JP2023148032A - Composition for oral use - Google Patents
Composition for oral use Download PDFInfo
- Publication number
- JP2023148032A JP2023148032A JP2022055854A JP2022055854A JP2023148032A JP 2023148032 A JP2023148032 A JP 2023148032A JP 2022055854 A JP2022055854 A JP 2022055854A JP 2022055854 A JP2022055854 A JP 2022055854A JP 2023148032 A JP2023148032 A JP 2023148032A
- Authority
- JP
- Japan
- Prior art keywords
- tocopherol
- oral
- ascorbic acid
- polyoxyethylene
- alkali metal
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 54
- -1 polyoxyethylene Polymers 0.000 claims abstract description 67
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 43
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 42
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 40
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims abstract description 36
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000011627 DL-alpha-tocopherol Substances 0.000 claims abstract description 34
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 claims abstract description 34
- 239000002211 L-ascorbic acid Substances 0.000 claims abstract description 34
- 229960000984 tocofersolan Drugs 0.000 claims abstract description 34
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 28
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 24
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 17
- 239000000194 fatty acid Substances 0.000 claims abstract description 17
- 229930195729 fatty acid Natural products 0.000 claims abstract description 17
- 150000005215 alkyl ethers Chemical class 0.000 claims abstract description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000000694 effects Effects 0.000 claims description 28
- 208000028169 periodontal disease Diseases 0.000 claims description 16
- 210000000981 epithelium Anatomy 0.000 claims description 14
- 210000000214 mouth Anatomy 0.000 claims description 11
- 208000003265 stomatitis Diseases 0.000 claims description 10
- 230000004888 barrier function Effects 0.000 claims description 8
- 150000005690 diesters Chemical class 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 7
- 230000000675 anti-caries Effects 0.000 claims description 4
- 102000005741 Metalloproteases Human genes 0.000 claims description 3
- 108010006035 Metalloproteases Proteins 0.000 claims description 3
- 239000011159 matrix material Substances 0.000 claims description 3
- 125000005037 alkyl phenyl group Chemical group 0.000 abstract description 3
- 235000002639 sodium chloride Nutrition 0.000 description 23
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 22
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 18
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 18
- 239000000463 material Substances 0.000 description 18
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 15
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 14
- 238000011156 evaluation Methods 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 11
- 102100030411 Neutrophil collagenase Human genes 0.000 description 11
- 101710118230 Neutrophil collagenase Proteins 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229910019142 PO4 Inorganic materials 0.000 description 9
- 239000011668 ascorbic acid Substances 0.000 description 9
- 235000010323 ascorbic acid Nutrition 0.000 description 9
- 230000004890 epithelial barrier function Effects 0.000 description 9
- 239000010452 phosphate Substances 0.000 description 9
- 241000894006 Bacteria Species 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000006378 damage Effects 0.000 description 7
- VIHIKSJKXIMMLV-FZTHFCCHSA-M potassium;[(2r)-2-[(1s)-1,2-dihydroxyethyl]-3-hydroxy-5-oxo-2h-furan-4-yl] [(2r)-2,5,7,8-tetramethyl-2-[(4r,8r)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] phosphate Chemical compound [K+].C([C@@](OC1=C(C)C=2C)(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC1=C(C)C=2OP([O-])(=O)OC1=C(O)[C@@H]([C@@H](O)CO)OC1=O VIHIKSJKXIMMLV-FZTHFCCHSA-M 0.000 description 7
- 239000004094 surface-active agent Substances 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 230000003239 periodontal effect Effects 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
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- 238000012360 testing method Methods 0.000 description 5
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 4
- HBXWUCXDUUJDRB-UHFFFAOYSA-N 1-octadecoxyoctadecane Chemical compound CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC HBXWUCXDUUJDRB-UHFFFAOYSA-N 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 4
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- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 4
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- MSCCTZZBYHQMQJ-AZAGJHQNSA-N Tocopheryl nicotinate Chemical compound C([C@@](OC1=C(C)C=2C)(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC1=C(C)C=2OC(=O)C1=CC=CN=C1 MSCCTZZBYHQMQJ-AZAGJHQNSA-N 0.000 description 4
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- 229940088598 enzyme Drugs 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 4
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
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- 229950009883 tocopheryl nicotinate Drugs 0.000 description 4
- 238000002834 transmittance Methods 0.000 description 4
- FDCJDKXCCYFOCV-UHFFFAOYSA-N 1-hexadecoxyhexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC FDCJDKXCCYFOCV-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- 238000002835 absorbance Methods 0.000 description 3
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- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
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Abstract
Description
本開示は、口腔用組成物等に関し、より詳細には、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩を含む、口腔用組成物等に関する。 The present disclosure relates to oral compositions, and more particularly, to oral compositions containing dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester alkali metal salt.
dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステル(本明細書において、「EPC」と称することがある)は、アスコルビン酸(ビタミンC)とトコフェロール(ビタミンE)とがリン酸を介してエステル結合した化合物であり、抗酸化作用、保湿作用を有し、育毛剤等の化粧料に使用されている(特許文献1)。 dl-α-tocopherol 2-L-ascorbic acid phosphodiester (herein sometimes referred to as “EPC”) is a compound in which ascorbic acid (vitamin C) and tocopherol (vitamin E) are combined via phosphoric acid. It is a compound with an ester bond, has antioxidant effect and moisturizing effect, and is used in cosmetics such as hair growth agents (Patent Document 1).
EPCは、口腔分野での応用が期待されているものの、実際に口腔領域においてどのような効果を発揮するかについては未だ報告がない。 Although EPC is expected to be applied in the oral cavity field, there have been no reports yet on what effects it actually exerts in the oral cavity field.
本開示は、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩を含む、口腔用組成物を提供することを課題とする。 An object of the present disclosure is to provide an oral composition comprising a dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester alkali metal salt.
本発明者らは、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩が、口腔粘膜上皮バリア機能の破壊を抑制すること、及びマトリックスメタロプロテアーゼ(Matrix metalloproteinase;MMP)の活性を阻害することを見出し、さらに改良を重ねた。 The present inventors demonstrated that dl-α-tocopherol 2-L-ascorbic acid phosphodiester alkali metal salt suppresses destruction of oral mucosal epithelial barrier function and inhibits matrix metalloproteinase (MMP) activity. After discovering that it inhibits the use of anti-oxidants, they made further 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.
dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩を含む、口腔用組成物(ただし、ポリオキシエチレンアルキルフェニルエーテル、ポリオキシエチレンアルキルエーテル、及びポリオキシエチレン脂肪酸エステルからなる群より選択される少なくとも1種を含む、口腔用組成物を除く)。
項2.
dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩を0.001~1質量%含有する、項1に記載の組成物。
項3.
前記dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩が、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルカリウム塩である、項1又は2に記載の組成物。
項4.
抗歯周病用、抗口腔粘膜炎用、又は抗う蝕用である、項1~3のいずれかに記載の組成物。
項5.
口腔粘膜上皮のバリア機能増強用である、項1~4のいずれかに記載の組成物。
項6.
口腔内のマトリックスメタロプロテアーゼ活性阻害用である、項1~5のいずれかに記載の組成物。
The present disclosure encompasses, for example, the subject matter described in the following sections.
Oral composition containing dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester alkali metal salt (provided that from the group consisting of polyoxyethylene alkylphenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester) (excluding oral compositions containing at least one selected type).
Item 2.
Item 2. The composition according to
Item 3.
Item 3. The composition according to
Item 4.
Item 4. The composition according to any one of
Item 5.
Item 5. The composition according to any one of
Item 6.
Item 6. The composition according to any one of
本開示の組成物は、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩を含み、口腔粘膜上皮バリア機能の破壊を抑制、及び/又はMMPの活性を阻害し得る。 The composition of the present disclosure contains dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester alkali metal salt, and can suppress destruction of oral mucosal epithelial barrier function and/or inhibit MMP activity.
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。
本開示に包含される口腔用組成物は、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩を含む。本明細書において当該組成物を、「本開示の口腔用組成物」と表記することがある。
Each embodiment included in the present disclosure will be described in further detail below.
Oral compositions encompassed by the present disclosure include dl-α-tocopherol 2-L-ascorbic acid phosphate diester alkali metal salt. In this specification, the composition may be referred to as "the oral composition of the present disclosure."
dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステル(EPC)は、アスコルビン酸(ビタミンC)とトコフェロール(ビタミンE)とがリン酸を介してエステル結合した化合物であり、(アスコルビル/トコフェリル)リン酸とも称される。化学式を以下に示す。 dl-α-tocopherol 2-L-ascorbic acid phosphodiester (EPC) is a compound in which ascorbic acid (vitamin C) and tocopherol (vitamin E) are ester-bonded via phosphoric acid, and is called (ascorbyl/tocopheryl). Also called phosphoric acid. The chemical formula is shown below.
dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩としては、例えば、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルカリウム塩、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルナトリウム塩、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルリチウム塩等が挙げられる。中でも、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルカリウム塩が好ましい。
また、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩は、モノ塩であってもよく、ジ塩であってもよい。
Examples of the dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester alkali metal salt include dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester potassium salt, dl-α-tocopherol 2-L-ascorbic acid Examples include phosphoric acid diester sodium salt, dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester lithium salt, and the like. Among these, dl-α-tocopherol 2-L-ascorbic acid phosphate diester potassium salt is preferred.
Further, the alkali metal salt of dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester may be a monosalt or a di-salt.
本開示の口腔用組成物に含まれるdl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩の含有量は、例えば、0.001~1質量%程度とすることができる。当該範囲の上限若しくは下限は、例えば0.002、0.005、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、又は0.9質量%程度であってもよい。より具体的には、例えば、0.002~0.5質量%程度であってもよく、0.005~0.3質量%程度であってもよい。 The content of the dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester alkali metal salt contained in the oral composition of the present disclosure can be, for example, about 0.001 to 1% by mass. The upper limit or lower limit of the range is, for example, 0.002, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0. It may be about .09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9% by mass. More specifically, for example, it may be about 0.002 to 0.5% by mass, or about 0.005 to 0.3% by mass.
本開示の口腔用組成物は、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩を含むことにより、口腔粘膜上皮バリア機能の破壊を抑制する効果を奏する。このため、本開示の口腔用組成物は、口腔粘膜上皮のバリア機能増強用として好適に用いることができる。口腔粘膜上皮としては、特に限定されず、咀嚼粘膜(例えば、歯肉等)を構成する上皮(例えば、付着上皮、歯肉溝上皮等の歯肉上皮等)、被覆粘膜(例えば、頬粘膜等)を構成する上皮、特殊粘膜(例えば、舌粘膜等)を構成する上皮が挙げられる。 The oral composition of the present disclosure has the effect of suppressing destruction of the oral mucosal epithelial barrier function by containing the dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester alkali metal salt. Therefore, the oral cavity composition of the present disclosure can be suitably used for enhancing the barrier function of the oral mucosal epithelium. Oral mucosal epithelium is not particularly limited, and includes epithelium that constitutes masticatory mucosa (e.g., gingiva, etc.) (e.g., gingival epithelium such as adherent epithelium, gingival sulcus epithelium, etc.), and covering mucosa (e.g., buccal mucosa, etc.). Examples include epithelium constituting special mucous membranes (for example, tongue mucosa, etc.).
また、本開示の口腔用組成物は、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩を含むことにより、MMPの活性を阻害する効果を奏する。このため、本開示の口腔用組成物は、口腔内のマトリックスメタロプロテアーゼ(MMP)活性阻害用として好適に用いることができる。なお、本開示の口腔用組成物は、MMP活性阻害効果を奏することから、既に産生された好中球コラゲナーゼの活性を阻害することができる。
口腔内のマトリックスメタロプロテアーゼ(MMP)としては、例えば、MMP-1、2、3、8、9、13等が挙げられる。中でも、MMP-1及び8が好ましい。なお、MMP-1(EC 3.4.24.7)は、間質コラゲナーゼとも称される。また、MMP-8(EC 3.4.24.34)は、好中球コラゲナーゼとも称される。
Furthermore, the oral composition of the present disclosure exhibits the effect of inhibiting MMP activity by containing the alkali metal salt of dl-α-tocopherol 2-L-ascorbic acid phosphate diester. Therefore, the oral composition of the present disclosure can be suitably used for inhibiting matrix metalloproteinase (MMP) activity in the oral cavity. In addition, since the oral composition of the present disclosure exhibits an MMP activity inhibiting effect, it can inhibit the activity of already produced neutrophil collagenase.
Examples of matrix metalloproteinases (MMPs) in the oral cavity include MMP-1, 2, 3, 8, 9, and 13. Among these, MMP-1 and 8 are preferred. Note that MMP-1 (EC 3.4.24.7) is also called interstitial collagenase. MMP-8 (EC 3.4.24.34) is also called neutrophil collagenase.
また、歯肉上皮は、侵入してくる微生物に対するバリアを形成し、歯周組織を感染から守っていることが報告されている(非特許文献1)。また、Porphyromonas gingivalisのような歯周病菌は細菌性プロテアーゼを分泌し、歯肉上皮を破壊することで、歯周組織内への侵入を達成していることが知られている(非特許文献2)。そして、歯周病菌の組織内への侵入が進むと、それを排除するため好中球等の免疫細胞が集積し、MMPsの産生量が増加することが知られている。MMPsは細胞外基質(例えば、I型コラーゲン、II型コラーゲン、III型コラーゲン等のコラーゲン等)を分解するタンパク分解酵素であり、これにより歯周組織が破壊され、歯周病が進行する。実際、歯周病患者の歯肉溝浸出液(GCF)中のMMP-1、2、3、8、9、及び13の増加が観察されている(非特許文献3)。
本開示の口腔用組成物は、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩を含むことにより、口腔粘膜上皮バリア機能の破壊を抑制する効果、及び/又はMMPの活性を阻害する効果を奏することから、抗歯周病用として好適に用いることができる。つまり、本開示の口腔用組成物は、口腔粘膜上皮のバリア機能増強により、歯周病菌の歯周組織への進行を防ぐことができる。また、本開示の口腔用組成物は、口腔内のマトリックスメタロプロテアーゼ活性阻害により、歯周組織破壊を防ぐことができる。このため、初期から進行した状態まであらゆる歯周病の状況に適用することが期待できる。なお、本明細書において、「抗歯周病」とは、歯周病の発症予防及び/又は歯周病の進行抑制を意味する。
Furthermore, it has been reported that the gingival epithelium forms a barrier against invading microorganisms and protects the periodontal tissue from infection (Non-Patent Document 1). Furthermore, periodontal disease bacteria such as Porphyromonas gingivalis are known to secrete bacterial protease and destroy the gingival epithelium, thereby achieving invasion into the periodontal tissue (Non-patent Document 2). . It is known that as the invasion of periodontal disease bacteria into tissues progresses, immune cells such as neutrophils accumulate in order to eliminate them, and the amount of MMPs produced increases. MMPs are proteolytic enzymes that degrade extracellular matrices (eg, collagen such as type I collagen, type II collagen, and type III collagen), which destroys periodontal tissue and progresses periodontal disease. In fact, increases in MMP-1, 2, 3, 8, 9, and 13 have been observed in the gingival crevicular fluid (GCF) of patients with periodontal disease (Non-Patent Document 3).
The oral composition of the present disclosure contains the alkali metal salt of dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester, thereby suppressing the destruction of the oral mucosal epithelial barrier function and/or suppressing the activity of MMP. Since it has the effect of inhibiting periodontal disease, it can be suitably used as an anti-periodontal disease agent. That is, the oral composition of the present disclosure can prevent periodontal disease bacteria from progressing to the periodontal tissue by enhancing the barrier function of the oral mucosal epithelium. Furthermore, the oral cavity composition of the present disclosure can prevent periodontal tissue destruction by inhibiting matrix metalloprotease activity in the oral cavity. Therefore, it can be expected to be applied to all periodontal disease situations, from early stages to advanced stages. In addition, in this specification, "anti-periodontal disease" means prevention of onset of periodontal disease and/or suppression of progression of periodontal disease.
また、咬傷、火傷、化学療法や放射線療法等の副作用等で口腔粘膜に潰瘍が形成される(口腔粘膜炎)と上皮のバリア機能が喪失され、口腔細菌の感染が引き起こされることが報告されている(非特許文献4)。本開示の口腔用組成物は、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩を含むことにより、口腔粘膜上皮バリア機能の破壊を抑制する効果を奏することから、抗口腔粘膜炎用として好適に用いることができる。なお、本明細書において、「抗口腔粘膜炎」とは、口腔粘膜炎の発症予防及び/又は口腔粘膜炎の進行抑制を意味する。 Additionally, it has been reported that when ulcers are formed on the oral mucosa (oral mucositis) due to bites, burns, side effects of chemotherapy, radiation therapy, etc., the barrier function of the epithelium is lost, leading to oral bacterial infection. (Non-patent Document 4). The oral composition of the present disclosure has the effect of suppressing destruction of the oral mucosal epithelial barrier function by containing the dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester alkali metal salt. It can be suitably used for flames. In addition, in this specification, "anti-oral mucositis" means prevention of the onset of oral mucositis and/or suppression of the progression of oral mucositis.
また、象牙質は有機質であるコラーゲンを約20%程度含んでおり、象牙質う蝕の進行には脱灰とコラーゲンの分解を伴う。コラーゲンの分解としては、唾液中のMMPsが象牙質に浸透し、分解していると考えられている(非特許文献5)。本開示の口腔用組成物は、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩を含むことにより、MMPの活性を阻害する効果を奏することから、抗う蝕用として好適に用いることができる。なお、本明細書において、「抗う蝕」とは、う蝕の発症予防及び/又はう蝕の進行抑制を意味する。 Further, dentin contains approximately 20% collagen, which is an organic substance, and the progression of dentin caries is accompanied by demineralization and collagen decomposition. It is thought that collagen is degraded by MMPs in saliva penetrating into dentin and decomposing it (Non-Patent Document 5). The oral composition of the present disclosure exhibits the effect of inhibiting MMP activity by containing the dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester alkali metal salt, and is therefore suitably used for anti-caries purposes. be able to. In addition, in this specification, "anti-caries" means the prevention of the onset of caries and/or the suppression of the progression of caries.
本開示の口腔用組成物の適用対象としては、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)等が例示される。中でもヒトが好ましい。
本開示の口腔用組成物の適用対象となるヒトとしては、例えば、歯周病患者又はその疑いがあるヒト;口腔粘膜炎患者又はその疑いがあるヒト;う蝕患者又はその疑いがあるヒト;口腔粘膜上皮のバリア機能が減弱しているヒト;口腔内のマトリックスメタロプロテアーゼ活性が亢進しているヒト;等に限らず、健常者(例えば、歯周病の発症を予防したいヒト、歯周病の進行を抑制したいヒト、口腔粘膜炎の発症を予防したいヒト、口腔粘膜炎の進行を抑制したいヒト、う蝕の発症を予防したいヒト、う蝕の進行を抑制したいヒト等)等であってもよい。
Examples of subjects to which the oral composition of the present disclosure can be applied include mammals including humans (eg, dogs, cats, mice, rats, sheep, horses, cows, monkeys, etc.). Among these, humans are preferred.
Humans to whom the oral composition of the present disclosure is applied include, for example, periodontal disease patients or suspected patients; oral mucositis patients or suspected patients; caries patients or suspected patients; Not limited to people with a weakened barrier function of the oral mucosal epithelium; people with increased intraoral matrix metalloproteinase activity; healthy people (e.g., people who want to prevent the onset of periodontal disease, people with periodontal disease) people who want to suppress the progression of oral mucositis, people who want to prevent the onset of oral mucositis, people who want to suppress the progression of oral mucositis, people who want to prevent the onset of caries, people who want to suppress the progression of caries, etc.) Good too.
本開示の口腔用組成物は、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、タブレット、ドロップ等の形態(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。 The oral composition of the present disclosure can be, for example, a solid composition, a liquid composition, or the like. In addition, the oral composition of the present disclosure can be prepared in a conventional manner, for example, as an ointment, a paste, a paste, a gel, a liquid, a spray, a mouthwash, a liquid dentifrice, a toothpaste, a gum, a tablet, or a drop. It can be made into the following forms (dosage forms). Among these, mouth rinses, liquid dentifrices, toothpastes, ointments, pastes, liquids, and gels are preferred.
本開示の口腔用組成物は、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩の他、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 oral composition of the present disclosure further contains, in addition to dl-α-tocopherol 2-L-ascorbic acid phosphate diester alkali metal salt, one or more optional components that can be incorporated into the oral composition, for example. It's okay.
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;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。
なお、本開示の口腔用組成物からは、例えば、ポリオキシエチレンアルキルフェニルエーテル、ポリオキシエチレンアルキルエーテル、及びポリオキシエチレン脂肪酸エステルからなる群より選択される少なくとも1種を含む、口腔用組成物が除かれることが好ましい。
ポリオキシエチレンアルキルフェニルエーテルとしては、例えば、エチレンオキサイドの平均付加モル数が1~40であり、アルキル基の炭素数が7~30であるポリオキシエチレンアルキルフェニルエーテル等が挙げられる。ポリオキシエチレンアルキルエーテルとしては、例えば、エチレンオキサイドの平均付加モル数が1~40であり、アルキル基の炭素数が1~18であるポリオキシエチレンアルキルエーテル等が挙げられる。ポリオキシエチレン脂肪酸エステルとしては、例えば、エチレンオキサイドの平均付加モル数が1~40であり、アルキル基の炭素数が1~20であるポリオキシエチレン脂肪酸エステル等が挙げられる。
For example, a nonionic surfactant, an anionic surfactant, or an amphoteric surfactant can be blended as the surfactant. Specifically, for example, nonionic surfactants include sugar fatty acid esters such as sucrose fatty acid ester, maltose fatty acid ester, and lactose fatty acid ester; fatty acid alkanolamides; glycerin fatty acid ester; sorbitan fatty acid ester; fatty acid monoglyceride; diethyl sebacate. ; polyoxyethylene hydrogenated castor oil; fatty acid polyoxyethylene sorbitan, and the like. Examples of anionic surfactants include sulfuric 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 sarcosine and lauroyl methylalanine. Acyl amino acid salts such as sodium; sodium cocoyl methyl taurate and the like. Examples of zwitterionic surfactants include betaine acetate type surfactants such as betaine lauryldimethylaminoacetate and betaine coconut oil fatty acid amidopropyldimethylaminoacetate; imidazoline type surfactants such as sodium N-cocoyl-N-carboxymethyl-N-hydroxyethylethylenediamine; Examples include activators and the like. These surfactants may be used alone or in combination of two or more. The amount incorporated is usually 0.1 to 5% by mass based on the total amount of the composition.
In addition, from the oral composition of the present disclosure, for example, an oral composition containing at least one selected from the group consisting of polyoxyethylene alkyl phenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester. is preferably excluded.
Examples of the polyoxyethylene alkylphenyl ether include polyoxyethylene alkylphenyl ether in which the average number of added moles of ethylene oxide is 1 to 40 and the number of carbon atoms in the alkyl group is 7 to 30. Examples of polyoxyethylene alkyl ethers include polyoxyethylene alkyl ethers in which the average number of added moles of ethylene oxide is 1 to 40 and the number of carbon atoms in the alkyl group is 1 to 18. Examples of the polyoxyethylene fatty acid ester include polyoxyethylene fatty acid esters in which the average number of added moles of ethylene oxide is 1 to 40 and the number of carbon atoms in the alkyl group is 1 to 20.
また、香味剤として、例えば、メントール、カルボン、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、シトロネロール、α-テルピネオール、メチルアセタート、シトロネニルアセテート、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。 Further, as flavoring agents, for example, menthol, carvone, anethole, eugenol, methyl salicylate, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol, methyl acetate, citronenyl acetate, methyl eugenol, cineol, linalool, Ethyl linalool, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamic oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil, pimento oil, d-camphor, d- Flavoring agents such as borneol, fennel oil, cinnamon oil, cinnamaldehyde, peppermint oil, and vanillin can be used. These can be blended alone 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、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0.01~1質量%配合することができる。 Further, as a sweetening agent, for example, saccharin sodium, acesulfame potassium, stevioside, neohesperidyl dihydrochalcone, perillartin, thaumatin, asparatylphenylalanyl methyl ester, p-methoxycinnamic aldehyde, etc. can be used. These can be blended alone or in combination of two or more in an amount of, for example, 0.01 to 1% by mass based on 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 a wetting agent, sorbitol, 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。 As a binder, cellulose derivatives such as carboxymethylcellulose sodium, carboxymethylethylcellulose salt, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, crystalline cellulose, crystalline cellulose/carmellose sodium, and microorganism-produced substances such as xanthan gum. Molecules, natural polymers or natural gums such as gum tragacanth, gum karaya, gum arabic, carrageenan, dextrin, agar, pectin, pullulan, gellan gum, locust bean gum, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl methyl ether, Examples include 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. It will be done. These binders can be used alone or in combination of two or more.
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。これらは、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。 As preservatives, parabens such as methylparaben, ethylparaben, propylparaben, butylparaben, sodium benzoate, phenoxyethanol, alkyldiaminoethylglycine hydrochloride, etc. can be blended. These can be used alone or in combination of two or more.
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。これらは、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。 As a coloring agent, legal pigments such as Blue No. 1, Yellow No. 4, Red No. 202, and Green No. 3, mineral pigments such as ultramarine, reinforced ultramarine, and deep blue, titanium oxide, etc. may be blended. These can be used alone or in combination of two or more.
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, etc. may be blended. These can be used alone or in combination of two or more so that the pH of the composition is in the range of 4 to 8, preferably 5 to 7. The 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 composition of the present disclosure further contains vitamin E such as dl-α-tocopherol acetate, tocopherol succinate, or tocopherol nicotinate, an amphoteric bactericide such as dodecyldiaminoethylglycine, triclosan, Nonionic disinfectants such as isopropylmethylphenol, anionic disinfectants such as sodium lauroylsarcosine, cationic disinfectants such as cetylpyridinium chloride, chlorhexidine hydrochloride, benzalkonium chloride, benzethonium chloride, dextranase, amylase, protease, Enzymes such as mutanase, lysozyme, and lytic enzymes (Litech 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, copper chlorophyllin sodium, glycerophosphate, chlorophyll, sodium chloride, calopeptide, allantoin, carbazochrome, potassium nitrate, palatinit, etc. alone or in combination of two or more. Can be blended 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。これらは、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。 It is also possible to add alcohols, silicon, apatite, white petrolatum, paraffin, liquid paraffin, microcrystalline wax, squalane, plastibase, etc. as a base. These can be used alone or in combination of two or more.
本開示の口腔用組成物は、公知の方法または公知の方法から容易に想到する方法により調製することができる。例えば、dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルアルカリ金属塩及び必要に応じてその他の成分等を適宜混合することによって調製することができる。 The oral composition of the present disclosure can be prepared by a known method or a method easily derived from a known method. For example, it can be prepared by appropriately mixing dl-α-tocopherol 2-L-ascorbic acid phosphoric acid diester alkali metal salt and other components as necessary.
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。 Note that in this specification, the term "comprising" includes "consisting essentially of" and "consisting of." Additionally, the present disclosure encompasses any and all combinations of the features 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。 Further, the various characteristics (properties, structures, functions, etc.) described for each embodiment of the present disclosure described above may be combined in any manner in order to specify the subject matter covered by the present disclosure. That is, the present disclosure encompasses all subject matter consisting of any and all combinations of the combinable features described herein.
本開示の内容を以下の実験例を用いて具体的に説明する。しかし、本開示はこれらに何ら限定されるものではない。下記において、特に言及する場合を除いて、実験は大気圧及び常温条件下で行っている。また特に言及する場合を除いて、「%」は「質量%」を意味する。また、各表に記載される各成分の配合量値も特に断らない限り「質量%」を示す。 The contents of the present disclosure will be specifically explained using the following experimental examples. However, the present disclosure is not limited thereto. In the following, unless otherwise specified, experiments are conducted under atmospheric pressure and room temperature conditions. Further, unless otherwise specified, "%" means "% by mass". In addition, the blending amount of each component listed in each table is expressed in "% by mass" unless otherwise specified.
1.上皮バリア機能評価試験
細胞調整
歯肉上皮細胞株Epi4細胞をコンフルエントになるまでトランスウェル上で培養した。このとき、Epi4細胞は、細胞用培地としてEpilife(サーモフィッシャー)にSupplemental S7(サーモフィッシャー)を100分の1量加えた培地を用いて培養した。なお、トランスウェルは、インサートがウェルの中間にくるよう吊り下げ式にデザインされており、細胞透過性評価を可能とするツールである。
1. Epithelial barrier function evaluation test
Cell preparation Gingival epithelial cell line Epi4 cells were cultured on transwells until confluent. At this time, the Epi4 cells were cultured using a medium prepared by adding 1/100th the amount of Supplemental S7 (Thermo Fisher) to Epilife (Thermo Fisher) as a cell culture medium. The transwell is designed to be suspended so that the insert is placed in the middle of the well, and is a tool that enables cell permeability evaluation.
細菌調整
P.g菌(Porphyromonas gingivalis W83)は変法GAM培地(日水製薬)で培養し、培養後、10000rpmで遠心することにより回収し、OD600=1.0になるよう細胞用培地でP.g菌濃度を調整した。
Bacterial adjustment P. Porphyromonas gingivalis W83 was cultured in a modified GAM medium (Nissui Pharmaceutical Co., Ltd.), recovered by centrifugation at 10,000 rpm, and cultured in a cell culture medium to achieve an OD 600 of 1.0. g Bacteria concentration was adjusted.
素材調製
各評価素材を2.5%DMSO含有細胞用培地にそれぞれの評価濃度に調製した。用いた素材は、EPC-K(dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルカリウム塩)、APM(アスコルビン酸リン酸Mg)、VC(アスコルビン酸)、VEA(酢酸トコフェロール)、及びVEN(ニコチン酸トコフェロール)である。
Material Preparation Each evaluation material was prepared in a cell culture medium containing 2.5% DMSO to the respective evaluation concentration. The materials used were EPC-K (dl-α-tocopherol 2-L-ascorbic acid phosphate diester potassium salt), APM (Mg ascorbic acid phosphate), VC (ascorbic acid), VEA (tocopherol acetate), and VEN. (tocopherol nicotinate).
バリア機能評価
トランスウェル上に培養したEpi4細胞から培養培地を除去し、調製した各素材含有培地を300μlずつ添加し、1時間37℃、CO2濃度5%下でインキュベートした。このとき、素材を含まない培地処理をコントロールとした。
次に、調整したP.g菌液100μlを添加し、2時間37℃、CO2濃度5体積%下でインキュベートした。このとき、コントロールに対しては、P.g菌液添加しインキュベートしたもの(P.g.(+))、及びP.g菌を含まない培地のみ添加し、インキュベートしたもの(P.g.(-))を準備した。
インキュベート後、培地を除去し、PBSでwashし、1mg/mlに調整したFITC(Fluoresceinisothiocyanate)-dextran(4kDa)を添加し、1時間37℃でインキュベートした。トランスウェルを通過したFITC-dextranを回収し、蛍光プレートリーダー(Gemini XPS)にて蛍光強度(励起光:490nm、放出光:520nm)を測定した。コントロールに対してP.g菌液添加した場合(P.g.(+)素材なし)のFITC透過量を100%、コントロールに対してP.g菌を含まない培地のみ添加した場合(P.g.(-))のFITC透過量を0%になるように換算して、各濃度の素材を処理した際の透過率を算出した。結果を図1~3に示す。なお、図中の素材濃度は、調製時の濃度であり、終濃度(P.g菌添加後の濃度)は、当該濃度値の3/4になる。また、当該透過率が低いほど、上皮バリア機能が高いということができる。
Barrier Function Evaluation The culture medium was removed from the Epi4 cells cultured on the transwells, 300 μl of the prepared medium containing each material was added, and the cells were incubated for 1 hour at 37° C. under a 5% CO 2 concentration. At this time, a medium treatment containing no material was used as a control.
Next, the adjusted P. 100 μl of bacterial solution was added and incubated for 2 hours at 37° C. under a CO 2 concentration of 5% by volume. At this time, for the control, P. (P.g.(+)), and P.g. A culture medium containing no Pg bacteria was added and incubated (Pg (-)).
After incubation, the medium was removed, washed with PBS, and FITC (fluoresceinisothiocyanate)-dextran (4 kDa) adjusted to 1 mg/ml was added, followed by incubation at 37° C. for 1 hour. FITC-dextran that had passed through the transwell was collected, and the fluorescence intensity (excitation light: 490 nm, emission light: 520 nm) was measured using a fluorescence plate reader (Gemini XPS). P. vs. control. The amount of FITC permeation when G.g. bacterial solution was added (without P.g. (+) material) was 100%, and P.g. The amount of FITC permeation when only a medium containing no P.g. bacteria was added (P.g.(-)) was converted to 0%, and the transmittance when materials of each concentration were treated was calculated. The results are shown in Figures 1-3. Note that the material concentration in the figure is the concentration at the time of preparation, and the final concentration (concentration after addition of P.g bacteria) is 3/4 of the concentration value. Furthermore, it can be said that the lower the permeability, the higher the epithelial barrier function.
図1~3に示すとおり、EPC-Kは、P.g菌による口腔粘膜上皮バリアの破壊を抑制することが確認された。また、アスコルビン酸及びその誘導体であるAPM、並びにトコフェロールの誘導体であるVEA及びVENについては、同様の効果は確認されなかった。 As shown in Figures 1 to 3, EPC-K has P. It was confirmed that it suppresses the destruction of the oral mucosal epithelial barrier caused by G bacteria. Furthermore, similar effects were not confirmed for ascorbic acid and its derivative APM, and tocopherol derivatives VEA and VEN.
2.MMP活性測定試験
素材調製
各評価素材を溶媒(下記記載のキット付属のバッファー+5%DMSO)でそれぞれの評価濃度に調整し、評価素材溶液とした。用いた素材は、EPC-K(dl-α-トコフェロール 2-L-アスコルビン酸リン酸ジエステルカリウム塩)、VC(アスコルビン酸)、VEA(酢酸トコフェロール)、及びVEN(ニコチン酸トコフェロール)である。
2. MMP activity measurement test
Material Preparation Each evaluation material was adjusted to the respective evaluation concentration with a solvent (buffer included in the kit described below + 5% DMSO) to prepare an evaluation material solution. The materials used were EPC-K (dl-α-tocopherol 2-L-ascorbic acid phosphate diester potassium salt), VC (ascorbic acid), VEA (tocopherol acetate), and VEN (tocopherol nicotinate).
酵素活性測定
MMP-8(好中球コラゲナーゼ)活性は、MMP-8 fluorimetricdrug discovery kit(Enzo Life Sciences,Inc.,BML-AK415-0001)、MMP-1(線維芽細胞コラゲナーゼ)活性は、MMP-1 fluorimetricdrug discovery kit(Enzo Life Sciences,Inc.,BML-AK405-0001)を用いて評価を実施した。
調製した各素材溶液20μlに、キット付属のMMP-8を0.1μl及びキット付属のバッファーを69.9μl、もしくはキット付属のMMP-1を0.2μl及びキット付属のバッファーを69.8μl混和し、37℃で60分間反応させた。このとき、陽性コントロール(Cont.)として素材を添加せずバッファーを等量加えたサンプル、また基質のみのバックグラウンドの測定のためにMMP-8もしくはMMP-1を添加せずバッファーを等量加えたサンプル(NC)を用意した。
キット付属の蛍光基質をバッファーを用いて10倍希釈し、60分間反応後の溶液に10μl添加した。添加後、MMP-8は37℃で20分、MMP-1は37℃で60分反応させた後に、励起光:328nm、放出光:420nmの蛍光強度を測定した。陽性コントロールサンプル(Cont.)の蛍光強度からバックグラウンドとして基質のみの蛍光強度(NC)を引いた値を100%として、各素材溶液添加サンプルの蛍光強度から基質のみの蛍光強度(NC)をバックグラウンドとして引いた値の比率を酵素活性として算出した。なお、両キット添付の反応基質に対して、MMP-8の方がMMP-1より反応性が高かったため、本試験において反応性を同程度に近い条件で検討するためMMP-8、MMP-1それぞれ希釈率、反応時間を変えて試験を実施した。結果を図4及び5に示す。なお、図中の素材濃度は、素材調製時の濃度であり、終濃度(蛍光強度測定時の濃度)は、当該濃度値の1/5になる。
Enzyme activity measurement MMP-8 (neutrophil collagenase) activity was measured using MMP-8 fluorimetric drug discovery kit (Enzo Life Sciences, Inc., BML-AK415-0001), and MMP-1 (fibroblast collagenase) activity was measured using MMP-8 fluorimetric drug discovery kit (Enzo Life Sciences, Inc., BML-AK415-0001). - 1 The evaluation was performed using a fluorimetric drug discovery kit (Enzo Life Sciences, Inc., BML-AK405-0001).
Mix 0.1 μl of MMP-8 included in the kit and 69.9 μl of buffer included in the kit, or 0.2 μl of MMP-1 included in the kit and 69.8 μl of buffer included in the kit to 20 μl of each prepared material solution. , and reacted at 37°C for 60 minutes. At this time, as a positive control (Cont.), we used a sample in which no material was added and an equal amount of buffer was added, and to measure the background of only the substrate, MMP-8 or MMP-1 was not added and an equal amount of buffer was added. A sample (NC) was prepared.
The fluorescent substrate attached to the kit was diluted 10 times with a buffer, and 10 μl was added to the solution after 60 minutes of reaction. After the addition, MMP-8 was reacted at 37°C for 20 minutes and MMP-1 was reacted at 37°C for 60 minutes, and then the fluorescence intensity of excitation light: 328 nm and emission light: 420 nm was measured. The value obtained by subtracting the fluorescence intensity (NC) of only the substrate as a background from the fluorescence intensity of the positive control sample (Cont.) is set as 100%, and the fluorescence intensity (NC) of only the substrate is calculated as the background from the fluorescence intensity of each material solution added sample. The ratio of the value subtracted as the ground was calculated as the enzyme activity. In addition, MMP-8 was more reactive than MMP-1 with respect to the reaction substrates attached to both kits, so in this test, MMP-8 and MMP-1 Tests were conducted by changing the dilution rate and reaction time. The results are shown in Figures 4 and 5. Note that the material concentration in the figure is the concentration at the time of material preparation, and the final concentration (concentration at the time of fluorescence intensity measurement) is 1/5 of the concentration value.
図4及び5に示すとおり、EPC-Kは、濃度依存的にMMP活性(MMP-8及びMMP-1)を阻害することが確認された。また、アスコルビン酸、並びにトコフェロールの誘導体であるVEA及びVENについては、同様の効果は確認されなかった。 As shown in FIGS. 4 and 5, EPC-K was confirmed to inhibit MMP activity (MMP-8 and MMP-1) in a concentration-dependent manner. Furthermore, similar effects were not confirmed for ascorbic acid and tocopherol derivatives VEA and VEN.
3.細胞傷害性評価試験
細胞培養
口腔由来上皮細胞株(Ca9-22細胞)をコンフルエントになるまで96穴プレートで培養した。
3. Cytotoxicity evaluation test
Cell Culture Oral epithelial cell line (Ca9-22 cells) was cultured in a 96-well plate until confluent.
素材調製
評価溶液中の各界面活性剤の終濃度が、1%になるように0.5%DMSOを含有したPBSを溶媒として調整した。用いた界面活性剤は、ポリオキシエチレン(9)ラウリルエーテル、ポリオキシエチレン(20)セチルエーテル、ポリオキシエチレン(20)ステアリルエーテル、ポリオキシエチレン(10)オクチルフェニルエーテル、ポリオキシエチレングリコールモノラウレート、テトラオレイン酸ソルベス-60、セバシン酸ジエチル、及びポリオキシエチレン硬化ヒマシ油10である。
The final concentration of each surfactant in the material preparation evaluation solution was adjusted to 1% using PBS containing 0.5% DMSO as a solvent. The surfactants used were polyoxyethylene (9) lauryl ether, polyoxyethylene (20) cetyl ether, polyoxyethylene (20) stearyl ether, polyoxyethylene (10) octylphenyl ether, and polyoxyethylene glycol monolaur. ester, sorbeth-60 tetraoleate, diethyl sebacate, and polyoxyethylene hydrogenated castor oil 10.
細胞傷害性評価
培養したCa9-22細胞に調整した評価溶液100μlを添加し、常温で10分間静置した。10分後、PBS200μlで3回洗浄し、WST-1試薬(タカラバイオ)を30分間反応させた。反応後、450nm、600nmの吸光度を測定し、450nmの吸光度から600nmの吸光度を引いた値を算出した。算出した値の内、溶媒のみ処理の値を100%として細胞生存率を算出した。結果を図6及び7に示す。
図6及び7に示すとおり、ポリオキシエチレンアルキルフェニルエーテル(ポリオキシエチレン(10)オクチルフェニルエーテル)、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(9)ラウリルエーテル、ポリオキシエチレン(20)セチルエーテル、ポリオキシエチレン(20)ステアリルエーテル)、及びポリオキシエチレン脂肪酸エステル(ポリオキシエチレングリコールモノラウレート)については、口腔由来の細胞においては、細胞毒性が生じていることが確認された。一方、テトラオレイン酸ソルベス-60、セバシン酸ジエチル、ポリオキシエチレン硬化ヒマシ油10等の他の界面活性剤については、口腔由来の細胞においては、細胞毒性は生じないことが確認された。 As shown in FIGS. 6 and 7, polyoxyethylene alkyl phenyl ether (polyoxyethylene (10) octylphenyl ether), polyoxyethylene alkyl ether (polyoxyethylene (9) lauryl ether, polyoxyethylene (20) cetyl ether, It was confirmed that polyoxyethylene (20) stearyl ether) and polyoxyethylene fatty acid ester (polyoxyethylene glycol monolaurate) were cytotoxic to oral cavity-derived cells. On the other hand, it was confirmed that other surfactants such as sorbeth-60 tetraoleate, diethyl sebacate, and polyoxyethylene hydrogenated castor oil 10 did not cause cytotoxicity in oral cavity-derived cells.
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JP2022055854A JP2023148032A (en) | 2022-03-30 | 2022-03-30 | Composition for oral use |
PCT/JP2023/006641 WO2023189061A1 (en) | 2022-03-30 | 2023-02-24 | COMPOSITION CONTAINING DL-α-TOCOPHEROL 2-L-ASCORBIC ACID PHOSPHORIC ACID DIESTER ALKALI METAL SALT |
TW112108315A TW202345791A (en) | 2022-03-30 | 2023-03-07 | Composition containing dl-[alpha]-tocopherol 2-L-ascorbic acid phosphoric acid diester alkali metal salt |
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