WO1995011678A9 - Utilisation de substituts de nicotine pour le traitement du sevrage a la nicotine - Google Patents

Utilisation de substituts de nicotine pour le traitement du sevrage a la nicotine

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Publication number
WO1995011678A9
WO1995011678A9 PCT/US1994/012441 US9412441W WO9511678A9 WO 1995011678 A9 WO1995011678 A9 WO 1995011678A9 US 9412441 W US9412441 W US 9412441W WO 9511678 A9 WO9511678 A9 WO 9511678A9
Authority
WO
WIPO (PCT)
Prior art keywords
nicotine
substitute
sublingual
lobeline
administered
Prior art date
Application number
PCT/US1994/012441
Other languages
English (en)
Other versions
WO1995011678A1 (fr
Filing date
Publication date
Priority claimed from US08/145,203 external-priority patent/US5414005A/en
Application filed filed Critical
Priority to AU80960/94A priority Critical patent/AU8096094A/en
Publication of WO1995011678A1 publication Critical patent/WO1995011678A1/fr
Publication of WO1995011678A9 publication Critical patent/WO1995011678A9/fr

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Definitions

  • the present invention features methods and articles of manufacture for the administration of lobeline and other non-nicotine compounds that bind to nicotinic receptors to humans for the purpose of reducing symptoms of tobacco or nicotine withdrawal and as an aid in smoking cessation.
  • addiction to nicotine encompasses two key components.
  • One component is a physiological addiction to nicotine itself.
  • the physiological addiction is mediated through adaptive changes in specific brain nicotine receptors that lead to typical withdrawal symptoms upon abstaining from nicotine.
  • a second component is a complex behavioral component.
  • the behavior component is linked to learned internal cues associated with various positive or negative emotional feelings tied to tobacco smoking or abstinence.
  • the physiological addiction to nicotine is significant.
  • the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) lists the officially recognized diagnostic criteria for nicotine withdrawal as the presence of at least four of the following signs: (1) craving for nicotine; (2) irritability, frustration, anger; (3) anxiety; (4) difficulty concentrating; (5) restlessness; (6) decreased heart rate; and (7) increased appetite or weight gain.
  • Nicotine replacement therapies such as chewing gum and transdermal patches, in conjunction with behavioral counseling, are now commonly used to treat nicotine withdrawal and as an aid to smoking cessation.
  • long-term success through the use of nicotine replacement is low. In general, 25% or less of the individuals attempting to stop nicotine use are abstaining 12 months after treatment.
  • Lobeline is the principal alkaloid obtained from the dried leaves and tops of Lobelia inflata, an annual plant of the Lobeliaceae family.
  • Lobeline is a substituted piperidine compound that produces several physiological effects, some of which are similar to those produced by nicotine. It is believed that the pharmacological actions of lobeline are produced by its ability to bind to nicotine receptors in the brain and elsewhere in the body.
  • Lobeline has been proposed as a substitute for nicotine, to reduce dependence on nicotine and reduce the use of tobacco products. Although use of lobeline as a smoking cessation aid has been studied since at least the 1930 's, its efficacy nas been a matter of dispute.
  • Typical over-the-counter (OTC) products providing lobeline comprise NicobanTM, BantronTM, CigArrestTM, NicFit rM and Smoker's ChoiceTM. All lobeline containing smoking cessation products sold in recent years have been non-prescription OTC products. The FDA reports that there is no compelling proof that OTC smoking cessation aids are effective and has taken the unusual step of declaring all such OTC products mislabelled in order to remove such products from the market. Most of the OTC products administered lobeline orally for absorption in the gastrointestinal tract. The directions with such products recommend a daily dose of up to 6 milligrams. Antacids are incorporated in some of the products to overcome gastrointestinal discomfort, a side-effect similar to that caused by nicotine. Higher oral doses may not be feasible because of the concomitant gastric upset.
  • Lobeline is poorly absorbed from the gastrointestinal tract. Subjects desiring to substitute lobeline for nicotine are unable to take effective quantities of lobeline orally, due to adverse gastrointestinal effects. The oral products may not produce effective blood or tissue levels.
  • Smoker's Lozenges contains lobeline in a candy lozenge.
  • the lozenge is intended to dissolve slowly in the mouth to release lobeline.
  • a second product, Smoker's Gum contains lobeline in a gum base.
  • the gum is intended to release lobeline slowly as the gum is chewed.
  • the instructions with these products do not instruct users to retain the dissolved candy or gum fluids in the oral cavity.
  • the normal reflex would urge users to swallow, severely limiting any buccal absorption of lobeline. Absorption of swallowed lobeline from the gastrointestinal tract may not avoid first pass metabolism by the liver.
  • the present invention is directed methods and articles of manufacture for delivering an effective amount of lobeline to the nasal or sublingual mucosa.
  • the methods and articles of manufacture of the present invention provides relief from acute nicotine withdrawal, in a manner previously believed unattainable in a non-invasive dosage form. Such relief from acute nicotine withdrawal is directly applicable to individuals wanting to (1) temporarily abstain from smoking or otherwise using nicotine without suffering the full extent of nicotine withdrawal symptoms, or (2) cease using nicotine-containing products.
  • the present invention features methods and articles of manufacture for the treatment of nicotine withdrawal symptoms.
  • One method of the present invention comprises administering to a subject an effective amount of a nicotine substitute to the sublingual or nasal mucosa, or pulmonary tissues prior to or during a period in which the subject is experiencing nicotine withdrawal symptoms.
  • the nicotine substitute is absorbed through the sublingual or nasal mucosa or pulmonary tissues to alleviate the subject's desire for nicotine.
  • Nicotine refers to the active ingredient of tobacco products. Nicotine has the formula represented below:
  • nicotine substitute refers to non-nicotine compounds which bind nicotinic receptors. Such compounds exhibit, in In vitro binding assays, an affinity for nicotinic receptor-enriched brain tissue. Examples of such compounds comprise lobeline, arecoline, igaincolone, anabasine and cytisine.
  • Lobeline refers to: 2-[6-( ⁇ -hydroxyphenethyl)-l- merhyl-2-piperidyl acetophenone.
  • Lobeline is represented by the formula below:
  • lobeline as used herein includes lobeline free base and its various salts and lobeline analogs. Functional groups may be added or deleted from the formula above, while retaining the physiological activity of lobeline. Such alterations and deviations are encompassed within the term “lobeline analogs”.
  • Arecoline refers to methyl 1, 2, 5, 6-tetrahydro-l-methylnicotinate. Arecoline is represented by the formula below:
  • arecoline includes arecoline free base and its various salts and arecoline analogs. Functional groups may be added or deleted from the formula above while retaining the physiological activity of arecoline. Such alterations and deviations are encompassed within the term “arecoline analogs”.
  • Igarcolone refers to 1,2,5,6 - tetrahydro -l- methyl -4- pyridylmethylketone, the composition identified in the article by Requill et al, entitled “Behavior Effects of the Nicotinic Agonists N-(3 pyridyl-methyl) pyrrolidine and i35colone in Rats", Psychopharmacology, Berlin (1990), Vol. 102:4 pp. 521-8. Ilivecolone is represented by the formula below:
  • Anabasine refers to 2-(3-pyridyl) piperidine. Anabasine is represented by the formula below:
  • anabasine as used herein includes anabasine free base and its various salts and anabasine analogs. Functional groups may be added or deleted from the formula above while retaining the physiological activity of anabasine. Such alterations and deviations are encompassed by the term “anabasine analogs”.
  • Cytisine refers to 1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido-[1,2-a] [1.5] diazocin-8-one. Cytisine is represented by the formula below:
  • cytisine includes cytisine free base and its various salts and cytisine analogs. Functional groups may be added or deleted from the formula above while retaining the physiological activity of cytisine. Such alterations and deviations are encompassed by the term “cytisine analogs”.
  • administering means applying as a remedy, such as by the placement of a drug in a manner in which such drug would be received and be effective in carrying out its intended purpose.
  • sublingual refers to the area of the oral cavity below the tongue.
  • nasal refers to the air passages extending from the nose to the lungs .
  • mucosa refers to a mucous membrane.
  • pulmonary tissues refers to the bronchioles, alveolar ducts and alveoli.
  • subject refers to an individual who is to be treated.
  • long-term or sustained action refers to an action or duration of greater than 12 hours.
  • short-term means within a five minute period of time.
  • the nicotine substitute is administered as a soluble salt.
  • soluble salts of lobeline comprise hydrochloride, sulfate or palmoate salts.
  • a preferred soluble salt comprises the hydrochloride or the -sulfate salt which are more soluble than the palmoate.
  • the soluble salt is the sulfate salt.
  • the nicotine substitute is administered having an equivalent of 0.6 to 15 mg of lobeline free base and, more preferably, 2.5 to 15 mg 1-lobeline sulfate.
  • a particularly preferred amount is 5.0 to 10 mg 1-lobeline sulfate.
  • This amount of the nicotine substitute provides an effective level of drug through the sublingual or nasal mucosa or pulmonary tissues to alleviate nicotine withdrawal symptoms.
  • the nicotine substitute is administered to provide 30-140 mg lobeline free base per day in divided doses.
  • a more preferred range is 50-100 mg and, even more preferred 60-80 mg.
  • the nicotine substitute is administered up to 18 times per day and more preferably 6-9 times per day or upon the subject's perception of smoking withdrawal symptoms.
  • tablette refers to pharmaceutical dosage forms prepared by compressing or molding. Sublingual tablets are small and flat, for placement under the tongue and designed for rapid, almost instantaneous disintegration and release of drug to the sublingual mucosa. As used herein, the term “tablet” specifically excludes gums and lozenge dosage forms. The term “disintegration” means breaking apart and, as used herein, specifically excludes breaking apart caused by chewing, sucking, crushing or grinding in the oral cavity.
  • the sublingual tablets of the present invention disintegrate, to release the nicotine substitute for rapid absorption by the mucosa, within five minutes and, more preferably, within a two minute period of time.
  • the tablets generally comprise disintegrants to promote the rapid breaking up of the tablet.
  • the nicotine substitute released rapidly to the sublingual mucosa is absorbed and transported to active sites in the brain, mimicking the rapidly increasing nicotine blood levels individuals experience when smoking.
  • embodiments of the present method are ideally suited for treating acute nicotine withdrawal.
  • Embodiments are also ideally suited to treat transient cravings for nicotine often experienced by smokers treated with long * acting nicotine replacement therapy.
  • the nicotine substitute avoids first pass metabolism by the liver.
  • the nicotine substitute absorbed by the mucosa is most effective in addressing withdrawal symptoms.
  • the tablet comprises a taste masking flavoring, such as peppermint, spearmint and the like to improve user acceptance.
  • )ne embodiment of the present method features the nicotine substitute administered as a liquid.
  • the nicotine substitute is dissolved in the liquid as a soluble salt.
  • the liquid can be administered as a nasal spray, nasal drops or as a sublingual spray or drops.
  • Administration of the nicotine substitute as a nasal or sublingual spray or drops allows the nicotine substitute to be rapidly absorbed and avoid first pass metabolism in the liver.
  • the sprays and drops of the present invention can be administered by means of standard spray bottles or dropper bottles adapted for sublingual or nasal administration.
  • the nicotine substitute administered as a liquid is available for immediate absorption by the mucosa.
  • the nicotine substitute absorbed by the mucosa is transported to active sites in the brain, mimicking the rapidly increasing blood levels individuals experience with nicotine when smoking.
  • the drops and sprays for sublingual use are flavored to mask the taste of the nicotine substitute.
  • a preferred flavoring is chocolate, peppermint or spearmint. Flavoring increases user acceptability.
  • a further embodiment of the present method features the administration of a nicotine substitute as a fine liquid mist or a fine powder to the pulmonary tissues.
  • Administration of the nicotine substitute to the pulmonary tissues allow the nicotine substitute to avoid first pass metabolism in the liver.
  • the powders of nicotine substitute are preferably administered by devices such as turbo-inhalers and pressurized cartridge devices. Liquids of contrary nicotine substitute are administered to the pulmonary tissues by fine nebulizers and aerosols.
  • Administration of the nicotine substitute to the pulmonary tissues allows the nicotine substitute to be rapidly absorbed and avoids first pass metabolism in the liver.
  • the nicotine substitute absorbed by pulmonary tissues mimicks the rapidly increasing blood levels of individuals experience with nicotine when smoking.
  • One embodiment of the present invention features, as an article of manufacture, a dosage form for treating nicotine withdrawal symptoms comprising an effective amount of a nicotine substitute for application to the sublingual or nasal mucosa.
  • the lobeline is absorbed through the mucosa to alleviate nicotine withdrawal symptoms.
  • drug form refers to a pharmaceutical preparation for administering drug to a subject.
  • the dosage form administers an amount of nicotine substitute having a potency the equivalent of 0.6 to 15 mg of lobeline free base per dose and, more preferably, 2.5 to 15 mg of 1-lobeline sulfate.
  • a particularly preferred amount is 5.0 to 10.0 mg 1-lobeline sulfate.
  • the nicotine substitute is held in the dosage form as a soluble salt.
  • Preferred pharmaceutically acceptable salts comprise hydrochloride and the sulfate salts
  • a preferred dosage form is a sublingual tablet.
  • the sublingual tablet disintegrates and releases the nicotine substitute to the sublingual mucosa within a five minute period of time and most preferably within two minutes.
  • a further embodiment of the article of manufacture features a dosage form as a liquid.
  • the liquid delivers an effective amount of a nicotine substitute to the nasal or sublingual mucosa or the pulmonary tissues.
  • liquid formulation is preferably held in a spray bottle, or nasal drop bottle, fine nebulizer, or aerosol mist container, for ease of administration to the nasal mucosa or pulmonary tissues.
  • liquid formulations may be held in a dropper or spray bottle calibrated to deliver a predetermined amount of a nicotine substitute to the mucosa. Bottles with calibrated sprays or droppers are known in the art.
  • a further embodiment of the present invention features a dosage form as a powder.
  • the powder is micronized and delivers an effective amount of a nicotine substitute to the pulmonary tissues.
  • Embodiments of the present invention feature administering a nicotine substitute for acute nicotine replacement therapy.
  • Embodiments of the present invention are ideally suited for co-therapy with long-acting, sustained release drug formulations.
  • One embodiment of the present invention features a method of treating nicotine withdrawal symptoms comprising the steps of administering to a subject an effective amount of nicotine or a nicotine substitute by a sustained release drug formulation prior to or during a period in which the subject is experiencing nicotine withdrawal symptoms.
  • the nicotine or nicotine substitute released from the sustained release drug formulation provides a base level of nicotine or nicotine substitute to substantially alleviate the subject's desire for nicotine.
  • the method further comprises the step of administering to the subject an effective amount of a nicotine substitute to the sublingual or nasal mucosa or to the pulmonary tissue prior to or during a period in which the subject is experiencing acute nicotine withdrawal symptoms.
  • the nicotine substitute absorbed through the sublingual or nasal mucosa or to the pulmonary tissue alleviates the subject's short-term or immediate desire for nicotine in situations in which the withdrawal symptoms may be more intense.
  • the sustained release delivery system drug formulation may comprise a transdermal patch, or injectable of biodegradable polymers carrying nicotine or a nicotine substitute for sustained release for subcutaneous, intramuscular or intradermal administration.
  • Fig. 1 illustrates a nasal spray having a liquid containing a nicotine substitute for administration to the nasal or sublingual mucosa
  • Fig. 2 is a dropper bottle containing a liquid containing a nicotine substitute for administration to the nasal or sublingual mucosa;
  • Fig. 3 depicts graphically tobacco withdrawal symptoms index scores averaged for each individual plotted against the amount of lobeline sulfate administered per day;
  • Fig. 4 graphically depicts the reduction of nicotine withdrawal symptoms as a function of compliance with a therapeutic regimen comprising the method of the present invention.
  • One method of the present invention comprises the step of administering to a subject an effective amount of a nicotine substitute to the sublingual or nasal mucosa or to the pulmonary tissue prior to or during the period in which the subject is experiencing nicotine withdrawal symptoms.
  • the nicotine substitute is absorbed through the sublingual or nasal mucosa or pulmonary tissues to alleviate the subject's desire for nicotine.
  • the present invention features the administration of nicotine substitute through rapid release dosage forms such as sublingual tablets, and sublingual or nasal liquids or liquid mists or micronized powders.
  • Embodiments of the present invention are well suited for a wide variety of situations which may give rise to tobacco or nicotine withdrawal symptoms.
  • the present method and articles of manufacture allow for the immediate dosing of the subject, on an individual need basis. Coupled with appropriate behavior modification counseling, the present method and articles of manufacture can be an important part of a smoking cessation program.
  • embodiments of the present invention provide for a suitable nicotine replacement.
  • Smokeless administration of nicotine by patches and the like is not suitable for many hospitalized patients due to its effects on heart rate and blood pressure.
  • Some nicotine substitutes, such as lobeline, have little effect on blood pressure and heart rate.
  • individuals who want to abstain from nicotine for a short time may resume their tobacco use upon release from the hospital without any concern regarding the lingering effects of administration with long-acting nicotine.
  • Embodiments of the present invention feature the administration of nicotine substitutes in a fast acting form with no lingering effects which would be expected in long-acting patches or other sustained delivery forms. Thus, individuals upon the completion of the period of time in which they are unable to utilize tobacco products, may resume their customary usage of tobacco products.
  • Embodiments of the present method and articles of manufacture have application in situations in which former users of tobacco products may need temporary relief from tobacco withdrawal symptoms due to environmental factors that may initiate a specific craving for nicotine. Such individuals may have completed a smoking cessation program, and/or may also be utilizing a sustained action nicotine or nicotine substitute drug formulation and encounter unexpected cravings or desires for nicotine products.
  • Embodiments of the present invention feature the administration of a nicotine substitute in rapid acting dosage forms to alleviate acute nicotine craving.
  • Administration to the sublingual and nasal mucosa or pulmonary tissues avoids first pass metabolism and allows the nicotine substitute to be received at nicotine receptor sites in the brain to alleviate nicotine withdrawal symptoms.
  • Sublingual tablets are made in accordance with the formulation set forth in Table I .
  • the preferred formulation features a tablet with 7.5 mg lobeline sulfate and, most preferably, 7.5 mg 1-lobeline sulfate.
  • the dosage can be varied to provide 5.0 to 10.0 mg or smaller and as much as 15 mg or more of lobeline free base.
  • lobeline amounts in less than 0.6 mg may require the administration of more than one tablet to obtain the desired effect. Higher doses could, however, be required for individuals highly addicted to nicotine.
  • Lobeline, expressed as free base, amounts greater than 7.5 mg per dose are generally not required to produce the desired effect.
  • nicc-ine substitutes such as arecoline, igaincolone, anabasine and cytisine may be substituted for lobeline sulfate. Individuals skilled in the art would determine the appropriate amounts of the nicotine substitute based on the lobeline sulfate amounts.
  • mannitol, sodium saccharine, aspartame, prosweet, chocolate flavor, peppermint, magnasweet and vanilla are flavoring agents which are capable of masking the bitter taste of lobeline.
  • the flavoring agents may be deleted without sacrificing efficacy. However, patient compliance may be more difficult. Flavorings may be altered to suit individual needs and tastes.
  • D&C yellow is used as a colorant.
  • the colorant may be readily deleted or substituted with other dyes.
  • Magnesium stearate and Aerosil-200 are lubricants to release the tablet from press equipment. These ingredients may be substituted or deleted entirely depending on the manufacturing process.
  • Microcrystalline cellulose, mannitol and sodium starch glycolate provide the tablet core.
  • the cellulose and starch facilitate binding the core ingredients and facilitate tablet disintegration in the presence of moisture.
  • the relative amounts of these ingredients may be altered to adjust the disintegration of the tablet.
  • Other disintegrants may comprise starches, clays, celluloses, algins, gums, and crosslinked polymers. Quantities of all ingredients are weighed and all the ingredients, other than mannitol and Avicel, are passed through a 80 mesh stainless steel sieve. The materials are blended in a suitably sized polythene bag for about five minutes and transferred to suitable blender, such as a PK Blender.
  • the required quantities of mannitol and Avicel are passed through a 40 mesh stainless steel sieve and added to the PK Blender with the other ingredients.
  • the mixture is blended in the PK Blender for 10 minutes and unloaded.
  • a sample of the blend is subjected to inspection for potency and other quality determining criteria.
  • the bulk density is determined on the blend using bulk density apparatus set for 100 taps.
  • the tablet press is set for the designated punches and the blend is compressed at 80 mg tablet weight.
  • Tablets are administered by placing a single tablet under the tongue.
  • the tablet is allowed to disintegrate and release the nicotine substitute, lobeline.
  • the nicotine substitute, lobeline is absorbed by the sublingual mucosa.
  • Sublingual and nasal solutions are made in accordance with the formulation set forth in Table II.
  • Table II represents a preferred sublingual or nasal solution or a solution for forming a fine mist for administration to the pulmonary tissues. Individuals skilled in the art will readily recognize that modifications to the formulation can readily be made.
  • nicotine substitutes such as arecoline, igaincolone, anabasine and cytisine may be substituted for lobeline sulfate. Individuals skilled in the art would determine the appropriate amounts of these other nicotine substitutes based on the lobeline sulfate dosage.
  • sodium chloride is used to bring the solution to isotonicity. Such solutions are more comfortable for users; however, sodium chloride may be deleted if desired.
  • Benzalkonium chloride is used as a preservative. Preservatives may be omitted where storage and long term use are not important considerations. Benzalkonium chloride may be readily substituted with other preservatives which are recognized as safe and effective.
  • a nasal spray bottle generally designated by the numeral 11, is illustrated in Figure 1.
  • Bottle 11 comprises a collapsible container vessel 13, a nasal applicator 15 and a cap 17.
  • Nasal applicator 15 is sized to be received in the nasal passages of the nose.
  • Nasal applicator 15 has an opening 19 to release a spray or mist of a liquid (not shown) held in vessel 11.
  • the spray bottle 11 is designed to deliver an individual dose with one to three compressions of the bottle to deliver an effective dose of nicotine substitute to the nasal mucosa.
  • concentration of the nicotine substitute and lobeline in the liquid is preferably between 2.0 mg and 20.0 mg per ml in order to provide an effective dose upon one to three sharp compressions of the bottle.
  • Bottle 11 is designed to administer a range of liquid volume from 0.05 to 0.20 ml as a mist or spray.
  • one sharp compression delivers approximately 0.1 ml of liquid. Larger volumes are possible; however, larger volumes may allow the liquid to be received as a non-uniform coating of the nasal mucosa leading to variability in the amount of lobeline absorbed by the nasal mucosa. In addition, larger volumes may also have difficulty being retained on the nasal mucosa and run from the nasal passages, reducing the effectiveness of the administration.
  • the spray would be administered to one or both nostrils by placing the nasal applicator 15 in a nostril and making one to three sharp compressions on vessel 13.
  • Dropper bottle 21 has a containment vessel 23, a dropper 25 and a bulb 27.
  • dropper 25 is capable of being secured within the vessel 23.
  • Vessel 23 contains a liquid containing a nicotine substitute.
  • the dropper 23 is graduated with a marking 29 to indicate an appropriate dose of the nicotine substitute.
  • Drops may also be administered with a dropper bottle resembling the spray bottle of Fig. 1.
  • a dropper bottle resembling the spray bottle of Fig. 1.
  • Such bottle (not shown) has a dropper projecting from the containment vessel to deliver drops.
  • the liquid has a concentration of 2.0 mg and 20.0 mg/ml lobeline free-base equivalent to allow an effective dosage with 2-6 drops in one or more nostrils.
  • concentrations are possible; however, a large volume of drops may be required to produce a desired effect.
  • a large liquid volume may be difficult to retain in the nasal passages.
  • concentrations are possible; however, the small volume of drops may be difficult to dose accurately.
  • the drops are administered to one or both nostrils by tilting the head back and placing the drops in the nasal passages. The drops are then inhaled or withdrawn up the nasal passages.
  • liquids for administration to the sublingual mucosa a liquid having 0.6 to 7.5 mg equivalent of lobeline free-base is administered under the tongue.
  • Individuals would use the dropper by withdrawing a dose of the nicotine substitute containing liquid from the dropper bottle and administering the drops to the sublingual mucosa and holding the liquid in place as lobeline is absorbed through the sublingual mucosa.
  • the liquid is flavored to improve patient acceptance.
  • the liquid is preferably held in a dropper bottle as illustrated in Fig. 2 or the functional equivalent.
  • Example III This Example features the making of nicotine substitute powders and liquids for administration to pulmonary tissues. Powders of nicotine substitutes are finely ground and pulverized into 1-8 ⁇ m sized particles, with a mass median diameter of 3 and 6 ⁇ m. Such particles are combined with similarly sized excipients and loaded into propellant containing cartridges.
  • the excipients may comprise lubricants such as isopropyl mystistate, light mineral oil and other materials to allow slippage of the particles on the valve components. Substitutes may be used to fascilitate dispersal of particles. Other dispersing agents such as sorbitan trioleate, oleyl alcohol, oleic acid, lecithin and corn oil may be used to keep particles from agglomerating. However, excipients must be used sparingly in that the pulmonary tissues are sensitive to nonaqueous materials and particulates.
  • Liquids for use in inhalers have a nicotine substitute dissolved in an aqueous medium as described with respect to sublingual and nasal solutions. These solutions are combined with suitable propellants and loaded into cartridges.
  • Typical inhalers have a mouthpiece, valve and a pressurized cartridge containing the nicotine substitute and propellants.
  • the subject uses the inhaler by inserting the mouthpiece in the mouth and closing the lips about the mouthpiece.
  • the subject breathes in as the inhaler is activated.
  • the subject continues to breathe in slowly and deeply, and hold his or her breath for ten seconds.
  • the subject then breathes out slowly through the nose.
  • Powder and liquid aerosols are well characterized in the pharmaceutical arts. See Remington's Pharmaceutical Sciences, p. 1694-1712, Mack Publishing Company, Easton, Perm. (1990).
  • Example IV This example features the use of 2.5 mg lobeline sulfate sublingual tablets.
  • Lobeline sulfate is used as a model nicotine substitute.
  • JG is a 54 year old male who has smoked 1 to 1-1/2 packs of cigarettes per day for 40 years. He wants to quite smoking and has tried unsuccessfully to quit one time in the past. J.G. was given 12 2.5 mg lobeline-SL tablets to evaluate as aids in smoking cessation. On the morning of day number one he self-administered two tablets sublingually. One hour later he self-administered one tablet and then took one more approximately three hours later. He smoked five cigarettes over the course of day number one.
  • JG took one-half of a tablet at two separate times, one in the morning and one in the afternoon. He smoked only two cigarettes on that day.
  • JG continued taking one-half of a tablet daily until the supply was exhausted. During this time he smoked only one or two cigarettes each day.
  • SG is a 44-year old male who has smoked 1 to 1-1/2 packs of cigarettes per day for 15 years. He wants to quit smoking and has tried to quit ten times in the past, although unsuccessful in each case. He recently obtained a supply of nicotine transdermal patches to use in a smoking cessation program. However, he did not use them since he believes he would not be able to refrain from smoking and would, therefore, smoke cigarettes while using the patch and suffer the detrimental consequences of exposure to excess nicotine. SG was given eight 2.5 mg lobeline-SL tablets to evaluate as an aid for smoking cessation. On the morning of day number one he self-administered two tablets sublingually. Two and one-half hours later he self-administered a third tablet and then a fourth tablet approximately three hours later. He smoked only two cigarettes on day one, compared to the 20 to 30 he would have normally smoked.
  • This example describes the use of lobeline sublingual tablets of varying strength.
  • Sublingual tablets were prepared in accordance with Example I. These sublingual tablets comprised 2.5 mg 1-lobeline sulfate, 5.0 mg 1-lobeline sulfate, 7.5 mg 1-lobeline sulfate.
  • a placebo sublingual tablet was formed incorporating an inert material. These tablets were administered to 22 subjects who regularly smoked nicotine cigarettes. The strength and number of tablets administered per day determined the total daily dose.
  • TWSI Tobacco Withdrawal Syndrome Index
  • TWSI scores were obtained in three separate 42-44 hour sessions, one in each of three consecutive weeks.
  • the amount of lobeline sulfate administered sublingually per day was plotted against the Tobacco Withdrawal Syndrome Index (TWSI) score averaged for- each subject.
  • TWSI Tobacco Withdrawal Syndrome Index
  • P is used to indicate the use of placebo sublingual tablets containing no lobeline.
  • the line marked with “2” indicates the response to the use of 2.5 mg L-lobeline sulfate sublingual tablets.
  • the line marked “5" indicates the response to 5.0 mg L-lobeline sulfate sublingual tablets.
  • the line marked "7” indicates the response to 7.5 mg L-lobeline sulfate sublingual tablecs.
  • This example describes a study involving the use of lobeline sulfate sublingual tablets with 156 smokers.
  • Lobeline tablets were made in accordance with Example I.
  • the lobeline sulfate tablets were formulated to mask the taste of lobeline.
  • the placebo tablets were formulated to imitate the flavor of lobeline tablets.
  • the results of the low and medium doses of lobeline are not as clear as the high dose due to the small enrollment number of this study.
  • the low and medium doses may also be less than optimal for a percentage of the population.
  • the low and medium dose results are, therefore, more variable.
  • these results do suggest that lobeline administered sublingually is more effective than a placebo.

Abstract

La présente invention décrit des procédés et des articles manufacturés qui permettent de soulager les symptômes aigus du sevrage à la nicotine et contribuent à faciliter l'abandon du tabac. L'invention décrit des substituts de nicotine contenus dans des comprimés sublinguaux, ainsi que des préparations liquides permettant l'administration sur la muqueuse sublinguale ou nasale et les tissus pulmonaire, et une poudre à administrer sur les tissus pulmonaires.
PCT/US1994/012441 1993-10-28 1994-10-28 Utilisation de substituts de nicotine pour le traitement du sevrage a la nicotine WO1995011678A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU80960/94A AU8096094A (en) 1993-10-28 1994-10-28 Use of nicotine substitutes for the treatment of nicotine withdrawal

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US14430993A 1993-10-28 1993-10-28
US08/145,203 1993-10-28
US08/145,203 US5414005A (en) 1993-10-28 1993-10-28 Methods and articles of manufacture for the treatment of nicotine withdrawal and as an aid in smoking cessation
US08/144,309 1993-10-28

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WO1995011678A1 WO1995011678A1 (fr) 1995-05-04
WO1995011678A9 true WO1995011678A9 (fr) 1995-06-08

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PCT/US1994/012441 WO1995011678A1 (fr) 1993-10-28 1994-10-28 Utilisation de substituts de nicotine pour le traitement du sevrage a la nicotine

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PCT/US1994/012442 WO1995011679A1 (fr) 1993-10-28 1994-10-28 Utilisation de la lobeline dans le traitement de symptomes de sevrage de nicotine

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EP (1) EP0725640A1 (fr)
JP (1) JPH09507053A (fr)
AU (2) AU1045695A (fr)
CA (1) CA2174747A1 (fr)
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WO (2) WO1995011679A1 (fr)

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US6235734B1 (en) 1996-10-30 2001-05-22 Pfizer Inc Pyridone-fused azabicyclic- or cytisine derivatives, their preparation and their use in addiction therapy
ES2141024B1 (es) * 1997-10-03 2000-10-16 Manzanares Jesus Mari Gonzalez Preparado de accion antinicotinica.
GB2376884A (en) * 2001-06-26 2002-12-31 Peter Hajek Helping smokers stop
BRPI0415986A (pt) * 2003-10-28 2007-01-23 Alza Corp método e aparelho para reduzir a incidência do uso de tabaco
CN103284319A (zh) * 2013-06-20 2013-09-11 昌宁德康生物科技有限公司 一种金雀花碱替代尼古丁口腔雾化液及其制备方法

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GB1017032A (en) * 1963-12-12 1966-01-12 Aerosmoke Ltd Aerosol compositions
GB1056214A (en) * 1964-05-21 1967-01-25 Leo Baum Compositions containing lobeline sulphate
CH658594A5 (de) * 1982-02-22 1986-11-28 Bruss Ni Sanitarno Gigieniches Arzneipraeparat mit antinikotinwirkung und verfahren fuer seine herstellung.
US4665069A (en) * 1985-04-02 1987-05-12 Barnett Rosenberg Analgesic composition and method of relieving pain
GB2230439A (en) * 1989-04-20 1990-10-24 Alec Stanley Walter Shaw Nicotine lozenges

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