WO2000016762A2 - Method for reducing nicotine dependency - Google Patents

Method for reducing nicotine dependency Download PDF

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Publication number
WO2000016762A2
WO2000016762A2 PCT/US1999/021266 US9921266W WO0016762A2 WO 2000016762 A2 WO2000016762 A2 WO 2000016762A2 US 9921266 W US9921266 W US 9921266W WO 0016762 A2 WO0016762 A2 WO 0016762A2
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WO
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Prior art keywords
nicotine
dependency
reducing agent
nicotine dependency
dosage form
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Application number
PCT/US1999/021266
Other languages
French (fr)
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WO2000016762A3 (en
Inventor
Frank S. Caruso
Original Assignee
Algos Pharmaceutical Corporation
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Publication date
Application filed by Algos Pharmaceutical Corporation filed Critical Algos Pharmaceutical Corporation
Priority to AU62502/99A priority Critical patent/AU6250299A/en
Publication of WO2000016762A2 publication Critical patent/WO2000016762A2/en
Publication of WO2000016762A3 publication Critical patent/WO2000016762A3/en

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    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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

Definitions

  • This invention relates to a method for reducing nicotine dependency. More particularly, this invention is concerned with reducing nicotine dependency by aciministering to a nicotine-dependent individual a nicotine dependency-reducing amount of at least one nicotine dependency-reducing agent selected from the group consisting of dextromethorphan, dextrorphan and pharmaceutically acceptable salts thereof.
  • dextrometho ⁇ han dextrorphan and/or their pharmaceutically acceptable salt.
  • Dextrometho ⁇ han and its active metabolite dextro ⁇ han are known antagonists of the N-methyl-D-aspartate (NMDA) receptor. It has recently been discovered that dextrometho ⁇ han and dextro ⁇ han also block the neuronal nicotinic receptors in the central nervous system and autonomic nervous system. Either or both of these activities of dextrometho ⁇ han and dextro ⁇ han may play a role in their usefulness for reducing nicotine dependency.
  • NMDA N-methyl-D-aspartate
  • a method for reducing nicotine dependency comprises administering to a nicotine- dependent individual a nicotine dependency-reducing amount of at least one nicotine dependency-reducing agent selected from the group consisting of dextrometho ⁇ han, dextro ⁇ han and pharmaceutically acceptable salts thereof.
  • a unit dosage form for reducing nicotine dependency which comprises (a) nicotine in an amount sufficient to satisfy a nicotine-dependent individual's current nicotine urge and (b) a nicotine dependency-reducing amount of at least one nicotine dependency- reducing agent selected from the group consisting of dextrometho ⁇ han, dextro ⁇ han and pharmaceutically acceptable salts thereof.
  • a transdermal patch which contains at least one of dextrometho ⁇ han, dextro ⁇ han or pharmaceutically acceptable salt thereof.
  • nicotine-dependent individual is used herein to designate an individual who has become habituated to the consumption of nicotine in the form of one or more types of tobacco articles.
  • the expression “nicotine dependency-amount reducing amount” refers to that amount of nicotine dependency- reducing agent which when administered to a nicotine-dependent individual is effective to significantly reduce the number of nicotine urges experienced by the individual over a given period of time and/or to significantly reduce the quantity of nicotine consumed by the individual in satisfying the nicotine urges experienced over such period of time.
  • a nicotine dependency-reducing amount of at least one nicotine dependency-reducing agent is administered to the nicotine-dependent individual.
  • the useful nicotine dependency-reducing agents are dextrometho ⁇ han ((+))-3-hydroxy-N- memylmo ⁇ hinan), its metabolite dextro ⁇ han ((+)-3-hydroxy-N-memylmo ⁇ hinan), their mixtures and their pharmaceutically acceptable salts.
  • dextrometho ⁇ han in the form of its hydrobromide salt is preferred for use herein due to its ready availability and its established use in over- the-counter medications where it functions as a cough suppressant. While dextro ⁇ han and its pharmaceutically acceptable salts will also provide excellent results, it is not known to be in commercial manufacture at this time.
  • the preferred dosage of nicotine dependency-reducing agent can vary widely, e.g., from about 20 to about 300 mg/day and preferably from about 40 to about 180 mg/day (i.e., from four to six unit doses each containing from about 10 to about 30 mg/dose) but actual amounts will vary according to the particular formulation containing the active substances and the state and circumstances of the nicotine-dependent individual being treated.
  • t As t ose skilled in the art recognize, many factors that modify the action of the active substances herein will be taken into account by the treating physician such as, for example, the age, body weight, sex, diet and condition of the subject, the time of administration, the rate and route of administration and so forth. These amounts can be determined for a given set of conditions and for a particular drug combination in accordance with this invention employing routine experimental testing.
  • All routes of administration of the nicotine dependency-reducing agent are contemplated, e.g., topically, orally, parenterally, rectally, intravenously, intramuscularly, intrastemally, subcutaneously or by inhalation.
  • the nicotine dependency-reducing agent will ordinarily be formulated into any of numerous dosage forms together with one or more pharmaceutically acceptable ingredients in accordance with known and established pharmaceutical practice.
  • the nicotine dependency-reducing agent can be formulated as a liquid, powder, elixir, injectable solution, etc.
  • Formulations for topical administration to the skin can be provided as a transdermal patch.
  • the transdermal patch can be configured to contain a sufficient amount of the nicotine dependency-reducing so as to release the daily dosage amounts stated above, preferably over an extended period, e.g., about seven days.
  • Formulations for topical administration to the skin can also be provided as creams, gels, ointments or lotions.
  • Such formulations can, for example, be prepared with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilizing; dispersing, suspending, and/or coloring agents.
  • the nicotine dependency- reducing agent dosage unit can take the form of a buccal or sublingual tablet, drops or lozenges formulated in a known and conventional manner.
  • the nicotine dependency-reducing agent dosage unit can be provided as tablets or hard gelatin capsules wherein the nicotine dependency-reducing agent is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, as soft gelatin capsules wherein the nicotine dependency-reducing agent is mixed with water or miscible solvents such as propylene glycol; PEG's and ethanol, or an oleaginous medium, e.g., peanut oil, liquid paraffin or olive oil.
  • Formulations for oral use can also be inco ⁇ orated into a chewable gum prepared with a base such as a synthetic resin or chicle.
  • the nicotine dependency- reducing agent can also be presented as a bolus, electuary or paste.
  • the tablets can be coated according to methods well known in the art, i.e., with enteric coatings.
  • the nicotine dependency-reducing agent can also be formulated for administration by injection, conveniently intravenous, intramuscular or subcutaneous injection. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers.
  • the nicotine dependency-reducing agent dosage unit can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the nicotine dependency-reducing agent can also be formulated in rectal compositions such as suppositories or retention enemas containing, e.g., conventional suppository bases such as cocoa butter or other glyceride.
  • the nicotine dependency-reducing agent dosage unit can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the nicotine dependency-reducing agent dosage unit can be formulated with suitable polymeric or hydrophobic materials (e.g. , as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
  • the nicotine dependency-reducing agent dosage unit can be provided as a liquid spray, as a powder or in the form of drops.
  • the nicotine dependency-reducing agent dosage unit is conveniently delivered as an aerosol spray from a pressurized container or nebulizer.
  • the dosage can be controlled by a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insulator may be formulated containing a powder mix of nicotine dependency-reducing agent and a suitable powder base such as lactose or starch.
  • Aqueous suspensions can include pharmaceutically acceptable excipients such as suspending agents, e.g., sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as naturally occurring phosphatide, e.g., lecithin, or condensation products of an alkylene oxide with fatty acids, e.g., polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, e.g, heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, e.g., polyoxyethylene sorbitol monoleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, e.g., polyoxyethylene sorbitan monoleate.
  • the aqueous suspensions can also contain one or more preservatives, e.g., ethyl-or-n-propyl-p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or sodium or calcium cyclamate.
  • preservatives e.g., ethyl-or-n-propyl-p-hydroxy benzoate
  • coloring agents e.g., ethyl-or-n-propyl-p-hydroxy benzoate
  • flavoring agents e.g., ethyl-or-n-propyl-p-hydroxy benzoate
  • sweetening agents such as sucrose, saccharin or sodium or calcium cyclamate.
  • Nicotine can also be administered prior to, with or following the administration of the nicotine dependency-reducing agent.
  • the nicotine-dependent individual under treatment can continue to receive nicotine in progressively diminishing amounts in order to satisfy current but progressively diminishing nicotine- urges.
  • the nicotine can be provided in the form of a tobacco article, e.g., cigarette, cigar, chewing tobacco, etc., but is preferably provided as a non-tobacco dosage unit, i.e., a composition containing nicotine that has been extracted from its naturally occurring source.
  • the tobacco article (or package of tobacco articles such as a cigarette pack) can be packaged with the nicotine dependency-reducing agent in a suitable dosage form, e.g, tablet, capsule, transdermal patch, etc., to provide a single unit.
  • a suitable dosage form e.g, tablet, capsule, transdermal patch, etc.
  • the routes of administration and the dosage forms described above in connection with the nicotine dependency-reducing agent can also be used for the nicotine.
  • the invention contemplates using different routes of administration and different dosage forms for the nicotine dependency-reducing agent and the nicotine or the same route of administration and the same dosage form, even the same dosage umt, to deliver these agents.
  • the nicotine dependency-reducing agent can be orally administered in tablet or capsule form and the nicotine can be delivered via a spray, an inhalation unit or a transdermal patch or both the nicotine dependency- reducing agent and the nicotine can be coadministered from the same dosage unit, e.g., a transdermal patch.
  • the kit or single package unit may contain a first dosage form for delivering a desired dose of the nicotine dependency-redticing agent via a first route of administration and a second, and different, dosage form for delivering a desired dose of nicotine via a second, and different, route of administration.
  • the kit or single package unit can contain a tablet or capsule for delivery of the nicotine dependency-reducing agent and a spray, inhalant or transdermal patch for delivery of the nicotine.
  • the number of nicotine urges over a given period of time and/or the amount of nicotine consumed by the nicotine-dependent individual to satisfy such nicotine urges will become significantly less.
  • both the nicotine dependency-reducing agent, preferably dextrometho ⁇ han hydrobromide, and nicotine are coadministered from a single drug dosage unit.
  • a transdermal patch is an especially advantageous dosage form for delivering these two pharmacologic agents. Patches can contain progressively smaller doses of nicotine to correspond to the progressively decreased levels of nicotine dependency of the individual under treatment.
  • the nicotine dependency-reducing agent can also be administered with one or more other pharmacologically active substances, e.g., caffeine or caffeine equivalent as disclosed in U.S. Patent No. 5,599,554, the contents of which are inco ⁇ orated by reference herein.
  • the following examples are illustrative of the invention.
  • EXAMPLE 1 The subject was a 38-year old woman weighing 108 pounds. She had been smoking about one pack (20 cigarettes) per day of regular nicotine content cigarettes for 22 years. The subject took 30 mg dextrometho ⁇ han hydrobromide four times per day (every 4-6 hours) for approximately two weeks. She was instructed to smoke normally, i.e., whenever she had the desire to smoke.
  • EXAMPLE 2 The subject was a 64-year old woman weighing approximately 160 pounds. She had been smoking an average of two packs (40 cigarettes) per day for about 34 years. She had smoked regular nicotine level cigarettes for most of this time but had switched to "light" cigarettes within recent years. The subject took 30 mg dextrometho ⁇ han hydrobromide four times per day (every 4-6 hours). At the beginning of treatment, she was smoking 40 cigarettes per day. After 14 days of treatment with the dextrometho ⁇ han hydrobromide, she was smoking an average of 16 cigarettes per day. Also, she reported that her 10-year habit of getting up during the night to smoke ended on the night of the first day that she had begun taking the dextrometho ⁇ han hydrobromide. She also reported that with each successive day of treatment, her craving for a cigarette began later each morning. She also noted that she was putting out cigarettes before finishing them.

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Abstract

A method for reducing nicotine dependency is provided which comprises administering to a nicotine-dependent individual a nicotine dependency-reducing amount of at least one nicotine dependency-reducing agent selected from the group consisting of dextromethorphan, dextrorphan and pharmaceutically acceptable salts thereof.

Description

METHOD FOR REDUCING NICOTINE DEPENDENCY
BACKGROUND OF THE INVENTION
This invention relates to a method for reducing nicotine dependency. More particularly, this invention is concerned with reducing nicotine dependency by aciministering to a nicotine-dependent individual a nicotine dependency-reducing amount of at least one nicotine dependency-reducing agent selected from the group consisting of dextromethorphan, dextrorphan and pharmaceutically acceptable salts thereof.
The recognition of the harmful effects of tobacco has created numerous campaigns and programs by governmental agencies, various health groups and other interested organizations to disseminate information about the adverse health effects resulting from dependence on tobacco. Dependence on tobacco is based on nicotine, which is the reinforcing and addictive agent in tobacco. The reinforcing properties of nicotine is related to its release of dopamine at certain synapses within the mesolimbic system of the brain, particularly the nucleus accumbens. This is also critical to the reinforcing properties "of other drugs of abuse, e.g., opiates, cocaine, etc. Thus, the • release of dopamine by nicotine is believed to be linked to its addictive properties.
Various methods for reducing nicotine dependency, particularly in the case of tobacco smoking, are known. Illustrative of such methods are those described in, among others, U.S. Patent Nos. 4,920,989; 4,946,853; 4,953,572; 5,016,652; 5,026,697; 5,051,426; 5,219,858; 5,316,759; 5,362,496; 5,403,595; 5,480,651; 5,486,362; 5,536,503; 5,573,774; 5,574,052; 5,593,684; 5,596,007; 5,612,357; 5,616,585; 5,643,905; 5,656,255 and 5,662,920. However, none of these patents disclose the administration of dextromethoφhan, dextrorphan and/or their pharmaceutically acceptable salt. Dextromethoφhan and its active metabolite dextroφhan are known antagonists of the N-methyl-D-aspartate (NMDA) receptor. It has recently been discovered that dextromethoφhan and dextroφhan also block the neuronal nicotinic receptors in the central nervous system and autonomic nervous system. Either or both of these activities of dextromethoφhan and dextroφhan may play a role in their usefulness for reducing nicotine dependency.
SUMMARY OF THE INVENTION
In accordance with the present invention, a method for reducing nicotine dependency is provided which comprises administering to a nicotine- dependent individual a nicotine dependency-reducing amount of at least one nicotine dependency-reducing agent selected from the group consisting of dextromethoφhan, dextroφhan and pharmaceutically acceptable salts thereof.
Further in accordance with the present invention, a unit dosage form for reducing nicotine dependency is provided which comprises (a) nicotine in an amount sufficient to satisfy a nicotine-dependent individual's current nicotine urge and (b) a nicotine dependency-reducing amount of at least one nicotine dependency- reducing agent selected from the group consisting of dextromethoφhan, dextroφhan and pharmaceutically acceptable salts thereof.
Still further in accordance with the present invention, a transdermal patch is provided which contains at least one of dextromethoφhan, dextroφhan or pharmaceutically acceptable salt thereof.
The expression "nicotine-dependent individual" is used herein to designate an individual who has become habituated to the consumption of nicotine in the form of one or more types of tobacco articles. The expression "nicotine dependency-amount reducing amount" refers to that amount of nicotine dependency- reducing agent which when administered to a nicotine-dependent individual is effective to significantly reduce the number of nicotine urges experienced by the individual over a given period of time and/or to significantly reduce the quantity of nicotine consumed by the individual in satisfying the nicotine urges experienced over such period of time.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
By way of reducing nicotine dependency in a nicotine-dependent individual, a nicotine dependency-reducing amount of at least one nicotine dependency-reducing agent is administered to the nicotine-dependent individual. The useful nicotine dependency-reducing agents are dextromethoφhan ((+))-3-hydroxy-N- memylmoφhinan), its metabolite dextroφhan ((+)-3-hydroxy-N-memylmoφhinan), their mixtures and their pharmaceutically acceptable salts. Of the foregoing nicotine dependency-reducing agents, dextromethoφhan in the form of its hydrobromide salt is preferred for use herein due to its ready availability and its established use in over- the-counter medications where it functions as a cough suppressant. While dextroφhan and its pharmaceutically acceptable salts will also provide excellent results, it is not known to be in commercial manufacture at this time.
The preferred dosage of nicotine dependency-reducing agent can vary widely, e.g., from about 20 to about 300 mg/day and preferably from about 40 to about 180 mg/day (i.e., from four to six unit doses each containing from about 10 to about 30 mg/dose) but actual amounts will vary according to the particular formulation containing the active substances and the state and circumstances of the nicotine-dependent individual being treated. t As t ose skilled in the art recognize, many factors that modify the action of the active substances herein will be taken into account by the treating physician such as, for example, the age, body weight, sex, diet and condition of the subject, the time of administration, the rate and route of administration and so forth. These amounts can be determined for a given set of conditions and for a particular drug combination in accordance with this invention employing routine experimental testing.
All routes of administration of the nicotine dependency-reducing agent are contemplated, e.g., topically, orally, parenterally, rectally, intravenously, intramuscularly, intrastemally, subcutaneously or by inhalation.
The nicotine dependency-reducing agent will ordinarily be formulated into any of numerous dosage forms together with one or more pharmaceutically acceptable ingredients in accordance with known and established pharmaceutical practice. Thus, the nicotine dependency-reducing agent can be formulated as a liquid, powder, elixir, injectable solution, etc. Formulations for topical administration to the skin can be provided as a transdermal patch. The transdermal patch can be configured to contain a sufficient amount of the nicotine dependency-reducing so as to release the daily dosage amounts stated above, preferably over an extended period, e.g., about seven days. Formulations for topical administration to the skin can also be provided as creams, gels, ointments or lotions. Such formulations can, for example, be prepared with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilizing; dispersing, suspending, and/or coloring agents. For topical administration in the mouth, the nicotine dependency- reducing agent dosage unit can take the form of a buccal or sublingual tablet, drops or lozenges formulated in a known and conventional manner.
For oral administration, the nicotine dependency-reducing agent dosage unit can be provided as tablets or hard gelatin capsules wherein the nicotine dependency-reducing agent is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, as soft gelatin capsules wherein the nicotine dependency-reducing agent is mixed with water or miscible solvents such as propylene glycol; PEG's and ethanol, or an oleaginous medium, e.g., peanut oil, liquid paraffin or olive oil. Formulations for oral use can also be incoφorated into a chewable gum prepared with a base such as a synthetic resin or chicle. The nicotine dependency- reducing agent can also be presented as a bolus, electuary or paste. The tablets can be coated according to methods well known in the art, i.e., with enteric coatings. The nicotine dependency-reducing agent can also be formulated for administration by injection, conveniently intravenous, intramuscular or subcutaneous injection. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers. The nicotine dependency-reducing agent dosage unit can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The nicotine dependency-reducing agent can also be formulated in rectal compositions such as suppositories or retention enemas containing, e.g., conventional suppository bases such as cocoa butter or other glyceride.
The nicotine dependency-reducing agent dosage unit can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the nicotine dependency-reducing agent dosage unit can be formulated with suitable polymeric or hydrophobic materials (e.g. , as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
For intranasal administration, the nicotine dependency-reducing agent dosage unit can be provided as a liquid spray, as a powder or in the form of drops.
For administration by inhalation, the nicotine dependency-reducing agent dosage unit is conveniently delivered as an aerosol spray from a pressurized container or nebulizer. In the case of a pressurized aerosol, the dosage can be controlled by a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insulator may be formulated containing a powder mix of nicotine dependency-reducing agent and a suitable powder base such as lactose or starch.
Aqueous suspensions can include pharmaceutically acceptable excipients such as suspending agents, e.g., sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as naturally occurring phosphatide, e.g., lecithin, or condensation products of an alkylene oxide with fatty acids, e.g., polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, e.g, heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, e.g., polyoxyethylene sorbitol monoleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, e.g., polyoxyethylene sorbitan monoleate. The aqueous suspensions can also contain one or more preservatives, e.g., ethyl-or-n-propyl-p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or sodium or calcium cyclamate.
Nicotine can also be administered prior to, with or following the administration of the nicotine dependency-reducing agent. Thus, the nicotine- dependent individual under treatment can continue to receive nicotine in progressively diminishing amounts in order to satisfy current but progressively diminishing nicotine- urges. The nicotine can be provided in the form of a tobacco article, e.g., cigarette, cigar, chewing tobacco, etc., but is preferably provided as a non-tobacco dosage unit, i.e., a composition containing nicotine that has been extracted from its naturally occurring source. When the nicotine is provided in the form of a tobacco article, the tobacco article (or package of tobacco articles such as a cigarette pack) can be packaged with the nicotine dependency-reducing agent in a suitable dosage form, e.g, tablet, capsule, transdermal patch, etc., to provide a single unit.
The routes of administration and the dosage forms described above in connection with the nicotine dependency-reducing agent can also be used for the nicotine. The invention contemplates using different routes of administration and different dosage forms for the nicotine dependency-reducing agent and the nicotine or the same route of administration and the same dosage form, even the same dosage umt, to deliver these agents. Thus, e.g., the nicotine dependency-reducing agent can be orally administered in tablet or capsule form and the nicotine can be delivered via a spray, an inhalation unit or a transdermal patch or both the nicotine dependency- reducing agent and the nicotine can be coadministered from the same dosage unit, e.g., a transdermal patch.
When different routes of administration and different dosage forms are utilized, it is convenient to provide the dosage forms in a kit or single package unit. Thus, the kit or single package unit may contain a first dosage form for delivering a desired dose of the nicotine dependency-redticing agent via a first route of administration and a second, and different, dosage form for delivering a desired dose of nicotine via a second, and different, route of administration. By way of example, the kit or single package unit can contain a tablet or capsule for delivery of the nicotine dependency-reducing agent and a spray, inhalant or transdermal patch for delivery of the nicotine. A further example, already described above, is a kit or single package unit containing a tablet, capsule or transdermal patch for delivery of t e nicotine dependency-reducing agent and a pack of cigarettes for delivery of the nicotine (by inhalation).
As treatment with the nicotine dependency-reducing agent progresses, the number of nicotine urges over a given period of time and/or the amount of nicotine consumed by the nicotine-dependent individual to satisfy such nicotine urges will become significantly less.
In a preferred embodiment of this invention, both the nicotine dependency-reducing agent, preferably dextromethoφhan hydrobromide, and nicotine are coadministered from a single drug dosage unit. A transdermal patch is an especially advantageous dosage form for delivering these two pharmacologic agents. Patches can contain progressively smaller doses of nicotine to correspond to the progressively decreased levels of nicotine dependency of the individual under treatment.
In addition to or apart from nicotine, the nicotine dependency-reducing agent can also be administered with one or more other pharmacologically active substances, e.g., caffeine or caffeine equivalent as disclosed in U.S. Patent No. 5,599,554, the contents of which are incoφorated by reference herein. The following examples are illustrative of the invention. EXAMPLE 1 The subject was a 38-year old woman weighing 108 pounds. She had been smoking about one pack (20 cigarettes) per day of regular nicotine content cigarettes for 22 years. The subject took 30 mg dextromethoφhan hydrobromide four times per day (every 4-6 hours) for approximately two weeks. She was instructed to smoke normally, i.e., whenever she had the desire to smoke. Before dextromethoφhan treatment, she was smoking 20 cigarettes per day. After a few days of treatment with the dextromethoφhan hydrobromide, she was smoking approximately ten (10) cigarettes per day. She reported that her craving for cigarettes had become significantly reduced.
EXAMPLE 2 The subject was a 64-year old woman weighing approximately 160 pounds. She had been smoking an average of two packs (40 cigarettes) per day for about 34 years. She had smoked regular nicotine level cigarettes for most of this time but had switched to "light" cigarettes within recent years. The subject took 30 mg dextromethoφhan hydrobromide four times per day (every 4-6 hours). At the beginning of treatment, she was smoking 40 cigarettes per day. After 14 days of treatment with the dextromethoφhan hydrobromide, she was smoking an average of 16 cigarettes per day. Also, she reported that her 10-year habit of getting up during the night to smoke ended on the night of the first day that she had begun taking the dextromethoφhan hydrobromide. She also reported that with each successive day of treatment, her craving for a cigarette began later each morning. She also noted that she was putting out cigarettes before finishing them.

Claims

WHAT IS CLAIMED IS:
1. A method for reducing nicotine dependency which comprises administering to a nicotine-dependent individual a nicotine dependency-reducing amount of at least one nicotine dependency-reducing agent selected from the group consisting of dextromethoφhan, dextroφhan and pharmaceutically acceptable salts thereof.
2. The method of Claim 1 wherein the nicotine dependency- reducing agent is administered topically or orally.
3. The method of Claim 2 wherein the nicotine dependency- reducing agent is administered from a transdermal patch.
4. The method of Claim 1 wherein the nicotine dependency- reducing agent is coadministered with nicotine in a form other than a tobacco article.
5. The method of Claim 4 wherein the nicotine dependency- reducing agent is administered by a first route of administration employing va first dosage form and the nicotine is administered by a second route of administration employing a second dosage form.
6. The methdd of Claim 4 wherein the nicotine dependency- reducing agent and the nicotine are administered by the same route and from the same dosage form.
7. The method of Claim 6 wherein the nicotine dependency- reducing agent and the nicotine are coadministered from the same dosage unit.
8. The method of Claim 6 wherein the nicotine dependency- reducing agent and the nicotine are coadministered from the same transdermal patch.
9. A transdermal patch containing dextromethoφhan, dextroφhan, mixture thereof or pharmaceutically acceptable salt thereof.
10. A unit dosage form for reducing nicotine dependency which comprises (a) nicotine in an amount sufficient to satisfy a nicotine-dependent individual's current nicotine urge and (b) a nicotine dependency-reducing amount of at least one nicotine dependency-reducing agent selected from the group consisting of dextromethoφhan, dextroφhan and pharmaceutically acceptable salts thereof.
11. The unit dosage form of Claim 10 formulated for topical or oral administration.
12. The unit dosage form of Claim 10 which is a transdermal patch.
13. A kit or single package unit for reducing nicotine dependency in a nicotine-dependent individual which comprises a first dosage unit containing a nicotine dependency-reducing agent and a second dosage unit containing nicotine.
14. The kit or single package unit of Claim 13 wherein the first dosage unit delivers the nicotine dependency-reducing agent by a first route of administration and the second dosage unit delivers the nicotine by a second route of administration.
15. The kit or single package unit of Claim 14 wherein the first dosage form is an orally administered dosage form and the second dosage form is a spray, inhalant or transdermal patch.
16. The kit or single package unit of Claim 14 wherein the first dosage form is a tablet, capsule, or transdermal patch and the second dosage form is a tobacco article.
17. The kit or single package unit of Claim 16 wherein the tobacco article is a cigarette provided as a cigarette pack.
PCT/US1999/021266 1998-09-24 1999-09-23 Method for reducing nicotine dependency WO2000016762A2 (en)

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