D are high speed photographs showing the generation of a, thermal vapor of disopyramide from a film of drug coated on a substrate, prepared as described in Example 42. FIG. 25A shows the drug-coated substrate prior to heating (t=0 milliseconds (ms)). The photographs in FIGS. 25B-25D show formation of a thermal vapor as a function of time after initiation of substrate heating. As seen, 50 milliseconds after initiation of substrate heating (FIG. 25B), a thermal vapor is present over the substrate surface. The subsequent photographs show that the majority of the thermal vapor is formed prior to 100 milliseconds after initiation of substrate heating (FIG. 25C), with formation substantially completed by about 200 milliseconds after initiation of substrate heating (FIG. 25D).

Similar photographs are shown for buprenorphine in FIGS. 26A-26E. Upon heating of a buprenorphine substrate, prepared as described in Example 16, presence of a thermal vapor is evident in the photograph taken 50 milliseconds after heating was initiated (FIG. 26B). At 100 milliseconds (FIG. 26C) and 200 milliseconds (FIG. 26D) after initiation of substrate heating the thermal vapor was still observed in the photographs. Generation of the thermal vapor was complete by 300 milliseconds (FIG. 26E).

4. Modifications to Optimize Aerosol Purity and/or Yield

As discussed above, purity of aerosol particles for many drugs correlates directly with film thickness, where thinner films typically produce aerosol particles with greater purity. Thus, one method to optimize purity disclosed in this invention is the use of thinner films. Likewise, the aerosol yield may also be optimized in this manner. The invention, however, further contemplates strategies in addition to, or in combination with, adjusting film thickness to increase either aerosol purity or yield or both. These strategies include modifying the structure or form of the drug, and/or producing the thermal vapor in an inert atmosphere.

Thus, in one embodiment, the invention contemplates generation of and/or use of an altered form of the drug, such as, for example but not limitation, use of a pro-drug, or a free base, free acid or salt form of the drug. As demonstrated in various Examples below, modifying the form of the drug can impact the purity and or yield of the aerosol obtained. Although not always the case, the free base or free acid form of the drug as opposed to the salt, generally results in either a higher purity or yield of the resultant aerosol. Thus, in a preferred embodiment of the invention, the free base and free acid forms of the drugs are used.

Another approach contemplates generation of drug-aerosol particles having a desired level of drug composition purity by forming the thermal vapor under a controlled atmosphere of an inert gas, such as argon, nitrogen, helium, and the like. Various Examples below show that a change in purity can be observed upon changing the gas under which vaporization occurs.

More generally, and in another aspect, the invention contemplates a method of forming an article for use in an aerosol device, for producing aerosol particles of a drug composition that have the desired purity and a film that provides a desired percent yield. In the method, a drug film with a known film thickness is prepared on a heat-conductive, impermeable substrate. The substrate is heated to vaporize the film, thereby producing aerosol particles containing the drug compound. The drug composition purity of the aerosol particles in the thermal vapor is determined, as well as the percent yield, i.e., the fraction of drug composition film vaporized and delivered by the method. If the drug composition purity of the particles is less than about 90%, but greater than about 60%, more preferably greater than about 70%, or if the percent yield is less than about 50%, the thickness of the drug film is adjusted to a thickness different from the initial film thickness for testing. That is, a substrate having an adjusted film thickness is heated and the percent purity and percent yield are determined. The film thickness is continually adjusted until the desired drug composition aerosol purity and yield are achieved. For example, the initial film thickness can be between about 1-20 .mu.m. A second, different film thickness would be between about 0.05-10 .mu.m. This method is particularly suited for drug compositions that exhibit a percent yield of greater than about 30% and a drug composition aerosol purity of between about 60%-90%, more preferably between about 70%-90%.

Examples 166-233 correspond to studies conducted on drugs that when deposited as a thin film on a substrate produced a thermal vapor having a drug purity of less than about 90% but greater than about 60% or where the percent yield was less than about 50%. Purity of the thermal vapor of many of these drugs would be improved by using one or more of the approaches discussed above. More specifically, for some drugs a simple adjustment in film thickness, typically to a thinner film, improves purity of the aerosol particles. For other drugs, heating the substrate in an inert atmosphere, such as an argon or nitrogen atmosphere, alone or in combination with an adjustment in film thickness, achieves aerosol particles with the requisite purity of 90% or more and volatilization of a fraction of the drug film that is greater than about 50%.

Based on the studies conducted, the following drugs are particularly suited to the method and approaches to optimizing purity or yield: adenosine, amoxapine, apomorphine, aripiprazole, aspirin, astemizole, atenolol, benazepril, benztropine, bromazepam, budesonide, buspirone, caffeine, captopril, carbamazepine, cinnarizine, clemastine, clemastine fumarate, clofazimine, desipramine, dipyridamole, dolasetron, doxylamine, droperidol, enlapril maleate, fluphenazine, flurazepam, flurbiprofen, fluvoxamine, frovatriptan, hydrozyzine, ibutilide, indomethacine norcholine ester, ketorolac, ketorolac norcholine ester, levodopa, melatonin, methotrexate, methysergide, metoclopramide, nabumetone, naltrexone, nalmefene, perphenazine, pimozide, piroxicam, pregnanolone, prochlorperazine 2HCl, protriptyline HCl, protriptyline, pyrilamine, pyrilamine maleate, quinine, ramipril, risperidone, scopolamine, sotalol, sulindac, terfenadine, triamcinolone acetonide, trihexyphenidyl, thiothixene, telmisartan, temazepam, triamterene, trimipramine, ziprasidone, and zonisamide.

Examples 234-235 correspond to studies conducted on combinations of drugs that when deposited as a thin film of produced a thermal vapor (aerosol) having a drug purity of greater than 90% and a recovered yield of each drug in the aerosol of greater than 50%.

Example 235 corresponds to studies conducted on drugs that when deposited as a thin film on a substrate produce a thermal vapor having a drug purity of less than about 60%.

It will be appreciated that to provide a therapeutic dose the substrate surface area is adjusted according to the film thickness that yields the desired particle purity and percent yield, as discussed above.

III. Utility

Thin-Film Article, Device, and Methods

As can be appreciated from the above examples showing generation of a pure drug thermal vapor, from thin films (i.e. 0.02-20 .mu.m) of the drug, the invention finds use in the medical field in compositions and articles for delivery of a therapeutic of a drug. Thus, the invention includes, in one aspect, a drug-supply article for production of a thermal vapor that contains drug-aerosol particles. The drug-supply article includes a substrate coated with a film of a drug composition to be delivered to a subject, preferably a human subject. The thickness of the drug composition film is selected such that upon vaporizing the film by heating the substrate to a temperature sufficient to vaporize at least 50% of the drug composition film, typically to a temperature of at least about 200.degree. C., preferably at least about 250.degree. C., more preferably at least about 300.degree. C. or 350.degree. C., a thermal vapor is generated that has 10% or less drug-degradation product. The area of the substrate is selected to provide a therapeutic dose, and is readily determined based on the equations discussed above.

In another aspect the invention relates to a method of forming a drug-supply article comprised of a substrate and a film of a drug composition. The method includes identifying a thickness of drug composition film that yields after vaporization of the film the drug composition in a substantially non-pyrolyzed form, as evidenced, for example, by the purity of the vapor. This may be done by an iterative process where one first prepares on a heat-conductive substrate, a drug composition having a given film thickness, e.g., 1-10 microns. The substrate is then heated, e.g., to a selected temperature between 200.degree. C.-600.degree. C., preferably 250.degree. C. to 550.degree. C., more preferably, 300.degree. C.-500.degree. C., or 350.degree. C. to 500.degree. C., to produce an aerosol of particles containing the compound. As seen in the examples below, the aerosol may be collected in particle form or simply collected on the walls of a surrounding container. The purity of the drug composition is then determined, e.g., expressed as a weight percent or analytical percent degradation product. If the percent degradation product is above a selected threshold, e.g., 1, 2.5, 5, or 10 percent, the steps above are repeated with different compound thicknesses, typically with successively lower thicknesses, until the aerosolized compound is within the desired limit of degradation, e.g., 1, 2.5, 5, or 10%. Similarly, if the initial volatilization study shows very low levels of degradation, e.g., less than 0.1, 1, 2, or 5%, it may be desirable in subsequent tests to increase film thickness, to obtain a greatest film thickness at which an acceptable level of drug degradation is observed.

After identification of the film thickness that generates a highly pure thermal drug composition vapor (e.g., drug composition purity greater than about 90%), the area of substrate required to accommodate a therapeutic dose, when inhaled by a human, is determined. For example, the required oral dose for atropine is 0.4 mg (Example 10). Using the data shown in FIG. 6, a thermal vapor comprised of substantially non-pyrolyzed drug, e.g., a vapor having greater than about 90% drug purity, is produced from film thicknesses of less than about 10 .mu.m. Assuming unit density for atropine, a substrate area of about 0.8 cm.sup.2 coated with a 5 .mu.m thick drug film is required to accommodate the oral dose of 0.4 mg if a drug of 95% purity is desired. Selection of an atropine film thickness of about 1.7 .mu.m generated a thermal vapor having drug-aerosol particles with less than 2% pyrolysis (i.e., greater than 98% drug purity). Selection of a film having a thickness of 1.7 .mu.m requires a substrate area of at least about 2.4 cm.sup.2 to accommodate a dose of 0.4 mg.

The drug-delivery article comprised of a substrate coated with a thin drug film is particularly suited, in another aspect of the invention, for forming a therapeutic inhalation dose of drug-aerosol particles. The inhalation route of drug administration offers several advantages for many drugs, including rapid uptake into the bloodstream, and avoidance of the first pass effect allowing for an inhalation dose of a drug that can be substantially less, e.g., one half, that required for oral dosing. Efficient aerosol delivery to the lungs requires that the particles have certain penetration and settling or diffusional characteristics. For larger particles, deposition in the deep lungs occurs by gravitational settling and requires particles to have an effective settling size, defined as mass median aerodynamic diameter (MMAD), of between 1-3.5 .mu.m. For smaller particles, deposition to the deep lung occurs by a diffusional process that requires having a particle size in the 10-100 nm, typically 20-100 nm range. Particle sizes that fall in the range between 100 nm and 1 .mu.m tend to have poor deposition and those above 3.5 .mu.m tend to have poor penetration. Therefore, an inhalation drug-delivery device for deep lung delivery should produce an aerosol having particles in one of these two size ranges, preferably between about 1-3 .mu.m MMAD.

Accordingly, a drug-supply article comprised of a substrate and having a drug composition film thickness selected to generate a thermal vapor having drug composition-aerosol particles with less than about 10% drug degradation product is provided, more preferably less than about 5% drug degradation product, and most preferably less than about 2.5% drug degradation product. A gas, air or an inert fluid, is passed over the substrate at a flow rate effective to produce the particles having a desired MMAD. The more rapid the airflow, the more diluted, the vapor and hence the smaller the particles that are formed. In other words the particle size distribution of the aerosol is determined by the concentration of the compound vapor during condensation. This vapor concentration is, in turn, determined by the extent to which airflow over the surface of the heating substrate dilutes the evolved vapor. Thus, to achieve smaller or larger particles, the gas velocity through the condensation region of the chamber may be altered by modifying the gas-flow control valve to increase or decrease the volumetric airflow rate. For example, to produce condensation particles in the size range 1-3.5 .mu.m MMAD, the chamber may have substantially smooth-surfaced walls, and the selected gas-flow rate may be in the range of 4-50 L/minute.

Additionally, as will be appreciated by one of skill in the art, particle size may be also altered by modifying the cross-section of the chamber condensation region to increase or decrease linear gas velocity for a given volumetric flow rate, and/or the presence or absence of structures that produce turbulence within the chamber. Thus, for example to produce condensation particles in the size range 20-100 nm MMAD, the chamber may provide gas-flow barriers for creating air turbulence within the condensation chamber. These barriers are typically placed within a few thousands of an inch from the substrate surface.

Typically, the flow rate of gas over the substrate ranges from about 4-50 L/min, preferably from about 5-30 L/min.

Prior to, simultaneous with, or subsequent to passing a gas over the substrate, heat is applied to the substrate to vaporize the drug composition film. It will be appreciated that the temperature to which the substrate is heated will vary according to the drug's vaporization properties, but is typically heated to a temperature of at least about 200.degree. C., preferably of at least about 250.degree. C., more preferably at least about 300.degree. C. or 350.degree. C. Heating the substrate produces a drug composition vapor that in the presence of the flowing gas generates aerosol particles in the desired size range. In one embodiment, the substrate is heated for a period of less than about 1 second, and more preferably for less than about 500 milliseconds, still more preferably for less than about 200 milliseconds. The drug-aerosol particles are inhaled by a subject for delivery to the lung.

IV. Utility

Rapid-Heating Device and Method

In another general embodiment, there is provided a device for producing an aerosol of compound condensation particles, e.g., for use in inhalation therapy. The device has the elements described above with respect to FIGS. 2A and 2B, where the heat source is designed to supply-heat to the substrate in the device at a rate effective to produce a substrate temperature greater than, 200.degree. C. or in other embodiments greater than 250.degree. C., 300.degree. C. or 350.degree. C., and to substantially volatilize the drug composition film from the substrate in a period of 2 seconds or less. The thickness of the film of drug composition on the substrate is such that the device produces an aerosol containing less than 10% by weight drug degradation and at least 50% of the drug composition on the film.

The device includes a drug composition delivery assembly composed of the substrate, a film of the selected drug composition on the substrate surface, and a heat source for supplying heat to the substrate at a rate effective to heat the substrate to a temperature greater than 200.degree. C. or in other embodiments to a temperature greater than 250.degree. C., 300.degree. C. or 350.degree. C., and to produce substantially complete volatilization of the drug composition within a period of 2 seconds or less.

The drug composition in the assembly and device may be one that, when vaporized from a film on an impermeable surface of a heat conductive substrate, the aerosol exhibits an increasing level of drug degradation products with increasing film thicknesses, particularly at a thickness of greater than 0.05-20 microns. For this general group of drug compositions, the film thickness on the substrate will typically be between 0.05 and 20 microns, e.g., the maximum or near-maximum thickness within this range that allows formation of a particle aerosol with drug degradation less than 5%.

Alternatively, the drug may show less than 5-10% degradation even at film thicknesses greater than 20 microns. For these compounds, a film thickness greater than 20 microns, e.g., 20-50 microns, may be selected, particularly where a relatively large drug dose is desired.

The device is useful in a method for producing a condensation aerosol by the steps of heating the device substrate at a rate that heats the substrate to a temperature greater than 200.degree. C., or in other embodiments to a temperature greater than 250.degree. C., 300.degree. C., or 350.degree. C., and produces substantially complete volatilization of the compounds within a period of 2 seconds or less.

V. Examples

The following examples further illustrate the invention described herein and are in no way intended to limit the scope of the invention.

Materials

Solvents were of reagent grade or better and purchased commercially.

Unless stated otherwise, the drug free base or free acid form was used in the Examples.

Methods

A. Preparation of Drug-Coating Solution

Drug was dissolved in an appropriate solvent. Common solvent choices included methanol, dichloromethane, methyl ethyl ketone, diethyl ether, 3:1 chloroform:methanol mixture, 1:1 dichloromethane: methyl ethyl ketone mixture, dimethylformamide, and deionized water. Sonication and/or heat were used as necessary to dissolve the compound. The drug concentration was typically between 50-200 mg/mL.

B. Preparation of Drug-Coated Stainless Steel Foil Substrate

Strips of clean 304 stainless steel foil (0.0125 cm thick, Thin Metal Sales) having dimensions 1.3 cm by 7.0 cm were dip-coated with a drug solution. The foil was then partially dipped three times into solvent to rinse drug off of the last 2-3 cm of the dipped end of the foil. Alternatively, the drug coating from this area was carefully scraped off with a razor blade. The final coated area was between 2.0-2.5 cm by 1.3 cm on both sides of the foil, for a total area of between 5.2-6.5 cm.sup.2 Foils were prepared as stated above and then some were extracted with methanol or acetonitrile as standards. The amount of drug was determined from quantitative HPLC analysis. Using the known drug-coated surface area, the thickness was then obtained by: film thickness (cm)=drug mass (g)/[drug density (g/cm.sup.3).times.substrate area (cm.sup.2). If the drug density is not known, a value of 1 g/cm.sup.3 is assumed. The film thickness in microns is obtained by multiplying the film thickness in cm by 10,000.

After drying, the drug-coated foil was placed into a volatilization chamber constructed of a Delrin.RTM. block (the airway) and brass bars, which served as electrodes. The dimensions of the airway were 1.3 cm high by 2.6 cm wide by 8.9 cm long. The drug-coated foil was placed into the volatilization chamber such that the drug-coated section was between the two sets of electrodes. After securing the top of the volatilization chamber, the electrodes were connected to a 1 Farad capacitor (Phoenix Gold). The back of the volatilization chamber was connected to a two micron Teflon.RTM. filter (Savillex) and filter housing, which were in turn connected to the house vacuum. Sufficient airflow was initiated (typically 30 L/min=1.5 m/sec), at which point the capacitor was charged with a power supply, typically to between 14-17 Volts. The circuit was closed with a switch, causing the drug-coated foil to resistively heat to temperatures of about 280-430.degree. C. (as measured with an infrared camera (FLIR Thermacam SC3000)), in about 200 milliseconds. (For comparison purposes, see FIG. 4A, thermocouple measurement in still air.) After the drug had vaporized, airflow was stopped and the Teflon.RTM. filter was extracted with acetonitrile. Drug extracted from the filter was analyzed generally by HPLC UV absorbance generally at 225 nm using a gradient method aimed at detection of impurities to determine percent purity. Also, the extracted drug was quantified to determine a percent yield, based on the mass of drug initially coated onto the substrate. A percent recovery was determined by quantifying any drug remaining on the substrate and chamber walls, adding this to the quantity of drug recovered in the filter and comparing it to the mass of drug initially coated onto the substrate.

C. Preparation of Drug-Coated Aluminum Foil Substrate

A substrate of aluminum foil (10 cm.times.5.5 cm; 0.0005 inches thick) was precleaned with acetone. A solution of drug in a minimal amount of solvent was coated onto the foil substrate to cover an area of approximately 7-8 cm.times.2.5 cm. The solvent was allowed to evaporate. The coated foil was wrapped around a 300 watt halogen tube (Feit Electric Company, Pico Rivera, Calif.), which was inserted into a glass tube sealed at one end with a rubber stopper. Sixty volts of alternating current (driven by line power controlled by a Variac) were run through the bulb for 5-15 seconds, or in some studies 90 V for 3.5-6 seconds, to generate a thermal vapor (including aerosol) which was collected on the glass tube walls. In some studies, the system was flushed through with argon prior to volatilization. The material collected on the glass tube walls was recovered and the following determinations were made: (1) the amount emitted, (2) the percent emitted, and (3) the purity of the aerosol by reverse-phase HPLC analysis with detection typically by absorption of 225 nm light. The initial drug mass was found by weighing the aluminum foil substrate prior to and after drug coating. The drug coating thickness was calculated in the same manner as described in Method B.

D. Preparation of Drug-Coated Stainless Steel Cylindrical Substrate

A hollow stainless steel cylinder with thin walls, typically 0.12 mm wall thickness, a diameter of 13 mm, and a length of 34 mm was cleaned in dichloromethane, methanol, and acetone, then dried, and fired at least once to remove any residual volatile material and to thermally passivate the stainless steel surface. The substrate was then dip-coated with a drug coating solution (prepared as disclosed in Method A). The dip-coating was done using a computerized dip-coating machine to produce a thin layer of drug on the outside of the substrate surface. The substrate was lowered into the drug solution and then removed from the solvent at a rate of typically 5-25 cm/sec. (To coat larger amounts of material on the substrate, the substrate was removed more rapidly from the solvent or the solution used was more concentrated.) The substrate was then allowed to dry for 30 minutes inside a fume hood. If either dimethylformamide (DMF) or a water mixture was used as a dip-coating solvent, the substrate was vacuum dried inside a desiccator for a minimum of one hour. The drug-coated portion of the cylinder generally has a surface area of 8 cm.sup.2. By assuming a unit density for the drug, the initial drug coating thickness was calculated. The amount of drug coated onto the substrates was determined in the same manner as that described in Method B: the substrates were coated, then extracted with methanol or acetonitrile and analyzed with quantitative HPLC methods, to determine the mass of drug coated onto the substrate.

The drug-coated substrate was placed in a surrounding glass tube connected at the exit end via Tygon.RTM. tubing to a filter holder fitted with a Teflon.RTM. filter (Savillex). The junction of the tubing and the filter was sealed with paraffin film. The substrate was placed in a fitting for connection to two 1 Farad capacitors wired in parallel and controlled by a high current relay. The capacitors were charged by a separate power source to about 18-22 Volts and most of the power was channeled to the substrate by closing a switch and allowing the capacitors to discharge into the substrate. The substrate was heated to a temperature of between about 300-500.degree. C. (see FIGS. 5A & 5B) in about 100 milliseconds. The heating process was done under an airflow of 15 L/min, which swept the vaporized drug aerosol into a 2 micron Teflon.RTM. filter.

After volatilization, the aerosol captured on the filter was recovered for quantification and analysis. The quantity of material recovered in the filter was used to determine a percent yield, based on the mass of drug coated onto the substrate. The material recovered in the filter was also analyzed generally by HPLC. UV absorbance at typically 225 nm using a gradient method aimed at detection of impurities, to determine purity of the thermal vapor. Any material deposited on the glass sleeve or remaining on the substrate was also recovered and quantified to determine a percent total recovery ((mass of drug in filter+mass of drug remaining on substrate and glass sleeve)/mass of drug coated onto substrate). For compounds without UV absorption GC/MS or LC/MS was used to determine purity and to quantify the recovery. Some samples were further analyzed by LC/MS to confirm the molecular weight of the drug and any degradants.

E. Preparation of Drug-Coated Stainless Steel Cylindrical Substrate

A hollow stainless steel cylinder like that described in Example D was prepared, except the cylinder diameter was 7.6 mm and the length was 51 mm. A film of a selected drug was applied as described in Example D.

Energy for substrate heating and drug vaporization was supplied by two capacitors (1 Farad and 0.5 Farad) connected in parallel, charged to 20.5 Volts. The airway, airflow, and other parts of the electrical set up were as described in Example D. The substrate was heated to a temperature of about 420.degree. C. in about 50 milliseconds. After drug film vaporization, percent yield, percent recovery, and purity analysis were done as described in Example D.

F. Preparation of Drug-Coated Aluminum Foil Substrate

A solution of drug was coated onto a substrate of aluminum foil (5 cm.sup.2-150 cm.sup.2; 0.0005 inches thick). In some studies, the drug was in a minimal amount of solvent, which was allowed to evaporate. The coated foil was inserted into a glass tube in a furnace (tube furnace). A glass wool plug was placed in the tube adjacent to the foil sheet and an air flow of 2 L/min was applied. The furnace was heated to 200-550.degree. C. for 30, 60, or 120 seconds. The material collected on the glass wool plug was recovered and analyzed by reverse-phase HPLC analysis with detection typically by absorption of 225 nm light or GC/MS to determine the purity of the aerosol.

G. Preparation of Drug-Coated Aluminum Foil Substrate

A substrate of aluminum foil (3.5 cm.times.7 cm; 0.0005 inches thick) was precleaned with acetone. A solution of drug in a minimal amount of solvent was coated onto the foil substrate. The solvent was allowed to evaporate. The coated foil was wrapped around a 300 watt halogen tube, (Feit Electric Company, Pico Rivera, Calif.), which was inserted into a T-shaped glass tube sealed at two ends with parafilm. The parafilm was punctured with ten to fifteen needles for air flow The third opening was connected to a 1 liter, 3-neck glass flask. The glass flask was further connected to a piston capable of drawing 1.1 liters of air through the flask. Ninety volts of alternating current (driven by line power controlled by a Variac) was run through the bulb for 6-7 seconds to generate a thermal vapor (including aerosol) which was drawn into the 1 liter flask. The aerosol was allowed to sediment onto the walls of the 1 liter flask for 30 minutes. The material collected on the flask walls was recovered and the following determinations were made: (1) the amount emitted, (2) the percent emitted, and (3) the purity of the aerosol by reverse-phase HPLC analysis with detection by typically by absorption of 225 nm light. Additionally, any material remaining on the substrate was collected and quantified.
 

Claim 1 of 28 Claims

1. A device for producing a condensation aerosol comprising (a) a chamber comprising an upstream opening and a downstream opening, the openings allowing gas to flow therethrough (b) a heat-conductive substrate, the substrate located at a position between the upstream and downstream openings, (c) a drug composition film on the substrate, the film comprising a therapeutically effective dose of a drug when the drug is administered in aerosol form (d) a heat source for supplying heat to said substrate to produce a substrate temperature greater than 300.degree. C., and to substantially volatilize the drug composition film from the substrate in a period of 2 seconds or less, and (e) means for producing an air flow across the substrate producing aerosol particles by condensation, wherein the device produces a condensation aerosol containing about 10% or less by weight drug composition degradation products and at least 50% of the drug composition of said film.

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