EP2086527A2 - Systèmes destinés à mettre fin à l'usage du tabac - Google Patents

Systèmes destinés à mettre fin à l'usage du tabac

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Publication number
EP2086527A2
EP2086527A2 EP07867592A EP07867592A EP2086527A2 EP 2086527 A2 EP2086527 A2 EP 2086527A2 EP 07867592 A EP07867592 A EP 07867592A EP 07867592 A EP07867592 A EP 07867592A EP 2086527 A2 EP2086527 A2 EP 2086527A2
Authority
EP
European Patent Office
Prior art keywords
nicotine
formulation
patient
group
container
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP07867592A
Other languages
German (de)
English (en)
Other versions
EP2086527A4 (fr
Inventor
Igor Gonda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aradigm Corp
Original Assignee
Aradigm Corp
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
Priority claimed from US11/931,921 external-priority patent/US20080138399A1/en
Priority claimed from US11/932,402 external-priority patent/US20080138294A1/en
Priority claimed from US11/932,437 external-priority patent/US8256433B2/en
Priority claimed from US11/931,867 external-priority patent/US20080138398A1/en
Application filed by Aradigm Corp filed Critical Aradigm Corp
Publication of EP2086527A2 publication Critical patent/EP2086527A2/fr
Publication of EP2086527A4 publication Critical patent/EP2086527A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058—Chewing gums
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates generally to systems and kits for treating conditions responsive to nicotine therapy. More specifically, the invention relates to systems used in pulmonary administration of a nicotine containing formulation to effect nicotine addiction related to the use of tobacco products.
  • Smoking a cigarette delivers nicotine directly 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. As such, the dopaminergic reward system is activated which eventually results in nicotine dependency. Complex behavioral and social aspects of smoking, e.g., the hand-to- mouth ritual, etc., are also habit-forming.
  • Nicotine can be administered orally. However, after oral administration it is absorbed from the gut into the portal blood and degraded promptly by the liver. Nicotine can also be administered parenterally, e.g., intravenously, transcutaneously, mucosally, etc. Although preparations of nicotine appropriate for intravenous administration have been available for some time, intravenous cannulation as a means for gaining access to the circulation for the administration of nicotine on demand is not a socially acceptable alternative to cigarette smoking. There are also a number of commercially available nicotine replacement therapies that deliver nicotine to the systemic circulation via absorption through mucosal membranes or the skin. These include nicotine-containing chewing gum, sachets, transdermal patches, capsules, tablets, lozenges, nasal sprays and oral inhalation devices.
  • nicotine delivery via inhalation offers the benefit of addressing the psychological component of cigarette, cigar, and pipe 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.
  • the invention includes a systems, kits and methods for quickly raising a patient's plasma level of nicotine to satisfy the patient's craving for nicotine at a rate substantially the same as obtained via smoking and thereafter gradually reducing the peak plasma level in order to reduce the patient's craving for the drug.
  • the invention is also applicable to other addictive drugs such as narcotics, etc.
  • Methods of the invention are typically carried out using a system that includes a plurality of groups of containers wherein each container within a group confines the same amount of drug and as such provides substantially the same maximum plasma concentration of the drug to a patient upon delivery by inhalation. Subsequently used groups of containers allow the patient to titrate the dose upward or downward to an optimal level to eliminate their acute cravings.
  • the patient After the patient is able to replace cigarettes, or any other form of tobacco, with an inhaled nicotine formulation they will enter a treatment phase designed to reduce the maximum concentration of the drug in the plasma in a gradual manner so as to wean the patient off of the drug.
  • the weaning process can be carried out in a number of different ways, each of which results in a gradual reduction in the peak plasma level.
  • formulations within the different groups can have decreasing amounts or concentrations of the drug such as nicotine or morphine. It is also possible to reduce the peak plasma level by increasing the particle size of the aerosol created in order to move the deposition of the drug to a higher level of the respiratory tract and thereby reduce the overall rate of absorption leading to a reduction in peak plasma level.
  • the drug within a formulation which provides for a delayed or controlled release of the drug which again leads to a reduction in the peak plasma level.
  • Other adjustments in the formulation are possible such as reducing the pH in that higher pH formulations (more basic) tend to be absorbed more quickly as compared to lower peak formulations. All or any of these parameters can be varied individually or together with any other in order to obtain a desired result.
  • the system of the invention may be beneficial to deliver a lower dose of nicotine to the patient using the system of the invention.
  • This approach may be used for example to accustom the patient to use of the system and to protect the patient from possible adverse effects of applying larger doses of nicotine from the onset of treatment.
  • the nicotine dose may be increased with time, thereby replacing the nicotine acquired from the cigarette.
  • the dosage supplied by the system of the invention may be decreased to alleviate the nicotine addition itself.
  • a single inhalation may provide either a single dose of nicotine equivalent to that contained in an entire cigarette or a more complex formulation that provides rapid or immediate release via a first component and controlled or sustained release of nicotine via a second component.
  • nicotine delivery using a more complex formulation is even more pharmacologically similar to that presented by a smokable product which provides nicotine such as a cigarette.
  • Smoking provides a large dose of nicotine to the smoker during a short period of time. This can not be obtained with a conventional gum (buccal delivery) or patch (transdermal delivery) nicotine delivery system. As a result the patient often reverts to smoking to obtain the necessary high (immediate or fast) peak level of nicotine.
  • the present invention can be used in combination with a steady state delivery system (e.g. gum or patch) in order to satisfy both the short and long term cravings of the patient.
  • a steady state delivery system e.g. gum or patch
  • the delivery system of the present invention provides pharmaceutical grade nicotine in a pharmaceutically acceptable carrier. The system reduces the number of smokers being treated that end up reverting to cigarette smoking. By using the invention to gradually reduce the nicotine plasma levels necessary to satisfy a patient's nicotine craving the overall system leads to permanent elimination of nicotine cravings allowing the patient to break their nicotine addiction.
  • the invention includes a system for aiding a patient reduce or completely quit smoking which system can include a plurality of containers provided in groups of containers along with a device for aerosolizing formulation in the containers.
  • a container confining one or more nicotine formulations can be loaded into drug delivery devices which convert the contents to an aerosol and allow for aerosolized delivery of the formulation.
  • the device can be designed so as to avoid overdosing such as by restricting the number of doses and/or the interval between doses.
  • the device can also force the patient to reduce the frequency of administration by providing time lock-outs and provide rewards for reducing the number of uses.
  • the device can be coordinated with containers and force the patient to use containers which provide lower peak plasma levels.
  • the physician can be provided with programming authorization which can make it possible to program the device individually for the patient and obtain the most desirable results in terms of weaning the patient off of the drug.
  • An aerosol drug delivery device of the invention can also be programmed in order to record information with respect to a range of different parameters.
  • the device can electronically record the date and time of drug delivery and can specifically indicate the dose administered by electronically matching the delivery with an electronic indication on the drug packet inserted into the device.
  • Other parameters can also be recorded such as the average time between dosing for the patient.
  • This information can be tied to a reward system whereby the patient is provided with rewards when the system calculates that, on average, the frequency of use is decreasing and/or the dose required to satisfy the patient's craving is reduced.
  • the device can also be designed to allow the patient to enter information such as where the patient was and the circumstances under which the cravings increased. Such information could be used in combination with counseling in order to determine how to best treat the patient.
  • a formulation comprised of nicotine, as well as a system for aiding a patient in quitting smoking is disclosed.
  • the amount of nicotine aerosolized or effectively delivered to the patient can be changed in several different ways using devices of the system, the formulation, or formulation containers loaded into the devices.
  • 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 patient.
  • a system is referred to here as a unit dose solution aerosolizer. Examples are described in U.S. Patent 5,544,646. 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.
  • MDI metered dose inhaler
  • Yet another means to achieve gradually lower peak plasma levels of nicotine is by reducing the deposition in the lung, especially in the "deep" lung. This can be achieved by changing the particle or droplet size produced by MDIs. This can be achieved through increasing the valve orifice in the MDI, or by changing the formulation, e.g., by increasing the concentration of non- volatile components.
  • a dry powder inhaler When using a dry powder inhaler, an MDI, 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.
  • valve opening size and/or the amount of time the valve is opened to release aerosol can be changed as can the formulation in the device.
  • the system for aerosolizing liquid formulation is adjusted at different points so that different amounts of nicotine are aerosolized and the patient can be gradually weaned off of nicotine.
  • the "craving" is thought to be related to the peak plasma levels of nicotine, reducing the amount and/or moving the site of deposition of nicotine loaded droplets through droplet size engineering to reduce the extent and rate of absorption from the respiratory tract are ways of gradually weaning the smokers of their habit.
  • 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.
  • 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 pore size is in a preferred range then a relatively high amount of the formulation aerosolized will reach the patient's deep lungs and rapidly move from the lungs into the patient's circulatory system.
  • the pores larger the aerosolized particles created also become larger.
  • the larger particles will not move into the deep lungs as efficiently as the smaller particles.
  • a significant number of particles with aerodynamic size greater than 5 micron would deposit in the oropharynx from where they are not rapidly absorbed into the patient's circulatory system.
  • the pH of the formulation can be set at any desired level which is not damaging to lung surfaces. Although it is desirable to have a low pH formulation (acidic) to avoid interaction with certain types of plastic containers it is generally more desirable to have a high pH formulation (basic) to increase the absorption of the nicotine from the lung into the circulatory system.
  • a patient could be dosed initially on a high pH formulation which provides for a more rapid and complete infusion of the nicotine into the circulatory system as compared to a low pH formulation. The patient could then be weaned off of the high pH formulation toward a neutral pH and finally toward a low pH formulation.
  • the patient could be initially dosed on a formulation with a pH of 9 which is later reduced to 8 and thereafter reduced to 7, 6 and 5.
  • Other variations and incremental changes in the pH are also possible with the caveat that the formulation, when deposited within the respiratory tract, is not causing changes in the local pH that would damage lung surfaces.
  • Adjustments in the pH can be carried out alone or in combination with adjustments in the concentration of nicotine in the formulation. Either or both of these parameters can be changed in combination with changing the particle size of the aerosol created.
  • a formulation with a higher concentration of nicotine provides more nicotine to the patient provided the same amount of formulation is aerosolized. By increasing the particle size the particles will generally deposit higher up in the patient's respiratory tract which slows the extent and the rate of absorption of the nicotine and leads to a reduction in peak levels of a patient's nicotine plasma level.
  • the nicotine can be encapsulated in some manner or included with an excipient which provides for a more controlled release as compared to an immediate release formulation.
  • a plurality of different groups of containers are produced.
  • the groups of containers are different from each other in that they contain different amounts of nicotine, concentrations and/or formulations with different pHs.
  • the groups of 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, or 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.
  • 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, rather than to the oral mucosa or through the skin, the nicotine is immediately delivered, along with freshly oxygenated blood, to the heart via the pulmonary arteries where it is then pumped via the aorta to the arterial circulatory system, which is responsible for the delivery of oxygenated blood to the patient's entire body.
  • the carotid arteries transport the nicotine-containing oxygenated blood directly to the brain where it is then perfused throughout the brain by the neuro vasculature system.
  • the patient's serum nicotine level in the brain is quickly raised to a desired level-as quickly as if the user were smoking, . providing the "rush" effect.
  • the smoker is not immediately deprived of the psychological pleasures of smoking and, as such, is more likely to successfully complete the smoking-cessation treatment.
  • the inventive methodologies are able to produce arterial plasma concentrations of nicotine similar to those experienced during cigarette smoking.
  • the patient's dependence on nicotine is reduced by gradually changing one or more parameters to move the patient away from needing any nicotine in any form.
  • the dose of nicotine delivered to the deep lung, from which it is absorbed most rapidly 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 slower and the peak nicotine blood plasma level is lower.
  • a method of treatment comprising:
  • the method is preferably further comprised of:
  • the devices and methods of the invention can be configured in order to target certain areas of the respiratory tract, it will be understood by those skilled in the art that it will not be possible to provide a system or produce a method which exclusively administers particles only to a particular area of a respiratory tract. In general, smaller size particles will deposit in the lung more deeply as compared to larger size particles. Further, it is generally not desirable to make the particles smaller than 0.5 micron in that the particles which are very small can be inhaled and exhaled back out without being deposited at all, unless the subject holds their breath for sufficient length of time, typically several seconds, for those particles to deposit.
  • Another method of treatment includes the steps of:
  • the method may further include the step of:
  • this method may further include the steps of:
  • step (d) performing step (c) over a first period of time wherein the nicotine is present in a first amount and/or concentration; and [0050] (e) performing step (c) over a second period of time wherein the nicotine is present in a second amount and/or concentration which is different than the first amount and/or concentration.
  • this method may further include the steps 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 arterial circulatory system of the patient at levels sufficient to simulate cigarette smoking.
  • An aspect of the invention is that the nicotine levels are raised almost immediately upon administration.
  • Another aspect 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, decreasing dose size, concentration, or number of doses.
  • Still another aspect of the invention is that aerosolized particles of nicotine having an aerodynamic 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 the immediate effects of 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 break their nicotine addiction.
  • An aspect 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 aspect of the invention is that it allows the patient to be weaned off of
  • Fig. 1 compares the arterial nicotine profiles produced for cigarettes and various nicotine replacement therapies. The data is adapted from Rielles, N.A.,
  • Fig. 2 depicts the mean arterial plasma nicotine concentrations for 16 human patients.
  • Fig. 3 depicts the mean craving scores for 16 human patients.
  • Fig. 4 summarizes the modified Fagerstrom test for evaluating intensity of physical dependence on nicotine. Adapted with permission from Heatherton TF,
  • an "antidepressant” refers to a substance that is used in the treatment of mood disorders, as characterized by various manic or depressive affects.
  • anxiolytic refers to any compound that has the effect of relieving anxiety.
  • a "bioadhesive component” is one which aids the compound containing it in associating with biological tissue.
  • 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:
  • Nicotine is approximately 10% of the particulate 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. Metabolism is largely due to oxidation. Cotinine is a major metabolite; however, there are at least 4 primary metabolites of nicotine and all are encompassed by the use of this term herein.
  • form of 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, 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. Free base nicotine is particularly potent and more addictive than nicotine salts which display a lower affinity to nicotinic receptors.
  • a pharmaceutically active nicotine formulation is a formulation having at least one form of nicotine as a component, and may include additional additives and drug dosages.
  • 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.
  • 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, and one component which releases nicotine or a nicotine derivative or nicotine substitute over a prolonged period of time.
  • diameter is used herein to refer to particle size as given in the
  • 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 range of about 0.5 ⁇ m to about 2 ⁇ m.
  • 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 ⁇ m to 4 ⁇ m and a pore density in the range of 1 x 10 4 to about 1 x 10 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.
  • 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 in that what is intended by the method of treatment of the invention is to allow a patient to overcome an addiction to nicotine and thereby allow the patient to quit smoking.
  • the treating effect of the invention provides a psychological effect in that the invention originally delivers high doses of nicotine in a manner that simulates the nicotine delivery obtained from a cigarette. The patient then becomes accustomed to relying on the methodology of the invention to provide an immediate "rush” of nicotine. Eventually, the treatment of the invention reduces the amount of nicotine so as to allow the patient to completely “wean” off of nicotine and to quit smoking.
  • the present invention provides systems and methods for supplying nicotine therapy to a patient.
  • Certain formulations used in the systems of the invention contain at least two forms of nicotine that in combination mimic the pharmacological delivery of nicotine produced by smoking a cigarette.
  • the invention provides a nicotine dosage that rapidly peaks, mirroring the peak arterial concentration produced by smoking tobacco ( Figure 1).
  • Figure 1 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 also 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. Changes in the size of aerosolized particles may be through milling of the powder nicotine formulations provided, or by modification of the delivery device(s) of the invention. For example, a finer aerosol may be formed from a liquid nicotine formulation of the invention by rapidly 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 the patient's lung can be gradually varied in a number of different ways. Firstly, it can be increased or decreased by increasing/decreasing the concentration of nicotine in the aerosolized formulation. Secondly, it can be varied by merely changing the number of administrations of aerosolized doses. Thirdly, it can be varied by changing the size of the dose aerosolized and inhaled by the patient. 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. Lastly, all or any number of these parameters can be changed from one group of packages to the next, and therefore be engineered such that a gradual reduction in the peak plasma levels of nicotine is achieved.
  • the present invention replaces the nicotine that a smoker receives from smoking a cigarette by providing a rapid pulse of bioavailable nicotine to the smoker on demand that may be optionally followed by a slow release of nicotine which provides a prolonged circulating concentration of nicotine when a second, slower releasing form of nicotine is also used. More specifically, the present invention provides a treatment methodology wherein a patient's initial arterial nicotine plasma concentration over a selected time, i.e., the arterial nicotine plasma concentration-rate profile, substantially correlates to that of the patient when smoking a cigarette.
  • 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 patient'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.
  • one method of practicing the present invention is to provide a formulation comprising two forms of nicotine, one that produces fine particles of small diameter and another that produced larger particles.
  • the larger particles deposit in the upper respiratory tract providing low level sustained drug release, while the smaller particles penetrate to the deep lung providing a rapid pulse of available nicotine similar to that provided by a cigarette.
  • 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.
  • Some alternatives to this embodiment of the invention include the administration of the first nicotine form in a manner providing a rapid pulse of available nicotine to the user's bloodstream. This may be accomplished by inhalation of the first form.
  • the second form of nicotine may then be administered in an alternative manner, such as buccally in a tablet, capsule, caplet, lozenge, troche, gelcap, quick dissolve strip; transdermally such as via a patch or cream; or intranasally.
  • 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, frustration or anger, anxiety, drowsiness, sleep disturbances, impaired concentration, nervousness, restlessness, decreased heart rate, increased appetite and weight gain.
  • pulmonary, oral, or parenteral administration of nicotine could be of value for the treatment of other diseases, such as for patients suffering from neurodegenerative diseases, psychiatric disorders and other central nervous system disorders responsive to nicotinic receptor modulation (see U.S. 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).
  • Such diseases include, but are not limited to, senile dementia of the Alzheimer's type, Parkinson's disease, schizophrenia, obsessive-compulsive behavior, Tourette's Syndrome, depression, attention deficit disorder, myasthenia gravis and drug addiction. These embodiments and others are discussed in greater detail, below.
  • Tobacco-less 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 drugs, excipients, permeation enhancers, preservatives, absorption enhancers, binding agents, buffers, and the like that enhance the efficacy or ease the use of the claimed invention.
  • 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. Methods of formulating liquids and liquid inhalers are disclosed in U.S. Patent Nos.
  • Formulations of the present invention are tailored to provide a rapid increase of arterial nicotine concentration. Preferably this rapid increase in arterial nicotine concentration mimics that produced when smoking a cigarette.
  • certain nicotine formulations of the invention include two forms of nicotine that in combination more closely mimic the pharmacological profile of nicotine delivery of a cigarette.
  • the nicotine forms of the invention may be powders, emulsions, semisolids, 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. When a formulation containing two forms of nicotine is inhaled, the first form of nicotine has a smaller particle diameter than the second form of nicotine.
  • the first form of nicotine is preferentially inhaled as this method of administration provides the most rapid delivery without resorting to invasive techniques such as injection. Inhalation allows for a suitable first form of nicotine arterial concentration in the patient within 5 minutes of delivery. Typically this arterial concentration is at least 10, 12, 14 or 15ng/ml, and this concentration is achieved within 5, preferably within 4, 3, 2, or 1 minute or less from inhalation of the claimed formulation.
  • the particle or droplet size of the first form of nicotine is controlled and kept small in order to allow the particles to reach the deep lung.
  • this size is between about 1 ⁇ m and about 4 ⁇ m in diameter, more preferably about 2 or 3 ⁇ m.
  • the first form of nicotine may have a fluid component having a basic pH, preferably having a pH of more than 7.5, 8.0, or 8.5.
  • a basic pH facilitates formation of the more potent free base form of nicotine, which is a more potent form than nicotine salts.
  • the nicotine forms of the claimed formulation may be encapsulated for example in microspheres. Encapsulation allows the nicotine forms of the formulation to be segregated and therefore they may be delivered with different additives, including buffers adjusting pH, due to their respective microenvironments.
  • the second form of nicotine in the formulations of the invention is present in an amount to maintain a second form of nicotine arterial concentration in the patient for at least 60 minutes after delivery.
  • This second form of nicotine arterial concentration is generally lower than the first form of nicotine arterial concentration, typically being at least about 8 ng/ml, preferably about 6 ng/ml, more preferably at least about 5ng/ml, or at least about 4, 3, 2 ng/ml.
  • Delivery of the second form of nicotine may be performed using any suitable method with preferable methods being buccally (e.g., as a gum, quick dissolve strip, or lozenge composition), transdermal patch, inhalation, or other method that allows for sustained release of the second form of nicotine over a period of several minutes to hours, preferably at least 30, 40, or 60 minutes, more preferably 90 or 120 minutes.
  • the second form of nicotine may be delivered at any pH, but is more preferably delivered as a salt at neutral or acidic pH, e.g., within a pH range of 7 to 3. Acidic pH values are particularly preferred, e.g. pH 5, 4 or 3.
  • a preferred method of administering the formulations of the invention is through inhalation.
  • the second form of nicotine When inhaled, the second form of nicotine generally has a larger particle size than the first form of nicotine. As discussed elsewhere in this specification, the larger particle size results in the second form of nicotine being deposited preferentially in the upper respiratory tract rather than the deep lung. Deposition in the higher respiratory airways results in the second form of nicotine reaching the blood system and the receptors of the patient's central nervous system more slowly than is the case for the first form of nicotine deposited in the deep lung. This aids in the sustained release of lower levels of second form of nicotine to the blood as desired in mimicking the pharmacological administration of nicotine via a cigarette.
  • particles or droplets of the formulation containing the second form of nicotine are preferably in the range between about 4 ⁇ m and about 12 ⁇ m, more preferably between about 5 ⁇ m and about lO ⁇ m, preferentially between about 6 ⁇ m and about 8 ⁇ m in diameter, as these sizes facilitate deposition of the particles or droplets in the upper airway passages of the lung.
  • this component of the formulation may optionally include a slow release component such as cyclodextrin.
  • the second form of nicotine may also be encapsulated using any of the methodologies well known to those of skill in the art including packaging within microspheres. Encapsulation in microspheres has the added advantage of facilitating delivery of the first and second forms of nicotine at different pH values.
  • the first form of nicotine may be delivered in free base form having a basic pH whereas the second form of nicotine is delivered in salt form as an acidic pH.
  • the free base form interacts with the nicotinic receptor eliciting a larger response than more basic forms of the drug.
  • microspheres for use in the invention include polyglycolide microspheres. Microspheres may also optionally include a bioadhesive component such as hyaluronic acid.
  • Microspheres and liposomes of the present invention may be constructed using techniques well-known to those of skill in the art.
  • liposomes containing the second form of nicotine of the present invention may be prepared, for example, by suspending a thin layer of purified phospholipids in a solution containing the second form of nicotine and then treating the suspension in a conventional manner such as ultrasonication.
  • a "Liposome” is a closed vesicle of lipid bilayer encapsulating an aqueous compartment therein. It is known that the lipid bilayer membrane structure is extremely similar to biological membranes. 3. Supplemental Drugs
  • the tobacco-less compositions of the present invention may optionally include supplemental pharmaceutically-active components. 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 patient-user.
  • Particularly preferred supplemental drugs 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 IA 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 drugs may be delivered concomitantly with the formulations of the present invention, or may be administered independently. Supplemental drug delivery may be via any suitable method known in the art including orally, inhalation, injection, etc.
  • the formulations of the present invention are administered to a human and may contain one or more pharmaceutically-acceptable excipients, or carriers. Suitable excipients and their formulations are described in Remington's Pharmaceutical Sciences, 16th ed., 1980, Mack Publishing Co., edited by Oslo et ah Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic.
  • the pharmaceutically-acceptable excipients include liquids such as saline, Ringer's solution and dextrose solution.
  • the pH of the solution is preferably from about 3 to about 8, and more preferably from about 3 to about 7, although the pH may be varied according to the drug cocktail.
  • the formulation may also comprise a lyophilized powder or other optional excipients suitable to the present invention including sustained release preparations such as semipermeable matrices of solid hydrophobic polymers, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles as discussed above. 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 the concentration of the nicotine formulation being administered.
  • the medicaments of the present invention may optionally include other pharmacologic agents used to treat the conditions listed above, such as UTP, amiloride, antibiotics, bronchodilators, anti-inflammatory agents, and mucolytics (e.g. n-acetyl-cysteine).
  • pharmacologic agents used to treat the conditions listed above, such as UTP, amiloride, antibiotics, bronchodilators, anti-inflammatory agents, and mucolytics (e.g. n-acetyl-cysteine).
  • mucolytics e.g. n-acetyl-cysteine
  • the medicaments of the present invention may also be administered sequentially or concurrently with the one or more other pharmacologic agents.
  • the amounts of medicament and pharmacologic agent depend, for example, on what type of pharmacologic agent(s) are used, and the scheduling and routes of administration.
  • Tobacco-less formulations of the present invention may also include a propellant suitable for aerosolizing the pharmaceutically active nicotine formulation.
  • Suitable propellants are well-known in the art and include compressed air, nitrogen, hydrofluoroalkanes (HFAs) and the like.
  • HFAs hydrofluoroalkanes
  • An important aspect of any propellant used in the present invention is that it not react with nicotine or other pharmaceutically-active components of the tobacco-less formulations of the claimed invention. IH. Methodology
  • the treatment methodology begins with particles of a given size, carries out treatment for a given period of time after which the particles are increased in size.
  • the particles initially administered to the patient penetrate deeply into the lung, i.e., the smallest particles ⁇ e.g., 0.5 to 2 microns ( ⁇ )) target the alveolar ducts and the alveoli.
  • the deepest part of the lung is targeted with the smallest particles the patient receives an immediate "rush" from the nicotine delivered which closely matches that received when smoking a cigarette.
  • 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.
  • the desired result is to obtain particles which have a diameter in the range of 0.5 ⁇ m to about 2 ⁇ m.
  • the particles will fall above and below the desired range. However, if the majority of the particles (50% or more) fall within the desired range then the desired area of the lung will be predominantly targeted.
  • the patient is allowed to take a single inhalation of the tobacco-less formulation of the invention when a cigarette is desired.
  • the patient would be instructed to inhale the tobacco-less formulation when the patient would normally smoke a cigarette.
  • the concentration of the nicotine in the tobacco-less 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 patient would begin the treatment with a low dose of the tobacco-less formulation of the invention and this dosage would gradually be raised as the patient grew more tolerant of the formulation. While increasing the tobacco-less formulation dosage to the most effective dose for that particular patient, the patient would gradually cease smoking until the tobacco- less formulation completely replaced the cigarette. Once the cigarette habit is broken, the patient would gradually lower the dosage of the tobacco-less formulation until the nicotine addiction was broken.
  • Another treatment methodology would gradually increase the size of the particles for the first form of nicotine.
  • the increased particle size targets predominantly the respiratory tract above the alveolar ducts and below the small bronchi.
  • This can generally be accomplished by creating aerosolized particles of nicotine which have a size and range of about 2 ⁇ m to about 4 ⁇ m.
  • Administration is carried out in the same manner as described above. Specifically, the patient administers the aerosolized nicotine when nicotine cravings are experienced. Since the patient has become adjusted to receiving the nicotine "rush” from the smaller sized particles, the patient will expect and is therefore likely to experience the same "rush” when administering the slightly larger particles.
  • the effect will be less immediate, or less intensive, depending on the magnitude and timing of the peak, as a consequence of the particles being deposited predominantly in a higher region of the respiratory tract.
  • This procedure is carried out over a period of time, e.g., days or weeks.
  • the dose may remain constant.
  • the treatment can be completed after any phase, e.g. after the second phase.
  • a third phase of treatment is carried out.
  • the particle size of the first form of nicotine is increased again.
  • the particles are increased to a size in a range from about 4 ⁇ m to about 8 ⁇ m or, alternatively, perhaps as large as 12 ⁇ m.
  • These larger particles will target predominantly 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. Alternatively, the patient can try to wean off of nicotine by delivering fewer doses during a given time period, or by decreasing the dose per use, as discussed below.
  • the same size dose (volume of aerosol formulation) 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 amount of nicotine, concentration of nicotine and particle sizes created by the formulation are all maintained the same from one group of packets to the next.
  • the pH of the formulation within the packets from one group to the next is changed and is generally changed from a high or basic pH to a low or acidic pH.
  • the pH of the packets within a first group could be at 9.0 and the pH of the formulation in a second group of packets could be 8.0, followed by a third group at 7.0 followed by a fourth group at 6.0 followed by a fifth group at 5.0.
  • the variation in pH from one group to the next can be in any amount and the pH can begin and end at any point provided the resulting formulation does not cause damage to the lungs of the patient to an unacceptable degree.
  • the pH of the first form of nicotine is varied from basic to acid thereby gradually decreasing the amount of free base nicotine in the formulation.
  • the pH of the second form of nicotine may also be adjusted, but preferably remains constant, typically at a neutral or acidic pH level.
  • the nicotine forms of the invention may include variations of all or any of the different parameters which include amount of nicotine, concentration of nicotine, particle size of aerosol created and pH of the formulation. Any one, two, three or four of the parameters can be varied from one administration to the next.
  • the tobacco-less formulation described herein are intended to be administered by inhalation.
  • Commercially available nebulizers for liquid formulations including jet nebulizers and ultrasonic nebulizers may be useful for administration.
  • Liquid formulations may be directly nebulized and lyophilized power nebulized after reconstitution.
  • the tobacco-less formulation may be aerosolized using a metered dose inhaler, or inhaled as a powder, for example lyophilized, spray-dried, freeze-dried or milled powder.
  • a liquid medicament may be directly instilled in the nasotracheal or endotracheal tubes in intubated patients.
  • Effective dosages and schedules for administering the medicament may be determined empirically, and making such determinations is within the skill in the art Those skilled in the art will understand that the dosage of tobacco-less formulation of the invention that must be administered will vary depending on, for example, the person receiving the formulation, the route of administration, the particular type of formulation used and other drugs being administered to the patient. As previously noted, the formulation of the present invention may be administered in a single dose, or as multiple doses over time.
  • Smokers wishing to quit may be treated solely with respiratory nicotine as indicated above, i.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 administration, in accordance with the present invention, and nicotine which is administered to the mucosa.
  • the aspects of the invention described above such as changing the amount, concentration, or pH of the formulation or changing the particle size of the aerosol created with the formulation can be done independent of the delivery device.
  • the device can be designed so as to avoid overdosing. This can be carried out by mechanically or electronically monitoring the number of doses a patient has delivered and locking out further use for a given time interval.
  • this system can be used as a safety feature.
  • the device can be programmed in order to force the frequency of administration. This could be done in order to aid the patient in reducing the times the dose is delivered and thereby moving the patient forward towards a point in time when the patient no longer needs nicotine.
  • any of the devices suitable for use with the invention could be designed to force the patient to use only a certain dosage form of the tobacco-less formulation for a given period of time and then require that the patient use another dosage form.
  • the device can be programmed to start the patient with, for example, a relatively high dose which can be quickly administered and thereafter allowing the device only to be activated when a second group with a smaller amount, lower concentration, etc. is used in the device.
  • the devices suitable for use with the invention can also be programmed to be patient and physician specific.
  • the device can include a lock-out component which prevents the device being used except in the presence of another component which could, for example, be a wristband worn by the patient.
  • the device could also be programmable only by a particular physician equipped with a device which sends a signal allowing the device to be reprogrammed.
  • 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 of speed. Either or both of these parameters can be changed by themselves, together or in combination with the other parameters relating to the formulation and particle size.
  • the tobacco-less 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 can be varied in size and randomly placed on the membrane. If the size of the openings is varied, the size of the particles formed will also vary. In general, it is preferable to have the opening sizes within 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.
  • 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 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 4 ⁇ to 8 ⁇ , which will target predominantly 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 "monodispersed" 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 aerosolized tobacco-less nicotine formulation particles is increased in gradient fashion by using porous membranes that create "polydispersed" aerosols, wherein the particles within the aerosol created have different particle sizes.
  • Membranes which have a broad range of pore sizes are used to produce nicotine particles of varying sizes.
  • 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 N£ «g/JMe ⁇ i 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 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 0.5 to 3 mg, and more preferably about 1 mg of nicotine are delivered to the lungs of the patient in a single dose to achieve peak blood plasma concentrations of 10 to 50 ng/mL. It is understood in the art that approximately twice the aerosolized dose must be delivered to the patient to achieve a given dose delivered to the lungs (lung dose). These specific amounts should not be relied on. Alternatively, the amounts should be measured, adjusted, re-measured and readjusted as needed to obtain the appropriate dosing.
  • An aspect of the invention is to initially set out to deliver the nicotine preparation in a manner that satisfies the craving for high plasma levels of nicotine in the subject and then gradually changing the nature of the inhaled nicotine formulation in terms of the amount of nicotine, its concentration as well as site of deposition so as to gradually reduce the peak plasma nicotine levels to wean the subject off tobacco.
  • the amount needed will vary based on many factors including how much the patient smokes, and the patient's age, sex, weight and condition.
  • the amount of nicotine administered 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, and demographic factors may also help to determine the amount of nicotine sufficient to satisfy the smoker's craving for the drug.
  • Administering nicotine using the methods of the present invention can involve the daily administration of anywhere from 0.05 mg to 200 mg of nicotine, but more preferably involves the administration of approximately 10 to 100 mg per day, but these amount ranges should not be relied on. Amounts should be determined as indicated above.
  • the delivery of a large, or bolus, dose of nicotine has been avoided due to concerns about toxicities associated with nicotine.
  • the present invention includes systems for delivering a bolus dose of nicotine in a single inhalation with no dose- related acute serious side effects and a resultant decrease in acute nicotine cravings.
  • the nicotine doses safely delivered approximate the equivalent of an entire cigarette (approximately 1 to 3mg of nicotine).
  • the present invention also includes systems for delivery of the nicotine formulations described above. These systems typically include an inhaler that is capable of delivering a complete dose of the nicotine to the patient in a single puff or two puffs, or more. Nicotine dosages may be as high as that provided by smoking an entire cigarette or more, and may be modulated as described above according to the treatment provided. Systems of the present invention are also characterized as being used preferentially by smokers looking to break a smoking habit. Typical users of the present invention will have Fagerstrom scores between 4 and 10. The Fagerstrom test is well known in the art and is summarized in Figure 4. Briefly, a patient is presented with a series of six questions that are scored based on the answer provided.
  • the invention is a system that delivers tobacco- less nicotine formulations. These formulations are delivered directly to the patient's circulatory system via the lungs. In this manner the nicotine formulation of the system provides a peak nicotine arterial concentration in the patient within 5 minutes of being inhaled by the patient.
  • the invention includes a system having multiple groups of containers.
  • Each container of each group contains a pharmaceutically active nicotine formulation that is substantially identical to that contained in every other container of the group, with the formulations in the respective groups of containers differing, as described in greater detail below.
  • the amount of nicotine formulation confined by the first group of containers is larger than the amount of nicotine formulation confined by the second group of containers. This may be necessary as the first group of containers is intended to provide a bolus of drug to the patient in a manner that provides a rapid increase in arterial nicotine concentration in a short period of time, typically less than five minutes.
  • the nicotine formulation in the first group of containers is functionally characterized as producing a peak in nicotine arterial concentration in a patient within 5 minutes of delivery.
  • the formulation is delivered either directly to the circulatory system via inhalation.
  • the formulation is physically characterized as preferably being a powder or a liquid, and preferably is stored and delivered as a basic composition with a pH of greater than 7, preferably 7.5, 8, or 9.
  • the formulation is finely milled with particles that contain nicotine having diameter typically between l ⁇ m and 5 ⁇ m. This facilitates delivery of the drug by inhalation into the airways and alveoli, typically in a single dose.
  • the nicotine formulation in each of the other group of containers is also substantially identical, but is physically, chemically or quantitatively different from the nicotine formulation confined by each other group of containers.
  • this second nicotine formulation differs from the first formulation as the second formulation is a slow-release form maintaining a second form of nicotine plasma concentration in the patient for at least 60 minutes after delivery.
  • the second nicotine formulation is usually delivered in a slow release formula and/or in the form of a gum, creme, fast dissolve strip, transdermal patch, or other medium that either releases the drug over time or delivers the drug in a manner that is slower than that provided for the first nicotine formulation discussed above.
  • each group of containers is unique from all other groups of 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.
  • differences may be a result of changes to the nicotine formulation, such as concentration, particle size of powders, pH or any other parameter that would be obvious to those skilled in the art.
  • 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 patient flow rate or any other parameter that would be obvious to those skilled in the art.
  • Still another aspect of the claimed invention is a system that has two groups of containers where each container of each group has at least one exit pore and confines substantially identical pharmaceutically active nicotine formulations, wherein the exit pore of each container of the first group is identical, the exit pore of each container of the second group is identical, and the exit pore of a first group container is different from the exit pore of a second group container.
  • the patient will typically take one dose of the nicotine.
  • the patient may deliver the drug in incremental dosages. Multiple dosing may be provided to address the habitual puffing of a cigarette. In such circumstances the cumulative effect of incremental dosages is to deliver the same dose of nicotine as typically provided in one dosing event using the present invention. Dosing is discussed in greater detail, above.
  • a variety of methods may be utilized to assess the craving for nicotine, including but not limited to, the nicotine craving test specified by the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) (see (1991) J. Am. Med. Assoc. 266:3133); the Shiffman-Jarvik Craving Subscale (see O'Connell and Martin (1987) J. Consult. Clin. Psychol. 55:367-371 and Steur and Wewers (1989) ONF 16:193-198, also describing a parallel visual analog test); West et al. (1984) Br. J. Addiction 79:215-219; and Hughes et al. (1984) Psychopharmacology 83:82-87, each of which is expressly incorporated herein by reference.
  • a preferred nicotine craving scale is that specified in DSM-HI-R, supra.
  • a subject is asked to rate the severity of his craving for nicotine on a scale between 0 and 4, wherein 0 is none; 1 is slight; 2 is mild; 3 is moderate; and 4 is severe.
  • the subject should attain at least a one unit, and preferably at least a two unit, decrease in his craving for nicotine as measured by the protocol set forth in DSM- III-R from about 2 to 30 minutes after administration of the oral nicotine formulation. More preferably, the maximum reduction in craving for nicotine will occur from about 2 to 20 minutes, and more preferably from about 2 to 10 minutes after administration of the oral nicotine formulation.
  • the Shiffman-Jarvik Craving Scale is a six-item, forced-choice, self-report tool that measures cigarette craving. Each item has seven possible responses which correspond to scores ranging from 1 (no craving) to 7 (high craving). A mean score is obtained to determine the respondent's level of craving. A typical craving score measured 48 hours after the initiation of a smoking cessation program is between about 4 and 5; while a two-week follow-up craving scale will typically be between about 3 and 4.
  • the subject should attain at least a one unit, and preferably at least a two unit, decrease in his craving for nicotine as measured by the protocol set forth in the Shiffman-Jarvik Craving Scale from about 2 to 30 minutes after administration of the oral nicotine formulation. More preferably, the maximum reduction in craving for nicotine will occur from about 2 to 20 minutes, and more preferably from about 2 to 10 minutes after administration of the oral nicotine formulation.
  • the "craving questionnaire" craving scale employs a five item questionnaire that asks subjects to rate how much they had been missing their cigarettes, how difficult it had been to be without cigarettes, how much they had been aware of not smoking, how pre-occupied they had been with thinking about cigarettes, and how much they had craved their cigarettes.
  • the subject responds to each question with a number between 1 and 3, where 1 is low and 3 is high.
  • the ratings are combined to give a single craving score. According to this craving scale, a combined score of between about 9 and 12 is typical.
  • the subject should attain at least a three unit, and preferably at least a four unit, decrease in his craving for nicotine as measured by the protocol set forth for use with this craving questionnaire from about 2 to 30 minutes after administration of the oral nicotine formulation. More preferably, the maximum reduction in craving for nicotine will occur from about 2 to 20 minutes, and more preferably from about 2 to 10 minutes after administration of the oral nicotine formulation.
  • a subject's frequency of smoking can be quantified using an eight-question scale, termed the Fagerstrom Nicotine Tolerance Scale (see Fagerstrom (1978) Addict. Behav. 3:235-241 and Sachs (1986) Clinics in Geriatric Medicine 2:337- 362) which provides a relative index of the degree of physical dependency that a patient has for nicotine. This test is shown in Figure 4.
  • a similar smoking cessation program can be developed for the moderate smoker, i.e., those scoring 6 or less on the Fagerstrom test.
  • a transdermal patch with a moderate loading of nicotine typically in the range of about 10-40 mg, and preferably, about 25-30 mg
  • the second phase of this smoking cessation program will consist of administration of a lower dosage transdermal patch, typically containing nicotine in the range of about 10-30 mg, and preferably, about 20-25 mg, optionally, with the transmucosal administration of nicotine, will be used for a period of from about 4 to 8 weeks.
  • either the patch or transmucosal administration will be used alone.
  • Fagerstrom tests have a variety of uses in practicing the instant invention.
  • the Fagerstrom test may be used to estimate nicotine tolerance and therefore the initial nicotine dose in treatment.
  • Cravings scores may be used to determine the effectiveness of a given formulation dosage in suppressing the desire to smoke or chew tobacco.
  • the quantification of cotinine, a nicotine metabolite, in saliva is the quantification of cotinine, a nicotine metabolite, in saliva.
  • the quantification of cotinine in blood fluids can be accomplished by gas-liquid chromatography, radioimmunoassay, and liquid chromatography. (For a discussion of liquid chromatographic assays for cotinine, see Machacek and Jiang (1986) Clin. Chem. 32:979-982, herein incorporated by references.)
  • the present invention may optionally include the direct or indirect measurement of nicotine blood levels as an integral part of methods for treating conditions responsive to nicotine therapy, and particularly for smoking cessation therapy and for reducing nicotine craving.
  • the nicotine blood levels can be measured before, during, or after the administration of the formulations of the invention, as an aid in determining the amount of nicotine to be administered and the frequency of administration.
  • saliva samples are taken from the patients and used for measurement of cotinine, as a biochemical marker of nicotine blood plasma levels.
  • Cotinine levels are determined using any of the analytical methods known to those skilled in the art.
  • the cotinine assay would be portable and easily and simply accomplished by the patient, as in an assay kit or strip indicator.
  • the AERx Essence System known in the art was used to deliver single- bolus doses of aerosolized nicotine to healthy adult male smokers.
  • the AERx Essence is an all-mechanical, nonpropellant driven, hand-held device that uses individually packaged, single-use, dosage form strips.
  • a uniformly fine, respirable aerosol is created when the drug solution is "extruded” through an array of submicron sized holes drilled into the dosage form strip.
  • the fine aerosol that is generated allows the deep-lung deposition needed to achieve rapid and efficient absorption of drug similar to that obtained by smoking.
  • Acute Craving Patients were asked to rate their nicotine craving on a scale of 0 to 10 pre- and post-dosing. Nearly all subjects reported an acute reduction in craving or an absence of craving immediately following study dosing. A mean reduction in craving from baseline was observed following all three dose levels ( Figure 3). Combining all dose levels, mean craving declined from 4.9 to 1.4 within 5 minutes post-dosing, and remained below pre-dose baseline for the 4 hours of monitoring.
  • AERx Essence delivers inhaled nicotine with a PK profile that is consistent with the rapid delivery and absorption seen with cigarette smoking, and acute craving following inhaled nicotine via the AERx Essence appears to be acutely reduced
  • This example demonstrates the effectiveness of different nicotine dosage forms of the invention.
  • the aim of the example is to illustrate that generically available nicotine formulations are suitable for use in the present invention.
  • Nicotine bitartrate was better in this pH range as compared to nicotine sulphate in terms of ensuring that there was no loss of nicotine into the polymeric dosage form materials.
  • This system consists of the AERx® StripTM, a single-use disposable dosage form, and the AERx® device, which has two hand-held configurations: an electromechanical version and an all-mechanical version.
  • Nicotine formulations were packaged under aseptic conditions into the
  • Aerosol generation using the AERx® System is completed in one or two seconds via mechanical pressurization of the nicotine formulation.
  • This pressurization causes the seal in the AERx® Strip between the drug reservoir and a nozzle array to peel open. This leads to the nicotine formulation being expelled through the nozzle array as a fine aerosol.
  • the particle size of the aerosol can be modified to optimize regional lung deposition.
  • the electromechanical AERx® system was modified to allow addition of dose titration capabilities into the system for this program.
  • HPLC high performance liquid chromatography
  • the HPLC method was suitably modified for functional (aerosol) testing of AERx®-nicotine and a partial qualification conducted.
  • the analytical performance parameters evaluated were: standard linearity, range, accuracy, precision, limit of quantitation (LOQ), system suitability, specificity and solution stability.
  • the functional test method, in conjunction with the RP-HPLC method was qualified for use in determining emitted dose and particle size distribution of aerosolized nicotine. Nicotine working standard linearity, r2, was 1.000 and the linear concentration range was 0.5 to 40.0 ⁇ g/mL (Table 4).
  • Nicotine salts After evaluation of availability of various grades of nicotine salts on the market, nicotine bitartrate and nicotine sulphate were selected for further screening. Both salts were purchased from Nicobrand Limited, Northern Ireland.
  • a 0.9-1.0 mg lung dose was estimated as an efficacious upper end dose based on available literature. Estimating a 60% deep lung delivery efficiency for AERx®, the nicotine concentration chosen at the upper end was 32.0 mg/mL. Using the three step dose reduction strategy described above, the lower nicotine concentration was estimated to be 10.7 mg/mL. Initial formulation studies used a lower concentration of 8.0 mg/mL (prior to the finalization of a three-step dose reduction strategy), which was later finalized (using a three step dose reduction strategy) to be 10.7 mg/mL.
  • pH 3.0 was chosen for use with polymeric products as the proportion of ionized species is maximized at this pH while maintaining acceptable safety profiles for an inhaled product.
  • AERx® dosage forms were filled with nicotine bitartrate and nicotine sulphate at both 10.7 and 32.0 mg/mL of nicotine and stored at 40°C/15% R.H. (accelerated storage condition recommended for semi-permeable containers, ICH QlA) for a period of 14 days.
  • ED emitted dose
  • a known dose of each nicotine formulation was loaded into AERx® Strips and then aerosolized onto standardized collection filters. The filters were rinsed thoroughly with the assay diluent. Spiking studies were conducted to verify that all of the nicotine was recovered from the filter. The amount of nicotine in the rinsate was quantified by HPLC.
  • the ED data was excellent for the partial extrusion as well as multiple concentrations dose reduction strategies evaluated. Emitted dose in percent at the three levels using the partial extrusion strategy was 20.4, 17.2 and 18.8 with standard deviations of 1.4, 0.8 and 1.0 respectively (see Table 11). The percent emitted dose for the successive concentrations of 32.0, 21.3 and 10.7 mg/mL was 60.0, 61.7 and 62.7 with the standard deviations being 3.0, 2.8 and 3.2 respectively (see Table 12).
  • Table 11 Emitted dose performance using partial dose settings using 32 mg/mL nicotine bitartrate
  • Partial extrusion of an AERx® Strip was carried out by altering the settings for the piston position, to program it to aerosolize only a portion of the contents of the AERx® Strip. Testing was done using nicotine formulations, with the results being presented in Table 11. The delivered dose in percent of emitted dose at the three levels was 36.1, 30.5 and 33.4 with standard deviations of 1.3, 1.1 and 1.3 respectively. This corresponds to a nicotine dose of 0.33 mg, 0.28 mg and 0.30 mg at the three dose levels respectively.
  • Particle size distribution is a key determinant of the regional lung deposition of inhaled aerosols.
  • a cascade impactor (Series 20-800 Mark II, Thermo Andersen), which size selectively collects the aerosol by inertial impaction on a series of stages, was used to characterize the aerosol PSD.
  • the PSD was characterized in terms of Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation ( ⁇ g).
  • MMAD denotes the particle size at which half of the total aerosol mass is contained in larger particles and half in smaller particles.
  • the ⁇ g indicates the variability of aerosol particle sizes.
  • An aerosol composed of identical size particles would have a ⁇ g of 1.0; ⁇ g of ⁇ 1.3 is considered monodisperse; ⁇ g of >1.3 is considered polydisperse.
  • R.H. as the formulation selected was quite simple and did not require refrigerated storage.
  • the strips were loaded with 50 ⁇ L of nicotine formulation, sealed and stored at 25°C/40% R.H., as well as at the accelerated storage condition of 40°C/15% R.H. for up to 1 month.
  • the formulations in the strips were characterized for concentration, pH and content uniformity, in addition to measurement of aerosol performance (emitted dose, particle size distribution) with the AERx® Strips in storage.
  • the results from the one month stability study indicated maintenance of pH, concentration, as well as aerosol performance over the tested stability duration at the primary as well as accelerated storage condition (Tables 15 & 16).
  • the emitted dose (ED) performance at both the concentrations was within normal variability.
  • the MMAD was 2.4 and 2.8 to 2.9 for the two formulation strengths respectively; with GSD's of 1.3, indicating the monodispersity of the aerosol.
  • the fine particle fraction under 3.5 ⁇ m was about 82% for the 10.7 mg/mL formulation and 72% for the 32.0 mg/mL formulation.
  • a high fraction of the emitted aerosol in the respirable range ensures that majority of the aerosol will result in deep lung deposition.
  • the data indicates acceptable stability of the formulations in AERx® strips for the duration of the stability study. In the next part of the development program, it will be important to finalize the final formulation concentrations (dependent on the chosen dose reduction and commercialization strategy) and generate stability data to support any proposed clinical studies.
  • the example above supports the feasibility of delivery of nicotine for smoking cessation using the AERx® System with an aqueous formulation that was stable at room temperature for a period of at least a month (duration of stability study).
  • the typical MMAD of the aerosols using either dose reduction strategy was 2.6 ⁇ m, whereas the GSD was 1.3.
  • the fine particle fraction was 80%, ensuring deposition of the majority of the emitted aerosol in the deep lung, mimicking smoking, and important for a successful smoking cessation product.
  • the preceding merely illustrates the principles of the invention.

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Abstract

La présente invention concerne d'une manière générale un système, une trousse et un procédé qui permettent de traiter des états physiques réagissant à la nicotine thérapeutique. Plus spécifiquement, l'invention concerne l'administration pulmonaire d'une formulation contenant de la nicotine afin de mettre fin au tabagisme.
EP07867592A 2006-12-01 2007-11-30 Systèmes destinés à mettre fin à l'usage du tabac Withdrawn EP2086527A4 (fr)

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
US86823806P 2006-12-01 2006-12-01
US91104407P 2007-04-10 2007-04-10
US91318507P 2007-04-20 2007-04-20
US91651007P 2007-05-07 2007-05-07
US91719007P 2007-05-10 2007-05-10
US98207007P 2007-10-23 2007-10-23
US11/931,921 US20080138399A1 (en) 1999-07-16 2007-10-31 Dual release nicotine formulations, and systems and methods for their use
US11/932,402 US20080138294A1 (en) 1999-07-16 2007-10-31 Systems and methods for effecting cessation of tobacco use
US11/932,437 US8256433B2 (en) 1999-07-16 2007-10-31 Systems and methods for effecting cessation of tobacco use
US11/931,867 US20080138398A1 (en) 1999-07-16 2007-10-31 Dual release nicotine formulations, and systems and methods for their use
PCT/US2007/024641 WO2008069972A2 (fr) 2006-12-01 2007-11-30 Systèmes destinés à mettre fin à l'usage du tabac

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EP07867591A Withdrawn EP2086317A4 (fr) 2006-12-01 2007-11-30 Formulations de nicotine, trousses, systèmes et procédés d'utilisation
EP07867592A Withdrawn EP2086527A4 (fr) 2006-12-01 2007-11-30 Systèmes destinés à mettre fin à l'usage du tabac

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US8252321B2 (en) 2004-09-13 2012-08-28 Chrono Therapeutics, Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
JP5254616B2 (ja) 2004-09-13 2013-08-07 クロノ セラピューティクス、インコーポレイテッド 生物学的同調性（ｂｉｏｓｙｎｃｈｒｏｎｏｕｓ）経皮的薬物送達
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WO2011023796A1 (fr) * 2009-08-31 2011-03-03 Abbott Healthcare Products B.V. Bifeprunox destiné au traitement de l'addiction
TWI484958B (zh) * 2011-05-19 2015-05-21 Heglund A S 用於戒菸之口腔吸收尼古丁組成物
US20130017259A1 (en) 2011-07-06 2013-01-17 The Parkinson's Institute Compositions and Methods for Treatment of Symptoms in Parkinson's Disease Patients
RU2541312C2 (ru) * 2011-08-31 2015-02-10 Александр Васильевич Иващенко Фармацевтическая композиция, способ ее получения и устройство для ее применения
US10556011B2 (en) 2011-12-02 2020-02-11 Joshua D. Levine Method and system for adding sensory conditioning cues in a pharmacotherapeutic regimen
US10034988B2 (en) 2012-11-28 2018-07-31 Fontem Holdings I B.V. Methods and devices for compound delivery
US10194693B2 (en) 2013-09-20 2019-02-05 Fontem Holdings 1 B.V. Aerosol generating device
CA2974324A1 (fr) 2015-01-28 2016-08-04 Zita S. Netzel Procedes et systemes d'administration de medicament
WO2016145373A1 (fr) 2015-03-12 2016-09-15 Chrono Therapeutics Inc. Système d'entrée d'état de manque et de support
US11224594B2 (en) * 2015-09-16 2022-01-18 Philip Morris Products S.A. Nicotine formulations and methods of making and using the same
US10149844B2 (en) 2015-09-16 2018-12-11 Philip Morris Products S.A. Inhalable nicotine formulations, and methods of making and using thereof
US9585835B1 (en) * 2015-09-16 2017-03-07 Sansa Corporation (Barbados) Inc. Inhalable nicotine formulations and methods of making and using the same
US20170071248A1 (en) 2015-09-16 2017-03-16 Sansa Corporation (Barbados) Inc. System and Method for Controlling the Harshness of Nicotine-Based Dry Powder Formulations
AU2018205529B2 (en) 2017-01-06 2023-08-10 Morningside Venture Investments Limited Transdermal drug delivery devices and methods
CN110300588A (zh) * 2017-03-07 2019-10-01 菲利普莫里斯生产公司 可吸入尼古丁调配物及其制造和使用方法
JP7420797B2 (ja) 2018-05-29 2024-01-23 モーニングサイド ベンチャー インベストメンツ リミテッド 薬剤送達の方法及びシステム
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WO2008069972A3 (fr) 2008-10-30
WO2008069972A2 (fr) 2008-06-12
EP2086317A4 (fr) 2010-03-03

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