Note: Descriptions are shown in the official language in which they were submitted.
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
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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
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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,
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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.
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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:
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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
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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
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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.
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~ 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.
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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.
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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$~
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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)
21 74747
.,
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
-14- -
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
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~ WO 95/11679 2 1 7 4 7 4 7 PCT/IJS94/124~2
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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.
EXA21PLE I I
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.
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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
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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)
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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
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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
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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
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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:
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