CN108969500A

CN108969500A - For combining the composition of the aldehyde in oral cavity

Info

Publication number: CN108969500A
Application number: CN201810750529.3A
Authority: CN
Inventors: O.苏奧瓦尼伊米; M.萨拉斯普罗
Original assignee: Biohit Oy
Current assignee: Biohit Oy
Priority date: 2013-02-01
Filing date: 2014-01-31
Publication date: 2018-12-11
Also published as: CN105307649A; EP2950794A4; MX2015009972A; EP2950794A1; FI20135097L; WO2014118438A1; EA201591203A1

Abstract

The present invention relates to the non-toxic composites of buccal tablet, sublingual tablets or lozenge form; it includes the combination of activating agent and xylitols; the activating agent includes one or more aldehyde bonded cysteine compounds; the cysteine compound is selected from L- and D-Cys, n-acetylcysteine and its pharmaceutically acceptable salt; the composition further includes one or more nontoxic additives and optional other additives, and the nontoxic additive includes one or more aromatic and one or more fillers or adhesive or both.

Description

For combining the composition of the aldehyde in oral cavity

The application be the applying date be on January 31st, 2014, it is entitled " to be used for application No. is 201480007086.9 In conjunction with the composition of the aldehyde in oral cavity " application for a patent for invention divisional application.

Technical field

The present invention relates to the composition for reducing risk of cancer in the oral cavity of object to be placed on, the composition contains at least It is formed in a kind of oral cavity for being intended for being incorporated in the object or the component of harmful aldehyde of aggregation and for reducing at least portion The active component for the microorganism for dividing ground that the aldehyde is caused to be formed.

Background technique

Since many kinds of substance enters body, the susceptible a large amount of adverse conditions in the oral cavity of people by respiratory tract and alimentary canal.Some Even deteriorated by the system of defense (such as by tooth microorganism) of body oneself.For example, saprodontia is a kind of relevant disease of diet, Its serious health problems for persistently becoming most industrial countries and developing country.

Research has confirmed that xylitol may be used as safe and efficient dental caries limitation substance.It is naturally occurring with low amounts Carbohydrate sample substance in almost all of plant and animal tissue.Xylitol molecules contain tridentate ligand (H-C- OH)₃, can be reacted with a variety of cationic (calcium ions in such as tooth mineral matter) and oxyacid, to form complex compound And chelate.In limitation dental caries, xylitol rots to work by the metabolism and thereby prophylaxis of teeth for inhibiting sugar.Therefore by it It mixes in chewing gum and tablet and in health care products (such as dentifrice and oral rinse), mainly as sweetener, That is sugar replacement.

But many harmful substances for terminating at oral cavity will also result in cancer.Alcohol and smoking are upper gastrointestinal cancers Risks and assumptions, and their use in conjunction can make occur upper gastrointestinal cancer risk be increased up to 150 times (Salaspuro, 2003；With Francheschi et al. 1990).

As confirmed in cell culture and zoopery, the first metabolin acetaldehyde of ethyl alcohol is highly toxic, cause Mutation and carcinogenic (IARC, 1999).In addition, epidemiology, science of heredity, microbiological and biochemical research it is strong Prompt strongly, acetaldehyde be in mankind's upper digestive tract part and accumulation procarcinogen (Salaspuro, 2009;Seitz and Stickel, 2010).As a result, international cancer research institution (International Agency for Research on Cancer, IARC) will be present in pick-me-up recently and the acetaldehyde that is endogenously formed from ethyl alcohol to be classified as the mankind carcinogenic Object (the 1st group) (Secretan et al. 2009).

As smoking and being exposed to the consequence of air pollution, acetaldehyde is also formed in oral cavity, pharynx and epithelium healing.Channel syndrome Real, the acetaldehyde that long-term smoking can dramatically increase the saliva originating from microorganism generates.In fact, it has been confirmed that, have with having cigarette smoking The risk of cancer of pass is not only caused by commonly known polycyclic aromatic hydrocarbon (PAH), and largely (for up to 40%) by second Aldehyde and formaldehyde cause, and methacrylaldehyde causes for up to 88.5% other poisonous effects.Thus, it is recommended that reducing in cigarette Aldehyde (Haussmann, 2012).

Such as aldehyde can be initially formed from alcohol by oral microorganism.These include oral bacteria and micro- life in the oral cavity Object, such as streptococcus (streptococci), lactobacillus (lactobacilli), Corynebacterium (corynebacteria), oral spirochete (oral spirochetes), anaerobic cocci (anaerobic cocci), and especially Be porphyromonas gingivalis (Porphyromonas gingivalis) and various Mycotoruloides (Candida) kind, including it is smooth Candida albicans (C. glabrata), Candida parapsilosis (C. parapsilosis), Candida tropicalis (C. tropicalis), Candida dubliniensis (C. dubliniensis), candida guilliermondi (C. guilliermondii), Candida albicans (C. albicans) and candida krusei (C. krusei) (in pharynx).Specifically, it has already been proven that belong to most crowds' Normal oral flora Streptococcus viridans (Streptococcus viridans), neisseria (Neisseria) group is carefully Bacterium and Mycotoruloides (Candida) plant and can generate a large amount of acetaldehyde from ethyl alcohol and the alcoholic fermentation passed through since glucose.

Our research has confirmed that all food (including beverage) containing sugared (sucrose, maltose, lactose) can contain (or being formed in food) a large amount of acetaldehyde (5-2000 μM) and ethyl alcohol (0.1-0.5/1000).Some Yoghourts, yogurt and fruit Juice contains so many acetaldehyde and ethyl alcohol (PCT/FI2006/000104).In addition, for example glucose can be by such as oral cavity Mycotoruloides kind is metabolized to pyruvic acid (salt), and is hereafter metabolized to acetaldehyde and ethyl alcohol.Fructose can similarly be metabolized to pyruvic acid (salt) or it is metabolized to glycerol.

Average magnitude by the saliva of people's secretion is daily 1.5 liters.The influence area of aldehyde contained in saliva include oral cavity, Pharynx, esophagus stomach function regulating.Therefore, the influence of these aldehyde can extend to entire upper digestive tract region.

The prior art includes such publication: it discloses the pharmaceutical composition of the compound containing binding acetaldehyde, it Effect be based on the acetaldehyde formed in active principle and blood flow and/or cell or the second for being carried into blood flow and/or cell The reaction of aldehyde, such as US 5 202 354, US 4 496 548, US 4 528 295, US 5 922 346.In addition, having mentioned Show using the preparation containing amino acid, be inhaled into oral cavity or chew in the oral cavity, is formed with reducing from such as smoke of tobacco Harmful free radicals compound influence.It is believed that amino acid will affect multiple tissues and and radical reaction after being absorbed (US 5,922,346, WO 99/00106).But these will not target the acetaldehyde in oral cavity.

WO 02/36098 prompted the compound containing free sulfhydryl groups and/or amino for part and it is long-term in conjunction with coming from The purposes of the acetaldehyde of saliva, stomach or large intestine.By the compound and can make they discharged under conditions of oral cavity, stomach or large intestine to Few 30 minutes material mixings.Similarly, WO 2006/037848 has been prompted for removing or reducing the saliva in smoking process In aldehyde, composition comprising one or more free sulfhydryl groups and/or amino.

Above-mentioned bibliography all without provide be in oral cavity influence for a long time it is specially designed containing cysteine Composition.In addition, their production aldehyde abilities all without targeting oral microorganism.

Summary of the invention

It is an object of the present invention to provide new compositions, it can be used for reducing the aldehyde in the oral cavity of object, and The aldehyde in stomach is also reduced indirectly.

Specifically, it is an object of the present invention to provide such Combination novas to be worked by least two different approaches Object, so that providing is reducing the synergistic effect in the aldehyde.

It is also another object of the present invention to provide new compositions, the aldehyde bonded compound in the composition is sheltered The taste of (one or more).

The present invention realize these and other objects and its better than known compositions and method the advantages of, such as below Described in and it is claimed as.

Therefore, it is an object of the invention to the composition comprising one or more aldehyde bonded compounds.

The present invention is based on following discoveries, and aldehyde (such as acetaldehyde) is formed in the oral cavity, such as the knot of microbial activity Fruit.Cysteine and its derivative covalently can combine these aldehyde and thereby inactivate their mutagenic and toxic property Matter, and xylitol can kill or at least inactivate oral microorganism, i.e., and such microorganism for causing acetaldehyde to generate.

According to the present invention, the composition includes the combination of reactive compound, and the reactive compound includes a kind of or more Kind of cysteine compound and xylitol are combined into pastille or buccal tablet or sublingual by means of at least one nontoxic additive Tablet.The additive (one or more) is specifically selected from such additive: under oral conditions, causing active ingredient Object from pastille or tablet sustained release into saliva in.

More accurately speaking, composition according to the present invention is characterized in that, described in the characteristic of claim 1 Content.

The present invention provides important advantages.The composition comprising aldehyde bonded cysteine compound can be used for The risk for developing carcinoma of mouth is reduced, and reduces the cancer for developing stomach, intestines and/or colon indirectly (because saliva can take aldehyde Band is to these regions) risk.

In addition, when they and feed are associatedly consumed, or when they are associatedly consumed with consumption alcohol, it is of the invention Composition is particularly effective and particularly useful for aldehyde bonded.

It is same for smoking or consuming the other way of tobacco, i.e., it when them and smokes or using tobacco When other way is associatedly consumed, composition of the invention is particularly effective and particularly useful for aldehyde bonded.

Specifically, the content of the aldehyde formed in the alcohol contained by the food or pick-me-up be it is maximum (it is i.e. most harmful and It is most carcinogenic) when, or when the harmful constituent of smoke of tobacco concentrates in saliva, composition of the invention can be released in the oral cavity Put aldehyde bonded compound.

Since aldehyde also partly causes tobacco addiction, it is associated with when by this composition with smoking or using the other way of tobacco When ground is applied, the present invention also will lead to the mitigation of the habituation.

Detailed description of the invention

Fig. 1 shows that the average acetaldehyde of the Mycotoruloides isolate in incubating generates (± SEM).

Fig. 2 show together with placebo and with contain 1.25 mg, 2.5 mg, 5 mg or 10 mg L-cysteines Suction tablet smoke together 5 min later saliva acetaldehyde (SEM).

Specific embodiment

The present invention relates to compositions, to be placed in the oral cavity of object, and (all in conjunction with the aldehyde in oral cavity containing being intended for Such as acetaldehyde, formaldehyde, methacrylaldehyde, propionic aldehyde and butyraldehyde) reactive compound (including one or more cysteine compounds) (tie Close the compound of aldehyde), and be intended for destroying and (killing) being present in the xylitol of at least some of oral cavity microorganism, and The combination of one or more harmless nontoxic additives for people (or animal) consumption.

The purpose of composition of the invention is the wind for reducing cancer or poisonous effect in the oral cavity and in the gastrointestinal tract Danger.

The composition is by making at least some aldehyde be combined into the cysteine compound (one or more) of harmless form And work, and xylitol kills at least some of oral cavity and is responsible for generating the microorganism of aldehyde.Thus, the effect is collaboration Because small amount of aldehyde will be generated, and realize effective combination of the small amount of aldehyde, so as to cause with use previous solution Significant more effective reduction of the content that certainly scheme reaches compared to the aldehyde in saliva.

In the light of recent researches, xylitol inhibit significantly at least Mycotoruloides from ethyl alcohol generate acetaldehyde.It can be by yield It is reduced to 40-100 μM of mutagenesis acetaldehyde level or less.In the presence of no xylitol, the average acetaldehyde in ethyl alcohol incubation is produced Life is high (> 200 μM).It has been confirmed that, xylitol can inhibit to produce the glycometabolism and thereby prophylaxis of teeth of sour oral bacteria in the past It rots.It needs 5-6 grams and exposure 3 times a day can be only achieved the effect.However, it has proven that the xylose determining alcohol of at least 65mM Also there is antimicrobial acivity to ear pathogenic bacteria.

A purpose using the additive (one or more) is so that reactive compound is combined into pastille, or combine At buccal tablet or sublingual tablets.Specifically, at least one additive is selected from can cause half Guang under conditions of oral cavity Propylhomoserin compound (one or more) is from pastille or tablet sustained release into the carrier or adhesive in saliva.

According to a preferred embodiment of the invention, at least one additive of composition is formed as into pastille or tablet On coating, the pastille or tablet contain the remaining ingredient of composition.Preferably, such coating is by least the one of xylitol At least part of any other aromatic of part or composition is formed.

Term " additive " includes carrier, filler and adhesive and aromatic, colorant and non-functional herein Additive.These additives are nontoxic, and the release for preferably controlling activating agent particularly occurs in the oral cavity, and most appropriate Ground is with continuous fashion.These preparations intention put in the oral cavity, such as between cheek or lip and gum or they be intended to sucked.

The composition includes a effective amount of above-mentioned cysteine compound (one or more).Herein, effective quantity is Refer to combine or inactivate the amount of a certain amount of aldehyde, a certain amount of aldehyde is in the digestion process of food or beverage or is consuming It carries later from food, beverage or tobacco to oral cavity or forms (such as by microbial activity therein) in the oral cavity.

In general, the single unit or preparation of the composition are comprising 1-30mg, preferably 1-20mg, more preferable 1-10mg and most Suitably 2-6mg cysteine (one or more).However, it is possible to 1-2 in these units of one-time use.

The content of cysteine compound (one or more) is then preferably the 1-50%, more preferable 5- of composition weight 40%, most suitably 20-30%.In general, the content is 20-25 weight %.

The cysteine compound is preferably chosen from L- and D-Cys, their derivative (such as N- acetyl group Cysteine) and their pharmaceutically acceptable salt.

The composition also includes a effective amount of above-mentioned xylitol.Herein, effective quantity is to refer at least cause oral cavity Production acetaldehyde bacterium measurable inactivation amount.

In general, the individual unit or preparation of the composition include 50-500mg, preferably 50-300mg, more preferable 100- 300mg and most suitably 200-300mg xylitol.But as set forth above, it is possible to 1-2 unit of one-time use.

The content of xylitol is then preferably the 10-90%, more preferable 10-60%, especially 20-60% of composition weight, most Suitably 40-60%.In general, the content is about 50%.

The final concentration of 110 mM xylitols is equal to the 17mg/mL being easy to get in the oral cavity.It can detecte in saliva Concentration higher than 30mg/mL, and have been found that the level keeps significant and increases, for up to 30 min.Thus, it is excellent according to the present invention The initial xylose determining alcohol for being to provide at least 17mg/ml of choosing (in saliva).

For example, L-cysteine is cysteine easy to oxidize, it cannot be effectively combined and inactivation is present in oral cavity In aldehyde, especially when being used alone in conventional immediate release dosage form.But the present invention provides a kind of dosage forms, i.e., Make also generate long term, and the xylose with composition in the case where not using the additive for extending active constituent release Alcohol provides synergistic effect together.

Composition is preferably configured to coating pastille, buccal tablet or sublingual tablets, and will be present in composition At least one aromatic (including xylitol) includes in the coating.An advantage using coating is that it will shelter cysteine The unpleasant taste of compound (one or more).

Since cysteine is easy to oxidize, it is contemplated that it will also be readily converted into the oral cavity pharmaceutically without Active cystine.When cysteine being added in pastille according to the present invention or buccal tablet or sublingual tablets, this is It is proved to occur.On the contrary, cysteine is held up in an active in the oral cavity to be reached when such as applying in the present invention 20 minutes.

Preferably, the additive used is selected from such additive: its release that can control activating agent, so that these are changed Object is closed in the time more than 1 minute, but usually less than 20 minutes, preferably 1-15 minute, most suitably at 5-10 points It is locally discharged in the oral cavity in clock.

According to a preferred embodiment of the invention, with feed associatedly (i.e. before it will feed, in feeding process In or after feed soon) or with consumption alcohol associatedly (i.e. before it will consume one alcohol, consuming one alcohol In the process or after consuming one alcohol) application composition.

Another preferred embodiment according to the present invention uses associatedly (i.e. shortly with smoking or the other of tobacco It will smoke before (or other uses of tobacco), during the smoking (or other uses of tobacco) or in smoking (or tobacco Other uses) after soon) application composition.

Term " i.e. will ... before " and refers to (or use tobacco in feed, consumption alcohol or smoking " soon later " Other way) before or after at most 5 minutes time ranges, preferably up to 2 minutes time ranges, more preferably up to 1 point The time range of clock, and most suitably at most 0.5 minute time range before or after feed, consumption alcohol or smoking.

But the composition can also use in a continuous manner, such as every 10 minutes.One according to the present invention preferably Embodiment, in 5-15 minutes sections, more new dosage was (if alcohol consumption or smoking continue preferably in 5-10 minutes sections If a section for being longer than the section).

" smoking " indicates the suction (using any other application of snuff, chewing tobacco or tobacco product) of any tobacco product, Wherein described tobacco product or part thereof is put in the oral cavity or is guided to oral cavity.Therefore, the tobacco product can be cigarette, Cigar, snuff, chewing tobacco or pipe tobacco.But the present invention is most suitable for associatedly using with using the tobacco product for generating flue gas.

After in placing it oral cavity in 5-10 minutes sections, the composition discharges the big of aldehyde bonded compound Part.

" combination of aldehyde " preferably indicates free sulfhydryl groups or the amino or both of aldehyde and cysteine (or similar compound) Between chemical reaction, wherein the aldehyde and " aldehyde bonded compound " are jointly formed biggish molecule.With cysteine In reaction, such as acetaldehyde mainly makes own be bound to the sulfydryl and amino of cysteine, and forms 2- methyl-L- thiazolidine- 4- formic acid (and water).

According to the present invention, it is for organism from the compound that aldehyde obtains and the chemical bonding with cysteine Safety.

But aldehyde (being in free form) is not harmless for object.Nocuousness/cause of the acetaldehyde in such as human mouth Cancer content is substantially 20-800 μm of ol/l saliva, and will cause the Cancer-causing mutation of cellular level down to about 20-50 μM of content.One As for, be considered mutagenic more than 40-100 μM of level.In addition, formaldehyde can cause certain carcinogenesis, and propylene Aldehyde will cause other poisonous effects.

By applying composition of the invention, the aldehyde in saliva can be made to be reduced to substantially below without using described Aldehyde, which means that the correspondence feelings than not using composition according to the present invention can be maintained at by level when composition Shape is low at least 20%, preferably it is low > 40% and most preferably low > 60% level.

By consumption alcoholic beverage (especially strong alcoholic beverage) or contain spirituous food, as the consequence of smoking, With when consuming product (such as food) containing aldehyde, can cause in human mouth and the esophagus in gastrointestinal tract, stomach or its Such harmful or carcinogenic aldehyde in its part.

The aldehyde can be formed from ethyl alcohol in the oral cavity, usually be formed by oral microorganism." oral microorganism " is intended to packet Include oral bacteria and microorganism in the oral cavity, such as streptococcus (streptococci), lactobacillus (lactobacilli), Corynebacterium (corynebacteria), oral spirochete (oral spirochetes), anaerobic cocci (anaerobic cocci), and especially porphyromonas gingivalis (Porphyromonas gingivalis) and various beads Pseudomonas (Candida) kind, including Candida glabrata (C. glabrata), Candida parapsilosis (C. parapsilosis), heat Band candida albicans (C. tropicalis), Candida dubliniensis (C. dubliniensis), candida guilliermondi (C. guilliermondii), Candida albicans (C. albicans) and candida krusei (C. krusei) (in pharynx).But It is that the aldehyde can also be formed in the beverage or in food or it can be added as former state in beverage or food.

" alcoholic beverage " is the beverage containing ethyl alcohol, their ethanol content becomes in 0.7 volume % between 84 volume % Change.

" alcohol food " indicates the food containing at least ethyl alcohol of 0.7 weight %.Such food can be, for example, fermentation Fruit juice or preserved fruit, or with a small amount of alcohol corrosion-resistant food, cake, jelly, and the mousse (mousse) seasoned with ligueur, Or corresponding alcoholic product.

" food containing aldehyde " indicates even before consumption containing the food of aldehyde.Acetaldehyde can be in the food from ethyl alcohol shape At the ethyl alcohol is associatedly generated with fermentation, such as in beer, applejack, grape wine, home brew and other alcoholic beverage And in many fruit juice.In certain food (such as certain dairy products), acetaldehyde is used for anti-corrosion purpose and tarts up, or Person as microbial activity result and form acetaldehyde in the product.For example, juice containing candy or containing confectionery generally can be described Microorganism provides suitable substrate.Also the acetaldehyde of high concentration can be formed in the dairy products (such as yogurt) of fermentation.In the feelings Under condition, the microorganism for being mainly used for preparing yogurt generates acetaldehyde.For alcoholic beverage, sherry and kappa degree this applejack (Calvados) also contain especially a large amount of acetaldehyde.

Even if when consuming low alcoholic beverage or food (i.e. only containing those of a small amount of alcohol (even < 0.7%)), root According to the beneficial using being also possible to of composition of the invention, because even these contents are also carcinogenic on long terms.

Additive (one or more) in the composition includes the combination of substance, and the substance can be especially as Carrier, filler, adhesive and other types of additive and work.

Such as aromatic (other than xylitol) may be used as additive, and can be selected from multiple kinds of carbohydrate, it is all Such as glucose, sorbierite, eucalyptol, thymol, sucrose, saccharin sodium, gaultherolin and menthol, it is preferably chosen from grape Sugar, sorbierite and sucrose.

The content of such aromatic in the composition is preferably 20-80 weight %, most suitably 20-45 weight Measure %.One unit dose usually contains 100-500 mg aromatic (other than xylitol), such as glucose, sorbierite And sucrose.

The use of one or more fillers is in the present invention preferred.These fillers can be selected from suitable for example Additive is not expanded such as compressed tablets.These especially include phosphate, hydrophosphate, cellulose and their derivative, with And fatty acid salt.Most suitably, calcium monohydrogen phosphate, microcrystalline cellulose or magnesium stearate (or two or more in these are selected Combination) in the composition be used as filler.

The ratio of filler (one or more) in the composition is preferably 5-80 weight %, more preferably 10- 50 weight %, most suitably 10-30 weight %.

In order to promote to keep composition in the oral cavity, it is preferred that include in the composition at least one adhesive or Adhesive is preferably chosen from polymer, such as cellulose derivative, chitosan, alginate, polyethylene glycol, carbomer or poly- Ka Bofei is most appropriately selected from the carbomer of hydroxypropyl methyl cellulose or its derivative or carbopol grade.

Such adhesive is potentially used in the coating on buccal tablet or sublingual tablets or on pastille, to promote unit dose Measure the adherency to oral mucosa.For this purpose, the polymer for forming gel in the condition in oral cavity is particularly preferred.It is such The polymer for forming gel includes above-mentioned adhesive.

The ratio of the optional adhesive of this in the composition is preferably 1-50 weight %, more preferably 5-40 weight % is measured, and is most suitably 10-30 weight %.

The additive (one or more) of composition according to the present invention can also include one or more hydrophobic compounds, It is preferably added in the coating on buccal tablet or sublingual tablets or pastille, to prevent or slow down and cysteine compound (one Kind or it is a variety of) contact water.

A particularly preferred embodiment according to the present invention, the composition by cysteine compound, xylitol, Aromatic and (one or more) compositions of optional adhesive (one or more) and filler.

Another particularly preferred embodiment according to the present invention, the composition include it is one or more selected from chromium, Vitamin A. D. E and C, niacin, biotin, thiamine, vitamin B2, B5, B6 and B12, folic acid and trace element are (all Such as chromium, manganese, selenium, zinc and iron) other additives, to add other health benefits.

In preparing coated tablet, it is preferred that the coated graininess of preparation coating blend contains cysteine Mixture, the coating blend include at least part and optional aromatic (one or more) of xylitol.In order to most The taste for effectively sheltering cysteine compound (one or more), by at least major part of aromatic (one or more) (> 50 weight %) is added in coating blend, such as 80-100 weight %.Most suitably, the xylitol of 50-100 weight % there is also In coating, usually 80-100 weight %.

Following non-limiting embodiments are merely intended to explain the advantages of obtaining using the present invention.

Embodiment

Embodiment 1

Select the laboratory of 7 Mycotoruloides kinds and be clinically separated object for studying, be Candida glabrata, Candida parapsilosis, Candida tropicalis, Candida dubliniensis, candida guilliermondi, candida krusei and Candida albicans.

These yeast separation objects (1 x 10 350 μ l being suspended in phosphate buffered saline (PBS) (PBS)⁷A bacterium colony is formed Unit) aliquot be transferred into gas chromatography phial.Hereafter, 50 μ l are added and contain ethyl alcohol (12 mM of final concentration) PBS buffer solution and 50 μ l contain the PBS buffer solution of glucose, fructose or xylitol (110 mM of final concentration), and seal pipe immediately Shape bottle.Sample is incubated 30 minutes at 37 DEG C, and passes through rubber septum injection 50 μ l, the 6 M perchloric acid (PCA) of phial to stop Only react.The acetaldehyde formed by gas chromatography measurement (referring to Fig. 1).

Xylitol (p < 0.0001) makes the amount of the acetaldehyde generated from ethyl alcohol reduce 84%.In the presence of no xylitol, Average acetaldehyde generation in ethyl alcohol incubation is 220.5 μM, and the average acetaldehyde generation in ethyl alcohol-xylitol incubates is 32.8 µM。

Incubating altogether together with glucose makes the amount of the acetaldehyde generated reduce 23%, and incubation makes to generate altogether together with fructose The amount of acetaldehyde reduce 29%.

Thus, glucose and fructose do not have significantly affecting as xylitol.In fact, taking in proprietary xylitol The concentration of the representative concentration found in the oral cavity in product process, the cause that discovery xylitol can be such that Mycotoruloides generates from ethyl alcohol Carcinous acetaldehyde is reduced to 40-100 μM of Mutagenicity or less.

Have found certain variation that the acetaldehyde between different Mycotoruloides kinds generates.It was found that Candida glabrata isolate is most The high producer, and candida krusei isolate is lowest manufactured person.Correspondingly, when together with 110mM ethyl alcohol altogether incubate 10 points Zhong Shi, xylitol makes alcohol dehydrogenase (ADH) activity of Candida glabrata isolate reduce by 61%, and makes Candida albicans isolate Alcohol dehydrogenase (ADH) activity reduce by 100%.When being incubated altogether together with 11 mM ethyl alcohol, in Candida glabrata isolate Reduction is 66%, and the reduction in Candida albicans isolate is 100%.

Embodiment 2

It is prepared for suction tablet, it includes:

20 mg of L-cysteine

Xylitol (or equivalent sugar or sugar alcohol) 750 mg

Appropriate flavoring agent

10 mg of magnesium stearate.

Prepare composition as follows: by the major part of cysteine and residual components (a part for reserving xylitol does not use) It is mixed into powdered piece, and it is pressed into suction tablet, it is coated with the xylitol reserved.

Embodiment 3

Sublingual tablets is prepared, it includes:

10 mg of L-cysteine

250 mg of xylitol

Appropriate flavoring agent

5 mg of magnesium stearate.

Prepare composition as follows: by the major part of cysteine and residual components (a part for reserving xylitol does not use) It is mixed into powdered piece, and it is pressed into sublingual tablets, it is coated with the xylitol reserved.

Embodiment 4

Two individuals test the preparation prepared according to embodiment 2.Before smoking, then 5 minutes in smoking process with Afterwards, that is, 0min, 5min, 10min and 15min after testee starts smoking, the saliva acetaldehyde for measuring testee contain Amount.Each testee aspirates cigarette, and at the same time, as they suck placebo tablet, receives from their oral cavity Collect saliva.It smokes and continues 5min.In another experiment, testee by suck the tablet containing 20 mg cysteines come It repeats to study.

Before smoking, the saliva acetaldehyde of each testee is low-down.In second test, acetaldehyde contains Amount has already decreased to immeasurablel level after 5 minutes at first.

Embodiment 5

5 smokers's (age 29 ± 2.8) participate in research, wherein 3 cigarettes of suction (between have removing phase).In suction every When cigarette (in 5 minutes), volunteer sucks the unwitting tablet for preparing according to embodiment 2, containing placebo, 1.25 mg, 2.5 mg, 5 mg, 10 mg or 20 mg L-cysteines.From start smoking count 0,5,10,20 minute after, Pass through the acetaldehyde in gas chromatography analysis saliva sample.

L-cysteine tablet (mg of 5 mg, 10 and 20) eliminates all acetaldehyde from tobacco (referring to figure from saliva 2).Average saliva acetaldehyde after smoking immediately is for placebo and 5 mg, 10 mg and 20 mg L-cysteine tablets For be 191.2 ± 48.5 μM, 0 μM, 0 μM, 0 μM respectively.

Studies have shown that can be in smoking process fully 5 mg L-cysteines are when with tablet delivery is melted Inactivate the acetaldehyde of the carcinogenicity in saliva.Compared with placebo, the L-cysteine tablet of 1.25 mg can be such that the amount of acetaldehyde reduces About 2/3.

Embodiment 6

It is prepared for pastille, it includes:

3 mg of L-cysteine (0.6%)

224 mg of sorbierite (44.8%)

250 mg of xylitol (50.0%)

12.5 mg (2.5%) of aromatic (flavoring agent) (one or more)

10 mg of magnesium stearate (2.0%)

0.5 mg of silica (0.1%).

It prepares composition as follows: being initially formed premix, L-cysteine, aromatic containing grinding form, two The sorbierite of silica and first part.Then, the first mixer is added in the remainder of sorbierite and xylitol In premix in (Muller mixer), hereafter magnesium stearate is added to the mixture to be formed (in high shear Collette Mixer) in.Then final mixture is transferred to final mixer (Muller mixer) to provide uniform mixing It is suppressed and is coated in final stage by object.

Document

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Claims

1. being in the non-toxic composite of buccal tablet, sublingual tablets or lozenge form, which is characterized in that it includes the group of activating agent It closes comprising

One or more aldehyde bonded cysteine compounds are selected from L- and D-Cys, n-acetylcysteine And its pharmaceutically acceptable salt, and

Xylitol,

And be characterized in that, it further includes one or more nontoxic additives and optional other additives, described nontoxic to add Adding agent includes one or more aromatic and one or more fillers or adhesive or both.

2. composition according to claim 1, for reducing the risk for the cancer for developing mouth area.

3. composition according to claim 1 or 2, the composition be intended in feeding process or after, in beverage wine During smart beverage or after or in smoking process be administered to object, to reduce the wind for the cancer for developing oral cavity or gastric area domain Danger.

4. composition described in any one of -3 according to claim 1, the composition includes per unit dose 1-30mg, excellent Selection of land 1-20 mg, more preferably 1-10 mg and the most suitably cysteine compound (one or more) of the amount of 2-6 mg.

5. composition described in any one of -4 according to claim 1, the composition include per unit dose 50-500mg, Preferably 50-300mg, more preferably 100-300mg and the most suitably xylitol of the amount of 200-300mg.

6. composition described in any one of -5 according to claim 1, the composition in 1-20 minutes, preferably in 1- Release of active compounds in 15 minutes, usually in 5-10 minutes.

7. composition described in any one of -6 according to claim 1, wherein the aromatic is selected from multiple kinds of carbohydrate, Such as glucose, sorbierite, eucalyptol, thymol, sucrose, saccharin sodium, gaultherolin and menthol, are preferably chosen from Portugal Grape sugar, sorbierite and sucrose.

8. composition described in any one of -7 according to claim 1, the composition has 20-80 weight %, preferably The fragrance level of 20-45 weight %.

9. composition described in any one of -8 according to claim 1, the composition further contains one or more fill out Agent is filled, phosphate, hydrophosphate, cellulose and their derivative and fatty acid salt is preferably chosen from, is most appropriately selected from Calcium monohydrogen phosphate, microcrystalline cellulose or magnesium stearate or the combination of two or more in these.

10. composition according to claim 9, wherein the ratio of the filler (one or more) in the composition is 5-80 weight %, preferably 10-50 weight %, most suitably 10-30 weight %.

11. composition described in any one of -10 according to claim 1, the composition further contains at least one viscous Mixture or adhesive are preferably chosen from polymer, such as cellulose derivative, chitosan, alginate, polyethylene glycol, card wave Nurse or polycarbophil are most appropriately selected from the carbomer of hydroxypropyl methyl cellulose or its derivative or carbopol grade.

12. composition according to claim 11, wherein the ratio of adhesive or adhesive in the composition is 1- 50 weight %, preferably 5-40 weight % and most suitably 10-30 weight %.

13. composition described in any one of -12 according to claim 1, the composition has been formulated into using coating The coated buccal tablet of mixture, sublingual tablets or pastille, the coating blend include at least part of xylitol and appoint The aromatic (one or more) of choosing.

14. composition described in any one of -13 according to claim 1, the composition has been formulated into using coating The coated graininess of mixture contains the mixture of cysteine, the coating blend include xylitol at least part and Optional aromatic (one or more).

15. composition described in 3 or 14 according to claim 1, wherein the xylitol of the 50-100 weight % using the composition Form the coating blend.