U.S. patent application number 10/481053 was filed with the patent office on 2004-10-07 for coated nicotine-containing chewing gum, manufacture and use thereof.
Invention is credited to Lindberg, Nils-Olof, Lindell, Katarina E.A., Olsson, Roland.
Application Number | 20040194793 10/481053 |
Document ID | / |
Family ID | 20284551 |
Filed Date | 2004-10-07 |
United States Patent
Application |
20040194793 |
Kind Code |
A1 |
Lindell, Katarina E.A. ; et
al. |
October 7, 2004 |
Coated nicotine-containing chewing gum, manufacture and use
thereof
Abstract
A coated chewing gum product for the delivering of nicotine in
any form to a subject by a rapid transmucosal uptake in the oral
cavity comprising at least one gum core, nicotine in any form
and/or a nicotine mimicking agent, at least one coating layer and
optionally at least one or more other additive, wherein said at
last one coating layer is buffered. Also contemplated is a method
for the delivering of nicotine in any form, a method for the
reduction of the urge to smoke or use tobacco as well as a method
for producing said coated chewing gum and the use of the same form
obtaining a quick transmucosal uptake of the nicotine in the oral
cavity of a subject.
Inventors: |
Lindell, Katarina E.A.;
(Eslov, SE) ; Lindberg, Nils-Olof; (Malmo, SE)
; Olsson, Roland; (Helsingborg, SE) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
ONE LIBERTY PLACE, 46TH FLOOR
1650 MARKET STREET
PHILADELPHIA
PA
19103
US
|
Family ID: |
20284551 |
Appl. No.: |
10/481053 |
Filed: |
May 25, 2004 |
PCT Filed: |
June 14, 2002 |
PCT NO: |
PCT/SE02/01158 |
Current U.S.
Class: |
131/270 ;
131/271 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 3/04 20180101; A23G 4/126 20130101; A61P 25/00 20180101; A61P
25/16 20180101; A23G 4/046 20130101; A23G 4/06 20130101; A61P 1/04
20180101; A23G 4/20 20130101; A61K 9/0058 20130101; A61K 31/465
20130101; A61P 1/00 20180101; A61P 25/28 20180101; A61P 25/34
20180101; A61P 43/00 20180101; A23B 4/10 20130101 |
Class at
Publication: |
131/270 ;
131/271 |
International
Class: |
A24F 047/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 20, 2001 |
SE |
0102197-1 |
Claims
What is claimed:
1. A coated chewing gum product comprising at least one buffered or
non-buffered chewing gum core; at least one of nicotine in any form
or a nicotine mimicking agent, at least one coating layer and
optionally one or more other additive(s), wherein said coating
layer is buffered.
2. The product according to claim 1, wherein the at least one
chewing gum core is buffered.
3. The product according to claim 1, wherein the nicotine in any
form is a part of the at least one coating layer or at least one of
the at least one coating layers.
4. The product according to claim 1, wherein the nicotine in any
form is a part of the chewing gum core or at least one of the
chewing gum cores.
5. The product according to claim 1, wherein the at least one
coating layer is buffered and upon administration of the gum to a
subject the pH of the saliva of the subject is increased by 0.3-4
pH units.
6. The product according to claim 5, wherein the at least one
coating layer is buffered and upon administration of the gum to a
subject the pH of the saliva of the subject is increased by 0.5-2
pH units.
7. The product according to claim 1 comprising nicotine in any form
and a nicotine mimicking agent.
8. The product according to claim 1, wherein the at least one
coating layer is buffered by the use of a buffer selected from the
group consisting of a carbonate, glycinate, phosphate,
glycerophosphate, acetate, gluconate or citrate of an alkali metal,
and mixtures thereof, whereby optionally the buffer is
microencapsulated, and wherein the optional buffering of the at
least one chewing gum core is obtained by the use of a buffer
selected from the group consisting of a carbonate, glycinate,
phosphate, glycerophosphate, acetate, gluconate or citrate of an
alkali metal, and mixtures thereof.
9. The product according to claim 8 wherein the carbonate is
monocarbonate, bicarbonate or sesquicarbonate and the alkali metal
is potassium, sodium, or ammonium.
10. The product according to claim 1, wherein the nicotine in any
form is selected from the group consisting of a nicotine salt, the
free base form of nicotine, a nicotine derivative, a nicotine
inclusion complex or nicotine in any non-covalent binding, and
mixtures thereof.
11. The product accord to claim 10 wherein the nicotine derivative
is a nicotine cation exchanger and the nicotine in any non-covalent
binding is nicotine bound to zeolites, nicotine bound to cellulose
or nicotine bound to starch microspheres.
12. The product according to claim 10, wherein the nicotine
inclusion complex is a cyclodextrin complex.
13. The product according to claim 12, wherein the cyclodextrin
complex is .beta.-cyclodextrin.
14. The product according to claim 11, wherein the nicotine cation
exchanger is a polyacrylate cation exchanger.
15. The product according to claim 10, wherein the nicotine salt is
a salt formed with tartrate, citrate or malate.
16. The product according to claim 1, wherein the nicotine in any
form is present in an amount of 0.05-10 mg calculated as the free
base form of nicotine per piece coated chewing gum product.
17. The product according to claim 16, wherein the nicotine in any
form is present in an amount of 0.5-6 mg calculated as the free
base form of nicotine per piece coated chewing gum product.
18. The product according to claim 17, wherein the nicotine in any
form is present in an amount of 2-5 mg calculated as the free base
form of nicotine per piece coated chewing gum product.
19. The product according to claim 3, wherein at least one coating
layer comprises nicotine in any form in an amount of 0-10 mg
calculated as the free base form of nicotine.
20. The product according to claim 19, wherein at least one coating
layer comprises nicotine in any form in an amount of 0.2-6 mg
calculated as the free base form of nicotine.
21. The product according to claim 20, wherein at least one coating
layer comprises nicotine in any form in an amount of 0.5-5 mg
calculated as the free base form of nicotine.
22. The product according to claim 1, wherein the nicotine
mimicking agent is an agent with acrid burning taste.
23. The product according to claim 22, wherein the nicotine
mimicking agent is capsaicin, piperine, zingerone or mixture
thereof.
24. The product according to claim 1, wherein the optional one or
more additive is selected from the group consisting of stabilisers,
softeners, thickening agents, emulsifiers, glidants, lubricants,
sweeteners, flavours, aromatics, enhancers, colouring agents,
vitamins, minerals, and mixtures thereof.
25. The product according to claim 24 wherein the stabilizer is a
preservative.
26. The product according to claim 25 wherein the preservative is
an antioxidant.
27. The product according to claim 3, wherein in the coating, the
nicotine and the buffer are in separate layers.
28. The product according to claim 27 wherein said layers are
separated by a moisture barrier, said moisture barrier comprising
substances selected from the group consisting of ethylcellulose,
hydroxypropyl methylcellulose, polymethacrylates and combinations
thereof.
29. The product of claim 28 wherein the nicotine is in the form of
nicotine hydrogen tartrate and said moisture barrier further
comprises at least one plasticizer or hydrophobic lipid-based
film.
30. The product of claim 28 wherein the nicotine is in the form of
nicotine hydrogen tartrate and said moisture barrier further
comprises one or more plasticizers and hydrophobic lipid-based
films.
31. The product of claim 29 wherein the lipid-based film comprises
stearic acid.
32. A method for delivering nicotine in any form to a subject
comprising the steps of a) administering to a subject a coated
chewing gum product according to claim 1 into the oral cavity of
the subject, and b) allowing the nicotine in any form in the coated
chewing gum product to be released in the saliva in the oral cavity
and absorbed into the systemic circulation of the subject.
33. The method according to claim 32, wherein said administration
results in a t.sub.max of nicotine in venous blood of the subject
after about 5-20 minutes.
34. The method according to claim 32, wherein said nicotine in any
form is a part of the at least one coating layer and said nicotine
is released from the at least one coating layer and absorbed,
resulting in a t.sub.max of nicotine in venous blood of the subject
after about 3-15 minutes.
35. The method according to claim 32, further comprising the step
of c) administering the nicotine in any form in a sustained way
over a period of time to the subject.
36. The method according to claim 35, wherein the period of time is
at least 10, 20, 30, 40, 50 or 60 minutes.
37. A method for obtaining reduction of the urge to use tobacco
containing material, comprising the steps of a) replacing at least
partly the tobacco containing material with a coated chewing gum
produt according to claim 1, b) administering said coated chewing
gum product into the oral cavity of the subject, and c) allowing
the nicotine in any form in the coated chewing gum product to be
released in the saliva in the oral cavity and absorbed by the
subject.
38. The method according to claim 37 wherein said method reduces
the urge to smoke, provides a sense of smoking satisfaction without
smoking or combinations thereof.
39. The method according to claim 37, wherein said administration
results in a t.sub.max of nicotine in venous blood of the subject
after about 5-20 minutes.
40. The method according to claim 37, wherein said nicotine in any
form is a part of the at least one coating layer and said nicotine
is released from the at least one coating layer and absorbed,
resulting in a t.sub.max of nicotine in venous blood of the subject
after about 3-15 minutes.
41. The method according to claim 37, further comprising the steps
of administering the nicotine in any form in a sustained way over a
period of time to the subject.
42. The method according to claim 41, wherein the period of time is
at least 10, 20, 30, 40, 50 or 60 minutes.
43. The method according to claim 37, wherein said method is
performed in combination with at least one other method for
obtaining reduction of the urge to smoke or use tobacco.
44. A system for delivering nicotine in any form to a subject,
comprising a coated chewing gum product according to claim 1 and at
least one other means or method for obtaining reduction of the urge
to smoke or use of tobacco.
45. The system according to claim 44, wherein the at least one
other means or method is a concomitant or concurrent means or
method selected from the group consisting of administration through
mouth sprays, nasal sprays, transdermal patches, inhaling devices,
lozenges, tablets, parenteral methods, subcutaneous methods,
intravenous methods, rectal methods, vaginal methods, and
transmucosal methods.
46. The system according to claim 45, wherein the at least other
means or method comprises administration of nicotine.
47. A system for obtaining reduction of the urge to smoke or use of
tobacco or for providing a sense of smoking satisfaction without
smoking comprising a coated chewing gum product according to claim
1 and at least one other means or method for obtaining reduction of
the urge to smoke or use of tobacco.
48. The system according to claim 47, wherein the at least one
other means or method is a concomitant or concurrent means or
method selected from the group consisting of administration through
mouth sprays, nasal sprays, transdermal patches, inhaling devices,
lozenges, tablets, parenteral methods, subcutaneous methods,
intravenous methods, rectal methods, vaginal methods, and
transmucosal methods.
49. The system according to claim 48, wherein the at least other
means or method comprises administration of nicotine.
50. A method for producing a coated chewing gum product according
to claim 1, comprising the steps of a) providing at least one
chewing gum core, b) providing nicotine in any form, c) providing
at least one coating that is buffered, d) adding the nicotine in
any form to the at least one of the chewing gum core or the at
least one coating, and e) coating the at least one chewing gum core
with at least one layer of the at least one buffered coating
layer.
51. The method of claim 50 wherein said chewing gum core comprises
nicotine.
52. The method according to claim 50, further comprising the steps
of f) buffering the at least one chewing gum core, g) providing at
least one coating layer not being buffered, and optionally h)
adding the nicotine in any form to at least one of said at least
one coating layer not being buffered, and optionally i) providing
the nicotine in the coating and the buffer in the coating in
separate layers, preferably separated by a moisture barrier.
53. The method according to claim 50, further comprising the steps
of f) buffering the at least one chewing gum core, or g) providing
at least one coating layer not being buffered, and optionally h)
adding the nicotine in any form to at least one of said at least
one coating layer not being buffered, and optionally i) providing
the nicotine in the coating and the buffer in the coating in
separate layers, preferably separated by a moisture barrier.
54. The method according to claim 50, wherein the nicotine in any
form is selected from the group consisting of a nicotine salt, the
free base form of nicotine, a nicotine derivative, a nicotine
inclusion complex or nicotine in any non-covalent binding, and
mixtures thereof.
55. The method accord to claim 54 wherein the nicotine derivative
is a nicotine cation exchanger and the nicotine in any non-covalent
binding is nicotine bound to zeolites, nicotine bound to cellulose
or nicotine bound to starch microspheres.
56. The method according to claim 50, wherein the at least one
coating layer is buffered by the use of a buffer selected from the
group consisting of a carbonate, glycinate, phosphate,
glycerophosphate or citrate of an alkali metal, and mixtures
thereof, wherein the at least one coating layer is buffered and
upon administration of the gum to a subject the pH of the saliva of
the subject is increased by 0.3-4 pH units.
57. The method according to claim 56, wherein the carbonate is
bicarbonate or sesquicarbonate and the alkali metal is potassium,
sodium, or ammonium.
58. The method according to claim 57, wherein the at least one
coating layer is buffered and upon administration of the gum to a
subject the pH of the saliva of the subject is increased by 0.5-2
pH units.
59. The method according to claim 50, wherein the provision of the
at least one chewing gum core in step a) comprises the steps of a1)
providing a gum core dough, a2) mixing, rolling and scoring;
moulding; or extruding the gum dough.
60. The method according to claim 50, wherein the provision of the
chewing gum core in step a) is obtained by direct compressing of
the ingredients.
61. The method according to claim 50, wherein coating the at least
one chewing gum core with at least one layer of the at least one
buffered coating comprises the steps of film coating, or press
coating, or sugar coating, or melt coating, or combinations
thereof.
62. A chewing gum product according to claim 1 for use in
therapy.
63. The product according to claim 62, wherein the therapy is
treatment of a disease selected from the group consisting of
Alzheimer's disease, Crohn's disease, Parkinson's disease,
Tourette's syndrome, and ulcerous colitis.
64. The product according to claim 62, wherein the therapy is
treatment of post-smoking-cessation weight control.
65. A method of treating a disease selected from the group
consisting of Alzheimer's disease, Crohn's disease, Parkinson's
disease, Tourette's syndrome and ulcerous colitis comprising the
steps of administering a chewing gum product of claim 1 to a
subject.
66. A method of post-smoking-cessation weight control comprising
the steps of administering a chewing gum product of claim 1 to a
subject.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is the national stage filing under 35
U.S.C. .sctn. 371 of International Application No. PCT/SE02/01158
filed Jun. 14, 2002 and published Dec. 27, 2002, as International
Publication No. WO 02/102357 which in turn claims priority under 35
U.S.C. .sctn. 119 to Swedish Patent Application No. 0102197, filed
Jun. 20, 2001. The disclosures of these applications are
incorporated herein by reference in their entirety.
FIELD
[0002] This invention relates to a coated chewing gum product for
delivering nicotine to a subject. Also contemplated is a method and
a system for delivering nicotine as well as use and production of
said coated chewing gum product
BACKGROUND
[0003] Tobacco Dependence and Reduction Thereof.
[0004] In recent years, with the recognition of the harmful effects
of tobacco smoking, there have been numerous campaigns and programs
by governmental agencies and various health groups and other
interested organisations to disseminate information about the
adverse health effects resulting from tobacco smoking. Moreover,
and as a result of this recognition of the harmful effects, there
have been many programs directed to attempts in reducing smoking
incidence.
[0005] Nicotine is an organic compound and is the principal
alkaloid of tobacco. Nicotine is the chief addictive ingredient in
the tobacco used in cigarettes, cigars, snuff and the like.
Nicotine is also an addictive drug, though, and smokers
characteristically display a strong tendency to relapse after
having successfully stopped smoking for a time. Nicotine is the
worlds second most used drug, after caffeine from coffee and
tea.
[0006] The main problem with tobacco smoking is its enormous
implications on health. Today it is estimated that smoking related
diseases cause some 3-4 million deaths per year. In the US Surgeon
General's 1988 report on The Health Consequences of Smoking, it was
estimated that in the US alone about 300.000 deaths are caused each
year by diseases related to cigarette smoking. In fact, excessive
smoking is now recognised as one of the major health problems
throughout the world. This grim consequence of tobacco smoking has
urged many medical associations and health authorities to take very
strong actions against the use of tobacco.
[0007] Even though tobacco smoking is decreasing in many developed
countries today it is hard to see how the societies could get rid
of the world's second most used drug.
[0008] The most advantageous thing a heavy smoker can do is to
reduce or preferably even stop smoking completely. Experience
shows, however, that most smokers find this extremely difficult
since, mostly, tobacco smoking results in a dependence disorder or
craving. The WHO has in its International Classification of
Disorders a diagnosis called Tobacco Dependence. Others like the
American Psychiatric Association call the addiction Nicotine
Dependence. It is generally accepted that these difficulties to
stop smoking result from the fact those heavy smokers are dependent
on nicotine. The most important risk factors are, however,
substances that are formed during the combustion of tobacco, such
as carbon monoxide, tar products, aldehydes, and hydrocyanic
acid.
[0009] Effects of Nicotine
[0010] The administration of nicotine can give satisfaction and the
usual method is by smoking, either by smoking e.g., a cigarette, a
cigar or a pipe. However, smoking has health hazards and it is
therefore desirable to formulate an alternative way of
administering nicotine in a pleasurable manner that can be used to
facilitate withdrawal from smoking and/or used as a replacement for
smoking.
[0011] When smoking a cigarette, nicotine is quickly absorbed into
the smoker's blood and reaches the brain within around ten seconds
after inhalation. The quick uptake of nicotine gives the consumer a
rapid satisfaction, or kick. The satisfaction, then, lasts during
the smoking time of the cigarette and for a period of time
thereafter. The poisonous, toxic, carcinogenic, and addictive
nature of smoking has provided efforts for methods, compositions
and devices, which help in breaking the habit of smoking
cigarettes.
[0012] Nicotine is an addictive poisonous alkaloid
C.sub.5H.sub.4NC.sub.4H- .sub.7NCH.sub.3, derived from the tobacco
plant. Nicotine is also used as an insecticide. Approximately forty
milligrams of nicotine is able to kill an adult (Merck Index).
[0013] Nicotine Replacement Products
[0014] One way to reduce smoking is to provide nicotine in a form
or manner other than by smoking and some products have been
developed to fulfil this need. Nicotine containing formulations are
currently the dominating treatments for tobacco dependence.
[0015] The successes in achieving reduction in the incidence of
smoking have been relatively poor using presently known products.
The present state of the art involves both behavioural approaches
and pharmacological approaches. More than 80% of the tobacco
smokers who initially quit smoking after using some behavioural or
pharmacological approach to singly reduce smoking incidence
generally relapse and return to the habit of smoking at their
former rate of smoking within about a one year's period of
time.
[0016] As an aid for those who are willing to stop smoking there
are several ways and forms of nicotine replacement products
available on the market; such as nicotine chewing gum. Several
methods and means have been described for diminishing the desire of
a subject to use tobacco, which comprises the step of administering
to the subject nicotine or a derivative thereof as described in
e.g., U.S. Pat. No. 5,810,018 (oral nicotine spray), U.S. Pat. No.
5,939,100 (nicotine containing microspheres) and U.S. Pat. No.
4,967,773 (nicotine containing lozenge).
[0017] Nicotine-containing nose drops have been reported (Russell
et al., British Medical Journal, Vol. 286, p. 683 (1983); Jarvis et
al., Brit. J. of Addiction, Vol. 82, p. 983 (1987)). Nose drops,
however, are difficult to administer and are not convenient for use
at work or in other public situations. Ways of administrating
nicotine by way of delivering directly into the nasal cavity by
spraying is known from U.S. Pat. No. 4,579,858, German Patent No.
32 41 437 and International Publication No. WO/9312764. There may,
though, be local nasal irritation with use of nasal nicotine
formulations. The difficulty in administration also results in
unpredictability of the dose of nicotine administered.
[0018] The use of skin patches for transdermal administration of
nicotine has been reported (Rose, in Pharmacologic Treatment of
Tobacco Dependence, (1986) pp. 158-166, Harvard Univ. Press).
Nicotine-containing skin patches that are in wide use today can
cause local irritation and the absorption of nicotine is slow and
affected by cutaneous blood flow.
[0019] Also, inhaling devices resembling a cigarette are known for
uptake of nicotine vapours as suggested in U.S. Pat. No. 5,167,242.
Said means and methods address the problems associated with
addiction to nicotine.
[0020] Nicotine Chewing Gum
[0021] One of the most successful approaches to date in reducing
the incidence of smoking relies upon nicotine containing chewing
gum that is designed to reduce smoking withdrawal symptoms. The
reported success rate is approximately twice that of placebo. The
use of the nicotine gum suffers from several problems e.g., that it
has been found that the nicotine containing gum does not
sufficiently rapidly satisfy the craving that most smokers
experience.
[0022] Prior Art and Problems Thereof
[0023] One successful product that is used as a smoking substitute
and/or as a smoking cessation aid and which is based on nicotine,
is the chewing gum Nicorette.RTM.. This product was one of the
first nicotine replacement forms that was approved by the Food and
Drug Administration (FDA) and is still one of the most used
nicotine replacement products. Nicorette.RTM. chewing gum has been
on the market in about 60 countries for several years. In this
chewing gum the nicotine is present in the form of a complex with
an insoluble cation-exchanger (polacrilex) that is dispersed in a
gum base. The nicotine is slowly released from the gum due to
chewing and will reach similar plasma levels as when smoking a
cigarette after about 30 minutes depending on the chewing
technique, i.e., slow or active. Patents related to this product
are, e.g., the U.S. Pat. Nos. 3,877,468, 3,901,248 and
3,845,217.
[0024] WO 98/23165 discloses a chewing gum wherein nicotine may be
in the coating. This concept may provide rapid release of the
nicotine from the coated chewing gum, but not a sufficiently rapid
buccal uptake of the nicotine. The fraction of the released
nicotine that is not immediately absorbed will be flushed down in
the gastrointestinal (G.I.) tracts by the saliva, thereby possibly
causing hiccups and other G.I. side effects. Once absorbed by the
G.I. route this swallowed nicotine will be subjected to first pass
metabolism.
[0025] WO 00/13662 discloses a chewing gum for systemic, oral
administration of an active whereby said active is administered by
the chewing gum composition in a bi-phasic manner. The bi-phasic
delivery is obtained by the gum matrix as such, not from any
coating.
[0026] WO 00/19977 discloses a substantially moisture free and
possibly coated chewing gum for delivery of an active. The possible
coating is not said to be buffered.
[0027] It is highly desirable in light of the aforementioned
problems to develop means and methods for the administration of
nicotine to give a satisfaction to a person craving for nicotine or
to provide a sense of smoking satisfaction without smoking, which
can also avoid problems associated with the prior art means and
methods. In this respect, the present invention addresses this need
and interest.
SUMMARY
[0028] In view of the foregoing disadvantages known in the art when
trying to deliver nicotine to a subject so as to obtain a rapid
transmucosal uptake of nicotine in the oral cavity of the subject
the present invention provides a new and improved product, systems
and methods for obtaining a rapid transmucosal uptake of nicotine
in the oral cavity of the subject.
[0029] An object of the present invention is to provide an
efficient and effective product, as well as methods and systems for
a rapid uptake of nicotine in a subject to avoid the disadvantages
of such previously known products and methods.
[0030] Thus, the present invention provides a method for delivering
nicotine in any form to a subject comprising administering to a
subject said coated chewing gum product containing nicotine in any
form into the oral cavity of the subject and allowing the nicotine
in any form in the coated chewing gum product to be released in the
saliva in the oral cavity and absorbed into the systemic
circulation of the subject as well as a method for producing said
coated chewing gum.
[0031] The present invention also provides a method for obtaining
reduction of the urge to smoke or use tobacco containing material
and/or for providing a sense of smoking satisfaction without
smoking, comprising the steps of replacing at least partly the
tobacco containing material with above said coated chewing gum
product, administering to a subject a coated chewing gum product
containing nicotine in any form into the oral cavity of the subject
and allowing the nicotine in any form of the coated chewing gum
product to be released in the saliva in the oral cavity and
absorbed by the subject.
[0032] Furthermore, the present invention provides a system for
delivering nicotine in any form to a subject, comprising said
coated chewing gum product and at least one other means for
obtaining reduction of the urge to smoke or use of tobacco as well
as a system for obtaining reduction of the urge to smoke or
otherwise use of tobacco and/or for providing a sense of smoking
satisfaction without smoking, comprising a coated chewing gum
product according to above and at least one other method for
obtaining reduction of the urge to smoke or otherwise use of
tobacco. Said system may be a system wherein the at least other
method is selected from the group consisting of administration
through mouth sprays, nasal sprays, transdermal patches, inhaling
devices, lozenges, tablets and parenteral methods, subcutaneous
methods, intravenous methods, rectal methods, vaginal methods and
transmucousal methods; or otherwise use of tobacco.
[0033] Still furthermore the present invention relates to a coated
chewing gum product comprising at least one chewing gum core,
nicotine in any form and/or a nicotine mimicking agent, at least
one coating layer and optionally at least one or more other
additive, wherein said at least one coating layer is buffered.
[0034] Said product may further comprise at least one core being
buffered and further may also the nicotine in any form be a part of
the at least one coating layer or at least one of the at least one
coating layers. The at least one coating is buffered, according to
the invention, in such a way that upon administration of the gum
the pH of the saliva is increased by 0.3-4 pH units, or preferably
increased by 0.5-2 pH units. Said product is buffered by the use of
a buffer selected from the group consisting of a carbonate,
including bicarbonate or sesquicarbonate, glycinate, phosphate,
glycerophosphate or citrate of an alkali metal, such as potassium
and sodium, e.g., trisodium and tripotassium citrate, or ammonium,
and mixtures thereof.
[0035] Use of said product will according to the invention rapidly
deliver nicotine in any form to a subject and will also be used for
obtaining a quick and/or sustained and/or complete reduction of the
urge to smoke or use tobacco and/or for providing a sense of
smoking satisfaction without smoking resembling the sense of
smoking satisfaction and reduction of the urge to smoke obtained
after regular smoking or use of tobacco.
DETAILED DESCRIPTION
[0036] Definitions
[0037] As used herein, the term "chewing gum product" intends to
mean all chewable gum products.
[0038] The term "fast reduction of the urge to smoke or use
tobacco" is herein intended to mean an initial priming of the
subject so as to achieve a reduction of the urge to smoke or use
tobacco.
[0039] The term "sustained" is herein intended to mean prolonged
over time.
[0040] The term "complete reduction" or "complete" is herein
intended to mean complete or substantially complete reduction.
[0041] The term "controlled release" is intended to mean a release
of a substance from a gum by the aid of active chewing of the gum
in the oral cavity of the subject, whereby the active chewing is
controlling the amount of substance released.
[0042] The term "slow release" is intended to mean that the
nicotine is released from the gum upon, e.g., chewing, over a
period of time e.g., several minutes to an hour.
[0043] The term "unit formula" is intended to mean one chewing gum
product.
[0044] The term "transient" is intended to mean a non-permanent
change, upon which the relevant state, e.g., biological or
physiological state, after a certain period of time will return to
its value or behaviour prior to said change.
[0045] The term "buccal" and "buccally" are herein intended to
pertain to all of or any part of the tissue of the oral cavity.
[0046] The Coated Chewing Gum
[0047] Presently existing nicotine chewing gums provide a slow
release and a slow uptake of nicotine. This will not resemble the
actual sense of satisfaction when smoking, where an initial fast
uptake of nicotine is achieved giving the smoker, i.e., the
subject, a sense of satisfaction. Accordingly, as revealed above,
the present invention relates to a coated chewing gum product for
improving the absorption of nicotine in a subject, and wherein the
absorption is quicker than by using current means and methods known
in the art of nicotine chewing gums. Such a rapid transmucosal
uptake of the nicotine in the oral cavity is expected to give more
of a cigarette like sense of satisfaction and a more rapid
reduction of the urge to smoke and use tobacco.
[0048] According to the invention, a coated chewing gum product is
used for improving the absorption of said nicotine. The coated
chewing gum product comprises at least one chewing gum core,
nicotine in any form and/or a nicotine mimicking agent, at least
one coating layer and at least one other additive, wherein at least
one of said coating layer is buffered.
[0049] Also, the at least one core may be buffered in different
embodiments. The core may be buffered with the same or different
ways of buffering as the at least one coating layer.
[0050] Said buffering of the at least one coating layer and
optionally the at least one core generates a coated chewing gum
product giving improved absorption kinetics of nicotine compared to
in the art known chewing gum products.
[0051] The chewing gum product may be a medicated chewing gum.
Medicated chewing gums are herein intended to mean solid or
semi-solid, single-dose preparations with a base consisting mainly
of gum that are intended to be chewed but not swallowed, where the
chewing gums act as a drug delivery system. They contain one or
more active substances, which are released by chewing. After
dissolution or dispersion of the active substance in the saliva,
such chewing gums are used for i) local treatment of mouth diseases
and ii) systemic delivery after absorption through transmucosal
uptake throughout the oral cavity.
[0052] The Buffering Agent
[0053] Absorption of nicotine from the oral cavity to the systemic
circulation is dependent on the pH of the saliva, pH of the blood
plasma and the pKa of nicotine, which is about 7.8. Assuming a pH
of the plasma of 7.4 and of the saliva of 6.8 only about 10% of the
nicotine will be in the free base form. Thus, in order to promote
absorption of nicotine in a free base form, which is the form
predominantly absorbed through the mucosa, the pH of the saliva
must be increased. At a pH of 8.8 about 90% of the nicotine will
then be in the free base form.
[0054] Thus according to the invention, the coated chewing gum
product is buffered. This may be achieved by including
physiologically acceptable buffering substances or agents, or by
other means. With other means it is intended to include buffering
by any component in the product, which may not normally act as a
buffering agent, such as a self-buffering additive or gum base.
[0055] According to the invention, at least one coating layer is
buffered. In specific embodiments, also the at least one core is
buffered.
[0056] In specific embodiments, the at least one coating layer is
buffered in such a way that upon administration of the gum the pH
of the saliva is increased 0.3-4 pH units, preferably 0.5-2 pH
units. The buffering is designed so as to achieve a transient
buffering of the saliva of a subject during melting, disintegration
or dissolution of the coating layer or layers. As the change is
transient, the pH will return to its normal value after a certain
period of time.
[0057] Similarly, the at least one core may be buffered. This may
allow said change in the pH to be ensured during chewing of the
core of the gum product, where the chewing allows the suitable
buffer agent or substance or other means to produce a transient
change in the pH of the saliva, e.g., an increase in the pH.
[0058] By employing the said change, here as an increase, in said
pH of the saliva the transmucosal uptake of nicotine in the oral
cavity is changed, e.g., increased compared to the nicotine uptake
when the saliva is not buffered according to the invention. Also,
since the transmucosal uptake of nicotine in the oral cavity
according to the invention is faster than for nicotine not being
buffered according to the invention, less nicotine will be
swallowed to reach the gastrointestinal (G.I.) tract. The nicotine
that reaches the G.I. tract will be subjected to first pass
metabolism which reduces the total amount of intact nicotine
absorbed. This means that the bio-availability of nicotine that is
not co-administered with a buffer according to the invention will
generally be lower than when administered together with a
buffer.
[0059] Further embodiments of the invention includes combinations
wherein the at least one coating layer is buffered by the use of a
buffer selected from the group consisting of a carbonate including
bicarbonate or sesquicarbonate, glycinate, phosphate,
glycerophosphate or citrate of an alkali metal, such as potassium
or sodium, or ammonium, and mixtures thereof.
[0060] Further embodiments may use trisodium or tripotassium
citrate, and mixtures thereof.
[0061] Still further embodiments may use different phosphate
systems, such as trisodium phosphate, disodium hydrogen phosphate;
and tripotassium phosphate, dipotassium hydrogen phosphate, and
calcium hydroxide, sodium glycinate; and mixtures thereof.
[0062] Alkali metal carbonates, glycinates and phosphates are
preferred buffering agents.
[0063] The one or more buffering agents may to some extent be
microencapsulated or otherwise coated as granules with polymers
and/or lipids being less soluble in saliva than is the one or more
buffering agents. Such microencapsulation controls the dissolution
rate whereby is extended the time frame of the buffering
effect.
[0064] In order to increase the buffering capacity still further
without correspondingly increasing the pH, one may in specific
embodiments use a second or auxiliary buffering agent to the first
buffering agent, such as e.g., sodium or potassium bicarbonate
buffers. The second or auxiliary buffering agent may be selected
from the group consisting of alkali metal bicarbonates that are
preferred for this purpose. Thus, further embodiments of the
invention may comprise a mixture of an alkali metal carbonate or
phosphate and alkali metal bicarbonate.
[0065] The amount of the buffering agent or agents in the chewing
gum composition is preferably sufficient in the specific
embodiments to raise the pH of the saliva to above 7, as specified
above, to transiently maintain the pH of the saliva in the oral
cavity above 7, e.g., pH 7-11.
[0066] The nicotine may be administered in different forms, e.g.,
in different complexes or salts. The amount of buffer required to
achieve such an increase in pH of the different administered
nicotine form is readily calculated by the skilled man in the art.
The extent and duration of the increase in pH is dependent on type
and amount of the buffering agent(s) used as well as where, i.e.,
in the at least one coating layer and optionally in the at least
one core, the buffer is distributed in the product and is further
described within the paragraphs below.
[0067] The Coating of the Gum Core
[0068] The process of coating a chewing gum is well known in the
art. The present invention provides a coating, to facilitate the
uptake of administered nicotine in any form to the subject. Known
intentions of coating a chewing gum product may be to add
crispiness, enhance taste, or to protect the gum, e.g., during
storage, or as to tone down bad or irritating taste of the gum
product.
[0069] According to the invention, the chewing gum is a coated
chewing gum comprising at least one coating layer.
[0070] The different embodiments according to the invention may use
sugar coating, film coating, press/compression coating or melt
coating.
[0071] For the film and sugar coating, the coating procedure may be
manual or the coating may be sprayed onto the gum core/pellet in
rotating pans of different shapes or fluidised beds in combination
with evaporation of the solvent, e.g., water or organic
solvent.
[0072] Sugar coating is a multistep process and may be divided into
the following steps: 1. sealing of the cores; 2. subcoating; 3.
smoothing, or glossing; 4. colouring; 5. polishing; and 6.
optionally printing
[0073] Sugar coated cores have a smoother profile with less visible
edges remaining from the original core. Sub-coating, e.g., either
by dusting with powder on the sucrose solution or application of
dry powder in the sucrose solution, may be used. The core may be
sugar coated by a panning technique, e.g., using a sugar coating
pan, or other more sophisticated techniques capable of some degree
of automation.
[0074] The sugar in a sugar coating may not be just sucrose. Also
other types of sugar may do as well, e.g., sugar alcohols
(polyalcohol, polyol).
[0075] The sugar used in the sugar coating may according to
specific embodiments also be an artificial sweetener, being low or
substantially free of calories and less caries promoting than
regular sugar, or a combination with sugar and/or sugar
alcohol.
[0076] Film coating involves the deposition, usually by a spray
method, of a thin film of polymer surrounding the core. The
solution may be sprayed on to a rotated, mixed bed. The drying
conditions permit the removal of the solvent so as to leave a thin
deposition of coating material around each core.
[0077] The composition of the coating solutions and suspensions may
differ during different parts of the process.
[0078] Press coating involves the compaction of granular material
around an already manufactured core. Using press/compression
coating, a further core is pressed on the outside of the initial
core/cores.
[0079] Example 1-4 describes four different coatings and coating
compositions that may be used according to the invention, i.e.,
sugar coating in example 1, film coating in example 2, press
coating in example 3 and melt coating in example 4, all onto a
chewing gum core. The coating is buffered in each case and contains
nicotine as well. The coatings in example 1-4 may be combined with
different cores. Examples of cores are given in Example 5 and
further described below.
[0080] If nicotine hydrogen tartrate (NHT) is used as the nicotine
form then NHT and buffer are suitably separated from each other in
the coating by keeping them in separate layers, especially when
sugar coating is used. A moisture barrier between the
NHT-containing layer and the coating comprising the buffer may be
applied to prevent interaction between the acid salt NHT and the
buffer during the coating process. Suitable moisture barriers are
e.g. ethylcellulose or a combination of ethylcellulose and
hydroxypropyl methylcellulose (HPMC) and/or plasticizer from an
organic solvent or solvent mixture, aqueous ethylcellulose
dispersion such as Aquacoat EDC (FMC Corp.) or Surelease (Colorcon)
preferably in combination with plasticizer, Sepifilm LP 007 or LP
010 (Seppic)--based mainly on HPMC and stearic acid--, Opadry AMB
or High Performance Opadry II (Colorcon)--based mainly on
polyvinylalcohol--, and polymethacrylates as Eudragit L30 D-55 or
EPO (Rohm). Depending on the type of barrier film selected the
moisture barrier preferably accounts for a weight of around 0.3% to
around 5% of the total weight of the coating.
[0081] An additive may be added to the coating or the core/s.
Additives are further described in the paragraph entitled "Other
additives to the chewing gum".
[0082] The Core
[0083] The amount of gum base in the coated chewing gum according
to the invention is about 15-80% by weight of the total gum core,
and preferably at least about 40%. The amount of gum base employed
for the most desirable slow release of nicotine is usually in the
higher ranges when nicotine is employed per se or when an absorbed
form is used.
[0084] The gum base may be of any conventional nature known in the
art. For example it may comprise a gum base of natural or synthetic
origin readily available from a commercial source. Natural gum
bases include, e.g., chicle, jelutong-, lechi de caspi-, soh-,
siak-, katiau-, sorwa-, balata-, pendare-, malaya-, and peach gums,
natural cautchouc and natural resins such as dammar and mastix.
Synthetic gum bases are a mixture of:
[0085] elastomers (polymers, masticating substances),
[0086] plasticizer (resin, elastomers, solvent, hydrophobic
resin),
[0087] filler (texturizer, water-insoluble adjuvant),
[0088] softener (fat),
[0089] emulsifier,
[0090] wax,
[0091] antioxidant,
[0092] and anti-tacking agents (vinyl polymer, hydrophilic
resin).
[0093] Other examples of gum bases are gums including agar,
alginate, arabic gum, carob gum, carrageenan, ghatti gum, guar gum,
karaya gum, pectin, tragacanth gum, locust beam gum, gellan gum and
xanthan gum.
[0094] Examples of gelling agents comprise gum arabic, starch,
gelatine, agar, and pectin.
[0095] When the nicotine in any form and the buffering agent or
agents are incorporated in the chewing gum mass in accordance with
the present invention, it is possible to employ a wide variety of
chewing gum compositions and amounts of the chewing gum base.
Different chewing gum products may be composed depending on the
consumers preference and the purpose of use, in respect of the
nicotine level, nicotine distribution and other additives.
[0096] The Active Ingredient
[0097] According to the invention, the chewing gum product
comprises nicotine in any form and/or a nicotine mimicking agent.
In specific embodiments, the nicotine is part of the at least one
coating layer or at least one of the at least one coating
layers.
[0098] In still further embodiments, the nicotine is a part of the
chewing gum core or at least one of the chewing gum cores.
[0099] In still even further embodiments, the nicotine is part of
the at least one coating layer or at least one of the at least one
coating layers and the chewing gum core or at least one of the
chewing gum cores to give a fast transmucosal uptake of the
nicotine in the oral cavity of a subject so as to obtain a rapid
kick or reduction of the urge to smoke and/or use tobacco. Thereby
may also be achieved a systemic maintenance level of nicotine.
[0100] The nicotine should be in a saliva soluble form to
facilitate the release of the agent into the saliva in the oral
cavity and, further, the subsequent uptake of the nicotine from the
saliva in the oral cavity into the systemic circulation of the
subject.
[0101] In preferred embodiments, the nicotine in any form is
selected from the group consisting of a nicotine salt, the free
base form of nicotine, a nicotine derivative, such as a nicotine
cation exchanger, a nicotine inclusion complex or nicotine in any
non-covalent binding; nicotine bound to zeolites; nicotine bound to
cellulose or starch microspheres; and mixtures thereof. Still,
further the inclusion complex may be a cyclodextrin, such as
.beta.-cyclodextrin. Even further the cation exchanger may be a
polyacrylate. Even more further, the nicotine salt may be a
tartrate, hydrogen tartrate, citrate or malate.
[0102] According to the invention, the uptake of the nicotine
through any tissue or mucosa in the oral cavity, i.e., the
absorption kinetics, is improved in relation to the uptake obtained
by known chewing gum products for nicotine uptake.
[0103] The nicotine may act as a stimulant to e.g., obtain a rapid
reduction of the urge to smoke or to use tobacco.
[0104] With nicotine it is intended to include nicotine,
3-(1-methyl-2-pyrrolidinyl)-pyridine, with its base form, including
synthetic nicotine as well as nicotine extracts from tobacco
plants, or parts thereof, such as the genus Nicotiana alone or in
combination; or pharmaceutically acceptable salts.
[0105] The most preferable embodiment incorporates nicotine as the
free base form or as a water-soluble pharmaceutically acceptable
salt, either per se or adsorbed on a adsorbent, or as a complex
with a cation exchanger or mixtures of the foregoing, as an
inclusion complex, such as a cyclodextrin complex, e.g.,
.beta.-cyclodextrin, but any other suitable pharmaceutically
acceptable form may also be employed.
[0106] Numerous nicotine salts are known, and may be used, e.g.,
the salts presented in Table 1, such as preferably the tartrate,
hydrogen tartrate, citrate, malate, and/or hydrochloride.
1TABLE 1 Possible acids used for nicotine salt formation Molar
ratio* of Acid acid:nicotine Formic 2:1 Acetic 3:1 Propionic 3:1
Butyric 3:1 2-Methylbutyric 3:1 3-Methylbutyric 3:1 Valeric 3:1
Lauric 3:1 Palmitic 3:1 Tartaric 2:1 Citric 2:1 Malic 2:1 Oxalic
2:1 Benzoic 1:1 Gentisic 1:1 Gallic 1:1 Phenylacetic 3:1 Salicylic
1:1 Phthalic 1:1 Picric 2:1 Sulfosalicylic 1:1 Tannic 1:5 Pectic
1:3 Alginic 1:2 Hydrochloric 2:1 Chloroplatinic 1:1 Silicotungstic
1:1 Pyruvic 2:1 Glutamic 1:1 Aspartic 1:1 *recommended upon
production
[0107] The product according to the invention may also comprise a
nicotine mimicking agent. Such an agent may be any suitable agent
with an acrid burning taste. Examples of nicotine mimicking agents
with an acrid burning taste are capsaicin, piperine and
zingerone.
[0108] One or more additives may be added to the coating or the
core/s. Additives are further described in the paragraph entitled
"Other additives to the chewing gum".
[0109] Amount and Distribution of the Nicotine in the Coated
Chewing Gum
[0110] The nicotine in any form is according to the invention
formulated to provide the subject with a dose to achieve an effect.
The effect may be to provide a sense of smoking satisfaction
without smoking. Another effect of the administered nicotine in any
form may be a reduction of the urge to smoke or use tobacco.
[0111] The effect may also be a combination of reduction of said
urge and providing a sense of smoking satisfaction without smoking.
The amount of the nicotine should be sufficient to provide such an
effect in a subject. This amount may, of course, vary from person
to person.
[0112] According to the invention, embodiments of the chewable gum
product comprise embodiments wherein nicotine in any form is
present in an amount of 0.05-10 mg calculated as the free base form
of nicotine per piece coated chewing gum product. This may in
different embodiments include 0.05, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9,
or 10 mg calculated as the free base form of nicotine per piece
coated chewing gum product.
[0113] Still preferred embodiments may contain embodiments where
the nicotine in any form is present in an amount of 0.5-6 mg
calculated as the free base form of nicotine per piece coated
chewing gum product.
[0114] Even more preferred embodiments contain the nicotine in any
form in an amount of 0.5-4 mg calculated as the free base form of
nicotine per piece coated chewing gum product.
[0115] According to certain embodiments of the invention, the
nicotine in any form is part of the at least one coating layer or
at least one of the at least one coating layer.
[0116] The nicotine in any form may be in an amount of 0-10 mg
calculated as free base form in at least one of the at least one
coating layer. Still further embodiments comprise nicotine in an
amount of 0.2-6 mg in at least one of the at least one coating
layers, or even more preferably, in an amount of 0.5-5 mg in at
least one of the at least one coating layer.
[0117] The nicotine in any form may be distributed in the core
and/or different coating layers in different embodiments. Different
distributions of the nicotine throughout the coated chewing gum
will imply administration of the nicotine to the subject in
different ways. This may, then, provide several possibilities to
adjust the composition of the coated chewing gum according to
different needs of different subjects depending on the urge to
smoke or use tobacco of the subject.
[0118] Release and Uptake of Nicotine
[0119] Presently existing nicotine chewing gums provide a slow
release and a slow uptake of the nicotine compared to smoking. The
slow uptake of the nicotine provides a t.sub.max, i.e., the
time-point where the nicotine has its maximum level measured in the
plasma of venous blood, after a single dose at about 30 minutes
after administration. The t.sub.max is initially preceded by a lag
period of a couple of minutes where no nicotine can be detected in
the blood. Then, the plasma level is gradually increasing till the
t.sub.max is reached.
[0120] The time point for reaching a sense of satisfaction or
reduction of urge to smoke or use tobacco after the initial lag
period is individual, but may in existing chewing gums generally be
reached after approximately 30 minutes when regarded as coinciding
with t.sub.max. According to the present invention, such a sense of
satisfaction may be reached after a shorter period of time due to a
rapid initial burst dose of nicotine in the coating followed by a
rapid transmucosal uptake in the oral cavity due to the buffered
coating.
[0121] The release of the nicotine in the coated chewing gum
according to the invention proceeds in at least one step.
[0122] I) If the nicotine is, as in preferred embodiments, in a
defined amount, such as the amounts described above according to
different embodiments, in at least one of the at least one coating
layers defined above the release of the nicotine takes place when
the coating of the coated chewing gum is allowed to melt,
disintegrate or dissolve to uncover the chewable gum core in said
product. The nicotine and forms thereof is released from the
coating into the saliva in the oral cavity during the time period
when the coating is allowed to melt, disintegrate or dissolve.
[0123] When the at least one coating layer is allowed to melt,
disintegrate or dissolute a chewable gum is uncovered. The nicotine
in any form may then further be released to the subject.
[0124] II) The nicotine in any form from the chewable gum is
released by controlled release, e.g., by chewing the gum core
whereby the chewing is controlling the amount of released nicotine
from the gum core. The release of the nicotine is thereby sustained
over a period of time. This period of time may be, in different
embodiments about 10, 20, 30, 40, 50, or 60 minutes.
[0125] The dissolution of the one or more buffering agents in the
coating, and optionally in the core(s), provides for optimized
adjustment of the pH of the liquid in the oral cavity.
[0126] The release may be varied by the incorporation of the
nicotine in any form in a given quantity into the coating layers
and/or the gum core.
[0127] Suitable cat ion exchangers are given in table 2 and are
further disclosed in U.S. Pat. No. 3,845,217, hereby included as a
reference. Preferred are nicotine cation exchangers of
polyacrylates, such as the Amberlite collection from Rohm &
Haas in table 2. Examples of different salts are given in Table
1.
2TABLE 2 Representative cation exchangers Name Manufacturer
Amberlite IRC 50 Rohm & Haas Amberlite IRP 64 Rohm & Haas
Amberlite IRP 64M Rohm & Haas BIO-REX 70 BIO-RAD Lab. Amberlite
IR 118 Rohm & Haas Amberlite IRP 69 Rohm & Haas Amberlite
IRP 69M Rohm & Haas BIO-REX 40 BIO-RAD Lab. Amberlite IR 120
Rohm & Haas Dowex 50 Dow Chemical Dowex 50W Dow Chemical
Duolite C 25 Chemical Process Co Lewatit S 100 Farbenfabriken Bayer
Ionac C 240 Ionac Chem. Wofatit KP S 200 I.G. Farben Wolfen
Amberlyst 15 Rohm & Haas Duolite C-3 Chemical Process Duolite
C-10 Chemical Process Lewatit KS Farbenfabriken Bayer. Zerolit 215
The Permutit Co. Duolite ES-62 Chemical Process BIO-REX 63 BIO-RAD
Lab. Duolite ES-63 Chemical Process Duolite ES-65 Chemical Process
Ohelex 100 BIO-RAD Lab. Dow Chelating Resin A-1 Dow Chemical
Company Purolite C115HMR Purolite International Ltd. CM Sephadex
C-25 Pharmacia Fine Chemicals SE Sephadex C-25 Pharmacia Fine
Chemicals
[0128] Not only the amount of the nicotine released from the
different parts of the chewing gum product is of value as known in
the art, but also, according to the present invention the specific
transmucosal uptake from the oral cavity of the nicotine to the
systemic circulation of the subject whereby the one or more
buffering agents account for provision of a suitable adjustment of
the pH of the liquid of the oral cavity. The uptake according to
the invention is further discussed in the method paragraphs
below.
[0129] Other Additives to the Chewing Gum
[0130] Other additives may be added optionally to the chewing gum
core and/or to coating layers in the chewing gum.
[0131] Optional additives comprise at least one or more additive
selected from the group consisting of stabilisers, such as
preservatives, e.g., antioxidants; softeners, thickening agents,
emulsifiers, glidants, lubricants, sweeteners, flavours, aromatics,
enhancers, colouring agents, vitamins, minerals, fluorine and tooth
whitening agents and mixtures thereof. According to the invention,
at least one of such additives is optionally added to the
product.
[0132] Enhancers are added essentially to improve, i.e., increase,
the transmucosal uptake from the oral cavity.
[0133] Sweeteners are added essentially to improve the taste.
[0134] Sweeteners comprise one or more synthetic or natural sugars,
i.e., any form of carbohydrates suitable for use as sweetener, as
well as so called artificial sweeteners such as saccarin, sodium
saccarin, aspartame, e.g., NutraSweet.RTM., acesulfame K or
acesulfame, potassium acesulfame, thaumatin, glycyrrhizin,
sucralose, dihydrochalcone, alitame, miraculin, monellin,
stevside.
[0135] Suitable sweeteners may be selected from the group
consisting of sugar alcohols, such as sorbitol, xylitol, single
sugars including sugars extracted from sugar cane and sugar beet
(sucrose), dextrose (also called glucose), fructose (also called
leavulose), and lactose (also called milk sugar); sorbitol,
mannitol, glycerol, xylitol, maltitol syrup (or hydrogenated starch
hydrolyzate), isomalt, lactitol; and mixtures of sugars including
glucose syrup, e.g., starch hydrolysates, containing a mixture of
dextrose, maltose and a range of complex sugars, invert sugar
syrup, e.g., sucrose inverted by invertase (also called sucrase or
sacchrase) containing a mixture of dextrose and fructose, high
sugar content syrups such as treacle and honey containing a mixture
of particular leavulose, dextrose, maltose, lactitole, sucrose,
resins, dextrin and higher sugars; and malt or malt extracts.
[0136] The flavour and aroma additives may comprise one or more
synthetic or natural flavouring or aromatizing agents.
[0137] Flavour and aroma agents may be selected from essential oils
including distillations, solvent extractions, or cold expressions
of chopped flowers, leaves, peel or pulped whole fruit comprising
mixtures of alcohols, esters, aldehydes and lactones; essences
including either diluted solutions of essential oils, or mixtures
of synthetic chemicals blended to match the natural flavour of the
fruit, e.g., strawberry, raspberry and black currant; artificial
and natural flavours of brews and liquors, e.g., cognac, whisky,
rum, gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and
mint; fruit juices including expelled juice from washed, scrubbed
fruits such as lemon, orange, and lime; spear mint, pepper mint,
wintergreen, cinnamon, cacoe/cocoa, vanilla, liquorice, menthol,
eucalyptus, aniseeds nuts (e.g., peanuts, coconuts, hazelnuts,
chestnuts, walnuts, colanuts), almonds, raisins; and powder, flour,
or vegetable material parts including tobacco plant parts, e.g.,
genus Nicotiana, in amounts not contributing significantly to the
level of nicotine, and ginger.
[0138] Colouring additives may be selected from dyes being approved
as a food additive.
[0139] Stabilizing additives may be selected from the group
consisting of antioxidants including vitamin E, i.e., tocopherole,
ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated
hydroxyanisole, edetic acid and edetate salts; and preservatives
including citric acid, tartaric acid, lactic acid, malic acid,
acetic acid, benzoic acid, and sorbic acid. Preferred embodiments
comprise an antioxidant as the stabiliser, and even more preferably
the antioxidant vitamin E and/or butylated hydroxytoluene
(BHT).
[0140] Method for Delivering Nicotine in any Form to a Subject
[0141] According to the invention, a method for delivering nicotine
in any form to a subject comprises the steps of
[0142] a) administering to a subject a coated chewing gum product
containing nicotine in any form according to the invention into the
oral cavity of the subject, and
[0143] b) allowing the nicotine in any form in the coated chewing
gum product to be released in the saliva in the oral cavity and
absorbed into the blood plasma of the subject.
[0144] According to the invention, the transmucosal uptake of the
nicotine in the oral cavity is more rapid than with presently known
chewing gum not being buffered in the coating. One embodiment
results in a t.sub.max of nicotine in venous blood of the subject
after about 5-20 minutes.
[0145] In still one embodiment, said nicotine in any form is
absorbed resulting in a t.sub.max of nicotine in venous blood of
the subject after about 3-15 minutes.
[0146] The method for delivering nicotine in any form may further
comprise the steps of
[0147] c) administering the nicotine in any form in a sustained way
over a period of time to the subject.
[0148] Such a time period may be at least 10, 20, 30, 40, 50 or 60
minutes.
[0149] Method for Obtaining Reduction of the Urge to Smoke or Use
of Tobacco
[0150] A method for obtaining reduction of the urge to smoke or use
tobacco containing material and/or for providing a sense of smoking
satisfaction without smoking according to the invention comprises
the steps of
[0151] a) replacing at least partly the tobacco containing material
with a coated chewing gum according to any of claims 1-20,
[0152] b) administering to a subject a coated chewing gum product
containing nicotine in any form according to any of claims 1-20
into the oral cavity of the subject, and
[0153] c) allowing the nicotine in any form in the coating of the
coated chewing gum product to be released in the saliva in the oral
cavity and absorbed by the subject.
[0154] In one embodiment said nicotine in any form results in a
t.sub.max of nicotine in venous blood of the subject after about
5-20 minutes.
[0155] In a further embodiment, the absorbing of said nicotine
released from the at least one coating layer is resulting in a
t.sub.max of nicotine in venous blood of the subject after about
3-15 minutes.
[0156] In still another embodiment, the method according to the
invention further comprises the steps of administering the nicotine
in any form in a sustained way over a period of time to the
subject.
[0157] The period of time may be at least 10, 20, 30, 40, 50 or 60
minutes.
[0158] Even further embodiments of the method for delivering
nicotine to a subject may comprise the steps of combining at least
one other method for obtaining reduction of the urge to smoke or
use of tobacco.
[0159] Tobacco containing material may be material used for e.g.,
smoking, snuffing or chewing and may comprise a cigarette, a
cigarr, snuff, pipe tobacco and also chewing tobacco.
[0160] The coated chewing gum product may be used for obtaining a
quick and/or sustained and/or complete reduction of the urge to
smoke or use of tobacco and/or for providing a sense of smoking
satisfaction without smoking as further discussed below.
[0161] The fast relief provides the subject with a sense of rapid
smoking satisfaction without smoking. Such a satisfaction will
decrease the craving more rapidly than other known nicotine chewing
gum products.
[0162] The quick craving relief is obtained when a dosage of
nicotine is released from at least one of the at least one coating
layers of the coated chewing gum in embodiments wherein nicotine is
in the coating layers in the presence of one or more buffering
agents in the coating and optionally in the core(s). This provides
the subject with an initial rapid transmucosal uptake of nicotine
in the oral cavity that will induce an initial peak, a maximum, in
the blood plasma nicotine levels after a certain time, t.sub.max.
The result will be that the subject gets a feeling or sense of
satisfaction and the initial craving will disappear.
[0163] One embodiment reduces the urge to smoke or use of tobacco
by reaching a t.sub.max of nicotine in venous blood of the subject
after about 5-20 minutes by the use of a coated chewing gum
according to the invention.
[0164] Still one embodiment reduces the urge to smoke or use of
tobacco quickly resulting in a t.sub.max of nicotine in venous
blood of the subject after about 3-15 minutes when said nicotine in
any form is released from the at least one coating layer after use
of a coated chewing gum according to the invention.
[0165] Sustained Reduction of the Urge to Smoke or Use of
Tobacco
[0166] Still, to continue the feeling or sense of satisfaction of
the subject, and to avoid that the craving returns, a sustained
craving relief may be obtained after the initial craving relief. A
sustained craving relief is obtained by chewing the gum part, or
core, of the coated chewing gum to allow a sustained uptake of the
nicotine. The sustained craving relief and/or feeling or sense of
satisfaction of the subject will continue as long as the subject
maintains the blood plasma levels of nicotine at a level high
enough to reach this sense of feeling.
[0167] The subject may achieve this by chewing the gum part of the
chewing gum over a period of time, such as 10, 20, 30, 40, 50, or
even 60 minutes or longer, e.g., a slow release of the nicotine
caused by a controlled release, e.g., by individual chewing.
[0168] Cessation of the Urge to Smoke or Use of Tobacco
[0169] For some of the users, it may be a goal to terminate the
usage of nicotine completely, due to several reasons e.g., health,
economical, social or behavioural. This may be achieved by further
decreasing the amount of nicotine in any form gradually over time.
In a specific embodiment of the invention, the method described
above for obtaining craving relief may further comprise the steps
of decreasing the amount of nicotine in the total coated chewing
gum product described above gradually over time, so as to achieve a
complete relief of tobacco craving. This method results in a
weaning process gradually over time.
[0170] Different types of smokers reach the sense of reduced
craving at different plasma levels of nicotine. This may, of
course, affect the individual types of administration programs of a
coated chewing gum according to the invention. Different types of
smokers include e.g., peak seekers or smokers that crave for a
plasma level of nicotine constantly being above the level for
withdrawal symptoms.
[0171] One strategy may be to lower the frequency of the
administered coated chewing gums. Other embodiments include varying
the dose of the nicotine in said gums as well as the combination of
these two. Also, the strategy may include a coated chewing gum with
substantially no nicotine in any form. Such a gum may be
administered at the end of the treatment period, when the craving
is low or substantially absent.
[0172] Systems for Delivering Nicotine and for Obtaining Craving
Relief
[0173] According to the invention there is a system for delivering
nicotine in any form to a subject. Such a system comprises a coated
chewing gum according to the invention and at least one other means
for obtaining reduction of the urge to smoke.
[0174] Another system according to the invention may also be a
system for obtaining reduction of the urge to smoke or use of
tobacco and/or for providing a sense of smoking satisfaction
without smoking. Such a system comprises a coated chewing gum
product according to the invention and at least one other method
for obtaining reduction of the urge to smoke or use tobacco. Other
methods may also be a concomitant or concurrent method selected
from the group consisting of administration through mouth sprays,
nasal sprays, transdermal patches, inhaling devices, lozenges,
tablets and parenteral methods, subcutaneous methods, intravenous
methods, rectal methods, vaginal methods and transmucosal methods;
or use of tobacco.
[0175] In a specific embodiment, the at least other method
comprises administration of nicotine.
[0176] Use of the Coated Chewing Gum
[0177] The use of the coated chewing gum product according to the
invention is for obtaining a fast and/or sustained and/or complete
reduction of the urge to smoke and use tobacco or for providing a
sense of smoking without smoking as described above.
[0178] The dose of the nicotine is chosen to give the subject an
individual sensory perception and satisfaction with an effect of
the nicotine in any form. The use of the coated chewing gum product
may also be a sole use according to the invention or a combination
with other means or methods known in the field of drug abuse.
Specifically, the present invention may be used in combination with
other means as described above in the methods in the paragraphs
above.
[0179] The use may give a quick reduction of the urge to smoke or
use tobacco obtained reaching a t.sub.max of nicotine in venous
blood after e.g., about 5-20 minutes.
[0180] In a specific embodiment, the use of the coated chewing gum
according to the invention will reduce the urge to smoke or use
tobacco by reaching a t.sub.max, of nicotine in venous blood of the
subject after about 3-15 minutes when said nicotine in any form is
released from the at least one coating layer.
[0181] According to the invention, a use of a coated chewing gum
product according to the invention is also disclosed for delivering
nicotine in any form to a subject.
[0182] In one embodiment, the delivering of nicotine in any form
results in a t.sub.max of nicotine in venous blood of the subject
after about 5-20 minutes.
[0183] In still another embodiment, the delivering of nicotine in
any form results in a t.sub.max of nicotine in venous blood of the
subject after about 3-15 minutes when said nicotine in any form
released from the at least one coating layer is absorbed.
[0184] Production of the Coated Chewing Gum
[0185] Coated chewing gum products according to the invention can
be maintained in several production steps depending on the total
number of cores and the total number of coated layers to be
included.
[0186] A method for the production of the coated chewing gum
according to the invention is disclosed.
[0187] The method comprises the steps of
[0188] a) providing at least one chewing gum core, and/or providing
at least one nicotine containing chewing gum core,
[0189] b) providing nicotine in any form,
[0190] c) providing at least one coating layer that is
buffered,
[0191] d) adding the nicotine in any form to the at least one
chewing gum core and/or to the at least one coating, and
[0192] e) coating the at least one chewing gum core with the at
least one coating layer that is buffered.
[0193] The method may in specific embodiments further comprise
[0194] f) buffering the at least one chewing gum core, and/or
[0195] g) providing at least one coating layer not being buffered,
and optionally
[0196] h) adding the nicotine in any form to at least one of said
at least one coating layer not being buffered, and optionally
[0197] i) providing the nicotine in the coating and the buffer in
the coating in separate layers, preferably separated by a moisture
barrier.
[0198] In one embodiment, the nicotine is selected from the group
consisting of a nicotine salt, the free base form of nicotine, a
nicotine derivative, such as a nicotine cation exchanger, a
nicotine inclusion complex or nicotine in any non-covalent binding;
nicotine bound to zeolites; nicotine bound to cellulose or starch
microspheres; and mixtures thereof.
[0199] The at least one coating layer may in some embodiments be
buffered by the use a buffer selected from the group consisting of
a carbonate buffer, such as the carbonate, bicarbonate,
sesquicarbonate of an alkali metal, e.g., potassium, sodium; or
ammonium; sodium glycinate, alkali metal phosphate, sodium or
potassium glycerophosphate, trisodium or tripotassium citrate, and
mixtures thereof wherein the at least one coating layer is buffered
in such a way that upon administration of the gum the pH of the
saliva is increased by 0.3-4 pH units. The buffering may be
transient.
[0200] In still further embodiments, the at least one coating layer
is buffered in such way that upon administration of the gum the pH
of the saliva is increased by 0.5-2 pH units. The core/pellet
composition may be formed simply by mixing, rolling and scoring or
compression of the chewing gum base with at least one of the forms
of nicotine, e.g., the nicotine-ion exchanger complex, or the
nicotine as a free base or a salt. Before adding any solid
component, except for the gum base, it is desirable to grind and
size the solid component first, to ensure good distribution. The
mixing is preferably conducted at a suitably elevated temperature
depending on the viscosity of the gum core used. The increase in
temperature decreases the viscosity of the gum and thereby enables
the nicotine and other additives to be evenly and intimately
distributed within the core/pellet of the chewing gum.
[0201] Example 5 describes the mixing, rolling and scoring as well
as the compression of gum cores. In principle, this procedure may
be applied for coated chewing gum products up to at least 10 mg
unit formula.
[0202] Mixing, rolling and scoring is done by a conventional
procedure. Double sigma blade mixers are used for mixing the gum
base with the other components of the formulation. The gum base is
softened in the mixer. By heat (from the heating jacket) and
mixing, the gum base becomes plastic. So, the softened base is
mixed with the liquid components, e.g., flavours, liquid, sorbitol
and glycerol, nicotine in base form, when used, and the solid
materials, e.g., nicotine in any form other than in liquid form,
buffer, bulk sweetener, colour as a powder mixture. The warm mass
is discharged from the mixer in form of loaves stacked on trays on
a truck and stored in a conditioned area until the next step
starts. This is to cool the gum.
[0203] After this, the rolling and scoring takes place. The gum is
extruded into a thick sheet, which is rolled by multiple sets of
calender rolls to the correct thickness. The scoring rolls, usually
two sets, cut the gum into the correct size.
[0204] The sheets are then transferred to a conditioned area on
trays, where the sheets are cooled to make them brittle enough to
be broken. The conditioned gum sheets are then passed through a
breaker, which is a rotating drum that parts the sheets into
separate pieces of gum along the scores.
[0205] At a sorting stage deformed gums are sorted away. The
accepted gums are passed through a metal detector.
[0206] Chewing gums produced by compression, i.e., tabletted gums
are made out of a special gum base. Such a gum base gives a rapid
hydration of the cud in the mouth. High velocity mixers can be used
for granulation to give correctly sized particles of the mixture.
This mixture is then compressed in a tablet machine.
[0207] At a sorting stage deformed gums are sorted away. The
accepted gums are passed through a metal detector.
[0208] In one embodiment of the method disclosed, the provision of
the at least one chewing gum core in step a) above comprises the
further steps of
[0209] a1) providing a gum core dough,
[0210] a2) mixing, rolling and scoring; molding; or extruding the
gum dough.
[0211] In still another embodiment, the provision of the chewing
gum core in step a) is obtained by direct compressing of the
ingredients.
[0212] Conveniently, the compositions of additives according to the
invention, e.g., the buffer system, are made simultaneously,
according to known procedures in the art for formulating the
buffers. Depending on the physical properties of the buffer system
incorporated, it may be convenient to add the buffer system/s
either with the liquid part or with he solid part of the
composition. In the case of buffering systems available as fine
powders, it may, of course, be most convenient to add those powders
with the solid, powdered part of other additives.
[0213] The gum mass with additives is cooled, rolled, scored and
hardened sufficiently, and then coated according to the paragraph
The coating of the gum core/pellet.
[0214] According to the method disclosed in the invention, some
embodiments are disclosed where the coating of the at least one
chewing gum core with at least one layer of the at least one
buffered coating comprises the steps of
[0215] a) film coating, and/or
[0216] b) press coating, and/or
[0217] c) sugar coating, and/or
[0218] d) melt coating.
[0219] The product may then be analysed and further wrapped.
[0220] Use for Therapy and Treatment
[0221] The coated chewing gum product according to the invention
may be used in therapy. Said therapy may be a treatment of a
disease selected from the group consisting of Alzheimer's disease,
Crohn's disease, Parkinson's disease, Tourette's syndrome, ulcerous
colitis and post-smoking-cessation weight control.
[0222] The nicotine may also be used for the production of a
chewing gum product according to the invention for the treatment of
a disease selected from the group consisting of Alzheimer's
disease, Crohn's disease, Parkinson's disease, Tourette's syndrome,
ulcerous colitis and post-smoking-cessation weight control.
[0223] Also disclosed is the use of a chewing gum product for the
production of a nicotine containing chewing gum product according
to the invention for the treatment of a disease selected from the
group consisting of Alzheimer's disease, Crohn's disease,
Parkinson's disease, Tourette's syndrome, and ulcerous colitis.
[0224] Analysis of Nicotine
[0225] The analysis of nicotine uptake and effect according to the
invention may be done according to standard procedure known in the
art, e.g., using a bioanalys for the determination of nicotine or
its metabolites in the plasma of a subject.
EXAMPLES
[0226] The below examples are illustrative and non-limiting.
Example 1
Buffered Sugar Coating
[0227] This example describes without limiting the invention a
sugar coating, wherein the coating is buffered and wherein the
nicotine is in the coating.
[0228] Objective
[0229] The objective of this example is to provide a sugar coated
chewing gum, wherein the coating is buffered and wherein the
nicotine is in the coating. The nicotine is in the amount of 1, 2,
4 or 5 mg, respectively.
[0230] Material Sugar Coating*
[0231] A. Nicotine Free Base
3 1 mg 2 mg 4 mg 5 mg unit unit formula unit formula unit formula
formula Component (mg) (mg) (mg) (mg) Sorbitol 19.0 22.2 28.7 31.9
Mannitol 29.4 29.4 29.4 29.4 Xylitol 162 162 162 162 Water q.s.**
q.s. q.s. q.s. Gelatin 3.4 3.4 3.4 3.4 Titanium dioxide 2.5 2.5 2.5
2.5 Sodium carbonate 10 15 20 20 Nicotine free base 1 2 4 5 *sugar
coating in this example denotes sugar alcohols, not saccharose
based sugar. **q.s. = quantum satis.
[0232] B. Nicotine Hydrogen Tartrate
4 1 mg 5 mg unit formula unit formula Component (mg) (mg) Sorbitol
19.0 31.9 Mannitol 29.4 29.4 Xylitol 162 162 Water q.s. q.s.
Gelatin 3.4 3.4 Sodium carbonate 15 40 Titanium dioxide 2.5 2.5
Nicotine hydrogen tartrate, N.H.T. 3.1 15.4 (corresponding to
nicotine free base) 1 5
[0233] Results and discussion
[0234] Other amounts of nicotine are possible.
Example 2
Buffered Film Coating
[0235] This example describes without limiting the invention a film
coated chewing gum, wherein the coating is buffered and wherein the
nicotine is in the coating.
[0236] Objective
[0237] The objective of this example is to provide a film coated
chewing gum, wherein the coating is buffered and wherein the
nicotine is in the coating. The nicotine is in the amount of 1, 2,
4 or 5 mg, respectively.
[0238] Material Film Coating
[0239] A. NHT
5 1 mg unit 4 mg tablet unit formula 2 mg unit formula formula
Component (mg) (mg) (mg) HPMC.sup.a, 5cPs 15.9 15.9 15.9 20 20
PEG.sup.b 4000/6000 4.8 0 4.8 0 4.8 Water 27 27 27 34 34 Ethanol
221 221 221 278 278 NHT, 3.1 (1) 6.2 (2) 6.2 (2) 12.3 (4) 12.3 (4)
(corresponding to nicotine free base, mg) Paraffin wax 0.7 0.7 0.7
0.7 0.7 Sodium carbonate 15 20 20 35 35 .sup.a= HPMC =
hydroxypropyl methylcellulose .sup.b= PEG = polyethylene glycol
[0240] B. Nicotine Free Base
6 1 mg 2 mg 4 mg 5 mg unit unit formula unit formula unit formula
formula Component (mg) (mg) (mg) (mg) HPMC.sup.a, 5cPs 19.0 19.0
19.0 19.0 PEG.sup.b 4000/6000 4.8 4.8 4.8 4.8 Water 27 27 27 27
Ethanol 221 221 221 221 Paraffin wax 0.7 0.7 0.7 0.7 Sodium
carbonate 15 15 20 20 Nicotine free base 1 2 4 5
Example 3
Buffered Press Coating
[0241] This example describes without limiting the invention a
press coated chewing gum, wherein the coating is buffered and
wherein the nicotine is in the coating.
[0242] Objective
[0243] The objective of this example is to provide a press coated
chewing gum, wherein the coating is buffered and wherein the
nicotine is in the coating. The nicotine is in the amount of 1, 2,
4 or 5 mg, respectively.
[0244] Material Press Coating
[0245] A. NHT
7 1 mg unit 2 mg unit 4 mg unit 5 mg unit Component formula formula
formula formula Xylitab 100 734 731 725 722 HPMC, 3cPs 238 238 238
238 Sodium carbonate 10 20 30 40 Magnesium stearate 10 10 10 10
Nicotine hydrogen 3.1 6.2 12.3 15.4 tartrate, corresponding to 1 2
4 4 nicotine free base
[0246] B. NRC or NCC
8 2 mg unit 4 mg unit formula (mg) formula (mg) Component NRC NCC
NRC NCC Xylitab 100.sup.a 727 720 717 703 HPMC, 3cPs 238 238 238
238 Sodium carbonate 15 15 30 30 Magnesium stearate 10 10 10 10 NRC
10 -- 20 -- (corresponding to 2 -- 4 -- nicotine free base) NCC --
17.1 -- 34.2 (corresponding to -- 2 -- 4 nicotine free base)
Example 4
Buffered Melt Coating
[0247] This example describes without limiting the invention a melt
coated chewing gum, wherein the coating is buffered and wherein the
nicotine is in the coating.
[0248] Objective
[0249] The objective of this example is to provide a melt coated
chewing gum, wherein the coating is buffered and wherein the
nicotine is in the coating. The nicotine is in the amount of 1, 2,
4 or 5 mg, respectively.
[0250] Material Melt Coating
[0251] A. NHT
9 1 mg unit 2 mg unit 4 mg unit 5 mg unit Component formula formula
formula formula Hydrogenated 176 176 176 176 vegetable oil, type
II, (Akopol E) Cocoa, alkalized 198 197 192 191 Aspartame 2.4 2.4
2.4 2.4 Sodium carbonate 15 20 30 40 Lecithin 4 4 4 4 Nicotine
hydrogen 3.1 6.2 12.3 15.4 tartrate, (corresponding to 1 2 4 5
nicotine base, mg)
[0252] B. Nicotine Free Base
10 1 mg unit 2 mg unit 4 mg unit 5 mg unit Component formula
formula formula formula Hydrogenated 176 176 176 176 vegetable oil,
type II, (Akopol E) Cocoa, alkalized 198 197 192 191 Aspartame 2.4
2.4 2.4 2.4 Sodium carbonate 15 15 20 20 Lecithin 4 4 4 4 Nicotine
free base 1 2 4 5
Example 5
Manufacture of Cores
[0253] This example describes without limiting the invention the
manufacture of different cores according to the invention.
[0254] Objective
[0255] The objective of this example is to provide a core suitable
for a chewing gum product according to the invention. The nicotine
is incorporated as the free base (NFB), nicotine
.beta.-cyclodextrin complex (NCC), nicotine hydrogen tartrate (NHT)
or as a nicotine resin complex (NRC). The amount of nicotine in
each fomula unit, i.e., per tablett core, is 1, 2, 4, or 6 mg.
[0256] Principle
[0257] The core is formed by a mixing, rolling and scoring process
or by a compression process.
[0258] Composition of the Cores
[0259] A. Manufactured by Tablet Compression Process.
11 6 mg 4 mg 2 mg 1 mg unit formula unit formula unit formula unit
formula (mg) (mg) (mg) (mg) Active ingredients Nicotine resin
complex 20% 30 20 10 5 Other ingredients Chewing gum base for 500
500 500 500 compression.sup.a Xylitol 191 211 221 226 Sorbitol 100
100 100 100 Encapsulated peppermint oil 100 100 100 100 Sodium
carbonate anhydr. 40 30 20 10 Sodium bicarbonate -- -- 10 20
Magnesium stearate 15 15 15 15 Talcum 15 15 15 15 Magnesium oxide 5
5 5 5 Acesulfame K 2 2 2 2 Aspartame 2 2 2 2 .sup.aCafosa Gum
S/A
[0260] B. Manufactured by Mixing Rolling and Scoring
12 6 mg 4 mg 2 mg 1 mg Unit formula Unit formula Unit formula Unit
formula (mg) (mg) (mg) (mg) Active ingredients Nicotine
.beta.-cyclodextrin complex 52.2 34.8 17.4 8.7 11.5% Other
ingredients Chewing gum base.sup.a 650 650 650 650 Xylitol 233 250
268 276 Peppermint oil 30 30 30 30 Sodium carbonate anhydr. 30 25
20 20 Sodium bicarbonate -- 5 10 10 Acesulfame K 2 2 2 2
Levomenthol 2 2 2 2 Magnesium oxide 1 1 1 1 .sup.aCafosa Gum
S/A
[0261] C. Manufactured by Mixing Rolling and Scoring
13 6 mg Unit 4 mg Unit 2 mg Unit 1 mg Unit formula formula formula
formula (mg) (mg) (mg) (mg) Active ingredients Nicotine free base 6
4 2 1 Other ingredients Chewing gum base.sup.a 620 620 620 620
Xylitol 308 310 312 313 Peppermint oil 30 30 30 30 Sodium carbonate
30 25 20 10 anhydr. Sodium bicarbonate -- 5 10 20 Acesulfame K 2 2
2 2 Levomenthol 2 2 2 2 Magnesium oxide 2 2 2 2 .sup.aCafosa Gum
S/A
[0262] D. Manufactured by Mixing Rolling and Scoring
14 6 mg Unit 4 mg 2 mg Unit 1 mg formula Unit formula formula Unit
formula (mg) (mg) (mg) (mg) Active ingredients Nicotine hydrogen
18.5 12.3 6.2 3.1 tartrate Other ingredients Chewing gum base.sup.a
660 660 660 660 Xylitol 246 263 269 272 Fruit flavour 30 30 30 30
Sodium carbonate 40 30 20 10 anhydr. Sodium bicarbonate -- -- 10 20
Acesulfame K 2 2 2 2 Aspartame 2 2 2 2 Magnesium oxide 1 1 1 1
.sup.aCafosa Gum S/A
[0263] E. Manufactured by Mixing Rolling and Scoring
15 6 mg 4 mg 2 mg 1 mg Unit formula Unit formula Unit formula Unit
formula (mg) (mg) (mg) (mg) Active ingredients Nicotine resin
complex 20% 30 20 10 5 Other ingredients Chewing gum base.sup.a 660
660 660 660 Xylitol 235 255 265 270 Peppermint oil 30 30 30 30
Sodium carbonate anhydr. 40 30 20 10 Sodium bicarbonate -- -- 10 20
Acesulfame K 2 2 2 2 Levomenthol 2 2 2 2 Magnesium oxide 1 1 1 1
.sup.aCafosa Gum S/A
[0264] Procedures
[0265] I) Mixing, Rolling and Scoring
[0266] Mixing, rolling and scoring is done by a conventional
procedure. Double sigma blade mixers are used for mixing the gum
base with the other components of the formulation. The gum base is
softened in the mixer. By heat (from the heating jacket) and
mixing, the gum base becomes plastic. So, the softened base is
mixed with the liquid components, e.g., flavours, liquid, sorbitol
and glycerol, when used and the solid materials, e.g., nicotine in
any form, buffer, bulk sweetener, colour) as a powder mixture. The
warm mass is discharged from the mixer in form of loaves stacked on
trays on a truck and stored in a conditioned area until the next
step starts. This is to cool the gum.
[0267] After this, the rolling and scoring takes place. The gum is
extruded into a thick sheet, which is rolled by multiple sets of
calender rolls to the correct thickness. The scoring rolls, usually
two sets, cut into the correct size.
[0268] The sheets are then transferred to a conditioned area on
trays, where the sheets are cooled to make them brittle enough to
be broken. The conditioned gum sheets are then passed through a
breaker, which is a rotating drum that parts the sheets into
separate pieces of gum along the scores.
[0269] At a sorting stage deformed gums are sorted away. The
accepted gums are passed through a metal detector.
[0270] II) Compression
[0271] Chewing gums produced by compression (usually being a dry
method), i.e., tabletted gums are made out of a special gum base.
High velocity mixers can be used for granulation to give correctly
sized particles of the mixture. This mixture is then compressed in
a tablet machine.
[0272] At a sorting stage deformed gums are sorted away. The
accepted gums are passed through a metal detector.
[0273] All publications and patent documents cited above are hereby
incorporated by reference in their entirety for all purposes to the
same extent as if each were so individually denoted.
* * * * *