WO2014150245A1 - Procédé pour l'inhalation de nicotine sans fumée - Google Patents

Procédé pour l'inhalation de nicotine sans fumée Download PDF

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Publication number
WO2014150245A1
WO2014150245A1 PCT/US2014/022707 US2014022707W WO2014150245A1 WO 2014150245 A1 WO2014150245 A1 WO 2014150245A1 US 2014022707 W US2014022707 W US 2014022707W WO 2014150245 A1 WO2014150245 A1 WO 2014150245A1
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WO
WIPO (PCT)
Prior art keywords
nicotine
volume
formulation
air
inhaler
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Application number
PCT/US2014/022707
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English (en)
Inventor
Igor Gonda
Original Assignee
Aradigm Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aradigm Corporation filed Critical Aradigm Corporation
Publication of WO2014150245A1 publication Critical patent/WO2014150245A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0065—Inhalators with dosage or measuring devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/06—Inhaling appliances shaped like cigars, cigarettes or pipes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/006—Sprayers or atomisers specially adapted for therapeutic purposes operated by applying mechanical pressure to the liquid to be sprayed or atomised
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/04—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/002—Details of inhalators; Constructional features thereof with air flow regulating means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/0003—Accessories therefor, e.g. sensors, vibrators, negative pressure
    • A61M2016/0015—Accessories therefor, e.g. sensors, vibrators, negative pressure inhalation detectors
    • A61M2016/0018—Accessories therefor, e.g. sensors, vibrators, negative pressure inhalation detectors electrical
    • A61M2016/0024—Accessories therefor, e.g. sensors, vibrators, negative pressure inhalation detectors electrical with an on-off output signal, e.g. from a switch
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/0003—Accessories therefor, e.g. sensors, vibrators, negative pressure
    • A61M2016/003—Accessories therefor, e.g. sensors, vibrators, negative pressure with a flowmeter
    • A61M2016/0033—Accessories therefor, e.g. sensors, vibrators, negative pressure with a flowmeter electrical
    • A61M2016/0039—Accessories therefor, e.g. sensors, vibrators, negative pressure with a flowmeter electrical in the inspiratory circuit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • the invention relates generally to inhalation systems that provide tobacco users
  • 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.
  • 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.
  • other devices such as dry powder inhalers, evaporation-condensation aerosol generation
  • 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 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.
  • 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.
  • the aerosol particles may deposit by sedimentation and diffusion.
  • 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. [0009] 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.
  • 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.
  • small particles that have a high likelihood to enter the small airways and alveoli should be used as well.
  • 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.
  • 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 lmg/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.
  • 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.
  • 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. Patent Nos. 5,167,242; 5,400,808; 5,501,236; 4,800,903; 4,284,089;
  • a droplet ejection device U.S. Patent 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.
  • the invention in general includes various elements that alone, or in
  • 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,
  • 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.
  • the nicotine is of pharmaceutical grade, i.e., of high purity
  • 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.
  • 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.
  • an inhalation dosing event we mean a single breath during which a satisfactory dose of nicotine is delivered.
  • 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.
  • 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.
  • 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.
  • US patents Johansson et al. 5,392, 768, Ritson et al. 5,394,866 and Goodman et al. 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 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.
  • 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.
  • 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
  • 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”.
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • 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
  • AERX Essence i.e., AERX Essence
  • 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
  • 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.
  • 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.
  • 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.
  • a steady state delivery system e.g. gum or patch or chewing tobacco
  • 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.
  • a system is referred to here as a unit dose solution aerosolizer. Examples are described in U.S. Patent 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.
  • 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.
  • Nicotine aerosol formed by reaction of nicotine vapors with pyruvic acid was described by Rose et al.
  • the inhalers may be metered dose inhaler (MDI) devices.
  • MDI metered dose inhaler
  • Pressurized canisters conventionally used for MDIs can contain different
  • 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.
  • 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.
  • Adjustments in the pH can be carried out alone or in combination with
  • adjustments in the concentration of nicotine in the formulation 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 provides more nicotine to the user for the same amount of formulation aerosolized.
  • 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.
  • 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.
  • each container contains different amounts of nicotine, concentrations and/or formulations with different pHs.
  • 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.
  • 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.
  • 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.
  • 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.
  • the user would inhale 0.5 mg of nicotine dispersed in 2 L of air in 4 seconds.
  • 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.
  • 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.
  • 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.
  • 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.
  • Figure 1 is a schematic diagram of one possible drug delivery device
  • Nicotine is approximately 10% of the particulate weight in cigarette smoke.
  • nicotine is intended to mean the naturally occurring alkaloid known as nicotine, having the chemical name S-3-(l- methyl-2-pyrrolidinyl)pyridine, which may be isolated and purified from nature or synthetically produced in any manner.
  • Nicotine is a colorless to pale yellow, strongly alkaline, oily, volatile, hygroscopic liquid having a molecular weight of 162.23 and the formula:
  • 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.
  • 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. Patent Nos.
  • 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).
  • 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.
  • the particles should have a diameter in a preferred range of about 0.5 ⁇ to about 3 ⁇ .
  • 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 ⁇ to 4 ⁇ and a pore density in the range of 1 x 10 4 to about 1 x 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.
  • smoke-free nicotine generally implies that the nicotine is not in the form of smoke generated from combustion of parts of tobacco plants.
  • 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.
  • 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:
  • pH levels for the formulation are pH levels for the formulation.
  • nicotine different concentrations, volumes, or both
  • additives in the formulation e.g., for volatility, taste and smell
  • additives in the formulation to suppress airway irritation e.g., for volatility, taste and smell
  • 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).
  • 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.
  • 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
  • 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
  • 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.
  • Figure 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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. Patent Nos. 5,187,169; 5,227,391; 5,272,155; 5,276,043;
  • kits thus may provide an easy means for the user to select the most preferred form of nicotine for their particular needs.
  • 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.
  • 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. Patent 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.
  • 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.
  • 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.
  • the nicotine forms are suitable for formation of aerosols that are amenable to inhalation.
  • Some embodiments of the invention include two forms of nicotine.
  • 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.
  • 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.
  • 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.
  • 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
  • Supplemental components may be delivered concomitantly with the
  • formulations of the present invention 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.
  • 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.
  • HFA hydrofluorolalkanes
  • 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.
  • 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.
  • Smoke-free nicotine formulations of the present invention may also be provided.
  • propellants suitable for aerosolizing the nicotine formulation are well-known in the art and include compressed air, nitrogen, chlorofluorocarbons (CFCs), hydrofluoroalkanes (HFAs) and the like.
  • COFCs chlorofluorocarbons
  • HFAs hydrofluoroalkanes
  • 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.
  • 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 ⁇ , deposit predominantly on the upper airways of the respiratory tract.
  • particles having a diameter in a range of about >2 microns ( ⁇ ) to ⁇ 5 microns ( ⁇ ) deposit predominantly in the central airways.
  • Smaller particles less than about 2 microns ( ⁇ ) 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.
  • 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.
  • the bolus volume can be reduced from 1-2 Liters to 0.5 to 1 Liter, or even less than 0.5 L.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ to about 3 ⁇ . 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
  • 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.
  • the present invention 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.
  • 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.
  • 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.
  • the smoke-free nicotine formulation of the invention is forced through the openings or pores of a porous membrane to create an aerosol.
  • the openings are all uniform in size and are positioned at uniform distances from each other.
  • the openings When the openings have a pore size in the range of 0.25 ⁇ to 1 ⁇ they will produce an aerosol having particle sizes in the range of approximately 0.5 ⁇ to 2 ⁇ , 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 ⁇ to 4 ⁇ will create particles having a diameter of approximately 4 ⁇ to 8 ⁇ , 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.
  • a device comprised of a container that includes an opening covered by a porous membrane, such as the device disclosed in U.S. Patent 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.
  • 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.
  • 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.
  • Cigarettes contain 6 to 11 mg of nicotine, of which the smoker typically
  • 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.
  • peak plasma concentrations of 10 to 40 ng/mL of nicotine achieved within 5 to 7 minutes by cigarette smoking, are believed typical.
  • 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.
  • 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.
  • 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.
  • 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.
  • the aerosol bolus volume and the timing of delivery of the aerosol bolus 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • BT- bitartrate salt either sodium for Placebo, or nicotine for active
  • S- sulphate salt either sodium for Placebo, or nicotine for active

Abstract

L'invention concerne de manière générale un système ou un coffret qui distribue de la nicotine pour cibler les régions du tractus respiratoire afin d'obtenir l'impact maximal sur un état de manque avec un nombre minimal de sensations indésirables. Plus particulièrement, l'invention concerne l'administration pulmonaire de nicotine à partir de systèmes d'inhalation de nicotine qui ciblent la distribution au poumon profond, en réduisant à un minimum un dépôt dans les voies aériennes supérieures et centrales.
PCT/US2014/022707 2013-03-15 2014-03-10 Procédé pour l'inhalation de nicotine sans fumée WO2014150245A1 (fr)

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EP3214957B1 (fr) 2014-11-07 2019-02-13 Nicoventures Holdings Limited Récipient contenant une solution à base de nicotine
US10952468B2 (en) 2013-05-06 2021-03-23 Juul Labs, Inc. Nicotine salt formulations for aerosol devices and methods thereof
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