METHODS FOR INHALATION OF SMOKE-FREE NICOTINE

Abstract

The invention relates generally to a system or kit that delivers nicotine to target the regions of the respiratory tract to achieve the maximum impact on craving with a minimum number of unwanted sensations. More specifically, the invention relates to pulmonary administration of nicotine from nicotine inhalation systems that target delivery to the deep lung, minimizing deposition in the upper and central airways.

Description

FIELD OF THE INVENTION

The invention relates generally to inhalation systems that provide tobacco users (smokers, users of chewing tobacco, tobacco oral pouches and so on) with an aerosol bolus of nicotine that is directed to specific parts of the respiratory tract to enhance the desired features of the product designed for a specific group of users, or for an individual. More specifically, the invention provides inhalers and containers of nicotine which can deliver nicotine aerosols to reduce the potential for excessive airway irritation while providing the other desirable effects of nicotine such as rapid reduction of craving for cigarettes and for other tobacco products for smoking such as pipes, cigars, little cigars, as well as non-smoking forms of tobacco such as tobacco snuff and chewing tobacco and so on.

BACKGROUND

Nicotine is the principal, pharmacologically active component of tobacco. The users of tobacco products use them primarily for the experience they receive from nicotine, either in the form of tobacco smoke, or chewing tobacco, or oral tobacco pouches. The tobacco-smoke free inhalers such as electronic cigarettes also are marketed to provide the key nicotine experience. It is challenging to be successful to achieve that goal of satisfactory experience for the broad range of users. While other aspects of the use of the product are also important, such as flavor/taste and smell and the nature of the inhaler, to be well accepted, it is important that the use of the product is tolerable and it does not provoke unacceptable levels of airway irritation. Some degree of irritation, however, is not merely acceptable to some smokers but they may miss it when they try to switch from cigarettes to a smoke-free form of nicotine.

The human respiratory tract consists of upper airways—oral and nasal cavities, central or conducting airways including the trachea and the bronchial tree, and the alveolar region in which the gas exchange takes place. The latter region has very a very large surface area that is also very permeable to nicotine. If nicotine containing droplets are delivered to this region of the respiratory tract, nicotine is absorbed very rapidly into the blood stream and causes an almost instantaneous effect in the brain.

This effect causes very rapid and sustained reduction of craving for cigarettes (Gonda, I. et al. 2009 Smoking Cessation Approach via Deep Lung Delivery of ‘Clean’ Nicotine, In: Respiratory Drug Delivery, Europe, 2009, eds. PR Byron et al., pp. 57-62).

Nicotine can be delivered by a variety of methods suitable for inhalation as a vapor, or in nicotine particles that are liquid, solid or semi-solid: for example, in the form of tobacco smoke from cigarettes, cigars and pipes, by generation of liquid mists containing nicotine or its salts dissolved or dispersed in water and other solvents and carriers such as propellants, or using other devices (such as dry powder inhalers, evaporation-condensation aerosol generation) that may form particles containing nicotine, or a mixture of nicotine vapor and particles containing nicotine.

Inhaling nicotine may elicit a variety of sensory effects depending on the properties of the system that generates the inhalable form of nicotine, typically a dispersion of solid or liquid particles in a gas, i.e., an aerosol, the composition of the aerosol containing the nicotine, as well as the mode of breathing the person is using to inhale the nicotine aerosol. The smaller particles containing nicotine (for example, from cigarette smoke) when inhaled deeply deposit in the distal parts of the respiratory tract—bronchioli and alveoli, where nicotine is rapidly absorbed through the arteries and delivered to the brain. On the other hand, bigger particles and shallow breathing (e.g., from pipes or cigars), as well as inhalation from some of the nicotine vapor inhalers, results in buccal and upper respiratory deposition that leads to slower absorption into the body and into the brain (Hukkanen et al., Pharmacol Rev 57:79-115, 2005), and can lead to cough or other unpleasant side effects.

Attempts at satisfying smokers used to cigarette smoke with inhaled pure nicotine have not been successful when the particle size and the mode of inhalation did not match the smokers' preferred experience. For example, Burch et al. (Amer Rev. Resp. Dis. 1989, 140:955-957) used a large droplet aerosol (aerodynamic diameter ˜4 micrometers) of a high pH (˜10) aqueous formulation. Although this form of nicotine reached similar nicotine blood levels to cigarettes over a comparable time course, a significant number of the smokers dropped out from the study due to excessive airway irritation and most of the users reported cough. The authors suggested that this was probably related to the combination of upper airway deposition and possibly also the high pH.

An “aerosol bolus” is generally defined as a small volume of gas, typically air, in which the nicotine formulation is dispersed. Such a bolus can be inhaled at different parts of the respiratory cycle. However, when such a bolus is inhaled at the beginning of the inspiration and the remainder of the inspiration is completed with a gas that does not contain the aerosol, then the “bolus” can deposit the nicotine almost entirely in the alveolar regions and the remainder of the respiratory tract (upper and central airways) are filled with gas not containing nicotine. Therefore, selective delivery of nicotine to the alveolar spaces can be achieved, especially if the particles containing nicotine are small and the inspiratory flow rate is low to avoid inertial impaction in upper and central airways. However, if the inhalation rate is too slow, the aerosol particles may deposit by sedimentation and diffusion. Furthermore, droplets containing nicotine may shrink or grow depending on the vapor pressure and even solid particles containing nicotine can take up water in the humid environment in the lung. Therefore, to achieve selective deposition in various parts of the respiratory tract to elicit the most desirable sensory effects in a smoker, it is necessary to design nicotine inhalation systems that can vary the composition of the nicotine formulation, the particle size of the nicotine aerosol, the inspiratory flow rate and the position of the aerosol bolus during the inspiration.

The nicotine inhalation system can therefore consist of containers and inhalers, or inhalers that contain the nicotine formulation, that are intended to deliver a bolus of nicotine-containing aerosol, for example, to the distal lung. This is accomplished by 1. creating small aerosol droplets or particles containing nicotine, e.g., particles primarily between 1-4 microns in size, 2. using the aerosol bolus volume of less than 1 L, and ideally <500 mL, 3. delivering the aerosol bolus early in the inspiration so that the majority of the aerosol reaches the distal airways, and 4. inhaling at an inspiratory flow rate that minimizes the deposition of the nicotine carrying particles or droplets in the upper and conducting airways. This inhalation flow rate depends on the particle aerodynamic size which can also vary as a result of condensation and evaporation. Aerodynamic size depends on the actual physical size of the particle (length, width, thickness, radius), shape and density.

If a smoker at the beginning of the smoking quitting process desires to have a feeling of irritation at the back of the mouth, or would like to feel some of the same airway irritation she or he had while using a product that produces tobacco smoke, such as cigarettes, cigars or pipes, then the deposition in these parts of the respiratory tract can be increased to enhance the desirable sensory effects. In this case, the use of larger droplet sizes and higher inspiratory flow rates would be used to achieve “throat” deposition, and using larger volumes of aerosol to fill more of the airways to provide the airway sensation would be desirable. However, to elicit rapidly the desirable effects of nicotine in the brain, small particles that have a high likelihood to enter the small airways and alveoli should be used as well. For smokers accustomed to shallow breathing typical of, e.g., puffing from a pipe or more typical among cigar smokers, the nicotine-containing aerosol can be delivered from the inhaler in a small bolus delivered during such a shallow inhalation, producing slower rise in nicotine blood levels and lower peaks (Hukkanen et al., Pharmacol Rev 57:79-115, 2005). The concentration of nicotine in the formulation and the amount (volume or weight) of the formulation can be varied such as to provide an appropriate dose to the user to elicit the desired satisfaction of craving without excessive irritation. For example, the volume of the liquid formulation can range from 1 to 100 microliters and the concentration of the nicotine in the formulation can range from 100% down to about 1 mg/mL of nicotine, giving doses of nicotine in the range from about 0.05 to 1.5 mg of nicotine per inhalation, preferably from 0.1 to 1 mg.

This invention therefore enables accomplishment of a variety of sensory effects for smokers who would like to use a smoke-free nicotine inhaler instead of tobacco products that deliver nicotine via inhalation of tobacco smoke. For users of smokeless tobacco such as snuff, tobacco pouches and chewing tobacco, the inhaler provides an alternative of using pure, pharmaceutical grade nicotine rather than the mixture of a variety of chemicals found in tobacco, some of them known to be toxic. A suitable inhalation system consists of an inhaler filled with a supply of nicotine, or a combination of an inhaler with a supply of refills containing nicotine formulations. Such a product can be designed to provide the users with a selection of a particular combination of inspiratory flow rate and actuation of the nicotine aerosol delivery at a particular portion of the inspiration. They may be also able to select the particle size and the dose they inhale. The dose can be controlled by varying the concentration of nicotine in the formulation and the amount of formulation they inhale. They can inhale the whole dose in a single inspiration, or they can divide it into multiple puffs. The sensory effect in the brain and in the respiratory tract can be also modulated by the pH of the formulation, the rate of release of nicotine from the formulation and by having additives such as flavors, scents and substances that can increase or decrease the rate of absorption of nicotine as well as increase or decrease the feeling of irritation in the airways. For example, it is known that hyperosmotic formulations where the osmotic agent can be substances such as sodium chloride or mannitol, or cough inducing substances such as citric acid, can be added to the formulation to achieve the desirable sensations.

Nicotine delivery via inhalation in the form preferred by the user offers the benefits of addressing the many psychological components of cigarette, cigar, and pipe smoking, as well as the use of so-called electronic cigarettes and other nicotine delivery devices and products that the user may to wish to replace for a product that better addresses their needs. Some nicotine inhalation systems release nicotine as a vapor (see U.S. Pat. Nos. 5,167,242; 5,400,808; 5,501,236; 4,800,903; 4,284,089; 4,917,120; 4,793,366), aerosol (see U.S. Pat. Nos. 5,894,841; 5,834,011) or dry powder (see U.S. Pat. No. 5,746,227) when air is inhaled through the inhaler. A droplet ejection device (U.S. Pat. No. 5,894,841) has also been described that delivers a controlled dose of nicotine via inhalation. These systems deliver low doses of nicotine to the mouth and throat, where nicotine is absorbed through the mucosal membranes into the circulation. Some nicotine inhalation systems feature devices that simulate or approximate the look, feel and taste of cigarettes. However, none of such inhalation systems possess the features that would be able to satisfy the wide range of individual sensory perception needs that satisfy each smoker, and each smoker at every occasion when they wish to use nicotine. It is therefore also attractive to provide the user with an alternative system or product in the form of a purified nicotine that does not contain the many toxic substances contained in tobacco. Further, ideally this purity is retained throughout the manufacture, storage and use of the product by having a nicotine formulation that is stable. It is generally undesirable for the nicotine to be accidentally inhaled by people other than the user, and therefore the inhaler is preferably designed to minimize such inadvertent exposure (“second hand smoking”).

SUMMARY

The invention in general includes various elements that alone, or in combination with each other, can cause one or more sensory effects when a subject (user of the nicotine inhaler) is inhaling from a device that produces a smoke free aerosol containing nicotine. The invention includes systems and methods for delivering a specified volume of nicotine containing aerosol per breath—an aerosol bolus or a series of aerosol boluses—to satisfy the craving for nicotine while reducing the side effects such as bad taste and airway irritation associated with products that deliver nicotine primarily to the upper and central airways—nasal cavity, oropharyngeal cavity, trachea and the bronchial tree. The invention provides a device, system and method that allows for adjustments in delivery parameters and formulation quantity and quality that result in sensations that some users may find undesirable or unpleasant, and yet other users, or even the same users on other occasions, find desirable in a nicotine inhaler. Methods of the invention are typically carried out using a system that includes an inhaler containing a reservoir of formulation containing purified nicotine, or an inhaler that is using a plurality of groups of containers which contain nicotine or nicotine formulations for inhalation wherein the containers are designed for use with the inhalers and include different amounts of nicotine in the different groups of containers.

Preferably, the nicotine is of pharmaceutical grade, i.e., of high purity minimizing the potential of delivery of many toxic substances that are contained in tobacco. It is also desirable that the nicotine formulation is stable during manufacture, storage and use so that the high purity of nicotine is retained to minimize potential harmful effects for the user. It is also desirable that the use of the nicotine inhaler does not inadvertently expose other people than the user to the nicotine contained in the inhaler, i.e., that the inhaler is unlikely to cause “second hand smoking”.

An aspect of the invention is a nicotine inhaler comprised of a container, a mouthpiece, an input port, a valve, a flow rate monitor and a programmable control component. The container holds a formulation which can be aerosolized wherein the formulation comprises a pharmaceutically acceptable carrier and smoke-free nicotine. The mouthpiece is connected to the inhaler in a manner such that the aerosolized nicotine formulation can be inhaled by the user. The input port is a port through which air can be drawn from the surrounding area into a user's lungs. The valve is positioned between the input port and mouthpiece to allow regulation of air flow to the mouthpiece. The inhaler may also have a flow rate monitor positioned between the input port and the valve, and measures the flow rate and may thereby calculate the volume of air passing the monitor. The programmable control component is connected to and receives information from both the flow rate monitor and the valve. The programmable control component sends signals which allow for inhaled flow volume to be set by a user in an individualized manner based on the particular needs of the user.

It is also possible to design the nicotine inhaler with fixed values of the inspiratory flow rate and fixed value of the aerosol-free air inhaled by the user prior to the delivery of the aerosol bolus containing the nicotine formulation. For example, the device can have a valve whose opening needs to be triggered by the user. Once the valve opens, a rate-controlling element in the valve prevents the user from inhaling at an inspiratory rate exceeding the desired inspiratory flow rate. Furthermore, the generation of the aerosol bolus can be delayed mechanically through a “latency” built into the system so that the user first inhales a volume of air free of any nicotine aerosol followed by a bolus of aerosol containing the nicotine formulation. An example of such a latency design is the use of a moving piston that exerts pressure on a container that is filled with a liquid formulation of nicotine. This formulation is extruded through a nozzle containing a multiplicity of holes to form an aerosol of a desired droplet size. The volume of the aerosol bolus is predetermined by the combination of the volume of the formulation in the nicotine container, the rate at which this volume is extruded through the nozzle to be converted into the nicotine containing aerosol and the inspiratory flow rate.

The volume of gas (typically air) entering a user's respiratory tract can be set with respect to two or three different stages of an inhalation dosing event. By an inhalation dosing event, we mean a single breath during which a satisfactory dose of nicotine is delivered. Alternatively, the satisfactory dose is achieved in a small number of breaths, spaced by short periods, preferably less than 2 minutes. The placement of the bolus of the aerosolized nicotine formulation within a breath is then selected to achieve the desirable effect to satisfy the craving for nicotine without undue undesirable sensations. For example, the inhaler is designed such that the user starts inhaling and initially inhales a volume of air within a range of 0% to about 25% (or 5% to 20%) of the user's total inhaled volume. The user continues breathing and in a second stage, the volume of air is within a range of from about 50% to 100% (or 60% to 80%) of the user's total inhaled volume. This second volume contains the aerosolized nicotine formulation. The third stage is designed to be within a range of 0% to 25% (or 5% to 20%) of the total inhaled volume. Using these volumes and the aerodynamic size of the nicotine containing particles around 3 microns+/−50% and low inspiratory flow rates in the range of 10-60 L/min, and preferably no higher than 30 L/min (the rates to be lower for bigger particle size), the above described volumes will result in preferential delivery of the nicotine dose to the alveoli and small airways. It is well known (G. Taylor, The absorption and metabolism of xenobiotics in the lung, Advanced Drug Delivery Reviews, 1990 Vol. 5, pp. 37-61) that these parts of the respiratory tract have very high surface area and are highly permeable which then results in very rapid absorption of nicotine into the blood stream from which it is very rapidly moving into the brain. The control of these volumes can be achieved by a variety of methods. For example, US patents Johansson et al. U.S. Pat. No. 5,392,768, Ritson et al. U.S. Pat. No. 5,394,866 and Goodman et al. U.S. Pat. No. 5,404,871 disclose programmable inhalers that deliver a specified amount of aerosolized formulation at the preset points in the inhalation. The rate of delivery of the nicotine can be controlled by varying the rate of extrusion of the liquid formulation from the container. The delivery can be also stopped at a pre-set time or a pre-set value of inhaled volume.

Another example of a method of controlling the placement of the bolus of air containing nicotine particles during an inhalation (i.e., during a single inspiratory breathing maneuver) is using a container with a liquid formulation whereby the liquid formulation is extruded through a porous membrane by applying pressure to the liquid container. For preferential deep lung delivery, the start of the extrusion of the formulation should commence as early as possible from the moment the user starts inhaling. This can be accomplished, e.g., by using a valve in the device that opens when the user actuates the device. The actuation simultaneously opens the valve and commences the extrusion of the liquid, using, e.g., a piston powered by a compressed spring. This device was used in a study with a nicotine inhaler in smokers (Gonda, I. et al. 2009 Smoking Cessation Approach via Deep Lung Delivery of ‘Clean’ Nicotine, In: Respiratory Drug Delivery, Europe, 2009, eds. PR Byron et al., pp. 57-62). The duration of the extrusion of the desired amount of formulation needs to be designed in such a way that it will be completed before the user fills their respiratory tract completely with air. Ideally for preferential delivery of nicotine into the deep lung to get the best satisfaction of craving for cigarettes smokers and to minimize the irritation in the mouth and the airways, the last volume of clean air following the inhalation of the aerosolized formulation should be large enough to fill both the upper and central (conducting) airways, i.e., it “pushes” the aerosolized nicotine formulation into the lung periphery (alveolar region), It is possible to use an inhaler device of the invention in order to measure the user's total lung volume and use that information in connection with the programmable control component to provide for the user individualized delivery of smoke and tobacco free nicotine. It is also possible to estimate each user's total lung volume. The lung volume can be estimated by first determining the user's lean body weight in pounds and relating that number to milliliters of lung volume. The anatomical “dead volume” (i.e., the part of the lung in which gas exchange is absent and which represents the conducting airways) in a person breathing at rest can be estimated to be approximately equal, in milliliters, to the lean body weight of the person in pounds. For preferential deep lung delivery, the last volume of air that follows the air that was filled with the aerosolized nicotine formulation, should be at least equal to this “dead volume”.

In one embodiment of the invention the programmable control component is replaced with an adjustment control component which is connected to the valve. The adjustment control component is adjusted manually or electronically in order to allow inhaled flow volume to be set by the user in the three stages of an inhalation event described above. For example, for preferential delivery of nicotine into the deep lungs (alveolar region), the first volume is about 0.1% to 15% of a total inhaled lung volume, a second stage comprising aerosolized formulation is within a range of 10% to 90% of the total inhaled lung volume, and a third stage comprising particle free air which is at least 10% of the total inhaled lung volume.

The nicotine inhaler device may include a flow rate monitor in the form of a propeller or in the form of a flow transducer.

An aspect of the invention is a method which comprises three steps. Most inhalation devices will have some degree of latency, meaning that the user begins to inhale first aerosol-free air. For deep lung delivery, this volume—the first step—should be small. In the second step, the aerosolisation of the smoke free nicotine formulation, containing preferably 0.1-1 mg of nicotine, proceeds; the aerosol is substantially comprised of droplets having an aerodynamic diameter of about 3 microns±50%. The aerosolized formulation is inhaled with a volume of air (containing aerosol) of about 1000 ml (or less, preferably no more than 20% of the total volume of air inhaled). In the third step, the user inhales additional air which is free of a nicotine-containing aerosol; this additional air fills the conducting and upper airways.

The method may be carried out wherein the aerosol comprises 0.1 to 1 mg of nicotine and wherein the formulation is aerosolized in a period of time of 1 second or less and further wherein the inhalation of air which is free of aerosolized formulation continues until the user completes the inhalation. This third volume should be equal to or exceed the “dead volume” of the lung (˜100-200 mL), and preferably at least 10% of the total volume inhaled.

The invention can be designed in the form of a kit and the kit can include a single inhaler or multiple inhalers. In general the system will be a kit which includes a single inhaler and multiple containers which are designed specifically to fit within the inhaler so that the contents of the containers in the form of tobacco free nicotine can be aerosolized into smoke free particles which have a diameter of about 3 microns±50%. Still smaller particles may be used but if their aerodynamic diameter is less than about 1 micron, then the user would be advised to hold their breath for the maximum deposition in the deep lung.

The system via the inhaler allows the user to inhale a first volume of inhaled air free of nicotine aerosol as a first volume, followed in the same breath by a second volume of air in which the nicotine aerosol is dispersed, and followed by a third volume of inhaled air free of aerosolized nicotine in the same breath as the first and second volumes. The system can be arranged such that the first volume is in a range of 0 to 500 ml (or 50 ml to 400 ml), the second volume is in a range of 500 to 3000 ml (or 1000 ml to 2600 ml) and the third volume is in a range of 0 to 500 ml (or 50 ml to 400 ml).

One form of this invention relates to the previously described nicotine inhaler (i.e., AERX Essence), which is an example of a “soft mist inhaler”, that satisfies the craving for cigarettes by delivery of a suitable single dose of nicotine in a single inhalation, rather than multiple puffs that would emulate smoking a cigarette (Gonda, I. et al. 2009 Smoking Cessation Approach via Deep Lung Delivery of ‘Clean’ Nicotine, In: Respiratory Drug Delivery, Europe, 2009, eds. PR Byron et al., pp. 57-62). Although the current invention is not limited to such a particular inhalation device, a single bolus inhalation may provide either a dose of nicotine equivalent to that contained in an entire cigarette or a more complex formulation that provides both a rapid- and sustained release of nicotine. Smoking a cigarette can provide a large dose of nicotine (approximately 1 mg) to the smoker during a short period of time of 1 to a few minutes. The bolus nicotine system described in this invention can deliver a comparable dose of nicotine in a single bolus inhalation that avoids deposition in the upper and central airways to improve the tolerability by reducing airway irritation and avoid bad taste sensation while at the same time satisfying the craving for cigarettes. The bolus nicotine system can also deliver a higher or a lower dose, depending on the concentration of the nicotine in the formulation and the volume of the formulation that is transformed into aerosol. By changing the droplets size, or by changing the volume of inhaled air that contains the nicotine aerosol, or by changing the inspiratory flow rate, or the place during the inspiration where the nicotine aerosol is delivered, it is possible by using one aspect, or multiple aspects of this invention, to deposit the nicotine in various parts of the respiratory tract, predominantly in one location, or more evenly spread over multiple parts of the respiratory tract. These different deposition patterns according to this invention are used to cause a variety of sensations. The rate of entry into the brain is also affected by these methods.

The inhaler may also use a multiple dose container with liquid formulation of nicotine in another type of “soft mist inhaler”, such as Respimat developed by the company Boehringer-Ingelheim.

The present invention can be used in combination with a steady state delivery system (e.g. gum or patch or chewing tobacco) in order to satisfy the short term and long term needs of the user, respectively.

A preferred system of the invention aerosolizes liquid nicotine formulation by applying force to a container of nicotine formulation and causing the nicotine formulation to be moved through a porous membrane which results in creating particles of nicotine formulation which are inhaled by the user. Such a system is referred to here as a unit dose solution aerosolizer. Examples are described in U.S. Pat. No. 5,544,646. The source of the force, or the energy, that causes the aerosolization, could be a compressed spring, compressed or liquefied gas, electric battery and others known in the art.

Dry powder inhalers containing nicotine formulations can also be used. Using the dry powder inhaler technology, the packets of dry powder nicotine formulation loaded into the device can contain different amounts, preferably 0.1 to 1 mg of nicotine per dose, or different concentrations of nicotine, can be made in different particle sizes and may contain formulations that modulate the rate of release and absorption of nicotine into the body following inhalation. They may also have pH-modulators and additives affecting taste, smell and color. The aerosolization of the nicotine powder formulation can be accomplished using the user's breathing as the energy source, or compressed gas, or a battery that drives an electric motor with a propeller or a source of vibrations that disperse the powder.

Evaporation-condensation nicotine inhalers were described for example by Alexza Corporation and by Chrysalis. Nicotine aerosol formed by reaction of nicotine vapors with pyruvic acid was described by Rose et al. Additionally, the inhalers may be metered dose inhaler (MDI) devices.

Pressurized canisters conventionally used for MDIs can contain different concentrations of nicotine along with the propellant, different formulations with propellants to generate different droplet sizes, different flavors and scents. The size of the valve can be varied to provide different doses of nicotine. Nicotine in MDIs can be in liquid formulations of nicotine or its salts, nicotine salt and nicotine derivative dispersions as well as in formulations that affect the rate at which the nicotine enters the brain.

One embodiment of the invention involves the use of a system which aerosolizes liquid formulations of nicotine contained within individual packets which packets include a porous membrane. As indicated above the rate and amount of nicotine that can be absorbed is varied by changing the amount of, concentration of and/or pH of the nicotine in the packets. However, it is also possible to decrease the rate at which nicotine is delivered to the user's circulatory system by changing the size of the pores in the membrane. When the pore size is small then a relatively-high amount of the formulation aerosolized will reach the user's deep lungs and rapidly move from the lungs into the circulatory system. However, by making the pores larger the aerosolized particles created also become larger. The larger particles will not move into the deep lungs as efficiently as the smaller particles. For example, with oral inhalation at high to moderate inspiratory flow rates, a significant number of particles with aerodynamic size greater than 5 micron would deposit in the oropharynx from where they are not rapidly absorbed into the user's circulatory system.

The pH of the formulation can be set at any desired level which is not damaging to lung surfaces. Although it is desirable to have a low pH formulation (acidic) to avoid interaction with certain types of plastic containers, it may be more desirable for a current user of cigarettes to have a high pH formulation (basic) to increase the absorption rate of the nicotine from the lung into the circulatory system to emulate the nicotine experience from cigarette smoke. Such high pH may, however, also cause greater airway irritation to the user. It is the purpose of this invention to have extensive flexibility to combine various aspects of the invention to satisfy each user's individual preferences in terms of nicotine effects in the brain, such as satisfying the craving feelings, and at the same time to have the desirable airway sensation so as to avoid excessive irritation that would prevent some people from using the inhaler but have it present for those who prefer to have some degree of irritation in their airways when they inhale nicotine so as to emulate the effects of inhaling certain types of tobacco smoke as different types of tobacco and the products that generate the smoke (cigarettes, cigars, pipes etc.) will produce different sensations in the person who wants to switch to a pure smoke-free nicotine inhaler providing similar sensation. These differences in the nature of the tobacco, tobacco smoke and the mode of administration also affect the pharmacokinetics of nicotine (Hukkanen et al., Pharmacol Rev 57:79-115, 2005).

Adjustments in the pH can be carried out alone or in combination with adjustments in the concentration of nicotine in the formulation. Either or both of these parameters can be changed in combination with changing the particle size of the aerosol created to provide a different experience with each container in a sampling kit. A formulation with a higher concentration of nicotine, of course, provides more nicotine to the user for the same amount of formulation aerosolized. By increasing the particle size the particles will generally deposit higher up in the respiratory tract which slows the extent and the rate of absorption of the nicotine and leads to a reduction in peak nicotine plasma level. Still further, it is possible to vary all or any of these parameters in combination with a formulation which provides for a controlled release of the nicotine. Thus, for example, the nicotine can be encapsulated in some manner or included with an excipient which provides for a more controlled, slower release as compared to an immediate release formulation.

In one embodiment of the invention, there can be containers that are different from each other in that they contain different amounts of nicotine, concentrations and/or formulations with different pHs. Alternatively, each container is different from each other in that they have different porous membranes with particle size that leads to a deposition pattern in the body that in turn yields slower absorption and lower peak plasma levels of nicotine. It is possible to combine all or any of these features together. More specifically, it is possible to produce containers which contain (1) varying concentrations of nicotine; (2) varying amounts of nicotine formulations; (3) varying formulation pH; or (4) have porous membranes which have different size or amounts of pores so as to more or less efficiently aerosolize the formulation present in the container or that produce droplets or particles that deposit in a manner in which nicotine is absorbed less effectively in certain parts of the respiratory tract and at a lower or higher rate. By having different inhalers and different containers available, the user can select the combination which provides the most preferred combination of sensations when inhaling the nicotine aerosol.

The same dose of nicotine can be, for example put in different groups of containers in the form of different concentrations by adjusting the volume of the formulation to be aerosolized. For example 50 microliters of a nicotine formulation containing 10 mg of nicotine per mL can be aerosolized in 4 seconds which at 30 L per min (0.5 L/sec) inspiratory flow rate will be inhaled in 2 L of air provided the aerosol is delivered from the beginning of the inspiration and the aerosol generation is spread over the 4 seconds. In this example, the user would inhale 0.5 mg of nicotine dispersed in 2 L of air in 4 seconds. It is also possible to double the nicotine concentration in the formulation to 20 mg of nicotine per mL and use only 25 microliters of the formulation which could be delivered from the beginning of the inspiration in one second using again an inspiratory flow rate of 30 L/min (0.5 L/sec). In this case, the same dose of nicotine (0.5 mg) would be delivered in 1 sec in the first 0.5 L of the inhaled air and then if the user continues inhaling, this “bolus” would be chased by clean air thus pushing the nicotine deep into the lung, avoiding practically any deposition in the conducting airways as long as the particle size is kept small. For some inhalers, there can be initially a “latency period”, meaning that following the beginning of inhalation, there is a delay before the nicotine formulation is aerosolized. This means that the initial volume of inhaled air is nicotine free, the second volume contains the nicotine formulation and the third volume which is also free of the nicotine formulation is inhaled. For preferential deep lung delivery, the third volume needs to be sufficiently large to push the nicotine containing air into the “deep lung” (alveoli) from the mouth and the conducting airways. For very small particles that are preferred to selective deep lung delivery (<2 microns), breath holding may be desirable as well to allow these particles to deposit in the broncho-alveolar spaces instead of being exhaled if no breath-holding is used.

The user's experience will be affected by the nature of the nicotine container, thus enabling the user to select the most preferred type of container for future use. The kit may also contain different delivery devices which can be used in combination with the different containers, or the devices themselves may contain formulations and components whereby each device provides a different experience for the user. For example, the dose of nicotine delivered to the deep lung, from which it is absorbed most rapidly, differs by varying the size distribution of the aerosolized nicotine particles delivered to the user. This affects the amount of nicotine delivered to the user's deep lungs vs. other parts of the respiratory tract, with the result that nicotine absorption rate varies and the peak nicotine blood plasma levels are different between the different containers or devices. The deposition profile will also result in aerosols with preferred sensation in the brain and no, or some degree of airway irritation.

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. On the contrary, the dimensions of the various features are arbitrarily expanded or reduced for clarity. Included in the drawings are the following figures:

FIG. 1 is a schematic diagram of one possible drug delivery device and system for the delivery of aerosolized nicotine in accordance with an embodiment of the invention.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

Nicotine is approximately 10% of the particulate weight in cigarette smoke. Brand differences change this percentage. The term “nicotine” is intended to mean the naturally occurring alkaloid known as nicotine, having the chemical name S-3-(1-methyl-2-pyrrolidinyl)pyridine, which may be isolated and purified from nature or synthetically produced in any manner. This term is also intended to encompass the commonly occurring salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, pyruvate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluene sulfonate, camphorate and pamoate salts. Nicotine is a colorless to pale yellow, strongly alkaline, oily, volatile, hygroscopic liquid having a molecular weight of 162.23 and the formula:

Structure and ionization of nicotine: It is monoprotonated at most physiological pH values. The diprotonated ion would exist at pH values found in the stomach. Metabolism is largely due to oxidation. Cotinine is a major metabolite; however, there are at least 4 primary metabolites of nicotine and all are encompassed by the use of this term herein.

The term “nicotine” or “form of nicotine” further includes any pharmacologically acceptable derivative, metabolite or analog of nicotine which exhibits pharmacotherapeutic properties similar to nicotine. Such derivatives and metabolites are known in the art, and include cotinine, norcotinine, nornicotine, nicotine N-oxide, cotinine N-oxide, 3-hydroxycotinine and 5-hydroxycotinine or pharmaceutically acceptable salts thereof. A number of useful derivatives of nicotine are disclosed within the Physician's Desk Reference (most recent edition) as well as Harrison's Principles of Internal Medicine. In addition, applicants refer to U.S. Pat. Nos. 5,776,957; 4,965,074; 5,278,176; 5,276,043; 5,227,391; 5,214,060; 5,242,934; 5,223,497; 5,278,045; 5,232,933; 5,138,062; 4,966,916; 4,442,292; 4,321,387; 5,069,094; 5,721,257; all of which are incorporated herein by reference to disclose and describe nicotine derivatives and formulations.

“Free base nicotine” refers to the form of nicotine that predominates at high pH levels. The physiologically active form of nicotine is thought to be the S-(−)-isomer. Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

The term “dual-release” is used herein to refer to a formulation comprised of two components, one which releases nicotine or a nicotine derivative or nicotine substitute immediately or substantially faster than the other component (e.g., 50% or more, 100% or more, 200% or more), and one component which releases nicotine or a nicotine derivative or nicotine substitute over a prolonged period of time at a rate substantially slower than the other component (e.g., 50% or less, 75% or less).

The terms “modulated release” and “controlled release” are used herein to refer to formulations that in some way affect the amount and rate of entry of nicotine into the brain. This may be the result of pH of the formulation, encapsulation of nicotine and adding substances that impact the dissolution, release, absorption, distribution and elimination of nicotine in any part of the human or animal body.

The term “diameter” is used herein to refer to particle diameter, or size, as given in the “aerodynamic” size of the particle. The aerodynamic diameter is a measurement of a particle of unit density that has the same terminal sedimentation velocity in air under normal atmospheric conditions as the particle in question. In connection with the present invention, it is important that particles, on average, have the desired aerodynamic size so that the particles can be inhaled and targeted to a specific area of the lungs. For example, to target the alveolar ducts and alveoli for oral inhalation at moderate to high inspiratory flow rates, the particles should have a diameter in a preferred range of about 0.5 μm to about 3 μm.

The term “porous membrane” shall be interpreted to mean a membrane of material in the shape of a sheet having any given outer perimeter shape, but preferably covering a package opening which is in the form of an elongated rectangle, wherein the sheet has a plurality of openings therein, which openings may be placed in a regular or irregular pattern, and which openings have a diameter in the range of 0.25 μm to 4 μm and a pore density in the range of 1×10⁴ to about 1×10⁸ pores per square centimeter. The membrane functions to form an aerosolized mist when the formulation is forced through it. Those skilled in the art may contemplate other materials which achieve this function as such materials are intended to be encompassed by this invention.

The terms “experience”, “experiencing”, and the like with respect to the use of a nicotine product are used interchangeably herein to generally mean obtaining an overall sensation, or appreciation, of the product by the users.

All publications mentioned herein are incorporated herein by reference to described and disclose specific information for which the reference was cited in connection with. The publications discussed herein are provided solely for their stated disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such publications by virtue of prior invention. Further, the actual publication date may be different from that stated on the publication and as such may require independent verification of the actual publication dates.

The term “smoke-free” nicotine generally implies that the nicotine is not in the form of smoke generated from combustion of parts of tobacco plants. Typically, the nicotine in such smoke-free form could be nicotine or nicotine derivatives obtained from tobacco plants or synthetically manufactured. It will be inhaled without many of the components that are present in tobacco smoke such as carbon monoxide and particles or droplets containing tar. Because of the volatile nature of nicotine, some of the nicotine may be in the form of nicotine vapor and the remainder, if any, may be in droplets or solid particles, or both.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS OF THE INVENTION

I. Introduction

The present invention provides systems and methods for facilitation of a variety of nicotine inhalers, or nicotine inhaler kits to enable the user to select their favorite product which has the desirable effects in the brain and only a degree of airway sensation or irritation that is preferred by the user. Different containers or inhalers of the invention provide different type of experience for the user. The experience can be affected by containers, or inhalers, or combinations of devices and containers that supply the nicotine formulation whose use will provide different:

• • particle size for the inhaled particles; and/or
  • aerosol bolus volume; and/or
  • points during inspiration at which the aerosol bolus of nicotine is initiated; and/or
  • points during inspiration at which the aerosol bolus of nicotine is terminated; and/or
  • the volume of air inhaled, in the same breath, following the inhalation of the nicotine-containing aerosol, and/or
  • pH levels for the formulation; and/or
  • amounts of nicotine (different concentrations, volumes, or both); and/or
  • additives in the formulation (e.g., for volatility, taste and smell); and/or
  • additives in the formulation to suppress airway irritation.

The kit may also contain different devices (“inhalers”) that differ in shape, color, size of the mouthpiece as well as the resistance to inhalation through the device (resulting in different levels of breathing effort by the user). These inhaler devices may also have features that make it possible to vary the size of the nicotine aerosol bolus and vary the points during the inhalation when the bolus delivery starts and ends.

The present invention is also advantageous in that the kit provides a rapid, cost-effective method for the nicotine user to select the system that is the best match for them based on their needs and preferences. Changes in the size of aerosolized particles from each container or device in the kit may be through milling of the powder nicotine formulations provided, or by modification of the delivery device(s) of the invention. For example, a finer aerosol may be formed from a liquid nicotine formulation of the invention by passing the liquid through a porous membrane having pores with a smaller diameter.

The invention provides a means whereby the amount of nicotine delivered to different parts of the user's body can be selected from different containers whose properties can be varied in a number of different ways. Firstly, the nicotine dose absorbed into the blood stream of the user can be increased or decreased by increasing/decreasing the concentration of nicotine in the aerosolized formulation or increasing/decreasing the duration of the aerosol generation/inhalation. Secondly, it can be varied by changing the size of the dose, or the density of the aerosol inhaled by the user. It can be also changed by varying the aerosol bolus volume: when initiating the inhalation bolus early in the inspiration maneuver, the aerosol can be carried into the lung by chasing the early delivered bolus with clean air. For example, the initial bolus could be in 0.5 L of air and the user would inhale a total of 2 L. This will target the aerosol to the more peripheral airways and minimize deposition in the oropharyngeal region and central airways thereby reducing airway sensation that some users may perceive as undesirable irritation. The amount delivered to the lung will affect the rate of absorption and therefore the time and magnitude of the nicotine peak. The rate of absorption can be also varied by changing the pH of formulation. The taste and scent of the formulations can be varied from container to container, or from device to device. The devices can be varied in size, color, shape and so on. Lastly, all or any number of these parameters can be changed, and therefore be engineered such that a somewhat different experience with every container and device in the kit is obtained.

FIG. 1 shows a cross sectional schematic view of a particular embodiment of a nicotine inhaler 100 of the invention. The user can inhale air from the tubular channel 102 in the direction of the arrow shown. A small amount of air such as an amount in a range of 5 to 10 milliliters of air may be withdrawn from the channel 102 when the patient is prompted to inhale after an exhaling. The prompting can be by a sound such as a tonal sound generated by the device, a vibration or by voice instructions generated by the device. After the first step of inhaling particle free air the mechanism 108 can apply force against the container 104 which includes a liquid formulation of nicotine and a pharmaceutically acceptable carrier. That formulation is force through the porous membrane 106 via a channel. The small holes in the porous membrane cause the liquid formulation to be aerosolized and forced into the channel 102. The user then inhales the aerosolized particles along with air, and inhales air in an amount in the range of about 10% to 90% of the user's total inhaled volume. Thereafter, the user continues some inhalation of particle free air in an amount of about 10% or less of the user's total lung volume. This forces the aerosolized particles deep into the user's lungs.

Those skilled in the art will understand that multiple different types of mechanisms and sensing devices may be used with the device. Specifically, valves may be included within the channel 102 and flow rate sensors may be included as well. The valves and flow sensors may be used in order to control the stages of the delivery and may be adjustable for particular users based on their total lung volume. The mechanism 108 can be triggered by a breath-actuated valve, or by the user, or by a mechanical or electronic means that senses the user's breathing and triggers the mechanism at a predetermined volume of inhaled air. In a particular embodiment described in the examples, the user begins inhaling while the inspiratory valve is closed, then pushes a button placed on the outer surface of the device. The pushing of the button opens the inspiratory valve and also actuates the mechanism 108—a spring loaded piston—that compresses the container which holds the aqueous formulation of nicotine which is then extruded through an array of holes with sub-micron exit orifices causing the formulation to form a fine nicotine-containing aqueous mist. The volume of space in the device between the valve and the user can determine the first volume. The first volume can also be determined by the time delay from the first inhalation to the formation of the aerosol together with the inspiratory flow rate regulated by the inspiratory valve. The first volume is the aerosol-free air. The second volume is determined by any or all of (1) the time the valve is open, (2) the duration of the aerosol generation and (3) the user's inspiratory flow rate. The third volume is determined as the difference between the total volume inhaled (preferably a deep inhalation to emulate the nicotine effects of cigarettes) and the size of the first and second volumes.

The treatment methodology of the present invention creates an aerosol of nicotine particles. The nicotine particles may be formed from any liquid containing nicotine including a solution, or suspension of nicotine, or a dry powder formulation, and aerosolized in any known manner including (1) moving the formulation through a porous membrane in order to create particles or (2) a dry powder where the particles of powder have been designed to have a desired diameter and the dry powder formulation is dispersed using external sources of energy such as compressed air, or the user's own breathing. Increasing the size of the particles from about 1-2 micrometers upwards causes the particles to be deposited higher in the respiratory tract. Higher regions of the respiratory tract have less tissue surface area than lower regions and also may be more susceptible to cough and sensations of irritation. As the overall rate of absorption is directly proportional to the surface area of the tissue on which the particles are deposited, nicotine is absorbed more slowly through the mucosal membranes of the upper respiratory tract. Thus the effect of increasing particle size and/or inspiratory flow rate is to deposit the inhaled particles in a higher region of the respiratory tract with a concomitant reduced absorption rate from the respiratory tract. Delivering the nicotine aerosol bolus at the beginning of a slow inspiration, if given in small enough particles to avoid inertial deposition in bigger airways, enhances preferential deposition in the alveolar regions and therefore rapid absorption into the blood stream and effects in the brain.

Another treatment methodology of the present invention is to create a liquid or liquid suspension containing two different forms of nicotine or nicotine derivatives, one for rapid release and one for slow or delayed release.

Nicotine aerosols can be also generated by evaporation of nicotine, or nicotine containing substances or formulations, and then condensing these vapors or reacting the vapors with other substances that will then form inhalable nicotine particles. Those skilled in the art know that by changing the composition, the devices, the conditions of the aerosolization and so on, nicotine containing particles that differ in particle size, composition, shape, rates of nicotine release and absorption etc. can be made based on the evaporation-condensation and vapor phase reactions that lead to the formation of nicotine containing particles.

Taste and scent additives can be also incorporated in such nicotine inhalation systems.

The method of the invention has also applicability to smokers wishing to quit or trying to quit for health reasons who have experienced all or any of the nicotine withdrawal symptoms associated with smoking cessation, such as craving for nicotine, irritability, frustration or anger, anxiety, drowsiness, sleep disturbances, impaired concentration, nervousness, restlessness, decreased heart rate, increased appetite and weight gain.

While particularly applicable to smoking cessation, pulmonary, oral, or parenteral administration of nicotine could be of value for the treatment of other diseases, such as for patients suffering from neurodegenerative diseases, psychiatric disorders and other central nervous system disorders responsive to nicotinic receptor modulation (see U.S. Pat. Nos. 5,187,169; 5,227,391; 5,272,155; 5,276,043; 5,278,176; 5,691,365; 5,885,998; 5,889,029; 5,914,328). Such diseases include, but are not limited to, senile dementia of the Alzheimer's type, Parkinson's disease, schizophrenia, obsessive-compulsive behavior, Tourette's Syndrome, depression, attention deficit disorder, myasthenia gravis and drug addiction. These embodiments and others are discussed in greater detail, below. The kit thus may provide an easy means for the user to select the most preferred form of nicotine for their particular needs.

(i) Smoke-Free Nicotine Formulations

Smoke-free formulations of the present invention are preferably suitable for formation of aerosols. Certain formulations of the invention contain at least two forms of nicotine. Preferable embodiments are powders, semisolids, liquids, semiliquids and suspensions (e.g., suspensions of liposomes). The formulations may optionally include other active ingredients, excipients, taste and scent providing substances, colors, permeation or absorption enhancers, preservatives, binding agents, buffers, and the like that would be likely to affect the experience of the user. Typical nicotine forms of the invention include nicotine dissolved in water or dry powder nicotine with a carrier used to adjust the pH to the desired range. Liquid formulations can include water, alcohol, propellants and other carrier liquids. Volatile carriers such as propellants and ethanol are preferred as they partly or entirely evaporate and thus result in smaller particle size. Several propellants, water and ethanol have been extensively used in inhalation products and their safety is therefore very well documented. Methods of formulating liquids and liquid inhalers are disclosed in U.S. Pat. Nos. 5,364,838; 5,709,202; 5,497,763; 5,544,646; 5,718,222; 5,660,166; 5,823,178; and 5,910,301; all of which are incorporated by reference to describe and disclose such. Contemplated components of the claimed invention are discussed in greater detail, below.

A. Suitable Forms of Nicotine

Formulations of nicotine for inhalation of the present invention are tailored to provide a rapid increase of arterial nicotine concentration using the compositions in some of the containers and devices. To this end, different containers and devices in the kit of the invention include means of generating nicotine aerosols that can mimic, or improve, the experience of the users of a variety of systems delivering nicotine such as cigarettes, cigars, pipes, water pipes, electronic cigarettes, pharmaceutical nicotine mouth sprays and so on. The nicotine forms of the invention may be powders, emulsions, semi-solids, semi-liquids, suspension, liquids, or encapsulated. Preferably the nicotine forms are suitable for formation of aerosols that are amenable to inhalation. Some embodiments of the invention include two forms of nicotine. When a formulation containing two forms of nicotine is inhaled, the first form of nicotine may have a smaller particle diameter than the second form of nicotine. This allows the first form of nicotine to be deposited in the deep lung where it is rapidly transferred to the user's blood stream and reaches the users central nervous system within 5 minutes, preferably in less than 4, 3, 2 or 1 minute. The larger particle size of the second form of nicotine results in deposition of this nicotine form higher up in the respiratory tract. As a result, the second form of nicotine is absorbed more slowly to the user's circulatory system with a more sustained effect. The rates can be also varied by formulations that modulate the release of nicotine in time, or by mixing several different formulations together that provide different rates of release and absorption of nicotine into the blood stream, and therefore into the brain, to match the preferred sensation for the user. Another way to modulate the rates is to use different chemical forms of nicotine—one that acts rapidly while a derivative of nicotine may act more slowly.

B. Supplemental Agents

In addition to the nicotine forms discussed above, the smoke-free nicotine compositions of the present invention may optionally include supplemental active components that can modulate or enhance the experience by the user. These supplemental components may aid in delivery of the nicotine forms of the formulation, treat diseases, or make the formulations of the invention more acceptable to the user. The provision of these choices in the sample kit will facilitate rapid and cost-effective means of selecting the most favorable new system of nicotine delivery for the user.

When the primary use is for therapeutic purposes, particularly preferred supplemental components include antidepressants and anxiolytics such as selective serotonin reuptake inhibitors, e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and the like. Serotonin and norepinephrine reuptake inhibitors are also preferred, such as duloxetine, venlafaxine, and the like. Norepinephrine and dopamine reuptake inhibitors such as bupropion may also be used. Tetracyclic antidepressants such as mirtazapine; combined reuptake inhibitors and receptor blockers such as trazodone, nefazodone, maprotiline; tricyclic antidepressants, such as amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline and trimipramine; monoamine oxidase inhibitors, such as phenelzine, tranylcypromine, isocarboxazid, selegiline; benzodiazepines such as lorazepam, clonazepam, alprazolam, and diazepam; serotonin 1A receptor agonists such as buspirone, aripiprazole, quetiapine, tandospirone and bifeprunox; and a beta-adrenergic receptor blocker, such as propranolol, may also be added to enhance the claimed smoke-free nicotine formulations of the present invention. Substances that are thought to provide health benefits, energy boosts, concentration aids and so on may also be added, such as caffeine, taurine, resveratrol, quercetin and so on.

Supplemental components may be delivered concomitantly with the formulations of the present invention, or may be administered independently from a different device or container in the sampling kit. Supplemental component delivery may be via any suitable method known in the art including oral, inhalation, injection, etc.

C. Acceptable Excipients

The formulations of the present invention are administered to a human and may contain one or more acceptable excipients, or carriers. Suitable excipients and their formulations are described, e.g., in Remington's Pharmaceutical Sciences, 16th ed., 1980, Mack Publishing Co., edited by Oslo et al. It will be apparent to those persons skilled in the art that certain excipients may be more preferable depending upon, for instance, the route of administration and the concentration of the nicotine aerosol being administered. Water, ethanol and hydrofluorolalkanes (HFA) are particularly extensively used liquids for inhalation products. Glycerin and glycols have been also used in inhalation products. Lactose and mannitol have been used extensively in dry powder inhalation formulations.

Optional Additives

The components of the present invention may optionally include substances that affect the taste sensation, such as menthol, alcohol, fruit flavors, salt, sugar, acids and bases as well as scents. It is known that nicotine irritates the airways and therefore substances that may mask this irritation, or suppress the consequences of such irritation, are added, such as cough suppressants, menthol, eucalyptus oil, codeine, bronchodilators and so on. If the nicotine inhaler is used to prevent or treat diseases, other pharmacologic agents used to treat the conditions listed above, such as UTP, amiloride, antibiotics, anti-inflammatory agents, mucolytics and mucoactive drugs such as mannitol, acetylcysteine, drugs to prevent and treat COPD, anti-Parkinson's drugs, drugs for Alzheimer's disease, obesity prevention and control and anti-depressants may be used to provide the patient with a choice that suits their needs and preferences.

D. Propellants

Smoke-free nicotine formulations of the present invention may also be delivered with devices or containers that use propellants suitable for aerosolizing the nicotine formulation. Suitable propellants are well-known in the art and include compressed air, nitrogen, chlorofluorocarbons (CFCs), hydrofluoroalkanes (HFAs) and the like. An important aspect of any propellant used in the present invention is that it does not react with nicotine or other components of the smoke-free nicotine formulations of the claimed invention if such reaction were to impact adversely the quality of the product.

(ii) Methodology

The penetration of aerosolized nicotine particles into the respiratory tract is determined largely by the size distribution of the particles carrying the nicotine and the way the user breathes just before, during and after the administration of the aerosol by inhalation. Larger particles, i.e., particles with a diameter greater than or equal to 5 μm, deposit predominantly on the upper airways of the respiratory tract. At normal breathing rates, particles having a diameter in a range of about >2 microns (μ) to <5 microns (μm) deposit predominantly in the central airways. Smaller particles less than about 2 microns (μm) penetrate to the peripheral region of the lungs if they are delivered early in the breath at a low inhalation rate and the user inhales deeply. As observed with cigarette smoke, breath-holding enhances the deposition of very small particles in the respiratory tract.

The inhalation maneuver, and the timing of the delivery of the aerosol bolus, also affects the site of deposition. To avoid deposition in the upper and central (or “conducting”) airways, so as to minimize the irritation and bad taste caused by the inhaled nicotine, the bolus volume can be reduced from 1-2 Liters to 0.5 to 1 Liter, or even less than 0.5 L. For an inhalation maneuver at 30 L/min flow rate, a total inhaled volume of 1-2 Liters can thus be delivered in 2-4 seconds and less than 1 second for an inhaled volume less than 0.5 L. If the user inhales 2 L of aerosol in a total volume of 2 L of inhaled air, then much of the respiratory tract is in contact with the nicotine aerosol. By timing the delivery of a smaller bolus of aerosol to start with the initiation of inspiration, the aerosol will target the more distal airways as the remainder of the inhaled air will not contain any nicotine aerosol, thus reducing deposition in the upper and central airways and therefore ameliorating the irritation caused by the nicotine aerosol. Interestingly, some smokers prefer to feel some degree of airway irritation when they are inhaling nicotine and the inhalation system of this invention describes the means whereby the user can select the most suitable nicotine inhaler that suits their preference.

When the deepest part of the lung is targeted with the smallest particles the user receives an immediate “rush” from the nicotine. These small particles can be obtained by milling powder into the desired size and inhaling the powder or by creating a solution or suspension and aerosolizing the formulation, e.g. by nebulization or by moving the solution or suspension through the pores of a membrane. In either case, the desired result is to obtain particles which have a diameter in the range of 0.5 μm to about 3 μm. Those skilled in the art will understand that some of the particles will fall above and below the desired range. However, if the majority of the particles (50% or more) fall within the desired range then the desired area of the lung will be predominantly targeted as long as the aerosol is not being generated continuously throughout the inhalation. Alternatively, the user inhales slowly to avoid the deposition of even some bigger particles at the back of the mouth and in the airways. The device can be also designed such that the inspiratory flow rate is restricted to prevent high inspiratory flow rates. This can emulate the resistance that the user would experience inhaling, e.g., from a cigarette or a cigar.

In contrast to the emulation of the effect of receiving nicotine from tobacco smoke from cigarettes, the present invention also describes the generation of large droplets that are delivered in shallow volumes of air similar to the way that many smokers would get their nicotine from cigars or pipes. The combination of the large droplets and shallow inhalation limits the nicotine delivery to the upper and central airways, leading to relatively slower absorption rates and greater sensation of the nicotine in these parts of the respiratory tract.

(iii) Nicotine Delivery Devices

The aspects of the invention described above such as changing the amount, concentration, or pH of the formulation or changing the particle size of the aerosol created with the formulation can be done independent of the delivery device. However, there are a number of features which can be included in the inhalation system which are specific to the device which delivers the formulation. For example, the device can be designed so as to avoid overdosing. This can be implemented by limiting the overall number of refills per day, by adding a dose counter to the device, or electronically by monitoring the number of doses a user has delivered and locking out further use for a given time interval. Thus, the electronics can be used as a safety feature.

Devices suitable for use with the invention can also be programmed to release larger or lesser amounts of formulation and fire the aerosol at different rates. The inhalation device can also limit the inspiratory flow rate or guide the user with various sensory signals to inhale within a specified range of inspiratory flow rates. The device may also have the ability to deliver a bolus of nicotine aerosol at different volumes during inspiration to target different areas of the respiratory tract. Either or both of these parameters can be changed by themselves, together or in combination with the other parameters related to the formulation and particle size.

Precision delivery of small molecule drugs including nicotine via the lung for systemic effects is known to be possible. An electronic inhaler capable of delivering a liquid formulated drug stored in a unit dose packages has been described and disclosed in U.S. Pat. No. 5,718,222 entitled “Disposable Package for Use in Aerosolized Delivery of Drugs,” and is incorporated herein by reference. A formulation of nicotine can be prepared for delivery with this system. The device program can be varied to provide different amount of nicotine, different spray patterns and so on to achieve the most satisfactory experience for the user.

In one embodiment, the smoke-free nicotine formulation of the invention is forced through the openings or pores of a porous membrane to create an aerosol. In a specific embodiment, the openings are all uniform in size and are positioned at uniform distances from each other. In general, it is preferable to have the opening sizes within the range of about 0.25 μm to about 6 μm which will create particle sizes of about 0.5 μm to 12 μm which are preferred with respect to inhalation applications for nicotine that can provide the desired sensations for the user. When the openings have a pore size in the range of 0.25 μm to 1 μm they will produce an aerosol having particle sizes in the range of approximately 0.5 μm to 2 μm, which is particularly useful for delivering nicotine to the alveolar ducts and alveoli and avoiding deposition in the upper airways, one of the sites which causes irritation as long as adequate volume of air is inhaled. A pore size of 2 μm to 4 μm will create particles having a diameter of approximately 4 μm to 8 μm, which will target predominantly the area of the respiratory tract from the small bronchi upward unless the user is inhaling very slowly in which case deeper lung deposition can be achieved, or very fast in which case predominantly upper respiratory tract deposition will be achieved. It is well known to those of ordinary skill in the art that the relationship between particle size and the site of deposition is complex and depends on many additional factors but that all other things being equal, increasing the aerodynamic size of the particles above 1 micron upwards will cause shift of deposition in the respiratory tract from the deep lung towards the oropharyngeal cavity.

A device comprised of a container that includes an opening covered by a porous membrane, such as the device disclosed in U.S. Pat. No. 5,906,202, may be used to deliver nicotine. The device may be designed to have the shape and/or bear the markings of a pack of cigarettes, and the user may be able to select from kits with various scents and flavors of tobacco. These features and others that address the behavioral component of cigarette smoking may enhance the effectiveness of the method described herein.

The device of this invention can also be designed in such a way that the nicotine formulation containing aerosol is inhaled during a specific period of the inhalation. Preferably to emulate the effects of cigarette smoke, the bolus is delivered in a relatively small volume at the beginning of an inspiration and at a low inspiratory flow rate to avoid deposition in the upper and central airways and enhance deposition and rapid absorption in the alveolar regions of the lung.

(iv) Dosing

Cigarettes contain 6 to 11 mg of nicotine, of which the smoker typically absorbs 1-3 mg [Henningfield N Engl J Med 333:1196-1203 (1995)]. Factors influencing nicotine absorption include user-dependent factors, such as smoking behavior, lung clearance rate, morphological factors, and physiological factors, such as tidal volume, inspiratory and expiratory flow rate, particle size, shape and density. The systemic dose of nicotine per puff from a cigarette is extremely variable. However, peak plasma concentrations of 10 to 40 ng/mL of nicotine, achieved within 5 to 7 minutes by cigarette smoking, are believed typical. In accordance with the present invention, 0.05 mg to 10 mg, preferably 0.1 to 3 mg, and more preferably about 0.2-1 mg of nicotine are delivered to the lungs of the users in a single dose to achieve peak blood plasma concentrations of 10 to 50 ng/mL. However, these needs including the dose tend to be quite personal and therefore the key aspect of the invention is to provide each user with an optimum sensation that can be achieved through the choice of the attributes of the nicotine inhalation systems described in this invention that include the features of the inhaler device, the nicotine container, the formulation and adjustment of those aspects of the nicotine inhalation system that affect the nicotine dose delivered to various parts of the respiratory tract. Some users may prefer to get a higher dose infrequently whereas others may prefer more frequent administrations of lower doses of nicotine. An aspect of the invention is to offer the user nicotine preparations in a variety of forms with the view that one such form in the kit will be the best to satisfy the user. The user will then continue using the particular embodiment of the nicotine inhaler that suits her or his individual needs, or several embodiments if their preferences vary from time to time. The nature of the formulation/device combination from the kit that will be most preferred will vary based on many factors including how much the user smokes, what kind of tobacco product including specific brands of cigarettes, cigars, pipes, pipe tobacco or roll-your-own tobacco, and the user's age, sex, weight and condition.

The amount of nicotine per puff preferred by the user as well as total daily nicotine intake will vary based on factors such as the age, weight and frequency of smoking or nicotine tolerance of the smoker as well as concomitant use of other nicotine-containing products. Other factors, such as daily stress patterns, and demographic factors may also help to determine the amount of nicotine sufficient to satisfy the user's preferences.

To achieve different sensations from different containers, the nicotine formulation in each container can be physically, chemically or quantitatively different from the nicotine formulation confined by other containers. The nicotine formulation contained in each container in an initial sampling kit is unique from all containers in the effective amount and rate of absorption of nicotine that it delivers to the lungs and from the lungs into the systemic circulation. These differences may be a result of changes to the nicotine formulation, such as concentration, particle size of powder particles or liquid droplets, pH or any other parameter that would be obvious to those skilled in the art. Derivatives of nicotine with different pharmacological properties and different pharmacokinetic and pharmacodynamics properties can be also used. In addition, the differences may be a result of variations that alter the efficiency of delivery of the formulation to the deep lung, such as membrane pore size or number, control of user's inspiratory flow rate and the placing of the nicotine aerosol bolus in a certain portion of the inspired air or any other parameter that would be obvious to those skilled in the art.

To achieve different sensations from different containers and inhalers, it is also possible to vary the aerosol bolus volume and the timing of delivery of the aerosol bolus; that is, the points during the inspiration at which the aerosol bolus of nicotine is initiated and terminated. For example, a smaller bolus volume delivered early in the inspiration will go “deeper” into the lung whereas that same bolus delivered near the end of the inspiration will be delivered more centrally, with the potential to result in more mouth and throat deposition. A larger volume aerosol bolus will result in deposition occurring over a wider range of locations, with the ability to target both the oropharynx and deep lung in one breath. To summarize, the volume of the nicotine formulation to be aerosolized can be varied such that a defined volume of the respiratory tract is reached with the nicotine aerosol. By changing the concentration of nicotine in the formulation, different nicotine doses can be delivered to the same defined volume of the respiratory tract.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

Although the foregoing invention has been described in some detail by way of illustration and example for clarity and understanding, it will be readily apparent to one of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit and scope of the appended claims.

As can be appreciated from the disclosure provided above, the present invention has a wide variety of applications. Accordingly, the following examples are offered for illustration purposes and are not intended to be construed as a limitation on the invention in any way. Those of skill in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results.

EXAMPLES

Example 1

Single-Dose Application of Deep Lung Nicotine Formulation

The AERx Essence System known in the art is an example of a device that can make different size droplets from liquid formulations of nicotine. It was used to deliver doses of aerosolized nicotine to healthy adult male smokers (Gonda, I. et al. 2009 Smoking Cessation Approach via Deep Lung Delivery of ‘Clean’ Nicotine, In: Respiratory Drug Delivery, Europe, 2009, eds. PR Byron et al., pp. 57-62). The AERx Essence is an all-mechanical, non-propellant driven, hand-held device that uses individually packaged, single-use, dosage form strips. Each one of these can be presented in the sampling kit which is the subject of this invention. The containers or strips in the sampling kit can have nozzles that vary in exit hole sizes between the containers, thus producing aerosols of different particle size. Alternatively, or additionally, each container can have a different amount of nicotine, achieved by varying the concentration of nicotine in the containers, or the amount of formulation, or both. A uniformly fine, respirable aerosol is created when the drug solution is “extruded” through an array of submicron or micron sized holes drilled into the dosage form strip. The size of the holes will determine the droplet size of the aerosol. The fine aerosol that is generated with sub-micron holes allows the deep-lung deposition needed to achieve rapid and efficient absorption of drug similar to that obtained by smoking. If bigger holes are made, the nicotine aerosols deposit in more proximal airways and are absorbed more slowly.

In three series of experiments subsequent to those reported in, e.g., Gonda, I. et al. 2009 Smoking Cessation Approach via Deep Lung Delivery of ‘Clean’ Nicotine, In: Respiratory Drug Delivery, Europe, 2009, eds. PR Byron et al., pp. 57-62, three healthy volunteers (two ex-smokers and one non-smoker) were given a variety of doses and a variety of formulations. The AERx Essence device was used. The volumes of the liquid formulation, the concentration of the nicotine as well as the qualitative aspects of the formulation were varied. Nicotine bitartrate (BT) and sulphate (S) as well as sodium salts of the bitartrate and sulphate (“placebo) were used. Menthol flavor was tested, too. The sensory perceptions and effects, such as “buzz”, “hit”, “effect” or “rush” in the head typical of the sensation desired by smokers, as well as airway irritation and cough were recorded. In these experiments, the first volume was kept small as it only had a short latency incorporated in the design of the inhaler device: the user first started to inhale via the mouthpiece of the inhaler with the inlet air valve closed, then pushed a button on the inhaler that released the piston which moved and made contact with the dosage form containing the formulation, forcing the liquid formulation of nicotine through the nozzle (porous membrane) in the nicotine-containing dosage form and at the same time opening the entry valve to allow the air to provide the carrier for the nicotine spray formulation. (A longer latency can be designed, e.g., by delaying the piston movement after the inhalation starts.) The second and third volume were varied by varying the amount of fill in the dosage form—the smaller the fill volume, the smaller the second volume and the larger the third volume as the subjects in the study were encouraging to take a deep breath with every inhalation. The inspiratory flow rate was kept nearly constant at 30 L/min by the design of the inspiratory valve in the inhaler. The droplet size was controlled by the size of the exit holes in the nozzle (“porous membrane”) with near monodisperse aerosols with mass median aerodynamic diameter 2-3 micrometers (Cipolla, D. C., Bruinenberg, P., Eliahu, P., Johansson, E., Marjason, J. K., Morishige, R. J., Mudumba, S, and Otulana, B. A. (2008). Development of an Inhaled AERx Essence® Nicotine Product for Smoking Cessation, In: Respiratory Drug Delivery 2008″, R. N. Dalby, P. R. Byron, J. Peart, J. D. Suman, S. J. Farr, P. M. Young (eds), published by Davis Healthcare International Publishing, LLC, River Grove, Ill., USA, pp. 365-369).

Volunteer 1
	Fill
Salt/Conc./pH	volume	Comment
Nicotine Bitartrate/3.2	40 μL	Slight irritation, no “extra buzz”,
mg/mL/3.3		no taste
Nicotine Sulfate/	40 μL	Slight cough, buzz, no taste
10 mg/mL/6.7
Na Sulfate/Placebo/6.4	40 μL	No buzz, no taste
Na Sulfate/Placebo/6.4	40 μL	No sensation
Nicotine Bitartrate/10	40 μL	No taste, buzz
mg/mL/3.2
Nicotine Sulfate/	40 μL	No taste, buzz
10 mg/mL/3.0
Nicotine Bitartrate/3.2	40 μL	No taste, buzz
mg/mL/3.0
Nicotine Bitartrate/3.2	40 μL	Easy to inhale, delayed mild rush
mg/mL/6.6		at 30-60 secs.
Nicotine Sulfate/	40 μL	Strong immediate effect, slight
20 mg/mL/6.5		cough (did not inhale full dose)
Nicotine Bitartrate/20	40 μL	Strongest effect of the day, slight
mg/mL/3.2		cough
Nicotine Sulfate/	40 μL	Slight cough, feel strong buzz
20 mg/mL/3.1
Nicotine Bitartrate/20	40 μL	Strong immediate high buzz,
mg/mL/6.9		slight cough
Na Bitartrate/Placebo/	40 μL	No taste
3.1
Na Bitartrate/Placebo/	40 μL	No taste
6.0
Na Sulfate/Placebo/3.2	40 μL	No taste
Na Bitartrate3X/	40 μL	No taste
Placebo/3.2
Na Sulfate3X/Placebo/	40 μL	No taste
6.7
Na Bitartrate3X/	40 μL	No taste
Placebo/6.7
Na Sulfate3X/Plac/2.8	40 μL	No taste
Nicotine Sulfate/	40 μL	Cough, big hit
30 mg/mL/3.2
Nicotine Sulfate/	15 μL	Big hit, buzz
60 mg/mL/3.3
Nicotine Sulfate/	25 μL	Big hit, coughing, buzz
40 mg/mL/3.3
Nicotine Sulfate/	40 μL	Big hit, coughing, buzz
20 mg/mL/3.3
Nicotine Sulfate/	20 μL	Big hit, no cough, buzz
60 mg/mL/3.3
Menthol Solution 0.8	20 μL	Taste of menthol, no irritation
mg/mL
Nicotine Sulfate/	20 μL	Slight irritation, some buzz
60 mg/mL/6.7		“slight acidic feel”, euphoric
		feelings
Nicotine Sulfate/	20 μL	No irritation, “good buzz”
30 mg/mL/6.7
Nicotine Sulfate/	20 μL	Slight irritation, no buzz, slight
30 mg/mL/6.7		acidic feel
Nicotine Sulfate/	20 μL	No irritation, good buzz
60 mg/mL/3.3
Nicotine Sulfate/	20 μL	Slight irritation, good buzz
30 mg/mL/3.3
Nicotine Bitartrate/60	20 μL	Easy to inhale, really good buzz
mg/mL/2.9
Nicotine Bitartrate/30	20 μL	Easy to inhale, good buzz
mg/mL/2.9
Nicotine Bitartrate/30	20 μL	Easy to inhale, slight airway
mg/mL/6.1		irritation
Volunteer 2:
BT—bitartrate salt (either sodium for Placebo, or nicotine for active);
S—sulphate salt (either sodium for Placebo, or nicotine for active)
			Estimated
Concentration			lung dose	Presence/
(nicotine,		Vol	of nicotine	Intensity	Adverse
mg/mL)	pH	(μL)	(mg)	of “buzz”	effects
BT Placebo	3.1	40	0	None	None
BT Placebo	6.0	40	0	None	None
S Placebo	3.2	40	0	None	None
BT 3X Placebo	3.2	40	0	None	None
S 3X Placebo	6.7	40	0	None	None
BT 3X Placebo	6.7	40	0	None	None
S 3X Placebo	2.8	40	0	None	None
Nicotine BT 10	3.2	40	0.16	None	Slight
					irritation
					to central
					airway
Nicotine S 30	3.2	40	0.48	None	Major
					irritation of
					the airway,
					unable to
					inhale
					complete dose
Volunteer 3
Concentration			Estimated	Presence/
(nicotine,		Vol	lung dose	Intensity	Adverse
mg/mL)	pH	(μL)	(mg)	of “buzz”	effects
Nicotine	2.9	20	0.32	Really	Slight
bitartrate, 30				good buzz	irritation
mg/mL

These results illustrate several key features of the invention: 1) the sensory perceptions of nicotine are effective in humans as evidenced by the lack of sensory perception with the placebo formulations (those that did not contain any nicotine or menthol) vs. the nicotine-containing formulations as well as by the dose-dependence of the effects, 2) within a subject the sensory perception are quite reproducible if the same nicotine inhalation is used, although the differences between individuals are significant both in terms of perception of the effects on the brain as well as the airway sensations, 3) the smaller second volume followed by a larger third volume is generally causing less airway sensation and cough, 4) the effects in the brain desired by smokers (“hit”, “buzz”, “effect”, “rush”) occur with higher doses, and 5) the nature of the formulation, such as pH, can modulate these sensory perceptions.

The preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims.

Claims

1. A nicotine inhaler, comprising:

a container holding an aerosolizable formulation comprised of nicotine;

a drive mechanism which applies energy to the formulation to create aerosolized particles having an aerodynamic diameter in a range of from 0.5 microns to 10 microns;

a mouthpiece from which air and aerosolized formulation are inhaled;

an input port through which air is drawn;

a flow controller positioned between the input port and the mouthpiece;

an actuation mechanism which provides for three stages of an inhalation event, wherein a first stage comprising particle free air is within a range of 0.1% to 15% of a total inhaled lung volume, a second stage comprising aerosolized formulation is within a range of 10% to 90% of the total inhaled lung volume, and a third stage comprising particle free air which is at least 10% of the total inhaled lung volume.

2. The nicotine inhaler of claim 1, wherein the formulation has a volume of 10 to 50 microliters, contains 0.1 mg to 1 mg of nicotine and is forced through the porous membrane by the drive mechanism resulting in aerosolized particles which have an aerodynamic diameter of about 3 microns±50%.

3. The nicotine inhaler of claim 1, wherein the actuation mechanism completes the first stage, second stage and third stage within a period of time of 5 seconds or less wherein the actuation mechanism and flow controller are connected in a manner which provides control over the volume inhaled in each of the three stages of the inhalation event.

4. A nicotine inhaler, comprising:

a container holding an aerosolizable formulation comprised of nicotine;

a drive mechanism which applies energy to the formulation to create aerosolized particles having an aerodynamic diameter in a range of from 0.5 microns to 10 microns;

a mouthpiece from which air and aerosolized formulation are inhaled;

an input port through which air is drawn;

a flow controller positioned between the input port and the mouthpiece;

an actuation mechanism which provides for three stages of an inhalation event, wherein a first stage comprising particle free air is within a range of 2 ml to about 500 ml, a second stage comprising aerosolized formulation is within a range of about 100 ml to about 2000 ml, and a third stage comprising particle free air in a volume which is at least 100 mL.

5. The nicotine inhaler of claim 4, wherein the formulation has a volume of 10 to 50 microliters, contains 0.1 mg to 1 mg of nicotine and is forced through the porous membrane by the drive mechanism resulting in aerosolized particles which have an aerodynamic diameter of about 3 microns±50%.

6. The nicotine inhaler of claim 4, wherein the actuation mechanism completes the first stage, second stage and third stage within a period of time of 5 seconds or less wherein the actuation mechanism and flow controller are connected in a manner which provides control over the volume inhaled in each of the three stages of the inhalation event.

7. A nicotine inhaler, comprising:

a container holding an aerosolizable formulation comprised of nicotine;

a drive mechanism which applies energy to the formulation to create aerosolized particles having an aerodynamic diameter in a range of from 0.5 microns to 10 microns;

a mouthpiece from which air and aerosolized formulation are inhaled;

an input port through which air is drawn;

instructions advising the user to take a shallow breath;

an actuation mechanism aerosolizing the formulation of nicotine in a volume of air less than 500 mL.

8. The nicotine inhaler of claim 7, wherein the formulation is a liquid formulation, the container comprises a porous membrane, and nicotine is present in the formulation in the container in an amount in the range of 0.1 mg to 10 mg of nicotine in a liquid formulation having a volume of 5 to 100 microliters; and

the actuation mechanism aerosolizes formulation into air having a volume in the range of 100 milliliters to 400 milliliters.

9. A system, comprising:

a nicotine inhaler; and

a nicotine container adapted to fit in the inhaler;

wherein the inhaler enables the user to inhale a first volume of inhaled air free of the nicotine aerosol, followed in the same breath as the first volume by a second volume of air in which the nicotine aerosol is dispersed, and followed by a third volume of inhaled air free of nicotine aerosol in the same breath as the first and second volumes.

10. The system as claimed in claim 9,

wherein a first stage comprising particle free air is within a range of 0.1% to 15% of a total inhaled lung volume, a second stage comprising aerosolized formulation is within a range of 10% to 90% of the total inhaled lung volume, and a third stage comprising particle free air which is at least 10% of the total inhaled lung volume.

11. The system as claimed in claim 9, wherein a first stage comprising particle free air is within a range of 2 ml to about 500 ml, a second stage comprising aerosolized formulation is within a range of about 100 ml to about 2000 ml, and a third stage comprising particle free air in a volume which is at least 100 mL.

12. The system in claim 9, wherein the third volume is greater than 180 mL up to any remaining lung volume of the user after the first and second volumes are inhaled.

13. A system, comprising:

a nicotine inhaler; and

a plurality of nicotine containers adapted to fit in the inhaler wherein each container holds a liquid formulation comprising a pharmaceutically acceptable carrier and nicotine;

wherein the inhaler enables the user to inhale the first volume of inhaled air free of the nicotine aerosol, followed in the same breath as the first volume by the second volume of air in which the nicotine aerosol is dispersed, and followed by the third volume of inhaled air free of nicotine aerosol in the same breath as the first and second volumes.

14. The system as claimed in claim 13, wherein

a first stage comprising particle free air is within a range of 2 ml to about 500 ml, a second stage comprising aerosolized formulation is within a range of about 100 ml to about 2000 ml, and a third stage comprising particle free air in a volume which is at least 100 mL.

15. The system in claim 13 wherein

a first stage comprising particle free air is within a range of 0.1% to 15% of a total inhaled lung volume, a second stage comprising aerosolized formulation is within a range of 10% to 90% of the total inhaled lung volume, and a third stage comprising particle free air which is at least 10% of the total inhaled lung volume.

16. A method, comprising:

prompting a user to exhale and thereafter inhale a first volume of particle free air from a mouthpiece of a device loaded with a formulation comprising nicotine and a pharmaceutically acceptable carrier;

aerosolizing the formulation;

prompting the user to inhale a volume of aerosolized formulation; and

prompting the user to inhale a second volume of particle free air,

wherein the first volume of particle free air has a volume in a range of 0.1% to 10% of the users total lung volume,

wherein the aerosolized formulation inhaled with air has a volume in a range of from 50% to 90% of the user's total lung volume; and

wherein the second volume of particle free air has a volume of 10% or more of the users total lung volume.

17. The method of claim 16, wherein the user is a user craving nicotine.

18. The method as claimed in claim 16, wherein the formulation is a liquid formulation and is forced through a porous membrane by a drive mechanism resulting in aerosolized particles for formulation having an aerodynamic diameter of about 3 microns±50% and the formulation contains 0.1 mg to 1 mg of nicotine in a volume of formulation of 5 to 100 microliters.

19. The method as claimed in claim 18, wherein the formulation has a volume in the range of 5 to 50 microliters and the method is carried out in a period of time of 5 seconds or less.

20. A method, comprising:

aerosolizing a formulation comprising nicotine in a pharmaceutically acceptable carrier in an amount in the range of 0.1 to 1 mg in order to create an aerosol comprised of droplets having an aerodynamic diameter of 3.0+/−50% microns or less;

inhaling the aerosolized formulation with a volume of air of 1000 ml or less; and

inhaling additional air into the lungs following the inhalation of the aerosolized formulation wherein the additional air is free of aerosol.