WO2022131108A1 - 真皮再生促進剤 - Google Patents
真皮再生促進剤 Download PDFInfo
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- WO2022131108A1 WO2022131108A1 PCT/JP2021/045233 JP2021045233W WO2022131108A1 WO 2022131108 A1 WO2022131108 A1 WO 2022131108A1 JP 2021045233 W JP2021045233 W JP 2021045233W WO 2022131108 A1 WO2022131108 A1 WO 2022131108A1
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- Prior art keywords
- imidazolidinone
- hydroxyethyl
- ltbp2
- derivative
- dermal
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
Definitions
- the present invention relates to a dermis elasticity improving agent, a dermis wrinkle improving agent, a dermis papillary layer fiber growth promoter, a dermis papillary layer fiber stabilizer, and an LTBP2 and / or fibrillin-1 production promoter.
- (2-Hydroxyethyl) -2-Imidazolidinone or a derivative thereof as an active ingredient a dermis elasticity improving agent, a dermis wrinkle improving agent, a dermis papillary layer fiber growth promoter, and a dermis papillary layer fiber stabilizing agent.
- agents and LTBP2 and / or fibrillin-1 production promoters are examples of agents.
- the decrease in collagen which is the main component of the matrix, is associated with the decrease in sagging and firmness of the skin, and the decomposition and degeneration of elastin caused by the expression of elastin-degrading enzymes is considered to be the cause of the decrease in elasticity, and the collagen production is enhanced.
- An agonist, a collagen-degrading enzyme inhibitor, an elastin-degrading enzyme inhibitor, and the like are blended as an anti-aging agent.
- these drugs show a certain effect, they have not yet shown a sufficient effect.
- Patent Document 1 describes an anti-aging skin external preparation that is effective in restoring / maintaining the firmness and elasticity of the skin, reducing wrinkles / sagging, and reducing pigmentation, and can restore and maintain a youthful skin condition.
- an anti-aging skin external preparation which is characterized by containing niacin and ubiquinone.
- Patent Document 2 describes new agents effective in preventing and suppressing skin aging from the viewpoint of the relationship between heparanase and skin aging, and whitening agents effective in preventing and suppressing pigmentation such as age spots, freckles, and dullness.
- a cyclic carboxamide derivative having a specific structure is disclosed.
- An object of the present invention is to find a substance and composition effective for improving skin elasticity and wrinkles from the viewpoint of maintaining or improving quality of life (QOL) in terms of both health and beauty.
- heparanase activity inhibitors such as 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof promote the production of LTBP2 and / or fibrillin-1 in fibroblasts. It has been found that it exhibits an effect of improving dermis elasticity, an effect of improving dermis wrinkles, an effect of promoting dermal papilla fiber growth, and an effect of stabilizing dermis papillary layer fiber.
- a dermis elasticity improving agent which comprises 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient.
- a dermis wrinkle improving agent containing 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient.
- An agent for promoting dermal papilla fiber growth which comprises 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient.
- a dermis papillary layer fiber stabilizer containing 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient.
- 1- (2-Hydroxyethyl) -2-imidazolidinone or a derivative thereof has the following general formula (I) :.
- n is an integer of 1 to 3
- R 1 is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group
- X is ⁇ CH 2 ⁇ or. It is a group represented by -N (R 2 )-, and R 2 means a hydrocarbon group having 1 to 6 carbon atoms which may be substituted with a hydrogen atom or a hydroxyl group.
- a cosmetological method for improving the elasticity of the dermis which comprises increasing the production of LTBP2 and / or fibrillin-1.
- a cosmetic method for preventing or ameliorating wrinkles which comprises increasing the production of LTBP2 and / or fibrillin-1.
- a cosmetological method for preventing or improving wrinkles which comprises stabilizing the localization of LTBP2 and / or fibrillin-1.
- a cosmetological method for preventing or improving wrinkles which is characterized by increasing the expression of PDGF-BB.
- the agents according to the present disclosure increase and / or stabilize dermal papillary layer fibers by promoting the production of LTBP2 and / or fibrillin1, and are therefore effective for improving dermal elasticity and / or dermal wrinkles, for example. It can be suitably used as a cosmetic composition for cosmetics and the like.
- FIG. 1 is a graph showing the results of examining the PDGFB gene expression level in the epidermis of an artificial skin model (skin three-dimensional model) by quantitative PCR analysis.
- the results of treatment with a combination of heparanase inhibitor (BIPBIPU) and MMP inhibitor (CGS27023A) are shown relative to the control (Cont) on the left.
- FIG. 4 is a graph showing changes in gene expression of fibroblasts by PDGF-BB. From the left, the results of LTBP2, type V collagen (COL5A1), type III collagen (COL3A1), type I collagen (COL1A1), and fibrillin 1 (FBLN1) are the results of treatment with control (cont) and 10 ng / mL PDGF-BB.
- FIG. 3A is an image showing changes in the localization of LTBP2 due to a heparanase inhibitor. The results of investigating changes in LTBP2 localization in an organ culture model are shown. From the top, the results of treatment with a control (Cont), a combination of a heparanase inhibitor (BIPBIPU) and an MMP inhibitor (CGS27023A), and treatment with S-173 (HEI) are shown.
- FIG. 3B is an image showing changes in the localization of LTBP2 due to a heparanase inhibitor. The results of examining changes in LTBP2 localization in a three-dimensional skin model are shown.
- FIG. 4A is an image showing changes in the localization of LTBP2 and fibrillin-1 due to a heparanase inhibitor. The results of investigating changes in the localization of LTBP2 and fibrillin-1 in an organ culture model are shown. From the top, the results of treatment with a control (Cont), a combination of a heparanase inhibitor (BIPBIPU) and an MMP inhibitor (CGS27023A), and treatment with S-173 (HEI) are shown.
- FIG. 4A is an image showing changes in the localization of LTBP2 and fibrillin-1 due to a heparanase inhibitor. The results of investigating changes in the localization of LTBP2 and fibrillin-1 in an organ culture model are shown. From the top, the results of treatment with a control (Cont), a combination of a heparanase inhibitor (BIPBIPU) and an MMP inhibitor (CGS27023A), and treatment with S-173 (HEI) are shown.
- FIG. 4B is an image showing changes in the localization of LTBP2 and fibrillin-1 due to a heparanase inhibitor.
- the results of investigating changes in the localization of LTBP2 and fibrillin-1 in a three-dimensional skin model are shown. From the top, the results of treatment with a control (Cont), a combination of a heparanase inhibitor (BIPBIPU) and an MMP inhibitor (CGS27023A), and treatment with S-173 (HEI) are shown.
- FIG. 5 is a graph showing that LTBP2 and heparan sulfate bind in a concentration-dependent manner as a result of investigating the binding between heparan sulfate and LTBP2.
- Figure 6 shows the subject's water evaporation on both cheeks measured 3 times with Vapometer (Delfin), the stratum corneum water content measured 5 times with Corneometer (MPA580, Courage + Khazakaelectronic GmbH), and skin elasticity measured 3 times with Cutometer. It is a graph which shows the result of this.
- FIG. 7 is a graph showing the results of measuring the thickness of the papillary dermis layer with an acoustic microscope.
- FIG. 8 is a graph showing changes in the wrinkle area ratio (%) due to the use of the cream preparation (Active) containing 1.5% HEI and the cream preparation (Placebo) not containing 1.5% HEI. Results are shown at 0 months (0M), 1 month (1M), and 2 months (2M) from the start of application.
- Dermis elasticity improving agent which comprises 1- (2-hydroxyethyl) -2-imidazolidinone (HEI) or a derivative thereof as an active ingredient. ..
- 1- (2-hydroxyethyl) -2-imidazolidinone (HEI) may be referred to as S-173 or S173.
- HAI (2-Hydroxyethyl) -2-imidazolidinone
- the derivative of 1- (2-hydroxyethyl) -2-imidazolidinone can be, for example, a compound represented by the following general formula (I):
- n is an integer of 1 to 3
- R 1 is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group
- X is ⁇ CH 2 ⁇ or. It is a group represented by -N (R 2 )-, and R 2 means a hydrocarbon group having 1 to 6 carbon atoms which may be substituted with a hydrogen atom or a hydroxyl group.
- Heparanase is an enzyme that exists in various cells and specifically degrades the heparan sulfate chain of various heparan sulfate proteoglycans.
- epidermal keratinized cells constituting the epidermis, fibroblasts of the dermis, vascular endothelial cells and the like are produced. It is known that the production is also increased in various cancer cells, and it is suggested that it is related to the malignancy of cancer.
- Heparan sulfate proteoglycan functions to accumulate heparan sulfate-binding growth factors (bFGF, HGF, VEGF, HB-EGF, etc.) extracellularly.
- Pearlcan a type of proteoglycan heparan sulfate, is also present in the basement membrane of the epidermis at the boundary between the epidermis and the dermis. It controls the movement of growth factors between.
- perlecan present in the epidermal basement membrane also controls the action of growth factors on the epidermal basal cells bound to the epidermal basement membrane, and it has been clarified that it is essential for good proliferation and differentiation of the epidermis. ..
- HEI 1- (2-hydroxyethyl) -2-imidazolidinone
- MMP matrix metalloproteinase
- the dermis elasticity improving agent according to the present disclosure is a composition for use in improving dermis elasticity, which contains 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient. Can also be expressed as. Such compositions can be used especially for non-therapeutic cosmetic applications.
- one embodiment of the present disclosure relates to the use of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof in improving dermal elasticity.
- 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof may be used in the form of a composition in combination with other components.
- one embodiment of the present disclosure relates to the use of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof in the manufacture of a dermal elasticity improver.
- one embodiment of the present disclosure comprises administering 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof to a subject (eg, human) to improve dermal elasticity.
- a subject eg, human
- LTBP2 and / or Fibrillin-1 Production Promoter One embodiment according to the present disclosure comprises LTBP2 and / or a derivative thereof of 1- (2-hydroxyethyl) -2-imidazolidinone as an active ingredient. / Or related to the production promoter of fibrillin-1. As detailed in the Examples section, we now show that 1- (2-hydroxyethyl) -2-imidazolidinone promotes the production of LTBP2 and / or fibrillin-1 in human fibroblasts. Found to have. The increase or decrease in the production of LTBP2 and / or fibrillin-1 can be examined by, for example, quantitative PCR analysis.
- the LTBP2 and / or fibrillin-1 production promoter contains 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient, LTBP2 and / or.
- it can be expressed as a composition for use in promoting the production of fibrillin-1.
- Such compositions can be used especially for non-therapeutic cosmetic applications.
- one embodiment of the present disclosure relates to the use of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof in promoting the production of LTBP2 and / or fibrillin-1.
- 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof may be used in the form of a composition in combination with other components.
- one embodiment of the present disclosure relates to the use of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof in the production of LTBP2 and / or fibrillin-1 production promoters.
- one embodiment of the present disclosure comprises administering 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof to a subject (eg, a human), LTBP2 and / or.
- the present invention relates to a method for promoting the production of fibrillin 1.
- one embodiment according to the present disclosure relates to a cosmetological method for improving the elasticity of the dermis, which is characterized by increasing the production of LTBP2 and / or fibrillin-1.
- one embodiment of the present disclosure relates to a cosmetological method for preventing or ameliorating wrinkles, characterized by increased production of LTBP2 and / or fibrillin-1.
- one embodiment of the present disclosure is characterized by stabilizing the localization of LTBP2 and / or fibrillin-1 just below the basement membrane to prevent or improve wrinkles (particularly dermal wrinkles). Regarding beauty methods to do.
- PDGF-BB promotes the production of LTBP2 and fibrillin 1, and thus one embodiment according to the present disclosure is characterized by increasing the expression of PDGF-BB. Also related to beauty methods to prevent or improve wrinkles (especially dermal wrinkles).
- the beauty method according to the present disclosure is a non-therapeutic method and does not include so-called medical practice.
- An embodiment according to the present disclosure comprises 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient.
- accelerators As detailed in the Examples section, the inventor has now found that 1- (2-hydroxyethyl) -2-imidazolidinone has the effect of promoting the growth of dermal papilla fibers.
- the increase in dermal papilla layer fibers can be evaluated, for example, by measuring the thickness of the dermal papilla layer with an acoustic microscope (for example, AMS-50SI manufactured by Hyundai Motor Co., Ltd.).
- Some embodiments are characterized by containing 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient, wherein the dermal papilla fibers are dermal papilla oxytalan fibers.
- the papillary layer fiber growth promoter Regarding the papillary layer fiber growth promoter.
- the dermal papillary layer fiber growth promoter contains 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient, and promotes dermal papillary layer fiber growth. It can also be expressed as a composition for use in. Such compositions can be used especially for non-therapeutic cosmetic applications.
- one embodiment of the present disclosure relates to the use of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof in promoting dermal papilla fiber growth.
- 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof may be used in the form of a composition in combination with other components.
- one embodiment of the present disclosure relates to the use of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof in the production of a dermal papillary layer fiber growth promoter.
- one embodiment according to the present disclosure comprises administering 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof to a subject (eg, human). Regarding the method of promoting growth.
- Dermal Papillary Fiber Stabilizer One embodiment according to the present disclosure comprises 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient. Regarding agents. As detailed in the Examples section, the inventor has now found that 1- (2-hydroxyethyl) -2-imidazolidinone has the effect of promoting the growth of dermal papilla fibers. Stabilization of the dermal papilla layer fibers can be evaluated, for example, by measuring the thickness of the dermal papilla layer with an acoustic microscope (for example, AMS-50SI manufactured by Hyundai Motor Co., Ltd.).
- an acoustic microscope for example, AMS-50SI manufactured by Nissan Motor Co., Ltd.
- Some embodiments are characterized by containing 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient, wherein the dermal papilla fibers are dermal papilla oxytalan fibers.
- the papillary layer fiber growth promoter Regarding the papillary layer fiber growth promoter.
- the dermal papillary layer fiber stabilizer according to the present disclosure contains 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient, and dermis papillary layer fiber stabilization. It can also be expressed as a composition for use in. Such compositions can be used especially for non-therapeutic cosmetic applications.
- one embodiment according to the present disclosure relates to the use of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof in dermal papillary layer fiber stabilization.
- 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof may be used in the form of a composition in combination with other components.
- one embodiment according to the present disclosure relates to the use of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof in the production of a dermal papilla layer fiber stabilizer.
- one embodiment according to the present disclosure comprises administering 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof to a subject (eg, human). Regarding stabilization method.
- a dermis wrinkle improving agent which comprises 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient.
- 1- (2-hydroxyethyl) -2-imidazolidinone has the effect of improving human dermal wrinkles. Fine wrinkles due to dryness are commonly referred to as epidermal wrinkles, while deep wrinkles at the corners of the eyes are defined as deep wrinkles with changes in the dermis and fat layer.
- the technique disclosed in the present application is epoch-making in that it can improve deep dermal wrinkles by promoting the regeneration of the papillary layer (elastin fibers of the papillary layer) in addition to the fine wrinkles of the epidermis. So far, dermal wrinkles have been improved by suppressing the decomposition of common matrices such as collagen, elastin, and hyaluronic acid in the dermis, or simply promoting the production of collagen, elastin, and hyaluronic acid. It was a theory between.
- treatment with 1- (2-hydroxyethyl) -2-imidazolidinone produces PDGF-BB from the epidermis and acts on PDGFR ⁇ -positive fibroblasts in the papillary layer. Increases the production of collagen and elastin.
- 1- (2-hydroxyethyl) -2-imidazolidinone promotes the regeneration of good basement membrane microstructure by suppressing the decomposition of the basement membrane. The important point is that a normal matrix can be constructed in the papillary layer by the interaction between the matrix whose production is promoted by PDGF-BB and the basement membrane formed by the suppression of degradation. The improvement of dermis wrinkles can be evaluated using, for example, an image analysis device or the like.
- the dermis wrinkle improving agent according to the present disclosure contains 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof as an active ingredient, and has a composition for use in improving dermis wrinkles. It can also be expressed as a thing. Such compositions can be used especially for non-therapeutic cosmetic applications.
- one embodiment according to the present disclosure relates to the use of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof in the improvement of dermal wrinkles.
- 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof may be used in the form of a composition in combination with other components.
- one embodiment according to the present disclosure relates to the use of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof in the production of a dermal wrinkle improving agent.
- one embodiment of the present disclosure comprises administering 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof to a subject (eg, human) to improve dermal wrinkles.
- a subject eg, human
- One embodiment according to the present disclosure relates to a screening method for a dermal elasticity improving agent using the expression of LTBP2 and / or fibrillin-1 as an index.
- one embodiment according to the present disclosure relates to a method for screening a dermal wrinkle improving agent using the expression of LTBP2 and / or fibrillin-1 as an index.
- Such a screening method determines, for example, a step of contacting a cell with a test compound, a step of measuring the expression of LTBP2 and / or fibrillin 1, and the presence or absence of an increase in the expression of LTBP2 and / or fibrillin 1 depending on the presence or absence of the compound.
- Including the process of Increased expression of LTBP2 and / or fibrillin-1 can be assessed by measuring mRNA and protein levels by known techniques.
- the compound to be screened for example, a compound contained in a compound library or a library of extracts such as microorganisms, animals and plants can be used.
- one embodiment according to the present disclosure relates to a dermis elasticity improving agent and a screening method using the expression of PDGF-BB as an index.
- a screening method includes, for example, a step of contacting cells with a test compound, a step of measuring the expression of PDGF-BB, and a step of determining the presence or absence of an increase in the expression of PDGF-BB depending on the presence or absence of the compound.
- Increased expression of PDGF-BB can be assessed by measuring mRNA and protein levels by known methods.
- the compound to be screened for example, a compound contained in a compound library or a library of extracts such as microorganisms, animals and plants can be used.
- one embodiment according to the present disclosure relates to a screening method for a dermis wrinkle improving agent using the expression of PDGF-BB as an index.
- a screening method includes, for example, a step of contacting cells with a test compound, a step of measuring the expression of PDGF-BB, and a step of determining the presence or absence of an increase in the expression of PDGF-BB depending on the presence or absence of the compound.
- Increased expression of PDGF-BB can be assessed by measuring mRNA and protein levels by known methods.
- the compound to be screened for example, a compound contained in a compound library or a library of extracts such as microorganisms, animals and plants can be used.
- Formulation 1- (2-Hydroxyethyl) -2-imidazolidinone or a derivative thereof can be synthesized by a known method, or a commercially available product can be easily purchased.
- 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof can be made into an inorganic salt or an organic salt by a known method.
- the salt used in the embodiment according to the present disclosure is not particularly limited, and examples of the inorganic salt include hydrochloride, sulfate, phosphate, hydrobromide, sodium salt, potassium salt, magnesium salt, and the like. Calcium salt, ammonium salt and the like can be mentioned.
- the organic salt include acetate, lactate, maleate, fumarate, tartrate, citrate, methanesulfonate, p-toluenesulfonate, triethanolamine salt, diethanolamine salt, amino acid salt and the like. Can be mentioned.
- the agent according to the present disclosure may contain only one 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof alone, but any combination of two or more of the above compounds or salts thereof. And may be included in proportions.
- the content of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof or a salt thereof in the agent according to the present disclosure is particularly limited as long as it is sufficient to effectively exert the desired effect. However, it may be appropriately selected according to the intended use of the agent. However, in general, the ratio of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof or a salt thereof to the whole agent is usually 0.0001% by mass or more, particularly 0.0001% by mass or more, and usually 5% by mass or less. Above all, it is preferably 1.5% by mass or less. When two or more kinds of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof or a salt thereof are used, the total amount thereof may satisfy the above range.
- the agent according to the present disclosure is 1- (2-hydroxyethyl) -2 as long as the action of 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof or a salt thereof is not substantially impaired.
- any other component may be contained.
- Other components include other compounds with heparanase activity inhibitory activity or other activity (MMP inhibitory activity, especially MMP-9 inhibitory activity, etc.) (CGS27023A, BIPBIPU, etc.), pharmaceutically acceptable carriers and / Alternatively, an auxiliary agent may be mentioned. Examples of other ingredients include crude drugs (see Japanese Patent Application No.
- heparanase inhibitors such as valerian extract, lily extract, long-lived herb extract, mukuroji extract, and chimpi extract, mangostin extract, turmeric extract, and (tormentilla extract).
- examples include, but are not limited to, crude drugs that act as MMP inhibitors (see Japanese Patent Application No. 2018-545781).
- MMP molecular pressure regulator
- One of these other components may be used alone, or two or more thereof may be used in any combination and ratio.
- some aspects of the invention are a compound having both heparanase inhibitory activity and MMP (particularly MMP-9) inhibitory activity, and / or a combination of a heparanase inhibitor and an MMP (particularly MMP-9) inhibitor.
- the present invention relates to an agent such as a dermis elasticity improving agent, a dermis wrinkle improving agent, a dermis papillary layer fiber growth promoting agent, a dermis papillary layer fiber stabilizing agent, an LTBP2 and / or a fibrillin 1 production promoting agent.
- an agent such as a dermis elasticity improving agent, a dermis wrinkle improving agent, a dermis papillary layer fiber growth promoting agent, a dermis papillary layer fiber stabilizing agent, an LTBP2 and / or a fibrillin 1 production promoting agent.
- the agent according to the present disclosure can be produced according to a conventional method, and as a component constituting the external skin preparation, 1- (2-hydroxyethyl) -2-imidazolidinone or a derivative thereof or a salt thereof or Although two or more types can be prepared alone, the components usually used for skin external preparations such as cosmetics including non-pharmaceutical products and pharmaceuticals, such as oils, surfactants, powders, coloring materials, water, alcohols, etc. Sticky agents, chelating agents, silicones, antioxidants, ultraviolet absorbers, moisturizers, fragrances, various medicinal ingredients, preservatives, pH adjusters, neutralizers and the like can be appropriately blended as needed.
- cosmetics including non-pharmaceutical products and pharmaceuticals, such as oils, surfactants, powders, coloring materials, water, alcohols, etc.
- Sticky agents, chelating agents, silicones, antioxidants, ultraviolet absorbers, moisturizers, fragrances, various medicinal ingredients, preservatives, pH adjusters, neutralizers and the like can be appropriately blended
- the administration route and dosage form of the agent according to the present disclosure are not limited, and may be appropriately selected according to the intended use.
- Examples of the route of administration include local administration (external skin application, etc.), oral administration, parenteral administration (intravenous administration, intraperitoneal administration, etc.), etc., which are used as agents according to the present disclosure such as dermis regeneration promoting agents. If so, it is preferable to use it as a skin external preparation.
- the dosage form includes solution system, solubilization system, emulsification system, powder dispersion system, water-oil two-layer system, water-oil-powder three-layer system, etc.
- Examples thereof include ointments, creams, emulsions, lotions, gels, aerosols and the like.
- solid preparations such as tablets, coated tablets, sugar-coated tablets, granules, powders, capsules (for example, hard or soft gelatin capsules), liquid preparations such as oral liquids and syrups (solutions, suspensions), etc.
- liquid preparations such as oral liquids and syrups (solutions, suspensions), etc.
- parenteral administration the form such as an injection solution can be mentioned.
- the agent according to the present disclosure includes 1- (2- (2-hydroxyethyl) -2-imidazolidinone according to the present disclosure or a derivative thereof or a salt thereof, as long as the action thereof is not substantially impaired.
- other one or more arbitrary components such as a carrier and / or an auxiliary agent may be blended.
- Other components are not particularly limited and may be appropriately selected depending on the intended use, dosage form, administration form and the like of the pharmaceutical composition, and examples thereof include pharmaceutically acceptable carriers and / or adjuvants. ..
- Auxiliaries include, for example, diluents, binders, disintegrants, thickeners, dispersants, reabsorption promoters, flavoring agents, buffers, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents. , Stabilizers, pH adjusters and the like.
- the agent according to the present disclosure when used as a skin external preparation, components usually used for the external preparation, such as a whitening agent, a moisturizer, an antioxidant, an oily component, an ultraviolet absorber, a surfactant, and a thickening agent, are used. Agents, alcohols, powder components, coloring agents, aqueous components, water, various skin nutrients and the like can be appropriately blended as needed.
- metal ion blocking agents such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, preservatives such as methylparaben, ethylparaben, butylparaben, caffeine, tannin, Bellapamil, tranexamic acid and its derivatives, licorice extract, glabridin, hot water extract of karin fruit, various crude drugs, tocopherol acetate, glycyrrhizinic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbic acid phosphate, Whitening agents such as ascorbic acid glucoside, arbutin, and kodiic acid, sugars such as glucose, fructose, mannose, sucrose, and trehalose, and vitamin A derivatives such as retinoic acid, retinol, retinol acetate, and retinol palmitate should be added as appropriate. Can be done
- the dosage form of the external skin preparation is not particularly limited, and is, for example, a solution system, a solubilization system, an emulsification system, a powder dispersion system, a water-oil two-layer system, and a water-oil-powder three-layer system.
- Ointments, gels, aerosols and the like can be taken in any dosage form.
- the form of use is not particularly limited, and for example, any form such as a lotion, a milky lotion, a cream, an essence, a jelly, a gel, an ointment, a pack, a mask, and a foundation can be taken.
- the agent according to the present disclosure By applying the agent according to the present disclosure to the skin, it can be used as a cosmetic method for preventing the formation of dermal wrinkles and / or reducing / eliminating the formed dermal wrinkles.
- the usage and dosage of the external skin preparation according to the present disclosure in such a cosmetic method are not particularly limited, and are appropriately determined depending on the dosage form and the condition of the dermal wrinkles to be treated, but are typically several times a day. For example, 1 to 5 times, an appropriate amount, for example, 0.1 ml to 1 ml per 1 square cm 2 , can be rubbed directly on the skin, or the appropriate amount can be soaked in gauze and then applied to the skin.
- EFT-400 Three-dimensional skin model (EFT-400) purchased from MatTeK was used as an MMP-9 inhibitor CGS27023A (reference 1) (final concentration 10-5 M) and a heparanase inhibitor BIPBIPU (reference).
- Reference 2 final concentration 10-5 M
- the cells were cultured in a special medium (EFT400-ASY) supplemented with HEI (final concentration 0.01%).
- EFT400-ASY a medium containing an equal amount of DMSO solvent not containing these inhibitors.
- Medium was exchanged once every 2 days, and tissue pieces were collected on the 4th and 7th days.
- Paraffin blocks, sectioned skin models, and fresh human skin were dehydrated and fixed with cold acetone according to the AMeX method, then replaced with acetone, methyl benzoate, and xylene in this order, and embedded in paraffin. Sections were prepared with a thickness of 3 ⁇ m, and sections for tissue staining were prepared.
- Paraffin sections prepared with various immunostaining thicknesses of 3 ⁇ m were deparaffinized with xylene and then hydrated with EtOH.
- Antibodies to type V collagen (Acris, AM10159PU-N, V13F6, mouse monoclonal antibody), antibodies to cytokerald 14 (K-14) (Fitzgerald, 20R-CP002, guniea pig polyclonal antibody), antibodies to fibrillin-1 (Abcam, 11C1.3, mouse monoclonal antibody), antibody against ⁇ 6 integrin (Santa Cruz, GOH-3, sc-19622, rat monoclonal antibody), antibody against LTBP2 (Protein-tech Group, 17708-1-AP, rabbit polyclonal antibody) Fluorescent immunostaining was performed using.
- Subjects (20-30s, 50s-60s) who gave informed consent to the gene expression of LTBP2 purchased and obtained fibroblasts derived from abdominal skin from KAC Co., Ltd. The cells were cultured in DMEM medium containing 10% serum. The cells were seeded on a 6-well plate at 250,000 cells / well, and 2 days later, mRNA was extracted using the RNeasy mini kit (QUIAGEN), and cDNA was synthesized using SuperScript VILO (invitrogen). Then, using the synthesized cDNA, quantitative PCR analysis was performed using platinum SYBER green (invitrogen). The primers of the genes used are shown in Table 2.
- Binding assay of LTBP2 and heparan sulfate Heparan sulfate was immobilized (biotinylated) by ring-opening reaction of heparan sulfate purchased from Biochemical Industry with sodium hypoiodide and adding it to a carbobind plate (corning). The method for immobilizing heparan sulfate on the plate is the same as that described in Reference 5). Recombinant human LTBP2 (abcam) of various concentrations was added to this heparan sulfate plate and reacted at room temperature for 2 hours.
- the acquired replica is used to analyze the wrinkle area using a square with a side of 10 mm as the base point at a point 5 mm away from the outside eye angle to the outside of the face.
- the rate (%) was calculated.
- Figure 1 shows the results of quantitative PCR analysis of the PDGFB gene expression level in the epidermis of an artificial skin model (skin three-dimensional model) that promotes PDGF-BB production by heparanase inhibitors and MMP inhibitors .
- the results in Figure 1 show that treatment with a heparanase inhibitor (BIPBIPU) and an MMP inhibitor (CGS27023A) increases PDGFB production.
- BIPBIPU heparanase inhibitor
- CCS27023A MMP inhibitor
- Fig. 2 shows the results of investigating the effects of PDGF-BB on fibroblasts and the gene expression of fibrillin and LTBP2. The results in FIG. 2 show that PDGF-BB also promotes the production of LTBP2 and fibrillin-1.
- LTBP2 localization change by heparanase inhibitor From the above results, an inhibitor that has the effect of simultaneously inhibiting the enzyme activities of both heparanase and MMP when heparanase inhibitor (BIPBIPU) and MMP inhibitor (CGS27023A) are allowed to act simultaneously.
- BIPBIPU heparanase inhibitor
- CCS27023A MMP inhibitor
- 3A and 3B show that treatment with a heparanase inhibitor (BIPBIPU), an MMP inhibitor (CGS27023A), and a compound (HEI) having an inhibitory effect on both MMP and heparanase enzymes increased the production of LTBP2 and heparan sulfate. It is shown that it can be stably localized in the basement membrane by binding to.
- BIPBIPU heparanase inhibitor
- CCS27023A MMP inhibitor
- FIGS. 4A and 4B show that fibrillin-1 is mediated directly below the basement membrane via LTBP2 by treatment with a heparanase inhibitor (BIPBIPU), an MMP inhibitor (CGS27023A), or a compound that inhibits both heparanase and MMP enzymes (HEI). It is shown that it can be stably localized in.
- BIPBIPU heparanase inhibitor
- HEI heparanase inhibitors
- FIG. 5 shows the results of investigating the binding of heparan sulfate and LTBP2 using a plate on which heparan sulfate is immobilized. The results in FIG. 5 show that LTBP2 and heparan sulfate bind in a concentration-dependent manner.
- FIG. 6 show that treatment with a serum containing 1.5% of the compound HEI, which inhibits the activity of both heparanase and MMP enzymes, improves the elasticity of the dermis.
- the thickness of the dermal papilla layer was measured with an acoustic microscope AMS-50SI (Honda Motor Co., Ltd.). The results are shown in Figure 7.
- the results in FIG. 7 show that treatment with HEI promotes the growth of dermal papilla fibers and stabilizes the dermal papilla fibers.
- CGS 27023A a non-peptidic, potenti, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits. Journal of medicinal chemistry. 1997; 40 (16): 2525-32. 3) Iriyama S, Yamanishi H, Kunizawa N, Hirao T, Amano S. 1-(2-Hydroxyethyl) -2-imidazolidinone, a heparanase and matrix metalloproteinase inhibitor, improves epidermal basement membrane structure and epidermal barrier function. Experimental dermatology. 2019 28 (3): 247-53.
- the agents according to the present disclosure increase and / or stabilize dermal papillary layer fibers by promoting the production of PDGF-BB, LTBP2 and / or fibrillin 1, thereby improving dermal elasticity and / or dermal wrinkles. It can be suitably used as a cosmetic composition such as an effective cosmetic product.
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Abstract
Description
(1) 1-(2-ヒドロキシエチル)-2-イミダゾリジノンまたはその誘導体を有効成分として含有することを特徴とする、真皮弾力改善剤。
(2) 1-(2-ヒドロキシエチル)-2-イミダゾリジノンまたはその誘導体を有効成分として含有することを特徴とする、真皮シワ改善剤。
(3) 1-(2-ヒドロキシエチル)-2-イミダゾリジノンまたはその誘導体を有効成分として含有することを特徴とする、真皮乳頭層線維増大促進剤。
(4) 1-(2-ヒドロキシエチル)-2-イミダゾリジノンまたはその誘導体を有効成分として含有することを特徴とする、真皮乳頭層線維安定化剤。
(5) 真皮乳頭層線維が、真皮乳頭層オキシタラン線維であ(3)または(4)に記載の剤。
(6) 1-(2-ヒドロキシエチル)-2-イミダゾリジノンまたはその誘導体を有効成分として含有することを特徴とする、LTBP2および/またはフィブリリン1の産生促進剤。
(7) 1-(2-ヒドロキシエチル)-2-イミダゾリジノンまたはその誘導体が、下記一般式(I):
で示される環状カルボキサミド誘導体である、(1)~(6)のいずれか一項に記載の剤。
(8) LTBP2および/またはフィブリリン1の産生を増大させることを特徴とする、真皮の弾力を改善する美容方法。
(9) LTBP2および/またはフィブリリン1の産生を増大させることを特徴とする、シワを防止または改善する美容方法。
(10)LTBP2および/またはフィブリリン1の局在安定化を特徴とする、シワを防止または改善する美容方法。
(11) LTBP2および/またはフィブリリン1の発現を指標とする、真皮弾力改善剤のスクリーニング方法。
(12) LTBP2および/またはフィブリリン1の発現を指標とする、真皮シワ改善剤のスクリーニング方法。
(13) PDGF-BBの発現を増大させることを特徴とする、シワを防止または改善する美容方法。
(14) PDGF-BBの発現を指標とする、真皮弾力改善剤のスクリーニング方法。
(15) PDGF-BBの発現を指標とする、真皮シワ改善剤のスクリーニング方法。
本開示に係る一実施形態は、1-(2-ヒドロキシエチル)-2-イミダゾリジノン(HEI)またはその誘導体を有効成分として含有することを特徴とする、真皮弾力改善剤に関する。なお、本明細書においては、1-(2-ヒドロキシエチル)-2-イミダゾリジノン(HEI)をS-173またはS173と表記する場合もある。
本開示に係る一実施形態は、1-(2-ヒドロキシエチル)-2-イミダゾリジノンまたはその誘導体を有効成分として含有することを特徴とする、LTBP2および/もしくはフィブリリン1の産生促進剤に関する。実施例の欄で詳述するように、本発明者は今回、1-(2-ヒドロキシエチル)-2-イミダゾリジノンがヒト線維芽細胞におけるLTBP2および/もしくはフィブリリン1の産生を促進させる効果を有することを見出した。LTBP2および/もしくはフィブリリン1の産生量の増減は、例えば、定量PCR解析を行なうことで調べることができる。
本開示に係る一実施形態は、1-(2-ヒドロキシエチル)-2-イミダゾリジノンまたはその誘導体を有効成分として含有することを特徴とする、真皮乳頭層線維増大促進剤に関する。実施例の欄で詳述するように、本発明者は今回、1-(2-ヒドロキシエチル)-2-イミダゾリジノンが真皮乳頭層線維の増大を促進させる効果を有することを見出した。真皮乳頭層線維の増大は、例えば、真皮乳頭層の厚みを音響顕微鏡(例えば、本田電子株式会社製のAMS-50SI)にて測定することにより評価することができる。
本開示に係る一実施形態は、1-(2-ヒドロキシエチル)-2-イミダゾリジノンまたはその誘導体を有効成分として含有することを特徴とする、真皮乳頭層線維安定化剤に関する。実施例の欄で詳述するように、本発明者は今回、1-(2-ヒドロキシエチル)-2-イミダゾリジノンが真皮乳頭層線維の増大を促進させる効果を有することを見出した。真皮乳頭層線維の安定化は、例えば、真皮乳頭層の厚みを音響顕微鏡(例えば、本田電子株式会社製のAMS-50SI)にて測定することにより評価することができる。
本開示に係る一実施形態は、1-(2-ヒドロキシエチル)-2-イミダゾリジノンまたはその誘導体を有効成分として含有することを特徴とする、真皮シワ改善剤に関する。実施例の欄で詳述するように、本発明者は今回、1-(2-ヒドロキシエチル)-2-イミダゾリジノンがヒトの真皮シワを改善剤させる効果を有することを見出した。乾燥による小ジワは俗に表皮性のシワと言われ、一方で目尻の深いシワは真皮や脂肪層の変化を伴う深いシワと定義されている。本願に開示の技術は、表皮性の小ジワに加えて、乳頭層(乳頭層のエラスチン線維)の再生を促すことで真皮性の深いシワの改善をもなしえた点で画期的である。これまで、真皮性のシワでは、真皮のコラーゲン、エラスチン、ヒアルロン酸などといった一般的なマトリックスの分解抑制によって改善が成される、または単純にコラーゲン、エラスチン、ヒアルロン酸産生促進というのが当業者の間でのセオリーであった。本願に開示の技術では、1-(2-ヒドロキシエチル)-2-イミダゾリジノンを処置することで表皮からPDGF-BBが産生され、乳頭層のPDGFRβ陽性の線維芽細胞に作用することで、コラーゲン、エラスチンの産生を高める。一方で1-(2-ヒドロキシエチル)-2-イミダゾリジノンは基底膜の分解を抑えることで良好な基底膜微細構造の再生を促進させる。このPDGF-BBによって産生促進されたマトリックスと、分解抑制によって形成された基底膜が相互作用することで、正常なマトリックスを乳頭層で構築できる点が重要なポイントとなる。なお、真皮シワの改善は、例えば、画像解析装置等を用いて評価することができる。
本開示に係る一実施形態は、LTBP2および/またはフィブリリン1の発現を指標とする、真皮弾力改善剤のスクリーニング方法に関する。また、本開示に係る一実施形態は、LTBP2および/またはフィブリリン1の発現を指標とする、真皮シワ改善剤のスクリーニング方法に関する。このようなスクリーニング方法は、例えば、細胞と試験化合物を接触させる工程、LTBP2および/またはフィブリリン1の発現を測定する工程、該化合物の有無によるLTBP2および/またはフィブリリン1の発現の増加の有無を決定する工程を含む。LTBP2および/またはフィブリリン1の発現の増加は、mRNA量やタンパク質量を既知の手法により測定することにより評価することができる。スクリーニングの対象となる化合物は、例えば、化合物ライブラリーや、微生物・動植物等の抽出物のライブラリーに含まれるものが使用されうる。
1-(2-ヒドロキシエチル)-2-イミダゾリジノンまたはその誘導体は、公知の方法により合成することができ、または市販品を容易に購入することができる。
皮膚モデルの培養
MatTeK社から購入した皮膚三次元モデル(EFT-400)を、MMP-9阻害剤であるCGS27023A(参考文献1)(終濃度10-5M)、ヘパラナーゼ阻害剤であるBIPBIPU(参考文献2)(終濃度10-5M)、MMP-9とヘパラナーゼの両方を阻害する効果を持つ独自開発成分、1-(2-ヒドロキシエチル)-2-イミダゾリジノン(参考文献3)(以下HEI、最終濃度0.01%)を添加した専用培地(EFT400-ASY)中で培養した。対照ではこれらの阻害剤を含めないDMSO溶媒を等量加えた培地で培養を行った。2日に1回培地交換を行い、4日目、7日目に組織片を回収した。
インフォームドコンセントを行った被験者(20代から30代)の腹部の新鮮皮膚サンプルを株式会社KACから購入取得した。参考文献4に記載の方法と同じ方法にて、取得されたサンプルに50mJ/cm2のUVBを照射し、CGS27023A(終濃度10-5M)、BIPBIPU(終濃度10-5M)、HEI(最終濃度0.01%)を含むWilliam’s E培地(Thermo Fisher Science, Waltham, MA)で培養した。対照は、CGS27023A、BIPBIPU、HEIを添加せず、DMSO溶媒を等量加えた培養培地を用いて培養した。毎日培地交換を行い、5日目に皮膚片を回収した。
回収した皮膚モデル、新鮮ヒト皮膚をAMeX法に従って、冷アセトンを用いて脱水固定後、アセトン、安息香酸メチル、キシレンの順で置換し、パラフィンに包埋した。3μmの厚さで切片を作成し、組織染色用の切片を作成した。
3μmの厚さで作成したパラフィン切片を、キシレンで脱パラフィン後、EtOHを使って水和化した。V型コラーゲンに対する抗体(Acris, AM10159PU-N, V13F6, mouse monoclonal antibody)およびサイトケラチン14(K-14)に対する抗体(Fitzgerald, 20R-CP002, guniea pig polyclonal antibody)、フィブリリン-1に対する抗体(Abcam, 11C1.3, mouse monoclonal antibody)、α6インテグリンに対する抗体(Santa Cruz, GOH-3, sc-19622, rat monoclonal antibody)、LTBP2に対する抗体(Protein-tech Group, 17708-1-AP, rabbit polyclonal antibody)を用いて蛍光免疫染色を行った。
回収した皮膚モデルの表皮のみをピンセットで剥がして、ジルコニアボールを入れた1mL Trizol溶液に表皮を入れて、組織破砕機にて3分振動させ表皮を破砕した。クロロホルム、イソプロパノールを用いてRNAを抽出し、RNeasy mini kit(QIAGEN)を用いてRNAを精製し、NanoDropにてRNA濃度を測定後、SuperScript VILO(Invitrogen)を用いてcDNAを合成した。その後合成したcDNAを用いて、platinum SYBER green(invitrogen)を用いて定量PCR解析を行った。使用した遺伝子のプライマーを表1に示す。
インフォームドコンセントを行った被験者(20~30代、50代~60代)腹部皮膚由来の線維芽細胞を株式会社KACから購入取得した。10%血清を含むDMEM培地にて培養した。6well plateに25万細胞/wellで播種し、2日後にRNeasy mini kit(QUIAGEN)を用いてmRNAを抽出、SuperScript VILO(invitrogen)を用いてcDNAを合成した。その後合成したcDNAを用いて、platinum SYBER green(invitrogen)を用いて定量PCR解析を行った。使用した遺伝子のプライマーを表2に示す。
生化学工業から購入したヘパラン硫酸を次亜ヨウ素酸ナトリウムにて開環反応させ、カルボバインドプレート(コーニング)に添加することで、ヘパラン硫酸を固相化した(ビオチン化ヘパラン硫酸をプレートへ固相化する方法については、参考文献5に記載された方法と同じ方法で実施)。このヘパラン硫酸プレートに各種濃度のrecombinant human LTBP2(abcam)を添加し、室温で2時間反応させた。PBSで3回洗浄後、HRP標識-anti-LTBP2抗体を添加、室温で2時間反応させた後にPBSで3回洗浄を行った。TMBで発色反応後1N HClで反応を停止させ、OD475nmを測定することで、結合LTBP2量を算出した。
インフォームドコンセントを行った被験者(14カ月)の線維芽細胞を株式会社KACから購入取得した。10%血清を含むDMEM培地にて培養した。6well plateに25万細胞/wellで播種し、1日後に、10ng/mLのrecombinant human PDGF-BB (R&D sysytems社)を添加し、1日後にRNeasy mini kit(QUIAGEN)を用いてmRNAを抽出、SuperScript VILO(invitrogen)を用いてcDNAを合成した。その後合成したcDNAを用いて、platinum SYBER green(invitrogen)を用いて定量PCR解析を行った。使用した遺伝子のプライマーを表3に示す。
30代~50代の健常な日本人女性30名に、1.5% HEIを含む美容液/含まない美容液を半顔で4週間使用していただいた。適用開始から0週後、2週後、4週後に試験施設まで来ていただき、恒温恒湿室にて順化頂いた後に、両頬の水分蒸散量をVapometer(デルフィン社)で3回、角層水分量をCorneometer(MPA580、Courage+Khazaka electronic GmbH)で5回、肌の弾力をCutometerで3回、真皮乳頭層の厚みを音響顕微鏡AMS-50SI(本田電子株式会社)にて測定した。
30代~50代の健常な日本人女性34名に、1.5% HEIを含むクリーム製剤/含まないクリーム製剤を目尻に0.1mLずつ、1日2回、2カ月間使用していただいた。適用開始から0カ月後、1か月後、2か月後に試験施設まで来ていただき、恒温恒湿室にて順化頂いた後に、レプリカ剤(SILFLO(Flexico、England))を外眼角から外側に一辺4cmの円形に塗布してレプリカを採取した。取得したレプリカを反射用レプリカ解析システムASA-03RXDおよび反射型三次元皮膚解析ソフトを用いて、外眼角から顔の外側に5mm離れた点を基点として1辺10mmの正方形を解析領域として、シワ面積率(%)を算出した。0カ月、1か月、2か月の左右のシワ面積率(%)を算出した後、割付表に基づき、アクティブ、プラセボに分け、アクティブ、プラセボの使用前(0カ月)、1か月後、2か月後の測定値を比較した。
ヘパラナーゼ阻害剤とMMP阻害剤によるPDGF-BB産生促進
人工皮膚モデル(皮膚三次元モデル)の表皮におけるPDGFB遺伝子発現量を定量PCR解析にて調べた結果を図1に示す。図1の結果は、ヘパラナーゼ阻害剤(BIPBIPU)とMMP阻害剤(CGS27023A)による処置により、PDGFBの産生量が増加することを示している。
ヘパラナーゼ阻害剤とMMP阻害剤を処置することで表皮中のPDGFB遺伝子量が増加したことから、表皮中でPDGF-BBタンパク質量が増加したと推察される。PDGF-BBは基底膜を通過して真皮の線維芽細胞へ作用することから、PDGF-BBが線維芽細胞に与える影響を次に検討した。これまでに、PDGF-BBを線維芽細胞に作用させると、V型コラーゲンの産生が亢進することを明らかにしているが、エラスチン線維形成に関わるフィブリリン1やLTBP2の発現に与える影響は明らかになっていない。そこで、PDGF-BBを線維芽細胞に作用させ、フィブリリンやLTBP2の遺伝子発現に与える影響を調べた結果を図2に示す。図2の結果は、PDGF-BBがLTBP2、フィブリリン1の産生も促進することを示している。
上記結果から、ヘパラナーゼ阻害剤(BIPBIPU)とMMP阻害剤(CGS27023A)を同時に作用させた場合、もしくはヘパラナーゼとMMPの両方の酵素活性を同時に阻害する効果を持つ阻害剤HEIを作用させた場合、表皮中のPDGF-BB量が増加し、真皮乳頭層の線維芽細胞のフィブリリン、LTBP2の産生量が高まる可能性が考えられる。またヘパラナーゼ阻害剤(BIPBIPU、HEI)を作用させることで、基底膜成分パールカンのヘパラン硫酸鎖の分解が抑制され、ヘパラン硫酸結合ドメインを持つLTBP2が基底膜と接着する仮説が考えられた。そこで、器官培養ヒト皮膚モデルと皮膚三次元モデルにおけるLTBP2局在の変化を調べた結果を図3Aおよび3Bに示す。図3Aおよび3Bの結果は、ヘパラナーゼ阻害剤(BIPBIPU)、MMP阻害剤(CGS27023A)、MMPとヘパラナーゼの両酵素の阻害効果を持つ化合物(HEI)による処置により、LTBP2の産生量が高まり、ヘパラン硫酸に結合することで、基底膜に安定的に局在できることを示している。
器官培養ヒト皮膚モデルと皮膚三次元モデルにおけるフィブリリン1とLTBP2局在の変化を調べた結果を図4Aおよび4Bに示す。図4Aおよび4Bの結果は、ヘパラナーゼ阻害剤(BIPBIPU)、MMP阻害剤(CGS27023A)、もしくはヘパラナーゼとMMPの両酵素を阻害する化合物(HEI)による処置により、LTBP2を介してフィブリリン1が基底膜直下に安定的に局在できることを示している。また、この結果は、ヘパラナーゼ阻害剤(BIPBIPU、HEI)による処置が、真皮乳頭層オキシタラン線維に影響を及ぼすことを示している。
ヘパラン硫酸とLTBP2の結合について、ヘパラン硫酸を固相化したプレートを用いて調べた結果を図5に示す。図5の結果は、LTBP2とヘパラン硫酸が濃度依存的に結合することを示している。
30代~50代の健常な日本人女性30名に、1.5% HEIを含む美容液/含まない美容液を半顔で4週間使用していただいた。適用開始から0週後、2週後、4週後に試験施設まで来ていただき、恒温恒湿室にて順化頂いた後に、両頬の水分蒸散量をVapometer(デルフィン社)で3回、角層水分量をCorneometer(MPA580、Courage+Khazaka electronic GmbH)で5回、肌の弾力をCutometerで3回測定した。結果を図6に示す。図6の結果は、ヘパラナーゼとMMPの両酵素の活性を阻害する化合物HEIを1.5%含む美容液の処置により、真皮の弾力が改善することを示している。また、真皮乳頭層の厚みを音響顕微鏡AMS-50SI(本田電子株式会社)にて測定した。結果を図7に示す。図7の結果は、HEIによる処置により、真皮乳頭層線維の増大が促進され、真皮乳頭層線維が安定化することを示している。
30代~50代の健常な日本人女性34名に、1.5% HEIを含むクリーム製剤(アクティブ)/含まないクリーム製剤(プラセボ)を目尻に使用頂き、レプリカを採取し、シワ面積率(%)を算出した。結果を図8に示す。図8の結果は、HEIを含むアクティブ製剤と処置により、シワ面積率(%)が有意に低下していたことを示す。一方、プラセボ製剤を処置した群では変化が見られなかった。アクティブ側では使用前後で減少が確認されたことから、マンホイットニーU検定を行ったところ、アクティブ側のシワ面積率(%)は使用前後で有意に減少が確認された。
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