JP2008515859A - Methods and formulations for binding aldehydes in saliva - Google Patents

Abstract

  The object of the present invention is the use of one or more free sulfhydryls and compounds containing amino groups for the manufacture of compositions that locally bind aldehydes in saliva during smoking.

Description

  The present invention relates to a composition for locally binding aldehydes in saliva during smoking. The present invention also relates to methods, kits and tobacco products for reducing the risk of developing cancers of the oral cavity and pharynx, larynx, esophagus and stomach.

  The main causes of cancer of the upper gastrointestinal tract are smoking and drinking. In the United States, it is estimated that 80% of these cancers can be avoided by stopping drinking and smoking. Both drinking and tobacco have been shown to be independent risk factors for upper gastrointestinal cancer. In addition, several epidemiological studies have confirmed that alcohol and tobacco correlate synergistically with cancer risk.

  Acetaldehyde has been shown to be very toxic and mutagenic under various experimental conditions. Epidemiological and biochemical experiments in high-drinking Asians with aldehyde dehydrogenase-2 (ALDH2) deficiency strongly suggest that acetaldehyde is a localized and local carcinogen in humans. This deletion results in the accumulation of aldehydes in saliva and also leads to a significantly increased risk of upper GI tract cancer.

  We show that the average in vivo concentration of salivary acetaldehyde in smokers is about twice that of nonsmokers after ethanol intake through a 160-minute follow-up period, even without smoking (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 saliva acetaldehyde for smokers was significantly higher than that of non-smokers, 114.8 ± 11.5 μM × hour vs. 54.2 ± 8.7 μM × hour (p = 0.002). ).

  During cigarette smoking, in vivo salivary acetaldehyde increased 10-fold from the level of ethanol alone intake. Salivary acetaldehyde increased immediately after starting smoking, but also decreased rapidly when smoking was stopped (FIG. 2). The area under the curve of salivary acetaldehyde for smokers is 7 times higher than for non-smokers, and this difference is very significant, 369.5 ± 12.2 μM × hour vs. 54.2 ± 8.7 μM × hour respectively. (P = 0.001). The difference in acetaldehyde concentration was significant at all time points from 40 to 160 minutes (p ≦ 0.05).

  During active smoking, salivary acetaldehyde increased by 261.4 ± 45.5 μM from the basal level. Salivary acetaldehyde increased immediately after starting smoking, but also decreased rapidly when smoking was stopped (Figure 3).

  The patent literature suggests that oral licking or chewing formulations are used to reduce the effects of harmful free radical compounds formed in connection with the use of or exposure to tobacco products Yes. For example, Hersch, US Pat. No. 5,922,346 and Hersch, WO 1999/000106 suggest formulations containing L-glutathione, selenomethionine, vitamin C, vitamin E, vitamin A and L-cysteine. L-glutathione was thought to be used to protect cells against oxidative stress by oxidizing themselves. Therefore, the combination of L-glutathione function and other enzyme systems is to be reduced. L-cysteine delivery agents increase endothelial cell reduced glutathione levels and protect cells from damage by endogenous hydrogen peroxide. This patent publication suggests formulations in the form of chewable gums, tablets, lozenges or gels.

  WO 02/36098 suggests the use of free sulfhydryls and / or amino groups to bind acetaldehyde locally for long periods in saliva, stomach or large intestine. This compound was mixed with a substance capable of releasing an acetaldehyde-binding substance for at least 30 minutes under conditions of the oral cavity, stomach or large intestine. The purpose was to bind the increased acetaldehyde that occurs in association with alcoholic beverage consumption or smoking.

  We suggest the use of the composition to reduce the blood concentration of acetaldehyde to prevent and treat hangover symptoms and to prevent and treat liver damage associated with acetaldehyde. For example, US 5,202,354 describes a composition comprising an acetaldehyde-binding substance such as L-cysteine, ascorbic acid or a salt thereof, a disulfide-type thiamine derivative, or a salt thereof, and a bile elimination promoter. US 4,528,295 describes a composition comprising methionine, vitamin B6 and potassium citrate.

  Some patent publications suggest the addition of compounds capable of binding harmful substances from tobacco smoke during smoking to cigarette filters. For example, US Pat. No. 5,829,449 suggests a composition for inclusion in a cigarette, cigar or pipe. This patent publication can include the composition in the tobacco itself, in a filter for filtering tobacco smoke after igniting, or in the paper or leaf wrapped around the tobacco product. It could be said that this composition can reduce free radical damage to the oropharyngeal cavity, respiratory organs and lungs caused by tobacco smoke. The composition comprises L-glutathione and a selenium source such as L-selenomethionine or L-selenocysteine. The composition may also include L-cysteine and N-acetyl-1-cysteine.

  U.S. Pat. No. 4,532,947 suggests a filter for use in connection with cigarette cigarettes containing a non-toxic salt of 2-mercapto-alkalene sulfonate and / or cysteine and acetylcysteine. These compositions were added to cigarette filters or cigarette holders containing filters for the purpose of reducing toxic tobacco materials in situ while smoking cigarettes.

  It is an object of the present invention to provide methods and compositions for removal or reduction of aldehyde content in saliva during smoking. The compositions and methods of the present invention are very useful for locally binding the increased amount of aldehyde that occurs in connection with smoking.

  The present invention is based on the surprising discovery that dangerous amounts of aldehydes that occur locally in smoking saliva can be bound locally and rapidly in a chemically stable form by the use of the formulations of the present invention. Based. The substances that bind aldehydes are released in saliva at a sufficiently high concentration throughout the period in which the aldehydes are affected, so the local concentration of aldehydes in saliva remains low. In this way, the local risk of developing cancer caused by aldehydes is reduced.

  Aldehydes present in tobacco smoke, especially acetaldehyde, dissolve very quickly in saliva. It would be advantageous if the aldehyde could reduce the concentration of aldehydes dissolved in saliva or completely remove aldehydes from saliva before damaging oral, upper respiratory or gastric mucosal cells is there. The formulations of the present invention bind aldehydes very efficiently in saliva and maintain aldehyde concentrations at very low or non-smoking status levels. The prior literature does not suggest a formulation or method that keeps the aldehyde concentration in saliva essentially low or prevents the increase in aldehyde concentration during smoking.

  According to the present invention, compounds containing one or more free sulfhydryls and / or amino groups are used to produce compositions that are used to locally bind aldehydes in saliva.

  More specifically, the use of the invention is characterized by what is stated in claim 1.

  According to the present invention, the composition comprises one or more substances that bind aldehydes, optionally mixed with a carrier suitable for human consumption (licking and / or chewing and / or holding) in the oral cavity. The material included in the composition is selected such that the material can bind aldehydes and is released within a short time.

  The present invention also provides a method according to claim 10 for reducing the action of aldehydes that cause cancer in the human oral cavity, pharynx, larynx, esophagus and stomach.

  By this method, aldehydes contained in saliva are locally bound into a safe form by use of a composition that releases one or more aldehyde-binding substances.

  Furthermore, the present invention provides a composition according to claim 19, a kit according to claim 28 and a tobacco product according to claim 30.

  US 5,829,449 and US 4,532,947 disclose tobacco products and filters that contain compounds capable of binding harmful substances from tobacco smoke. However, it has been found that such filters cannot bind acetaldehyde because the filter is too dry for the reaction to occur. Acetaldehyde-binding substances in tobacco product filters do not solve the problem of reducing or removing acetaldehyde or other aldehydes in saliva during smoking. The filters and other tobacco products disclosed in US Pat. No. 5,829,449 and US Pat. No. 4,532,947 are aimed at binding harmful substances from tobacco smoke rather than from saliva. For example, for the prevention and elimination of free radical damage induced by products that act systemically through blood circulation as described in US 4,528,295 and US 5,202,354 or as described in US 5,922,346 Nor the acetaldehyde-binding substance releasing product described in WO0236098 does not solve the problem.

  To date, no methods or formulations have been presented to locally reduce the acetaldehyde content of saliva during smoking. The preparations described in the prior art aim at systemic reduction of the blood acetaldehyde concentration, and the claimed effect is based on the reaction of the active substance with blood and / or intracellular acetaldehyde. For example, formulations aimed at preventing free radical damage as described in US 5,922,346 function locally and systemically via buccal mucosal absorption or via swallowing. Since the formulation contains only a small amount of acetaldehyde-binding substance, which is further involved in other chemical reactions, the local effect of acetaldehyde binding of the formulation in the oral cavity is not effective. The formulation is also suggested to be used as a daily dose, eg in the morning and evening, and is not specifically associated with smoking. Formulations that alter / increase intracellular protection mechanisms against acetaldehyde toxicity, eg, by low-dose cysteine, protect the upper gastrointestinal mucosa from high acetaldehyde exposure during active smoking (or directly bind acetaldehyde) Is not enough.

  The present invention provides considerable advantages. The present composition comprising a substance capable of binding aldehyde (s) can be used to reduce the risk of developing oral cancer. In particular, the composition of the present invention can be used for heavy smokers. The average amount of saliva secreted by humans is 1.5 liters per day. Areas affected by aldehyde (s) contained in saliva include the oral cavity, pharynx, esophagus, and stomach. The compositions of the present invention can reduce the risk of developing cancer in all of these areas.

  An advantage of aldehyde-binding substances, such as cysteine, is that the binding of harmful aldehydes is not limited to aldehydes but can be combined with other harmful and toxic compounds of tobacco smoke dissolved in saliva.

  In the following, the present invention will be considered in more detail with the help of a detailed description and examples.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows in vivo salivary acetaldehyde after ingestion of ethanol in smokers (no simultaneous smoking) and non-smokers.
FIG. 2 shows in vivo salivary acetaldehyde after ingestion of ethanol in smokers (with simultaneous smoking) and non-smokers. The difference in acetaldehyde concentration is significant at all time points between 40 and 160 (p ≦ 0.05).
FIG. 3 shows the smoker's salivary acetaldehyde after smoking a cigarette (no simultaneous drinking).
FIG. 4 shows salivary acetaldehyde after 5 minutes smoking with placebo and 1.25 mg, 2.5 mg, 5 mg or 10 mg cysteine tablets.
Figures 5, 6 and 7 show various ways of attaching the formulation to a cigarette or cigar.
FIG. 8 shows a holder that maintains contact with the saliva of the formulation during smoking through which tobacco smoke is inhaled.
Figures 9 and 10 show impregnation of an aldehyde-binding substance on the holder or holder surface.
FIG. 11 shows the impregnation of an aldehyde-binding substance on a cigarette filter or filter surface.

DETAILED DESCRIPTION OF THE INVENTION “Aldehyde-binding substance” means a compound containing one or more free sulfhydryl groups and / or one or more amino groups. Preferred compounds according to the present disclosure have one or more free sulfhydryl groups and one or more amino groups. Amino group means an _-NH 2, -N, -NH- and _NH ^{3 +} groups.

“Aldehydes” include C ₁ -C ₄ aldehydes that may contain double bonds in the hydrocarbon chain. Examples of these aldehydes include formaldehyde, acetaldehyde, crotonaldehyde and acrolein, with acetaldehyde being particularly important.

Although we are with particular reference to acetaldehyde in the following description, other C ₁ -C ₄ aldehydes also, mutatis mutandis, it is to be understood to be taken into account.

  “Aldehyde-binding substance” also means a compound that converts to an aldehyde-binding substance in the oral cavity. Such compounds are for example methionine and cystine.

  “Acetaldehyde binding” means a chemical reaction between acetaldehyde and a compound having a free sulfhydryl and an amino group, where acetaldehyde together with “acetaldehyde-binding substance” forms a macromolecule, and Water can be formed during the reaction. For example, when reacting with cysteine, acetaldehyde itself binds to both sulfhydryl and amino groups to form 2-methyl-L-thiazolidine-4-carboxylic acid and water. Acetaldehyde can itself bind to the amino group of almost any protein, thereby forming a Schiff base or a 2-methyl-imidazole ring.

  Preferred compounds according to the present disclosure are cysteine, its derivatives, compounds that convert to cysteine and other compounds that function in a similar manner. Suitable materials for use according to the present disclosure are in particular cysteines and N-acetyl-cysteines, preferably L- and D-cysteines.

  Preferred aldehyde-binding substances are those that are not inherently harmful to humans or that do not form harmful substances from aldehydes by chemical bonding. It is also advantageous if the compound has no unpleasant taste or odor.

〔式中、
Ｒ^１は水素または１−４個の炭素原子のアシル基であり、
Ｒ^２はスルフヒドリルまたはスルホン基であり、
ｎは１または２の整数である。〕
の化合物を含む。 Suitable compounds for binding aldehydes, particularly aldehydes in saliva, are also of the formula:

[Where,
R ¹ is hydrogen or an acyl group of 1-4 carbon atoms;
R ² is a sulfhydryl or sulfone group,
n is an integer of 1 or 2. ]
Of the compound.

  Advantageously, a Schiff base is formed in the reaction of an acetaldehyde-binding compound and acetaldehyde according to the present disclosure. The acetaldehyde-binding molecule should contain one or more free amino groups and one or more free-SH groups. -When the SH group is in the proper position on the molecule, it promotes the formation of a Schiff base and stabilizes the adduct formed.

Amino acids or other compounds that suitably bind aldehydes, particularly acetaldehyde, contain one or more free sulfhydryl (SH) groups and amino (—NH ₂ , —N, —NH— or NH ₃ ⁺ ) groups, and including:
L-cysteine,
D-cysteine,
Cystine,
Cysteic acid,
Cysteine-glycine,
Threo or erythro-β-phenyl-DL-cysteine,
β-tetramethylene-DL-cysteine,
Methionine,
D-penicillamine and its N-terminal dipeptide,
Semicarbazide,
Reduced glutathione,
β-mercaptoethylamine,
D, L-homocysteine,
N-acetylcysteine,
L-cysteinyl-L-valine,
β, β-tetramethylene-DL-cysteine,
Cysteinyl-glycine,
Mercaptoethylglycine,
Tre- (5) -β-phenyl-DL-cysteine,
Erythro-β-phenyl-DL-cysteine,
Thiamine hydrochloride,
Mercaptan.

  Some of the present acetaldehyde-binding substances or other aldehyde-binding substances can be improved by vitamins such as L-ascorbic acid.

  The aldehyde-binding compound of the present invention must be non-toxic. Compounds suitable for the formulations of the present invention should not be harmful to health in the amounts used in the present invention.

  It is also advantageous if the compound is free of an unpleasant or strong taste or odor. The unpleasant taste of the active compound can be masked by the use of suitable sweetening and flavoring agents, but the composition is kept simple by the use of a compound having a mild and / or pleasant taste and its manufacture Can be easily done. Another way to reduce the strong taste of the compounds is to use them in the smallest possible amount.

  Tobacco can be used by smoking, chewing and soaking and sniffing. According to our study, smoking, among other things, seems to result in the formation of acetaldehyde in the oral cavity. Smoking in connection with the present invention typically means the use of cigarettes or cigars or alternatively pipe smoking.

  “Acetaldehyde (or other aldehydes) short-term binding” means that acetaldehyde formed during smoking binds immediately, and the binding effect lasts for a length or several minutes of smoking a cigar or cigarette Means that. This binding effect preferably lasts at least 5 minutes, more preferably at least 10 minutes, most preferably at least 15 minutes.

  Cigarette smoking Cigarette smoking can last longer and therefore formulations that can bind acetaldehyde for more than 15 minutes are advantageous. However, this time is preferably less than 30 minutes. Alternatively, the cigar smoker may use more than one formulation during one cigar smoking.

  A formulation according to the present disclosure must be capable of releasing acetaldehyde (or other aldehydes) binding substance into saliva under conditions that diffuse into the oral cavity within 30 minutes and preferably within 15 minutes from when the formulation comes into contact with saliva. I must. The acetaldehyde-binding substance should therefore be released within 0-5 minutes, more preferably within 0-10 minutes, most preferably within 0-15 minutes from when the formulation comes into contact with saliva. The release of the acetaldehyde-binding substance preferably continues essentially for the time of smoking a cigar or cigarette, ie the actual smoking time and several minutes longer.

  The “harm / carcinogenic acetaldehyde content” of the human oral cavity, esophagus, stomach, and large intestine is about 20-800 μmol per liter of saliva, although it is difficult to define the content of acetaldehyde that would not be harmful. Such a content of harmful or carcinogenic acetaldehyde in the human oral cavity can be obtained, for example, in connection with smoking and / or drinking.

  Maintaining the acetaldehyde (or other aldehydes) content essentially lower than when the formulation of the present invention is not used is that the saliva acetaldehyde content is at least 20%, preferably at least 20% less than when the composition is not used. Meaning to maintain a level of 40%, more preferably at least 60%, and most preferably at least 80% lower.

  As used herein, “in connection with smoking” means the period from the start of smoking to the end of smoking, when smoking is stopped, and one or two minutes before and after the actual smoking.

  “Topical preparations to be placed in the oral cavity” are all preparations that can be swallowed or chewed in the oral cavity or placed between the cheek, lips or tongue and gums (gingiva), and the release of substances has a local effect in the oral cavity. Means all formulations intended to have. The preparation preferably has an action on the pharynx, esophagus or stomach.

  The term “composition” means here a composition comprising the active substance (s), optionally mixed with a suitable carrier. The composition may be in the form of a topical formulation suitable for use in the oral cavity.

  The topical formulations of the present invention may be selected from the group consisting of chewable tablets or electuary, buccal tablets, sublingual tablets, candy, pastilles, chewing gum, bubble gum, gels and lozenges.

  The compounds used in the formulation that bind aldehydes, particularly acetaldehyde, can be compounds containing one or more free sulfhydryls and amino groups.

  In addition to the acetaldehyde-binding, so-called active substance (s), the formulation preferably comprises at least one carrier substance that does not prevent or promote the release of the active substance. The preparation preferably has a form that promotes retention in the oral cavity during smoking. The formulation can be round or oval, convex, ring-shaped and is sufficiently small to have a form that does not interfere with or alter smoking behavior.

  The formulation may be placed in the oral cavity during smoking or may be attached to the tobacco product in any suitable manner. The formulation may remain attached to the tobacco product during smoking, or may be separated from the tobacco product and placed in the oral cavity at the beginning of smoking.

  The ability to keep the amount of active substance as small as possible is advantageous, if the taste of the substance is unpleasant, thereby eliminating or reducing the need to mask the taste. A human using the composition need not ingest the compound at too high a concentration. This preparation or cheap.

  The product according to the invention preferably comprises 1 to 300 mg of aldehyde-binding substance, in particular acetaldehyde-binding substance, more preferably the amount is 1 to 250 mg, even more preferably 1 to 200 mg, still more preferably 1 to 150 mg, Most preferred is 1 to 100 mg. Higher doses are particularly preferred when the goal is the combination of various aldehydes in addition to acetaldehyde. If the purpose is in particular acetaldehyde binding, the dose may be low.

  According to a preferred embodiment of the present invention, the formulation of the present invention is 1-50 mg, more preferably 5-30 mg, more preferably 5-10 mg, or even 1-5 mg, typically 10-20 mg, or 1-20 mg. Contains 15-20 mg of an aldehyde-binding substance, in particular an acetaldehyde-binding substance or substance.

  The amount of this substance is preferably higher if the formulation remains attached to the tobacco product during smoking compared to placing the formulation in the oral cavity at the start of smoking.

  Within the scope of the present invention are other formulations and compositions for use with tobacco products in addition to the above formulations and which can release aldehyde binding substances into saliva during smoking.

For example, the composition comprising the active substance (s) can be concentrated and / or dried and / or impregnated in tobacco products, filters or holders. The composition is preferably attached to the part of the tobacco product, filter or holder that is placed in the oral cavity when smoking. This is about 1 to 10 mm from the end of the tobacco product. Advantageously, the composition may be attached to a tobacco product, filter or holder. This means that the concentration of the aldehyde-binding substance (s) is preferably higher on the surface of the tobacco product compared to the inside of the tobacco product, filter or holder. The composition can be concentrated and / or dried and / or impregnated onto, for example, tobacco product paper, or a filter or holder surface. The tobacco product paper can be protected by a non-porous material so that the aldehyde binding material is not adsorbed into the paper and through the paper to the tobacco product or filter or holder. Alternatively, the composition can be impregnated into the surface area of tobacco products, filters or holders. This area may be 1 or 2 mm inside from the surface of the tobacco product, filter or holder.

  The impregnated filter can also be separated from the tobacco product, for example attached to the tobacco product or located in the holder of the tobacco product.

  The amount of aldehyde-binding substance is preferably higher for these applications than in formulations held in the oral cavity. The amount of aldehyde binding substance is greater than 5 mg, preferably greater than 10 mg, more preferably greater than 20 mg, most preferably greater than 30 mg, and even more preferably greater than 50 mg per tobacco product or filter or holder. Small amounts are preferred if the composition is concentrated and / or dried and / or impregnated only on the surface of the filter, tobacco product or holder.

In addition to the active substance (s), the composition may include:
1. Pharmaceutically acceptable diluents (bulking agents, fillers), 2. Sweetening agents such as sugars and sugar alcohols, 3. Flavoring agents, and 4. Lubricants / Glidants. The sugar can include, for example, sucrose, fructose or glucose or combinations thereof. The sugar alcohol may comprise mannitol, sorbitol, maltitol, lactitol, isomalt or xylitol or combinations thereof. Preferably none of these additives react with other ingredients in the formulation. A preferred sweetening agent is mannitol because it is not too sweet and its amount in the formulation is relatively high and therefore acts as a diluent at the same time.

  Flavoring agents may include, for example, spearmint, peppermint, menthol, citrus fruit, eucalyptus or anise fruit or combinations thereof.

  The formulation may also contain other ingredients such as halitosis masking agents, breath fresheners and / or caries prevention agents, or the formulation may contain vitamins. The formulation can also include a salivary secretion enhancer. However, these additional components should not prevent the rapid tail loss of aldehyde-binding substances into the saliva. As noted above, the formulation must efficiently release the aldehyde-binding substance so that a significant amount of aldehyde binds in saliva before the aldehyde affects mucosal cells in the oral cavity.

According to one preferred embodiment of the invention, the formulation (eg one tablet) comprises or consists essentially of:

The formulation can be a electuary comprising:

  The composition is produced by mixing the powder mass by a known method and compressing it into a lozenge.

  Increasing the amount of aldehyde-binding substance may require masking the taste of the aldehyde-binding substance, so increase the amount of diluent (s) / sweetening agent (s) and flavor. obtain.

According to another preferred embodiment of the invention, the formulation comprises or consists essentially of:

  The gum base may include a medicated chewing gum (Morjaria, Y. et al., Drug Delivery Systems & Sciences, vol. 4, no 1, 2004.) that includes natural or synthetic elastomers, plasticizers, waxes and lipids. Natural gum bases including chicle and smoked natural rubber have been approved by the FDA. However, modern gum bases are mostly synthetic and include styrene butadiene rubber, polyethylene and polyvinyl acetate. The gum base comprises 15 to 40% of the chewing gum. The rest consists of drugs, sugars, sweeteners, softeners, flavors and colorants. Most drug delivery systems utilizing chewing gum are manufactured using conventional methods. However, directly compressible powdered gum is a recent alternative to medicinal chewing gum. Pharmagum is a new gum system that is compactable. It is a mixture of polyol (s) and / or sugar and gum base. Formulations containing Pharmagums can be compressed into gum tablets using a conventional tablet press. This manufacturing process is fast and cheap. The amount of gum base including sweetener is 50-500 mg, preferably 500-1500 mg in the formulation.

  Pharmagum S contains gum base and sorbitol, Pharmamagum M contains gum base, mannitol and isomalt.

The formulation can be a chewing gum comprising:

  The composition is made by mixing a mass of powder and compressing it into a chewable tablet.

The formulation can be a buccal tablet comprising:

Non-ionized macromolecules include, for example, methyl cellulose (MC), hydroxypropyl cellulose (HPC), and hydroxypropyl-methyl cellulose (HPMC), and polyethylene glycol (PEG). Ionized polymers include, for example, sodium carboxy-methylcellulose (NaCMC), alginic acid, sodium alginate, chitosan, polycarbophil (Noveon ^™ ), and carbomer (Carbopol ^™ ).

The formulation can also be a sublingual tablet comprising or consisting essentially of:

  Diluents include, for example, lactose, calcium phosphate, starch, carboxymethylcellulose, hydroxymethylcellulose. The sweetening agent can be, for example, mannitol or xylitol.

According to one preferred embodiment of the present invention, the formulation of the present invention is provided in a kit comprising:
A plurality of cigarettes or cigarettes and a plurality of formulations comprising aldehyde-binding substance (s) in an amount capable of binding aldehydes in saliva during smoking to the level at which the aldehyde was essentially prior to smoking.

  Preferably, the formulation is capable of binding one, two or three cigarettes or aldehydes in saliva during cigar smoking.

  The kit may include a cigarette pack or box for cigars or cigarettes in conjunction with other boxes or packs for the formulation. The cigar or cigarette and the formulation can be in the same or different packs or boxes. The two packs or boxes may be separate or connected. Preferably, the kit comprises essentially the same or a greater number of formulations as cigars or cigarettes.

  According to another preferred embodiment of the invention, the formulation can be attached to tobacco products such as cigars, cigarettes, holders or pipes. The formulation can be in any suitable form such as chewable tablets or lozenges, buccal tablets, sublingual tablets, cantes, pastilles, lozenges, chewing gums or gels. The formulation can be any shape, circular, oval, convex, nail-shaped, cylindrical, annular or rectangular.

  According to one more preferred embodiment of the present invention, the formulation may be attached to the cigar, cigarette, holder or pipe in a separable manner. The person who started smoking should separate the preparation from tobacco products by hand, with teeth or in some other way, chew, lick or place the preparation in the mouth, for example under the tongue or between cheeks Maintain the gum thereby maintaining contact with the saliva of the formulation.

  If the formulation remains attached to the tobacco product during smoking, the formulation is preferably placed in the oral cavity during smoking, in a cigar or cigarette (with or without a filter), holder or pipe Put on the part. This is because the formulation must come into contact with saliva during smoking. The formulation is preferably attached to the surface of a cigar, cigarette, pipe or holder and near or at the tip. The formulation should also readily release aldehyde-binding substances into saliva. The diameter of the formulation can be about the same as that of a cigar or cigarette, about 3 to 10 mm, preferably about 3 to 8 mm. The formulation may be attached to or near the tip of a cigar, cigarette, holder or pipe by a non-toxic adhesive-like substance or by use of a tape-like system. Adhesive-like materials suitable for food use are known to those skilled in the art. Such materials are, for example, starch-based, sugar-based or protein-based adhesive-like materials.

  According to one preferred embodiment of the invention, the formulation may remain attached to the tobacco product mechanically, for example by pressing it against the tobacco product. The formulation may include protrusions that leave the formulation attached to tobacco products, particularly cigars or cigarettes. Alternatively, the shape and size of the formulation may be suitable to keep it attached to the tobacco product, for example a ring shape or a semi-ring shape.

  According to another preferred embodiment of the invention, the formulation may remain attached to a cigar, cigarette, holder or pipe by use of an arrangement to keep the formulation in contact with the tobacco product, filter or holder. The arrangement can be a medium that holds or carries the formulation. This arrangement can be, for example, a tube forming part that extends the tobacco product by about 1 to 5 mm. It carries the formulation in such a way that when the tobacco product is placed in the oral cavity during smoking, the formulation comes into contact with saliva while at the same time smoke exits through the arrangement. This arrangement can be some inert material such as plastic. The formulation and the arrangement can be attached to the tobacco product by the tobacco product manufacturer or smoker.

  According to one more preferred embodiment of the present invention, a composition comprising aldehyde-binding substance (s) is impregnated into a part placed in the oral cavity when smoking cigars or cigarettes (with or without filters) Can do. The composition may also be impregnated in a cigarette or cigar holder. The composition can also be impregnated into a separate filter, which can be placed at the tip of the tobacco product with a holder if desired. According to a preferred embodiment of the present invention, the composition may be impregnated and / or concentrated and / or dried on the surface of cigars, cigarettes, filters or holders used during smoking. The composition may be impregnated with a suitable material such as, for example, cellulose directly on or attached to the surface of a cigar, cigarette or holder.

  Compositions that contain aldehyde-binding substance (s) and are concentrated and / or dried and / or impregnated into tobacco products, filters or holders, especially cigars, cigarettes, filters or holder surfaces, are in solution or solid form For example, it can be used as a powder with or without a carrier, if desired. The composition may comprise the same ingredients as the topical formulation. It can also include a diluent, which can be any suitable volatile diluent that evaporates during the formulation, preferably water.

Administration of an aldehyde binding composition The amount of aldehyde formed in saliva as a result of smoking is related to smoking, preferably the formulation, preferably one or two formulations at the same time, eg in the oral cavity, sublingually. Or can be reduced by placing it on the cheek or between the cheek and gingiva, which suitably and preferably continuously cysteine (or an aldehyde-binding agent having essentially the same effect as cysteine) at a constant rate, And preferably releases until one tobacco product is used. When the next tobacco product is started, a new aldehyde-binding formulation is placed in the mouth. The aldehyde content of saliva is reduced by more than 20%, preferably more than 40%, more preferably more than 60% and typically 60-80% compared to placebo. According to a preferred embodiment of the present invention, the formulation can reduce the aldehyde content of saliva during smoking of a cigar, cigarette or pipe to the level that the aldehyde was before smoking.

  The use of an aldehyde binding formulation is repeated as many times as starting a new tobacco product. It is advantageous if the formulation is already placed in the oral cavity before starting a new cigar, cigarette or pipe.

  Preferably, the amount of aldehyde-binding substance (s) in a formulation should be essentially sufficient for the aldehyde in saliva to bind to the level at which the aldehyde was prior to smoking. The aldehyde-binding composition is attached to the tobacco product, filter or holder by an adhesive-type substance, by placement or in any other manner, or by concentration, drying or impregnation of the composition into a tobacco product, filter or holder If so, the concentration of active substance is essentially sufficient to bind saliva aldehydes during smoking of a single tobacco product, preferably this amount is at least 2, preferably at least 5 More preferably at least 10 times higher.

本組成物は粉末の塊を混合し、それを舐剤に圧縮することにより製造した。 Example 1
A lozenge containing the following was manufactured:

The composition was made by mixing a lump of powder and compressing it into a lozenge.

Example 2
The electuary was prepared as in Example 1 except that it contained 1.25 mg, 2.5 mg, 5 mg and 10 mg cysteine.

本組成物を、粉末の塊を混合し、それをチューインガムに圧縮することにより製造した。５００mg Pharmagum SまたはMおよび２０mg ステアリン酸マグネシウムを含む他の組成物を製造した。 Example 3
A chewing gum was made containing:

The composition was made by mixing a mass of powder and compressing it into chewing gum. Other compositions containing 500 mg Pharmagum S or M and 20 mg magnesium stearate were prepared.

本組成物を、粉末の塊を混合し、それをバッカル錠に圧縮することにより製造した。 Example 4
A buccal tablet was prepared containing:

The composition was made by mixing the powder mass and compressing it into buccal tablets.

本組成物を、粉末の塊を混合し、それを舌下錠に圧縮することにより製造した。 Example 5
A sublingual tablet was prepared containing:

The composition was made by mixing the powder mass and compressing it into sublingual tablets.

Example 6
The formulation produced in Example 1 was tested by two subjects. The acetaldehyde content of the subject's saliva was measured before smoking and every 5 minutes after smoking, that is, 0 minutes, 5 minutes, 10 minutes and 15 minutes after the subject started smoking. Both subjects smoked a cigarette at the same time, collected saliva in their mouths, and licked the placebo tablets. Smoking lasted 5 minutes. In the second study, subjects repeated the study by licking a tablet containing 20 mg cysteine.

  Prior to smoking, the acetaldehyde content of saliva was very low in both subjects. In the second test, the acetaldehyde content was reduced to an unmeasurable level already in the first 5 minutes.

Example 7
Five smokers (age 29 ± 2.8) participated in this study and smoked three cigarettes (during the washout period). During each cigarette smoking (5 minutes), the volunteer blindly licked a tablet containing placebo, 1.25 mg, 2.5 mg, 5 mg, 10 mg or 20 mg L-cysteine. Acetaldehyde was analyzed by gas chromatograph from saliva samples at 0, 5, 10, 20 minutes after the start of smoking.

  L-cysteine tablets (5 mg, 10 and 20 mg) completely removed tobacco-derived acetaldehyde from saliva (see FIG. 4). The average salivary acetaldehyde concentration immediately after smoking was 191.2 ± 48.5 μM, 0 μM, 0 μM, and 0 μM for placebo, 5 mg, 10 mg, and 20 mg L-cysteine tablets, respectively.

  This study shows that 5 mg of L-cysteine administered by melting tablets completely inactivates salivary carcinogenic acetaldehyde already smoked. The 1.25 mg L-cysteine tablet reduced the acetaldehyde content to 1/3 compared to placebo.

Example 8
Producing lozenges, chewing gum, buccal tablets and sublingual tablets containing 5 mg L-cysteine.

Example 9
A cigarette (1) is produced in a conventional manner. The cigarette may include a filter (2) or no filter. A cysteine-containing preparation (3) is prepared as described above. The form of the formulation can be any suitable form, such as round, oval, convex, nail-shaped, ring-shaped, tube or square. This formulation (3) is attached to the cigarette (1) with an adhesive-like substance suitable for human use. As shown in FIG. 5A, the cysteine composition is in the form of a ball and is attached to the portion of the cigarette that is placed in the oral cavity when smoking, and FIG. 5B shows the cigarette and the formulation as a cross-sectional view. In FIG. 6A, the formulation (3) is at the tip of the cigarette (1), and that portion of the cigarette is placed in the oral cavity when smoking. FIG. 6B is a cross-sectional view thereof. In FIG. 7A, the formulation (3) has a square shape, which is bent around the tip of the cigarette, and that portion of the cigarette (1) is placed in the oral cavity during smoking, and FIG. It is. In FIG. 8, a cylinder (5) is attached to the tip of the filter (2) of the cigarette (1). The preparation (3) containing cysteine is located in the cylinder. In FIG. 9, the holder (4) or the holder surface is impregnated with cysteine (3). In FIG. 10, the holder (4) or the holder surface is impregnated with a cysteine-containing composition (3) and the shape of the holder is suitable for having a suitable cigar. In FIG. 11, the filter (2) or filter surface of the cigarette (1) is impregnated with cysteine (3).

FIG. 1 shows in vivo salivary acetaldehyde after ingestion of ethanol in smokers (no concurrent smoking) and non-smokers. FIG. 2 shows in vivo salivary acetaldehyde after ingestion of ethanol in smokers (with simultaneous smoking) and non-smokers. The difference in acetaldehyde concentration is significant at all time points between 40 and 160 (p ≦ 0.05). FIG. 3 shows the smoker's salivary acetaldehyde after smoking a cigarette (no simultaneous drinking). FIG. 4 shows salivary acetaldehyde after 5 minutes smoking with placebo and 1.25 mg, 2.5 mg, 5 mg or 10 mg cysteine tablets. FIG. 5 shows various ways of attaching the formulation to a cigarette or cigar. FIG. 6 shows various ways of attaching the formulation to a cigarette or cigar. FIG. 7 shows various ways of attaching the formulation to a cigarette or cigar. FIG. 8 shows a holder that maintains contact with the saliva of the formulation during smoking through which tobacco smoke is inhaled. FIG. 9 shows impregnation of the aldehyde-binding substance on the holder or the holder surface. FIG. 10 shows impregnation of the aldehyde-binding substance on the holder or the holder surface. FIG. 11 shows the impregnation of an aldehyde-binding substance on a cigarette filter or filter surface.

Claims (40)

  Use of a compound capable of binding aldehydes and comprising one or more free sulfhydryls and amino groups for the manufacture of a formulation for locally binding aldehydes in saliva during smoking, said formulation Comprises an effective amount of the aldehyde-binding substance (s) and a non-toxic carrier, which allows the release of the aldehyde-binding substance (s) during smoking of a single tobacco product. Use.   Use according to claim 1, characterized in that the carrier allows the release of aldehyde-binding substances into saliva under conditions that diffuse in the oral cavity in less than 30 minutes. The formulation has the formula:

[Wherein R ¹ is hydrogen or an acyl group containing 1 to 4 carbon atoms;
R ² is a sulfhydryl group or sulfonic acid, and n is 1 or 2. ]
Use according to claim 1 or 2, characterized in that it comprises one or more compounds.   The formulation comprises L-cysteine, D-cysteine, cystine, cysteic acid, cysteine-glycine, threo- or erythro-β-phenyl-DL-cysteine, β-tetramethylene-DL-cysteine, methionine, D-penicillamine and its N-terminal dipeptide, semicarbazide, reduced glutathione, β-mercaptoethylamine, D, L-homocysteine, N-acetylcysteine, L-cysteinyl-L-valine, β, β-tetramethylene-DL-cysteine, cysteinyl-glycine One or more selected from the group consisting of: mercaptoethyl-glycine, tre- (5) -β-phenyl-DL-cysteine, erythro-β-phenyl-DL-cysteine, thiamine hydrochloride and mercaptan Characterized by containing substances Use as set forth in claim 1 in any one of 3.   Use according to any one of claims 1 to 4, characterized in that the formulation comprises an aldehyde-binding substance to which the aldehyde itself binds via both sulfhydryl and amino groups.   The aldehyde-binding substance is selected from the group consisting of L-cysteine, D-cysteine, a derivative of cysteine, and a substance that can be converted into cysteine, according to any one of claims 1 to 5. use.   7. Use according to any one of claims 1 to 6, characterized in that the aldehyde is acetaldehyde.   8. The carrier according to any one of the preceding claims, characterized in that the carrier comprises a substance selected from the group consisting of pharmaceutically acceptable diluents, sweeteners, flavoring agents and lubricants / glidents. Use according to 1.   9. The composition according to claim 1, wherein the composition is in the form of a formulation selected from chewable tablets, buccal tablets, sublingual tablets, candy, pastilles, lozenges, chewing gums or bubble gums and gels. Or use according to item 1.   A method of reducing the risk of cancer of the oral cavity and pharynx, larynx, esophagus and stomach, with an effective amount of aldehyde-binding substance (s) and aldehyde-binding substance (s) under conditions that diffuse into the saliva oral cavity. A method characterized in that the aldehyde in saliva is locally bound during smoking by use of a composition comprising a carrier that enables the release of   11. The composition of claim 10, wherein the composition reduces the amount of one aldehyde during cigar, cigarette or pipe smoking to substantially the level of aldehydes in saliva prior to smoking. The method described.   12. A method according to claim 10 or 11, characterized in that the carrier comprises a substance selected from the group consisting of pharmaceutically acceptable diluents, sweeteners, flavoring agents and lubricants / flow agents.   13. The composition according to any of claims 10 to 12, characterized in that the composition is in the form of a formulation selected from chewable tablets, buccal tablets, sublingual tablets, candy, pastilles, lozenges, chewing gums or bubble gums and gels. The method according to claim 1.   In connection with smoking, at least one formulation is placed in the oral cavity, the formulation essentially releasing the aldehyde-binding substance (s) into saliva when using one tobacco product The method according to any one of claims 10 to 13.   15. A method according to any one of claims 10 to 14, characterized in that the composition is attached to a tobacco product, filter or holder.   16. A method according to claim 15, characterized in that the composition is attached to the part of the tobacco product, filter or holder that is placed in the oral cavity when smoking.   17. The composition releases aldehyde-binding substance (s) into saliva when it comes into contact with saliva during smoking and uses essentially one tobacco product. The method described in 1.   18. A method according to any one of claims 15 to 17, characterized in that the composition is separable from tobacco products, filters or holders.   A composition comprising aldehyde-binding substance (s), wherein the composition is attached to a tobacco product, filter or holder for binding aldehydes in saliva during smoking ,Composition.   20. Composition according to claim 19, characterized in that it is attached to the part of the tobacco product, filter or holder that is placed in the oral cavity when smoking.   21. Composition according to claim 19 or 20, characterized in that the composition comprises a substance selected from the group consisting of pharmaceutically acceptable diluents, sweeteners, flavoring agents and lubricants / flow agents. .   22. A composition according to any one of claims 19 to 21, characterized in that the composition is in the form of a formulation selected from chewable tablets, buccal tablets, sublingual tablets, candy, pastilles, lozenges, chewing gums and gels. A composition according to 1.   23. Composition according to any one of claims 19 to 22, characterized in that the composition is attached to a tobacco product, filter or holder with or without the use of an adhesive-like substance. .   24. A composition according to any of claims 19 to 23, wherein the composition is attached using a structure for contacting the composition with a tobacco product, filter or holder.   25. A method according to any one of claims 19 to 24, wherein the composition is attached by impregnation and / or concentration and / or drying of the composition into a tobacco product, filter or holder.   26. The concentration according to any one of claims 19 to 25, wherein the concentration of the aldehyde binding substance (s) is higher on the surface of the tobacco product, filter or holder than inside the tobacco product, filter or holder. Composition.   27. A composition according to any one of claims 19 to 26, wherein the composition is attached to the surface of a tobacco product, filter or holder. -Multiple cigarettes or cigarettes, and-multiple formulations containing aldehyde-binding substance (s) in an amount capable of binding aldehydes in saliva during smoking to the level at which the aldehyde was essentially prior to smoking. Including kit.   30. The kit of claim 28, wherein the formulation is capable of binding aldehydes in saliva during smoking of one, two or three cigars or cigarettes. -A tobacco product, filter or holder; and-an amount of aldehyde attached to the tobacco product, filter or holder and capable of binding aldehydes in saliva during smoking to the level at which the aldehyde was essentially prior to smoking. Tobacco products, filters or holders comprising the composition comprising the substance (s).   31. Tobacco product according to claim 30, characterized in that the composition is attached to the part of the tobacco product, filter or holder that is placed in the oral cavity when smoking.   32. The tobacco product according to claim 30 or 31, wherein the composition comprises a substance selected from the group consisting of pharmaceutically acceptable diluents, sweeteners, flavoring agents and lubricants / flow agents.   33. A tobacco product according to any one of claims 30 to 32, wherein the composition is in the form of a formulation selected from chewable tablets, buccal tablets, sublingual tablets, candy, pastilles, lozenges, chewing gums and gels. .   34. A tobacco product according to any one of claims 30 to 33, wherein the composition is separable from a tobacco product, filter or holder.   35. A tobacco product according to any one of claims 30 to 34, wherein the composition is attached with or without an adhesive-like substance.   36. The tobacco product according to any one of claims 30 to 35, wherein the composition is attached using an arrangement for contacting the composition with a tobacco product, filter or holder.   37. A tobacco product according to any one of claims 30 to 36, wherein the composition is attached by impregnating and / or concentrating and / or drying the tobacco product, filter or holder of the composition.   38. The concentration of the aldehyde-binding substance (s) is higher on the surface of the tobacco product, filter or holder than on the interior of the tobacco product, filter or holder. Tobacco products.   39. A tobacco product according to any one of claims 30 to 38, wherein the composition is attached to the surface of a tobacco product, filter or holder.   40. The tobacco product according to any one of claims 30 to 39, wherein the tobacco product is a cigar, cigarette or pipe.

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