WO2013001167A1 - Compositions non toxiques pour réduire le risque de cancer causé par des microbes buccaux - Google Patents

Compositions non toxiques pour réduire le risque de cancer causé par des microbes buccaux Download PDF

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Publication number
WO2013001167A1
WO2013001167A1 PCT/FI2012/050680 FI2012050680W WO2013001167A1 WO 2013001167 A1 WO2013001167 A1 WO 2013001167A1 FI 2012050680 W FI2012050680 W FI 2012050680W WO 2013001167 A1 WO2013001167 A1 WO 2013001167A1
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Prior art keywords
cysteine
composition
combination product
mouthwash
derivative
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PCT/FI2012/050680
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English (en)
Inventor
Mikko Salaspuro
Osmo Suovaniemi
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Biohit Oyj
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Publication of WO2013001167A1 publication Critical patent/WO2013001167A1/fr

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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
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K9/08—Solutions

Definitions

  • the present invention concerns compositions and combinations for decreasing the risk of cancer caused by oral microbes. These products are aimed to be used during or after the use of ethanol-containing mouthwashes.
  • the first metabolite of ethanol, acetaldehyde, is highly toxic, mutagenic, and carcinogenic, as shown in cell culture and animal experiments (IARC, 1999). Furthermore,
  • Bio films are surface-associated communities of microorganisms embedded in an extracellular polymeric substance, which upon contact with the host may affect tissue homeostasis and result in disease (Hojo et al.2009, Beikler and Flemming 2011). It is estimated that about 80 % of the world's microbial biomass resides in a biofilm state and that microbial bio films cause more than 75 % of all microbial infections found in humans. The oral cavity is replete with bio films colonizing mucous membranes, dental materials and teeth (Beikler and Flemming 2011).
  • Oral biofilms are strongly associated with the etiology of periodontal diseases, dental caries, pulpal diseases, apical periodontitis, peri- implant diseases, candidiosis and many systemic diseases.
  • the estimated national expenditures for oral bio film-associated diseases in the USA have almost doubled from 1997 to 2006. In 2006, the national expenditures for oral bio film-associated diseases totalled $81 billion and were greater than for any other medical conditions e.g. $78.0 billion for heart conditions and $68.1 billion for trauma-related disorders (Beikler and Flemming 2011).
  • Biofilms can never be completely eliminated. However, the pathogenic nature of the dental plaque biofilm can be diminished by reducing the bioburden and effectively maintaining a normal flora with oral hygiene procedures that include daily tooth-brushing, flossing and rinsing with an antimicrobial mouthrinse (Iacopino 2009).
  • N-acetylcysteine is able demolish the biofilm formed by Helicobacter pylori (Cammarota et al. 2010). Furthermore, we were able to demonstrate that L-cysteine is able to demolish or prevent the formation of H. pylori bio film (FI 20115377). A high concentration (40mg/ml) of N-acetylcysteine has been shown to prevent the biofilm formation of Staphylococcus epidermis (Leite et al. 2011). However, there is no evidence that neither N-acetylcysteine nor L-cysteine has any effect on the bio films formed by oral microbes. Further, due to the differences in the conditions in the mouth and the stomach, a similar effect cannot be considered likely.
  • Acetaldehyde can be eliminated from saliva after intake of alcoholic beverages and during smoking with a semi-essential amino acid, cysteine, particularly in the form of L-cysteine (Salaspuro et al. 2002, 2006), when released in a controlled manner.
  • a specific formulation releasing L-cysteine in a controlled manner e.g. the formulation known as Acetium ®
  • Acetium ® the formulation known as Acetium ®
  • compositions used alone or in combination products or combination treatments to eliminate carcinogenic acetaldehyde formed by oral microbes in association with the use of ethanol-containing mouthwashes.
  • a further object is to use these compositions and combination products to at least in part demolish or prevent the formation of biofilms by oral microbes.
  • compositions or combination products containing a cysteine or a derivative thereof, optionally together with xylitol since there is recent evidence suggesting that xylitol inhibits the production of acetaldehyde by the Candida species (Uittamo et al. 2011).
  • the invention is based on the finding that cysteine and its derivatives are able to bind covalently to acetaldehyde and thus inactivate its mutagenic properties.
  • L-cysteine is an easily oxidized cysteine that is not able to bind and inactivate acetaldehyde when used alone in a conventional immediate-release solid dosage form.
  • the present invention provides a dosage form that gives a long-term effect despite the lack of carriers prolonging the release of the active ingredient.
  • the saliva contains high concentrations of enzymes and other similar molecules, which have the purpose of degrading the components of ingested food.
  • mouthwash contains molecules having the purpose of degrading plaque and other harmful deposits. 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 now been shown not to be true when adding the cysteine to a mouthwash. On the contrary, the cysteine, when administered using the compound or combination of the present invention, remains active in the mouth for up to 10 minutes.
  • the products of the present invention In addition to inactivating the mutagenic properties of the acetaldehyde formed and carried to the saliva from alcohol that has either been carried to the saliva with a mouthwash or with consumed food products or drinks, the products of the present invention also destroy bio films formed via the action of oral microbes, and prevent oral infections, such as osteitis and osteomyelitis. This, in turn, prevents the formation of other oral infections, such as parodontitis, caries, osteitis and osteomyelitis.
  • the present invention concerns compositions and combinations for decreasing the risk of cancer caused by oral microbes. These products are aimed to be used during or after the use of mouthwashes that either contain ethanol or are used in connection with consuming food products or drinks containing or capable of forming ethanol.
  • the components of the combination products may be administered either at the same time or separately. Most suitably, they are, however, administered in a manner providing at least partial overlap of the period of action of the cysteine and the active agents of the mouthwash, such as the fluorine compound. This administration provides a synergy between the cysteine and the active agents of the mouthwash.
  • “In connection with consuming food products or drinks containing or capable of forming ethanol” herein refers to the period of time that begins from starting the consumption and ends, when there is no more alcohol in the blood.
  • the term “mouthwash” is intended to include all aqueous solutions suitable for use in rinsing or washing the mouth or the teeth. Generally, these are developed to have an antiplaque and/or antigingivitis effect, or to merely improve the smell of the breath of the subject.
  • oral microbes are intended to include oral bacteria and microbes in the oral cavity, such as streptococci, lactobacilli, corynebacteria, oral spirochetes, anaerobic cocci, and the specific Porphyromonas gingivalis.
  • Said composition is a non-toxic liquid composition in the form of said mouthwash or an effervescent tablet for decreasing the risk of cancer caused by oral microbes, which liquid composition or effervescent tablet comprises cysteine or a derivative thereof, intended for decreasing the risk of cancer caused by oral microbes, and for decreasing the risk of oral infections also caused by said oral microbes.
  • Said combination is a non-toxic combination product including a mouthwash and an effervescent tablet or a powder or granules dissolving easily in an aqueous solution, such as a mouthwash, which tablet, powder or granules comprise cysteine or a derivative thereof, whereby the combination is intended for decreasing the risk of cancer caused by oral microbes, and for decreasing the risk of oral infections also caused by said oral microbes.
  • the effervescent tablet, powder or granules can be dissolved either in the mouthwash or in a glass of water prior to use.
  • the mouthwash often contains a liquid medium including ethanol and a fluorine compound.
  • acetaldehyde when in contact with the oral microbes, starts producing acetaldehyde, which accumulates in the mouth and in the gastrointestinal tract, to where it is conducted after mixing with saliva.
  • Acetaldehyde is known to cause cancer.
  • Controlled-release compositions for eliminating this acetaldehyde are known, but none of these compositions are effective in decreasing the risk caused by the ethanol in a mouthwash, which is kept in the mouth during a prolonged period of time (for a number of mouthwashes, the recommendation is about 30 seconds), i.e. longer than it takes to swallow.
  • a "food product” refers to any foodstuff that is suitable for food, especially one that is packed, bottled or, in another way, prepared to be delivered to consumers.
  • the product meant for consumers also means, among others, that the markings of the product be intelligible to consumers.
  • the food product can also be, for example, a food product that is delivered to a restaurant or a shop to be conveyed to the
  • a “drink” refers to any drinkable liquid product that is suitable for consumption.
  • a “drink product” refers to any drinkable liquid, especially one that is packed or bottled to be delivered to consumers. Thus, the product does not refer to drinking water or juice supplied to humans or animals in laboratory tests, for example.
  • the above mentioned ethanol-containing drinks generally have an ethanol content varying within 0.7% by volume and 84% by volume.”
  • Alcoholic foodstuffs refer to foodstuffs containing at least 0.7% 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
  • the use of the products according to the invention can be of benefit even, when light alcoholic drinks are or have been enjoyed or foodstuffs are or have been consumed, which contain small amounts of alcohol.
  • Some foodstuffs as such can also contain acetaldehyde, in which case the products of the present invention give an essentially equal benefit.
  • Acetaldehyde is contained in foodstuffs, which have ethanol that is generated in connection with fermentation, such as beer, cider, wine, home-brewed beer, and other alcoholic drinks, as well as many juices.
  • acetaldehyde is used for preservation purposes and to add flavour, or the acetaldehyde is formed in the product as a consequence of microbial activity.
  • sugary juices or sugar-containing foodstuffs in general, provide a good substrate for microbes.
  • acetaldehyde High concentrations of acetaldehyde are formed, for example, in fermented milk products, such as yoghurt.
  • fermented milk products such as yoghurt.
  • the microbes used to make yoghurt produce acetaldehyde in the yoghurt.
  • sherry and Calvados contain especially large amounts of acetaldehyde.
  • acetaldehyde in a foodstuff can be defined by standard methods that are well known by those skilled in the art, such as liquid or gas chromatographic methods.
  • Acetaldehyde can be defined, for example, by means of the gas chromatographic method, which is described in the publication Homann et al. 1997.
  • High acetaldehyde levels in saliva after ethanol consumption Methodological aspects and pathogenic implications.
  • the amount of cysteine or derivative thereof that is needed in the mouthwash or the effervescent tablet is about 0.1 to 5.0 mM according to our studies; in some cases, a cysteine concentration of 1 to 10 mM may be enough; in other words, the amount of cysteine to be added is about 12.1 mg/1 to 6.05 g/1 or, correspondingly, from 121 mg/1 to 1.21 g/1 of foodstuff.
  • the amount of cysteine or derivative can be higher, as toxicity is not an issue.
  • the invention concerns a mouthwash including a cysteine compound, whereby the acetaldehyde-binding compound is present in the same
  • composition as the ethanol or the component capable of producing ethanol, whereby the cysteine is administered at exactly the same time as the ethanol.
  • the invention concerns an effervescent tablet to be dissolved in a non-toxic liquid composition, such as a mouthwash, just prior to use or consumption.
  • the invention concerns a combination product of a mouthwash and a cysteine-containing effervescent tablet, the mouthwash either containing ethanol or being used in connection with consuming food products or drinks containing or capable of forming ethanol, whereby the effervescent tablet is added to the mouthwash just prior to use.
  • the cysteine is administered at exactly the same time as the ethanol or the component capable of producing ethanol.
  • the invention concerns a combination product of a mouthwash and a cysteine-containing effervescent tablet, the mouthwash either containing ethanol or being used in connection with consuming food products or drinks containing or capable of forming ethanol, whereby the effervescent tablet is added to a glass of water just prior to use, which formed cysteine-containing liquid is administered after a short period of time, preferably instantly or at least within 1-2 minutes after the regular use of the mouthwash.
  • the cysteine is administered after the ethanol administration.
  • the administration of the cysteine or cysteine derivative and the mouthwash is most preferably carried out simultaneously.
  • the combination product may, for example, be added into vessels, such as bottles, containing a unit dose of both the mouthwash and the effervescent tablet (or powder or granules), where the mouthwash suitably is stored in the bottle and the effecrvescent tablet (or powder or granules) in the cap.
  • vessels such as bottles
  • the effecrvescent tablet or powder or granules
  • the above described liquid composition is a mouthwash, which in turn particularly is selected from ethanol-containing mouthwashes.
  • the cysteine or cysteine derivative of the composition or the combination product is selected from compounds of Formula (I)
  • R 1 is hydrogen or an acyl group with 1-4 carbon atoms
  • R 2 is a sulfhydryl or sulfone group
  • n 1 or 2
  • These compounds include L-cysteine, D-cysteine, cystine, cysteic acid, cysteine glycine, threo- -phenyl-DL-cysteine, erythro- -phenyl-DL-cysteine, ⁇ -tetramethylene-DL- cysteine, D-penicillamine and an N-terminal dipeptide of D-penicillamine, D,L- homocysteine, N-acetylcysteine, L-cysteinyl-L- valine, ⁇ - ⁇ -tetramethylene-DL-cysteine, cysteinyl glycine, tre(5)- ⁇ -phenyl-DL-cysteine, erythro- ⁇ -phenyl-DL-cysteine, cysteine hydrochloride, or a salt of any of these compounds.
  • the compound is selected from L-cysteine, D-cysteine, D-penicillamine, N- acetylcysteine, a compound converting to cysteine in the conditions of the mouth, a salt thereof, or a structural analogue of any of these compounds, capable of binding
  • the cysteine is L-cysteine
  • the cysteine derivative is N-acetylcysteine.
  • L-cysteine is used.
  • the mouthwash is based on water, excluding alcohol, and comprising one or more aromatic agents, particularly for improving the taste of the mouthwash or the breath of the subject, and optionally one or more antimicrobial agents, and is intended for use just after consuming alcohol and/or smoking.
  • Further additives may also be included, such as agents reducing the sensitivity of the nerve endings of teeth (e.g. potassium nitrate), and/or xylitol.
  • the mouthwash is based on water, but comprises also an alcohol as well as one or more aromatic agents, particularly for improving the taste of the mouthwash or the breath of the subject, and optionally one or more antimicrobial agents. Further additives may also be included, such as agents reducing the sensitivity of the nerve endings of teeth (e.g. potassium nitrate).
  • the "ethanol” is intended to include, in addition to ethanol, also other similar alcohols, such as denatured alcohol and propyl alcohol, or a combination of two or more of these alcohols, particularly in a relative amount of 1 to 30 w-% of the entire mouthwash. Many mouthwashes contain 15 to 25 w-% ethanol, and the present invention is highly suitable for use in mouthwashes with such contents. However, it is preferred to minimize the amount of ethanol to 1 to 5 w-% of the entire mouthwash.
  • the aromatic agents are selected from, for example, sorbitol, eucalyptol, thymol, sucralose, sodium saccharine, methyl salicylate, menthol and xylitol.
  • the antimicrobial agent is preferably sodium fluoride, most suitably in a relative amount of 0.01 to 0.03 w-% of the entire mouthwash.
  • additives may also have further functions, such as decreasing the risk of oral infections.
  • the amount of mouthwash administered is preferably 10 to 30 ml per unit dose, more preferably about 20 ml per unit dose, and is most suitably dosed 1 to 2 times a day (e.g. once in the morning and once in the evening).
  • the unit dose of the mouthwash is generally used by mixing in the mouth for about 30 seconds. However, the desired effect is obtained at least to some extent already by a mixing time of 10 seconds, and no harmful effect takes place with a mixing time of 1 minute.
  • the mouthwash can optionally contain a further additive functioning by preventing the oxidation of the cysteine or its derivative.
  • the L-cysteine/mouthwash composition markedly decreased the concentration of acetaldehyde in the saliva for up to ten minutes after rinsing of the mouth with this mouthwash for 30 seconds.
  • Iacopino AM Current concepts in oral-systemic health. JCDA 2009; 75: 180-181.
  • Salaspuro V Hietala J, Kaihovaara P, Pihlajarinne L, Marvola M, Salaspuro M. Removal of acetaldehyde from saliva by a slow-release buccal tablet of L-cysteine. Int J Cancer. 2002 Jan 20;97(3):361-364.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un produit se présentant sous la forme d'une composition liquide non toxique, par exemple un bain de bouche, ou sous la forme d'un comprimé effervescent, pour réduire le risque de cancer causé par les microbes buccaux, ladite composition comprenant de la cystéine ou un dérivé correspondant. Autre possibilité : le produit se présente sous la forme d'un produit combiné non toxique comprenant un comprimé effervescent, un poudre ou des granulés comprenant de la cystéine ou un dérivé correspondant et un bain de bouche, ce produit combiné étant destiné à réduire le risque de cancer causé par des microbes buccaux. Les composants de ce produit combiné peuvent être administrés simultanément ou séparément.
PCT/FI2012/050680 2011-06-29 2012-06-28 Compositions non toxiques pour réduire le risque de cancer causé par des microbes buccaux WO2013001167A1 (fr)

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FI20115680 2011-06-29
FI20115680A FI20115680L (fi) 2011-06-29 2011-06-29 Nestemäisiä farmaseuttisia koostumuksia tai yhdistelmätuotteita

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014118438A1 (fr) * 2013-02-01 2014-08-07 Biohit Oyj Composition pour lier des aldéhydes dans la bouche

Citations (4)

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Publication number Priority date Publication date Assignee Title
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WO2002036098A1 (fr) * 2000-10-30 2002-05-10 Licentia Ltd Procede et preparation permettant de lier l'acetaldehyde dans la salive, l'estomac et le gros intestin
WO2002041837A2 (fr) * 2000-11-22 2002-05-30 Rxkinetix, Inc. Traitement de mucosite
WO2006103316A1 (fr) * 2005-04-01 2006-10-05 Biohit Oyj Préparation alimentaire se liant à l'acétaldéhyde présent dans la bouche et dans l'appareil digestif, et méthode d'élaboration de ladite préparation

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EP0198058A1 (fr) 1984-10-29 1986-10-22 Centre National De La Recherche Scientifique (Cnrs) Polymeres photosensibles, leur preparation et compositions filmogenes les contenant pour la photogravure
WO2002036098A1 (fr) * 2000-10-30 2002-05-10 Licentia Ltd Procede et preparation permettant de lier l'acetaldehyde dans la salive, l'estomac et le gros intestin
WO2002041837A2 (fr) * 2000-11-22 2002-05-30 Rxkinetix, Inc. Traitement de mucosite
WO2006103316A1 (fr) * 2005-04-01 2006-10-05 Biohit Oyj Préparation alimentaire se liant à l'acétaldéhyde présent dans la bouche et dans l'appareil digestif, et méthode d'élaboration de ladite préparation

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WO2014118438A1 (fr) * 2013-02-01 2014-08-07 Biohit Oyj Composition pour lier des aldéhydes dans la bouche
CN105307649A (zh) * 2013-02-01 2016-02-03 拜奥希特公司 用于结合口腔中的醛的组合物
CN108969500A (zh) * 2013-02-01 2018-12-11 拜奥希特公司 用于结合口腔中的醛的组合物

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