U.S. patent application number 11/783333 was filed with the patent office on 2008-01-03 for method and preparation for binding aldehydes in saliva.
This patent application is currently assigned to BIOHIT OYJ. Invention is credited to Martti Marvola, Mikko Salaspuro, Ville Salaspuro, Osmo Suovaniemi.
Application Number | 20080000489 11/783333 |
Document ID | / |
Family ID | 38875318 |
Filed Date | 2008-01-03 |
United States Patent
Application |
20080000489 |
Kind Code |
A1 |
Suovaniemi; Osmo ; et
al. |
January 3, 2008 |
Method and preparation for binding aldehydes in saliva
Abstract
The object of the invention is the use of compounds comprising
one or more free sulphlydryl or amino groups for preparing a
pharmaceutical composition for locally binding acetaldehyde in
saliva, the stomach or the large intestine, and pharmaceutical
compositions comprising the said compounds.
Inventors: |
Suovaniemi; Osmo; (Helsinki,
FI) ; Salaspuro; Mikko; (Helsinki, FI) ;
Salaspuro; Ville; (Espoo, FI) ; Marvola; Martti;
(Helsinki, FI) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W.
SUITE 800
WASHINGTON
DC
20037
US
|
Assignee: |
BIOHIT OYJ
|
Family ID: |
38875318 |
Appl. No.: |
11/783333 |
Filed: |
April 9, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/FI2005/000429 |
Oct 10, 2005 |
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11783333 |
Apr 9, 2007 |
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10415422 |
Nov 21, 2003 |
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PCT/FI01/00948 |
Oct 30, 2001 |
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11783333 |
Apr 9, 2007 |
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60617299 |
Oct 8, 2004 |
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60660723 |
Mar 11, 2005 |
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Current U.S.
Class: |
131/359 |
Current CPC
Class: |
A24D 3/061 20130101;
A61K 31/197 20130101; A24D 3/14 20130101 |
Class at
Publication: |
131/359 |
International
Class: |
A24B 15/00 20060101
A24B015/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 30, 2000 |
FI |
2000-2392 |
Claims
1-40. (canceled)
41. A method for decreasing the risk of cancer of the mouth and
pharynx, or larynx, oesophagus and stomach, comprising
administering to a smoking subject, a composition comprising: (A)
an effective amount of an aldehyde binding substance(s) comprising
one or more free sulphhydryl and amino groups, and (B) a carrier,
wherein upon administering, said composition releases said aldehyde
binding substance(s) into saliva of said subject, whereby aldehyde
in said saliva is bound by said aldehyde binding substance(s)
during smoking by said subject.
42. The method according to claim 41, wherein said administering
results in lowering of the amount of aldehyde during smoking of one
cigar, cigarette or pipe essentially to the level of aldehyde in
saliva before smoking.
43. The method according to claim 41, wherein the carrier is
selected from the group consisting of a pharmaceutically acceptable
diluent, sweetening agent, flavouring agent and
lubricant/glident.
44. The method according to claim 41, wherein the composition is in
a preparation form selected from the group consisting a chewable
tablet, buccal tablet, sublingual tablet, candy, pastille, lozenge,
chewing gum, bubble gum and gel.
45. The method according to claim 44, wherein during smoking by
said subject, at least one of said preparation form is placed in
the mouth of said subject, wherein said preparation form releases
aldehyde-binding substance(s) to saliva essentially during the time
when 1 tobacco product is smoked by said subject.
46. The method according to claim 41, wherein the composition is
attached to a tobacco product, tobacco filter or a tobacco
holder.
47. The method according to claim 46, wherein the composition is
attached to that part of a tobacco product, tobacco filter or
tobacco holder which is put to the mouth of said subject during
smoking.
48. The method according to claim 46, wherein the composition comes
into contact with saliva during smoking by said subject, and said
composition releases aldehyde-binding substance(s) to saliva
essentially during the time when 1 tobacco product is smoked by
said subject.
49. The method according to claim 46, wherein the composition is
detachable from the tobacco product, tobacco filter or tobacco
holder.
50. The method according to claim 41, wherein the carrier allows
for the release of the aldehyde-binding substance(s) to saliva
within less than 30 minutes after administration.
51. The method according to claim 41, wherein the aldehyde-binding
substance(s) is represented by the following formula:
R.sup.1--NH--CH--COOH (CH.sub.2).sub.n--R.sup.2 wherein R.sup.1 is
hydrogen or an acyl group containing 1-4 carbon atoms, R.sup.2 is a
sulphhydryl group or sulphonic acid, and n is 1 or 2.
52. The method according to claim 41, wherein the aldehyde-binding
substance(s) is selected from the group consisting of L-cysteine,
D-cysteine, cystine, cysteic acid, cysteine glycine, threo- or
erythro-.beta.-phenyl-DL-cysteine, B-tetramethylene-DL-cysteine,
methionine, D-penicillamine and its N-terminal dipeptides,
semicarbazide, reduced glutathione, .beta.-mercaptoethylamine,
D.sub.5L-homocysteine, N-acetylcysteine, L-cysteinyl-L-valine,
.beta.,.beta.-tetramethylene-DL-cysteine, cysteinyl glycine,
mercaptoethyl glycine, tre-(5)-.beta.-phenyl-DL-cysteine,
erythro-.beta.-phenyl-DL-cysteine, thiamine hydrochloride and
mercaptane.
53. The method according to claim 41, wherein said aldehyde-binding
substance(s) binds aldehyde both through a sulphhydryl and an amino
group.
54. The method according to claim 41, wherein said aldehyde-binding
substance(s), is selected from the group consisting of L-cysteine,
D-cysteine, a derivative of cysteine and a substance that is
capable of converting to cysteine.
55. The method according to claim 41, wherein said aldehyde is
acetaldehyde.
56. A tobacco product, tobacco filter or tobacco holder for use in
binding-aldehyde in saliva during smoking comprising a composition
comprising an aldehyde-binding substance(s) comprising one or more
free sulphhydryl and amino groups, attached thereto in an amount
capable of lowering aldehyde in saliva during smoking essentially
to a level of aldehyde before smoking.
57. The tobacco product, tobacco filter or tobacco holder according
to claim 56, wherein the composition is attached to that part of a
tobacco product, tobacco filter or tobacco holder which is put to
the mouth during smoking.
58. The tobacco product, tobacco filter or tobacco holder according
to claim 56, wherein the composition comprises a carrier selected
from the group consisting of a pharmaceutically acceptable diluent,
sweetening agent, flavouring agent and lubricant/glident.
59. The tobacco product, tobacco filter or tobacco holder according
to claim 56, wherein the composition is in a preparation form
selected from the group consisting of a chewable tablet, buccal
tablet, sublingual tablet, candy, pastille, lozenge, chewing gum,
bubble gum and gel.
60. The tobacco product, tobacco filter or tobacco holder according
to claim 56, wherein the composition is attached to a tobacco
product, tobacco filter or tobacco holder with or without an
adhesive like-material.
61. The tobacco product, tobacco filter or tobacco holder according
to claim 56, wherein the composition is attached so that the
composition remains in contact with the tobacco product, tobacco
filter or tobacco holder.
62. The tobacco product, tobacco filter or tobacco holder according
to claim 56, wherein the composition is attached by impregnating
and/or concentrating and/or drying the composition to a tobacco
product, tobacco filter or tobacco holder.
63. The tobacco product, tobacco filter or tobacco holder according
to claim 56, wherein the aldehyde-binding substance(s) is present
in a higher concentration on the surface of said tobacco product,
tobacco filter or tobacco holder than inside of said tobacco
product, tobacco filter or tobacco holder.
64. The tobacco product, tobacco filter or tobacco holder according
to claim 56, wherein the composition is attached to the surface of
a tobacco product, tobacco filter or tobacco holder.
65. The tobacco product, tobacco filter or tobacco holder according
to claim 56, wherein the tobacco product is a cigar or a cigarette,
the tobacco filter is a cigarette filter, and the tobacco holder is
a pipe.
66. A kit comprising: (A) a plurality of cigars or cigarettes, and
(B) a plurality of preparations comprising an aldehyde binding
substance(s) comprising one or more free sulphhydryl and amino
groups, in an amount capable of lowering aldehyde in saliva during
smoking essentially to a level of aldehyde before smoking.
67. The kit according to claim 66, wherein the preparation(s) is
capable of lowering aldehyde in saliva during smoking of 1, 2 or 3
cigars or cigarettes.
Description
[0001] This invention relates to compositions for locally binding
aldehydes in saliva during smoking. This invention relates also to
a method, a kit and a tobacco product for decreasing the risk of
developing cancer of the mouth and pharynx, larynx, oesophagus and
stomach.
[0002] The main causes for upper digestive tract cancers are
smoking and alcohol drinking. It has been estimated, for United
States, that up to 80% of these cancers can be avoided by
abstaining from alcohol drinking and smoking. Both alcohol drinking
and tobacco have been shown to be independent risk factors for
upper digestive tract cancers. Additionally, several
epidemiological studies have confirmed that alcohol and tobacco
interact in a multiplicative way to the cancer risk.
[0003] Acetaldehyde has been shown to be highly toxic and mutagenic
under various experimental conditions. Epidemiological and
biochemical studies on Asian heavy drinkers with aldehyde
dehydrogenase-2 (ALDH2)-deficiency strongly suggest that
acetaldehyde is a local and topical carcinogen in man. This
deficiency results in the accumulation of acetaldehyde in saliva
and also in markedly increased risk for upper GI-tract cancers.
[0004] We have shown that the mean in vivo concentration of
salivary acetaldehyde in smokers, even without smoking, is about
two times higher than in non-smokers after ethanol ingestion
throughout the follow-up period of 160 minutes (FIG. 1) (Salaspuro
V, Salaspuro M. Synergistic effect of alcohol drinking and smoking
on in vivo acetaldehyde concentration in saliva. Int J. Cancer.
2004 Sep. 10; 111(4):480-3; incorporated herein by reference). The
area under the curve of salivary acetaldehyde in smokers was
significantly higher than in non-smokers, 114.8.+-.11.5
.mu.M.times.h vs. 54.2.+-.8.7 .mu.M.times.h, respectively
(p=0.002).
[0005] During the period of cigarette smoking the in vivo salivary
acetaldehyde was increased to ten-fold from the levels derived from
the sole ethanol ingestion. The salivary acetaldehyde increased
immediately when the smoking was started but also declined rapidly
after the cessation of smoking (FIG. 2). The area under the curve
of salivary acetaldehyde in smokers was seven times higher than in
non-smokers and the difference was highly significant,
369.5.+-.12.2 .mu.M.times.h vs. 54.2.+-.8.7 .mu.M.times.h,
respectively (p=0.001). Differences between acetaldehyde
concentrations are significant at all time points from 40 to 160
min (p.ltoreq.0.05).
[0006] During active smoking the salivary acetaldehyde increased to
261.4.+-.45.5 .mu.M from the basal level. The salivary acetaldehyde
increased immediately when the smoking was started but also
declined rapidly after the cessation of smoking (FIG. 3).
[0007] In patent literature it has been suggested that
preparations, which are sucked or chewed in the mouth be used to
decrease the effect of the harmful free radical compounds that are
formed in connection with using tobacco products or being exposed
to them. For example Hersch, U.S. Pat. No. 5,922,346 and Hersch, WO
1999/000106 suggest a preparation, which comprises L-glutathione,
selenomethionine, Vitamin C, Vitamin E, Vitamin A and L-cysteine.
It was believed that L-glutathione is employed in protecting cells
against oxidative stress by itself being oxidized. Thus,
L-glutathione functions in combination with other enzyme systems in
order to be reduced. L-cysteine delivery agent enhances endothelial
cell reduced glutathione concentration and protects cells from
damage from endogenous hydrogen peroxide. The patent publications
suggest the use of the preparation in the form of chewable gum,
tablet, lozenge or gel.
[0008] WO 02/36098 suggests the use of compounds comprising free
sulphhydryl and/or amino group for locally binding acetaldehyde in
the long term in saliva, the stomach or the large intestine. The
compounds were mixed to a substance capable of releasing the
acetaldehyde binding substances for at least 30 minutes in the
conditions of the mouth, stomach or large intestine. The aim was to
bind the increased acetaldehyde that occurs in connection with
consuming alcoholic drinks or smoking.
[0009] There are several patent publications, which suggest
compositions for reducing the blood level of acetaldehyde in order
to prevent and treat hangover symptoms and prevent and treat liver
damages associated with acetaldehyde. For example U.S. Pat. No.
5,202,354 describes a composition comprising acetaldehyde binding
substance, such as L-cysteine, ascorbic acid or salt thereof, a
disulfide type thiamine derivative, or a salt thereof, and a
cholagogue. U.S. Pat. No. 4,528,295 describes a composition
comprising methionine, vitamin B6 and potassium citrate.
[0010] Some patent publications suggest the addition of compounds
capable of binding harmful substances from tobacco smoke during
smoking to cigarette filters. For example, U.S. Pat. No. 5,829,449
suggests a composition for inclusion within a cigarette, cigar or
pipe. The patent publication suggests that the composition can be
included within the tobacco itself, a filter for filtering tobacco
smoke once burned or within the paper or wrapper surrounding the
tobacco product. The composition was said to be capable of reducing
free radical damage to the oro-pharyngeal cavity, respiratory tract
and lungs resulting from tobacco smoke. The composition included
L-glutathione, and a source of selenium, such as L-selenomethionine
or L-selenocysteine. The composition may comprise also L-cysteine
and N-acetyl-l-cysteine.
[0011] U.S. Pat. No. 4,532,947 suggests a filter for use in
association with tobacco cigarette, which comprises non-toxic salts
of 2-mercapto-alkalene sulphonates and/or cysteine and
acetylcysteine. These compositions were to be added to cigarette
filters or cigarette holders comprising a filter for the purposes
of reducing toxic tobacco substances in situ, while smoking
cigarettes.
[0012] The object of the invention is to provide a method and a
composition for removing or decreasing the aldehyde content of the
saliva during smoking. The composition and the method according to
the invention are very useful in locally binding the increased
amount of aldehyde that occurs in connection with smoking.
[0013] The invention is based on the surprising observation that
the harmful amount of aldehydes locally occurring in saliva during
smoking can be bound locally and quickly into a chemically safe
form by using the preparations according to the present invention.
As the substances that bind aldehydes are released in contents high
enough to saliva throughout the period of effect of the aldehydes,
the local concentration of aldehydes in saliva remains low. In this
way, the local risk of contracting cancer caused by aldehydes
decreases.
[0014] Aldehydes, in particular acetaldehyde present in tobacco
smoke dissolves very quickly into saliva. It is of advantage, if
the content of aldehydes dissolved in saliva can be lowered or the
aldehydes entirely removed from saliva, before the aldehyde has
caused damage to the mucosal cells in mouth or in upper respiratory
tract or in stomach. The preparations of the present invention are
able to bind aldehydes very effectively in saliva keeping the
aldehyde content much lower or at the level of non-smoking
situation. The prior art does not suggest preparations or methods,
which would keep the aldehyde concentration in saliva essentially
lower or prevent the increase of aldehyde concentration during
smoking.
[0015] According to the invention, compounds that comprise one or
more free sulphhydryl and/or amino groups are used to prepare a
composition, which is used to locally bind the aldehydes in
saliva.
[0016] More specifically, the use according to the invention is
characterized by what is stated in claim 1.
[0017] According to the invention, the composition comprises one or
more substances that bind aldehydes optionally admixed with a
carrier suitable for human consumption (sucking and/or chewing
and/or keeping) in mouth. The substances contained by the
composition are selected so that the substances are capable of
binding aldehydes and are released within a short period of
time.
[0018] This invention provides also a method according to claim 10
for decreasing the effect of aldehydes, which causes cancer, in
human mouth, pharynx, larynx, oesophagus and stomach.
[0019] According to the method, the aldehydes contained in saliva
are locally bound into a safe form by using a composition that
releases one or more aldehyde-binding substances.
[0020] Furthermore, this invention provides a composition according
to claim 19, a kit according to claim 28 and a tobacco product
according to claim 30.
[0021] U.S. Pat. No. 5,829,449 and U.S. Pat. No. 4,532,947 disclose
tobacco products and filters comprising compounds capable of
binding harmful substances from tobacco smoke. However, it has
turned out, that such filters are not capable of binding
acetaldehyde, since the filter is too dry to let the reaction
happen. The presence of acetaldehyde binding substances in tobacco
product filters does not solve the problem of decreasing or
removing the acetaldehyde or other aldehydes in saliva during
smoking. The filters and other tobacco products disclosed in U.S.
Pat. No. 5,829,449 and U.S. Pat. No. 4,532,947 are aimed for
binding harmful substances from tobacco smoke, not from saliva.
Neither do products effecting systemically through blood
circulation as described for example in U.S. Pat. No. 4,528,295 and
U.S. Pat. No. 5,202,354 or which are aimed for preventing and
ameliorating free radical damage induced by smoking as described in
U.S. Pat. No. 5,922,346, or products releasing acetaldehyde binding
substances very slowly as described in WO 0236098, solve the
problem.
[0022] So far, neither a method nor a preparation has been
presented, which would locally decrease the acetaldehyde content of
saliva during smoking. The preparations according to the prior art
are aimed for systemically reducing blood acetaldehyde
concentration and the alleged effect is based on the reaction of
the effective substances to the acetaldehyde inside blood and/or
cells. Preparations, which are aimed for preventing free radical
damage as described for example in U.S. Pat. No. 5,922,346 function
locally and systemically through buccal mucosal absorption or
through swallowing. Since the preparations comprise only low
amounts of acetaldehyde binding substances, which in addition are
involved in other chemical reactions, the local effect of
acetaldehyde binding of the preparations in mouth is not
significant. The preparations are also suggested to be used as a
daily dosage, for example in the morning and in the evening, not
specifically connected to smoking. Preparations
affecting/increasing intracellular protection mechanisms, for
example by low-dose cysteine, against acetaldehyde toxicity are
insufficient to protect (or to bind acetaldehyde directly) upper
gastrointestinal tract mucosa from the high acetaldehyde exposure
during active smoking.
[0023] The present invention provides considerable advantages. The
compositions comprising substances capable of binding aldehyde(s)
can be used to decrease the risk of developing cancer of the mouth.
In particular, the compositions according to the invention can be
used for heavy smokers. The average amount of saliva excreted by a
human is 1.5 litres a day. The areas of influence of the
aldehyde(s) contained in the saliva include the mouth, the pharynx,
the oesophagus, and the stomach. The compositions of the present
invention are capable of decreasing the risk of developing cancer
of all these areas.
[0024] An advantage of the aldehyde-binding substances, for example
cysteine is, that the binding of harmful aldehydes is not limited
only to aldehydes, but they are able to bind also other harmful and
toxic compounds of tobacco smoke dissolved into saliva.
[0025] In the following, the present invention is examined more
closely with the aid of a detailed description and examples.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 shows in vivo salivary acetaldehyde after ethanol
ingestion in smokers (without concomitant smoking) and in
non-smokers.
[0027] FIG. 2 shows in vivo salivary acetaldehyde after ethanol
ingestion in smokers (with concomitant smoking) and in non-smokers.
Differences between acetaldehyde concentrations are significant at
all time points from 40 to 160 min (p.ltoreq.0.05).
[0028] FIG. 3 shows salivary acetaldehyde in smokers after smoking
one cigarette (without concomitant alcohol drinking).
[0029] FIG. 4 shows the salivary acetaldehyde after 5 min smoking
with placebo, and with 1.25 mg, 2.5 mg, 5 mg or 10 mg cysteine
tablets.
[0030] FIGS. 5, 6 and 7 show various ways of attaching the
preparation to a cigarette or cigar.
[0031] FIG. 8 shows a holder which keeps the preparation in contact
with saliva during smoking and through which tobacco smoke is
inhaled.
[0032] FIGS. 9 and 10 show the impregnation of a holder or the
surface of a holder with aldehyde binding substances.
[0033] FIG. 11 shows the impregnation of a filter or the surface of
a filter of a cigarette with aldehyde binding substances.
DETAILED DESCRIPTION OF THE INVENTION
[0034] "The aldehyde-binding substance" refers to a compound
comprising one or more free sulphhydryl groups and/or one or more
amino groups. According to the disclosure preferred compounds have
one or more free sulphhydryl groups and one or more amino groups.
By amino groups are meant --NH.sub.2, --N, --NH-- and
NH.sub.3.sup.+ groups.
[0035] The "aldehydes" comprise C.sub.1-C.sub.4 aldehydes
potentially containing a double bond in the hydrocarbon chain.
Examples of these aldehydes include formaldehyde, acetaldehyde,
crotonaldehyde and acrolein, acetaldehyde being particularly
important.
[0036] Although, we refer specifically to acetaldehyde in the
following description, it should be understood that other
C.sub.1-C.sub.4 aldehydes are also, mutatis mutantis,
considered.
[0037] "The aldehyde-binding substance" refers also to compounds
that are converted in mouth to an aldehyde binding substance. Such
compounds are for example methionine and cystine.
[0038] "The binding of acetaldehyde" refers to a chemical reaction
between the acetaldehyde and the compound that has a free
sulphhydryl and amino group, wherein the acetaldehyde jointly with
the "acetaldehyde-binding substance" forms a larger molecule, and
water can be formed in the reaction. For example, when reacting
with cysteine, the acetaldehyde binds itself both to the
sulphhydryl and the amino group and forms
2-methyl-L-thiazolidine-4-carboxylic acid and water. The
acetaldehyde can bind itself to the amino group of almost any
protein, whereby Schiff's base or a 2-methyl-imidazole ring is
formed.
[0039] Preferred compounds according to the disclosure are
cysteine, its derivatives, compounds that are converted to cysteine
and other compounds that function in a similar manner. Suitable
substances for the use according to the disclosure are in
particular cysteines and N-acetyl-cysteines, preferably L- and
D-cysteines.
[0040] Preferred aldehyde-binding substances are naturally those
that are not harmful for humans or which do not form harmful
substances from aldehyde by chemical binding. It is also of
advantage, if the compounds do not have unpleasant taste or
smell.
[0041] Suitable compounds for binding aldehydes, in particular
acetaldehyde in saliva also include the compounds according to the
formula: ##STR1## wherein R.sup.1 is hydrogen or an acyl group with
1-4 carbon atoms, R.sup.2 is a sulphhydryl or sulphonic group n is
an integer of 1 or 2.
[0042] Advantageously, in a reaction of the acetaldehyde binding
compounds according to the disclosure with acetaldehyde, a Shiff's
base is formed. The acetaldehyde binding molecule should contain
one or more free amino groups and one or more free --SH groups.
When the --SH group is at a suitable place of the molecule, it
facilitates the forming of a Shiffs base and stabilizes the formed
adduct.
[0043] Amino acids or other compounds that suitably bind aldehyde,
in particular acetaldehyde comprise one or more free sulphhydryl
(SH) group and amino (--NH.sub.2, --N, --NH-- or NH.sub.3.sup.+)
group and comprise:
L-cysteine,
D-cysteine,
Cystine,
Cysteic acid,
Cysteine glycine,
Threo or erythro-.beta.-phenyl-DL-cysteine,
.beta.-tetramethylene-DL-cysteine,
Methionine,
D-penicillamine and its dipeptides with N-terminals,
Semicarbazide,
Reduced glutathione,
.beta.-mercaptoethylamine,
D,L-homocysteine,
N-acetylcysteine,
L-cysteinyl-L-valine,
.beta.,.beta.-tetramethylene-DL-cysteine,
Cysteinyl-glycine,
Mercaptoethylglycine,
Tre-(5)-.beta.-phenyl-DL-cysteine,
Erythro-.beta.-phenyl-DL-cysteine,
Thiaminhydrochloride,
Mercaptanes.
[0044] The effect of some of the acetaldehyde-binding or other
aldehyde-binding substances may be improved by vitamins, such as
L-ascorbic acid.
[0045] The aldehyde-binding compounds according to the present
invention should be non-toxic. Compounds suitable for the
preparations according to the present invention should cause no
health hazard in the amounts used in the invention.
[0046] It is also of advantage, if the compounds do not have
unpleasant or very strong taste or smell. It is possible to mask
the unpleasant taste of the effective compound by using suitable
sweeteners and flavourings, but by using compounds having mild
and/or pleasant taste it is possible to keep the composition
simple, and its production is easier. Another way of decreasing the
significance of the taste of the compounds is to use them in as
small amounts as possible.
[0047] Tobacco can be used by smoking, chewing and dipping and
snuffing. According to our studies, especially smoking seems to
cause the formation of acetaldehyde in the mouth. Smoking in
connection with the present invention means typically the use of
cigarettes or cigars or alternatively pipe smoking.
[0048] "The short-term binding of acetaldehyde" (or other
aldehydes) means that acetaldehyde formed during smoking is bound
immediately and that the binding effect lasts as long as one cigar
or cigarette is smoked or a few minutes longer. The binding effect
lasts preferably at least 5 minutes, more preferably at least 10
minutes, most preferably at least 15 minutes.
[0049] Cigar smoking may last longer than cigarette smoking and
therefore a preparation capable of binding acetaldehyde longer than
15 minutes is of advantage. However, the time is preferably shorter
than 30 minutes. Alternatively, a person smoking a cigar may use
more than one preparation during smoking of one cigar.
[0050] The preparation according to the present disclosure should
be able for the release of the acetaldehyde (or other aldehydes)
binding substance to saliva at the conditions prevailing in the
mouth within less than 30 minutes and preferably within less than
15 minutes from the point of time when the preparation is contacted
with the saliva. Acetaldehyde binding substances should thus be
released within 0-5 minutes, more preferably within 0-10 minutes,
most preferably within 0-15 minutes from the point of time when the
preparation is contacted with the saliva. The release of
acetaldehyde binding substances lasts preferably essentially the
time of smoking of one cigar or cigarette i.e. the time of actual
smoking and a couple of minutes longer.
[0051] "A harmful/carcinogenic content of acetaldehyde" in the
human mouth, oesophagus, stomach, and large intestine is about
20-800 .mu.mol/l of saliva, although it is difficult to define an
amount of acetaldehyde, which would not be harmful. Such a harmful
or carcinogenic content of acetaldehyde in the human mouth can be
obtained in connection with for example smoking and/or alcohol
drinking.
[0052] Keeping the acetaldehyde (or other aldehydes) content
essentially lower than without the use of the preparation of the
present invention means keeping the acetaldehyde content of saliva
at a level that is at least 20%, preferably at least 40%, more
preferably at least 60%, and most preferably at least 80% lower
than when not using the composition.
[0053] "In connection with smoking" herein refers to the period of
time that begins from starting to smoke and ends, when smoking is
stopped and 1 or 2 minutes before and after the actual smoking.
[0054] "A local preparation that is placed in the mouth" refers to
all preparations that are sucked or chewed in the mouth or that may
be placed between the cheek, the lip or the tongue and the gum
(gingiva), and in which the release of the substance is intended to
have a local effect in the mouth. Preferably the preparation has
effect also in the pharynx, the oesophagus or the stomach.
[0055] The term "composition" means here the composition comprising
the effective substance(s) optionally admixed with a suitable
carrier. The composition may be in the form of a local preparation
suitable for use in mouth.
[0056] A local preparation according to the invention may be
selected from the group of chewable or sucking tablets, buccal
tablets, sublingual tablets, candies, pastilles, chewing gums,
bubble gums, gels and lozenges.
[0057] The compounds that are used in the preparation that binds
aldehydes, in particular acetaldehyde, can be compounds comprising
one or more free sulphhydryl and amino groups.
[0058] In addition to the acetaldehyde-binding, so-called effective
substance(s), the preparation comprises preferably at least one
carrier substance that does not hinder or facilitates the release
of the effective substance. It is preferred that the preparation
has a form that facilitates keeping it in the mouth when smoking.
The preparation may be circular or oval, convex, ring-formed and
small enough and have a form that does not harm or change the
smoking action.
[0059] The preparation may be put to the mouth during smoking or it
may be attached by a suitable way to the tobacco product. The
preparation may be kept attached to the tobacco product during
smoking or it may be detached from the tobacco product and put to
the mouth when starting to smoke.
[0060] It is of advantage, if the amount of the effective substance
can be kept as low as possible, since there is then no or minor
need to mask the taste of the compound, if the taste of the
substance is unpleasant. The person using the composition need not
consume too high concentrations of the compound. The preparation
will also be less expensive.
[0061] The preparation of the present invention comprises
preferably 1 to 300 mg aldehyde-binding, in particular
acetaldehyde-binding substances, more preferably the amount is 1 to
250 mg, still more preferably 1 to 200 mg, even more preferably 1
to 150 mg, most preferably 1 to 100 mg. Higher amounts are
specifically preferred when the aim is to bind various aldehydes in
addition to acetaldehyde. The amount may be lower, if the aim is,
in particular, to bind acetaldehyde.
[0062] According to a preferred embodiment of the invention the
preparation of the present invention comprises 1-50 mg, more
preferably 5-30 mg, more and more preferably 5-10 mg, or even 1-5
mg, typically 10-20 mg, or 1-20 mg, in some embodiments 15-20 mg
aldehyde-binding, in particular acetaldehyde-binding substance or
substances.
[0063] The amount of the substances may preferably be higher, if
the preparation is kept attached to the tobacco product during
smoking as compared to, when the preparation is put to the mouth
when starting to smoke.
[0064] Within the scope of the present invention are in addition to
the above-disclosed preparations also other preparations and
compositions used with tobacco products, which are able to release
aldehyde-binding substances to saliva during smoking.
[0065] For example, a composition comprising the effective
substance(s) may be concentrated and/or dried and/or impregnated to
a tobacco product, to a filter or to a holder. The composition is
preferably attached to that part of a tobacco product, filter or
holder, which is put to the mouth when smoking. This may be about 1
to 10 mm from the tip of the tobacco product. Advantageously, the
composition is attached to the surface of the tobacco product,
filter or holder. This means that the concentration of the
aldehyde-binding substance(s) is preferably higher on the surface
of a tobacco product compared to the concentration inside of the
tobacco product, filter or holder. The composition may, for
example, be concentrated and/or dried and/or impregnated on the
surface of the paper of a tobacco product, or filter or on the
surface of a holder. The paper of a tobacco product may be
protected by nonporous material not to let the aldehyde-binding
substances to become absorbed into the paper and through the paper
to the tobacco product or filter or holder. Alternatively the
composition may be impregnated to the surface area of a tobacco
product, to a filter or to a holder. The area may extend 1 or 2 mm
from the surface towards the inside of the tobacco product, filter
or holder.
[0066] The impregnated filter may also be separate from the tobacco
product and may, for example, be attached to the tobacco product or
located into a holder of a tobacco product.
[0067] The amount of aldehyde-binding substances may in these
applications preferably be higher than in a preparation kept in the
mouth. The amount of aldehyde-binding substances may be more than 5
mg, preferably more than 10 mg, more preferably more than 20 mg,
most preferably more than 30 mg, even more preferably more than 50
mg per one tobacco product or filter or holder. Smaller amounts are
preferred, if the composition is concentrated and/or dried and/or
impregnated only to the surface of a filter, a tobacco product or a
holder.
[0068] In addition to the effective substance(s), the composition
may comprise:
[0069] 1. pharmaceutically acceptable diluents (fillers, bulking
agents), 2. sweetening agents such as sugars and sugar alcohols, 3.
flavouring agents and 4. lubricants/glidants. Sugars may comprise
for example sucrose, fructose or glucose or a combination of these.
Sugar alcohols may comprise mannitol, sorbitol, maltitol, lactitol,
isomalt or xylitol or a combination of these. Preferably, none of
the additives reacts with other ingredients in the preparation. A
preferable sweetening agent is mannitol, because it is not very
sweet and its amount in the preparation can be quite high and thus
its acts at the same time as a diluent.
[0070] Flavouring agents may comprise for example spearmint,
peppermint, menthol, citrus fruit, eucalyptus or aniseed or a
combination of these.
[0071] The preparation may comprise also other components, such as
agents masking oral malodor, agents acting as breath freshener
and/or agents preventing dental caries, or the preparation may
comprise vitamins. The preparation may comprise also agents
enhancing the excretion of saliva. However, these additional
components should not prevent the quick release of the aldehyde
binding substance to the saliva. As described here earlier, the
preparation should release aldehyde binding substance so
effectively that an essential amount of aldehyde is bound in
saliva, before aldehyde affects the mucous membrane cells in
mouth.
[0072] According to one preferred embodiment of the present
invention the preparation (for example one tablet) may comprise or
consist essentially of: TABLE-US-00001 Aldehyde binding
substance(s) 1-50 mg Diluent(s)/Sweetening agent(s) 50-750 mg
Flavouring agent(s) q.s. Lubricant (s) (0.5-3 wt %) 5-25 mg
[0073] The preparation may be a sucking tablet comprising:
TABLE-US-00002 Acetaldehyde-binding substances 1-50 mg sugar or
sugar alcohol, such as mannitol 50-750 mg Flavouring agent q.s.
Magnesium stearate 5-25 mg
[0074] The composition is prepared by mixing the powder mass and
compressing it into sucking tablets by well known methods.
[0075] If the amount of aldehyde-binding substances is increased,
the amount of diluent(s)/sweetening agent(s) and flavouring agents
may be increased also, since the taste of aldehyde-binding
substances may be needed to be masked.
[0076] According to another preferred embodiment of the present
invention the preparation may comprise or consist essentially of:
TABLE-US-00003 Aldehyde-binding substances 1-50 mg Gum base
comprising sweetening or other agents 500-1500 mg Flavouring agent
q.s. Lubricant (0.5-3 w-%) 5-30 mg
[0077] The gum base may comprise medical chewing gums (Morjaria, Y.
et al., Drug Delivery Systems & Sciences, vol. 4, no 1, 2004.),
which comprise natural or synthetic elastomers, plasticizers, waxes
and lipids. Natural gum bases including chicle and smoked natural
rubber are permitted by FDA. However, modern gum bases are mostly
synthetic and include styrenebutadiene rubber, polyethylene and
polyvinylacetate. The gum base makes up to 15 to 40% of the chewing
gum. The remainder consists of drug, sugar, sweeteners, softeners,
flavouring and colouring agents. The majority of chewing gum based
drug delivery systems are manufactured using conventional
processes. However, directly compressible powdered gums are modern
alternatives for medical chewing gums. Pharmagum is a compactable
new gum system. It is a mixture of polyol(s) and/or sugars with gum
base. Formulation containing Pharmagums can be compacted into a gum
tablet using conventional tablet presses. The manufacturing process
is rapid and cheap. The amount of the gum base comprising
sweetening agents may be in a preparation 50-500 mg, preferably
500-1500 mg.
[0078] Pharmagum S contains gum base and sorbitol, Pharmagum M
contains gum base, mannitol and isomalt.
[0079] The preparation may be a chewing gum comprising:
TABLE-US-00004 Acetaldehyde-binding substances 1-50 mg Pharmagum S
500-1500 mg Flavouring agent q.s. Magnesium stearate (0.5-3 w-%)
5-30 mg
[0080] The composition is prepared by mixing the powder mass and
compressing it into chewing tablets.
[0081] The preparation may be a buccal tablet, which comprises:
TABLE-US-00005 Acetaldehyde-binding substances 1-50 mg Non-ionised
macromolecules 5-25 mg Ionising macromolecules 2-10 mg Flavouring
agent(s) q.s. Lubricants 0.5-3 w %
[0082] Non-ionised macromolecules include, for example,
methylcellulose (MC), hydroxypropylcellulose (HPC), and
hydroxypropyl-methylcellulose (HPMC), and polyethylene glycol
(PEG). Ionising polymers include, for example, sodium
carboxy-methyl cellulose (NaCMC), alginic acid, sodium alginate,
chitosan, polycarbophil (Noveon.TM.), and carbomer
(Carbopol.TM.).
[0083] The preparation may also be a sublingual tablet, which
comprises or consists essentially of: TABLE-US-00006
Acetaldehyde-binding substances 1-50 mg Diluent(s)/Sweetening
agent(s) q.s. 50-500 mg Flavouring agent(s) q.s. Lubricants 0.5-3 w
%
[0084] Diluents include, for example lactose, calcium phosphates,
starch, carboxymethylcellulose, hydroxymethylcellulose. Sweetening
agent can be for example mannitol or xylitol.
[0085] According to one preferred embodiment of the invention the
preparations of the invention are provided in a kit comprising:
[0086] a plurality of cigars or cigarettes, and [0087] a plurality
of preparations comprising aldehyde binding substance or substances
in an amount capable of binding aldehyde in saliva during smoking
essentially to a level the aldehyde was before smoking.
[0088] Preferably, the preparation is capable of binding aldehyde
in saliva during smoking of 1, 2 or 3 cigarettes or cigars.
[0089] The kit may comprise a tobacco pack or box for cigars or
cigarettes connected with another box or pack for the preparations.
The cigars or cigarettes and the preparations may be in the same or
separate pack or box. The two packs or boxes may be separate or
connected. Preferably, the kit comprises essentially the same or
higher number of preparations as cigars or cigarettes.
[0090] According to another preferred embodiment of the invention
the preparation may be attached to a tobacco product, such as a
cigar, cigarette, holder or pipe. The preparation may be in any
suitable form, such as chewing or sucking tablet, buccal tablet,
sublingual tablet, candy, pastille, lozenge, chewing gum or gel.
The preparation may be of any suitable shape, such as circular,
oval, convex, nail-like, cylinder-like, ring-like or
rectangular.
[0091] According to one further preferred embodiment of the
invention the preparation may be attached to a cigar, cigarette,
holder or pipe in a detachable way. A person starting smoking may
detach the preparation from the tobacco product by hands, by teeth
or by some other way and chew, suck or keep the preparation in
mouth, for example under the tongue or between the cheek and the
gum thereby keeping the preparation in contact with saliva.
[0092] If the preparation is kept attached to the tobacco product
during smoking, the preparation is preferably attached to that part
of a cigar or cigarette (with or without a filter), holder or pipe,
which is put to the mouth during smoking. This is because the
preparation should come into contact with saliva during smoking.
The preparation is preferably attached to the surface and near the
tip or at the tip of a cigar, cigarette, pipe or holder. The
preparation should also release the aldehyde-binding substances
easily to saliva. The diameter of the preparation may be about the
same as the diameter of a cigar or cigarette, about 3 to 10 mm,
preferably about 3 to 8 mm. The preparation may be attached to the
tip or near the tip of a cigar, cigarette, holder or pipe by a
non-toxic adhesive-like material or by using a tape-like system.
Adhesive-like materials suitable for foodstuff use are known to a
person skilled in the art. Such materials are for example
starch-based, sugar-based or protein-based adhesive-like
materials.
[0093] According to one preferred embodiment of the invention the
preparation may be attached to the tobacco product mechanically,
for example by pressing it to the surface of the tobacco product.
The preparation may comprise a projection with which the
preparation is kept attached to the tobacco product, in particular
to a cigar or cigarette. Alternatively the shape and size of the
preparation may be suitable in order to keep it attached to the
tobacco product, for example ring-formed or half-ring-formed.
[0094] According to another preferred embodiment of the invention
the preparation may be kept attached to the cigar, cigarette,
holder or pipe by using an arrangement for keeping the preparation
in contact with the tobacco product, filter or holder. The
arrangement may be a vehicle holding or carrying the preparation.
The arrangement may, for example, be a cylinder-formed part, which
lengthens the tobacco product by about 1 to 5 mm. It may carry the
preparation in such a way that the preparation becomes in contact
with saliva when the tobacco product is put into mouth during
smoking allowing at the same time the smoke go through the
arrangement. The arrangement may be some inert material, such as
plastic. The preparation and the arrangement may be attached to the
tobacco products by the manufacturer of the tobacco products or by
the smoker.
[0095] According to one further preferred embodiment of the
invention a composition comprising aldehyde binding substance(s)
may be impregnated to that part of a cigar or cigarette (with or
without filter), which is put to mouth when smoking. The
composition may be impregnated also to a holder for cigarette or
cigar. The composition may be impregnated also to a separate
filter, which may be put in front of the tobacco product optionally
with a holder. According to preferred embodiments of the invention
the composition is impregnated and/or concentrated and/or dried to
the surface of a cigar, cigarette, filter or to the surface of a
holder, which is used when smoking. The composition may, for
example, be impregnated directly to the surface of a cigar,
cigarette or holder or into a suitable material, such as cellulose,
which is attached to the surface.
[0096] A composition comprising aldehyde-binding substance(s) and
concentrated and/or dried and/or impregnated to a tobacco product,
to a filter or to a holder, in particular to the surface of a
cigar, cigarette, filter or to the surface of a holder, may be used
as a solution or in solid form, for example as a powder optionally
with or without a carrier. The composition may comprise the same
components as the local preparation. It may comprise also a
diluent, which may be any suitable, volatile diluent, preferably
water, which is evaporated during the preparation procedure.
Administration of Aldehyde-Binding Compositions
[0097] The content of aldehyde formed in saliva as a consequence of
smoking can be decreased so that in connection with smoking, a
preparation, preferably one or two preparations at a time, is/are
placed in the mouth, under the tongue or in the cheek, or between
the cheek and gum for example, which at a suitable and preferably
at a constant rate release(s) cysteine (or an aldehyde-binding
agent having essentially the same effect as cysteine) continuously
and preferably until one tobacco product is used. When starting the
next tobacco product, a new aldehyde-binding preparation is placed
in the mouth. The aldehyde content of saliva decreases by over 20%,
preferably by over 40%, more preferably over 60%, typically by
60-80% compared to placebo. According to a preferred embodiment of
the invention the preparation is able to decrease aldehyde content
of saliva during the smoking of one cigar, cigarette or pipe to a
level aldehyde was before smoking.
[0098] The use of aldehyde-binding preparation is repeated as many
times as a new tobacco product is started. It is of advantage, if
the preparation is placed in the mouth already before starting a
new cigar, cigarette or pipe.
[0099] Preferably the amount of aldehyde-binding substance(s) in
one preparation should be essentially sufficient to bind aldehyde
in saliva to a level aldehyde was before smoking. If the
aldehyde-binding composition is attached to a tobacco product,
filter or holder, by an adhesive-type material, by an arrangement
or by any other way or by concentrating, drying or impregnating the
composition to the tobacco product, filter or holder, the amount of
the effective substance should essentially be sufficient to bind
aldehyde in saliva during the smoking of one tobacco product,
preferably the amount should be at least 2, preferably at least 5,
more preferably at least 10 times higher.
EXAMPLES
Example 1
[0100] A sucking tablet was prepared comprising: TABLE-US-00007
Cysteine 20 mg Mannitol (or equivalent sugar or sugar alcohol) 750
mg Flavouring agent q.s. Magnesium stearate 10 mg
[0101] The composition was prepared by mixing the powder mass and
compressing it into sucking tablets.
Example 2
[0102] Sucking tablets were prepared as in Example 1, but
comprising 1.25 mg, 2.5 mg, 5 mg and 10 mg cysteine.
Example 3
[0103] A chewing gum was prepared comprising: TABLE-US-00008
Cysteine 20 mg Pharmagum S, M or C 1000 mg Flavouring agent q.s.
Magnesium stearate 20 mg
[0104] The composition was prepared by mixing the powder mass and
compressing it into chewing gums. Another composition was prepared
comprising 500 mg Pharmagum S or M and 20 mg magnesium
stearate.
Example 4
[0105] A buccal tablet was prepared comprising: TABLE-US-00009
Cysteine 20 mg Methocel 25 mg Carbopol 7 mg Flavouring agent q.s.
Magnesium stearate 2 mg
[0106] The composition was prepared by mixing the powder mass and
compressing it into buccal tablets.
Example 5
[0107] A sublingual tablet was prepared comprising: TABLE-US-00010
Cysteine 10 mg Mannitol 250 mg Flavouring agent q.s. Magnesium
stearate 5 mg
[0108] The composition was prepared by mixing the powder mass and
compressing it into sublingual tablets.
Example 6
[0109] The preparation prepared in Example 1 was tested by two test
persons. The acetaldehyde content of saliva of the test persons was
measured before smoking and then after each 5 min during smoking,
i.e. 0 min, 5 min, 10 min and 15 min after the test persons had
started smoking. Both of the test persons smoked one cigarette at
the same time collecting saliva to their mouth and sucking a
placebo tablet. The smoking lasted 5 min. In the second test the
test persons repeated the study by sucking a tablet comprising 20
mg cysteine.
[0110] Before smoking the acetaldehyde content of saliva was very
low by both of the test persons. In the second test the
acetaldehyde content had decreased to a non-measurable level
already after first 5 minutes.
Example 7
[0111] Five smokers (age 29.+-.2.8) participated in the study, in
which three cigarettes were smoked (wash-out periods between).
During every cigarette smoking (in 5 min time) volunteers sucked
blinded tablets containing placebo, 1.25 mg, 2.5 mg, 5 mg, 10 mg or
20 mg L-cysteine. Acetaldehyde was analysed from salivary samples
gas chromatographically at 0, 5, 10, 20 min from the beginning of
smoking.
[0112] L-cysteine tablets (5 mg, 10 and 20 mg) totally eradicated
the tobacco-originated acetaldehyde from the saliva (see FIG. 4).
The mean salivary acetaldehyde concentrations immediately after
smoking were 191.2.+-.48.5 .mu.M, 0 .mu.M, 0 .mu.M, 0 .mu.M with
placebo, 5 mg, 10 mg and 20 mg L-cysteine tablets,
respectively.
[0113] The study shows that already 5 mg of L-cysteine administered
by melting-tablet totally inactivates carcinogenic acetaldehyde in
the saliva during smoking. 1.25 mg L-cysteine tablet lowers the
amount of acetaldehyde about to third compared to placebo.
Example 8
[0114] Sucking tablets, chewing gum, buccal tablet and sublingual
tablets are prepared comprising 5 mg L-cysteine.
Example 9
[0115] A cigarette (1) is prepared according to conventional
methods. The cigarette may comprise a filter (2) or it may be
without a filter. A cysteine comprising preparation (3) is prepared
as disclosed here earlier. The shape of the preparation may be any
suitable shape, such as circular, oval, convex, nail-formed,
ring-formed, cylinder or rectangular. The preparation (3) is
attached to the cigarette (1) by an adhesive-like material suitable
for human use. As shown in FIG. 5A the cysteine composition is in
the shape of a ball attached to that part of the cigarette, which
is put to the mouth when smoking, in FIG. 5 B is shown the
cigarette with the preparation as a cross-section. In FIG. 6A the
preparation (3) is at the tip of the cigarette (1) at that part of
the cigarette, which is put into mouth when smoking. FIG. 6B is a
cross-section of the same. In FIG. 7A the preparation (3) is
rectangular and it is bent around the tip of the cigarette at that
part of the cigarette (1), which is put to the mouth when smoking,
FIG. 7B is cross-section of the same. In FIG. 8 a cylinder (5) is
attached to the tip of the filter (2) of a cigarette (1). A
preparation (3) comprising cysteine is located inside the cylinder.
In FIG. 9 a holder (4) or the surface of a holder is impregnated by
cysteine (3). In FIG. 10 a holder (4) or the surface of a holder is
impregnated by cysteine comprising composition (3) and the shape of
the holder is suitable for holding in particular a cigar. In FIG.
11 the filter (2) or the surface of a filter of the cigarette (1)
is impregnated by cysteine (3).
* * * * *