Source: https://patents.google.com/patent/CA2576961A1/en
Timestamp: 2019-04-25 07:26:35+00:00

Document:
2004-08-12 Application filed by Alexza Pharmaceuticals, Inc., Ron L. Hale, Mingzu Lei, Krishnamohan Sharma, Peter M. Lloyd, Patrik Munzar, Dennis Solas, Matthew D. Stracker, Alexza Molecular Delivery Corporation filed Critical Alexza Pharmaceuticals, Inc.
Aerosol drug delivery devices (10) incorporating percussively activated heat packages (32) are disclosed. The heat packages include a percussive igniter (40) and a fuel (50) capable of undergoing an exothermic oxidation-reduction reaction when ignited by the percussive igniter. The drug delivery devices disclosed can be activated by an actuation mechanism to vaporize a thin solid film (56) comprising a drug disposed on the exterior of a heat package. Metal coordination complexes of volatile drugs, and in particular nicotine, from which the drug can be selectively vaporized when heated are also disclosed.
The use of aerosol drug delivery devices comprising thin films of nicotine metal salt complexes for the treatment of nicotine craving and for effecting smoking cessation are also disclosed.
 Cigarette smoking provides an initial sharp rise in nicotine blood level as nicotine is absorbed through the lungs of a smoker. In general, a blood level peak produced by cigarettes of between 30-40 ng/mL is attained within 10 minutes of smoking.
The rapid rise in nicotine blood level is postulated to be responsible for the postsynaptic effects at nicotinic cholinergic receptors in the central nervous system and at autonomic ganglia which induces the symptoms experienced by cigarette smokers, and may also be responsible for the craving symptoms associated with cessation of smoking.
in less than 200 msec in an air flow can produce drug aerosols having high yield and high purity with minimal degradation of the drug. Condensation drug aerosols can be used for effective pulmonary delivery of drugs using inhalation medical devices.
Devices and methods in which thin films of drugs deposited on metal substrates are vaporized by electrically resistive heating have been demonstrated. Chemically-based heat packages which can include a fuel capable of undergoing an exothermic metal oxidation-reduction reaction within an enclosure can also be used to produce a rapid thermal impulse capable of vaporizing thin films to produce high purity aerosols, as disclosed, for example in 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, the entirety of both of which are herein incorporated by reference. These devices and methods are appropriate for use with compounds that can be deposited as physically and chemically stable solids.
Unless vaporized shortly after being deposited on the metal surface, liquids can evaporate or migrate from the surface. Therefore, while such devices can be used to vaporize liquids, the use of liquid drugs can impose certain undesirable complexity. Nicotine is a liquid at room temperature with a relatively high vapor pressure. Therefore, known devices and methods are not particularly suited for producing nicotine aerosols using the liquid drug.
 Accordingly, a first aspect of the present disclosure provides a drug delivery device comprising a housing defining an airway, wherein the airway comprises at least one air inlet and a mouthpiece having at least one air outlet, at least one percussively activated heat package disposed within the airway, at least one drug disposed on the at least one percussively activated heat package, and a mechanism configured to impact the at least one percussively activated heat package.
Drugs that can be coated as thin films (either solids or viscous liquids) are particularly suited for this aspect of the invention. Likewise, as discussed below, volatile or liquid drugs that can form a complex and then coated as a thin film are also suitable for use in this aspect of the invention. For purposed of clarity, "percussively activated heat package"
herein means a heat package that has been configured so that it can be fired or activated by percussion.
An "unactivated heat package" or "non-activated heat package" refers herein to a percussively activated heat package in a device, but one that is not yet positioned in the device so that it can be directly impacted and fired, although the heat package itself is configured to be activated by percussion when so positioned.
Description of the Drawings  Fig. 1 is an isometric view of a drug delivery device according to certain embodiments.
 Fig. 2 is a cross-sectional view of a drug delivery device incorporating percussively ignited heat packages according to certain embodiments.
 Fig. 3 is a cross-sectional view of a heat package according to certain embodiments.
 Fig. 4 is a cross-sectional view of a drug delivery device in which each heat package is disposed within a recess according to certain embodiments.
 Fig. 5 is another view of heat packages disposed within recesses.
 Figs. 6A-6E illustrate additional embodiments of heat packages.
 Fig. 7 shows a conceptual summary of the use of metal coordination complexes to stabilize volatile compounds, and subsequently selectively volatilize the organic compound from a solid thin film of the metal coordination complex.
 Fig. 8 is a chart showing percent nicotine aerosol yield of selectively volatilized solid thin films of a (nicotine)2-ZnBr2 metal coordination complex.
 Fig. 9 is a chart showing percent nicotine aerosol purity of selectively volatilized solid thin films of a (nicotine)2-ZnBr2 metal coordination complex.
Description of Various Embodiments  Unless otherwise indicated, all numbers expressing quantities and conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about."
 In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including," as well as other forms, such as "includes" and "included," is not limiting. Also, terms such as "element" or "component" encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise.
 Vaporization of thin films comprising a drug can be used for administering aerosols of a drug to a user. Inhalation drug delivery devices in which an aerosol is produced by vaporizing a solid thin film of a drug are described, for example, in U.S. Patent Application No. 10/850,895, the disclosure of which is incorporated herein by reference. In such devices, inhalation on the device by a patient activates a heating element on which is disposed a thin solid film of a drug. The fast thermal impulse vaporizes the drug which forms an aerosol in the air flow generated by the patient's inhalation. The aerosol is ingested by the patient and delivered to the patient's lung where the drug can be rapidly and efficiently absorbed into the patient's systemic circulation. Devices in which a fia.el capable of undergoing an exothermic metal oxidation-reduction reaction to provide heat to vaporize a substance have also been described (see, for example, "Staccato Device Application." The thin films of metal coordination complexes of volatile compounds disclosed herein can be used in similar devices and in a similar manner to produce high purity drug aerosols.
cigarette smoker typically inhales about 10 times over a period of about 5 minutes.
Therefore, a nicotine delivery device capable of simulating the use profile of cigarette smoking would include from 5 to 20 doses of about 200 g each of nicotine, which could then be intermittently released upon request by the user. While such protocols can be accommodated by previously described portable multi-dose drug delivery devices, for example, as disclosed in U.S. Application No. 10/861,554, entitled "Multiple Dose Condensation Aerosol Devices and Methods of Forming Condensation Aerosols, filed June 3, 2004 such devices employ electrically resistive heating to vaporize a thin solid film, and therefore require a relatively expensive and bulky power source such as a battery. Portable multi-dose drug delivery devices which do not incorporate batteries, which are readily disposable, and which are amenable to high volume, low cost manufacturing can be useful, particularly for nicotine replacement therapies.
mechanically actuated, percussively ignited, chemical heat package, can provide a compact, self-contained heating system capable of vaporizing thin films of drugs, for use in portable, multi-dose and single-dose drug delivery devices.
 Fig. 1 shows an isometric view of a multi-dose drug delivery device incorporating a percussive heat package, and a mechanical actuation mechanism.
A drug delivery device 10 includes a housing comprising an endpiece 12, and a mouthpiece 14.
Endpiece 12 and mouthpiece 14 define an internal airway having at least one air inlet 16 (hidden), and at least one air outlet 18 defined by mouthpiece 14. A manually actuated push-button switch 20 is incorporated into endpiece 12. Endpiece 12 and mouthpiece 14 can be separate units that can be separably, rotatably, or fixedly connected at interface 22.
The dimensions of drug delivery device 10 can be such that the device can be easily and ergonomically handled. For the purposes of nicotine replacement therapy, it can be useful that the look and feel of drug delivery device 10 simulate that of a cigarette, cigarillo or a cigar. For example, in certain embodiments, the length of endpiece 12 can be 1.4 inches with an outer diameter of 1.2 inches, and the length of mouthpiece 14 can be 1.8 inches to 2.5 inches. Mouthpiece 14 can have a diameter the same as that of endpiece 12 at interface 22, and can be tapered toward air outlet 18 as appropriate for user convenience and comfort, as well as to facilitate inhalation and delivery of a drug aerosol into the lungs of a user. The cross-sectional area of air outlet 18 can range from about 0.01 in2 to about 1.5 in2. The internal airway defined by endpiece 12 and mouthpiece 14 can accommodate an air flow rate typically produced during inhalation. For exainple, the airway defined by endpiece 12, and mouthpiece 14 can accommodate an air flow rate ranging from 10 L/min to 200 L/min. Endpiece 12 and mouthpiece 14 can be formed from a polymer or polymer composite, or from any other material capable of providing structural support for the internal components, including, for example, metals, alloys, composites, ceramics, and combinations thereof. The exterior surface of endpiece 12 and mouthpiece 14 can further be textured or include molded inserts to enhance the tactile and/or aesthetic qualities. The wall thickness of endpiece 12 and mouthpiece 14 can be any appropriate thickness that provides mechanical integrity to the delivery device and physical support for the internal components. In certain embodiments, endpiece 12 and mouthpiece 14 can be fabricated by injection molding methods using low cost plastics and/or plastic components.
 Fig. 2 shows a cut-away cross-sectional view of multi-dose drug delivery device 10. Mouthpiece 14 is slidably connected at interface 22 to endpiece 12, and as illustrated in Fig. 2, is pulled slightly apart from endpiece 12 in a partially disassembled configuration. Mouthpiece 14 includes an internal baffle 25 having a hole 27.
In certain embodiments, the slidable connection at interface 22 can be used to rotate mouthpiece 14 with respect to endpiece 12 to orient hole 27 with respect to components retained within endpiece 12, and in particular, to align hole 27 with an individual heat package 32. Baffle 25 diverts air flowing in the airway through hole 27. When a patient inhales on mouthpiece 14, air enters air inlet 16, passes through plurality of holes 63, is diverted by baffle 25 through hole 27, and exits the device through air outlet 18.
 Fig. 3 shows a cross-sectional view of an embodiment of heat package 32. Each heat package 32 includes a percussive igniter 40 and a heating element 39.
Percussive igniter 40 includes mechanically deformable tube 42, an anvil 44 coaxially disposed within deformable tube 42, and held in place by indentations 46. An initiator composition 48 is disposed on a region of anvil 44. When mechanically impacted with sufficient force, deformable tube 42 is deformed, compressing initiator composition 48 between deformable tube 42 and anvil 44 causing initiator composition 48 to deflagrate and eject sparks. The interior 52 of heating element 39 includes a fuel 50 capable of producing a rapid, high intensity heat impulse when ignited. Examples of appropriate fuels are disclosed herein. The exterior surface 54 of heating element 39 includes a thin film 56 of a drug or drug-containing composition. Deflagration of initiator composition 48 causes f-uel 50 to ignite. The heat generated by burning fuel 50 heats exterior surface 54 of heating element 39. The thermal energy from exterior surface 54 is transferred to and vaporizes thin film 56 of drug or drug containing composition from exterior surface 54. The drug vapor can condense in the air flow in device 10 (see Figs. 1-2) to form a drug aerosol.
 In Fig. 2, heat packages 32 are shown in an open configuration, meaning that there is not a feature separating each heat package 32 from adjacent heat packages.
Fig. 4 shows another embodiment of a multi-dose drug delivery device incorporating a plurality of heat packages. In Fig. 4, heat packages 32 are formed from a sealed, cylindrical enclosure. One end of each heat package 32 comprises a percussive igniter 110, and the opposing end comprises a heating element 111. Each heat package 32 is retained by mounting plate 55. Heating element 111 of each heat package 32 is disposed within cylindrical recess 60. Fig. 5 show more clearly the heat package 32 disposed witllin the cylindrical recess 50. Recesses 60 can prevent drug vaporized from a heat package 32 from depositing on an adjacent heat package. Preventing deposition of vaporized drug on adjacent heat packages can be useful for maintaining a consistent amount of drug aerosol generated for each actuation of the device, and/or can facilitate producing high purity aerosols.
 As shown in Fig. 2, endpiece 12 includes a base section 35 and a mounting section 37 which are fixedly connected to form a single unit. Base section 35 includes one or more air inlets 16, a revolver mechanism 38 configured to provide an impact force for activating the percussive igniters, and a manually actuated push-out switch 20. Air inlets 16 include one or more holes in one end of endpiece 12.
Revolver mechanism 38 includes a shaft on which is mounted a first torsion spring 41 and a second torsion spring 43. Torsion springs 41, 43 are wound around revolver mechanism 38, with a first end 45 fixed to shaft 38 and with a second end or striker arm 47 extending toward and capable of impacting the percussive igniters of heat packages 32. Push-out switch 20 including manual slide 49, compression spring 51 and engagement arm 53 is also incorporated into endpiece 12. Spring 51 maintains slide 20 in a pushed-in or non-actuated position. In a non-actuated position, striker arm 47 rests against a heat package 32 or a rest pin (not shown). Pushing out on slide 20 causes engagement arm to pull striker arm 47 off a heat package 32 so that striker arm 47 is free to impact the percussive igniter of a subsequent heat package.
 Actuation mechanisms other than the mechanical mechanism using torsion springs and a push-out switch can be used to provide a mechanical impact to activate a percussive igniter. Such actuation mechanisms include mechanical mechanisms, electrical mechanisms and inhalation mechanisms. Examples of other mechanical mechanisms include, but are not limited to, releasing a compression spring to impact the percussive igniter, releasing or propelling a mass to impact the percussive igniter, moving a lever to release a pre-stressed spring, and rotating a section of the device to stress and release a spring to impact a percussive igniter.
Regardless of the mechanism employed in a particular drug delivery device, the actuation mechanism will produce sufficient impact force to deform the outer wall of the percussive igniter, and cause the initiator composition to deflagrate.
 In certain embodiments, a drug delivery device can be a single dose device comprising a single heat package. In certain embodiments, wlierein a section comprising the one or more percussively ignited heat package, and a section comprising the actuation mechanism are separable by the user, when the one or more heat packages have been activated, a new section comprising unused heat packages with a drug coating can be inserted, and the section comprising the actuation mechanism reused. In certain embodiments, the one or more heat packages and actuation mechanisms can be provided as a single unit that is not designed to be separated by a user. In such embodiments, after the one or more doses have been activated, the entire device can be discarded.
Thus, in certain embodiments, the drug delivery device comprising a percussively activated heat package will comprise parts and materials that are low-cost and disposable.
 Figs. 6A- 6F show embodiments of heat packages comprising a percussive igniter. The heat packages 70 shown in Figs. 6A-6F substantially comprise a sealed tube or cylinder 76 having a first end 72 and a second end 74. For use in a portable medical device, it is important that a heat package remain sealed when ignited and withstand any internal pressure generated by the burning fuels. In Figs.
6A, and 6C-6F, first end 72 of heat package 70 is integral with the tubular body portion 76 or formed from the same part as tubular body portion 76. In Fig. 6B, first end 72 is a separate section and second end 74 is a separate section. Sections 72, 74 can be sealed at interface 78 by any appropriate means capable of withstanding the pressure and temperatures generated during combustion of the initiator and fuel compositions such as by soldering, welding, crimping, adhesively affixing, mechanically coupling, or the like.
Second end 74 can also be sealed by similar means, and in certain embodiments, can include an insert, which may be thermally conductive or non-conductive.
 Fig. 6A shows an embodiment of a heat package 70 having a coaxially positioned anvil 80 held in place by indentations 86, 87. Anvil 80 extends substantially the length of heat package 70. A thin coating of an initiator composition 82 is disposed toward one end of anvil 80, and a coating of a metal oxidation/reduction fuel composition 84 as disclosed herein is disposed on the other end of anvil 80. Indentations 87 provide space between anvil 80 and the inner wall of tube 70 to allow sparks produced during deflagration of initiator composition 82 to strike and ignite fuel composition 84. Anvil 80 can include features to facilitate retention of a greater amount of fuel and/or to facilitate assembly. For example, the end of anvil 80 on which fuel 84 is disposed can include fins or serrations to'increase the surface area.
 In Fig. 6C, anvil 100 comprises a fuel. Initiator composition 82 is disposed on part of the surface of anvil 100. Activation of initiator composition 82 can cause anvi1100 to ignite. End section 102 can be made of a thermally insulating material to facilitate mounting heat package 70. Use of a fuel extending substantially the length of the heat package can provide a larger usefully heated area.
space in center region 97 can provide a volume in which released gases can accumulate to reduce the internal pressure of heat package 70.
 Fig. 3, as discussed above, shows another embodiment of a heat package.
part of anvi144 is coated with an initiator composition 48. Second section 39 comprises an enclosure having a wall thickness and cross-sectional dimension greater than that of first section 40. Such a design may be useful to increase the amount of fuel, to increase the external surface area on which a substance can be disposed, to provide a volume in which gases can expand to thereby reduce the pressure within the enclosure, to provide a greater fuel surface area for increasing the burn rate, and/or to increase the structural integrity of first section 40. In Fig. 3, fuel 50 is shown as a thin layer disposed along the inner wall of second section 39. Other fuel configurations are possible. For example, the fuel can be disposed only along the horizontal walls, can completely or partially fill internal area 52, and/or be disposed within fibrous matrix disposed throughout area 52. It will be appreciated that the shape, structure, and composition of fuel 50 can be determined as appropriate for a particular application that, in part, can be determined by the thermal profile desired. Heat package 32 further includes a thin film of substance 56 disposed on the outer surface of second section 39.
 A heat package, such as shown in Fig. 3, and Figs. 6A-6F, can have any appropriate dimension which can at least in part be determined by the surface area intended to be heated and the maximum desired temperature. Percussively activated heat packages can be particularly useful as compact heating elements capable of generating brief heat impulses such as can be used to vaporize a drug to produce a condensation aerosol for inhalation. In such applications, the length of a heat package can range from 0.4 inches to 2 inches and have a diameter ranging from 0.05 inches to 0.2 inches. In certain embodiments the anvil can be coiled in which case the length of the anvil can vary to based on the tightness of the coil and length required to ignite the fuel.
The optimal dimensions of the anvil, the dimensions of the enclosed cylinder, and the amount of fuel disposed therein for a particular application and/or use can be determined by standard optimization procedures.
 Percussively activated initiator compositions are well known in the art.
Initiator compositions for use in a percussive ignition system will deflagrate when impacted to produce intense sparking that can readily and reliably ignite a fuel such as a metal oxidation-reduction fuel. For use in enclosed systems, such as for example, for use in heat packages, it can be useful that the initiator compositions not ignite explosively, and not produce excessive amounts of gas. Certain initiator compositions are disclosed in U.S. Patent Application No. 10/851,018 entitled "Stable Initiator Compositions and Igniters," filed May 20, 2004, the entirety of which is incorporated herein by reference.
Initiator compositions comprise at least one metal reducing agent, at least one oxidizing agent, and optionally at least one inert binder.
 In certain embodiments, an oxidizing agent can comprise oxygen, an oxygen based gas, and/or a solid oxidizing agent. In certain embodiments, an oxidizing agent can comprise a metal-containing oxidizing agent. Examples of metal-containing oxidizing agents include, but are not limited to, perchlorates and transition metal oxides.
oxides of tungsten, such as W03; oxides of magnesium, such as MgO; and oxides of niobium, such as Nb205. In certain embodiments, the metal-containing oxidizing agent can include more than one metal-containing oxidizing agent.
 In certain embodiments, a metal reducing agent and a metal-containing oxidizing agent can be in the form of a powder. The term "powder" refers to powders, particles, prills, flakes, and any other particulate that exhibits an appropriate size and/or surface area to sustain self-propagating ignition. For example, in certain embodiments, the powder can comprise particles exhibiting an average diameter ranging from 0.01 m to 200 m.
 In certain embodiments, the amount of oxidizing agent in the initiator composition can be related to the molar amount of the oxidizer at or near the eutectic point for the fuel compositions. In certain embodiments, the oxidizing agent can be the major component and in others the metal reducing agent can be the major component.
Also, as known in the art, the particle size of the metal and the metal-containing oxidizer can be varied to determine the bum rate, with smaller particle sizes selected for a faster burn (see, for example, PCT WO 2004/01396). Thus, in some embodiments where faster burn is desired, particles having nanometer scale diameters can be used.
 In certain embodiments, aluminum can be use-'d as a metal reducing agent. Aluminum can be obtained in various sizes such as nanoparticles, and can form a protective oxide layer and therefore can be commercially obtained in a dry state.
 In certain embodiments, the initiator composition can include more than one metal reducing agent. In such compositions, at least one of the reducing agents can be boron. Examples of initiator compositions comprising boron are disclosed in U.S.
Patent Nos. 4,484,960, and 5,672,843. Boron can enhance the speed at which ignition occurs and thereby can increase the amount of heat produced by an initiator composition.
can be titanium, zirconium, aluminum, boron or other metal, and colloidal particles based on transition metal hydroxides or oxides. Examples of binding agents include, but are not limited to, soluble silicates such as sodium-silicates, potassium-silicates, aluminum silicates, metal alkoxides, inorganic polyanions, inorganic polycations, inorganic sol-gel materials such as alumina or silica-based sols. Other useful additive materials include glass beads, diatomaceous earth, nitrocellulose, polyvinylalcohol, guar gum, ethyl cellulose, cellulose acetate, polyvinylpyrrolidone, fluoro-carbon rubber (Viton) and other polymers that can function as a binder. In certain embodiments, the initiator composition can comprise more than one additive material.
 In certain embodiments, additive materials can be useful in determining certain processing, ignition, and/or bum characteristics of an initiator composition. In certain embodiments, the particle size of the components of the initiator can be selected to tailor the ignition and burn rate characteristics as is known in the art, for example, as disclosed in U.S. Patent No. 5,739,460.
 In certain embodiments particularly appropriate for use in medical applications, it is desirable that the additive not be an explosive, as classified by the U.S.
Department of Transportation, such as, for example, nitrocellulose. In certain embodiments, the additives can be Viton, Laponite or glass filter. These materials bind to the components of an initiator composition and can provide mechanical stability to the initiator composition.
 The ratio of metal reducing agent to metal-containing oxidizing agent can be selected to determine the appropriate bum and spark generating characteristics. In certain embodiments, an initiator composition can be formulated to maximize the production of sparks having sufficient energy to ignite a fuel. Sparks ejected from an initiator composition can impinge upon the surface of a fuel, such as an oxidation/reduction fuel, causing the fuel to ignite in a self-sustaining exothermic oxidation-reduction reaction. In certain embodiments, the total amount of energy released by an initiator composition can range from 0.25 J to 8.5 J. In certain embodiments, a 20 m to 100 m thick solid film of an initiator composition can burn with a deflagration time ranging from 5 milliseconds to 30 milliseconds. In certain embodiments, a 40 m to 100 m thick solid film of an initiator composition can burn with a deflagration time ranging from 5 milliseconds to 20 milliseconds. In certain embodiments, a 40 m to 80 m thick solid film of an initiator composition can burn with a deflagration time ranging from 5 milliseconds to 10 milliseconds.
Al, 55.4% M O3, 8.9% B, and 1.8% nitrocellulose; 26.5% Al, 51.5% MoO3, 7.8% B, and 14.2% Viton; 47.6% Zr, 47.6% MoO3, and 4.8% Laponite, where all percents are in weight percent of the total weight of the composition.
boron, and 14-15% Viton, where all percents are in weight percent of the total weight of the composition. In certain embodiments, the aluminum, boron, and molybdenum trioxide are in the form of nanoscale particles. In certain embodiments, the Viton is Viton A500.
 In certain embodiments, the percussively activated initiator compositions can include compositions comprising a powdered metal-containing oxidizing agent and a powdered reducing agent comprising a central metal core, a metal oxide layer surrounding the core and a flurooalkysilane surface layer as disclosed, for example, in U.S. Patent No. 6,666,936.
 The fuel can comprise a metal reducing agent an oxidizing agent, such as, for example, a metal-containing oxidizing agent. In certain embodiments, the fuel can comprise a mixture of Zr and MoO3, Zr and Fe203, Al and MoO3, or Al and Fe203.
by with to 90% by weight, and the amount of metal containing oxidizing agent can range from 40% by weight to 10% by weight.
 Examples of useful metal reducing agents for forming a fuel include, but are not limited to, molybdenum, magnesium, calcium, strontium, barium, boron, titanium, zirconium, vanadium, niobium, tantalum, chromium, tungsten, manganese, iron, cobalt, nickel, copper, zinc, cadmium, tin, antimony, bismuth, aluminum, and silicon.
In certain embodiments, a metal reducing agent can be selected from aluminum, zirconium, and titanium. In certain embodiments, a metal reducing agent can comprise more than one metal reducing agent.
chromium, such as Cr03 and Cr203; manganese, such as Mn02; cobalt such as Co304; silver such as Ag20; copper, such as CuO; tungsten, such as W03; magnesium, such as MgO; and niobium, such as Nb205. In certain embodiments, the metal-containing oxidizing agent can include more than one metal-containing oxidizing agent.
 In certain embodiments, the metal reducing agent forming the solid fuel can be selected from zirconium and aluminum, and the metal-containing oxidizing agent can be selected from MoO3 and Fe203.
can be titanium, zirconium, aluminum, boron or otller metal, and colloidal particles based on transition metal hydroxides or oxides. Examples of binding agents include, but are not limited to, soluble silicates such as sodium-silicates, potassium-silicates, aluminum silicates, metal alkoxides, inorganic polyanions, inorganic polycations, inorganic sol-gel materials such as alumina or silica-based sols. Other useful additive materials include glass beads, diatomaceous earth, nitrocellulose, polyvinylalcohol, guar gum, ethyl cellulose, cellulose acetate, polyvinylpyrrolidone, fluoro-carbon rubber (VITON) and other polymers that can function as a binder.
 Other useful additive materials include glass beads, diatomaceous earth, nitrocellulose, polyvinylalcohol, and other polymers that may function as binders. In certain embodiments, the fuel can comprise more than one additive material.
The components of the fuel comprising the metal, oxidizing agent and/or additive material and/or any appropriate aqueous- or organic-soluble binder, can be mixed by any appropriate physical or mechanical method to achieve a useful level of dispersion and/or homogeneity. In certain embodiments, the fuel can be degassed.
 In certain embodiments the anvil can be formed from a combustible metal alloy or metal/metal oxide composition, such as are known in the art, for example, PYROFUZE. Examples of fuel compositions suitable for forming the anvil are disclosed in U.S. Patent Nos, 3,503,814; 3,377,955; and PCT Application No. WO 93/14044, the pertinent parts of each of which are incorporated herein by reference.
 In certain embodiments, the fuel can be supported by a malleable fibrous matrix which can be packed into the heat package. The fuel comprising a metal reducing agent and a metal-containing oxidizing agent can be mixed with a fibrous material to form a malleable fibrous fuel matrix. A fibrous fuel matrix is a convenient fuel form that can facilitate manufacturing and provides faster bum rates. A fibrous fuel matrix is a paper-like composition comprising a metal oxidizer and a metal-containing reducing agent in powder form supported by an inorganic fiber matrix. The inorganic fiber matrix can be formed from inorganic fibers, such as ceramic fibers and/or glass fibers. To form a fibrous fuel, the metal reducing agent, metal-containing oxidizing agent, and inorganic fibrous material are mixed together in a solvent, and formed into a shape or sheet using, for example, paper-making equipment, and dried. The fibrous fuel can be formed into mats or other shapes as can facilitate manufacturing and/or burning.
 In certain embodiments, a substance disposed on a heat package can comprise a therapeutically effective amount of at least one physiologically active compound or drug. A therapeutically effective amount refers to an amount sufficient to effect treatment when administered to a patient or user in need of treatment.
Treating or treatment of any disease, condition, or disorder refers to arresting or ameliorating a disease, condition or disorder, reducing the risk of acquiring a disease, condition or disorder, reducing the development of a disease, condition or disorder or at least one of the clinical symptoms of the disease, condition or disorder, or reducing the risk of developing a disease, condition or disorder or at least one of the clinical symptoms of a disease or disorder. Treating or treatment also refers to inhibiting the disease, condition or disorder, either physically, e.g. stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both, and inhibiting at least one physical parameter that may not be discernible to the patient. Further, treating or treatment refers to delaying the onset of the disease, condition or disorder or at least symptoms thereof in a patient which may be exposed to or predisposed to a disease, condition or disorder even though that patient does not yet experience or display symptoms of the disease, condition or disorder.
 In certain embodiments, the amount of substance disposed on a support can be less than 100 micrograms, in certain embodiments, less than 250 micrograms, and in certain embodiments, less than 1,000 micrograms, and in other embodiments, less than 3,000 micrograms. In certain embodiments, the thickness of a thin film applied to a heat package can range from 0.01 m to 20 m, and in certain embodiments can range from 0.5 m to 10 m.
 While it will be recognized that extent and dynamics of thermal degradation can at least in part depend on a particular compound, in certain embodiments, thennal degradation can be minimized by rapidly heating the substance to a temperature sufficient to vaporize and/or sublime the active substance. In certain embodiments, the substrate can be heated to a temperature of at least 250 C in less than 500 msec, in certain embodiments, to a temperature of at least 250 C in less than 250 msec, and in certain embodiments, to a temperature of at least 250 C in less than 100 msec.
 Examples of drugs that can be vaporized from a heated surface to form a high purity aerosol include albuterol, alprazolam, apomorphine HCI, aripiprazole, atropine, azatadine, benztropine, bromazepam, brompheniramine, budesonide, bumetanide, buprenorphine, butorphanol, carbinoxamine, chlordiazepoxide, chlorpheniramine, ciclesonide, clemastine, clonidine, colchicine, cyproheptadine, diazepam, donepezil, eletriptan, estazolam, estradiol, fentanyl, flumazenil, flunisolide, flunitrazepam, fluphenazine, fluticasone propionate, frovatriptan, galanthamine, granisetron, hydromorphone, hyoscyamine, ibutilide, ketotifen, loperamide, melatonin, metaproterenol, methadone, midazolam, naratriptan, nicotine, oxybutynin, oxycodone, oxymorphone, pergolide, perphenazine, pindolol, pramipexole, prochlorperazine, rizatriptan, ropinirole, scopolamine, selegiline, tadalafil, terbutaline, testosterone, tetrahydrocannabinol, tolterodine, triamcinolone acetonide, triazolam, trifluoperazine, tropisetron, zaleplon, zolmitriptan, and zolpidem. These drugs can be vaporized from a thin film having a thickness ranging from 0.1 m to 20 m, and corresponding to a coated mass ranging from 0.2 mg to 40 mg, upon heating the thin film of drug to a temperature ranging from 250 C to 550 C within less than 100 msec, to produce aerosols having a drug purity greater than 90% and in many cases, greater than 99%.
 At 25 C, nicotine is a colorless to pale yellow volatile liquid.
Nicotine has a melting point of -79 C, a boiling point at 247 C, and a vapor pressure of 0.0425 m.inHg. The liquid nature prevents formation of stable films and the high vapor pressure can result in evaporation during shelf-life storage. While various approaches for preventing nicotine evaporation and degradation during shelf-life storage have been considered, for example, delivery from a reservoir via ink jet devices, chemical encapsulation of nicotine as a cyclodextrin complex, and nicotine containment in blister packs, such implementations have not been demonstrated to be amendable to low-cost manufacturing.
volatile compound, such as nicotine, can form a complex with a metal or metal-containing complex to form a metal coordination complex of the compound. The metal coordination complex can include other ligands in addition to the volatile compound. The metal coordination complex comprising the volatile compound can be stable at standard temperature, pressure and environmental conditions. The metal coordination complex can be suspended or dissolved in a solvent, and the suspension or solution applied or deposited onto a substrate. After removing the solvent, a thin film of the metal coordination complex comprising the compound remains on the substrate. When complexed, the compound is stable such that the compound will not volatilize or degrade under standard conditions, and can be selectively volatilized when heated.
 Appropriate metals and metal-containing compounds for forming thin films of volatile organic compounds are (i) capable of forming a stable composition at standard temperatures, pressures, and environmental conditions; (ii) capable of selectively releasing the volatile organic compound at a temperature that does not degrade, appreciably volatize, or react the metal-containing compound; (iii) capable of forming a complex with the volatile organic compound which is soluble in at least one organic solvent; and (iv) capable of releasing the volatile organic compound without appreciable degradation of the organic compound. In certain embodiments, the metal coordination complex comprises at least one metal salt. In certain embodiments, the at least one metal salt is selected from a salt of Zn, Cu, Fe, Co, Ni, Al, and mixtures thereof.
In certain embodiment, the metal salt comprises zinc bromide (ZnBr2).
 In certain embodiments, a stabilized, volatile organic compound such as a drug can be selectively volatilized from a metal coordination complex when heated to a temperature ranging from 100 C to 600 C, and in certain embodiments can be selectively volatilized when heated to temperature ranging from 100 C to 500 C., in other embodiments it can be selectively volatilized when heated to temperature ranging from 100 C to 400 C. As used herein, "selectively vaporize" refers to the ability of the organic compound to be volatilized from the complex, while the metal and/or metal-containing compound is not volatilized, does not degrade to form volatile products, and/or does not react with the organic compound to form volatile reaction products comprising components derived from the metal-containing compound. Use of the term "selectively vaporize" includes the possibility than some metal-containing compound, degradation product, and/or reaction product may be volatilized at a temperature which "selectively vaporizes" the organic complex. However, the amount of metal-containing compound, degradation product, and/or reaction product will not be appreciable such that a high purity of organic compound aerosol is produced, and the amount of any metal-containing compound and/or derivative thereof is within FDA guidelines.
 Metal coordination complexes of zinc bromide (ZnBr2) and nicotine were prepared and evaluated. ZnBr2 is an off-white solid having a melting point of 394 C, a boiling point of 650 C, and a decomposition temperature of 697 C. ZnBr2 is stable under normal temperatures and pressures. The (nicotine)2-ZnBr2 metal salt complex was prepared as disclosed herein. The (nicotine)2-ZnBr2 metal salt complex is a solid with a melting point of 155 C.
 The nicotine aerosol yield was determined by measuring the amount of nicotine in the aerosol produced by vaporizing thin films of the (nicotine)2-ZnBr2 complex. Thin film coatings of (nicotine)2-ZnBr2 having a thickness of 2 m or 6 m were prepared as disclosed herein. The amount of nicotine comprising a 2 m, and 6 m thin film of (nicotine)2-ZnBr2 was about 1.17 mg and about 3.5 mg, respectively. The metal foil substrate on which a thin film of (nicotine)2-ZnBr2 was disposed, was positioned within an airflow of about 20 L/min. Films were heated to a maximum temperature of 300 C, 350 C, 400 C or 500 C within less than about 200 msec, by applying a current to the metal foil substrate. The aerosol produced during selective vaporization of the (nicotine)2-ZnBr2 film was collected on an oxalic acid coated filter, and the amount of collected nicotine determined by high pressure liquid chromatography.
The percent nicotine yield in the aerosol was the amount of nicotine collected on the filter as determined by HPLC divided by the amount of nicotine in the thin film deposited on the metal foil substrate.
when the metal foil was heated to a maximum temperature of 300 C, and increased to about 73 1 percent when the metal foil was heated to a maximum temperature of 400 C.
 The purity of nicotine in an aerosol produced by vaporizing thin films of (nicotine)2-ZnBr2 was also determined. The percent purity of nicotine in the aerosol was determined by comparing the area under the curve representing nicotine with the area under the curve for all other components separated by HPLC. As shown in Fig.
and about 99.99 %, respectively. The nicotine purity of the aerosol decreased when the thin film of (nicotine)2-ZnBr2 was heated to a maximum temperature of greater than 300 C.
Also, for a given vaporization temperature, the purity of the nicotine aerosol derived from a 6 m thick thin film of (nicotine)2-ZnBr2 was greater than the purity of the nicotine aerosol derived from a 2 m thick solid film of (nicotine)2-ZnBr2.
 Metal coordination complexes can be used to stabilize volatile compounds such as nicotine for use in drug delivery devices as disclosed herein. A metal coordination complex comprising a drug can be applied as a thin film to the exterior surface of a percussively activated heat package. For example, a metal coordination complex comprising a drug can be applied to element 30 of Fig. 2 or element 111 of Fig.
4. Activation of a percussive igniter can ignite a fuel and heat the exterior surface of the heat package and the thin film of a metal coordination complex comprising the drug. The drug can then be selectively vaporized from the metal coordination complex.
Thin films of metal coordination complexes comprising drugs and/or other volatile compounds can be used in other drug delivery devices. For example, in certain embodiments, thin films of metal coordination complexes can be used in drug delivery devices in which a resistively heat metal foil as disclosed in U.S. Application No. 10/861,554 is used to heat a thin solid film disposed thereon. In certain embodiments, thin films of metal coordination complexes can be used in drug delivery devices in which an electrically resistive heating element is used to ignite a spark-generating initiator composition, which when activated, ignites a metal oxidation/reduction fuel as disclosed in U.S.
 In certain embodiments, thin films of a metal coordination complex of a drug can be used to provide multiple doses of a drug provided on a spool or reel of tape.
For example, a tape can comprise a plurality of drug supply units with each drug supply unit comprising a heat package on which a thin film comprising a metal coordination complex comprising a drug is disposed. Each heat package can include an initiator composition that can be ignited, for example, by resistive heating or percussively, and a fuel capable of providing a rapid, high temperature heat impulse sufficient to selectively vaporize the drug from the metal coordination complex. Each heat package can be spaced at intervals along the length of the tape. During use, one or more heat packages can be positioned within an airway and, while air is flowing through the airway, the heat package can be activated to selectively vaporize the drug from the metal coordination complex. The vaporized drug can condense in the air flow to form an aerosol comprising the drug which can then be inhaled by a user. The tape can comprise a plurality of thin films that define the regions where the initiator composition, fuel, and thin film comprising a drug are disposed. Certain of the multiple layers can further provide unfilled volume for released gases to accumulate to minimize pressure buildup.
The plurality of layers can be formed from any material which can provide mechanical support and that will not appreciably chemically degrade at the temperatures reached by the heat package. In certain embodiments, a layer can comprise a metal or a polymer such as polyimide, fluoropolymer, polyetherimide, polyether ketone, polyether sulfone, polycarbonate, or other high temperature resistance polymers. In certain embodiments, the tape can further comprise an upper and lower layer configured to physically and/or environmentally protect the drug or metal coordination complex comprising a drug. The upper and/or lower protective layers can comprise, for example, a metal foil, a polymer, or can comprise a multilayer comprising metal foil and polymers. In certain embodiments, protective layers can exhibit low permeability to oxygen, moisture, and/or corrosive gases. All or portions of a protective layer can be removed prior to use to expose a drug and fuel. The initiator composition and fuel composition can comprise, for example, any of those disclosed herein. Thin film heat packages and drug supply units in the form of a tape, disk, or other substantially planar structure, can provide a compact and manufacturable method for providing a large number of doses of a substance.
Providing a large number of doses at low cost can be particularly useful in certain therapies, such as for example, in administering nicotine for the treatment of nicotine craving and/or effecting cessation of smoking.
 Fig. 10 illustrates a certain embodiment of a drug supply unit configured for use in a drug delivery device designed for multiple uses using a spool or reel of tape.
As shown in Fig. 10, a tape 406 in the form of a spool or reel 400 comprises a plurality of drug supply units 402, 404. The plurality of drug supply units 402, 404 can comprise a heating unit on which is disposed a thin film of a drug or a drug/complex to be thermally vaporized. Covering the thin film is a fine mesh 407 e.g., metal wire, to hold or retain the drug and/or drug complex on the heating unit. The complex can have adhesion difficulties particularly at thick film thicknesses, the use of the mesh can help prevent flaking or dissociation of the drug complex from the surface of the tape or reel The mesh can be a layer the covers the length of the tape 406 or separate units of mesh to cover each area of drug film. Each of the plurality of drug supply units 402, 404 can comprise the same features as those described herein. In certain embodiments, tape 406 can comprise a plurality of heating units. Each heating unit can comprise a solid fuel and an initiator composition adjacent to the solid fuel, which upon striking of the initiator composition can cause the initiator composition to spark and ignite the fuel, resulting in vaporization of the drug. The tape can be advanced in a device using a reel mechanism (not shown) and a spring or other mechanism can be used to actuate the initiator composition by striking.
Examples  Embodiments of the present disclosure can be further defined by reference to the following examples, which describe in detail preparation of the compounds of the present disclosure. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, may be practiced without departing from the scope of the present disclosure.
Example 1 Preparation of Solid Thin Films of Nicotine Metal Coordination Complexes  A solution of 2% oxalic acid was prepared by dissolving 20 g of oxalic acid in 1 L of acetone. Glass fiber filters (Whatman) were coated with oxalic acid by dipping the filters in the 2% oxalic acid solution for about 10 seconds. The oxalic acid coated filters were air dried.
 A(nicotine)2-ZnBr2(5) complex was prepared by first dissolving solid ZnBr2 in ethanol to form a 1 M solution. A 2M nicotine solution was prepared by suspending nicotine in ethanol. The ZnBr2 and nicotine solutions were combined and mixed. The resulting solid complex was repeatedly washed with methanol using vacuum filtration, and subsequently dried. The molar ration of nicotine to ZnBr2 in the nicotine-ZnBr2 complex was 2:1.
 To coat metal foils, the (nicotine)2-ZnBr2 complex was dissolved in chloroform. The (nicotine)2-ZnBr2 complex was hand coated onto 0.005 inch thick stainless foils. The coatings were dried under vacuum for about 1 hour at 25 C. The coatings of (nicotine)2-ZnBr2 complex were stored in a vacuum and protected from light prior to use.
TFA. The purities of the extracts were determined using high pressure liquid chromatography and are shown in Fig. 9. A Varian HPLC system having a single XTerra RP 18, 4.6 x mm column, with an eluant solution comprising a 75% aqueous phase of perchloric acid solution with one ampoule of 1-octanesulfonic acid sodium salt concentrate at pH 2, and a 25% organic phase of acetonitrile was used. The HPLC was performed under isocratic run conditions for 20 minutes.
oxalic acid solution for about 10 seconds. The oxalic acid coated filters were air dried overnight.
 A(nicotine)a-ZnBr2(s) complex was prepared by first dissolving solid ZnBr2 in ethanol to form a 1 M solution. A 2M nicotine solution was prepared by suspending nicotine in ethanol. The ZnBr2 and nicotine solutions were combined and mixed. The resulting solid complex was repeatedly washed with methanol using vacuum filtration, and subsequently dried. The molar ration of nicotine to ZnBr2 in the nicotine-ZnBr2 complex was 2:1.
(nicotine)2-ZnBr2 complex solution was coated onto both sides of an area of 1.27 cm x 2.3 cm of stainless steel. This corresponds to a 6 m film thickness coating which contained about 3.5 mg of nicotine The coatings were dried under vacuum for about 1 hour at 25 C. The coatings of (nicotine)2-ZnBr2 complex were stored in a vacuum for at least 30 minutes and protected from light prior to use.
 The coatings of (nicotine)2-ZnBr2 complex were vaporized by applying a current of 13.OV to the metal foil sufficient to heat the coatings to temperature of 350 C.
The aerosol formed by vaporizing the coating in an air flow of 28.3 L/min was analyzed by collected the aerosol on oxalic acid coated filters using an 8 stage Anderson impactor.
The MMAD of the nicotine aerosol from the 2 m thick (nicotine)2-ZnBr2 complex was determined to be 2.00. Likewise, the MMAD of the nicotine aerosol from the 6 m thick (nicotine)2-ZnBr2 complex was determined to be 1.79. After vaporization the filters were extracted with 5 mL of 0.1 % trifluoroacetic acid / DI H20 and analyzed by HPLC. The purity of the nicotine aerosol from the 2 m thick (nicotine)2-ZnBr2 complex was determined to be greater than 97%. Whereas the purity of the the nicotine aerosol from the 6 m thick (nicotine)2-ZnBr2 complex was determined to be greater than 97%.
Example 3 Preparation of Initiator Composition for Percussive Heat Packages  An initiator composition was formed by combining 620 parts by weight of titanium having a particle size less than 20 urn, 100 parts by weight of potassium chlorate, 180 parts by weight red phosphorous, 100 parts by weight sodium chlorate, and 620 parts by weight water, and 2% polyvinyl alcohol binder.
for about 1 hour. The dried, coated wire anvil was inserted into a 0.003 inch thick or 0.005 inch thick, soft walled aluminum tube that was about 1.65 inches long with an outer diameter of 0.058 inches. The tube was crimped to hold the wire anvil in place and sealed with epoxy.
 In the other end of the aluminum tube was placed the fuel. In order to form a mat of heating powder fuel using glass fiber as the binder, 1.3 grams of glass fiber filter paper was taken and added to about 50 mL of water with rapid stirring.
After the glass fiber had separated and become suspended in the water, 6 g of MoO3 was added.
This was followed with the addition of 3.8 g of Zr (3 m). After stirring for 30 min, at room temperature the mixture was filtered on standard filter paper and the resulting mat dried at high vacuum at 60 C. A 0.070 inch thick mat was formed which rapidly burns.
After manually packing the fuel in the end of the heat package that did not contain the anvil, the fuel end of the soft walled aluminum tube was sealed.
 In other embodiments, the fuel was packed into a 0.39 inch length of aluminum sleeve having a 0.094in outer diameter and inserted over a soft walled aluminum tube (0.003 inch thick or 0.0005 inch thick) that was about 1.18 inches long with an outer diameter of 0.058 that was sealed at one end and had a dried coated wire anvil inserted. The fuel coated aluminum sleeve was sealed until the soft walled aluminum tube by crimping.
19.04% MoO3 : 4.8% Laponite RDS.
of the wet Zr was dispensed into a 50 mL centrifuge tube and centrifuged (Sorvall 6200RT) for 30 minutes at 3,200 rpm. The DI water was removed to leave a wet Zr pellet.
 To prepare a 15% Laponite RDS solution, 85 grams of DI water was added to a beaker. While stirring, 15 grams of Laponite RDS (Southern Clay Products, Gonzalez, TX) was added, and the suspension stirred for 30 minutes.
 The reactant slurry was prepared by first removing the wet Zr pellet as previously prepared from the centrifuge tube and placed in a beaker. Upon weighing the wet Zr pellet, the weight of dry Zr was determined from the following equation: Dry Zr (g) = 0.8234 (Wet Zr (g)) - 0.1059.
Ultra-Turrax mixing motor with a S25N-8G dispersing head (setting 4). The amount of 15% Laponite RDS previously determined was then added to the reactant slurry, and mixed for an additional 5 minutes using the IKA Ultra-Turrax mixer. The reactant slurry was transferred to a syringe and stored for at least 30 minutes prior to coating.
 The Zr : MoO3 : Laponite RDS reactant slurry was then deposited into the heat packages and allowed to dry.
Example 5 Generation of an Alnrazolam Aerosol using Vaporization from a Percussively I2nited Heat Package  On an assembled heat package was coated manually a solution of alprazolam in dichloromethane using a syringe to apply the coating solution to the end of the heat package containing the fuel (full length of heat package was 1.18 in., drug coated length of the heat package was about 0.39 in). Two to three microliters of solution containing the alprazolam were applied to coat 0.125 mg of alprazolam at a film thickness of 1.58 m. The coated heat package was dried for at least 30 minutes inside a fume hood. The last traces of solvent were removed in vacuo for 30 minutes prior to vaporization experiments.
membrane filter (25 mm diameter, 1 m pore size, Pall Life Sciences) mounted in a Delrin filter (25mm) holder (Pall Life Sciences). The filter was extracted with 1m1 of acetonitrile (HPLC grade). The filter extract was analyzed by high performance liquid chromatography (HPLC) using a C-18 reverse phase column (4.6 mm ID x 150 mm length, 5 m packing, "Capcell Pak UG120," Shiseido Fine Chemicals, Tokyo, Japan).
with a recovered yield of 100%. To increase the purity of the aerosol, one can use lower temperatures for vaporization.
Example 6 Generation of a Pramipexole Aerosol using Vaporization from a Percussively Iiinited Heat Package  On an assembled heat package was coated manually a solution of pramipexole in methanol using a syringe to apply the coating solution to the end of the heat package containing the fuel (full length of heat package was 1.18 in., drug coated length of the heat package was about 0.39 in). Two to three microliters of solution containing the pramipexole were applied to coat 0.500 mg of pramipexole at a film thickness of 6.33 m. The coated heat package was dried for at least 30 minutes inside a fume hood. The last traces of solvent were removed in vacuo for 30 minutes prior to vaporization experiments.
membrane filter (25 mm diameter, 1 m pore size, Pall Life Sciences) mounted in a Delrin filter (25mm) holder (Pall Life Sciences). The filter was extracted with Iml of acetonitrile (HPLC grade). The filter extract was analyzed by high performance liquid chromatography (HPLC) using a C-18 reverse phase column (4.6 mm ID x 150 mm length, 5 m packing, "Capcell Pak UG120," Shiseido Fine Chemicals, Tokyo, Japan).
For pramipexole; a binary mobile phase of eluant A(10mM NH4HCO3 in water) and eluant B(10mM NH4HCO3 in methanol) was used with a 5-95% linear gradient of B(29 min) at a flow rate of 0.9mL/min. Detection was at 200-400 nm using a photodiode array detector. Purity was calculated by measuring peak areas from the chromatogram.
The purity of the resultant aerosol was determined to be 98.8% with a recovered yield of 95.6%. To increase the purity of the aerosol, one can use lower temperatures for vaporization.
Example 7 Generation of a Ciclesonide Aerosol using Vaporization from a Percussively Ignited Heat PackaLye  On an assembled heat package was coated manually a solution of ciclesonide in chloroform using a syringe to apply the coating solution to the end of the heat package containing the fuel (full length of heat package was 1.18 in., drug coated length of the heat package was about 0.39 in). Two to three microliters of solution containing the ciclesonide were applied to coat 0.200 mg of ciclesonide at a film thickness of 2.53 m. The coated heat package was dried for at least 30 minutes inside a fume hood. The last traces of solvent were removed in vacuo for 30 minutes prior to vaporization experiments.
B linear gradient (24 min) at a flow rate of 1 mL/min. Detection was at 200-400 nm using a photodiode array detector. Purity was calculated by measuring peak areas from the chromatogram. The purity of the resultant aerosol was determined to be 85.6%.
To increase the purity of the aerosol, one can use lower temperatures for vaporization Example 8 Firing of Pyrofuze as Fuel using Percussive Ignition  Rather than packing the heat packages with a fuel, the feasibility of using a wire as the fuel was determined.
and a mechanism configured to impact the at least one percussively activated heat package.
a percussive initiator composition disposed within the enclosure, wherein the initiator composition is configured to be ignited when the deformable region of the enclosure is deformed; and a fuel disposed within the enclosure configured to be ignited by the initiator composition.
4. The drug delivery device of claim 2, wherein the drug is disposed on a surface of the heat package as a thin film.
5. The drug delivery device of claim 4, wherein the thickness of the thin film ranges from 0.01 µm to 20 µm.
6. The drug delivery device of claim 4, wherein the thickness of the thin film ranges from 0.5 µm to 10 µm.
7. The drug delivery device of claim 2, wherein the drug is vaporized when heated to a temperature of at least 250 °C.
8. The drug delivery device of claim 2, wherein the drug is selected from at least one of the following: albuterol, alprazolam, apomorphine HC1, aripiprazole, atropine, azatadine, benztropine, bromazepam, brompheniramine, budesonide, bumetanide, buprenorphine, butorphanol, carbinoxamine, chlordiazepoxide, chlorpheniramine, ciclesonide, clemastine, clonidine, colchicine, cyproheptadine, diazepam, donepezil, eletriptan, estazolam, estradiol, fentanyl, flumazenil, flunisolide, flunitrazepam, fluphenazine, fluticasone propionate, frovatriptan, galanthamine, granisetron, hydromorphone, hyoscyamine, ibutilide, ketotifen, loperamide, melatonin, metaproterenol, methadone, midazolam, naratriptan, nicotine, oxybutynin, oxycodone, oxymorphone, pergolide, perphenazine, pindolol, pramipexole, prochlorperazine, rizatriptan, ropinirole, scopolamine, selegiline, tadalafil, terbutaline, testosterone, tetrahydrocannabinol, tolterodine, triamcinolone acetonide, triazolam, trifluoperazine, tropisetron, zaleplon, zolmitriptan, and zolpidem.
9. The drug delivery device of claim 2, wherein the drug is selected from the group consisting of nicotine, pramipexole, and a respiratory steroid.
10. The drug delivery device of claim 9, wherein the respiratory steroid is selected from budesonide, ciclesonide, fluisolide, fluticasone propionate, and triamcinolone acetonide.
11. The drug delivery device of claim 2, wherein the mechanism configured to impact is actuated mechanically, electrically, or by inhalation.
a mechanism coupled to the airflow sensitive actuator configured to activate the heat package; and wherein the heat package is activated by an airflow in the airway produced by inhaling through the mouthpiece.
a pre-stressed spring disposed within the housing configured to impact the percussively activated heat package when released; and a lever rotatably coupled to the diaphragm and the housing, which upon rotation, releases the spring to impact the percussively activated heat package, wherein the heat package is activated by an airflow in the airway, produced by inhaling through the mouthpiece.
and a lever coupled to the switch, which upon actuation, releases the spring to impact the percussively activated heating element.
a lever coupled to the switch, which upon actuation, releases the spring, propelling the mass to impact the percussively activated heat package.
16. The drug delivery device of claim 11, wherein the mechanically actuated mechanism configured to impact comprises a mass configured to impact the percussively activated heat package.
17. The drug delivery device of claim 11, wherein the mechanically actuated mechanism configured to impact comprises a rotatable sleeve that stresses and releases a spring when rotated.
18. The drug delivery device of claim 4, wherein the thin film comprises a metal coordination complex of a drug.
19. The drug delivery device of claim 18, wherein the metal coordination complex comprises at least one metal salt and at least one drug.
20. The drug delivery device of claim 19, wherein the at least one metal salt is selected from a salt of Zn, Cu, Fe, Co, Ni, Al, and mixtures thereof.
21. The drug delivery device of claim 18, wherein the solid thin film comprises a metal coordination complex of zinc bromide and nicotine.
22. The drug delivery device of claim 21, wherein the ratio of zinc bromide to nicotine is about 1: 2.
23. The drug delivery device of claim 18, wherein the metal coordination complex is soluble in at least one organic solvent.
24. The drug delivery device of claim 18, wherein the drug is selectively vaporizable from the metal coordination complex when the metal coordination complex comprising the drug heated to a temperature ranging from 100 °C to 500 °C.
25. The drug delivery device of claim 15, wherein the at least one drug is selected from nicotine, pramipexole, budesonide, cicliesonide, flunisolide, flutuicasone propionate, and triamcinolone acetonide.
26. The drug delivery device of claim 2, wherein an aerosol comprising the drug is formed in the airway when the heat package is activated.
27. The drug delivery device of claim 26, wherein the vapor purity of the drug forming the aerosol is at least 95%.
28. The drug delivery device of claim 2, wherein an air flow through the airway ranges from 10 L/min to 200 L/min.
29. The drug delivery device of claim 2, wherein the device comprises a plurality of percussively activated heat packages.
30. The drug delivery device of claim 30, wherein each of the plurality of heat packages is disposed within a recess.
31. The drug delivery device of claim 30, wherein the device further comprises a mechanism configured to advance actuation to an unactivated heat package.
a mechanical mechanism configured to advance actuation to an unactivated heat package; and a mechanically actuated mechanism configured to impact the at least one percussively activated heat package.
33. The device of claim 32, wherein the air outlet has a cross sectional area between about .01 in2 to 1.5 in2.
34. The device of claim 33, wherein an air flow through the airway ranges from L/min to 200 L/min.
35. The device of claim 32, wherein the device comprises at least five percussively activated heat packages.
36. The device of claim 35, wherein the device comprises at least ten percussively activated heat packages.
37. The drug delivery device of claim 32, wherein each heat package is disposed within a recess.
40. The drug delivery device of claim 32, wherein the mechanically actuated mechanism configured to impact comprises a mass configured to impact the percussively activated heat package.
41. The drug delivery device of claim 32, wherein the mechanically actuated mechanism configured to impact comprises a rotatable sleeve that stresses and releases a spring when rotated.
42. The drug delivery device of claim 32, wherein the drug disposed on the percussively activated heat packages is disposed as a thin film.
43. The drug delivery device of claim 42, wherein the thin film comprises a metal coordination complex of a drug.
44. The drug delivery device of claim 43, wherein the metal coordination complex comprises at least one metal salt and at least one drug.
45. The drug delivery device of claim 44, wherein the at least one metal salt is selected from a salt of Zn, Cu, Fe, Co, Ni, Al, and mixtures thereof.
46. The drug delivery device of claim 42, wherein the thin film comprises a metal coordination complex of zinc bromide and nicotine.
47. The drug delivery device of claim 46, wherein the ratio of zinc bromide to nicotine is about 1: 2.
48. The drug delivery device of claim 32, wherein the at least one drug is selected from at least one of the following: albuterol, alprazolam, apomorphine HCl, aripiprazole, atropine, azatadine, benztropine, bromazepam, brompheniramine, budesonide, bumetanide, buprenorphine, butorphanol, carbinoxamine, chlordiazepoxide, chlorpheniramine, ciclesonide, clemastine, clonidine, colchicine, cyproheptadine, diazepam, donepezil, eletriptan, estazolam, estradiol, fentanyl, flumazenil, flunisolide, flunitrazepam, fluphenazine, fluticasone propionate, frovatriptan, galanthamine, granisetron, hydromorphone, hyoscyamine, ibutilide, ketotifen, loperamide, melatonin, metaproterenol, methadone, midazolam, naratriptan, nicotine, oxybutynin, oxycodone, oxymorphone, pergolide, perphenazine, pindolol, pramipexole, prochlorperazine, rizatriptan, ropinirole, scopolamine, selegiline, tadalafil, terbutaline, testosterone, tetrahydrocannabinol, tolterodine, triamcinolone acetonide, triazolam, trifluoperazine, tropisetron, zaleplon, zolmitriptan, and zolpidem.
49. The drug delivery device of claim 32, wherein the at least one drug is selected from the group consisting of nicotine, pramipexole, and a respiratory steroid.
50. The drug delivery device of claim 49, wherein the respiratory steroid is selected from budesonide, ciclesonide, fluisolide, fluticasone propionate, and triamcinolone acetonide.
51. The drug delivery device of claim 32, wherein the at least one drug is selected from nicotine, pramipexole, budesonide, cicliesonide, flunisolide, flutuicasone propionate, and triamcinolone acetonide.
wherein the percussively activated heat package vaporizes the at least one drug to form an aerosol comprising the drug in the airway which is inhaled by the patient.
a thin film comprising at least one drug disposed on each of the percussively activated heat packages; and a manually operated switch coupled to at least one spring configured to impact at least one percussively activated heat package disposed within the airway, wherein when actuated, the drug is vaporized to form an aerosol comprising the drug in the airway.
54. A method of treating nicotine craving and effecting smoking cessation by administering a condensation aerosol comprising nicotine.
55. The method of claim 54, wherein the nicotine aerosol is provided by a drug delivery device comprising a percussively activated heat package.
56. The method of claim 54, wherein the nicotine aerosol is formed by selectively vaporizing nicotine from a thin film comprising metal coordination complex of nicotine.
57. A thin film comprising a metal coordination complex comprising a volatile compound, and which is selectively vaporizable from the metal coordination complex when heated.
58. The thin film of claim 57, wherein the thin film comprises a metal coordination complex of a drug.
59. The thin film of claim 58, wherein the metal coordination complex comprises at least one metal salt and at least one drug.
60. The thin film of claim 59, wherein the at least one metal salt is selected from a salt of Zn, Cu, Fe, Co, Ni, Al, and mixtures thereof.
61. The thin film of claim 58, wherein the drug is selected from the group consisting of nicotine, pramipexole, budesonide, cicliesonide, flunisolide, flutuicasone propionate, and triamcinolone acetonide.
62. The thin film of claim 58, wherein the thin film comprises a metal coordination complex of zinc bromide and nicotine.
64. The thin film of claim 58, wherein the metal coordination complex is soluble in at least one organic solvent.
65. The thin film of claim 58, wherein the drug is selectively vaporizable from the metal coordination complex when the metal coordination complex comprising the drug heated to a temperature ranging from 100 °C to 500 °C.
66. The thin film of claim 58, wherein the thickness of the thin film ranges from 0.01 µm to 20 µm.
67. The thin film of claim 58, wherein the thickness of the thin film ranges from 0.5 µin to 10 µm.
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