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WO2001005459A1 - Systeme permettant d'arreter de fumer - Google Patents

Systeme permettant d'arreter de fumer Download PDF

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Publication number
WO2001005459A1
WO2001005459A1 PCT/US2000/019034 US0019034W WO0105459A1 WO 2001005459 A1 WO2001005459 A1 WO 2001005459A1 US 0019034 W US0019034 W US 0019034W WO 0105459 A1 WO0105459 A1 WO 0105459A1
Authority
WO
WIPO (PCT)
Prior art keywords
nicotine
formulation
patient
containers
aerosolizing
Prior art date
Application number
PCT/US2000/019034
Other languages
English (en)
Inventor
Stephen J. Farr
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
Priority to AU59312/00A priority Critical patent/AU777326B2/en
Priority to JP2001510544A priority patent/JP4999245B2/ja
Priority to EP00945354A priority patent/EP1218048A4/fr
Priority to CA2378913A priority patent/CA2378913C/fr
Publication of WO2001005459A1 publication Critical patent/WO2001005459A1/fr

Links

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
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24F—SMOKERS' REQUISITES; MATCH BOXES; SIMULATED SMOKING DEVICES
    • A24F40/00—Electrically operated smoking devices; Component parts thereof; Manufacture thereof; Maintenance or testing thereof; Charging means specially adapted therefor
    • A24F40/40—Constructional details, e.g. connection of cartridges and battery parts
    • A24F40/42—Cartridges or containers for inhalable precursors
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24F—SMOKERS' REQUISITES; MATCH BOXES; SIMULATED SMOKING DEVICES
    • A24F40/00—Electrically operated smoking devices; Component parts thereof; Manufacture thereof; Maintenance or testing thereof; Charging means specially adapted therefor
    • A24F40/10—Devices using liquid inhalable precursors
    • 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
    • A61M2209/00—Ancillary equipment
    • A61M2209/06—Packaging for specific medical equipment

Definitions

  • This invention relates generally to a method for treating conditions responsive to nicotine therapy. More specifically, the invention relates to pulmonary administration of nicotine to effect smoking cessation.
  • Nicotine is a principal component of tobacco, and the most pharmacologically active. It is physically addictive, making it extremely difficult for a smoker to quit.
  • Smoking a cigarette delivers nicotine vapors to the lungs, where nicotine is rapidly absorbed through the arteries and delivered to the brain. Nicotine interacts with nicotinic cholinergic receptors in the brain to induce the release of neurotransmitters and produce an immediate reward—the "rush" that smokers experience—that is associated with a rapid rise in blood level. A persistent stimulus is also produced, and is associated with a high blood level of nicotine. Complex behavioral and social aspects of smoking, e.g., the hand-to-mouth ritual, etc., are also habit-forming. A therapeutic approach to aid in smoking cessation is to provide the smoker with nicotine from sources other than cigarettes. A number of nicotine replacement therapies have been developed to accomplish this result.
  • Nicotine delivery via inhalation offers the benefit of addressing the psychological component of cigarette smoking in addition to the physiological dependence on nicotine. 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; 4,917,120; 4,793,366), aerosol (see U.S. Patent Nos. 5,894,841; 5,834,011) or dry powder (see U.S. Patent No. 5,746,227) when air is inhaled through the inhaler. A droplet ejection device (U.S. Patent No. 5,894,841) has also been described that delivers a controlled dose of nicotine via inhalation.
  • Some inhalation therapies feature devices that simulate or approximate the look, feel and taste of cigarettes.
  • nicotine replacement therapies such as transdermal and buccal systems, provide a low, steady-state blood level of nicotine to the patient. The need remains for an smoking cessation therapy that delivers a precise dose of nicotine to the lungs in a profile that mimics the blood levels achieved by cigarette smoking— providing an initial sharp rise in blood level followed by a slow release of nicotine— making it possible for the user to be weaned off of nicotine and to quit smoking.
  • a system for aiding a patient in quitting smoking is disclosed.
  • the system is comprised of a means for the delivery of aerosolized nicotine which makes it possible to gradually decrease the amount of nicotine that the patient receives.
  • the system comprises a means for aerosolizing a formulation comprised of nicotine and a means for decreasing the amount of nicotine formulation which is aerosolized and/or the amount which actually reaches the patient's circulatory system.
  • the amount of nicotine aerosolized or effectively delivered to the patient can be changed in several different ways using either the device aerosolization mechanism, the formulation or formulation containers loaded into the device.
  • a preferred system of the invention aerosolizes the liquid 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 patient.
  • This system modifies the amount of nicotine aerosolized by providing a plurality of different containers or different groups of containers wherein the different containers or groups of containers contain different concentrations of nicotine.
  • a patient using the system can utilize packets of nicotine formulation containing a high concentration initially and then gradually switch towards lower and lower concentrations so that the patient receives essentially the same amount of aerosolized formulation but receives gradually reduced amounts of nicotine due to the reduced concentration of the nicotine in the formulation.
  • the same procedure described above can also be carried with a dry powder inhaler (DPI).
  • DPI dry powder inhaler
  • the packets of dry powder nicotine formulation loaded into the device can initially contain a relatively high concentration of nicotine. Thereafter, the concentration of nicotine in the dry powder formulation added into the device is gradually decreased.
  • MDI metered dose inhaler
  • MDI metered dose inhaler
  • the desired result of reducing the amount of nicotine delivered to the patient can be obtained.
  • the same results could be obtained by gradually decreasing the amount of formulation released when the value of a container is opened.
  • a dry power inhaler or a system which aerosolizes a liquid formulation by moving the formulation through a porous membrane it is possible to decrease the amount of nicotine gradually by making changes in the device, or more specifically the operation of the device.
  • a dry powder inhaler often utilizes a burst of air in order to aerosolize the dry powder.
  • the burst of air could be decreased so that not all of the powder is fully aerosolized or so that the powder is not aerosolized in a completely efficient manner.
  • the system for aerosolizing liquid formulation is adjusted at different points so that different amount of pressure are applied to the formulation making it possible to aerosolize decreasing amounts of formulation and allowing the patient to be gradually weaned off of nicotine.
  • the most preferred 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.
  • the amount of nicotine that can be changed by changing the amount of or concentration of nicotine in the packets.
  • the pore size is in a preferred range then a relatively high concentration of the formulation aerosolized will reach the patient's lungs and move from the lungs into the patient's circulatory system.
  • by making the pores larger the aerosolized particles created also become larger. The larger particles will not move into the lungs as efficiently as the smaller particles.
  • the larger particles may be deposited in areas where they are not readily absorbed into the patient's circulatory system.
  • a plurality of different containers are produced.
  • the containers are different from each other in that they contain different amounts or concentrations of nicotine.
  • the containers are different from each other in that they have different porous membranes on them which make it possible to aerosolize the formulation in a somewhat less efficient manner over time. It is possible to combine both or all three features together. More specifically, it is possible to produce containers which contain (1) smaller concentrations of nicotine; (2) smaller amounts of nicotine; or (3) have porous membranes which have different size or amounts of pores so as to less efficiently aerosolize the formulation present in the container.
  • a method for aiding in smoking cessation and for treating conditions responsive to nicotine therapy by the administration of nicotine is disclosed.
  • a formulation comprised of nicotine is aerosolized.
  • the aerosol is inhaled into the lungs of the patient. Once inhaled, particles of nicotine deposit on lung tissue and from there enter the patient's circulatory system. Because delivery is to the lungs, the patient's serum nicotine level is quickly raised to a desired level-as quickly as if the user were smoking.
  • the methods of the invention produce arterial concentrations of nicotine similar to cigarette smoking.
  • the patient's dependence on nicotine is reduced by gradually reducing the dose of nicotine.
  • the dose of nicotine is reduced by progressively increasing the size distribution of the aerosolized nicotine particles delivered to the patient. This decreases the amount of nicotine delivered to the patient's lungs, with the result that nicotine absorption is less immediate and the blood plasma level is lower.
  • a method of treatment comprising:
  • the method is preferably further comprised of:
  • An aspect of the invention is a method of treatment whereby nicotine or a nicotine substitute is aerosolized, inhaled into areas of the respiratory tract including the lungs and provided to the circulatory system of the patient at levels sufficient to simulate cigarette smoking.
  • An advantage of the invention is that the nicotine levels are raised almost immediately on administration.
  • Another advantage of the invention is that the patient can gradually be weaned off of the immediate effect of nicotine obtained via smoking and gradually weaned off of the need of nicotine by, respectively, increasing particle size and decreasing dose size or concentration.
  • a feature of the invention is that aerosolized particles of nicotine having a diameter of about 0.5 to 8 microns ( ⁇ ) are created and inhaled deeply into the lungs, thereby enhancing the speed and efficiency of administration.
  • An aspect of the invention is a method whereby larger and larger particles of aerosolized nicotine are administered to a patient over time in order to first wean a smoking patient off of the addiction to immediate nicotine and thereafter reduce the amount of nicotine in order to wean the patient completely off of the addiction to nicotine, thereby allowing the patient to quit smoking.
  • a feature of this invention is that it allows for the formation of nicotine particles in different sizes designed for delivery to different areas of a patient's lungs.
  • An advantage of the invention is that it allows the patient to be weaned off of (1) the need for immediate nicotine delivery as obtained when smoking, and (2) the need for nicotine at all.
  • FIG. 1 is a schematic view of a human lung branching pattern.
  • FIG. 2 is a schematic view of a human respiratory tract.
  • nicotine is intended to mean the naturally occurring alkaloid known as nicotine, having the chemical name S-3-(l-memyl-2-pyrroh(-inyl)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:
  • Nicotine is approximately 10% of the paniculate weight in cigarette smoke. Brand differences change this percentage. It is monoprotonated at most physiological pH values. The diprotonated ion would exist at pH values found in the stomach. Metabohsm 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.
  • nicotine further includes any pharmacologically acceptable derivative, metabolite or analog of nicotine which exhibits pharmacotherapeutic properties similar to nicotine.
  • derivatives and metabolites are known in the art, and include cotinine, norcotinine, nomicotine, 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.
  • the physiologically active form of nicotine is 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.
  • upper airways and the like are used interchangeably herein to define an area of the respiratory system which includes the oropharyngeal region and trachea. This area is the first area which air enters upon inhalation (see FIG. 1).
  • central airways central airways
  • bronchial airways and the like are used interchangeably herein to refer to a region of the respiratory system that includes generations 1 through 16 of the airways (see FIG. 1) which removes particles larger than 3 ⁇ in diameter. They are the conductive airways that also clean particles from the lung using a mucosal clearance mechanism. Upon inhalation, air passes through the upper airways into the central airways.
  • pulmonary region peripheral region
  • peripheral region includes generations 17 through 23 of the airways (see FIG. 1). Drugs delivered to this area generally have a systemic effect.
  • alveolar ducts refer to components in the pulmonary region of the lung which are approximately 3 ⁇ in diameter where gas exchange occurs between the air in the lungs and the circulatory system.
  • the term "diameter” is used herein to refer to particle 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. This is pointed out in that it is difficult to accurately measure the diameter of small particles using current technology and the shape of such small particles may be continually changing. Thus, the diameter of one particle of material of a given density will be said to have the same diameter as another particle of the same material if the two particles have the same terminal sedimentation velocity in air under the same conditions. In connection with the present invention, it is important that particles, on average, have the desired diameter so that the particles can be inhaled and targeted to a specific area of the lungs.
  • An acceptable range for particle diameter varies depending on the area of the respiratory tract being targeted.
  • the particles should have a diameter in a range of about 0.5 ⁇ to about 2 ⁇ .
  • the diameter should be in the range of from about 2 ⁇ to about 4 ⁇ , and to target the small bronchi and above the particles should have a diameter of from about 4 ⁇ to about 8 ⁇ .
  • 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 10 8 pores per square centimeter.
  • the porous membrane may be merely an area of the package which has pores therein wherein the pores have a size and a density as described above.
  • the configuration and arrangement of the pore density may be changed so as to provide pores which are capable of creating the desired amount of aerosol.
  • the porous membrane or area of the container may have some 10 to 10,000 pores therein which pores are positioned in an area of from about 1 mm 2 to about 1 cm 2 .
  • the membrane is preferably comprised of a material having a density in the range of 0.25 to 3.0 mg/cm 2 , more preferably 1.7 mg/cm 2 , and a thickness of about 2 ⁇ to 20 ⁇ , more preferably about 8 ⁇ to 12 ⁇ .
  • the membrane material is preferably hydrophobic and includes materials such as polycarbonates and polyesters which may have the pores formed therein by any suitable method including anisotropic etching or by etching through a thin film of metal or other suitable material Pores can be created m the membrane which may be an area of the contamer by use of techniques such as etching, plating or laser drilling
  • the membrane mate ⁇ als may have pores with a conical configuration and have sufficient structural integrity so that it is maintained intact (will not rupture) when subjected to force m the amount of about 20 to 200 psi while the formulation is forced through the pores
  • the membrane functions to form an aerosolized mist when the formulation is forced through it Those skilled m the art may contemplate other mate ⁇ als which achieve this function as such mate ⁇ als are intended to be encompassed by this mvention
  • treatment means obtaining a desired pharmacological and/or physiological effect
  • the terms are used in a manner somewhat differently than the terms are typically used m that what is intended by the method of treatment of the mvention is to allow a patient to overcome an addiction to mcotme and thereby allow the patient to quit smoking
  • the treatmg effect of the mvention provides a psychological effect m that the mvention onginally delivers high doses of mcotme m a manner that simulates the mcotme delivery obtained from a cigarette
  • the patient then becomes accustomed to relying on the methodology of the mvention to provide an immediate "rush” of mcotme Thereafter, the particles of the aerosol are made larger This prevents the particles from penetrating deeply into the lung and, therefore, to some extent, diminishes the "rush” of mcotme
  • the same amount of mcotme is still given to the patient m order to satisfy the overall mcotme craving Eventually, the treatment
  • the steady state delivery of mcotme as therapy for smokers wishing to quit is characte ⁇ zed by slow absorption and low blood levels of mcotme, which limits its utility
  • the present mvention replaces the mcotme that a smoker receives from smoking a cigarette in a therapeutically effective manner by providing a rapid pulse of bioavailable nicotine to the smoker on demand
  • One means currently available for a true pulsatile, rapid onset replacement therapy is intravenous administration
  • preparations of mcotme approp ⁇ ate for intravenous administration have been available for some time, intravenous cannulation as a means for gaining access to the circulation for the administration of mcotme on demand is not a socially acceptable alternative to cigarette smoking
  • the treatment methodology of the present mvention creates an aerosol of mcotme particles
  • the mcotme particles may be formed from any liquid containing mcotme including a solution or suspension of mcotme and aerosolized in any known manner including (1) moving the formulation through a porous membrane m order to create particles or (2) a dry powder where the particles of powder have been designed to have a desired diameter
  • the rate of particle absorption is directly proportional to the surface area of the tissue on which the particles are deposited Accordingly, mcotme is absorbed more slowly through the mucosal membranes of the upper respiratory tract which have a smaller surface area than through the airways m the lower respiratory tract which have a larger surface area
  • the overall effect of mcreasmg the size of the mcotme particles is to reduce the rate at which mcotme is absorbed mto the circulation, thereby reducmg the smoker's physiological dependence on the quick rush of mcotme expe ⁇ enced when smoking
  • the treatment methodology begms with particles of a given size, car ⁇ es out treatment for a given penod of time after which the particles are increased m size
  • the particles initially administered to the patient penetrate deeply mto the lung, / e , the smallest particles (e g 0 5 to 2 ⁇ ) target the alveolar ducts and the alveoli
  • the patient receives an immediate "rush" from the mcotme delivered which closely matches that received when smoking a cigarette
  • These small particles can be obtamed by milling powder mto the desired size and inhaling the powder or by creatmg a solution or suspension and moving the solution or suspension through the pores of a membrane
  • the desired result is to obtain particles which have a diameter in the range of 0 5 ⁇ to about 2 ⁇
  • the desired result is to obtain particles which have a diameter in the range of 0 5 ⁇ to about 2 ⁇
  • the desired result is to obtain particles which have a diameter in the range of 0 5 ⁇ to about 2
  • the patient would be instructed to repeatedly administer the smallest size particles when the patient would normally smoke a cigarette. In this manner, the patient will become accustomed to finding that the device administers nicotine into the patient in the same manner that a cigarette does.
  • the concentration of the nicotine in the liquid formulation could be reduced gradually over time. This could be done over a sufficiently long period of time so as to allow the patient to "wean" off of nicotine.
  • the amount of nicotine is kept substantially constant but the size of the aerosolized particles created are increased.
  • the second phase of the treatment methodology is to increase the size of the particles so as to target the respiratory tract above the alveolar ducts and below the small bronchi.
  • the treatment can be completed after any phase, e.g. after the second phase.
  • a third phase of treatment is carried out.
  • the particles are increased again.
  • the particles are increased to a size in a range from about 4 ⁇ to about 8 ⁇ or, alternatively, perhaps as large as 12 ⁇ .
  • These larger particles will target the upper airways.
  • the larger particles will give a very small immediate "rush” but will still be absorbed through the mucous membranes of the patient's respiratory tract.
  • the patient will be administering nicotine doses which may be the same as those doses administered at the beginning of treatment.
  • the treatment can take a number of different directions.
  • the patient can attempt to stop administration by immediate and complete cessation of nicotine delivery.
  • the patient can try to wean off of nicotine by delivering fewer doses during a given time period.
  • the same size dose volume of aerosol formulation
  • the same size dose is administered and delivered, creating the same amount of aerosol, but wherein the aerosolized particles contain progressively less nicotine (i.e., more dilute concentration).
  • the amount of nicotine can be decreased until the patient is receiving little or no nicotine.
  • the invention is particularly suited for smokers in that smokers are accustomed to inhaling their source of nicotine.
  • Other treatments such as those involving the transdermal delivery of nicotine via a nicotine "patch” or buckle delivery via a nicotine “gum” do not match the means which a smoker usually obtains nicotine.
  • the present invention provides a method wherein the patient obtains an influx of nicotine into the circulatory system at a rate which substantially matches the rate which nicotine would enter the circulatory system when smoking. This is obtained because, at least at first, the invention provides sufficiently small particles such that they are inhaled deeply into the lung, i.e. 50% or more of the particles are inhaled deeply into the lung and thereby quickly enter the patient's circulatory system.
  • the present invention is advantageous in that the rate at which the delivered nicotine enters the circulatory system can be gradually decreased by gradually increasing the size of the aerosolized particles delivered to the patient. This can be done over any desired period of time and in any desired number of phases.
  • the invention provides a means whereby the amount of nicotine delivered to the patient can be gradually decreased in a number of different ways. Firstly, it can be decreased by decreasing the concentration of nicotine in the aerosolized formulation. Secondly, it can be decreased by merely decreasing the number of administrations of aerosolized doses. Thirdly, it can be decreased by decreasing the size of the dose aerosolized and inhaled by the patient.
  • One aspect of the invention is a method of treatment, comprising:
  • the particles targeting this area will have a relatively small size, e.g. 0.5 micron to about 2 microns in diameter.
  • the patient inhales the aerosolized particles of (a) into the respiratory tract, preferably targeted to a specific area of the lower respiratory tract where the deposited particles cross into the patient's circulatory system.
  • steps (a) and (b) are repeated a plurality of times. Specifically, the patient may repeat these steps any number of times such as every time the patient would normally smoke a cigarette. At this point the patient could continue the treatment protocol in this manner and gradually decrease the number of times the patient administers aerosolized nicotine until the patient is no longer addicted to nicotine. Decreasing the amount of aerosolized nicotine could also be done by decreasing the concentration of nicotine within the aerosolized particles decreasing the concentration of nicotine in the formulation and/or decreasing the size of the aerosolized dose.
  • step (d) which involves aerosolizing formulation comprised of nicotine in order to create aerosolized particles which are larger in size than the aerosolized particles produced in step (a).
  • aerosolizing formulation comprised of nicotine in order to create aerosolized particles which are larger in size than the aerosolized particles produced in step (a).
  • These larger particles are directed towards a particular area of the patient's respiratory tract, e.g. the mid-region of the patient's respiratory tract. (See Figures 1 and 2)
  • These particles could have a size in the range of about 2 microns to about 4 microns.
  • step (d) the patient inhales the aerosolized particles of (d) thereby targeting the particular desired area of the patient's respiratory tract such as the mid region.
  • steps (d) and (e) are repeated a plurality of times.
  • the patient can decrease the amount of nicotine being delivered as indicated in the same manner as indicated above step (c).
  • the method of the invention can be continued so that a third phase of treatment can be carried out which phase is similar to the two phases described above.
  • the treatment could involve as many as 24 phases which target specific defined regions of a patients respiratory tract using particles which are continually larger in size in each of the 24 phases (see Figure 1 and Table 1 below). Because it may not be practical to specifically design the particles so that they are all larger in each of the phases the formulations may be designed so that a certain percentage of the particles within each phase of delivery is larger than the particles in the preceding phase.
  • the method of the invention can be carried out using 1 to 24 different phases with each phase targeting a higher level of the respiratory tract (See Table 1).
  • the higher levels of the respiratory tract can be targeted using larger and larger particles.
  • a mcot e formulation is forced through the openings or pores of a porous membrane to create an aerosol
  • the opemngs are all umform in size and are positioned at umform distances from each other
  • the opemngs can be va ⁇ ed in size and randomly placed on the membrane If the size of the openings is vaned, the size of the particles formed will also vary In general, it is preferable to maintain umform opening sizes m order to create uniform particle sizes, and it is particularly preferable to have the opening sizes withm the range of about 0 25 ⁇ to about 6 ⁇ which will create particle sizes of about 0 5 ⁇ to 12 ⁇ which are preferred with respect to inhalation applications When the openings have a pore size in the range of 0 25 ⁇ to 1 ⁇ they will produce an aerosol having particle sizes m the range of 0 5 ⁇ to 2 ⁇ , which is particularly useful for delivering nicotine to the alveolar ducts and alveoli.
  • Pore sizes having a diameter of about 1 ⁇ to 2 ⁇ will produce particles having a diameter of about 2 ⁇ to 4 ⁇ , which are particularly useful for delivering nicotine to the area above the alveolar ducts and below the small bronchi.
  • a pore size of 2 ⁇ to 4 ⁇ will create particles having a diameter of of 4 ⁇ to 8 ⁇ , which will target the area of the respiratory tract from the small bronchi upward.
  • the size of the aerosolized nicotine particles is increased in a stepwise manner by using porous membranes that create "monodisperse" aerosols, wherein all the particles within the aerosol created have essentially the same particle size. Nicotine particles of increasing size are produced by using membranes of increasing pore sizes.
  • the size of the aerosolized nicotine particles is increased in gradient fashion by using porous membranes that create "multi-disperse" aerosols, wherein the particles within the aerosol created have different particle sizes.
  • Membranes which have an increasing range of pore sizes are used to produce nicotine particles of increasing size.
  • Nicotine can be administered orally. However, after oral aclministration it is absorbed from the gut into the portal blood and degraded promptly by the liver. Thus, insignificant amounts reach the patient's systemic circulation. Nicotine can also be administered parenterally. However, when so administered it is rapidly absorbed and metabolized making it difficult to sustain therapeutic levels in plasma over time. In view of such, effective therapy has been carried out using other means of delivery (e.g., transdermal patches, gum).
  • the present invention uses intrapulmonary delivery to avoid first pass liver metabolism and to obtain quick infusion into the patient's systemic circulatory system. The present invention aclministers sufficient nicotine by inhalation to temporarily produce a rapid increase in the patient's blood level, and thereafter allow the patient's nicotine level to return to a therapeutically effective level.
  • the amount of drug aerosolized will be greater than the amount that actually reaches the patient's circulation. For example, if the inhalation system used is only 50% efficient then the patient will aerosolize a dose which is twice that needed to raise the patient's nicotine level to the extent needed to obtain the desired results. More specifically, when attempting to administer 1 mg of nicotine with a delivery system known to be 50% efficient, the patient will aerosolize an amount of formulation containing about 2 mg of nicotine.
  • 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 may include the scent of tobacco.
  • Cigarettes contain 6 to 11 mg of nicotine, of which the smoker typically absorbs 1-3 mg; see Henningfield NEngl JMed 333:1196-1203 (1995).
  • Factors influencing nicotine absorption include subject-dependent factors, such as smoking behavior, lung clearance rate, etc., morphological factors, and physiological factors, such as tidal volume, inspiratory and expiratory flow rate, particle size and density. See Darby et al, Clin Pharmacokinet 9:435-439 (1984).
  • the systemic dose of nicotine per puff is extremely variable, however, peak plasma concentrations of 25-40 ng/mL of nicotine, achieved within 5-7 minutes by cigarette smoking, are believed typical.
  • 0.1 mg to 10 mg, preferably 1 to 3 mg, and more preferably about 2 mg of nicotine are delivered to the lungs of the patient in a single dose to achieve peak blood plasma concentrations of 15-40 ng/mL.
  • the amount of a nicotine ad ⁇ ninistered will vary based on factors such as the age, weight and frequency of smoking or nicotine tolerance of the smoker. Other factors, such as daily stress patterns, demographic factors may also determine, in part, the amount of nicotine sufficient to satisfy the smoker's craving for nicotine.
  • Administering nicotine using the methods of the present invention can involve the daily administration of anywhere from 5 mg to 200 mg of nicotine, but more preferably involves the administration of approximately 10 to 100 mg per day.
  • the nicotine is in a liquid form or is dissolved or dispersed within a pharmaceutically acceptable, liquid excipient material to provide a liquid, flowable formulation which can be readily aerosolized.
  • the container will include the formulation having nicotine therein in an amount of about 10 mL to 300 mL, more preferably about 200 mL.
  • the large variation in the amounts which might be delivered is due to different delivery efficiencies for different devices.
  • Administration may involve several inhalations by the patient, with each inhalation providing nicotine from the device.
  • the device can be programmed so as to release the contents of a single container or to move from one container to the next on a package of interconnected containers. Delivering smaller amounts from several containers can have advantages.
  • the patient is treated in the three different phases.
  • the aerosolized liquid particles or dry powder particles have a size and a range of 0.5 ⁇ to about 2 ⁇ .
  • the particles of nicotine having this size are administered in a dosage amount which is substantially equivalent to the doses or amount which the patient would received from a single cigarette or, alternatively, the dosage amount which the patient would received from a single puff on a single cigarette. Assuming that the patient receives the dosage amount of a single cigarette then the patient will be administered approximately 1 to 3 mg of nicotine each time the formulation is aerosolized.
  • the particles having a size of 0.5 ⁇ to about 2 ⁇ will be administered to the patient over a plurality of days (e.g., 2 to 7 days) or perhaps a plurality of weeks (e.g., 2 to 4 weeks). If the device and/or dosage containers are designed to deliver a dosage equivalent to a puff on a cigarette then substantially smaller doses are delivered. If each dose corresponds to a puff on a cigarette then a patient may be directed to continually take aerosolized doses equivalent to a cigarette puff over a period of one to ten minutes or any period of time equivalent to what that patient normally takes to smoke one cigarette. This constitutes the first phase of treatment.
  • the method of the invention may be completed. However, as indicated above the method may be continued by repeating phases such as the first phase using continually larger particles and/or continuing more dilute solutions of nicotine and/or smaller doses of nicotine.
  • the patient is preferably administered the same dosage amount of nicotine with each inhalation, e.g., the patient is administered 1 to 3 mg of nicotine each time formulation is aerosolized.
  • the size of the particles is increased to a size and range from 2 ⁇ to about 4 ⁇ .
  • the particle size is increased in order to target an area of the lungs where the nicotine will be absorbed into the circulatory system more slowly. Specifically, the larger particles target an area of the lungs above the alveolar ducts and below the small bronchi.
  • a ⁇ rninistration is carried out over a plurality of days or a plurality of weeks in the same manner as indicated above.
  • the patient preferably administers nicotine from a device of the invention when the patient would normally smoke a cigarette.
  • the treatment can be completed pursuant to the present invention by using only the two phases. However, it is preferable to include three or more phases.
  • the same dose is administered each time nicotine formulation is aerosolized. Accordingly, 1 to 3 mg of nicotine is delivered to the patient at each dose. However, the dose is delivered by using aerosolized particles which have a diameter of 4 ⁇ or more, e.g., in the range of from 4 ⁇ to about 8 ⁇ . These larger particles are designed to target the area of the respiratory tract at the small bronchi or higher.
  • aerosolized particles which have a diameter of 4 ⁇ or more, e.g., in the range of from 4 ⁇ to about 8 ⁇ . These larger particles are designed to target the area of the respiratory tract at the small bronchi or higher.
  • the nicotine targets the upper airways it will not immediately enter the patient's circulatory system. However, the nicotine will, eventually, cross the mucous membranes of the upper respiratory tract and enter the circulatory system. Thus the patient will be administered nicotine but will become less accustomed to having the immediate "rush" obtained from smoking.
  • the third phase the patient has been weaned away from the need for the "rush" of nicotine.
  • the third phase is then used to continually reduce the number of administrations needed and thereby reduce the amount of nicotine administered.
  • the patient's dependency on nicotine is slowly reduced and then eliminated thereby allowing the patient to quit smoking.
  • the present invention includes the administration of cotinine and other nicotine derivatives provided such derivatives do not result in unacceptable adverse effects.
  • the method of the invention has applicability to smokers wishing to quit or trying to quit who have experienced all or any of the nicotine withdrawal symptoms associated with smoking cessation, such as craving for nicotine, irritability, mood ability, frustration or anger, anxiety, drowsiness, sleep disturbances, impaired concentration, nervousness, restlessness, decreased heart rate, increased appetite and weight gain.
  • pulmonary 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; 5,278,176; 5,691,365; 5,885,998; 5,889,029; 5,914,328).
  • 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.
  • a formulation may include a buffer to enhance absorption. Any absorption enhancers including ammonia could be used with the formulation.
  • a typical formulation is only nicotine dissolved in water or dry powder nicotine.
  • Formulations of nicotine include aqueous formulations, aqueous saline formulations, and ethanol formulations. All of these formulations may be included with additional components such as permeation enhancers, buffers, preservatives and excipient and carrier components and additives normally included within formulations for aerosolized drug delivery.
  • Nicotine is freely soluble in water.
  • An aqueous nicotine solution may be readily aerosolized and inhaled.
  • the nicotine solution can be placed in a low boiling point propellant in a pressurized canister and released using a conventional metered dose inhaler (MDI) device.
  • MDI metered dose inhaler
  • the MDI device is modified so that the aerosolized dose is released each time at the same inspiratory flow rate and inspiratory volume. When this is done the patient is more likely to receive the same dose each time.
  • a device for obtaining repeating dosing with an MDI canister is taught in U.S. Patent No. 5,404,871.
  • a dry powder formulation comprising a pharmacologically acceptable salt of nicotine alone or with additives such as components to prevent the particles from sticking together may be used.
  • SUPPLEMENTAL TREATMENT METHODOLOGY Smokers wishing to quit may be treated solely with respiratory nicotine as indicated above, z. e. by intrapulmonary delivery.
  • Transdermal nicotine is preferably administered to maintain a steady state level of nicotine within the circulatory system.
  • Nasal or buccal formulation could be used for nasal or buccal delivery which could supplement aerosolized delivery.
  • a plurality of different treatments and means of administration can be used to treat a single patient.
  • a patient can be simultaneously treated with nicotine by transdermal administration, nicotine via pulmonary admimstration, in accordance with the present invention, and nicotine which is administered to the mucosa.

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Abstract

L'invention concerne un système permettant à un patient de recevoir, de façon espacée dans le temps, des doses de nicotine graduellement réduites, ce qui permet de sevrer progressivement le patient pour supprimer sa dépendance vis-à-vis de la nicotine, et donc lui permettre d'arrêter de fumer. Ledit système comprend des moyens permettant de transformer une formulation en aérosol ainsi que des récipients destinés à contenir ladite formulation. Cette formulation renferme de la nicotine incorporée dans un excipient pharmaceutiquement acceptable. De préférence, on produit une pluralité de récipients, la concentration en nicotine des différents récipients appartenant à différents groupes de récipients allant en s'amenuisant. Le patient commence donc par utiliser les récipients ayant la concentration la plus élevée, puis il utilise progressivement les récipients ayant une concentration en nicotine de moins en moins forte, jusqu'à stopper sa dépendance vis-à-vis de la nicotine.
PCT/US2000/019034 1999-07-16 2000-07-12 Systeme permettant d'arreter de fumer WO2001005459A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU59312/00A AU777326B2 (en) 1999-07-16 2000-07-12 System for effecting smoke cessation
JP2001510544A JP4999245B2 (ja) 1999-07-16 2000-07-12 禁煙を達成するためのシステム
EP00945354A EP1218048A4 (fr) 1999-07-16 2000-07-12 Systeme permettant d'arreter de fumer
CA2378913A CA2378913C (fr) 1999-07-16 2000-07-12 Systeme permettant d'arreter de fumer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14414099P 1999-07-16 1999-07-16
US60/144,140 1999-07-16

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WO2001005459A1 true WO2001005459A1 (fr) 2001-01-25

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US (1) US20020179102A1 (fr)
EP (1) EP1218048A4 (fr)
JP (1) JP4999245B2 (fr)
AU (1) AU777326B2 (fr)
CA (1) CA2378913C (fr)
WO (1) WO2001005459A1 (fr)

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US20020179102A1 (en) 2002-12-05
CA2378913A1 (fr) 2001-01-25
AU5931200A (en) 2001-02-05
JP2003504165A (ja) 2003-02-04
JP4999245B2 (ja) 2012-08-15
CA2378913C (fr) 2010-02-23
EP1218048A4 (fr) 2009-08-26
AU777326B2 (en) 2004-10-14

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