U.S. patent application number 10/285016 was filed with the patent office on 2003-06-19 for device and method for treating combination dependencies.
This patent application is currently assigned to Addiction Therapies, Inc.. Invention is credited to Fox, Barbara S..
Application Number | 20030111088 10/285016 |
Document ID | / |
Family ID | 21936748 |
Filed Date | 2003-06-19 |
United States Patent
Application |
20030111088 |
Kind Code |
A1 |
Fox, Barbara S. |
June 19, 2003 |
Device and method for treating combination dependencies
Abstract
The present invention is directed to an oral medication delivery
device and a method of using the device to reduce the incidence of
tobacco smoking and/or treat a second dependency in a person. The
device comprises a tubular chamber having a first end suitable for
taking in liquid or gas from an external source and a second end
suitable for the application of oral suction. The chamber contains
nicotine, another drug, and a retainer for preventing release of
the drugs from the first end of the chamber.
Inventors: |
Fox, Barbara S.; (Wayland,
MA) |
Correspondence
Address: |
HALE AND DORR, LLP
60 STATE STREET
BOSTON
MA
02109
|
Assignee: |
Addiction Therapies, Inc.
|
Family ID: |
21936748 |
Appl. No.: |
10/285016 |
Filed: |
October 31, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10285016 |
Oct 31, 2002 |
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10045235 |
Oct 29, 2001 |
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Current U.S.
Class: |
131/273 ;
131/270 |
Current CPC
Class: |
A24F 42/20 20200101;
A47G 21/183 20130101; A61J 15/0011 20130101; A61M 15/06 20130101;
A24F 42/60 20200101; A61J 7/0038 20130101 |
Class at
Publication: |
131/273 ;
131/270 |
International
Class: |
A24F 047/00 |
Claims
What is claimed is:
1. An oral medication delivery device comprising: (a) a tubular
chamber having a first end suitable for taking in a liquid from an
external source and a second end suitable for oral application of
suction; (b) nicotine and a second drug contained within the
tubular chamber; and (c) a retainer in the tubular chamber for
preventing release of the nicotine, second drug, or liquid from the
first end of the chamber, wherein the liquid enters the chamber
from the external source through the first end of the chamber, and
then the liquid, the nicotine, and the second drug are delivered
through the second end of the chamber, when oral suction is applied
to the second end of the chamber.
2. The device of claim 1, wherein the tubular chamber approximates
the size and shape of a conventional cigarette.
3. The device of claim 1, wherein the tubular chamber approximates
the size and shape of a conventional drinking straw.
4. The device of claim 1, wherein the retainer is fixed proximal to
the first end of the chamber.
5. The device of claim 1, wherein the retainer is transportable
toward the second end of the chamber with the nicotine, second
drug, and liquid when suction is applied to the second end of the
chamber.
6. The device of claim 1, wherein the second drug is
naltrexone.
7. The device of claim 6, wherein the tubular chamber contains from
about 4 milligrams to about 25 milligrams of naltrexone.
8. The device of claim 1, wherein the tubular chamber contains from
about 4 milligrams to about 12 milligrams of nicotine.
9. The device of claim 1, wherein the nicotine is selected from the
group consisting of levo nicotine, dextro nicotine, racemic
mixtures thereof, and pharmaceutically acceptable salts
thereof.
10. The device of claim 1, wherein the nicotine and the second drug
are in the form of coated particles of powdered drug.
11. The device of claim 10, wherein the drug particles are coated
to enhance palatability.
12. The device of claim 1, wherein the nicotine and the second drug
are incorporated in spheres comprising at least one material
selected from the group consisting of sugar, starch, acacia, sodium
alginate, carbomer, cellulose, dextrotes, ethyl cellulose, methyl
cellulose, and povidone.
13. The device of claim 1, wherein a solution of nicotine and the
second drug is formed when the liquid enters the chamber and
contacts the nicotine and the second drug.
14. The device of claim 13, wherein the solution is a
suspension.
15. A method for reducing the incidence of tobacco smoking and
alcohol consumption by a person, the method comprising orally
administering nicotine and naltrexone to the person using an oral
delivery device, the device comprising: (a) a tubular chamber
having a first end suitable for taking in a liquid from an external
source and a second end suitable for oral application of suction;
(b) nicotine and naltrexone contained within the tubular chamber;
and (c) a retainer in the tubular chamber for preventing release of
the nicotine, naltrexone, or liquid from the first end of the
chamber, wherein oral administration comprises application of oral
suction by the person to the second end of the chamber, wherein the
liquid enters the chamber from the external source through the
first end of the chamber, and then the liquid and the nicotine and
naltrexone are delivered through the second end of the chamber into
the mouth of the person.
16. The method of claim 15, wherein a single dose of nicotine and
naltrexone administered to the person includes from about 4
milligrams to about 12 milligrams of nicotine and from about 4
milligrams to about 25 milligrams of naltrexone.
17. The method of claim 15, wherein the total daily dose of
nicotine administered to the person is from about 4 milligrams to
about 144 milligrams of nicotine.
18. The method of claim 15, wherein the total daily dose of
naltrexone administered to the person is from about 4 milligrams to
about 300 milligrams of naltrexone.
19. The method of claim 15, wherein a solution of nicotine and
naltrexone is formed when the liquid enters the chamber and
contacts the nicotine and naltrexone.
20. The method of claim 19, wherein the solution has an acidic pH.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The field of the present invention is pharmacology. More
specifically, the invention relates to methods and medication
delivery devices for promoting smoking cessation and/or treating
another dependency.
[0003] 2. Summary of the Related Art
[0004] Cigarette smoking is the leading cause of preventable
disease and death in the United States. Each year, over 400,000
adults die from tobacco-related diseases (A Report of the Surgeon
General, Rockville, Md.: Public Health Service (2000)). In addition
to health risks facing smokers themselves, the annoyance and risks
of second-hand smoke are receiving increased attention. Although
airlines, workplaces, and restaurants often ban smoking, almost 88%
of non-smokers have detectable blood levels of nicotine metabolites
(Morbidity and Mortality Weekly, Nov. 5, 1999). Environmental
tobacco smoke remains a preventable health hazard for smokers'
co-workers and family members (A Report of the Surgeon General,
Rockville, Md.: Public Health Service (2000)).
[0005] Unfortunately, 48 million adults in the United States, 24.7%
of the population, continue to smoke. Despite public health
initiatives, smoking prevalence among adults has not changed
significantly throughout the 1990's (Morbidity and Mortality
Weekly, Nov. 5, 1999). Although most smokers in the United States
wish to stop smoking, and over one third of them attempt to give up
smoking each year, only about 2.5% succeed (A Report of the Surgeon
General, Rockville, Md.: Public Health Service (2000)).
[0006] Various techniques have been advanced to aid smoking
cessation. The five major pharmacotherapies for treating tobacco
dependence are nicotine gum (see, e.g., U.S. Pat. No. 3,845,217);
nicotine transdermal patch (see, e.g., U.S. Pat. No. 4,915,950);
nicotine nasal spray (see, e.g., AU 664 41); nicotine inhaler (see,
e.g., U.S. Pat. Nos. 4,920,989 and 4,953,572); and
sustained-release bupropion hydrochloride (see, e.g., Jorenby et
al., N. Engl. J. Med., 340:685-91(1999)). Other examples of smoking
cessation aids include nicotine nose drops (see, e.g., U.S. Pat.
No. 4,579,858); nicotine lozenges (see, e.g., U.S. Pat. Nos.
4,806,35 and 5,549,906); smoke-free cigarettes (see, e.g., U.S.
Pat. Nos. 4,284,089, 4,676,259, 4,736,755, 4,813,437, 5,284,163,
and 6,041,789); compositions comprising nicotine metabolites (see,
e.g. U.S. Pat. No. 5,869,505); and drinkable nicotine solutions
(see, e.g., WO 99/55371).
[0007] Studies have shown that smokers using nicotine gum, patch,
nasal spray, inhaled nicotine, or nicotine sublingual tablets are
about 1.5 to 2 times more likely to stop smoking than smokers using
no cessation aid, and evidence suggests that bupropion may be even
more effective (see, Silagy et al., Cochrane Database Syst. Rev.,
No. 2, p.CD000146 (2000)). However, each of the existing smoking
cessation aids has drawbacks, and none has proven fully
effective.
[0008] For example, nicotine gum and lozenges can cause high
localized nicotine concentration in the mouth, which tastes
unappealing, and the gum may be difficult to chew. In addition,
chewing gum or eating lozenges may appear unprofessional. Nicotine
patches may irritate the skin, and some smokers are dissatisfied
with the lack of rapid nicotine absorption from the patch. Nicotine
nasal sprays may irritate the nose and throat. More importantly,
none of these smoking cessation aids simulates the tactile
sensations or hand-to-mouth behaviors that form an integral part of
the smoker's addiction.
[0009] Studies have shown that sensory aspects affect smoking
behavior and cigarette cravings as much as nicotine intake does.
Indeed, smokers attempting to give up cigarettes have complained
that, aside from experiencing nicotine withdrawal, they miss the
sensations and hand-to-mouth behaviors associated with smoking
(see, Rose, Ann. Rev. Med., 47:493-507 (1996)). In a study prepared
for the American Lung Association, 41% of smokers reported that
their most recent attempt to stop smoking was unsuccessful because
they missed having something to hold or to do with their hands
(Smoking Cessation Study, Yankelovich Partners, Jul. 27, 1998).
Cigarette smoking involves a hand-to-mouth ritual that may be
repeated over 70,000 times per year. Since smoking cessation
requires giving up a highly ingrained habitual motion as well as
giving up nicotine, an effective smoking cessation aid should
address the behavioral components of smoking as well as providing
nicotine replacement therapy. A smoking cessation aid should give
the smoker the comfort of an oral and tactile ritual, while at the
same time supplying nicotine. However, a smoking cessation device
that is too similar to a conventional cigarette and provides oral
sensations and tactile stimuli that too closely mimic tobacco
smoking may not be ideal. A smoker using such a device might find
it too easy to relapse into cigarette smoking (see, e.g., Schneider
et al., Addiction, 91:1293-1306 (1996)). Thus, a smoking cessation
aid that provides the synergistic combination of nicotine plus oral
and tactile stimuli, while not too closely approximating a
conventional tobacco cigarette, seems most desirable.
[0010] Among the existing smoking cessation aids, patches provide
no oral or tactile stimulus, gum, lozenges, and drinkable solutions
stimulate only the mouth, and nasal sprays stimulate only the
airways. These aids lack the important synergistic combination of
nicotine, oral stimulation, and hand-to-mouth behaviors that
smokers desire.
[0011] Some existing smoking cessation aids, such as nicotine
inhalers and various smoke-free cigarettes, do provide nicotine as
well as some behavioral aspects of smoking. However, these products
have major drawbacks. For example, U.S. Pat. No. 4,953,572 (Rose et
al.) discloses a nicotine aerosol spray designed to simulate the
sensations of inhaling tobacco smoke. The spray may be administered
through inhalation from a hand-held nebulizer. However, the
nicotine dose of the spray, which is limited by the volatility of
the inhaler's nicotine base at room temperature, is low compared to
that of tobacco smoke, and thus may be insufficient for many
smokers. Additionally, such a spray may irritate the oral
cavity.
[0012] U.S. Pat. No. 5,284,163 (Knudsen et al.) discloses a
smoke-free cigarette substitute comprising a nicotine granulate in
a tubular sleeve. The end of the sleeve contains a gum plug, which
is bitten off and held in the mouth as chewing gum. When a person
draws on the cigarette, nicotine granulate is pulled into the mouth
and can be chewed into the gum, thus dispensing nicotine into the
oral cavity. This product may possess the drawbacks of nicotine
chewing gum described above. Also, as with any smoke-free
cigarette, using it may approximate the behavioral aspects of
smoking so closely that smoking cessation becomes more
difficult.
[0013] U.S. Pat. Nos. 4,284,089 and 4,813,437 (Ray) disclose
non-pyrolytic devices shaped like ordinary cigarettes and
containing porous polymer plugs holding volatile liquid nicotine.
Drawing on the device delivers nicotine vapors to a person's lungs.
However, these devices are unable to deliver sufficient uniform
doses of nicotine. Additionally, the vaporizable nicotine tastes
unpleasant and is unstable, such that the devices have a very short
shelf life.
[0014] U.S. Pat. No. 6,041,789 (Bankert et al.) addresses some of
these problems with a non-pyrolytic cigarette substitute that
delivers a nicotine-simulating vapor mixture with a cigarette-like
taste and aroma. Instead of vaporizable nicotine, the device
contains a volatile nicotinomimetic agonist and volatile
palatability enhancing agents. However, this device does not
actually deliver nicotine. Additionally, the cigarette-like
structure, taste, and aroma may make the device so similar to a
conventional cigarette that smokers using it as a cessation aid are
likely to relapse.
[0015] Japanese Pat. No. 02190178 (Akimichi et al.) discloses a
smoke-free tobacco "perfume solution" that may be vaporized and
administered through a "tubular flexible casing." However, the
solution may present health risks due to the carcinogens and
irritating particulates contained in tobacco. Additionally, as with
other smoke-free cigarettes, using the device may approximate the
actual tastes, smells, and motions of cigarette smoking so closely
that smoking cessation is made more difficult.
[0016] U.S. Pat. No. 5,293,883 (Edwards) discloses a non-pyrolytic
cigarette containing two tobacco-filled chambers, which house
unburned and pre-burned tobacco, and a mouth filter that holds
nicotine-filled ampules that release pure liquid nicotine into a
person's mouth when the person breaks them open by biting or
manually crushing the mouth filter. This device provides nicotine
and a cigarette-like taste, but it may suffer from the drawbacks of
liquid nicotine described above. Additionally, as discussed above,
the device presents the health hazards of tobacco and may make
smoking cessation more difficult by too closely approximating
actual tobacco cigarettes.
[0017] Thus, a continuing need exists for new and improved smoking
cessation aids to help reduce the ongoing public health hazards
associated with cigarette smoking and second-hand smoke.
Particularly needed is a smoking cessation aid that synergistically
provides an easily controllable nicotine dose in a non-irritating
form along with a delivery device that supplies the oral and
tactile stimulation that smokers crave, without too closely
approximating actual cigarette smoking.
[0018] Alcoholism is another prevalent addictive disorder that
poses an enormous public health problem, costing an estimated $165
billion per year in the U.S. (see Substance Abuse: The Nation's
Number One Health Problem, Schneider Institute for Health Policy,
Brandeis University, Robert Wood Johnson Foundation (2001)).
Approved pharmacotherapy treatments for alcoholism include
disulfuram and naltrexone. Naltrexone is an opioid receptor
antagonist that is believed to reduce the reinforcing properties of
alcohol, thus leading to the extinction of drinking behavior and
decreased craving (Sinclair, Alcohol Alcohol. 36:2-10 (2001)).
Naltrexone also appears to affect the hypothalamic pituitary
adrenal axis, and may thus have a more direct effect on alcohol
craving (O'Malley et al., Psychopharmacol. (Berl) 160:19-29 (2002).
Although published reports regarding the efficacy of naltrexone
have been mixed (O'Malley et al., Psychiat. Ann. 25:681-688 (1995);
Krystal et al., N. Engl. J. Med. 345:1734-1739 (2001)), naltrexone
is the most effective medication currently available in the U.S.
for treating alcoholism (Kranzler et al., Alcohol Clin. Exp. Res.
25:1335-1341 (2001)). A combination therapy of naltrexone and
nicotine for smoking cessation also has been proposed (U.S. Pat.
No. 6,004,970). Data indicate that the combination of nicotine and
naltrexone does not pose any significant safety issues. Several
clinical studies investigating the effect of naltrexone on smoking
cessation (Sutherland et al., Psychopharmacol. (Berl), 120:418-425
(1995); Wewers et al., Psychopharmacol. (Berl), 140:185-190 (1998);
Hutchison et al., Psychopharmacol. (Berl), 142:139-143 (1999); Wong
et al., Addiction 94:1227-1237 (1999); King et al., Pharmacol.
Biochem. Behav. 66:563-572 (2000)) found only small effects on
smoking cessation, but found that the combination of naltrexone and
nicotine was well-tolerated in patients.
[0019] Naltrexone is available in a solid oral dosage form for once
daily dosing, and poor dosing compliance is believed to be a
primary factor leading to relapse to drinking (Namkoong et al., J.
Clin. Psychiatry 60:449-453 (1999)). An injectable
sustained-release formulation of naltrexone, designed to deliver
clinically effective levels of naltrexone for approximately one
month, is also under development (DrugAbuse Sciences, Hayward,
Calif.; Alkermes, Inc., Cambridge, Mass.). This depot formulation
is intended to increase compliance and therefore efficacy of the
naltrexone treatment. However, alcoholics may be reluctant to
commit to such a depot product that interferes with the action of
opiate analgesics. Several investigators have explored the use of
naltrexone in association with different behavioral therapies
(Sinclair, Alcohol Alcohol. 36:2-10 (2001); Carroll et al., Arch.
Gen. Psychiatry 58:755-761 (2001); Anton et al., J. Clin.
Psychopharmacol. 21:72-77 (2001); Preston et al., Drug Alcohol
Depend., 54:127-135 (1999); Heinala et al., J. Clin.
Psychopharmacol., 21:287-292 (2001)). In some of these studies,
naltrexone has been used in novel ways, e.g., dosing in
anticipation of heavy drinking (Sinclair, Alcohol Alcohol. 36:2-10
(2001)). A need exists for alternative dosing approaches to
increase efficacy and improve patient compliance with
naltrexone.
[0020] Cigarette smoking is much more common in alcoholics than in
the general population, with as many as 80-95% of alcoholics being
smokers (Hays et al., Ann. Behav. Med. 21:244-250 (1999); Daeppen
et al., Alcohol Alcohol. 35:171-175 (2000)). This high percentage
of co-morbidity reflects overlapping biochemical mechanisms of
alcohol and nicotine in the central nervous system, which seem to
result in even greater dependency on both drugs (Almeida et al.,
Neuropharmacol. 39:2740-2755 (2000); Narahashi, et al., Alcohol
Clin. Exp. Res. 25:152S-156S (2001)). Traditionally, there has been
some reluctance to treat alcohol and nicotine dependence
concurrently. There is evidence that smoking can increase the
likelihood that alcoholics will stop drinking, possibly due to the
reinforcing activity of nicotine, and the ability of the hand and
mouth behaviors of smoking to provide a substitute for drinking
(Narahashi et al., Alcohol Clin. Exp. Res. 25:152S-156S (2001);
Palfai et al., J. Abnorm. Psychol. 109:96-105 (2000); Schmidt et
al., Alcohol 24:111-5 (2001)). However, increased awareness of the
harm caused by smoking has led to an increased interest in treating
nicotine and alcohol dependence concurrently (Saxon et al., J.
Subst. Abuse Treat. 14:333-337 (1997); Hurt et al., Alcohol Clin.
Exp. Res., 18:867-872 (1994); Kalman et al., J. Subst. Abuse Treat.
20:233-238 (2001)). Thus, a need exists for new products that
provide combination therapy for smoking and alcoholism.
SUMMARY OF THE INVENTION
[0021] The present invention solves the foregoing problems by
providing a medication delivery device that provides nicotine along
with another drug in non-irritating solution form, and offers oral
and tactile stimulation. The combination formulation is
particularly useful for administering nicotine and naltrexone to
treat patients who are smokers and also suffer from another
dependency, such as alcoholism.
[0022] Accordingly, one aspect of the invention provides an oral
medication delivery device. The device includes a tubular chamber
having a first end suitable for taking in a liquid from an external
source and a second end suitable for oral application of suction.
Nicotine and a second drug other than nicotine are contained within
the tubular chamber. A retainer prevents release of the nicotine,
second drug, or liquid from the first end of the chamber. When oral
suction is applied to the second end of the chamber, liquid enters
the chamber from the external source through the first end of the
chamber, and then the liquid, the nicotine, and the second drug are
delivered through the second end of the chamber.
[0023] In some embodiments, the tubular chamber of the device
approximates the size and shape of a conventional cigarette. In
other embodiments, the tubular chamber approximates the size and
shape of a conventional drinking straw. In certain embodiments, the
retainer is fixed proximal to the first end of the chamber. In
other embodiments, the retainer is transportable toward the second
end of the chamber with the nicotine, second drug, and liquid when
suction is applied to the second end of the chamber.
[0024] In some embodiments, the second drug is naltrexone. In
certain embodiments, the tubular chamber contains from about 4
milligrams to about 25 milligrams of naltrexone. In particular
embodiments, the tubular chamber contains from about 4 milligrams
to about 12 milligrams of nicotine. In specific embodiments, the
nicotine is selected from the group consisting of levo nicotine,
dextro nicotine, racemic mixtures thereof, and pharmaceutically
acceptable salts thereof.
[0025] In some embodiments, the nicotine and the second drug are in
the form of coated particles of powdered drug. In particular
embodiments, the drug particles are coated to enhance palatability.
In certain embodiments, the nicotine and the second drug are
incorporated in spheres comprising at least one material selected
from the group consisting of sugar, starch, acacia, sodium
alginate, carbomer, cellulose, dextrotes, ethyl cellulose, methyl
cellulose, and povidone. In some embodiments, a solution of
nicotine and the second drug is formed when the liquid enters the
chamber and contacts the nicotine and the second drug. In specific
embodiments, the solution is a suspension.
[0026] Another aspect of the invention provides a method for
reducing the incidence of tobacco smoking and alcohol consumption
by a person. The method includes orally administering nicotine and
naltrexone to the person using an oral delivery device. The device
includes a tubular chamber having a first end suitable for taking
in a liquid from an external source and a second end suitable for
oral application of suction. Nicotine and naltrexone are contained
within the tubular chamber. A retainer prevents release of
nicotine, naltrexone, or liquid from the first end of the chamber.
In the method, oral administration includes application of oral
suction by the person to the second end of the chamber. Upon the
application of oral suction, the liquid enters the chamber from the
external source through the first end of the chamber, and then the
liquid and the nicotine and naltrexone are delivered through the
second end of the chamber into the mouth of the person.
[0027] In some embodiments of the method, a single dose of nicotine
and naltrexone administered to the person includes from about 4
milligrams to about 12 milligrams of nicotine and from about 4
milligrams to about 25 milligrams of naltrexone. In certain
embodiments, the total daily dose of nicotine administered to the
person is from about 4 milligrams to about 144 milligrams of
nicotine. In particular embodiments, the total daily dose of
naltrexone administered to the person is from about 4 milligrams to
about 300 milligrams of naltrexone. In some embodiments, a solution
of nicotine and naltrexone is formed when the liquid enters the
chamber and contacts the nicotine and naltrexone. In specific
embodiments, the solution has an acidic pH.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 is a diagrammatic representation of a frontal view of
a nicotine delivery device of the invention that approximates the
shape and size of a conventional drinking straw.
[0029] FIG. 2 is a diagrammatic representation of a frontal view of
a nicotine delivery device of the invention that approximates the
shape and size of a conventional cigarette.
[0030] FIG. 3 is a graphic representation illustrating plasma
levels of nicotine observed in subjects following administration of
a single dose of nicotine using a straw-like nicotine delivery
device according to certain embodiments of the invention containing
4 mg, 8 mg, or 12 mg of nicotine, as compared to nicotine plasma
levels observed for nicotine gum (2 mg or 4 mg), nasal spray,
inhaler, and patch (60 min.) formulations.
[0031] FIG. 4 is a graphic representation illustrating plasma
levels of nicotine observed over time in subjects following
administration of a single dose of 8 mg nicotine or repeated doses
of 8 mg nicotine every 1.5 hours using a straw-like nicotine
delivery device according to certain embodiments of the
invention.
DETAILED DESCRIPTION
[0032] The patents, published patent applications, and literature
references cited herein are hereby incorporated by reference to the
same extent as if each were specifically and individually indicated
to be incorporated by reference. Any inconsistency between these
publications and the present disclosure shall be resolved in favor
of the present disclosure.
[0033] The present invention provides smoking cessation methods and
smoking cessation aids that deliver a nicotine solution through a
tubular device to a user. Combination therapies are also provided
that deliver a second drug along with nicotine to treat a second
dependency. For example, a second drug is provided to treat
alcoholism as well as promoting smoking cessation. The second drug
is not nicotine. The advantage of delivering nicotine, alone or in
combination with another drug, through a tubular device is that the
oral and tactile sensations experienced by the user approximate the
ingrained hand-to-mouth behaviors associated with smoking and other
dependencies, such as drinking. Thus, the device of the present
invention offers oral and manual focus, which helps to alleviate
cravings by providing an object to manipulate and chew.
[0034] As shown in FIG. 1, the device of the invention may
approximate a conventional drinking straw in size and shape.
Alternatively, as shown in FIG. 2, the device may approximate a
conventional cigarette in size and shape. Referring to the figures,
the device comprises an elongated tubular chamber 10, with a first
end 12 adapted for drawing in air or liquid from an external source
and a second end 14 adapted for the application of oral suction,
and that the dimensions of the device are similar to the dimensions
of a conventional drinking straw or a conventional cigarette. In
some embodiments, as shown in FIG. 1, the device approximates a
conventional drinking straw in shape and size. In certain
embodiments, the chamber 10 is from about 13 to about 20
centimeters long, with a diameter of from about 4 to about 8
millimeters. In some instances, the chamber 10 is from about 15 to
about 17 centimeters long, with a diameter of from about 6 to about
7 millimeters. Alternatively, as shown in FIG. 2, the device
approximates a conventional cigarette in shape and size. In at
least some such embodiments, the chamber 10 is from about 7 to
about 11 centimeters long, with a diameter of from about 7 to about
10 millimeters. For example, the chamber 10 is from about 8 to
about 10 centimeters long, with a diameter of about 8 millimeters.
Examples of the tubular delivery devices of the present invention
include, without limitation, devices such as those disclosed in
U.S. Pat. No. 5,718,681 (Manning) and U.S. Pat. Nos. 5,780,058,
5,985,324, 5,989,590, 6,024,721, and 6,106,845 (Wong et al.).
[0035] Materials for making the tubular chamber 10 of the present
invention may include, without limitation, paper, plastic such as
propylene/styrene copolymers, polypropylene, high density
polyethylene, low density polyethylene, ethylene vinyl acetate
copolymer, and the like.
[0036] The tubular chamber 10 of the device of the present
invention contains nicotine 16 that will be delivered to the user.
The nicotine 16 may be in any useful form, such as levo nicotine,
dextro nicotine, or a racemic mixture thereof. Pharmaceutically
acceptable salt forms of nicotine are also suitable for use in the
present invention. Nonlimiting examples of such suitable salt forms
of nicotine include the dihydrochloride, sulfate, bitartrate,
salicylate, hydrogen tartrate, and hemisulfate salts. Nicotine and
its salt forms are commercially available, for example, from
Sigma-Aldrich, St. Louis, Mo. The term "nicotine" as used herein
also includes analogs of nicotine having a similar pharmacological
effect to nicotine itself.
[0037] In some embodiments, the nicotine 16 is a granulate. The
term "granulate" means that the nicotine is in the form of a
particulate such as grains or beads. In certain embodiments, the
size of the grains or beads is small enough not to be felt as
separate particles in the mouth, for example, less than about 200
micrometers in diameter.
[0038] In some embodiments, the nicotine granulate comprises
particles of powdered nicotine which have been coated according to
standard techniques known in the art (see, e.g., Deasy, Crit Rev.
Ther. Drug Carrier Systems, 8:39-89 (1991)). The term "powdered"
means composed of fine particles. Glatt Air Technique (Ramsay,
N.J.) and Particle and Coating Technologies, Inc. (St. Louis, Mo.)
provide particle coating services. Suitable coatings include,
without limitation, hydroxy propyl cellulose, sugar, starch,
polymer, resin, gum, wax, and fat. In certain embodiments, the
diameter of the nicotine particles before coating is less than
about 200 micrometers, for example, from about 20 to about 100
micrometers, or from about 40 to about 60 micrometers.
[0039] In some embodiments, the nicotine granulate comprises
particles of powdered nicotine that are incorporated into
microspheres, which may be coated as described above. Suitable
materials for the microspheres include, without limitation, sugar,
starch, acacia, sodium alginate, carbomer, cellulose, dextrotes,
ethyl cellulose, methyl cellulose, povidone, and mixtures thereof.
For example, the microspheres may comprise a degradable
composition. The microspheres have a diameter of between about 300
micrometers and about 1000 micrometers, for example, between about
500 micrometers and about 600 micrometers. U.S. Pat. No. 5,939,100
(Albrechtson et al.) discloses further examples of nicotine
microspheres.
[0040] In certain embodiments, the coating on the nicotine
particles or microspheres is designed to mask the taste of the
nicotine, and thus enhance palatability. In some instances, the
coating is formulated such that most, but not all, of the nicotine
taste is masked. The advantage of such a formulation is that enough
of the nicotine taste is masked that the nicotine particles are
palatable, but enough nicotine taste remains that the user is aware
that nicotine is being ingested. Thus, in some embodiments, the
formulation may comprise both coated and uncoated particles. The
coating on the particles or microspheres also may be designed to
achieve other functions, including, but not limited to, preventing
clumping and preventing water absorption.
[0041] In certain embodiments, a single dose of nicotine 16 from
the device of the present invention contains a therapeutically
effective amount of nicotine. The term "single dose" means the
quantity of nicotine 16 provided in the chamber 10 and delivered to
the user upon application of oral suction to the second end 14 of
the chamber 10. The term "therapeutically effective amount" means
an amount sufficient to reduce a smoker's need for nicotine from
burnt tobacco. This amount can be determined by the user's
physician. An advantage of the smoking cessation devices of the
invention is their ability to deliver a large dose of nicotine when
necessary, or a smaller dose of nicotine when appropriate. In
certain embodiments, from about 1 milligram to about 40 milligrams
of nicotine are provided by the device. Useful amounts include from
about 1 milligram to about 5 milligrams, from about 4 milligrams to
about 12 milligrams, from about 4 milligrams to about 20
milligrams, from about 5 milligrams to about 15 milligrams, from
about 5 milligrams to about 20 milligrams, and from about 20
milligrams to about 40 milligrams of nicotine provided by the
device in a single dose. A smoker attempting to stop smoking may
use the device of the present invention from about 1 to about 12
times per day, for example, from about 5 to about 12 times per day,
such that a total daily dose of from about 1 milligram to about 480
milligrams, for example, from about 5 milligrams to about 480
milligrams, of nicotine is delivered, depending on perceived need.
Useful total daily doses include from about 1 milligram to about 60
milligrams, from about 4 milligrams to about 144 milligrams, from
about 4 milligrams to about 240 milligrams, from about 5 milligrams
to about 180 milligrams, from about 5 milligrams to about 240
milligrams, and from about 240 milligrams to about 480 milligrams
of nicotine. The term "total daily dose" means the quantity of
nicotine delivered to the user during a 24-hour period.
[0042] In certain embodiments, such a dosing regimen provides a
blood level of nicotine of at least about 5 nanograms of nicotine
per milliliter of blood, with a maximum peak of about 60 nanograms
of nicotine per milliliter of blood. For example, the blood level
of nicotine in the user of the device is from about 10 nanograms to
about 50 nanograms of nicotine per milliliter of blood. In
particular embodiments, the user's blood level of nicotine is about
20 nanograms of nicotine per milliliter of blood.
[0043] In some embodiments, blood levels of nicotine are measured
by gas chromatography with nitrogen phosphorous detection as
described, for example, by Jacob et al., J. Chromatography, 222:
61-70 (1981). The dosing frequency may be adjusted so as to achieve
a steady state concentration of nicotine in the blood. In at least
some embodiments, the steady state blood levels of nicotine fall
within the blood level ranges described above. The quantities of
nicotine described above are sufficient to deliver a
therapeutically effective amount of nicotine into the user's
metabolism, even after first-pass absorption by the liver. It will
be understood by those skilled in the art that the doses and blood
levels of nicotine will vary according to the preferences,
metabolism, and former smoking habits of the individual user of the
smoking cessation aid of the present invention.
[0044] In one device encompassed by the present invention, the
nicotine granulate is delivered to the user as a nicotine solution.
The term "solution," as used herein, refers to a liquid into which
the nicotine is dissolved, or a suspension or emulsion of nicotine
in a liquid. Delivery of nicotine as a solution provides several
advantages. Swallowing the solution provides the oral stimulation
that smokers crave. However, the solution does not irritate the
oral cavity as does nicotine gum. Additionally, nicotine in
solution form is absorbed in the body more slowly than nicotine
from a nasal spray. Such slow absorption allows for less frequent
dosing and provides less potential for abuse. Finally, delivery of
liquid along with the nicotine prevents high local concentrations
of nicotine, which may result in cramping, for example, when a
nicotine capsule is swallowed.
[0045] In some devices, the first end 12 of the chamber 10 is
placed in contact with an external source of liquid and the user
applies oral suction to the second end 14 of the chamber 10.
According to one method of the invention, a liquid is drawn into
the first end 12 of the chamber 10 from the external source. The
liquid then forms a suspension of the nicotine 16 granulate as it
is drawn through the chamber 10, and the suspension is delivered
through the second end 14 of the chamber 10 into the user's mouth.
Some or all of the nicotine 16 granulate also may dissolve in the
liquid, such that the nicotine 16 is delivered as a solution. WO
99/55371 (Westman et al.) discloses non-limiting nicotine solutions
whose properties may be desirable for use with the present
invention.
[0046] In at least some embodiments, the external source of liquid
to be drawn into the tubular chamber 10 of a device of the
invention is a beverage. Sometimes, the beverage contains a
flavoring, which helps to make the nicotine solution palatable.
This is less crucial where the nicotine taste has already been
masked by coating the particles of the nicotine granulate. The term
"palatable" means that the taste of the solution is tolerable to
the user. The beverage may comprise, but is not limited to, coffee,
soda, sugar, fruit juice, carbonation, or ethyl alcohol, such as
wine, beer, or hard liquor. In some instances, the beverage does
not contain solids such as pulp. In certain embodiments, to be
palatable, the nicotine solution has an acidic pH. The term "acidic
pH" means a pH of less than about 6.9. For example, the nicotine
solution has a pH of less than about 5.5, or a pH from about 2.0 to
about 4.0. Flavorings such as coffee, alcohol, and fruit juice may
be used to regulate the pH of the nicotine solution. For example,
lime juice, cranberry juice, grapefruit juice, orange juice, tonic
water, soda, and wine have pH's from about 2.0 to about 4.0, and
beer, seltzer water, coffee, and have pH's less than about 6.9.
[0047] An advantage of the devices of the present invention is
their compatibility with beverages that are acidic, as the majority
of popular beverages are. Existing smoking cessation devices, such
as nicotine gum and nicotine inhalers, may not be used in
combination with acidic beverages because an alkaline environment
is required for buccal absorption of the nicotine delivered by such
devices. Acidic beverages must be avoided for a period of about one
hour surrounding each use of a smoking cessation device relying on
buccal absorption of nicotine. Thus, smokers attempting to use such
devices to give up smoking must also avoid consuming a majority of
beverages much of the time. In contrast, patients using nicotine
delivery devices of the invention, through which nicotine is orally
ingested, may consume acidic beverages whenever they choose.
[0048] The tubular chamber 10 of the device of the present
invention may comprise two or more lumens. The multiple lumens
provide a plurality of smaller cross-sectional flow paths, which
help to optimize the flow velocity and flow volume of the liquid
from the external source, thus assuring rapid, uniform, and
complete delivery of the nicotine 16 contained within the chamber
10. The nicotine 16 may be contained in one of the lumens, or in
multiple lumens. The multiple lumens may be of identical size or of
different sizes.
[0049] Alternatively, the chamber 10 of the device of the present
invention contains a preformulated solution of nicotine 16 such as,
for example, a nicotine suspension. About 1 milliliter to about 40
milliliters of nicotine solution may be provided in the chamber.
For example, from about 1 milliliter to about 10 milliliters, or
from about 1 milliliter to about 5 milliliters, of solution are
provided. Single doses of nicotine, total daily doses of nicotine,
and nicotine blood levels are as described above for the nicotine
granulate.
[0050] In another method of the invention, the user applies oral
suction to the second end 14 of the chamber 10 of the device, such
that a gas such as air is drawn through the first end 12 of the
chamber 10 into the device. As the air is drawn into the chamber
10, the nicotine 16 solution contained in the chamber 10 is
delivered through the second end 14 of the chamber 10 into the
user's mouth.
[0051] Alternatively, the user places the first end 12 of the
chamber 10 in contact with an external source of a liquid and
applies oral suction to the second end 14 of the chamber 10, such
that the liquid is drawn into the first end 12 of the chamber 10
from the external source. As the liquid is drawn through the
chamber 10, it is mixed with the solution of nicotine 16 contained
in the chamber 10, and the mixture is delivered through the second
end 14 of the chamber 10 into the user's mouth. The external source
of liquid often is a beverage, as described above for the device in
which the chamber 10 contains a nicotine 16 granulate. In certain
embodiments, the beverage comprises flavorings and pH ranges as
described above.
[0052] The nicotine 16 solution contained within the chamber 10 may
itself contain the flavorings described above. In some embodiments,
the solution is pre-formulated to fall within the aforementioned pH
levels through use of an acid such as, for example, carbonic acid,
citric acid, acetic acid, tartaric acid, maleic acid, ascorbic
acid, adipic acid, or combinations thereof. Such pre-formulation to
optimize flavoring and pH is especially desirable if the user will
be drawing air, rather than liquid, through the first end of the
chamber, such that the nicotine 16 solution contained in the
chamber 10 is delivered without any liquid from an external source
that might enhance palatability.
[0053] The chamber 10 of the device of the present invention
further contains a retainer 18 for preventing release of nicotine
16 from the first end 12 of the chamber 10. The term "retainer"
refers to a disc, float, plug, or other restriction that blocks the
diameter of the chamber 10 such that the nicotine 16 contained
within the chamber 10 cannot be released from the first end 12 of
the chamber 10. The retainer 18 allows gas or liquid from an
external source to enter the first end 12 of the chamber 10, but
prevents release of nicotine 16 from the first end 12 of the
chamber 10. The retainer 18 also discourages release from the first
end 12 of the chamber 10 of liquid drawn into the chamber 10 from
an external source or contained within the chamber 10 as part of a
pre-formulated solution of nicotine 16.
[0054] The retainer 18 may be fixed proximal to the first end 12 of
the chamber 10. "Proximal to" the first end 12 of the chamber 10
means toward or at the first end 12 of the chamber 10.
Alternatively, the retainer 18 may be transportable toward the
second end 14 of the chamber 10. For example, the retainer 18 is
transported toward the second end 14 of the chamber 10 as the user
applies oral suction to the second end 14 of the chamber 10. Gas or
liquid from an external source is drawn through the first end 12 of
the chamber 10 into the device, and the nicotine 16 solution in the
chamber 10 is delivered into the user's mouth. As it is drawn
toward the second end 14 of the chamber 10 behind the nicotine 16
solution, the transportable retainer 18 assures that all of the
nicotine 16 in the chamber 10 is cleanly delivered through the
second end 14 of the chamber 10 into the user's mouth. The second
end 14 of the chamber 10 is constructed such that the retainer 18
itself is blocked from entering the user's mouth. For example, the
diameter at the second end 14 of the chamber 10 may be smaller than
the diameter elsewhere in the chamber 10 and smaller than the
diameter of the retainer 18, such that the retainer 18 may pass
from the first end 12 of the chamber 10 to the second end 14 of the
chamber 10, but cannot pass through the second end 14 of the
chamber 10 into the user's mouth. The diameter at the second end 14
of the chamber 10 may be made smaller than the diameter elsewhere
in the chamber 10 by a crimping of the chamber 10, a series of
dimples in the circumference of the chamber 10, or a continuous
indentation in the circumference of the chamber 10 at the second
end 14 of the chamber 10. A transportable retainer 18 is
particularly useful when the device is prefilled with liquid, i.e.,
contains a pre-formulated solution of nicotine 16.
[0055] The retainer 18 may comprise a restriction and a plug. The
term "restriction" means that the diameter near the first end 12 of
the chamber 10 is smaller than the diameter elsewhere in the
chamber 10 and smaller than the diameter of the plug, such that the
plug is contained within the chamber 10 and prevents release of
nicotine 16 through the first end 12 of the chamber 10. The
restriction may result from, for example, a crimping of the chamber
10, a series of dimples in the circumference of the chamber 10, or
a continuous indentation in the circumference of the chamber 10
near the first end 12 of the chamber 10.
[0056] The retainer 18 may alternatively comprise a particle
barrier with apertures or slits that allow liquid to pass through
the barrier when oral suction is applied to the second end 14 of
the chamber 10. A cap may be placed over the first end 12 of the
chamber 10 prior to use to avoid any possible loss of nicotine 16
or entry of contaminants through the particle barrier apertures or
slits. The apertures must be small enough that nicotine 16 cannot
pass through them and be released from the first end 12 of the
chamber 10. The slits are easier to manufacture and seal the
chamber 10 more completely prior to use than the apertures do.
Alternatively, the barrier is made from a material such as fine
mesh or porous paper that will retain the nicotine 16 in the
chamber 10 but requires no barrier apertures or slits to allow
liquid to be drawn into the chamber 10. Sometimes, for ease in
construction, the barrier is cone-shaped and located all the way at
the first end 12 of the chamber 10.
[0057] Alternatively, the retainer 18 comprises a one-way plug or
valve. The plug or valve seals the first end 12 of the chamber 10
at atmospheric pressure. However, when suction is applied to the
second end 14 of the chamber 10, the plug is deformed and permits
liquid from an external source to flow around the plug and into the
chamber 10 through the first end 12 of the chamber 10. In certain
embodiments, the plug has a density of less than one, such that it
is drawn toward the second end 14 of the chamber 10 when suction is
applied to the second end 14 of the chamber 10 and the nicotine 16
contained within the chamber 10 is delivered into the mouth of the
user. When suction is removed from the second end 14 of the chamber
10, the plug relaxes, seals the chamber 10, and remains stationary.
Transportation of the plug all the way to the second end 14 of the
chamber 10 indicates that the entire dose of nicotine 16 contained
within the chamber 10 has been delivered.
[0058] The retainer 18 alternatively comprises a cylindrical body
with at least one protrusion on its exterior surface. Liquid from
an external source is drawn through or around the retainer 18 and
into the chamber 10, but the protrusions prevent nicotine 16
solution from leaking through or around the sides of the retainer
18 and out of the first end 12 of the chamber 10. The protrusions
are fins, ridges, or rings which act as a seal for the chamber 10
and also create friction or drag between the retainer 18 and the
chamber 10, which allows time for the liquid from the external
source to mix with the nicotine 16 after passing through or around
the retainer 18.
[0059] The retainer 18 of the present invention may be made from,
for example, thermoplastic materials or low or high density foam
materials such as, without limitation, ethylene vinyl acetate
copolymers, polyolefins such as polyethylene, polypropylene, and
the like, or closed cell foam. Alternatively, the retainer 18 may
comprise, for example, a compressible plug of bonded fibers. The
fibers may be polymeric fibers, such as polyolefin fibers with or
without a polyester core, polyester, cellulose acetate, nylon,
felt, or cotton. In certain embodiments, the uncompressed fiber
plug has a diameter slightly larger than the diameter of the
chamber 10. Thus, after insertion in the chamber 10, the plug seals
and prevents the release of nicotine 16 from the chamber 10, but
still allows liquid to be drawn into the chamber 10 when oral
suction is applied to the second end 14 of the chamber 10.
[0060] In some embodiments, the chamber 10 of the device of the
present invention also contains a removable end cap 20 or seal
located at the second end 14 of the chamber 10. The removable end
cap 20 or seal prevents the nicotine 16 granulate or pre-formulated
nicotine 16 solution contained within the chamber 10 from being
released through the second end 14 of the chamber 10 during
shipping and storage of the device. Before using the device, the
user removes the end cap 20 or seal from the second end 14 of the
chamber 10 so that the nicotine 16 granulate or pre-formulated
nicotine 16 solution contained within the chamber 10 may be
delivered through the second end 14 of the chamber 10 into the
user's mouth. Materials for making the end cap 20 or seal of the
present invention may include, without limitation, paper, foil,
plastic such as propylene/styrene copolymers, polypropylene, high
density polyethylene, low density polyethylene, ethylene vinyl
acetate copolymer, and the like.
[0061] In some instances, the device, itself, may comprise a
flavoring, such that it tastes pleasant for chewing as, before, or
after the nicotine dose has been delivered. The flavoring may be,
for example, sugar, cinnamon, spearmint, peppermint, wintergreen,
bubble gum, fruit, chocolate, anise, nut, coffee, tobacco, or
combinations thereof. Sometimes, the flavoring is selected from the
group consisting of spearmint, peppermint, wintergreen, and
cinnamon.
[0062] The device as described in detail above provides the novel
synergistic combination of oral and tactile stimulation along with
a controlled dose of nicotine in non-irritating solution form.
Smokers attempting to stop smoking may use the device as an aid
that can satisfy nicotine needs and at the same time prevent
cigarette cravings by providing a substitute for the hand-to-mouth
behavioral component of smoking. The synergistic combination of the
present invention provides an important new method for reducing the
incidence of tobacco smoking in smokers who appreciate the health
risks of smoking and wish to stop.
[0063] In some alternative embodiments, the device as described
herein contains another drug along with nicotine in the tubular
chamber 10. As a non-limiting example, the additional drug is
naltrexone. The nicotine/naltrexone combination device is useful
for treating alcoholics who are also smokers. The combination
treatment promotes decreased alcohol consumption as well as smoking
cessation. The nicotine promotes smoking cessation and also
improves compliance with naltrexone. The nicotine/naltrexone
tubular delivery device may improve the efficacy of naltrexone even
beyond the expected improvement due to increased compliance.
Alcohol dependence, like tobacco dependence, involves situational
craving and ritualized manual and oral behaviors that accompany
drug delivery (Weinstein et al., Alcohol Clin. Exp. Res.,
22:1376-1381 (1998); Tiffany et al., Addiction 95:S145-153 (2000)).
A tubular oral nicotine/naltrexone delivery device as described
herein provides an effective substitute for the hand and mouth
behaviors associated with drinking as well as smoking. In addition,
the increased frequency of dosing with this delivery device, as
compared to once-daily or depot formulations of naltrexone,
encourages alcoholics to become more actively involved in their
treatment, and thus be more likely to focus on and achieve
recovery.
[0064] Naltrexone is safe in a broad range of doses. Typically,
naltrexone is administered to alcoholics at a dose of 50 mg/day in
a single daily dose (Krystal, et al., N. Engl. J. Med.
345:1734-1739 (2001); Anton et al., J. Clin. Psychopharmacol.
21:72-77 (2001); Heinala et al., J. Clin. Psychopharmacol.
21:287-292 (2001)). However, opioid dependent patients usually
receive 100 mg/day three times per week (Carroll et al., Arch. Gen.
Psychiatry 58:755-761 (2001); Preston et al., Drug Alcohol Depend.
54:127-135 (1999)), and doses as high as 250 mg/day have been
tested in the treatment of gambling (Kim et al. Biol. Psychiatry
49:914-921 (2001)). In at least some instances, a total daily dose
of between about 4 mg and about 300 mg naltrexone is administered.
Naltrexone is well-suited for combination with nicotine in a
multidose dosage form. Naltrexone has a plasma half-life of 4 hours
(Meyer et al., J. Clin. Psychiatry, 45:15-19 (1984)), so dosing at
between about 5 to about 10 times per day is expected to maintain
active plasma levels. As explained above with respect to nicotine
dosing, those of skill in the art will understand that the
particular dosing schedule for an individual patient can be
determined by a physician. In evaluating dosages of naltrexone, the
physician can monitor patients for accumulation of the major
metabolite of naltrexone, 6.beta.-naltrexol, which is also
pharmacologically active and has a half life of 12 hours (Meyer et
al., J. Clin. Psychiatry, 45:15-19 (1984)).
[0065] In some embodiments, a delivery device as described herein
contains nicotine in amounts as described above, and from about 4
milligrams to about 25 milligrams of naltrexone. Useful amounts
include from about 6 milligrams to about 20 milligrams, from about
8 milligrams to about 15 milligrams, from about 8 milligrams to
about 12 milligrams, and from about 6 milligrams to about 10
milligrams of naltrexone provided by the device in a single dose.
In certain embodiments, a patient attempting to stop smoking and/or
drinking alcohol is instructed to use the device from about 1 to
about 12 times per day, for example, from about 5 to about 10 times
per day, such that a total daily dose of from about 4 milligrams to
about 300 milligrams, for example, from about 20 milligrams to
about 200 milligrams, of naltrexone is delivered. Useful total
daily doses include from about 40 milligrams to about 100
milligrams, from about 60 milligrams to about 100 milligrams, and
from about 60 milligrams to about 200 milligrams of naltrexone.
Such a dosing regimen provides naltrexone blood levels of at least
about 2 nanograms of naltrexone per milliliter of blood, with a
maximum peak of about 60 nanograms of naltrexone per milliliter of
blood. For example, a blood level of between about 5 ng and about
40 ng of naltrexone per milliliter of blood is achieved. In certain
embodiments, a peak blood level of about 30 nanograms of naltrexone
per milliliter of blood is achieved. In at least some embodiments,
the dosage regimen is adjusted to achieve steady state blood levels
of naltrexone. Naltrexone levels are measurable using high pressure
liquid chromatography.
[0066] The following nonlimiting examples further illustrate
certain embodiments of the present invention:
EXAMPLE 1: SAFETY AND PHARMACOKINETICS STUDY
[0067] 1. Device
[0068] Nicotine is administered orally using a straw-like smoking
cessation device of the invention as shown in FIG. 1. The chamber
10 is a plastic drinking straw. The retainer 18 is a filter at the
first end 12 of the straw. The user places the first end 12 of the
device in a glass of apple juice and applies oral suction to the
second end 14 of the device, such that the juice and nicotine 16
are delivered into the user's mouth.
[0069] The nicotine 16 in the device is in the form of coated sugar
spheres of nicotine bitartrate having a diameter of approximately
500 micrometers. The nicotine spheres are prepared by spraying
nicotine bitartrate dihydrate with a binder onto sugar spheres and
applying a film coating. Using a Wurster processing unit, particles
are suspended in air using a controlled airflow system and a
coating suspension is added at a controlled rate via a
pneumatically atomized nozzle. As atomized droplets of the coating
solution contact the particles, they spread and coalesce on the
particle surface. Excess moisture from the applied liquid
evaporates in the apparatus, leaving a coated dry substance. Mixing
of the coating suspension occurs throughout the manufacturing
process to ensure uniformity of the suspension.
[0070] 2. Administration
[0071] On day one, following overnight abstinence from smoking,
healthy adult smokers who wish to give up smoking receive a single
dose of nicotine or placebo. Smokers are assigned to each dosage
group in a double blind, randomized manner, as is well known in the
art. The following data are collected before dosing, every thirty
minutes for the first two hours after dosing, and every hour for
the following six hours: plasma levels of nicotine and cotinine,
vital signs, adverse events, and patient's assessment of cigarette
cravings. Baseline and endpoint clinical chemistry, hematology,
urinalysis, and ECG are also monitored.
[0072] On day eight, again following overnight abstinence from
smoking, the same subjects receive the same dose of nicotine or
placebo. The dose is repeated periodically throughout the day. The
following data are collected as described above before the first
dosing and one hour after each dose is administered: plasma levels
of nicotine and cotinine, vital signs, adverse events, and
patient's assessment of cigarette cravings. Baseline and endpoint
clinical chemistry, hematology, urinalysis, and ECG are also
monitored. The data are used to evaluate the safety and
pharmacokinetics of nicotine delivery by the smoking cessation
device.
EXAMPLE 2: EFFICACY STUDY
[0073] In a double blind study, three hundred healthy adult smokers
who wish to give up smoking use the smoking cessation device as
described in Example 1 to deliver nicotine or placebo over a ten
week period. Each device contains 5-10 mg of nicotine or placebo.
Subjects are instructed to use the device as needed for smoking
urges, but not to exceed 12 doses per day. Patients are
concurrently enrolled in a counseling program to provide behavioral
support for smoking cessation. Smoking abstinence data are
collected during the last eight weeks of treatment, serving as the
primary endpoint. Abstinence is defined as four weeks of continuous
abstinence from smoking during the study period. Subjects have
weekly clinic visits for monitoring plasma levels of nicotine and
cotinine, vital signs, adverse events, and patient's assessment of
cigarette cravings. Baseline and endpoint clinical chemistry,
hematology, urinalysis, and ECG are also monitored.
EXAMPLE 3: PHARMACOKINETICS AND SAFETY STUDY
[0074] A placebo-controlled double blind trial was performed with
three doses of nicotine (4 mg, 8 mg, and 12 mg) or placebo
delivered using a straw-like delivery device as described in
Example 1. There were 6 subjects per treatment group. In Part A of
the study, subjects received a single dose, and in Part B, the same
subjects received 8 doses of nicotine, one dose every 1.5 hours.
Apple juice was used as the beverage for delivering nicotine from
the straw-like device.
[0075] As shown in FIG. 3, delivery of nicotine using the
straw-like device generated plasma levels of nicotine comparable to
or greater than plasma levels observed for marketed nicotine
replacement products (Schneider et al., Clin. Pharmacokinet.
40:661-684 (2001)). As shown in FIG. 4, peak plasma levels were
achieved between 1 and 2 hours post dosing, with nicotine levels in
most subjects already increased 15 minutes after dosing. The
kinetics were very similar to those of nicotine gum. Repeated
dosing with nicotine every 1.5 hours led to continuous increases in
plasma nicotine over the 10.5 hour sampling period. In both the
single dose and repeated dose parts of the study, the lowest plasma
levels of nicotine were observed in the 4 mg dose group, with
higher plasma levels observed in the 8 mg and 12 mg dose
groups.
[0076] The 4 mg and 8 mg doses of nicotine in the straw-like
delivery device were well tolerated. The adverse events observed,
lightheadedness, nausea, and vomiting, were those expected for a
nicotine product. Nausea and vomiting were seen only with the 12 mg
dose. Occasional increases in vital sign measurements were seen,
but these were neither dose nor time dependent, and were not
sustained. There were no clinically significant changes in clinical
chemistry, hematology, urinalysis or ECG values.
[0077] Over the course of the repeat dosing session, craving for
cigarettes decreased in all subjects receiving nicotine. There was
no net effect on craving in the placebo group.
EXAMPLE 4: NICOTINE/NALTREXONE DEVICE
[0078] A straw-like nicotine/naltrexone delivery device is prepared
as described for the nicotine delivery device in Example 1.
Naltrexone coated sugar spheres are prepared using the techniques
described for preparing the nicotine coated sugar spheres in
Example 1, but using naltrexone hydrochloride instead of nicotine
bitartrate. The naltrexone coated sugar spheres are prepared to
have a strength of approximately 10 mg naltrexone HCl per 150-200
mg loose coated sugar spheres. The naltrexone coated sugar spheres
are combined with nicotine coated sugar spheres to prepare a
nicotine/naltrexone delivery device similar to the device described
in Example 1, but containing naltrexone as well as nicotine. Each
device contains 8 mg nicotine and 10 mg naltrexone.
[0079] Patients diagnosed as alcoholics and smokers are instructed
to use the device throughout the day as needed to administer a dose
of nicotine and naltrexone in response to cravings for either
tobacco or alcohol. Patients are instructed not to exceed one dose
every 1.5 hours or 10 doses per day. Patients are monitored for
progress toward cessation of smoking and/or drinking alcohol, i.e.
for changes in smoking and/or alcohol consumption levels.
EQUIVALENTS
[0080] While the foregoing invention has been described in some
detail for purposes of clarity and understanding, it will be
appreciated by one skilled in the art from a reading of this
disclosure that various changes in form and detail can be made
without departing from the scope of the invention and the attached
claims.
* * * * *