Nicotine Delivery Systems

Abstract

Nicotine delivery devices and systems, particularly smoking cessation systems, are provided by the present disclosure. Such devices and systems generate nicotine-containing aerosols for inhalation to mimic smoking. The devices are adaptable to control the amount of nicotine delivered and to gradually decrease the amount of nicotine delivered to the user over time. Treatment methods for patients to quit 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

[Technical field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims priority to U.S. Provisional Application Serial Nos. 63 / 294498, filed December 29, 2021; 63 / 332112, filed April 18, 2022; 63 / 388509, filed July 12, 2022; and 63 / 418442, filed October 21, 2022, which applications are incorporated by reference herein in their entireties to the fullest extent permitted by law.

[0002] [Technical field] The present disclosure relates to methods and devices for inhalation drug delivery. Preferred devices are inhalation systems that create an experience similar to smoking, including, but not limited to, devices having an array of nozzles for forming a nicotine-containing aerosol. Preferably, the inhalation system controls the amount of nicotine delivered by reducing the amount to substantially zero over a predetermined period of time. [Background technology]

[0003] The present disclosure generally relates to devices, systems, and methods for facilitating smoking cessation and the treatment and management of tobacco and e-cigarette addiction. Tobacco addiction through cigarettes directly affects 34.2 million people in the United States, leads to over 480,000 preventable deaths, and costs the U.S. economy over $891 billion annually. Tobacco addiction is a chronic disease, and various drugs and methods have been attempted to treat the disease. Currently, there are seven types of drugs approved by the FDA for the treatment of tobacco addiction: nicotine replacement therapy (NRT) gums, lozenges, patches, buccal inhalers, and nasal sprays, and the prescription drugs varenicline and bupropion.

[0004] The most commonly used method to manage tobacco dependence in smokers is NRT, and the most commonly used medication within that product class is NRT gum. However, this product has a failure rate of over 91% one year after the initiation of abstinence, clearly highlighting the need for new pharmacotherapies with greater 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, which use heat to form vapor that condenses into an aerosol, are available as smoking replacement devices, but are not approved for use as smoking cessation products. Available data suggests that more than 50% of e-cigarette users also smoke cigarettes, increasing their exposure to harmful tobacco combustion products rather than helping them break their tobacco addiction. E-cigarettes do not have a sufficiently good safety profile to promote their use as a treatment for tobacco addiction in the United States, because the use of heat in forming aerosol is known to produce carcinogenic compounds, including formaldehyde and acetaldehyde. Thus, there is a need in the art for a safe and effective inhalant for use as a smoking cessation treatment that avoids the shortcomings of oral medications and e-cigarettes.

[0006] Aqueous inhalation solutions have many desirable properties. Most of the existing aqueous inhalation systems are single-dose, with the user pouring the formulation from a vial into a container and then breathing through the device for several minutes, followed by an extensive cleaning procedure. These products are not useful for applications that require immediate availability when needed, such as pain or cravings. The only system, the Respimat inhaler (Boehringer Ingelheim), delivers multiple doses without filling or cleaning. However, because the Respimat is an all-mechanical inhaler, it cannot perform functions such as dose control, usage monitoring, etc. Thus, there is a need for an easy-to-use, multi-dose aqueous inhalation system with the ability to control the delivered dose. Summary of the Invention

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

[0008] The present disclosure provides, in certain embodiments, a smoke-free inhaler comprising: a durable portion (or system or element) of the inhaler comprising a controller; and a multi-dose cartridge configured for releasable attachment to the durable portion of the inhaler; wherein the cartridge comprises: (a) an aerosolizer; (b) a formulation chamber containing a formulation including an active pharmaceutical ingredient; (c) an air bubble remover; and (d) a filter. In certain embodiments, the durable portion 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 elements selected from one or more of the following: a motor; a gear head; an eccentric element; a rotor that causes at least one roller to circulate; and an alignment cam. The pump head assembly may comprise elements selected from one or more of the following: a support surface; a ring; and a portion of a tube. The inhaler may further comprise a recirculation system comprising one or more elements selected from the following: an air bubbler; an air bubbler 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 a filter may have a pore size of about 5 μm or less, or about 2 μm or less, or about 1 μm or less.

[0011] The present disclosure provides, in some embodiments, an inhaler that contains multiple doses of an aqueous formulation, such as a solution or suspension, of one or more active pharmaceutical ingredients.

[0012] The disclosure also provides that in certain aspects, the active pharmaceutical ingredient is an addictive substance; and / or a substance to which chronic users develop tolerance. In one embodiment, the amount of active pharmaceutical ingredient (API) delivered is repeatedly adjusted by the controller, the adjustments including one or more of the following: (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 in active pharmaceutical ingredient delivered followed by a period of decrease in active pharmaceutical ingredient delivered.

[0013] An important aspect of the present disclosure relates to smoking cessation devices, systems, formulations, and methods, and although formulations containing nicotine are described, other active pharmaceutical ingredients may also be delivered using the disclosed system. Such non-nicotine APIs may or may not include nicotine to promote smoking cessation or for use in smoking or electronic smoking replacement. It will also be understood that the system may be used in indications other than smoking cessation, and active compounds other than nicotine or other drugs for smoking may be used. While high molecular weight compounds of more than 10 kDa for systemic effects may be delivered, preferred applications include compounds of any molecular weight for local or targeted pulmonary treatment, and low molecular weight compounds, preferably less than or about 10 kDa, preferably less than or about 5 kDa, more preferably less than or about 1 kDa, for systemic effects, for more rapid systemic effects compared to other delivery routes, including but not limited to subcutaneous, transdermal, intradermal, oral, buccal, ocular, or nasal.

[0014] In some embodiments, therapeutic applications using the aerosol device disclosed herein require dose variation over time or dose personalization for individual patients. Variation may include tapering to avoid withdrawal symptoms of legal or illegal, medical or recreational compounds. Variation may include intensification, e.g., by increasing tolerance over time, of compounds including, but not limited to, opioids, e.g., fentanyl or morphine, and their pharmaceutically acceptable salts. Variation may also include doses selected by the patient (i.e., self-titration) or caregiver, e.g., titration of analgesic strength based on perceived pain, or titration of oral hypoglycemic drugs, including, but not limited to, insulin or glucagon-like peptides, based on measured blood glucose levels and / or expected food intake.

[0015] As a non-limiting example, fentanyl or a salt thereof may be used with the aerosol device disclosed herein. In one embodiment, fentanyl is inhaled voluntarily from the device, with a lockout period between doses to prevent overdosing. The initial maximum tolerated dose of about 10-40 μg / hr, or about 20-30 μg / hr, or about 25 μg / hr, may be intensified up to about 25-100 mcg / hr, or about 35-65 mcg / hr, or about 50 mcg / hr. Dose escalation may occur over a period ranging from about 1 week to 10 weeks, or 2 weeks to 5 weeks, or about 3 weeks. When termination of treatment is desired, the dose may be tapered 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 tapering of the dose may be used to avoid addiction and abuse of opioids such as fentanyl.

[0016] The present disclosure further provides a companion application capable of one or more of the following: controlling communication with the smoking cessation device, where the communication is preferably wireless, and more preferably Bluetooth; controlling the smoking cessation device; updating firmware on the smoking cessation device; displaying data generated by the smoking cessation device; and enabling data and other information to be input, for example, by a user, a caregiver, or a medical professional.

[0017] In one embodiment, the companion application further comprises functions selected from training, coaching, reinforcing, and rewarding the user. Preferably, the companion application resides on a computing device. The computing device may be an essentially non-portable system such as a desktop computer, but the preferred computing device is portable and is selected from the list including smartphones, tablets, smart watches, laptop computers, smart glasses, and virtual reality systems. In another embodiment, the application resides in the cloud and functions such as the user interface and a system for communicating with the smoking cessation device reside on the computing device.

[0018] In one embodiment, the formulation container contains a first formulation, preferably the first formulation includes an active pharmaceutical ingredient, such as nicotine. In this embodiment, the formulation container also contains a second formulation, preferably the second formulation does not include an active pharmaceutical ingredient, such as nicotine. In another embodiment, the formulation container contains only a single formulation.

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

[0020] The formulation container can contain at least one formulation chamber, where the formulation chamber is a flexible bag that is entirely contained within the container. Preferably, the formulation chamber is watertight, airtight, and includes a water vapor barrier to ensure a sealed dosage form. In one embodiment, the formulation chamber may be attached to the inner surface of the formulation container at one or more points, for example, but not limited to, the side of the chamber is attached to the inner side of the wall of the formulation container, or the top of the formulation chamber is attached to the inner wall of the top of the formulation container.

[0021] The present disclosure provides a formulation container (hereinafter referred to as a cartridge) that is part of a component that includes a mouthpiece, where the component is disposable, and further where the component has a passageway (hereinafter referred to as an airway) that allows the flow of air and aerosol to be inhaled by the user. In one embodiment, the airway can be partially or essentially completely surrounded by the formulation container or by one or more formulation containers. In another embodiment, the airway is located adjacent to the formulation container, and in a third embodiment, the airway is partially or completely separated from the formulation container. Both of the above-mentioned embodiments have the advantage that the formulation container(s) and other components of the cartridge are replaced in a single operation. This type of mouthpiece / formulation container combination is described in patent application PCT / US2021 / 064426, which is incorporated herein by reference in its entirety. Optionally, the airway inlet may be present in a durable part that controls the inhaler, and may be located in the airway part, a mechanism that is also present in the durable part and allows breath actuation of the aerosol. This mechanism is preferably a pressure tap that leads to a pressure transducer that is read by a controller in the durable part.

[0022] In another embodiment, the cartridge further comprises a nebulizer. The nebulizer can be selected from a vibrating mesh, a condensation aerosol generator, an ultrasonic nebulizer, a dry powder disperser, a jet nebulizer, a swirl nebulizer, a flow blurring nebulizer, and a flow focusing nebulizer. Preferably, the nebulizer is a vibrating mesh nebulizer. Preferably, the nebulizer is located between the airway and at least one formulation container.

[0023] The present disclosure also provides that all components that come into contact with the formulation(s) during storage and / or use are contained within the disposable cartridge, and none of the components of the durable system of the aerosolization system come into direct contact with the formulation. The cartridge is preferably designed to limit the possibility of misuse or abuse of the formulation and the associated overdose or addiction. For this reason, it is preferred that components that come into direct contact with nicotine, such as the mixing chamber, tubing, bubbler, filter, and aerosolizer, are essentially completely contained within the cartridge.

[0024] In some embodiments, the nicotine formulation comprises nicotine or a salt of nicotine. Such formulations include, but are not limited to, essentially neat nicotine, or a nicotine suspension, or a nicotine solution. One embodiment of the formulation comprises nicotine and a lipophilic solvent. The lipophilic solvent preferably comprises an alcohol, such as ethanol. Other embodiments include, but are not limited to, a glycol, such as propylene glycol. Another embodiment of the formulation is a salt of nicotine, preferably nicotine tartrate, more preferably nicotine bitartrate dihydrate, in a solvent that comprises water. Alternatively, the formulation is USP nicotine dissolved in a formulation of water or a combination of water and ethanol. The formulation may also include various excipients, such as surfactants (preferably Tween 20 or Tween 80), stabilizers, absorption enhancers, antimicrobial agents, etc. In some embodiments, the formulation comprises a dissolved salt of nicotine and water. In other cases, the formulation consists essentially of a carrier such as water and a dissolved salt of nicotine (eg, nicotine bitartrate dihydrate).

[0025] In one embodiment, the companion application or firmware calculates a starting dose of an active ingredient, such as nicotine, that is personalized for the user based on factors selected from the user's nicotine exposure and smoking history, including the amount of nicotine per day, the number of cigarettes per day, the number of packs per day, the brand of cigarettes smoked, the number of puffs per day of the electronic smoking system, the electronic smoking system used, the electronic smoking fluid used, the concentration of nicotine in the electronic smoking fluid used, the usage of other tobacco products, including, but not limited to, pipes, chewing tobacco, and snuff; lifetime cigarette use, e.g., measured by pack-years of smoking; and current craving level. For example, craving levels may be measured by: the Fagerstrom Test for Nicotine Dependence; the user's physical characteristics, including the user's health, age, sex, height, weight, ethnicity, and genetic makeup; past use of other smoking cessation methods, including gums, patches, buccal systems, inhalants, behavioral therapies, and software applications; and the user's usage of the smoking cessation systems disclosed herein.

[0026] In another embodiment, the starting dose of the active ingredient is selected by a physician based on patient characteristics, such as body weight, smoking history, tolerance to the active ingredient, age, etc. In one embodiment, the starting dose of the 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 one embodiment, the system monitors the inhalation rate during delivery and turns off the aerosolizer when the flow falls below a level that can effectively carry the aerosol. If the user desires a lower dose, the user can remove the mouthpiece from the mouth and continue inhaling, which is the same as with a cigarette.

[0027] In some embodiments, the system, for example the firmware or companion application of the device, adjusts the amount of active ingredient (preferably nicotine) delivered per puff and decreases the amount of nicotine delivered as smoking cessation therapy progresses.The adjustment of the amount of active ingredient may be personalized for the subject based on factors including the user's smoking history, including the amount of nicotine per day, the number of cigarettes per day, the number of packs per day, the brand of cigarettes smoked, the nicotine content of the cigarettes smoked, the number of puffs per day of the electronic smoking system, the electronic smoking system used, the electronic smoking fluid used, the usage of other tobacco products, including but not limited to pipes, chewing tobacco, and snuff; lifetime cigarette usage, for example measured by pack-years of smoking, and current craving level. For example, craving level can be measured by: Fagerstrom's Nicotine Dependence Test; physical characteristics of the user, including health, age, sex, height, weight, ethnicity, and genetics; past history of use of other smoking cessation methods, including but not limited to gums, patches, oral systems, and inhalants, and past history of use of the smoking cessation system disclosed herein, including but not limited to the number of puffs per day, the number of administration events per day, the total number of puffs and administration events, current cravings, reported success in not using cigarettes, reported success in not using e-cigarettes, past and new health problems, and the rate of change of any of the aforementioned factors. 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 is controlled when the user inhales deeply at or above a predetermined flow rate, but the use of the system is otherwise optional, and the user can perform as many puffs per administration event and as many administration events per day as he or she desires.

[0028] In another embodiment, the dose per puff is adjusted by controlling the concentration of nicotine delivered, which may be adjusted according to an algorithm, where the algorithm is used over the course of a treatment to reduce the dose of nicotine delivered via the smoking cessation system, such that the dose of nicotine delivered to the user is 0 milligrams per milliliter or essentially 0 milligrams per milliliter at the end of the treatment. One embodiment of the algorithm predetermines the appropriate dose level for each treatment, where the actual concentration is calculated by the ratio of the number of past effective pulses to the number of sham pulses, the actual concentration is compared to the predetermined concentration, and then the pulse system pumps a corresponding number of pulses of nicotine-containing or non-nicotine-containing formulation to balance the actual concentration with the predetermined concentration. In the above embodiment, the firmware or companion application controls components including microfluidic valves, pumps, etc., as determined by the algorithm, where the components may be arranged to allow flow from multiple (preferably two) formulation chambers to achieve the appropriate concentration of nicotine according to the algorithm.

[0029] To achieve the appropriate nicotine concentration throughout the treatment, each dose or puff is provided with a valve position to regulate the flow of multiple (preferably two) formulations, depending on the embodiment, based on a comparison between the actual nicotine concentration level on a given day and a predetermined nicotine concentration level. In one embodiment, a valve is used to partially restrict the flow of each of the multiple formulations to achieve the appropriate nicotine concentration. In another embodiment, a valve is used that completely blocks the flow of at least one formulation while allowing the flow of another formulation, where there are essentially two valve positions, referred to herein as 0 and 1, and each dose or puff is associated with 0 or 1, depending on the embodiment, based on a comparison between the actual nicotine concentration level on a given day and a predetermined nicotine concentration level, and this flow maintains the appropriate concentration of nicotine in the smoking cessation system throughout the treatment course. In one embodiment, there are two microfluidic pumps, each pumping from a nicotine-containing formulation or a non-nicotine-containing formulation, and the operation of the pumps is governed by the aforementioned algorithm. For example, the actual concentration of nicotine is compared to a predetermined concentration of nicotine on a given day, and if the actual concentration is higher than the predetermined concentration, the non-nicotine pump pumps the formulation for the next pumping cycle. Preferably, this comparison occurs every dosing event, more preferably every puff.

[0030] These and other objects, advantages, and features of the present invention will become apparent to those skilled in the art upon reading the details of the formulations and methodologies described in more detail below. Additional embodiments of the present devices, formulations, processes, methods of treatment, and the like will become apparent from the following specification, drawings, examples, and claims. As can be understood from the foregoing and following description, every feature described herein, 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 combinations are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment or aspect. Additional aspects and embodiments are described in the following specification and claims, particularly when considered in conjunction with the accompanying examples and drawings.

[0031] [Brief description of the drawings] 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. Conversely, dimensions of the various features have been arbitrarily enlarged or reduced for clarity. The patent or application document 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. The drawings include the following figures: [Brief description of the drawings]

[0032] [Figure 1] 1 is a cross-sectional view of one embodiment of an inhalation device of the present disclosure. [Diagram 2] FIG. 1 is a cross-sectional view of one embodiment of a mouthpiece having an integrated formulation cavity of the present disclosure. [Diagram 3] FIG. 1 is a cross-sectional view of one embodiment of a mouthpiece, aerosolization system, and fluid system of the present disclosure. [Figure 4] FIG. 1 is a cross-sectional view of one embodiment of an aerosolization system and a fluid system of the present disclosure. [Diagram 5] FIG. 1 is a cross-sectional view of one embodiment of a fluid system of the present disclosure. [Figure 6] FIG. 2 is a cross-sectional view of another embodiment of a fluid system of the present disclosure. [Figure 7] 1 is a general cross-sectional view of one embodiment of the device of the present disclosure. [Figure 8] FIG. 1 is a cross-sectional view of one embodiment of the durability system of the present disclosure. [Figure 9] FIG. 2 is a cross-sectional view of one embodiment of a cartridge of the present disclosure. [Figure 10a-10b] FIG. 13 is a cross-sectional view of one embodiment of a fluid connection point between a cartridge and a durability system body of the present disclosure. [Figure 11a-11b] 13A-13C are cross-sectional views of alternative embodiments of fluid connection points between the cartridge and durability system body of the present disclosure. [Figure 12] FIG. 2 is a cross-sectional view of one embodiment of a cartridge of the present disclosure. [Figure 13] 1 is a cross-sectional view of an alternative embodiment of the cartridge of the present disclosure having a recirculation system and a bubble remover. [Figure 14] 1 is a graph showing the calculation results of a given algorithm for a daily adjusted down-titration dosing regimen. [Figure 15] 15 is a graph showing the error of the down-titration dosing regimen of FIG. 14. [Figure 16] 1 is a graph showing a down-titration dosing regimen adjusted for each dosing event. [Figure 17] 17 is a graph showing the error of the down-titration dosing regimen of FIG. 16. [Figure 18] FIG. 2 is a cross-sectional view of one embodiment of the cartridge of the present invention having an integral filter. [Figure 19a] FIG. 2 is a cross-sectional view of one embodiment of a separable pump motor and pump head of the present disclosure, prior to attachment of the cartridge to the durable portion. [Figure 19b] FIG. 19b is a cross-sectional view of the embodiment of FIG. 19a during attachment of the cartridge to the durable portion. [Figure 19c] FIG. 19b is a cross-sectional view of the embodiment of FIG. 19a after attachment of the cartridge to the durable portion. [Figure 20a] FIG. 2 is a cross-sectional view of one embodiment of the bubble remover of the present disclosure. [Figure 20b] FIG. 20b is an isometric view of the bubble remover of FIG. 20a. [Figure 21] 13 is a graph showing measurements of emitted dose uniformity of aerosols generated using the embodiment of FIG. 12. [Figure 22] 14 is a graphical plot of the average aerosolized volume over a two week period using the embodiment of FIG. 13. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] Various aspects and embodiments will now be fully described in this specification. However, these aspects and embodiments may be embodied in many different forms and should not be construed as limiting; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the subject matter to those skilled in the art. All publications, patents, and patent applications cited in this specification, whether supra or infra, are incorporated herein by reference in their entirety.

[0034] Where a range of values ​​is provided, unless the context clearly indicates otherwise, it is understood that each intermediate value, to the tenth of the unit of the lower limit, between the upper and lower limits of that range is also specifically disclosed. Each subrange between any stated or intermediate value in a stated range and any other stated or intermediate value in that stated range is encompassed within the invention. The upper and lower limits of these subranges may be independently included or excluded within the range, and each range in which neither limit is included or both limits are included within the subrange is also encompassed within the invention, except for the specifically excluded limit in the stated range. Where a stated range includes one or both of the limits, ranges excluding one or both of those included limits are also encompassed within the invention.

[0035] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the publication dates provided may be different from the actual publication dates, which may need to be independently confirmed.

[0036] [A. Definition] Unless otherwise defined, 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.

[0037] It should be noted that the singular forms "a", "an" and "the" used in this specification and the appended claims include plural referents unless the context clearly indicates otherwise.Thus, for example, a reference to "a formulation" includes one or more such formulations, a reference to "the method" includes one or more methods and their equivalents known to those skilled in the art, and so forth.Furthermore, when the size of a region such as a hole is referred to as having a certain diameter, it will be understood that this includes other cross-sectional shapes that are not circular but have an area equivalent to a circle of a particular diameter.

[0038] About or Approximately: In general, variations above and below the stated ranges may be used to achieve substantially the same results as the values ​​within the ranges. As used herein, the terms "about" and "approximately" when referring to numerical values ​​shall have their plain and ordinary meaning to those of ordinary skill in the art to which the disclosed subject matter most closely pertains, or to which the range or element in question pertains. The amount of spread from an exact numerical boundary will depend on many factors. For example, some of the factors that may be considered include the importance of the element and / or the effect of a given amount of variation on the performance of the claimed subject matter, and other considerations known to those of ordinary skill in the art. The use of different significant digits for different numerical values ​​used herein is not meant to limit how the use of the word "about" or "approximately" serves to spread a particular numerical value or range. Also, the disclosure of a range is intended as a continuous range, including all values ​​between the minimum and maximum values, as well as the spread of the range given by the use of the term "about" or "approximately". Consequently, the recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if each separate value was individually recited herein.

[0039] Ad libitum: Administered according to the user's preference.

[0040] Aerosol head cavity: The cavity within the cartridge that contains one or more of the following: air, formulation, absorbent, or debubbler.

[0041] Aseptic filter: A filter used to remove microorganisms from a formulation. Preferred filters have pore sizes selected from about 0.22 μm, 0.2 μm, or 0.1 μm.

[0042] Atomizer: The component of the device, preferably the cartridge, of the present invention that generates the aerosol. Preferably, the atomizer is a vibrating mesh nebulizer.

[0043] Carrier: A liquid, preferably water, in which the active pharmaceutical ingredient is suspended or preferably dissolved.

[0044] Cartridge, disposable, etc.: A component of the device of the invention that contains the formulation and one or more of the formulation chamber, formulation cavity, and aerosol head cavity, bubbler, pump head components, tubing, airway, mouthpiece, and aerosolizer. The cartridge is releasably attached to a durable system and is typically used for a period of time that is preferably shorter than the period of time that the durable system is used.

[0045] Cigarette: An inhalation system that uses the combustion of tobacco to deliver nicotine.

[0046] Condensation aerosol: An aerosol formed by first forming a saturated vapor, which then condenses to form the aerosol.

[0047] Dead volume: The maximum internal volume of a reciprocating pump minus the swept volume of the pump.

[0048] Debubbler: A unit for removing air from a formulation, preferably using a hydrophobic porous material.

[0049] Dosing event: A series of puffs delivered by a user during a single use of a smoking cessation system.

[0050] Dry powder dispersing mechanism: A system for adding energy to a packed pharmaceutical powder to form an aerosol.

[0051] Durable system: A component that houses one or more of the following: electronics, microcontroller, battery, charging circuitry, lights, buttons, electrical connectors, and pump motors, gearheads, eccentric cams, and alignment cams.

[0052] Eccentric element or cam: An element that rotates and is not symmetric about its axis of rotation.

[0053] E-cigarette: An inhalation system that utilizes electrical power, preferably a battery power source, to deliver nicotine.

[0054] Electronic nicotine delivery systems: Electronic systems for smoking cessation therapy or smoking substitution.

[0055] Electrospray: A system for forming an aerosol in which a liquid flows from the end of a capillary tube through holes in a plate. When a voltage is applied between the capillary tube and the plate, the liquid forms a cone and a jet emerges from the tip of the cone. The jet flows through the holes and undergoes Raleigh breakup to form the aerosol.

[0056] Emitted dose: The volume of formulation, or amount of active pharmaceutical ingredient, emitted from an inhalation device, e.g., during one puff or one administration event.

[0057] Expanded: A material that has been expanded to make it porous, preferably a hydrophobic material.

[0058] Fagerstrom Test for Nicotine Dependence: A test to measure the severity of nicotine dependence.

[0059] Firmware: Computer code that is loaded onto a microcontroller.

[0060] Flow blurring: A method of forming an aerosol in which a liquid flows from a capillary and the liquid and high pressure gas co-flow rapidly (e.g., more rapidly than used in flow focusing) through holes in a plate. The liquid at the capillary outlet breaks down somewhat violently into droplets which are carried through the holes to form the aerosol.

[0061] Flow focusing: A method of forming an aerosol in which a liquid flows from a capillary tube and the liquid and pressurized gas co-flow through holes in a plate. The liquid forms a cone under the influence of the co-flowing gas, and a jet is formed at the apex of the cone, which undergoes Rayleigh fragmentation to form the aerosol.

[0062] Formulation cavity: The space within a cartridge of the present invention that houses the formulation chamber(s).

[0063] Formulation chamber: A container for the formulation used in the present invention. Preferred formulation chambers are flexible and collapse when the formulation is withdrawn therefrom.

[0064] Formulation pocket: The area directly behind the aerosolizer that contains the formulation and may contain a wicking element.

[0065] Gauge pressure: The pressure difference from the surrounding atmosphere.

[0066] Jet nebulizer: A system for generating an aerosol from a liquid in which a jet of compressed gas is forced through the liquid, forming, entraining, and dispersing droplets to form the aerosol.

[0067] MEMS: A method of manufacturing micron-sized structures, such as nozzle arrays, using techniques developed for the manufacture of microchips.

[0068] Microfluidics: Miniature pumps, valves, etc. suitable for use in handheld, portable devices.

[0069] Nebulizer: A device for producing an aerosol from one or more liquid formulations.

[0070] NRT: Nicotine replacement therapy.

[0071] Orientation agnostic: can be used in any orientation.

[0072] Pack years: A measure of lifetime exposure to cigarettes, calculated as the number of years smoked multiplied by the number of packs smoked per day.

[0073] PE: Polyethylene

[0074] Peristaltic pump: A device that pumps a formulation through a length of flexible tubing by sequentially compressing portions of the tubing length.

[0075] PET: Polyethylene terephthalate

[0076] Pharmacologically equivalent: Having essentially the same pharmacokinetic and pharmacodynamic profiles. Pharmacologically equivalent doses can often be determined by the ratio of molecular weights, i.e., having the same number of molecules.

[0077] Piezoelectric or Piezo: A component that expands when a voltage is applied to it.

[0078] PP: Polypropylene

[0079] PS: Polystyrene

[0080] PTFE: Polytetrafluoroethylene

[0081] Puff: A single inhalation containing nicotine.

[0082] Raleigh breakup: An aerosol formation in which a liquid is forced through one or more nozzle holes to form a liquid jet which, under the influence of surface tension, spontaneously breaks up into droplets having diameters approximately twice the diameter of the jet.

[0083] Smoking replacement, nicotine replacement, nicotine replacement therapy, NRT, etc.: A method of reducing the risks of smoking cigarettes by replacing cigarettes with a more benign form of nicotine, preferably the benign form of nicotine is inhaled.

[0084] Smoking cessation therapy, nicotine cessation therapy, etc.: A method of assisting tobacco users to quit smoking, preferably by providing a system that generates an aerosol containing nicotine, in which the nicotine is gradually tapered to essentially zero, thereby providing the smoker with the nicotine they crave and providing an experience that closely resembles smoking, with a pharmacokinetic profile of nicotine in plasma essentially the same as that experienced by a smoker after taking a puff on a cigarette.

[0085] Sintered: A porous material created by a process that causes powdered materials to coalesce into a porous mass without being liquefied by heating.

[0086] Stroke volume: The amount of fluid displaced by each cycle of a reciprocating pump.

[0087] Subject or patient: Used interchangeably herein, refers to a human or other mammal.

[0088] Substrate: A sheet of material, preferably stainless steel, containing the array of nozzle holes.

[0089] Swirl atomizer: A nebulizer that uses a rotating air current to create and disperse an aerosol.

[0090] Ultrasonic nebulizer: A system for creating an aerosol that applies ultrasonic energy directly to the formulation. Compare with the vibrating mesh nebulizer.

[0091] Vibrating mesh nebulizer: A system for creating an aerosol that ultrasonically vibrates a substrate containing an array of nozzle holes.

[0092] Wicking element: means a flexible material that, when placed in contact with a liquid, wicks up the liquid.

[0093] [B. Overview] The present disclosure relates to devices, formulations, and methods for inhalation drug delivery. In one embodiment, the device is an inhalation system that uses a device with an array of nozzles to form a nicotine-containing aerosol to create a smoking-like experience for the patient. Such an inhalation system controls the amount of nicotine delivered to the patient by reducing it to substantially zero over a predetermined time. More specifically, the smoking cessation system of the present disclosure comprises at least one of the following: (a) a portable smoking cessation device; (b) firmware contained within the device for controlling the device; (c) a formulation container; and (d) a companion application.

[0094] In one embodiment, the device is configured as a smoking cessation inhaler, comprising: a durable part (or system or element) controller and a cartridge configured to be detachably attached to the inhaler, where the cartridge comprises: (a) an aerosolizer; (b) a formulation chamber containing a formulation containing an active pharmaceutical ingredient; (c) a bubble remover; and (d) a filter. The smoking cessation system is designed to mimic smoking a cigarette by delivering a nicotine-containing composition with nicotine absorption kinetics close to those experienced in traditional cigarettes, without the use of exogenous excipients / substances as used in e-cigarettes and other devices. Thus, the pharmacokinetics (PK), safety profile, and user acceptability of the system make it an acceptable alternative to smoking and e-cigarettes, and particularly effective for smoking cessation. Like cigarettes, the aerosol device can relieve cravings after a few doses (or puffs). However, unlike smoking and e-cigarettes, the device does not rely on heat to vaporize nicotine. Nor does it rely on propellants or other potentially harmful auxiliary substances or excipients. Thus, the compact, handheld device of the present invention is easy to use, safe and effective in delivering nicotine similar to what smokers expect.

[0095] In one embodiment, the system initially creates a patient experience similar to smoking and controls the amount of nicotine administered to decrease substantially to zero over a predetermined period of time, such as about 10-16 weeks, about 13 weeks, about 20-32 weeks, or about 26 weeks, or about 2-4 months, about 3 months, about 5-7 months, or about 6 months.

[0096] More specifically, the aerosol device is configured to deliver nicotine such that pharmacokinetic values ​​are within about 5%, or 10%, or 15%, or 20%, or 25%, or 30% of those reported in cigarette smokers, where the values ​​are one or more of the following: (a) concentrations at 5, 10, and 15 minutes; (b) Cmax; (c) Tmax; and (d) AUC. Reports of cigarette PK values ​​are found in the literature. See, e.g., Benowitz NL, Clinical Pharmacology of Nicotine: Implications for Understanding, Preventing and Treating Tobacco Addiction See Clin. Pharmacol. Ther. 83(4) (2008); Le Nouez, Intl. J. Tuberculosis and Lung Dis. 7(9) (Sept. 2003).

[0097] In another aspect, the system of the present invention is configured and administered to a patient to significantly reduce nicotine craving as measured by a visual analog scale (VAS)-craving assessment. In some embodiments, the system reduces craving by about 30%, or 40%, or 50%, or 60%, or 70% compared to baseline.

[0098] In certain embodiments, the starting dose of the active ingredient is selected by a physician based on patient characteristics, such as weight, smoking history, tolerance to the active ingredient, age, etc. In one embodiment, the starting dose of the active ingredient is the same for all users.

[0099] For example, the device may be controlled such that upon initial use of the device, the initial total emitted dose per average inhalation of nicotine free base, or of another form of a pharmacologically equivalent amount, such as a salt of nicotine, is in the range of about 0.05 to about 2 mg, about 0.1 to about 1 mg, about 0.2 to about 0.5 mg, about 0.25 to about 0.3 mg. The amount of nicotine is then decreased, e.g., the flow rate of the nicotine-containing formulation is decreased and the flow rate of the non-nicotine-containing formulation is increased, so that after a period 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, the total emitted dose of nicotine per average inhalation may be approximately 0 mg, e.g., where the total aerosolized volume of the formulation is substantially constant. This is merely one example for clarity. The preferred starting amount of nicotine per puff is 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. The ending amount of nicotine is 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, or less than or about 0.2 mg / puff, less than or about 0.1 mg / puff, or about 0 mg / puff.

[0100] C. Aerosol Devices and Their Operation As mentioned above, the present disclosure relates in one embodiment to a smoking cessation inhaler comprising: a durable portion (or system or element) of the inhaler comprising a controller, and a multi-dose cartridge configured for releasable attachment to the durable portion of the inhaler; wherein the cartridge comprises: (a) an aerosolizer; (b) a formulation chamber containing a formulation including an active pharmaceutical ingredient; (c) an air bubble remover; and (d) a filter.

[0101] In one embodiment, the cartridge contains one drug chamber and the dose is controlled by one or more mechanisms selected from, but not limited to, the following: a pump, pumping time, a valve, valve open time, the value of the DC voltage applied to the aerosolizer, the amplitude of the AC voltage applied to the aerosolizer, and the duration of application of the voltage (e.g., the voltage applied to the aerosolizer).

[0102] In one embodiment, the algorithm seeks to adjust the amount of active ingredient (preferably nicotine) delivered by the system at a frequency selected from the list including, but not limited to: about once or more per day, about once or more per dosing event, or about once per puff. Preferably, the algorithm seeks to adjust the amount of active ingredient about once per day, preferably before the first puff of the day. A preferred algorithm modifies the dose based on parameters selected from the list including, but not limited to: number of puffs since first puff, number of dosing events since first dosing event, time since first puff, time since first dosing, days since first day, combinations thereof. A preferred algorithm is selected from the list including, but not limited to: linear increase or decrease by a parameter, quadratic increase by a parameter, higher order polynomial by a parameter, exponential increase or decrease by a parameter. Preferably, the algorithm seeks to vary the amount of active ingredient from an initial value to a final value over a period of time selected from the list including, but not limited to, the following: from about 1 day to about 1 year, from about 1 week to about 9 months, from about 1 month to about 6 months, from about 2 months to about 4 months, or about 3 months. Preferably, the algorithm seeks to increase the effective amount delivered, to decrease the effective amount delivered, or both. In a preferred embodiment, the algorithm seeks to decrease from a dose (preferably a starting dose) to a final dose (preferably about zero). In another preferred embodiment, the algorithm seeks to increase from a first dose at a first event (preferably a starting date) to a second dose at a second event (preferably a later date), a constant dose from the second event to a third event (preferably an even later date), and a decrease from the second dose to a final dose at a fourth event, where the final dose is preferably zero. Preferred events are selected from the list including, but not limited to, days, administration events, and puffs.

[0103] The smoking cessation system (preferably one or more of the smoking cessation device, firmware, and / or companion application) preferably includes means for monitoring, recording, displaying, and / or reporting various factors related to usage of the smoking cessation system, selected from a list including but not limited to: time, date, frequency, and / or total number of puffs, and / or number of administration events, and / or rate of change of any of the above. The system may also monitor, record, report, and / or display parameters related to the technique of use of the system, including but not limited to: depth of inhalation, rate of inhalation, and coordination of inhalation and push button actions. Reporting is selected from a list including but not limited to: reporting to the user, physician, nurse, physician group, HMO, insurance company, research organization such as clinical research organization, researchers, epidemiologists, manufacturers, help lines, caregivers, family, and / or friends. Reporting may require opt-in by the user, and reporting, data storage, and data transmission are preferably HIPAA compliant.

[0104] 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 healthcare provider, caregiver, family member, and / or supplier of the smoking cessation system. The information sent to the companion application may include information selected from a list including, but not limited to: time, date, and number of puffs and / or dosing events, current amount of active ingredient (preferably nicotine) per puff, battery status, remaining formulation, error codes, firmware revision, etc.

[0105] 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 calculates and instructs the smoking cessation device on the flow rates of the formulations (preferably the flow rates of the first and second formulations), thereby controlling the amount of active ingredient delivered (e.g., amount of nicotine per puff), as described above. The companion application may also instruct the smoking cessation device to power on, prepare for a replacement of the formulation container, display an indicator (e.g., a ready indicator), and utilize a given flow rate of the formulations (preferably two or more formulations).

[0106] In one embodiment, the firmware or companion application may incorporate a timing system and may be programmed or calculated for a lockout interval prior to the next puff and / or administration event. The lockout interval may be constant during a therapy, such as a smoking cessation therapy, but in a preferred embodiment, the lockout interval increases over time. The initial lockout interval and / or the rate of increase of the lockout interval may be fixed by programming in the companion application or firmware, but is preferably calculated by the companion application or firmware, as described above, based on previously entered information, for example, related to the user, the user's smoking history, and past usage of the smoking cessation system. 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. In some applications (e.g., delivery of opioids), the lockout interval may be prescribed by the prescribing physician.

[0107] Preferably, the smoking cessation device incorporates a mechanism for forming an aerosol from one or more formulations (hereinafter referred to as an aerosolizer). The aerosolizer may be selected from a list including, but not limited to: a vibrating orifice or an array of orifices (i.e., a vibrating mesh), a condensation aerosol, an ultrasonic nebulizer, a dry powder dispersion mechanism, a jet nebulizer, a vortex nebulizer, Rayleigh fragmentation, electrospray, flow focusing, or flow blurring. In a preferred embodiment, the fine aerosol is generated from one (preferably a plurality of) small holes. In a particularly preferred embodiment, the aerosolizer comprises an array of nozzle holes formed in an essentially rigid substrate (preferably a stainless steel substrate), the substrate being vibrated by a ring-shaped piezo element rigidly bonded to the periphery of the substrate on at least one side, where the array of holes is substantially centered on the opening of the ring-shaped piezo element. The substrate may include a protrusion, which may be in the shape of a cross section of a sphere protruding from the outlet side, the protrusion being substantially centered on the ring-shaped piezo element and having the array substantially centered on the protrusion. The protrusion extends towards the airway through which the user inhales, and preferably the protrusion extends into the airflow through the airway.

[0108] The piezo may be attached to the exit face of the substrate, or there may be two piezos, one attached to each side of the substrate. A preferred embodiment has a single piezo ring attached to the entrance face of the substrate, which removes the step from the piezo to the center of the ring from the airway where such a step may cause aerosol deposition. In a preferred embodiment, the substrate is a disk and the piezo is annular. A liquid is provided to the entrance side of the array, and the substrate is vibrated by the piezo, and an aerosol is formed at the exit side of the array. In one embodiment, the amplitude of the vibration is such that a single droplet is extruded from each nozzle hole with each vibration 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 Rayleigh breakup. Preferably, there are one or more holes, the outlet diameter of which is about 10 μm or less, preferably about 7.5 μm or less, about 6 μm or less, about 5 μm or less, about 4 μm or less, about 3 μm or less, about 2.5 μm or less, about 2 μm or less, about 1.5 μm or less, about 1 μm or less, preferably about 2.0 to 3.0 μm, about 2.2 to 2.8 μm, and most preferably about 2.5 μm. Preferably, the number of holes is less than about 100,000, about 1 to about 10,000, about 100 to about 5,000, about 500 to about 3,000, or about 750 to about 2,500, more preferably about 2,000 to 2,400. The flow path leading to the outlet of the orifice(s) can be any shape, including a cylinder, preferably a right circular cylinder. The preferred flow passage is tapered, decreasing in diameter from the entrance to the exit of the orifice, in order to reduce the pressure or other form of energy input (e.g. ultrasonic energy input) required to achieve flow through the orifice and aerosolization. Preferably, the taper is selected from cone, pyramid, and funnel. Preferably, the entrance side of the orifice is about 5 μm or more, about 10 μm or more, about 15 μm or more, about 20 μm or more, or about 25 μm or more.The array of holes may be fabricated using a method selected from the list including, but not limited to: laser drilling, including, but not limited to, UV laser, excimer laser, solid-state laser, diode-pumped laser, frequency-doubled laser, frequency-tripled laser; MEMS fabrication, molding, machining, 3D printing, stereolithography, water jet, wire EDM, etc. A surface treatment may be applied to the outlet side of the array to improve aerosolization performance. As an example, if the formulation is an aqueous formulation, a hydrophobic treatment may improve aerosolization performance. In another embodiment, a hydrophobic treatment may be applied to the inlet side of the array to prevent liquid outflow from the openings of the array. This hydrophobic treatment may be adapted to prevent liquid outflow from the openings at atmospheric pressure, within a pressure range, or up to a specific pressure, in one embodiment. Preferred treatments include plasma treatment, silicone, fluorinated liquid or polymer, and wax.

[0109] In a preferred embodiment, the aerosolizer is housed in an aerosolization head, where the aerosolization head comprises an aerosolizer, a pocket directly behind the aerosolizer that holds the formulation or mixture of formulations, and an inlet port for introducing the formulation into the pocket. Preferably, the aerosolization head, the formulation chamber or chambers that contain the formulation or formulations, and the cavity surrounding the formulation chamber(s) 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 the formulation or mixture of formulations, and the formulation contacts the backside of the substrate in the region of the nozzle array. In a preferred embodiment, the aerosolizer on the orifice inlet 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 that is introduced into the pocket as a by-product of the aerosolization process. It is important to remove the air in the pocket and not move the formulation in contact with the substrate. In another embodiment, the formulation is delivered to the inlet side of the array through a wicking element located in the pocket, where the wicking element can be, but is not limited to, a sponge; a foam, which can be an open-cell foam or a closed-cell foam, preferably a combination; a fabric, a thread, a yarn, a fiber, etc.; an absorbent paper product; etc. Preferably, the wicking element contacts the inlet side of the substrate or partially contacts the inlet side of the substrate. In one embodiment, the wicking element can be flush with the inlet side of the nozzle hole array. In another embodiment, the wicking element can be positioned at an angle so that it contacts only a portion of the nozzle hole array or does not contact any of the nozzle hole array, where the small space between the wicking element and the nozzle hole array is filled with liquid by the pumping action of the nozzle hole and serves to deliver the formulation to the nozzle hole.In yet another embodiment, a small ridge or ridges may be created in the wicking element, which is located directly behind the nozzle hole array, where the nozzle hole array is adjacent to or in contact with the ridge in the wicking element, creating a non-uniform surface contact between the wicking element and the inlet side of the aerosolizer. In another embodiment, the wicking element is separated from direct contact with the inlet side of the nozzle array by a porous spacing element that allows the flow of the formulation and unimpeded air flow, facilitating the removal of air. The spacing element may be a mesh, a plate with an array of through holes, a spacer with a single hole substantially the same size as the array, or a foam with a larger porosity and / or larger holes than the wicking element, where the element allows the formulation to flow from the wicking element to the inlet side of the nozzle array, while simultaneously removing the air that is generated and introduced from the aerosolizer into the aerosolization head. In one embodiment, the wicking element and the spacing element have a flat surface that is circular or substantially circular and has the same diameter as the hole in the center of the piezo ring. In another embodiment, the wicking elements may be larger or smaller in diameter than each other, and may be larger or smaller in diameter than the diameter of the center of the piezo ring, hi another embodiment, the wicking elements may be substantially the same diameter and contact the recess.

[0110] In one embodiment, the pocket, and likewise the formulation cavity or container, may be constructed of a relatively hard material, such as, but not limited to, plastic or metal materials, including PE, PS, PP, PET, stainless steel, aluminum, etc., and may be completely enclosed, except for the formulation entry path (and optionally the exit path). In another embodiment, the formulation pocket may include at least one air outlet that allows air generated within the formulation pocket to flow from the formulation pocket into the aerosol head cavity. When air released through the air outlet accumulates in the aerosol head cavity, it may approach or exceed the pressure of the formulation in the region of the air outlet, reducing or stopping the flow of air through the air outlet. Therefore, a vent is required to release air from the aerosol head cavity. In one embodiment, air is exhausted from the aerosol head cavity through the vent hole to the air outside the device. In another embodiment, air is exhausted through a vent hole leading into the formulation cavity, and the flow through is assisted by the drop in pressure in the formulation cavity that occurs when the formulation is pumped from one or more formulation chambers in the formulation cavity. Since the air generation rate and the formulation aerosolization rate are generally not equal, a small hole can be used to contact with the outside air. Preferably, the small hole is sized so that equilibration with the outside air requires more time than the time for aerosolization and removal of air from the formulation pocket. Preferably, the small hole is also small enough so that the diffusion of water vapor through the air outlet is small enough so that the evaporation rate of water into the aerosol head cavity saturates the air in the aerosol head cavity and reduces the evaporation rate of the formulation carrier.

[0111] Preferably, the air outlet is a small (possibly tapered) opening, and the inner surface of the aerosol outlet is hydrophobic, so that air can flow from the pocket through the air outlet, but the surface tension of water prevents or substantially prevents the flow of the liquid formulation through the opening. In one embodiment, there may be only one opening, preferably located at the top of the top, or in an alternative embodiment, at the side of the formulation pocket, where the air is separated from the formulation by buoyancy and can reside within the formulation pocket until it can exit the chamber under gravity. In another embodiment, the formulation pocket may include one or more openings, where air can immediately exit the pocket through the one or more openings under its buoyancy, preventing the accumulation of air in the pocket in any orientation, making the smoke-free system orientation agnostic.

[0112] In a preferred embodiment, the air outlet may be covered with a porous material, preferably a hydrophobic or superhydrophobic porous material, where the porous hydrophobic material allows air to exit through the opening and prevents or substantially prevents the formulation from exiting through the opening. The 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 treatment may be applied to these materials to increase their hydrophobicity. The opening may be a large area, including, for example, the wall or essentially the entire surface of the formulation pocket that is not closed by the aerosolizer. In this embodiment, the porous material that comprises the formulation pocket may allow air to exit the formulation pocket at any point along the porous material, preventing the creation of an air-filled headspace within the formulation pocket.

[0113] In a preferred embodiment, the cartridge may contain a system for recirculating the formulation or mixture of formulations (hereinafter referred to as the recirculation system). In a preferred embodiment, a first fluid passage extends from the formulation chamber to the pump element or one or more pump elements, a second fluid passage extends from the pump element to the pocket, and a third fluid passage extends from the pocket to the first fluid passage, creating a flow loop that allows recirculation. These passages may be, but are not limited to, tubes, channels, or mixtures thereof. In a preferred embodiment, located in or at the end of the one or more passages is a bubbler, where the flow through the one or more passages flows through the one or more bubbler. In a preferred embodiment, the bubbler comprises at least one bubbler flow path, preferably multiple flow paths, configured to allow flow through the bubbler, preferably the flow paths are narrow channels, at least one surface of each flow path is formed by a porous material, and the flow through the bubbler brings the formulation in the recirculation system into contact with the porous material, whereby air is expelled from the porous material. Preferably the porous material is as described above, and most preferably is an expanded or sintered PTFE or PE material. In a preferred embodiment there is a restriction in the passageway downstream from the debubbler which increases the pressure in the debubbler and increases the amount or rate of air displacement through the porous material.

[0114] In a preferred embodiment, the porous material is held taut against the surface opposite the porous material by means of compression. In another embodiment, the porous material may be held taut against the opposite surface by means including, but not limited to, gluing, tape, chemical bonding, or mechanical clamping. In the process of clamping, the porous material may be stretched beyond its natural state. In this embodiment, when the formulation flows under the porous material at a pressure above atmospheric pressure, it deforms the porous material away from the opposite surface. This creates a small cavity behind the porous material for the liquid to flow through. When the formulation stops flowing through the debubbler, the porous material bounces back to its starting position, reducing or eliminating the volume of the small cavity and pushing the formulation out of the outlet and / or inlet of the debubbler, minimizing the amount of formulation that may remain in contact with the porous material, thereby limiting the amount of carrier that may evaporate through the porous material. In one embodiment, the air that is exhausted through the porous material is exhausted from the cartridge, which may be achieved by placing the porous material on the outer surface of the cartridge. In another embodiment, air exits the cartridge through a passageway connecting the debubbler to the surface of the aerosolizing head. In another embodiment, the air exiting the debubbler flows into the formulation cavity, and the reduced pressure created in the formulation cavity by pumping the formulation from the formulation chamber(s) evacuates the debubbler, thereby restoring the pressure in the formulation cavity to substantially atmospheric pressure. In a particularly preferred embodiment, a chamber is attached behind the debubbler, and the air exiting the porous material of the debubbler enters the chamber. The chamber may be a plastic molded chamber with multiple (or preferably one) holes, where the holes are preferably less than about 5 mm in diameter, more preferably less than about 4 mm, more preferably less than about 3 mm, more preferably less than about 2 mm, more preferably less than about 1 mm, more preferably less than about 0.5 mm, and most preferably less than about 0.1 mm in diameter (or the area equivalent if the hole is not a circle).This allows the pressure build-up resulting from the air leaving the debubbler to be released through the holes, but limits evaporation of the formulation carrier through the porous material of the debubbler between dosing events. Preferably, the evaporation rate from all sources from the system (including the debubbler and nozzle array) is about 20 μl / day or less, about 10 μl / day or less, about 5 μl / day or less, about 2.5 μl / day or less, or about 1 μl / day or less. In one embodiment, the recirculation system may additionally include a sterile filter, preferably a filter having a pore size of about 0.1 to about 0.5 μm, about 0.15 to about 0.3 μm, preferably about 0.2 μm, to remove particulates and bacteria from the formulation. In a preferred embodiment, the sterile filter is placed in the second flow path between the pump and the formulation pocket, so that the formulation is not forced out of the nozzle hole because the high pressure required to force the formulation through the sterile filter is not present in the pocket. This design ensures that the formulation that is aerosolized and inhaled by the user is free of bacteria and particles that may be dangerous to the user and may block the nozzle orifice. The sterile filter is preferably a filter designed for use in the medical industry for the sterile filling of aqueous formulations. The sterile filter may be hydrophobic or hydrophilic, although the preferred embodiment uses a hydrophilic membrane.

[0115] In a related embodiment, the debubbler comprises a small debubbler cavity having small holes as described above that lead to the aerosol head cavity or formulation cavity, thereby limiting the evaporation rate of the formulation carrier through the debubbler. Preferably, the small holes in the above embodiments are on the order of 2 mm or less in diameter, on the order of 1.5 mm or less in diameter, on the order of 1 mm or less in diameter, on the order of 0.75 mm or less in diameter, on the order of 0.6 mm or less in diameter, on the order of 0.5 mm or less in diameter, on the order of 0.4 mm or less in diameter, on the order of 0.3 mm or less in diameter, or on the order of 0.2 mm or less in diameter.

[0116] In one embodiment, at least one formulation chamber is flexible and maintained in liquid contact with the recirculation system. When the ambient air pressure decreases, for example due to weather or descent from high altitude, the expansion of any air bubbles 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, in order to appropriately regulate the pressure of the recirculation system, allowing flow in and out of the formulation chamber, thereby keeping the system at or near atmospheric pressure when experiencing pressure changes in the external environment, altitude, or direction changes.

[0117] The formulation cavity in the cartridge may be, in one embodiment, a sealed volume that is partially filled with air. In a preferred embodiment, there may be at least one connection point between the pocket and the formulation cavity, and air may pass through the connection point. In one embodiment, the pocket and the formulation cavity are adjacent, and the opening may be a portion of the shared wall that is removed to facilitate this air passage. This opening may be covered, in one embodiment, with a porous material, preferably a porous material as described above, allowing air flow through the material, but blocking the flow of the formulation. In another embodiment, the cavity and the formulation container(s) do not share a common wall, and the opening may be a passage, preferably a tube, more preferably a machined channel, that allows air flow. In one embodiment, this passage may lead to a larger opening in the wall of the formulation cavity that is covered with a porous medium as described above. In the above embodiment, the formulation cavity may be an air-filled cavity.

[0118] In another embodiment, the aerosol head may contain an aerosol head cavity, adjacent to and optionally partially surrounding the formulation pocket. 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, all of the formulation leaving the formulation pocket is absorbed into the absorbent material. When the smoke-free system is used and an aerosol is generated, the formulation is pumped from the formulation chamber(s), reducing the pressure in the formulation cavity. This reduced pressure pulls air from the aerosol head cavity through the flow passage connecting the two components, reducing the air in the aerosol head cavity. This promotes the flow of air, e.g., generated by the aerosolization process, from the aerosol pocket into the aerosol head cavity, preferably through the porous hydrophobic material. The amount of air generated within the formulation pocket during the aerosolization process may be equal to or less than the amount of formulation pumped from the formulation chamber(s), thereby allowing all or substantially all of the air within the formulation pocket to exit the formulation pocket into the aerosol head cavity, which returns to atmospheric pressure or retains a slightly reduced pressure.

[0119] The aerosolizer is positioned so that the aerosol is generated in the device airway. For example, in an embodiment where the aerosolizer is a vibrating mesh aerosolizer, the side of the substrate containing the exit orifice(s) (herein referred to as the exit side) is flush or substantially flush with the wall of the airway. When activated, the aerosolizer generates an aerosol plume that travels into the airway perpendicular to the direction of the airflow (herein referred to as the dilution air) generated by the user, which picks up the aerosol at a 90° angle and carries it into the user's respiratory passage. The user inhales through the airway through a mouthpiece that extends from the end of the airway, which can be a hollow or partially hollow cavity of various lengths, shapes, and sizes. Preferably, at least a portion of the airway and the mouthpiece are also part of the cartridge.

[0120] The airway in the cartridge begins upstream from the aerosol generation point and ends at the tip of the mouthpiece that is inserted into the mouth of the user, downstream from the aerosol generation point. The airway may be curved upstream from the aerosol generation point, or straight at the aerosol generation point and further downstream, and more preferably is straight or substantially straight throughout the length of the airway. In another embodiment, the centerline of the airway may be substantially straight downstream from the aerosol generation point, and the walls may have a slight divergence angle, preferably the walls diverge from the centerline at an angle of about 7° or less, starting at a point downstream from the aerosol generation point and continuing to the tip of the mouthpiece that is inserted into the mouth of the user. The inner walls of the airway may, in one embodiment, include an arrangement of extrusions and grooves that run either vertically, horizontally, or a combination of both, which create intentional turbulence intended to separate aerosol particles before they coalesce. In a preferred embodiment, the inner walls of the airway are smooth or substantially smooth to allow uniform flow.

[0121] To prevent evaporation of the formulation from the aerosolization head, the formulation pocket is preferably substantially completely sealed within the aerosolization head, with the only opening being one or more formulation supply lines leading to the formulation chamber(s), the array of nozzle holes, and in various embodiments, the opening(s) allowing flow from the formulation pocket, and / or micropores in the porous material used to allow air to exit the formulation pocket. In one embodiment, to limit evaporation of the formulation carrier through the nozzle holes, and to limit drying of the formulation and generation of solids from formulation deposited at the outlet side of the nozzle, the outlet side of the array is sealed between doses by a sealing system that can be removably positioned in a first position to isolate the nozzle from air outside the device between doses or puffs, and can be moved to a second position when the user is inhaling through the airway. When the sealing system is in the first position between uses of the device, it substantially seals the area around the outlet of the nozzle array and maintains the area at substantially 100% relative humidity (due to evaporation of carrier from the formulation deposited on the outside of the nozzle), thereby preventing the wicking element or formulation pocket from losing carrier and increasing in concentration due to diffusion of the formulation carrier through the nozzle hole. In addition, any formulation that covers the outlet side of the substrate after aerosol generation cannot evaporate in a high relative humidity environment and therefore cannot leave a layer of dry formulation components that can disrupt subsequent aerosol generation. Closing of the sealing system in the first position can be achieved by an element that blocks air from entering or leaving all or part of the airway. In a related embodiment, sealing is achieved by a movable element that blocks the entrance to the airway in combination with a mouthpiece cover that is replaced by the user after administration. In this embodiment, the region of the airway that is sealed off from the surrounding air is an airtight, or substantially airtight, air-filled space in which aerosol droplets deposited by a preceding administration event are deposited on the airway walls by mechanisms including turbulent deposition, inertial impaction, interception, and gravitational settling.In a preferred embodiment, the aerosol sealing system is optimized so that the amount of formulation deposited on the wall is more than or essentially sufficient to saturate the air contained within the sealed portion of the airway with evaporated carrier, inhibiting further evaporation of carrier or drying of the formulation in, on, or around the nozzles or on the outlet side of the array of nozzles. In another embodiment, the sealing system comprises a lever arm or the like having a compliant material on one end, which can be, but is not limited to, silicone, rubber, PTFE, closed cell foam, or other flexible material, where the material contacts the substrate and blocks all or substantially all of the nozzles of the array when in the first position to prevent leakage, evaporation, and drying of the formulation. In another embodiment, there is an additional material attached to the compliant material, contacts the nozzles, is absorbent, and absorbs all of the formulation deposited on the substrate. In one embodiment, the movement of the sealing system from the first position to the second position is achieved by the pressure of the patient inhaling through the airway. In another embodiment, the movement of the sealing system is achieved by means of an electromechanical actuator, powered by the system battery and controlled by a microcontroller. Preferably, the opening and closing of the sealing system is actuated by the force of the user pressing a button, which preferably also prepares the device for delivery and / or triggers the start of aerosol generation. In one embodiment, this may be a mechanical system, and the movement of the sealing mechanism to the second position is powered by the physical force of the user pressing a button. In another embodiment, the movement is achieved by an electromechanical system, triggered by the user pressing a button. In one embodiment, the sealing system is returned to the first position by an electromechanical actuator. In another embodiment, the system is returned to the first position by a return spring or the like. In one embodiment, the aerosol generation is stopped when the user releases the button or when a predetermined amount of the 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 the lungs.

[0122] In one embodiment, the wicking element of the formulation pocket absorbs any liquid remaining on, in, or around the nozzle after aerosolization has finished. This prevents liquid from drying in and around the nozzle, which could otherwise dry out formulation components and disrupt future aerosolization. The wicking element may achieve this in any orientation, including being placed fully or partially flush or at an angle to the inlet side of the array of nozzles on the aerosolizer. In another embodiment, a reduced pressure may be created in the aerosolization head or a component of the aerosolization head such that the pressure in the formulation pocket is below atmospheric pressure at the end of aerosolization, where air may flow through the nozzle(s) into the formulation pocket of the aerosolization head and suck in any formulation that is in, on, or around the nozzle after aerosolization has finished. This may be achieved, for example, by running the pump element in reverse or by limiting the rate at which air can flow into the formulation cavity, resulting in a pressure drop and expansion of the aerosol cavity after aerosolization.

[0123] In a preferred embodiment, the aerosol is generated in the airway at an angle of essentially 90° to the direction of the dilution airflow through the airway. In this embodiment, the dilution airflow generated by the user inhaling picks up the aerosol at an angle of 90° and carries it from the airway through the mouthpiece into the user's mouth and lungs. In a preferred embodiment, the airflow through the airway is laminar, or substantially laminar. To reduce the amount of aerosol deposited on the airway walls, a preferred embodiment includes a pressure sensor that detects a pressure drop in the airway when the user is inhaling, whereupon the controller activates the aerosolizer and generates aerosol when it determines that a predetermined pressure drop has been exceeded. This ensures that aerosol is generated only when a sufficient amount of dilution air is flowing through the airway to pick up the aerosol and carry it into the user's mouth and lungs. In a preferred embodiment, the aerosol is generated for a period of time unless the user's inhalation rate falls below a threshold value while the aerosol is being generated, in which case the controller senses a lack of sufficient inhalation airflow rate and stops aerosolization. In one embodiment, the controller calculates the inhalation flow rate based on past calibrations of the measured pressure drop and calculates the inhalation volume, for example by integrating the inhalation flow rate over time. In this embodiment, the controller activates the aerosolizer both when the fixed time has not been reached and when the controller estimates, via a predefined algorithm, that the user has sufficient remaining lung volume to inhale the aerosol deep into the lungs. In one embodiment, if the aerosol generation is stopped before the fixed time is reached because the measured pressure falls below a predefined threshold, the controller restarts aerosol generation if the user increases the inhalation rate and the pressure threshold is exceeded again while still having sufficient lung volume remaining. If the targeted fixed aerosolization time is not achieved, the amount of formulation delivered to the aerosolization head via the pumping system is reduced accordingly to maintain an ideal pressure in the formulation pocket without the presence of an air-filled headspace.To guide the user to inhale at an appropriate flow rate, the device may present a signal, such as a sound, vibration, or preferably a light, when the appropriate flow rate is achieved. In one embodiment, the user is presented with a solid light, e.g., a green or blue light, when the user is inhaling within a pre-determined optimal range of flow rates, no light is presented when the user is inhaling at a flow rate below the optimal range, and a different light, e.g., a red and / or flashing light, when the inhalation flow rate exceeds the optimal range.

[0124] The pressure in the formulation pocket may be monitored via a pressure transducer, and the pumping system delivers formulation to the formulation pocket and maintains it at or just below the ideal pressure. In one embodiment, the ideal pressure is about 100 mmHg or less, about 50 mmHg or less, about 25 mmHg or less, about 10 mmHg or less, about 7.5 mmHg or less, about 5 mmHg or less, about 2.5 mmHg or less. Preferably, the pressure is substantially zero. Zero pressure is preferred to prevent liquid from being forced through the nozzle array. In one embodiment, the valve is located near the outlet of the formulation chamber. When the pressure transducer senses a gauge pressure above zero (pressure in the pocket is higher than the pressure of the ambient air), the valve opens, allowing the liquid to flow into the flexible formulation chamber to relieve the pressure. When the pressure transducer senses a gauge pressure below zero (pressure in the ambient air is higher than the pressure in the pocket), the valve closes, preventing the flexible formulation chamber from expanding and forcing air into the nozzle hole.

[0125] Preferably, the mouthpiece is rigidly attached to the cartridge housing, more preferably, it is a feature that is machined, preferably molded, as part of the cartridge housing. Preferably, the atomizing element is configured such that the piezo ring is attached to the substrate on the side of the substrate away from the airway, and the periphery of the substrate is flush with the airway wall, preventing a step that may result in non-laminar flow and aerosol deposition in the airway. Preferably, the aerosolizing head includes a structure that prevents the aerosolizer from dislodging or falling into the airway. Preferably, the aerosolizer is not rigidly attached to the aerosolizing head, but rather, the aerosolizer is attached to the aerosolizing head by a process or material, including but not limited to silicone adhesive, which prevents or substantially reduces the damping of the vibration of the piezoelectric transducer to avoid detrimental effects on aerosolization rate and quality. In a preferred embodiment, the adhesive, preferably silicone, also serves to seal the piezo and prevent the ingress of carrier from the formulation into the piezo.

[0126] The above components mouthpiece, airway, aerosolization head, pocket, formulation cavity, flow path, tube, and formulation chamber(s) may be contained within one component referred to as the cartridge. The cartridge comprises four main components; the mouthpiece, airway, aerosolization head and its subcomponents, and the formulation containment and delivery system and its subcomponents. Other components, including batteries, pressure transducers, pump motors, microcontrollers, button(s), indicator lights, displays, and other electronic components, are contained within the durable system element portion of the system, and the cartridge is removably attached to the durable system element.

[0127] In a preferred embodiment, the durability system includes a system for moving the liquid formulation from the formulation chamber(s) in the cartridge to the formulation pocket of the aerosolization head, preferably a system for pumping the formulation at a controlled flow rate, where the system may comprise one or more pumping mechanisms or other suitable systems (hereinafter referred to as pumping system and pump(s) respectively) for moving the liquid formulation. Preferably, the flow rate of each formulation (which flow may occur simultaneously and / or sequentially with aerosol generation) is determined by a calculation system, where the calculation system may be either located in the device or remotely located, for example in a mobile application that performs the necessary calculations to determine the appropriate flow rate. Furthermore, the pumping system may be intended to mix one or more formulations into one formulation, and this mixed formulation is delivered to the formulation pocket in the aerosolization head. In one embodiment, the flow of the formulation is achieved by a method including but not limited to the use of two separate microfluidic pumps, where one microfluidic pump drives the active ingredient (preferably nicotine)-containing formulation and one microfluidic pump drives the second, preferably non-active ingredient-containing formulation. In a preferred embodiment, the pumping system uses a microfluidic pump and tubing to create a fluid connection between the formulation container and the inlet port to the formulation chamber of the aerosolization head.

[0128] In one embodiment, the pumping system comprises a mixing system for mixing multiple (preferably two) formulations prior to aerosolization. In one embodiment, the sum of the volumes of the first and second formulations introduced into the mixing system is always the same. This can be the volume of formulation aerosolized by the aerosolization system per puff or per a certain number of puffs, for example, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 8 or more, 10 or more, 15 or more, or 20 or more puffs. In a preferred embodiment, the sum of the two volumes is variable and the volume can be selected from a list including, but not limited to: amount expected to be aerosolized, amount expected to be aerosolized per administration event, amount expected to be aerosolized per puff, amount previously aerosolized, amount previously aerosolized in an administration event, and amount previously aerosolized in a puff.

[0129] In a preferred embodiment, the pumping system includes a mixing system, where the output of two or more microfluidic pumps or equivalent mechanisms for moving formulations are combined into a homogenous, substantially homogenous, or partially homogenous formulation. The mixing system, in one embodiment, includes a mixing chamber, in which one or more formulations are mixed. The mixing chamber is a sealed cavity with inlets for two microfluidic pumps to supply fluids, and one outlet for supplying the mixed formulation to an aerosolizer, which outlet may be connected to elements including, but not limited to, a third microfluidic pump, a wicking element, preferably a foam material, or a combination of a microfluidic pump and a wicking element. The mixing chamber, in one embodiment, may include a mixing element, which may be, but is not limited to, a piezoelectric actuator that induces turbulence in the liquid to promote mixing. In a preferred embodiment, the mixing chamber is a formulation chamber in the aerosolization head, and the mixing chamber is in direct fluid contact with the aerosolizer.

[0130] In another preferred embodiment, the mixing system comprises multiple mixing chambers, preferably two mixing chambers. One example of how this can work is as follows: a first formulation is introduced into the first mixing chamber, which already contains a previously mixed formulation. This introduction forces a portion of the already mixed formulation into the second mixing chamber, and forces a portion of the mixed formulation in the second mixing chamber out of the mixing system towards the aerosolization mechanism. The second formulation is then introduced into the second chamber, and forces a portion of the previously mixed formulation out of the second chamber as before. Preferably, the volume and shape of the first and second mixing chambers, and the passages for the first and second formulations to enter and the passages for the mixed formulation to exit are configured such that unmixed first and second formulations do not exit the mixing system during this introduction step. The inlet port and the outlet port from the second mixing chamber are then closed, and liquid is shuttled between the two chambers until the contents are thoroughly mixed. This forcing can be achieved by using one or more pumps between the two mixing chambers. Preferably, the two mixing chambers themselves have a pumping function. For example, they can each have flexible walls that can be pushed into the chamber by an actuating mechanism. To perform reciprocating pumping, the inlet to a chamber and the outlet from the second chamber are closed, and the actuating mechanism of one and then the other is alternately actuated to perform reciprocating pumping between the two chambers.

[0131] In another embodiment, there is no mixing chamber, and the formulation(s) are mixed within the pumping system itself, preferably within the tubes, channels, or other passages that make up the pumping system, where the passages may be characterized by features (both moving and non-moving) such as long, relatively narrow passages, tortuous paths, vanes, paddles, etc. to promote mixing. In a preferred embodiment, the formulation(s) pumped from the formulation(s) chamber(s) are pumped into a tube, channel, or other passage, where the formulations are mixed within the passage, and then the mixed or substantially mixed formulations are delivered into the formulation chamber of the aerosolization head.

[0132] In a related embodiment, the pumps that deliver the two formulations from the formulation chamber(s) are configured as chamber-type micropumps, each with n chambers, where 1 / n is the desired reformulation of the dosage control. To titrate the dose, the flow paths connecting the most distal m chambers of the first formulation and the most distal nm chambers of the second formulation are opened, and the micropump is used to pump the formulation back and forth between the two lines to effect mixing. As an example, when n=10, m=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 result in formulation concentrations of 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, and 0% of the original active ingredient-containing formulation concentration.

[0133] In one embodiment, the pumping system comprises two separate microfluidic pumps, one microfluidic pump driving a first formulation containing an active ingredient (preferably nicotine) and one microfluidic pump driving a second (preferably non-active ingredient-containing) formulation. The output from the microfluidic pumps is delivered directly to the formulation pocket of the aerosolization head, which may be an empty chamber or may comprise a wicking element. One embodiment may comprise an absorbent wicking element, where the output of each microfluidic pump, or equivalent mechanism for moving fluid, is fed to the wicking element. In another embodiment, the two formulations essentially mix completely in the formulation pocket of the aerosolization head, and the aerosol formed by the aerosolizer is composed of droplets containing essentially the same concentration of at least one active ingredient. In another embodiment, no mixing or incomplete mixing occurs in the formulation pocket, and the aerosol formed has particles with different concentrations of at least one active ingredient.

[0134] In another embodiment, the pumping system includes a microfluidic pump, which is used to pump at least one formulation, preferably two or more formulations, from separate formulation chambers, and includes a valve for controlling the flow of the formulation from the formulation chamber or chambers. In a preferred embodiment, one or more passages located upstream from the pump connect the formulation chamber or chambers to a central passage, preferably a tube, which then connects directly to the input of the microfluidic pump and proceeds to the outlet of the microfluidic pump for delivery to a mixing element, which is preferably a formulation pocket of the aerosolization head. In one embodiment, a valve is placed at the convergence point where one or more passages join the central passage upstream of the pump, the position of the valve can be controlled via an electronic signal, and the valve is placed to block flow from all but one of the formulation chambers, thus controlling which of the formulations is pumped into the pumping system. In another embodiment, each of the one or more passages connecting to the one or more formulation chambers includes an electronically controlled valve that can be positioned in an open position that allows the formulation to flow through the pumping system or in a closed position that does not allow the formulation to flow through the pumping system. In another embodiment, each of the one or more passages connecting to the one or more formulation chambers includes a valve that can be positioned to partially restrict the flow of the formulation through the passage. In this embodiment, the position of the one or more valves is independently controlled to determine the flow of each of the one or more formulations to achieve a suitable mixture of the formulations. In the above embodiment, the position of the valve(s) is controlled to achieve a particular mixture of the one or more formulations, which may be determined by one or more factors, including but not limited to the length of time, the duration of use of the system, the number of inhalations, and the number of administration events.

[0135] In a preferred embodiment, the system includes only a single formulation and a single pump.

[0136] In one embodiment where a microfluidic pump in a durable system is used, there are at least two fluid connection points between the cartridge and the durable system, one for each formulation chamber to allow the formulation to flow from the formulation chamber(s) to the pump(s) in the durable system, and one to allow the formulation to flow from the pump to the aerosolization head when the cartridge is connected to the durable system. When a cartridge that no longer contains a sufficient amount of formulation to allow proper use (hereinafter referred to as a "used cartridge") is removed from the durable system of the device and replaced with a new cartridge, it is important that contaminants are not introduced into the system. It is also important to avoid air ingress, as this can prevent proper aerosolization and require restarting the pump. The fluid connection points can be films of materials, including but not limited to metal foils, polymers, or mesh materials, that are pierced when connecting to the durable system. Preferred materials for the films include but are not limited to PTFE, polypropylene, and / or silicone. In another embodiment, the connection points can be valves that open when connecting the cartridge to the durable system. In a preferred embodiment, the connection point(s) may comprise at least one pierceable silicone septum, preferably two pierceable septums, one located on the surface of the durable system and referred to as the first septum, and one located on the mating surface of the cartridge and referred to as the second septum, and may comprise a needle, preferably a non-coring needle, attached to either the cartridge or the durable system. Upon attachment of the cartridge to the durable system, the needle pierces the septum to create a water-tight and air-tight seal. Preferably, the needle may be retracted through and out of the septum, preferably by means of, but not limited to, a spring, upon connection and release of the cartridge from the durable system.In embodiments where the needle is attached to the durable system, the withdrawal and retraction of the needle through the septum can be accomplished by: 1) rigidly connecting the second septum to the cartridge; 2) slidably connecting the first septum to the durable system such that the spring is compressed and presses the first septum against the stop. Upon connecting the cartridge to the durable system, the first septum compresses the spring and moves so that the needle pierces the first septum, whereby the needle extends from the first septum, penetrates the second septum, and exits the other side of the second septum into the fluid passage or tube leading to the formulation chamber. In a preferred embodiment, at least one of the pierceable silicone septums, preferably the first septum, covers the tip of the needle when the cartridge is removed from the durable system, where the septum is self-repairing and thus creates an airtight seal over the tip of the needle to prevent such ingress of air and contaminants. The connection point may also be any other embodiment that allows fluid to pass between the cartridge and the durable system when the cartridge is connected to the durable system, but does not allow fluid flow, evaporation, air ingress, or contamination of the formulation when the cartridge is not connected.

[0137] In one embodiment, the pump is a peristaltic pump, comprising components selected from, but not limited to, a motor, a gearhead, a rotor or eccentric cam, a registration cam, a ring, a portion of flexible tubing, and a support surface for the tubing. In one embodiment of the peristaltic pump, the motor rotates a rotor, which causes at least one roller to move in a circular motion, as it rotates along a portion of flexible tubing and compresses it against a support surface to create flow through the tubing. In another embodiment of the peristaltic pump, the motor rotates an eccentric cam, which is surrounded by a ring (characterized by a diameter sufficient for the eccentric cam to fit completely within the ring), and then upon actuation of the motor, the eccentric cam rotates, thereby moving the ring, which sequentially compresses a portion of the tubing against a support surface in a circular pattern, thereby creating flow through the tubing. In an embodiment in which the system comprises a durable system device and a separable multi-dose cartridge, the motor, gearhead, and eccentric cam or rotor are preferably part of the durable system, and the tubing, ring, and support surface are preferably part of the disposable.

[0138] In one embodiment, the pumping system includes a pump, preferably a peristaltic pump, used to pump at least one formulation, preferably two or more formulations, from separate formulation chambers, and includes a valve for controlling the flow of the formulation from the formulation chamber. In one embodiment, one or more passages located upstream from the pump connect the formulation chamber or chambers to a central passage, preferably a tube, which then connects directly to the input of the peristaltic pump and proceeds to the outlet of the peristaltic pump for delivery to the formulation pocket. In one embodiment, a valve is placed at or near the convergence point where one or more passages join the central passage upstream of the pump, where the state of the valve (allows flow, blocks flow, optionally controls flow rate) can be controlled mechanically and / or via electronic signals, and the valve is positioned to block flow from all, all but one, all but a subset, or none of the formulation chambers, thus controlling which of the formulation or formulations are pumped into the pumping system. In another embodiment, each of the one or more passages connecting to the one or more formulation chambers includes an electronically controlled valve that can be positioned in an open position that allows the formulation to flow through the pumping system or in a closed position that does not allow the formulation to flow through the pumping system. In another embodiment, each of the one or more passages connecting to the one or more formulation chambers includes a valve that can be positioned to partially restrict the flow of the formulation through the passage. In this embodiment, the position of each of the one or more valves is independently controlled to determine the flow of each of the one or more formulations to achieve a suitable mixture of the formulations. In the above embodiment, the state of the valve(s) is controlled to achieve a particular mixture of the one or more formulations, which may be determined by one or more factors, including but not limited to the length of time, duration of use of the system, number of inhalations, and number of administration events.

[0139] Preferably, before the cartridge is first used, the outlet of the formulation chamber(s) is closed to ensure that the contained formulation(s) only contacts the formulation chamber(s) during storage and transport, and only contacts any tubes, flow channels, pockets, or aerosolizers during and after first use, such that the chamber material can be selected for long-term storage properties including, but not limited to, water (or other carrier) vapor transmission rate, elution potential, extractability, and / or drug stability, and the materials of other portions of the flow channels can be selected for other properties including, but not limited to, mechanical flexibility, ease of manufacture, aerosolization performance, etc.

[0140] Preferably, in the above-mentioned embodiment, the elements selected from, but not limited to, the motor, gear head, electronic device, battery, button, light, display, aerosolizer, eccentric, ring, or rotor of the peristaltic pump are components of the durable system, where the elements selected from, but not limited to, the aerosolizer; the pump head, including the elements selected from, but not limited to, the support surface, flexible tubing, rotor, eccentric, and ring; the formulation(s), formulation chamber, passage, tubing, filter, and bubble remover are all components of the cartridge. This ensures that the formulation(s) never come into direct fluid contact with any durable system components of the device, and the drug contact surface is entirely contained within the cartridge. To achieve this, the peristaltic pump motor is disposed within the durable system, and is disposed such that when the cartridge is attached to the durable system, the tubing is compressed by the outer diameter of the ring (both of which are part of the cartridge), and when the pump motor, which is part of the durable system, is activated, the motor rotates the rotor or eccentric cam of the pump, which in turn compresses a portion of the tubing to create flow. This connection of the two critical components of the pumping system, the peristaltic pump and the tubing, is achieved only by attaching the cartridge to the durability system of the device.

[0141] The pumping system incorporates a feeding mechanism for transporting the formulation, preferably a mixture of formulations, to the aerosolizer. The feeding mechanism may incorporate a micropump, a peristaltic pump, or other active pumping components to pump the liquid from the mixing element to the aerosolizer. Preferably, the aforementioned pumping mechanism is also used to feed the formulation to the aerosolizer, and the feeding mechanism is essentially only one or more passages. The pumping mechanism may feed the formulation to the aerosolizer at a flow rate substantially the same as the rate at which the aerosolizer consumes the formulation during aerosolization, in one embodiment this is achieved by a flow path that delivers the formulation to the wicking element, where the formulation may be delivered to the center, end, or any other part of the wicking element, and in another embodiment this is achieved by a flow path that delivers the formulation into a formulation pocket that does not have a wicking element. The pumping mechanism may also feed the formulation to the aerosolizer during, before, and after aerosolization at a flow rate that is greater than, equal to, or less than the aerosolization rate. Preferably, the formulation pockets and other formulation-containing volumes are free of any air-filled headspace. In this embodiment, formulation is withdrawn from the formulation chamber during aerosolization and can be subsequently replenished as necessary to prevent an air-filled headspace behind the aerosolizer.

[0142] The durability system includes 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 (preferably containing lithium); a printed circuit board; a charging port, which is preferably mechanically attached to the printed circuit board and accessible from the outside of the device; a circuit for driving the liquid pumping system, a circuit for driving the aerosolizer, a light, a display, a button, and at least one pressure sensor. These circuits may be separate subsystems on the circuit board or may be integrated into an application specific integrated circuit. Preferably, the circuit board includes a computational system that powers the device's functions, controls the aerosolizer and pumping system, and, in one embodiment, determines and controls the appropriate flow rate and dispense volume for each microfluidic pump of the pumping system. The computational system controls factors selected from the list including, but not limited to: flow rate of one or more pumps, state of one or more valves controlling flow from one or more formulation chambers, voltage supplied to the aerosolizer, amplitude of vibration of components of the aerosolizer, duration of pumping of one or more pumps, duration of aerosolization of the aerosolizer; so that the amount of nicotine (or other active ingredient) delivered to the user is consistently reduced over time. For example, upon initial use of the device, the device may be controlled such that the initial total emitted dose of nicotine per average inhalation is in a range selected from the list including, but not limited to, about 0.05 to about 2 mg, about 0.1 to about 1 mg, about 0.2 to about 0.5 mg, about 0.25 to about 0.3 mg. Thereafter, the amount of nicotine decreases, e.g., the flow rate of the nicotine-containing formulation decreases and the flow rate of the non-nicotine-containing formulation increases, so that after a period 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, the total emitted dose of nicotine per average inhalation may be approximately 0 mg, e.g., where the total aerosolized volume of the formulation is substantially constant. This is just one example for clarity.The preferred starting amount of nicotine per puff is preferably about 2 mg / puff or more, about 1.5 mg / puff or more, about 1.2 mg / puff or more, about 1 mg / puff or more, about 0.8 mg / puff or more, about 0.6 mg / puff or more, about 0.5 mg / puff or more, about 0.4 mg / puff or more, or about 0.3 mg / puff or more. The ending amount of nicotine is preferably about 1 mg / puff or less, about 0.8 mg / puff or less, about 0.7 mg / puff or less, about 0.6 mg / puff or less, about 0.5 mg / puff or less, about 0.4 mg / puff or less, about 0.3 mg / puff or less, about 0.2 mg / puff or less, about 0.1 mg / puff or less, or about 0 mg / puff.

[0143] As will be described in more detail below, the components of the aerosol device are detailed in the accompanying figures. Figure 1 shows one embodiment of an aerosol device 101 of the present invention. The aerosol device 101 comprises a mouthpiece section 102, a microfluidic and aerosol section 103, and an electronics section 104. The mouthpiece section 102 comprises an inhalation flow path 105, a first formulation container 106 containing a first formulation 107, and a second formulation container 108 containing a second formulation 109. A housing 110 houses the microfluidic and aerosol section 103 and the electronics section 104. The mouthpiece 102 is attached to the housing 110 such that the inhalation flow path 105 is aligned with a nozzle array 112 formed in a substrate 111.

[0144] A first supply channel 113 connects to a first formulation container 106, which delivers a first formulation 107 to a microfluidic plate 115, and a second formulation 109 to the microfluidic plate 115 as well. The first formulation 107 and the second formulation 109 are mixed in a mixing chamber 116 and then delivered to the nozzle array 112 via a wicking element 117.

[0145] The microfluidic components on the microfluidic board 115 are controlled by electronics on a printed circuit board assembly (PCBA) 118, which is powered by a battery 119. The battery 119 is rechargeable and is charged by connecting a charging cable (not shown) to a charging receptacle 120.

[0146] 2 is a more detailed view of the mouthpiece 102. In this embodiment, the mouthpiece 102 includes a key 201. When the mouthpiece 102 is attached to the housing 110, the key 201 ensures that the mouthpiece 102 can only be attached in the correct orientation. The mouthpiece 102 also includes a latch mechanism 202 that ensures that the mouthpiece 102 can be positively, but removably, attached to the housing 110. A preferred latch 202 provides feedback to the user that the mouthpiece 102 is correctly attached to the housing 110. Preferred feedback includes, but is not limited to, an audible click and / or a tactile click. Item 203 is a pierceable element, preferably a membrane. When the mouthpiece 102 is attached to the durable portion 121, the supply tubes 113 and 114 pierce the pierceable membrane 203, allowing the flow of the formulation to the microfluidic plate 115.

[0147] The first formulation container 106 contains the first formulation 107. In one embodiment, the first formulation 107 is in direct contact with the walls of the first container 106, and the walls of the first container 106 have the necessary container closure properties, including acceptable extractability, acceptable leachability, materials consistent with stability for the first formulation 107, acceptable low binding to the major components of the formulation 107, and essentially impermeable to the carrier of the formulation 107. In one embodiment, the carrier comprises water and / or ethanol. The second formulation container 108 has essentially the same properties with respect to the second formulation 109.

[0148] In one embodiment, formulation 107 does not directly contact the walls of container 106, but rather the walls of container 106 surround and protect the primary container closure system for first formulation 107. The container closure system has the necessary properties, including acceptable extractability, acceptable leachability, materials consistent with stability for first formulation 107, acceptable low binding to the primary components of formulation 107, and essentially impermeable to the carrier of formulation 107. In one embodiment, the carrier comprises water and / or ethanol.

[0149] The container closures 106 and 108 may be essentially rigid and may comprise materials including, but not limited to, glass, preferably borosilicate glass, metal, preferably stainless steel, or polymers. The container closure system may comprise at least one wall that is flexible and comprises a polymer. A flexible container has the advantage of ensuring that the formulation can be pumped from the formulation container 106 without creating back pressure on the pump or requiring air to enter the formulation container 106, and without being directionally and gravity-dependent. In a preferred embodiment, the at least one flexible wall is a multi-layer laminate and may comprise one or more layers including, but not limited to: a drug contact layer, preferably comprising a relatively inert polymer, which may be, but is not limited to, polyethylene, or a fluoropolymer, preferably polytetrafluoroethylene (PTFE); a vapor permeable layer, preferably comprising a metal, preferably aluminum; and a structural layer, which is preferably a polyamide such as nylon. The second formulation container 108 preferably has a container closure system having essentially the same properties as the second formulation 109.

[0150] FIG. 3 shows details of the mouthpiece 102 that is attached to the microfluidic and aerosol section 103 of one embodiment of the present invention. The first supply channel 113 is in fluid contact with the first formulation 107 in the formulation container 106, so that a portion of the first formulation 107 can be withdrawn as needed. In the embodiment shown in FIG. 3, the pointed end 301 extends through the first pierceable septum 302. Preferably, the pointed end 301 is non-coring. Other methods of making a fluid connection to the formulation 107 can be used, such as a hole or connector through which the first supply channel 113 is provided. In one embodiment, the mouthpiece 102 is provided with a cap that prevents leakage from the hole or connector in the septum 302 and the ingress of contaminants into the hole or connector. Preferably, the hole or connector is one that is closed or sealed prior to inserting the first supply channel 113 into the formulation container 106. Similar discussion applies to the second formulation container 108 , the second formulation 109 , the second flow channel 114 , and the second septum 303 .

[0151] FIG. 4 shows the microfluidic and aerosol section 103 in more detail. The formulation 107 is drawn by the micropump 405 through the supply channel 113 and pumped into the mixer 116. In one embodiment, the first micropump 405 is a piston type micropump. The first micropump 405 cycles m times under the control of the controller on the PCBA 118 to dispense a volume of the first formulation 107 equal to m*V1 (where V1 is the stroke volume of the first micropump 405) into the mixing chamber 116. Similarly, the second micropump 406 dispenses a volume of the second formulation 109 (nm)*V2 (where V2 is the stroke volume of the second micropump 406) into the mixer 116. Preferably, V1=V2=V. In one embodiment, the first pump 405 pumps m cycles followed by the second pump 406 pumping nm cycles. In another embodiment, the second pump 406 pumps nm cycles followed by the first pump 405 pumping m cycles. In a preferred pump embodiment, pumps 405 and 406 pump into the mixer 116 substantially simultaneously to optimize mixing. After mixing, pump 404 delivers the mixed formulation to the aerosolizer via tube 403. In the illustrated embodiment, the aerosolizer is a vibrating mesh aerosolizer comprising piezo 401, substrate 111, and array of holes 112. Piezo 401 is mounted to housing 402.

[0152] In one embodiment, n is essentially fixed and unchanged over the life of the device 101, and m is varied to vary the amount of one or more active ingredients in the delivered aerosol. In another embodiment, n and m are variable and the pump is actuated after each dosing event. n and m generally vary between different administration events due to one or more factors which may include, but are not limited to: the desired delivered dose of one or more active ingredients, the desired delivered concentration of one or more active ingredients; the number of puffs taken in one or more past administration events, preferably the number of puffs taken in the previous administration event; the total duration of the puffs taken in one or more past administration events, preferably the total duration of the puffs taken in the previous administration event; the number of puffs expected to be taken in one or more future administration events, preferably the number of puffs expected to be taken in the next administration event; the expected total duration of the puffs expected to be taken in one or more future administration events, preferably the total duration of the puffs expected to be taken in the next administration event; the current aerosolization rate from the nozzle array 112; and / or the level of saturation of the wick 117.

[0153] In a preferred embodiment, n and m are variable and the pump is started after each puff. The values ​​of n and m generally vary between different puffs due to factors that may include, but are not limited to: the desired delivered dose of one or more active ingredients, the desired delivered concentration of one or more active ingredients; the number of puffs taken in one or more past administration events, preferably the number of puffs taken in the previous administration event; the total duration of the puffs taken in one or more past administration events, preferably the total duration of the puffs taken in the previous administration event; the number of puffs expected to be taken in one or more future administration events, preferably the number of puffs expected to be taken in the next administration event; the expected total duration of the puffs expected to be taken in one or more future administration events, preferably the total duration of the puffs expected to be taken in the next administration event; the current aerosolization rate from the nozzle array 112; the level of saturation of the wick 117: the duration of the previous puff; and / or the expected duration of the next puff.

[0154] In a particularly preferred embodiment, V1=V2=V, and after each puff the first formulation 107 is pumped by the first pump 405 in an amount equal to m*V and the second formulation is pumped in an amount equal to (nm)*V, where n*V is equal to the volume of mixed formulation removed from the wick 117 during the previous puff.

[0155] The mixing chamber 116 is shown as an essentially circular chamber. However, the mixing chamber 116 can be any shape, including but not limited to circular, elliptical, rectangular, disk-shaped, spherical, hemispherical, or combinations or cross sections thereof. Preferred shapes are those that promote mixing, including but not limited to long thin channels and / or serpentine shapes. The first formulation 107 and the second formulation 109 can be introduced into the mixing chamber in essentially any manner, but are preferably introduced to optimize mixing of the formulations 107 and 109. The introduction into the mixing chamber 116 can range from a direction essentially toward the center of the mixing chamber 116 to a direction essentially tangential to the walls of the mixing chamber 116. In a preferred embodiment, mixing is optimized by introducing the formulations into the mixing chamber 116 such that the flow directions of the first formulation 107 and the second formulation 109 intersect within the mixing chamber 116 and have substantial components pointing towards each other, preferably the flow lines (i.e., vectors that are the centerlines of the flow of the first formulation 107 and the second formulation 109) as they enter the mixing chamber 116 intersect at an angle of about 45° or more, preferably at an angle of about 60° or more, at an angle of about 90° or more, at an angle of about 120° or more, or at an angle of about 160° or more. In a preferred embodiment, the flow lines of the first formulation 107 and the second formulation 109 as they enter the mixing chamber 116 are substantially directly pointed towards each other.

[0156] It should be noted that while the fluidic system in this and subsequent embodiments is shown as a plate and may be referred to as a fluidic plate or a microfluidic plate, it is understood that there may be different embodiments of the fluidic system, including but not limited to: embodiments that do not use microfluidics, embodiments that include multiple plates, and / or embodiments that include separate components that are not mounted on a plate.

[0157] FIG. 5 shows another embodiment comprising a fluid plate 515. The fluid plate 515 comprises a first large pump 501 and a second large pump 502. In one embodiment, the stroke volume of each of the large pumps 501 and 502 is preferably greater than or approximately equal to m*V1+(nm)*V2. In another embodiment, the stroke volume+dead volume of each of the large pumps 501 and 502 is preferably greater than or approximately equal to m*V1+(nm)*V2. The function of the fluid plate 515 is as follows: the first formulation 107 is pumped into the first large pump 501 through the first flow path 503 using the first pump 405 with m cycles. The second formulation 109 is pumped into the second large pump 502 through the second flow path 504 using the second pump 406 with nm cycles. Valve 505 is closed and then pumps 501 and 502 are activated sequentially to move the formulation from large pump 501 to large pump 502 and then back to pump 501. This cycle is repeated until the formulation is well mixed. Finally, valve 505 is opened and large pumps 501 and 502 are activated simultaneously to push the mixed formulation into the wick supply channel 403.

[0158] FIG. 6 shows an embodiment of the invention without a mixing chamber. This embodiment may be used for reasons including, but not limited to, sufficient mixing occurs in the flow path 605, sufficient mixing occurs in the flow path 403, sufficient mixing occurs in the wick 117, and / or no mixing is required. For example, mixing may not be required if sufficient control of the amount of one or more active ingredients can be achieved, where the amount and / or concentration of one or more active ingredients in the aerosol particles is allowed to vary throughout the aerosol plume. The operation of the embodiment of FIG. 6 is similar to the above embodiment. The optional valve 505 is opened, and then m cycles of the first pump 405 pump the amount m*V1 of the first formulation 107 through the flow path 603. Subsequently, or preferably simultaneously, nm cycles of the second pump 406 pump the amount n*V2 of the second formulation 109 through the flow path 604. Finally, the optional valve 505 is closed.

[0159] 7 shows another embodiment of the invention comprising a durable system portion 701 of the invention and a multi-dose cartridge 702. In the illustrated embodiment, the durable system portion 701 comprises an electronics board 710, one or preferably two or more microfluidic pumps 709, and a battery 703 housed within a housing 708. The cartridge 702 comprises at least one formulation cavity 706, an aerosolization head 704, and a mouthpiece 705 housed within a housing 707.

[0160] 8 is a more detailed view of the durable system portion 701. In the illustrated embodiment, the electronics board 710 includes a microcontroller 803 that controls the battery charging circuitry 804, pump controller 805, and mesh piezo controller 814, and measures airway pressure using a pressure transducer 806. It will be appreciated that the electronics board 710 may actually include two or more separate boards and / or separate components that are not on the electronics board. Programming of the microcontroller 803 is accomplished through a connector 801, preferably a USB connector 801, accessed by a cable through a housing opening 802. Preferably, the cable also provides electrical current to charge the battery 703. The pump controller 805 controls at least one microfluidic pump 709. The pump 709 receives the formulation from the formulation cavity 706 via a liquid connection 807 and tubing 710. The liquid formulation is delivered by the pump 709 to the aerosolization head 704 via tubing 808 and liquid connection 815. The housing 708 includes an entrance to the inhalation airway 809. The entrance to the airway 809 is covered by a mesh 811. The mesh 811 may be a series of slots machined or molded into the housing 708, or may be a separate component attached to the housing 809. The mesh 811 serves two purposes: first, to keep objects that are too large to be dangerously inhaled out of the airway. Second, to create a measurable pressure drop so that aerosols are generated only if the user is inhaling at an optimal flow rate relatively early in the inhalation. In the embodiment shown in FIG. 8, the pressure in the airway 809 is measured by a pressure transducer 806 via a pressure tube 810. Based on the signal received from the pressure transducer 806 and a previously made measurement of the airflow / pressure relationship of the mesh 811, the microcontroller 803 can determine whether the user is inhaling at an optimal inhalation flow rate, and by integrating this flow rate over time, the controller can determine the user's inhaled volume.If the microcontroller 803 determines that the user has achieved the correct flow rate at the beginning of an inhalation, the controller turns on aerosol generation via the mesh piezo controller 814 and keeps aerosol generation on for a time selected from a list including, but not limited to, one or more of the following: a predetermined time that is constant during treatment, a predetermined time that varies during the course of treatment, for example to reduce the dose of nicotine over the course of treatment, and a time that is less than the predetermined time for a reason selected from the list including, but not limited to, the user stops inhaling, the user starts inhaling at a flow rate lower than the optimal flow rate, or the user stops holding down the button.

[0161] During, or preferably following, inhalation, the microcontroller 803 can determine the amount of aerosol generated, and based on the prescribed therapy and dosing algorithm, the microcontroller 803 can turn on the pump 709 for a determined amount of time and / or pumping cycles. In a preferred embodiment, the microcontroller 804 turns on the second pump 709 to pump the second formulation for a fixed, preferably different, amount of time.

[0162] The durability system 701 also includes one or more buttons 812. The buttons 812 may be pressed to accomplish a task selected from a list including but not limited to: power on the system, power off the system, display the status of the system, notify the system that the cartridge 702 replacement is complete, etc. In a preferred embodiment, the switch 812 is used only to power on or "wake up" the device, and the electronics board 710 includes wireless communication capabilities, and all other user communication with the controller 803 is done using a display device, e.g., phone, computer, tablet, etc. In another embodiment, the button 812 is pressed to wake the device or prepare it to deliver a puff, and the user must hold the button down. This may be useful if the button is in a position such that the device must be held in a predetermined way, selected from a list including but not limited to: a predetermined orientation, a predetermined position of the user's fingers, e.g., to ensure that the user does not block the air inlet 811. The durability system 701 also includes a light (preferably an LED) 813. The LED 813 may be one color, but is preferably multi-colored and / or flashing, and communicates multiple different types of information selected from a list including, but not limited to: the device is powered on, the inhalation flow rate is correct, the inhalation flow rate is incorrect (too low or too high), the battery needs charging, the battery is fully charged, the user should refer to the companion app for additional information, and / or the cartridge 702 needs to be replaced.

[0163] Figure 9 shows an example of a multi-dose cartridge of the embodiment of Figure 7. The formulation, preferably two or more formulations, is contained in a formulation chamber 901 located in the formulation cavity 706. Preferably, the formulation chamber 901 is filled without a gas headspace, for example by vacuum filling, to ensure that use of the device is orientation independent and that gas from the headspace is not drawn into the system with the resultant loss of delivered dose and / or loss of prime. Preferably, the flexible formulation chamber 901 is a flexible bag with a pharma- ceutically compatible drug contact surface (preferably polyethylene), a mechanical layer such as polyester or mylar, and a vapor permeable layer (preferably aluminum). Fluid connection to the durable system unit is made via liquid connection 906.

[0164] The aerosolization head comprises a piezo-actuated mesh 904 and an optional wicking element 902. The use of wicking element 902 ensures that the formulation is delivered to the mesh 904 regardless of the orientation of the device. A liquid formulation, preferably two or more liquid formulations, is delivered to the mesh 904 via a liquid connection 905.

[0165] It has been found that aerosol performance is optimized by having a small gap between the wicking element 902 and the mesh 904. The gap can be air, but is preferably created by including a non-vibrating mesh 903. The non-vibrating mesh 903 can be a metal or plastic wire or other porous mesh. In a preferred embodiment, the mesh 903 comprises a very thin section of a highly porous sponge material, e.g., more porous and / or containing larger pores than the wicking element 902. The vibrating mesh 904 can be held at a small angle relative to the mesh 903, e.g., about 5 degrees or less, about 2.5 degrees or less, about 1 degree or less, or about 0.5 degrees or less. In another embodiment, the vibrating mesh 904 and the mesh 903 are both held at a small angle relative to the wicking element 902, e.g., about 5 degrees or less, about 2.5 degrees or less, about 1 degree or less, or about 0.5 degrees or less.

[0166] 10 shows one embodiment of the liquid connectors 905, 906 and mating connectors 815 and 807. It is important to minimize, and preferably eliminate, the ingress of air and other contaminants into the fluid system of the durability system 701 and into the formulation chamber 901. Air in the system can cause loss of prime and reduced dose. Contaminants can expose the user to toxins, bacteria, or viruses. Dust or other particulates can block the nozzle holes.

[0167] 10a shows an embodiment of the fluid connection with the durable system 701 and cartridge 702 separated, either just prior to installation or just after removal of the cartridge. The formulation chamber 901 (or wicking element 902, in the case of fluid connectors 815 and 906) is kept out of air and other contaminants by a self-sealing, pierceable septum 1001. Fluids within the tubing 1005 and other fluidic components of the durable system 701 are similarly kept out of air and other contaminants by a septum 1002. The tip of the non-coring needle 1004 is sealed off by being embedded within the self-sealing, pierceable septum 1002.

[0168] FIG. 10b shows the embodiment of FIG. 10a with cartridge 702 attached to durable system 701. When cartridge 702 and durable system 701 are pressed together, septum 1001 enters septum pocket 1006 and contacts septum 1002. Further pressing forces septum 1002 further into pocket 1006, compressing spring 1003. Once durable system 101 and cartridge 102 are fully pressed (preferably accompanied by a tactile and / or audible click to provide feedback that cartridge 702 is properly attached to durable system 701), septa 1001 and 1002 are pressed into pocket 1006 far enough to expose the tip of needle 1004, allowing microfluidic pump 709 to draw liquid from chamber 901 or pump liquid into wicking element 902.

[0169] When the cartridge 702 is consumed, an indication is given to the user by light 813 and / or by a message (preferably accompanied by an audio tone and / or vibration) on a display device, preferably a smart phone. The user pulls the cartridge 702 and durability system 701 apart, releasing the bulkhead 1002 and returning the bulkhead 1002 under the bias of the spring 1003 to the position shown in FIG. 10a.

[0170] FIG. 11 shows an alternative embodiment of the fluid connector. In this embodiment, the spring 1003 is removed and its function is replaced by the compliance of a longer septum 1102. FIG. 11a shows the fluid connector when the durability system 701 and cartridge 702 are separated, and FIG. 11b shows them connected. A gap 1107 is included to allow for the expansion of the septum 1102 due to Poisson's ratio when it is compressed. The compliance of the septum 1102 can be adjusted by changing the length of the septum 1102 (with the depth of the pocket 1006 changing accordingly), the width of the septum 1102, the material of the septum 1102, and the width of the gap 1107.

[0171] FIG. 12 shows one embodiment of the cartridge. One or more flexible formulation chambers 1213 are connected via tube 1210 to one or more pumps 1207. The pump 1207 pumps the formulation into tube 1211, which carries the formulation into the formulation pocket 1202. During the process of aerosolization, the aerosolizer 1201 generates air that enters the formulation pocket 1202. As the pump 1207 pumps the formulation into the formulation pocket 1202, air exits the formulation pocket 1202 through opening 1226. The opening 1226 is covered by a hydrophobic porous element 1227, which allows air to escape but does not allow formulation to escape unless the pressure exceeds a certain threshold. A pressure transducer 1225 is provided inside the formulation pocket 1202. Preferably, pump 1207 pumps until the pressure measured by pressure transducer 1225 is in a predetermined range that is high enough to keep water in contact with aerosolizer 1201 and expel water through hydrophobic porous element 1227, but not so high that formulation is expelled through hydrophobic porous element 1227 or aerosolizer 1201. Optionally, aerosolizer 1201 can be treated with a hydrophobic coating to further reduce the probability that pressure within formulation pocket 1202 will push liquid out of the nozzle hole. Aerosolizer 1201 preferably comprises a nozzle hole, preferably a plurality of nozzle holes, preferably about 100 to about 10,000 nozzle holes, or about 500 to about 5,000 nozzle holes, or about 1,000 to about 4,000 nozzle holes, or about 1,000 to about 3,000 nozzle holes, preferably about 1,600 nozzle holes, or 2,000 nozzle holes. Preferably, the nozzle hole is substantially circular and has a diameter of about 10 μm or less, or about 7.5 μm or less, or about 6 μm or less, or about 5 μm or less, or about 4 μm or less, or about 3 μm or less, or about 2 μm or less, preferably in the range of about 2 μm to about 3 μm. In one embodiment, the maximum pressure in the formulation pocket 1202 is about 100 mbar or less, about 50 mbar or less, about 25 mbar or less, about 10 mbar or less, about 5 mbar or less, or about 2.5 mbar or less.

[0172] During storage of the cartridge and prior to first use, the valve 1209 remains closed to ensure stability and sterility of the formulation in the formulation chamber 1213. The valve 1209 may be operated by pinching the tube 1210. In a preferred embodiment, the valve 1209 is operated by pinching the outlet formulation chamber 1213 so that the formulation only comes into contact with the formulation chamber during storage. The valve 1209 may be opened electrically under the control of a microcontroller. In another embodiment, the valve 1209 may be opened by the user prior to first use, for example, by a method selected from a list including, but not limited to: pulling a pull tab, pressing a button, turning a knob, etc. Preferably, the valve is opened by the act of attaching the cartridge 702 to the durable system 701. In embodiments where the valve 1209 is electrically actuated, it may be closed between uses to prevent flow of the formulation. Preferably, valve 1209 remains open the entire time cartridge 702 is attached to durable system 701, taking advantage of the fact that the flexible formulation chamber 1213 allows the system to be kept in pressure equilibrium with the ambient air as the small aperture 1321 holds the formulation cavity 1224; when valve 1209 is open, all of the formulation in the cartridge is at the same pressure as the ambient air, minimizing the possibility of leakage, for example through the aerosolizer 1201 or hydrophobic porous membrane 1227.

[0173] Prior to the first use of the present invention, valve 1209 is opened and pump 1207 self-primes and then pumps formulation through the recirculation system for a sufficient time that essentially all of the air in the formulation pocket, tubes 1210, 1211, 1315, and 1305, bubbler eliminator 1304, and pump 1207 is forced out of the cartridge via aerosolizer 1201 and / or bubbler eliminator 1304. Pump 1207 self-primes and then pumps formulation into formulation pocket 1202 until pressure transducer 1225 determines that the pressure in the formulation pocket is at a predetermined pressure, ensuring that essentially all of the air in the formulation pocket 1222, tubes 1210, 1211, and pump 1207 is forced out of the cartridge via aerosolizer 1201 and / or hydrophobic porous membrane 1227.

[0174] The small holes 1221 allow the pressure in the formulation pocket 1222 and formulation cavity 1224 to equilibrate with the outside air, while being small enough to maintain a high relative humidity within the aerosol head cavity 1222 and formulation cavity 1224, thereby reducing evaporation of the formulation carrier through the hydrophobic porous membrane 1227. Because the flexible formulation chamber 1213 is equilibrated with the outside air, the formulation within the device is maintained at substantially the same pressure as the outside air, substantially reducing or eliminating pressure differentials across the nozzle hole of the aerosolizer 1201 due to, for example, changes in weather or altitude, which may cause formulation leakage or air ingress. In a related embodiment, the hydrophobic porous membrane 1227 removes air from the formulation into a small cavity which vents directly to the outside air, or to the aerosol head chamber 1222, or directly to the formulation cavity 1224, preferably through small holes as described above, to maintain a high relative humidity in the bubbler cavity, thereby reducing evaporation of the formulation carrier through the porous hydrophobic element 1227. If the formulation exits the hydrophobic porous membrane 1227, an optional absorbent material 1223 may be used to contain any leaked formulation. Preferably, absorbent material 1223 is not required.

[0175] The walls of the formulation pocket 1202 may include multiple openings 1226 and hydrophobic porous membrane 1227, preferably on different sides of the formulation pocket 1202, or the walls of the formulation pocket 1202 may themselves be constructed of the material of the hydrophobic porous membrane 1227, ensuring that air can escape from the pocket 1202 regardless of the orientation in which the device is held.

[0176] Optionally, one may choose to use a wicking element 1208. In this embodiment, the pump 1207 pumps the formulation into the tube 1211, which carries the formulation into the formulation pocket 1202, where it is absorbed by the wicking material 1208, which is located in the formulation pocket 1202 directly behind the aerosolizer 1201. The use of the wicking element 1208 may make the device less directionally dependent. Optionally, the wicking element 1208 may be separated from the aerosolizer 1201 by a spacing element 1206, which is located in direct contact with the aerosolizer 1201. The use of the spacing element 1206 is as follows: the formulation flows from the wicking element 1208 through the spacing element 1206 to the aerosolizer 1201. When the aerosolizer 1201 is activated, it pumps air into the formulation pocket 1202. Air moves into the formulation pocket 1202 through the spacing element 1206 and air exits the formulation pocket 1202 through the opening 1226 and the hydrophobic porous membrane 1227 .

[0177] 13 shows one embodiment of a cartridge using a recirculation system. One or more flexible formulation chambers 1213 are connected via tubing 1210 to one or more pumps 1207. The pump 1207 pumps the formulation into tubing 1211, which carries the formulation into the formulation pocket 1202. During the process of aerosolization, the aerosolizer 1201 generates air that enters the formulation pocket 1202. As the pump 1207 pumps the formulation into the formulation pocket 1202, the air is entrained in the liquid flow and exits the formulation pocket 1202 via tubing 1315, and the formulation and air flow into the debubbler 1304 via inlet opening 1316. The formulation passes through the debubbler 1304 and exits through outlet opening 1317. As the formulation and air flow passes through the air bubbler 1304, it comes into direct contact with the porous hydrophobic material 1303, and the air escapes the porous hydrophobic material 1303 and is then drawn through the opening 1214 into the reduced pressure environment of the formulation cavity 1224 (by the formulation being pumped from the formulation chamber(s) 1213). The outlet 1317 is preferably somewhat restrictive, so that the pressure in the air bubbler 1304 is high enough to force the air through the porous hydrophobic material 1303, but not so high that the formulation passes through the porous hydrophobic material 1303. The formulation then flows into the tube 1305 which connects to the tube 1210, where the formulation is then pumped again through the pump 1207, thus creating a recirculating flow system. In general, the pressure in the formulation pocket 1202 can be kept fairly low, substantially equal to the pressure in the air bubbler 1304, reducing the likelihood of the formulation flowing through the array of nozzle holes in the aerosolizer 1201. Optionally, the aerosolizer 1201 can be treated with a hydrophobic coating to further reduce the likelihood that pressure within the formulation pocket 1202 will push liquid out of the nozzle hole. Preferably, the pressure within the formulation pocket 1202 is on the order of 100 mbar or less, on the order of 50 mbar or less, on the order of 25 mbar or less, on the order of 10 mbar or less, on the order of 5 mbar or less, on the order of 2.5 mbar or less.

[0178] Because the formulation is recirculated and there is no concern of the formulation leaking out of the nozzle hole of the aerosolizer 1201, the system becomes insensitive to the pumping speed of the pump 1207 and the pumping time of the pump 1207, and pumping is decoupled from the rate and time of aerosolization by the aerosolizer 1201. Thus, the pump 1207 can pump for as long as necessary (including before aerosolization begins or after aerosolization has ended) at essentially any flow rate that excludes most or all air from the formulation. As the formulation is aerosolized and air exits through the porous hydrophobic element 1303, the volume of formulation in the loop drops and therefore the pressure in the loop drops. The reduced pressure in the tube 1305 draws the formulation from the formulation chamber 1213 through the tube 1210. Because air is introduced into the formulation during the aerosolization process and is subsequently essentially completely removed by the air bubbler 1304, the amount of formulation drawn from the formulation chamber 1213 is essentially equal to the amount of formulation aerosolized.

[0179] The small holes 1221 allow the pressure in the aerosol head cavity 1222 and formulation cavity 1224 to equilibrate with the outside air, while being small enough to maintain a high relative humidity within the aerosol head cavity 1222 and formulation cavity 1224, thereby reducing evaporation of the formulation carrier through the hydrophobic porous membrane 1303. Because the flexible formulation chamber 1213 is equilibrated with the outside air, the formulation within the device is maintained at substantially the same pressure as the outside air, substantially reducing or eliminating pressure differentials across the nozzle hole of the aerosolizer 1201 due to, for example, changes in weather or altitude, which may cause formulation leakage or air ingress. In a related embodiment, the debubbler 1304 removes air from the formulation into a small debubbler cavity which vents directly to the atmosphere, or to the aerosol head cavity 1222, or directly to the formulation cavity 1224, preferably through small holes as described above, to maintain a high relative humidity within the debubbler cavity, thereby reducing evaporation of the formulation carrier through the porous hydrophobic element 1303. When the formulation exits the debubbler, an optional absorbent material 1223 may be used to contain any leaked formulation. Preferably, no absorbent material 1223 is required.

[0180] FIG. 13 shows a valve 1209 at the outlet of the formulation chamber 1313. The valve 1209 can be a controlled valve, such as a needle valve. Preferably, the valve 1209 has only two states, open and closed. In one embodiment, during shipping and storage, the formulation chamber 1213 contains all the formulation in the cartridge, and the outlet of the formulation chamber 1213 is closed by the valve 1209. Preferably, the valve 1209 closes the outlet of the formulation chamber 1213 by pinching a portion of the formulation chamber 1213, which is made of the same material(s) as the rest of the formulation chamber 1213, which material is optimized for long-term storage of the formulation. In this way, during shipping and storage, the formulation only contacts the surfaces of the formulation chamber 1213 and does not contact the valve 1209 or any of the other flow components in the cartridge. In this way, the material of the formulation chamber 1213 can be optimized for drug contact and the materials of the other components can be optimized for performance. Prior to first use of the invention, valve 1209 is opened and pump 1207 self-primes and then pumps formulation through the recirculation system for a sufficient time that essentially all air within the formulation pockets, tubes 1210, 1211, 1315, and 1305, bubbler eliminator 1304, and pump 1207 is forced out of the cartridge, via aerosolizer 1201 and / or bubbler eliminator 1304. To facilitate priming of pump 1207, a similar valve may be placed on 1305 to ensure that pump 1207 does not simply pump air around the recirculation loop during priming.

[0181] In an embodiment with two or more formulation chambers 1213, two or more valves 1209 can serve to control the ratio of the two or more formulations, for example to reduce the concentration of nicotine. This can be done by varying the amount of flow restriction through the multiple valves 1209. However, a preferred method is to have only one of the valves 1209 open at any time, for example during a dosing event. In this way, the mixing ratio of the formulations can be controlled. Figures 14-17 show a numerical simulation of the application of this method to two formulation chambers, one with a placebo formulation and one with a nicotine concentration of 30 mg / ml. In Figures 14-17, it is assumed that: 1) the user uses the device 10 times per day (10 "dosing events"), 2) 7 puffs are taken at each dosing event, and 3) the goal of the algorithm is to cause the nicotine concentration to drop substantially linearly to substantially zero over 90 days. The algorithm used is to calculate the current concentration based on past dosing events. If the concentration is calculated to be above the target concentration, then a dose (either a dosing event or a puff) is taken by drawing formulation from a "sham" (zero concentration) formulation chamber 1213. If the calculated concentration is below the target concentration, then a dose is taken by drawing formulation from a formulation chamber 1213 containing an active pharmaceutical ingredient (preferably nicotine). Figure 14 shows the calculated concentration of nicotine to be delivered as described above, and the formulation chamber from which the formulation is drawn was selected at the start of each dosing event. Figure 15 shows the error (difference from the target nicotine concentration) of each dose delivered. It can be seen that with this algorithm, nicotine can be controlled to within ±2 mg / ml, i.e., within ±6.7% of the initial target concentration of nicotine. By removing the linear trend with the algorithm, it can be seen that the concentration can be controlled to approximately ±1.5 mg / ml. Figures 16 and 17 are similar to Figures 14 and 15, except that the selection of which formulation chamber 1213 to draw formulation from is made before each puff. As can be seen from FIG. 17, when using this algorithm, the concentration can be held to approximately ±0.45 mg / ml, or ±1.5%.

[0182] Preferably, the aerosolizer 1301 generates an aerosol in the inhalation airstream of the user as the user inhales through the device. In prior art devices using a vibrating mesh nebulizer, the aerosol is generated in a direction toward the outlet of the device and toward the user. In one embodiment, the airflow through the airway flows in a direction that is substantially perpendicular to the average direction of aerosol generation from the array of holes and substantially parallel to the aerosolizer 1301. This configuration has been found to more efficiently load the dose, disperse the aerosol, and reduce agglomeration of the aerosol particles, thereby increasing the emitted dose and reducing particle size.

[0183] FIG. 18 shows an embodiment of a recirculation system with a filter 1801. In embodiments of the invention where the aerosolizer comprises one or more nozzle holes, there is a concern that bacteria may enter through the nozzle holes and colonize the formulation in the recirculation loop. While bacteria could enter through the porous hydrophobic element 1303, this is less likely as they are only exposed through the small holes 1221. Viruses are much less of a concern as they can only reproduce within host cells and not within the aqueous formulation. Viruses exposed to the nozzle holes are more likely to be from air inhaled through the respiratory tract, so exposure to the user from simply breathing air is much greater than exposure to viruses inhaled within the formulation. In one embodiment, the formulation has a bacteriostatic agent to prevent bacterial reproduction. However, it is preferred that there is no bacteriostatic agent in the formulation to avoid exposing the user's lungs to the bacteriostatic agent. In the embodiment of FIG. 18, the system is provided with a filter 1801. The filter 1801 preferably has a pore size that captures essentially all bacteria that may be present in the formulation. Preferably, the pore size of the filter 1801 is about 1 μm or less, about 0.75 μm or less, about 0.5 μm or less, about 0.4 μm or less, about 0.2 μm or less, about 0.1 μm or less. A preferred filter 1801 has a pore size selected from about 0.1 μm, 0.2 μm, and 0.22 μm. In one embodiment, the filter 1801 used is a 0.2 um pore size nylon membrane filter, Omicron part number 170047R. The filter may be located anywhere in the recirculation loop, for example in tubes 1215, 1210, 1205, or 1211. However, it is preferred that filter 1801 is not placed between the outlet of 1202 and in front of the inlet of pump 1207 because, due to the small pore size and limited area available in filter 1801, the relatively high pressure required to pump through filter 1801 may cause the formulation to leak out of the nozzle hole(s) of aerosolizer 1201 or out of porous hydrophobic component 1303. Preferably, a filter is placed between pump 1207 and the inlet of formulation pocket 1202, either in tube 1211 or, preferably, at the inlet of formulation pocket 1202.With filter 1801 in place, whenever pump 1207 pumps formulation, formulation pocket 1202 is provided with bacteria-free formulation and any bacteria within pocket 1202 is swept into tubing 1215 and ultimately pumped around the recirculation loop and captured by filter 1801. In one embodiment, the system has a mode in which pump 1207 pumps a sufficient volume such that essentially all of the formulation initially within formulation pocket 1202 flows out of pocket 1302 and is replaced by bacteria-free formulation, such that pocket 1202 is filled aseptically. Preferably, the sufficient volume is greater than or approximately equal to the volume of the pocket 1202, on the order of 1.5 times the volume of the pocket 1202 or more, on the order of 2 times the volume of the pocket 1202 or more, on the order of 2.5 times the volume of the pocket 1202 or more, on the order of 3 times the volume of the pocket 1202 or more, on the order of 4 times the volume of the pocket 1202 or more, on the order of 5 times the volume of the pocket 1202 or more, on the order of 7.5 times the volume of the pocket 1202 or more, or on the order of 10 times the volume of the pocket 1202 or more. Preferably, the sufficient volume is pumped by the pump 1207 at times selected from one or more of the following list, including but not limited to: throughout the day, before the first dose of the day, before each dosing event, after each dosing event, before each puff, after each puff. It is important to ensure that the filter 1801 is intact, e.g., without tears or leaks, and has the correct pore size. This may be determined, for example, by having a pressure transducer in the tube 1211 between the pump 1207 and the filter 1801 to measure the pressure required to achieve a predetermined flow rate. A drop in pressure due to a failure of the filter 1801 may lead to a faster pump speed, in which case the failure may be detected with a flow meter. The flow meter should be placed between the outlet of the pump 1207 and the inlet of the filter 1801 because small leaks associated with the filter 1801 may not be detected elsewhere in the flow loop. In embodiments in which the pump 1207 is driven by a motor, for example when the pump 1207 is a peristaltic pump, a change in pump speed may be detected as a change in the motor speed.For a pump motor operated at a constant voltage, an increase in pump speed can be detected as a decrease in current due to an increase in the motor's back EMF. For a pump motor operated at a constant current, an increase in flow rate will result in an increase in the voltage required to maintain the current. For a pump operated at a constant pump motor speed that is pulse width modulated using an encoder, a decrease in pressure will result in a shorter pulse width being required to maintain the same speed.

[0184] Pump 1207 can be any type of pump capable of generating sufficient output pressure to achieve sufficient flow rate, for example through filter 1801. Preferred pumps are capable of generating high output pressure to enable pumping through 1801. Particularly preferred pumps are peristaltic pumps, including components selected from, but not limited to, a 12V 148 RPM motor, a gearhead, a rotor or eccentric, a ring, a section of flexible tubing, and a support surface for the tubing. Preferred motors and gearheads provide output shaft rotational speeds of about 50 to about 1000 RPM, about 75 to about 750 RPM, about 100 to about 500 RPM, about 125 to about 250 RPM, about 125 to about 200 RPM, or about 125 to about 175 RPM. Preferably, the motor, gearhead, and rotor or eccentric ring are part of the durability system 701, and the tubing, ring if required, and support surface are part of the cartridge 702. In one embodiment of a peristaltic pump, a motor rotates a rotor which causes at least one roller, preferably two or more or three rollers, to move in a circular motion as they rotate along a portion of a flexible tube and compress it against a support surface to create flow through the tube. Since the tube must be compressed in order for the rollers to compress, preferably each roller is provided with an angled cam surface which compresses the tube.

[0185] 19 shows a preferred embodiment of pump 1307, where the peristaltic pump comprises motor 1901, gear head 1902, shaft 1903; and eccentric cam 1904 and alignment cam 1910; both of which are mounted on shaft 1903, all of which are part of durability system 701. Ring 1905, tube 1907 (shown in FIG. 19a as compressed tube 1906 and uncompressed tube 1907), ring capture detail 1908, and support surface 1909 are all part of cartridge 702. The cartridge components are shown in cross section, but it will be appreciated that when viewed from above, ring 1905 is circularly symmetrical, as are support surface 1909 and tube 1907, except where tube 1906 is compressed by ring 1905, and where there are gaps in support surface 1909 where the input and output of tube 1907 enter. Preferably, at least one of the eccentric cam 1904, alignment cam 1910, and ring 1905 are made of a polymer having properties selected from a list including, but not limited to: a lubricious polymer, a fluorinated polymer, PTFE, Delrin, or Nylon. In an alternative embodiment, one of the eccentric cam 1904, alignment cam 1910, and ring 1905 is made of a metal, preferably stainless steel, and ring 1905 is a radial ball bearing.

[0186] FIG. 19a shows the pump configuration when a new cartridge 702 is ready to be installed. It can be seen from 19a that the eccentric cam 1904 is on the right side, while the ring 1905 is on the left side. In general, the relative positions of the eccentric cam 1904 and the ring 1905 are arbitrary, but they are unlikely to be aligned. It can be seen that without the alignment cam 1910, the ring 1905 and the eccentric cam 1904 would interfere when the cartridge 702 is being installed, which could lead to damage to the ring 1905 and / or the eccentric cam 1904. To avoid this, the alignment cam 1910 is mounted on the shaft 1903 above the eccentric cam 1904. As shown in FIG. 19b, when the cartridge 702 is pressed onto the durable system 701, the alignment cam 1910 contacts the ring 1905 and starts to move the ring 1905 to the left. 19c, when the cartridge 702 is fully seated, the ring 1905 moves to the right, which in turn compresses the tube to the right. When the motor 1901 is energized, the eccentric cam 1904 is rotated, which in turn compresses portions of the tube 1907, causing a flow of the formulation contained within the tube 1907.

[0187] When the cartridge 702 is attached to the durable system 701, the eccentric slides into the ring (characterized by a diameter sufficient for the eccentric to fit completely within the ring) and then the motor is activated, causing the eccentric to rotate, thereby moving the ring, which in turn compresses portions of the tubing in a circular pattern against the support surface, thereby creating flow through the tubing. In embodiments where the system comprises a durable system element and a separable multi-dose cartridge, the motor, gearhead, and eccentric or rotor are preferably part of the durable system element and the tubing, ring, and support surface are preferably part of the disposable element.

[0188] FIG. 20a shows an embodiment of the bubble remover 1304 in cross section, and FIG. 20b shows a perspective view of the same embodiment. The formulation and air flow into the bubble remover 1304 via the inlet channel 1316, as the formulation comes into contact with the porous hydrophobic material 1303, lifts and moves under the porous hydrophobic material 1303, and at least some of the air in the formulation exits through the pores of the porous hydrophobic material 1303 into the bubble remover cavity 2001. The formulation then exits the bubble remover 1304 through the outlet channel 1317. The optional divider(s) 2003 separate the bubble remover cavity 2001 into two or more channels, reducing the unconstrained extent of the porous hydrophobic material 1303, resulting in less lifting of the hydrophobic material 1303, thereby increasing the likelihood that air bubbles will come into contact with the porous hydrophobic material 1303. The outlet flow channel 1317 is somewhat restrictive and creates sufficient pressure to drive air under the porous hydrophobic material 1304 and through the pores of the porous hydrophobic material 1303. Preferred gauge pressures of the formulation and air under the porous hydrophobic material 1303 are about 10 to about 1000 mBar, about 20 to about 500 mBar, about 30 to about 250 mBar, about 40 to about 100 mBar, about 50 to about 80 mBar, or about 10, 20, 40, 80, 160, 320, or 640 mBar. Air exiting through the porous hydrophobic material 1303 into the debubbler chamber 2001 exits through the small holes 2002. The small holes 2002 are small holes as described above, and their diameter is selected so that little water vapor escapes, thus keeping the relative humidity in the debubbler chamber 2001 close to 100%, and limiting evaporation of the carrier through the pores of the porous hydrophobic material 1303. Preferably, evaporation through the hydrophobic material 1303 is less than about 10 μl / hr, less than about 5 μl / hr, less than about 2.5 μl / hr, less than about 1 μl / hr, or less than about 0.5 μl / hr. A desirable hydrophobic porous material for use in 1303 is POREX MD10 expanded PTFE, which has a typical airflow through the pores of 125 (minimum 70) l / hr / cm2 at 70 mbar, and a water entry pressure (WEP) of 270 (minimum 175) mbar.POREX Expanded PTFE has an airflow range of 2-125 l / hr / cm2 at 70 mbar and a WEP range of 175-1050 mbar, so various embodiments of this system can use expanded PTFE with an airflow and WEP that will output the desired airflow based on the internal pressure of the system. Additional hydrophobic porous materials that can be used include, but are not limited to, Versapor RC membranes: Versapor 200RC Part No. VRC02S7X10, Versapor 800RC Part No. VRC08S7X10, Versapor 1200RC Part No. VRC12S7X10, Versapor 3000RC Part No. VRC30S7X10, Versapor 5000RC Part No. VRC50S7X10.

[0189] D. Pharmaceuticals for Use in Aerosol Devices The active pharmaceutical ingredients (API) encompassed by the present disclosure include nicotine as a free base and its pharma- ceutically acceptable salts. In one embodiment, the pharmaceutical used in the aerosol device is nicotine bitartrate dihydrate. Other acids that may be mixed with the free base include, but are not limited to, tartaric acid, lactic acid, benzoic acid, levulinic acid, salicylic acid, and malic acid. The nicotine source of the nicotine-containing composition of the present invention may include nicotine in free base form, salt form, as a complex, as a solvate, or in other suitable forms. Nicotine is typically isolated in neat (liquid) form (e.g., as described above). In accordance with the present invention, nicotine is modified to provide other forms by incorporating nicotine as a component of a salt, cocrystal, or salt cocrystal, e.g., in the form of an oil, solid, semi-solid, etc. In some embodiments, certain salts, cocrystals, and salt cocrystals are desirably provided in solid form, e.g., solid, crystalline form. Advantageously (though not necessarily), the coformers (including acids) that combine with nicotine to form such nicotine salts, co-crystals, or salt co-crystals are "GRAS" (Generally Recognized as Safe) according to the U.S. Food and Drug Administration. Moreover, advantageously (though not necessarily), the nicotine salts, co-crystals, and / or salt co-crystals formed thereby are also GRAS. When the nicotinic compounds of the present invention contain relatively basic functional groups, such as in nicotine, 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 pharma- ceutically acceptable nicotine salts include tartrates (e.g., nicotine tartrate and nicotine hydrogen tartrate), chlorides (e.g., nicotine hydrochloride and nicotine dihydrochloride), sulfates, perchlorates, ascorbates, fumarates, citrates, malates, lactates, aspartates, salicylates, tosylates, succinates, pyruvates, etc.; nicotine salt hydrates (e.g., nicotine zinc chloride monohydrate), etc. Those skilled in the art will recognize that similar salts may be formed for agonist compounds that contain relatively basic functional groups.Additional acids which may form salts include formic, acetic, propionic, isobutyric, butyric, α-methylbutyric, isovaleric, levulinic, β-methylvaleric, caproic, 2-furoic, benzoic, phenylacetic, heptanoic, octanoic, nonanoic, oxalic, malonic, glycolic, benzenesulfonic, camphosulfonic, ethanesulfonic, gluconic, glucoronic, glutamic, hippuric, hydrobromic, isethionic, lactobionic, maleic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic, pantothenic, phosphoric, sulfuric, and the like, and other fatty acids having carbon chains up to about 20 carbon atoms. The inhalable substance vehicle may further include, for example, one or more of glycerin, water, and a flavorant. The amount of nicotine salt or polymorphic form incorporated may vary and, in some embodiments, may be an amount sufficient to provide 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 of nicotine per puff on the device.

[0190] Non-nicotine containing formulations for smoking cessation are also contemplated by the present disclosure. One such example is a formulation comprising: ascorbic acid (3 mg), mentha crispa (1.5 mg), mentha piperita (1 mg), chocamine (1 mg), damiana leaf 10:1 PE (1 mg), palmitoylethanolamide (600 mcg), nicotinic acid (500 mcg), 5-hydroxytryptophan (500 mcg), nicotine adenine mononucleotide (100 mcg), zeaxanthin (100 mcg), lutein (50 mcg), lycopene 5% (50 mcg), water (1 mL), lecithin (0.04 mL), wherein the formulation has a total volume of about 0.1 ml, 0.5 ml, 1 ml, 2.5 ml, 5 ml, 10 ml, 15 ml, or 20 ml or more.

[0191] Other active pharmaceutical ingredients contemplated by the present disclosure include opioids (e.g., fentanyl, morphine, hydrocodone, oxycodone, oxymorphone, codeine, hydromorphone, tapentadol), triptans, risperidone, insulin, epinephrine, atropine, ciprofloxacin, methocarbamol, benzodiazepines, PDE5 inhibitors, glucagon-like peptides, APIs for convulsions, and APIs for insomnia, vasodilators, APIs for asthma, APIs for COPD, APIs for depression, APIs for PTSD, APIs for depression, APIs for angina, APIs for hypoglycemia, APIs for osteoporosis, APIs for migraine, APIs for nausea, APIs for anaphylaxis, APIs for addiction, and APIs for sexual dysfunction.

[0192] [E. Preparations] The formulations used in the devices 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 particles to be inhaled must be small in size (e.g., 0.5-10, preferably 0.5-5 micrometers).

[0193] The concentration of the active ingredient used in the present disclosure may be selected to be close to the solubility limit, thus reducing the volume of formulation per puff that needs to be aerosolized, increasing the cartridge life and the time between battery charges. However, the concentration should not be so high that the active pharmaceutical ingredient goes out of solution with minor changes in concentration, temperature, etc. For example, for nicotine bitartrate dihydrate, the solubility limit is about 50 mg / ml. Preferred concentrations of nicotine free base 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 35 mg / ml or more, about 40 mg / ml or more, or about 45 mg / ml or more. Depending on the nicotine salt used, the amount of such salt may be adjusted to provide the desired dose of nicotine free base, i.e., the amount of free base may be calculated from the mass of nicotine salt present in the formulation.

[0194] In one embodiment, the formulation comprises nicotine free base in an amount of about 20 mg / ml to 50 mg / ml, or about 25 mg / ml to 35 mg / ml, and 0.9% sodium chloride solution, and may optionally include other excipients. In another embodiment, the formulation consists essentially of nicotine free base in an amount of about 20 mg / ml to 50 mg / ml, or about 25 mg / ml to 35 mg / ml, and 0.9% sodium chloride solution. The volume of 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, or about 10 to 20 microliters. Such a volume is delivered by the devices 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.

[0195] For very potent active ingredients, such as fentanyl, it may be desirable to reduce the concentration for safety purposes so that very small volumes do not need to be aerosolized. For example, the concentration of fentanyl may be 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 or less. In one embodiment, the concentration is 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.

[0196] The formulation may contain pharmaceutical excipients that can improve the stability of the dosage form or provide comfort during administration. Such excipients include carriers (e.g., water) and pharmaceutical solvents, isotonicity agents, pH adjusting agents or buffers, stabilizers, antimicrobial preservatives, dispersing agents and / or wetting agents.

[0197] Pharmaceutical solvents are used to dissolve or disperse pharma- ceutically active drugs and excipients. Solvents can be aqueous or non-aqueous. The formulations of the present invention can be formulated with a mixture of one or more pharma- ceutically acceptable solvents, 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. Pharmaceutical solvents can be used to prepare formulation concentrates and to reconstitute the dosage forms of the present invention. Pharmaceutically acceptable solvents, such as water, ethyl alcohol, isopropyl alcohol, etc., are evaporative and are typically used to dissolve or disperse drugs and excipients in formulation concentrates. Glycerol, propylene glycol, and polyethylene glycol are co-solvents and are used to aid in the solubilization of water-insoluble or poorly water-soluble drugs in formulation concentrates. Pharmaceutically acceptable reconstitution solvents, such as sterile water for injection, sterile saline, sterile phosphate buffer, and sterile 5% dextrose solution, are used to reconstitute the dosage forms of the present invention to form a solution or particulate suspension of the active pharmaceutical ingredient prior to oral inhalation via a nebulizer or aerosol device. The reconstitution solvent may be packaged in individual ampoules or unit-dose plastic containers for each unit of use, or in large-volume sterile containers from which a specific volume of the reconstitution solvent can be drawn without contaminating the solvent.

[0198] Tonicity agents are used to enhance the overall comfort of the patient when administering the reconstituted dosage form. It is preferable to adjust the osmolality of the reconstituted inhalation solution to about 275-305 (range 254-325) mOsm / Kg. Tonicity agents for inhalation are sodium chloride, dextrose, lactose, sodium phosphate, sorbitol, mannitol, and sucrose, or combinations thereof, in concentrations that produce an isotonic solution after the dosage form is reconstituted with 1-10 ml of sterile water for nebulization. The addition of sugars, such as dextrose, lactose, and sucrose, adds viscosity and adhesion to the formulation so that the dry pharmaceutical and formulation excipients can be better retained on the support material after the formulation concentrate is dried. Tonicity agents can also function as particle splitting agents, reducing the particle size of the active pharmaceutical ingredient after the formulation is impregnated or deposited on the support material, and aiding in the dissolution or dispersion of the active pharmaceutical ingredient particles when reconstituted with a pharmaceutical solvent. Alternatively, the dosage form can be formulated without the addition of a primary tonicity agent. The desired tonicity of the dosage form is achieved by reconstitution with sterile isotonic saline.

[0199] The formulations may also include pH adjusting or buffering agents to adjust or maintain the pH of the pharmaceutical dosage form in a desired range for the following reasons: (1) to provide an environment for better product stability within which the active pharmaceutical ingredient may exhibit better chemical stability; (2) to provide better comfort for the patient upon administration; and (3) to provide a pH range for better antimicrobial and preservative activity. The formulations and dosage forms of the present invention may be formulated with one or more pharma- ceutically acceptable pH adjusting or buffering agents such that, after reconstitution, the desired pH is between about 3 and about 8.

[0200] Pharmaceutically acceptable pH adjusting agents and buffering agents are selected from, but are 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. Stabilizers are antioxidants that can inhibit oxidation reactions and chelating agents that can chelate metals to improve the stability of active pharmaceutical ingredients and excipients, respectively.

[0201] The formulations and dosage forms of the present invention may be formulated with one or more pharma- ceutically acceptable stabilizers in concentrations appropriate for the intended pharmaceutical use, which may be selected from, but are not limited to, chelating agents such as EDTA and its sodium salt, citric acid, and sodium citrate, antioxidants such as vitamin E, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium pyrosulfite, sodium formaldehyde sulfoxylate, and thiourea. The addition of stabilizers to the dosage forms of the present invention can improve the stability of the pharmaceutical active and extend the shelf life.

[0202] Antimicrobial preservatives are used in pharmaceuticals to inhibit the growth of microorganisms. The dosage forms of the present invention can be formulated with one or more pharma- ceutically acceptable antimicrobial preservatives at appropriate concentrations to prevent the growth of microorganisms. Examples of pharma-ceutically 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.

[0203] Wetting agents or dispersing agents are used to enhance the wetting and aid in the dispersion of water-insoluble or poorly water-soluble particles. Examples of pharma- ceutically acceptable wetting and dispersing agents suitable for oral or nasal inhalation include poloxamers, oleic acid and its salts, lecithin and hydrogenated lecithin, sorbitan fatty acid esters oleyl alcohol, phospholipids including, but not limited to, phosphatidylglycerol and phosphatidylcholine, polyoxyethylene fatty alcohol ethers, polyoxypropylene fatty alcohol ethers, polyoxyethylene fatty acid esters, glycerin fatty acid esters, sphingolipids and glycolipids such as sphingomyelin, polyoxyethylene glycol fatty acid esters, polyol fatty acid esters, polyethylene glycol glycerin fatty acid esters, polypropylene glycol fatty acid esters, ethoxylated lanolin derivatives, polyoxyethylene fatty alcohols, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, propylene glycol alginate, dilauryl dimethylammonium chloride, D-α-tocopheryl-PEG 1000 succinate, polyoxyl 40 stearate (Polyoxy 40 stearate, polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene vegetable oil, fatty acid derivatives of amino acids, glyceride derivatives of amino acids, benzalkonium chloride, and bile acids.

[0204] [F. List of Additional Numbered Embodiments] The following additional numbered embodiments are understood to apply to any of the disclosures and claims in this application, and in determining the subject matter encompassed by these embodiments, a reference to "a system or device of any of the above embodiments" is understood to also be a reference to any of the following embodiments and claims. Additionally, the following list of embodiments is intended to supplement the preceding description, and the examples and claims that follow the list.

[0205] 1. A smoke-free system comprising: a. a durable system comprising an electronic device and a peristaltic pump motor assembly; b. a cartridge comprising an aerosolizer, a bubbler remover, a filter, a pump head, and one or more formulation chambers; and c. Wall charger and cable; Equipped with No smoking system.

[0206] 2. A system as described in paragraph 1, and an app for a portable device in communication with the system. system.

[0207] 3. A system according to any one of claims 1 to 2, The cartridge is removably connected to the durability system. system.

[0208] 4. A system according to any one of claims 1 to 3, Further comprising a controller and a mouthpiece. system.

[0209] 5. A method of treating a patient in need of smoking cessation therapy comprising: a. Providing a system as described in any one of claims 1 to 4; wherein said cartridge contains a nicotine formulation in one or more formulation chambers; and b. the patient administers the nicotine formulation by sealing his or her lips around the mouthpiece and inhaling a dose of the nicotine formulation; Including, wherein the patient administers to himself / herself multiple doses of the nicotine formulation, gradually decreasing the dose over time. method.

[0210] 6. The method according to claim 5, wherein the period is about 2-6 weeks, or about 3-5 weeks, or about 4-5 weeks, or about 4 weeks; method.

[0211] 7. The method according to numbers 5 and 6, The dose is gradually decreased by about 1% to 10% per day for a predetermined period of time. method.

[0212] 8. The method according to any one of claims 5 to 7, The nicotine formulation comprises nicotine free base in the form of a pharma- ceutically acceptable salt thereof. method.

[0213] 9. The method according to any one of claims 5 to 8, The nicotine formulation contains about 5 mg / ml to about 50 mg / ml of nicotine free base. method.

[0214] 10. The method according to any one of claims 5 to 9, The nicotine formulation comprises about 20 mg / ml to about 50 mg / ml of nicotine free base and a 0.9% sodium chloride solution. method.

[0215] 11. The method according to any one of claims 5 to 10, the system having a means for delivering the nicotine formulation in a volume of about 1-50 microliters, or about 1-30 microliters, or about 1-25 microliters, or about 1-20 microliters, or about 1-15 microliters, or about 5-20 microliters, or about 10-20 microliters per actuation; method.

[0216] 12. The method according to any one of claims 5 to 11, the system having a means for delivering the nicotine formulation in a volume of about 1-50 microliters, or about 1-30 microliters, or about 1-25 microliters, or about 1-20 microliters, or about 1-15 microliters, or about 5-20 microliters, or about 10-20 microliters per actuation; and Such a 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. method.

[0217] 13. A smoking cessation inhaler comprising: a durable part (or system or element) of the inhaler comprising a controller; and a multi-dose cartridge configured for releasable attachment to the durable portion of the inhaler; wherein the cartridge comprises: (a) an aerosolizer; (b) a formulation chamber containing a formulation including an active pharmaceutical ingredient; (c) an air bubbler; and (d) a filter; Smoking inhaler.

[0218] 14. An inhaler according to claim 13, Further comprising a pump motor assembly. Inhaler.

[0219] 15. An inhaler according to any one of claims 13 to 14, further comprising an air bubbler; an air bubbler chamber; a pocket; an aerosolizer; a filter; and a pump head. Inhaler.

[0220] 16. An inhaler according to any one of claims 13 to 15, The formulation contains about 5 mg / ml to about 50 mg / ml of nicotine free base. Inhaler.

[0221] 17. An inhaler according to any one of claims 13 to 16, The nicotine formulation comprises about 20 mg / ml to about 50 mg / ml of nicotine free base and a 0.9% sodium chloride solution. Inhaler.

[0222] 18. An inhaler according to any one of claims 13 to 17, further comprising a means for delivering a nicotine formulation in a volume of about 1-50 microliters, or about 1-30 microliters, or about 1-25 microliters, or about 1-20 microliters, or about 1-15 microliters, or about 5-20 microliters, or about 10-20 microliters per actuation; Inhaler.

[0223] 19. An inhaler according to any one of claims 13 to 17, a means for delivering a nicotine formulation in a volume of about 1-50 microliters, or about 1-30 microliters, or about 1-25 microliters, or about 1-20 microliters, or about 1-15 microliters, or about 5-20 microliters, or about 10-20 microliters per actuation; and Such a 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. Inhaler.

[0224] 20. An inhaler according to any one of claims 13 to 19, the inhaler delivers nicotine free base resulting in pharmacokinetic values ​​within about 5%, or 10%, or 15%, or 20%, or 25%, or 30% of those reported in cigarette smokers; wherein said values ​​are one or more of: (a) concentrations at 5, 10, and 15 minutes; (b) Cmax; (c) Tmax; and (d) AUC; Inhaler.

[0225] 21. An inhaler according to any one of claims 13 to 20, wherein a statistically significant number of patients using said inhaler report a reduction in nicotine craving as measured by a visual analog scale (VAS)-craving assessment. Inhaler.

[0226] 22. An inhaler as described in paragraph 21, the inhaler reduces cravings by about 30%, or 40%, or 50%, or 60%, or 70% compared to baseline; Inhaler.

[0227] 23. An inhaler according to any one of claims 13 to 22, The inhaler comprises only a single formulation and a single pump, Inhaler. EXAMPLES

[0228] [G. Example] The following examples are included to illustrate certain embodiments of the present disclosure. However, those of skill in the art should appreciate in light of this disclosure that changes can be made to the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the invention. Accordingly, all matters described should be interpreted as illustrative and not in a limiting sense.

[0229] [Example 1] One embodiment of the use of the system for smoking cessation is as follows: The system is supplied in a box with: a durable system part with an overwrapped electronic device and a peristaltic pump motor assembly; one or more individually packaged cartridges with an aerosolizer, a bubble remover, 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 that is downloaded onto a portable device such as a smartphone or tablet. One embodiment of the use of the system of the present invention is as follows: The user installs the app on their phone and is instructed on how to use the system (or optionally follows the paper instructions for use). Following the instructions, the user removes from the box, unwraps the durable system cartridge, and discards the overwrap. The included charger is attached via the USB-C charging connector and plugged in until the battery is fully charged (indicated by the light switching from red to green). The first disposable cartridge is removed from the overwrap and pressed against the durable system part until the detent feature is felt and a click is heard. Once the cartridge is loaded, the user presses a button on the app (or optionally, a button on the device) and the controller initiates a purge procedure, which involves turning the pump on long enough to remove air from the flow path, formulation pocket, and debubbler. The controller monitors the motor current to determine if the cartridge is properly loaded and pumping formulation. Once priming is complete, the user presses a button on the device. After approximately one second, a green flashing light on the device illuminates, indicating the device is ready to use.

[0230] The user then seals their lips around the mouthpiece and begins to inhale. The microcontroller reads the inhalation flow rate from the sensor, and while the flow rate is within the appropriate range, the controller vibrates the piezo, generating aerosol through the nozzle array into the user's inhalation flow. If the inhalation is within the desired flow rate range, a steady green light is illuminated to guide the user through the inhalation. Aerosol is generated for up to 0.5 seconds, or less if the user stops inhaling. The pump turns on when the aerosol first begins and remains on for 1 second after the end of aerosol generation, pushing air generated by the aerosolizer into the debubbler and replenishing the aerosolized formulation. The above steps are repeated based on the user's preference each time the user inhales through the device, as long as the flashing green light remains illuminated. If no inhalation is sensed for 5 minutes, the flashing green light turns off and the system goes into sleep mode. The user then presses a button to repeat the next steps as desired. When the formulation in the formulation chamber is depleted after approximately four weeks (based on frequency and amount of use), the user receives a text message and, by pressing a button, the device displays an alternating green and red flashing light indicating that a cartridge replacement is required. The user then removes the cartridge by pulling it away from the durable system portion, discards it, removes the wrap from the next cartridge, and installs the cartridge as before, optionally consulting the instructions. Throughout this process, the controller adjusts the concentration of the active ingredient, slowly tapering it down to essentially zero over the course of three months. During the course of treatment, as the battery depletes, the user receives a text message and the light displays a flashing red light. The user attaches the charger to the device and charges it until the device displays a solid green light indicating a full charge.

[0231] [Example 2] The embodiment shown in Figure 12 was tested 23 times for emitted dose efficiency using the method of USP 601: Delivered Dose Uniformity. A 10x saline formulation was used. The filter was washed with a predetermined amount of deionized water and the emitted dose was quantified using an electrical conductance method. Figure 20 shows the results. The emitted dose was an average of 82.01% of the aerosolized formulation amount. The USP 601 acceptance criteria of ±25% and ±35% are included for reference.

[0232] [Example 3] The embodiment of FIG. 13 was tested for aerosolized volume over a two week period. Ten dosing events were performed each day, spaced 90 minutes apart, with each dosing event including seven puffs spaced 30 seconds apart. A 3x saline formulation was used. The system was not disturbed during the experiment, except for occasionally filling the graduated cylinder with formulation. The change in volume of the formulation in the graduated cylinder was used to determine the total aerosolized volume each day. The aerosolizer was set to aerosolize 10 μl / puff before the start of the experiment. FIG. 22 shows the average aerosolized volume per puff for each day from day 6 to day 14. It can be seen from FIG. 22 that the embodiment of FIG. 13 can deliver a repeatable aerosolized volume for at least two weeks.

[0233] Although the present invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in the art that various modifications may be 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 appended claims.

Claims

1. 1. A smoking cessation inhaler comprising: a. Controller b. a cartridge configured to be releasably attached to the inhaler; Equipped with The cartridge comprises: (i) Aerosolizer (ii) a formulation chamber containing a formulation comprising an active pharmaceutical ingredient; (iii) air bubble remover; and (iv) a filter; Equipped with Smoking inhaler.

2. 2. An inhaler according to claim 1, Further comprising a pump motor assembly; and The cartridge includes a pump head assembly. Inhaler.

3. 3. An inhaler according to claim 2, The pump motor assembly may include components selected from one or more of the following: a. motor; b. Gear head; c. Eccentric cam; d. a rotor that causes at least one roller to move in a circular motion; and e. alignment cam; Equipped with Inhaler.

4. 4. An inhaler according to claim 2 or 3, The pump head assembly includes elements selected from one or more of the following: a. Support surface; b. Ring; and c. a section of tubing; Equipped with Inhaler.

5. An inhaler according to any preceding claim, Further comprising a recirculation system; Inhaler.

6. 6. An inhaler according to claim 5, The recirculation system may include a loop comprising one or more of the following: a. Air bubble remover; b. Air bubbler chamber; c. pocket; d. an aerosolizer; e. Filter; and f. pump head; Equipped with Inhaler.

7. An inhaler according to any preceding claim, The cartridge comprises a filter capable of removing bacteria from the formulation. Inhaler.

8. 8. An inhaler according to claim 7, The filter has a pore size of 5 μm or less. Inhaler.

9. 9. An inhaler according to claim 8, The pore size is 2 μm or less. Inhaler.

10. 10. An inhaler according to claim 9, The pore size is 1 μm or less. Inhaler.

11. An inhaler according to any preceding claim, The active pharmaceutical ingredient is an addictive substance; and / or a substance to which chronic users develop tolerance; Inhaler.

12. An inhaler according to any preceding claim, The amount of the active pharmaceutical ingredient delivered is repeatedly adjusted by the controller. Inhaler.

13. 13. An inhaler according to claim 12, The adjustment may include one or more of the following: a. increasing the amount of active pharmaceutical ingredient delivered; b. A reduction in the amount of active pharmaceutical ingredient delivered; and c. a period of increased active pharmaceutical ingredient delivered followed by a period of decreased active pharmaceutical ingredient delivered; Including, Inhaler.

14. An inhaler according to any preceding claim, Where the active pharmaceutical ingredient is: a. nicotine; b. Fentanyl; c. Triptans; d. Risperidone; e. insulin; f. epinephrine; g. Atropine h. ciprofloxacin; i. methocarbamol; j. Benzodiazepines k. opioids; l. PDE5 inhibitors; m. glucagon-like peptide; n. Medication for treating convulsions; o. medicines for treating insomnia; p. vasodilators; q. asthma medication; r. medication for COPD; s. Anxiety medication; t. medications for treating PTSD; u. medications for depression; v. drugs to treat angina pectoris; w. medication for treating hypoglycemia; x. drugs for treating osteoporosis; y. medications for migraine headaches; z. nausea medication; aa. Anaphylaxis treatment drugs; bb. Drugs for treating addiction; or cc. drugs for treating sexual dysfunction; Selected from: Inhaler.

15. A method for treating addiction, comprising: The use of an inhaler as claimed in any of the preceding claims. method.

16. 1. A method for treating withdrawal symptoms, comprising: The use of an inhaler as claimed in any of the preceding claims. method.

17. 1. A method of assisting a person in ceasing use of one of the following: a. smoking cigarettes; b. vaping nicotine; and c. chewing tobacco; By using an inhaler as claimed in any of the preceding claims, method.

18. 1. A smoke-free system comprising: a. a first formulation comprising an active ingredient; b. a second formulation; c. an aerosolizer; d. a mechanism for controlling the amount of the first formulation and the second formulation delivered to the aerosolizer; Including, wherein the mechanism comprises at least one pump, a durability system comprising a controller, a circuit board, and an energy storage element; No smoking system.

19. 20. The system of claim 18, further comprising: a cartridge removably attached to the durability system; The cartridge comprises: a. a first formulation container containing the first formulation; b. a second formulation container containing the second formulation; c. an aerosolizer; and d. a recirculation system to facilitate delivery of the first formulation and the second formulation, or some combination thereof, to the aerosolizer; Equipped with the durability system further comprises a mechanism for controlling the amount of the first formulation and the second formulation delivered to the aerosolizer; system.

20. A system according to any one of claims 18 to 19, the mechanism for controlling the amount of the first formulation and the second formulation delivered to the aerosolizer is contained entirely within the durability system of the smoke free system; and the first formulation and the second formulation are contained entirely within the cartridge and do not contact components of the durability system; system.

21. A system according to any one of claims 18 to 20, the mechanism for controlling the amount of the first formulation and the second formulation delivered to the aerosolizer is a pump. system.

22. 22. A system according to claim 21, comprising: The pump is a positive displacement pump. system.

23. A system according to any one of claims 18 to 22, comprising: a recirculation system that facilitates transport of the first formulation and the second formulation to the aerosolizer and is contained entirely within the cartridge. system.

24. 24. A system according to claim 23, comprising: The recirculation system comprises: a. a first formulation container containing the first formulation; b. a second formulation container containing the second formulation; c. blending the first formulation and the second formulation into a mixed formulation; d. Air bubbler element; e. an aerosolizer; and f. Means for permitting fluid flow to, through and between the elements of said recirculation system; Including, system.

25. 25. A system according to claim 24, comprising: The method of combining the first formulation and the second formulation is a connected central tube that transports the formulation to the aerosolizer. system.

26. 25. A system according to claim 24, comprising: The bubbler element comprises: a. a housing having small channels that allow liquid to flow through the bubbler element; b. a hydrophobic porous material; and c. and a pathway through said housing exposing said liquid to said hydrophobic porous material; Equipped with system.

27. 27. A system according to claim 26, comprising: The hydrophobic porous material is sintered PTFE. system.

28. 20. The system of claim 18, further comprising: The aerosolizer is a substrate having an array of holes, with piezos bonded to one or both sides of the substrate. system.

29. 25. A system according to claim 24, comprising: the means for allowing fluid to flow to, through and between elements of the recirculation system is a biocompatible tube; system.

30. 25. A system according to claim 24, comprising: Further comprising a sterilizing filter as an element of the recirculation system. system.

31. 31. A system according to claim 30, comprising: The sterilizing filter is disposed upstream of the aerosolizer; All formulations exposed to the aerosolizer, whether mixed or not, flow through the sterilizing filter before reaching the aerosolizer. system.

32. A system according to any one of claims 18 to 31, the first formulation is an aqueous formulation comprising nicotine free base or a pharma- ceutically acceptable salt thereof; and the second formulation is free of an active ingredient. system.

33. A system according to any one of claims 18 to 31, The first formulation is an ethanol formulation comprising nicotine free base or a pharma- ceutically acceptable salt thereof; and the second formulation is free of an active ingredient. system.

34. A system according to any one of claims 32 to 33, comprising: wherein the form of nicotine is nicotine bitartrate; system.

35. 20. The system of claim 18, further comprising: Where: a. the first formulation is contained within a first formulation container having at least one flexible wall; b. the second formulation is contained within a second formulation chamber having at least one flexible wall; c. the flexible wall is at least one of the following: i. a polyethylene layer; ii. a nylon layer; iii. an aluminum layer; and iv. a layer of mylar or aluminized mylar; Contains; system.

36. 36. A system according to claim 35, comprising: the structure of the first formulation chamber and the second formulation chamber is completely flexible; system.

37. 25. A system according to claim 24, comprising: further comprising at least one valve as part of the recirculation system. system.

38. 38. A system according to claim 37, comprising: The at least one valve may be arranged to completely or partially restrict flow from one or both formulation chambers to achieve the appropriate concentration of active ingredient in the mixed formulation. system.

39. A system according to any one of claims 18 to 38, comprising: wherein controlling the amount of the first formulation and the second formulation delivered includes at least one of the following: a. decreasing the amount of the first formulation delivered; b. Increasing the amount of the second formulation delivered; and c. essentially simultaneously decreasing the amount of said first formulation delivered and increasing the amount of said second formulation delivered; Including, wherein the total volume of the mixed formulation delivered remains essentially constant, system.

40. A system according to any one of claims 18 to 39, comprising: wherein control of the amount of the first formulation and the second formulation delivered is at least in part determined by one or more of the following: a. Number of puffs; b. The number of administration events; c. the number of days the system will be used; d. puff duration; e. smoking history; and f. a predetermined reduction rate; Based on system.

41. 25. A system according to claim 24, comprising: further comprising a means for regulating the concentration of nicotine delivered as an aerosol; The means includes a formulation chamber, a pump, a valve, a computing system, and a mobile application; system.

42. 25. A system according to claim 24, comprising: wherein the nicotine concentration of the mixed formulation is adjusted by adjusting the valve(s). system.

43. A system according to any one of claims 41 to 42, comprising: wherein the initial nicotine concentration is determined by a series of active inputs by a user to the mobile application to ascertain a measure of the user's level of nicotine dependence and passive inputs learned from a device monitoring the user's device usage, thereby determining the starting concentration required to manage the dependence. system.

44. A system according to any one of claims 41 to 43, comprising: the concentration of nicotine in the mixed formulation delivered to the user is gradually reduced by proportionally reducing the flow rate of a nicotine-containing formulation, while increasing the flow rate of a non-nicotine-containing formulation, such that the total volume of formulation delivered remains constant; system.

45. 45. A system according to claim 44, comprising: wherein the adjustment of the nicotine formulation concentration occurs automatically by means of said computing system. system.

46. A system according to any one of claims 44 to 45, comprising: the computing system executes an algorithm that utilizes as inputs the initial nicotine concentration and the length of the quit attempt time, and determines and implements a gradual reduction in the concentration of the nicotine formulation over that time period; wherein the nicotine formulation concentration corresponding to the end of the period is zero; and The algorithm may adjust both the nicotine concentration or duration in response to monitoring of the user's device usage; system.

47. A system according to any one of claims 44 to 46, comprising: The computing system predetermines and assigns an appropriate nicotine concentration for each day; Further wherein the actual nicotine concentration is calculated from a ratio of past pulses of the nicotine-containing formulation to the non-nicotine-containing formulation; and These concentrations are compared to determine the next action of the pumping system; system.

48. 48. A system according to claim 47, comprising: The next operation of the pumping system is to pump either nicotine or a non-nicotine containing formulation to equilibrate the actual nicotine concentration with the predetermined nicotine concentration. system.

49. A system according to any one of claims 44 to 48, comprising: The algorithm executes upon completion of every administration event. system.

50. A system according to any one of claims 44 to 49, comprising: The algorithm runs at the completion of every puff. system.

51. 13. A method for quitting smoking comprising the use of a system according to any preceding claim.

52. An inhalation device comprising an inhalation device of a system according to any of the preceding claims.

53. 10. A formulation comprising a mixed first and second formulation according to any of the preceding claims.

54. 13. A method of making an aerosol comprising an aerosolization system according to any of the preceding claims.

55. 13. A method or an aerosolization system according to any one of the preceding claims, comprising: the cartridge includes an airway through which the user inhales; and The airflow through the air passage flows in a direction substantially perpendicular to the average direction of aerosol generation of the plurality of nozzle holes. Method or aerosolization system.

56. 1. A smoke-free system comprising: a. a first formulation comprising an active ingredient; b. a second formulation; c. an aerosolizer; d. a mechanism for controlling the amount of the first formulation and the second formulation delivered to the aerosolizer; wherein said mechanism comprises at least one microfluidic pump; and e. a housing containing the controller, the circuit board, and the energy storage element; Including, No smoking system.

57. 57. A system as claimed in claim 56, comprising: a cartridge removably attached to the housing; The cartridge has a sealed container including a first formulation chamber containing the first formulation and a second formulation chamber containing the second formulation. system.

58. 58. A system according to claim 57, comprising: The active ingredient comprises nicotine free base or a pharma- ceutically acceptable salt thereof. system.

59. A system as claimed in any preceding claim, comprising: said first formulation being an aqueous formulation, the active ingredient of which is a salt form of nicotine, and said second formulation consisting of water; system.

60. A system according to any one of claims 58 to 59, comprising: The nicotine is nicotine bitartrate. system.

61. A system according to any one of claims 56 to 60, comprising: The first formulation is an ethanol formulation containing USP nicotine, and the second formulation contains ethanol. system.

62. A system according to any one of claims 56 to 61, comprising: The second formulation does not contain an active ingredient; system.

63. A system according to any one of claims 56 to 62, comprising: wherein the control includes one or more of the following: decreasing the amount of said first formulation delivered; increasing the amount of said second formulation delivered; and essentially simultaneously decreasing the amount of said first formulation delivered and increasing the amount of said second formulation delivered; Including, system.

64. A system according to any one of claims 56 to 63, comprising: The sealed container surrounds at least one container; and The at least one container has a flexible wall. system.

65. A system according to any one of claims 57 to 64, comprising: the container further comprises a pierceable septum; a non-coring needle extends out of the durability system; and the needle is configured to pierce the septum when the cartridge is installed in the durability system. system.

66. A system according to any one of claims 64 to 65, comprising: the flexible wall is a multi-layer laminate; and At least one of the layers comprises at least one of the following: a. polyethylene; b. Nylon; c. Mylar or aluminized Mylar; and d. Aluminum; Including, system.

67. A system according to any one of claims 56 to 66, comprising: The overall structure of the container is flexible; system.

68. A system according to any one of claims 56 to 67, comprising: wherein control is at least in part determined by one or more of the following: a. Number of puffs; b. The number of administration events; c. smoking history; d. puff duration; and e. a predetermined reduction rate; Based on system.

69. A system according to any one of claims 56 to 68, comprising: The mechanism comprises a first pump that pumps the first formulation into an element selected from: a. a chamber; b. a flow path; c. a wicking element; and / or d. a wicking element within the chamber or flow channel; wherein a second pump pumps said second formulation into the same element; and The first formulation and the second formulation are mixed within the element. system.

70. A system according to any one of claims 56 to 69, comprising: The system further comprises an aerosolization device; The aerosolization device comprises: a. a substrate having an array of holes; b. a piezo, one side of which is rigidly attached to said substrate and the other side of which is attached to said housing; and c. a wicking element in contact with a first surface of the array of holes; Equipped with system.

71. A system according to any one of claims 56 to 70, comprising: each reservoir within the enclosure of the cartridge is characterized by a connection point that allows liquid to flow from the cartridge into the durability system; system.

72. 72. A system according to claim 71, comprising: the connection point is characterized by a hollow needle on the durability system of the device that pierces a septum on a corresponding container; The hollow needle comprises: a. a spring spirally wound around said needle; and b. a silicone plug attached to the top of the spring and movable along the needle; Further characterized by: system.

73. 73. A system according to claim 72, comprising: The silicone plug is placed over the top of the hollow needle in its uncompressed, resting position to prevent air ingress or contamination. system.

74. A system according to any one of claims 72 to 73, comprising: When the cartridge is installed into the durable system, the silicone plug contacts the septum on the container, the spring is compressed, and the silicone plug slides down the length of the hollow needle, causing the hollow needle to protrude through the silicone plug and pierce the septum. system.

75. A system according to any one of claims 72 to 74, comprising: When the cartridge is removed from the durability system of the device, the spring is decompressed and the silicone plug returns to its natural rest position covering the top of the hollow needle. system.

76. A system according to any one of claims 56 to 75, comprising: wherein a first microfluidic pump delivers a nicotine-containing formulation to a mixing chamber, and a second microfluidic pump delivers a non-nicotine-containing formulation to said mixing chamber; system.

77. 77. A system as claimed in claim 76, comprising: the two microfluidic pumps are controlled by a controller system; where each microfluidic pump can have an independent flow rate different from the other; system.

78. A system according to any one of claims 59 to 77, comprising: Here, one microfluidic pump is connected to two flow paths, The flow path is connected to two formulation chambers; The microfluidic pump pumps both the active nicotine-containing formulation and the non-nicotine-containing formulation into the mixing chamber. system.

79. A system according to any one of claims 76 to 78, comprising: The mixing chamber is a formulation chamber in direct fluid contact with the aerosolizer. system.

80. 80. A system as claimed in claim 79, comprising: wherein one valve is used to determine which formulation chamber the microfluidic pump will pump from. system.

81. 80. A system as claimed in claim 79, comprising: wherein two valves, one for each formulation, are used to determine which formulation the microfluidic pump will pump; system.

82. A system according to any one of claims 80 to 81, comprising: The valve(s) may partially or completely obstruct the flow path to the formulation chamber to determine proper mixing of the formulation; system.

83. A system according to any one of claims 80 to 82, comprising: the valve is controlled by the device's circuitry located within the device housing; system.

84. A system according to any one of claims 69 to 83, comprising: The mixing chamber comprises a piezoelectric actuator as a mixing element. system.

85. A system according to any one of claims 69 to 84, comprising: The mixing chamber comprises a mixing element that is not characterized as a piezoelectric actuator. system.

86. A system according to any one of claims 56 to 85, comprising: the aerosolizer generates and breaks a fluid jet with each oscillation of the piezoelectric actuator to generate aerosol droplets. system.

87. A system according to any one of claims 69 to 86, comprising: the liquid formulation from the mixing chamber is delivered to the aerosolizer by a wicking material in fluid contact with both the mixing chamber or a fluid path extending from the mixing chamber and a first surface of the aerosolizer. system.

88. A system according to any one of claims 69 to 87, comprising: The liquid formulation from the mixing chamber is delivered to the aerosolizer or the wicking material by a third microfluidic pump. system.

89. A system according to any one of claims 69 to 88, comprising: the liquid formulation from the mixing chamber is delivered to the aerosolizer by a combination of a microfluidic pump and a wicking material; the microfluidic pump pumps liquid from the mixing chamber to the wicking material; and the wicking material is in constant contact with the first surface of the aerosolizer; system.

90. 1. A system for regulating the concentration of nicotine free base, or a pharma- ceutically acceptable salt thereof, delivered as an aerosol, comprising: Two microfluidic pumps, a mixing chamber, a computing system, and a mobile application Equipped with system.

91. 91. A system as claimed in claim 90, comprising: Wherein the nicotine concentration of the mixed formulation is adjusted by adjusting the flow rate of each microfluidic pump, system.

92. 1. A system for regulating the concentration of nicotine free base, or a pharma- ceutically acceptable salt thereof, delivered as an aerosol, comprising: A microfluidic pump, a mixing chamber, at least one valve, a computing system, and a mobile application Equipped with system.

93. 93. A system as claimed in claim 92, comprising: wherein the nicotine concentration of the mixed formulation is adjusted by adjusting the valve(s). system.

94. A system according to any one of claims 90 to 94, comprising: wherein the initial nicotine concentration is determined by a series of active inputs to the mobile application to ascertain a measure of the user's level of nicotine dependence and passive inputs learned from the device monitoring the user's device usage to determine the starting concentration required to manage that dependence. system.

95. A system according to any one of claims 90 to 95, comprising: the concentration of nicotine in the mixed formulation delivered to the user is gradually reduced by proportionally reducing the flow rate of a nicotine-containing formulation, while increasing the flow rate of a non-nicotine-containing formulation, such that the total volume of formulation delivered remains constant; system.

96. 96. A system as claimed in claim 95, comprising: wherein the adjustment of the nicotine formulation concentration occurs automatically by means of said computing system. system.

97. A system according to any one of claims 95 to 96, comprising: the computing system executes an algorithm that utilizes as inputs the initial nicotine concentration and the length of the quit attempt time, and determines and implements a gradual reduction in the concentration of the nicotine formulation over that time period; wherein the nicotine formulation concentration corresponding to the end of the period is zero; Additionally, the algorithm may adjust both the nicotine formulation concentration or duration in response to monitoring of the user's device usage; system.

98. A system according to any one of claims 95 to 97, comprising: The computing system predetermines and assigns an appropriate nicotine concentration for each day; Further wherein the actual nicotine concentration is calculated from a ratio of past pulses of the nicotine-containing formulation to the non-nicotine-containing formulation; and These concentrations are compared to determine the next action of the pumping system; system.

99. 99. A system as claimed in claim 98, comprising: The next operation of the pumping system is to pump either nicotine or a non-nicotine containing formulation to equilibrate the actual nicotine concentration with the predetermined nicotine concentration. system.

100. A system according to any one of claims 97 to 98, comprising: The algorithm executes upon completion of every administration event. system.

101. A system according to any one of claims 97 to 99, comprising: The algorithm runs at the completion of every puff. system.

Images