WO2018174286A1 - 角層機能改善剤 - Google Patents
角層機能改善剤 Download PDFInfo
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- WO2018174286A1 WO2018174286A1 PCT/JP2018/011910 JP2018011910W WO2018174286A1 WO 2018174286 A1 WO2018174286 A1 WO 2018174286A1 JP 2018011910 W JP2018011910 W JP 2018011910W WO 2018174286 A1 WO2018174286 A1 WO 2018174286A1
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- amino acid
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- stratum corneum
- skin
- ability
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- SVETUDAIEHYIKZ-IUPFWZBJSA-N tris[(z)-octadec-9-enyl] phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCCOP(=O)(OCCCCCCCC\C=C/CCCCCCCC)OCCCCCCCC\C=C/CCCCCCCC SVETUDAIEHYIKZ-IUPFWZBJSA-N 0.000 description 1
- 229960005066 trisodium edetate Drugs 0.000 description 1
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- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
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- 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 description 1
Images
Classifications
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
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Definitions
- the present invention is a stratum corneum capable of exhibiting functions such as a moisture retaining ability to retain moisture inside, a barrier ability to suppress the entry of foreign substances such as viruses and bacteria from the outside, and a function of preventing or improving fine lines. It relates to a function improver.
- the stratum corneum has functions such as a moisturizing ability to retain moisture inside and a barrier ability to suppress the entry of foreign substances such as foreign substances, viruses and bacteria from the outside world.
- Biological components such as sebum, intercellular lipids, and natural moisturizing factors are known as substances that act on these functions.
- Filaggrin stored in the granular layer of skin tissue is dephosphorylated and decomposed into filaggrin during keratinization.
- Filaggrin migrates from the granular layer to the stratum corneum and binds and aggregates with keratin fibers to form a keratin pattern. Thereafter, filaggrin is decomposed into low molecules such as urocanic acid and becomes a natural moisturizing factor involved in water retention and ultraviolet absorption. Therefore, it is considered that as the production of filaggrin is promoted, the amount of the natural moisturizing factor, which is a decomposition product thereof, is increased, and the moisture retaining ability of the skin is improved.
- Invasion of foreign substances such as viruses and bacteria from the outside is suppressed by factors constituting the stratum corneum such as corneocytes and intercellular lipids existing between the corneocytes. Therefore, if conditions such as the number and size of corneocytes are insufficient, gaps are generated in the stratum corneum, and the barrier ability is reduced.
- the keratinocytes including a structure in which keratin such as keratin 10 and filaggrin are aggregated, there is a peripheral zone that is a very strong and huge insoluble structure that lines the cell membrane of keratinocytes.
- the main structural elements in the peripheral zone are proteins such as involucrin produced in spinous cells and loricrin produced in granule cells, which are cross-linked by an enzyme such as transglutaminase (TG) 1. Therefore, filaggrin, involucrin, transglutaminase 1, keratin 10, and loricrin strongly influence the formation of keratinocytes and are considered to be related to the skin barrier ability.
- proteins such as involucrin produced in spinous cells and loricrin produced in granule cells, which are cross-linked by an enzyme such as transglutaminase (TG) 1. Therefore, filaggrin, involucrin, transglutaminase 1, keratin 10, and loricrin strongly influence the formation of keratinocytes and are considered to be related to the skin barrier ability.
- D-alanine and D-hydroxy are compounds that promote the production of laminin 332, a protein that is present in large amounts in the basement membrane that separates the epidermis from the dermis and is thought to play an important role in the structure and function of the skin.
- D-amino acid compounds such as proline (Patent Document 3) have been reported.
- a technique containing a D-amino acid such as D-lysine hydrochloride and a chelating agent as an external preparation for skin having effects such as a moisturizing effect and does not cause alteration such as odor and discoloration (patent document) 4).
- a stable and safe oral composition capable of acting on the skin barrier ability to reduce and / or prevent rough skin, at least one compound selected from D-glutamic acid and derivatives and / or salts thereof is used. Including techniques have been reported (see Patent Document 5).
- the specific peptide such as glycylproline and the extract of baboon are weak in promoting the expression of moisturizing-related proteins such as filaggrin, and are insufficient for use as an active ingredient of the moisturizing agent.
- Patent Document 3 discloses that when a D-amino acid compound such as D-aspartic acid is used, the production promoting effect of laminin 332 is not expressed. Also, there is no description or suggestion about the activity of proteins other than laminin 332 in the skin.
- Patent Document 4 D-lysine is used to suppress deterioration such as odor and discoloration when a chelate compound is used, and the moisturizing effect is expressed by both D-lysine and L-lysine compounds. ing. For this reason, it has not been concluded that only D-lysine in the racemate selectively affects the moisturizing ability. Further, the moisturizing effect of Patent Document 4 is determined only by the subjectivity of the subject. Patent Document 4 describes that when D-glutamic acid is orally administered, the TEWL value decreases. However, there is no description or suggestion that the effect is manifested in other dosage forms (eg, skin care products). Patent Documents 4 and 5 neither describe nor suggest that both the moisturizing ability and the barrier ability can be improved.
- the present invention has been made in view of the above-mentioned problems.
- the moisture retention capability of retaining moisture inside the barrier capability of suppressing the entry of foreign substances such as viruses and bacteria from the outside, prevention of fine lines, or It aims at providing the stratum corneum function improving agent which can exhibit functions, such as improvement ability.
- the specific D-amino acid is a moisturizing ability-related protein (filaggrin), a barrier ability-related protein (filaggrin, involucrin, transglutaminase 1, keratin 10, and loricrin), a fine wrinkle prevention or amelioration-related protein (filaggrin).
- the inventors have found that production is promoted, and arrived at the present invention based on such findings. That is, the present invention is as follows.
- the stratum corneum function improving agent according to the above [1], wherein the stratum corneum function improvement is retention of a stratum corneum moisture content.
- the D-amino acid is D-Arg, D-His, D-Leu, D-Pro, D-Ser, D-Val, D-allo-Thr, D-Asp, D-Lys, D-Trp.
- At least one selected from the group consisting of D-allo-Ile, D-Asn, D-Phe, D-Ala, D-Gln, D-Glu, D-Cys, D-Met, and D-Thr The stratum corneum function improving agent according to [1], wherein the stratum corneum function improvement is suppression of transepidermal water transpiration.
- the D-amino acid is D-His, D-Leu, D-Pro, D-Tyr, D-Asp, D-Lys, D-Trp, D-allo-Ile, D-Asn, D-Phe.
- the stratum corneum function improving agent according to [1] above.
- a moisturizing ability improving agent comprising an amino acid as an active ingredient.
- the D-amino acid is at least one selected from the group consisting of D-His, D-Leu, D-Lys, D-Trp, D-allo-Ile, D-Asn, and D-Phe.
- the above D-amino acid is at least one selected from the group consisting of D-His, D-Leu, D-Lys, D-Trp, D-allo-Ile, and D-Phe [5] ] Or the moisturizing ability improving agent according to [6].
- D-Arg, D-His, D-Leu, D-Pro, D-Ser, D-Val, D-allo-Thr, D-Asp, D-Lys, D-Trp, D-allo-Ile At least one D-amino acid selected from the group consisting of D-Asn, D-Phe, D-Ala, D-Glu, D-Cys, D-Met, D-Gln, and D-Thr Barrier ability improving agent.
- the D-amino acid is at least one selected from the group consisting of D-His, D-Leu, D-Lys, D-Trp, D-allo-Ile, D-Asn, and D-Phe.
- the D-amino acid is at least one D-amino acid selected from the group consisting of D-His, D-Leu, D-Lys, D-Trp, D-allo-Ile, and D-Phe.
- the D-amino acid is at least one selected from the group consisting of D-Leu, D-Lys, and D-Trp.
- a skin cosmetic or an external preparation for skin containing a production promoter [17]
- the specification of the amount of D-amino acid is The evaluation method according to [19] above, wherein the D-amino acid content per protein amount contained in the stratum corneum is measured. [21] The evaluation method according to [19] or [20] above, wherein the D-amino acid content is measured with a liquid chromatograph-tandem mass spectrometer. [22] The evaluation method according to [20] or [21], wherein the protein amount is measured by a BCA method. [23] The D-amino acid is D-Arg, D-His, D-Leu, D-Pro, D-Ser, D-Tyr, D-Val, D-allo-Thr, D-Asp, D-Lys.
- the subject is a woman in their 20s to 30s,
- the D-amino acid is D-Arg, D-His, D-Leu, D-Pro, D-Ser, D-Tyr, D-Val, D-allo-Thr, D-Asp, D-Lys, D-
- the subject is a woman in their 20s to 30s,
- the D-amino acid is D-His, D-Leu, D-Pro, D-Ser, D-Val, D-allo-Thr, D-Asp, D-Trp, D-allo-Ile, D-Asn and
- the subject is a woman in their 40s to 60s,
- the D-amino acid is D-Arg, D-His, D-Leu, D-Pro, D-Val, D-allo-Thr, D-Asp, D-Lys, D-Trp, D-allo-Ile,
- the subject is a woman in their 40s to 60s,
- the D-amino acid is D-Arg, D-His, D-Leu, D-Pro, D-Ser, D-Val, D-allo-Thr, D-Lys, D-Trp, D-allo-Ile,
- the subject is a woman in their 20s to 30s,
- the D-amino acid is at least one selected from the group consisting of D-Leu, D-Tyr, D-Asp, D-Lys, D-Trp, D-Asn, and D-Gln;
- the evaluation method according to [23] wherein the prevention or improvement ability is evaluated.
- the subject is a woman in their 40s to 60s, The evaluation method according to [23], wherein the D-amino acid is at least one of D-Asp and D-Lys, and at least the ability to prevent or improve fine lines is evaluated.
- [31] Selected by the evaluation method according to [19] above, which is contained in the stratum corneum of the skin measurement site of the subject before and after the administration of the skin cosmetic, the external preparation for skin, or the active ingredient candidate substances thereof Measuring the amount of D-amino acid constituting the correlation; and Identifying and comparing at least one selected from the group consisting of the amount of D-amino acid based on the correlation and the amount of stratum corneum moisture before and after administration, wrinkle area ratio, and transepidermal moisture transpiration. Evaluation method for skin cosmetics or external preparations for skin.
- a method for evaluating the effectiveness of a skin cosmetic or a topical skin preparation for a subject amino acids are prefixed with a conventional three-letter code (for example, “Asn”, “Gln”) with a configuration such as “L-”, “D-”, “D, L-”. May be expressed.
- the stratum corneum function-improving agent of the present invention has functions such as the ability to retain moisture inside the stratum corneum, the barrier ability to suppress the entry of foreign substances such as viruses and bacteria from the outside, and the ability to prevent or improve fine lines. Can demonstrate.
- FIG. 1 is a graph showing the amount of amplification (relative value to the amount of control amplification) of D-Asn (Example 1) moisturizing ability / barrier ability / wrinkle prevention or improvement ability-related protein gene (filaggrin).
- FIG. 2 is a graph showing the amount of amplification of D-Asn (Example 1) barrier ability-related protein gene (involucrin) (relative to the amount of control amplification).
- FIG. 3 is a graph showing the amount of amplification of D-Asn (Example 1) -related protein gene (keratin 10) (relative to the amount of control amplification).
- FIG. 1 is a graph showing the amount of amplification (relative value to the amount of control amplification) of D-Asn (Example 1) moisturizing ability / barrier ability / wrinkle prevention or improvement ability-related protein gene (filaggrin).
- FIG. 2 is a graph showing the amount of amplification of D-As
- FIG. 4 is a graph showing the amount of amplification of D-Asn (Example 1) -related protein gene (loricrin) (relative to the amount of control amplification).
- FIG. 5 is a graph showing the amount of amplification (relative value to the amount of control amplification) of D-Asp (Example 2) moisturizing ability / barrier ability / wrinkle prevention or improvement ability-related protein gene (filaggrin).
- FIG. 6 is a graph showing the amount of amplification of D-Asp (Example 2) -related protein gene (involucrin) (relative to the amount of control amplification).
- FIG. 7 is a graph showing the amount of amplification of D-Asp (Example 2) barrier ability-related protein gene (keratin 10) (relative to the amount of control amplification).
- FIG. 8 is a graph showing the amount of amplification of D-Asp (Example 2) barrier ability-related protein gene (loricrin) (relative to the amount of control amplification).
- FIG. 9 is a graph showing the amount of amplification of D-Asp (Example 2) barrier ability-related protein gene (transglutaminase 1) (relative to the amount of control amplification).
- FIG. 1 is a graph showing the amount of amplification of D-Asp (Example 2) barrier ability-related protein gene (keratin 10) (relative to the amount of control amplification).
- FIG. 8 is a graph showing the amount of amplification of D-Asp (Example 2) barrier ability-related protein gene (loricrin) (relative to the
- FIG. 10 is a diagram showing the correlation between the amount of D-Asp in the stratum corneum and the amount of water in the stratum corneum in women in their twenties to thirties.
- FIG. 11 is a diagram showing the correlation between the amount of D-Phe in the stratum corneum and the amount of water in the stratum corneum in women in their twenties to thirties.
- FIG. 12 is a diagram showing the correlation between the amount of D-allo-Ile in the stratum corneum and the amount of water in the stratum corneum in women in their 40s to 60s.
- FIG. 13 is a diagram showing the correlation between the amount of D-Asn in the stratum corneum and the amount of transepidermal water transpiration (TEWL) in women in their 20s to 30s.
- FIG. 14 is a diagram showing the correlation between the amount of D-Phe in the stratum corneum and the amount of transepidermal water transpiration (TEWL) in women in their 20s to 30s.
- FIG. 15 is a diagram showing the correlation between the amount of D-allo-Ile in the stratum corneum and the amount of transepidermal water transpiration (TEWL) in women in their 40s to 60s.
- FIG. 16 is a diagram showing the correlation between the amount of D-Asn in the stratum corneum and the wrinkle area ratio in women in their 20s to 30s.
- FIG. 17 is a diagram showing the correlation between the amount of D-Gln in the stratum corneum and the wrinkle area ratio in women in their 20s to 30s.
- FIG. 18 is a diagram showing the correlation between the amount of D-Lys in the stratum corneum and the wrinkle area rate in women in their 40s to 60s.
- FIG. 19 shows cell survival in normal human epidermal keratinocytes when D-Asn, D-Asp, D-Lys, D-Phe, D-Trp, D-allo-Ile, D-Ala, and D-Glu are added.
- FIG. 20 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-His is added.
- FIG. 21 is a graph showing the amount of filaggrin production in normal human neonatal epidermal keratinocytes when D-Leu is added.
- FIG. 22 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-Trp is added.
- FIG. 23 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-Ala is added.
- FIG. 20 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-His is added.
- FIG. 21 is a graph showing the amount of filaggrin production in normal human neonatal epidermal keratinocytes when D-Leu is added.
- FIG. 22 is a graph showing filaggrin production in normal human neonatal epidermal keratin
- FIG. 24 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-allo-Ile is added.
- FIG. 25 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-Asp is added.
- FIG. 26 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-Glu is added.
- FIG. 27 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-Lys is added.
- FIG. 28 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-Phe is added.
- FIG. 29 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-Pro is added.
- FIG. 30 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-Cys is added.
- FIG. 31 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-Met is added.
- FIG. 32 is a graph showing filaggrin production in normal human neonatal epidermal keratinocytes when D-Thr is added.
- agent simply refers to a stratum corneum function improving agent, a moisturizing ability improving agent, a barrier ability improving agent, a wrinkle prevention or improving agent, a gene expression promoting agent, and a production promoting agent.
- the stratum corneum function-improving agent is a barrier that, when applied to the skin, increases the moisture content of the stratum corneum or improves the moisture retention ability, and suppresses the entry of foreign substances such as viruses and bacteria from the outside world. That can exert any of the effects of improving performance and preventing or improving fine lines.
- moistureturizing ability refers to retention of the stratum corneum moisture content, and the higher the stratum corneum moisture content, the better the moisture retention ability.
- “Barrier ability” refers to suppression of transepidermal water transpiration, and the smaller the transepidermal water transpiration amount (hereinafter also referred to as “TEWL”), the better the barrier ability.
- prevention or improvement of fine wrinkles is evaluated by the wrinkle area ratio, and the smaller the wrinkle area ratio, the better the ability to prevent or improve fine lines.
- the stratum corneum function improving agent of the present invention includes D-Arg, D-His, D-Leu, D-Pro, D-Ser, D-Tyr, D-Val, D-allo-Thr, D-Asp, D- Selected from the group consisting of Lys, D-Trp, D-allo-Ile, D-Asn, D-Phe, D-Ala, D-Gln, D-Glu, D-Cys, D-Met, and D-Thr And at least one D-amino acid as an active ingredient.
- Such an amino acid can exhibit moisturizing ability (retaining or increasing the amount of water in the stratum corneum) as an improvement in stratum corneum function.
- the D-amino acid is preferably D-Arg, D-His, D-Leu, D-Tyr, D-Val, D-allo-Thr, D-Lys, D-Trp, D-allo-Ile, D- At least one D-amino acid selected from the group consisting of Asn, D-Phe, D-Gln, and D-Thr, more preferably D-His, D-Leu, D-Lys, D-Trp , D-allo-Ile, D-Asn, and D-Phe, and more preferably D-His, D-Leu, D-Lys, D- It is at least one D-amino acid selected from the group consisting of Trp, D-allo-Ile, and D-Phe.
- the D-amino acids are D-Arg, D-His, D-Leu, D-Pro, D-Ser, D-Val, D-allo-Thr, D-Asp, D-Lys, D-Trp, D -Be at least one selected from the group consisting of allo-Ile, D-Asn, D-Phe, D-Ala, D-Gln, D-Glu, D-Cys, D-Met and D-Thr
- Such amino acids can exhibit barrier ability (inhibition of transepidermal water transpiration) as an improvement in stratum corneum function.
- D-amino acids it has been demonstrated in the Examples that it promotes the expression of a moisturizing ability-related protein gene or the production of the protein (preferably filaggrin), so D-His, D-Leu, D It is preferably at least one selected from the group consisting of Lys, D-Trp, D-allo-Ile, D-Asn, and D-Phe, D-His, D-Leu, D-Lys, D More preferably, it is at least one selected from the group consisting of -Trp, D-allo-Ile, and D-Phe.
- D-amino acid is D-His, D-Leu, D-Pro, D-Tyr, D-Asp, D-Lys, D-Trp, D-allo-Ile, D-Asn, D-Phe, D-Ala.
- D-Gln, D-Glu, D-Cys, D-Met, and D-Thr are also preferably at least one selected from the group consisting of D-His, D-Leu, D-Tyr, D More preferably, it is at least one selected from the group consisting of -Lys, D-Trp, D-allo-Ile, D-Asn, D-Phe, D-Gln, and D-Thr.
- Such amino acids can exhibit the ability to prevent or improve fine wrinkles (reduction of wrinkle area ratio) as an improvement in stratum corneum function.
- D-amino acids D-Leu, D-Lys, D-Leu, D-Lys, and the like have been demonstrated in the Examples to promote the expression of moisturizing ability-related protein genes or the production of the protein (preferably filaggrin).
- At least one selected from the group consisting of D-Trp and D-Asn is more preferable, and at least one selected from the group consisting of D-Leu, D-Lys, and D-Trp is more preferable.
- the present inventors have found that there is a correlation between the content of D-amino acid contained in a very small amount in the living body and the skin's moisture retention ability, barrier ability, and ability to prevent or improve fine lines. Then, using the D-amino acid found to be correlated, the gene expression level of the protein and the expression level of filaggrin related to the moisturizing ability, barrier ability, prevention of wrinkle or ability to improve wrinkles were examined. There was a significant increase in the expression level of filaggrin. Therefore, among amino acids that have been regarded as racemic amino acids themselves as active ingredients, D-amino acids, which are contained in a very small amount in the living body, are effective in preventing skin moisturizing ability, barrier ability, fine lines, etc.
- the stratum corneum function-improving agent of the present invention utilizes the remarkable effect possessed by D-amino acids contained in a very small amount in the living body based on such novel findings.
- D-Cys may have low stability in the same way as L-Cys (Japanese Patent Laid-Open No. 2009-227660).
- D-Asp and D-Glu may need to be adjusted to a higher pH in order to improve solubility.
- D-form and L-form exist as optical isomers.
- natural proteins are composed of peptide bonds of L-amino acids.
- limonene is known to have optical isomers having different physiological activities.
- D-amino acids are currently at the research stage, and no systematic understanding has been made.
- D-amino acids may be their salts.
- the salt may be any pharmaceutically acceptable salt.
- alkali metal salts such as potassium salt and sodium salt
- alkaline earth metal salts such as calcium salt, barium salt and magnesium salt
- ammonium salts such as ammonium salt and tricyclohexylammonium salt
- monoethanolamine salt, diethanolamine salt examples thereof include alkanolamine salts such as ethanolamine salt, monoisopropyl alcoholamine salt, diisopropyl alcoholamine salt, and triisopropyl alcoholamine salt.
- the production method of D-amino acid is not particularly limited.
- a synthesis method, an extraction method, an enzyme method, and a fermentation method can be mentioned.
- Another example is a method of optical resolution of a racemic mixture of D, L-amino acids.
- the optical resolution is not particularly limited, and may be performed by a conventionally known method (for example, a method of preparing a diastereomeric salt using an optical resolution agent such as camphorsulfonic acid, and performing a resolution using a difference in solubility). Good.
- the stratum corneum function improvement is preferably at least one of retention of the stratum corneum moisture amount, suppression of transepidermal moisture transpiration, and reduction of the wrinkle area ratio.
- the retention of the stratum corneum moisture content can be evaluated, for example, by increasing the Corneometer measurement value or the Skicon measurement value.
- the suppression of transepidermal water transpiration can be evaluated, for example, by lowering the TEWL value.
- the wrinkle area ratio can be evaluated by, for example, producing a replica of the corner of the eye and measuring the wrinkle area ratio with an instrument.
- the moisturizing ability improving agent of the present invention includes D-Arg, D-His, D-Leu, D-Pro, D-Ser, D-Tyr, D-Val, D-allo-Thr, D-Asp, D-Lys. , D-Trp, D-allo-Ile, D-Asn, D-Phe, D-Ala, D-Gln, D-Glu, D-Cys, D-Met, and D-Thr At least one D-amino acid is used as an active ingredient.
- D-amino acids are D-Arg, D-His, D-Leu, D-Tyr, D-Val, D-allo-Thr, D-Lys, D-Trp, D-allo-Ile, D-Asn, D It is preferably at least one selected from the group consisting of -Phe, D-Gln and D-Thr.
- D-amino acids it has been demonstrated in the Examples that it promotes the expression of a moisturizing ability-related protein gene or the production of the protein (preferably filaggrin), so D-His, D-Leu, D From Asp, D-Lys, D-Trp, D-allo-Ile, D-Asn, D-Phe, D-Ala, D-Glu, D-Cys, D-Met, D-Thr, and D-Pro And at least one selected from the group consisting of: D-His, D-Leu, D-Lys, D-Trp, D-allo-Ile, D-Asn, and D-Phe.
- a moisturizing ability-related protein gene or the production of the protein preferably filaggrin
- the moisturizing ability improving agent of the present invention may contain a moisturizing ability improving component other than the above-mentioned D-amino acid, if necessary.
- the D-amino acid may be a salt thereof, and the salt of the D-amino acid is the same as described above.
- the moisturizing ability improving agent of the present invention has an effect of improving the moisturizing ability by maintaining or increasing the stratum corneum moisture content.
- Filagrin moves from the granule layer to the stratum corneum, binds and aggregates with keratin fibers, forms a keratin pattern, and then decomposes into low molecules such as urocanic acid, and is a natural moisturizing factor involved in water retention and ultraviolet absorption. It is known to be. Since natural moisturizing factor binds to and retains intracellular water, the amount of stratum corneum moisture can be increased as the natural moisturizing factor increases. Therefore, if the production of filaggrin can be promoted, a large amount of natural moisturizing factor, which is a decomposition product thereof, will be generated, and the moisturizing ability of the skin will be improved.
- the barrier ability improver of the present invention includes D-Arg, D-His, D-Leu, D-Pro, D-Ser, D-Val, D-allo-Thr, D-Asp, D-Lys, and D-Trp. , D-allo-Ile, D-Asn, D-Phe, D-Ala, D-Glu, D-Cys, D-Met, D-Gln, and D-Thr. -Amino acid as an active ingredient.
- D-amino acids are D-Arg, D-His, D-Leu, D-Val, D-allo-Thr, D-Lys, D-Trp, D-allo-Ile, D-Asn, D-Phe, D -Thr and at least one selected from the group consisting of D-Gln are preferred.
- these D-amino acids it has been demonstrated in the Examples that the production of barrier ability-related proteins (filaggrin, involucrin, transglutaminase 1, keratin 10, and loricrin) has been demonstrated in the Examples.
- the barrier ability improving agent of the present invention may contain a barrier ability improving component other than the above-mentioned D-amino acid, if necessary.
- the D-amino acid may be a salt thereof, and the salt of the D-amino acid is the same as described above.
- the barrier ability improving agent of the present invention has the effect of improving the barrier ability to suppress the entry of foreign substances such as viruses and bacteria from the outside world.
- Filaggrin, involucrin, transglutaminase 1, keratin 10 and loricrin are the main factors constituting keratinocytes, and are considered to prevent the formation of a gap in the stratum corneum by forming a strong stratum corneum.
- the agent for preventing or improving fine wrinkles of the present invention includes D-His, D-Leu, D-Pro, D-Tyr, D-Asp, D-Lys, D-Trp, D-allo-Ile, D-Asn, D-
- the active ingredient is at least one selected from the group consisting of Phe, D-Ala, D-Glu, D-Gln, D-Cys, D-Met, D-Thr, D-Pro, and D-Glu.
- the amino acid is from the group consisting of D-Leu, D-Tyr, D-Lys, D-Trp, D-allo-Ile, D-Asn, D-Phe, D-His, D-Gln, and D-Thr. At least one selected is preferred.
- D-amino acids it has been demonstrated in the Examples that it promotes the production of filaggrin, so D-Asp, D-Lys, D-Trp, D-allo-Ile, D-Asn, D-Phe, At least one selected from the group consisting of D-Ala, D-Glu, D-His, D-Pro, D-Cys, D-Met, D-Thr, and D-Leu is preferred, and D-Lys, D -At least one selected from the group consisting of -Trp, D-Asn, and D-Leu is more preferable, and at least one selected from the group consisting of D-Lys, D-Trp, and D-Leu is more preferable .
- the agent for preventing or improving fine wrinkles of the present invention may contain a component for preventing or improving fine wrinkles other than the above-mentioned D-amino acid, if necessary.
- the D-amino acid may be a salt thereof, and the salt of the D-amino acid is the same as described above.
- the agent for preventing or improving fine wrinkles of the present invention has an effect that fine wrinkles can be prevented or improved.
- the formation of wrinkles which is one of the typical aging changes in the skin, is said to start from the formation of fine lines due to the dryness of the skin.
- filaggrin moves from the granule layer to the stratum corneum, binds and aggregates with keratin fibers, forms a keratin pattern, and then decomposes into low molecules such as urocanic acid, and is involved in water retention and ultraviolet absorption. It is known to become a natural moisturizing factor. Since natural moisturizing factor binds to and retains intracellular water, the amount of stratum corneum moisture can be increased as the natural moisturizing factor increases.
- the expression promoter for the stratum corneum function-related protein gene of the present invention is from D-Asp, D-Lys, D-Trp, D-allo-Ile, D-Asn, D-Phe, D-Ala, and D-Glu. At least one selected from the group consisting of D-Lys, D-Trp, D-allo-Ile, D-Asn, and D-Phe is used as an active ingredient.
- the stratum corneum function-related protein (eg, filaggrin) production promoter of the present invention includes D-His, D-Leu, D-Pro, D-Asp, D-Lys, D-Trp, D-Allo-Ile,
- the active ingredient is at least one D-amino acid selected from the group consisting of D-Phe, D-Ala, D-Glu, D-Cys, D-Met, and D-Thr. More preferably, the active ingredient is at least one D-amino acid selected from the group consisting of D-Leu, D-Lys, D-Trp, D-allo-Ile, D-Phe, and D-Thr. .
- the stratum corneum function-related protein is at least one selected from filaggrin, involucrin, loricrin, keratin 10 and transglutaminase 1.
- Filaggrin is a protein strongly associated with moisturizing ability and a source of amino acids that are natural moisturizing factors. Therefore, it is a protein associated with fine wrinkle formation due to dry skin.
- the keratin filaments aggregate and contribute to the construction of strong keratin, so that the protein is also related to the barrier ability.
- Involucrin is a protein associated with barrier ability. It is a kind of protein that constitutes the stratum corneum, and is essential for the formation of a strong stratum corneum.
- Keratin 10 is a protein related to barrier ability.
- Loricrin is a protein associated with barrier ability. It is a kind of protein that constitutes the stratum corneum, and is essential for the formation of a strong stratum corneum.
- Transglutaminase 1 is an enzyme that crosslinks proteins. It is considered important for forming a strong stratum corneum.
- the skin cosmetic or external preparation for skin of the present invention contains at least one of the above agents. What is necessary is just to adjust content of the agent of this invention suitably according to the kind of skin cosmetics and a skin external preparation.
- the lower limit of the preferable content when converted in terms of the total amount of D-amino acids is usually 0.01% by mass or more, preferably 0.1% by mass or more, and more preferably 1% by mass or more.
- the upper limit is usually 30% by mass or less, preferably 10% by mass or less.
- the skin cosmetic and skin external preparation of the present invention may further contain at least one base selected from the group consisting of polyol compounds, surfactants, higher alcohols, thickeners, chelating agents, preservatives, and silicones. It is often preferred to include.
- polyol compound examples include ethylene glycol, butylene glycol, polyethylene glycol, butylethylpropane diol, polypropylene glycol copolymer, propylene glycol, dipropylene glycol, 1,3-butylene glycol, glycerin, diglycerin, and sorbitol. .
- at least one selected from the group consisting of butylene glycol, glycerin, polyethylene glycol, dipropylene glycol, and sorbitol is preferable.
- surfactant examples include polyoxyethylene sorbitan oleate, higher fatty acid soap, alkyl sulfate ester salt, polyoxyethylene alkyl ether sulfate salt, alkyl ether phosphate ester salt, N-acyl amino acid salt, acyl N-methyl Anionic surfactants such as taurine salts; cationic surfactants such as alkyltrimethylammonium chloride and dialkyldimethylammonium chloride; cocamidopropyl betaine, alkyldimethylaminoacetic acid betaine, alkylamidodimethylaminoacetic acid betaine, 2-alkyl-N-carboxyl -Amphoteric surfactants such as N-hydroxyimidazolinium betaine; glycerin fatty acid esters, polyglycerin fatty acid esters, lecithin derivatives (eg lysolecithin), polyoxyethylene (For example, polyoxyethylene hydrogenated castor
- Nonionic surfactants may be mentioned.
- glycerin fatty acid ester, polyglycerin fatty acid ester, lecithin derivative, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, and polyoxyethylene glycerin fatty acid ester are selected. At least one is preferred.
- Higher alcohol examples of the higher alcohol include cetanol, behenyl alcohol, and isohexadecyl alcohol. Among these, behenyl alcohol is preferable.
- thickener for example, polyacrylic acid, carrageenan, xanthan gum, sodium carboxymethylcellulose, carboxyvinyl polymer, polyoxyethylene glycol distearate, acrylic acid polymer, cellulose natural polymer, ethanol, neopentyl glycol dicaprate, An example is potassium myristate. Among these, at least one selected from the group consisting of acrylic acid polymers, xanthan gum, and cellulose natural polymers is preferable.
- chelating agent examples include ethylenediaminetetraacetic acid (derivative) such as etidronic acid and trisodium edetate. Of these, ethylenediaminetetraacetic acid is preferred.
- Preservative As the preservative, at least one of paraben and phenoxyethanol is preferable.
- the paraben include methyl paraben, propyl paraben, and butyl paraben.
- silicone examples include methylpolysiloxane, dimethylpolysiloxane, methylphenylpolysiloxane, decamethylcyclopentasiloxane, cyclohexasiloxane, cyclopentasiloxane, trimethylsiloxysilicic acid, polyoxyethylene / methylpolysiloxane copolymer, silicon Examples include fluid, silicone rubber, and silicone oil.
- the skin cosmetic or external preparation for skin of the present invention may contain one or more other bases other than those described above.
- Other bases may be bases used for normal skin cosmetics or skin external preparations, such as oil bases, water-soluble bases, emulsifiers, stabilizers, pH adjusters, preservatives, ultraviolet rays. Examples include absorbents, ultraviolet light scattering agents, other functional ingredients (bioactive ingredients), fragrances such as triethylhexanoin, dyes, solvents, natural product extracts, and amino acids (derivatives) other than the above D-amino acids.
- oily bases examples include vegetable oils such as castor oil, cottonseed oil, sesame oil, jojoba oil, olive oil, cacao butter; waxes such as owl, liquid lanolin, waxes such as candelilla wax, beeswax, carnauba wax; petrolatum, liquid paraffin , Higher hydrocarbons such as paraffin such as solid paraffin, squalane, olefin oligomer and plastibase; fatty acids such as lauric acid, myristic acid, stearic acid and palmitic acid and esters thereof; base wax such as white kerosene; natural polymer, water Examples thereof include polyisobutene.
- vegetable oils such as castor oil, cottonseed oil, sesame oil, jojoba oil, olive oil, cacao butter
- waxes such as owl, liquid lanolin, waxes such as candelilla wax, beeswax, carnauba wax
- petrolatum liquid paraffin , Higher hydro
- water-soluble base examples include polyvinyl alcohol, cellulose derivatives (for example, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, cationized cellulose), carboxyvinyl polymers, esters (for example, isopropyl myristate, isopropyl palmitate, stearyl stearate). Octyldodecyl myristate, octyldodecyl oleate, 2-ethylhexanoic acid triglyceride).
- emulsifier examples include stearyl alcohol, glyceryl monostearate, sorbitan monopalmitate, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, diglycerin monostearate, polysorbate 60. And myristoylmethyl- ⁇ -alanine (phytosteryl / decyltetradecyl).
- Examples of the stabilizer include spherical alkyl acrylate powder, dimethyl distearyl ammonium hectorite, ascorbic acid, sodium pyrosulfite, gellan gum, and pectin.
- Examples of the pH adjuster include phosphate buffer, sodium hydroxide, potassium hydroxide, and triethanolamine.
- Examples of the preservative include ethyl paraoxybenzoate, sodium benzoate, salicylic acid, sorbic acid, sodium bisulfite, and phenoxyethanol.
- Examples of the ultraviolet absorber include cinnamate derivatives such as butylmethoxybenzoylmethane, octyl paradimethylaminobenzoate, 2-ethylhexyl paramethoxycinnamate, and ethylhexyl dimethoxybenzylidenedioxoimidazolidinepropionate.
- Examples of the ultraviolet scattering agent include titanium oxide and zinc oxide.
- the solvent include an arginine aqueous solution and purified water.
- Examples of the dye include red 202, yellow 4, blue 1, bengara, yellow iron oxide, and black iron oxide.
- Other functional components include, for example, kojic acid, trioleyl phosphate, squalane, cetyl ethylhexanoate, tocopherol, mica, bis (N-lauroyl-L-glutamic acid / N-lauroyl-sarcosine) dimer linoleyl, Tocopherol acetate, thiotaurine, honey, lauroyl sarcosine isopropyl, lauroyl lysine, talc, dibutyl ethyl hexanoyl glutamide, dibutyl lauroyl glutamide, bentonite, taurine, arbutin, panthenol, niacinamide, pyridoxine hydrochloride, retinol, carotene, riboflavin, Ubiquinone, sodium hyaluronate, water-soluble collagen, sodium chondroitin sulfate, lactobacilli, fermente
- Examples of the natural product extract include lavender extract, peppermint extract, sage extract, anise extract, rose extract, cypress water, rooibos extract, lavender extract, and clara extract.
- Examples of amino acids (derivatives) include L-leucine, L-isoleucine, L-valine, L-phenylalanine, L-tryptophan, L-aspartic acid, sodium L-glutamate, L-lysine (hydrochloride), L-arginine.
- L-threonine L-alanine, L-proline, L-serine, glycine, acetylglutamine, L-histidine, pyridoxylserine, carnosine, acetylmethionine, acetylcysteine, sodium polyaspartate, citrulline, ornithine, betaine, L -Tyrosine, L-asparagine, L-methionine.
- the content of the other base may be set as appropriate and is not particularly limited.
- the dosage form of the skin cosmetic or skin external preparation of the present invention is not particularly limited, and examples thereof include liquids, lotions, ointments, creams, plasters, tape preparations, powder lotions, and gels. Among these, emulsions, creams, lotions, and gels are mentioned, and any of these is preferable.
- the use site of the skin cosmetic or external preparation of the present invention is not particularly limited, and is usually applied to the skin and mucous membrane. Among them, it is preferably used for the skin. Therefore, examples of usage forms of the skin cosmetic or external preparation for skin of the present invention include aqueous solutions, emulsions, powder dispersions, and emulsions (oil-in-water type, water-in-oil type, etc.). More specifically, liquids, oils, lotions, gels, sols, emulsions, suspensions, creams, ointments, patches, sticks and the like can be mentioned.
- Examples of so-called cosmetics include lotions such as lotions and beauty lotions; emulsions such as emollient emulsions, milky lotions, nourishing emulsions, and cleansing emulsions; creams such as emollient creams, massage creams, cleansing creams, and makeup creams; sprays;
- Examples include cosmetics for makeup such as packs, foundations, lipsticks, lipsticks, eye shadows, cheeks, funny, color powders, and cosmetics for skin cleaning such as facial cleansers, makeup removers, body shampoos, and soaps.
- they may be used as quasi-drugs, pharmaceuticals, and foods (including supplements and beverages).
- composition of the skin cosmetic or skin external preparation of the present invention as an emulsion or cream includes, for example, the agent of the present invention and a polyol group (at least selected from the group consisting of butylene glycol, glycerin, polyethylene glycol, and dipropylene glycol).
- a polyol group at least selected from the group consisting of butylene glycol, glycerin, polyethylene glycol, and dipropylene glycol.
- surfactant group at least one selected from the group consisting of glycerin fatty acid ester, polyglycerin fatty acid ester, and lecithin derivative), higher alcohol group (behenyl alcohol), and thickener group (acrylic acid) And at least one of a polymer and xanthan gum), a chelating agent group (ethylenediaminetetraacetic acid), a preservative group (at least one of paraben and phenoxyethanol), and silicone.
- surfactant group at least one selected from the group consisting of glycerin fatty acid ester, polyglycerin fatty acid ester, and lecithin derivative
- higher alcohol group behenyl alcohol
- thickener group acrylic acid
- chelating agent group ethylenediaminetetraacetic acid
- preservative group at least one of paraben and phenoxyethanol
- composition of the skin cosmetic or skin external preparation of the present invention as a lotion is, for example, the agent of the present invention and a polyol group (at least one selected from the group consisting of butylene glycol, glycerin, polyethylene glycol, and sorbitol).
- a polyol group at least one selected from the group consisting of butylene glycol, glycerin, polyethylene glycol, and sorbitol.
- a surfactant group at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, and polyoxyethylene glycerin fatty acid ester
- Sticky group at least one selected from the group consisting of acrylic acid-based polymer, xanthan gum, and cellulose-based natural polymer), chelating agent group (ethylenediaminetetraacetic acid), and preservative group (at least one of paraben and phenoxyethanol)
- a surfactant group at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, and polyoxyethylene glycerin fatty acid ester
- Sticky group at least one selected from the group consisting of acrylic acid-based polymer, xanthan gum, and cellulose-based natural polymer
- chelating agent group ethylenediaminetetraacetic acid
- the gel composition of the skin cosmetic or skin external preparation of the present invention includes, for example, the agent of the present invention, a polyol group (at least one selected from the group consisting of butylene glycol, glycerin, and polyethylene glycol), and an interface.
- a polyol group at least one selected from the group consisting of butylene glycol, glycerin, and polyethylene glycol
- Activator group at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, and polyoxyethylene glycerin fatty acid ester
- thickener group At least one selected from the group consisting of acrylic acid-based polymers, xanthan gum, and cellulose-based natural polymers
- chelating agent group ethylenediaminetetraacetic acid
- preservative group at least one of paraben and phenoxyethanol
- the moisturizing ability-improving agent of the present invention prevents rough skin, fine lines, itching and the like due to aging, drying, skin diseases (for example, atopic dermatitis, etc.), etc. Can be used for suppression and treatment.
- the barrier ability improving agent of the present invention is a rough skin caused by causes such as aging, dryness, skin diseases (such as atopic dermatitis) through the ability to improve the barrier ability to suppress the entry of foreign substances such as viruses and bacteria from the outside world, It can be expected to be used for prevention, suppression and treatment of inflammation and sensitive skin.
- the agent for preventing or improving fine wrinkles of the present invention can be expected to be used especially for the prevention, suppression and treatment of fine wrinkles due to drying through the effect of preventing or improving fine lines with a reduced wrinkle area ratio.
- the stratum corneum function-improving agent, gene expression promoting agent, skin cosmetic, or skin external preparation of the present invention has a moisturizing action that maintains or increases the amount of water in the stratum corneum, and the entry of foreign substances such as viruses and bacteria from the outside. Preventing rough skin, fine lines, itching, inflammation, sensitive skin caused by aging, dryness, skin diseases (for example, atopic dermatitis, etc.) Expected to be used for suppression and treatment.
- the evaluation method of the present invention is a method for measuring the moisture content of a subject's skin by measuring at least one selected from the group consisting of the moisture content of the stratum corneum of the subject's skin, the wrinkle area ratio, and the transepidermal moisture transpiration rate, Confirming at least one selected from the group consisting of the ability to prevent or improve fine wrinkles and barrier ability, collecting the stratum corneum from the measurement site of the subject's skin, and at least one D contained in the stratum corneum -Specifying the amount of amino acid, the relationship between the amount of D-amino acid and at least one selected from the group consisting of the ability to moisturize the skin, barrier ability, and the ability to prevent or improve fine lines, This is a skin evaluation method using D-amino acids, including comparison between the two.
- the evaluation method of the present invention is roughly classified into the following two embodiments.
- the relationship between each component and the moisturizing ability, barrier ability, wrinkle prevention or improvement ability of the skin is compared between the results of the subjects (preliminary subjects). If the correlation is confirmed, the correlation between the appearance of the skin and the amount of D-amino acid may be used. Is selected as an index for evaluating the skin of the subject (which may be the same as or different from the preliminary subject).
- the amount of D-amino acid in the stratum corneum before and after administration of a sample of skin cosmetics, topical skin preparations, and these candidate substances to the subject is specified and obtained in light of the above correlation. It is the embodiment which compares the evaluation of the obtained skin before and after administration and evaluates the sample or the effectiveness of the subject on the skin.
- the subject may be either male or female. However, women are preferable because they are sensitive to skin condition care, women in their twenties to thirties who start to be interested in aging skin condition care, or aging skin condition care Women in their 40s and 60s who often perform are more preferable.
- the moisture retention ability of the skin is usually evaluated by the stratum corneum moisture content.
- the skin barrier ability is usually evaluated by transepidermal water loss (TEWL).
- Skin wrinkle prevention or improvement ability is usually evaluated by the wrinkle area ratio.
- the stratum corneum present in the outermost layer of the epidermis serves as a barrier that separates the external environment from the inside of the body.
- the quality of the stratum corneum is a factor that determines the freshness of the skin.
- Constituents such as intercellular lipids and natural moisturizing factor (NMF) exist in the stratum corneum, and in addition to the evaporation of moisture from the inside of the skin, the stratum corneum itself retains appropriate moisture. Retaining skin surface softness and / or smoothness.
- the stratum corneum moisture content and TEWL are used as indexes for evaluating the quality of the stratum corneum.
- a method for measuring the amount of water in the stratum corneum which is the amount of water present in the stratum corneum of the skin
- a method of measuring the electrical impedance of the skin using a high-frequency current for example, a high-frequency current of 3.5 MHz through the electrode
- a method of measuring using a device such as Skicon-200EX (manufactured by Yayoi Co., Ltd.) that measures the conductance by flowing through, Corneometer (manufactured by Curage + Khazaka Germany) that estimates the water content from the electric capacity, a method using an infrared spectrum, and a microwave Examples thereof include a method and a photoacoustic method.
- a method of measuring the conductance on the skin surface is preferable. It can be said that the moisture content of the stratum corneum is superior in moisture retention.
- a TEWL measurement method for example, there is a method in which the skin is brought into contact with one of the cylindrical probes whose both ends are opened, and the amount of water evaporated from the skin surface is measured using a temperature / humidity sensor installed inside the probe. It is done.
- a measuring apparatus that employs this method, there is a Tewameter (registered trademark) TM300 manufactured by Curage + Khazaka. It can be said that the smaller the TEWL value, the better the barrier ability.
- Examples of the method for measuring the wrinkle area ratio include the following methods. Using SKIN CAST (manufactured by RSI), a replica of the corner of the eye was prepared, and this replica was measured using Primos lite 1813 (manufactured by GFMestechnik GmbH), and the wrinkle area ratio was calculated using the attached software. can do. It can be said that the smaller the wrinkle area ratio, the better the ability to prevent or improve fine lines.
- the method for confirming various functions of the skin is not limited to the above, and for example, other conventionally known methods that use indicators such as the number of days of horny layer turnover and the nucleated cell rate of the horny layer. It can also be confirmed.
- the skin measurement site is not particularly limited. However, from the viewpoint of evaluating the stratum corneum that acts as a barrier that prevents the external environment and the inside of the body, the site is preferably exposed to the outside in daily life. For example, cheeks and arms.
- the measurement site may be changed according to the measurement method. For example, when measuring the stratum corneum moisture content or TEWL value, the cheek can be measured, and when measuring the wrinkle area ratio, it can be measured at the corner of the eye. There may be one measurement location or two or more measurement locations.
- the stratum corneum may be collected from a predetermined measurement site on the skin by a conventionally known method such as a tape stripping method.
- the tape stripping method is a method of collecting a stratum corneum adhering to an adhesive surface by applying an adhesive tape to the skin and peeling off the adhesive tape.
- Examples of the method of collecting the stratum corneum include a method of collecting the stratum corneum attached to the adhesive tape when a commercially available adhesive tape is pressed against the measurement site and peeled off.
- Examples of commercially available adhesive tapes include Asahi Biomed's horny checker, Moritex's horny layer seal, PROMOTOOL's horny checker (disc type W, disc type G, PRO type), Integral's Corneofix, 3M's Examples thereof include transparent tape, 3M transparent double-sided tape, and Nichiban cello tape (registered trademark).
- the method for specifying the amount of D-amino acid is not particularly limited.
- a direct method (a method of separating by chromatography using a chiral stationary phase column after precolumn derivatization), an indirect method (diastereo with a chiral derivatization reagent). And a method of separating by chromatography on a reverse phase column).
- the direct method includes, for example, a method in which precolumn fluorescence derivatization is performed with NBD-F, followed by separation with a chiral column and fluorescence detection.
- the component of the D-amino acid to be specified may be one type or a combination of two or more types, and D-Arg, D-His, D-Leu, D-Pro, D-Ser, D-Tyr, D-Val, Includes D-allo-Thr, D-Asp, D-Lys, D-Trp, D-allo-Ile, D-Asn, D-Phe, D-Ala, D-Gln, D-Glu, and D-Met It is preferable.
- the more preferable D-amino acid described above correlates with at least one of the skin moisturizing ability, barrier ability, and fine wrinkle prevention or improvement ability of women in their 20s to 30s and 40s to 60s.
- the evaluation method of the present invention can be applied to the development of skin cosmetics such as ingredients derived from natural products, or skin external preparations.
- the component of D-amino acid is D-Arg, D-His, D-Leu, D-Pro, D-Ser, D-Tyr, D-Val. , D-allo-Thr, D-Asp, D-Lys, D-Trp, D-allo-Ile, D-Asn and D-Phe are preferred. Thereby, at least the moisture retention ability can be evaluated.
- D-amino acid components are D-His, D-Leu, D-Pro, D-Ser, D-Val, D-allo-Thr, D It is preferably at least one selected from the group consisting of -Asp, D-Trp, D-allo-Ile, D-Asn and D-Phe. Thereby, at least the barrier ability can be evaluated.
- the components of D-amino acid are D-Arg, D-His, D-Leu, D-Pro, D-Val, D-allo-Thr, D It is preferably at least one selected from the group consisting of -Asp, D-Lys, D-Trp, D-allo-Ile, D-Asn, and D-Gln. Thereby, at least moisture retention ability can be evaluated.
- the components of D-amino acid are D-Arg, D-His, D-Leu, D-Pro, D-Ser, D-Val, D-allo. It is preferably at least one selected from the group consisting of -Thr, D-Lys, D-Trp, D-allo-Ile, D-Phe, and D-Gln. Thereby, at least the barrier ability can be evaluated.
- the D-amino acid components are D-Leu, D-Tyr, D-Asp, D-Lys, D-Trp, D-Asn, and D- It is preferably at least one selected from the group consisting of Gln. Thereby, at least the ability to prevent or improve fine lines can be evaluated.
- the D-amino acid component is preferably at least one of D-Asp and D-Lys. Thereby, at least the ability to prevent or improve fine lines can be evaluated.
- the method for specifying the amount of D-amino acid is not particularly limited, and examples thereof include mass spectrometry using liquid chromatography (LC) or gas chromatography (GC), enzyme method using a quantitative enzyme, and bioassay method.
- LC liquid chromatography
- GC gas chromatography
- enzyme method using a quantitative enzyme enzyme method using a quantitative enzyme
- bioassay method bioassay method.
- the liquid chromatograph-tandem mass spectrometer is preferable because the identification of D-amino acid and the measurement of the content can be performed simultaneously.
- the amount of D-amino acid is preferably the content of D-amino acid per amount of protein contained in the stratum corneum. Thereby, the experimental error derived from the stratum corneum sampling method can be reduced.
- the method for measuring the protein amount is not particularly limited, and examples thereof include a measurement method using a spectrophotometer such as an ultraviolet absorption method, a BCA method, a Bradford method, a Raleigh method, and a burette method, and a measurement method by electrophoresis. . Among these, the BCA method is preferable.
- the relationship between at least one of stratum corneum moisture content, TEWL, and wrinkle area ratio, and the amount of D-amino acid is obtained from a plurality of subjects, and by comparing these, A D-amino acid that correlates with at least one of skin moisturizing ability, barrier ability, or fine wrinkle prevention or improvement ability can be specified.
- the comparison method is not particularly limited, and examples thereof include a method of plotting measured values of stratum corneum moisture content, TEWL, wrinkle area ratio, etc., and D-amino acid amount on a graph.
- the skin moisturizing ability, barrier ability, fine wrinkle prevention or improvement ability can be evaluated by the content of D-amino acid. Therefore, by comparing the content of D-amino acid with which the correlation was recognized before and after the administration of a sample such as skin cosmetics or external preparations for the same subject, The effectiveness can be confirmed. Therefore, it can be used as a method for confirming whether or not the subject is a skin cosmetic or an external preparation suitable for the subject.
- the evaluation method of the present invention only a short-term evaluation based on the stratum corneum moisture content, TEWL, or wrinkle area ratio as in the conventional measurement method before and after administering the skin cosmetic or the external preparation for skin. First, it can be evaluated whether or not the skin condition is improved in the long term by the content of D-amino acid.
- the stratum corneum moisture content was measured at the center of the subject's cheek using Skicon-200EX (manufactured by Yayoi Co., Ltd.).
- the TEWL value was measured at the center of the subject's cheek using a Tewmeter (registered trademark) TM300 (Courage + Khazaka Germany).
- the collected tape was sealed in a conical tube (50 ml) and stored at ⁇ 80 ° C.
- the collected tape (horny layer) was sonicated twice using a 95% aqueous methyl alcohol solution to extract water-soluble components.
- An internal standard solution (containing a plurality of D, L-amino acid stable isotopes such as D-Arg) was added to the extract.
- the obtained aqueous methyl alcohol solution was dried by a centrifugal evaporator to prepare a sample for D-amino acid analysis.
- the MicroBCA method was used, the same amount of the sample solution and the MicroBCA solution were added, and the mixture was heated and shaken (1100 rpm) at 50 ° C. for 1 hour.
- the protein was quantified by measuring the absorbance (562 nm) with a spectroscope.
- Table 3 shows the correlation between the D-amino acid content of the subject in the stratum corneum, the stratum corneum moisture content, the TEWL value, and the wrinkle area ratio.
- An absolute value of the correlation coefficient of 0.4 or more is evaluated as “A” as “strong correlation”, 0.3 or more is evaluated as “B” as “medium correlation”, and 0.2 or more is “weak” “C” was evaluated as “correlation”.
- the content of D-Asn, D-Asp, D-Lys, D-Trp, D-Leu, and D-Gln in the stratum corneum is at least one of young women and older women.
- the corneum moisture content, TEWL value, and wrinkle area ratio were correlated.
- D-Phe, D-allo-Ile, D-Arg, D-His, D-Pro, D-Ser, D-Val, and D-allo-Thr are contained in young and older women.
- Correlation was observed between stratum corneum water content and TEWL value for at least one female.
- the content of D-Tyr in the stratum corneum was found to correlate with the stratum corneum moisture content and the wrinkle area ratio for young women.
- the amino acid content is a value obtained by dividing the amino acid content obtained by the above-mentioned “D-amino acid quantitative analysis” by the protein amount obtained by the “protein quantitative analysis”.
- the amino acid content is a value obtained by dividing the amino acid content obtained by the above-mentioned “D-amino acid quantitative analysis” by the protein amount obtained by the “protein quantitative analysis”.
- the amino acid content is a value obtained by dividing the amino acid content obtained by the above-mentioned “D-amino acid quantitative analysis” by the protein amount obtained by the “protein quantitative analysis”.
- Examples 1 to 8 of the stratum corneum function improving agent (Gene expression test on D-amino acid “moisturizing / barrier ability / prevention or improvement of fine lines” using normal human epidermal keratinocytes)
- Normal human epidermal keratinocytes (Kurabo) were cultured in HuMedia KG2 (Kurabo) at 37 ° C., 5% CO 2 and saturated steam. Cells in a confluent state were seeded in a 6-well plate at a seeding density of 3.0 ⁇ 10 5 (cells / well).
- each target gene was increased by using D-Asp, D-Lys, D-Phe, D-Trp, D-allo-Ile, and D-Glu.
- D-Ala increased the expression levels of filaggrin, involucrin, keratin 10, and transglutaminase 1 target genes.
- D-Asn increased the expression levels of filaggrin, involucrin, keratin 10, and loricrin target genes.
- FIGS. 1 to 4 are graphs showing the amplification amounts of filaggrin, involucrin, keratin 10, and loricrin (relative to the control amplification amount) when D-Asn (Example 1) is used.
- FIGS. 5 to 9 are graphs showing the amount of amplification (relative to the amount of control amplification) of filaggrin, involucrin, keratin 10, loricrin, and transglutaminase 1 when D-Asp (Example 2) is used.
- 5 and 9 are 500 ⁇ M
- FIGS. 6 to 8 are 100 ⁇ M).
- D-amino acids promote the production of proteins that contribute to the ability to prevent or improve moisture retention, barrier ability, and fine lines, and are useful as active ingredients such as stratum corneum function improving agents.
- Example 9 (Cytotoxicity test: neutral red method) Normal human epidermal keratinocytes were seeded in a 6-well plate, and the following day, a sample prepared by adjusting D-amino acid (500 ⁇ M) in a cell culture medium was added. After 48 hours, the evaluation sample solution was removed from the plate and each well was rinsed with 2 ml of cell culture medium. A medium containing NR (neutral red (Kurabo)) was added dropwise at 2 ml / well and allowed to stand for 2 hours at 37 ° C., 5% CO 2 and saturated steam.
- NR neutral red
- the medium (with neutral red) was discarded, and a washing fixative (2 wt% calcium chloride solution and 2 wt% formalin solution mixed in equal amounts) was added at 2 ml / well, and allowed to stand for 1 minute, and then the wash fixative was removed.
- 2 ml / well of NR extract (50% by volume ethyl alcohol, 1% by volume acetic acid) was added and shaken for 15 minutes with a plate shaker. Incorporation of NR into living cells was examined by measuring the absorbance at 540 nm of the NR extract with a microplate reader (manufactured by Thermo Fisher Scientific).
- the absorbance of the NR extract of each sample-added cell at a predetermined concentration is set to a relative percentage, whereby the cells of each sample Toxicity was calculated. The results are shown in FIG.
- each D-amino acid evaluated was not cytotoxic at 500 ⁇ M. It was found that D-amino acid induces increase and decrease in gene expression that leads to various skin improvement effects such as moisturizing ability, barrier ability, and prevention or improvement of fine wrinkles at non-cytotoxic concentrations.
- Example 10 (Filaggrin production promotion test) Normal human newborn epidermal keratinocytes (Kurashiki Boseki Co., Ltd.) were cultured in HuMedia-KG2 (Kurashiki Boseki Co., Ltd.). Confluent cells were detached with trypsin and seeded at 15 ⁇ 10 4 (cells / well) in a 6-well plate. On the next day, after the cells adhere to the plate, each evaluation sample (control (no sample added), D-amino acid) and calcium chloride were added to the predetermined evaluation concentrations (0.5 mM, 1 mM or 5 mM for the sample, 1.3 mM for calcium chloride). The medium was replaced with the added HuMedia-KG2 and cultured for 5 days.
- the medium was changed with HuMedia-KG2 supplemented with the sample and calcium chloride once every 2 days or 3 days. After culturing, the medium was removed, washed twice with cold PBS ( ⁇ ), and 200 ⁇ L of an extract (M-PER (Thermo Fisher Scientific)) containing a protease inhibitor and a phosphatase inhibitor (EzRIPA Lysis (Ato Inc.)) was added. / Well added to each well and shaken for 5 minutes at 400 rpm on a multi shaker (As One Co., Ltd.) The cells were scraped with a scraper, and 200 ⁇ L of denaturant (EzApply (Ato shares) was added to the total amount of liquid including the precipitate.
- M-PER Thermo Fisher Scientific
- the gel was applied and electrophoresed for 1 hour at a constant current of 21 mA using an electrophoresis apparatus (Ato Co., Ltd.)
- the gel after electrophoresis was transferred to a PVDF membrane, washed with TBS-T (Ato Co., Ltd.), and then EzBlock BSA.
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Abstract
Description
皮膚の代表的な加齢変化の一つであるシワの形成は、皮膚の乾燥による小じわ形成から始まると言われている。そのため、フィラグリンの産生が促進され皮膚の保湿能が向上すると、乾燥を抑制して、小じわの形成を抑制することができると考えられる。
ケラチン10等のケラチンとフィラグリンとが凝集した構造体を包含する角質細胞の周辺には、角質細胞の細胞膜を裏打ちするきわめて強靭で巨大な不溶性構造物である周辺帯が存在している。周辺帯の主な構造要素は、有棘細胞で産生されるインボルクリン、顆粒細胞で産生されるロリクリン等のタンパク質であり、これらがトランスグルタミナーゼ(TG)1等の酵素により架橋されている。そのため、フィラグリン、インボルクリン、トランスグルタミナーゼ1、ケラチン10、ロリクリンは、角質細胞の形成に強く影響し、肌のバリア能と関連すると考えられる。
特許文献4には、D-グルタミン酸は、経口投与した場合に、TEWL値が低減することが記載されている。しかしながら、他の投与形態(例えば、スキンケア用品)で効果が発現されることは記載も示唆もされていない。
また、特許文献4及び5には、保湿能及びバリア能の両効能を向上し得ることは記載も示唆もされていない。
すなわち、本発明は、以下のとおりである。
〔1〕D-アルギニン、D-ヒスチジン、D-ロイシン、D-プロリン、D-セリン、D-チロシン、D-バリン、D-アロスレオニン、D-アスパラギン酸、D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン、D-フェニルアラニン、D-アラニン、D-グルタミン、D-グルタミン酸、D-システイン、D-メチオニン及びD-スレオニン(以下、本明細書中、それぞれ「D-Arg」、「D-His」、「D-Leu」、「D-Pro」、「D-Ser」、「D-Tyr」、「D-Val」、「D-allo-Thr」、「D-Asp」、「D-Lys」、「D-Trp」、「D-allo-Ile」、「D-Asn」、「D-Phe」、「D-Ala」、「D-Gln」、「D-Glu」、「D-Cys」、「D-Met」、「D-Thr」と略記する)からなる群から選択される少なくとも1種のD-アミノ酸を有効成分とする角層機能改善剤。
〔2〕角層機能改善が、角層水分量の保持である、上記〔1〕に記載の角層機能改善剤。
〔3〕前記D-アミノ酸が、D-Arg、D-His、D-Leu、D-Pro、D-Ser、D-Val、D-allo-Thr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Gln、D-Glu、D-Cys、D-Met、及びD-Thrからなる群から選択される少なくとも1種であり、角層機能改善が、経表皮水分蒸散の抑制である上記〔1〕に記載の角層機能改善剤。
〔4〕前記D-アミノ酸が、D-His、D-Leu、D-Pro、D-Tyr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Gln、D-Glu、D-Cys、D-Met、及びD-Thrからなる群から選択される少なくとも1種であり、角層機能改善が、シワ面積率の低減である上記〔1〕に記載の角層機能改善剤。
〔5〕D-Arg、D-His、D-Leu、D-Pro、D-Ser、D-Tyr、D-Val、D-allo-Thr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Gln、D-Glu、D-Cys、D-Met、及びD-Thrからなる群から選択される少なくとも1種のD-アミノ酸を有効成分とする保湿能改善剤。
〔6〕前記D-アミノ酸が、D-His、D-Leu、D-Lys、D-Trp、D-allo-Ile、D-Asn、及びD-Pheからなる群から選択される少なくとも1種である上記〔5〕に記載の保湿能改善剤。
〔7〕前記D-アミノ酸が、D-His、D-Leu、D-Lys、D-Trp、D-allo-Ile、及びD-Pheからなる群から選択される少なくとも1種である上記〔5〕又は〔6〕に記載の保湿能改善剤。
〔8〕D-Arg、D-His、D-Leu、D-Pro、D-Ser、D-Val、D-allo-Thr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Glu、D-Cys、D-Met、D-Gln、及びD-Thrからなる群から選択される少なくとも1種のD-アミノ酸を有効成分とするバリア能改善剤。
〔9〕前記D-アミノ酸が、D-His、D-Leu、D-Lys、D-Trp、D-allo-Ile、D-Asn、及びD-Pheからなる群から選択される少なくとも1種である上記〔8〕に記載のバリア能改善剤。
〔10〕前記D-アミノ酸が、D-His、D-Leu、D-Lys、D-Trp、D-allo-Ile、及びD-Pheからなる群から選択される少なくとも1種のD-アミノ酸である上記〔8〕又は〔9〕に記載のバリア能改善剤。
〔11〕D-His、D-Leu、D-Tyr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Glu、D-Gln、D-Cys、D-Met、及びD-Thrからなる群から選択される少なくとも1種を有効成分とする小じわ予防又は改善剤。
〔12〕前記D-アミノ酸が、D-Leu、D-Lys、D-Trp、及びD-Asnからなる群から選択される少なくとも1種である上記〔11〕に記載の小じわ予防又は改善剤。
〔13〕前記D-アミノ酸が、D-Leu、D-Lys、及びD-Trpからなる群から選択される少なくとも1種である上記〔11〕又は〔12〕に記載の小じわ予防又は改善剤。
〔14〕D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、及びD-Gluからなる群から選択される少なくとも1種を有効成分とするフィラグリン、インボルクリン、ロリクリン、ケラチン10、及びトランスグルタミナーゼ1から選ばれる少なくとも1種のタンパク質の遺伝子の発現促進剤。
〔15〕D-His、D-Leu、D-Pro、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Phe、D-Ala、D-Glu、D-Cys、D-Met、及びD-Thrからなる群から選択される少なくとも1種を有効成分とするフィラグリンの産生促進剤。
〔16〕上記〔1〕~〔4〕のいずれかに記載の角層機能改善剤、上記〔5〕~〔7〕のいずれかに記載の保湿能改善剤、上記〔8〕~〔10〕のいずれかに記載のバリア能改善剤、上記〔11〕~〔13〕のいずれかに記載の小じわ予防又は改善剤、上記〔14〕に記載の発現促進剤、又は上記〔15〕に記載の産生促進剤を含む皮膚化粧料又は皮膚外用剤。
〔17〕ポリオール化合物、界面活性剤、高級アルコール、増粘剤、キレート剤、防腐剤及びシリコーンからなる群より選択される少なくとも1種の基剤を更に含む上記〔16〕に記載の皮膚化粧料又は皮膚外用剤。
〔18〕剤形が、乳液、クリーム、化粧水、又はジェルである上記〔16〕又は〔17〕に記載の皮膚化粧料又は皮膚外用剤。
〔19〕被検者の肌の角層水分量、シワ面積率、及び経表皮水分蒸散量からなる群から選ばれる少なくとも1種を測定して前記被検者の肌の保湿能、小じわの予防又は改善能、及びバリア能からなる群から選ばれる少なくとも1種を確認すること、
前記被検者の前記肌の測定部位から角層を採取すること、
前記角層に含まれる少なくとも1種のD-アミノ酸量を特定すること、
前記肌の保湿能、バリア能、及び小じわの予防又は改善能からなる群から選ばれる少なくとも1種と前記D-アミノ酸量との関係を、被検者の結果の間で比較すること
を含む、D-アミノ酸による肌の評価方法。
〔20〕前記D-アミノ酸量の特定が、
前記角層に含まれるタンパク質量あたりのD-アミノ酸含有量の測定である上記〔19〕に記載の評価方法。
〔21〕前記D-アミノ酸含有量の測定を、液体クロマトグラフ-タンデム型質量分析計により行う上記〔19〕又は〔20〕に記載の評価方法。
〔22〕前記タンパク質量の測定をBCA法により行う上記〔20〕又は〔21〕に記載の評価方法。
〔23〕前記D-アミノ酸が、D-Arg、D-His、D-Leu、D-Pro、D-Ser、D-Tyr、D-Val、D-allo-Thr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Gln、D-Glu、及びD-Metからなる群から選択される少なくとも1種を含む上記〔19〕~〔22〕のいずれかに記載の評価方法。
〔24〕前記被検者が、20代から30代の女性であり、
前記D-アミノ酸が、D-Arg、D-His、D-Leu、D-Pro、D-Ser、D-Tyr、D-Val、D-allo-Thr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn及びD-Pheからなる群から選択される少なくとも1種であり、少なくとも保湿能を評価する、上記〔23〕に記載の評価方法。
〔25〕前記被検者が、20代から30代の女性であり、
前記D-アミノ酸が、D-His、D-Leu、D-Pro、D-Ser、D-Val、D-allo-Thr、D-Asp、D-Trp、D-allo-Ile、D-Asn及びD-Pheからなる群から選択される少なくとも1種であり、少なくともバリア能を評価する、上記〔23〕に記載の評価方法。
〔26〕前記被検者が、40代から60代の女性であり、
前記D-アミノ酸が、D-Arg、D-His、D-Leu、D-Pro、D-Val、D-allo-Thr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、及びD-Glnからなる群から選択される少なくとも1種であり、少なくとも保湿能を評価する、上記〔23〕に記載の評価方法。
〔27〕前記被検者が、40代から60代の女性であり、
前記D-アミノ酸が、D-Arg、D-His、D-Leu、D-Pro、D-Ser、D-Val、D-allo-Thr、D-Lys、D-Trp、D-allo-Ile、D-Phe、及びD-Glnからなる群から選択される少なくとも1種であり、少なくともバリア能を評価する、上記〔23〕に記載の評価方法。
〔28〕前記被検者が、20代から30代の女性であり、
前記D-アミノ酸が、D-Leu、D-Tyr、D-Asp、D-Lys、D-Trp、D-Asn、及びD-Glnからなる群から選択される少なくとも1種であり、少なくとも小じわの予防又は改善能を評価する、上記〔23〕に記載の評価方法。
〔29〕前記被検者が、40代から60代の女性であり、
前記D-アミノ酸が、D-Asp及びD-Lysの少なくともいずれかであり、少なくとも小じわの予防又は改善能を評価する、上記〔23〕に記載の評価方法。
〔30〕前記比較の結果、肌の角層水分量、シワ面積率、及び経表皮水分蒸散量からなる群から選ばれる少なくとも1種とD-アミノ酸量との間に相関関係が確認された場合に、前記相関関係を被検者の肌の評価の指標として選抜することを更に含む、上記〔19〕~〔29〕のいずれかに記載の評価方法。
〔31〕皮膚化粧料、皮膚外用剤、又はそれらの有効成分候補物質の投与前後の被検者の肌の測定部位の角層に含まれる、上記〔19〕に記載の評価方法で選抜された相関関係を構成するD-アミノ酸量を測定すること、及び、
前記D-アミノ酸量から前記相関関係に基づき投与前後の肌の角層水分量、シワ面積率、及び経表皮水分蒸散量からなる群から選ばれる少なくとも1種を特定し、比較すること
を含む、皮膚化粧料又は皮膚外用剤の評価方法。
〔32〕皮膚化粧料又は皮膚外用剤の投与前後の被検者の肌の測定部位の角層に含まれる、上記〔19〕に記載の評価方法で選抜された相関関係を構成するD-アミノ酸量を測定すること、及び、
前記D-アミノ酸量から前記相関関係に基づき投与前後の肌の角層水分量、シワ面積率、及び経表皮水分蒸散量からなる群から選ばれる少なくとも1種を特定し、比較すること
を含む、被検者への皮膚化粧料又は皮膚外用剤の有効性の評価方法。
本明細書中、アミノ酸を、慣用の3文字表記(例えば、「Asn」、「Gln」)に「L-」、「D-」、「D,L-」等の立体配置の接頭詞を付けて表すことがある。
本明細書中、角層機能改善剤とは、皮膚に適用した際に、角層水分量を増やす又は保持する保湿能の向上、外界からの、ウイルス、細菌等の異物の侵入を抑制するバリア能の向上、及び、小じわの予防又は改善能の向上のうちのいずれかの効果を発揮し得るものをいう。
本明細書中、「保湿能」は、角層水分量の保持をいい、角層水分量が多いほど保湿能に優れる。また、「バリア能」は、経表皮水分蒸散の抑制をいい、経表皮水分蒸散量(以下、「TEWL」ともいう)が小さいほどバリア能に優れる。さらに、「小じわの予防又は改善」は、シワ面積率で評価され、シワ面積率が小さいほど小じわの予防又は改善能に優れる。
また、D-アミノ酸は、D-Arg、D-His、D-Leu、D-Pro、D-Ser、D-Val、D-allo-Thr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Gln、D-Glu、D-Cys、D-Met及びD-Thrからなる群から選択される少なくとも1種であることが好ましく、D-Arg、D-His、D-Leu、D-Val、D-allo-Thr、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Gln、及びD-Thrからなる群から選択される少なくとも1種であることがより好ましい。かかるアミノ酸は、角層機能改善としてのバリア能(経表皮水分蒸散の抑制)を発揮し得る。これらのD-アミノ酸の中でも、保湿能関連タンパク質遺伝子の発現を、又は前記タンパク質(好ましくはフィラグリン)の産生を促進することが実施例で実証されているので、D-His、D-Leu、D-Lys、D-Trp、D-allo-Ile、D-Asn、及びD-Pheからなる群から選択される少なくとも1種であることが好ましく、D-His、D-Leu、D-Lys、D-Trp、D-allo-Ile、及びD-Pheからなる群から選択される少なくとも1種であることがより好ましい。
D-アミノ酸が、D-His、D-Leu、D-Pro、D-Tyr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Gln、D-Glu、D-Cys、D-Met、及びD-Thrからなる群から選択される少なくとも1種であることも好ましく、D-His、D-Leu、D-Tyr、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Gln、及びD-Thrからなる群から選択される少なくとも1種であることがより好ましい。かかるアミノ酸は、角層機能改善としての小じわの予防又は改善能(シワ面積率の低減)を発揮し得る。これらのD-アミノ酸の中でも、保湿能関連タンパク質遺伝子の発現を、又は前記タンパク質(好ましくはフィラグリン)の産生を促進することが実施例で実証されていることから、D-Leu、D-Lys、D-Trp、及びD-Asnからなる群から選択される少なくとも1種がさらに好ましく、D-Leu、D-Lys、及びD-Trpからなる群から選択される少なくとも1種がより好ましい。
本発明者らは、生体中にごく微量にしか含まれていないD-アミノ酸の含有量と肌の保湿能、バリア能、小じわの予防又は改善能に相関関係があることを見出した。そして、相関関係を見出したD-アミノ酸を用いて、保湿能、バリア能、小じわの予防又は改善能に関連するタンパク質の遺伝子発現量及びフィラグリンの発現量を検討したところ、タンパク質の遺伝子発現量及びフィラグリンの発現量に有意な増加がみられた。
従って、従来、ラセミ体としてのアミノ酸そのものが有効成分とみなされていたアミノ酸のうち、生体中にごく微量にしか含まれていないD-アミノ酸が、肌の保湿能、バリア能、小じわの予防又は改善能に関連するタンパク質の産生に強く影響し、有効成分として作用するという新規な知見を見出した。本発明の角層機能改善剤は、このような新規な知見に基づき、生体中にごく微量にしか含まれていないD-アミノ酸が有する顕著な効果を利用するものである。
なお、D-Cysは、L-Cysと同様に安定性が低い場合がある(特開2009-227660号公報)。また、D-Asp及びD-Gluは、溶解性を向上させるためにpHを高めに調整する必要が生じる場合がある。
本発明の保湿能改善剤は、D-Arg、D-His、D-Leu、D-Pro、D-Ser、D-Tyr、D-Val、D-allo-Thr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Gln、D-Glu、D-Cys、D-Met、及びD-Thrからなる群から選択される少なくとも一種のD-アミノ酸を有効成分とする。D-アミノ酸は、D-Arg、D-His、D-Leu、D-Tyr、D-Val、D-allo-Thr、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Gln及びD-Thrからなる群から選択される少なくとも1種であることが好ましい。これらのD-アミノ酸の中でも、保湿能関連タンパク質遺伝子の発現を、又は前記タンパク質(好ましくはフィラグリン)の産生を促進することが実施例で実証されているので、D-His、D-Leu、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Glu、D-Cys、D-Met、D-Thr、及びD-Proからなる群から選択される少なくとも一種であることが好ましく、D-His、D-Leu、D-Lys、D-Trp、D-allo-Ile、D-Asn、及びD-Pheからなる群から選択される少なくとも1種であることがより好ましく、D-His、D-Leu、D-Lys、D-Trp、D-allo-Ile、及びD-Pheからなる群から選択される少なくとも1種であることが更に好ましい。D-Arg、D-Ser、D-Tyr、D-Val、D-allo-Thr、D-Glnについては、保湿能関連タンパク質(好ましくはフィラグリン)の産生を促進することが実施例で実証されていない。しかしながら、これらのD-アミノ酸の含有量と肌の保湿能に相関関係がみられることから、他の作用機序により保湿能を向上させる有効成分となることは十分に推測される。
本発明の保湿能改善剤は、必要に応じて上記のD-アミノ酸以外の保湿能改善成分を含有していてもよい。
上記のD-アミノ酸は、それらの塩であってもよく、D-アミノ酸の塩としては前述したことと同様である。
本発明のバリア能改善剤は、D-Arg、D-His、D-Leu、D-Pro、D-Ser、D-Val、D-allo-Thr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Glu、D-Cys、D-Met、D-Gln、及びD-Thrからなる群から選択される少なくとも一種のD-アミノ酸を有効成分とする。D-アミノ酸は、D-Arg、D-His、D-Leu、D-Val、D-allo-Thr、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Thr、及びD-Glnからなる群から選択される少なくとも1種が好ましい。これらのD-アミノ酸の中でも、バリア能関連タンパク質(フィラグリン、インボルクリン、トランスグルタミナーゼ1、ケラチン10、及びロリクリン)の産生を促進することが実施例で実証されているので、D-アミノ酸は、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-His、D-Leu、D-Glu、D-Cys、D-Met、D-Thr、及びD-Proからなる群から選択される少なくとも一種であることが好ましく、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-His、及びD-Leuからなる群から選択される少なくとも1種であることがより好ましく、D-His、D-Leu、D-Lys、D-Trp、D-allo-Ile、及びD-Pheからなる群から選択される少なくとも1種であることが更に好ましい。
D-Arg、D-Ser、D-Val、D-allo-Thr、D-Glnについては、バリア能関連タンパク質(フィラグリン、インボルクリン、トランスグルタミナーゼ1、ケラチン10、及びロリクリン)の産生を促進することが実施例で実証されていない。しかしながら、これらのD-アミノ酸の含有量と肌のバリア能に相関関係がみられることから、他の作用機序によりバリア能を向上させる有効成分となることは十分に推測される。
本発明のバリア能改善剤は、必要に応じて上記のD-アミノ酸以外のバリア能改善成分を含有していてもよい。
上記のD-アミノ酸は、それらの塩であってもよく、D-アミノ酸の塩としては前述したことと同様である。
本発明の小じわ予防又は改善剤は、D-His、D-Leu、D-Pro、D-Tyr、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Glu、D-Gln、D-Cys、D-Met、D-Thr、D-Pro、及びD-Gluからなる群から選択される少なくとも1種を有効成分とする。アミノ酸は、D-Leu、D-Tyr、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-His、D-Gln、及びD-Thr、からなる群から選択される少なくとも1種が好ましい。これらのD-アミノ酸中でも、フィラグリンの産生を促進することが実施例で実証されているので、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、D-Glu、D-His、D-Pro、D-Cys、D-Met、D-Thr、及びD-Leuからなる群から選択される少なくとも1種が好ましく、D-Lys、D-Trp、D-Asn、及びD-Leuからなる群から選択される少なくとも1種がより好ましく、D-Lys、D-Trp、及びD-Leuからなる群から選択される少なくとも1種がさらに好ましい。D-Tyr、D-Glnについては、フィラグリンの産生を促進することが実施例で実証されていない。しかしながら、これらのD-アミノ酸の含有量とシワ面積率に相関関係がみられることから、他の作用機序により小じわを予防又は改善する有効成分となることは十分に推測される。
本発明の小じわ予防又は改善剤は、必要に応じて上記のD-アミノ酸以外の小じわ予防又は改善成分を含有していてもよい。
上記のD-アミノ酸は、それらの塩であってもよく、D-アミノ酸の塩としては前述したことと同様である。
本発明の角層機能関連タンパク質遺伝子の発現促進剤は、D-Asp、D-Lys、D-Trp、D-allo-Ile、D-Asn、D-Phe、D-Ala、及びD-Gluからなる群から選択される少なくとも1種、好ましくはD-Lys、D-Trp、D-allo-Ile、D-Asn、及びD-Pheからなる群から選択される少なくとも1種を有効成分とする。
また、本発明の角層機能関連タンパク質(例えば、フィラグリン)産生促進剤は、D-His、D-Leu、D-Pro、D-Asp、D-Lys、D-Trp、D-Allo-Ile、D-Phe、D-Ala、D-Glu、D-Cys、D-Met、及びD-Thrからなる群から選択される少なくとも1種のD-アミノ酸を有効成分とすることが好ましく、D-His、D-Leu、D-Lys、D-Trp、D-allo-Ile、D-Phe、及びD-Thrからなる群から選択される少なくとも1種のD-アミノ酸を有効成分とすることがより好ましい。
本明細書において、角層機能関連タンパク質は、フィラグリン、インボルクリン、ロリクリン、ケラチン10及びトランスグルタミナーゼ1から選ばれる少なくとも1種である。
フィラグリンは、保湿能に強く関連するタンパク質であり、天然保湿因子であるアミノ酸の供給源である。そのため、皮膚の乾燥による小じわ形成に関連するタンパク質である。また、ケラチンフィラメントが凝集し、丈夫なケラチンを構築するのにも寄与しているので、バリア能にも関連するタンパク質である。
インボルクリンは、バリア能に関連するタンパク質である。角層を構成するタンパク質の一種であり、丈夫な角層の形成に必須である。
ケラチン10は、バリア能に関連するタンパク質である。角層の主成分である。
ロリクリンは、バリア能に関連するタンパク質である。角層を構成するタンパク質の一種であり、丈夫な角層の形成に必須である。
トランスグルタミナーゼ1は、タンパク質を架橋する酵素である。丈夫な角層を形成するのに重要と考えられる。
本発明の皮膚化粧料又は皮膚外用剤は、上記の剤の少なくとも1つを含む。本発明の剤の含有量は、皮膚化粧料及び皮膚外用剤の種類に応じて適宜調整すればよい。D-アミノ酸の合計量で換算した場合の好適な含有量の下限は、通常、0.01質量%以上であり、好ましくは0.1質量%以上であり、さらに好ましくは1質量%以上である。その上限は、通常、30質量%以下であり、好ましくは10質量%以下である。
ポリオール化合物としては、例えば、エチレングリコール、ブチレングリコール、ポリエチレングリコール、ブチルエチルプロパンジオール、ポリプロピレングリコール共重合体、プロピレングリコール、ジプロピレングリコール、1,3-ブチレングリコール、グリセリン、ジグリセリン、ソルビトールが挙げられる。中でも、ブチレングリコール、グリセリン、ポリエチレングリコール、ジプロピレングリコール、及びソルビトールからなる群より選択される少なくとも1種であることが好ましい。
界面活性剤としては、例えば、ポリオキシエチレンソルビタンオレイン酸エステル、高級脂肪酸石けん、アルキル硫酸エステル塩、ポリオキシエチレンアルキルエーテル硫酸塩、アルキルエーテルリン酸エステル塩、N-アシルアミノ酸塩、アシルN-メチルタウリン塩等のアニオン界面活性剤;塩化アルキルトリメチルアンモニウム、塩化ジアルキルジメチルアンモニウム等のカチオン界面活性剤;コカミドプロピルベタイン、アルキルジメチルアミノ酢酸ベタイン、アルキルアミドジメチルアミノ酢酸ベタイン、2-アルキル-N-カルボキシ-N-ヒドロキシイミダゾリニウムベタイン等の両性界面活性剤;グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、レシチン誘導体(例えば、リゾレシチン)、ポリオキシエチレン型(例えば、ポリオキシエチレン硬化ヒマシ油、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ポリオキシプロピレンアルキルエーテル、ポリオキシエチレングリセリン脂肪酸エステル等)、多価アルコールエステル型、エチレンオキシド・プロピレンオキシドブロック共重合体等の非イオン界面活性剤が挙げられる。中でも、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、レシチン誘導体、ポリオキシエチレン硬化ヒマシ油、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ポリオキシプロピレンアルキルエーテル、及びポリオキシエチレングリセリ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種が好ましい。
高級アルコールとしては、例えば、セタノール、ベヘニルアルコール、イソヘキサデシルアルコールが挙げられる。中でも、ベヘニルアルコールが好ましい。
増粘剤としては、例えば、ポリアクリル酸、カラギーナン、キサンタンガム、カルボキシメチルセルロースナトリウム、カルボキシビニルポリマー、ポリオキシエチレングリコールジステアリン酸エステル、アクリル酸系ポリマー、セルロース系天然ポリマー、エタノール、ジカプリン酸ネオペンチルグリコール、ミリスチン酸カリウムが挙げられる。中でも、アクリル酸系ポリマー、キサンタンガム、及びセルロース系天然ポリマーからなる群より選択される少なくとも1種が好ましい。
キレート剤としては、例えば、エチドロン酸、エデト酸三ナトリウム等のエチレンジアミン四酢酸(誘導体)が挙げられる。中でも、エチレンジアミン四酢酸が好ましい。
防腐剤としては、パラベン及びフェノキシエタノールの少なくともいずれかが好ましい。パラベンとしては例えば、メチルパラベン、プロピルパラベン、ブチルパラベンが挙げられる。
シリコーンとしては、例えば、メチルポリシロキサン、ジメチルポリシロキサン、メチルフェニルポリシロキサン、デカメチルシクロペンタシロキサン、シクロヘキサシロキサン、シクロペンタシロキサン、トリメチルシロキシケイ酸、ポリオキシエチレン・メチルポリシロキサン共重合体、シリコンフルイド、シリコーンゴム、シリコーン油が挙げられる。
pH調整剤としては、例えば、リン酸塩緩衝剤、水酸化ナトリウム、水酸化カリウム、トリエタノールアミンが挙げられる。
保存剤としては、例えば、パラオキシ安息香酸エチル、安息香酸ナトリウム、サリチル酸、ソルビン酸、亜硫酸水素ナトリウム、フェノキシエタノールが挙げられる。
紫外線吸収剤としては、例えば、ブチルメトキシベンゾイルメタン、パラジメチルアミノ安息香酸オクチル、パラメトキシ桂皮酸2-エチルヘキシル等の桂皮酸誘導体、ジメトキシベンジリデンジオキソイミダゾリジンプロピオン酸エチルヘキシルが挙げられる。
紫外線散乱剤としては、例えば、酸化チタン、酸化亜鉛が挙げられる。
溶剤としては、例えば、アルギニン水溶液、精製水が挙げられる。
色素としては、例えば、赤202、黄色4、青色1、ベンガラ、黄酸化鉄、黒酸化鉄が挙げられる。
天然物抽出物としては、例えば、ラベンダーエキス、ペパーミントエキス、セージエキス、アニスエキス、バラエキス、ヒノキ水、ルイボスエキス、ラベンダー抽出物、クララエキスが挙げられる。
アミノ酸(誘導体)としては、例えば、L-ロイシン、L-イソロイシン、L-バリン、L-フェニルアラニン、L-トリプトファン、L-アスパラギン酸、L-グルタミン酸ナトリウム、L-リシン(塩酸塩)、L-アルギニン、L-スレオニン、L-アラニン、L-プロリン、L-セリン、グリシン、アセチルグルタミン、L-ヒスチジン、ピリドキシルセリン、カルノシン、アセチルメチオニン、アセチルシステイン、ポリアスパラギン酸ナトリウム、シトルリン、オルニチン、ベタイン、L-チロシン、L-アスパラギン、L-メチオニンが挙げられる。
上記の他の基剤の含有量は、適宣設定すればよく、特に限定されるものではない。
本発明のバリア能改善剤は、外界からの、ウイルス、細菌等の異物の侵入を抑制するバリア能改善作用を通じて、加齢、乾燥、皮膚疾患(アトピー性皮膚炎等)等の原因による肌荒れ、炎症、敏感肌などの予防、抑制、治療用として利用が期待できる。
本発明の小じわ予防又は改善剤は、シワ面積率の減少する小じわの予防又は改善作用を通じて、特に、乾燥による小じわの予防、抑制、治療用として利用が期待できる。
本発明の評価方法は、被検者の肌の角層水分量、シワ面積率、及び経表皮水分蒸散量からなる群から選ばれる少なくとも1種を測定して被検者の肌の保湿能、小じわの予防又は改善能、及びバリア能からなる群から選ばれる少なくとも1種を確認し、前記被検者の肌の測定部位から角層を採取すること、角層に含まれる少なくとも1種のD-アミノ酸量を特定すること、前記肌の保湿能、バリア能、及び小じわの予防又は改善能からなる群から選ばれる少なくとも1種と前記D-アミノ酸量との関係を、被検者の結果の間で比較することを含む、D-アミノ酸による肌の評価方法である。
本発明の評価方法は、大別すると、次の2つの実施態様がある。一実施態様は、肌の保湿能、バリア能、小じわの予防又は改善能と各成分との関係を、被検者(予備被検者)の結果の間で比較(同じ被検者の複数の結果の間での比較でもよいし、複数の異なる被検者の結果の間での比較でもよい)し、相関関係が確認された場合に、肌の外観とそのD-アミノ酸量との相関関係を被検者(予備被検者と同一でもよいし別でもよい)の肌の評価の指標として選抜する実施態様である。他の実施態様は、被検者に皮膚化粧料、皮膚外用剤、これらの候補物質等のサンプルを投与した前後の角層中のD-アミノ酸量を特定し、上記の相関関係に照らして得られた投与前後の肌の評価を比較して、サンプルの評価、又は、被検者の肌に対する有効性の評価を行う実施態様である。
表皮の最外層に存在する角層は、外部環境と体の中とを隔てるバリアの役割を果たす。そして、角層の質が肌の瑞々しさを決定づける要因となる。角層には細胞間脂質、天然保湿因子(NMF:Natural moisturizing factor)等の構成成分が存在しており、皮膚内部からの水分蒸発に加えて、角層自身が適度な水分を保持することで、皮膚表面の柔らかさ及び/又は滑らかさを保持している。角層水分量及びTEWLは、このような角層の質を評価する指標として用いられている。
本発明の評価方法において、肌の各種機能の確認方法は、上記に限定されず、例えば、角層ターンオーバー日数、角層の有核細胞率等の指標を利用する従来公知の他の方法で確認することもできる。
測定箇所は、1か所であってもよく、2か所以上であってもよい。
角層の採取方法としては、例えば、測定部位に市販の粘着テープを押し付けてはがした際に、粘着テープに付着した角層を採取する方法が挙げられる。市販の粘着テープとしては、例えば、アサヒバイオメッド社製角質チェッカー、モリテックス社製角層シール、PROMOTOOL社製角質チェッカー(ディスクタイプW、ディスクタイプG、PROタイプ)、Integral社製Corneofix、3M社製透明テープ、3M社製透明両面テープ、ニチバン社製セロテープ(登録商標)が挙げられる。
直接法としては、例えば、NBD-Fでプレカラム蛍光誘導体化をした後、キラルカラムで分離して蛍光検出する方法が挙げられる。詳細には、“Comprehensive analysis of branched aliphatic D-amino acids in mammals using an integrated multi-loop two-dimensional column-switching high-performance liquid chromatographic system combining reversed-phase and enantioselective columns.” J Chromatogr A. 2007 Mar 2;1143(1-2):105-11. Hamase K, Morikawa A, Ohgusu T, Lindner W, Zaitsu K.を参照し得る。
間接法としては、例えば、OPAとキラルチオールで誘導体化して逆相カラムで分離し、蛍光検出する方法、DBD-PyNCSで誘導体化して逆相カラムで分離して、質量分析計で検出する方法が挙げられる。詳細には、“High-performance liquid chromatography analysis of naturally occurring D-amino acids in sake.” J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Nov 1;879(29):3259-67. Gogami Y, Okada K, Oikawa T.“Determination of DL-amino acids, derivatized with R(-)-4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benz oxadiazole, in nail of diabetic patients by UPLC-ESI-TOF-MS” J. Chromatogr. B, 879, 3220-3228 (2011). J.Z. Min, S. Hatanaka, H.F. Yu, T. Higashi, S. Inagaki, T. Toyo’okaを参照し得る。
上記のより好ましいD-アミノ酸は、20代から30代、及び40代から60代の少なくともいずれかの年代の女性の肌の保湿能、バリア能、及び、小じわ予防又は改善能の少なくともいずれかと相関関係を有する成分であることが、本発明の相関評価方法から確認し得る。
本発明の評価方法の一実施態様により、特定のD-アミノ酸と肌の保湿能、バリア能、小じわ予防又は改善能との相関について新たな知見がもたらされる。そのため本発明の評価方法は、天然物に由来する成分等の皮膚化粧料、又は皮膚外用剤の開発へ応用し得る。
上述した中でも、D-アミノ酸の特定及び含有量の測定を同時に行うことができるので、液体クロマトグラフ-タンデム型質量分析計が好ましい。
タンパク質量の測定方法は、特に限定されず、例えば、紫外吸収法、BCA法、ブラッドフォード法、ローリー法、ビューレット法等の分光光度計を用いた測定方法、電気泳動による測定方法が挙げられる。中でも、BCA法が好ましい。
本発明の評価方法の他の実施態様により、皮膚化粧料又は皮膚外用剤を投与する前後で、従来の測定方法のように角層水分量、TEWL、又はシワ面積率による短期的な評価のみならず、D-アミノ酸の含有量により長期的に肌の状態が改善されるか否かを評価することができる。
被検者(全員女性、年齢構成:20-30代 31名、40-60代 40名:合計人数 71名)は洗顔した後、恒温恒湿室(湿度40%、室温20℃)にて20分間馴化した。
上記測定終了後、被検者の頬中央部に3cm×3cmにカットしたテープを貼付し、角層を採取した。1回目に採取した最表層の角層は分析には利用せず、2回目又は3回目に採取した角層を分析に利用した。
採取したテープは、コニカルチューブ(50ml)に入れて密閉し、-80℃にて保存した。採取したテープ(角層)を95%メチルアルコール水溶液を用いて超音波処理を2回繰り返し、水溶成分を抽出した。抽出液には内部標準液(D-Arg等複数種のD,L-アミノ酸安定同位体を含む)を添加した。得られたメチルアルコール水溶液を、遠心エバポレーターで乾固し、D-アミノ酸分析用のサンプルとした。
濃縮乾固したサンプルに50μLの水を添加してボルテックスミキサーで撹拌して再溶解し、サンプル溶液とした。20μLのサンプル溶液に、濃度200mMのほう酸緩衝液(pH8.8)を10μL加えて撹拌した後、5mg/mLの(R)-N-(hydroxysuccinimidyl carbamate)-β-(3-pyridyl)-alanine methyl ester/アセトニトリル溶液を20μL加えて室温で10分間反応させた。反応溶液に0.1M塩酸水溶液を60μL添加して分析サンプルとした。分析にはLC/MS/MSを用い、以下の条件で分析した。
装置 :Nexera X2(島津製作所製)
ガードカラム :Waters ACQUITY BEH C18 VanGuard(2.1×5mm、1.7μm)
カラム :Waters ACQUITY UPLC BEH C18(2.1×100mm、1.7μm)
移動相A :10mM重炭酸アンモニウム水溶液(pH9.5)
移動相B :80%メタノール/水
流速 :0.5mL/min
カラム温度 :50℃
サンプル注入量:1μL
装置 :Triple Quad 6500(SCIEX)
イオン化法 :ESI、 Positiveモード
スキャンタイプ:SRM(Selected Reaction Monitoring)
水溶成分を抽出した後の上記テープをマイクロチューブに入れ、ヘキサンを用いて不溶画分を溶出した。テープを除去した後、不溶画分をヘキサンにて洗浄し、タンパク質定量分析用サンプルとした。
上記「D-アミノ酸抽出操作」にて利用したチューブ等に、NaOH(0.5mol/L)-SLS(0.05wt%)水溶液を加え、60分間、90℃で加熱した。これらの溶液に溶出されたタンパク質を定量した。
表3に、被検者のD-アミノ酸の角層中の含有量と、角層水分量、TEWL値及びシワ面積率の相関を示す。相関係数の絶対値が0.4以上を「強い相関」として「A」と評価し、0.3以上を「中程度の相関」として「B」と評価し、0.2以上を「弱い相関」として「C」と評価した。
(正常ヒト表皮角化細胞を用いた、D-アミノ酸の「保湿・バリア能・小じわの予防又は改善能」に関する遺伝子発現試験)
正常ヒト表皮角化細胞(クラボウ社)をHuMedia KG2(クラボウ社)にて37℃、5%CO2、飽和蒸気下で培養した。コンフルエント状態になった細胞を、6ウェルプレートに3.0×105(細胞/well)の播種密度で播種した。
(細胞毒性試験:ニュートラルレッド法)
正常ヒト表皮角化細胞を6ウェルプレートに播種し、翌日、D-アミノ酸(500μM)を、細胞の培養用培地にて調整したサンプルを添加した。48時間後、プレートから評価サンプル溶液を取り除き、各ウェルを2mlの細胞の培地を用いてリンスした。NR(ニュートラルレッド(クラボウ社))入り培地を2ml/wellで滴下し、2時間、37℃、5%CO2、飽和蒸気下で静置した。
(フィラグリン産生促進試験)
正常ヒト新生児表皮角化細胞(倉敷紡績株式会社)をHuMedia-KG2(倉敷紡績株式会社)にて培養した。コンフルエントになった細胞をトリプシンにて剥がし、6ウェルプレートに15×104(細胞/ウェル)で播種した。翌日、細胞がプレートに接着後、各評価サンプル(コントロール(サンプル添加なし)、D-アミノ酸)及び塩化カルシウムを所定評価濃度(サンプルは0.5mM、1mMあるいは5mM。塩化カルシウムは1.3mM)を添加したHuMedia-KG2と交換し、5日間培養した。培養中、2日間あるいは3日間に一度、サンプル及び塩化カルシウムを添加したHuMedia-KG2で培地交換を行った。培養後、培地を取り除き、冷PBS(-)にて2回洗浄し、プロテアーゼインヒビターとフォスファターゼインヒビター(EzRIPA Lysis(アトー株式会社))を添加した抽出液(M-PER(Thermo Fisher Scientific社)を200μL/ウェルで各ウェルに添加し、マルチシェーカー(アズワン株式会社)にて400rpmで5分間振とうさせた。スクレーパーで細胞をかき集め、沈殿物を含めた液体全量に200μLの変性剤(EzApply(アトー株式会社)を添加後、振とう機(Bioer Technology社)にて1100rpm、100℃で5分間、加熱振とうした。得られた溶液を遠心分離機(株式会社トミー精工)で10000Gにて4℃で10分間遠心処理し、上澄みをウェスタンブロット用サンプルとした。ゲル1レーンあたり各ウェスタンブロット用サンプル10μL(プロフィラグリン)、又はウェスタンブロット用サンプルを20倍希釈した溶液5μL(GAPDH)をe-PAGEL 7.5%(ATTO社製)にアプライし、電気泳動装置(アトー株式会社)にて21mAの定電流で1時間泳動した。電気泳動後のゲルからPVDF膜に転写し、TBS-T(アトー株式会社)にて洗浄後、EzBlock BSA(アトー株式会社)を用いてブロッキングした。次に、1次抗体液(Anti Filaggrin (AKH1)抗体(Santa Cruz Biotechnology社)、Anti GAPDH(6C5)抗体(Santa Cruz Biotechnology社))にて抗原抗体反応を行った。2次抗体(Anti-IgG(H+L),Mouse,Goat-poly,HRP(KPL社))にて標識化し、化学発光法によりイメージアナライザー(Amersham社)でバンド強度(250-400kDa(プロフィラグリン),37kDa(GAPDH))を数値化した。プロフィラグリンの数値はGAPDHの数値で規格化したものを利用した。コントロール中のプロフィラグリン量を100%とした場合の、各サンプルのプロフィラグリン量を相対%にして算出した。結果を図20~32に示す。
図20~32から、各サンプルの添加により細胞のフィラグリン産生量が向上することがわかる。
Claims (29)
- D-アルギニン、D-ヒスチジン、D-ロイシン、D-チロシン、D-バリン、D-アロスレオニン、D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン、D-フェニルアラニン、D-グルタミン、及びD-スレオニンからなる群から選択される少なくとも1種のD-アミノ酸を有効成分とする角層機能改善剤。
- 角層機能改善が、角層水分量の保持である、請求項1に記載の角層機能改善剤。
- 前記D-アミノ酸が、D-アルギニン、D-ヒスチジン、D-ロイシン、D-バリン、D-アロスレオニン、D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン、D-フェニルアラニン、D-グルタミン、及びD-スレオニンからなる群から選択される少なくとも1種であり、角層機能改善が、経表皮水分蒸散の抑制である請求項1に記載の角層機能改善剤。
- 前記D-アミノ酸が、D-ヒスチジン、D-ロイシン、D-チロシン、D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン、D-フェニルアラニン、D-グルタミン、及びD-スレオニンからなる群から選択される少なくとも1種であり、角層機能改善が、シワ面積率の低減である請求項1に記載の角層機能改善剤。
- D-アルギニン、D-ヒスチジン、D-ロイシン、D-チロシン、D-バリン、D-アロスレオニン、D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン、D-フェニルアラニン、D-グルタミン、及びD-スレオニンからなる群から選択される少なくとも1種のD-アミノ酸を有効成分とする保湿能改善剤。
- 前記D-アミノ酸が、D-ヒスチジン、D-ロイシン、D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン、及びD-フェニルアラニンからなる群から選択される少なくとも1種である請求項5に記載の保湿能改善剤。
- 前記D-アミノ酸が、D-ヒスチジン、D-ロイシン、D-リシン、D-トリプトファン、D-アロイソロイシン、及びD-フェニルアラニンからなる群から選択される少なくとも1種である請求項5又は6に記載の保湿能改善剤。
- D-アルギニン、D-ヒスチジン、D-ロイシン、D-バリン、D-アロスレオニン、D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン、D-フェニルアラニン、D-グルタミン、及びD-スレオニンからなる群から選択される少なくとも1種のD-アミノ酸を有効成分とするバリア能改善剤。
- 前記D-アミノ酸が、D-ヒスチジン、D-ロイシン、D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン、及びD-フェニルアラニンからなる群から選択される少なくとも1種である請求項8に記載のバリア能改善剤。
- 前記D-アミノ酸が、D-ヒスチジン、D-ロイシン、D-リシン、D-トリプトファン、D-アロイソロイシン、及びD-フェニルアラニンからなる群から選択される少なくとも1種のD-アミノ酸である請求項8又は9に記載のバリア能改善剤。
- D-ヒスチジン、D-ロイシン、D-チロシン、D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン、D-フェニルアラニン、及びD-グルタミン、及びD-スレオニンからなる群から選択される少なくとも1種を有効成分とする小じわ予防又は改善剤。
- 前記D-アミノ酸が、D-ロイシン、D-リシン、D-トリプトファン、及びD-アスパラギンからなる群から選択される少なくとも1種である請求項11に記載の小じわ予防又は改善剤。
- 前記D-アミノ酸が、D-ロイシン、D-リシン、及びD-トリプトファンからなる群から選択される少なくとも1種である請求項11又は12に記載の小じわ予防又は改善剤。
- D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン、及びD-フェニルアラニンからなる群から選択される少なくとも1種を有効成分とするフィラグリン、インボルクリン、ロリクリン、ケラチン10及びトランスグルタミナーゼ1から選ばれる少なくとも1種のタンパク質の遺伝子の発現促進剤。
- D-ヒスチジン、D-ロイシン、D-リシン、D-トリプトファン、D-アロイソロイシン、D-フェニルアラニン、及びD-スレオニンからなる群から選択される少なくとも1種を有効成分とするフィラグリンの産生促進剤。
- 請求項1~4のいずれか1項に記載の角層機能改善剤、請求項5~7のいずれか1項に記載の保湿能改善剤、請求項8~10のいずれか1項に記載のバリア能改善剤、請求項11~13のいずれか1項に記載の小じわ予防又は改善剤、請求項14に記載の発現促進剤、又は請求項15に記載の産生促進剤を含む皮膚化粧料又は皮膚外用剤。
- ポリオール化合物、界面活性剤、高級アルコール、増粘剤、キレート剤、防腐剤及びシリコーンからなる群より選択される少なくとも1種の基剤を更に含む請求項16に記載の皮膚化粧料又は皮膚外用剤。
- 剤形が、乳液、クリーム、化粧水、又はジェルである請求項16又は17に記載の皮膚化粧料又は皮膚外用剤。
- 被検者の肌の角層水分量、シワ面積率、及び経表皮水分蒸散量からなる群から選ばれる少なくとも1種を測定して前記被検者の肌の保湿能、小じわの予防又は改善能、及びバリア能からなる群から選ばれる少なくとも1種を確認すること、
前記被検者の前記肌の測定部位から角層を採取すること、
前記角層に含まれる少なくとも1種のD-アミノ酸量を特定すること、
前記肌の保湿能、バリア能、及び小じわの予防又は改善能からなる群から選ばれる少なくとも1種と前記D-アミノ酸量との関係を、被検者の結果の間で比較すること
を含む、D-アミノ酸による肌の評価方法。 - 前記D-アミノ酸量の特定が、
前記角層に含まれるタンパク質量あたりのD-アミノ酸含有量の測定である請求項19に記載の評価方法。 - 前記D-アミノ酸含有量の測定を、液体クロマトグラフ-タンデム型質量分析計により行う請求項19又は20に記載の評価方法。
- 前記タンパク質量の測定をBCA法により行う請求項20又は21に記載の評価方法。
- 前記D-アミノ酸が、D-アルギニン、D-ヒスチジン、D-ロイシン、D-プロリン、D-セリン、D-チロシン、D-バリン、D-アロスレオニン、D-アスパラギン酸、D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン、D-フェニルアラニン、D-アラニン、D-グルタミン、D-グルタミン酸、及びD-メチオニンからなる群から選択される少なくとも1種を含む請求項19~22のいずれか1項に記載の評価方法。
- 前記被検者が、20代から30代の女性であり、
前記D-アミノ酸が、D-アルギニン、D-ヒスチジン、D-ロイシン、D-プロリン、D-セリン、D-チロシン、D-バリン、D-アロスレオニン、D-アスパラギン酸、D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン及びD-フェニルアラニンからなる群から選択される少なくとも1種であり、少なくとも保湿能を評価する、請求項23に記載の評価方法。 - 前記被検者が、20代から30代の女性であり、
前記D-アミノ酸が、D-ヒスチジン、D-ロイシン、D-プロリン、D-セリン、D-バリン、D-アロスレオニン、D-アスパラギン酸、D-トリプトファン、D-アロイソロイシン、D-アスパラギン及びD-フェニルアラニンからなる群から選択される少なくとも1種であり、少なくともバリア能を評価する、請求項23に記載の評価方法。 - 前記被検者が、40代から60代の女性であり、
前記D-アミノ酸が、D-アルギニン、D-ヒスチジン、D-ロイシン、D-プロリン、D-バリン、D-アロスレオニン、D-アスパラギン酸、D-リシン、D-トリプトファン、D-アロイソロイシン、D-アスパラギン、及びD-グルタミンからなる群から選択される少なくとも1種であり、少なくとも保湿能を評価する、請求項23に記載の評価方法。 - 前記被検者が、40代から60代の女性であり、
前記D-アミノ酸が、D-アルギニン、D-ヒスチジン、D-ロイシン、D-プロリン、D-セリン、D-バリン、D-アロスレオニン、D-リシン、D-トリプトファン、D-アロイソロイシン、D-フェニルアラニン、及びD-グルタミンからなる群から選択される少なくとも1種であり、少なくともバリア能を評価する、請求項23に記載の評価方法。 - 前記被検者が、20代から30代の女性であり、
前記D-アミノ酸が、D-ロイシン、D-チロシン、D-アスパラギン酸、D-リシン、D-トリプトファン、D-アスパラギン、及びD-グルタミンからなる群から選択される少なくとも1種であり、少なくとも小じわの予防又は改善能を評価する、請求項23に記載の評価方法。 - 前記被検者が、40代から60代の女性であり、
前記D-アミノ酸が、D-アスパラギン酸及びD-リシンの少なくともいずれかであり、少なくとも小じわの予防又は改善能を評価する、請求項23に記載の評価方法。
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WO2024143435A1 (ja) * | 2022-12-26 | 2024-07-04 | 味の素株式会社 | 肌状態改善用組成物 |
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