JP2023034868A - Hinokitiol-containing composition - Google Patents
Hinokitiol-containing composition Download PDFInfo
- Publication number
- JP2023034868A JP2023034868A JP2021141317A JP2021141317A JP2023034868A JP 2023034868 A JP2023034868 A JP 2023034868A JP 2021141317 A JP2021141317 A JP 2021141317A JP 2021141317 A JP2021141317 A JP 2021141317A JP 2023034868 A JP2023034868 A JP 2023034868A
- Authority
- JP
- Japan
- Prior art keywords
- hinokitiol
- cells
- composition
- bacteria
- oral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 239000000203 mixture Substances 0.000 title claims abstract description 54
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- 241000894006 Bacteria Species 0.000 claims abstract description 48
- 208000028169 periodontal disease Diseases 0.000 claims abstract description 15
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- 230000003213 activating effect Effects 0.000 claims description 4
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Abstract
Description
本開示は、ヒノキチオールを含有する組成物及びその用途等に関する。なお、本明細書に記載される全ての文献の内容は参照により本明細書に組み込まれる。 TECHNICAL FIELD The present disclosure relates to compositions containing hinokitiol, uses thereof, and the like. It should be noted that the contents of all documents mentioned herein are hereby incorporated by reference.
歯周病は細菌(歯周病菌)の感染によって引き起こされる炎症性疾患であり、このため歯周病の予防又は治療のために重要な要因の一つとして、歯周病菌の活動を抑制することが挙げられる。このため、歯周病菌の殺菌又は抑制を目的に、数多くの口腔用組成物が研究開発されてきている(例えば特許文献1)。 Periodontal disease is an inflammatory disease caused by infection with bacteria (periodontal disease bacteria). Therefore, one of the important factors for the prevention or treatment of periodontal disease is to suppress the activity of periodontal disease bacteria. is mentioned. For this reason, many oral compositions have been researched and developed for the purpose of sterilizing or suppressing periodontal disease bacteria (for example, Patent Document 1).
歯周病菌であるP. gingivalisは、細胞(特に歯肉上皮細胞)に侵入することが知られている。侵入したP. gingivalisは、強力な細胞傷害性を発揮する。侵入したP. gingivalisの幾分かはリソソームで分解されるが、この分解経路から回避するため細胞内でオートファジーを誘導する。これにより、P. gingivalisはオートファゴソームに取り込まれるが、このオートファゴソーム内で細胞内の分解反応から逃れ、増殖し、細胞傷害性を発揮するのである(非特許文献1)。さらには細胞内に侵入した菌の半数近くは初期エンドソームからrecycling pathwayを経由して細胞外に出て、周囲の細胞に再侵入する。このため、P. gingivalisは細胞間を往来し・生き長らえ・増殖し・感染を続けるのである(例えば次のウェブページを参照:http://web.dent.osaka-u.ac.jp/~prevent/research01.html)。 P. gingivalis, a periodontal pathogen, is known to invade cells, especially gingival epithelial cells. Invading P. gingivalis exerts potent cytotoxicity. Some of the invading P. gingivalis is degraded in lysosomes, and autophagy is induced in the cell to avoid this degradation pathway. As a result, P. gingivalis is incorporated into autophagosomes, where it escapes intracellular degradation reactions, proliferates, and exerts cytotoxicity (Non-Patent Document 1). Furthermore, nearly half of the bacteria that have invaded the cell exit the cell via the recycling pathway from early endosomes and re-invade the surrounding cells. For this reason, P. gingivalis can move between cells, survive, proliferate, and continue to infect (for example, see the following web page: http://web.dent.osaka-u.ac.jp/~ prevent/research01.html).
この歯肉上皮細胞内への歯周病菌の侵入は、上記の為害作用に加え、殺菌剤からの逃避につながる。すなわち、殺菌又は抑制効果を奏する有効成分を含有する口腔用組成物を口腔内に適用しても、この有効成分が細胞内に侵入している歯周病菌まで到達し難く、このために、歯周病菌を殺菌又は抑制することが難しくなる。このため、歯周病菌が細胞に侵入するのを抑制する手段が検討されている(特許文献2、3)。 The invasion of periodontal bacteria into the gingival epithelial cells leads to escape from the disinfectant, in addition to the above-mentioned harmful effects. That is, even if an oral composition containing an active ingredient that exhibits a bactericidal or inhibitory effect is applied in the oral cavity, it is difficult for the active ingredient to reach the periodontal bacteria that have invaded the cells. It becomes difficult to sterilize or suppress pericobacteria. Therefore, means for suppressing the invasion of periodontal bacteria into cells have been investigated (Patent Documents 2 and 3).
今回、本発明者らは、歯肉上皮細胞内へ侵入した歯周病菌を抑制(好ましくは殺菌)する手法について、検討を進めた。 This time, the present inventors have investigated a method for suppressing (preferably sterilizing) periodontal bacteria that have invaded gingival epithelial cells.
本発明者らは、ヒノキチオールが、口腔細胞内の消化活性を亢進する効果を奏すること、当該効果によって口腔細胞(特に歯肉上皮細胞)へ侵入した歯周病菌を抑制し得ること、を見いだし、さらに改良を重ねた。 The present inventors found that hinokitiol has the effect of enhancing digestive activity in oral cells, and that this effect can suppress periodontal bacteria that have invaded oral cells (especially gingival epithelial cells). Made improvements.
本開示は例えば以下の項に記載の主題を包含する。
項1.
ヒノキチオールを有効成分として含有する、口腔細胞内の消化活性を亢進するための、組成物。
項2.
ヒノキチオールを有効成分として含有する、口腔細胞のリソソーム内分解反応活性化用組成物。
項3.
ヒノキチオールを有効成分として含有する、口腔細胞又はそれより構成される組織の、歯周病菌への抵抗力強化用組成物。
項4.
ヒノキチオールを有効成分として含有する、口腔細胞又はそれより構成される組織の、歯周病菌への防御力強化用組成物。
項5.
ヒノキチオールを有効成分として含有する、口腔細胞又はそれより構成される組織内の歯周病菌排除用組成物。
項6.
ヒノキチオール含有濃度が50~2000ppmである、項1~5に記載の組成物。
項7.
口腔用組成物である、項1~6のいずれかに記載の組成物。
項8.
口腔細胞内にPorphyromonas gingivalisが存在する対象のための、項1~7のいずれかに記載の組成物。
項9.
口腔細胞が歯肉上皮細胞である、項1~8のいずれかに記載の組成物。
The disclosure includes, for example, subject matter described in the following sections.
Section 1.
A composition for enhancing digestive activity in oral cells, containing hinokitiol as an active ingredient.
Section 2.
A composition for activating the intralysosomal degradation reaction of oral cells, containing hinokitiol as an active ingredient.
Item 3.
A composition containing hinokitiol as an active ingredient for enhancing the resistance of oral cells or tissue composed thereof to periodontal bacteria.
Section 4.
A composition containing hinokitiol as an active ingredient for enhancing the defense ability of oral cells or tissue composed thereof against periodontal disease bacteria.
Item 5.
A composition for eliminating periodontal disease bacteria in oral cells or tissue composed thereof, containing hinokitiol as an active ingredient.
Item 6.
Item 6. The composition according to Items 1 to 5, wherein the concentration of hinokitiol is 50 to 2000 ppm.
Item 7.
Item 7. The composition according to any one of Items 1 to 6, which is an oral composition.
Item 8.
Item 8. The composition of any one of Items 1 to 7, for a subject having Porphyromonas gingivalis present in oral cells.
Item 9.
Item 9. The composition according to any one of Items 1 to 8, wherein the oral cells are gingival epithelial cells.
口腔細胞へ侵入した歯周病菌を抑制・排除し、細胞内を浄化することが可能となる。また、侵入した歯周病に対する抵抗力・防御力を口腔細胞に付与することができる。 It is possible to suppress and eliminate periodontal bacteria that have invaded oral cells and purify the cells. In addition, it is possible to provide oral cells with resistance and defense against invaded periodontal disease.
以下、本開示に包含される各実施形態について、さらに詳細に説明する。本開示は、ヒノキチオール含有組成物及びその用途等を好ましく包含するが、これらに限定されるわけではなく、本開示は本明細書に開示され当業者が認識できる全てを包含する。 Each embodiment included in the present disclosure will be described in further detail below. The present disclosure preferably includes, but is not limited to, hinokitiol-containing compositions and uses thereof, and includes everything disclosed herein and recognized by a person skilled in the art.
本開示に包含されるヒノキチオール含有組成物は、口腔細胞内の消化活性を亢進するための組成物である。本開示に包含される当該組成物を「本開示の組成物」ということがある。 A hinokitiol-containing composition included in the present disclosure is a composition for enhancing digestive activity in oral cells. Such compositions encompassed by the present disclosure are sometimes referred to as "compositions of the present disclosure."
ヒノキチオールは、以下の式: Hinokitiol has the following formula:
で表される化合物である。本開示の組成物に用いられるヒノキチオールは、合成品であってもよく、また天然物(例えばヒバ)から抽出されたものであってもよい。 It is a compound represented by Hinokitiol used in the composition of the present disclosure may be a synthetic product or may be extracted from a natural product (for example, Hiba).
本開示の組成物におけるヒノキチオール含有量は、効果が奏される範囲であれば、特に限定はされない。例えば、本開示の組成物には、ヒノキチオールが50~2000ppm程度含有されることが好ましい。当該範囲の上限又は下限は例えば60、70、80、90、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1050、1100、1150、1200、1250、1300、1350、1400、1450、1500、1550、1600、1650、1700、1750、1800、1850、1900、又は1950ppmであってもよい。例えば当該範囲は60~1500ppmであってもよい。特に限定はされないが、口腔細胞内の消化活性を亢進する効果がより一層強く奏されるという観点から、ヒノキチオール含有量は、300ppmであることが特に好ましい。また、特に限定はされないが、ヒノキチオールにより口腔細胞が大きく傷害されるのを避けるという観点から、ヒノキチオール含有量は、1000ppm未満が特に好ましく、中でも800、750、又は700ppm以下であることが好ましい。 The content of hinokitiol in the composition of the present disclosure is not particularly limited as long as it is within the range where the effect is exhibited. For example, the composition of the present disclosure preferably contains about 50 to 2000 ppm of hinokitiol. The upper or lower limit of the range is, for example, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, or 1950 ppm. For example, the range may be 60-1500 ppm. Although not particularly limited, the hinokitiol content is particularly preferably 300 ppm from the viewpoint that the effect of enhancing the digestive activity in oral cells is exhibited more strongly. Although not particularly limited, the hinokitiol content is particularly preferably less than 1000 ppm, and more preferably 800, 750, or 700 ppm or less, from the viewpoint of avoiding severe damage to oral cells by hinokitiol.
ヒノキチオールは、口腔細胞に適用されることで、口腔細胞内の消化活性を亢進する効果を奏する。これにより、口腔細胞内へ侵入した歯周病菌を効率よく消化し抑制することができる。特に、ヒノキチオールは、口腔細胞に適用されることで、リソソームでの分解反応を活性化し、これによって口腔細胞内の消化活性を亢進させ、口腔細胞内へ侵入した歯周病菌を効率よく消化し抑制することができる。 Hinokitiol exerts an effect of enhancing digestive activity in oral cells by being applied to oral cells. As a result, periodontal bacteria that have invaded into oral cells can be efficiently digested and suppressed. In particular, when hinokitiol is applied to oral cells, it activates the degradation reaction in lysosomes, thereby enhancing the digestive activity in oral cells and efficiently digesting and suppressing periodontal bacteria that have invaded oral cells. can do.
このため、ヒノキチオールを含有する本開示の組成物は、口腔用組成物として好ましく用いられる。また、特に歯周病の予防又は治療用として好ましく用いられる。すなわち、本発明に包含される組成物の特に好ましい一形態は抗歯周病口腔用組成物である。 Therefore, the composition of the present disclosure containing hinokitiol is preferably used as an oral composition. In addition, it is particularly preferably used for the prevention or treatment of periodontal disease. That is, one particularly preferred form of the composition encompassed by the present invention is an anti-periodontal oral composition.
また、本開示の組成物は、リソソーム内分解反応活性化用組成物としても好ましく用いることができる。当該リソソーム内分解反応活性化用組成物は、特に歯周病菌が侵入した(すなわち、歯周病菌が内部に存在する)口腔細胞のために好ましく用いることができる。 In addition, the composition of the present disclosure can also be preferably used as a composition for activating an intralysosomal degradation reaction. The composition for activating the intralysosomal degradation reaction can be preferably used particularly for oral cells invaded by periodontal bacteria (that is, periodontal bacteria exist inside).
また、本開示の組成物は、口腔細胞や、口腔細胞により構成される組織(特に歯周組織)における、歯周病菌への抵抗力を強化するため、若しくは、歯周病菌への防御力を強化するため、に好ましく用いることができる。 In addition, the composition of the present disclosure is used to strengthen the resistance to periodontal bacteria in oral cells and tissues composed of oral cells (especially periodontal tissue), or to improve the protective power against periodontal bacteria. For strengthening, it can be preferably used for.
口腔細胞としては、特に限定はされないが、歯肉上皮細胞が特に好ましい。歯周病菌が侵入しダメージを受けやすいのが歯肉上皮細胞であるからである。 The oral cells are not particularly limited, but gingival epithelial cells are particularly preferred. This is because gingival epithelial cells are susceptible to invasion and damage by periodontal disease bacteria.
なお、本開示の組成物が特に有効な歯周病菌としては、本発明の効果が奏される限り特に限定されないが、例えばPorphyromonas gingivalis(P.gingivalis)が好ましく挙げられる。 Periodontal disease bacteria for which the composition of the present disclosure is particularly effective are not particularly limited as long as the effects of the present invention are exhibited, but a preferred example is Porphyromonas gingivalis (P. gingivalis).
また、本開示組成物の適用対象としては、口腔細胞内に歯周病菌が侵入している(すなわち、口腔細胞内に歯周病菌が存在する)対象が好ましい。また、ヒトを含む哺乳動物(例えばイヌ、ネコ、マウス、ラット、ヒツジ、ウマ、ウシ、サル等)に好ましく用いることができ、特にヒトが好ましい In addition, the subject to which the composition of the present disclosure is applied is preferably a subject in which periodontal bacteria have invaded oral cavity cells (that is, subjects in which periodontal disease bacteria are present in oral cells). In addition, it can be preferably used for mammals including humans (e.g., dogs, cats, mice, rats, sheep, horses, cows, monkeys, etc.), with humans being particularly preferred.
本開示の組成物は、例えば、固形組成物、液体組成物等で有り得る。また、本開示の組成物は、本開示の組成物(特に口腔用組成物)は、常法に従って例えば軟膏剤、ペースト剤、パスタ剤、ジェル剤、液剤、スプレー剤、洗口液剤、液体歯磨剤、練歯磨剤、ガム剤等の形態(剤形)にすることができる。なかでも、洗口液剤、液体歯磨剤、練歯磨剤、軟膏剤、ペースト剤、液剤、ジェル剤であることが好ましい。 Compositions of the present disclosure can be, for example, solid compositions, liquid compositions, and the like. In addition, the composition of the present disclosure (particularly oral compositions) can be prepared according to conventional methods, such as ointments, pastes, pastes, gels, liquids, sprays, mouthwashes, and liquid dentifrices. It can be in the form (dosage form) of an agent, toothpaste, gum, or the like. Among them, mouthwashes, liquid dentifrices, toothpastes, ointments, pastes, liquids and gels are preferred.
本開示の組成物には、効果を損なわない範囲で、例えば口腔用組成物に配合し得る任意成分を単独で又は2種以上さらに含有してもよい。 The composition of the present disclosure may further contain, for example, one or two or more optional components that can be blended in an oral composition, as long as the effects are not impaired.
例えば、界面活性剤として、ノニオン界面活性剤、アニオン界面活性剤または両性界面活性剤を配合することができる。具体的には、例えば、ノニオン界面活性剤としてはショ糖脂肪酸エステル、マルトース脂肪酸エステル、ラクトース脂肪酸エステル等の糖脂肪酸エステル;脂肪酸アルカノールアミド類;グリセリン脂肪酸エステル;ソルビタン脂肪酸エステル;脂肪酸モノグリセライド;ポリオキシエチレン付加係数が8~10、アルキル基の炭素数が13~15であるポリオキシエチレンアルキルエーテル;ポリオキシエチレン付加係数が10~18、アルキル基の炭素数が9であるポリオキシエチレンアルキルフェニルエーテル;セバシン酸ジエチル;ポリオキシエチレン硬化ヒマシ油;脂肪酸ポリオキシエチレンソルビタン等が挙げられる。アニオン界面活性剤としては、ラウリル硫酸ナトリウム、ポリオキシエチレンラウリルエーテル硫酸ナトリウム等の硫酸エステル塩;ラウリルスルホコハク酸ナトリウム、ポリオキシエチレンラウリルエーテルスルホコハク酸ナトリウム等のスルホコハク酸塩;ココイルサルコシンナトリウム、ラウロイルメチルアラニンナトリウム等のアシルアミノ酸塩;ココイルメチルタウリンナトリウム等が挙げられる。両性イオン界面活性剤としては、ラウリルジメチルアミノ酢酸ベタイン、ヤシ油脂肪酸アミドプロピルジメチルアミノ酢酸ベタイン等の酢酸ベタイン型活性剤;N-ココイル-N-カルボキシメチル-N-ヒドロキシエチルエチレンジアミンナトリウム等のイミダゾリン型活性剤;N-ラウリルジアミノエチルグリシン等のアミノ酸型活性剤等が挙げられる。これらの界面活性剤は、単独または2種以上を組み合わせて配合することができる。その配合量は、通常、組成物全量に対して0.1~5質量%である。 For example, nonionic surfactants, anionic surfactants or amphoteric surfactants can be blended as surfactants. Specifically, for example, nonionic surfactants include sugar fatty acid esters such as sucrose fatty acid esters, maltose fatty acid esters, and lactose fatty acid esters; fatty acid alkanolamides; glycerin fatty acid esters; sorbitan fatty acid esters; fatty acid monoglycerides; Polyoxyethylene alkyl ether having an addition coefficient of 8 to 10 and an alkyl group having 13 to 15 carbon atoms; Polyoxyethylene alkylphenyl ether having a polyoxyethylene addition coefficient of 10 to 18 and an alkyl group having 9 carbon atoms; diethyl sebacate; polyoxyethylene hydrogenated castor oil; fatty acid polyoxyethylene sorbitan; Examples of anionic surfactants include sulfuric acid ester salts such as sodium lauryl sulfate and sodium polyoxyethylene lauryl ether sulfate; sulfosuccinates such as sodium lauryl sulfosuccinate and sodium polyoxyethylene lauryl ether sulfosuccinate; sodium cocoyl sarcosinate and lauroyl methylalanine. acyl amino acid salts such as sodium; cocoyl methyl taurate sodium; Zwitterionic surfactants include betaine acetate type surfactants such as betaine lauryldimethylaminoacetate and betaine coconut oil fatty acid amidopropyldimethylaminoacetate; imidazoline type surfactants such as N-cocoyl-N-carboxymethyl-N-hydroxyethylethylenediamine sodium. Active agent: amino acid-type active agent such as N-lauryldiaminoethylglycine, and the like. These surfactants can be blended singly or in combination of two or more. The blending amount thereof is usually 0.1 to 5% by mass based on the total amount of the composition.
また、香味剤として、例えば、メントール、カルボン酸、アネトール、オイゲノール、サリチル酸メチル、リモネン、オシメン、n-デシルアルコール、シトロネール、α-テルピネオール、メチルアセタート、シトロネニルアセタート、メチルオイゲノール、シネオール、リナロール、エチルリナロール、チモール、スペアミント油、ペパーミント油、レモン油、オレンジ油、セージ油、ローズマリー油、珪皮油、シソ油、冬緑油、丁子油、ユーカリ油、ピメント油、d-カンフル、d-ボルネオール、ウイキョウ油、ケイヒ油、シンナムアルデヒド、ハッカ油、バニリン等の香料を用いることができる。これらは、単独または2種以上を組み合わせて組成物全量に対して例えば0.001~1.5質量%配合することができる。 Flavoring agents such as menthol, carboxylic acid, anethole, eugenol, methyl salicylate, limonene, ocimene, n-decyl alcohol, citronol, α-terpineol, methyl acetate, citronenyl acetate, methyl eugenol, cineole, Linalool, ethyl linalool, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil, pimento oil, d-camphor, Perfumes such as d-borneol, fennel oil, cinnamon oil, cinnamaldehyde, peppermint oil and vanillin can be used. These may be blended singly or in combination of two or more in an amount of, for example, 0.001 to 1.5% by mass based on the total amount of the composition.
また、甘味剤として、例えば、サッカリンナトリウム、アセスルファームカリウム、ステビオサイド、ネオヘスペリジルジヒドロカルコン、ペリラルチン、タウマチン、アスパラチルフェニルアラニルメチルエステル、p-メトキシシンナミックアルデヒド等を用いることができる。これらは、組成物全量に対して例えば0.01~1質量%配合することができる。 Sweeteners that can be used include, for example, saccharin sodium, acesulfame potassium, stevioside, neohesperidyl dihydrochalcone, perillartine, thaumatin, aspartylphenylalanylmethyl ester, p-methoxycinnamic aldehyde, and the like. These can be blended, for example, in an amount of 0.01 to 1% by mass relative to the total amount of the composition.
さらに、湿潤剤として、ソルビット、エチレングリコール、プロピレングリコール、グリセリン、1,3―ブチレングリコール、ポリプロピレングリコール、キシリット、マルチット、ラクチット、ポリオキシエチレングリコール等を単独または2種以上を組み合わせて配合することができる。 Furthermore, as wetting agents, sorbit, ethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, polypropylene glycol, xylit, maltit, lactit, polyoxyethylene glycol, etc. may be blended alone or in combination of two or more. can.
粘結剤としては、カルボキシメチルセルロースナトリウム、カルボキシメチルエチルセルロース塩、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、エチルセルロース、結晶セルロース、結晶セルロース・カルメロースナトリウムなどのセルロース誘導体、キサンタンガムなどの微生物産生高分子、トラガントガム、カラヤガム、アラビヤガム、カラギーナン、デキストリン、寒天、ペクチン、プルラン、ジェランガム、ローカストビーンガム、アルギン酸ナトリウムなどの天然高分子または天然ゴム類、ポリビニルアルコール、ポリビニルピロリドン、カルボキシビニルポリマー、ポリビニルメチルエーテル、ポリアクリル酸ナトリウムなどの合成高分子、増粘性シリカ、ビーガムなどの無機粘結剤、塩化O-[2-ヒドロキシ-3-(トリメチルアンモニオ)プロピル]ヒドロキシエチルセルロースなどのカチオン性粘結剤が挙げられる。これら粘結剤は、単独であるいは2種以上を組み合わせて使用することができる。 Binders include sodium carboxymethyl cellulose, carboxymethyl ethyl cellulose salt, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, crystalline cellulose, cellulose derivatives such as crystalline cellulose and carmellose sodium, and microbial productivity such as xanthan gum. Natural polymers or natural gums such as molecules, tragacanth gum, karaya gum, gum arabic, carrageenan, dextrin, agar, pectin, pullulan, gellan gum, locust bean gum, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl methyl ether, Synthetic polymers such as sodium polyacrylate, thickening silica, inorganic binders such as Veegum, and cationic binders such as O-[2-hydroxy-3-(trimethylammonio)propyl]hydroxyethylcellulose chloride. be done. These caking agents can be used individually or in combination of 2 or more types.
防腐剤として、メチルパラベン、エチルパラベン、プロピルパラベン、ブチルパラベン等のパラベン類、安息香酸ナトリウム、フェノキシエタノール、塩酸アルキルジアミノエチルグリシン等を配合することができる。 As preservatives, parabens such as methylparaben, ethylparaben, propylparaben and butylparaben, sodium benzoate, phenoxyethanol, alkyldiaminoethylglycine hydrochloride, and the like can be added.
着色剤として、青色1号、黄色4号、赤色202号、緑3号等の法定色素、群青、強化群青、紺青等の鉱物系色素、酸化チタン等を配合してもよい。 As a coloring agent, legal dyes such as Blue No. 1, Yellow No. 4, Red No. 202 and Green No. 3, mineral dyes such as ultramarine blue, enhanced ultramarine blue and Prussian blue, titanium oxide, and the like may be blended.
pH調整剤として、クエン酸、リン酸、リンゴ酸、ピロリン酸、乳酸、酒石酸、グリセロリン酸、酢酸、硝酸、またはこれらの化学的に可能な塩や水酸化ナトリウム等を配合してもよい。これらは、組成物のpHが4~8、好ましくは5~7の範囲となるよう、単独または2種以上を組み合わせて配合することができる。pH調整剤の配合量は例えば0.01~2重量%であってよい。 As a pH adjuster, citric acid, phosphoric acid, malic acid, pyrophosphoric acid, lactic acid, tartaric acid, glycerophosphoric acid, acetic acid, nitric acid, or chemically possible salts thereof, sodium hydroxide, or the like may be added. These may be blended singly or in combination of two or more so that the pH of the composition is in the range of 4-8, preferably 5-7. The blending amount of the pH adjuster may be, for example, 0.01 to 2% by weight.
なお、本開示の口腔用組成物には、さらに、薬効成分として酢酸dl-α-トコフェロール、コハク酸トコフェロール、またはニコチン酸トコフェロール等のビタミンE類、ドデシルジアミノエチルグリシン等の両性殺菌剤、トリクロサン、イソプロピルメチルフェノール等の非イオン性殺菌剤、ラウロイルサルコシンナトリウム等のアニオン系殺菌剤、塩化セチルピリジニウム、塩酸クロルヘキシジン、塩化ベンザルコニウム、塩化ベンゼトニウム等のカチオン系殺菌剤、デキストラナーゼ、アミラーゼ、プロテアーゼ、ムタナーゼ、リゾチーム、溶菌酵素(リテックエンザイム)等の酵素、モノフルオロリン酸ナトリウム、モノフルオロリン酸カリウム等のアルカリ金属モノフルオロフォスフェート、フッ化ナトリウム、フッ化第一錫等のフッ化物、トラネキサム酸やイプシロンアミノカプロン酸、アルミニウムクロルヒドロキシルアラントイン、ジヒドロコレステロール、グリチルレチン酸、グリチルリチン酸、銅クロロフィリンナトリウム、グリセロフォスフェート、クロロフィル、塩化ナトリウム、カロペプタイド、アラントイン、カルバゾクロム、硝酸カリウム、パラチニット等を、単独または2種以上を組み合わせて配合することができる。 The oral cavity composition of the present disclosure further includes vitamin E compounds such as dl-α-tocopherol acetate, tocopherol succinate, or tocopherol nicotinate as active ingredients, amphoteric fungicides such as dodecyldiaminoethylglycine, triclosan, Nonionic fungicides such as isopropylmethylphenol, anionic fungicides such as sodium lauroyl sarcosinate, cationic fungicides such as cetylpyridinium chloride, chlorhexidine hydrochloride, benzalkonium chloride, and benzethonium chloride, dextranase, amylase, protease, Enzymes such as mutanase, lysozyme, lytic enzyme (retech enzyme), alkali metal monofluorophosphates such as sodium monofluorophosphate and potassium monofluorophosphate, fluorides such as sodium fluoride and stannous fluoride, tranexamic acid or epsilon aminocaproic acid, aluminum chlorohydroxyallantoin, dihydrocholesterol, glycyrrhetinic acid, glycyrrhizic acid, sodium copper chlorophyllin, glycerophosphate, chlorophyll, sodium chloride, calopeptide, allantoin, carbazochrome, potassium nitrate, palatinit, etc., either alone or in combination of two or more. They can be formulated in combination.
また、基剤として、アルコール類、シリコン、アパタイト、白色ワセリン、パラフィン、流動パラフィン、マイクロクリスタリンワックス、スクワラン、プラスチベース等を添加することも可能である。 As a base, alcohols, silicon, apatite, white petrolatum, paraffin, liquid paraffin, microcrystalline wax, squalane, plastibase, etc. can be added.
なお、本明細書において「含む」とは、「本質的にからなる」と、「からなる」をも包含する(The term "comprising" includes "consisting essentially of” and "consisting of.")。また、本開示は、本明細書に説明した構成要件の任意の組み合わせを全て包含する。 In this specification, the term "comprising" includes "consisting essentially of" and "consisting of." Also, the present disclosure encompasses any and all combinations of the constituent elements described herein.
また、上述した本開示の各実施形態について説明した各種特性(性質、構造、機能等)は、本開示に包含される主題を特定するにあたり、どのように組み合わせられてもよい。すなわち、本開示には、本明細書に記載される組み合わせ可能な各特性のあらゆる組み合わせからなる主題が全て包含される。 Also, the various characteristics (property, structure, function, etc.) described for each of the embodiments of the disclosure described above may be combined in any way to identify subject matter encompassed by the disclosure. That is, the present disclosure encompasses all subject matter consisting of any and all possible combinations of the features described herein.
以下、例を示して本開示の実施形態をより具体的に説明するが、本開示の実施形態は下記の例に限定されるものではない。なお、以下特に断らない限り、CO2濃度を示す%以外の%は質量%を示す。 Hereinafter, the embodiments of the present disclosure will be described more specifically with examples, but the embodiments of the present disclosure are not limited to the following examples. Unless otherwise specified, % other than % indicating CO 2 concentration indicates % by mass.
<P. gingivalisの培養>
106個/mLのPorphyromonas gingivalis OMZ314株(以下、P.g)を、10mL変法GAM培地を含む試験管に接種した。その後、37℃嫌気条件下で1日培養した(前培養)。
<P. Culture of gingivalis>
10 6 cells/mL of Porphyromonas gingivalis strain OMZ314 (hereinafter Pg) were inoculated into a test tube containing 10 mL modified GAM medium. After that, the cells were cultured under 37° C. anaerobic conditions for one day (preculture).
前培養で得られた菌液1mLを新しい10mL変法GAM培地を含む試験管に移し、37℃嫌気条件下で1日培養した(本培養)。 1 mL of the bacterial solution obtained in the pre-culture was transferred to a test tube containing 10 mL of new modified GAM medium, and cultured under 37° C. anaerobic conditions for 1 day (main culture).
本培養で得られたP.gを10%FBS含有MEM培地にてO.D600=0.1に調整し、P.g菌液として試験に用いた。 P. spp. 10% FBS-containing MEM medium. D600 was adjusted to 0.1 and P.D. It was used for the test as a g bacterial solution.
<歯肉上皮細胞の培養>
歯肉上皮細胞(Ca9-22株)を10%FBS含有MEM培地に懸濁し、2.0×105個/mLに調整した後、1mLずつ12ウェルプレートの各ウェルに分注し、37℃、5%CO2の条件下で1日培養し、試験に用いた。
<Culture of gingival epithelial cells>
Gingival epithelial cells (Ca9-22 strain) were suspended in 10% FBS-containing MEM medium and adjusted to 2.0×10 5 cells/mL, then 1 mL was dispensed into each well of a 12-well plate and placed at 37° C. It was cultured for 1 day under 5% CO2 conditions and used for the test.
<供試素材溶液の調製>
供試素材としてヒノキチオール、銅クロロフィリンナトリウム(銅クロ)、トコフェロール酢酸エステル(VEA)、トコフェロールニコチン酸エステル(VEN)、ピリドキシン塩酸塩(VB6)を用いた。各素材について、1%エタノールを10%FBS含有MEM培地で溶解した溶液を溶媒とし、所定の濃度となる溶液を調製した。以下、各素材の溶液は、当該溶媒で溶解したものを示す。
<Preparation of test material solution>
Hinokitiol, sodium copper chlorophyllin (copper chromate), tocopherol acetate (VEA), tocopherol nicotinate (VEN), and pyridoxine hydrochloride (VB6) were used as test materials. For each material, a solution of 1% ethanol dissolved in 10% FBS-containing MEM medium was used as a solvent to prepare a solution having a predetermined concentration. Hereinafter, the solutions of each material indicate those dissolved in the solvent.
P. gingivalis細胞内分解検討(実験1)
歯肉上皮細胞の培養後、培地をP.g菌液に置換し、37℃、5%CO2条件下で2時間共培養し、P.g菌の歯肉上皮細胞への侵入を誘導した。培養2時間後、リン酸緩衝生理食塩水(PBS)で細胞内に侵入していないP.g菌を洗浄した上で、濃度100ppmに調整した各素材溶液1mLを歯肉上皮細胞に添加し、37℃、5%CO2の条件の下2時間培養した。培養2時間後、PBSで洗浄して、新鮮な10%FBS含有MEM培地に置換し、37℃、5%CO2の条件の下20時間培養した。培養20時間後、PBSで洗浄して、0.25%Trypsin-EDTA溶液200μLを37℃で5分間処理して、細胞を剥がし、その後、10%FBS含有MEM培地1.8mLで反応を停止させ、溶液を回収した。回収した溶液を血液寒天培地に播種し、37℃、嫌気条件で5日間培養し、寒天培地上に形成されたコロニーをカウントすることで細胞内のP.g菌の分解活性を評価した。
Examination of P. gingivalis intracellular degradation (Experiment 1)
After culturing the gingival epithelial cells, the medium was changed to P. The strain was replaced with P.g bacterial solution and co-cultivated at 37° C., 5% CO 2 for 2 hours. g induced invasion of the bacteria into gingival epithelial cells. After 2 hours of culture, non-invaded P. spp. After washing the bacteria, 1 mL of each material solution adjusted to a concentration of 100 ppm was added to the gingival epithelial cells and cultured for 2 hours under conditions of 37° C. and 5% CO 2 . After 2 hours of culture, the cells were washed with PBS, replaced with fresh 10% FBS-containing MEM medium, and cultured for 20 hours under conditions of 37° C. and 5% CO 2 . After 20 hours of culture, the cells were washed with PBS, treated with 200 μL of 0.25% Trypsin-EDTA solution at 37° C. for 5 minutes to detach the cells, and then the reaction was stopped with 1.8 mL of MEM medium containing 10% FBS. , the solution was recovered. The recovered solution was inoculated on a blood agar medium, cultured at 37° C. under anaerobic conditions for 5 days, and colonies formed on the agar medium were counted to detect intracellular P. The decomposition activity of g bacteria was evaluated.
結果を、コントロール(素材を用いずに溶媒だけを用いて同様に行った検討)でのコロニー数を細胞内P.g菌数100%としたときの相対値で、図1に示す。ヒノキチオールが、歯肉上皮細胞に侵入したP.g菌の消化を効率的に亢進していることが分かった。 The results were obtained by comparing the number of colonies in the control (similar examination using only the solvent without using the material) to the intracellular P.C. Fig. 1 shows the relative value when the number of g bacteria is 100%. Hinokitiol inhibited P. cerevisiae that invaded gingival epithelial cells. It was found that the digestion of bacterium g was efficiently promoted.
P. gingivalis細胞内分解検討(実験2)
ヒノキチオールを異なる濃度で含む溶液を調製し、上記(実験1)と同様にして、ヒノキチオールの量(溶液濃度)によって、歯肉上皮細胞に侵入したP.g菌の消化亢進効果が変化するかを検討した。結果を図2に示す。(図1と同様に、コントロール(ヒノキチオールを用いずに溶媒だけを用いて同様に行った検討)でのコロニー数を細胞内P.g菌数100%としたときの相対値で示す。)ヒノキチオールの濃度が、約40ppmを超えると、歯肉上皮細胞に侵入したP.g菌の消化亢進効果が向上することがわかった。また、ヒノキチオールの濃度が、約300ppmを超えると、歯肉上皮細胞に侵入したP.g菌の消化亢進効果が一段と向上することがわかった。
P. Examination of intracellular decomposition of gingivalis (Experiment 2)
Solutions containing different concentrations of hinokitiol were prepared, and in the same manner as described above (Experiment 1), depending on the amount of hinokitiol (solution concentration), P. It was examined whether the digestive enhancement effect of g bacteria was changed. The results are shown in FIG. (Similar to Fig. 1, the number of colonies in the control (study conducted in the same way using only the solvent without using hinokitiol) is shown as a relative value when the number of intracellular P.g bacteria is 100%.) Hinokitiol When the concentration of P. is above about 40 ppm, P. It was found that the effect of promoting digestion of g bacteria was improved. In addition, when the concentration of hinokitiol exceeds about 300 ppm, P. spp. It was found that the effect of enhancing digestion of g bacteria was further improved.
P. gingivalis殺菌検討(実験3)
ヒノキチオールを異なる濃度で含む溶液を調製し、これに対し、1/10量のP.g菌液を添加し、37℃、嫌気条件下で2時間を培養した。その後、10倍量の殺菌剤不活化培地(変法GAM培地に0.07%レシチンと0.5%Tween 80を添加したもの)を加え、これを血液寒天培地に播種し、37℃、嫌気条件で5日間を培養した。その後、寒天培地上のコロニーをカウントすることでヒノキチオールのP.g菌殺菌効果を評価した。結果を、コントロール(ヒノキチオールを用いずに溶媒だけを用いて同様に行った検討)でのコロニー数をP.g菌数100%としたときの相対値で、図3に示す。ヒノキチオール自身には、P.g菌を殺菌する効果は、ほとんど無いないことがわかった。
P. gingivalis sterilization study (experiment 3)
Solutions containing different concentrations of hinokitiol were prepared, whereas 1/10 amount of P. g bacterial solution was added and cultured at 37° C. under anaerobic conditions for 2 hours. Then, 10 volumes of fungicide-inactivated medium (modified GAM medium supplemented with 0.07% lecithin and 0.5% Tween 80) was added, which was inoculated onto blood agar medium and anaerobicly treated at 37°C. conditions for 5 days. After that, by counting the colonies on the agar medium, P. hinokitiol was detected. g Bactericidal effect was evaluated. The results were compared with the number of colonies in the control (similar examination using only the solvent without using hinokitiol). Fig. 3 shows the relative value when the number of g bacteria is 100%. Hinokitiol itself includes P. It was found that there was almost no effect of sterilizing g bacteria.
また、以上の結果から、ヒノキチオールは、P.g菌を直接抑制しているのではなく、歯肉上皮細胞に侵入したP.g菌の消化を亢進させることにより、P.g菌を抑制する効果を奏し得ると考えられた。 Moreover, from the above results, hinokitiol is P. g that invaded gingival epithelial cells rather than directly suppressing the bacteria. By enhancing the digestion of P. g bacteria, P. g It was thought that the effect of suppressing g bacteria could be exhibited.
細胞傷害性評価試験(実験4)
上記(実験1)と同様の操作で歯肉上皮細胞を20時間培養までの工程を実施した後、PBSで洗浄の上、WST-1溶液を添加して、37℃、5%CO2の条件下で30分間反応させた。反応液を吸光プレートリーダーにて波長450nmにおける吸光度を測定した。このとき波長600nmにおける吸光度をブランク値とした。測定した吸光度から歯肉上皮細胞の生存率を算出した。結果を、コントロール(ヒノキチオールを用いずに溶媒だけを用いて同様に行った検討)での吸光度を生存率100%としたときの相対値で、図4に示す。ヒノキチオール濃度が1000ppm以上になると、歯肉上皮細胞の傷害が進む可能性が示唆された。
Cytotoxicity evaluation test (Experiment 4)
After carrying out the steps up to culturing the gingival epithelial cells for 20 hours in the same manner as in the above (Experiment 1), after washing with PBS, WST-1 solution was added, and the cells were placed under conditions of 37°C and 5% CO2. for 30 minutes. The absorbance of the reaction solution at a wavelength of 450 nm was measured using an absorption plate reader. At this time, the absorbance at a wavelength of 600 nm was taken as a blank value. The viability of gingival epithelial cells was calculated from the measured absorbance. The results are shown in FIG. 4 as relative values when the absorbance in the control (similar examination using only a solvent without using hinokitiol) is defined as 100% survival rate. It was suggested that when the hinokitiol concentration is 1000 ppm or more, damage to gingival epithelial cells may progress.
細胞内分解活性化検討(実験5)
リソソーム酵素の活性をモニターすることができるキットであるLysoliveTM EsterGreenTM(Marker Gene Tchnologies, Inc)を用いて、歯肉上皮細胞内の消化活性(リソソーム内分解酵素活性)を検討した。
Examination of activation of intracellular degradation (Experiment 5)
Using Lysolive ™ EsterGreen ™ (Marker Gene Technologies, Inc), a kit capable of monitoring the activity of lysosomal enzymes, the digestive activity in gingival epithelial cells (intralysosomal degrading enzyme activity) was examined.
実験1と同様に以下の操作で素材溶液の2時間処理の工程まで実施し、PBSで洗浄したのちに、キットの添付説明書に従い0.1%DMSO含有MEM培地で調整したLysoliveTM EsterGreenTMを歯肉上皮細胞に添加し、これを37℃、5%CO2の条件で遮光しながら1時間培養した。培養後、PBSで洗浄したのちに、新鮮な10%FBS含有MEM培地に交換し、リソソーム活性にて検出される蛍光(励起光:490nm、放出光:525nm)を蛍光顕微鏡にて観察した(図5a)。また、視野内にある細胞数と、その細胞内に存在する蛍光染色されたリソソーム活性画分の面積をカウントし、細胞内分解酵素量(リソソーム活性画分の面積/細胞数)を算出した。結果を図5bに示す。図5a及び図5bのHT100ppmはヒノキチオール濃度100ppm溶液を用いたことを示す。当該結果から、ヒノキチオールは、リソソーム酵素活性を向上させることが分かった。よって、当該結果からも、ヒノキチオールは歯肉上皮細胞に侵入したP.g菌の消化を亢進させることにより、P.g菌を抑制する効果を奏し得ると考えられた。 In the same manner as in Experiment 1, the following operations were carried out up to the step of treating the material solution for 2 hours, and after washing with PBS, Lysolive TM EsterGreen TM adjusted with 0.1% DMSO-containing MEM medium according to the instructions attached to the kit was added. It was added to gingival epithelial cells and cultured for 1 hour at 37° C. and 5% CO 2 while shielding from light. After culturing, the cells were washed with PBS and replaced with fresh 10% FBS-containing MEM medium, and fluorescence detected by lysosomal activity (excitation light: 490 nm, emission light: 525 nm) was observed under a fluorescence microscope (Fig. 5a). In addition, the number of cells in the field of view and the area of the fluorescently-stained lysosomal active fraction present in the cells were counted, and the amount of intracellular degrading enzymes (area of lysosomal active fraction/number of cells) was calculated. The results are shown in Figure 5b. HT100 ppm in FIGS. 5a and 5b indicates that a hinokitiol concentration of 100 ppm solution was used. From the results, it was found that hinokitiol improves lysosomal enzyme activity. Therefore, this result also suggests that hinokitiol inhibits P. cerevisiae that has invaded gingival epithelial cells. By enhancing the digestion of P. g bacteria, P. g It was thought that the effect of suppressing g bacteria could be exhibited.
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