WO2010024204A1 - Wrinkle-diminishing agent - Google Patents

Wrinkle-diminishing agent Download PDF

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Publication number
WO2010024204A1
WO2010024204A1 PCT/JP2009/064666 JP2009064666W WO2010024204A1 WO 2010024204 A1 WO2010024204 A1 WO 2010024204A1 JP 2009064666 W JP2009064666 W JP 2009064666W WO 2010024204 A1 WO2010024204 A1 WO 2010024204A1
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Prior art keywords
pro
wrinkle
present
group
val
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PCT/JP2009/064666
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French (fr)
Japanese (ja)
Inventor
誠 常長
祐輔 原
和毅 木暮
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株式会社資生堂
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Publication of WO2010024204A1 publication Critical patent/WO2010024204A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • 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
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • 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
    • A61P17/18—Antioxidants, e.g. antiradicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/92—Oral administration

Definitions

  • the present invention relates to a safe wrinkle preventing / improving agent having an effect of suppressing wrinkle generation and improving wrinkles. More particularly, the present invention relates to a wrinkle prevention / improving agent having a wrinkle prevention / improvement effect to prevent / improve wrinkles due to aging or photoaging.
  • compositions intended to resist skin aging such as wrinkles are conventionally known.
  • Val-Pro-Pro, Ile-Pro-Pro, and salts thereof according to the present invention are known substances, and are used for hair restoration / hair growth agents (Patent Document 1), for dullness prevention / treatment agents (Patent Document 2). ), And Val-Pro-Pro is known for its anti-stress effect and use as a functional food (Patent Document 4).
  • Patent Document 1 hair restoration / hair growth agents
  • Patent Document 2 for dullness prevention / treatment agents
  • Val-Pro-Pro is known for its anti-stress effect and use as a functional food
  • it is novel to have the wrinkle improving effect of the present invention.
  • the copper complex of Ala-His-Lys is known as a use for treating excess dye (Patent Document 3), it is novel to have the effect of the present invention.
  • JP 2002-284647 A JP 2002-284668 A JP 2005-511650 A Japanese Patent Application Laid-Open No. 11-100348
  • the present invention has been made in view of the above circumstances, and its purpose is to provide a safe wrinkle prevention / improving agent having an excellent wrinkle prevention / improvement effect such as prevention / improvement of wrinkles due to aging or photoaging. It is in.
  • Val-Pro-Pro As a result of intensive studies to solve the above problems, the present inventors have found that Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof. It has been found that it is a highly safe compound that exhibits excellent wrinkle prevention and improvement effects such as preventing and improving fine lines caused by drying, and more specifically preventing and improving wrinkles caused by photoaging. It came to complete.
  • the present invention provides a wrinkle prevention / improving agent.
  • the wrinkle prevention / improving agent of the present invention is one or two selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof. Contains more than one type of compound.
  • the present invention provides an oral wrinkle preventing / ameliorating agent.
  • the oral wrinkle preventing / ameliorating agent of the present invention is one kind selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof. Contains two or more compounds.
  • the present invention provides an injection.
  • the injection of the present invention is one or more selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof. Contains compounds.
  • the injection of the present invention may further contain a biocompatible gel.
  • the biocompatible gel may be hyaluronic acid and / or collagen.
  • an amino acid when an amino acid is represented, it is represented by a conventional three-letter code such as Val or Pro, and unless otherwise specified, represents an L-form amino acid.
  • an amino acid refers to any compound in which an amino group and a carboxyl group are bonded via at least one carbon atom and can be polymerized by a peptide bond.
  • the amino acid residue which comprises a peptide is shown by the said usual 3 letter notation, and is represented by connecting with a hyphen.
  • Val-Pro means a dipeptide in which the carboxyl group of L-valine and the amino group of L-proline are peptide-bonded.
  • the derivatives means Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, its side chain, the amino group of the N-terminal amino acid, or the C-terminal amino acid. Or a covalent bond to any of the atomic groups.
  • Any of the atomic groups includes a protecting group such as an N-phenylacetyl group or a 4,4′-dimethoxytrityl (DMT) group, and a biopolymer such as a protein, peptide, sugar, lipid, nucleic acid, or the like.
  • Synthetic polymers such as polystyrene, polyethylene, polyvinyl, and polyester, and functional groups such as ester groups, but are not limited thereto.
  • the ester group may include, for example, methyl ester, ethyl ester, other aliphatic esters, or aromatic esters.
  • salt includes acid salts, metal salts, amine salts and the like.
  • the acid salt may include hydrochloride, sulfate, phosphate, lactate, and the like.
  • the metal salt may include an alkali metal salt, an alkaline earth metal salt, and the like.
  • the amine salt may include a triethylamine salt, a benzylamine salt, or the like.
  • a wrinkle prevention / improving agent having an excellent wrinkle prevention / improvement effect can be obtained.
  • one or more compounds selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof are provided. Used.
  • Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys and their derivatives and / or salts according to the present invention can be synthesized by known methods, extracted from animals, plants, microorganisms, etc. -It can be obtained by purification.
  • Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, their derivatives and / or salts related to the present invention are all excellent in preventing and improving wrinkles as will be proved later.
  • one or more compounds selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof according to the present invention Is added as an active ingredient in the preparation of a wrinkle prevention / improving agent.
  • the wrinkle prevention / improving agent has a very wide application range, and is applied to various fields such as cosmetics, pharmaceutics, foods including quasi-drugs, and preferably used by being blended in a skin external preparation.
  • composition a wrinkle prevention / improving agent (hereinafter simply referred to as “composition”) as a composition containing the above compound, and the composition exhibits excellent effects such as a wrinkle prevention / improving agent.
  • the content is preferably 0.001 to 10.0% by weight, preferably 0.01 to 5.0% by weight in the total amount of the composition. Is more preferable, and 0.1 to 1.0% by weight is most preferable.
  • the wrinkle prevention / improving agent according to the present invention can be produced according to a conventional method.
  • the component constituting the wrinkle prevention / improving agent is selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof.
  • it is possible to prepare using only one or two or more kinds of compounds it is usually used for skin external preparations such as cosmetics and pharmaceuticals including quasi-drugs as long as the effects of the present invention are not impaired.
  • Other components to be used can be appropriately blended as necessary.
  • oils examples include oils, surfactants, powders, coloring materials, water, alcohols, thickeners, chelating agents, silicones, antioxidants, ultraviolet absorbers, and humectants. , Fragrances, various medicinal ingredients, preservatives, pH adjusters, neutralizers and the like.
  • the wrinkle prevention / improving agent is used in the form of cosmetics, pharmaceutical compositions, etc., and exhibits an excellent wrinkle prevention / improvement effect.
  • it is preferably applied to cosmetics, pharmaceuticals, etc., and is used in a form of an external preparation for skin that is externally applied to the skin.
  • the wrinkle prevention / improving agent of the present invention can be applied to the skin to prevent wrinkle formation and / or reduce or eliminate wrinkles formed.
  • the usage and dosage of the wrinkle prevention / improving agent of the present invention in such a cosmetic method are not particularly limited and are appropriately determined depending on the dosage form and the condition of wrinkles on the skin to be treated. Applicable amount, for example, 1 to 5 times, for example, 0.1 mL to 1 mL per 1 cm 2 , can be directly rubbed into the skin, or the appropriate amount can be soaked in gauze or the like and applied to the skin.
  • the dosage form of the wrinkle prevention / improving agent is not particularly limited as long as it can exert the effects of the present invention.
  • a solution system a solubilization system, an emulsification system, a powder dispersion system, a water-oil two-layer system , Water-oil-powder three-layer system, ointment, gel, aerosol, etc.
  • the wrinkle prevention / improving agent is applied, for example, in the field of cosmetics including quasi-drugs and pharmaceuticals, and the product forms include, for example, ointments, creams, emulsions, lotions, essences, jellies, gels, packs, Arbitrary forms such as a mask and a foundation can be taken.
  • the wrinkle prevention / improving agent is not particularly limited as long as the oral wrinkle prevention / improving agent dosage form exhibits the effects of the present invention. It can be in the form of a drink, a jelly type beverage or the like.
  • the wrinkle prevention / improving agent is useful as an injectable dosage form for cosmetic surgery and the like, and those containing a biocompatible gel are preferably used. If it is used for etc., it will not specifically limit. Among them, it is preferable to contain hyaluronic acid, type I collagen and the like.
  • the present invention will be specifically described with reference to examples and the like, but the technical scope of the present invention is not limited to these examples and the like.
  • the blending amount is expressed as a percentage by weight unless otherwise specified.
  • the total irradiation dose was 4.6 J / cm 2 .
  • the amount of ultraviolet rays used was a value measured with UVRADIOMETER (UVR-305 / 365D (II), Topcon). After the UV irradiation was completed, a photograph of the back of the mouse was taken, and the degree of wrinkle generation was determined by a method in which the method of Bisett et al. (Bissett DL. Evaluation was performed according to the criteria shown in Table 5 below.
  • the wrinkle evaluation work was individually performed by three measurers, and then a score was determined for the degree of wrinkle generation (hereinafter simply referred to as “score”) through discussion.
  • the following tests were conducted using only hairless mice that formed wrinkles with a score of 7 or higher.
  • the mice were divided into groups of 5 mice so that the average score of each group was the same.
  • Example 1 Val-Pro-Pro formulation, Table 1
  • Example 2 Ile-Pro-Pro formulation, Table 2
  • Comparative Example 1 no drug formulation, Table 4
  • the composition was applied at 100 ⁇ L per time, once a day, 5 days a week, and continuously for 6 weeks.
  • Example 3 Al-His-Lys hydrochloride combination, Table 3
  • Comparative Example 2 no drug combination, Table 4
  • the average value of the degree of wrinkle improvement in the group applied with the composition of Comparative Example 2 was 1.0 point, whereas that in the group applied with the composition of Example 3 was 2.6 points.
  • the application of the composition of Example 3 significantly accelerated wrinkle reduction (Table 7).
  • the risk factor P was less than 0.05.
  • Tables 8 to 20 show preparations for the preparation of wrinkle prevention / amelioration agents according to the present invention, such as external preparations for skin, injections and oral preparations. All of the external preparations for skin had excellent wrinkle prevention and improvement effects.
  • the injection and oral wrinkle prevention / improving agent according to the present invention can also provide wrinkle prevention / improvement effects.
  • Propylene glycol is added to ion-exchanged water, dissolved, heated and maintained at 70 ° C (aqueous phase). The other ingredients were mixed, heated and melted, and kept at 70 ° C. (oil phase). The oil phase was added to the aqueous phase, pre-emulsified, and uniformly emulsified with a homomixer, and then cooled to 30 ° C. while stirring well.
  • Propylene glycol was added to ion-exchanged water, dissolved, heated and maintained at 70 ° C (aqueous phase). The other ingredients were mixed, heated and melted, and kept at 70 ° C. (oil phase). The oil phase was added to the aqueous phase, preliminarily emulsified, and uniformly emulsified with a homomixer, and then cooled to 30 ° C. while stirring well.
  • phase A A carboxyvinyl polymer was dissolved in a small amount of ion-exchanged water (phase A). Polyethylene glycol 1500 and triethanolamine were added to the remaining ion-exchanged water, dissolved by heating and kept at 70 ° C. (aqueous phase). The other ingredients were mixed, heated and melted, and kept at 70 ° C. (oil phase). The oil phase was added to the aqueous phase for preliminary emulsification, and the A phase was added, and the mixture was uniformly emulsified with a homomixer and cooled to 30 ° C. while stirring well after the emulsification.
  • phase A Polyethylene glycol 1500 and triethanolamine were added to the remaining ion-exchanged water, dissolved by heating and kept at 70 ° C. (aqueous phase). The other ingredients were mixed, heated and melted, and kept at 70 ° C. (oil phase). The oil phase was added to the aqueous phase for preliminary emulsification, and the A phase was
  • the oil phase part was melt
  • the water phase part was dissolved at 70 ° C., the oil phase part was mixed with the water phase part, emulsified with an emulsifier and then cooled to 30 ° C. with a heat exchanger.
  • Carboxyvinyl polymer was uniformly dissolved in ion-exchanged water, while sarcosine and polyoxyethylene (50 mol) oleyl alcohol ether were dissolved in 95% ethanol and added to the aqueous phase. Next, other components were added, and the mixture was neutralized with caustic soda and L-arginine to increase the viscosity.
  • the A phase, the B phase, and the C phase were uniformly dissolved, and the B phase was added to the A phase to solubilize. Subsequently, after adding this to the C phase, it filled and manufactured.
  • Formulation Example 15 Oral preparation 1 g of tripeptide (Ile-Pro-Pro) and 99 g of lactose are mixed well to prepare 100 g of powder.
  • Formulation Example 16 Oral preparation 10 g of tripeptide (Val-Pro-Pro), 350 g of lactose, 360 g of 6% HPC lactose, 65 g of potato starch and 15 g of talc stearate are mixed well and compressed to prepare 1000 tablets. To do.
  • Formulation Example 17 Jelly Beverage 8 g of granulated sugar and 6 g of thickening polysaccharide were mixed in advance, water was added to make the total amount 100 g, and dissolved by heating. After removing the heat, 2 g of Val-Pro-Pro tripeptide, 10 g of isotonic mix, 0.09 g of vitamin mix and 0.3 g of citric acid were added to prepare a jelly beverage by a conventional method.
  • the injection and oral wrinkle prevention / improving agent according to the present invention can also provide wrinkle prevention / improvement effects.

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Abstract

Disclosed is a safe anti-wrinkle/wrinkle-diminishing agent that has a comprehensive anti-wrinkle/wrinkle-diminishing effect, such as preventing/diminishing wrinkles that are due to aging or photo-aging. The anti-wrinkle/wrinkle-diminishing agent contains one type or two or more types of compounds selected from a group comprised of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and/or salts thereof.

Description

しわ改善剤Wrinkle improver
　本発明はしわの発生を抑制し、しわを改善させる効果を有する安全なしわ防止・改善剤に関する。さらに詳しくは加齢や光老化によるしわを防止・改善するしわ防止・改善効果を有する安全なしわ防止・改善剤に関する。 The present invention relates to a safe wrinkle preventing / improving agent having an effect of suppressing wrinkle generation and improving wrinkles. More particularly, the present invention relates to a wrinkle prevention / improving agent having a wrinkle prevention / improvement effect to prevent / improve wrinkles due to aging or photoaging.
　老化は全身の臓器で進行しているが、その中でも目で見ることができる皮膚、とりわけ特に意識が集中しやすい顔面については、老化とともに発生するしわ及び小ジワが、世の多くの中高年齢者、とりわけ女性を悩ませている。従来、しわ改善用化粧料の必要性が叫ばれてきていたが、老化及びしわに関するメカニズムについて明らかではない部分が多かったため、従来の化粧料においては、ムコ多糖類やコラーゲンなどの生化学製品及び合成高分子製品を配合してしわ改善のための水分保持に努めるという方法を選択してきたにすぎない。 Aging is progressing in the organs of the whole body, but wrinkles and fine wrinkles that occur with aging are particularly visible on the skin that can be seen with the eyes, especially on the face where the consciousness is particularly concentrated. Especially annoying women. Conventionally, the necessity of a wrinkle-improving cosmetic material has been screamed, but there are many parts that are not clear about the mechanisms related to aging and wrinkles, so in conventional cosmetics, biochemical products such as mucopolysaccharides and collagen and They have only selected a method of blending synthetic polymer products and trying to retain moisture to improve wrinkles.
　しかしながら、上記の方法だけでは、皮膚の老化及びしわの発生を充分に防止することができない。近年、老化に関する研究が進められ、皮膚老化の原因としてマクロ的に見れば加齢が重要な因子であり、さらに乾燥、酸化、太陽光（紫外線）等も皮膚老化に関わる直接的な因子として挙げられてきている。それら因子の中でも太陽光（紫外線）は、光老化と呼ばれる変化において重要な役割を果たしていることが明らかとなってきた。上に記した顔面は、全身で最も光老化が進行しやすい部位であるが、光老化した皮膚では真皮の最も主要なマトリックス成分であるコラーゲン線維が著明に減少していることも明らかとなってきた。そしてしわ・小ジワの発生、ハリの消失といった現象がコラーゲン線維の減少と密接に関係していることも示唆されてきている。さらに最近になって皮膚の血管系及びリンパ系と皮膚の老化の関与についての報告が多数なされてきている。このように、しわの発生及び皮膚老化に関しては、様々な皮膚老化因子、中でも太陽光（紫外線）曝露に伴い、真皮における主要な細胞である線維芽細胞の増殖活性やコラーゲン等の合成機能の低下によるコラーゲン等のターンオーバー速度の低下、加えて血管系の減少による老廃物の蓄積、栄養供給の低下が生じる。その結果として、皮膚の弾力がなくなり、しわが発生し、皮膚の老化が進行する。 However, skin aging and wrinkle generation cannot be sufficiently prevented only by the above method. In recent years, research on aging has been promoted, and aging is an important factor as a cause of skin aging, and dryness, oxidation, sunlight (ultraviolet rays), etc. are also cited as direct factors related to skin aging. It has been. Among these factors, it has become clear that sunlight (ultraviolet rays) plays an important role in a change called photoaging. The face described above is the most prone to photoaging in the whole body, but it is also clear that collagen fibers, which are the main matrix components of the dermis, are markedly reduced in photoaged skin. I came. It has also been suggested that the occurrence of wrinkles and wrinkles and the disappearance of tension are closely related to the decrease in collagen fibers. More recently, there have been many reports on the involvement of skin aging and lymphatic system and skin aging. In this way, wrinkle generation and skin aging are associated with various skin aging factors, especially sun light (ultraviolet light) exposure, and the proliferative activity of fibroblasts, which are the main cells in the dermis, and the degradation of synthetic functions such as collagen As a result, the turnover rate of collagen and the like is reduced due to aging, and in addition, the accumulation of waste products due to the reduction of the vascular system and the reduction of nutrient supply occur. As a result, the elasticity of the skin is lost, wrinkles are generated, and skin aging progresses.
　このようなしわなどの皮膚の老化に抗するために意図された様々な組成物が、従来知られている。 Various compositions intended to resist skin aging such as wrinkles are conventionally known.
　また、本発明に係るＶａｌ－Ｐｒｏ－Ｐｒｏ、Ｉｌｅ－Ｐｒｏ－Ｐｒｏ及びそれらの塩は公知物質であり、育毛・養毛剤の用途（特許文献１）、くすみの予防・治療剤の用途（特許文献２）は知られており、Ｖａｌ－Ｐｒｏ－Ｐｒｏについては、抗ストレス効果、機能性食品としての用途が公知である（特許文献４）。しかしながら、本発明のしわ改善効果を有することは新規である。また、Ａｌａ－Ｈｉｓ－Ｌｙｓの銅錯体は色素過剰の処置の用途（特許文献３）として知られているが、本発明の効果を有することは新規である。
特開２００２－２８４６４７号公報 特開２００２－２８４６６８号公報 特表２００５－５１１６５０号公報 特開平１１－１００３２８号公報 In addition, Val-Pro-Pro, Ile-Pro-Pro, and salts thereof according to the present invention are known substances, and are used for hair restoration / hair growth agents (Patent Document 1), for dullness prevention / treatment agents (Patent Document 2). ), And Val-Pro-Pro is known for its anti-stress effect and use as a functional food (Patent Document 4). However, it is novel to have the wrinkle improving effect of the present invention. Further, although the copper complex of Ala-His-Lys is known as a use for treating excess dye (Patent Document 3), it is novel to have the effect of the present invention.
JP 2002-284647 A JP 2002-284668 A JP 2005-511650 A Japanese Patent Application Laid-Open No. 11-100348
　本発明は上記事情に鑑みてなされたもので、その目的は加齢や光老化によるしわを防止・改善する等の優れたしわ防止・改善効果を有する安全なしわ防止・改善剤を提供することにある。 The present invention has been made in view of the above circumstances, and its purpose is to provide a safe wrinkle prevention / improving agent having an excellent wrinkle prevention / improvement effect such as prevention / improvement of wrinkles due to aging or photoaging. It is in.
　本発明者らは上記課題を解決するために、鋭意研究を重ねた結果、Ｖａｌ－Ｐｒｏ－Ｐｒｏと、Ｉｌｅ－Ｐｒｏ－Ｐｒｏと、Ａｌａ－Ｈｉｓ－Ｌｙｓと、それらの誘導体及び／又は塩とが乾燥により生じる小じわを防止・改善し、さらに詳しくは光老化により生じるしわを防止・改善する等の優れたしわ防止・改善効果を発揮し、かつ安全性の高い化合物であることを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have found that Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof. It has been found that it is a highly safe compound that exhibits excellent wrinkle prevention and improvement effects such as preventing and improving fine lines caused by drying, and more specifically preventing and improving wrinkles caused by photoaging. It came to complete.
　すなわち本発明は、しわ防止・改善剤を提供する。本発明のしわ防止・改善剤は、Ｖａｌ－Ｐｒｏ－Ｐｒｏと、Ｉｌｅ－Ｐｒｏ－Ｐｒｏと、Ａｌａ－Ｈｉｓ－Ｌｙｓと、それらの誘導体及び／又は塩とからなる群から選択される１種類又は２種類以上の化合物を含む。 That is, the present invention provides a wrinkle prevention / improving agent. The wrinkle prevention / improving agent of the present invention is one or two selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof. Contains more than one type of compound.
　本発明は、経口しわ防止・改善剤を提供する。本発明の経口しわ防止・改善剤は、Ｖａｌ－Ｐｒｏ－Ｐｒｏと、Ｉｌｅ－Ｐｒｏ－Ｐｒｏと、Ａｌａ－Ｈｉｓ－Ｌｙｓと、それらの誘導体及び／又は塩とからなる群から選択される１種類又は２種類以上の化合物を含む。 The present invention provides an oral wrinkle preventing / ameliorating agent. The oral wrinkle preventing / ameliorating agent of the present invention is one kind selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof. Contains two or more compounds.
　本発明は、注射剤を提供する。本発明の注射剤は、Ｖａｌ－Ｐｒｏ－Ｐｒｏと、Ｉｌｅ－Ｐｒｏ－Ｐｒｏと、Ａｌａ－Ｈｉｓ－Ｌｙｓと、それらの誘導体及び／又は塩とからなる群から選択される１種類又は２種類以上の化合物を含む。 The present invention provides an injection. The injection of the present invention is one or more selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof. Contains compounds.
　本発明の注射剤は、生体親和性ゲルをさらに含む場合がある。 The injection of the present invention may further contain a biocompatible gel.
　前記生体親和性ゲルは、ヒアルロン酸及び／又はコラーゲンの場合がある。 The biocompatible gel may be hyaluronic acid and / or collagen.
　本明細書でアミノ酸を表す場合、Ｖａｌ、Ｐｒｏ等の慣用の３文字表記で表すこととし、特に断りのない限りＬ体のアミノ酸を表す。本明細書において、アミノ酸は、アミノ基とカルボキシル基とが少なくとも１個の炭素原子を介して結合した化合物であって、ペプチド結合により重合することが可能ないずれかの化合物を指す。また、本明細書でペプチドを表す場合、ペプチドを構成するアミノ酸残基は、前記慣用の３文字表記で示され、ハイフンで結んで表される。例えば２個のアミノ酸の３文字表記がハイフンで結ばれて表される場合には、左側のアミノ酸のカルボキシル基と右側のアミノ酸のアミノ基とがペプチド結合したジペプチドであることを表す。したがって、例えばＶａｌ－Ｐｒｏは、Ｌ－バリンのカルボキシル基とＬ－プロリンのアミノ基とがペプチド結合したジペプチドであることを意味する。 In this specification, when an amino acid is represented, it is represented by a conventional three-letter code such as Val or Pro, and unless otherwise specified, represents an L-form amino acid. In the present specification, an amino acid refers to any compound in which an amino group and a carboxyl group are bonded via at least one carbon atom and can be polymerized by a peptide bond. Moreover, when a peptide is represented in this specification, the amino acid residue which comprises a peptide is shown by the said usual 3 letter notation, and is represented by connecting with a hyphen. For example, when the three-letter code of two amino acids is connected by a hyphen, it represents a dipeptide in which the carboxyl group of the left amino acid and the amino group of the right amino acid are peptide-bonded. Thus, for example, Val-Pro means a dipeptide in which the carboxyl group of L-valine and the amino group of L-proline are peptide-bonded.
　本明細書において「それらの誘導体」とは、Ｖａｌ－Ｐｒｏ－Ｐｒｏか、Ｉｌｅ－Ｐｒｏ－Ｐｒｏか、Ａｌａ－Ｈｉｓ－Ｌｙｓかが、その側鎖か、Ｎ末端アミノ酸のアミノ基か、Ｃ末端アミノ酸のカルボキシル基かにおいて、いずれかの原子団と共有結合したものを指す。前記いずれかの原子団は、Ｎ－フェニルアセチル基、４，４'－ジメトキシトリチル（ＤＭＴ）基等のような保護基と、タンパク質、ペプチド、糖、脂質、核酸等のような生体高分子と、ポリスチレン、ポリエチレン、ポリビニル、ポリエステル等のような合成高分子と、エステル基等のような官能基とを含むがこれらに限定されない。前記エステル基は、例えば、メチルエステル、エチルエステルその他の脂肪族エステルか、芳香族エステルかを含む場合がある。 In the present specification, “the derivatives” means Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, its side chain, the amino group of the N-terminal amino acid, or the C-terminal amino acid. Or a covalent bond to any of the atomic groups. Any of the atomic groups includes a protecting group such as an N-phenylacetyl group or a 4,4′-dimethoxytrityl (DMT) group, and a biopolymer such as a protein, peptide, sugar, lipid, nucleic acid, or the like. Synthetic polymers such as polystyrene, polyethylene, polyvinyl, and polyester, and functional groups such as ester groups, but are not limited thereto. The ester group may include, for example, methyl ester, ethyl ester, other aliphatic esters, or aromatic esters.
　本明細書において「塩」とは、酸塩、金属塩、アミン塩等を含む。前記酸塩は、塩酸塩、硫酸塩、リン酸塩、乳酸塩等を含む場合がある。前記金属塩は、アルカリ金属塩、アルカリ土類金属塩等を含む場合がある。前記アミン塩は、トリエチルアミン塩、ベンジルアミン塩等を含む場合がある。 In this specification, “salt” includes acid salts, metal salts, amine salts and the like. The acid salt may include hydrochloride, sulfate, phosphate, lactate, and the like. The metal salt may include an alkali metal salt, an alkaline earth metal salt, and the like. The amine salt may include a triethylamine salt, a benzylamine salt, or the like.
　本発明によれば、優れたしわ防止・改善効果を有するしわ防止・改善剤が得られる。 According to the present invention, a wrinkle prevention / improving agent having an excellent wrinkle prevention / improvement effect can be obtained.
　以下、本発明を実施するための最良の形態について詳述する。 Hereinafter, the best mode for carrying out the present invention will be described in detail.
　本発明においては、Ｖａｌ－Ｐｒｏ－Ｐｒｏと、Ｉｌｅ－Ｐｒｏ－Ｐｒｏと、Ａｌａ－Ｈｉｓ－Ｌｙｓと、それらの誘導体及び／又は塩とからなる群から選択される１種類又は２種類以上の化合物が用いられる。 In the present invention, one or more compounds selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof are provided. Used.
　本発明に係るＶａｌ－Ｐｒｏ－Ｐｒｏと、Ｉｌｅ－Ｐｒｏ－Ｐｒｏと、Ａｌａ－Ｈｉｓ－Ｌｙｓと、それらの誘導体及び／又は塩とは、公知の方法により合成することや、動植物や微生物等から抽出・精製することにより得ることができる。本発明に関わるＶａｌ－Ｐｒｏ－Ｐｒｏと、Ｉｌｅ－Ｐｒｏ－Ｐｒｏと、Ａｌａ－Ｈｉｓ－Ｌｙｓと、それらの誘導体及び／又は塩とは、いずれも後で証明するように優れたしわ防止・改善効果を有する。したがって、本発明に係るＶａｌ－Ｐｒｏ－Ｐｒｏと、Ｉｌｅ－Ｐｒｏ－Ｐｒｏと、Ａｌａ－Ｈｉｓ－Ｌｙｓと、それらの誘導体及び／又は塩とからなる群から選択される１種類又は２種類以上の化合物は、しわ防止・改善剤の調製の際に有効成分として配合される。 Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys and their derivatives and / or salts according to the present invention can be synthesized by known methods, extracted from animals, plants, microorganisms, etc. -It can be obtained by purification. Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, their derivatives and / or salts related to the present invention are all excellent in preventing and improving wrinkles as will be proved later. Have Accordingly, one or more compounds selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof according to the present invention Is added as an active ingredient in the preparation of a wrinkle prevention / improving agent.
　このしわ防止・改善剤は、いずれも本発明に係るＶａｌ－Ｐｒｏ－Ｐｒｏ、Ｉｌｅ－Ｐｒｏ－Ｐｒｏ、Ａｌａ－Ｈｉｓ－Ｌｙｓの前記新規な効果の発見に基づく新規で有用な用途を提供する。 These wrinkle prevention / improving agents all provide new and useful uses based on the discovery of the above-mentioned novel effects of Val-Pro-Pro, Ile-Pro-Pro, and Ala-His-Lys according to the present invention.
　前記しわ防止・改善剤はいずれも極めて応用範囲が広く、例えば、医薬部外品を含む化粧品、医薬品、食品等種々の分野に応用され、好適には皮膚外用剤に配合されて活用される。 The wrinkle prevention / improving agent has a very wide application range, and is applied to various fields such as cosmetics, pharmaceutics, foods including quasi-drugs, and preferably used by being blended in a skin external preparation.
　したがって、本発明においては、前記Ｖａｌ－Ｐｒｏ－Ｐｒｏと、Ｉｌｅ－Ｐｒｏ－Ｐｒｏと、Ａｌａ－Ｈｉｓ－Ｌｙｓと、それらの誘導体及び／又は塩とからなる群から選択される１種類又は２種類以上の化合物を含む組成物としてのしわ防止・改善剤（以下、単に「組成物」という。）としても有用であり、該組成物はしわ防止・改善剤等優れた効果を発揮する。 Therefore, in the present invention, one or more selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof. It is also useful as a wrinkle prevention / improving agent (hereinafter simply referred to as “composition”) as a composition containing the above compound, and the composition exhibits excellent effects such as a wrinkle prevention / improving agent.
　本発明において組成物を調製する場合、前記Ｖａｌ－Ｐｒｏ－Ｐｒｏと、Ｉｌｅ－Ｐｒｏ－Ｐｒｏと、Ａｌａ－Ｈｉｓ－Ｌｙｓと、それらの誘導体及び／又は塩とからなる群から選択される１種類又は２種類以上の化合物のみを使用して調製することも可能であるが、その含有量は、前記組成物全量中０．００１～１０．０重量％が好ましく、０．０１～５．０重量％がより好ましく、０．１～１．０重量％が最も好ましい。 In the case of preparing the composition in the present invention, one kind selected from the group consisting of the Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof, or Although it is possible to prepare using only two or more kinds of compounds, the content is preferably 0.001 to 10.0% by weight, preferably 0.01 to 5.0% by weight in the total amount of the composition. Is more preferable, and 0.1 to 1.0% by weight is most preferable.
　本発明に係るしわ防止・改善剤は、定法に従って製造することができる。また、しわ防止・改善剤を構成する成分として、前記Ｖａｌ－Ｐｒｏ－Ｐｒｏと、Ｉｌｅ－Ｐｒｏ－Ｐｒｏと、Ａｌａ－Ｈｉｓ－Ｌｙｓと、それらの誘導体及び／又は塩とからなる群から選択される１種類又は２種類以上の化合物のみを使用して調製することも可能であるが、通常本発明の効果を損なわない範囲で、医薬部外品を含む化粧品や医薬品等の皮膚外用剤等に用いられる他の成分を、必要に応じて適宜配合することができる。前記他の成分（任意配合成分）としては、例えば、油分、界面活性剤、粉末、色材、水、アルコール類、増粘剤、キレート剤、シリコーン類、酸化防止剤、紫外線吸収剤、保湿剤、香料、各種薬効成分、防腐剤、ｐＨ調整剤、中和剤等が挙げられる。 The wrinkle prevention / improving agent according to the present invention can be produced according to a conventional method. The component constituting the wrinkle prevention / improving agent is selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof. Although it is possible to prepare using only one or two or more kinds of compounds, it is usually used for skin external preparations such as cosmetics and pharmaceuticals including quasi-drugs as long as the effects of the present invention are not impaired. Other components to be used can be appropriately blended as necessary. Examples of the other components (optional blending components) include oils, surfactants, powders, coloring materials, water, alcohols, thickeners, chelating agents, silicones, antioxidants, ultraviolet absorbers, and humectants. , Fragrances, various medicinal ingredients, preservatives, pH adjusters, neutralizers and the like.
　前記しわ防止・改善剤は、化粧料、医薬組成物等の形態で使用され、優れたしわ防止・改善効果を発揮する。特に、好適には化粧品、医薬品等に応用されて、皮膚に外用される皮膚外用剤の形態で、皮膚に直接塗布又は散布する投与方法により使用され、優れたしわ防止・改善効果を発揮する。 The wrinkle prevention / improving agent is used in the form of cosmetics, pharmaceutical compositions, etc., and exhibits an excellent wrinkle prevention / improvement effect. In particular, it is preferably applied to cosmetics, pharmaceuticals, etc., and is used in a form of an external preparation for skin that is externally applied to the skin.
　本発明のしわ防止・改善剤は肌に適用することでしわの形成の予防及び／又は形成されたしわの軽減・消失を図るための美容方法に利用できる。かかる美容方法における本発明のしわ防止・改善剤の用法、用量は特に限定されるものではなく、剤型や処置する肌のしわの状態により適宜決定されるが、典型的には、１日当たり数回、例えば１回～５回、適量、例えば１ｃｍ２当たり０．１ｍＬないし１ｍＬ、肌に直接すり込むか、又は、その適量をガーゼ等に染み込ませてから肌に貼付して使用することができる。 The wrinkle prevention / improving agent of the present invention can be applied to the skin to prevent wrinkle formation and / or reduce or eliminate wrinkles formed. The usage and dosage of the wrinkle prevention / improving agent of the present invention in such a cosmetic method are not particularly limited and are appropriately determined depending on the dosage form and the condition of wrinkles on the skin to be treated. Applicable amount, for example, 1 to 5 times, for example, 0.1 mL to 1 mL per 1 cm 2 , can be directly rubbed into the skin, or the appropriate amount can be soaked in gauze or the like and applied to the skin.
　前記しわ防止・改善剤の剤型としては、本発明の効果を発揮できるものであれば特に限定されず、例えば、溶液系、可溶化系、乳化系、粉末分散系、水－油二層系、水－油－粉末三層系、軟膏、ゲル、エアゾール等任意の剤型をとることができる。 The dosage form of the wrinkle prevention / improving agent is not particularly limited as long as it can exert the effects of the present invention. For example, a solution system, a solubilization system, an emulsification system, a powder dispersion system, a water-oil two-layer system , Water-oil-powder three-layer system, ointment, gel, aerosol, etc.
　前記しわ防止・改善剤は、例えば、医薬部外品を含む化粧品、医薬品の分野で応用され、その製品形態としては、例えば、軟膏、クリーム、乳液、化粧水、エッセンス、ゼリー、ジェル、パック、マスク、ファンデーション等の任意の形態をとることができる。 The wrinkle prevention / improving agent is applied, for example, in the field of cosmetics including quasi-drugs and pharmaceuticals, and the product forms include, for example, ointments, creams, emulsions, lotions, essences, jellies, gels, packs, Arbitrary forms such as a mask and a foundation can be taken.
　また、前記しわ防止・改善剤は、経口しわ防止、改善剤の剤形としても、本発明の効果を発揮するものであれば特に限定されず、賦形剤等と組み合わせることによりタブレットや顆粒とすることや、ドリンク剤、ゼリータイプ飲料などの形態をとることが可能である。 The wrinkle prevention / improving agent is not particularly limited as long as the oral wrinkle prevention / improving agent dosage form exhibits the effects of the present invention. It can be in the form of a drink, a jelly type beverage or the like.
　また、前記しわ防止・改善剤は、注射剤の剤形として、美容外科用途などとして有用であり、生体親和性ゲルを含むものが好適に用いられるが、ここでいう生体親和性ゲルは通常医薬品などに使用されるものであれば特に限定されるものではない。中でもヒアルロン酸、I型コラーゲンなどを含むことが好適である。 In addition, the wrinkle prevention / improving agent is useful as an injectable dosage form for cosmetic surgery and the like, and those containing a biocompatible gel are preferably used. If it is used for etc., it will not specifically limit. Among them, it is preferable to contain hyaluronic acid, type I collagen and the like.
　本発明を実施例等により具体的に説明するが、これらの実施例等により本発明の技術的範囲が限定されるものではない。配合量は、特に断りのない限り重量百分率で表される。 The present invention will be specifically described with reference to examples and the like, but the technical scope of the present invention is not limited to these examples and the like. The blending amount is expressed as a percentage by weight unless otherwise specified.
　１．ヘアレスマウスを用いた光老化しわ改善試験
　１－１．方法
　マウスはＨｒ－１（Ｓｋｈ－１）ヘアレスマウス（星野実験動物；６週齢～１０週齢）を用い、シュワルツらの方法（Ｈａｒａｔａｋｅ　Ａ．ｅｔ　ａｌ．Ｊ．Ｉｎｖｅｓｔ．Ｄｅｒｍａｔｏｌ．１０８：７６９－７７５，１９９７．）を一部変更して、ＵＶＢを繰り返し照射する方法（Ｎａｇａｎｕｍａ　Ｍ．ｅｔ　ａｌ．Ｊ．Ｄｅｒｍａｔｏｌ．Ｓｃｉ．２５：２９－３５，２００１．Ｓｃｈｗａｒｔｚ　Ｅ．Ｊ．Ｉｎｖｅｓｔ．Ｄｅｒｍａｔｏｌ．９１：１５８－１６１，１９８８．）に準じてしわを形成させた。すなわち背部にＵＶＢ（光源；東芝エレクトリック製　東芝　ＦＬ－２０　ＳＥ蛍光ランプ）を週３回、１０週間照射した。開始後の照射量は３６ｍＪ／ｃｍ２／回とし、２週目以降は徐々に増加させ、１０週目は２１６ｍＪ／ｃｍ２／回とした。総照射量は４．６Ｊ／ｃｍ２であった。紫外線量はＵＶＲＡＤＩＯＭＥＴＥＲ（ＵＶＲ－３０５／３６５Ｄ（ＩＩ）、トプコン）にて測定した値を用いた。紫外線照射の終了後、マウス背部の写真を撮影し、ビセットらの方法（Ｂｉｓｓｅｔｔ　ＤＬ．ｅｔ　ａｌ．Ｐｈｏｔｏｃｈｅｍｉｓｔｒｙ　ａｎｄ　Ｐｈｏｔｏｂｉｏｌｏｇｙ　４６：３６７－３７８，１９８７．）を一部変えた方法でしわの生成の度合いを下記の表５に示す判定基準に従って評価した。しわの評価作業は３名の測定者が個別に行い、その後合議によって、しわの生成の度合いについての評点（以下、単に「評点」という。）を決定した。評点７以上のしわを形成したヘアレスマウスのみを用いて以下に示す試験を行った。前記マウスを５匹ずつの群に、かつ、各群の評点の平均値が同程度となるように分けた。各群のマウスに対して、実施例１（Ｖａｌ－Ｐｒｏ－Ｐｒｏ配合、表１）、実施例２（Ｉｌｅ－Ｐｒｏ－Ｐｒｏ配合、表２）又は比較例１（薬剤無配合、表４）の組成物を、１回当たり１００μＬ、１日１回、週５日、６週間連続で、それぞれ塗布した。塗布の終了後、マウス背部の写真を撮影し、表５に示した判定基準に従い、マウスのしわの生成の度合いを評価した。マウスの群名を伏せた状態で、３名の測定者が個別に評価した後、合議によって評点を決定した。決定した評点を用いて、式（１）によりしわ改善度を算出した。
　「しわ改善度」＝「組成物塗布前の評点」－「６週間の組成物塗布後の評点」　…式（１） 1. 1. Photo-aging wrinkle improvement test using hairless mice 1-1. Method Hr-1 (Skh-1) hairless mice (Hoshino experimental animals; 6 to 10 weeks old) were used, and the method of Schwartz et al. (Haratake A. et al. J. Invest. Dermatol. 108: 769-) was used. 775, 1997.) with partial modification of UVB (Naganuma M. et al. J. Dermatol. Sci. 25: 29-35, 2001. Schwartz E. J. Invest. Dermatol. 91: 158-161, 1988.) wrinkles were formed. That is, the back was irradiated with UVB (light source; Toshiba FL-20 SE fluorescent lamp manufactured by Toshiba Electric) three times a week for 10 weeks. Irradiation amount after the start of the 36mJ / cm 2 / times, 2 weeks later is gradually increased, 10 weeks was 216mJ / cm 2 / times. The total irradiation dose was 4.6 J / cm 2 . The amount of ultraviolet rays used was a value measured with UVRADIOMETER (UVR-305 / 365D (II), Topcon). After the UV irradiation was completed, a photograph of the back of the mouse was taken, and the degree of wrinkle generation was determined by a method in which the method of Bisett et al. (Bissett DL. Evaluation was performed according to the criteria shown in Table 5 below. The wrinkle evaluation work was individually performed by three measurers, and then a score was determined for the degree of wrinkle generation (hereinafter simply referred to as “score”) through discussion. The following tests were conducted using only hairless mice that formed wrinkles with a score of 7 or higher. The mice were divided into groups of 5 mice so that the average score of each group was the same. For each group of mice, Example 1 (Val-Pro-Pro formulation, Table 1), Example 2 (Ile-Pro-Pro formulation, Table 2) or Comparative Example 1 (no drug formulation, Table 4). The composition was applied at 100 μL per time, once a day, 5 days a week, and continuously for 6 weeks. After the application was completed, a photograph of the back of the mouse was taken, and the degree of wrinkle generation in the mouse was evaluated according to the criteria shown in Table 5. After three mice were evaluated individually with the group name of the mouse lying down, the score was determined by consultation. Using the determined score, the wrinkle improvement degree was calculated by the equation (1).
“Wrinkle improvement” = “Score before applying composition” − “Score after applying composition for 6 weeks” (1)
　また、同様のしわ改善試験を、実施例３（Ａｌａ－Ｈｉｓ－Ｌｙｓ塩酸塩配合、表３）の組成物と、比較例２（薬剤無配合、表４）の組成物とについて実施した。 In addition, the same wrinkle improvement test was carried out for the composition of Example 3 (Ala-His-Lys hydrochloride combination, Table 3) and the composition of Comparative Example 2 (no drug combination, Table 4).
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　１－２．結果
　表６及び７にしわ改善試験の結果を示す。比較例１の組成物を塗布した群ではしわ改善度の平均値は１．４点であったのに対し、実施例１、実施例２の組成物を塗布した群ではそれぞれ２．６点、２．８点であり、実施例１又は２の組成物の塗布によりしわの減少は顕著に促進された（表６）。実施例１又は２の組成物を塗布した群のしわ改善度と、比較例１の組成物を塗布した群のしわ改善度との間でマンホイットニー検定を実施したところ危険率Ｐはいずれも０．０５未満であり、観察されたしわの減少は統計学的に有意であった（表６）。以上より、Ｖａｌ－Ｐｒｏ－Ｐｒｏ又はＩｌｅ－Ｐｒｏ－Ｐｒｏを含む組成物は、紫外線により形成された皮膚のしわの改善に効果を有することが確認された。 1-2. Results Tables 6 and 7 show the results of the wrinkle improvement test. In the group to which the composition of Comparative Example 1 was applied, the average value of the degree of wrinkle improvement was 1.4 points, whereas in the group to which the compositions of Example 1 and Example 2 were applied, 2.6 points, It was 2.8 points, and wrinkle reduction was significantly promoted by application of the composition of Example 1 or 2 (Table 6). When the Mann-Whitney test was performed between the wrinkle improvement degree of the group to which the composition of Example 1 or 2 was applied and the wrinkle improvement degree of the group to which the composition of Comparative Example 1 was applied, all of the risk factors P were 0. The observed wrinkle reduction was statistically significant (Table 6). From the above, it has been confirmed that the composition containing Val-Pro-Pro or Ile-Pro-Pro has an effect on improving wrinkles of skin formed by ultraviolet rays.
　また、比較例２の組成物を塗布した群ではしわ改善度の平均値は１．０点であったのに対し、実施例３の組成物を塗布した群では２．６点であり、実施例３の組成物の塗布によりしわの減少は顕著に促進された（表７）。実施例３の組成物を塗布した群のしわ改善度と、比較例２の組成物を塗布した群のしわ改善度との間でマンホイットニー検定を実施したところ危険率Ｐは０．０５未満であり、観察されたしわの減少は統計学的に有意であった（表７）。以上より、Ａｌａ－Ｈｉｓ－Ｌｙｓ塩酸塩を含む組成物は、紫外線により形成された皮膚のしわの改善に効果を有することが確認された。 In addition, the average value of the degree of wrinkle improvement in the group applied with the composition of Comparative Example 2 was 1.0 point, whereas that in the group applied with the composition of Example 3 was 2.6 points. The application of the composition of Example 3 significantly accelerated wrinkle reduction (Table 7). When the Mann-Whitney test was performed between the wrinkle improvement degree of the group applied with the composition of Example 3 and the wrinkle improvement degree of the group applied with the composition of Comparative Example 2, the risk factor P was less than 0.05. There was a statistically significant reduction in wrinkles observed (Table 7). From the above, it was confirmed that the composition containing Ala-His-Lys hydrochloride has an effect in improving wrinkles of the skin formed by ultraviolet rays.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
　２．しわ防止・改善剤の製剤例
　表８～２０に本発明に係るしわ防止・改善剤の製剤例として皮膚外用剤、注射剤及び経口剤を示す。なお、いずれの皮膚外用剤も優れたしわ防止・改善効果を有していた。本願発明による注射剤、経口しわ防止・改善剤についても、しわ防止・改善効果が得られるものである。 2. Formulation Examples of Wrinkle Prevention / Improvement Agents Tables 8 to 20 show preparations for the preparation of wrinkle prevention / amelioration agents according to the present invention, such as external preparations for skin, injections and oral preparations. All of the external preparations for skin had excellent wrinkle prevention and improvement effects. The injection and oral wrinkle prevention / improving agent according to the present invention can also provide wrinkle prevention / improvement effects.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
（製法）イオン交換水にプロピレングリコールと苛性カリを加え溶解し加熱して７０℃に保った（水相）。他の成分を混合し加熱融解して７０℃に保った（油相）。水相に油相を徐々に加え、全部加え終わってからしばらくその温度に保ち反応を起こさせた。その後ホモミキサーで均一に乳化し、よくかきまぜながら３０℃まで冷却して製造した。 (Production method) Propylene glycol and caustic potash were added to ion-exchanged water, dissolved, heated and maintained at 70 ° C (water phase). The other ingredients were mixed, heated and melted, and kept at 70 ° C. (oil phase). The oil phase was gradually added to the aqueous phase, and after the addition was completed, the temperature was maintained for a while to cause the reaction. Thereafter, the mixture was uniformly emulsified with a homomixer and cooled to 30 ° C. while stirring well.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
（製法）イオン交換水にプロピレングリコールを加え溶解し加熱して７０℃に保つ（水相）。他の成分を混合し加熱融解して７０℃に保った（油相）。水相に油相を加え、予備乳化を行い、ホモミキサーで均一に乳化した後、よくかきまぜながら３０℃まで冷却して製造した。 (Production method) Propylene glycol is added to ion-exchanged water, dissolved, heated and maintained at 70 ° C (aqueous phase). The other ingredients were mixed, heated and melted, and kept at 70 ° C. (oil phase). The oil phase was added to the aqueous phase, pre-emulsified, and uniformly emulsified with a homomixer, and then cooled to 30 ° C. while stirring well.
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
（製法）イオン交換水にプロピレングリコールを加え溶解し加熱して７０℃に保った（水相）。他の成分を混合し加熱融解して７０℃に保った（油相）。水相に油相を加え予備乳化を行い、ホモミキサーで均一に乳化した後、よくかきまぜながら３０℃まで冷却して製造した。 (Manufacturing method) Propylene glycol was added to ion-exchanged water, dissolved, heated and maintained at 70 ° C (aqueous phase). The other ingredients were mixed, heated and melted, and kept at 70 ° C. (oil phase). The oil phase was added to the aqueous phase, preliminarily emulsified, and uniformly emulsified with a homomixer, and then cooled to 30 ° C. while stirring well.
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
（製法）少量のイオン交換水にカルボキシビニルポリマーを溶解した（Ａ相）。残りのイオン交換水にポリエチレングリコール１５００とトリエタノールアミンを加え加熱溶解して７０℃に保った（水相）。他の成分を混合し加熱融解して７０℃に保った（油相）。水相に油相を加え予備乳化を行い、Ａ相を加えホモミキサーで均一に乳化し、乳化後よくかきまぜながら３０℃まで冷却して製造した。 (Production method) A carboxyvinyl polymer was dissolved in a small amount of ion-exchanged water (phase A). Polyethylene glycol 1500 and triethanolamine were added to the remaining ion-exchanged water, dissolved by heating and kept at 70 ° C. (aqueous phase). The other ingredients were mixed, heated and melted, and kept at 70 ° C. (oil phase). The oil phase was added to the aqueous phase for preliminary emulsification, and the A phase was added, and the mixture was uniformly emulsified with a homomixer and cooled to 30 ° C. while stirring well after the emulsification.
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
（製法）油相部を７０℃にて溶解した。水相部を７０℃にて溶解し、水相部に油相部を混合し、乳化機で乳化後熱交換機で３０℃まで冷却して製造した。 (Manufacturing method) The oil phase part was melt | dissolved at 70 degreeC. The water phase part was dissolved at 70 ° C., the oil phase part was mixed with the water phase part, emulsified with an emulsifier and then cooled to 30 ° C. with a heat exchanger.
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
（製法）イオン交換水にカルボキシビニルポリマーを均一に溶解し、一方、９５％エタノールにサルコシン、ポリオキシエチレン（５０モル）オレイルアルコールエーテルを溶解し、水相に添加した。次いで、その他の成分を加えた後、苛性ソーダ、Ｌ－アルギニンで中和させ増粘して製造した。 (Production Method) Carboxyvinyl polymer was uniformly dissolved in ion-exchanged water, while sarcosine and polyoxyethylene (50 mol) oleyl alcohol ether were dissolved in 95% ethanol and added to the aqueous phase. Next, other components were added, and the mixture was neutralized with caustic soda and L-arginine to increase the viscosity.
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
（製法）Ａ相、Ｃ相をそれぞれ均一に溶解し、Ｃ相にＡ相を加えて可溶化した。次いで、Ｂ相を加えた後充填を行い製造した。 (Manufacturing method) The A phase and the C phase were uniformly dissolved, and the A phase was added to the C phase and solubilized. Subsequently, after adding B phase, it filled and manufactured.
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
（製法）Ａ相、Ｂ相、Ｃ相をそれぞれ均一に溶解し、Ａ相にＢ相を加えて可溶化した。ついで、これをＣ相に加えた後充填を行い製造した。 (Manufacturing method) The A phase, the B phase, and the C phase were uniformly dissolved, and the B phase was added to the A phase to solubilize. Subsequently, after adding this to the C phase, it filled and manufactured.
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
（製法）イオン交換水にプロピレングリコールを加え、溶解し加熱して７０℃に保った（水相）。他の成分を７０℃にて混合溶解した（油相）。上記水相に油相を添加し、ホモミキサーで均一に乳化し、冷却後充填を行い製造した。 (Production Method) Propylene glycol was added to ion-exchanged water, dissolved, heated and kept at 70 ° C. (aqueous phase). Other components were mixed and dissolved at 70 ° C. (oil phase). An oil phase was added to the aqueous phase, and the mixture was uniformly emulsified with a homomixer, and filled after cooling.
　以下、製剤例１０～１３については、製剤例２～３と同様にしてクリームを製造した。 Hereinafter, for Formulation Examples 10 to 13, creams were produced in the same manner as Formulation Examples 2 to 3.
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
　製剤例１～１３で製造されたしわ防止・改善剤はいずれも実施例１と同様のしわ防止・改善試験においてしわ防止・改善効果を示した。 All the wrinkle prevention / improving agents produced in Formulation Examples 1 to 13 showed wrinkle prevention / improvement effects in the same wrinkle prevention / improvement test as in Example 1.

Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021

　製剤例１５：経口剤
　トリペプチド（Ｉｌｅ－Ｐｒｏ－Ｐｒｏ)１ｇと乳糖９９ｇとをよく混和し、散剤１００ｇを調整する。　
Formulation Example 15: Oral preparation 1 g of tripeptide (Ile-Pro-Pro) and 99 g of lactose are mixed well to prepare 100 g of powder.

　製剤例１６：経口剤
　トリペプチド（Ｖａl－Ｐｒｏ－Ｐｒｏ)１０ｇと、乳糖３５０ｇ、６％ＨＰＣ乳糖３６０ｇ、バレイショでんぷん６５ｇおよびステアリン酸タルク１５ｇとをよく混合して打錠し、錠剤１０００個を調整する。　
Formulation Example 16: Oral preparation 10 g of tripeptide (Val-Pro-Pro), 350 g of lactose, 360 g of 6% HPC lactose, 65 g of potato starch and 15 g of talc stearate are mixed well and compressed to prepare 1000 tablets. To do.

　製剤例１７：ゼリー飲料
　グラニュー糖８ｇ、増粘多糖類を６ｇをあらかじめ混合し水を加え全量を１００ｇとし、加熱溶解した。あら熱を除去した後、Ｖａl－Ｐｒｏ－Ｐｒｏトリペプチド２ｇと、アイソトニックミックス１０ｇ、ビタミンミックス０．０９ｇおよびクエン酸０．３ｇとを加え、常法によりゼリー飲料を作製した。　
Formulation Example 17: Jelly Beverage 8 g of granulated sugar and 6 g of thickening polysaccharide were mixed in advance, water was added to make the total amount 100 g, and dissolved by heating. After removing the heat, 2 g of Val-Pro-Pro tripeptide, 10 g of isotonic mix, 0.09 g of vitamin mix and 0.3 g of citric acid were added to prepare a jelly beverage by a conventional method.
　本願発明による注射剤、経口しわ防止・改善剤についても、しわ防止・改善効果が得られるものである。
  The injection and oral wrinkle prevention / improving agent according to the present invention can also provide wrinkle prevention / improvement effects.

Claims (1)

  1. 　Ｖａｌ－Ｐｒｏ－Ｐｒｏと、Ｉｌｅ－Ｐｒｏ－Ｐｒｏと、Ａｌａ－Ｈｉｓ－Ｌｙｓと、それらの誘導体及び／又は塩とからなる群から選択される１種類又は２種類以上の化合物を含むことを特徴とする、しわ防止・改善剤。 Including one or more compounds selected from the group consisting of Val-Pro-Pro, Ile-Pro-Pro, Ala-His-Lys, and derivatives and / or salts thereof, Wrinkle prevention / improving agent.
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JPH1149628A (en) * 1997-07-31 1999-02-23 Shiseido Co Ltd Cosmetic for improving wrinkle
JP2002128651A (en) * 2000-10-25 2002-05-09 Kose Corp Photoaging inhibitor and skin care preparation characterized by comprising the same
JP2002284668A (en) * 2001-03-26 2002-10-03 Cosmo Products Kk Preventive and therapeutic agent against darkening
JP2005511650A (en) * 2001-10-05 2005-04-28 プロサイト コーポレイション Treatment of skin hyperpigmentation
JP2007515381A (en) * 2003-11-17 2007-06-14 セダーマ Composition comprising a mixture of tetrapeptide and tripeptide
JP2005220085A (en) * 2004-02-06 2005-08-18 Kose Corp Antioxidant and skin care preparation for external use, using the same and method for activating cell by using the same
JP2007530488A (en) * 2004-03-26 2007-11-01 ディーエスエム アイピー アセッツ ビー．ブイ． Amino acid and peptide conjugates of arylalkyl acids for cosmetic applications
JP2006265253A (en) * 2005-03-24 2006-10-05 Neutrogena Corp Water-in-silicone emulsion composition

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