CA2174747A1 - Use of lobeline for the treatment of nicotine withdrawal - Google Patents
Use of lobeline for the treatment of nicotine withdrawalInfo
- Publication number
- CA2174747A1 CA2174747A1 CA002174747A CA2174747A CA2174747A1 CA 2174747 A1 CA2174747 A1 CA 2174747A1 CA 002174747 A CA002174747 A CA 002174747A CA 2174747 A CA2174747 A CA 2174747A CA 2174747 A1 CA2174747 A1 CA 2174747A1
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- lobeline
- nicotine
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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Abstract
The present application features methods and articles of manufacture for alleviating acute symptoms of nicotine withdrawal and as an aid in smoking cessation. The invention features lobeline held in sublingual tablets for administration to the sublingual and nasal mucosa.
Description
wo 95/11679 2 1 7 4 7 4 7 PCT/US9~112442 USE OF LOBELINE FOR THE TREATMENT OF NICOTINE WITHDRAWAL
. .
., Field of the Invention 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 a. aid in smoking cessation.
Backqround of the Invention Greater understanding of the adverse health effects of tobacco consumption and associated nicotine intake has led to a marked increase in research on the nature of nicotine addiction and its treatment. Addiction to nicotine, as described in past U.S. Surgeon General's reports on smo~_ng, is widespread, with over ~0 million smokers in the United States alone. Addiction to nicotine is a major barrier to an individual ' s ability to successfully and perrn~n~ntly stop smok ing .
As with other addictions, addiction to nicotine encompasses two key c~ ~nts. One component is a physiological addiction to nicotine itself. The physiological addiction is mediated through adaptive changes in specif ic brain nicotine receptors that lead to typical withdrawal symptoms upon abstaining from nicotine. A second cnTnr~n~nt is a complex behavioral com~nent. The behavior c~rnr~n~nt is linked to learned intern~._ cues associated with various positive or nagative emotional feelings tied to tobacco smoking or abstinence.
The physiological addiction to nicotine is significant. The American Psychiatric Association's Diagnostic and Statistical r~Sanual of Mental Disorders (third edition, revised) lists the officially recognized diagnostic criteria for nicotine withdrawal as the presence of at least SUBSTITUTE SH~ET (RU~26~
WO 95/11679 PCT/US94112442 ~
2l74747 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 .
Differing approaches to smoking cessation attempt to address the physiological addition and the behavior component. The approaches range from stopping "cold turkey,'' hypnosis, electroshock, acupuncture, behavioral counseling, to various forms of therapeutic support. ~icotine replacement therapies such as chewing gum and transdermal patches, in conjunction with behavioral counselling, are now commonly used to treat nicotine withdrawal and as an aid to smoking cessation. However, 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.
There is a great need for treatment systems which promote permanent smoking cessation. There also is a need for products that provide temporary relief of tobacco/nicotine withdrawal symptoms for individuals who use tobacco products, when such use is temporarily interrupted.
Individuals who use tobacco, and do not intend to stop such use, must often refrain from such use for extended periods of time. Airline personnel and passengers, hospital workers and patients, individuals working in chemical plants or with flammable materials and the like may need to temporarily curtail the use of tobacco products. The occurrence of nicotine withdrawal is also frequently associated with reduction in task performance efficiency.
Prevention of nicotine withdrawal may alleviate or prevent such reductions in task performance.
Individuals who have stopped tobacco use and are past acute withdrawal symptoms often have acute nicotine SUBSTITUTE SH~IET (RULE26) 217~747 wo 95111679 Pcr/USs~/124~2 cravings. A reduction in nicotine craving is useful for such individuals encountering situations that increase their urge to use tobacco . Such relief may increase the individual ' s ability to maintain abstinence from tobacco use.
Lobeline is the principal alkaloid obtained f rom 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 ' s potency in causing peripheral pharmacological effects, such as increases in blood pressure and heart rate, is significantly less than that of nicotine.
Lobeline has been proposed as a s~stitute f or 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 has been a matter of dispute.
Typical over-the-counter ~OTC) products providing lobeline comprise icoban'~, Bantron~, CigArrest~, NicFit~ and Smoker ' s Choice~ . 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, SUBSTITUTE SHEET (RULE26) WO 95/11679 PCTtUS9Jtl2442 ~
. .
., Field of the Invention 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 a. aid in smoking cessation.
Backqround of the Invention Greater understanding of the adverse health effects of tobacco consumption and associated nicotine intake has led to a marked increase in research on the nature of nicotine addiction and its treatment. Addiction to nicotine, as described in past U.S. Surgeon General's reports on smo~_ng, is widespread, with over ~0 million smokers in the United States alone. Addiction to nicotine is a major barrier to an individual ' s ability to successfully and perrn~n~ntly stop smok ing .
As with other addictions, addiction to nicotine encompasses two key c~ ~nts. One component is a physiological addiction to nicotine itself. The physiological addiction is mediated through adaptive changes in specif ic brain nicotine receptors that lead to typical withdrawal symptoms upon abstaining from nicotine. A second cnTnr~n~nt is a complex behavioral com~nent. The behavior c~rnr~n~nt is linked to learned intern~._ cues associated with various positive or nagative emotional feelings tied to tobacco smoking or abstinence.
The physiological addiction to nicotine is significant. The American Psychiatric Association's Diagnostic and Statistical r~Sanual of Mental Disorders (third edition, revised) lists the officially recognized diagnostic criteria for nicotine withdrawal as the presence of at least SUBSTITUTE SH~ET (RU~26~
WO 95/11679 PCT/US94112442 ~
2l74747 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 .
Differing approaches to smoking cessation attempt to address the physiological addition and the behavior component. The approaches range from stopping "cold turkey,'' hypnosis, electroshock, acupuncture, behavioral counseling, to various forms of therapeutic support. ~icotine replacement therapies such as chewing gum and transdermal patches, in conjunction with behavioral counselling, are now commonly used to treat nicotine withdrawal and as an aid to smoking cessation. However, 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.
There is a great need for treatment systems which promote permanent smoking cessation. There also is a need for products that provide temporary relief of tobacco/nicotine withdrawal symptoms for individuals who use tobacco products, when such use is temporarily interrupted.
Individuals who use tobacco, and do not intend to stop such use, must often refrain from such use for extended periods of time. Airline personnel and passengers, hospital workers and patients, individuals working in chemical plants or with flammable materials and the like may need to temporarily curtail the use of tobacco products. The occurrence of nicotine withdrawal is also frequently associated with reduction in task performance efficiency.
Prevention of nicotine withdrawal may alleviate or prevent such reductions in task performance.
Individuals who have stopped tobacco use and are past acute withdrawal symptoms often have acute nicotine SUBSTITUTE SH~IET (RULE26) 217~747 wo 95111679 Pcr/USs~/124~2 cravings. A reduction in nicotine craving is useful for such individuals encountering situations that increase their urge to use tobacco . Such relief may increase the individual ' s ability to maintain abstinence from tobacco use.
Lobeline is the principal alkaloid obtained f rom 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 ' s potency in causing peripheral pharmacological effects, such as increases in blood pressure and heart rate, is significantly less than that of nicotine.
Lobeline has been proposed as a s~stitute f or 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 has been a matter of dispute.
Typical over-the-counter ~OTC) products providing lobeline comprise icoban'~, Bantron~, CigArrest~, NicFit~ and Smoker ' s Choice~ . 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, SUBSTITUTE SHEET (RULE26) WO 95/11679 PCTtUS9Jtl2442 ~
a side-effect similar to that caused by nicotine. Higher oral doses may not be feasible because of the concomitant gastric upset.
Although there have been reports of using lobeline in ,.
oral formulations at doses in excess of 10 mg~day, nausea and even vomiting have been associated with such doses. A
further problem with such oral dose regimens is that self-administration of as many as 18 tablets per day has been reguired. Patients may consider such a dosing regimen as intrusive, and such dosing regimen does not permit the physician to carefully control the administration of the drug or monitor patient compliance.
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.
One product presently available, 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 w- th 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.
These OTC products, as with other lobeline OTC
products, have been subjected to FDA action questioning the efficacy of the formulation. It was believed that effective doses of lobeline could not be obtained without an invasive dosage form, such as injection.
SUBSTITUTESH~ET (RU~ E26) WO 95/11679 ~ ¦ 7 4 7 4 7 PCT/US94/12.11t 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 nico ~ne without suffering the full extent of nicotine withdrawal symptoms, or ~2) cease using nicotine-containing products.
Summary of the Invention The present invention features m~thods and articles of manufacture for the treatment of nicotine withdrawal symptoms. One method of the present invention comprises administering to a ~ubject an effective amount of lobeîine 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 .
The term "nicotine" refers to the active ingredient of tobacco products. Nicotine has the formula represented below:
SUBSTITUT~ ~H~ (RULE26) WO 95/11679 PCT/[IS9~/12442 2174747 -6- e Lobeline refers to: 2-[6-(B-hydroxyphenethyl)-l-methyl-2-piperidyl acetophenone. Lobeline is represented by the formula below.
o ~H2~ H2C~ H
The term "lobeline" as u~ed 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.
The term "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 ef f ect .
The term "sublingual" refers to the area of the oral cavity below the tongue. The term ''nasal" refers to the air passages extending from the nose to the lungs. The term "mucosa" refers to a mucous membrane.
The term "subject" refers to an individual who is to be treated.
As used herein, long-term or sustained action refers to an action or duration of greater than 12 hours. As used herein, "short-term" means within a five minute period of time .
Preferably lobeline is administered as a soluble salt. Soluble salts of lobeline comprise hydrochloride, ~ulfate or palmoate salts. A preferred soluble salt SUBSTITUTE SH~Er (RllLE 26) ~ WO 95/11679 2 1 7 4 7 ~ 7 PC'r/US9.1/12442 comprises the hydrochloride or the sulfate salt which are more soluble than the palmoate, Most preferably, the soluble salt is the sulfate salt.
Preferably, 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 pre--rred 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.
Preferably the nicotine substitute is administered as a soluble salt. In t~e case of lobeline, soluble salts of lobeline comprise hydrochloride, sulfate or palmoate salts.
A preferred soluble salt comprises the hydrochloride or the sulf ate salt which are more soluble than the palmoate . Most preferably, the soluble salt is the sulfate salt.
Preferably, 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 an effective level of drug through the sublingual or nasal mucosa or pulmonary tissues to alleviate nicotine withdrawal symptoms.
Preferably, the nicotine substitute is administered to provide 30 to 140 mg lobeline free bdse per day in divided doses. A more preferred range is 50 to 100 mg and, even more preferred, 60 to 80 mg.
Preferably, 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 .
One embodiment of the present method features lobeline administered as a sublingual tablet. As used herein, the term "tablet" refers to pharmaceutical dosage forms prepared by compressing or molding. Sublingual tablets are small and SUBSTITUTE SHEET (RlJLE26) woss/1l67s Pcrluss4ll2442 o 21 74747 - =
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 to break apart; and, as used herein, specifically excludes brealcing apart as a result of chewing, sucking and grinding in the oral cavity.
Preferably, 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. Thus, 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.
Sublingual administration of lobeline avoids first pass metabolism by the liver. Thus, lobeline absorbed by the mucosa is most effective in addressing withdrawal symptoms.
Preferably the tablet comprises 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.
SUBSTITUTE SHEET (RULE26) ~ WO 95/11679 2 l 7 4 7 4 7 PCT/US94112442 _ g _ The term "dosage form" refers to a pharmaceutical preparation for sdministering drug to a subject.
Preferably, 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 . o mg lobeline sulfide.
Preferably, the lobeline is held in the dosage form as a soluble salt. Preferred pharmaceutically acceptable salts comprise hydrochloride and sulfide salts.
A preferred dosage form is a sublingual tablet.
Preferably, the sublingual tablet disintegrates and releases lobeline to the sublingual mucosa within a f ive minute period of time and most preferably within two minutes.
Ernbodiments 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.
SUBSTITUTE S~EE~ (RUlE26) WO 95/11679 PCT/I~S9411244t ~
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 .
Other features and advantages of the present invention will be apparent from the following description which depict or describe preferred embodiments of the present invention and the principles thereof and what is now considered to be the best mode to apply these principles.
- Brief Description of the Drawinqs Fig. 1 depicts graphically tobacco withdrawal symptoms index scores averaged for each individual plotted against the amount of lobeline sulfate administered per day; and 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 invent i on .
Detailed Description of the Invention The present invention is described in detail as methods and articles of manufacture for the treatment of nicotine withdrawal symptoms. 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.
SllBSTITUTE SH~ET (RULE 26) ~ WO 95/11679 2 1 7 4 7 4 7 PCT/IIS94112442 Embodiments of the present invention are well suited for a wide variety of situations which may give rise to tobacco or nicotine withdrawal symptoms. For those active tobacco users who want to stop permanently, the present method and articles of manufacture allow for the immediate dosing of the subject, on an individual need basis. Coupled with appropriate behavior modi~ication counselling, the present method and articles of manufacture can be an important part of a smoking cessation program.
For subjects who need to abstain from tobacco and nicotine, due to hospitalization or other medical necessities, 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 pr~-sure. Lobeline has little effect on blood pressure and heart rate. Moreover, individuals who want to abstain from nicotine for a short time ~ay 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.
In situations which require indivicuals to abstain from smoking due to restrictions encountered in every day situations, such individuals are able to alleviate nicotine withdrawal symptoms with a rapid acting nicotine substitute.
For example, airline personnel and passengers are often unable to utilize tobacco products during flight.
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.
SUBSTITUTE SHEEr (RU~ E$~
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 f actors 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 lobeline in rapid acting dosage forms to alleviate acute nicotine craving .
Such a broad spectrum of applications is not found in other nicotine withdrawal remedies. The administration of lobeline in a non-invasive drug formulation which is ef f ect ive i s surpr i s ing and unexpected .
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 symptorns.
Other features and advantages of the present invention are disclosed in the following examples which exemplify preferred embodiments of the present invention.
EXAMPLE I ~ ~=
Sublinqual Tablets Sublingual tablets are made in accordance with the formulation set forth in Table I.
SUBSTITUTE SHE~ ~RULE 26) ., Lobeline Sulfate 2.5-15 mg Mannitol, USP (DC grade) 16.5-31.5 mg Microcryst, Cellulose 34-40.35 mg Sodium Starch Glycolate NF 2.6 mg OSodium Saccharin, USP 0.5-2.00 mg Aspartame (NEUTRASWEET'M) O - 4.00 mg Flavor S.D. Peppermint, FCC 0.40-0.75 mg MAGNASWEETIa MM 188M 0.25-0.5 mg Vanilla flavor #800 0.2-0.30 mg PROSWEET~ #560 (mm54) 0.0-0.75 mg Chocolate Flavor #682 0.0-2.00 mg D&C Yellow #10, Aluminum Lake 0.0-0.2 mg Magnesium stearate, I~IF 0.5 mg AEROSIL 200~ 0.4 mg TOTAL 80-85 mg The formulation set forth in Table i ,t:p,~se~ a preferred sublingual tablet formula. Individuals skilled in the art will recognize that modifications to theformulation can be readily made.
The preferred formulation features a tablet with 5-10.0 mg lobeline sulfate and, most preferably, 7.5 mg lobeline sulfate. However, dosage can be varied to provide 0.6 mg or smaller and as much as 15.0 mg or more. However, lobeline amounts in less than 0.6 mg may require the d~ ldliOn 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.
S~Er ~1 74 '47 In the above formulation, mannitol, sodium saccharine, aspartame, PROSWEETTM, chocolate flavor, peppermint, MAGNASWEET'M and vanilla are flavoring agents which are capable of masking the bitter taste of lobeline. The flavoring agents may be deleted without sacrificin~ 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 AEROSlL-2001Mare lubricants to release the tabiet 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 d;DirlL~y~d~iull rate of the tablet.
Other d;~ L~u~ llL~ may comprise starches, clays, celluloses, algins, gums and crosslinked polymers.
Quantities of all ingredients are weighed and all the ingredients, other than mannitol and AVICELIM, are passed through a 80 mesh stainless steel sieve. The materials are blended in a suitably sized polyethylene bag for about five minutes and ~,d"~r, l,~d to suitable blender, such as a PK Blender. The required quantities of mannitol and AVICELD' 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 ~157j.1 A~Eh!~D S ~E~
~ WO 95/11679 2 1 7 4 7 4 7 PCT/IJS94/124~2 100 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 tongu~. The lobeline is absorbed by the sublingual mucosa.
This example features the use of 2 . 5 mg lobeline sulfate sublingual tablets.
Experience of JG
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 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 f ive cigarettes over the course of day number one.
One the second day JG took two tablets, one in the morning and one in the early afternoon. He smoked only two cigarettes that day.
On the third day JG took one-half of a tablet at three separates times, spread evenly throughout each day. He smoked only two cigarettes that day.
On the fourth day, 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.
On the f if th day, JG took one-half of a tablet in the morning. He smoked only one cigarette that day.
SUBSTITUTE SHEET (RULE26) WO 9~;111679 PCTIUS94112442 0 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.
When asked the reason he reduced his smoking level, he -~
replied that he had much less desire to smoke and the cigarettes tasted bad when he did smoke.
Exper ience of SG
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 conse~uences 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.
On the second day, SG took the remaining four tablets periodically throughout the day and smoked four cigarettes.
When asked why he smoked fewer than his usual number of cigarettes, he responded that he just did not have the urge to smoke. ~hree weeks after this two-day evaluation SG
was smoking only 7 or 8 cigarettes per day.
EX~MPLE I I I
~his example describes the use of lobelir~e sublingual tablets of varying strength. Sublingual tablets were S~IBSTITUTE SHEEl (RU~ E 26) 2l 74747 WO95111679 PCT/lJS9~/12412 prepared in accordance with Example I. These sublingual tablets comprised 2 . 5 mg l-lobeline sulfate, 5 . O mg l-lobeline sulfate, 7.5 mg l-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.
The subjects spent two nights in the clinic and abstained from smoking over the full time. Subjects entered the clinic at noon on Day 1 and immediately ceased tobacco consumption. At 7: Oo a .m. the next morning they started taking either placebo or l-lobeline sulfate sublingual tablets, which they continued to take periodical " over the next 16 hours, the total amount taken being dependent on the dose group to which they belongel and the strength of tablet.
Tobacco Withdrawal Syndrome Irdex ~TWSI ~ scores were taken periodically throughout the day. The TWSI is a system for evaluating symptoms of tobacco smoking withdrawal on a 0-4 scale. The components of TWSI which were evaluated comprised anxiety, anger, craving for a cigarette, restlessness and difficulty c~ncentrating. The TWSI scores ~ere obtained in three separate 42-44 hour sessions, one in each of three consecutive weeks. The amount of lobeline sulfate administered subling~ ly per day was plotted against the Tobacco Withdrawal Syndrome Index (TWSI) score averaged for each subject. In Figure 3, "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. And, the line marked ~'7"
indicates the response to 7 . 5 mg L-lobeline sulfate SllBSTITUTE SHEEr (RUl E 26) Wo 95/11679 2 1 7 4 7 4 7 Pcr/uss4l12442 ~
sublingual tablets. These results suggest a marked reduction in nicotine withdrawal symptoms with increasing doses of L-lobeline sulfate. These results suggest that an effective amount is approximately 30-90 mg L-lobeline sulfate administered sublingually per day.
EXAMPLE IV
This example describes a study involving the use of lobeline sulfate sublingual tablets with 156 smokers.
These smokers were randomly divided into four groups.
One group received 30 mg l-lobeline sulfate/per day administered as 5 mg l-lobeline sulfate sublingual tablets 6 times per day. A second group received 45 mg l-lobeline sulfate/per day administered as 5 mg l-lobeline sulfate sublingual tablets nine times a day. A third group received 67 . 5 mg l-lobeline sulfate/per aay administered as 7 . 5 mg l-lobeline sulfate sublingual tablets 9 times per day. A
fourth group received a placebo administered nine times per day. Each individual of each group received brief (5 to l0 minutes) once a week behavioral counseling.
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 study suggest that lobeline, administered sublingually, in rapid disintegrating tablets, can be administered safely with no clinically significant adverse effects. The results of the study suggest that lobeline, administered sublingually, in rapid disintegrating tablets is effective to alleviate tobacco withdrawal symptoms and reduce the number of cigarettes smoked per day.
SUBSTITUTE SHEEr (RU~E 26) .
W095/11679 2 1 7 4 7 4 7 PCT/US94/1~442 Results of the study with respect to smoking activity are summarized in Table 1 below:
, -Table l P~c~ I. PHA~F. ~ h C'~ 'ORI~G ACI'rVlTY
Group Cigarcttes Smoked Pcr Week pre-Study ¦ Study Weeks 3-6 All Subjects ~linus Dropouts Placbo (n=29) 214 45 Low (n=17) 215 38 Medium (n=22) 199 69 High (n=18) 203 34 2 77% Compliant to Therapy Placebo (n=19) 223 39 Low (n-6) æ4 41 Medium (n=13) 198 49 High (n=9) 215 13 100% Compliant to Therapy Placebo (n=9) 233 60 Low (n=5) 244 48 Mcoium (n=5) æ8 63 High (n=2) 257 Consistent with FDA guidelines, treatment efficacy was evaluated during weeks 3-6 of the study. ~he 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. However, these SUBSTITUTE SHEET (RU~ E 26) WO95/11679 PC~/US94112442 1~
results do suggest that lobeline administered sublingually is more effective than a placebo. The results suggesting a reduction of cigarettes smoked, from well over 200, down to one to 13, with respect high doses of lobeline, is striking.
Results of the study with respect to abstinence rates are summar i zed in Table 2 below:
Table 2 rrrP~ M SI . PIIASP 2 h- A¦~INP.~CP RATF.
Grou n Successes F~ulures Dropouts Pfficacy ~
P for All for All, Subjects Mu)us % Dropouts %
All Subjects Placebo 38 8 28 2 21 22 L~w 39 7 18 14 18 28 Me~Dum 39 7 22 10 18 24 High 38 6 17 15 16 26 2 77% C mpDant ~o ~h~rapy 'lacebo ~ S 19 ' ~w _11 4 6 ~le~Dum R 4 14 ~ligh ~ S 9 100% C mplia ~t to lberapy plsto~bo 14 4 10 ,.o High 7 2 Me~Dum 8 2 o Hiyh 3 Smoking activity, expressed either as the number of cigarettes smoked or as total abstinence from smoking, was clearly reduced for those subjects who complied with therapy to an extent of taking at least 77% of their rec ~ '~d doses. With respect to Table 2, within those individuals who were identified as 100% compliant, there is one individual SUBSTITUTE SHEET (RUI E26) -WO 95/11679 2 1 7 4 7 4 7 PCT/IJS9.S/12442 who received high dose lobeline and who smoked one cigar and as a result is identified as a failure. This individual apparen- y did not understand that he was not allowed to smoke a .- gar and still be considered abstinent from smoking. However, had this individual not smoked that one cigar, the efficacy of high dose lobeline would be even higher at 6696. The results of the low and medium doses of lobeline are variable due to the small enrollment numbers.
The results at the lower doses may also be more variable because such dose may be less than optimal for part of the population. These results are striking in demonstrating a high level of efficacy in promoti~g abstinence.
The results with respect to smoking withdrawal scores, for the high dose lobeline group compared to placebo is set f orth in Eigure 2 .
The difference between t~ lacebo and the lobeline group became greater as complian~ to therapy increased, again ir~dicating that lobeline reduces tobacco withdrawal symptoms. The results of Figure 1 are striking in demonstrating a reduction in smoking withdrawal symptoms.
Thus, while preferred embodiments of the present invention have been described, the present invention is capable of variation and modification and, therefore, the present invention should not be limited to the precise details set forth, but should include such changes and alterations as fall within the purview of the following claims .
~hat is claimed is:
SUBSTITUT~ SHEET (RU~ ~26)
Although there have been reports of using lobeline in ,.
oral formulations at doses in excess of 10 mg~day, nausea and even vomiting have been associated with such doses. A
further problem with such oral dose regimens is that self-administration of as many as 18 tablets per day has been reguired. Patients may consider such a dosing regimen as intrusive, and such dosing regimen does not permit the physician to carefully control the administration of the drug or monitor patient compliance.
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.
One product presently available, 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 w- th 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.
These OTC products, as with other lobeline OTC
products, have been subjected to FDA action questioning the efficacy of the formulation. It was believed that effective doses of lobeline could not be obtained without an invasive dosage form, such as injection.
SUBSTITUTESH~ET (RU~ E26) WO 95/11679 ~ ¦ 7 4 7 4 7 PCT/US94/12.11t 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 nico ~ne without suffering the full extent of nicotine withdrawal symptoms, or ~2) cease using nicotine-containing products.
Summary of the Invention The present invention features m~thods and articles of manufacture for the treatment of nicotine withdrawal symptoms. One method of the present invention comprises administering to a ~ubject an effective amount of lobeîine 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 .
The term "nicotine" refers to the active ingredient of tobacco products. Nicotine has the formula represented below:
SUBSTITUT~ ~H~ (RULE26) WO 95/11679 PCT/[IS9~/12442 2174747 -6- e Lobeline refers to: 2-[6-(B-hydroxyphenethyl)-l-methyl-2-piperidyl acetophenone. Lobeline is represented by the formula below.
o ~H2~ H2C~ H
The term "lobeline" as u~ed 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.
The term "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 ef f ect .
The term "sublingual" refers to the area of the oral cavity below the tongue. The term ''nasal" refers to the air passages extending from the nose to the lungs. The term "mucosa" refers to a mucous membrane.
The term "subject" refers to an individual who is to be treated.
As used herein, long-term or sustained action refers to an action or duration of greater than 12 hours. As used herein, "short-term" means within a five minute period of time .
Preferably lobeline is administered as a soluble salt. Soluble salts of lobeline comprise hydrochloride, ~ulfate or palmoate salts. A preferred soluble salt SUBSTITUTE SH~Er (RllLE 26) ~ WO 95/11679 2 1 7 4 7 ~ 7 PC'r/US9.1/12442 comprises the hydrochloride or the sulfate salt which are more soluble than the palmoate, Most preferably, the soluble salt is the sulfate salt.
Preferably, 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 pre--rred 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.
Preferably the nicotine substitute is administered as a soluble salt. In t~e case of lobeline, soluble salts of lobeline comprise hydrochloride, sulfate or palmoate salts.
A preferred soluble salt comprises the hydrochloride or the sulf ate salt which are more soluble than the palmoate . Most preferably, the soluble salt is the sulfate salt.
Preferably, 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 an effective level of drug through the sublingual or nasal mucosa or pulmonary tissues to alleviate nicotine withdrawal symptoms.
Preferably, the nicotine substitute is administered to provide 30 to 140 mg lobeline free bdse per day in divided doses. A more preferred range is 50 to 100 mg and, even more preferred, 60 to 80 mg.
Preferably, 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 .
One embodiment of the present method features lobeline administered as a sublingual tablet. As used herein, the term "tablet" refers to pharmaceutical dosage forms prepared by compressing or molding. Sublingual tablets are small and SUBSTITUTE SHEET (RlJLE26) woss/1l67s Pcrluss4ll2442 o 21 74747 - =
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 to break apart; and, as used herein, specifically excludes brealcing apart as a result of chewing, sucking and grinding in the oral cavity.
Preferably, 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. Thus, 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.
Sublingual administration of lobeline avoids first pass metabolism by the liver. Thus, lobeline absorbed by the mucosa is most effective in addressing withdrawal symptoms.
Preferably the tablet comprises 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.
SUBSTITUTE SHEET (RULE26) ~ WO 95/11679 2 l 7 4 7 4 7 PCT/US94112442 _ g _ The term "dosage form" refers to a pharmaceutical preparation for sdministering drug to a subject.
Preferably, 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 . o mg lobeline sulfide.
Preferably, the lobeline is held in the dosage form as a soluble salt. Preferred pharmaceutically acceptable salts comprise hydrochloride and sulfide salts.
A preferred dosage form is a sublingual tablet.
Preferably, the sublingual tablet disintegrates and releases lobeline to the sublingual mucosa within a f ive minute period of time and most preferably within two minutes.
Ernbodiments 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.
SUBSTITUTE S~EE~ (RUlE26) WO 95/11679 PCT/I~S9411244t ~
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 .
Other features and advantages of the present invention will be apparent from the following description which depict or describe preferred embodiments of the present invention and the principles thereof and what is now considered to be the best mode to apply these principles.
- Brief Description of the Drawinqs Fig. 1 depicts graphically tobacco withdrawal symptoms index scores averaged for each individual plotted against the amount of lobeline sulfate administered per day; and 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 invent i on .
Detailed Description of the Invention The present invention is described in detail as methods and articles of manufacture for the treatment of nicotine withdrawal symptoms. 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.
SllBSTITUTE SH~ET (RULE 26) ~ WO 95/11679 2 1 7 4 7 4 7 PCT/IIS94112442 Embodiments of the present invention are well suited for a wide variety of situations which may give rise to tobacco or nicotine withdrawal symptoms. For those active tobacco users who want to stop permanently, the present method and articles of manufacture allow for the immediate dosing of the subject, on an individual need basis. Coupled with appropriate behavior modi~ication counselling, the present method and articles of manufacture can be an important part of a smoking cessation program.
For subjects who need to abstain from tobacco and nicotine, due to hospitalization or other medical necessities, 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 pr~-sure. Lobeline has little effect on blood pressure and heart rate. Moreover, individuals who want to abstain from nicotine for a short time ~ay 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.
In situations which require indivicuals to abstain from smoking due to restrictions encountered in every day situations, such individuals are able to alleviate nicotine withdrawal symptoms with a rapid acting nicotine substitute.
For example, airline personnel and passengers are often unable to utilize tobacco products during flight.
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.
SUBSTITUTE SHEEr (RU~ E$~
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 f actors 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 lobeline in rapid acting dosage forms to alleviate acute nicotine craving .
Such a broad spectrum of applications is not found in other nicotine withdrawal remedies. The administration of lobeline in a non-invasive drug formulation which is ef f ect ive i s surpr i s ing and unexpected .
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 symptorns.
Other features and advantages of the present invention are disclosed in the following examples which exemplify preferred embodiments of the present invention.
EXAMPLE I ~ ~=
Sublinqual Tablets Sublingual tablets are made in accordance with the formulation set forth in Table I.
SUBSTITUTE SHE~ ~RULE 26) ., Lobeline Sulfate 2.5-15 mg Mannitol, USP (DC grade) 16.5-31.5 mg Microcryst, Cellulose 34-40.35 mg Sodium Starch Glycolate NF 2.6 mg OSodium Saccharin, USP 0.5-2.00 mg Aspartame (NEUTRASWEET'M) O - 4.00 mg Flavor S.D. Peppermint, FCC 0.40-0.75 mg MAGNASWEETIa MM 188M 0.25-0.5 mg Vanilla flavor #800 0.2-0.30 mg PROSWEET~ #560 (mm54) 0.0-0.75 mg Chocolate Flavor #682 0.0-2.00 mg D&C Yellow #10, Aluminum Lake 0.0-0.2 mg Magnesium stearate, I~IF 0.5 mg AEROSIL 200~ 0.4 mg TOTAL 80-85 mg The formulation set forth in Table i ,t:p,~se~ a preferred sublingual tablet formula. Individuals skilled in the art will recognize that modifications to theformulation can be readily made.
The preferred formulation features a tablet with 5-10.0 mg lobeline sulfate and, most preferably, 7.5 mg lobeline sulfate. However, dosage can be varied to provide 0.6 mg or smaller and as much as 15.0 mg or more. However, lobeline amounts in less than 0.6 mg may require the d~ ldliOn 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.
S~Er ~1 74 '47 In the above formulation, mannitol, sodium saccharine, aspartame, PROSWEETTM, chocolate flavor, peppermint, MAGNASWEET'M and vanilla are flavoring agents which are capable of masking the bitter taste of lobeline. The flavoring agents may be deleted without sacrificin~ 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 AEROSlL-2001Mare lubricants to release the tabiet 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 d;DirlL~y~d~iull rate of the tablet.
Other d;~ L~u~ llL~ may comprise starches, clays, celluloses, algins, gums and crosslinked polymers.
Quantities of all ingredients are weighed and all the ingredients, other than mannitol and AVICELIM, are passed through a 80 mesh stainless steel sieve. The materials are blended in a suitably sized polyethylene bag for about five minutes and ~,d"~r, l,~d to suitable blender, such as a PK Blender. The required quantities of mannitol and AVICELD' 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 ~157j.1 A~Eh!~D S ~E~
~ WO 95/11679 2 1 7 4 7 4 7 PCT/IJS94/124~2 100 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 tongu~. The lobeline is absorbed by the sublingual mucosa.
This example features the use of 2 . 5 mg lobeline sulfate sublingual tablets.
Experience of JG
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 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 f ive cigarettes over the course of day number one.
One the second day JG took two tablets, one in the morning and one in the early afternoon. He smoked only two cigarettes that day.
On the third day JG took one-half of a tablet at three separates times, spread evenly throughout each day. He smoked only two cigarettes that day.
On the fourth day, 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.
On the f if th day, JG took one-half of a tablet in the morning. He smoked only one cigarette that day.
SUBSTITUTE SHEET (RULE26) WO 9~;111679 PCTIUS94112442 0 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.
When asked the reason he reduced his smoking level, he -~
replied that he had much less desire to smoke and the cigarettes tasted bad when he did smoke.
Exper ience of SG
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 conse~uences 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.
On the second day, SG took the remaining four tablets periodically throughout the day and smoked four cigarettes.
When asked why he smoked fewer than his usual number of cigarettes, he responded that he just did not have the urge to smoke. ~hree weeks after this two-day evaluation SG
was smoking only 7 or 8 cigarettes per day.
EX~MPLE I I I
~his example describes the use of lobelir~e sublingual tablets of varying strength. Sublingual tablets were S~IBSTITUTE SHEEl (RU~ E 26) 2l 74747 WO95111679 PCT/lJS9~/12412 prepared in accordance with Example I. These sublingual tablets comprised 2 . 5 mg l-lobeline sulfate, 5 . O mg l-lobeline sulfate, 7.5 mg l-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.
The subjects spent two nights in the clinic and abstained from smoking over the full time. Subjects entered the clinic at noon on Day 1 and immediately ceased tobacco consumption. At 7: Oo a .m. the next morning they started taking either placebo or l-lobeline sulfate sublingual tablets, which they continued to take periodical " over the next 16 hours, the total amount taken being dependent on the dose group to which they belongel and the strength of tablet.
Tobacco Withdrawal Syndrome Irdex ~TWSI ~ scores were taken periodically throughout the day. The TWSI is a system for evaluating symptoms of tobacco smoking withdrawal on a 0-4 scale. The components of TWSI which were evaluated comprised anxiety, anger, craving for a cigarette, restlessness and difficulty c~ncentrating. The TWSI scores ~ere obtained in three separate 42-44 hour sessions, one in each of three consecutive weeks. The amount of lobeline sulfate administered subling~ ly per day was plotted against the Tobacco Withdrawal Syndrome Index (TWSI) score averaged for each subject. In Figure 3, "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. And, the line marked ~'7"
indicates the response to 7 . 5 mg L-lobeline sulfate SllBSTITUTE SHEEr (RUl E 26) Wo 95/11679 2 1 7 4 7 4 7 Pcr/uss4l12442 ~
sublingual tablets. These results suggest a marked reduction in nicotine withdrawal symptoms with increasing doses of L-lobeline sulfate. These results suggest that an effective amount is approximately 30-90 mg L-lobeline sulfate administered sublingually per day.
EXAMPLE IV
This example describes a study involving the use of lobeline sulfate sublingual tablets with 156 smokers.
These smokers were randomly divided into four groups.
One group received 30 mg l-lobeline sulfate/per day administered as 5 mg l-lobeline sulfate sublingual tablets 6 times per day. A second group received 45 mg l-lobeline sulfate/per day administered as 5 mg l-lobeline sulfate sublingual tablets nine times a day. A third group received 67 . 5 mg l-lobeline sulfate/per aay administered as 7 . 5 mg l-lobeline sulfate sublingual tablets 9 times per day. A
fourth group received a placebo administered nine times per day. Each individual of each group received brief (5 to l0 minutes) once a week behavioral counseling.
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 study suggest that lobeline, administered sublingually, in rapid disintegrating tablets, can be administered safely with no clinically significant adverse effects. The results of the study suggest that lobeline, administered sublingually, in rapid disintegrating tablets is effective to alleviate tobacco withdrawal symptoms and reduce the number of cigarettes smoked per day.
SUBSTITUTE SHEEr (RU~E 26) .
W095/11679 2 1 7 4 7 4 7 PCT/US94/1~442 Results of the study with respect to smoking activity are summarized in Table 1 below:
, -Table l P~c~ I. PHA~F. ~ h C'~ 'ORI~G ACI'rVlTY
Group Cigarcttes Smoked Pcr Week pre-Study ¦ Study Weeks 3-6 All Subjects ~linus Dropouts Placbo (n=29) 214 45 Low (n=17) 215 38 Medium (n=22) 199 69 High (n=18) 203 34 2 77% Compliant to Therapy Placebo (n=19) 223 39 Low (n-6) æ4 41 Medium (n=13) 198 49 High (n=9) 215 13 100% Compliant to Therapy Placebo (n=9) 233 60 Low (n=5) 244 48 Mcoium (n=5) æ8 63 High (n=2) 257 Consistent with FDA guidelines, treatment efficacy was evaluated during weeks 3-6 of the study. ~he 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. However, these SUBSTITUTE SHEET (RU~ E 26) WO95/11679 PC~/US94112442 1~
results do suggest that lobeline administered sublingually is more effective than a placebo. The results suggesting a reduction of cigarettes smoked, from well over 200, down to one to 13, with respect high doses of lobeline, is striking.
Results of the study with respect to abstinence rates are summar i zed in Table 2 below:
Table 2 rrrP~ M SI . PIIASP 2 h- A¦~INP.~CP RATF.
Grou n Successes F~ulures Dropouts Pfficacy ~
P for All for All, Subjects Mu)us % Dropouts %
All Subjects Placebo 38 8 28 2 21 22 L~w 39 7 18 14 18 28 Me~Dum 39 7 22 10 18 24 High 38 6 17 15 16 26 2 77% C mpDant ~o ~h~rapy 'lacebo ~ S 19 ' ~w _11 4 6 ~le~Dum R 4 14 ~ligh ~ S 9 100% C mplia ~t to lberapy plsto~bo 14 4 10 ,.o High 7 2 Me~Dum 8 2 o Hiyh 3 Smoking activity, expressed either as the number of cigarettes smoked or as total abstinence from smoking, was clearly reduced for those subjects who complied with therapy to an extent of taking at least 77% of their rec ~ '~d doses. With respect to Table 2, within those individuals who were identified as 100% compliant, there is one individual SUBSTITUTE SHEET (RUI E26) -WO 95/11679 2 1 7 4 7 4 7 PCT/IJS9.S/12442 who received high dose lobeline and who smoked one cigar and as a result is identified as a failure. This individual apparen- y did not understand that he was not allowed to smoke a .- gar and still be considered abstinent from smoking. However, had this individual not smoked that one cigar, the efficacy of high dose lobeline would be even higher at 6696. The results of the low and medium doses of lobeline are variable due to the small enrollment numbers.
The results at the lower doses may also be more variable because such dose may be less than optimal for part of the population. These results are striking in demonstrating a high level of efficacy in promoti~g abstinence.
The results with respect to smoking withdrawal scores, for the high dose lobeline group compared to placebo is set f orth in Eigure 2 .
The difference between t~ lacebo and the lobeline group became greater as complian~ to therapy increased, again ir~dicating that lobeline reduces tobacco withdrawal symptoms. The results of Figure 1 are striking in demonstrating a reduction in smoking withdrawal symptoms.
Thus, while preferred embodiments of the present invention have been described, the present invention is capable of variation and modification and, therefore, the present invention should not be limited to the precise details set forth, but should include such changes and alterations as fall within the purview of the following claims .
~hat is claimed is:
SUBSTITUT~ SHEET (RU~ ~26)
Claims (17)
1. A method of treating nicotine withdrawal symptoms, comprising:
(a) administering to a subject an effective amount of lobeline or lobeline analog to the sublingual mucosa, prior to or during a period in which the subject is experiencing nicotine withdrawal symptoms, said lobeline absorbed through the sublingual mucosa to alleviate the subject's desire for nicotine.
(a) administering to a subject an effective amount of lobeline or lobeline analog to the sublingual mucosa, prior to or during a period in which the subject is experiencing nicotine withdrawal symptoms, said lobeline absorbed through the sublingual mucosa to alleviate the subject's desire for nicotine.
2. The method of claim 1 wherein the equivalent of 0.6 to 15 mg lobeline free base is administered per dose.
3. The method of claim 1 wherein the lobeline or lobeline analog is 1-lobeline sulfate.
4. The method of claim 3 wherein the 1-lobeline sulfate is present in an amount of 2.5 to 15 mg.
5. The method of claim 2 wherein said lobeline is administered as a soluble salt.
6. The method of claim 5 wherein said salt is a sulfate or hydrochloride salt.
7. The method of claim 1 wherein said lobeline is administered as a sublingual tablet.
8. The method of claim 1 wherein said lobeline is available for absorption within a five-minute period.
9. The method of claim 1 wherein said lobeline is available for absorption within a two-minute period.
10. As an article of manufacture, a dosage form for treating nicotine withdrawal symptoms comprising:
an effective amount of lobeline or lobeline analog held in a sublingual tablet for application to the sublingual mucosa, said tablet releasing said lobeline or lobeline analog upon disintegration of the tablet and said lobeline or lobeline analog being absorbed through the mucosa to alleviate nicotine withdrawal symptoms.
an effective amount of lobeline or lobeline analog held in a sublingual tablet for application to the sublingual mucosa, said tablet releasing said lobeline or lobeline analog upon disintegration of the tablet and said lobeline or lobeline analog being absorbed through the mucosa to alleviate nicotine withdrawal symptoms.
11. The dosage form of claim 10 wherein said sublingual tablet disintegrates within a five-minute period.
12. The dosage form of claim 10 wherein said sublingual tablet disintegrates within a two-minute period.
13. The dosage form of claim 10 wherein said effective amount is the equivalent of 0.6 to 15 mg of lobeline free base per dose.
14. The dosage form of claim 10 wherein the lobeline or lobeline analog is 1-lobeline sulfate.
15. The dosage form of claim 14 wherein the 1-lobeline sulfate is in an amount of 2.5 to 15 mg.
16. The dosage form of claim 8 wherein said lobeline or lobeline analog is a soluble salt.
17. A method of treating nicotine withdrawal symptoms, comprising:
(a) administering to a subject an effective amount of nicotine or lobeline by a sustained release dosage form prior to or during a period in which the subject is experiencing nicotine withdrawal symptoms, said nicotine or lobeline released from said sustained release dosage form providing a base level of nicotine or lobeline to alleviate the subject's long term desire for nicotine; and (b) administering to a subject an effective amount of lobeline to the sublingual mucosa, prior to or during a period in which the subject is experiencing nicotine withdrawal symptoms, said lobeline absorbed through the sublingual mucosa to alleviate the subject's acute desire for nicotine.
(a) administering to a subject an effective amount of nicotine or lobeline by a sustained release dosage form prior to or during a period in which the subject is experiencing nicotine withdrawal symptoms, said nicotine or lobeline released from said sustained release dosage form providing a base level of nicotine or lobeline to alleviate the subject's long term desire for nicotine; and (b) administering to a subject an effective amount of lobeline to the sublingual mucosa, prior to or during a period in which the subject is experiencing nicotine withdrawal symptoms, said lobeline absorbed through the sublingual mucosa to alleviate the subject's acute desire for nicotine.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2174747A1 true CA2174747A1 (en) | 1995-05-04 |
Family
ID=26841884
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002174747A Abandoned CA2174747A1 (en) | 1993-10-28 | 1994-10-28 | Use of lobeline for the treatment of nicotine withdrawal |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0725640A1 (en) |
| JP (1) | JPH09507053A (en) |
| AU (2) | AU1045695A (en) |
| CA (1) | CA2174747A1 (en) |
| TW (1) | TW261531B (en) |
| WO (2) | WO1995011679A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (en) * | 1997-10-03 | 2000-10-16 | Manzanares Jesus Mari Gonzalez | PREPARED FOR ANTHINYCOTINIC ACTION. |
| GB2376884A (en) * | 2001-06-26 | 2002-12-31 | Peter Hajek | Helping smokers stop |
| BRPI0415986A (en) * | 2003-10-28 | 2007-01-23 | Alza Corp | method and apparatus for reducing the incidence of tobacco use |
| CN103284319A (en) * | 2013-06-20 | 2013-09-11 | 昌宁德康生物科技有限公司 | Oral cavity atomized liquid with cytosine replacing nicotine and preparation method thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (en) * | 1982-02-22 | 1986-11-28 | Bruss Ni Sanitarno Gigieniches | MEDICINAL PRODUCT WITH ANTINICOTINE EFFECT AND METHOD FOR THE PRODUCTION THEREOF. |
| 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 |
-
1993
- 1993-11-08 TW TW082109338A patent/TW261531B/zh active
-
1994
- 1994-10-28 WO PCT/US1994/012442 patent/WO1995011679A1/en not_active Application Discontinuation
- 1994-10-28 EP EP95901081A patent/EP0725640A1/en not_active Withdrawn
- 1994-10-28 AU AU10456/95A patent/AU1045695A/en not_active Abandoned
- 1994-10-28 CA CA002174747A patent/CA2174747A1/en not_active Abandoned
- 1994-10-28 JP JP7512876A patent/JPH09507053A/en not_active Ceased
- 1994-10-28 WO PCT/US1994/012441 patent/WO1995011678A1/en active Application Filing
- 1994-10-28 AU AU80960/94A patent/AU8096094A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU8096094A (en) | 1995-05-22 |
| JPH09507053A (en) | 1997-07-15 |
| WO1995011679A1 (en) | 1995-05-04 |
| AU1045695A (en) | 1995-05-22 |
| WO1995011678A1 (en) | 1995-05-04 |
| TW261531B (en) | 1995-11-01 |
| EP0725640A1 (en) | 1996-08-14 |
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