WO2014118438A1 - Composition for binding aldehydes in the mouth - Google Patents

Composition for binding aldehydes in the mouth Download PDF

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Publication number
WO2014118438A1
WO2014118438A1 PCT/FI2014/050076 FI2014050076W WO2014118438A1 WO 2014118438 A1 WO2014118438 A1 WO 2014118438A1 FI 2014050076 W FI2014050076 W FI 2014050076W WO 2014118438 A1 WO2014118438 A1 WO 2014118438A1
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Prior art keywords
composition according
composition
xylitol
cysteine
mouth
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PCT/FI2014/050076
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French (fr)
Inventor
Osmo Suovaniemi
Mikko Salaspuro
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Biohit Oyj
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Priority to EA201591203A priority Critical patent/EA201591203A1/en
Priority to MX2015009972A priority patent/MX2015009972A/en
Priority to EP14746925.8A priority patent/EP2950794A4/en
Priority to CN201480007086.9A priority patent/CN105307649A/en
Publication of WO2014118438A1 publication Critical patent/WO2014118438A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a composition that is to be placed in the mouth of a subject to decrease the risk of cancer, the composition containing at least one component that is intended for binding the harmful aldehydes that are formed or gathered in the mouth of said subject, as well as a component for decreasing the activity of the microbes at least partially responsible for said formation of aldehydes.
  • xylitol can be used as a safe and effective caries- limiting substance. It is a carbohydrate-like substance naturally occurring in low amounts in almost all plant and animal tissues.
  • the xylitol molecule contains a tridentate ligand (H-C-OH)3, which is capable of reacting with various cations (such as the calcium ion in tooth minerals) and oxyacids, thus forming complexes and chelates.
  • H-C-OH tridentate ligand
  • xylitol functions by inhibiting the metabolism of sugars and thus preventing tooth decay. It is therefore incorporated in chewing gums and tablets as well as in health care products such as dentifrice and oral rinses, mainly as a sweetener, i.e.
  • Acetaldehyde is also formed in the mouth, the pharynx, and the upper airways as a consequence of smoking, and exposure to air contamination. It has been proven that chronic smoking significantly increases the acetaldehyde production of saliva originated in microbes. In fact, it has been demonstrated that the cancer risk associated with cigarette smoking is not only caused by the commonly known polycyclic aromatic hydrocarbons (PAH), but to a significant degree (up to 40%) by acetaldehyde and formaldehyde, whereas acrylic aldehyde causes up to 88.5% of the other toxic effects. Thus, a lowering of the aldehyde-content in cigarettes has been recommended (Haussmann, 2012).
  • PAH polycyclic aromatic hydrocarbons
  • the aldehyde can be formed for example by oral microbes.
  • oral bacteria and microbes in the oral cavity such as streptococci, lactobacilli, corynebacteria, oral spirochetes, anaerobic cocci, and specifically Porphyromonas gingivalis, and various Candida species, including C. glabrata, C. parapsilosis, C. tropicalis, C. dubliniensis, C. guilliermondii, C. albicans, and C. krusei (in the pharynx).
  • glucose can be metabolized by e.g. Candida species in the mouth into pyruvate and thereafter into acetaldehyde and ethanol.
  • Fructose can similarly be metabolized into pyruvate or alternatively into glycerol.
  • the average amount of saliva secreted by a human is 1.5 litres per day.
  • the areas of influence of the aldehydes contained in the saliva include the mouth, the pharynx, the oesophagus and the stomach. Consequently, the effects of these aldehydes may extend to the whole upper digestive tract area.
  • the prior art includes publications that disclose pharmaceutical compositions containing compounds that bind acetaldehyde, their effect being based on the reaction of the effective substances with the acetaldehyde formed in or carried to the blood stream and/or the cells, for example US 5 202 354, US 4 496 548, US 4 528 295, US 5 922 346. Further, suggestions have been made to use preparations containing amino acids, which are sucked or chewed in the mouth, to reduce the effect of detrimental free radical compounds, which are formed for example from tobacco smoke. It is believed that, after being absorbed, the amino acids affect various tissues and react with the free radicals (US 5,922,346, WO 99/00106). However, these do not target the acetaldehyde in the mouth.
  • WO 02/36098 suggests the use of compounds containing a free sulfhydryl and/or amino group for a local and long-term binding of acetaldehyde from saliva, the stomach or the large intestine.
  • the compounds were mixed with a substance that enabled them to be released for at least 30 minutes in the conditions of the mouth, the stomach or the large intestine.
  • WO 2006/037848 suggests a composition comprising one or more free sulphhydryl and/or amino groups for removing or decreasing the aldehyde content of the saliva during smoking.
  • One object of the present invention is thus a composition, which comprises one or more aldehyde-binding compounds.
  • the composition comprises a combination of active compounds including one or more cysteine compounds, and xylitol, bound into a lozenge, or a buccal or sublingual tablet, with the help of at least one non-toxic additive.
  • the additive(s) are particularly selected from those that, in the conditions of the mouth, cause the sustained release of the active compounds from the lozenge or the tablet into the saliva.
  • composition according to the invention is characterized by that, which is stated in the characterizing part of claim 1.
  • the invention provides considerable advantages.
  • the compositions comprising the aldehyde-binding cysteine compounds can be used to reduce the risk of developing the cancer of the mouth, and indirectly of the stomach, the intestine and/or the colon due to the saliva being capable of carrying aldehyde to these areas.
  • compositions of the present invention are particularly effective and particularly useful for binding aldehyde when they are consumed in connection with eating, or when they are consumed in connection with consuming alcohol.
  • the compositions of the present invention are particularly effective and particularly useful for binding aldehyde when they are consumed in connection with smoking or other ways of using tobacco.
  • the composition of the invention is capable of releasing the aldehyde-binding compounds in the mouth during the time when the content of the aldehydes formed from the alcohol contained in foodstuff or alcohol-containing drinks is the largest, i.e. the most harmful and carcinogenic, or during the time when the harmful components of tobacco smoke are concentrated in the saliva. Since aldehydes are also partly responsible for tobacco addiction, the present invention will also result in a reduction of said addiction when the present compositions are administered in connection with smoking or other ways of using tobacco.
  • Figure 1 shows the mean acetaldehyde production ( ⁇ SEM) by Candida isolates in incubations.
  • FIG. 2 shows the salivary acetaldehyde (SEM) after 5 min of smoking with a placebo, and with sucking tablets containing 1.25 mg, 2.5 mg, 5 mg or 10 mg of L-cysteine.
  • SEM salivary acetaldehyde
  • the present invention concerns a composition that is to be placed in the mouth of a subject and contains a combination of active compounds including one or more cysteine compounds (i.e. aldehyde-binding compounds) that are intended for binding the aldehydes, such as the acetaldehyde, formaldehyde, acrylic aldehyde, propionaldehyde and butyraldehyde, in the mouth, and xylitol intended for destroying (i.e. killing) at least some of the microbes present in the mouth, as well as one or more non-toxic additives, which are harmless for human (or animal) consumption.
  • cysteine compounds i.e. aldehyde-binding compounds
  • composition of the invention is to decrease the risk for cancer or toxic effects in the mouth, and in the gastrointestinal tract.
  • composition functions by the cysteine compound(s) binding at least some of the aldehydes into a harmless form, whereas the xylitol kills at least some of the microbes in the mouth that are responsible for generating aldehydes.
  • the effect is synergistic, as a smaller amount of aldehydes will be produced, and an effective binding of said smaller amount of aldehydes is achieved, thus resulting in a considerably more efficient reduction of the aldehyde contents in the saliva compared to the contents achieved using prior solutions.
  • xylitol significantly inhibits at least candidal acetaldehyde production from ethanol. It reduces the production below the mutagenic acetaldehyde level of 40- ⁇ ⁇ . In the absence of xylitol, the mean acetaldehyde production in ethanol incubation is high (>200 ⁇ ). Xylitol has previously been shown to inhibit the metabolism of sugars by acidogenic oral bacteria and thus prevent tooth decay. Five to six grams and three daily exposures are required for this effect. However, a xylitol concentration of at least 65mM has been shown to also have antimicrobial activity against otopathogenic bacteria.
  • One objective of using said additive(s) is to bind the active compounds into a lozenge, or into a buccal or sublingual tablet.
  • at least one of the additives is selected from the carriers or binders capable of causing the sustained release of said cysteine compound(s) from the lozenge or the tablet into the saliva in the conditions of the mouth.
  • At least one of the additives of the composition is formed into a coating on the lozenge or the tablet containing the remaining constituents of the composition.
  • a coating is formed from at least a portion of the xylitol or at least a portion of any further aromatic agents of the composition.
  • additive here includes carriers, fillers and binders, as well as aromatic agents colorants and non- functional additives. These additives are non-toxic, and preferably control the release of the active agents to take place specifically in the mouth, and most suitably in a sustained manner. These formulations are intended to be placed in the mouth, for example between the cheek or the lip and the gum, or they are intended to be sucked.
  • the composition comprises an effective amount of the above mentioned cysteine compound(s).
  • an effective amount means an amount capable of binding or inactivating the amount of aldehyde carried to the mouth from foodstuff, drinks or tobacco, or formed in the mouth, for example by the microbial activity therein, during the digestion of foodstuff or drinks in connection with or after the consumption.
  • a single unit, or formulation, of the composition comprises l-30mg, preferably l-20mg, more preferably 1-1 Omg, and most suitably 2-6mg of the cysteine(s). However, 1-2 of these units can be administered at once.
  • the content of the cysteine compound(s) is then preferably 1-50%, more preferably 5- 40%), most suitably 20-30%), of the weight of the composition. Typically, the content is 20-25w-%.
  • the cysteine compounds are preferably selected from L- and D-cysteine, their derivatives, such as N-acetyl cysteine, as well as the pharmaceutically acceptable salts thereof.
  • the composition also comprises an effective amount of the above mentioned xylitol.
  • effective amount means an amount capable of at least causing a measurable inactivation of the acetaldehyde-producing bacteria of the mouth.
  • a single unit, or formulation, of the composition comprises 50-500mg, preferably 50-300mg, more preferably 100-300mg, and most suitably 200-300mg of xylitol.
  • 1-2 units can be administered at once.
  • the content of xylitol is then preferably 10-90%, more preferably 10-60%, particularly 20-60%), and most suitably 40-60%) of the weight of the composition. Typically, the content is about 50%>.
  • a final concentration of HOmM xylitol equals to 17mg mL readily available in the oral cavity. Concentrations higher than 30mg mL can be detected in saliva, and the levels have been found to remain significantly elevated for up to 30 rain. Thus, it is preferred according to the present invention to provide an initial xylitol concentration (in the saliva) of at least 17mg/rnl,
  • L-cysteine is an easily oxidized cysteine that is not able to effectively bind and inactivate the aldehyde present in the mouth, particularly when used alone in a conventional immediate-release dosage form.
  • the present invention provides a dosage form that gives a long-term effect even in cases, where additives prolonging the release of the active ingredient are not used, and provides a synergistic effect together with the xylitol of the composition.
  • composition is preferably formulated into coated lozenges, buccal tablets or sublingual tablets, and at least one of the aromatic agents present in the composition (including the xylitol) is included in the coating.
  • An advantage of using the coating is that it will mask the unpleasant taste of the cysteine compound(s).
  • cysteine Since cysteine is easily oxidized, it would be expected that it would also be easily transformed into the pharmaceutically inactive cystine in the mouth. This has been shown not to be true when adding the cysteine into a lozenge or a buccal or sublingual tablet according to the invention. On the contrary, the cysteine, when administered as in the present invention, remains in active form in the mouth for up to 20 minutes.
  • the used additives are selected from those capable of controlling the release of the active agents so that these compounds are released locally in the mouth during a time of more than one minute, but generally less than 20 minutes, preferably 1 - 15 minutes, most suitably in 5 - 10 minutes.
  • the composition is administered in connection with eating, i.e. just before, during or just after eating, or in connection with consuming alcohol, i.e. just before, during or after consuming a dose of alcohol.
  • the composition is administered in connection with smoking or other use of tobacco, i.e. just before, during or just after smoking (or other use of tobacco).
  • just before and “just after” mean a time frame of up to 5 minutes before or after eating, consuming alcohol or smoking (or otherwise using tobacco), preferably a time frame of up to 2 minutes, more preferably a time frame of up to 1 minute, and most suitably a time frame of up to 0.5 minutes before or after eating, consuming alcohol or smoking.
  • compositions can also be used in a continuous way, for example every 10 minutes.
  • the dosage is renewed at 5 to 15 minute intervals, preferably at 5 to 10-minute intervals, if alcohol consumption or smoking is continued for an interval longer than the said one.
  • “Smoking” refers to the smoking of any tobacco product, using snuff, chewing tobacco, or any other use of a tobacco product, wherein the tobacco product or a part thereof is placed in the mouth or is conducted to the mouth.
  • the tobacco product can thus be a cigarette, a cigar, snuff, chewing tobacco or pipe tobacco.
  • the invention is, however, most suitable for use in connection with using smoke-generating tobacco products.
  • the composition releases a major portion of the aldehyde-binding compound during an interval of 5-10 minutes after placing it in the mouth.
  • binding of aldehyde preferably refers to a chemical reaction between the aldehyde and the free sulphhydryl or amino group or both of the cysteine (or similar compound), wherein the aldehyde jointly with the "aldehyde-binding compound” forms a larger molecule.
  • acetaldehyde mainly binds itself to the sulphhydryl and the amino group of the cysteine, and forms 2-methyl-L-thiazolidine-4- carboxylic acid (and water).
  • the compounds obtained from aldehydes by chemical binding with cysteine are safe for the organism.
  • the aldehydes (in free form) are not harmless for the subject.
  • a harmful/carcinogenic content of acetaldehyde in e.g. the human mouth is roughly 20 to 800 ⁇ / ⁇ of saliva, and a content of as low as about 20 to 50 ⁇ causes carcinogenic mutations on the cell level. Generally levels of above 40 to ⁇ are considered mutagenic.
  • formaldehyde is responsible for some carcinogenic effect, while acrolein causes other toxic effects.
  • the aldehyde content in the saliva can be reduced to a level that is essentially lower than without the use of the composition, which means that the aldehyde content can be kept at a level that is at least 20% lower, preferably >40% lower, and most preferably >60% lower than in a corresponding situation without using the composition according to the invention.
  • Such a harmful or carcinogenic content of aldehyde in the human mouth, as well as in the oesophagus, stomach or other part of the gastrointestinal tract, can be caused by consuming alcoholic drinks, particularly strong alcoholic drinks, or foodstuffs containing alcohol, as a consequence of smoking, and when consuming products (e.g. foodstuffs) containing aldehyde.
  • the aldehyde can be formed from the ethanol in the mouth, generally by oral microbes.
  • oral microbes are intended to include oral bacteria and microbes in the oral cavity, such as streptococci, lactobacilli, corynebacteria, oral spirochetes, anaerobic cocci, and specifically Porphyromonas gingivalis, and various Candida species, including C. glabrata, C. parapsilosis, C. tropicalis, C. dubliniensis, C. guilliermondii, C. albicans, and C. krusei (in the pharynx).
  • the aldehyde can also be formed in the drink or in the foodstuff, or it can be added as such into the drink or the foodstuff.
  • Alcohol drinks are ethanol-containing drinks, their ethanol content varying within 0.7% by volume and 84% by volume.”
  • Alcohol foodstuffs refer to foodstuffs containing at least 0.7% by weight of ethanol. Such foodstuffs can be, for example, fermented juices or preserves, or foodstuffs preserved with small amounts of alcohol, pastries, jellies, and mousse seasoned with liqueur or corresponding products containing alcohol.
  • Aldehyde-containing foodstuffs refers to foodstuffs containing aldehyde even prior to consumption. Acetaldehyde can be formed in said foodstuffs from ethanol that is generated in connection with fermentation, such as in beer, cider, wine, home-brewed beer, and other alcoholic drinks, as well as in many juices. In certain foodstuffs, such as some dairy products, acetaldehyde is used for preservation purposes and to add flavour, or the acetaldehyde is formed in the product as a consequence of microbial activity. For example, sugary juices or sugar-containing foodstuffs, in general, provide a suitable substrate for said microbes.
  • acetaldehyde High concentrations of acetaldehyde are also formed in fermented dairy products, such as yoghurt. In that case, mainly the microbes used to make yoghurt produce the acetaldehyde. As for alcoholic drinks, sherry and Calvados contain also especially large amounts of acetaldehyde.
  • compositions according to the invention can be of benefit even, when light alcoholic drinks or foodstuffs are consumed, i.e. those containing only small amounts of alcohol (even ⁇ 0.7%), since even these contents are carcinogenic in the long run.
  • the additive(s) in the composition include a combination of substances, which can function specifically as carriers, fillers, binders and other types of additives.
  • aromatic agents in addition to the xylitol can be used as additives, and can be selected from various carbohydrates, such as glucose, sorbitol, eucalyptol, thymol, sucrose, sodium saccharine, methyl salicylate and menthol, preferably from glucose, sorbitol and sucrose.
  • carbohydrates such as glucose, sorbitol, eucalyptol, thymol, sucrose, sodium saccharine, methyl salicylate and menthol, preferably from glucose, sorbitol and sucrose.
  • the content of such aromatic agents in the composition is preferably 20 - 80 w-%, most suitably 20 - 45 w-%.
  • One unit dose generally contains 100 - 500 mg of aromatic agents (in addition to xylitol), such as glucose, sorbitol and sucrose.
  • filler(s) are preferred in the present invention.
  • these fillers can be selected from non-swelling additives that are suitable for example in pressing tablets. These include, among others, phosphates, hydrogen phosphates, celluloses and their derivatives, as well as salts of fatty acids. Most suitably, calcium hydrogen phosphate, microcrystalline cellulose or magnesium stearate (or a combination of two or more of these) is selected to be used in the composition as a filler.
  • the portion of the filler(s) in the composition is preferably 5-80w-%, more preferably 10- 50w-%, most suitably 10-30w-%.
  • At least one binder or adhesive agent in the composition preferably selected from polymers, such as cellulose derivatives, chitosanes, alginates, polyethylene glycols, carbomers or polycarbophils, most suitably selected from hydroxypropyl methyl cellulose or its derivative or a Carbopol grade of a carbomer.
  • polymers such as cellulose derivatives, chitosanes, alginates, polyethylene glycols, carbomers or polycarbophils, most suitably selected from hydroxypropyl methyl cellulose or its derivative or a Carbopol grade of a carbomer.
  • Such adhesive agents can possibly be used in coatings on the buccal or sublingual tablets or on lozenges, to facilitate the adhesion of the unit dose to the mucous membranes of the mouth.
  • a polymer that forms a gel in the conditions of the mouth is particularly preferred.
  • Such gel-forming polymers include the above mentioned binders.
  • the portion of this optional adhesive agent in the composition is preferably l-50w-%, more preferably 5-40w-% and most suitably 10-30w-%.
  • the additive(s) of the composition according to the invention can also include one or more hydrophobic compounds, preferably added to a coating on the buccal or sublingual tablets or on lozenges, to prevent or slow down water coming into contact with the cysteine compound(s).
  • the composition consists of a cysteine compound, xylitol, an aromatic agent, as well as optional binder(s) and filler(s).
  • the composition includes one or more further additive(s) selected from the group comprising chromium, vitamins A, D, E, and C, niacin, biotin, thiamine, vitamins B2, B5, B6, and B12, folic acid, as well as trace elements, such as chromium, manganese, selenium, zinc and iron, to add further health benefits.
  • further additive(s) selected from the group comprising chromium, vitamins A, D, E, and C, niacin, biotin, thiamine, vitamins B2, B5, B6, and B12, folic acid, as well as trace elements, such as chromium, manganese, selenium, zinc and iron, to add further health benefits.
  • a main part (>50% by weight) of the aromatic agent(s) will be added to the coating mixture, for example 80 to 100% by weight.
  • 50 to 100% by weight of the xylitol will also be present in the coating, typically 80 to 100% by weight.
  • Example 1 Laboratory and clinical isolates of seven Candida species were selected for the study, being C. glabrata, C. parapsilosis, C. tropicalis, C. dubliniensis, C. guiUiermondii, C. krusei, and C. albicans.
  • Xylitol (p ⁇ 0.0001) reduced the amount of acetaldehyde produced from ethanol by 84%. In the absence of xylitol, the mean acetaldehyde production in ethanol incubation was 220.5 ⁇ , and in ethanol- xylitol incubation 32.8 ⁇ .
  • xylitol reduced the alcohol dehydrogenase (ADH) activity of the C. glabrata isolate by 61 > and of the C. albicans isolate by 100%) when coincubated with 1 lOmM ethanol for 10 minutes.
  • ADH alcohol dehydrogenase
  • a sucking tablet comprising:
  • Xylitol (or an equivalent sugar or sugar alcohol) 750 mg
  • the composition was prepared by mixing the cysteine and most of the remaining ingredients (leaving a portion of the xylitol unused) into a powdery mass and compressing it into sucking tablets, which were coated with the remaining xylitol.
  • a sublingual tablet was prepared, comprising:
  • the composition was prepared by mixing the cysteine and most of the remaining ingredients (leaving a portion of the xylitol unused) into a powdery mass and compressing it into sublingual tablets, which were coated with the remaining xylitol.
  • Example 4 Two individuals tested the preparation prepared according to Example 2. The salivary acetaldehyde contents of the testees were measured before smoking and then after 5 minutes during smoking, i.e., Omin, 5min, lOmin, and 15min after the testees started smoking. Each testee smoked one cigarette and, at the same time, saliva was collected from their mouths, as they sucked placebo tablets. Smoking lasted for 5min. In another test, the testees repeated the study by sucking tablets containing 20 mg of cysteine.
  • Example 5 Five smokers (of the age of 29 ⁇ 2.8) participated in the study, in which three cigarettes were smoked (with cleaning periods in between). While smoking each cigarette (in 5 minutes time), the ceremoniies sucked tablets blindfold, containing a placebo, 1.25 mg, 2.5 mg, 5 mg, 10 mg or 20 mg of L-cysteine, prepared according to Example 2. The acetaldehyde in the saliva samples was analysed by gas chromatography after 0, 5, 10, 20 minutes from starting to smoke.
  • the L-cysteine tablets (5 mg, 10 and 20 mg) removed from the saliva all of the acetaldehyde originating from tobacco (see Fig. 2).
  • the average salivary acetaldehyde contents immediately after smoking were 191.2 ⁇ 48.5 ⁇ , 0 ⁇ , 0 ⁇ , 0 ⁇ with the placebo and the 5 mg, 10 mg, and 20 mg L-cysteine tablets, respectively.
  • the L- cysteine tablet of 1.25 mg reduced the amount of acetaldehyde by about two thirds compared with the placebo.
  • a lozenge was prepared, comprising:
  • Aromatic (flavouring) agent(s) 12.5 mg (2.5%) Magnesium stearate 10 mg (2.0%)
  • the composition was prepared by first forming a pre-mix containing the L-cysteine in ground form, the aromatic agents, the silicon dioxide and a first portion of the sorbitol. Subsequently, the remaining portion of the sorbitol as well as the xylitol are added to the pre-mix in a first mixer (a Muller mixer), whereafter the magnesium stearate is added to the formed mix (in a high shear Collette mixer). The final mix is then transferred to a final mixer (a Muller mixer) to provide a homogeneous mix, which is compressed and coated in a final stage.
  • a first mixer a Muller mixer
  • the magnesium stearate is added to the formed mix (in a high shear Collette mixer).
  • the final mix is then transferred to a final mixer (a Muller mixer) to provide a homogeneous mix, which is compressed and coated in a final stage.

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Abstract

The present invention concerns a non-toxic composition in the form of buccal tablets, sublingual tablets or lozenges, which comprises a combination of active agents including one or more aldehyde-binding cysteine compound(s) selected from the group of L-and D-cysteine, N-acetyl cysteine, and the pharmaceutically acceptable salts thereof,and xylitol, which composition further comprises one or more non-toxic additives that include one or more aromatic agents as well as one or more fillers or binders or both,and optional further additives.

Description

COMPOSITION FOR BINDING ALDEHYDES IN THE MOUTH
Field of the invention
The present invention relates to a composition that is to be placed in the mouth of a subject to decrease the risk of cancer, the composition containing at least one component that is intended for binding the harmful aldehydes that are formed or gathered in the mouth of said subject, as well as a component for decreasing the activity of the microbes at least partially responsible for said formation of aldehydes.
Description of related art Due to the large variety of substances entering the body through the respiratory tract and the digestive tract, the mouth of a human is susceptible to a large number of harmful conditions. Some are even worsened by the body's own defence system, such as by dental microbes. For example, dental caries is a diet-associated disease, which continues to be a serious health problem in most industrialized and developing countries.
Studies have shown that xylitol can be used as a safe and effective caries- limiting substance. It is a carbohydrate-like substance naturally occurring in low amounts in almost all plant and animal tissues. The xylitol molecule contains a tridentate ligand (H-C-OH)3, which is capable of reacting with various cations (such as the calcium ion in tooth minerals) and oxyacids, thus forming complexes and chelates. In limiting caries, xylitol functions by inhibiting the metabolism of sugars and thus preventing tooth decay. It is therefore incorporated in chewing gums and tablets as well as in health care products such as dentifrice and oral rinses, mainly as a sweetener, i.e. a sugar substitute. However, many of the harmful substances ending up in the mouth also cause cancer. Both alcohol and smoking are risk factors for upper digestive tract cancers, and the combined use thereof multiplies the risk of developing an upper digestive tract cancer to as much as 150-fold (Salaspuro, 2003; and Francheschi et al. 1990). The first metabolite of ethanol, acetaldehyde, is highly toxic, mutagenic, and carcinogenic, as shown in cell culture and animal experiments (IARC, 1999). Furthermore, epidemiological, genetic, microbiological and biochemical studies strongly suggest that acetaldehyde acts as a local and cumulative carcinogen in the upper digestive tract in humans (Salaspuro, 2009; Seitz and Stickel, 2010). Consequently, acetaldehyde present in alcoholic beverages and formed endogenously from ethanol was recently classified as carcinogenic to humans (group 1) by the International Agency for Research on Cancer (IARC) (Secretan et al. 2009).
Acetaldehyde is also formed in the mouth, the pharynx, and the upper airways as a consequence of smoking, and exposure to air contamination. It has been proven that chronic smoking significantly increases the acetaldehyde production of saliva originated in microbes. In fact, it has been demonstrated that the cancer risk associated with cigarette smoking is not only caused by the commonly known polycyclic aromatic hydrocarbons (PAH), but to a significant degree (up to 40%) by acetaldehyde and formaldehyde, whereas acrylic aldehyde causes up to 88.5% of the other toxic effects. Thus, a lowering of the aldehyde-content in cigarettes has been recommended (Haussmann, 2012). From alcohol, the aldehyde can be formed for example by oral microbes. These include oral bacteria and microbes in the oral cavity, such as streptococci, lactobacilli, corynebacteria, oral spirochetes, anaerobic cocci, and specifically Porphyromonas gingivalis, and various Candida species, including C. glabrata, C. parapsilosis, C. tropicalis, C. dubliniensis, C. guilliermondii, C. albicans, and C. krusei (in the pharynx). Particularly Streptococcus viridans, Neisseria group bacteria and Candida species belonging to the normal oral flora of the vast majority of the population have been shown to be capable of producing significant amounts of acetaldehyde from ethanol and by alcohol fermentation from glucose. Our studies have shown that all sugar (saccharose, maltose, lactose) containing foodstuffs including beverages, can contain - or in the foodstuff is formed - significant amounts of acetaldehyde, 5 to 2000 μΜ and ethanol, 0.1 to 0.5 per mille. Some sour milks, yoghurts and juices contain acetaldehyde and ethanol as such (PCT/FI2006/000104). Further, for example glucose can be metabolized by e.g. Candida species in the mouth into pyruvate and thereafter into acetaldehyde and ethanol. Fructose can similarly be metabolized into pyruvate or alternatively into glycerol. The average amount of saliva secreted by a human is 1.5 litres per day. The areas of influence of the aldehydes contained in the saliva include the mouth, the pharynx, the oesophagus and the stomach. Consequently, the effects of these aldehydes may extend to the whole upper digestive tract area. The prior art includes publications that disclose pharmaceutical compositions containing compounds that bind acetaldehyde, their effect being based on the reaction of the effective substances with the acetaldehyde formed in or carried to the blood stream and/or the cells, for example US 5 202 354, US 4 496 548, US 4 528 295, US 5 922 346. Further, suggestions have been made to use preparations containing amino acids, which are sucked or chewed in the mouth, to reduce the effect of detrimental free radical compounds, which are formed for example from tobacco smoke. It is believed that, after being absorbed, the amino acids affect various tissues and react with the free radicals (US 5,922,346, WO 99/00106). However, these do not target the acetaldehyde in the mouth. WO 02/36098 suggests the use of compounds containing a free sulfhydryl and/or amino group for a local and long-term binding of acetaldehyde from saliva, the stomach or the large intestine. The compounds were mixed with a substance that enabled them to be released for at least 30 minutes in the conditions of the mouth, the stomach or the large intestine. Similarly, WO 2006/037848 suggests a composition comprising one or more free sulphhydryl and/or amino groups for removing or decreasing the aldehyde content of the saliva during smoking.
None of the above described references provide a cysteine-containing composition that has been specifically designed for a long-term effect in the mouth. Further, none of them target the aldehyde-producing capability of the oral microbes. Brief description of the invention
It is an aim of the present invention to provide new compositions, which can be used to reduce the aldehyde content in the mouth of a subject, and indirectly also in the stomach.
Particularly, it is an aim of the invention to provide such new compositions functioning by at least two different routes, thus providing a synergistic effect in the reduction of said aldehyde content.
It is also an aim of the present invention to provide new compositions, which mask the taste of the aldehyde-binding compound(s) in the composition.
These and other objects, together with the advantages thereof over known compositions and methods are achieved by the present invention, as hereinafter described and claimed. One object of the present invention is thus a composition, which comprises one or more aldehyde-binding compounds.
The invention is based on the finding that aldehydes, such as acetaldehyde, are formed in the mouth, for example as a result of microbial activity. Cysteine and its derivatives are able to bind covalently to these aldehydes and thus inactivate their mutagenic and toxic properties, whereas xylitol is able to kill or at least inactivate oral microbes (i.e. also such microbes that are responsible for the production of acetaldehyde. According to the invention, the composition comprises a combination of active compounds including one or more cysteine compounds, and xylitol, bound into a lozenge, or a buccal or sublingual tablet, with the help of at least one non-toxic additive. The additive(s) are particularly selected from those that, in the conditions of the mouth, cause the sustained release of the active compounds from the lozenge or the tablet into the saliva.
More precisely, the composition according to the invention is characterized by that, which is stated in the characterizing part of claim 1. The invention provides considerable advantages. The compositions comprising the aldehyde-binding cysteine compounds can be used to reduce the risk of developing the cancer of the mouth, and indirectly of the stomach, the intestine and/or the colon due to the saliva being capable of carrying aldehyde to these areas.
Furthermore, the compositions of the present invention are particularly effective and particularly useful for binding aldehyde when they are consumed in connection with eating, or when they are consumed in connection with consuming alcohol. The same is true for smoking or other ways of consuming tobacco, i.e. the compositions of the present invention are particularly effective and particularly useful for binding aldehyde when they are consumed in connection with smoking or other ways of using tobacco.
Particularly, the composition of the invention is capable of releasing the aldehyde-binding compounds in the mouth during the time when the content of the aldehydes formed from the alcohol contained in foodstuff or alcohol-containing drinks is the largest, i.e. the most harmful and carcinogenic, or during the time when the harmful components of tobacco smoke are concentrated in the saliva. Since aldehydes are also partly responsible for tobacco addiction, the present invention will also result in a reduction of said addiction when the present compositions are administered in connection with smoking or other ways of using tobacco.
Brief Description of the Drawings
Figure 1 shows the mean acetaldehyde production (± SEM) by Candida isolates in incubations.
Figure 2 shows the salivary acetaldehyde (SEM) after 5 min of smoking with a placebo, and with sucking tablets containing 1.25 mg, 2.5 mg, 5 mg or 10 mg of L-cysteine. Detailed description of the invention
The present invention concerns a composition that is to be placed in the mouth of a subject and contains a combination of active compounds including one or more cysteine compounds (i.e. aldehyde-binding compounds) that are intended for binding the aldehydes, such as the acetaldehyde, formaldehyde, acrylic aldehyde, propionaldehyde and butyraldehyde, in the mouth, and xylitol intended for destroying (i.e. killing) at least some of the microbes present in the mouth, as well as one or more non-toxic additives, which are harmless for human (or animal) consumption.
The aim of the composition of the invention is to decrease the risk for cancer or toxic effects in the mouth, and in the gastrointestinal tract.
The composition functions by the cysteine compound(s) binding at least some of the aldehydes into a harmless form, whereas the xylitol kills at least some of the microbes in the mouth that are responsible for generating aldehydes. Thus, the effect is synergistic, as a smaller amount of aldehydes will be produced, and an effective binding of said smaller amount of aldehydes is achieved, thus resulting in a considerably more efficient reduction of the aldehyde contents in the saliva compared to the contents achieved using prior solutions.
According to recent studies, xylitol significantly inhibits at least candidal acetaldehyde production from ethanol. It reduces the production below the mutagenic acetaldehyde level of 40-Ι ΟΟμΜ. In the absence of xylitol, the mean acetaldehyde production in ethanol incubation is high (>200μΜ). Xylitol has previously been shown to inhibit the metabolism of sugars by acidogenic oral bacteria and thus prevent tooth decay. Five to six grams and three daily exposures are required for this effect. However, a xylitol concentration of at least 65mM has been shown to also have antimicrobial activity against otopathogenic bacteria.
One objective of using said additive(s) is to bind the active compounds into a lozenge, or into a buccal or sublingual tablet. Particularly, at least one of the additives is selected from the carriers or binders capable of causing the sustained release of said cysteine compound(s) from the lozenge or the tablet into the saliva in the conditions of the mouth.
According to a preferred embodiment of the invention, at least one of the additives of the composition is formed into a coating on the lozenge or the tablet containing the remaining constituents of the composition. Preferably, such a coating is formed from at least a portion of the xylitol or at least a portion of any further aromatic agents of the composition.
The term "additive" here includes carriers, fillers and binders, as well as aromatic agents colorants and non- functional additives. These additives are non-toxic, and preferably control the release of the active agents to take place specifically in the mouth, and most suitably in a sustained manner. These formulations are intended to be placed in the mouth, for example between the cheek or the lip and the gum, or they are intended to be sucked. The composition comprises an effective amount of the above mentioned cysteine compound(s). Here an effective amount means an amount capable of binding or inactivating the amount of aldehyde carried to the mouth from foodstuff, drinks or tobacco, or formed in the mouth, for example by the microbial activity therein, during the digestion of foodstuff or drinks in connection with or after the consumption.
Typically, a single unit, or formulation, of the composition comprises l-30mg, preferably l-20mg, more preferably 1-1 Omg, and most suitably 2-6mg of the cysteine(s). However, 1-2 of these units can be administered at once. The content of the cysteine compound(s) is then preferably 1-50%, more preferably 5- 40%), most suitably 20-30%), of the weight of the composition. Typically, the content is 20-25w-%.
The cysteine compounds are preferably selected from L- and D-cysteine, their derivatives, such as N-acetyl cysteine, as well as the pharmaceutically acceptable salts thereof. The composition also comprises an effective amount of the above mentioned xylitol. Here and effective amount means an amount capable of at least causing a measurable inactivation of the acetaldehyde-producing bacteria of the mouth. Typically, a single unit, or formulation, of the composition comprises 50-500mg, preferably 50-300mg, more preferably 100-300mg, and most suitably 200-300mg of xylitol. However, as stated above, 1-2 units can be administered at once.
The content of xylitol is then preferably 10-90%, more preferably 10-60%, particularly 20-60%), and most suitably 40-60%) of the weight of the composition. Typically, the content is about 50%>.
A final concentration of HOmM xylitol equals to 17mg mL readily available in the oral cavity. Concentrations higher than 30mg mL can be detected in saliva, and the levels have been found to remain significantly elevated for up to 30 rain. Thus, it is preferred according to the present invention to provide an initial xylitol concentration (in the saliva) of at least 17mg/rnl,
For example, L-cysteine is an easily oxidized cysteine that is not able to effectively bind and inactivate the aldehyde present in the mouth, particularly when used alone in a conventional immediate-release dosage form. However, the present invention provides a dosage form that gives a long-term effect even in cases, where additives prolonging the release of the active ingredient are not used, and provides a synergistic effect together with the xylitol of the composition.
The composition is preferably formulated into coated lozenges, buccal tablets or sublingual tablets, and at least one of the aromatic agents present in the composition (including the xylitol) is included in the coating. An advantage of using the coating is that it will mask the unpleasant taste of the cysteine compound(s).
Since cysteine is easily oxidized, it would be expected that it would also be easily transformed into the pharmaceutically inactive cystine in the mouth. This has been shown not to be true when adding the cysteine into a lozenge or a buccal or sublingual tablet according to the invention. On the contrary, the cysteine, when administered as in the present invention, remains in active form in the mouth for up to 20 minutes.
Preferably, the used additives are selected from those capable of controlling the release of the active agents so that these compounds are released locally in the mouth during a time of more than one minute, but generally less than 20 minutes, preferably 1 - 15 minutes, most suitably in 5 - 10 minutes.
According to a preferred embodiment of the present invention, the composition is administered in connection with eating, i.e. just before, during or just after eating, or in connection with consuming alcohol, i.e. just before, during or after consuming a dose of alcohol.
According to another preferred embodiment of the invention, the composition is administered in connection with smoking or other use of tobacco, i.e. just before, during or just after smoking (or other use of tobacco).
The terms "just before" and "just after" mean a time frame of up to 5 minutes before or after eating, consuming alcohol or smoking (or otherwise using tobacco), preferably a time frame of up to 2 minutes, more preferably a time frame of up to 1 minute, and most suitably a time frame of up to 0.5 minutes before or after eating, consuming alcohol or smoking.
However, the compositions can also be used in a continuous way, for example every 10 minutes. According to a preferred embodiment of the invention the dosage is renewed at 5 to 15 minute intervals, preferably at 5 to 10-minute intervals, if alcohol consumption or smoking is continued for an interval longer than the said one.
"Smoking" refers to the smoking of any tobacco product, using snuff, chewing tobacco, or any other use of a tobacco product, wherein the tobacco product or a part thereof is placed in the mouth or is conducted to the mouth. The tobacco product can thus be a cigarette, a cigar, snuff, chewing tobacco or pipe tobacco. The invention is, however, most suitable for use in connection with using smoke-generating tobacco products. The composition releases a major portion of the aldehyde-binding compound during an interval of 5-10 minutes after placing it in the mouth. The "binding of aldehyde" preferably refers to a chemical reaction between the aldehyde and the free sulphhydryl or amino group or both of the cysteine (or similar compound), wherein the aldehyde jointly with the "aldehyde-binding compound" forms a larger molecule. In the reaction with cysteine, for example acetaldehyde mainly binds itself to the sulphhydryl and the amino group of the cysteine, and forms 2-methyl-L-thiazolidine-4- carboxylic acid (and water).
According to the invention, the compounds obtained from aldehydes by chemical binding with cysteine are safe for the organism. However, the aldehydes (in free form) are not harmless for the subject. A harmful/carcinogenic content of acetaldehyde in e.g. the human mouth is roughly 20 to 800 μιηοΐ/ΐ of saliva, and a content of as low as about 20 to 50μΜ causes carcinogenic mutations on the cell level. Generally levels of above 40 to ΙΟΟμΜ are considered mutagenic. Further, formaldehyde is responsible for some carcinogenic effect, while acrolein causes other toxic effects.
By administering the composition of the invention, the aldehyde content in the saliva can be reduced to a level that is essentially lower than without the use of the composition, which means that the aldehyde content can be kept at a level that is at least 20% lower, preferably >40% lower, and most preferably >60% lower than in a corresponding situation without using the composition according to the invention.
Such a harmful or carcinogenic content of aldehyde in the human mouth, as well as in the oesophagus, stomach or other part of the gastrointestinal tract, can be caused by consuming alcoholic drinks, particularly strong alcoholic drinks, or foodstuffs containing alcohol, as a consequence of smoking, and when consuming products (e.g. foodstuffs) containing aldehyde. The aldehyde can be formed from the ethanol in the mouth, generally by oral microbes. The "oral microbes" are intended to include oral bacteria and microbes in the oral cavity, such as streptococci, lactobacilli, corynebacteria, oral spirochetes, anaerobic cocci, and specifically Porphyromonas gingivalis, and various Candida species, including C. glabrata, C. parapsilosis, C. tropicalis, C. dubliniensis, C. guilliermondii, C. albicans, and C. krusei (in the pharynx). However, the aldehyde can also be formed in the drink or in the foodstuff, or it can be added as such into the drink or the foodstuff.
"Alcoholic drinks" are ethanol-containing drinks, their ethanol content varying within 0.7% by volume and 84% by volume."
"Alcoholic foodstuffs" refer to foodstuffs containing at least 0.7% by weight of ethanol. Such foodstuffs can be, for example, fermented juices or preserves, or foodstuffs preserved with small amounts of alcohol, pastries, jellies, and mousse seasoned with liqueur or corresponding products containing alcohol.
"Aldehyde-containing foodstuffs" refers to foodstuffs containing aldehyde even prior to consumption. Acetaldehyde can be formed in said foodstuffs from ethanol that is generated in connection with fermentation, such as in beer, cider, wine, home-brewed beer, and other alcoholic drinks, as well as in many juices. In certain foodstuffs, such as some dairy products, acetaldehyde is used for preservation purposes and to add flavour, or the acetaldehyde is formed in the product as a consequence of microbial activity. For example, sugary juices or sugar-containing foodstuffs, in general, provide a suitable substrate for said microbes. High concentrations of acetaldehyde are also formed in fermented dairy products, such as yoghurt. In that case, mainly the microbes used to make yoghurt produce the acetaldehyde. As for alcoholic drinks, sherry and Calvados contain also especially large amounts of acetaldehyde.
The use of the compositions according to the invention can be of benefit even, when light alcoholic drinks or foodstuffs are consumed, i.e. those containing only small amounts of alcohol (even <0.7%), since even these contents are carcinogenic in the long run. The additive(s) in the composition include a combination of substances, which can function specifically as carriers, fillers, binders and other types of additives.
For example aromatic agents (in addition to the xylitol) can be used as additives, and can be selected from various carbohydrates, such as glucose, sorbitol, eucalyptol, thymol, sucrose, sodium saccharine, methyl salicylate and menthol, preferably from glucose, sorbitol and sucrose.
The content of such aromatic agents in the composition is preferably 20 - 80 w-%, most suitably 20 - 45 w-%. One unit dose generally contains 100 - 500 mg of aromatic agents (in addition to xylitol), such as glucose, sorbitol and sucrose.
The use of one or more filler(s) is preferred in the present invention. These fillers can be selected from non-swelling additives that are suitable for example in pressing tablets. These include, among others, phosphates, hydrogen phosphates, celluloses and their derivatives, as well as salts of fatty acids. Most suitably, calcium hydrogen phosphate, microcrystalline cellulose or magnesium stearate (or a combination of two or more of these) is selected to be used in the composition as a filler. The portion of the filler(s) in the composition is preferably 5-80w-%, more preferably 10- 50w-%, most suitably 10-30w-%.
To facilitate keeping the composition in the mouth, it is preferred to include at least one binder or adhesive agent in the composition, preferably selected from polymers, such as cellulose derivatives, chitosanes, alginates, polyethylene glycols, carbomers or polycarbophils, most suitably selected from hydroxypropyl methyl cellulose or its derivative or a Carbopol grade of a carbomer.
Such adhesive agents can possibly be used in coatings on the buccal or sublingual tablets or on lozenges, to facilitate the adhesion of the unit dose to the mucous membranes of the mouth. For this purpose, a polymer that forms a gel in the conditions of the mouth is particularly preferred. Such gel-forming polymers include the above mentioned binders. The portion of this optional adhesive agent in the composition is preferably l-50w-%, more preferably 5-40w-% and most suitably 10-30w-%.
The additive(s) of the composition according to the invention can also include one or more hydrophobic compounds, preferably added to a coating on the buccal or sublingual tablets or on lozenges, to prevent or slow down water coming into contact with the cysteine compound(s).
According to a particularly preferred embodiment of the invention, the composition consists of a cysteine compound, xylitol, an aromatic agent, as well as optional binder(s) and filler(s).
According to another particularly preferred embodiment of the invention, the composition includes one or more further additive(s) selected from the group comprising chromium, vitamins A, D, E, and C, niacin, biotin, thiamine, vitamins B2, B5, B6, and B12, folic acid, as well as trace elements, such as chromium, manganese, selenium, zinc and iron, to add further health benefits.
In preparing the coated tablets, it is preferred to formulate a granular cysteine-containing mixture coated with a coating mixture including at least a portion of the xylitol and optionally the aromatic agent(s). To most effectively mask the taste of the cysteine compound(s), at least a main part (>50% by weight) of the aromatic agent(s) will be added to the coating mixture, for example 80 to 100% by weight. Most suitably, 50 to 100% by weight of the xylitol will also be present in the coating, typically 80 to 100% by weight.
The following non-limiting examples are intended to merely illustrate the advantages obtained using the invention. Examples Example 1 Laboratory and clinical isolates of seven Candida species were selected for the study, being C. glabrata, C. parapsilosis, C. tropicalis, C. dubliniensis, C. guiUiermondii, C. krusei, and C. albicans.
Aliquots of 350 μΐ of these yeast isolates (1 x 107 colony forming units), suspended in phosphate buffered saline (PBS) were transferred into gas chromatography vials. Thereafter, 50 μΐ of PBS buffer containing ethanol (final concentration 12 mM) and 50 μΐ PBS buffer containing glucose, fructose or xylitol (final concentration 110 mM) was added, and the vials were immediately sealed. The samples were incubated at 37 °C for 30 minutes, and the reactions stopped by injecting 50 μΐ of 6 M perchloric acid (PCA) through the rubber septum of the vial. The formed acetaldehyde was measured by gas chromatography (see Fig. 1).
Xylitol (p < 0.0001) reduced the amount of acetaldehyde produced from ethanol by 84%. In the absence of xylitol, the mean acetaldehyde production in ethanol incubation was 220.5μΜ, and in ethanol- xylitol incubation 32.8μΜ.
Coincubation with glucose reduced the amount of produced acetaldehyde by 23%, and coincubation with fructose by 29%>. Thus, glucose and fructose did not have an equally significant effect with xylitol. In fact, at concentrations that are representative of those found in the oral cavity during the intake of proprietary xylitol products, xylitol was found to reduce the production of carcinogenic acetaldehyde from ethanol by Candida below the mutagenic level of 40-100μΜ. Some variation was found in acetaldehyde production between the different Candida species. C glabrata isolates were found to be the highest producers, and C krusei isolates the lowest producers. Correspondingly, xylitol reduced the alcohol dehydrogenase (ADH) activity of the C. glabrata isolate by 61 > and of the C. albicans isolate by 100%) when coincubated with 1 lOmM ethanol for 10 minutes. When coincubated with 1 1 mM ethanol, the reduction was 66% in C. glabrata isolate and 100% in C. albicans isolate.
Example 2
A sucking tablet was prepared, comprising:
L-cysteine 20 mg
Xylitol (or an equivalent sugar or sugar alcohol) 750 mg
Flavouring q.s.
Magnesium stearate 10 mg
The composition was prepared by mixing the cysteine and most of the remaining ingredients (leaving a portion of the xylitol unused) into a powdery mass and compressing it into sucking tablets, which were coated with the remaining xylitol.
Example 3
A sublingual tablet was prepared, comprising:
L-cysteine lO mg
Xylitol 250 mg
Flavouring q.s.
Magnesium stearate 5 mg
The composition was prepared by mixing the cysteine and most of the remaining ingredients (leaving a portion of the xylitol unused) into a powdery mass and compressing it into sublingual tablets, which were coated with the remaining xylitol.
Example 4 Two individuals tested the preparation prepared according to Example 2. The salivary acetaldehyde contents of the testees were measured before smoking and then after 5 minutes during smoking, i.e., Omin, 5min, lOmin, and 15min after the testees started smoking. Each testee smoked one cigarette and, at the same time, saliva was collected from their mouths, as they sucked placebo tablets. Smoking lasted for 5min. In another test, the testees repeated the study by sucking tablets containing 20 mg of cysteine.
Before smoking, the salivary acetaldehyde content of each testee was very low. In the second test, the acetaldehyde content had reduced to a non-measurable level already after the first 5 minutes.
Example 5 Five smokers (of the age of 29 ± 2.8) participated in the study, in which three cigarettes were smoked (with cleaning periods in between). While smoking each cigarette (in 5 minutes time), the voluntaries sucked tablets blindfold, containing a placebo, 1.25 mg, 2.5 mg, 5 mg, 10 mg or 20 mg of L-cysteine, prepared according to Example 2. The acetaldehyde in the saliva samples was analysed by gas chromatography after 0, 5, 10, 20 minutes from starting to smoke.
The L-cysteine tablets (5 mg, 10 and 20 mg) removed from the saliva all of the acetaldehyde originating from tobacco (see Fig. 2). The average salivary acetaldehyde contents immediately after smoking were 191.2 ± 48.5 μΜ, 0 μΜ, 0 μΜ, 0 μΜ with the placebo and the 5 mg, 10 mg, and 20 mg L-cysteine tablets, respectively.
The study showed that even 5 mg of L-cysteine, when delivered with a melting tablet, completely inactivated the carcinogenic acetaldehyde in the saliva during smoking. The L- cysteine tablet of 1.25 mg reduced the amount of acetaldehyde by about two thirds compared with the placebo.
Example 6
A lozenge was prepared, comprising:
L-Cysteine 3 mg (0.6%)
Sorbitol 224 mg (44.8%)
Xylitol 250 mg (50.0%)
Aromatic (flavouring) agent(s) 12.5 mg (2.5%) Magnesium stearate 10 mg (2.0%)
Silicon dioxide 0.5 mg (0.1%)
The composition was prepared by first forming a pre-mix containing the L-cysteine in ground form, the aromatic agents, the silicon dioxide and a first portion of the sorbitol. Subsequently, the remaining portion of the sorbitol as well as the xylitol are added to the pre-mix in a first mixer (a Muller mixer), whereafter the magnesium stearate is added to the formed mix (in a high shear Collette mixer). The final mix is then transferred to a final mixer (a Muller mixer) to provide a homogeneous mix, which is compressed and coated in a final stage.
Literature
Francheschi et al. Cancer Res 1990; 50:6502 - 07 Haussmann, H.-J. Chem. Res. Toxicol. 2012; 25, 794 - 810
International Agency for Research on Cancer, 1999; Acetaldehyde. In: Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide. IARC Monographs on the evaluation on the Carcinogenic Risks to Humans, vol 71, pp. 319-335.
Salaspuro, M. Best Pract Res Clin. Gastroenterol 2003; 17:679 - 94
Salaspuro M. Acetaldehyde as a common denominator and cumulative carcinogen in digestive tract cancers. Scand J Gastroenterol 2009; 44: 912-925.
Salaspuro VJ, Hietala JM, Marvola ML, Salaspuro MP. Eliminating carcinogenic acetaldehyde by cysteine from saliva during smoking. Cancer Epidemiol Biomarkers Prev. 2006 Jan;15(l): 146-149. Secretan B, Straif K, Baan R, Grosse Y, El Ghissassi, Bouvard V et al. A review of human carcinogens - Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 2009; 10: 1033-1034.
Seitz HK, Stickel F. Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism. Genes Nutr 2010; 5: 121-128.

Claims

Claims:
1. A non-toxic composition in the form of buccal tablets, sublingual tablets or lozenges, characterized in that it comprises a combination of active agents including
- one or more aldehyde-binding cysteine compound(s) selected from the group of L- and D-cysteine, N-acetyl cysteine, and the pharmaceutically acceptable salts thereof, and
- xylitol,
and in that it further comprises one or more non-toxic additives that include one or more aromatic agents as well as one or more fillers or binders, or both, and optional further additives.
2. The composition according to Claim 1 for use in decreasing the risk of developing cancer of the area of the mouth.
3. The composition according to Claim 1 or 2, which is intended for administration to a subject during or after eating, during or after drinking alcoholic drinks, or during smoking to reduce the risk of developing cancer of the area of the mouth or the stomach.
4. The composition according to any of Claims 1 to 3, which comprises cysteine compound(s) in an amount of 1 to 30mg, preferably 1 to 20 mg, more preferably 1 to 10 mg, and most suitably 2 to 6 mg, per unit dose.
5. The composition according to any of Claims 1 to 4, which comprises xylitol in an amount of 50-500mg, preferably 50-300mg, more preferably 100-300mg, and most suitably 200-300mg, per unit dose.
6. The composition according to any of Claims 1 to 5, which releases the active compounds within 1 to 20 minutes, preferably within 1 to 15 minutes, typically within 5 to 10 minutes.
7. The composition according to any of Claims 1 to 6, wherein the aromatic agents are selected from various carbohydrates, such as glucose, sorbitol, eucalyptol, thymol, sucrose, sodium saccharine, methyl salicylate and menthol, preferably from glucose, sorbitol and sucrose.
8. The composition according to any of Claims 1 to 7, having a content of aromatic agents of 20-80w-%, preferably 20-45w-%.
9. The composition according to any of claims 1 to 8, further containing one or more filler(s), preferably selected from phosphates, hydrogen phosphates, celluloses and their derivatives, as well as salts of fatty acids, most suitably selected from calcium hydrogen phosphate, microcrystalline cellulose or magnesium stearate, or a combination of two or more of these.
10. The composition according to Claim 9, wherein the portion of the filler(s) in the composition is 5-80w-%, preferably 10-50w-%, most suitably 10-30w-%.
11. The composition according to any of claims 1 to 10, further containing at least one binder or adhesive agent, preferably selected from polymers, such as cellulose derivatives, chitosanes, alginates, polyethylene glycols, carbomers or polycarbophils, most suitably selected from hydroxypropyl methyl cellulose or its derivative or a Carbopol grade of a carbomer.
12. The composition according to Claim 11, wherein the portion of binder or adhesive agent in the composition is l-50w-%, preferably 5-40w-% and most suitably 10-30w-%.
13. The composition according to any of claims 1 to 12, which has been formulated into buccal tablets, sublingual tablets or lozenges, which have been coated using a coating mixture that includes at least a portion of the xylitol and optionally the aromatic agent(s).
14. The composition according to any of claims 1 to 13, which has been formulated into a granular cysteine-containing mixture coated with a coating mixture including at least a portion of the xylitol and optionally the aromatic agent(s).
15. The composition according to Claim 13 or 14, wherein the coating mixture is formed using 50 to 100 % by weight of the xylitol of the composition.
PCT/FI2014/050076 2013-02-01 2014-01-31 Composition for binding aldehydes in the mouth WO2014118438A1 (en)

Priority Applications (4)

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EA201591203A EA201591203A1 (en) 2013-02-01 2014-01-31 COMPOSITION FOR CONNECTING ALDEHYDES IN THE ORAL CAVITY
MX2015009972A MX2015009972A (en) 2013-02-01 2014-01-31 Composition for binding aldehydes in the mouth.
EP14746925.8A EP2950794A4 (en) 2013-02-01 2014-01-31 Composition for binding aldehydes in the mouth
CN201480007086.9A CN105307649A (en) 2013-02-01 2014-01-31 Composition for binding aldehydes in the mouth

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FI20135097A FI20135097L (en) 2013-02-01 2013-02-01 Composition for binding aldehydes in the mouth

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CN107835684A (en) * 2015-03-06 2018-03-23 拜奥希特公司 Composition for preventing hangover symptoms

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WO2006037848A1 (en) * 2004-10-08 2006-04-13 Biohit Oyj Method and preparation for binding aldehydes in saliva
WO2009034232A1 (en) * 2007-09-14 2009-03-19 Biohit Oyj Preparation and a component intended to be added to a tobacco product
US20090197956A1 (en) * 2008-02-04 2009-08-06 Arbor Pharmaceuticals, Inc. Treatment of acute otitis media with xylitol and n-acetylcysteine
WO2013001167A1 (en) * 2011-06-29 2013-01-03 Biohit Oyj Non-toxic compositions for decreasing the risk of cancer caused by oral microbes

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FI121528B (en) * 2000-10-30 2010-12-31 Biohit Oyj Pharmaceutical composition to reduce the risk of sunk in cancer by binding acetaldehyde in saliva, stomach and colon
FI122914B (en) * 2005-04-01 2012-08-31 Biohit Oyj Food composition for binding of acetaldehyde in the mouth and in the digestive tract and process for the preparation of the composition
FI20115377A (en) * 2011-04-18 2012-10-19 Biohit Oyj Medical products for use in conditions related to microbial infections of upper respiratory and digestive organs

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WO2006037848A1 (en) * 2004-10-08 2006-04-13 Biohit Oyj Method and preparation for binding aldehydes in saliva
WO2009034232A1 (en) * 2007-09-14 2009-03-19 Biohit Oyj Preparation and a component intended to be added to a tobacco product
US20090197956A1 (en) * 2008-02-04 2009-08-06 Arbor Pharmaceuticals, Inc. Treatment of acute otitis media with xylitol and n-acetylcysteine
WO2013001167A1 (en) * 2011-06-29 2013-01-03 Biohit Oyj Non-toxic compositions for decreasing the risk of cancer caused by oral microbes

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107835684A (en) * 2015-03-06 2018-03-23 拜奥希特公司 Composition for preventing hangover symptoms

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CN105307649A (en) 2016-02-03
EP2950794A4 (en) 2016-11-09
MX2015009972A (en) 2016-03-11
EP2950794A1 (en) 2015-12-09
CN108969500A (en) 2018-12-11
FI20135097L (en) 2014-08-02
EA201591203A1 (en) 2016-01-29

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