Aerosol delivery systems

Abstract

Nicotine delivery devices and systems, particularly smoking cessation systems are provided by the present disclosure. Such devices and systems produce a nicotine-containing aerosol for inhalation that mimics smoking. The devices are capable of being adapted to control the amount of nicotine delivered to taper the amount of nicotine delivered to the user over time. Methods for treating patients to stop smoking are also disclosed. The devices, systems and methods can also be used to deliver other drugs disclosed herein, such as opioids (e.g., fentanyl).

Description

AEROSOL DELIVERY SYSTEMSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial Nos. 63 / 523,261 filed on June 26, 2023 and 63 / 545,753 filed on October 26, 2023, which are incorporated herein by reference in their entireties to the full extent permitted by law.TECHNICAL FIELD

[0002] The present disclosure relates to methods and devices for inhalation drug delivery. Preferred devices are inhalation systems which create an experience that is similar to smoking and include, but are not limited to, devices with arrays of nozzles for forming a nicotine containing aerosol. Preferably, the inhalation systems control the amount of nicotine delivered by reducing it essentially to zero over a predetermined amount of time.BACKGROUND

[0003] The present disclosure generally relates to devices, systems, and methods for promoting smoking cessation and the treatment and management of tobacco and e-cigarette addiction. Tobacco addiction via cigarettes directly impacts 34.2 million people in the United States, leading to over 480,000 preventable deaths and costing the US economy over $891 billion annually. Tobacco addiction is a chronic disease and various agents and methods have been attempted to treat the disease. Today, there are seven FDA-approved medication types for the treatment of tobacco addiction: nicotine replacement therapy (NRT) gums, lozenges, patches, a buccal inhaler, and a nasal spray, as well as well as the prescription drugs varenicline and bupropion.

[0004] The most common method used to manage a smoker’s tobacco addiction is NRT, and within that product class the most commonly used medication is NRT gum. However, this product has a failure rate over 91% at one year from the outset of abstinence, clearly highlighting the need for new a new pharmacotherapeutic treatment that has higher efficacy (see https: / / health.gov / healthypeople / objectives-and-data / browse-objectives / tobacco-use / increase- successful-quit-attempts-adults-who-smoke-tu-14).

[0005] Non-FDA approved products, such as e-cigarettes and vaping devices that use heat to form a vapor which condenses to an aerosol, are available as smoking replacement devices, but havenot been approved for use as smoking cessation products. Available data suggest that over 50% of e-cigarette users also smoke cigarettes, increasing their exposure to harmful tobacco combustion products rather than helping them quit their tobacco addiction. E-cigarettes do not have a sufficiently good safety profile to promote their use as a medical treatment for tobacco addiction in the US, as the use of heat in the formation of the aerosol is known to create carcinogenic compounds including formaldehyde and acetaldehyde. Accordingly, there is a need in the art for a safe and effective inhalation for use as a smoking cessation therapeutic that avoids the disadvantages of oral medications and e-cigarettes.

[0006] Aqueous inhalation solutions have many desirable properties. Most existing aqueous inhalation systems are single dose, wherein the user pours formulation from a vial into a container, and then breathes through the device for a period of several minutes to get a dose, followed by an extensive cleaning procedure. These products are not useful for application that require immediate availability when needed, for example pain or craving. Only one system, the Respimat inhaler (Boehringer Ingelheim) delivers multiple doses without filling or cleaning. However, Respimat is an all-mechanical inhaler, and thus cannot perform such functions as dose control, usage monitoring, and the like. Therefore, there is a need for an easy to use, multidose, aqueous inhalation system that has the ability to control the delivered dose.SUMMARY

[0007] The present disclosure is directed to smoking cessation therapy and more particularly, a smoking cessation system comprising at least one of (a) a portable smoking cessation device; (b) firmware contained in the device for controlling the device; (c) a formulation chamber; and (d) a companion application. In one embodiment, the system creates a patient experience that is similar to smoking and controls the amount of nicotine administered reducing it essentially to zero over a predetermined amount of time, for example about 10 to 16 weeks, about 13 weeks, about 20 to 32 weeks, about 26 weeks, about 2 months to 4 months, about 3 months, about 5 to 7 months, about 6 months, or about 12 weeks.

[0008] The present disclosure provides in certain embodiments a smoking cessation inhaler, comprising: a durable unit of the inhaler comprising a controller and a multiplicity of multidose cartridges configured to be separably attached to the durable part of the inhaler wherein thecartridges comprise (a) an aerosolizer; (b) a formulation chamber containing a formulation comprising an active pharmaceutical ingredient; (c) a debubbler; and (d) a fdter. In certain aspects, the durable part of the inhaler further comprises a pump motor assembly and the cartridge comprises a pump head assembly.

[0009] In one embodiment, the pump motor assembly comprises an element chosen from one or more of: a motor; a gearhead; a spring, and a clutch pressure plate. Preferably the motor assembly is mounted in a durable housing, which housing also captures the pressure plate and thereby compresses the spring. The pump head assembly may comprise an element chosen from one or more of: a clutch disk, a cam shaft, a bearing, preferably 2 or more bearings, a support surface; a ring; and a section of tubing. The inhaler may further comprise a recirculation system comprising one or more elements selected from: a debubbler; a debubbler chamber; a pocket; an aerosolizer; a filter; and a pump head.

[0010] In another embodiment, the cartridge comprises a filter capable of removing bacteria from the formulation. Such filter may have a pore size of about 5 pm or less, or about 2 pm or less, or about 1 pm or less.

[0011] The present disclosure provides for in certain aspects an inhaler that contains multiple doses of an aqueous formulation, for example a solution or suspension of one or more active pharmaceutical ingredients.

[0012] The present disclosure also provides in certain aspects that the active pharmaceutical ingredient is an addictive substance; and / or a substance to which a chronic user will develop tolerance. In one embodiment, the amount of the active pharmaceutical ingredient (API) delivered is repeatedly adjusted by the controller wherein the adjustment comprises one or more of: (a) an increase in the amount of active pharmaceutical ingredient delivered; (b) a decrease in the amount of active pharmaceutical ingredient delivered; and (c) a period of increase of active pharmaceutical ingredient delivered followed by a period of decrease of active pharmaceutical ingredient delivered.

[0013] Although a significant aspect of the present disclosure relates to smoking cessation devices, systems, formulations, and methods, and describes formulations containing nicotine, other active pharmaceutical ingredients can be delivered using the disclosed system. Such non-nicotine APIs may or may not also include nicotine to facilitate smoking cessation or for use in smoking or vaping replacement. It will also be understood that the system can be used in indications other than smoking cessation, and active compounds other than nicotine or other drugs for smoking may be used. While large molecular weight compounds greater than 10 kDa for systemic effect may be delivered, preferred applications include compounds of any molecular weight for topical or targeted lung treatment, and small molecular weight compounds of less than or about 10 kDa, preferably less than or about 5 kDa, more preferably less than or about 1 kDa, for systemic effect, preferably more rapid systemic effect as compared to other routes of delivery including, but not limited to, subcutaneous, transdermal, intradermal, oral, buccal, ocular, or nasal.

[0014] In some embodiments, the treatment applications employing the aerosol device disclosed herein are those that require changes to the dose over time or personalization of dose for individual patients. Changes may include tapering to avoid withdrawal symptoms of legal or illegal, medical or recreational, compounds. Changes may include ramping up, for example due to the increased tolerance over time of compounds including, but not limited to, opioids, for example fentanyl or morphine and pharmaceutically acceptable salts thereof. Changes may also include doses selected by a patient (i.e., self-titration) or caregiver, for example titration of pain medication strength based on perceived pain, or titration of diabetes medications including, but not limited to, insulins or glucagon-like peptides, based on measured blood glucose and / or expected prandial intake.

[0015] By way of a non-limiting example, fentanyl or salts thereof may be used with the aerosol device disclosed herein. In one embodiment, the fentanyl is inhaled from the device ad libitum, but with a lockout period between doses to prevent overdoses. A starting maximum allowed dose of about 10-40 pg per hour, or about 20-30 pg / hr, or about 25 pg / hr may be ramped up to a maximum of from about 25-100 mcg / hr, or about 35-65 mcg / hr, or about 50 mcg / hr. The dose escalation may occur over a period of time ranging from about 1 week to 10 weeks, or 2 weeks to 5 weeks, or about 3 weeks. When it is desired to end the therapy, the dose may be ramped down to about zero at a rate of about 2% to about 25% per week, or at a rate of about 3.5% to about 20% per week, or at a rate of about 5% to about 15% per week. This ramping down of the dose may be used to avoid addiction and abuse opioids such as fentanyl.

[0016] The present disclosure further provides a companion application capable of one or more of: controlling communication with the smoking cessation device, wherein the communication is preferably wireless, more preferably Bluetooth; controlling the smoking cessation device; updating firmware for the smoking cessation device; displaying data generated by the smoking cessation device; and allowing entry of data and other information, for example by the user, caregiver, or healthcare professional. In a preferred embodiment, the companion embodiment only sends communication to the smoking cessation device as required for pairing, linking, and / or handshaking, and companion app does not otherwise send data to or control the smoking cessation device. Preferably the inhaler of the present disclosure does not require the use of the App, and an App may not be made available.

[0017] In one embodiment, the companion application further comprises functionality chosen from training, coaching, reinforcing, and rewarding the user. Preferably, the companion application resides on a computing device. The computing device may be an essentially nonportable system such as a desktop computer, but preferred computing devices are portable and selected from a list which includes smart phones, tablets, smart watches, laptop computers, smart glasses, and virtual reality systems. In another embodiment, the application resides in the cloud, with functionality such as a user interface and a system for communicating with the smoking cessation device residing on the computing device.

[0018] In certain embodiments, a formulation chamber contains a first formulation, preferably wherein the first formulation is comprised of an active pharmaceutical ingredient such as nicotine. In this embodiment, the formulation chamber also contains a second formulation, preferably wherein the second formulation does not contain an active pharmaceutical ingredient such as nicotine. In another embodiment, the formulation chamber contains only a single formulation.

[0019] In another embodiment, the smoking cessation system comprises one or more formulation cavities containing one or more formulation chambers. The formulation cavities may all contain the same formulation, or different formulations, for example, differing amounts and / or concentrations of nicotine or one or more other active pharmaceutical ingredients.

[0020] The formulation cavity can contain at least one formulation chamber, wherein the formulation chamber is a flexible bag housed entirely in the cavity. Preferably, the formulationchamber is watertight, airtight, and contains a water-vapor barrier to ensure a sealed dosage form. The formulation chamber, may, in one embodiment, be bonded to the inner surface of the formulation chamber at one or more points, such as, but not limited to, the side of the chamber being bonded to the side of the inner side of a wall of the formulation chamber, or the top of the formulation chamber being bonded to the inner wall of the top of the formulation chamber.

[0021] The present disclosure provides a formulation chamber that is part of a component comprising a mouthpiece, hereinafter referred to as the cartridge, wherein this component is multidose disposable and further wherein this component has a through passage that allows for air and aerosol flow to be inhaled by the user, hereinafter referred to as the air channel. In one embodiment, the air channel may be partly or essentially entirely encircled by the formulation chamber or by the one or more formulation chambers. In another embodiment, the air channel is positioned adjacent to the one or more formulation chambers, and wherein in a third embodiment the air channel is partly or entirely separated from the formulation chambers. All of the above- mentioned embodiments have the advantage that the formulation chamber(s) and other components of the cartridge such as a mouthpiece, or an aerosolizer are changed in a single action. Mouthpiece / formulation chamber combinations of this type are described in patent applications PCT / US2021 / 064426 and PCT / US22 / 82580, incorporated herein by reference in their entirety. Optionally, an air channel inlet may reside in the durable unit, and disposed in the air channel inlet a mechanism that allows for breath actuation of the aerosol. This mechanism is preferably a flow- resistive element, for example an orifice plate, and a pressure tap leading to a pressure transducer which is read by a controller in the durable part. Preferably the pressure transducer resides on a printed circuit board which is in the durable unit.

[0022] In another embodiment, the cartridge is further comprised of an aerosolizer. Any suitable aerosolizer may be used and may be chosen from the list which includes but is not limited to a vibrating mesh, a condensation aerosol generator, an ultrasonic nebulizer, a dry powder disperser, a jet nebulizer, a swirl nebulizer, a flow blurring aerosolizer, and a flow focusing aerosolizer. Preferably, the aerosolizer is a vibrating mesh aerosolizer. In one embodiment, the aerosolizer is situated between the air channel and at least one formulation chamber. In a preferred embodiment, the aerosolizer is located in an air channel wall which is opposite the formulation chamber.

[0023] The present disclosure also provides that all of the components that contact the formulation or formulations during storage and / or use are contained within the cartridge, and none of the components of the durable unit of the aerosolization system are in direct contact with a formulation. It is preferable that the cartridge is designed in such a way to limit the possibility of misuse or abuse of a formulation and concomitant overdose or poisoning. For this reason, it is preferred that the components that are in direct contact with the nicotine, such as formulation chambers, mixing chambers, tubing, pump heads, debubblers, filters, and aerosolizers are essentially fully contained within the cartridge.

[0024] In certain embodiments, the nicotine formulations comprise nicotine or salts of nicotine. Such formulations include, but not limited to, essentially neat nicotine, or nicotine suspensions, or a nicotine solution. One formulation embodiment comprises nicotine and a lipophilic solvent. Lipophilic solvents preferably include an alcohol such as ethanol. Other embodiments include, but are not limited to, a glycol, such as propylene glycol. Another formulation embodiment is a salt of nicotine, preferably nicotine tartrate, more preferably nicotine bitartrate dihydrate, in a solvent comprising water. Alternatively, the formulation is USP nicotine dissolved in a formulation of water or a combination of water and ethanol. The formulation may also comprise various excipients such as surfactants, preferably Tween 20 or Tween 80, stabilizers, absorption enhancers, antimicrobial agents, and the like. The formulation may include a PH buffer, for example a phosphate buffer. In certain embodiments, the formulation comprises a dissolved salt of nicotine and water. In other cases, the formulations consist essentially a carrier, such as water, and a dissolved salt of nicotine (e.g., nicotine bitartrate dihydrate). A preferred formulation is essentially comprised only of 90 mg / ml nicotine bitartrate dihydrate in water.

[0025] In another embodiment, the starting dose of active ingredient is selected by a physician based on patient characteristics such as weight, smoking history, tolerance to the active ingredient, age, and the like. In a one embodiment, the starting dose of active ingredient is the same for all users, for example, the starting dose of nicotine per puff is about 0.05 mg or more, 0.075 mg or more, 0.1 mg or more, 0.15 mg or more, 0.2, mg or more, 0.25 mg or more, 0.3 mg or more, 0.4 mg or more, or 0.5 mg or more. In a preferred embodiment, the starting dose is the same for all users.

[0026] In one embodiment, the system monitors the inhalation rate during delivery, and turns off the aerosolization if the flow drops below a level that can effectively entrain the aerosol. If the user desires a lower dose, they can remove the mouthpiece from their mouth and continue inhaling, much as is done with a cigarette. This may be described in a label.

[0027] In certain embodiments, the system, for example the companion application or preferably the device firmware adjusts the target amount of an active ingredient, preferably nicotine, delivered per puff, and reduces the amount of nicotine delivered as the smoking cessation therapy progresses. Preferably, the adjustment of the amount of active ingredient per puff is the same for all users. In one embodiment, the amount of nicotine per puff, when and if the user inhales deeply at or above a predetermined flow rate, is controlled, but the use of the system is otherwise ad libitum, and the user may have as many puffs per dosing event and as many dosing events per day that they may want.

[0028] In another embodiment, the dose per puff is adjusted by control of delivered nicotine concentration, which concentration may be adjusted in accordance with an algorithm, wherein this algorithm is used to reduce the dose of nicotine delivered via the smoking cessation system over the course of treatment, wherein the dose of nicotine delivered to the user is, or essentially is, 0 milligrams at the end of the treatment. One embodiment of the algorithm determines a maximum dose level for each puff, which maximum dose level decreases, preferably linearly decreases.

[0029] These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the formulations and methodology as more fully described below. Additional embodiments of the present devices, formulations, processes, methods of treatment and the like will be apparent from the following description, drawings, examples, and claims. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment or aspect. Additionalaspects and embodiments are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The invention is best understood from the following detailed description when read in conjunction with the accompanying drawings. It is emphasized that, according to common practice, the various features of the drawings are not to-scale. On the contrary, the dimensions of the various features are arbitrarily expanded or reduced for clarity. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the USPTO upon request and payment of the necessary fee. Included in the drawings are the following figures:

[0031] Figure l is a cross-sectional view of an embodiment of the device of the present disclosure in its entirety.

[0032] Figure 2 is a cross-sectional view of an embodiment of the durable unit of the present disclosure.

[0033] Figure 3 is a cross-sectional view of an embodiment of the cartridge of the present disclosure.

[0034] Figure 4 is a schematic view of the functional components of an embodiment of the cartridge of the present disclosure.

[0035] Figure 5a is an embodiment of the separable pump of the present disclosure, showing the pump separated before the cartridge is attached to the durable

[0036] Figure 5b is the embodiment of figure 5a wherein the two parts of the pump are engaged when the cartridge is attached to the durable.

[0037] Figure 6a is a cross section of the pump head of the embodiment figure 5, wherein the eccentric is at an angular position that is sub optimal for long term storage.

[0038] Figure 6b is the embodiment of figure 6a that has been stored at the angular position of figure 6a and then used.

[0039] Figure 6c is a cross section of the pump head of the embodiment figure 6a, showing a worst-case outcome when the eccentric is at an angular position that is sub optimal for long term storage.

[0040] Figure 6d is the embodiment figure 6a wherein the eccentric is at an angular position that is more optimized for long term storage.

[0041] Figure 7a a is a cross-sectional view of an embodiment of the mouthpiece cap.

[0042] Figure 7b a is a cross-sectional view of an embodiment of a cartridge that can be used with the mouthpiece cap of figure 7a.

[0043] Figure 7c is the mouthpiece cap of figure 7a attached to the cartridge of figure 7b.

[0044] Figure 8 is a graph showing the measured emitted dose uniformity of aerosol generated using an embodiment of the present disclosure.

[0045] Figure 9 is a graphical plot of average aerosolized volume over 2 weeks using an embodiment of the current disclosure.

[0046] Figure 10a is a graph of average plasma levels of nicotine over 120 minutes achieved with an embodiment of the present disclosure.

[0047] Figure 10b is a graph of data disclosed in Figure 10a, displayed over 30 minutes.

[0048] Figure 11 is a graph the data of figure 10a after the third delivered dose, compared to cigarettes and gum.

[0049] Figure 12a is a graph of craving over time achieved with an embodiment of the present disclosure.

[0050] Figure 12b is a graph of the data of Figure 12a, only the third dose.

[0051] Figure 13 is a graph the data of figure 12b, compared to nicotine patch and nicotine gum.DETAILED DESCRIPTION OF THE INVENTION

[0052] The various aspects and embodiments will now be fully described herein. These aspects and embodiments may, however, be embodied in many different forms and should not be construed as limiting; rather, these embodiments are provided so the disclosure will be thorough and complete, and will fully convey the scope of the present subject matter to those skilled in theart. All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0053] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range, is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where neither, or both, limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0054] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.A. DEFINITIONS

[0055] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

[0056] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a formulation” includes one or more such formulations and reference to “the method” includes reference to one or more methods and equivalents thereof known to those skilled in the art, and so forth. Further, where the size of an area, such as a hole, is referred to ashaving a certain diameter, it will be understood that this encompasses other cross-sectional shapes that are not circular but have an area equivalent to a circle of the specified diameter.

[0057] Ad libitum: Dosed according to the preference of the user.

[0058] Aerosol head cavity: A cavity in the cartridge that contains one or more of air, formulation, an absorbing material, or a debubbler.

[0059] Aerosolization time: The amount of time that an aerosolizer is energized, or a target amount of time that an aerosolizer is energized, during a puff. Controlling aerosolization time is a preferred method for controlling a dose.

[0060] Air channel: An air flow path through an inhaler, preferably through a cartridge. An air channel through a cartridge is preferably substantially straight, has minimal steps or other features in the walls, does not contract in the direction of airflow, may be of constant cross section or have an expanding section. Preferably aerosol is generated into an air channel, preferably wherein the average direction of aerosol generation is substantially perpendicular to the airflow through the air channel.

[0061] Air channel inlet: An air flow passage through a durable unit. Preferred air channel inlets have an entry on a side of a durable, which is preferably protected by a screen or logo plate. Preferably the direction of flow into the inlet is substantially perpendicular to the direction of flow through an air channel in the cartridge. Preferred air channel inlets have an approximately 90° bend, preferably a bend with an average radius of curvature of approximately 1 cm or more. Preferred air channel inlets have an orifice plate, downstream from which is a hole in the air channel inlet wall through which the pressure, and thereby the air flow rate, can be monitored. Preferably the orifice plate is downstream from the approximately 90° bend, as the orifice plate can also have the function of laminarizing flow and removing flow non-uniformities caused by the bend.

[0062] Aseptic filter, or filter: A filter used to remove microbes from a formulation. Preferred filters have pore sizes selected from about 0.22pm, 0.2pm, or 0.1pm.

[0063] Atomizer: A component of the device of the current invention, preferably of the cartridge, which generates an aerosol. Preferably the atomizer is a vibrating mesh atomizer.

[0064] Area under the curve, AUC: A pharmacokinetic statistic which is calculated as the integral of the plasma concentration of an active pharmaceutical ingredient. AUCti-t2 is the integral from tl (usually t = 0) to a second time t2 which is often the final sampling timepoint. AUCo-oc is the integral extrapolated to infinity.

[0065] Cam Shaft: A drive shaft comprised of an eccentric for driving a pump head.

[0066] Carrier: A liquid, preferably water, into which an active pharmaceutical ingredient is suspended or preferably dissolved.

[0067] Cartridge, disposable, and the like: A component of the device of the current invention with contains the formulation and one or more of a formulation chamber, a formulation cavity, and aerosol head cavity, a debubbler, components of a pump head, tubing, an airway, a mouthpiece, and an aerosolizer. The cartridge is separably attached to a durable system and preferably is generally used for a period of time which is shorter than the period of time the durable system is used for.

[0068] Cartridge identifier: A mechanism for a controller in a durable unit to distinguish an unused cartridge from a previously used cartridge, another user’s cartridge, a cartridge containing a different medication, and / or a spent or expired cartridge.

[0069] Check valve: An element placed in a flow path that only allows flow in one direction.

[0070] Cigarette: An inhalation system that utilizes combustion of tobacco to deliver nicotine.

[0071] Clamp: A mechanism for keeping a formulation chamber closed during shelf-life storage, and which opens, preferably opens automatically, when a cartridge is attached to a durable unit. The clamp may be a mechanical unit which is sprung and held closed by an escapement, which escapement is release by a component, such as a cam, attached to or actuated by, the durable unit. Another embodiment of the clamp is a peel seal that is peels open when a formulation chamber is pressurized upon attachment of a cartridge to a durable unit.

[0072] Clutch disk: Component used to transmit torque from a motor and gear head in a durable to a pump head in a cartridge, by engaging with a clutch pressure plate.

[0073] Clutch Pressure Plate: A component of a transmission that that is forced under the urging of a spring or other compliant element axially toward a clutch disk, thereby enabling thetransmission of torque from a motor to a pump head. Preferably the clutch pressure plate is in the durable unit and the clutch disk is in the cartridge, but the clutch pressure plate can be in the cartridge and the clutch disk can be in the durable. The clutch pressure plate may engage the clutch disk just using friction, but preferably has features, for example grooves or ridges, which engage with mating features on the clutch

[0074] Cmax: The maximum concentration in the plasma concentration curve achieved or measured after delivery of an active pharmaceutical ingredient or other compound.

[0075] Condensation aerosol: An aerosol that is formed by first forming a saturated vapor, which vapor condenses to form an aerosol.

[0076] Controller: a component, preferably electronic, that controls the functioning of the inhalers, gathers data and writes some of this data to memory. A controller may be mechanical, use analog control electronics, but preferably the controller comprises a digital integrated circuit, for example a micro-controller or microprocessor.

[0077] Debubbler: A unit for removing air from a formulation, preferably by the use of a hydrophobic porous material.

[0078] Distal: Farther from the air inlet of an inhaler.

[0079] Dosing event: A series of puffs that are conducted by a user during a single use of a smoking cessation system. Preferably a dosing event is limited to 7 puffs, and after 7 puffs the user must start a new dosing event, for example by pressing a button or replacing and removing a mouthpiece cap. Preferably the amount of nicotine that can be inhaled during a nicotine dosing event at the beginning of the therapy is approximately equal to, more preferably similar to but somewhat less than, what a smoker would inhale from an entire cigarette, and the amount of nicotine that a smoker can inhale is decreased from there over the course of the therapy.

[0080] Dry powder dispersing mechanism: A system for adding energy to a packed pharmaceutical powder to form an aerosol.

[0081] Durable unit: A component which contains one or more of: Electronics, a microcontroller, a battery, a battery charging circuit, a light, a button, an electrical connector, and pump motor, a gear head, a pressure plate, an eccentric cam, and an alignment cam.

[0082] Durable Housing: A component, preferably plastic, that surrounds the Electronic and other components in a durable system. Preferred durable housings have through holes for the passage of things selected from the list that includes but is not limited to: a pressure plate, a pogo pin, an LED, light from an LED, a connector or jack, preferably USB, more preferably USB C, a button.

[0083] Eccentric element or cam: An element which is rotated and is not symmetric around the axis of rotation.

[0084] e-cigarette: An inhalation system that utilizes electrical power, preferably battery power, to deliver nicotine.

[0085] Electronic nicotine delivery systems: An electronic system for smoking cessation therapy or smoking replacement.

[0086] Electrospray: A system for forming an aerosol wherein liquid flows out of the end of a capillary and through a hole in a plate. When a voltage is applied between the capillary and the plate, the liquid forms a cone with a jet coming off the tip of the cone. The jet flows through the hole and undergoes Raleigh breakup to form an aerosol.

[0087] Emitted Dose: The volume of formulation, or the amount of active pharmaceutical ingredient that is emitted from an inhalation device, for example during 1 puff or one dosing event.

[0088] Expanded: A material, preferably a hydrophobic material, which is stretched to make it porous.

[0089] Fagerstrom Test for Nicotine Dependence: A test for the severity of nicotine addiction.

[0090] Firmware: Computer code that is loaded onto a controller, microcontroller, microprocessor, or the like.

[0091] Flow blurring: A method of forming an aerosol wherein liquid flows from a capillary and the liquid and a highly pressurized gas co-flow rapidly (for example more rapidly than is used in flow focusing) through a hole in a plate. The liquid at the exit of the capillary is somewhat violently converted to droplets, which are carried through the hole to form an aerosol.

[0092] Flow channel: A channel or tube which runs carries formulation between two components of the cartridge. Examples include the first flow channel that runs from theformulation chamber to the pump and may comprise a clamp or a valve, the second flow channel that runs from the pump to the pocket and may comprise a filter and / or a debubbler, and the third flow channel that runs from the pocket back to the first flow channel and may comprise a debubbler and or a check valve.

[0093] Flow focusing: A method of forming an aerosol wherein liquid flows from a capillary and the liquid and a pressurized gas co-flow through a hole in a plate. The liquid forms a cone under the influence of the co-fl owing gas, and a jet is formed at the tip of the cone, which jet undergoes Raleigh breakup to form an aerosol.

[0094] Formulation cavity: A void in the cartridge of the current invention that contains the formulation chamber or chambers.

[0095] Formulation chamber: A container of formulation for use in the current invention. Preferred formulation chambers are flexible and collapse as formulation is drawn out of them.

[0096] Formulation pocket: A region directly behind the aerosolizer which contains formulation and may also contain a wicking element.

[0097] Gauge pressure: Pressure difference relative to the surrounding atmosphere.

[0098] Headspace: A volume of gas that is contained in the formulation chamber during shelf life. This gas could be any gas that is suitable for fdling and formulation stability. Preferred gasses include air, but preferably is an inert gas such as nitrogen, helium, or argon. Preferably the volume of the headspace is essentially zero.

[0099] Inhalation profile: The inhalation flow rate (e.g., in liters / minute) over time, or a graph thereof.

[0100] Inhalation flow rate range: A range of inhalation flow rates wherein when the user inhales at a rate within this range, the inhaler will deliver an aerosol.

[0101] Inhalation flow rate minimum: A flow rate (for example in LPM) which the user’s inhalation flow rate must be equal to exceed in order that aerosol is generated, i.e., the lower end of the inhalation flow rate range.

[0102] Inhalation flow rate maximum A flow rate (for example in LPM) which the user’s inhalation flow rate must be equal to or less than in order that aerosol is generated, i.e., the maximum of the inhalation flow rate range.

[0103] Jet nebulizer: A system for creating an aerosol from a liquid, wherein a jet of compressed gas is forced through a liquid, forming, entraining, and dispersing the droplets to form an aerosol.

[0104] Label: Information about a pharmaceutical product for users and care givers. Labels may be applied directly to the product or the packaging of the product, may be a paper product contained in the packaging or otherwise given to the user with the product, or may be information that is readily available, for example on the internet.

[0105] MEMS: A method of fabricating micron sized structures, for example nozzle arrays, using the technology developed for the fabrication of microchips.

[0106] Mouthpiece cap, cap: A removable component that covers the mouthpiece exit, keeping it clean and blocking foreign materials from entering the air channel, where they may be later inhaled. Preferred mouthpiece caps have an incorporated nozzle plug.

[0107] Nebulizer: A device for creating an aerosol from one or more liquid formulations.

[0108] Nozzle plug, plug, and the like: A device that blocks the exit of one or more nozzle holes between uses of the device. Preferably the nozzle plug is comprised of a compliant element so that it forms a good seal in the event, for example, of a nozzle array that is on a dimple in a substrate. Preferably the nozzle plug substantially fully blocks the exit of substantially all the holes in the nozzle array. Preferred materials for the nozzle plug include silicone, which is overmolded onto a rigid material, preferably a polymer. Preferably, the nozzle plug is incorporated into a mouthpiece cap and is removed and replaced when the mouthpiece cap is moved and replaced.

[0109] NRT: Nicotine Replacement Therapy.

[0110] Orifice plate: An item which transverses the air inlet channel and creates a repeatable flow restriction for use in monitoring the airflow through an inhaler. Preferred orifice plates arerelatively thing in the flow direction and contain one or more through holes each of which has a controlled cross-sectional area.

[0111] PE: Polyethylene

[0112] Peristaltic Pump: A device which pumps a formulation through a length of flexible tubing by sequentially compressing portions of the length of tubing by the use of a compressing element, for example one or more rollers, or preferably a ring driven by an eccentric.

[0113] PET: Polyethylene terephthalate

[0114] Pharmacologically Equivalent: Having essentially the same pharmacokinetic and pharmacodynamic profile. It is often the case that a pharmacologically equivalent dose can be determined by the ratios of the molecular weights, i.e., having the same number of molecules.

[0115] Piezoelectric or Piezo: A component which expands when a voltage is applied to it.

[0116] Priming: The act of drawing formulation out of the formulation chamber and thereby displacing air in the fluidics system. Preferably substantially all of the air is forced out of a debubbler.

[0117] Prime: The state of being primed.

[0118] Spent: A property of the cartridge where the formulation is nearly completely removed from the formulation chamber.

[0119] Sprung Electrical Connection: A component that makes a temporary electrical connection between the cartridge and the durable unit by way of a conductor that is spring loaded and biased toward a mating electrical contact. Preferred sprung electrical connections include pogo pins wherein a spring biases a captured pin toward a mating contact, preferably a pad on a printed circuit board attached to the mating component. Sprung electrical connections can be used to transmit signals or power between a durable unit and a cartridge.

[0120] PP: Polypropylene

[0121] Proximal: in a location that is closer to the air inlet channel

[0122] PS: Polystyrene

[0123] PTFE: Polytetrafluoroethylene

[0124] Puff: A single inhalation wherein an aerosolized drug formulation is drawn into the lungs of a user.

[0125] Raleigh breakup: The formation of an aerosol wherein liquid is forced through one or more nozzle holes to form liquid jets, which jets spontaneously break up, under the influence of surface tension, into droplets with diameters approximately two times the diameter of the jet.

[0126] Recirculation system: A fluidics system in a cartridge wherein formulation is pumped around a loop. In one embodiment, formulation flows from a formulation chamber, optionally through a clamp to a pump, then through a second flow channel that may contain a filter and / or a debubbler, into a pocket, then exits the pocket into a third flow channel that may contain a debubbler and / or a check valve, and then back to the first flow channel.

[0127] Compression set, set, and the like: A condition wherein a component, for example tubing, is under stress for an extended period, resulting in a permanent distortion.

[0128] Smoking replacement, nicotine replacement, nicotine replacement therapy, NRT, and the like: A method of reducing or eliminating the act of smoking cigarettes or e-cigarettes by replacing the cigarettes with a more benign form of nicotine, for example wherein the benign form of nicotine is nicotine salt in water, which formulation is formed into an aerosol and inhaled.

[0129] Smoking cessation therapy, nicotine cessation therapy, and the like: A method of helping tobacco users to quit, preferably by supplying a system that creates an aerosol that contains nicotine, wherein nicotine is gradually tapered down to essentially zero, thereby giving smokers the nicotine they are craving, an experience very similar to smoking, and a pharmacokinetic profile of plasma nicotine essentially identical to that experienced by the smoker after taking a puff from a cigarette.

[0130] Sintered: A porous material created through the process of coalescing a powdered material into a porous mass by means of heating without liquefaction.

[0131] Subject, user, or patient: A human or other mammal who uses the inhaler of the present disclosure.

[0132] Substrate: A sheet of material, preferably stainless steel, which contains an array nozzle holes which may be substantially centered on a dimple formed in the substrate.

[0133] T max : The time after dosing wherein Cmax is achieved.

[0134] Swirl atomizer: A nebulizer that utilizes rotating airflow to form and disperse an aerosol.

[0135] Ultrasonic nebulizer: A system for creating an aerosol that applies ultrasonic energy directly to the formulation. Compare to vibrating mesh nebulizer.

[0136] Vibrating mesh nebulizer: A system for creating an aerosol that ultrasonically vibrates a substrate which contains an array of nozzle holes.

[0137] Visual Analog Scale, VAS: A way of quantifying a perception, such as nicotine craving. A preferred VAS scale is a number line from one to ten, whereon a subject in a clinical trial marks their perceived level of craving.

[0138] Wicking element: A flexible material that when placed in contact with a liquid will soak up the liquid.B. OVERVIEW

[0139] The present disclosure relates to devices, formulations and methods for inhalation drug delivery. In certain embodiments, the devices are inhalation systems which create an experience to patients that is similar to smoking, employing devices with arrays of nozzles for forming a nicotine-containing aerosol. Such inhalation systems control the amount of nicotine delivered to the patient by reducing it essentially to zero over a predetermined amount of time. More particularly, the smoking cessation system of the present disclosure comprises at least one of (a) a portable smoking cessation device; (b) firmware contained in the device for controlling the device; (c) a formulation chamber; and (d) a companion application.

[0140] In certain embodiments, the device is configured as a smoking cessation inhaler, comprising: a durable unit comprised of a controller, and a cartridge configured to be separably attached to the durable unit wherein the cartridge comprises (a) an aerosolizer; (b) a formulation chamber containing a formulation comprising an active pharmaceutical ingredient; (c) a clamp that keeps the chamber closed during shelf life, (d) a recirculation system, (e) a means of identifying the cartridge, (f) debubbler; and (g) a filter. The smoking cessation system is designed to mimic smoking cigarettes by delivering a nicotine-containing composition with nicotine absorption kinetics close to what is experienced with conventional cigarettes or e-cigarettes.Preferably the Aerosolizer does use heat to form the aerosol, as is done in e-cigarettes. Preferably the formulation minimizes the use of excipients / substances, for example as used in e-cigarettes and other devices. Accordingly, the pharmacokinetics (PK), pharmacodynamics, and safety profile of the present system is an acceptable alternative to smoking and e-cigarette use and particularly effective for smoking cessation. Like cigarettes, the present aerosol device can mitigate cravings after several doses (or puffs). Yet, unlike smoking and e-cigarettes, the present device does not rely on heat to vaporize the nicotine. Nor does it rely on propellants or other potentially harmful auxiliary or excipient substances. Thus, the compact, hand-held device of the present invention is easy to use, safe and effective in delivering nicotine in a way which is similar to what a smoker expects and craves.

[0141] In one embodiment, the system creates a patient experience that is initially similar to smoking and controls the amount of nicotine administered, reducing it essentially to zero over a predetermined amount of time, for example about 10 to 16 weeks, about 13 weeks, about 20 to 32 weeks, about 26 weeks, about 12 weeks, about 2 months to 4 months, about 3 months, about 5 to 7 months, or about 6 months.

[0142] More particularly, the present aerosol device is configured to deliver nicotine resulting in pharmacokinetic values that are within about 5%, or 10%, or 15%, or 20%, or 25%, 30%, or 50% of those reported in cigarette smokers, wherein the values are one or more of (a) plasma concentration at 30 seconds, 1 minute, 3 minutes, 5 minutes, 10 minutes and 15 minutes; (b) Cmax; (c) Tmax; and (d) an AUC. The reported PK values for cigarettes are stated in the literature. See, e.g., Benowitz NL, Clinical Pharmacology of Nicotine: Implications for Understanding, Preventing and Treating Tobacco Addiction. Clin. Pharmacol. Ther. 83(4) (2008); Le Nouez, Inti. J. Tuberculosis and Lung Dis. 7(9) (Sept. 2003).

[0143] In another aspect, the system of the present invention is configured and dosed in patients to significantly decrease nicotine cravings as measured by the visual analog scale (VAS)-craving assessment. In some embodiments, the present system decreases cravings by about 30% or more, 40% or more, 50% or more, 60% or more, or 70% or more, 75% or more, 80% or more, or about 100% compared to baseline.

[0144] In certain embodiments, the starting dose of active ingredient is selected by a physician based on patient characteristics such as weight, smoking history, tolerance to the active ingredient,age, and the like. In one embodiment, the starting dose of active ingredient is the same for all users.

[0145] For example, upon the initial use of the device, the device may be controlled such that an initial total emitted dose of nicotine free base, or a pharmacologically equivalent amount of another form, for example a salt of nicotine, per average inhalation ranges from about 0.05 to about 2 mg, from about 0.1 to about 1 mg, from about 0.2 to about 0.5 mg, from about 0.25 to about 0.3 mg, whereupon the amount of nicotine will be decreased, for example the aerosolization time of a nicotine containing formulation will be decreased, such that after a period of time selected from about 1 week to about 1 year, about 1 month to about 6 months, about 2 months to about 4 months, preferably about 3 months, 90 days or 12 weeks, the aerosolization time, and thereby the total emitted dose of nicotine per puff may be approximately 0 mg. This serves as an example only for the purpose of clarification. Preferred starting amounts of nicotine per puff are preferably greater than or about 2 mg / puff, greater than or about 1.5 mg / puff, greater than or about 1.2 mg / puff, greater than or about 1 mg / puff, greater than or about 0.8 mg / puff, greater than or about 0.6 mg / puff, greater than or about 0.5 mg / puff, greater than or about 0.4 mg / puff, greater than or about 0.3 mg / puff, greater than or about 0.2 mg / puff, or greater than or about 0.1 mg / puff. Ending amounts of nicotine are preferably less than or about 1 mg / puff, less than or about 0.8 mg / puff, less than or about 0.7 mg / puff, less than or about 0.6 mg / puff, less than or about 0.5 mg / puff, less than or about 0.4 mg / puff, less than or about 0.3 mg / puff, less than or about 0.2 mg / puff, less than or about 0.1 mg / puff, or about 0 mg / puff.C. AEROSOL DEVICE AND ITS OPERATION

[0146] As described above, the present disclosure relates, in certain embodiments, to a smoking cessation inhaler, comprising: a durable unit of the inhaler comprising components selected from (a) a controller; (b) an electrical cell or battery, (c) a battery charging circuit, (d) a pressure transducer, (c) a pump motor assembly; (d) one or more sprung electrical contacts; (e) a connector for a charging cable; (f) one or more light indicators; (g) a button; (h) an air inlet channel; (i) an orifice plate; and (j) a PCB comprised of one or more of the previous components and additional electronic components, and a multidose cartridge configured to be separably attached to the durable part of the inhaler wherein the cartridge comprises (s)an aerosolizer; (b) a formulation chamber; (c) a formulation comprising an active pharmaceutical ingredient; and one or more of:(b) a mouthpiece, (c) an air channel (d) a recirculation system, (e) a formulation pocket containing formulation that is in contact with and provides formulation to the aerosolizer; (f) a cartridge identifier; (g) a debubbler; (h) a filter; (i) a pump head; (j) a PCB; (k) a sprung electrical contact; (1) a pad for a sprung electrical contact; (m) a clamp; (n) a button; and / or (d) a power transmission mechanism to drive the pump head. .

[0147] In one embodiment, the cartridge comprises at least one formulation chamber, and the dose is controlled by one or more mechanisms chosen from, but not limited to, a pump, a pumping time, a valve, a valve open time, value of a DC voltage applied to an aerosolizer, the amplitude of an AC voltage applied to an aerosolizer (for example sine wave, square wave, triangle wave, and the like), a duty cycle of a square wave, and an aerosolization time.

[0148] In one embodiment, an algorithm calls for the adjustment of the amount of active ingredient, preferably nicotine, delivered by the system, which adjustment occurs at a frequency selected from the list comprising but not limited to about once per 10 days or greater, about once per week or greater, about once per day or greater, about once per dosing event or greater, or about once per puff or greater. Preferably the algorithm calls for the adjustment of the of the amount of active ingredient about once per day, preferably before the first puff of the day, alternatively at the same time of day that the first dosing event of the therapy occurred. Preferred algorithms change the dose based on a parameter selected from the list comprising but not limited to the number of puffs since the first puff, number of dosing events since the first dosing event, time from the first puff, time from the first dose, days since the first day, a combination thereof. Preferred algorithms selected from the list comprising but not limited to a linear increase or decrease with the parameter, a quadratic increase with the parameter, a higher order polynomial with the parameter, an exponential increase or decrease with the parameter, or a stepwise reduction wherein each step is characterized by one of the previous reduction algorithms. Preferably, the algorithm calls for the change of the amount of active ingredient delivered from an initial value to a final value over a time period selected from the list comprising but not limited to about 1 day to about 1 year, about 1 week to about 9 months, about 1 month to about 6 months, about 2 months to about 4 months, about 90 days, about 12 weeks, or about 3 months. Preferably the algorithm calls for an increase in the amount active delivered, a decrease in the amount of active delivered, or both. In one preferred embodiment, the algorithm calls for a decrease fromone dose, preferably a starting dose, to a final dose, preferably about zero. In another preferred embodiment, the algorithm calls for an increase from an initial dose at a first event, preferably a starting day, to a second dose at a second event, preferably a later day, a constant dose from the second event to a third event, preferably a still later day, and a decrease from the second dose to a final dose at a fourth event, wherein the final dose is preferably zero. Preferred events are selected from the list comprising but not limited to days, dosing events, and puffs. In a preferred embodiment, the dose is reduced by linearly reducing the maximum aerosolization time per puff from a starting dose which is the same for all users to essentially zero over a period of about 12 weeks.

[0149] The smoking cessation system, preferably one or more of the smoking cessation device, firmware, and or companion application, is preferably comprised of a way of monitoring, recording, displaying, and / or reporting various factors related to the usage of the smoking cessation system, selected from the list including but not limited to the time, date, frequency, total number of puffs, and / or the number of dosing events and / or rate of change of any of the preceding. The system may also monitor, record, report, and / or display parameters related to the usage technique of the system, including but not limited to depth of inhalation, rate of inhalation, inhalation profile, amount of aerosol / puff, and coordination of a button push with the inhalation maneuver. Reporting is selected from a list including but not limited to reporting to a user, physician, nurse, physician group, HMO, insurance company, research organization for example a clinical research organization, investigator, epidemiologist, manufacturer, help line, care giver, family member, and / or friend. Reporting may require opt in by the user, and reporting, data storage, and data transmission are preferably HIPAA compliant.

[0150] In one embodiment, there may be a one-way data flow from the smoking cessation device to the companion application. In this embodiment, the companion application may perform functions selected from a list including but not limited to displaying information, reporting information, for example to a health care provider, care giver, family member, and / or to the supplier of the smoking cessation system. The information transmitted to the companion application may include information selected from the list including but not limited to the time, date, and number of puffs and / or dosing events, remaining amount of an active ingredient, preferably nicotine, amount of nicotine aerosolized per puff, quality of inhalation, inhalationprofile, per puff, battery status, remaining formulation, error codes, firmware revision, and the like.

[0151] In another embodiment, there may be a two-way data flow that allows the companion application to communicate with and / or control the smoking cessation device. In a preferred embodiment, the companion application will calculate and instruct the smoking cessation device as to a formulation flow rate, preferably the flow rates of a first and a second formulation, thereby controlling the amount of an active ingredient, for example the amount of nicotine per puff, delivered, as described previously. The companion application may also instruct the smoking cessation device to turn on, to ready itself for a change of formulation chamber, to display an indicator, for example a ready indicator, to utilize a given rate of flow of a formulation, preferably 2 or more formulations.

[0152] In one embodiment, the firmware or the companion application may incorporate a timing system, and be programmed for, or may calculate, a lockout interval before the next puff and / or dosing event. The lockout interval may be constant for the duration of the therapy, for example the smoking cessation therapy, pain management therapy, or opioid addition therapy, but in a preferred embodiment the lockout interval is increased over time. The initial lockout interval, and / or the rate of increase of the lockout interval, may be fixed by programming of the companion application or the firmware, but is preferably calculated by the companion application or firmware based on previously entered information related to, for example, the user, the users smoking history, and the previous usage of the smoking cessation system, as described above. Preferably the smoking cessation system incorporates one or more indications that the lockout interval has elapsed. Preferred indications include but are not limited to a light, a message on a display, a notification, a sound, and / or a vibration. For some applications, for example the delivery of opioids, the lockout interval and / or amount of opioid per puff, may be prescribed by the prescribing physician.

[0153] Preferably, the smoking cessation device incorporates a mechanism for forming an aerosol from one or more formulations, hereinafter referred to as the aerosolizer. The aerosolizer may be selected from the list including but not limited to a vibrating orifice or array of orifices (i.e., a vibrating mesh), a condensation aerosol generator, an ultrasonic nebulizer, a dry powderdispersing mechanism, a jet nebulizer, a swirl aerosolizer, Raleigh breakup, an electrospray, flow focusing, or flow blurring. In a preferred embodiment, a fine aerosol is generated from one, preferably a plurality, of small holes. In a particularly preferred embodiment, the aerosolizer is comprised of an array of nozzle holes formed in an essentially rigid substrate, preferably a stainless-steel substrate, which substrate may have a dimple substantially centered on the substrate and that extends out from the substrate in the direction of aerosol generation, and upon which dimple the array of nozzle holes is substantially centered. The substrate is resonantly oscillated by a ring-shaped piezo element that is rigidly bonded to the perimeter of the substrate on at least one side, wherein the dimple and array of holes are substantially centered in the opening of the ring-shaped piezo element. The substrate may be comprised of a dimple which may be in the shape of a section of a sphere, protruding from the exit side of the substrate, which dimple is substantially centered in the middle of the ring-shaped piezo element and has the array substantially centered on the protrusion. The protrusion extends toward an air channel through with the user inhales, and preferably the protrusion extends into the airflow through the air channel.

[0154] The piezo may be attached to the exit face of the substrate, or there may be two piezos, one attached to each face of the substrate. A preferred embodiment has a single piezo ring attached to the entrance face of the substrate, which allows the substrate (other than the dimple) to be substantially co-planar with an interior wall of the air channel, and removes the step from the piezo to the center of the ring and / or a step from the air channel where such a step can cause air recirculation and aerosol deposition. In a preferred embodiment, the substrate is substantially a disk and the piezo is an annulus. When liquid is supplied to the entrance side of the array and the substrate is resonantly oscillated by the piezo, an aerosol is formed at the exit-side of the array. In one embodiment, the amplitude of the oscillation is such that a single droplet is forced out of each nozzle hole with each oscillation cycle of the piezo. Alternatively, a length of liquid jet may be extruded from the exit nozzle of each hole, which length of liquid jet breaks up into droplets via the process of Raleigh breakup. Preferably there is a one or more nozzle holes with an exit diameter which is less than or about 10 pm, preferably less than or about 7.5 pm, less than or about 6 pm, less than or about 5 pm, less than or about 4 pm, less than or about 3 pm, less than or about 2.5 pm, less than or about 2 pm, less than or about 1.5 pm, less than or about 1 pmpreferably between about 2.0 and 3.0 pm, between about 2.2 and 2.8 pm, most preferably about 2.5 pm. Preferably there are less than about 100,000 holes, between about 1 and about 10,000 holes, between about 100 and about 10000 holes, between about 500 and about 5000 holes, or between about 1000 and about 4000, between about 2000 and 3000 holes, or about 2600 holes. The channel through the substrate leading to the exit of the orifice(s) may be any shape, including a cylinder, preferably a right circular cylinder. Preferred channels are tapered, decreasing in diameter from the entrance of the orifice to the exit, in order to reduce the pressure or other form of energy input, for example ultrasonic energy input, required to achieve flow through the orifice and aerosolization. Preferably, the taper is chosen from a cone shape, a pyramidal shape, and funnel shape. Preferably the inlet side of the orifices is greater than or about 5 pm, greater than or about 10 pm, greater than or about 15 pm, greater than or about 20 pm, or greater than or about 25 pm. The array of holes can be fabricated using a method selected from the list including but not limited to laser drilling including but not limited to UV lasers such as solid state or excimer lasers, diode pumped lasers, frequency doubled lasers, frequency tripled lasers; MEMS fabrication, molding, machining, 3D printing, stereo lithography, water jet, wire EDM, and the like. A surface treatment may be applied to the exit side of the array to improve aerosolization performance. By way of example, if the formulation is an aqueous formulation, then a hydrophobic treatment may improve aerosol performance. In another embodiment, a hydrophobic treatment may be applied to the entrance side of the array in order to prevent liquid egress out of the apertures in the array. This hydrophobic treatment, may, in one embodiment, be tailored to prevent liquid egress out of the apertures at atmospheric pressure, within a range of pressures, or up to a specific pressure, which pressure may be (gauge pressure) about 0.25 kPa or more, about 0. 5 kPa or more about 0.75 kPa or more, about 1 kPa or more, about 2 kPa or more. Preferably the hydrophobic treatment is sufficient to prevent liquid egress at a pressure head equal to the maximum height of the formulation chamber above the aerosolizer when the inhaler is in an orientation where the chamber is directly above the formulation chamber. Preferred treatments include plasma treatment, silicone, fluorine-based liquids or polymers, and waxes.

[0155] In a preferred embodiment, the aerosolizer is contained within the cartridge, wherein the aerosolization head comprises the aerosolizer, a pocket directly behind the aerosolizer holding a formulation or a mixture of formulations and an entry port for formulation to be introduced intothe pocket. Preferably the aerosolization head, one or more formulation chambers containing one or more formulations, and a cavity that surrounds the formulation chamber or chambers are integrated into the cartridge. In a preferred embodiment there is a formulation pocket in the aerosolization head directly behind the nozzle array. Preferably this pocket is substantially filled with a formulation or mixture of formulations, and the formulation is in contact with the back of the substrate in the area of the nozzle array. In a preferred embodiment the aerosolizer, on the orifice entrance side, is in direct fluid contact with the formulation or mixture of formulations in the pocket. The formulation pocket may also contain air, including air introduced into the pocket as a byproduct of the aerosolization process. It is important that the air in the pocket be removed so that it does not displace the formulation in contact with the substrate and / or cause a loss of prime of the pump.

[0156] In one embodiment, the pocket, and similarly the formulation cavity or container is constructed of a relatively hard material, such as a plastic or metal material, including but not limited to PE, PS, PP, PET, stainless steel, aluminum and the like, and the pocket may be entirely enclosed other than a path for ingress, and optionally a path for egress, of formulation.

[0157] In a preferred embodiment, an air release opening may be covered with a porous material, preferably a hydrophobic or superhydrophobic porous material, wherein the porous hydrophobic material allows for air to exit through the opening and prevents, or substantially prevents the exit of formulation through the opening. This porous material may be, but is not limited to, a metal mesh, a plastic mesh, or, in a preferred embodiment, a PFTE or PE material, preferably an expanded or sintered PTFE or PE material. A hydrophobic coating or process may be applied to these materials to enhance their hydrophobicity. The opening may be a large area, for example comprising a wall of or essentially the entire surface of the formulation pocket not closed by the aerosolizer. In this embodiment the porous material that comprises the formulation pocket may allow air to exit from the formulation pocket at any point along the porous material, preventing the creation of an air-filled headspace within the formulation pocket.

[0158] In a preferred embodiment the cartridge may contain a system for recirculating formulation or mixture of formulations, hereinafter referred to as a recirculation system. In a preferred embodiment a first flow channel extends from the formulation chamber to one or morepumping elements, a second flow channel extends from the pumping element to the pocket, and a third flow channel extends from the pocket to the first flow channel, creating a flow loop that enables recirculation. These flow channels may be, but are not limited to, tubes, channels, or mixtures thereof. The recirculation system has numerous advantages. One is that the amount of formulation that is pumped into the pocket need not be exquisitely controlled such that there is not too little formulation pumped into the pocket, which over time can lead to air filling the pocket and failure of aerosolization. Similarly, if too much formulation is pumped into the pocket, the pressure can rise, leading to leakage through the nozzles. In addition, the recirculation system enables the use of a filter and / or a debubbler, as discussed below.

[0159] In a preferred embodiment, situated in or at an end of one or more the flow channels is a debubbler, wherein the flow through the one or more flow channels flows through the one or more debubblers. In a preferred embodiment the debubbler comprises at least one debubbler channel configured to allow flow through the debubbler, preferably a multiplicity of the channels, preferably wherein the channels are narrow channels, wherein at least one surface of each channel is formed by a porous material and flow through the debubbler brings the formulation in the recirculation system into contact with the porous material upon which the air is expelled out of the porous material. Preferably the porous material is as described above, most preferably an expanded or sintered PTFE or PE material. In a preferred embodiment there is a restriction in the flow channel downstream from the debubbler, wherein this restriction increases the pressure within the debubbler to increase the amount or rate of air clearance through the porous material. The recirculation system described above allows for pumping of an amount of formulation that ensures complete debubbling of the formulation without overly pressuring the pocket.

[0160] In a preferred embodiment, the porous material is held taut against a surface by means of compression. In another embodiment the porous material may be held taut against the surface by means including, but not limited to, gluing, taping, chemically binding, or mechanically clamping. In the process of clamping, the porous material may be stretched beyond its natural state. In this embodiment, when formulation flows under the porous material at a pressure above atmospheric pressure it deforms the porous material away from the contacting surface. This creates a small cavity behind the porous material for liquid flow. When the formulation stops flowing through the debubbler the porous material rebounds to its starting position, reducing or eliminating thevolume of the small cavity and pushing the formulation out of the exit and / or entrance of the debubbler, minimizing the amount of formulation that may remain in contact with the porous material, thereby limiting the amount of carrier that can evaporate through the porous material. In one embodiment the air that is expelled through the porous material is expelled out of the cartridge, wherein this may be accomplished by having the porous material positioned on the exterior surface of the cartridge. In another embodiment air exits the cartridge via a passageway connecting the debubbler to the surface of the aerosolization head. In another embodiment the air that is expelled from the debubbler flows into the formulation cavity, wherein the reduced pressure that is created in the formulation cavity by formulation being pumped out of the formulations chamber(s) pulls the air from the debubbler, thereby restoring the pressure in the formulation cavity substantially to atmospheric pressure. In a particularly preferred embodiment, there is a debubbler cavity attached to the back of the debubbler, wherein the air and any water vapor that exits from the porous material of the debubbler enters the debubbler cavity. The debubbler cavity may be a plastic molded manifold with a multiplicity of, or preferably one, hole, wherein this hole is preferably less than about 5mm in diameter, more preferably less than about 4 mm, more preferably less than about 3 mm, more preferably less about than 2 mm, more preferably less than about 1 mm, more preferably less than about 0.5mm, and most preferably less than about 0.1mm in diameter (or the equivalent area if the hole is not a circle). This small hole allows the pressure increase in the cavity from the air that exits from the debubbler to be released out of the hole, but limits evaporation of formulation carrier through the porous material of the debubbler between dosing events. Preferably the rate of evaporation from the system from all sources (including the debubbler and the nozzle array) is less than or about 20 pl / day, less than or about 10 pl / day, less than or about 5 pl / day, less than or about 2.5 pl / day, or less than or about 1 pl / day.

[0161] In one embodiment the recirculation system may additionally contain an aseptic filter, preferably a filter with a pore size of about 0.1 to about 0.5 pm, about 0.15 to about 0.3 pm, preferably about 0.2 pm, about 0.22 pm, or about 0.1 pm, to remove particulates and bacteria from the formulation. In a preferred embodiment the aseptic filter is located in the second channel, between the pump and the formulation pocket, in order that the high pressure required to force formulation through the aseptic filter is not present in the pocket and therefore does not force formulation out of the nozzle holes. This design ensures that the formulation which enters thepocket, and which is subsequently aerosolized and inhaled by the user is made free of bacteria and particles that might pose a danger to the user and also might block nozzle holes. The aseptic filter is preferably a filter that is designed to be used for aseptic filling of aqueous formulations in the medical industry. The aseptic filter may be hydrophobic or hydrophilic, wherein a preferred embodiment would use a hydrophilic membrane.

[0162] In one embodiment, the formulation chamber is flexible and maintained in liquid contact with the recirculation system. If there is a reduction in surrounding air pressure, for example due to weather or an increase in altitude, the expansion of any air bubble in the recirculation system will expand the formulation chamber rather than forcing liquid out of the nozzle. The expandable formulation chamber may be left open to the recirculation system at all times or may be opened and closed under the control of an electronically enabled valve or clamp in order to properly regulate the pressure of the recirculation system by allowing for flow into and out of the formulation chamber to keep the system at, or approximately at, atmospheric pressure as it experiences pressure changes in the external environment, altitude, or changes in orientation.

[0163] In one embodiment, the formulation chamber is filled such that it contains little or no headspace. Preferably the headspace is sufficiently low such that if all of the headspace is drawn out of the chamber during normal operation, it does not significantly disrupt aerosolization or cause a loss of prime. Preferably the chamber shape and orientation are such that if the device is used and the pump is activated in any expected orientation, preferably in an orientation that the label says it should be used in, the headspace is in a location in the formulation chamber wherein it would not be drawn out of the chamber, for example where the headspace is higher than the outlet of the formulation chamber due to the buoyancy of the headspace. Preferably the system is such that if all of the headspace is drawn out of the chamber during priming or use it is released out of the debubbler and does not impact the prime.

[0164] In one embodiment the formulation chamber is both flexible and compliant. This compliant nature allows the material that comprises the formulation chamber to stretch and for the chamber to be ‘overfilled’, such that the pressure in the overfilled chamber is higher than atmospheric pressure. The formulation chamber should be overfilled with a volume that is sufficient to create a pressure that will enable the system to prime in an any orientation even theones where the formulation chamber is creating a negative pressure head. To achieve this, the compliance of the chamber and any compliant tubing can be optimized such that the required overfill volume is achieved at a pressure which is high enough to force the overfill volume out of the chamber during priming, but not so high that it impacts the functioning of the clamp or the stability of the formulation and chamber during storage. In one embodiment the formulation chamber may be overfilled by a volume less than or equivalent to the volume of the loop of the recirculation system, such that after priming the formulation chamber has been depleted of the full volume that it was overfilled with and the pressure within the formulation chamber when the device is at rest has returned to atmospheric pressure. Due to the cartridge design of the invention disclosed herein, a user will be attaching multiple unprimed cartridges during the time they use the product. This compliant formulation chamber provides an efficient priming mechanism that requires little to no extra steps on behalf of the user.

[0165] In another embodiment, the formulation chamber is filled and closed such that the pressure in the chamber on storage is approximately equal to atmospheric pressure. In this embodiment, the act of attaching the cartridge to the durable pressurizes the formulation chamber to enable priming. This can be accomplished by having a chamber compressing element that extends out of the durable unit; enters into the formulation cavity; and compresses the formulation chamber; or preferably a chamber compressing element that is captured in the cartridge and is forced forward when the cartridge is attached to the durable unit, either by an actuating element that extends out of the durable unit and enters the cartridge, or by the chamber compressing element extending out of the cartridge and being pressed into the cartridge by the durable unit. The sequence of events may be as follows: The user is informed that cartridge is spent and needs to be replaced. The user removes and disposes of the spent cartridge. The user then acquires another cartridge and pushes it onto the durable, whereupon the chamber compressing element is forced forward and begins to compress the formulation chamber. As the user continues to push the cartridge toward the durable, the formulation chamber is opened. In one embodiment, this is accomplished by an actuator attached to the durable, for example a pin protruding from the durable, or from a chamber compressing element, into the cartridge, opening a clamp or valve. In another embodiment, the formulation chamber is opened by the pressurization of the formulation chamber causing a peel seal to peel open in a controlled region to form a flow channel out of theformulation chamber. This controlled area may be defined by a clamping mechanism that has a relief or opening in the controlled region, a peel seal in the controlled region which is weaker as compared to a seal around the remainder of the perimeter of the formulation chamber, for example a weaker heat seal in the controlled region, or a combination of the two. The weaker seal may be accomplished by a weaker adhesive, or a different heat seal coating. Preferably the weaker seal is a weaker heat seal formed from the same material that is used to heat seal two or more layers of the chamber together and is made weaker by the use during sealing of a different temperature in the controlled region, a different dwell time in the controlled region, a different heat-sealing pressure in the controlled region, or a combination thereof. In the embodiment where the formulation chamber is opened by opening a mechanical clamp, the clamp is made from a rigid material such as spring steel, preferably a polymer for example a nylon, preferably a glass filled nylon. Preferably the mechanical clamp is opened when the cartridge is attached to the durable, for example by pin or cam that extends from durable unit or from a chamber compressing element.

[0166] One observed effect that is present in multiple embodiments, including that of the recirculation system, is the leaking of formulation, particularly nicotine formulation, out of the nozzle holes in the piezoelectric aerosolizer. There are a number of ways to mitigate this effect, including but not limited to the methods described in this paragraph. In one embodiment the substrate of the piezoelectric aerosolizer is hydrophobic, which may be accomplished by the means of utilizing a hydrophobic or superhydrophobic material for the substrate and / or adding a hydrophobic or superhydrophobic surface treatment to the substrate, which may be accomplished using a plasma treatment, evaporative hydrophobic coating, or other treatment. The aforementioned methods may be used in isolation or combination with one another and may be applied to the interior side of the substrate (the side exposed to the pocket), the exterior side of the substrate (the side exposed to the air channel), or both sides of the substrate. With reference to a surface treatment, a particular hydrophobicity may be accomplished by adjusting the thickness of the treatment that is applied to the surface of the substrate. In one embodiment the hydrophobicity will be optimized using this method of adjusting the thickness of the surface treatment to prevent solution from leaking out of the nozzle holes when the device is not generating an aerosol while still enabling proper passage of the formulation through the nozzle holes during aerosolization to create a respirable aerosol plume. In one embodiment a check valvemay be placed in the recirculation system, preferably between the formulation chamber and the formulation pocket, preferably in the third flow channel. This check valve may be, but is not limited to, a duckbill valve, an umbrella valve, a Belleville valve, a ball valve, a dome valve, a cross-slit valve, an x-fragm valve, or any combination thereof. This valve may have a positive cracking pressure, or may have a cracking pressure of zero, such that formulation can only flow through the valve in one direction, which is the direction in which the pumping mechanism pumps the formulation through the recirculation system. By placing this one-way check valve downstream from the debubbler, formulation is prevented from flowing in the backward direction from the formulation chamber, through the debubbler, and into the pocket, which may otherwise occur if a check valve is not used. This backward flow may be caused by a gravitationally induced pressure differential between the formulation chamber and the pocket, as there are multiple orientations in which the device can be held where the formulation chamber is above the pocket. This pressure difference may cause formulation to flow in the backward direction through the third flow channel, and result in formulation leaking through the nozzle holes as the system attempts to equilibrate the pressure. The one-way check valve positioned in the third flow channel will prevent this backwards flow and eliminate the leaking effect that may be caused from the pressure head between the formulation chamber and the pocket.

[0167] In another embodiment which may or may not be used with the check valve described above, is a nozzle plug that blocks the exit of one or more nozzle holes between uses of the device. Preferably the nozzle plug is compliant so that it forms a good seal in the event, for example, of a nozzle array that is on a dimple in a substrate. Preferred materials for the nozzle plug include silicone, which is overmolded onto a rigid material, preferably a polymer. Preferably, the nozzle plug is incorporated into mouthpiece cap and is removed and replaced when the mouthpiece cap is moved and replaced. In addition to stopping formulation from leaking out of the nozzles as described above, the nozzle plug has other advantages such as limiting evaporation of a carrier and preventing contamination of the formulation.

[0168] In another embodiment the peristaltic pump is designed such that at every point of rotation the tubing is fully compressed between the compressing element and the shoulder of the peristaltic pump, sealing off any liquid flow and eliminating nozzle leakage caused by pressure transmitted to the pocket through the pump. This pump design serves a similar function to thecheck valve mentioned above and may be used in conjunction with the check valve and / or the nozzle plug. The check valve, nozzle plug, and / or the peristaltic pump design may be used in combination with a hydrophobic substrate or treatment.

[0169] One problem with peristaltic pumps is that the tubing running through the pump can take a set due to creep, which can reduce pumping rate. This problem is especially significant during storage, where the mechanism that sequentially compresses the tubing in the pump head will be in a fixed position for as long as 1 year, 2 years, or even more. This problem is especially acute if the fixed position is close to the pump inlet. The permanent compression of the tubing, exacerbated by the reduced pressure downstream from the pump inlet when the pump is running, can significantly slow or even completely block flow through the pump. To address this issue, the orientation of the compressing member during storage can be set so that the tubing is compressed close to the pump exit. Even if this section of the tubing takes a set, as the pump sequentially compresses sections of the tubing upstream from the location of the set the elevated pressure due to the pumping action will keep the tubing open in the location of the set, significantly reducing and potentially even substantially eliminating any reduction in pumping rate cause by the set.

[0170] In one embodiment the pumping mechanism is actuated in the backward direction after aerosolization. This may occur, but is not limited to, after each puff, a set number of puffs, a dosing event, a set number of dosing events, every day, or a set number of days. This may be implemented to alleviate an undesirable leaking effect that can be caused by the presence of an air bubble between the pump and the pocket. For example, if an aseptic filter does not allow air to pass through it. When a hydrophilic aseptic filter is used, air that is in the recirculation system may become trapped at the entrance side of the aseptic filter and become compressed while the pumping system is pumping in the forward direction. When the pump stops actuating (i.e., the puff is over) the pressurized air bubble may begin to expand, creating an increased pressure within the recirculation system that forces formulation out of the nozzle holes to equilibrate. In this instance, implementing a period of ‘backward pumping’ will pump formulation from the loop of the recirculation system and back into the formulation chamber, allowing the increased volume of the expanding air bubble to be offset by a decrease in the volume of formulation in the loop such that no formulation is forced out of the nozzle holes.

[0171] In an alternate embodiment the aseptic filter may be contained within an aseptic filter housing that incorporates a debubbler to prevent the buildup of air at the entrance side of the aseptic filter. By way of example, the aseptic filter housing may be a box, wherein one face of the box comprises an aseptic filtering material and one, many, or every other face of the box comprises a debubbler material, preferably the same debubbler material that is mentioned elsewhere in this disclosure. In a preferred embodiment, the debubbler material and the filter material are contained in a housing and are very close to each other, preferably in contact, when there is no pressure in the system. When the pump runs, formulation is introduced between the filter material and the debubbler material. This formulation will be at the pressure required to pump liquid at the pumping rate through the filter. This pressure will separate the two materials, creating a path for flow of the formulation. The pressure will additionally force any air in the system through the debubbler. Because the gap between the two material is small even when pressurized, any air is in intimate contact with the debubbler and will be efficiently removed. In this embodiment, air that builds up at the entrance side of the aseptic filter will escape the recirculation system through the debubbler material, eliminating the concern of the air bubble expansion increasing the pressure of the loop and forcing formulation out of the nozzle holes. This aseptic filter housing that includes a debubbler element may be used in combination with reverse pumping. In an alternative embodiment the aseptic filter may be comprised of a hydrophobic material that allows air to pass through it, alleviating the aforementioned problem and need for reverse pumping. Any of these embodiments may also be used in combination with a hydrophobic nozzle substrate or coating and the use of a one-way check valve downstream from the debubbler.

[0172] In another embodiment, the aerosol head contains an aerosol head cavity, adjacent to and optionally at least partially surrounding the formulation pocket and debubbler. In one embodiment the aerosol head cavity may also contain an absorbent material, which may be, but is not limited to, a sponge, foam, cloth, paper, or other absorbent material. In this embodiment any formulation or carrier that does exit through the debubbler material, condenses in the aerosol head cavity, or otherwise enters the aerosol head cavity, will be absorbed into the absorbent material.

[0173] The aerosolizer is positioned such that aerosol is generated into the device air channel. For example, in the embodiment wherein the aerosolizer is a vibrating mesh aerosolizer, the side of the substrate that contains the exit orifice(s), herein referred to as the exit side, is flush, orsubstantially flush, with a wall of the air channel. When actuated, the aerosolizer injects formulation into the air channel essentially perpendicularly to the direction of the air flow that is generated by the user, herein referred to as the dilution air, wherein the dilution air entrains the formulation at a 90° angle and carries into the user’s respiratory tract. In one embodiment, the formulation is injected into the air channel over a range of angles, and the average direction of the introduction of the formulation into the air channel is essentially perpendicular to the average direction of airflow or substantially perpendicular to the airflow nearest the aerosolizer. The user inhales through this air channel via a mouthpiece that extends from the end of the air channel, wherein this mouthpiece may be a hollow or partially hollow cavity of varying lengths, shapes, and sizes. Preferably the mouthpiece, and at least a section of the air channel, are part of the cartridge.

[0174] The air channel in the cartridge originates upstream from the point of aerosol generation and ends at the tip of the mouthpiece that is inserted into the user’s mouth, downstream from the point of aerosol generation. The air channel may be curved upstream from the point of aerosol generation and straight at and downstream from the point of aerosol generation, may be straight or substantially straight throughout the length of the air channel. In another embodiment the centerline of the air channel may be substantially straight downstream from the point of aerosol generation, and the walls may have a slight divergent angle, preferably the walls diverge from the centerline at an angle of less than or about 7° beginning at a point downstream of the point of aerosol generation and continuing as far as to the tip of the mouthpiece that is inserted into the user’s mouth. The interior walls of the air channel may, in one embodiment, contain an arrangement of extrusions and grooves, running either vertically, horizontally, or a combination of both, such that they create a purposeful turbulence that is intended to separate aerosol particles before they agglomerate. In a preferred embodiment the inside walls of the air channel are smooth or substantially smooth to allow for uniform flow.

[0175] In a preferred embodiment, the centerline of the air channel in the cartridge is essentially straight, is essentially perpendicular to the average direction that the formulation is injected into the air channel, and a wall of the air channel diverges at least over part of the length of the air channel. In another embodiment, the aerosolizer is in the diverging part of the air channel, and thus injects the aerosol into the flow at an average angle from perpendicular to the centerline, saidangle being equal to the divergence angle of the wall into which the aerosolizer is placed. Preferably one wall is comprised of a substrate, and that wall is substantially planar proximal to the aerosolizer. Preferably the air channel cross section is rectangular, and preferably two or more walls diverge. Preferably the divergence angle from the centerline of the air channel is less than or about 7°. Preferably the divergence begins near the aerosolizer, somewhat distal to the aerosolizer, or preferably close to the proximal edge of the aerosolizer. In the embodiment where two wall diverge, preferably they both begin to diverge at the same location in the air channel. In one embodiment, the divergence of the wall from which the formulation is injected into the air channel starts to diverge somewhat distal to where the opposite wall starts to diverge. There are many advantages to this configuration. Diverging walls will be less likely to be impacted by aerosol particles. Diverging walls with a divergence angle less than 7° will insure that flow stays attached to the walls, reducing the inhalation pressure required to achieve a given flow rate, and furthermore will slow down the aerosol, resulting in reduce deposition in the back of the user’s throat.

[0176] In a preferred embodiment, the air channel in the cartridge has at least one divergence angle, and the plug has a face with a similar angle, and upon insertion of the plug into the air channel, the divergence angle acts as a cam surface and forces the compliant portion of the plug down onto a nozzle, ensuring a good seal.

[0177] To prevent evaporation of formulation from the aerosolization head, the formulation pocket is preferably substantially completely sealed in the aerosolization head, with, for example, the only openings leading to one or more first flow channels, the array of nozzle holes, and preferably one or more opening(s) to allow for flow out of the formulation pocket to one or more second flow channels. In one embodiment, in order to limit evaporation of formulation carrier through the nozzle holes and also to limit drying of formulation and creation of solids from formulation deposited at the exit side of the nozzle due to said evaporation, the exit side of the array is sealed between doses by a sealing system that can be removably positioned in a first position to isolate the nozzles from the air outside of the device when between doses or puffs, and can be moved to a second position prior to when a user is inhaling through the air channel. In one embodiment of the sealing system, when the sealing system is in the first position between uses of the device, it will substantially seal a region around the exit of the nozzle array to maintain thatregion as essentially 100% relative humidity (due to evaporation of carrier from formulation that has deposited outside of the nozzles) and thereby keep the wicking element or formulation pocket from losing carrier and increasing concentration due to diffusion of formulation carrier through the nozzle holes. In addition, any formulation coating the exit side of the substrate after aerosol generation cannot evaporate in the high relative humidity environment, and therefore cannot leave a layer of dried formulation components that can disrupt subsequent aerosol generation. The closing of the sealing system in the first position can be accomplished by an element that blocks the air into and out of all of or a section of the air channel. In one embodiment, the sealing is accomplished by a moveable element that blocks the entrance to the air channel in combination with a mouthpiece cap that is replaced by the user after dosing In this embodiment the region of the air channel that is sealed off from the surrounding air is an air-tight, or substantially air-tight, air-filled space, wherein aerosol droplets deposited by the preceding dosing event are on the air channel walls due to mechanisms including turbulent deposition, inertial impaction, interception, and gravitational settling. In a preferred embodiment, the aerosol sealing system is optimized such that the amount of formulation deposited on the walls is more than enough or essentially just enough to saturate the air contained in the sealed off section of the air channel with evaporated carrier, inhibiting further evaporation of carrier or drying of the formulation that is in, on, or around the nozzles or the exit side of the array of nozzles. In another embodiment the sealing system comprises a lever arm or the like with a compliant element on one end, which compliant element may be comprised of, but is not limited to, a material selected from silicone, rubber, PTFE, a closed cell foam, or another flexible material, whereupon the material is in contact with the substrate and blocks all or substantially all of the nozzles of the array when in the first position, to prevent formulation leakage, evaporation, and drying. In another embodiment, an additional material which is attached to the compliant material and is in contact with the nozzles and is absorbent, and absorbs any formulation deposited on the substrate. In one embodiment, the movement of the sealing system from the first to the second position is accomplished by the pressure of a user inhaling through the air channel. In another embodiment the movement of the sealing system is accomplished by means of an electromechanical actuator powered by a system battery and controlled by a microcontroller. In one embodiment the opening and closing of the sealing system is actuated by the force of the user pressing a button, which preferably also readiesthe device for delivery and / or triggers the start of aerosol generation. In one embodiment this may be a mechanical system, wherein the moving of the sealing mechanism to the second position is powered by the physical force of the user pushing the button. In another embodiment, the moving is accomplished by an electro-mechanical system that is triggered by the user pressing the button. In one embodiment, the sealing system is returned to the first position by an electro-mechanical actuator. In another embodiment, the system is returned to the first position by a return spring or the like. In one embodiment, aerosol generation is stopped when the user releases the button, or when a predetermined amount of formulation has been aerosolized, whichever comes first, and the sealing system is returned to its position sealing the nozzle array after a predetermined delay to allow the user to inhale the aerosol deep into their lungs. In yet another embodiment, the sealing system is comprised of a nozzle plug that is integrated into a mouthpiece cap that is removed prior to dosing and replaced after dosing. Preferably the nozzle plug is comprised of a compliant element as described above and is further comprised of a protuberance that contacts and block the exit of the nozzle holes.

[0178] In one embodiment the wicking element of the formulation pocket absorbs any liquid that remains on, in, or around the nozzles after aerosolization has ended. This will prevent liquid from drying in and around the nozzles, which might otherwise result in dried formulation components and disrupt future aerosolization. The wicking element may accomplish this in any orientation, including being positioned entirely or partly flush, or angled, against the entrance-side of the array of nozzles on the aerosolizer. In another embodiment a reduced pressure may be created within the aerosolization head, or components of the aerosolization head, such that, at the end of aerosolization, the pressure in the formulation pocket is below atmospheric pressure, whereupon air will flow into the formulation pocket of the aerosolization head through a nozzle or nozzles, and may suck in any formulation that is in, on, or around the nozzles after aerosolization has ended. This may be accomplished, for example, by running a pumping element backward, or by limiting the rate at which air can flow into the formulation cavity, resulting in reduced pressure and expansion of the formulation pocket after aerosolization.

[0179] In a preferred embodiment, the aerosol is generated into an air channel at an essentially 90° angle to the direction of dilution air flow through the air channel. In this embodiment, the dilution air flow, as generated by the user inhaling, entrains the aerosol at a 90° angle and carriesit out of the air channel and into the user’s mouth and lungs via the mouthpiece. In a preferred embodiment the airflow through the air channel is laminar, or substantially laminar, flow. To reduce the amount of aerosol deposited on the air channel walls a preferred embodiment contains a pressure sensor that detects a pressure drop distal to an orifice plate in the air channel when the user is inhaling and based on previous calibration of the measured pressure drop thereby calculates an inhalation flow rate. After a user starts inhaling, the controller energizes or continues energizing the aerosolizer only if it determines that the user is inhaling in a predetermined inhalation flow rate range. This ensures that aerosol is only generated when there is a sufficient amount of dilution air flowing through the air channel to entrain the aerosol and carry it into the user’s mouth and lungs, and not so rapidly that there is increased aerosol deposition in the air channel, user mouth and throat, and in the conducting airways of the user’s lungs. Preferably the inhalation flow rate minimum is between about 5 and about 60 LPM, about 7.5 and about 40 LPM, about 10 and about 20 1pm, or is about 15 LPM. Preferably the inhalation flow rate maximum is between about 15 and about 100 LPM, about 20 and about 60 LPM, about 30 and about 50 1pm, or is about 45 LPM. In a preferred embodiment the aerosol is generated for a targeted amount of time unless the user’s inhalation flow rate drops below the inhalation flowrate minimum, or the user’s inhalation flow rate exceeds the inhalation flow rate maximum while the aerosol is being generated, in which case the controller senses the incorrect inhalation airflow rate and stops the aerosolization. In one embodiment, the controller calculates an inhaled volume, for example by integrating the inhalation flow rate over time. In this embodiment, the controller turns on or keeps on the aerosolizer if and only if the user’s inhalation flow rate is in withing the inhalation flow rate range, the target of aerosolization time has not been reached, and the controller estimates that the user has sufficient remaining lung volume to inhale the aerosol deep into their lungs. Preferably, the generation is disabled when the user has inhaled 1 liter or more, 1.25 liter or more, 1.5 liter or more, or 2 liters or more. In one embodiment, if the aerosol generation was stopped before the fixed amount of time was reached because the inhalation flow rate went outside the inhalation flow rate range, the controller will re-start aerosol generation if the user again achieves an inhalation flow rate within the inhalation flow rate range while still having sufficient lung volume remaining to fully inhale the aerosol into the deep lung. Preferably the controller will not energize the aerosol if a volume of about 4.5 liters or more, about 4 liters or more, about 3.5 litersor more, about 3 liters or more, about 2.5 liters or more, or about 2 liters or more, or about 1.5 liters or more have been inhaled during a puff. In the case that the target fixed amount of aerosolization time is not achieved, an amount of formulation delivered to the aerosolization head is reduced accordingly (for example by reducing the duration of pumping formulation around the recirculation system) to maintain an ideal pressure within the formulation pocket In one embodiment the device will delay the onset of aerosolization to a time somewhat after when the inhalation flow rate minimum has first been exceeded during a puff. This is done to avoid turning on the aerosol in the situation where the user is going to inhale too rapidly, i.e., the inhalation flow rates starts at zero, rises through the inhalation flow rate minimum, continues to rise relatively quickly to above the flow rate maximum. For example, the aerosol may be delayed by about 10 ms, by about 25 ms, by about 50 ms, by about 75 ms, by about 100 ms, by about 150 ms, by about 200 ms, by about 250 ms, by about 300 ms, by about 400 ms, or by about 500 ms from when the inhalation rate is first measured to exceed the inhalation flow rate minimum. To guide the user to inhale at the correct flow rate, the device may present a signal, such as a sound, vibration, or preferably a light when an adequate flow rate is achieved. Preferably the device incorporates one or more lights, such as LED lights. In a preferred embodiment, the device is comprised of a multi color LED. In one embodiment, the user is presented with a steady light, for example a green or blue light, when the user is inhaling withing a predetermined optimal range of flow rates, no light when the user inhaling at a flow rate below the optimal range, and a different, for example red and / or flashing light, when the inhalation flow rate is above the optimal range. This same light may also, for example, flash slowly blue when the inhaler is ready to deliver a puff, or slowly red when the device is on but not ready to deliver a puff, for example when the user has reached the maximum number of puffs in a dosing event, the battery needs charging, and / or the cartridge needs to be replaced due to being spent or expired.

[0180] Preferably, a mouthpiece is rigidly attached to the cartridge housing, more preferably is a feature that is machined, preferably molded, as a part of the cartridge housing. Preferably the atomizer is configured such that a piezo ring is attached to a substrate on the side of the substrate away from the air channel, and the perimeter of the substrate is flush with the air channel wall, to prevent a step which can result in non-laminar flow, for example recirculation flow, and thereby cause aerosol deposition in the air channel. Preferably the aerosolization head contains a structurethat prevents the aerosolizer from becoming dislodged or falling into the air channel. Preferably the aerosolizer is not rigidly bonded to the aerosolization head, rather the aerosolizer is bonded to the aerosolization head by a process or material, including but not limited to silicone adhesion, wherein this bonding prevents, or substantially reduces, damping of the oscillations of the piezoelectric transducer in order to avoid a deleterious impact on aerosolization rate and quality. In a preferred embodiment, the adhesive, preferably silicone, also serves to seal the piezo and prevent the leakage of formulation into the air channel.

[0181] The above-mentioned components, the mouthpiece, air channel, aerosolization head, pocket, formulation cavity, channels, tubing, and formulation chambers(s), may be contained in a component referred to as the cartridge. The cartridge comprises four primary components: namely the mouthpiece, the air channel, the aerosolization head and its sub -components, and the formulation containment and delivery system and its sub-components. Other components, including battery, pressure transducers, pump motors, microcontroller, button(s), indicator lights, displays, and other electronic components are contained within the durable unit part of the system, and the cartridge can be removably attached to the durable unit.

[0182] In one embodiment, the inhaler comprises a pump, for example a peristaltic pump comprised of components selected from but not limited to a motor, a gear head, a rotor or eccentric cam, an alignment cam, a ring, a section of flexible tubing, and a support surface for the tubing. In one embodiment of the peristaltic pump a motor turns a rotor, which rotor circularly translates at least one roller, whereupon the roller rolls along a piece of flexible tubing and compresses it against a supporting surface in order to create flow through the tubing. In another embodiment of the peristaltic pump, the motor turns an eccentric cam, wherein this eccentric cam is surrounded by a ring, characterized by being of sufficient diameter that the eccentric cam fits completely within the ring, and whereupon activation of the motor the eccentric cam rotates and thereby translates the ring, causing the ring to sequentially compress sections of the tubing against a supporting surface in a circular pattern, thereby creating flow through the tubing. In an embodiment wherein the system is comprised of a durable unit device and a separable multidose cartridge, the motor, gear head, ring and eccentric cam or rotor are part of the durable unit and the tubing, ring, and support surface are part of the cartridge. In a preferred embodiment the motor and gear head are part of the durable, the eccentric cam and ring, tubing, and support surface arepart of the cartridge and a transmission element that transmits torque from the gear head shaft to the eccentric. The transmission element is comprised of a spring and a pressure plate that are in the durable and a clutch disk that is in the cartridge, along with a drive shaft rigidly attached to the clutch plate and eccentric, with bearings on either side of the eccentric that support the drive shaft against the rotating load of the eccentric. The bearings can be of any suitable design including ball bearings, but are preferably simple bearings, preferably constructed of a lubricious polymer such as Delrin or PTFE.

[0183] In one embodiment the durable unit is comprised of an air channel inlet, wherein the inlet is comprised of two stages of mesh, a first mesh and a second mesh, which regulate the amount of air entering the air channel and the resultant pressure drop in the air channel. The first mesh is positioned on the outside of the device, wherein air must pass through the first mesh to arrive at the second mesh. In one embodiment the first mesh comprises a logo plate, wherein the logo plate is a component that may be fixedly or detachably coupled with the housing of the durable unit of the device or molded as part of the housing of the durable unit. The logo plate also may not be a separate component that is attached, in any way, to the durable unit of the device, but rather a surface that is machined, or otherwise fabricated, into the same surface as the housing of the durable unit of the device. This first mesh may be characterized by having the design of, but not limited to, a company’s name, logo, icon, or other design, trademarked, copyrighted, or otherwise. Said design may form a mesh by utilizing holes, slits, or other through-ways of various shapes and sizes to create the desired design, which will allow air to flow through these through-ways that comprise the design, essentially serving as a mesh. One benefit of this mesh logo design is for the purpose of branding, wherein the first mesh to the air inlet also serves as a means of brand identification and brand design. A second benefit of this mesh logo design is that it makes it very difficult to cover enough of the mesh with the thumb or fore fingers to entirely block or significantly restrict the flow of air through the air inlet and into the air channel. A third benefit of the mesh logo design is that it serves as a barrier to large objects becoming lodged in the air channel. Once air passes through the first mesh it arrives at the second mesh.

[0184] Different amounts of air, depending on how much of the first mesh the user’ s fingers are blocking, may pass through the first mesh. The second mesh is inset within the device and is not accessible to the user, preventing it from being blocked or disrupted by the user holding the device.This second mesh is used to set the airflow and the pressure drop through the air channel, for example to allow for a repeatable pressure drop that can be calibrated to determine flow rate using a pressure transducer. In one embodiment this measurement of the flow rate can be used to turn on aerosol generation when the user achieves a predetermined flow rate, and may also be used to turn off the aerosol generation if the flow rates go outside of a pre-specified range. This second mesh may be machined as a component of the durable unit of the device, wherein any combination of a grid like structure, holes, slits, or other throughways of various shapes and sizes may comprise the second mesh. The second mesh may also be a separate component that is coupled to the durable unit of the device, wherein the mesh material may be, but is not limited to, a plastic, a metal, or fabric mesh material that allows for airflow. The logo plate that contains the first mesh is preferably coupled to the device in such a way that the logo plate is placed over the second mesh. This prevents the user from being able to cover the second mesh with any portion of their hand, since it is positioned behind the logo plate and is not accessible from the exterior face of the device. The second mesh may be significantly more restrictive than the first mesh, such that when the first mesh is partially obstructed due to the hand positioning of the user, the impact of the increased restriction due to the partial obstruction on the calculated flow rate is minimal.

[0185] In one embodiment of the described device, the piezoelectric transducer may be actuated for a “cleaning phase” to perform one or many functions that include, but are not limited to, clearing foreign material, including but not limited to liquid, dried drug formulation, dust, or the like off of a piezoelectric transducer, clearing foreign material off of a substrate that comprises the aerosolizer, clearing foreign material off of an external region of a substrate that is comprised of at least one nozzle hole, clearing foreign material out of one or more nozzles, or clearing any debris, contaminants, or potential clogging materials out of the interior region of a substrate. Said cleaning phase may be accomplished by various means, including but not limited to, increasing a voltage, utilizing a specific wave form, utilizing a different frequency than that which the device is typically operated at, or any combination thereof. The cleaning phase may be run prior to each actuation of the device, after each actuation of the device, or both prior to and after the completion of each actuation of the device. The cleaning phase may also be conducted at specified times during the treatment period, for example, every morning at a specific time or before a first use of a day, for the duration of the device use.

[0186] In one embodiment the pump in the cartridge comprises one or more ball bearings comprised of a multiplicity of balls that maintain a spacing between concentric bearing races. In one embodiment, a ball bearing comprises a pump ring that is fit to a rotating shaft with an eccentric element, hereinafter referred to as the cam shaft, wherein the pump ring rotationally compresses sequential sections of tubing against a stiff wall, hereinafter referred to as the support surface, whereupon this rotational compression of the tubing creates liquid flow through the tubing. The cam shaft is rotated by its connection to a rotating motor shaft, which is rotated by the torque supplied by a motor, wherein the motor is a component of the durable unit of the device. The cam shaft contains an eccentric cam that fits within the center opening of the pump ring. The eccentric cam is fixed to the cam shaft, such that it pushes one section of the pump ring toward the support surface, compressing the tubing at that one point. Because the eccentric cam is fixed to the cam shaft, as the cam shaft rotates the eccentric cam also rotates, creating a force that rotationally pushes out on the ball bearing and compresses the corresponding sections of tubing against the support surface. This rotational compression of the tubing that is created by the eccentric cam offsetting the pump ring creates liquid flow through the tubing. In alternative embodiments this pumping system may utilize a different ring to compress the tubing, which may be, but is not limited to, a PTFE bearing, Delrin bearing, metal bearing, or other bearing or ringshaped component, preferably one made of a lubricious material.

[0187] In one embodiment there is another bearing, preferably two other bearings, which may be of any material construction as is the pump ring referenced above, hereinafter referred to as the stabilizing bearings, preferably with one placed vertically above and the other vertically below the pump ring, still within the cartridge. The stabilizing bearing that is placed vertically above the pump ring may have an outside diameter which is smaller than the outside diameter of the pump ring, while the stabilizing bearing that is placed vertically below the pump ring may have an outside diameter which is larger than the pump ring, thereby simplifying assembly. In a preferred embodiment, one or both of the stabilizing bearings have an inside diameter that is sufficiently smaller than the ring such that when the ring is biased to one side both stabilizing bearings are captured in cylindrical cavities that are concentric with the support surface, such that the cam shaft may run through the center of both bearings and the ring. The stabilizing bearings may, in one embodiment, contain a flange or lip that contacts a corresponding lip in their respective cylindricalcavities to keep them captured within those cavities so that they may move. As the cam shaft rotates, rotationally offsetting the pump ring and compressing the tubing, the force exerted by the pump ring compressing the tubing against the support surface is counteracted by the two stabilizing bearings. This balance of force is necessary for a detachably coupled design between the durable housing and the cartridge, where the motor is housed in the durable component and the pump is housed in the cartridge. This 2-bearing design prevents the torque around the top bearing exerted on the cam shaft by the eccentric from causing the cam shaft, and thereby the clutch plate, from wobbling, and thereby causing the cartridge to lift off the durable or from otherwise moving unintentionally.

[0188] The motor assembly, located in the durable housing, is mechanically and removably connected to the pump head which is located in the cartridge. The end of the motor shaft is fitted with a component that has one or more teeth, grooves, bumps or other alignment features, hereinafter referred to as the pressure plate, wherein alignment features fit into corresponding alignment features in a receiving component that is attached to the bottom end of the cam shaft, hereinafter referred to as the clutch plate. The pressure plate, clutch disk, and a spring that biases the pressure plate forward are hereinafter referred to together as the clutch. When these two components fit together (i.e., the clutch is engaged) the motor rotates the motor shaft, which, because of the mechanical connection, rotates the cam shaft. The rotation of the cam shaft creates liquid flow via the rotational compression of the tubing against the support surface by the pump ring. The pressure plate may be comprised of one or a plurality of teeth, including but not limited to the range of 1 - 25 teeth, preferably 1-10 teeth, more preferably 1-6 teeth. One tooth may be envisioned as a flat blade, similar to the design or function of a flat blade screwdriver. Alternatively, 4 teeth may be envisioned as similar to a Phillips head screwdriver, and 6 teeth may be envisioned as similar to a hex screwdriver or spline wrench.

[0189] In one embodiment the pressure plate may be slidably positioned along the motor shaft and urged toward the end of the shaft by a spring, for example a coil spring which is preferably tapered, wherein the motor shaft runs through the center of the spring. The spring may be fixedly coupled to the pressure plate, or the pressure plate may be resting on the spring. The spring is captured on the motor shaft between the motor and the pressure plate. The end of the pressure plate extends through a hole out of a surface of the durable housing, and when the cartridge andthe durable component are separated, the pressure plate is captured onto the motor shaft, for example by hole being smaller than a lip on the pressure plate. The pressure plate has a hollow cavity or through hole that is approximately the same size and cross-sectional shape as the motor shaft. When the pressure plate is depressed on the motor shaft it compresses the spring. When the pressure plate is released, the spring returns it to the end of the motor shaft. A motor housing is built around the motor, motor shaft, and the pressure plate, wherein the motor housing is an enclosed cavity with a hole in the top, wherein the pressure plate extends through this hole when it is not depressed on the motor shaft (i.e., the spring is in its uncompressed position). The pressure plate contains a circular lip that is extruded around the entire bottom potion component, with this lip having a diameter that is larger than that of the component itself, and also larger than the diameter of the hole in the motor housing. When the spring is in its uncompressed position this lip on the pressure plate contacts the top surface of the motor housing, wherein the portion of the pressure plate that engages with the clutch disk is able to extend through the hole and engage, but the pressure plate remains captured on the motor shaft and cannot be forced off the end of the motor shaft by the force of the spring. The spring is attached to said lip on the pressure plate. The spring may be a cylindrical or conical spring.

[0190] This spring-loaded pressure plate design allows the clutch to engage regardless of the orientation of the two components when they are initially attached. It is likely that, when the durable unit and cartridge are attached, the teeth and corresponding slots on the clutch components, in any embodiment with any number of teeth and slots, may not be aligned in a way that the teeth slide into the slots. This, in an embodiment where the pressure plate is not spring loaded, may prevent the cartridge from being able to be completely and securely attached to the durable with the clutch engaged. The spring loaded pressure plate allows, in an instance where the teeth and slots of the clutch components are initially not aligned, the pressure plate to be depressed on the motor shaft by compressing the spring, allowing the cartridge to be fully and securely attached to the durable unit of the device regardless of the orientation of the clutch components. When the motor is actuated the motor shaft will rotate, rotating the pressure plate, which will allow the teeth on the pressure plate to align with the slots on the clutch disk, whereupon the spring will force the teeth into the corresponding slots, engaging the two components of the clutch, which will, in turn, rotate the cam shaft and result in effective liquidpumping. In one embodiment, the motor-clutch and clutch disks may be switched, such that the pressure plate contains the slots, and the clutch disk contains the teeth.

[0191] In one embodiment the connection between the durable unit of the device and the cartridge is partially or entirely secured by magnets placed in one or both the durable, the cartridge.

[0192] In one embodiment the disclosed system may contain code that automatically shuts off all device functionality after a prespecified amount of time, for example 90 days, or after a prespecified number of puffs. This may be done to prevent abuse and misuse of the system for longer than the intended treatment duration and to eliminate or significantly reduce the risk of a user becoming addicted to the product. The code may also lock out the user from using it for a pre-specified amount of time after each use or limit the amount of nicotine delivered in a prespecified amount of time, for example per hour or per day. In a preferred embodiment, there is a mechanism to turn on or wake up the controller, for example pressing a button or removing a mouthpiece cap. In the embodiment with the mouthpiece cap, the device preferably is turned off by replacing the cap. In the embodiment with the button, the device preferably turns off automatically after a predetermined amount of time.

[0193] In one embodiment the formulation chamber is a flexible bag, as described above, that comprises two pieces of material that are folded and sealed together to create a voluminous chamber. To accomplish this, two pieces of material are used, wherein these pieces of material may have the shape approximate to a kite, with two short sides of equal length meeting at a point, hereinafter referred to as the top point, two long sides of equal length meeting at an opposing point, hereinafter referred to as the bottom point, and with the short sides and long sides meeting at points hereinafter referred to as the side points. A heat seal between the two pieces of material may be placed along the two short sides, creating an airtight seal from one side point to the top point, to the opposing side point. The heat seal may further be placed down the length of the long sides, but not all the way to the bottom point, such that a piece of tubing may be inserted inside the formulation chamber at the bottom point. The top kite shaped piece of material may then be creased, beginning at the bottom point and running into the center of the material, whereupon this crease may be heat sealed to form a ridge on the material. A similar ridge may be created on thebottom piece of material. The remaining length of the long sides may now be heat sealed as close to the piece of tubing that is inserted into the bag as possible. This creates four flaps of material (the two ridges and the two heat-sealed lengths of the long sides), which all may be wrapped in the same direction around the piece of tubing that is inserted into the formulation chamber at the bottom point. In one embodiment these flaps may be partially cut to make it easier to wrap the flaps around the tubing. These flaps may be sealed to the tubing using a component that may be, but is not limited to, one piece of heat shrink tubing, multiple pieces of heat shrinking tubing, an adhesive, or other means. The ridges that are formed on the top and bottom pieces of material that form the bag are responsible for creating an expandable structure, wherein this bag may be inflated to a specific volume that is dependent, among other factors, on the size of the ridge that is created along the two surfaces of the bag and may be entirely deflated to an internal volume of approximately 0ml.

[0194] Preferably, the exit of the one or more formulation chambers are closed before the cartridge is first used to ensure that the one or more contained formulations are only in contact with the formulation chamber during storage and transport, and only in contact with any tubing, channels, pockets, or aerosolizer during and after first use. This allows the chamber materials to be selected for their long-term storage properties, including but not limited to water (or other carrier) vapor transmission rate, leachables, extractables, sterility, and / or drug stability, and the materials of the other portions of the flow path can be chosen for other properties, including but not limited to mechanical flexibility, ease of manufacture, aerosolization performance, and the like.

[0195] Preferably, in the above-mentioned embodiment, elements selected from but not limited to electronics, a battery, a button, a light, a display, an aerosolizer, a pressure transducer, and pump components selected from but not limited to a motor, gear head, spring, and clutch pressure plate of a peristaltic pump are components of the durable unit, wherein elements selected from but not limited to an aerosolizer, a pump head comprised of elements selected from but not limited to a support surface, flexible tubing, rotor, eccentric, and a ring or rotor; one or more formulations, formulation chambers, flow channels, tubes, filters, and debubblers, are all components of the cartridge. This ensures that the one or more formulations are never in direct fluid contact with any durable unit component of the device and the drug contact surfaces are contained wholly in thecartridge. To accomplish this, the peristaltic pump motor assembly comprised of a motor, gear head, output shaft, spring, and pressure plate and the clutch disk, eccentric cam shaft, pump ring, support surface, tubing, bearings, and formulation will be located in the durable unit such that, when the cartridge is attached to the durable unit, tubing will be positioned to be compressed by with the outer diameter of the ring, both of which are parts of the cartridge, wherein upon actuation of the pump motor which is part of the durable unit, the motor will turn the eccentric cam shaft of the pump which displaces the ring to sequentially compress sections of the tubing in order to create flow. This connection of the two important components of the pumping system, the pump head and the pump motor assembly, will be accomplished solely by attaching the cartridge to the durable unit of the device.

[0196] The durable unit contains elements selected from but not limited to a power source, which may be, but is not limited to, a battery or cell, preferably a rechargeable battery or cell which is preferably comprised of lithium, preferably a single cell of lithium polymer; a printed circuit board, a charging port which is preferably mechanically attached to the printed circuit board and is accessible from the exterior of the device, a circuit for driving the liquid pumping system, a circuit for driving the aerosolizer, one or more lights preferably 3 lights, an optional display, a button, a Bluetooth circuit and at least one pressure sensor. These elements may be discrete subsystems on or off the circuit board, may be incorporated in an application specific integrated circuit, or a combination thereof. Preferably the circuit board powers the functionality of the device and controls the aerosolizer and pumping system, and, in one embodiment, is comprised of a computing system that determines and controls the proper flow rate and dispensed volume for each pump of the pumping system. The computing system controls an element selected from a list including but not limited to the flow rate of one or more pumps, the state of one or more valves controlling flow from one or more formulation chambers, the voltage supplied to an aerosolizer, the amplitude of oscillation of a component of an aerosolizer, a duration of pumping of one or more pumps, a duration of aerosolization of an aerosolizer, such that the amount of nicotine, or other active ingredient, delivered to the user is consistently controlled and lowered or raised over time. For example, upon the initial use of the device, the device may be controlled such that an initial total emitted dose of nicotine per average inhalation is in a range selected from a list including but not limited to from about 0.05 to about 2 mg, from about 0.1 to about 1 mg,from about 0.2 to about 0.5 mg, from about 0.15 to about 0.2 mg, whereupon the amount of nicotine will be decreased, for example the duration of aerosolization of a nicotine containing formulation will be decreased, such that after a period of time selected from about 1 week to about 1 year, about 1 month to about 6 months, about 2 months to about 4 months, preferably about 3 months, 12 weeks, or 90 days, the total emitted dose of nicotine per average inhalation may be approximately 0 mg. This serves as an example only for the purpose of clarification. Preferred starting amounts of nicotine per puff are preferably greater than or about 2 mg / puff, greater than or about 1.5 mg / puff, greater than or about 1.2 mg / puff, greater than or about 1 mg / puff, greater than or about 0.8 mg / puff, greater than or about 0.6 mg / puff, greater than or about 0.5 mg / puff, greater than or about 0.4 mg / puff, or greater than or about 0.3 mg / puff, greater than or about 0.2 mg / puff, greater than or about .15 mg / puff, or greater than or about .01 mg / puff. Ending amounts of nicotine are preferably less than or about 1 mg / puff, less than or about 0.8 mg / puff, less than or about 0.7 mg / puff, less than or about 0.6 mg / puff, less than or about 0.5 mg / puff, less than or about 0.4 mg / puff, less than or about 0.3 mg / puff, less than or about 0.2 mg / puff, less than or about 0.1 mg / puff, or about 0 mg / puff.

[0197] The aerosol device may be connected to other hardware and software companion devices, including but not limited to a cell phone, computer, tablet, smart glasses, and smart watch. These devices may communicate information between each other to diagnose, prevent, mitigate, cure, or treat a disease or health condition, or to inform the diagnosis, prevention, mitigation, cure, or treatment of a disease or health condition, or to provide a person or their physician information and / or data related to a health condition, diagnosis, prognosis, or treatment. In one embodiment, a system may be created that uses biometric data to determine that a person is experiencing, or is about to experience, a craving, whereupon that craving detection can be transmitted to both the aerosol device to ready the device to deliver an aerosol, and to the user to alert them to use their aerosol device to treat their current or impending craving. In one embodiment, this may be accomplished by a smart watch powered detection algorithm, a smart phone, and the aerosol device described herein. In a further embodiment, the operation of the aerosol device may be linked to the craving detection, such that the device is electronically locked and will not generate an aerosol until a craving is detected, which triggers the device to unlock and allows a dose of medicine to be delivered to the user during an inhalation. In this embodiment, the cravingdetection acts as an electronic key that allows the device to deliver a dose of medicine. This system of unlocking the aerosol device only when a craving is detected ensures that both the intended user can’t misuse, overuse, overdose, or otherwise abuse the medication in the aerosol device, and also that only the intended user who is wearing the smartwatch can use the device. If done appropriately, this method of craving detection and just in time intervention to treat the craving may occur in its entirety before the user feels the craving, allowing addiction to be treated without the user ever being exposed to cravings. This method can be applied to sensations conditions including but not limited to craving, pain, onset of migraine, onset of seizure, and the like, and may be used for substances that include, but are not limited to nicotine, opioids, partial opioid agonists, benzodiazepines, alcohol, marijuana, and any other substances of an addictive nature or that can be habit forming and cause dependence. This method may also be used to detect and provide just in time intervention for pain, including but not limited to breakthrough cancer pain and post-surgical pain. In this use case, pain is detected instead of craving, and the aerosol device is unlocked when the pain signal is detected by the algorithm, enabling the user to take a dose of their pain medicine to preemptively eliminate the pain. Many pain indications include the delivery of opioids, and this system allows for the safe and controlled delivery of opioids for pain management while minimizing the risk of misuse, abuse, and overdose by either the user or other people.

[0198] Other possible control functions may include one or more of reducing the amount of medication delivered over time, increasing the amount of medication delivered over time, individual changes in dose based on a prescribing physician’ s instructions, locking the device after a dosing event, unlocking the device based on biometric identification of a prescribed user, locking the device for a predetermined amount of time, or locking the device based on an amount of medication previously used, when a cartridge needs changing, when a battery needs charging, and the like.

[0199] In one embodiment, any of the aerosol device embodiments described above may include 2 piezoelectric aerosolizers instead of 1 piezoelectric aerosolizer, allowing for a greater aerosol output. These piezoelectric aerosolizers may be placed on the same face, the opposite face, or adjacent faces of the air channel. In one embodiment the piezoelectric aerosolizers are positioned directly opposite each other. In another embodiment the piezoelectric aerosolizers are positionedone distal to the other, for example on the same face. In yet another embodiment the piezoelectric aerosolizers are positioned one above the other on opposite or adjacent faces of the air channel.

[0200] Figure 1 shows an embodiment of the current invention comprised of durable unit section 200 and multidose cartridge 300 of the current invention. In the embodiment shown, durable unit section 200 is comprised ofPCB 201, pump motor assembly 202, and battery 203 contained within housing 204. Cartridge 300 is comprised of formulation chamber 301, pump head 302, aerosolizer 304, and mouthpiece 305, comprising or contained within housing 306.

[0201] Figure 2 is a more detailed view of durable unit section 200. In the embodiment shown, PCB 201 is comprised of microcontroller 205, which controls battery charging circuit 206, and aerosolizer controller 208, Bluetooth module 209, and measures air channel pressure using pressure transducer 210. It will be understood that PCB 201 may actually be comprised of two or more separate boards and / or discrete components that are not on an PCB, and further the components of the above functional units may be distributed on different areas or sides of PCB 201. Charging of battery 203, and optionally programming of microcontroller 205 is achieved through connector 211, preferably USB connector 211, accessed by a cable through housing opening 212. Pump controller 213 controls pump motor assembly 214. Housing 204 is comprised of air channel inlet 215. The inlet to air channel 215 is covered by mesh 216. Mesh 216 may be a series of machined or molded slots in housing 204 or may be a separate component attached to housing 214. Mesh 214 serves two purposes: One is to keep the air channel clear of objects that are large enough to be dangerous if inhaled. Another purpose is to create a pressure drop that can be measured by pressure transducer 210 in order to only generate aerosol if the user is inhaling at an optimal flow rate relatively early in the inhalation. These two functions may be separated into two separate components, for example and mesh or orifice plate in the air channel, for example at the end of the curved section of the air channel, and a mesh or grill on the inlet to block things that might be inhaled or interfere with the calibration of flow rate. Based on the signal received from pressure transducer 210 which via air connection 220, and a previously conducted measurement of the airflow / pressure relationship of mesh 216, microcontroller 205 can determine if the user is inhaling at the optimal inhalation flow rate, and by integrating this flow rate over time the controller can determine the user’s inhaled volume. Air connection 220 may be in the form of a piece of if microcontroller 205 determines the user has achieved the correctflow rate early in the inspiration, the controller turns on the aerosol generation via mesh piezo controller 208, and as long at the user continues to inhale the prescribed flow rate, keeps the aerosol generation on for a time selected from a list including but not limited to one or more of: a predetermined time that is constant during the therapy, a predetermined time that varies during the course of the therapy, for example to reduce the dose of nicotine over the course of the therapy, and a time which is shorter than the predetermined time for a reason selected from a list including but not limited to the user stops inhaling, the user begins to inhale at a lower than optimal flow rate, the user begins inhaling at a higher than optimal rate, the user stops holding down a button, a determination is made by microcontroller 205 that the use may have insufficient lung volume remaining to finish the inhalation.

[0202] Air connection 220 is shown as a section of tubing that connects to orifice 221 in the wall of air channel 217. Orifice 221 should be small enough that it does not adversely impact air flow through channel 215, but large enough that it does not restrict flow and increase the time constant of the measurement of pressure. Preferably the time constant of the measurement is less than or about 100 ms, less than or about 10 ms, or less than or about 1 ms. Preferably, the diameter of the orifice is less than or about 5 mm, less than or about 2.5 mm, less than or about 1 mm, less than or about 0.5 mm.

[0203] During, or preferably subsequent to inhalation, microcontroller 205 can determine the amount of aerosol that has been generated and based on this the prescribed therapy and a dosing algorithm, microcontroller 205 can turn on pump motor assembly 214 via pump controller 213 for a determined amount of time and / or pumping cycles.

[0204] Durable unit 200 also includes one or more buttons 217. Button 217 can be pushed to accomplish a task selected from the list including but not limited to: turning on the system, turning off the system, displaying the status of the system, informing the system that a replacement of cartridge 300 is complete, and the like. In one embodiment, switch 217 is only used to turn the device on or “wake up” the device, PCB 201 is comprised of wireless communication (preferably Bluetooth) module 209, and all other user communication with controller 205 is done with a display device, for example a phone, computer, tablet, and the like. In another embodiment button 217 is pressed to wake up the device or ready the device to deliver a puff and the user mustcontinue holding down the button. This can be useful if the button is situated in such a way that the device must held in a prescribe way selected from a list including but not limited to a prescribed orientation, a prescribed placement of the user’s fingers and hand, for example to ensure that the user does not block air inlet 216. In another embodiment, the inhaler comes with a mouthpiece cap and includes a system for sensing when the cap is in place. When the cap is removed, the device turns on, and when (and preferably only when) the cap is replaced, the device turns off.

[0205] Preferably button 217 is only pressed to turn on the device, or the device is turned on or turned off by a mouthpiece cap, and all other communication coming from the inhaler comes from one or more LEDs 218. LEDs 218 may be one color, but preferably are multi-color and / or capable of flashing to communicate multiple different type of information selected from the list including but not limited to: The device is on, the inhalation flow rate is correct, the inhalation flow rate is incorrect (too low or too high), battery 203 will require charging soon, battery 203 requires charging, the battery charging is complete, the user should consult a companion app for additional information, cartridge 300 needs to be replaced soon, and / or cartridge 300 needs to be replaced.

[0206] In a preferred embodiment there are three LEDs 218. A first LED 218 is on the top of the device when being held in an instructed way during inhalation and is visible to the user during inhalation. The functioning of first LED 218 may be as follows: When the inhaler is turned on and is ready for a puff, LED 218 flashes slowly blue. When the user begins inhaling at the correct flow rate, flashing blue LED 218 becomes steady blue. If the user begins to inhale to rapidly, LED 218 flashes red, and if the user begins to inhale too slowly LED 218 is extinguished. If there are still puffs remaining in a given dosing event, after an inhalation LED 218 will again flash slowly blue, showing that it is ready for the next puff. If the user chooses to not take another puff, the inhaler will turn off automatically after a preset time. In the embodiment with the mouthpiece cap sensor, the device will instead only turn off when the mouthpiece cap is replaced. If there are no more puffs left in a given dosing event, the user will not be able to take another puff, and LED 218 will instead flash red slowly, and time out when a fixed time has passed or in the embodiment with the mouthpiece cap sensor, the device will only turn off when the mouthpiece cap is replaced. If the device is turned on when either the battery needs to be charged or the cartridge needs to be replaced, the user will not be able to take a puff, and first LED 218 will flash red slowly. Preferablythere is a second LED 218 that flashes red when the battery will soon need charging and illuminates steady red if the battery needs charging. Preferably second LED 218 is identified, for example, with the word “BATTERY” or abbreviation “BATT.” printed on housing 204. Preferably there is a third LED 218 the flashes red when the cartridge will soon need replacing and illuminates steady red if the cartridge needs replacing. Preferably second LED 218 is identified, for example, with the word “CARTRIDGE” or abbreviation “CART.” printed on housing 204. Preferably the second and third LEDs 218 are in a location which is not directly in the line of sight of the user when inhaling so they are not confused with the first LED, for example on another side of the inhaler. Preferably the second and third LEDs 218 are located substantially next to each other, so the user only has to look in one place to ascertain the status of the device and determine if an action is required or will be required soon.

[0207] Durable unit 200 is also comprised of contacting mechanism 219 which makes a breakable electrical connection with printed circuit board (PCB) 313 in cartridge 300 (see below and figure 3). Mechanism 219 transmits power for aerosolizer 304 to cartridge 300, and also allows the transfer of data between durable 200 and cartridge 300. Data may be selected from the list including but not limited to whether cartridge 300 is attached to durable 200, identification of cartridge 300, or whether a mouthpiece cap is attached.

[0208] Figure 3 shows an example of the multidose cartridge of the embodiment of figure 1. Formulation 307 is contained within formulation chamber 301. Preferably formulation chamber 301 is filled substantially without a gas headspace, for example by vacuum filling, to ensure that the device usage is orientation independent and to ensure that gas from a headspace is not pulled into the system, resulting in low delivered dose and / or loss of prime. Preferably formulation chamber 301 is a flexible bag that is comprised of a pharmaceutically compatible drug contact surface, preferably polyethylene or COC, a mechanical layer such as polyester or mylar, and a vapor transmission layer, preferably aluminum.

[0209] The cartridge is comprised of aerosolizer 304. Preferably aerosolizer 304 creates an aerosol into the inhalation airflow of the user as the user inhales through mouthpiece 314. In prior art devices using a vibrating mesh nebulizer, the aerosol is generated in a direction toward the exit of the device and toward the user. In one embodiment of the current invention, the airflow throughthe air channel flows in a direction which is substantially perpendicular to the average direction of aerosol generation from the array of holes, and substantially parallel to aerosolizer 304. It has been found that this configuration more efficiently entrains the dose and disperses the aerosol, reducing aggregation of aerosol particles, thereby increasing emitted dose, and reducing particle size. Preferably the average direction of aerosolization is at an angle to the average direction of airflow, said angle being greater than about 0, greater than or about 10°, greater than or about 20°, greater than or about 30°, greater than or about 45°, greater than or about 60°, greater than or about 80°, greater than or about 90°, or about 93°.

[0210] Aerosolizer 304 generates an aerosol from formulation 307 which is contained in formulation pocket 307. When pump head 302 is driven by pump motor module 214, it pumps formulation 307 out of chamber 301 through clamp 311 and first flow channel 312. It is important that chamber 301 be flexible as the pressure of formulation 307 would drop very rapidly out of a rigid chamber 301, unless air were drawn into a rigid chamber 301 which could contaminate formulation 307. Formulation 307 is then pumped into pocket 308 through second flow channel 309, in which flow channel 309 is situated debubbler / filter module 310. Module 310 ensures that the liquid introduced into pocket 308 is free of air bubbles, dust particles, and / or bacteria. Third flow channel 313 is a return path to first flow channel 312, creating a recirculation system.

[0211] In a preferred embodiment, contacting mechanism 219 is comprised of sprung electrical connections, and PCB 313 is comprised of pads for contacting with the sprung electrical connections. It is important that durable 200 be able to determine if a new cartridge 300 has been attached. For example, if a new cartridge 300 is attached, a priming procedure must be performed, and a calculation of the amount of formulation 307 remaining in new cartridge 300 has to be reinitialized. Identifying a new cartridge 300 can be done in many ways. In one embodiment a single prescription for cartridges 300 is filled with 7 cartridges 300. Seven distinct cartridges 300 can be identified with 4 sprung electrical connections and pads: 1 for a ground connection, and 3 that are either connected or not connected to ground, allowing for 8 (23) states of cartridge 300. This allows for detecting that no cartridge 300 is attached, wherein no sprung electrical connections get connected to ground, and identifying 7 different cartridges. However, this is problematic as you either have to inventory 7 different types of cartridge, or put them in the right configurationwhen packaged. Preferably PCB 313 has a small EEPROM chip. In one embodiment, the EEPROM chip is factory programmed with a unique or substantially unique identifier. In a preferred embodiment, when a cartridge 300 is first attached, durable 200 writes aunique cartridge serial number to the EEPROM, for example the durable serial number plus an 8-bit identifier. If this cartridge is ever re-attached or if another user’s cartridge is reattached, this can be readily determined by reading the EEPROM. Other information can be written to the EEPROM, including but not limited to time and date of first use, most recent use, manufacture, and / or expiry; error messages; lot number or serial number of cartridge and / or durable; and the like.[00212J Figure 4 shows an embodiment of the cartridge that uses a recirculation system. One or more flexible formulation chambers 401 which contain 1 or more formulations 402 are connected to one or more pumps 403 via first flow channel 404. Clamp 405 holds chamber 401 closed during storage to avoid contamination of and loss of carrier from formulation 401, and opens automatically, preferably mechanically, when the cartridge is attached to the durable unit. To facilitate priming, when the cartridge is attached to a durable unit, chamber compressor 406 compresses formulation chamber 401 and forces formulation 402 into first flow channel 404. In a preferred embodiment, The cartridge contains component 407, preferably a simple printed circuit board 407, which PCB 407 has conducting pads which make electrical connection to the durable unit by way of sprung electrical connections, preferably by way of pogo pins. These electrical connections can be used to transmit power and ground, for example to drive aerosolizer 412 and electronics on board 407, and / or to store and share data, for example to identify the specific cartridge being used or to determine if a component, for example a mouthpiece cap or a nozzle plug, are in place. Many different ways can be used to identify the cartridge, for example electrical connections, fusible links, and the like. Preferably PCB 407 contains an EEPROM. This EEPROM may have a unique identifier written to it at the factory to identify the cartridge, or it may be programmed by the controller when the cartridge is attached to the durable.

[0213] In one embodiment, if a cartridge that has never been used before is attached to the durable, the controller in the durable writes a unique identifying number to the EEPROM on PCB 407 in the cartridge. The controller then starts a priming sequence wherein pump 403 is run for a period of time that is sufficient to drive all air in first flow channel 404, pump 403, pocket 408,second flow channel 409 and third flow channel 410 out of debubbler 411 and replace this air with formulation 402 throughout the recirculation system.

[0214] During the process of aerosolization, aerosolizer 412 may generate air that goes into formulation pocket 408. As pump 403 pumps formulation 402 into formulation pocket 408, the air is entrained in the liquid flow and exits formulation pocket 408 via third flow channel 410, wherein formulation and air flow into debubbler 411 via entrance opening 413. The formulation passes through hydrophobic porous membrane 414 into debubbler manifold 415 and out small opening 421. As the flow of formulation and air passes through debubbler 411 it comes into direct contact with porous hydrophobic material 414, wherein the air passes out of the porous hydrophobic material 414 and into manifold 415, and ultimately out small hole 421. Small hole 421 allows the pressure in debubbler manifold 415 to equilibrate with the outside air after air has been released into it via porous hydrophobic material 414, while being small enough, for example significantly smaller in area than to the total porous open area in porous membrane 414, to maintain a high relative humidity in manifold 415, thereby reducing evaporation of formulation 402 carrier through hydrophobic porous membrane 414. Debubbler exit 416 is preferably somewhat restrictive, such that the pressure in debubbler 411 is sufficiently high to force the air through porous hydrophobic material 414, but not so high that formulation 402 passes through porous hydrophobic material 414. Formulation 402 then continues through third flow channel 410 which connects to first flow channel 404, wherein formulation 402 is then pumped back through pump 403, thus creating a recirculating flow system. In general, the pressure in formulation pocket 408 can be kept quite low, substantially equal to the pressure in debubbler 411, reducing the possibility that formulation will flow through the array of nozzle holes in aerosolizer 412. Optionally, aerosolizer 412 can be treated with a hydrophobic coating to further lessen the probability that the pressure in formulation pocket 408 will force liquid out of the nozzle holes. Preferably the pressure in formulation pocket 408 is less than or about 100 mbar, less than or about 50 mbar, less than or about 25 mbar, less than or about 10 mbar, less than or about 5 mbar, less than or about 2.5 mbar.

[0215] Because the formulation recirculates, and there is no concern formulation will leak out of the nozzle holes of aerosolizer 412, the system becomes insensitive to the rate of pumping of pump 403 and the duration of pumping of pump 403, and the pumping becomes decoupled fromthe rate and duration of aerosolization by aerosolizer 412. Because of this, pump 403 can pump for as long as required (including before the start of aerosolization or after the aerosolization has concluded) at essentially any rate of flow that will eliminate most or all of the air from formulation 402, as long as this pumping does not create a pressure that drives formulation 302 out of the nozzle holes of aerosolizer 412. When formulation 402 is aerosolized, and when air exits through porous hydrophobic element 414, the volume of formulation in the loop goes down, and thus the pressure in the loop goes down. The reduced pressure in first flow channel 404 draws formulation 401 from formulation chamber 402. Because the air that is introduced into formulation 402 during the aerosolization process is essentially completely removed by debubbler 411, the amount of formulation drawn out of formulation chamber 401 is essentially equal to the amount of formulation aerosolized. In some embodiments, especially when formulation 402 has a reduced surface tension, formulation 402 may still leak out of the nozzles of aerosolizer 412 when pump 403 is running. This is exacerbated when aerosolizer 412 is not running, as aerosolizer 412 reduces any buildup of pressure in pocket 408 by removing formulation 402 from pocket 408. For this reason, it is preferred that pump 403 only run when aerosolizer 412 is on, more preferably for less time than aerosolizer 412 is on. In one embodiment, pump 403 turns on when or after aerosolizer 412 starts, and then turns off at or before the time aerosolizer 412 turns off. In one embodiment pump 403 turns off at a fixed time before the aerosolizer turns off, for example between about 0 ms and about 10 ms, between about 10 ms and about 50 ms, between about 50 ms and about 100 ms, between about 100 ms and about 200 ms, between about 200 ms and about 500 ms, before aerosolizer 412 turns off.

[0216] Figure 4 shows clamp 405 at the exit of formulation chamber 401. Preferably, clamp 405 has only two states, open and closed. In one embodiment, during shipping and storage, formulation chamber 401 contains all the formulation 402 that is in the cartridge, and the exit of formulation chamber 401 is closed by clamp 405. Preferably clamp 405 closes the exit of formulation chamber 401 by pinching off a section of formulation chamber 401, which section is made of the same material(s) as the rest of formulation chamber 401, which materials have been optimized for long term storage of the formulation. In this way, during transport and storage prior to fist use, formulation 402 only contacts the surface of formulation chamber 401, and not clamp 405 or any of the other flow components in the cartridge, thereby insuring that the materials offormulation chamber 401 can be optimized for drug contact, sterility, stability, and to minimize loss of carrier during storage, and the materials of the other drug contacting components can be optimized for performance.

[0217] Before the first use of the current invention, valve 405 is opened, and pump 403 selfprimes and then pumps the formulation though the recirculation system for sufficient time that essentially all of the air in formulation pocket 408, flow channels 404, 409, and 410, debubbler 411, and pump 403 is forced out of the cartridge, via aerosolizer 412 and / or debubbler 411.

[0218] In some instances, pump 403 will not self-prime. To facilitate priming of pump 403, chamber compressing element 406 may be used. Chamber compressing element 406 is configured such that when the cartridge is attached to the durable unit, chamber compressing element 406 is moved such that chamber pressurizing unit 406 compresses formulation chamber 402, forcing liquid into first flow channel 404 until pump 403 will prime when running. In a first embodiment, pressurizing element 406 may be in the form a finger that is attached to the durable unit, and when the cartridge is attached to the durable unit, pressurizing element 406 enters the cartridge through opening 420. In a second embodiment, pressurizing element 406 is not attached to the cartridge, but is captured inside the cartridge, extends somewhat out of opening 420, and is pushed in by the durable when the cartridge is attached to the durable. In a preferred third embodiment, pressurizing element 406 may be molded as part of cartridge housing, wherein the connection to the housing is bendable, and when the cartridge is attached to the durable, the connection bends, displacing pressurizing element 406 in such a way that it pressurizes chamber 401. The second and third embodiments have the advantage that opening 420 does not present a straight path the formulation chamber 401, such that the system cannot be abused by withdrawing formulation 402 out through opening 420, for example with a hypodermic syringe. This is especially important when formulation 402 contains a controlled substance, for example an opioid or a benzodiazepine.

[0219] In another embodiment, there is check valve 418 in third flow channel 410. This check valve can help with priming by blocking any flow of formulation or air from flowing backward though third flow channel 410. It also has another advantage when the inhaler is stored between dosing events it prevents formulation 401 in formulation chamber 401 from exerting a pressurehead on the formulation in pocket 408 and possibly causing liquid to flow out of a nozzle in aerosolizer 412 when formulation chamber 401 is above pocket 408.

[0220] In the embodiments of current invention where the aerosolizer is comprised of one or more nozzle holes, there is a concern that bacteria might enter through the nozzle holes and colonize the formulation in the recirculation loop. It is also possible for bacteria to enter through porous hydrophobic element 414, although this is less likely because the pore size in hydrophobic mesh 414 is quite small, and it is only exposed to the outside air via small hole 421 which is protected inside of the cartridge. Viruses are much less of a concern as they can only reproduce in a host cell, not in water-based formulations. Any virus exposure to a nozzle hole is most likely from air being inhaled through the air channel, leading to much larger exposure to a user from them simply breathing the air than they could get from any exposure to viruses that get into the formulation and then are inhaled. In one embodiment, the formulation has a bacterio-static agent to stop bacteria from reproducing. However, it is preferred to not have a bacteriostatic agent in the formation so as to not exposure the user’s lungs to this agent. In the embodiment of figure 4, the system is supplied with filter 419. Filter 419 preferably has a pore size that will capture essentially all bacteria that might get into the formulation. Preferably the pore size of filter 419 is less than or about 1 pm, less than or about 0.75 pm, less than or about 0.5 pm, less than or about 0.4 pm, less than or about 0.2 pm, less than or about 0.1 pm. Preferred filters 419 have a pore size selected from about 0.1 pm, 0.2 pm, and 0.22 pm. In one embodiment, the filter 419 used is a 0.2 um pore size nylon membrane filter from Omicron part number 170047R. The filter may be placed anywhere in the recirculation loop, for example first flow channel 404, second flow channel 409, or third flow channel 410. However, it is preferred that filter 419 not be placed between the exit of pocket 408 and before the intersection of second flow channel 410 and third flow channel 404, as the relatively high pressures required to pump formulation 402 though filter 419 due to the small pore size and limited area available for filter 419 could cause formulation to leak out of the nozzle hole or holes of aerosolizer 412 or out of the porous hydrophobic component 414. Placing the filter in first flow channel 404 is also not preferred because of the limited reduction in input pressure that pump 403 can achieve. Preferably the filter is placed between pump 403 and the inlet to formulation pocket 408, near the end of or at the end of second flow path 409. With filter 419 in place, any time pump 403 pumps formulation, formulation pocket 408 is supplied with bacteria-free formulation, and any bacteria in pocket 408 will be swept into third flow channel 410, and ultimately pumped around the recirculation loop to be captured by fdter 419. In one embodiment, the system has a mode wherein pump 403 pumps a sufficient volume such that essentially all of the formulation initially in formulation pocket 408 will flow out of pocket 408 and be replaced by bacteria free formulation, resulting in an aseptic fill of pocket 408. Preferably, the sufficient volume is greater than or about equal to the volume of pocket 408, greater than or about 1.5 times the volume of pocket 408, greater than or about 2 times volume of pocket 408, greater than or about 2.5 times to the volume of pocket 408, greater than or about 3 times to the volume of pocket 408, greater than or about 4 times to the volume of pocket 408, greater than or about 5 times to the volume of pocket 408, greater than or about 7.5 times to the volume of pocket 408, or greater than or about 10 times to the volume of pocket 408. Preferably, the sufficient volume is pumped by pump 403 at a time selected from the list including but limited to over the course of a day, before the first dose of the day, before each dosing event, after each dosing event, before each puff, after each puff. In a preferred embodiment, the Pump 403 is pumping during each puff.

[0221] It is important to be sure that filter 419 is intact, for example has no rips or leaks, and has the correct pore size. This can be determined by measuring the pressure required to achieve a predetermined flow rate, for example having a pressure transducer in tube 409 between pump 403 and filter 419. Reduction in the pressure due to a failure of filter 419 may lead to a faster pumping rate, in which case the failure may be detected with a flow meter. In the embodiment where pump 403 is driven by a motor, for example where pump 403 is a peristaltic pump, a change in pumping rate could be detected as a change in motor speed. For a pump motor run at constant voltage, an increase in pump speed could be detected as a decrease in current due to the increase in the motor back emf For a pump motor run at constant current, an increase in flow rate would result in an increase in required voltage to maintain the current. For a pump motor controlled with a pulse width modulated scheme, a decrease in pressure would result in a shorter required pulse width to maintain the same speed.

[0222] Pump 403 may be any type of pump capable of generating a sufficient output pressure to achieve a sufficient flow rate, for example through filter 419. Preferred pumps 403 can generate high output pressures to enable pumping through filter 419. A particularly preferred pump 403 is a peristaltic pump comprised of components selected from but not limited to a motor, for examplea motor that runs at about 150 RPM at 12V, a gear head, a rotor or eccentric, a ring, a section of flexible tubing, and a support surface against which to compress the tubing. Preferred motors and gearheads result in an output shaft rotation rate of from about 10 to about 500 RPM, from about 20 to about 250 RPM, from about 30 to about 150 RPM, from about 40 to about 100 RPM, from about 50 to about 75 RPM, or from about 55 to about 65 RPM, or about 60RPM. Preferably, the motor, gearhead are part of the durable, and the tubing, an eccentric, a ring, and support surface are part of the cartridge, and a clutch mechanism allows the motor and gearhead to drive the eccentric. In one embodiment of the peristaltic pump a motor turns a rotor, which rotor circularly translates at least one roller, preferably two or more or three or more rollers, whereupon the rollers roll along a piece of flexible tubing and compresses it against a supporting surface to create flow through the tubing.

[0223] Figure 5 shows a peristaltic pump embodiment of the current invention, wherein the peristaltic pump is comprised of motor 501, gear head 502, shaft 503, clutch spring 504, clutch pressure plate 505 which is comprised of ribs 509 , all of which comprise the durable unit; and drive shaft 507 which is comprised of clutch disk 506, eccentric 508, and grooves 510; ring 511; small bearing 512; large bearing 513; Tubing which loops through the pump head around ring 511 and is displayed here in cross section as uncompressed tubing 514 and compressed tubing 515; and ring aligning cam surface 516; all of which comprise the cartridge. Small bearing 512, pump head 511, and large bearing 513 get successively larger to facilitate assembly. As shown in Figure 5a, initially the durable and cartridge are separated. In figure 5b, the cartridge and the durable have been attached to each other. Clutch pressure plate 505 engages with clutch disk 506. The engagement may be due to friction between clutch disk 506 and clutch pressure plate 505, but preferably clutch pressure plate 505 has radial mating ridges 509 for example with a rectangular or triangular cross section, that mate with mating grooves on clutch disk 506. It will understood that pressure plate 505 may have ridges, grooves, bumps, other engaging features, or combinations thereof that mate with negatives of the features on clutch disk 506. In general, engagement features 509 on clutch disk 506 and mating engagement features 510 on clutch pressure plate 505 will not be rotationally aligned, i.e., the ridges 509 and grooves 510 are not engaged, when the cartridge is first attached to the durable. Spring 504 needs to be of length and spring constant such that when the features are fully misaligned, clutch pressure plate 505 slides on shaft 1903 andcompresses spring 504, allowing the durable and cartridge to be attached. The durable and cartridge must be attached sufficiently, for example through the use of magnets, detents, snaps, or the like such that the cartridge and durable are held together against the force of compressed spring 504. When the motor is first energized after each attachment of the durable to a cartridge, clutch pressure plate 505 rotates relative to clutch disk 506 until the features 509 and 510 are aligned, at which time the features snap into engagement under the urging of spring 504, and clutch disk 506 rotates. This in turn causes shaft 507 and eccentric 508 to rotate. The rotation of eccentric 508 sequentially compresses sections of tubing 515 via ring 511, creating a pumping action. Small bearing 512 and large bearing 513 keep shaft 507 in position and aligned under the rotating torque and force cause by the force of eccentric 508 against tubing 515.

[0224] Figure 6 shows a cross-section of an embodiment of pump head 511 of figure 5. Pump head 511 is comprised of support surface 601, tubing 602 containing formulation 603, ring 604, and eccentric 605. Figure 6a shows eccentric 605 and ring 604 in a rotational position that is sub- optimal for long term storage, because during storage tubing 602 can be under compression for two years or more, depending on the shelflife of the cartridge, which can potentially cause tubing 604 to be permanently compressed, i.e. can cause it to take a set. Figure 6b shows the pump head of 6a after it has been stored, and then used. There is a set 606 in tubing 602 in the region that ring 604 was stored in. Because this section of tubing 602 does not completely recover, set 606 will reduce the pumping rate by percent reduction in the volume of formulation 603 in tubing 602 due to set 606. Figure 6c shows a condition wherein the flow restriction due to set 606 reduces the flow through the set such that not enough of formulation 603 can flow to completely fill the downstream portion of tubing 602 eccentric 605 completes a revolution. In the worst case, set 602 completely blocks the flow. In this case the pump rate is reduced by the entire volume of the loop of tubing that is downstream from set 602, because water cannot flow past set 602 and the section of tubing 602 downstream from set 606 cannot fill with formulation 603. The solution to this problem is to position eccentric 604 during manufacture of the cartridge to a position close to the formulation flow exit of the pump head, as shown in figure 6d. In this position any set in tubing 602 due to the compression of tubing 602 will be close to the formulation flow exit. This high pressure from the pump will fully inflate the region of the set and all of formulation 603 that isupstream from the set will be pumped out. The region downstream from the set will be minimized, which minimizes the reduction in flow due to the set.

[0225] A sample assembly procedure of the pump components into the cartridge housing is as follows: Preferably small bearing 512 is simply a hole the housing. In the event that a reduced friction bearing is required, small bearing 512 can be a ball bearing, or preferably a simple bearing fabricated from a lubricious material such as PTFE or Delrin, and is pressed into a recess in the housing. Preferably support structure 601 comprises the housing of the cartridge, and a loop of tubing 602 is placed inside of support structure 601. Ring 604 is then placed inside of this loop. Large bearing 513 is then pressed into its recess. Drive shaft 507, which is comprised of eccentric 508, is then inserted. Cam surface 516 biases ring 511 to the side as drive shaft 507 is inserted, so that ring 511 is in position for eccentric 508 to slide into ring 511. Finally, clutch disk 506 is rotated such that ring 604 is compressing tubing 602 at a point close to the exit of the pump as shown in figure 6d, which ensures that if the tubing takes a set on storage the impact on the pumping rate is minimized.

[0226] Figure 7 shows an embodiment wherein the debubbler and filter are in a single module. Formulation and air flow from pump 701 into debubbler / filter module 702 via module entrance703, whereupon the formulation comes into contact with porous hydrophobic material 704 and filter material 705. Any air bubbles in the formulation exit through porous hydrophobic material704, and liquid formulation flows through filter material 705. Filtered and debubbled formulation then flows to pocket 706, wherein it is aerosolized by aerosolizer 707. Preferably filter material 705 and porous hydrophobic material 704 are very close together, preferably touching, so that any air bubbles are in contact with porous hydrophobic material 704, ensuring efficient debubbling. Given a desired flow rate, the formulation pressure between pump 701 and filter material 705 is determined by the pore size, porosity, and area of filter 705. It is important that the properties of porous hydrophobic material 704 including pore size, porosity, and hole size are selected such that the pressure be sufficiently high that bubbles are efficiently removed, but not so high that formulation is forced through porous hydrophobic material 704, Preferred gauge pressures for the formulation and air under porous hydrophobic material 704 are from about 10 to about 1000 mBar, from about 20 to about 500 mBar, from about 30 to about 250 mBar, from about 40 to about 100 mBar, from about 50 to about 80 mBar, or about 10, 20, 40, 80, 160, 320, or 640 mBar.The air that exits through porous hydrophobic material 704 into debubbler manifold 702 exits through small hole 708. Small hole 708 is a small hole as described previously, and its diameter is chosen such that very little water vapor escapes and thus the relative humidity in debubbler manifold 702 remains close to 100%, limiting the evaporation of carrier through the pores of porous hydrophobic material 704. Preferably the evaporation through hydrophobic material 704 is less than about 10 pl / hour, less than about 5 pl I hour, less than about 2.5 pl / hour, less than about 1 pl / hour, or less than about 0.5 pl / hour. A desired hydrophobic porous material used for 704 is POREX MD10 expanded PTFE with typical airflow through the pores of 125 (min 70) l / hr / cm2 at 70 mbar and water entry pressure (WEP) of 270 (min 175) mbar. The airflow of POREX expanded PTFE can range from 2-125 l / hr / cm2 at 70 mbar and the WEP can range from 175-1050 mbar so various embodiments of this system can use expanded PTFE with airflows and WEP that output the desired airflow based on the internal pressure of the system. Additional hydrophobic porous materials that can be used are Versapor RC Membranes including but not limited to Versapor 200RC part number VRC02S7X10, Versapor 800RC part number VRC08S7X10, Versapor 1200RC part number VRC12S7X10, Versapor 3000RC part number VRC30S7X10, Versapor 5000RC part number VRC50S7X10.

[0227] Figure 8a shows a cross-section of an embodiment of the current invention comprised of mouthpiece cap 801. Mouthpiece cap 801 is comprised of nozzle plug 803. Nozzle plug 803 is comprised of tapered plug carrier 804, and a compliant component 805, which is overmolded onto plug carrier 804. Plug carrier 804 is comprised of a relatively rigid material, preferably a mold- injected plastic. Overmolded component 805 is comprised of a compliant material, preferably silicone. The shore hardness of overmolded component is in the range of about 5 to about 60, 10 to about 40, 25 to about 35, or about 25. Overmolded component 805 is comprised of protrusion 806 which protrudes out of the side of nozzle plug 803. Mouthpiece cap 801 is also comprised of handle 808 and cover 807. Mouthpiece cap 801 is further comprised of Rib 809, further described below.

[0228] Figure 8b is an embodiment of the cartridge that mates with the mouthpiece cap of figure 8a. Cartridge 802 is comprised of cartridge shroud 809 which forms mouthpiece 810. Cartridge 802 is further comprised of aerosolizer 811. Aerosolizer 811 is comprised of substrate 812 and piezo ring 813. Dimple 814 is formed in substrate 8812 and contains an array of nozzle holes.

[0229] Cartridge 802 is further comprised of PCB 815. PCB 815 has pads on the bottom that contact with sprung electrical connections which are situated in the durable. In one embodiment, PCB 815 is also comprised of EEPROM 816. EEPROM 816 is used by the durable to identify cartridge 802. In one embodiment, cartridge 802 reads a factory programmed serial number from EEPROM 816. In another embodiment, the durable writes a unique or sufficiently unique serial number to EEPROM 816. This information will be used to identify when the previously used cartridge is replaced with another cartridge. This may be required, for example, to trigger a priming routine for a new cartridge or to reset a calculated amount of formulation still contained in cartridge 816. EEPROM 816 may also contain additional information, including the formulation, active pharmaceutical ingredient, strength, amount of formulation, and the like. EEPROM 816 may also contain an expiry date, for example as factory -written shelf-life expiry date, or an in-use expiry date that is written by the durable when cartridge 802 is first attached.

[0230] Cartridge 802 is comprised of air channel 819, through which the user inhales, and into which the aerosol is generated. In the embodiment of figure 8b, air channel 819 has an essentially uniform cross section until it reaches the edge of piezo ring 813, where it starts to expand. Past this point the walls have an angle relative to the uniform section (i.e., the half opening angle) of less than or about 20°, less than or about 15°, less than or about 10°, or less than or about 7°, preferably about 7°. This expansion has many benefits. One is it gets the walls of air channel 819 father away from the aerosol plume, minimizing aerosol deposition. Another advantage is it acts as a diffuser and slows down the aerosol before it enters the mouth of the user, minimizing aerosol deposition in the mouth and throat of the user. In the embodiment where the angle is less than or about 7°, the airflow can remain attached to the walls (as opposed to separating from the walls and creating a central plume with turbulent eddys between the plume and the walls) and the flow velocity can be reduced by the ratio of the air channel cross-sectional area before and after the expansion. The expansion also helps in positioning nozzle plug 803, as described further below. Cartridge 802 also contains button 817 and groove 818.

[0231] Figure 8c shows an embodiment of the current invention with mouthpiece cap 801 in place on cartridge 802. In this position, cover 807 fully envelops mouthpiece 810, keeping it clean prior to use. Mouthpiece cap 801 also blocks the entrance to air channel 819, keeping air channel819 free of dust and contaminants, and also ensuring that physical objects that might be inhaled do not enter the airway. In this configuration, protrusion 806 is in contact with dimple 814, thereby blocking the exits of the nozzle holes. This is advantageous for several reasons. It eliminates the possibility of evaporation of carrier and ingress of contaminants, bacteria, or viruses between uses of the inhaler. It also blocks flow of liquid formulation out of the nozzle holes, which is especially a problem when the active pharmaceutical ingredient, excipients, or carrier reduce the surface tension of the formulation, allowing the formulation to wick through the nozzles due to capillary effects. Finally, protrusion 806 can act like a detent, holding mouthpiece cap 801 in place on cartridge 802.

[0232] As shown in figure 8b, rib 809 slid into and through groove 718. The engagement of rib 809 with groove 718 ensures that the mouthpiece cap cannot be attached to cartridge 802 in the wrong orientation, in which wrong orientation protrusion 806 would not be in contact with dimple 714. In addition, when fully inserted, rib 809 contacts and actuates button 817. This is important so that the controller in the durable can verify that mouthpiece cover 801 is fully attached to cartridge 802. In a preferred embodiment, button 817 is also used to turn the device on and off. It will be understood that rib 809 can be a pin or any other shape that can contact switch 817.

[0233] By way of example, a possible usage scenario is as follows: The user grasps handle 808 and detaches mouthpiece cover 801. Preferably mouthpiece cover 801 is tethered to cartridge 802 or to the durable so it will not get lost. Preferred tethers have sufficient width that they resist twisting and thereby the user is guided to the correct orientation of mouthpiece cap 801 when it is reattached to cartridge 802. Removing mouthpiece cap 801 also releases button 817. Button 817 is electrically connected to the electronics in the durable via sprung electrical connections that contact pads on the bottom of PCB 815, and when button 817 is released, this is sensed by the electronics in the durable and the microcontroller is awakened. If the microcontroller determines that there is sufficient battery charge, sufficient formulation remaining, and the cartridge is not expired, it presents the user with a flashing blue light, otherwise it is a flashing red light. If the light is flashing blue, the user takes one or more puffs, after which the light again flashes blue, unless the user has taken the maximum number puffs in a dosing event, in which case the light flashes red. In either case, the flashing continues until the mouthpiece cover is reattached. Thisgives the user immediate feedback, in the form of the stopping of the flashing, that mouthpiece cover has been correctly reattached.D. PHARMACEUTICAL AGENTS USED IN THE AEROSOL DEVICE

[0234] The active pharmaceutical ingredients (APIs) encompassed by the present disclosure include nicotine freebase and pharmaceutically acceptable salts of nicotine. In one embodiment, the pharmaceutical agent used in the aerosol device is nicotine bitartrate dihydrate. Other acids that can be mixed with the freebase include, but are not limited to, tartaric, lactic, benzoic, levulinic, salicyclic, and malic acids. The source of nicotine of the nicotine-containing compositions of the invention can include nicotine in free base form, salt form, as a complex, as a solvate, or other suitable form. Nicotine is typically isolated (e.g., as described above) in neat (liquid) form. According to the present invention, nicotine is modified such that it is provided in other forms by incorporating the nicotine as a component of a salt, co-crystal, or salt co-crystal, e.g., in the form of an oil, solid, semi-solid, etc. In some embodiments, certain salts, co-crystals, and salt co-crystals are desirably provided in solid form, e.g., solid, crystalline form. Advantageously (although not necessarily), coformers (including acids) that are combined with nicotine to form such nicotine salts, co-crystals, or salt co-crystals are “GRAS” (Generally Regarded As Safe) according to the U.S. Food and Drug Administration. Furthermore, it is beneficial (although again, not necessary) for the nicotine salts, co-crystals, and / or salt co-crystals produced thereby to also be GRAS. When nicotinic compounds of the present invention contain relatively basic functionalities, as in nicotine, for example, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Exemplary pharmaceutically acceptable nicotine salts include tartrate (e.g., nicotine tartrate and nicotine bitartrate), chloride (e.g., nicotine hydrochloride and nicotine dihydrochloride), sulfate, perchlorate, ascorbate, fumarate, citrate, malate, lactate, aspartate, salicylate, tosylate, succinate, pyruvate, and the like; nicotine salt hydrates (e.g., nicotine zinc chloride monohydrate), and the like. One skilled in the art will appreciate that analogous salts can be formed for agonist compounds comprising relatively basic functionalities. Additional acids that can form salts include formic, acetic, propionic, isobutyric, butyric, alphamethylbutyric, isovaleric, levulinic, beta-methylvaleric, caproic, 2-furoic, benzoic, phenylacetic, heptanoic, octanoic, nonanoic, oxalic, malonic, glycolic acid, benzenesulfonic, camphosulfonic,ethanesulfonic, gluconic, glucoronic, glutamic, hippuric, hydrobromic, isethionic, lactobionic, maleic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic, pantothenic, phosphoric, sulfuric and the like as well as other fatty acids having carbon chains of up to about 20 carbon atoms. The inhalable substance medium can further comprise, for example, one or more of glycerin, water, and a flavorant. The amount of nicotine salt or polymorph form incorporated can vary and, in some embodiments, can be that amount sufficient to provide nicotine in an amount of about 0.01 mg to about 0.5 mg, about 0.05 mg to about 0.3 mg, or about 0.1 mg to about 0.2 mg per puff on the device.[00235J Other active pharmaceutical ingredients contemplated by the present disclosure include an opioid (preferably fentanyl or buprenorphine, but may also be morphine, hydrocodone, pethidine, methadone, oxycodone, oxymorphone, codeine, hydromorphone (Dilaudid), or tapentadol), a triptan, risperidone, insulin, epinephrine, atropine, ciprofloxacin, methocarbamol, a benzodiazepine (preferably Alprazolam, Clonazapam, Lorazepam, Diazepam or Triazolam), a non-benzodiazepine hypnotic (preferably zelplon, ramelteon, or exzopiclone), a PDE5 inhibitor, a glucagon-like peptide, an API for cramps, and API for insomnia, a vasodilator, an API for asthma, an API for COPD, an API for depression, an API for PTSD, an API for depression, an API for angina, an API for hypoglycemia, an API for osteoporosis, an API for migraine, an API for nausea, an API for anaphylaxis, an API for poisoning, and an API for sexual dysfunction.E. FORMULATIONS

[0236] The formulations used in the device herein and delivered to patients can take a variety of different forms. Generally, such forms are sterile solutions or suspensions that are non-pyrogenic and formulated to be suitable for oral inhalation. The inhaled particles should be small in size (e.g., 0.5 to 10, preferably 0.5 to 5 micrometers).

[0237] Concentrations of active ingredients used in the present disclosure may be selected to be close to the solubility limit so as to reduce the volume of formulation per puff that needs to be aerosolized, increasing the lifetime of the cartridge, and the time between battery charges. However, the concentration should not be so high that slight changes in concentration, temperature, etc. cause the active pharmaceutical ingredient to come out of solution. For example, for nicotine bitartrate dihydrate, the solubility limit is about 150 mg / ml. Preferred concentrations of nicotine, expressed as freebase, for use in the device of the present disclosure include, but are not limited to, about 5 mg / ml or more, about 10 mg / ml or more, about 15 mg / ml or more, about 20 mg / ml or more, about 25 mg / ml or more, about 30 mg / ml or more, about 50 mg / ml or more, about 75 mg / ml or more, or about 90 mg / ml or more. Depending on the salt of nicotine employed, the amount of such salt can be adjusted to provide the desired dose of nicotine freebase, i.e., the amount of freebase can be calculated from the mass of nicotine salt present in the formulation.

[0238] In one embodiment, the formulation comprises nicotine freebase in an amount of about 20 mg / ml to 50 mg / ml, or about 25 mg / ml to 35 mg / ml, about 50 mg / ml to about 125 mg / ml, and about 90 mg / ml; and 0.9% sodium chloride solution, and optionally other excipients. The volume of the nicotine-containing solution delivered per actuation of the device of the present disclosure may be about 1 to 50 microliters, or about 1 to 30 microliters, or about 1 to 25 microliters, or about 1 to 20 microliters, or about 1 to 15 microliters, or about 5 to 20 microliters, about 9 to about 13 microliters, or about 10 to 20 microliters. Such volume is delivered by the device of the present disclosure in about 0.1 to 2.5 seconds, or about 0.25 to 2 seconds, or about 0.5 to 1.5 seconds, or about 0.75 to 1.25 seconds, or about 1 second.

[0239] For highly potent active ingredients, for example fentanyl, it may be desirable to reduce the concentration for safety so that there is no need to aerosolize very small volumes. For example, the concentration of fentanyl may be less than or about 10 mg / ml, 5 mg / ml, 2.5 mg / ml, 1 mg / ml, 0.5 mg / ml, 0.25 mg / ml, 0.1 mg / ml, 0.05 mg / ml, or 0.025 mg / ml. In one embodiment, the concentration is from about 0.5 to about 1 mg / ml, or 0.05 to about 0.5 mg / ml, or about 0.1 to about 0.3 mg / ml.

[0240] The formulations may contain pharmaceutical excipients that can either improve the stability of the dosage form or provide comfort during administration. Such excipients include1carriers (e.g., water) and pharmaceutical solvents, tonicity adjusting agents, pH adjusting or buffering agents, stabilization agents, antimicrobial preservatives, dispersing and / or wetting agents, or flavor-masking agents.

[0241] Pharmaceutical solvents are used to dissolve or disperse pharmaceutically active medicaments and excipients. The solvent may be aqueous or non-aqueous. A formulation of the present invention may be formulated with one or a mixture of more than one pharmaceutically acceptable solvent and is selected from, but not limited to, glycerol, propylene glycol, polyethylene glycol, polypropylene glycol, ethyl alcohol, isopropyl alcohol, water, mineral oil, peanut oil, and corn oil. The pharmaceutical solvents may be used to prepare the formulation concentrate as well as used for reconstitution of the dosage form of the present invention. Pharmaceutically acceptable solvents such as water, ethyl alcohol, isopropyl alcohol are evaporable and are usually used to dissolve or disperse the medicament and excipients in the formulation concentrate. Glycerol, propylene glycol and polyethylene glycol are co-solvents and are used to assist in solubilization of water insoluble or poorly water soluble medicaments in the formulation concentrate. Pharmaceutically acceptable reconstituting solvents such as sterile water for injection, sterile normal saline solution, sterile phosphate buffer solution and sterile 5% dextrose solution are used for reconstitution of the dosage form of the present invention to form a solution or a fine particle suspension of pharmaceutically active ingredient prior to oral inhalation via a nebulizer or aerosol device. The reconstituting solvents may be packaged in individual ampoules or unit dose plastic containers for unit of use or may be packaged in large volume sterile container from which a specific volume of the reconstituting solvent can be withdrawn without contaminating the solvent.

[0242] Tonicity-adjusting agents are used to enhance the overall comfort to the patient upon administration of the reconstituted dosage form. It is preferred to adjust the osmolality of the reconstituted inhalation solution to about 275 to 305 (range 254 to 325) mOsm / Kg. Tonicityadjusting agents for inhalation use are sodium chloride, dextrose, lactose, sodium phosphate, sorbitol, mannitol and sucrose or combination thereof at a concentration to generate an isotonic solution after the dosage form is reconstituted with 1 to 10 ml of sterile water for nebulization. The addition of sugars such as dextrose, lactose and sucrose add stickiness and adherent characteristics to the formulation so that the dried-medicament and formulation excipients can bebetter retained on the supporting material after the formulation concentrate is dried. The tonicityadjusting agent can also function as a particle partition agent to reduce particle size of the pharmaceutically active ingredient after the formulation is impregnated in or deposited on the supporting material and to assist in dissolution or dispersion of pharmaceutically active ingredient particles upon reconstitution with the pharmaceutical solvent. Alternately, the dosage form may be formulated without the addition of a major tonicity-adjusting agent. The desired tonicity of the dosage form is achieved by reconstituting with a sterile isotonic saline solution.

[0243] The formulations may also comprise pH adjusting or buffering agents to adjust or maintain the pH of pharmaceutical dosage form to a desired range for the following reasons: (1) To provide an environment for a better product stability that pharmaceutical active ingredient may express a better chemical stability within certain pH range; (2) to provide better comfort for the patient at administration; and (3) to provide a pH range for better antimicrobial preservative activity. Formulations and dosage forms of the present invention may be formulated with one or more pharmaceutically acceptable pH adjusting or buffering agents so that, after reconstitution, the desired pH is between about 3 to about 8, about 4 to about 6, about 4, or about 5.

[0244] Pharmaceutically acceptable pH-adjusting and buffering agents are selected from, but not limited to, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, phosphoric acid, fumaric acid, citric acid, tartaric acid, maleic acid, succinic acid, ammonia solution, ammonium carbonate, sodium borate, sodium carbonate, triethanolamine, trolamine and sodium hydroxide. Stabilizing agents are antioxidant and chelating agents that are capable of inhibiting oxidation reaction and chelating metals, respectively, to improve stability of pharmaceutically active ingredient and excipients.

[0245] Formulations and dosage forms of the present invention may be formulated with one or more pharmaceutically acceptable stabilization agents at a concentration suitable for the intended pharmaceutical applications, and may be selected from, but not limited to, chelating agents such as EDTA and its sodium salt, citric acid and sodium citrate, anti-oxidation agents such as Vitamin E, ascorbic acid, ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium metabisulfite, sodium formaldehyde sulfoxylate, and thiourea. The addition of a stabilizing agent to a dosageform of the present invention can improve stability of the pharmaceutical active substance and prolong the shelf life.

[0246] Antimicrobial preservative agents are used in pharmaceutical preparations to inhibit the growth of microorganisms. Dosage forms of the present invention may be formulated with one or more pharmaceutically acceptable anti-microbial preservatives at suitable concentrations to prevent microbial growth. Examples of pharmaceutically acceptable preservatives suitable for oral or nasal inhalation include, but are not limited to, parabens, benzalkonium chloride, benzethonium chloride, benzoic acid, sorbic acid or potassium sorbate, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, and thimerosal.

[0247] Wetting or dispensing agents are used to increase wettability and assist in dispersing of water insoluble or poorly water-soluble particles. Examples of pharmaceutically acceptable wetting and dispersing suitable for oral or nasal inhalation agents are, poloxamers, oleic acid and its salts, lecithin and hydrogenated lecithin, sorbitan fatty acid esters oleyl alcohol, phospholipids including but not limited to phosphatidylglycerol, phosphatidylcholine and others, polyoxyethylene fatty alcohol ethers, polyoxypropylene fatty alcohol ether, polyoxyethylene fatty acid ester, glycerol fatty acid esters, glycolipid such as sphingolipid and sphingomyelin, polyoxyethylene glycol fatty acid ester, polyol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polypropylene glycol fatty acid esters, ethoxylated lanolin derivatives, polyoxyethylene fatty alcohol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, propylene glycol alginate, dilauryldimethylammonium chloride, D-a-tocopheryl-PEG 1000 succinate, Poly oxy 40 stearate, poly oxy ethylene-poly oxypropylene block copolymers, polyoxyethylene vegetable oils, fatty acid derivatives of amino acids, glyceride derivatives of amino acids, benzalkonium chloride, bile acids.F. LIST OF ADDITIONAL NUMBERED EMBODIMENTS

[0248] The additional numbered embodiments below will be understood to apply to any of the disclosure and claims in this application, and, in determining the subject matter encompassed by these embodiments, the references to the “system or device of any of the above embodiments” will be understood to also be a reference to any of the embodiments and claims below. Further,the following list of embodiments is intended to supplement the preceding description as well as the Examples and Claims that follow the list.

[0249] 1. A smoking cessation system, comprising: a. A durable unit, comprising electronics and a peristaltic pump motor assembly; b. A cartridge comprising an aerosolizer, a debubbler, a filter, a pump head and one or more formulation chambers; and c. A wall charger and cable.

[0250] 2. The system of No. 1, further comprising an app for a portable device that communicates with the system.

[0251] 3 The system of any one of Nos. 1-2, wherein the cartridge is removably connected to the durable unit.

[0252] 4. The system of any one of Nos. 1-3, further comprising a controller and a mouthpiece.

[0253] 5. A method of treating a patient in need of smoking cessation therapy, comprising: a. Providing a system of any one of Nos. 1-4 wherein the cartridge comprises a nicotine formulation in the one or more formulation chambers; b. Administering the nicotine formulation by the patient sealing her / his lips around the mouthpiece and inhaling a dose of the nicotine formulation, wherein the patient administers to herself / himself multiple gradually decreasing doses of the nicotine formulation over time.

[0254] 6. The method of No. 5 wherein the period of time is about 2-6 weeks, or about 3-5 weeks, or about 4-5 weeks or about 4 weeks.

[0255] 7. The method of Nos. 5-6, wherein the dose gradually decreases by about l%-10% per day during the predetermined period of time.

[0256] 8. The method of Nos. 5-7, wherein the nicotine formulation comprises nicotine free base of a pharmaceutically acceptable salt thereof.

[0257] 9. The method of Nos. 5-8, wherein the nicotine formulation comprises about 5 mg / ml to about 50 mg / ml of nicotine free base.

[0258] 10. The method of Nos. 5-9, wherein the nicotine formulation comprises about 20 mg / ml to about 50 mg / ml of nicotine free base and 0.9% sodium chloride solution.

[0259] 11 The method of Nos. 5-10, wherein the system has means for delivering a volume of the nicotine formulation per actuation of about 1 to 50 microliters, or about 1 to 30 microliters, or about 1 to 25 microliters, or about 1 to 20 microliters, or about 1 to 15 microliters, or about 5 to 20 microliters, or about 10 to 20 microliters.

[0260] 12. The method of Nos. 5-11, wherein the system has means for delivering a volume of the nicotine formulation per actuation of about 1 to 50 microliters, or about 1 to 30 microliters, or about 1 to 25 microliters, or about 1 to 20 microliters, or about 1 to 15 microliters, or about 5 to 20 microliters, or about 10 to 20 microliters, and wherein such volume is delivered by the system in about 0.1 to 2.5 seconds, or about 0.25 to 2 seconds, or about 0.5 to 1.5 seconds, or about 0.75 to 1.25 seconds, or about 1 second.

[0261] 13. A smoking cessation inhaler, comprising: a durable part (or system or element) of the inhaler comprising a controller and a multidose cartridge configured to be separably attached to the durable part of the inhaler wherein the cartridge comprises (a) an aerosolizer; (b) a formulation chamber containing a formulation comprising an active pharmaceutical ingredient; (c) a debubbler; and (d) a filter.

[0262] 14. The inhaler of No. 13, further comprising a pump motor assembly.

[0263] 15. The inhaler of Nos. 13-14, further comprising a debubbler; a debubbler chamber; a pocket; an aerosolizer; a filter; and a pump head.

[0264] 16. The inhaler of Nos. 13-15, wherein the formulation comprises about 5 mg / ml to about 50 mg / ml of nicotine free base.

[0265] 17. The inhaler of Nos. 13-16, wherein the nicotine formulation comprises about 20 mg / ml to about 50 mg / ml of nicotine free base and 0.9% sodium chloride solution.

[0266] 18. The inhaler of Nos. 13-17, further comprising means for delivering a volume of the nicotine formulation per actuation of about 1 to 50 microliters, or about 1 to 30 microliters, or about 1 to 25 microliters, or about 1 to 20 microliters, or about 1 to 15 microliters, or about 5 to 20 microliters, or about 10 to 20 microliters.

[0267] 19. The inhaler of Nos. 13-17, further comprising means for delivering a volume of the nicotine formulation per actuation of about 1 to 50 microliters, or about 1 to 30 microliters, or about 1 to 25 microliters, or about 1 to 20 microliters, or about 1 to 15 microliters, or about 5 to 20 microliters, or about 10 to 20 microliters, and wherein such volume is delivered by the inhaler in about 0.1 to 2.5 seconds, or about 0.25 to 2 seconds, or about 0.5 to 1.5 seconds, or about 0.75 to 1.25 seconds, or about 1 second.

[0268] 20. The inhaler of Nos. 13-19, wherein the inhaler delivers nicotine free base resulting in pharmacokinetic values that are within about 5%, or 10%, or 15%, or 20%, or 25%, or 30% of those reported in cigarette smokers, wherein the values are one or more of (a) concentration at 5 minutes, 10 minutes and 15 minutes; (b) Cmax; (c) Tmax; and (d) AUC.

[0269] 21. The inhaler of Nos. 13-20, wherein a statistically significant number of patients who use the inhaler report a decrease of nicotine cravings as measured by the visual analog scale (VAS)- craving assessment.

[0270] 22. The inhaler of No. 21, wherein the inhaler decreases cravings by about 30%, or 40%, or 50%, or 60%, or 70% or 90% or 100%compared to baseline.

[0271] 23. The inhaler of Nos. 13-22, wherein the inhaler comprises only a single formulation and a single pump.

[0272] 24. An inhaler, comprising:A recirculation system comprising a first fluid pathway that extends from a formulation chamber to a pumping element;A second fluid pathway that extends from the pumping element to a pocket directly behind an aerosolizer; andA third fluid pathway that extends from the pocket back to the first fluid pathway.

[0273] 25. The inhaler of No. 24, further comprising a filter placed between the pump and the pocket.

[0274] 26. The inhaler of No. 25, wherein the filter has a pore size of about 0.1 to about 0.5 mm.

[0275] 27. The inhaler of No. 26, wherein the pore size of the filter is selected from about 0.1mm, about 0.2mm, and about 0.22mm.

[0276] 28. The inhaler of No. 27, further comprising a pump which pump is driven by a motor, wherein whether the filter is intact can be determined by one or more of: an increase in motor speed, a decrease in current, an increase in voltage, a shorter required pulse.

[0277] 29. The inhaler of No. 24, further comprising a debubbler.

[0278] 30. The inhaler of No. 29, wherein the debubbler is a hydrophobic porous element.

[0279] 31. The inhaler of No. 24, wherein the inhaler is comprised of a durable unit device, and a multidose cartridge configured to be separably attached to the durable.

[0280] 32. The inhaler of No. 31, further comprising a pump, wherein the cartridge contains components of a pump head and the durable unit contains a pump motor and a gear head.

[0281] 33. The inhaler of No. 32, wherein the pump is a peristaltic pump.

[0282] 34. The inhaler of No. 33, wherein the formulation chamber is flexible.

[0283] 35. The inhaler of No. 34, further comprising a valve placed close to the outlet of the formulation chamber, wherein the valve is opened upon connection of the cartridge to the durable unit.

[0284] 36. An inhaler, comprising: a nozzle array which is formed in a substrate; and a sealing system with a compliant material on one end; wherein the material is in contact with the substrate and blocks all or substantially all of the nozzles of the array when in the first position; further wherein the sealing system can be moved to a second position when the user is inhaling through the air channel.

[0285] 37. The inhaler of No. 36, further wherein the inhaler vibrates the substrate which contains the array of nozzle holes.

[0286] 38. The inhaler of No. 37, wherein the inhaler creates an aerosol into the inhalation airflow of the user, and further wherein the airflow flows in a direction which is substantially perpendicular to the average direction of aerosol generation from the array of holes.

[0287] 39. The inhaler of No. 38, further comprising a pressure sensor that detects a pressure drop in the air channel when the user is inhaling, whereupon when the controller determines that a predetermined pressure drop has been exceeded, it actuates the aerosolizer and thus the generation of aerosol.

[0288] 40. The inhaler of No. 39, wherein the controller senses the lack of sufficient inhalation airflow rate and stops the aerosolization.

[0289] 41. The inhaler of No. 40, wherein the controller will re-start aerosol generation if the user increases their inhalation rate and again exceeds the pressure threshold

[0290] 42. An inhaler, comprising: a durable unit device, and a multidose cartridge configured to be separably attached to the durable; and a formulation chamber containing a formulation comprising an active pharmaceutical ingredient: wherein the formulation chamber is flexible and collapses as formulation is drawn out of it, and a valve placed close to the outlet of the formulation chamber; wherein the valve is opened upon connection of the cartridge to the durable unit.

[0291] 43. The inhaler of No. 42, wherein one or more of a filter, a debubbler, flexible tubing, a rotor, an eccentric, a ring, a support surface, flexible tubing are components of the cartridge; wherein the drug contact surfaces are wholly contained in the cartridge.

[0292] 44. The inhaler of No. 43, wherein a computing system controls an element selected from a list including but not limited to: a flow rate of one or more pumps, a state of one or more valves, a voltage supplied to the aerosolizer, the amplitude of oscillation of a component of the aerosolizer, a duration of pumping of one or more pumps, a duration of aerosolization of the aerosolizer, such that the amount of nicotine, or other active ingredient, delivered to the user is consistently lowered over time.

[0293] 45. The inhaler of No. 44, wherein the element is a duration of aerosolization of an aerosolizer.

[0294] 46. The inhaler of No. 45, wherein the pump is turned on for a determined amount of time based on an amount of aerosol generated.G. EXAMPLES

[0295] The following examples are included to demonstrate certain embodiments of the present disclosure. Those of ordinary skill in the art should, however, in light of the present disclosure,appreciate that modifications can be made to specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. Therefore, all matter set forth is to be interpreted as illustrative and not in a limiting sense.EXAMPLE 1

[0296] An embodiment of the use of the system for smoking cessation is as follows. The system is supplied in a box comprising a durable unit section comprised of electronics and a peristaltic pump motor assembly in an overwrap; one or more individually wrapped cartridges comprised of an aerosolizer, a debubbler, a filter, a pump head, and one or more formulation chambers; a wall charger and cable, and instructions for use. The system also includes an app which is downloaded onto a portable device such as a smart phone or tablet. An embodiment of the use of the system of the current invention is as follows. The user installs the app on their phone and receives instructions on how to use the system (or optionally follows the paper instructions for use). Following the instructions, the user removes from the box and unwraps the durable unit cartridge and discards the overwrap. A supplied charger is attached via a USB-C charging connector and plugged in until the battery is fully charged, as indicated by a light switching from red to green. A first cartridge is removed from its overwrap and pressed onto the durable unit section, until a de-tenting feature is felt and heard to click. When the cartridge is installed, the user removes a mouthpiece cap, and a controller begins a purging procedure entailing turning on the pump for a sufficiently long time to remove air from flow channels, a formulation pocket, and a debubbler / filter module. The controller monitors the motor current and determines that the cartridge has been installed properly and is pumping formulation. When priming is complete, a blue flashing light on the device illuminates, indicating that the device is ready to use.The user then seals their lips around the mouthpiece and begins inhaling. The microcontroller reads the inhalation flow rate from a sensor, and while the flow rate is in the correct range, the controller causes a piezo to oscillate, generating an aerosol through a nozzle array into the user’s inhalation flow. The green light is illuminated steadily when the inhalation is in the desired flow rate range, guiding the inhalation of the user. The aerosol is generated for a maximum of 1 second, less if the user does not inhale at the prescribed flow rate or stops inhaling. The pump is turned on when the aerosol first starts and stays on until 200 ms before the end ofaerosol generation, pushing air generated by the aerosolizer into the debubbler, and replenishing formulation that has been aerosolized. The above steps are repeated upon each time the user inhales through the device based on the desire of the user, for as long as the flashing green light is illuminated. When the user replaces the mouthpiece cap, the flashing green light is extinguished, and the system is put into a sleep mode. Later, the user then removes the mouthpiece cap and repeats the subsequent steps as desired. When the formulation in a formulation chamber is depleted after approximately 1 week (based on the frequency and amount of usage), pushing the button presents a flashing red light. The user looks at the side of the device and discovers a red light next to the word “cartridge”, indicating that cartridge needs to be replaced. The user then removes the cartridge by pulling it away from the durable unit section and disposes of it, removes the overwrap from the next cartridge, and attaches the cartridge as before, optionally while viewing the instructions. During this whole process, the controller adjusts the aerosolization time, slowly tapering down to essentially zero over the course of 12 weeks. During the course of therapy, when the battery becomes depleted, the device presents a flashing red light. Upon looking at the side of device, the user discovers a red light next to the word “battery”. The user attaches a charger to the device and charges until the device displays a steady green light, indicating that charging is complete.EXAMPLE 2The embodiment shown in Figure 4 was tested for emitted dose efficiency 23 times using the method of USP 601 : Delivered Dose Uniformity. A formulation of lOx normal saline was used. The filter was washed with a predetermined amount of deionized water and emitted dose was quantified using an electrical conductance method. Figure 9 shows the results. The emitted dose averaged 82.01% of the amount of formulation aerosolized. The acceptance criteria of USP 601 of ± 25% and ± 35% are included for reference.EXAMPLE 3

[0297] The embodiment of Figure 4 was tested for aerosolized volume over a period of two weeks. Ten (10) dosing events separated by 90 minutes were performed each day, and each dosing event was comprised of 7 puffs separated by 30 seconds. A formulation of 3X normal saline was used. During the experiment, the system was not disturbed except to occasionally fill a graduated cylinder with formulation. The change of the volume of formulation in the graduated cylinder wasused to determine the total aerosolized volume each day. The aerosolizer was configured before the start of the experiment to aerosolize 10 pl / puff. Figure 10 presents the average aerosolized volume per puff for each of days 6 through 14. It can be seen from Figure 22 that the embodiment of Figure 13 is capable of delivering a repeatable aerosolized volume for at least a period of 2 weeks.EXAMPLE 4

[0298] A Clinical trial was conducted in 10 smokers using the device of the current invention as described in figure 4. Subjects were admitted to the clinic the day before dosing to ensure sufficient wash out of nicotine. Subjects self-administered 3 doses of a 90 mg / ml nicotine bitartrate dihydrate aerosol separated by 120 minutes. The first dose was a single puff wherein the aerosolization time was 0.6 seconds and 0.1 mg (nicotine freebase equivalent) was delivered to the subject. The second dose was 0.2 mg delivered over 1.2 seconds. The third dose was 1.5 mg delivered over 7 puffs of 1.2 second aerosolization time, similar to smoking a cigarette. The target inhalation rate was in the range of 15 - 45 LPM. All subject achieved the target aerosolization time every time they took a puff.

[0299] Subjects were first trained in the use of the device. For each puff, the subject pressed a button, and was presented with a slowly flashing blue light, indicating that the inhaler was ready to use. When the subject started inhaling, if and when they achieved the correct inhalation rate, they were presented with a steady blue light, and aerosol generation was started. If they inhaled above 45 LPM, they were presented with a rapidly flashing red light, and the aerosolizer was turned off. If they inhaled below 15 LPM, the light was extinguished, and the aerosol was turned off. If in either case they then achieved the correct flow rate, the aerosolizer was turned back on. In all cases, if the total aerosolization time reached the target of 0.6s or 1.2s, the aerosolizer was turned off.

[0300] After each dosing event, arterial samples were taken at baseline and 0.5, 1, 1.5, 2, 3, 5, 7, 10, 15, 30, 60, and 120 minutes after the end of dosing. The 2ndand 3rddoses used the 120 minutes sample of the previous dose as a baseline. Vital signs (SaCh, heart rate and blood pressure), ECG, and Peak Expiratory Flow Rate (PEFR) were taken within 30 minutes before each dose. Vital signs were measured at 15, 30, 90, and 105 minutes post dose, and ECG and PEFR were measuredat 30 and 60 minutes post dose. A Visual Analog Scale (VAS) was used to measure craving within 30 minutes before dosing, and at 2, 5, 15, 30, 60, and 105 minutes post dose.

[0301] Figure 11 presents the average results the venous nicotine level measurements from all 10 subjects. Peak plasma levels of nicotine averaged over all 10 subjects were seen at the first sampling time point of 30 seconds for all three dose levels. Tmax and AUC are suggestive of dose proportionality, although the levels for dose 3 are not 7 times as high as those for dose 2 due to the fact that significant clearance occurred over the approximate 5 minutes that it took to deliver dose 3.

[0302] Figure 12 shows a comparison of venous nicotine levels achieved with the current invention (dose 3) vs. those expected from cigarettes and 4 mg nicotine gum. The results from the current invention were quite similar to a cigarette. This will to lead to an experience that is similar to smoking, and is expected to result in an easier switch from smoking to the using the inhaler of the current invention. By contrast the nicotine gum had a much lower Cmaxand AUC, despite the fact that the nicotine gum delivered nearly 3 times as much nicotine. Tmax was also much longer for the gum, at approximately 30 minutes as would be expected for oral or buccal delivery. This delay will lead to a concomitant delay in relief from craving and can be expected to cause higher rates of failure of the therapy.

[0303] Figure 13 shows the reduction in craving (average over all 10 subjects) as measured by VAS. Significant reduction in craving was seen at all dose levels, and after Dose 3 craving was essentially eliminated.

[0304] Figure 14 shows a comparison of VAS levels achieved using the current invention (dose 3, 1.5 mg), and current state of the art: a 10 mg patch, and 4 and 6 mg gum. It can be seen that although significantly lower amounts of nicotine were delivered with the current invention, significantly faster and more complete elimination of craving was achieved with the current invention. Thus, and because the success rates using the current state of the art therapies are quite low (—10%) it can be expected that significantly higher smoking cessation success rates will be achieved with the current invention.

[0305] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes maybe made, and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

CLAIMSWhat is claimed is:

1. An inhaler having one or more holes, comprising:A nozzle plug that blocks the exit of the one or more nozzle holes between uses of the device; wherein the nozzle plug is incorporated onto a mouthpiece cap.

2. The inhaler of claim 1, wherein the nozzle plug is comprised of a compliant element.

3. The inhaler of claim 2, wherein the compliant element is overmolded onto a rigid material.

4. The inhaler of claim 3, wherein the inhaler comprises an aerosolizer, wherein the aerosolizer is comprised of an array of nozzle holes formed in an essentially rigid substrate.

5. The inhaler of claim 4, wherein the array of nozzle holes is comprised of between 500 and 5000 holes, and the nozzle plug substantially fully blocks the exit of substantially all the holes in the nozzle array.

6. An inhaler, comprising a pump, a cartridge comprised of a pump head, and a durable unit comprised of a pump motor assembly, wherein the cartridge is separably attached to the durable unit, wherein the pump head is comprised of an eccentric cam, a ring, wherein the eccentric cam rotates and thereby translates the ring.

7. The inhaler of claim 6, wherein the pump motor assembly is comprised of a clutch pressure plate that is slidably positioned on a motor shaft and urged toward the end of the shaft by a spring.

8. The inhaler of claim 7, wherein the pump head is comprised of a clutch disk, and when the cartridge and the durable have been attached to each other, the clutch pressure plate engages with the clutch disk, such that when the when the motor is energized, the clutch pressure plate rotates and causes the clutch disk to rotate, which causes the eccentric to rotate.

9. The inhaler of claim 8, wherein the pressure plate is comprised of engaging features which mate with negatives of the features on the clutch disk.

10. The inhaler of claim 9, wherein in general the engagement features on the clutch disk and the mating engagement features on the clutch pressure plate are not aligned when the cartridge is first attached to the durable.

11. A method of manufacture of the cartridge of claim 6, wherein the eccentric is placedclose to a formulation flow exit of the pump head.

12. An inhaler, comprising: a flexible formulation chamber; and a chamber compressing element; wherein the compressing element is configured such that when the cartridge is attached to the durable unit, the compressing element compresses the formulation chamber and forces liquid out of the formulation chamber.

13. The inhaler of claim 12, where the chamber compressing element is attached to the durable unit, and when the cartridge is attached to the durable the chamber compressing element enters the cartridge through an opening in the cartridge.

14. The inhaler of claim 12, wherein the chamber compressing element is captured inside the cartridge.

15. The inhaler of claim 12, wherein the chamber compressing element is bendably attached to the housing of the cartridge.

16. The inhaler of claim 12, wherein the formulation chamber is comprised of a clamp that keeps the chamber closed during shelf life, and the clamp opens as the formulation chamber is being compressed.

17. The inhaler of claim 16, wherein the clamp is a peel seal, and the compression of the formulation chamber causes a pressurization of the formulation chamber causing a peel seal to peel open to form a flow channel out of the formulation chamber.

18. The inhaler of claim 16, wherein the clamp is a mechanical clamp, and the moving of the chamber compressing element causes the opening of the clamp.

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