Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
• • 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
  • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• • 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
  • 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

Definitions

• the present invention features methods and articles of manufacture for the administration of lobeline 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 anc 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 has been a matter of dispute.
• Typical over-the-counter (OTC) products providing lobeline comprise icobanTM, BantronTM, CigArrestTM, NicFitTM 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 mislabeled 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 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 treatmen" of nicotine withdrawal symptoms.
• One method of the _ resent invention comprises administering to a subject an effective amount of lobeline or a lobeline analog to the sublingual mucosa prior to or during a period in which the subject is experiencing nicotine withdrawal symptoms.
• the lobeline is absorbed through the sublingual mucosa to alleviate the subject's desire for nicotine.
• Nicotine refers to the active ingredient of tobacco products. Nicotine has the formula represented below:
• Lobeline refers to: 2-_6-( ⁇ -hydroxyphenethyl)-l- methyl-2-piperidyl acetophenone.
• Lobeline is represented by the formula below.
• lobeline as used herein includes lobeline free base and its various salts. 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.
• 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.
• an “effective amount” is an amount of a drug which, if administered to a subject will cause a desired therapeutic effect.
• 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.
• 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.
• lobeline is administered as a soluble salt.
• Soluble salts of lobeline comprise hydrochloride, sulfate or pal oate salts.
• a preferred soluble salt comprises the hydrochloride or the sulfate salt which are more soluble than the palmoate. Most preferably, the soluble salt is the sulfate salt.
• lobeline is administered in an amount equivalent to 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 10.0 mg lobeline sulfate. This amount of lobeline provides an effective level of lobeline through the sublingual mucosa to alleviate nicotine withdrawal symptoms.
• 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 7.5 mg of lobeline free base.
• This amount of the nicotine substitute provides *n 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 to 140 mg lobeline free base per day in divided doses.
• a more preferred range is 50 to 100 mg and, even more preferred, 60 to 80 mg.
• the nicotine substitute is administered up to 18 times per day and more preferably, 6 to 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.
• disintegration means to break apart; and, as used herein, specifically excludes breaking apart as a result of chewing, sucking and grinding in the oral cavity.
• the sublingual tablets of the present invention disintegrate, to release lobeline 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 provide the rapid breaking up of the tablets.
• Lobeline 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.
• lobeline 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.
• a taste masking flavoring such as peppermint, spearmint and the like to improve user acceptance.
• 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 lobeline or lobeline analogs for application to the sublingual mucosa.
• the lobeline is absorbed through the mucosa to alleviate nicotine withdrawal symptoms.
• dosage form refers to a pharmaceutical preparation for administering drug to a subject.
• the dosage form administers the equivalent of 0.6 to 15 mg of lobeline free base per dose and, more preferably, 2.5 to 15 mg lobeline sulfate.
• a particularly preferred amount is 5.0 to 10.0 mg lobeline sulfide.
• the lobeline is held in the dosage form as _. soluble salt.
• Preferred pharmaceutically acceptable salts comprise hydrochloride and sulfide sal_.s.
• a preferred dosage form is a sublingual tablet.
• the sublingual tablet disintegrates and releases lobeline to the sublingual mucosa within a five minute period of time and most preferably within two minutes.
• Embodiments of the present invention feature administering lobeline 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 lobeline by a sustained release drug formulation prior to or during a period in which the subject is experiencing nicotine withdrawal symptoms.
• the nicotine or lobeline released from the sustained release drug formulation provides a base level of nicotine or lobeline to substantially alleviate the subject's desire for nicotine.
• the method further comprises the step of administering to the subject an effective amount of lobeline to the sublingual mucosa prior to or during a period in which the subject is experiencing acute nicotine withdrawal symptoms.
• the lobeline absorbed through the sublingual mucosa 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 lobeline for sustained release for subcutaneous, intramuscular or intradermal administration.
• Fig. 1 depicts graphically tobacco withdrawal symptoms index scores averaged for each individual plotted against the amount of lobeline sulfate administered per day;
• Fig. 2 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 lobeline or lobeline analog to the sublingual mucosa prior to or during the period in which the subject is experiencing nicotine withdrawal symptoms.
• the lobeline or lobeline analog is absorbed through the sublingual mucosa to alleviate the subject's desire for nicotine.
• the present invention features the administration of lobeline through rapid release dosage forms such as sublingual tablets.
• Embodiments of the present invention are wel "1 suited for a wide variety of situations wlr ' ch may give ris ⁇ _ to tobacco or nicotine witndrawal 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 su table 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.
• Lobeline has little effect on blood pressure and heart rate.
• individuals who want to abstain from nicotine for a short time nay resume their tobacco use upon release from the hospital without any concern regarding the lingering effects of administration with long-acting nicotine or nicotine substitutes.
• Embodiments of the present invention feature the administration of lobeline 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.
• Embodiments of the present invention feature the administration of lobeline in rapid acting dosage forms to alleviate acute nicotine craving.
• Administration to the sublingual mucosa avoids first pass metabolism and allows the lobeline 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.
• Flavor S.D. Peppermint, FC Magnasweet MM 188M Vanilla flavor #800 Prosweet #560 (mm54)
• the preferred formulation features a tablet with 5-10.0 mg lobeline sulfate and, most preferably, 7.5 mg lobeline sulfate.
• dosage can be varied to provide 0.6 mg or smaller and as much as 15.0 mg or more.
• 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.
• 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 rate of the tablet.
• Other disintegrants may comprise starches, clays, celluloses, algin ⁇ , 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 polyethylene bag for about five minutes and transferred to suitable blender, such as a PK Blender.
• 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 lobeline.
• the tablets described in this example disintegrate within seconds of being placed under the tongue.
• the lobeline is absorbed by the sublingual mucosa.
• EXAMPLE II This example features the use of 2.5 mg lobeline sulfate sublingual tablets.
• 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 smokmg 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 ⁇ ublingually. 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 took one-half of a tablet in the morning. He smoked only one cigarette 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 ⁇ moked 1 to 1-1/2 pack ⁇ 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 transder al patches to u ⁇ e in a ⁇ moking cessation program. However, he did not use them since he believes he would not be able to refrain___from smoking and would, therefore, ⁇ moke cigarettes- ⁇ vfbook using the patch and suffer the detrimental con ⁇ equences of exposure to excess nicotine.
• SG was given eight 2.5 mg lobeline-SL tablets to evaluate as an aid for smoking cessation.
• EXAMPLE III Thi ⁇ example de ⁇ cribes the use of lobeline sublingual tablets of varying strength.
• Sublingual tablets were prepared in accordance with Example _.. These ⁇ ublingual tablet ⁇ 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 tablet ⁇ were administered to 22 subjects who regularly smoked nicotine cigarette ⁇ . The ⁇ trength and number of tablet ⁇ admini ⁇ tered per day determined the total daily do ⁇ e.
• TWSI Tobacco Withdrawal Syndrome Index
• 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 respon ⁇ e to 5.0 mg L-lobeline sulfate sublingual tablets.
• the line marked “7” indicates the response to 7.5 mg L-lobeline sulfate sublingual tablets.
• the smokers were randomly divided into four groups .
• One group received 30 mg l-lobeline ⁇ ulfate/per day administered as 5 mg l-lobeline sulfate sublingual tablets 6 times per day.
• a second group received 45 mg l-lobeline ⁇ ulfate/per day admini ⁇ tered a ⁇ 5 mg l-lobeline sulfate sublingual tablets nine time ⁇ a day.
• a third group received 67.5 mg l-lobeline ⁇ ulfate/per day administered a ⁇ 7.5 mg l-lobeline ⁇ ulfate ⁇ ublingual tablet ⁇ 9 times per day.
• a fourth group received a placebo admini ⁇ tered nine times per day.
• Each individual of each group received brief (5 to 10 minutes) once a week behavioral counseling.
• Lobeline tablets were made in accordance with Example I.
• the lobeline sulfate tablets were formulated to ma ⁇ k the ta ⁇ te of lobeline.
• the placebo tablet ⁇ were formulated to imitate the flavor of lobeline tablets.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Immunology (AREA)
• Hematology (AREA)
• Urology & Nephrology (AREA)
• Molecular Biology (AREA)
• Microbiology (AREA)
• Pathology (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Psychiatry (AREA)
• Neurosurgery (AREA)
• Cell Biology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Biotechnology (AREA)
• Addiction (AREA)
• Food Science & Technology (AREA)
• Physics & Mathematics (AREA)
• Analytical Chemistry (AREA)
• Biochemistry (AREA)
• General Physics & Mathematics (AREA)
• Neurology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (5)

Publications (1)

Family

ID=26841884

Family Applications (1)

Country Status (6)

Families Citing this family (5)

Family Cites Families (5)

• 1993
  • 1993-11-08 TW TW082109338A patent/TW261531B/zh active
• 1994
  • 1994-10-28 CA CA002174747A patent/CA2174747A1/en not_active Abandoned
  • 1994-10-28 AU AU80960/94A patent/AU8096094A/en not_active Abandoned
  • 1994-10-28 AU AU10456/95A patent/AU1045695A/en not_active Abandoned
  • 1994-10-28 WO PCT/US1994/012441 patent/WO1995011678A1/en active Application Filing
  • 1994-10-28 EP EP95901081A patent/EP0725640A1/en not_active Withdrawn
  • 1994-10-28 WO PCT/US1994/012442 patent/WO1995011679A1/en not_active Application Discontinuation
  • 1994-10-28 JP JP7512876A patent/JPH09507053A/ja not_active Ceased

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events