U.S. patent application number 10/499552 was filed with the patent office on 2005-03-24 for tobacco and/or tobacco substitute composition for use as a snuff in the oral cavity.
Invention is credited to Hansson, Henri, Hovgaard, Lars, Spegel, Christer.
Application Number | 20050061339 10/499552 |
Document ID | / |
Family ID | 8160931 |
Filed Date | 2005-03-24 |
United States Patent
Application |
20050061339 |
Kind Code |
A1 |
Hansson, Henri ; et
al. |
March 24, 2005 |
Tobacco and/or tobacco substitute composition for use as a snuff in
the oral cavity
Abstract
A novel composition for the use as snuff in the oral cavity, the
composition comprising tobacco and/or a tobacco substitute
encapsulated in a membrane material comprising one or more
membranes at least one of which being water permeable and
water-insoluble. A novel composition enables a selective release of
e.g. nicotine while it at the same time reduces the release of
substances, which normally lead to unwanted side effects. The novel
compositions may be used as a healthier alternative to snuff and
other tobacco products such as, e.g., cigarettes, cigars and pipe.
Methods for giving up smoking, reducing nicotine craving, reducing
side effects normally related to smoking and snuffing of tobacco as
welt a method for the preparation of a composition according to the
invention.
Inventors: |
Hansson, Henri;
(Helsingborg, SE) ; Hovgaard, Lars; (Farum,
DE) ; Spegel, Christer; (Lund, SE) |
Correspondence
Address: |
EDWARDS & ANGELL, LLP
P.O. BOX 55874
BOSTON
MA
02205
US
|
Family ID: |
8160931 |
Appl. No.: |
10/499552 |
Filed: |
November 18, 2004 |
PCT Filed: |
December 17, 2002 |
PCT NO: |
PCT/EP02/14853 |
Current U.S.
Class: |
131/352 |
Current CPC
Class: |
A24B 15/16 20130101;
A24B 13/00 20130101 |
Class at
Publication: |
131/352 |
International
Class: |
A24B 015/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 21, 2001 |
DK |
PA 2001 01945 |
Claims
1. A composition for use in the oral cavity comprising a material
selected from the group consisting of tobacco and tobacco in
combination with a tobacco substitute, the material being
encapsulated in a membrane material comprising one or more
membranes at least one of which being water permeable and
water-insoluble, and wherein the impurity index of the
composition--when determined as described herein--is at the most
3.0 such as, e.g., at the most 2.75, at the most 2.5, at the most
2.0, at the most 1.75, at the most 1.5, at the most 1.5 or at the
most 1.4 when measured after 90 min.
2. A composition according to claim 1 for use as snuff.
3. A composition according to claim 1, wherein the composition is
not in the form of a chewing gum.
4. A composition according to claim 1, wherein at least one
membrane is a synthetic or semi-synthetic membrane.
5. A composition according to claim 1, wherein at least one
membrane is made from natural rubber.
6. A composition according to claim 1, wherein at least one
membrane is a biocompatible membrane.
7. A composition according to claim 1, wherein the membrane is of a
polymeric material such as one selected from the group consisting
of cellulose acetate and derivates thereof, carboxymethyl
cellulose, polycellulose esters, other cellulose derivatives such
as, e.g., ethylcellulose, propylcellulose, polyethylene,
polypropylene, polystyrene, polyvinyl chloride, polyvinyl acetate,
polymers of methacrylates and acrylates, natural rubber,
polycarbonates, polyethylene terephthalate, polyesters, polyamides
and nylon.
8. A composition according to claim 1, wherein at least one of the
membranes has predominantly hydrophilic character.
9. A composition according to claim 1, wherein at least one of the
membranes has predominantly hydrophobic character.
10. A composition according to claim 1, wherein nicotine and/or a
nicotine derivative, analog, salt, solvate or a mixture thereof is
released from the tobacco or the tobacco substitute.
11. A composition according to claim 10, wherein the release is a
controlled release.
12. A composition according to claim 10, wherein the nicotine
and/or nicotine derivative, analog, salt, solvate or a mixture
thereof is selected from the group consisting of nor-nicotine,
lobeline, methylanabasine, anabasine, nicotine hydrochloride,
nicotine dihydrochloride, nicotine sulphate, nicotine monotartrate,
nicotine bitartrate, nicotine salicylate or nicotine zinc chloride
monohydrate.
13. A composition according to claim 1, which i) is designed to
release nicotine and/or a nicotine derivative, analog, salt,
solvate or a mixture thereof in a sufficient amount and/or at a
sufficient rate to enable a desired effect and ii) is designed to
retain substances, which normally give rise to side-effects, and/or
to release such substances in a substantially low amount and/or at
a substantially slow rate.
14. A composition according to claim 1, wherein at least one of the
membranes comprising the membrane material has a molecular weight
cut-off of from about 500 to about 40,000 such as, e.g., from about
500 to about 5,000, from about 800 to about 4,000, from about 1,000
to about 3,500, or from about 2,000 to about 40,000, from about
3,000 to about 30,000, from about 5,000 to about 25,000, from about
7,500 to about 20,000 or from about 10,000 to about 20,000.
15. A composition according to claim 1, wherein at least one of the
membranes comprising the membrane material has a thickness of from
about 2 to about 200 .mu.m such as, e.g., from about 5 to about 100
.mu.m, from about 7.5 to about 50 .mu.m, from about 7.5 to about 40
.mu.m, from about 7.5 to about 35 .mu.m, from about 7.5 to about 30
.mu.m or from about 7.5 to about 25 .mu.m.
16. A composition according to claim 1, wherein at least about 50%
w/w of the total content of nicotine and/or nicotine derivative,
analog, salt, solvate or a mixture thereof is released within at
the most 60 min when subject to the release test described
herein.
17. A composition according to claim 1, wherein at the most 25% w/w
of the total content of nicotine and/or nicotine derivative,
analog, salt, solvate or a mixture thereof is released within at
the most 60 min when subject to the release test described
herein.
18. A composition according to claim 1, wherein at least about 50%
w/w of the total content of nicotine and/or nicotine derivative,
analog, salt, solvate or a mixture thereof is released within at
the most 120 min when subject to the release test described
herein.
19. A composition according to claim 1, wherein the release of
nicotine and/or nicotine derivative, analog, salt, solvate mixture
thereof from the tobacco or the tobacco substitute has the
following characteristics:
10 time (min) % w/w released of total nicotine content 0 from about
0 to about 20 such as, e.g., from about 0 to about 15 or from about
0 to about10 3 from about 0.5 to about 40 such as, e.g., from about
0.5 to about 35, from about 0.5 to about 30, from about 1 to about
25 or from about 1 to about 20 30 from about 2 to about 65 such as,
e.g., from about 2 to about 60, from about 5 to about 60, from
about 5 to about 55, from about 7.5 to about 55 or from about 10 to
about 50 90 from about 10 to about 100 such as, e.g., from about 10
to about 95, from about 15 to about 90. from about 20 to about 90,
from about 25 to about 85, from about 30 to about 80, from about 35
to about 80 or from about 40 to about 80 180 from about 40 to about
100 such as, e.g., from about 45 to about 100, from about 50 to
about 100, from about 55 to about 100, from about 60 to about 100,
from about 65 to about 100 or from about 70 to about 100
and the release is determined as described herein.
20. A composition according to claim 1, wherein the release of
nicotine and/or nicotine derivative, analog, salt, solvate mixture
thereof from the tobacco or the tobacco substitute has the
following characteristics:
11 time (min) % w/w released of total nicotine content 0 from about
0 to about 15 3 from about 1 to about 25 30 from about 7.5 to about
55 90 from about 36 to about 80 180 from about 65 to about 100
and the release is determined as described herein.
21. A composition according to claim 1, wherein the release of
nicotine and/or nicotine derivative, analog, salt, solvate or a
mixture thereof from the tobacco or the tobacco substitute has the
following characteristics:
12 time (min) % w/w released of total nicotine content 0 from about
0 to about 10 3 from about 1 to about 20 30 from about 10 to about
50 90 from about 40 to about 90 180 from about 70 to about 100
and the release is determined as described herein.
22. A composition according to claim 1, wherein the release of
nicotine and/or nicotine derivative, analog, salt, solvate or a
mixture thereof from the tobacco or the tobacco substitute has the
following characteristics:
13 time % w/w released of (min) total nicotine content 0 from about
0 to about 10 3 from about 1 to about 20 30 from about 30 to about
50 90 from about 65 to about 90
and the release is determined as described herein in.
23. A composition according to claim 1, wherein the tobacco is
processed from the leafs of the plant family Solanaceae and the
genus Nicotiana, such as, e.g., Nicotiana tabacum and Nicotiana
rustica.
24. A composition according to claim 1, comprising nicotine and/or
nicotine derivative, analog, salt, solvate or a mixture thereof as
claimed in claim 12 together with tobacco in the form of snuff
tobacco and/or a suitable filler substance.
25. A composition according to claim 1, wherein the composition
further comprises sweeteners, aromas, taste additives, detergents,
pH adjusting substances, preservatives, buffers, release modifying
agents and/or fillers.
26. A composition according to claim 1, wherein the composition
further comprises chemical compounds that enables enhances the
release of nicotine from tobacco such as, e.g., pH regulating
buffers, e.g. carbonates buffers oil, organic solvents and herbal
extracts.
27. A composition according to claim 1, wherein the tobacco or
tobacco substitute contains nicotine and/or nicotine derivative,
analog, salt, solvate or a mixture thereof in an concentration of
about from 0% w/w to about 30% w/w such as, e.g., from about 0.5%
w/w to about 25% w/w, from about 0.1% w/w to about 20% w/w, from
about 0.1% w/w to about 15% w/w, from about 0.1% w/w to about 10%
w/w, from about 0.1% w/w to about 9% w/w or from about 0.1% w/w to
about 8% w/w.
28. A composition according to claim 1, wherein the membrane
material is composed of at least two different kinds of membranes
with respect to e.g. thickness, molecular weight cut-off,
hydrophilic/hydrophobic nature and water permeability.
29. A composition according to claim 1, wherein the composition has
a size and/or shape, which is suitable for application under the
upper lip of a human.
30. A composition according to claim 1, containing a mixture of
tobacco and a tobacco substitute.
31. A composition according to claim 1 for use as a smoke
substitute.
32. A composition according to claim 30 for use in reducing
nicotine craving and/or nicotine abstinence.
33. A method for controlling the release of nicotine and/or
nicotine derivative, analog, salt, solvate or a mixture thereof
from tobacco and/or tobacco substitute in the oral cavity, the
method comprising encapsulating a material selected from the group
consisting of tobacco and tobacco in combination with a tobacco
substitute in a membrane material comprising one or more membranes
at least one of which being water permeable and water-insoluble so
that nicotine and/or nicotine derivative, analog, salt, solvate or
a mixture thereof is released in a sufficient amount and/or at a
sufficient rate to i) enable a desired effect and ii) retain
substances, which normally give rise to side-effects, and/or
release such substances in a substantially low amount and/or at a
substantially slow rate.
34. A method for delivering nicotine and/or derivative, analog,
salt or solvate thereof to a person in need thereof, the method
comprising applying a composition according to claim 1 to the oral
cavity.
35. A method for giving up smoking, the method comprising applying
a composition according to claim 1 to the oral cavity.
36. A method for reducing nicotine craving, the method comprising
applying a composition according to claim 1 to the oral cavity.
37. A method for reducing side effects related to smoking and/or
snuffing tobacco, the method comprising applying a composition
according to claim 1 to the oral cavity.
38. Use of a composition according to claim 1 as an alternative to
and/or substitute for smoking tobacco.
39. A method for the preparation of a composition according to
claim 1, the method comprising encapsulating tobacco and/or a
tobacco substitute in a membrane material comprising one or more
membranes at least one of which being a water permeable and a
water-insoluble membrane.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a novel composition for the
use as snuff in the oral cavity, the composition comprising tobacco
and/or a tobacco substitute encapsulated in a membrane material
comprising one or more membranes at least one of which being water
permeable and water-insoluble. A novel composition enables a
selective release of e.g. nicotine while it at the same time
reduces the release of substances, which normally lead to unwanted
side effects. The novel compositions may be used as a healthier
alternative to snuff and other tobacco products such as, e.g.,
cigarettes, cigars and pipe.
[0002] The invention also relates to methods for giving up smoking,
reducing nicotine craving, reducing side effects normally related
to smoking and snuffing of tobacco as well to a method for the
preparation of a composition according to the invention.
BACKGROUND OF THE INVENTION
[0003] The use of tobacco is deeply rooted in a large part of the
world population. In the Scandinavian countries and in particular
Sweden the use of moist snuff (snus) is very common as an
alternative to smoking. Snuff is fermented and milled/grinded
tobacco with a relatively large water content (40-60% w/w),
normally to be used under the front upper lip of a human being.
[0004] Tobacco itself varies somewhat in nicotine content due to
its natural origin. To adjust the nicotine release in moist snuff,
various buffer systems may be added, e.g. carbonates. The moist
snuff is either packed loosely, as bulk in a box or as single doses
in small non-woven bags. A number of the filled and sealed bags are
then packed in a box.
[0005] The moist snuff as a single dose has become popular due to
the ease of use compared to the bulk product. The popularity of
moist snuff is most probably due to its pharmacological nicotine
absorption profile. The dose of nicotine and speed of absorption is
approximately 10 ng per ml over 10 minutes. Plasma nicotine
concentrations rapidly increase within the first few minutes of the
use of snuff and reach levels comparable to those obtained from
smoking cigarettes within 30 min of use. Measurements of plasma
nicotine concentrations after a single day of moist snuff
consumption also yielded levels similar to cigarette use.
[0006] The kinetics is slightly slower compared to the kinetics
when smoking tobacco, such as e.g. cigarettes and cigars; however,
the overall amount of nicotine absorbed is higher when snuff is
employed.
[0007] Like the daily use of cigarettes, cigar, pipe and other
smoke products, a daily use of snuff burdens the users body with a
number of harmful compounds endogenous to tobacco.
[0008] The disadvantage of snuff is the vast number of compounds,
more or less harmful to the body, e.g. different tobacco-specific
nitrosamines, which are compounds known to cause different diseases
such as, e.g., gastrointestinal disorders and cancer.
[0009] Various tobacco products and/or devices for tobacco products
wherein the user achieves the desired effect from nicotine, but at
the same time avoids the harmful substances released from the
tobacco are already known from the literature.
[0010] In U.S. Pat. No. 4,848,376 an inhalation device is presented
where tobacco is used more or less as in a cigarette and the
nicotine is liberated due to elevated temperatures, though below
the combustion temperature of tobacco.
[0011] U.S. Pat. No. 4,141,369 describes a method of inhaling the
nicotine from tobacco without combustion of the tobacco.
[0012] Another way of avoiding the harmful substances contained in
tobacco is to substitute tobacco with nicotine.
[0013] In U.S. Pat. No. 4,655,231 an artificial dry snuff
containing nicotine is suggested. The snuff, composed of pure
nicotine salts and excipients e.g. powdered organic sugars, is
intended for the administration to the nasal membranes. This is a
medicinal nasal composition not based on natural tobacco.
[0014] Various devices have also be constructed in order to deliver
nicotine from a tobacco composition placed in the oral cavity:
[0015] U.S. Pat. No. 5,346,734 describes a perforated latex oral
pouch for loose, moist snuff, the pouch serving as a barrier to
avoid direct physical contact between the tobacco product and the
gum. The pouch has to be filled by the user, cut to fit the mouth
cavity of the user and is re-usable.
[0016] U.S. Pat. No. 6,162,516 describes a shield, which also has
to be filled with snuff by the user, the shield acting as a barrier
to reduce tobacco contact with the sensitive inner cheek lining and
gum surfaces while using snuff.
[0017] Both U.S. Pat. No. 5,346,734 and U.S. Pat. No. 6,162,516 do
provide the user with a protective device to avoid a direct contact
of the tobacco fibers in the snuff with the oral tissues, but no
means have been taken in order to avoid or reduce the release of
potentially harmful and unwanted substances. Thus, potentially
harmful and unwanted substances are still released from the tobacco
into the oral cavity.
[0018] None of the above documents has solved the problems
concerning eliminating or delaying the release in the oral cavity
of unwanted and harmful substances when using a tobacco containing
product as a snuff. Thus, there is still a need for the development
of tobacco containing products, which do not deliver unwanted and
harmful substances to the body after application.
DISCLOSURE OF THE INVENTION
[0019] Accordingly, the present invention provides a composition
wherein the release of nicotine from snuff can be designed freely,
even though the release of unwanted and harmful substances from the
tobacco is dramatically reduced.
[0020] Thus, the present invention provides a composition for use
in the oral cavity comprising tobacco and/or a tobacco substitute
encapsulated in a membrane material comprising one or more
membranes at least one of which being water permeable and
water-insoluble.
[0021] The gist of the invention is the employment of a membrane
material which makes it possible to deliver nicotine and/or a
nicotine derivative, analog, salt, solvate or a mixture thereof in
a predetermined manner and--at the same time--has the properties of
withholding the substances which are unwanted to such a degree that
the side-effects normally observed in connection with the use of
snuff in the oral cavity are dramatically reduced.
[0022] Tobacco
[0023] The tobacco used in the novel snuff composition according to
the invention may be natural tobacco leaves in order to preserve
the authentic taste and feeling of tobacco. The tobacco plant
belongs to the family Solanaceae and the genus Nicotiana. More than
60 tobacco species exists, the most commonly used in smoking or
snuffing tobacco products being Nicotiana tabacum and Nicotiana
rustica. To manufacture moist snuff, the tobacco, which typically
has a content of from about 1% to 8% nicotine, is dried, milled and
mixed with a fermentative solution. The mixture is then fermented,
typically for 5 days to 4 weeks at elevated temperature. After this
the tobacco mass is mixed with a suitable buffer, such as e.g.
carbonate, so a pH of about 6 to 8 for the moist snuff mixture is
obtained, to enable and enhance the release of nicotine or a
derivative thereof from the tobacco. The water content in the final
product may lie in the range from about 10% to about 60%.
[0024] To the moist snuff additional compounds may be added, such
as e.g. sweeteners, aroma substances and other taste additives,
detergents and preservative, release modifying agents, and other
liquids such as oil, organic solvents and herbal extracts.
[0025] In another embodiment of the invention the natural fermented
tobacco may be partly or fully substituted with a tobacco
substitute, such as, e.g., nicotine and/or a nicotine derivative,
analog, salt, solvate or a mixture thereof selected from the group
consisting of nor-nicotine, lobeline, methylanabasine, anabasine,
nicotine hydrochloride, nicotine dihydrochloride, nicotine
sulphate, nicotine monotartrate, nicotine bitartrate, nicotine
salicylate or nicotine zinc chloride monohydrate. To maintain the
same feeling of having the moist snuff product in the oral cavity,
some additional filler may be added, such as, e.g., non-digestible
fibers.
[0026] Whether natural tobacco and/or a tobacco substitute are used
for the novel snuff composition, the tobacco and/or tobacco
substitute may preferably have a content of nicotine and/or a
nicotine derivative, analog, salt, solvate or a mixture thereof,
from about 0% w/w to about 30% w/w such as, e.g., from about 0.5%
w/w to about 25% w/w, from about 0.1% w/w to about 20% w/w, from
about 0.1% w/w to about 15% w/w, from about 0.1% w/w to about 10%
w/w, from about 0.1% w/w to about 9% w/w or from about 0.1% w/w to
about 8% w/w.
[0027] Membrane Material
[0028] According to the invention, the tobacco and/or tobacco
substitute is enclosed in a membrane material. The membrane
material may comprise one or more membranes. In the present context
the term "membrane" describes a thin polymeric film having natural
pores and acting as a selective permeability barrier. The term does
not include papermade material or polymeric materials in which
not-naturally occurring openings have been made.
[0029] At least one of the membranes may be water-insoluble to
prevent spreading of the snuff in the oral cavity, and to maintain
the beneficial properties of the selective membrane material during
use, with respect to the withholding of unwanted substances
[0030] At least one of the membranes may be water permeable in
order to allow water to diffuse into the encapsulated tobacco
and/or tobacco substitute and to allow e.g. nicotine to diffuse
through the polymeric membrane material and thus becoming available
for absorption.
[0031] The membranes may have a predominantly hydrophilic or
hydrophobic nature. The hydrophilic or hydrophobic nature of the
membrane has an effect on the release of substances such as, e.g.,
nicotine through the membrane, since the flow of substances through
the membrane is dependent on the ability of the membrane to
hydrate, e.g. create hydro-channels through the membrane. These
hydro-channels are a prerequisite for molecular transport when dry
polymeric membranes are used. In general, the flow of hydrophilic
substances through a hydrophobic membrane is slower compared to a
hydrophilic membrane. This is probably due to less swelling of the
hydrophobic membrane pores, i.e. in the hydrophobic membranes
nicotine diffusion occurs through well-organized polymeric material
and hydrophobic organized water.
[0032] One or more of the membranes used for making the composition
may be a synthetic or semi-synthetic membrane. Below is given some
examples of natural, synthetic and semi-synthetic hydrophilic and
hydrophobic membranes, which may be used in a novel snuff
composition according to the invention.
[0033] Examples of membranes are membranes made of cellulose
acetate and derivates thereof, carboxymethyl cellulose membranes,
polycellulose ester membranes, other cellulose derivatives such as,
e.g., ethylcellulose, propylcellulose, polyethylene membranes,
polypropylene membranes, polystyrene membranes, polyvinyl chloride
membranes, polyvinyl acetate membranes, membranes made of polymers
of methacrylates and acrylates, natural rubber membranes,
polycarbonate membranes, polyethylene terephthalate membranes,
polyester membranes, polyamide membranes and nylon membranes.
[0034] At least the outer membrane in the membrane material
enclosing the tobacco and/or tobacco substitute may be made from a
biocompatible and physiologically acceptable polymeric material,
since the novel snuff composition has to be placed close to or in
contact with the mucous membrane in the oral cavity during use.
[0035] Furthermore, at least one of the membranes in a membrane
material may be surface treated with e.g. polycarbophils to obtain
a bioadhesiveness of the novel snuff composition in the oral
cavity.
[0036] The molecular weight cut off of the membrane material used
in the novel snuff composition may be varied to obtain a desired
release of nicotine and other substances through the membrane
material. The molecular weight cut-off of a membrane is defined as
the molecular weight of the smallest molecule of which 90% will be
prevented from permeating the membrane. In addition to molecular
weight, the exact permeability of a molecule is dependent on the
shape, the degree of hydration and the charge of the molecule.
[0037] At least one of the membranes comprising the membrane
material may have a molecular weight cut-off from about 500 to
about 40,000 such as, e.g., from about 500 to about 5,000, from
about 800 to about 4,000, from about 1,000 to about 3,500; or from
about 2,000 to about 40,000, from about 3,000 to about 30,000, from
about 5,000 to about 25,000, from about 7,500 to about 20,000 or
from about 10,000 to about 20,000.
[0038] The release of nicotine and/or other substances through the
membrane material is also dependent on the thickness of the
membrane materiel. The diffusion process of molecules through the
membrane is decreased when the membrane thickness is increased and
vice versa. Thus, the thickness of the membrane material may be
varied in respect of obtaining a desired release of nicotine and
other substances through the membrane material.
[0039] The lower limit for the membrane material thickness is
determined by what is possible from a practical point of view, and
the upper value is restricted by what will allow a comfortable fit
of the novel snuff composition in the oral cavity of the user.
[0040] Accordingly, at least one of the membranes comprising the
membrane material may have a thickness of from 2 to about 200 .mu.m
such as, e.g., from about 5 to about 100 .mu.m, from about 7.5 to
about 50 .mu.m, from about 7.5 to about 40 .mu.m, from about 7.5 to
about 35 .mu.m, from about 7.5 to about 30 .mu.m or from about 7.5
to about 25 .mu.m.
[0041] Release Profiles
[0042] To obtain an effect from the novel snuff composition,
nicotine or a nicotine derivative, analog, salt, solvate or a
mixture thereof, selected from the group consisting of
nor-nicotine, lobeline, methylanabasine, anabasine, nicotine
hydrochloride, nicotine dihydrochloride, nicotine sulphate,
nicotine monotartrate, nicotine bitartrate, nicotine salicylate or
nicotine zinc chloride monohydrate, has to be released from the
composition.
[0043] The release profile may be designed with respect to the rate
and amount of nicotine and unwanted substances released by the
membrane.
[0044] The release of nicotine and/or a derivative, analog, salt,
solvate or a mixture thereof from a novel snuff composition may be
designed to be released in a sufficient amount and/or a sufficient
rate to enable a desired effect and on the other hand be designed
to retain substances, which normally give rise to side-effects,
such as, e.g., nitrosamines, and/or to release such substances in a
substantially low amount and/or at a substantially slow rate.
[0045] As a measure of the selective release of nicotine or a
derivative, analog, salt, solvate or a mixture thereof, the
Impurity Index --IPI--is introduced.
[0046] The IPI is calculated from the UV-spectra recorded from 200
nm to 900 nm as described in Example 2, and is defined as the ratio
of the sum of peak heights other than that of nicotine (i.e. thus
including unwanted and harmful substances) to the peak height of
nicotine. In other words, a low IPI reflects that a large amount of
nicotine is released through the membrane compared to the amount of
unwanted substances.
[0047] In a preferred embodiment of the invention the impurity
index IPI is at the most 3.0 such as, e.g. at the most 2.75, at the
most 2.5, at the most 2.0, at the most 1.75, at the most 1.5, at
the most 1.5 or at the most 1.4 when measured after 90 min.
[0048] In one embodiment of the invention the release profile of
nicotine and/or a derivative, analog, salt, solvate or a mixture
thereof from the invention could e.g., be fast and equivalent to
the release of nicotine from the commercially available moist
snuff, while maintaining a low IPI value, i.e. limiting the release
of unwanted substances.
[0049] Moreover, a composition according to the invention can be
designed to release nicotine and/or a derivative, analog, salt,
solvate or mixture thereof in a controlled manner such as, e.g.,
fast (faster than from the reference product employed in the
examples herein), relatively fast (i.e. similar or almost similar
to the reference product employed in the examples herein), delayed
(i.e. with a lag time in which period no nicotine is released
followed by a release of nicotine), prolonged or sustained (i.e. a
relatively slower release than the reference product to avoid any
peak concentration and to obtain a relatively constant plasma
concentration of nicotine after application).
[0050] In another embodiment of the invention the release of
nicotine or a derivative, analog, salt, solvate or a mixture
thereof, may be delayed compared to the commercially available
moist snuff, to mimic the effect of nicotine replacement products
such as, e.g., patches.
[0051] The release of nicotine or a derivative, analog, salt,
solvate or a mixture thereof, may be determined by the release test
described in Example 1, but other suitable methods for determining
the release of nicotine may also be used, i.e. the embodiments of
the invention described below referrer to Example 1 without
limiting the relevant release tests to the one described in Example
1.
[0052] The tobacco and/or tobacco substitute composition may be
designed so that at least about 50% w/w of the total content of
nicotine and/or a derivative, analog, salt, solvate or a mixture
thereof is released within at the most 60 min when subject to the
release test described in Example 1 below.
[0053] In a further embodiment of the invention the tobacco and/or
tobacco substitute composition may be designed so that at the most
25% w/w of the total content of nicotine and/or a derivative,
analog, salt, solvate or a mixture thereof is released within at
the most 60 min when subject to the release test described in
Example 1 below.
[0054] In yet another embodiment the tobacco and/or tobacco
substitute composition may be designed so that at least about 50%
w/w of the total content of nicotine and/or a derivative, analog,
salt, solvate or a mixture thereof is released within at the most
120 min when subject to the release test described in Example 1
below.
[0055] Below follows release profiles for compositions according to
the invention. The release profiles are described as % w/w released
of total nicotine content as a function of time, measured at 0, 3,
30, 90 and 180 minutes. However, the release profiles according to
the invention also includes profiles described by only one or any
combination of the values below, i.e. a release profile according
to the invention could be defined by e.g. the % w/w release of
nicotine at 3 minutes and 90 min, or at 3 and 90 and 180 minutes,
or at 90 and 180 minutes or any possible combination of the values
shown below.
[0056] A composition according to the invention is suitable
designed to release nicotine and/or a derivative, analog, salt,
solvate or a mixture thereof from the tobacco or the tobacco
substitute with the following characteristics:
1 time (min) % w/w released of total nicotine content 0 from about
0 to about 20 such as, e.g., from about 0 to about 15 or from about
0 to about 10, 3 from about 0 to about 40 such as, e.g., from about
0 to about 35, from about 0 to about 30, from about 0 to about 25,
from about 0 to about 20, 30 from about 2 to about 100, such as,
e.g., from about 2 to about 90, from about 2 to about 80, from
about 2 to about 70, from about 2 to about 65, from about 2 to
about 60, from about 5 to about 60, from about 5 to about 55, from
about 7.5 to about 55 or from about 10 to about 50, op til 100 90
from about 10 to about 100 such as, e.g., from about 10 to about
95, from about 15 to about 90, from about 20 to about 90, from
about 25 to about 85, from about 30 to about 80, from about 35 to
about 80 or from about 40 to about 80, 180 from about 40 to about
100 such as, e.g. from about 45 to about 100, from about 50 to
about 100, from about 55 to about 100, from about 60 to about 100,
from about 65 to about 100 or from about 70 to about 100,
[0057] and the release is determined as described herein in Example
1.
[0058] More specifically, a composition according to the invention
releases nicotine and/or a derivative, analog, salt, solvate or a
mixture thereof from the tobacco or the tobacco substitute with the
following release profile characteristics:
2 time (min) % w/w released of total nicotine content 0 from about
0 to about 15 3 from about 1 to about 25 30 from about 7.5 to about
55 90 from about 35 to about 80 180 from about 65 to about 100
[0059] and the release is determined as described herein in Example
1.
[0060] In a further embodiment, a composition according to the
invention releases nicotine and/or derivative, analog, salt or
solvate thereof from the tobacco or the tobacco substitute with the
following release profile characteristics:
3 time (min) % w/w released of total nicotine content 0 from about
0 to about 10 3 from about 1 to about 20 30 from about 10 to about
50 90 from about 40 to about 90 180 from about 70 to about 100
[0061] and the release is determined as described herein in Example
1.
[0062] In a still further embodiment, a composition according to
the invention releases nicotine and/or a derivative, analog, salt,
solvate or a mixture thereof from the tobacco or the tobacco
substitute with the following release profile characteristics:
4 time (min) % w/w released of total nicotine content 0 from about
0 to about 10 3 from about 1 to about 20 30 from about 30 to about
50 90 from about 65 to about 90
[0063] and the release is determined as described herein in Example
1.
[0064] Design of Membrane Material
[0065] As described above, membrane material properties such as
hydrophobicity, hydrophilicity, molecular weight cut-off and
membrane thickness may be used in designing a desired release
profile for nicotine or a derivative, analog, salt, solvate or
mixture thereof.
[0066] In the following are given some examples of how membrane
materials can be designed. The examples are for illustrative
purposes and are not intended to limit the invention in any
way.
[0067] A multilayer membrane is e.g. designed to contain one
membrane material being hydrophilic and a second membrane material
being lipophilic. Both membrane components are chosen in such a
manner that the membrane material has a molecular cut off large
enough for the relatively small nicotine molecule to pass through
with ease.
[0068] The amphiphilic nature of nicotine enables it to pass both
hydrophilic and hydrophobic materials while a majority of both
hydrophilic and lipophilic unwanted and harmful substances are
excluded from permeation through the membrane material. Many other
combinations of different types of membranes are of course possible
and based on the disclosure herein a skilled person will know how
to chose different membranes in order to obtain a suitable
release.
[0069] Another example of a composition according to the invention
is a composition wherein the membrane material is a bi-layer
membrane with one membrane being preferentially hydrophilic and one
membrane being predominantly hydrophobic. Both membranes possess
high permeability to nicotine while maintaining low aqueous pore
diffusion. The release profile of nicotine could either be
identical to the release profile of original snuff or it could be
designed to have a prolonged or sustained release. The unwanted and
harmful substances from the tobacco should substantially be
maintained inside the membrane.
[0070] Shape and Size of a Composition According to the
Invention
[0071] A composition according to the invention may attain all
possible sizes and shapes, such as, e.g. round, circular, oblong,
elliptical, square, rectangular or trapezoidal. The shape and/or
size chosen may be such as to allow a comfortable fit in the oral
cavity.
[0072] The location in the oral cavity of a composition according
to the invention may be centered or to the sides under the upper
front lip, centered or to the sides under the lower front lip,
under the tongue or in the cheeks.
[0073] Other Aspects of the Invention
[0074] In other aspects, the invention also relates to use of a
composition according to the invention as a smoke substitute and it
can be used by persons who suffer from nicotine craving or who want
to give up or reduce smoking. In such cases, the content of tobacco
and/or a tobacco substitute is adjusted to the individual purposes
and it is possible to design a kit comprising compositions
according to the invention with different concentrations of tobacco
and/or a tobacco substitute. Such compositions in a kit could e.g.
contain compositions with a decreasing content of tobacco or
nicotine.
[0075] In a still further aspect of the invention it relates to a
method for preparing a composition according to the invention.
[0076] The details and description relating to the composition
aspects apply mutatis mutandi to the other aspects of the
invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0077] FIG. 1 shows the release profile from moist tobacco using
side-by-side diffusion cells equipped with specific membranes
having different physical properties.
[0078] FIG. 2 shows the impurity index (IPI) for various
hydrophilic membranes with different thickness and molecular weight
cut-offs. The reference is filter paper.
[0079] FIG. 3 shows the maximum flux of nicotine as a function of
membranes thickness for a hydrophilic membrane with a molecular
weight cut-off of 13,000. The reference flux illustrates the flux
through filter paper.
[0080] The following examples are intended to illustrate the
invention without limiting it thereto.
EXAMPLES
Example 1
[0081] Diffusion Profiles of Hydrophobic Membranes and Hydrophilic
Membranes with Different Physical Properties
[0082] Membranes made of regenerated cellulose acetate dialysis
tubing with varying MW cut-off together with vinyl and polyethylene
membranes with various thicknesses were tested with respect to the
diffusion profiles over the membranes of nicotine released from
tobacco.
[0083] Diffusion Chamber Experiment
[0084] In a side-by-side diffusion chamber separated by a membrane,
1 g of snuff tobacco (SVENSKT SNUS, GOTHIATEK, General) was placed
in an aqueous PBS (phosphate buffered saline according to Ph. Eur.)
with a pH of 6.6 on the donor side of the membrane in the diffusion
chamber. In the receiver chamber PBS with a pH of 6.6 was placed.
The cells of the diffusion chamber were kept at a temperature of
37.degree. C. .+-.0.5.degree. C. by attachment to a water bath. The
temperature control was made in order to simulate the environment
of the oral cavity.
[0085] Diffusion profiles were constructed by sampling from the
receiver chamber at 0, 3, 30, 60, 90, 120, (110 min for the
polyethylene membrane) and 180 min after the start of the diffusion
experiment. The concentration of nicotine in the receiver chamber
was measured by HPLC, using a C-18, 5.mu., 4.5 mm.times.15 cm
column, employing a mobile phase consisting of 70% v/v 0.1 M
phosphate buffer (pH 4.5), 30% acetonitrile, and 2.3 g sodium
dodecyl sulphate/liter at a flow rate of 1 ml/min and a temperature
of 40.degree. C. The sample volume was 10 .mu.l and detection was
carried out using a UV-detector running at 260 nm.
[0086] The membranes used were regenerated cellulose acetate
dialysis tubing with varying MW cut-off and vinyl and polyethylene
membranes with varying thickness.
[0087] As a reference a piece of filter paper with a average pore
size of 8.8 .mu.m, mimicking the commercially used non-woven bag
for snuff, was used.
[0088] Reference Filter Paper
[0089] Table 1 shows a comparison of the release profile of
nicotine for a commercial non-woven snuff-bag, and a piece of
filter paper used as reference in the experiments. The measurements
were performed as described above, and the results are the mean of
2 single runs.
5TABLE 1 Comparison of the nicotine release profile for a
commercial non-woven filter and a reference paper filter Nicotine
released (mg/ml) Filter type 15 sec. 30 min. 60 min. 90 min.
Reference paper 11.5 64.4 92.0 202.4 filter Commercial non- 9.4
65.8 90.1 205.5 woven filter
[0090] The results from Table 1 show that the reference filter
paper exerts no barrier function to the transport of nicotine.
[0091] Hydrophobic Membranes
[0092] Hydrophobic membranes, e.g. vinyl and polyethylene
membranes, show a slower nicotine release profile compared to
hydrophilic membranes (see FIG. 1). The slower profile is probably
due to less swelling of the hydrophobic membrane pores, i.e. in the
hydrophobic membranes nicotine diffusion occurs through
well-organized polymeric material and hydrophobic organized water
rather than through aqueous pores.
[0093] In Table 2 below are given the results from the
above-mentioned experiment.
[0094] Hydrophilic Membranes
[0095] FIG. 1 shows that the release of nicotine over a hydrophilic
membrane made of regenerated cellulose acetate dialysis tubing is
high and close to the nicotine release over the reference filter
paper. FIG. 1 also shows that the physical properties, i.e. the
molecular weight cut-off and thickness of the hydrophilic membrane,
affect the permeability of nicotine as stated below.
[0096] A membrane with a relatively small molecular weight cut-off,
e.g. a molecular weight cut-off of 3,500, tends to have a sigmoid
release profile for nicotine. In other words, a considerable lag
time is expected before the nicotine starts to permeate the
membrane, even though the size of a nicotine molecule is
significantly smaller than the molecular weight cut-off of
3,500.
[0097] However, a membrane with a higher molecular weight cut-off,
e.g. a molecular weight cut-off of 13,000, seems to have a release
profile for nicotine that is very close to the release profile for
nicotine of the reference filter paper.
[0098] This difference may be due to a much lower aqueous mobility
of nicotine in the membrane with a molecular weight cut-off of
3,500, compared to the membrane with a molecular weight cut-off of
13,000.
[0099] FIG. 1 also shows that when the thickness of a membrane
increases, then the flux of nicotine through the membrane
decreases.
[0100] Example 1 shows that it is possible to design a polymeric
membrane which gives rise to a release profile of nicotine from
moist tobacco through the membrane very similar to the release
profile through a commercial non-woven snuff-bag, i.e. with respect
to the shape of the profile and the individual release data (time,
percentage released). Especially, it seems that a hydrophilic
membrane material is suitable. Furthermore, the release profile is
dependent of the molecular weight cut-off of the membrane, the
thickness of the membrane and of the membrane material itself.
[0101] Example 1 also shows that some hydrophobic membranes, e.g.
vinyl and polyethylene membranes, have a slower nicotine release
profile compared to the hydrophilic membranes.
[0102] All these observations make it possible to design membranes,
which enable a specific release of nicotine, i.e. it is possible to
design membranes having desired release characteristics e.g. a
quick or a slow release of nicotine dependent on the purpose of the
composition. In other words, the specific features of a membrane or
a membrane material can be used to design a controlled and
well-defined release profile for the release of nicotine from a
composition according to the invention.
6TABLE 2 Release of nicotine from membranes of various kinds,
thicknesses and pore sizes Release of nicotine (%) Membrane 0 min 3
min 30 min 90 min 120 min 180 min Reference filter 4.7 18.7 46.5
80.8 88.8 100 (original) 23 .mu.m 2.4 4.1 36.6 73.2 83.7 100
cellulose membrane 13,000 MW cut-off 46 .mu.m cellulose 1.6 2.4
33.3 69.1 79.2 100 membrane 13,000 MW cut-off 93 .mu.m cellulose 0
0 17.2 43.9 49.0 69.7 membrane 13,000 MW cut-off 25 .mu.m cellulose
0.9 2.7 11.6 67.0 75.9 100 membrane 3,500 MW cut-off 50 .mu.m
cellulose 0.9 1.7 4.3 49.9 56.8 80.0 membrane 3,500 MW cut-off 20
.mu.m Polyetylene 0 0 3.0 -- 22* -- *Measured after 110 min
Example 2
[0103] Selectivity of the Release of Tobacco Components Over
Membranes with Different Properties
[0104] Membranes made from regenerated cellulose acetate dialysis
tubing with varying thickness and molecular weight cut-off were
tested for their selectivity in transporting nicotine across the
membrane, while unwanted and potentially harmful substances are
retained in the tobacco.
[0105] To examine the selectivity of the membranes, an experimental
set-up as described in Example 1 was used.
[0106] As membranes were used regenerated cellulose acetate with
molecular weight cut-off of 3,500 and a thickness of 25.2 .mu.m or
a molecular weight cut-off of 13,000 and a thickness of 23.2 .mu.m
or 46.4 .mu.m. Samples were withdrawn at 3, 30 and 90 minutes after
the start of the experiment and an UV spectrum from 200 nm to 900
nm was recorded for each sample.
[0107] As previous described, the Impurity Index --IPI--was
introduced as a measure for the selective release of nicotine. The
IPI is calculated from the UV-spectra recorded from 200 nm to 900
nm, and is defined as the ratio of the sum of peak heights other
than that of nicotine (i.e. thus including unwanted and harmful
substances) to the peak height of nicotine. All measurements are
performed in the receiver chamber, i.e. after permeation through
the membrane in question. The IPI is measured 3, 30 and 90 min
after start of the experiment, cf. above. In those cases where any
additionally substances are added to the tobacco composition such
as, e.g., sweeteners, flavors, detergents, buffers, etc. the peak
heights of these are normally not included when calculating the sum
of peak height as described above.
[0108] As mentioned before, a low IPI reflects that a large amount
of nicotine is released through the membrane compared to the amount
of unwanted substances. Table 3 shows IPI values calculated for the
reference filter paper and for hydrophilic membranes with different
molecular weight cut-off and different thickness.
7TABLE 3 Impurity index (IPI) calculated for the reference filter
paper membrane and hydrophilic regenerated cellulose acetate
membranes with different physical properties Impurity index (IPI)
Membrane 1 Membrane 2 Membrane 3 Time Thick: 25.2 .mu.m Thick: 23.2
.mu.m Thick 46.4 .mu.m (min) MWCO 3,500 MWCO 13,000 MWCO 13,000
Reference 3 0.9 0.75 1.05 1.64 30 1.17 1.24 1.17 2.91 90 1.26 1.35
1.25 3.35 IPI = .SIGMA. Peak height other substances/.SIGMA. Peak
height nicotine MWCO = molecular weight cut-off
[0109] The results in Table 3 show that the amount of unwanted
substances can be decreased almost three times when a cellulose
membrane with a thickness and a molecular weight cut-off in the
range described in Table 3 is used compared to the reference filter
paper.
[0110] As shown in FIG. 1, the decrease in IPI is not merely a
result of a decrease in the overall release rate. Accordingly, the
release profiles relating to nicotine and employing cellulose
membranes with a molecular weight cut-off of 13,000 are only a few
percent lower than the release profile for the reference filter
paper. Thus, employment of such membranes enables a release, which
permits release of wanted substances (i.e. nicotine) while
retaining unwanted substances.
[0111] The results from Table 3 and FIG. 1 indicate that the
release rate of unwanted substances increases with decreasing
membrane thickness. However, it is important to note that such an
increase seems to correspond to the increase in the release rate of
nicotine, i.e., a decrease in membrane thickness will not lead to a
more pronounced release of unwanted substances. In other words, the
IPI value is not increasing when the thickness of the membrane with
a molecular weight cut-off of 13,000 is decreased from 46.4 .mu.m
to 23.2 .mu.m.
Example 3
[0112] Optimization of Membrane Properties with Respect to
Molecular Weight Cut-Off, Thickness and Low IPI Values
[0113] Example 2 shows that no significant loss in membrane
selectivity .mu.s observed as the membrane thickness is being
decreased. Therefore, further studies to investigate the
relationship between membrane thickness, molecular weight cut-off
of the membrane and amount of nicotine transferred over the
membrane were performed by analyzing selected data from Example
1.
[0114] From FIG. 1, the maximum slope for each release profile has
been deduced. The maximum slope, i.e. percentage nicotine release
per time unit, dR/dt represents the maximum flux of nicotine
through the membranes (see Table 4).
8TABLE 4 Values for the maximum flux (% nicotine released per time
unit, dR/dt) and lag time for different thicknesses of membranes
with cut off 3500 Mw, 13000 Mw and reference filter Maximum flux
Molecular weight Thickness Lag time of nicotine cut-off (.mu.m)
(min) (dR/dt) .infin. 0 1.250 (reference pouch) 13,000 MW CO 23.2 0
1.205 membrane 46.4 0 1.144 92.8 0 0.637 3,500 MW CO 25.2
.apprxeq.50 1.250 membrane 50.4 .apprxeq.50 1.204
[0115] FIG. 3 shows a plot of the maximum flux as a function of
membrane thickness for the cellulose membrane with a molecular
weight cut-off of 13,000. The Figure shows that the flux of
nicotine through a membrane is approaching the flux through a
reference filter paper, which practically has no barrier to the
nicotine diffusion, at a membrane thickness of about 10 .mu.m.
[0116] A hydrophilic membrane with a molecular cut off about 13,000
does not seem to give rise to any boundary layer/membrane effects
or any major diffusion limitations for nicotine. A thickness of
approx. 10 .mu.m will give a release profile equal to the original
commercially available non-woven moist snuff pouches.
Example 4
[0117] Studies of Nicotine Uptake in Humans from a Novel Snuff
Composition
[0118] The sensation of nicotine uptake in humans when using
commercially available bag-snuff compared to a novel snuff
composition according to the invention was studied.
[0119] In the study, the uptake of nicotine from 1 g of snuff
(SVENSKT SNUS, GOTHIATEK, General) in original non-woven pouches
was compared to the uptake of nicotine from 1 g of snuff contained
in a regenerated cellulose membrane with a molecular weight cut-off
of 13,000 and a thickness of 23.2 aim.
[0120] The study was performed with human volunteers who were not
snuff users.
[0121] Each individual placed a portion of snuff under the upper
lip, and they scored their observations concerning the sensation of
taking up nicotine into the blood stream within certain time
intervals.
[0122] The sensation of taking up nicotine into the blood stream
from the oral cavity was scored using a scale rating from zero to
five, with zero indicating no feeling and 5 indicating a very
strong feeling of uptake, leading to dizziness and nausea.
[0123] The results from the study of nicotine uptake are shown in
Table 5.
9TABLE 5 Sensation of nicotine uptake from commercially available
bag-snuff and from a snuff composition according to the invention
Commercially Moist snuff placed in available a membrane with bag
snuff MW CO 13,000 Time (min) Subject 0 2 4 6 8 10 0 2 4 6 8 12 16
Volunteer 0 0 2 3 5 5 0 0 1 2 3 4 5 #1 Volunteer 0 0 1 4 5 5 0 0 1
3 4 4 5 #2 Volunteer 0 0 1 3 4 5 0 0 1 2 3 4 4 #3
[0124] It is evident from the results shown in Table 5, that the
novel snuff composition gives rise to a nicotine effect in the
volunteers. Four minutes after the commercially available bag snuff
or the novel snuff composition was placed in the oral cavity, two
of the volunteers felt a nicotine effect, which they gave a scoring
of one. One of the volunteers felt an one-degree higher effect from
the commercially available bag snuff compared to the novel snuff
composition
[0125] The results also show that the effect of nicotine uptake
from the novel snuff composition is slightly delayed compared to
the sensation of nicotine uptake from the commercially available
bag snuff. When using the commercially available bag snuff, the
volunteers feel an effect rated 5 after 8 to 10 minutes. When using
the novel snuff composition the volunteers feel the maximum effect
between 12 to 16 minutes.
* * * * *