WO2021033661A1 - Activateur de cellules épithéliales gingivales - Google Patents

Activateur de cellules épithéliales gingivales Download PDF

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Publication number
WO2021033661A1
WO2021033661A1 PCT/JP2020/030990 JP2020030990W WO2021033661A1 WO 2021033661 A1 WO2021033661 A1 WO 2021033661A1 JP 2020030990 W JP2020030990 W JP 2020030990W WO 2021033661 A1 WO2021033661 A1 WO 2021033661A1
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Prior art keywords
gingival
epithelial cell
gingival epithelial
oil
hinokitiol
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PCT/JP2020/030990
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English (en)
Japanese (ja)
Inventor
岡本　浩明
牧 中村
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小林製薬株式会社
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Publication of WO2021033661A1 publication Critical patent/WO2021033661A1/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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • 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
    • 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

Definitions

  • the present invention relates to an oral composition used to activate gingival epithelial cells or enhance cell proliferation.
  • the present invention also relates to oral compositions used to enhance the barrier function of the gingiva or to repair periodontal tissue.
  • Periodontal disease is an inflammatory disease of the periodontal tissue, caused by the host response to bacterial invasion and infection.
  • Periodontium is composed of its constituent cells and immune cells that increase mainly during infection, and it is known that the responsiveness of each cell to infection and inflammation regulates various immune responses to bacteria. ..
  • Bacterial invasion into the periodontium is usually due to the adhesion of the gingival junction epithelium to the enamel via the hemidesmosome bond composed of laminin 5 and integrin ⁇ 6 ⁇ 4 and the physical barrier of the gingival junction epithelium and the gingival sulcus epithelium. It is protected by function and expression of antibacterial peptides such as ⁇ -defensin.
  • the living body Against the ever-present bacteria, the living body undergoes a primary defense reaction (innate immunity) by phagocytic cells such as saliva containing antibacterial substances, antibodies centered on IgG, gingival crevicular fluid containing cytokines, and neutrophils.
  • innate immunity phagocytic cells
  • phagocytic cells such as saliva containing antibacterial substances, antibodies centered on IgG, gingival crevicular fluid containing cytokines, and neutrophils.
  • the gingival junction epithelium and the gingival sulcus epithelium are parts that are less keratinized or keratinized than other oral epithelsium (outer marginal epithelium), and the cell layer is thin, but this structure is conversely the blood vessels that are subcutaneously connected.
  • phagocytic cells neutrophils, etc.
  • chemokines such as IL-8 produced by the gingival junction epithelium in response to bacteria and leukotriene B4 and other leukocyte mobilization-inducing substances by the host induces exudation of neutrophils from inside the blood vessels. ..
  • neutrophils exert their ability to feed on bacteria with the help of complement and antibodies.
  • Bacteria that have been eaten are killed in phagosomes and either excreted extracellularly or remain intracellular. Normally, it is considered that the equilibrium state is locally maintained by repeating such a biological response and escapes from periodontal tissue destruction due to bacterial invasion. Furthermore, as a protective measure against plaque as periodontal tissue, it is known that the basal cells of the gingival junction epithelium and the gingival sulcus epithelium proliferate to strengthen the physical barrier of the living body (the above is non-patent). Reference 1).
  • gingival epithelial cells (gingival junction epithelial cells and gingival crevicular epithelial cells) play a protective function against the invasion of bacteria into the periodontium.
  • hinokitiol has been known to have antibacterial action, anti-inflammatory action, tissue astringent action, etc., and is added to the oral composition for the purpose of prevention and treatment of gingival inflammation and periodontal disease. Further, it is known that it has a hair follicle function activating action (Patent Document 1) and has an action of enhancing the skin cell proliferation action of psychosaponin (Patent Document 2). However, it has not been known that it acts on gingival epithelial cells to promote the proliferation of living cells (cell activation).
  • An object of the present invention is to provide a new use based on the new action found for hinokitiol. Specifically, it is an object of the present invention to provide applications as a gingival epithelial cell activator, a gingival epithelial cell proliferation enhancer, a gingival barrier function enhancer, and a periodontal tissue repair agent based on the action of hinokitiol. ..
  • the present inventors have newly found in daily research that hinokitiol has an action of activating gingival epithelial cells and promoting cell proliferation. It is considered that such an action of hinokitiol can protect the periodontium from tissue destruction due to bacterial invasion and enhance the defense function (barrier function) of gingival epithelial cells against bacterial invasion and plaque.
  • the present invention has been completed based on such findings, and includes the following embodiments.
  • Item 1 A gingival epithelial cell activator, which comprises hinokitiol as an active ingredient.
  • Item 2. A gingival epithelial cell proliferation enhancer, which comprises hinokitiol as an active ingredient.
  • Item 3. A gingival barrier function enhancer characterized by containing hinokitiol as an active ingredient.
  • Item 4. A periodontal tissue restoration agent characterized by containing hinokitiol as an active ingredient.
  • the oral composition is selected from the group consisting of gingival epithelial cell activation action, gingival epithelial cell proliferation enhancing action, gingival barrier function enhancing action, and periodontal tissue repairing action.
  • a method of using hinokithiol which comprises imparting at least one action to be performed.
  • the method of use is for producing at least one oral composition selected from the group consisting of a gingival epithelial cell activator, a gingival epithelial cell proliferation enhancer, a gingival barrier function enhancer, and a periodontal tissue repair agent. It can be rephrased as the use of hinokithiol.
  • gingival epithelial cells By treating the oral cavity with the gingival epithelial cell activator of the present invention, gingival epithelial cells can be activated. Further, by treating the oral cavity with the gingival epithelial cell proliferation enhancer of the present invention, the proliferation of gingival epithelial cells can be enhanced. Furthermore, by treating the oral cavity with the gingival barrier function enhancer of the present invention, the gingival epithelial cells are activated or cell proliferation is enhanced, and as a result, the gingival barrier function (defense function) against bacteria, plaque, etc. is enhanced. It is expected that the periodontal pocket formation is suppressed and the periodontal epithelial tissue is regenerated.
  • the periodontium repair agent of the present invention by treating the oral cavity with the periodontium repair agent of the present invention, the periodontal tissue damaged by bacteria, plaque, etc. is repaired as a result of activation of gingival epithelial cells or promotion of cell proliferation.
  • the oral composition for various purposes of the present invention the physical barrier of the living body can be strengthened by proliferating gingival epithelial cells (gingival junction epithelial cells, gingival sulcus epithelial cells).
  • gingival epithelial cells gingival junction epithelial cells, gingival sulcus epithelial cells.
  • the oral compositions for various purposes of the present invention can be effectively used as a gingival strengthening agent.
  • the time course of proliferation of gingival epithelial cells cultured in the presence of hinokitiol (Example 1: 600 nM, Example 2: 300 nM, Example 3: 60 nM) or in the absence of hinokitiol (Comparative Example) is shown.
  • the gingival epithelial cell activator, the gingival epithelial cell proliferation enhancer, the gingival barrier function enhancer, and the periodontal tissue repair agent of the present invention are all characterized by containing hinokitiol as an active ingredient.
  • Hinokitiol is a compound represented by the following formula.
  • Hinokitiol (2-hydroxy-4-isopropylcyclohepta-2,4,6-trien-1-one, also known as " ⁇ -thujaplicin" is contained in essential oils such as Taiwan Hinoki and Aomori Hiba. It is a natural product contained in Thujaplicin, and although it has low toxicity, it has a wide antibacterial spectrum and is a crystalline substance having an excellent antibacterial action. A salt is formed when it comes into contact with a metal ion, and in the present invention, the salt is also collectively referred to as hinokitiol.
  • Hinokitiol can be isolated from the essential oils extracted from the above-mentioned Taiwan cypress and Hiba, but recently, it is also produced and provided by chemical synthesis.
  • the hinokitiol used in the present invention may be of natural origin or synthetic product. Further, the essential oil or a crude product of the essential oil may be used regardless of the refined product as long as the effect of the present invention is not impaired.
  • this agent Amount of hinokithiol in the gingival epithelial cell activator, gingival epithelial cell proliferation enhancer, gingival barrier function enhancer, or periodontal tissue repair agent (hereinafter collectively referred to as "this agent") of the present invention. Is not particularly limited as long as it is the amount of hinokithiol that exerts each effect when each agent is applied to the oral cavity as an oral composition.
  • this drug when this drug is an oral composition to be applied to the oral cavity as it is, it can be appropriately selected and set from the range of 0.005 to 0.5% by mass. It is preferably 0.01 to 0.3% by mass, and more preferably 0.02 to 0.2% by mass.
  • this drug when used, for example, diluted 10-fold with water at the time of use, it may contain hinokitiol so that the concentration after dilution is within the above range.
  • the oral composition when used, for example, diluted 10-fold with water at the time of use, the oral composition may be prepared so as to contain, for example, hinokitiol at a concentration of 0.05 to 5% by mass. it can.
  • this drug can be applied to the above-mentioned oral compositions (including those used as is and diluted before use) to activate gingival epithelial cells, enhance gingival epithelial cell proliferation, enhance gingival barrier function, or repair periodontal tissue.
  • the content of hinokithiol is not particularly limited as long as the oral composition can be prepared, and is in the range of, for example, 0.1 to 100% by mass. Can be set as appropriate from.
  • the gingival epithelial cell activating effect of the gingival epithelial cell activator is evaluated by culturing the gingival epithelial cells in the presence of the target gingival epithelial cell activator, as shown in Experimental Example 1 described later. can do.
  • the gingival epithelial cell proliferation-enhancing effect of the gingival epithelial cell proliferation-enhancing agent can be determined by the same method.
  • Both the gingival barrier function enhancing effect of the gingival barrier function enhancing agent and the periodontal tissue repairing effect of the periodontal tissue repairing agent are obtained as a result of activation of gingival epithelial cells or increased proliferation of gingival epithelial cells. (See Non-Patent Document 1). Therefore, these effects can also be determined by the same method as described above.
  • the gingival epithelial cell activator, gingival epithelial cell proliferation enhancer, gingival barrier function enhancer, or periodontium repair agent of the present invention are each an oral composition for activating gingival epithelial cells and an oral composition for enhancing gingival epithelial cell proliferation.
  • an oral composition for enhancing the gingival barrier function, or an oral composition for periodontal tissue restoration When applied into the oral cavity as a substance, an oral composition for enhancing the gingival barrier function, or an oral composition for periodontal tissue restoration, each effect can be exhibited.
  • this drug may be used as it is or diluted with water as an oral composition to be applied into the oral cavity, or it may be added to these oral compositions to provide gingival epithelium.
  • this drug may be finally used in the form of an oral composition, and can be prepared and provided in a form suitable for it.
  • hinokitiol is a crystal that is slightly soluble in water, for example, when this drug is used as an additive to an oral composition, hinokitiol is prepared in a liquid state in which it is dissolved in a soluble solvent such as ethanol or propylene glycol. It is preferable to be done.
  • Examples of the form of the oral composition include any form such as tablets, pills, granules, liquids, suspensions, emulsions, sheets, gels, foams and pastes. These forms include, specifically, dentifrices (including powder, liquid, cream, and paste formulations), mouthwashes (including liquid and foam formulations), ointments, and pastilles. Agents, gingival cream, gingival gel, artificial tooth stabilizers, troches, chewing agents (including chewing gum, gummy, etc.), patches (films, packs), candies (candy, tablets [cool confectionery, mint tablets, supplements] Including] etc.) etc. are included.
  • gingival epithelial cells When prepared in such a form and applied in the oral cavity, it can effectively activate gingival epithelial cells, promote the proliferation of gingival epithelial cells, enhance the gingival barrier function, or repair periodontal tissue. As a result, it is possible to strengthen the gingiva and effectively deal with the prevention or treatment of oral diseases related to periodontal tissues such as periodontitis, gingival inflammation, root membrane inflammation, periodontitis, peri-implantitis, etc. become.
  • oral compositions can contain various components used in the art according to each form, and do not limit them as long as they do not interfere with the effects of the present invention.
  • abrasives e.g., dentifrices
  • wetting agents e.g., dentifrices
  • binders e.g., binders
  • foaming agents e.g., binders
  • surfactants e.g., surfactants, sweeteners, fragrances, coloring agents, preservatives, etc.
  • sweeteners e.g., abrasives, wetting agents, binders, foaming agents, thickeners, surfactants, sweeteners, fragrances, coloring agents, preservatives, etc.
  • Medicinal ingredients eg, anti-inflammatory agents, etc.
  • Silica-based abrasives such as precipitated silica, silica gel, aluminosilicate, zircon
  • [Wetting agent] Polyhydric alcohols such as glycerin, concentrated glycerin, diglycerin, sorbitol, maltitol, dipropylene glycol, propylene glycol, 1,3-butylene glycol, xylitol and the like.
  • Cellulose-based binders such as sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl ethyl cellulose, and methyl cellulose, xanthan gum, carrageenan, guagam, sodium alginate, cationized cellulose, montmorillonite, gelatin, Sodium polyacrylate, etc.
  • N-acyl amino acid salts such as sodium lauryl sulfate, sodium lauroyl sarcosin, sodium alkyl sulfosuccinate, sodium coconut oil fatty acid monoglycerin sulfonate, sodium ⁇ -olefin sulfonate, N-acylglutamate, 2-alkyl-N -Carboxymethyl-N-Hydroxyethyl imidazolinium betaine, multitoll fatty acid ester, sucrose fatty acid ester, polyglycerin fatty acid ester, fatty acid diethanolamide, polyoxyethylene sorbitan monostearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene Fatty acid ester, alkyl glycoside, etc.
  • [Consolidating agent] Glycerin, sorbitol, propylene glycol, polyethylene glycol having a molecular weight of 200 to 6000, ethylene glycol, 1,3-butylene glycol, reduced starch saccharified product, etc.
  • Anionic surfactants, nonionic surfactants, amphoteric surfactants, cationic surfactants and the like can be blended.
  • the anionic surfactant include sodium alkyl sulfate such as sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acylsarcosine such as sodium N-lauroyl sarcosin and sodium N-myristyl sarcosin, sodium dodecylbenzene sulfonate, and hydrogenated coconut fatty acid.
  • Monoglyceride N-acylglutamate such as sodium monosulfate, sodium lauryl sulfoacetate, sodium N-palmitoyl glutamate, sodium N-methyl-N-acyltaurine, sodium N-methyl-N-acylalanine, sodium ⁇ -olefin sulfonate, etc.
  • the nonionic surfactant include polyoxyethylene hydrogenated castor oil, sucrose fatty acid ester, alkylol amide, polyoxyethylene sorbitan monostearate, polyoxyethylene polyoxypropylene glycol, alkyl glucoside, decaglyceryl laurate and the like. Used.
  • amphoteric surfactants include betaine lauryldimethylaminoacetate, acyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, coconut oil fatty acid amide propyl dimethylaminoacetic acid betaine, and coconut oil fatty acid amide propyl. Betaine etc.
  • Parabens such as methylparaben, ethylparaben, propylparaben and butylparaben, sodium benzoate, phenoxyethanol, alkyldiaminoethylglycine hydrochloride and the like.
  • Fluorine compounds such as sodium fluoride, sodium monofluorophosphate, tin fluoride, water-soluble phosphate compounds such as potassium salt of orthophosphate and sodium salt, sodium polyphosphate, tranexamic acid, epsilon-aminocaproic acid , Allantin, Allantin Chlorhydroxyaluminum, Ascorbic acid, dl- ⁇ -tocopherol acetate, dl-fa- ⁇ -tocopherol nicotinate, pyridoxin hydrochloride, dihydrocholesterol, ⁇ -bisabolol, chlorhexidine salts, sodium azulene sulfonate, guaizrene sulfone Copper compounds such as acid, glycyrrhetin, glycyrrhetinic acid, copper gluconate, aluminum lactate, strontium chloride, potassium nitrate, velverine, hydroxamic acid and its derivatives,
  • the blending amount of these optional components can be a normal amount used in the art as long as the effects of the present invention are not impaired.
  • This drug which is thus prepared in the form of an oral composition, can be treated in the oral cavity of a target subject by normal use according to the form.
  • each effect of this drug can be exhibited by brushing the subject's teeth with this drug.
  • each effect of this drug can be exhibited by washing (rinsing) the oral cavity of the subject with this drug.
  • the concentration of hinokitiol in the oral cavity including saliva is in the range of 1 nM to 20 mM, preferably 10 nM to 10 mM. It is preferably prepared to be 50 nM to 5 mM.
  • the number of times this drug is applied intraorally is not particularly limited, and it can be applied once or multiple times a day, preferably after meals and / and before and after bedtime.
  • the test sample solution shown in Table 1 was added, and the culture sample was cultured in an incubator (37 ° C., 5% CO 2 ) for 24 hours, 48 hours, or 72 hours. ..
  • the medium and test sample solution were removed, the gingival epithelial cells were washed with PBS, 100 ⁇ L of CCK diluted solution (same as above) was added, and the mixture was allowed to stand in an incubator (37 ° C., 5% CO 2 ) for 1 hour. After that, the absorbance at wavelengths of 450 nm and 650 nm was measured.
  • the number of living cells in the cultured samples (Comparative Examples, Examples 1 to 3) is the difference between the absorbance at a wavelength of 450 nm and the absorbance at 650 nm (absorbance 450 nm -absorbance 650 nm ) with the difference in the initial sample (absorbance 450 nm -absorbance 650 nm ). It was calculated by comparison.
  • Example 1 As shown in Table 2 and FIG. 1, the number of viable gingival epithelial cells cultured in the presence of hinokithiol (Example 1) as compared with the number of viable gingival epithelial cells cultured in the absence of hinokithiol (Comparative Example). ⁇ 3) were all increasing. Further, it was confirmed that in the 24-hour culture, Example 1 showed a higher proliferative tendency than Examples 2 and 3, and after 48 hours, Examples 1 and 2 exhibited a higher enhancing effect than Examples 3. Was done. From the above, it was found that hinokitiol has an action of activating gingival epithelial cells and promoting their cell proliferation.
  • the preparation of the present invention having the forms of a dentifrice (Table 3), a mouthwash (Table 4), and a gel (Table 5) can be prepared by the following formulation.

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Abstract

Le problème à résoudre par la présente invention est de fournir une composition orale devant être utilisée pour activer des cellules épithéliales gingivales ou favoriser la prolifération des cellules. Le problème à résoudre par la présente invention est également de fournir une composition orale devant être utilisé pour améliorer la fonction de la barrière gingivale ou réparer un tissu parodontal. La solution selon l'invention porte sur un activateur de cellules épithéliales gingivales, un promoteur de prolifération de cellules épithéliales gingivales, un activateur de fonction de barrière gingivale ou un agent de réparation de tissu parodontal, chacun étant préparé à l'aide d'hinokitiol en tant que principe actif.
PCT/JP2020/030990 2019-08-19 2020-08-17 Activateur de cellules épithéliales gingivales WO2021033661A1 (fr)

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JP2019-149851 2019-08-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7204846B1 (ja) 2021-08-31 2023-01-16 サンスター株式会社 ヒノキチオール含有組成物

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Publication number Priority date Publication date Assignee Title
JPS63188619A (ja) * 1987-01-29 1988-08-04 Shiseido Co Ltd 口腔用組成物
JP2002047162A (ja) * 2000-08-01 2002-02-12 Asahi Kasei Corp 口腔用組成物
WO2018066341A1 (fr) * 2016-10-06 2018-04-12 ライオン株式会社 Composition pour cavité buccale, et procédé d'inhibition de variation de couleur de préparation et de séparation de liquide associés
JP2019214538A (ja) * 2018-06-14 2019-12-19 小林製薬株式会社 歯肉組織細胞への歯周病菌の侵入抑制剤
JP2020109071A (ja) * 2018-12-28 2020-07-16 小林製薬株式会社 歯周病原因菌産生システインプロテアーゼ活性抑制剤

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Publication number Priority date Publication date Assignee Title
JPS63188619A (ja) * 1987-01-29 1988-08-04 Shiseido Co Ltd 口腔用組成物
JP2002047162A (ja) * 2000-08-01 2002-02-12 Asahi Kasei Corp 口腔用組成物
WO2018066341A1 (fr) * 2016-10-06 2018-04-12 ライオン株式会社 Composition pour cavité buccale, et procédé d'inhibition de variation de couleur de préparation et de séparation de liquide associés
JP2019214538A (ja) * 2018-06-14 2019-12-19 小林製薬株式会社 歯肉組織細胞への歯周病菌の侵入抑制剤
JP2020109071A (ja) * 2018-12-28 2020-07-16 小林製薬株式会社 歯周病原因菌産生システインプロテアーゼ活性抑制剤

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Title
DOMON, HISANORI, HIYOSHI TAKUMI, MAEKAWA TOMOKI, YONEZAWA DAISUKE, TAMURA HIKARU, KAWABATA SHIGETADA, YANAGIHARA KATSUNORI, KIMURA: "Antibacterial activity of hinokitiol against both antibiotic-resistant and - susceptible pathogenic bacteria that predominate in the oral cavity and upper airways", MICROBIOLOGY AND IMMUNOLOGY, vol. 63, no. issue 6, June 2019 (2019-06-01), pages 213 - 222, XP055794843, DOI: 10.1111/1348-0421.12688 *
SHOJI, SHIGERU ET AL.: "Study on cell activation by Hinokitiol -Expression of VEGF and IL -8", ORAL THERAPEUTICS AND PHARMACOLOGY, vol. 25, no. 3, 1 December 2006 (2006-12-01), pages 103 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7204846B1 (ja) 2021-08-31 2023-01-16 サンスター株式会社 ヒノキチオール含有組成物
JP2023034868A (ja) * 2021-08-31 2023-03-13 サンスター株式会社 ヒノキチオール含有組成物

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