WO2016031605A1 - 外用組成物 - Google Patents

外用組成物 Download PDF

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WO2016031605A1
WO2016031605A1 PCT/JP2015/073020 JP2015073020W WO2016031605A1 WO 2016031605 A1 WO2016031605 A1 WO 2016031605A1 JP 2015073020 W JP2015073020 W JP 2015073020W WO 2016031605 A1 WO2016031605 A1 WO 2016031605A1
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Prior art keywords
vitamin
acid
present
compound
tocopherol
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PCT/JP2015/073020
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English (en)
French (fr)
Japanese (ja)
Inventor
中村　浩之
伊東　忍
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株式会社 Ｉｔｏ Ｒｅｓｅｒｃｈ
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Publication of WO2016031605A1 publication Critical patent/WO2016031605A1/ja

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    • 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
    • A61K8/67—Vitamins
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention relates to a compound having an acetyl ester structure of (R 5 —C ( ⁇ O) —CH 2 —), a production method thereof, and use thereof.
  • a compound having an acetyl ester structure of (R 5 —C ( ⁇ O) —CH 2 —) By containing the compound of the present invention as an active ingredient of the present compound, stronger whitening action, free radical inhibiting action, anti-wrinkle action, anti-acne action, moisturizing action, skin and mucosal barrier function enhancing action, UV-induced inflammation inhibition It exerts action and anti-decubitus action.
  • the present invention relates to a stable and highly safe composition, and can be used as a composition for external use for humans and animals including cosmetics, quasi drugs, pharmaceuticals, veterinary drugs, and aquatic animal drugs.
  • Vitamin C L-ascorbic acid
  • Vitamin E ⁇ , ⁇ , ⁇ , ⁇ -tocopherol and tocotrienols and their optical isomers D and L forms
  • Vitamin E itself is insoluble in water and soluble in oil, but vitamin C is water-soluble.
  • Many types of vitamin C derivatives are known, and the following known patent documents exist (Patent Documents 1-5).
  • Non-patent Document 1 ⁇ -vitamin E is fat-soluble and works as an antioxidant in the sebum layer and cell membrane in the body, preventing the spread of lipid peroxidation chain reaction that causes serious damage to the skin.
  • ⁇ -vitamin E not only suppresses oxidative damage of proteins and DNA, but also functions as an ultraviolet (UV) absorber (maximum absorption: 292 nm) (Non-patent document 3), and further suppresses skin immune disorders (non-patented) Document 4) (Non-patent document 5) and the effect of inhibiting DNA damage have also been reported. (Non-patent document 6).
  • UV absorber maximum absorption: 292 nm
  • Non-patent document 4 Non-patent document 5
  • Alpha vitamin E protects UV rays by increasing the SOD activity of the dermis, thereby suppressing the reduction of epidermal glutathione peroxidase and SOD caused by UV irradiation, and at the same time increasing the glutathione and vitamin C levels of the skin.
  • Non-patent Document 7 the antioxidant network of the skin is controlled to suppress UV irradiation injury. It has been confirmed that the content ratio of ⁇ -type vitamin E is high in some tissues such as skin, and a movement to re-evaluate the role of ⁇ -type in living bodies is occurring (Non-patent Document 8).
  • the composition of vitamin E in the human epidermis has been reported to be ⁇ vitamin E: 87%, ⁇ -vitamin E: 9%, ⁇ -Toe: 3%, ⁇ -Toe: 1%.
  • Toe tocotrienols
  • Non-patent Document 10 ⁇ Toe is known to suppress UV damage and also inhibit lipid peroxidation of benzoyl peroxide used for acne treatment and the like. It has been reported that ⁇ and ⁇ vitamin E also inhibit thymidine dimer formation of DNA (Non-patent Document 11). There is also a report that melanin production inhibitory action is remarkable for ⁇ types other than ⁇ (Non-patent Document 12)). Conventionally, acetic acid and nicotinic acid ester of dl- ⁇ vitamin E have been used in pharmaceuticals and cosmetics for the purpose of improving peripheral circulation disorders (Non-patent Document 13). EPC in which vitamin E and vitamin C are bound by a phosphate ester has been reported to suppress oxidative damage due to ischemia (Non-patent Document 14).
  • vitamin C and vitamin E derivatives there are two serious problems with vitamin C and vitamin E derivatives described in these known documents. That is, higher fatty acid ester derivatives of vitamin C-2-phosphate such as salts of vitamin C-2-phosphate (Patent Document 6) and salts of vitamin C-2-phosphate-6-palmitate (patents) Reference 7) and tocopheryl maleate C-2-maleate (Patent Document 8) are quickly converted non-enzymatically to vitamin C due to the weak chemical bond between vitamin C and phosphate or vitamin C and maleic acid. End up. For this reason, it decomposes
  • vitamin C-2-sulfate salts L-ascorbic acid-2-O-phosphate- ⁇ -tocopherol diester (Patent Document 9), vitamin C-2-glucoside (Patent Document 10) and higher fatty acid esters thereof
  • Patent Document 11 vitamin C in which two molecules are bonded with an ester is not only difficult to be decomposed non-enzymatically due to the strong binding of these esters to vitamin C. It takes a long time of 24 hours or more to be decomposed even by an enzyme.
  • Enzyme activity such as esterase that converts to vitamin simplex for water-soluble vitamins and fat-soluble vitamin derivatives, not limited to vitamin C and vitamin E derivatives, depends on the stereospecificity of the enzyme and the tissue and cell type in which the enzyme exists. It is virtually impossible to infer the conversion rate of a derivative, including the reaction rate of the enzyme, from the molecular structure of the derivative, and it can be estimated by clinical tests, tests using actual tissues, cell tests or reaction tests using actual enzymes. It becomes clear for the first time.
  • vitamin C and vitamin E are mainly metabolized in the liver and most of them are excreted from the body and are not reused. If cultured cells are not cultured for more than 24 hours, the effect cannot be exerted. This is meaningless because the experimental conditions differ from those applied to actual skin.
  • Non-patent Document 15 There is also a report that the combined application of vitamin C and vitamin E shows higher protective action due to the formation of erythema and samban cell and DNA thymidine dimer than the single application. Is considered effective. Not only external use but also oral administration is effective. When vitamin C and vitamin E were orally administered at the same time for 8 days, the erythema reaction due to ultraviolet rays was slowed (Non-patent Document 16). On the other hand, when a large amount of vitamin C alone is taken, active oxygen may be generated. However, natural polyphenols are also known to suppress prooxidant conversion of vitamin C (Non-patent Document 17).
  • vitamin E which is effective in preventing cell membrane oxidation
  • vitamin C instead of hydrocarbons modified to vitamin C derivatives.
  • vitamin E since vitamin E has a hydrocarbon chain in its molecule, it can be given moderate hydrophobicity when combined with vitamin C, so these derivatives improve cell membrane permeability and skin barrier permeability. It is possible.
  • vitamin C is water-soluble and vitamin E is highly viscous and water-soluble, it is difficult to use in combination.
  • Vitamin E is mixed with fat to reduce viscosity and emulsify.
  • both of them are powerful reducing agents, so they are prone to oxidative degradation, causing browning and off-flavour, and cytotoxicity and irritation problems due to prooxidants.
  • there is a method of using a stabilized vitamin C derivative and vitamin E derivative together there is a problem that it is expensive to add two derivatives at the same time, and the side chain is modified to each derivative.
  • Patent Document 15 As vitamin C and vitamin E derivatives, ⁇ -tocopheryl glyceryl vitamin C is known (Patent Document 15). Furthermore, L-vitamin C-2-O-maleic acid- ⁇ -tocopherol diester is disclosed by (Patent Document 16).
  • Patent Document 17 water-soluble phosphate diester compounds of vitamin E and vitamin C
  • Patent Document 18 water-soluble phosphate diester compounds of vitamin E and vitamin C
  • Patent Document 19 tocopherol / tocotriphenol-L-vitamin C-6-dicarboxylic acid Diester
  • Patent Document 20 ⁇ -tocopherylglyceryl vitamin C
  • L-vitamin C-2-O-maleic acid- ⁇ -tocopherol diester is a derivative because its ester bond is too weak and it is rapidly degraded even in water where no enzyme is present.
  • these problems are caused by the problem of the enzymatic binding power of the ester structure of vitamin C or vitamin E derivatives, and here are caused by the bioenzymatic degradation ability of the phosphate ester. That is, this problem can be solved if an ester structure molecule capable of controlling ideal stability and degradability for biological enzymes is found.
  • the conventional derivative in which vitamin C and vitamin E are combined has a problem that the ester bond is too strong or too weak to exhibit a sufficient effect in the administration tissue.
  • This structure is named as an acetyl diester-linked vitamin C derivative because the oxygen of vitamin C and the R—O—C ( ⁇ O) —CH 2 — structure are bonded by an ester.
  • vitamin C derivatives or vitamin E derivatives which are compounds having an acetyl ester structure of —O—C ( ⁇ O) —CH 2 — Then, it was recognized that the ester bond is not too weak and not too strong and can solve the conventional problems as described above. That is, the inventors succeeded in synthesizing a compound containing the acetyl diester-linked vitamin CE derivative of the present invention and examined its effect. As a result, the inventors found that the acetyl ester structure has an appropriate decomposition efficiency and completed the present invention.
  • a method for confirming these liquid crystal structures observation of a maltase cross image using a polarizing microscope is performed. That is, in the liquid crystal composition, a maltase cross image having a shape unique to the lamellar liquid crystal can be confirmed by observation with a polarizing microscope. In addition, the liquid crystal structure can be confirmed by a transmission electron microscope (TEM) using a resin foam-embedded ultrathin cutting method or a frozen section method.
  • TEM transmission electron microscope
  • the present invention provides a vitamin C and E derivative, that is, a compound containing a vitamin CE derivative in which tocopherol and vitamin C are bonded via —O—C ( ⁇ O) —CH 2 —. Furthermore, the purpose of this compound is to provide cosmetics, pharmaceuticals, feed additives, food additives, and antioxidants containing these compounds.
  • vitamin C or vitamin E derivatives are summarized as follows. 1) When vitamin C with an ester bond that is too strong and vitamin E-linked derivative bond are too strong, it is physically stable, but it is difficult to separate into vitamin C and tocopherol in the target tissue and has vitamin C activity. There is a problem that the tocopherol activity is low. Enzymes that degrade ascorbic acid-2-glucoside are extremely few in the skin, and sulfates and alkyl derivatives of ascorbic acid have very low vitamin C activity because there is almost no hydrolase in the body. .
  • Vitamin C and vitamin E-linked derivatives with too weak ester bonds If vitamin C and vitamin E are too weak, vitamin C and vitamin E will be released quickly, so that vitamin C and vitamin E will be rapidly oxidized and decomposed. There is a big problem with the stability in the formulation.
  • An aqueous solution containing 1% or more of the above is at 40 ° C. for 2 months. It causes one or more changes over time among browning, off-flavor, separation, precipitation, and titer reduction.
  • vitamin C derivatives of fatty acid esters cause inflammation in the skin (Non-patent Document 18), and it is necessary to employ hydrophobic side chains that do not have fatty acids that express toxicity.
  • vitamin E as a hydrophobic group that modifies vitamin C.
  • the biggest reason is that it is effectively used as vitamin E after being released from vitamin C in vivo.
  • vitamin E is recycled even if it becomes a vitamin E radical after scavenging the radicals, so there is also an advantage that the problem of prooxidant is less likely to occur.
  • the side chain of vitamin C is a fatty acid, it is difficult to be effectively used after release, but rather, it has a high risk of becoming a lipid peroxide and changing to one of the substances that damage cells. Remains.
  • vitamin C is water-soluble and vitamin E is fat. Since it is soluble, there is a problem that the derivative synthesis reaction is difficult to proceed, the yield is low, and the cost is high. Furthermore, since vitamin C and vitamin E are easily oxidized, they are decomposed during the reaction, and the yield is further reduced. Vitamin C in particular has four hydroxyl groups, making it difficult to react at a specific location, and it is extremely difficult to modify the side chain at a specific carbon position of vitamin C.
  • the present inventors have conducted various studies, and as a result, the acetyl diester-bound vitamin CE derivative of the present invention is not too weak or too strong, and therefore has high physiological activity and stability.
  • the present invention was completed by finding that it was excellent in safety, high in safety, and has a tissue target performance, and solved many manufacturing problems.
  • vitamin C and vitamin E can be separated by in vivo acetyltransferases such as acetyltransferase, and in vivo use performance is surprisingly improved compared to vitamin C alkyl derivatives. did.
  • acetyltransferases such as acetyltransferase
  • in vivo use performance is surprisingly improved compared to vitamin C alkyl derivatives.
  • 5,6-isopropylidene vitamin C and a halogenated acetyl compound are reacted in the presence of a catalyst selected from an alkali catalyst, an acid catalyst, and a phase transfer catalyst that does not produce a reaction product with the compound.
  • 5,6-isopropylidene acetyl diester-linked vitamin CE derivative was obtained by hydrolyzing 5,6-isopropylidene-linked vitamin CE derivative of the obtained 5,6-isopropylidene acetyl diester-linked vitamin CE derivative.
  • the 5,6-isopropylidene acetyl diester-linked vitamin CE derivative of the present invention is also confirmed to have stable antioxidant power and has no conventional problems that can be placed in enzymatic degradation. It can be used as a food or feed additive.
  • 5,6-isopropylidene vitamin C and a halogenated acetyl compound are dissolved in one or more solvents of a highly polar solvent selected from DMSO, THF, CH 2 Cl 2 and DMF, and t- 5,6-isopropylidene-linked vitamin CE derivative 5,6-isopropylidene obtained by reaction in the presence of one or more bases selected from BuOK, pyridine, KHCO3, K2CO3, Na2CO3, NaHCO3, CsCO3 It has been found that the acetyl diester-bonded vitamin CE derivative of the present invention can be obtained efficiently by hydrolyzing the.
  • the pKa of the hydroxyl groups at the 2nd and 3rd positions of vitamin C are 4.2 and 11.8, respectively, and they exist mainly as monoanions in the living body.
  • the hydroxyl group at the 2-position of vitamin C is more reactive than the hydroxyl group at the 3-position, and the radical is quickly stabilized by donating electrons or hydrogen from the hydroxyl group at the 2-position to the radical, and itself becomes the monoanion radical vitamin CH-. .
  • the monoanion radical becomes a monoanion and dehydrovitamin C by a bimolecular disproportionation reaction.
  • Vitamin C in which the 2nd and 3rd positions are not protected can supplement radicals at both the 2nd and 3rd positions (Non-patent Document 19).
  • Non-patent Document 20 A reaction system in which the vitamin C radical at the second position easily reacts with oxygen and generates superoxide is known (Non-patent Document 20). It is considered that there is a high possibility that the oxidation reaction is promoted more than the vitamin C radicals. It is estimated that vitamin C-2-Glu has a higher inhibitory effect on thymine degradation. Many vitamin C derivatives such as vitamin C phosphate (vitamin C-2-P) are protected only at the 2-position and reducing O- remains at the 3-position. It is thought that the effect as a scavenger can be exhibited even without conversion to.
  • vitamin C derivatives such as vitamin C-2-phosphate compensate for the disadvantages of vitamin C, which induces an oxidation reaction by ester modification at the 2-position (it becomes a prooxidant and promotes the oxidation reaction).
  • this derivative undergoes enzymatic degradation and is gradually converted to vitamin C. Since it has the ability to release vitamin C in vivo, high concentrations during administration such as vitamin C can be avoided. This is one of the great benefits.
  • vitamin C-2-glucoside has the property of not easily undergoing enzymatic hydrolysis in human serum.
  • a reaction system capable of efficiently producing the 2-position acetyl diester-bound vitamin CE derivative is required.
  • a derivative only at the 2-position from the mixed acetyl diester-linked vitamin CE derivatives at the 2-position and the 3-position must be efficiently selected and separated.
  • production was complicated and efficient because it was separated using a method such as chromatographic separation to obtain only the 2-position derivative from the 2-position and 3-position mixed vitamin CE derivatives. Was bad. There were also many synthetic reactions for obtaining a 2-position derivative, but all had problems with poor yields.
  • Vitamin C in which only the 3-position carbon position of 5,6-isopropylidene vitamin C is modified with an acetyl compound in high yield, including a production process in which it is dissolved in a highly polar solvent and reacted in the presence of KHCO3 as a base.
  • a method for producing acetyl tocopheryl diester derivatives has been found.
  • the compound is one or more selected from highly polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF) THF, CH 2 Cl 2 Vitamin C acetyl modified with an acetyl compound in high yield only at the 2-position carbon position of 5,6-isopropylidene vitamin C, including a production process in which it is dissolved in a solvent and reacted in the presence of t-BuOK as a base A process for producing tocopheryl diester derivatives has been found.
  • highly polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF) THF, CH 2 Cl 2 Vitamin C acetyl modified with an acetyl compound in high yield only at the 2-position carbon position of 5,6-isopropylidene vitamin C, including a production process in which it is dissolved in a solvent and reacted in the presence of t-BuOK as a base
  • t-BuOK as a base
  • the present invention includes the following items.
  • R 5 is vitamin E
  • the carbon at the 6-position of the chroman ring of vitamin E is in contact with R 5 of (R 5 —O—C ( ⁇ O) —CH 2 —) as shown in [Chemical Formula 3]. Combines with oxygen.
  • X is halogen.
  • Halogenoacetyl vitamin E and 5,6-isopropylidene vitamin C are dissolved in one or more single or mixed solvents selected from four solvents of DMSO, THF, CH 2 Cl 2 , and DMF, and t-BuOK, After reacting in the presence of one or more single or mixed bases selected from seven substances of pyridine, KHCO 3 , K 2 CO 3 , Na 2 CO 3 , NaHCO 3 , and CsCO 3 , 5,6-isopropyl
  • the process for producing a compound according to (2) comprising a step of hydrolyzing 5,6-isopropylidene of a redeneacetyl diester-linked vitamin CE derivative.
  • DMSO dimethyl sulfoxide
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • t-BuOK potassium tertiary butoxide.
  • the compound of (1) which is one or a mixture of two or more selected from halogenoacetylvitamin E represented by the following structural formula [Chemical Formula 6].
  • X represents a halogen atom.
  • a method for synthesizing four compounds comprising a production step in which vitamin E is dissolved in a solubilizing solvent and reacted with one or more single or mixed catalysts selected from an alkali catalyst, an acid catalyst, and a phase transfer catalyst and acetyl halide. .
  • the compound of (1) which is 5,6-isopyridene-vitamin C-3-acetyl diester vitamin E, which is one or a mixture of two or more selected from compounds represented by the following general formula [Chemical Formula 7].
  • 5,6-Isopyridene-vitamin C and a halogenated acetyl compound are prepared by dissolving the compound in a solvent of DMF and reacting in the presence of potassium hydrogen carbonate as a base.
  • a liquid crystal emulsion composition comprising the compound described above.
  • Antioxidant Group D
  • Kojic acid arbutin, sodium ascorbate phosphate, magnesium ascorbate phosphate, methyl ascorbate, ethyl ascorbate, sodium ascorbate sulfate, glucoside ascorbate, sodium palmitate ascorbate phosphate, sodium tocopheryl phosphate , (Ascorbyl / tocopheryl) phosphate K, tocopheryl ascorbyl maleate, caprylyl glyceryl ascorbate, hexyl glyceryl ascorbate, myristyl glyceryl ascorbate, glyceryl ascorbate, bisglyceryl ascorbate, diglyceryl ascorbate, isostearyl ascorbyl lin Sodium acid, Ascorbyl stearate, Ascorbyl palmitate, Ascolic dipalmitate Bill, ellagic acid, resorcinol, butyl res
  • vitamin E is one or a mixture of two or more selected from the following vitamin E group: (Vitamin E group) DL- ⁇ -tocopherol, DL- ⁇ -tocopherol, DL- ⁇ -tocopherol, DL- ⁇ -tocopherol, D- ⁇ -tocopherol, D- ⁇ -tocopherol, D- ⁇ -tocopherol, D- ⁇ -tocopherol, ⁇ - Tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, DL- ⁇ -tocotrienol, DL- ⁇ -tocotrienol, DL- ⁇ -tocotrienol, D- ⁇ -tocotrienol, D- ⁇ -tocotrienol, D- ⁇ -tocotrienol, D- ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol,
  • the solvent of the solvent-soluble hydrocarbon according to claim 1 of the present invention means that when a single solvent such as methylene chloride, DMSO, THF, CH 2 Cl 2 , or DMF or a mixed solvent is heated to 40 ° C., DL- ⁇ -tocopherol is It is a solvent that can dissolve 1% by weight or more. Therefore, the solvent-soluble hydrocarbon of the present invention is a hydrocarbon compound that can be dissolved in this solvent at 40 ° C. by 1% by weight or more.
  • vitamin E falls under any of hydrocarbons, solvent-soluble hydrocarbons, benzene rings, chroman rings, and benzopyrans.
  • Vitamin C used in the synthesis of the present invention includes L-ascorbic acid or a salt thereof.
  • the salt herein include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt, but other salts are pharmacologically acceptable salts. Any one may be used.
  • vitamin E there are multiple types of vitamin E, and there are tocopherols and tocotrienols broadly, but vitamin E that can be used in the present invention is tocopherol and tocotrienols.
  • Vitamin E that can be used in the present invention includes D-type and L-type due to optical activity, and both types can be used in the present invention, and the DL type and all-rac type of the mixed type can also be used.
  • vitamin E has four types of ⁇ , ⁇ , ⁇ , and ⁇ depending on the position of the methyl group.
  • Tocotrienols also have the same vitamin E activity as tocopherols, and therefore can be used in the present invention.
  • the structures of tocopherol and tocotrienol that can be used in the present invention are shown below.
  • the vitamin E salt that can be used for the synthesis of the compound having the acetyl diester structure of the present invention is an alkali metal salt such as sodium salt or potassium salt and an alkali metal salt such as calcium salt or magnesium salt. Any salt other than the above, such as an ammonium salt, may be used as long as it is a pharmacologically acceptable salt.
  • any of the D and L stereoisomers of the D / L notation named by corresponding to glyceraldehyde can be used.
  • a racemic mixture (denoted as rac-) or a DL type (denoted as DL-), which is a mixture thereof, can also be used as the production raw material of the present invention.
  • Vitamin E R6 -CH 2 -CH 2 -CH 2 -CH ( -CH 2) -CH 2 -CH 2 -CH (-CH 2) -CH 2 -CH 2 -CH (-CH 2) -CH 2 -CH 2 -CH (-CH 2) -CH Three Is the structure of tocopherol.
  • the vitamin C of the present invention is L-ascorbic acid and D-ascorbic acid, and L-ascorbic acid is desirable from the viewpoint of biological activity.
  • vitamin E that can be used for the compound having an acetyl diester structure of the present invention
  • all the vitamin E described above can be used.
  • Specific examples of vitamin E that can be used in the present invention are tocopherol and tocotrienol, and all four types of ⁇ can be used for each.
  • Examples of the pharmacologically acceptable salt of the present invention include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and ammonium salt. Any salt other than these can be used as appropriate as long as it is a pharmacologically acceptable salt.
  • the compound having an acetyl diester structure of the present invention can be appropriately synthesized by, for example, the following synthesis method or a similar manner.
  • the production method of the present invention will be described below, but the protecting group for the hydroxyl groups at the 5- and 6-positions of vitamin C is not limited to the following isopropylidene group, and may be an acyl group such as a benzylidene group, for example. An isopropylidene group is common.
  • These protecting groups can be easily removed by acidifying the reaction solution.
  • a general acidic compound such as an inorganic acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or an organic acid such as acetic acid or citric acid can be used.
  • vitamin E is dissolved in a solvent that can dissolve more than 5% by weight, such as methylene chloride. Stir at room temperature. After completion of the reaction, chloroform and ethyl acetate are added to dilute, and the organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and sodium sulfate is removed by filtration and the like. The residue obtained by evaporating the extraction solvent without drying over anhydrous sodium sulfate was mixed with 1-propanol or 1-propanol and one or more organic solvents such as n-hexane, cyclohexane or petroleum ether.
  • a solvent that can dissolve more than 5% by weight such as methylene chloride.
  • the residue obtained by evaporating the extraction solvent without drying over anhydrous sodium sulfate was mixed with 1-propanol or 1-propanol and one or more organic solvents such as n-hexane, cyclohexane or petroleum ether. May be added to crystallize the compound.
  • the obtained residue can be purified by column chromatography or the like to obtain 5,6-isopropylidene vitamin C-3-acetyl diester vitamin E represented by the following [Chemical Formula 11] as a solid.
  • R 6 is a hydrocarbon constituting vitamin E.
  • 5,6-Isopropylidene vitamin C-3-acetyl diester vitamin E is dissolved in a suitable solvent such as methanol, the above-mentioned general acidic compound such as hydrochloric acid is added, and the mixture is heated and stirred. Thereafter, the solid is collected by filtration, and diluted with chloroform or ethyl acetate. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and sodium sulfate is removed by filtration.
  • the residue obtained by evaporating the extraction solvent without drying over anhydrous sodium sulfate was mixed with 1-propanol or 1-propanol and one or more organic solvents such as n-hexane, cyclohexane or petroleum ether. May be added to crystallize the compound.
  • the solvent can be distilled off and combined with the solid collected by filtration, and the resulting residue can be purified by column chromatography or the like to obtain vitamin C-3-acetyl diester vitamin E as a solid.
  • R 6 is a hydrocarbon constituting vitamin E.
  • the method for producing vitamin C-2-acetyl diester vitamin E of the present invention is as follows. Under low oxygen conditions, t-BuOK (potassium tertiary butoxide, potassium tert-butoxide, potassium 2-methylpropan-2-olate) is selected from highly polar solvents such as DMSO, DMF, THF, CH 2 Cl 2 Suspended in the above solvent and cooled, the highly polar solvent in which 5,6-isopropylidene vitamin C was dissolved was added dropwise. Then, the highly polar solvent of halogenated vitamin E acetyl monoester is added and stirred.
  • highly polar solvents such as DMSO, DMF, THF, CH 2 Cl 2
  • R 6 is a hydrocarbon constituting vitamin E.
  • 5,6-Isopropylidene vitamin C-2-acetyl diester vitamin E is dissolved in a suitable solvent such as alcohol, and the above-mentioned general acidic compound such as HCl is added and stirred. Water is added to the reaction mixture, and the mixture is diluted with chloroform and ethyl acetate.
  • the organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and sodium sulfate is removed by filtration.
  • the residue obtained by evaporating the extraction solvent without drying over anhydrous sodium sulfate was mixed with 1-propanol or 1-propanol and one or more organic solvents such as n-hexane, cyclohexane or petroleum ether. May be added to crystallize the compound.
  • the solvent is distilled off, and the resulting residue is purified by column chromatography or the like to obtain L-vitamin C-2-acetyl diester vitamin E as an individual.
  • R 6 is a hydrocarbon constituting vitamin E.
  • the present compound thus obtained may be obtained as a pharmacologically acceptable salt by a known method. Conversion to a salt may be performed after isolation from the reaction solution, or may be performed without isolation from the reaction solution.
  • This compound has radical scavenging action, active oxygen scavenging action, anti-inflammatory action, and anti-acne action, so it suppresses erythema, which is inflammation caused by ultraviolet rays, sun protection method by ultraviolet rays, skin and whitening (stains, freckles, etc.)
  • erythema which is inflammation caused by ultraviolet rays, sun protection method by ultraviolet rays, skin and whitening (stains, freckles, etc.)
  • melanin pigmentation melanin pigmentation
  • anti-wrinkle for the prevention of melanin pigmentation
  • it has a collagen-producing action, and since it has a collagen-producing action, it has the effect of stabilizing wound healing agents and other cosmetic ingredients (antioxidation).
  • -It can be added as appropriate to cosmetics and pharmaceuticals such as lotion and lotion.
  • the following components can be simultaneously blended as necessary in the prescriptions of pharmaceuticals, quasi drugs, cosmetics, feed additives, food additives, and antioxidants containing the compound of the present invention.
  • these components include nicotinic acids such as nicotinic acid, nicotinic acid amide, and benzyl nicotinate, vitamins A such as retinoic acid, retinoic acetate, and vitamin A oil, riboflavin, riboflavin acetate, and flavin adenine diene.
  • Vitamin B2 such as nucleotides, vitamin B6 such as pyridoxine hydrochloride and pyridoxine dioctanoate, vitamin C such as L-vitamin C, L-vitamin C-2-sodium sulfate, and L-vitamin C dipalmitate , Pantothenic acids such as calcium pantothenate, pantothenyl ethyl ether, D-pantothenyl alcohol, acetyl pantothenyl ethyl ether, vitamin D such as cholecalciferol, ergocalciferol, ⁇ -Tocopherol, tocopherol acetate, dl- ⁇ -tocopherol nicotinate, dl- ⁇ -tocofur succinate Vitamin E such as role, other vitamins; glycine, alanine, phenylalanine, valine, leucine, isoleucine, serine, threonine, asparagine, aspartic
  • carboxyvinyl polymer carboxymethyl cellulose, hydroxypropyl Cellulose derivatives such as pyrmethylcellulose, surfactants such as sodium stearyl sulfate, diethanolamine cetyl sulfate, cetyltrimethylammonium saccharin, polyethylene glycol isostearate, diglyceryl diisostearate, phospholipids, Preservatives such as ethyl paraben, propyl paraben, butyl paraben, hinokitiol, salicylic acid derivatives, glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, anti-inflammatory agents such as allantoin and zinc oxide, other pH regulators, buffers, fragrances and coloring Agents and the like.
  • surfactants such as sodium stearyl sulfate, diethanolamine cetyl sulfate, cetyltrimethylammonium saccharin, polyethylene glycol isostearate, diglyceryl di
  • the following components can be simultaneously blended in the pharmaceutical, quasi-drug, cosmetic, feed additive, food additive, and antioxidant formulation containing the compound of the present invention as required.
  • One or more compounds selected from phosphoric acid, sodium tocopheryldimethylglycine, and tocopheryl retinoic acid can be contained at the same time.
  • the compounds of the present invention can be used in pharmaceuticals, quasi drugs and cosmetics effective for the following diseases. Radical disease, adult disease, cerebral infarction, myocardial infarction, cardiovascular disorder, analgesic effect, inflammation, necrosis, diabetes, pigmentation, acne, seborrhea, wrinkles, sagging, obesity, swelling, hair loss, pore enlargement, rough skin, Wounds, growth inhibition, stress.
  • Radical disease adult disease, cerebral infarction, myocardial infarction, cardiovascular disorder, analgesic effect, inflammation, necrosis, diabetes, pigmentation, acne, seborrhea, wrinkles, sagging, obesity, swelling, hair loss, pore enlargement, rough skin, Wounds, growth inhibition, stress.
  • radical diseases include skin aging, pigmentation, hemorrhoids, cancer, seborrhea, sunburn, cancer, acne, burns, sagging skin, obesity, hair loss, stress, psychosis, dementia, Parkinson Disease, HIV, cold, influenza, infection, myocardial infarction, ischemic heart disease, heart failure, angina, arrhythmia, arteriosclerosis, liver lipid metabolism disorder, hyperlipidemia, essential hypertension, hypertension, arteriosclerosis , Coronary sclerosis, thrombosis, obstructive arteriosclerosis, vascular disorder, peripheral vascular disorder, cholestasis, hypercholesterolemia, pancreatic disorder, organ failure, acute chronic hepatitis, gastric ulcer, duodenal ulcer, ulcer Ulcerative colitis, digestive organ disorder cholecystitis, diabetes, arthritis treatment, rheumatism, liver failure, liver disorder, ischemic liver disorder, liver lipid metabolism disorder, gallbladder disorder, organ transplant disorder, diabetes, poisoning, organ
  • Non-patent Document 21 Non-patent Document 21
  • Non-patent Document 22 Non-patent Document 22
  • radical diseases related to the present invention include the following diseases. That is, the radical diseases that are the targets of the drug of the redox control composition of the present invention include organ failure and tissue damage at the time of organ transplantation performed for tissue replacement. That is, cells and tissues due to heart transplantation surgery such as heart, liver, kidney, pancreas, gallbladder, thymus, stomach, lung, intestine, skin, coronary artery recanalization and the like, bypass surgery, and diseases and events described below And organ damage associated with the stoppage or delay of blood flow flowing into the body, and damage to cells and tissues that occur during or after reperfusion after the stop of blood flow, or damage to death or organ failure.
  • the present invention is effective for these diseases.
  • the present invention also relates to vascular thrombosis, anemia, ischemia, vascular sclerosis, vasoconstriction, hemorrhage (OBAYASHI, PROC. SOC. EXP. BIOL. WED., 196, 196, 164-169, 1990).
  • Examples include, for example, damage to cells and tissues associated with physical reduction or cessation of blood flow velocity caused by the above, death, and diseases and insufficiency of organs including blood vessels.
  • the redox control composition of the present invention includes oxygen deficiency caused by a decrease in oxygen pressure in blood vessels, and temporary deficiency of oxygen deficient tissues in cells or tissues caused by chemical substances such as agricultural chemicals and carbon monoxide poisoning.
  • Organs including cell death, blood vessel damage, death or blood vessels found when blood flow is sent to cells or tissue under normal or close conditions by appropriate treatment or event such as blood transfusion Diseases and insufficiency, and the like are also effective.
  • the redox control composition of the present invention is also effective for ischemic reperfusion diseases, and examples thereof include ischemic reperfusion myocardial injury (NARITA.WJ, J.LAB.CLIN.MED., 110, 153-158, 1987, Smith, LL Phil. Trans. R.
  • INOUE INMUCOSAL IMMUNOLOGY, 527-530, ELSEVIER, AMSTERDAM, 1990, Nakahama, Liver, 32: 1101-1123, 1991, Takekawa, Liver, 30: 459-467, 1989, Shirasugi, Nissho Gaien, 26: 358, 1993
  • Ischemia / Reperfusion Kidney Disorder Ischemia-reperfusion pancreatic injury (ISAJI, S .: MIE MED. J., 35: 109-123, 198).
  • Ischemia-reperfusion gallbladder disorder TOKA, GASTROENT.JPN, 26: 633-644, 1991
  • ischemia-reperfusion cardiovascular disorder ischemia-reperfusion gastrointestinal disorder (Iwai, Nisshokai, 87: 1662 -1669, 1990, NAITO, Y., FREE RED. RES. COMMS., 16: 13.5, 1992)
  • ischemia-reperfusion muscular disorder ischemia-reperfusion vascular disorder, ischemia-reperfusion ophthalmology, etc.
  • the redox control composition of the present invention is also effective in the following various disorders induced by active oxygen.
  • the present invention provides the human epidermal keratinization as described above for growing human epidermal keratinocytes by adding to a serum-free medium for human epidermal keratinocytes, or for treating burns, wounds or aza
  • a composition for promoting cell proliferation and tissue formation is included.
  • the following inflammations are included in the radical diseases that are treated symmetrically by the pharmaceuticals of the present invention.
  • Specific inflammatory diseases to be treated by the present invention include hemorrhoids, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout attack, acute otitis media, cystitis, prostate Examples include inflammation, toothache, conjunctivitis, keratitis, iridocyclitis, pleurisy, sinusitis and the like.
  • This compound is suitably used as a pharmaceutical orally or parenterally.
  • any form such as a solid preparation such as a tablet, a granule, a powder and a capsule or a liquid preparation such as an injection and an eye drop can be prepared by a known method.
  • excipients commonly used excipients, binders, thickeners, dispersants, resorption accelerators, buffers, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents, stabilization
  • Various additives such as an agent and a pH adjuster may be appropriately used.
  • the anti-inflammatory agent of the present compound may appropriately contain other anti-inflammatory agents or other kinds of medicinal components as long as the object of the present invention is not violated.
  • the treatment of burns, wounds, aza and the like of the present invention can be used as a specific purpose.
  • the administration method is parenterally, and examples of the administration form include creams, ointments, cataplasms, masks and the like.
  • One specific form of the pharmaceutical, quasi-drug, cosmetic, and veterinary drug of the present invention is a tissue absorption-promoting pharmaceutical and cosmetic.
  • These products contain a water-absorbing polymer composition in the formulation or product and contain substances that suppress moisture evaporation for a long time. Since these preparations can be kept wet with water for a long time, the main components dissolved and dispersed in water can continue to penetrate into the tissue, and the amount of drug transferred to the tissue can be greatly increased. .
  • the drug permeability to the tissue can be increased more effectively using a device such as iontophoresis or electroporation.
  • the water-absorbing polymer used in the present invention is not particularly limited as long as it has the ability to absorb and retain moisture.
  • any of the polymer compositions that have been conventionally used for cosmetics and medical use can be used.
  • polyglycolic acid PGA
  • polylactic acid PLA
  • poly ( ⁇ -hydroxy acid) polymer poly- ⁇ -hydroxybutyric acid (PHB)
  • poly ( ⁇ -hydroxyalkanoate) polymer polymer
  • PCL poly- ⁇ -caprolactone
  • PBS polybutylene succinate
  • PES polyethylene succinate
  • polyalkylene alkanoate polyester polymer, polypropylene polymer, polyamide polymer, Polytetrafluoroethylene polymer, PGA-PLA polymer cage, polydioxanone polymer cage, chitin / chitosan polymer, ethylene-methacrylic acid copolymer Combined ionomer, ethylene-acrylic acid copolymer ionomer, propylene-methacrylic acid copolymer ionomer, propylene-acrylic acid copolymer ionomer, butylene-acrylic acid copolymer ionomer,
  • It also contains at least one group selected from the group consisting of alkoxy groups, amino groups, mercapto groups, vinyl groups, epoxy groups, acetal groups, maleic acid groups, oxazoline groups and carboxylic acid groups, And a copolymer polymer having a low viscosity of 1 or more, specifically, methyl methacrylate-butadiene-styrene resin, acrylonitrile-butadiene rubber, EVA / PVC / graft copolymer, vinyl acetate-ethylene Copolymer resin, ethylene- ⁇ -olefin copolymer, propylene- ⁇ -olefin copolymer, hydrogenated styrene-isopropylene-block copolymer, polyamino acid polymer, polysaccharide chain polymer, polynucleic acid Polymers, hydroxyapatite polymers, calcium phosphate polymers, cellulose, hydroxymethyl and hydroxypropyl cellulose , Hyaluronic acid,
  • Polyethylene includes very low density polyethylene, low density polyethylene, linear low density polyethylene, medium density polyethylene, and high density polyethylene.
  • the inclusion of the polymer improves practical problems such as the brittleness of the water-absorbing polymer.
  • a polyolefin-based resin is contained, a hydrophobic effect can be obtained and the hydrolysis resistance of the water-absorbing polymer can be improved.
  • a compatibilizing agent for compatibilizing these polymers can be contained by a conventional method.
  • examples thereof include ionomer resins, oxazoline compatibilizing agents, elastomer compatibilizing agents, reactions, and the like.
  • Examples of such compatibilizers and copolymer compatibilizers are not limited thereto.
  • ions can be added to these polymer compositions.
  • alkali metal ions such as Li +, Na + and K +
  • alkaline earth metal ions such as Mg2 +, Ca2 +, Sr2 + and Ba2 +
  • transition metals such as Zn2 +, Cu2 +, Mn2 +, Ni2 +, Co2 +, Co3 +, Fe3 + and Cr3 + Ions are used.
  • anions such as Cl-, Br-, I- etc. can be blended with the cation host polymer.
  • a reactive compatibilizing agent can be added to the polymer composition of the present invention.
  • a reactive compatibilizing agent include a compound having a double bond, a carboxyl group, an epoxy group, an isocyanate group, etc. (low molecular weight Compound or polymer) that reacts with one or both of the polymers to be compatibilized in the molding process and acts as a surfactant based on the graft or block structure to function as a compatibilizer.
  • E-GMA-VA ethylene glycidyl methacrylate copolymer
  • E -MAH-EA ethylene ethyl maleate anhydride acrylate copolymer
  • EGMA-AS ethylene glycidyl methacrylate-acrylonitrile styrene
  • EGMA-PMMA ethylene glycidyl methacrylate-polymethyl methacrylate
  • APEW acid-modified polyethylene Wax
  • VESTANAT T1890 (Degussa). Only one of these reactive compatibilizers may be used, or two or more thereof may be mixed and used as necessary.
  • the formulation and preparation of the present invention has a porous structure in which fine holes or spaces having a diameter of 1 nm to 1 mm are present, such as a commercially available membrane filter for removing bacteria, more anti-inflammatory factors can be obtained. It is effective because it can incorporate a simple substance or a complex molecule selected from a free radical scavenging factor, a cell growth factor, an anti-infective factor, and a tissue formation inducing factor.
  • a hollow fiber structure is selected from more anti-inflammatory factor, free radical scavenging factor, cell growth factor, anti-infective factor, tissue formation inducing factor, or a single molecule or a complex molecule thereof It is effective to be able to capture.
  • PVP polyvinylpyrrolidone
  • -(Average molecular weight 6000), sodium polymethacrylate, CMC (carboxymethylcellulose), hydroxypropylmethylcellulose, hydroxyethylcellulose, complex hydroxypropyl, hydroxypropylcellulose, poly Acrylic acid and its derivatives, polyacrylamide and its derivatives, carrageenan, xanthan gum, guar gum, karaya gum, agar, locust bean gum, pectin, gati gum, polyethylenimines, carrageenan, complex carrageenan There are natural gums. Specific product names include, for example, polyvinyl alcohol film MONOSOL (Fura Co., Ltd., St. Paul, Minnesota).
  • inorganic salts and organic acids can be added as stabilizers.
  • these stabilizers are as follows. ZnO, MgO, MnO, CaO, calcium hydroxide, aluminum oxide, aluminum hydroxide, aluminum salt, zinc acetate, glucan, gelatin, quaternary ammonium salt, ethanolamines, alginic acid, cetyltrimethylammonium bromide, calcium alginate, Examples include calcium oxide, alginic acid, alginic acid / zinc, sodium alginate, kelp extract, zinc chloride, calcium hydroxide, zinc oxide, sodium chloride, calcium chloride, ammonium calcium alginate, and complex ammonium calcium alginate.
  • a crosslinking agent for changing the viscosity of these water-absorbing polymers can be added. Specific examples thereof include Kymene 5 (available from Hercules, Wilmington, Del.) There is.
  • reducing agents can be used in combination with the compound of the present invention as a quality-preserving agent.
  • sulfites such as sodium hydrogen sulfite, sodium sulfite and sodium dithionite, thiols including thiols, alcohols (eg 2 ⁇ ⁇ -mercaptoethanol, dithiothreitol and dithioerythritol), mercapto Thiocyanate such as acetic acid, sodium thioglycolate, thiolactic acid, thioglycolamide, glycerol monothio, borohydride (eg, sodium borohydride, lithium borohydride), tertiary amine, eg, sodium thiocyanate Thiosulfates such as sodium thiosulfate, cyanides such as sodium cyanide, thiophosphates such as sodium thio, arsenous acid such as sodium arsenite, phosphines such as triphenylpho
  • clay materials such as bentonite clay or montmorillonite clay, fumed silica, kaolin, allantoin, aluminum hydroxide gel, calamine, cocoa butter, dimethicone, cod liver oil, glycerin, kaolin, petrolatum, lanolin, mineral oil, shark Liver oil, white petrolatum, talc, starch, zinc acetate, zinc carbonate, zinc oxide, yeast extract, aldioxa, aluminum acetate, microporous cellulose, cholecalciferol, colloidal oatmeal, cysteine hydrochloride, dexpanthanol, per-balsam oil, protein hydrolyzate, racemethionine, sodium bicarbonate, vitamin A, sucrose fatty acid ester, polyethylene glycol and its derivatives, fatty acid ester, alkyl ethoxylate type, fatty acid ester ethoxylate ,
  • the water-absorbing polymer composition used in the present invention is a biodegradable polymer, it is particularly suitable when it is preferable for a living body not to remain as a foreign body because it is absorbed after wound healing.
  • the compound of the present invention can be used by being incorporated in a porous material.
  • porous materials include polyolefins containing fibrous structures, PET, cellulose, and cellulose-based fibers, as well as reticulated foams, cellulose sponges, polyurethane foams, and Foams including porous, open cell foams such as HIPS can be used.
  • the water-absorbing polymer soot material further includes other additives such as organic or inorganic fillers, flame retardants, anti-blocking agents, crystallization accelerators, gas adsorbents, anti-aging agents (esters, amides). Etc.), antioxidants, ozone degradation inhibitors, UV absorbers, light stabilizers, tackifiers, plasticizers (fatty acids such as stearic acid and oleic acid or their metal salts), softeners (mineral oil, wax, etc.) , Paraffins, etc.), stabilizers, lubricants, mold release agents, antistatic agents, modifiers, colorants, coupling agents, preservatives, antifungal agents and the like may be appropriately blended.
  • additives such as organic or inorganic fillers, flame retardants, anti-blocking agents, crystallization accelerators, gas adsorbents, anti-aging agents (esters, amides). Etc.), antioxidants, ozone degradation inhibitors, UV absorbers, light stabilizers,
  • a water-absorbing polymer, a polymer other than the water-absorbing polymer, and a water-absorbing polymer material containing a compatibilizer are molded by conventional methods to form various molded articles. Further, if necessary, an additive may be added to the water-absorbing polymer material to form a coating material, a coating material, or an adhesive material. Various molded products from the water-absorbing polymer material can be produced by a conventional molding method.
  • extrusion molded products injection molded products, blow molded products, sheets or films extruded from T-dies, inflation films, fibers by melt spinning, yarns, strings, ropes, multifilaments, Fiber structures such as monofilaments, flat yarns, staple fibers, spunbond nonwoven fabrics, flash spun nonwoven fabrics, and various foam molded products can be obtained.
  • the compounds of the present invention can be used in combination with the following vitamin derivatives.
  • components generally used in pharmaceuticals, medical materials, and cosmetics can be blended in amounts that do not impair the effects of the present invention.
  • materials that can be added to the production of the present invention for example, oil, higher alcohol, fatty acid, UV absorber, powder, pigment, surfactant, polyvalent alcohol / sugar, polymer, physiologically active ingredient, Solvents, antioxidants, fragrances, preservatives, etc.
  • the present invention is of course not limited to these examples.
  • blended with this invention For example, the component as described in (patent document 28) is mentioned.
  • composition for promoting cell growth and tissue formation of the present invention and the pharmaceutical and cosmetic containing the same may be in any dosage form and form as long as they are used in contact with the skin at the time of use. It is more preferable to use it in contact with the skin in the vicinity of the site where metabolism is desired.
  • a sunscreen agent and the like are included in a broad sense, and any type can be used as long as it can be brought into contact with the skin at the time of use. Regardless of the gender and age of the user.
  • the composition for promoting cell growth and tissue formation of the present invention and the cosmetic containing the composition may be in any shape, and in addition to solid, liquid, semi-solid, gas, powder, granule, tablet shape Although many forms, such as a gel form and a foam form, are mentioned, it is not limited to this in particular.
  • the cosmetics of this invention can use what can generally be used as cosmetics among the other components mentioned above, In addition to these, the existing cosmetic raw material can also be used further.
  • composition for promoting cell growth and tissue formation and the cosmetic of the present invention are prepared by dissolving, mixing, or dispersing the above-described components according to a conventional method according to the mode using the above-described components so as to have a predetermined content. Can be manufactured.
  • additives such as a stabilizer, a buffer, a preservative, and an isotonic agent can be contained.
  • this compound is used as an external preparation for cosmetics, quasi-drugs or pharmaceuticals, or used as an external preparation such as a pack, patch, or tape, the type of the compound, the type of cosmetic to be formulated, Usually, it is preferable to add about 0.001 to 50 (w / w)%, although it varies depending on the purpose of blending. In the case of a powder, 100 (w / w)% bulk powder can also be used.
  • the dose of the present invention varies depending on the weight and age of the patient and the target animal, the type and state of the target disease, and the administration method.
  • the dose is about 1 mg to about 1 mg once a day.
  • 60 kg body weight should be administered several times a day, about 1 mg to about 50 g once a day.
  • an eye drop it is preferable to administer an eye drop having a concentration of about 0.001 to 1 (w / v)% several times a day for a 60 kg body weight.
  • the effective amount to be administered as a composition with a suitable diluent of the present invention and a pharmacologically usable carrier is 0.001 to 1 g / cm 2 skin / day, divided into 1 to several times per day and 2 Administer for more than a day.
  • the masking agent is a patch for adsorbing the substance of the present invention together with water on a face or other skin with a water absorbent substance for the purpose of pigmentation, wrinkles, acne care and the like.
  • the amount of this compound to be added to products as cosmetics, external preparations, or oral preparations varies depending on the type of the compound, the type of product to be blended, the blending purpose, etc., but is usually about 0.001 to 5 (w / w )%, Preferably about 0.005 to 2 (w / w)%.
  • the radical disease of claim 13 of the present invention includes arrhythmia, arteriosclerosis, ischemic heart disease, heart failure, myocardial infarction, liver injury, ischemic liver injury, digestive organ failure, vascular disorder, pancreatic disorder, gallbladder disorder, organ transplant disorder
  • arrhythmia arteriosclerosis
  • ischemic heart disease heart failure
  • myocardial infarction liver injury
  • ischemic liver injury digestive organ failure
  • vascular disorder pancreatic disorder
  • gallbladder disorder organ transplant disorder
  • organ transplant disorder include adult diseases such as diabetes, hypertension, organ failure, and lifestyle-related diseases.
  • diseases caused by free radicals in the living body or active oxygen are one of the basic causes or the causative factors.
  • the compound of the present invention can be further improved in stability by making it an emulsion composition having a liquid crystal structure, and can also enhance the transdermal absorbability and improve the skin moisturizing performance.
  • the presence of the emulsion composition having a liquid crystal structure which is characterized by blending the compound of the present invention, can be easily confirmed by observing a maltase cross image with a polarizing microscope.
  • the liquid crystal structure can be confirmed by a transmission electron microscope (TEM) using a resin foam-embedded ultrathin cutting method or a frozen section method.
  • the present invention contains physiologically active components including the compound of the present invention, and has a strong whitening effect, free radical inhibitory effect, anti-wrinkle effect, anti-acne action, moisturizing action, barrier function enhancing action, ultraviolet ray-derived inflammation It exhibits inhibitory action, anti-decubitus action, etc. and is highly safe with low irritation, useful as cosmetics, quasi drugs, feed additives, food additives, pharmaceuticals, veterinary drugs, aquatic animal drugs A composition for external use can be provided.
  • the present invention contains a strong whitening action, free radical inhibiting action, anti-wrinkle action, anti-acne action, moisturizing action, barrier function enhancing action characterized in that it contains an ascorbic acid derivative that is a compound of the present invention as an active ingredient.
  • the present invention provides a composition for external use, which has an ultraviolet ray-derived inflammation-inhibiting action and an anti-decubitus action, is stable, has low irritation and high safety, and includes cosmetics, quasi drugs, pharmaceuticals, veterinary drugs, and aquatic animal drugs. be able to.
  • the compound of the present invention has a comprehensive evaluation that summarizes the results of titer change, tissue absorption, enzymatic degradation and antioxidant activity of skin tissue homogenate, and skin irritation.
  • the present invention exerts an extremely useful action in the industry as compared with the conventionally known vitamin C and vitamin E derivatives. Further, from the results of the effect test and skin irritation test described in the following examples, it is understood that the concentration of the compound of the present invention in the preparation is suitably within the range of 0.000001 to 0.1% by weight.
  • the effective concentration range in the preparations of the present invention is kojic acid, arbutin, sodium L-ascorbate, methyl L-ascorbate, ethyl L-ascorbate, L-ascorbic acid-2-glucoside, L-ascorbic acid-2-phosphate-6-palmitate 3Na, isostearyl ascorbyl phosphate 2Na, ellagic acid, resorcinol, L-cysteine, hydroquinone, tranexamic acid have an effective formulation concentration in the range of 0.1 to 10.0% by weight Compared to 100 times to 100000 times, it has a surprisingly strong effect.
  • MP-Biomedicals D- ⁇ -tocopherol (50% by weight), MP-Biomedicals D- ⁇ -tocopherol (5% by weight), Kanto Chemical Co. rac- ⁇ -tocopherol-tocopherol (5% weight), Kanto Chemical D- ⁇ -tocopherol (5% weight), Kanto Chemical rac- ⁇ -tocopheroltocopherol (5% weight), MP Biomedicals D - ⁇ -tocopherol (5% by weight), Sigma-Aldrich ⁇ D- ⁇ -tocotrienol (5% wt), Sigma-AldrichD D- ⁇ -tocotrienol (5% wt), D- ⁇ -tocotrienol (5% by weight) manufactured by Sigma-Aldrich®, D- ⁇ -tocotrienol (5% by weight) manufactured by Sigma-Aldrich®, D- ⁇ -tocotrienol (5% by weight) manufactured by Sigma-Aldrich®, D- ⁇ -tocotrienol (5% by weight) manufactured by Sigma-Aldrich
  • 5,6-Isopyridene-vitamin C-3-acetyl diester vitamin E (0.04 g, 0.058 mmol) prepared in the previous section was dissolved in methanol (5 ml), and 2N HCl (0.1 ml) was added at 50 oC. Stir for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • the 5,6-isopyridene-vitamin C-2-acetyl diester vitamin E (0.069 g, 0.1 mmol) of the present invention prepared in the previous section is dissolved in methanol (5 ml) and THF (2 ml), and 2N HCl ( 0.16 ml) was added and the mixture was stirred at 50 ° C. for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Vitamin E (0.051 g, 0.079 mmol) was obtained as a white solid.
  • the 1 H NMR, 13 C NMR and IR of this compound are as follows.
  • L-ascorbic acid-3-acetyl diester-DL- ⁇ -tocopherol (0.022 g, 0.033 mmol) was obtained as a white solid.
  • the 1 H NMR, 13 C NMR, IR, and elemental analysis values of this compound are as follows.
  • the compound of formula 20 (1.06 g, 1.54 mmol) prepared in the previous section was dissolved in methanol (15 ml), 2N HCl (2.5 ml) was added, and the mixture was stirred at 50 ° C. for 2 hours.
  • the solid was collected by filtration using a Kiriyama funnel, the filtrate was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • the compound of Formula 22 (0.696 g, 1.01 mmol) was dissolved in methanol (15 ml), 2N HCl (1.62 ml) was added, and the mixture was stirred at 50 ° C. for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • L-ascorbic acid-3-acetyl diester-DL- ⁇ -tocopherol AA-3-DL- ⁇ -Toc.
  • 5,6-Isopyridene-ascorbic acid-2-acetyl diester-DL- ⁇ -tocopherol IP-AA-2-DL- ⁇ -Toc.
  • L-ascorbic acid-2-acetyl diester-DL- ⁇ -tocopherol AA-2-DL- ⁇ -Toc.
  • 5,6-Isopyridene-ascorbic acid-3-acetyl diester-D- ⁇ -tocopherol IP-AA-3-D- ⁇ -Toc.
  • L-ascorbic acid-3-acetyl diester-d- ⁇ -tocopherol AA-3-D- ⁇ -Toc.
  • 5,6-Isopyridene-ascorbic acid-2-acetyl diester-D- ⁇ -tocopherol IP-AA-2-D- ⁇ -Toc.
  • L-ascorbic acid-2-acetyl diester-D- ⁇ -tocopherol AA-2-D- ⁇ -Toc.
  • the names and abbreviations of the existing vitamin C derivative groups used for the controls are as follows.
  • liquid crystal emulsion Ascorbic acid-2-phosphate Na: AA-2-P Ascorbic acid-2-glucoside: AA-2-G Ascorbic acid-2-potassium sulfate: AA-2-S Ascorbic acid-3-methyl: AA-3-M Ascorbic acid-2-phosphate-6-palmitic acid Na: AA-2-P-6-Pal Ascorbic acid-2-phosphate tocopherol K: AA-2-P-Toc Ascorbic acid-2-tocopherol maleate Na: AA-2-M-Toc
  • liquid crystal emulsion The emulsion having the liquid crystal structure of the present invention (hereinafter abbreviated as “liquid crystal emulsion”) was produced by the following method.
  • the synthesized 12 kinds of the compound of the present invention, the paste prepared for liquid crystal emulsion containing 10% by weight of the 12 kinds of the compound of the present invention, and the existing control ascorbic acid derivative described above -Seven kinds of existing vitamin C derivatives used in the base and the simple substance of vitamin C and vitamin E are gel base made by ITO (composition contents: glycerin: 34.45%, carbomer: 1.13%, polyacrylic acid Na: 0.38 %, Water: 63.92%, methyl paraben: 0.09%, propyl paraben: 0.03%) and 1% by weight to obtain a dispersion.
  • the liquid crystal emulsion paste was mixed at 10% by weight to obtain the liquid crystal emulsion of the present invention.
  • 12 types of this liquid crystal emulsion were appropriately diluted with purified water and observed with a polarizing microscope, a maltase cross image was obtained.
  • the results of the presence or absence of a maltase cross image at the time of observation with a polarizing microscope are shown in Table 1. This confirmed that the 12 types of emulsions were emulsions having a liquid crystal structure.
  • Each test substance obtained is stored at 40 ° C. for 6 months, and each titer is measured three times by high performance liquid chromatography.
  • vitamin C and vitamin E alone were used to measure percutaneous absorption into skin tissue. Twelve types of vitamin C derivatives of the present invention and four types of control vitamin C derivatives were mixed at 1% by weight with a polyacrylic acid gel base material manufactured by ITO Co. to obtain a dispersion. These gel dispersions were applied to a human three-dimensional epidermis model having a stratum corneum and a stratum corneum in an amount of 0.1 g per square centimeter, and this was cultured at 37 ° C.
  • B16 melanoma 4A5 was seeded in a 48-well microplate, cultured in DMEM medium containing 10% FBS under conditions of 37 ° C and 5% CO2 for 24 hours, and then an ascorbic acid derivative equivalent to 100 ⁇ mol / LM (present invention) And an ascorbic acid derivative of control) and a DMEM medium containing 10% FBS supplemented with 1 mmol / LM theophylline (same as above), and cultured at 37 ° C. under 5% CO 2 for 72 hours. After completion of the culture, the medium was removed and replaced with purified water, and the cells were crushed with ultrasound, and then divided into two for melanin quantification and protein quantification.
  • the cell disruption solution was solubilized in 1 mol / LN NaOH at 60 ° C. for 30 minutes, and the absorbance at 405 nm was measured with an absorptiometer. Protein quantification was performed at 37 ° C. for 30 minutes using Pierce BCA protein assay kit, and the absorbance at 570 nm was measured with a spectrophotometer (same as above). The absorbance of melanin and protein thus obtained was divided and used for calculation of the melanin production inhibition rate as the amount of melanin per unit protein.
  • the calculation formula for determining the melanin production inhibition rate is expressed as follows. It is shown by the following formula.
  • the ascorbic acid derivative of the present invention clearly demonstrates superior effects compared to the conventional control ascorbic acid derivative, based on the above-mentioned three tests, the skin tissue absorbability test and the melanin production inhibition test. It was confirmed.
  • AA-2-M had a lower melanin production inhibitory effect than the vitamin C derivative of the present invention was considered to be because the result of absorption to the skin was ⁇ , which was clearly inferior to the derivative of the present invention.
  • the vitamin C derivative of the present invention was higher.
  • the melanin production inhibitory action of the present invention was higher than that of the existing AA-2-P-Toc derivative because the phosphate-mediated diester derivative is not very stable, It has been found that the hydrolysis action by phosphatase is extremely difficult, and it was estimated that the ascorbic acid activity in the living body was lower than that of the derivative of the present invention.
  • Toxicity test for melanin-producing cells Toxicity tests on melanin-producing cells were performed using the 12 kinds of synthesized compounds of the present invention and a control whitening agent.
  • Mouse B16 mouse melanoma 4A5 cells B164A5 were used for the toxicity test on melanin producing cells.
  • B16 melanoma 4A5 is seeded in a 48-well microplate, cultured in DMEM medium containing 10% FBS under conditions of 37 ° C and 5% CO2, for 24 hours, and then ascorbic acid derivative equivalent to 1 mmol / LM of the present invention And 10% FBS-containing DMEM medium (same as above) for a whitening agent other than the existing vitamin C derivative to be compared and a control containing no medium components alone, and 72% under conditions of 37 ° C and 5% CO2. Time culture was performed.
  • the medium was replaced with DMEM medium containing 10% FBS containing 0.5 mg / mL MTT (same as above), and after 3 hours of culture, the medium was replaced with 0.04 mol / LN HCl / IPA to lyse the cells.
  • the cell lysate was measured for absorbance at 570 nm using an absorptiometer, and the cell growth rate was calculated.
  • the cell growth rate is expressed by the following formula, where the absorbance of cells treated with the sample is MTTs, and the absorbance of cells without added sample is expressed as MTTc.
  • Cell growth rate (%) ((MTTs / MTTc) -1) x 100
  • those having a positive cell growth rate relative to the whitening agent-free control Toxicity to cells is evaluated as negative, and those with a cell growth rate of 0 or a negative value (cells that do not grow at all, or conversely that cells are moribund and decreased) have a cytostatic effect.
  • the cytotoxicity was evaluated as positive.
  • the compound of the present invention was highly safe because it had a melanin inhibitory effect on pigment cells, but no toxicity to pigment cells such as a cell death promoting effect was observed.
  • a whitening agent containing existing natural phenols has a considerable inhibitory effect on pigment cells, and apparently the safety against pigment cells is inferior to that of the compound of the present invention.
  • Free vitamin C and vitamin E converted from derivatives are known to reduce cytotoxicity. Since these positive control compounds are highly toxic to pigment cells, the probability of developing erythema or vitiligo in the skin tissue increases, so the value of products containing them is remarkable. It is to reduce.
  • the compound of the present invention has low toxicity to pigment cells, and has been shown to be efficiently taken up into cells and express vitamin C and vitamin E activity at a high rate, such as cosmetics and topical medicines. Increased commercial value as a composition for external use, oral composition such as food additive and feed additive, radical disease therapeutic agent for humans and animals, cell growth promoting composition, antioxidant composition And proved its effectiveness. .
  • the cell lysate was measured for absorbance at 570 nm using an absorptiometer, and the cell growth rate was calculated.
  • the cell growth rate is expressed by the following formula, where the absorbance of cells treated with the sample is MTTs, and the absorbance of cells without added sample is expressed as MTTc.
  • Cell increase rate (%) ((MTTs / MTTc) -1) x 100 As a result, the cell increase rate after 3 days with respect to the control was measured and calculated. Those reduced are shown in Table 5 with a cross. For comparison, existing derivatives and vitamin C were used as control derivatives.
  • the vitamin C derivative of the present invention was cultured under conventional cell culture conditions for 3 days, the number of cells increased to a minimum of 30% or more compared to the additive-free control compared to the additive-free control.
  • Free forms of vitamin C and vitamin E converted from derivatives are known to increase cell growth rates. These control compounds represented by X are extremely low in cell growth rate, and thus markedly reduce the value of the products containing them.
  • the compound of the present invention has a cell growth rate. Is highly incorporated into cells and efficiently expressed in vitamin C and vitamin E, and is used for oral compositions such as cosmetics and topical medicines, food additives and feed additives. It increased the commercial value as a composition, a therapeutic agent for radical diseases for humans and animals, a cell growth promoting composition, and an antioxidant composition, and proved its usefulness and effectiveness. .
  • the cell growth rate was clearly inferior for the two types of controls, AsA-3-M and AA-2-P-Toc, as compared to all 12 derivatives of the present invention.
  • the conventional vitamin C derivative is good in stability, it is considered that the conversion rate of vitamin C in cells is poor.
  • Free forms of vitamin C and vitamin E converted from derivatives are known to increase cell growth rates.
  • These control compounds indicated by X are extremely low in cell proliferation rate, and thus significantly reduce the value of the products containing them, whereas the compounds of the present invention have a cell proliferation rate. It is highly incorporated into cells and is shown to express vitamin C and vitamin E activity at a high rate.
  • Oral compositions such as cosmetics and topical medicines, and food and feed additives. Products, human and animal radical disease therapeutic agents, cell growth promoting compositions, and antioxidant compositions, increasing their commercial value and proving their usefulness and effectiveness.
  • Ascorbic acid derivative of the present invention is clearly compared with the ascorbic acid derivative of the conventional control by the above four tests of stability test, skin tissue absorbability test, melanin production inhibition test and cell growth rate promotion test. It was confirmed that an excellent effect was exhibited.
  • the reason why the cell growth rate of AA-2-M was lower than that of the vitamin C derivative of the present invention was that the result of absorption to the skin was ⁇ , which was clearly inferior to the derivative of the present invention.
  • the amphiphilic performance is lower than that of the vitamin C derivative of the present invention, and the ability to permeate the skin barrier consisting of a multilayer of fat-soluble and water-soluble barrier This is probably because the vitamin C derivative of the present invention was higher.
  • the derivative of the present invention has a higher cell growth rate than the existing AA-2-P-Toc derivative because the phosphate-mediated diester derivative is extremely stable, It has been found that the hydrolysis action by phosphatase is extremely difficult, and it was estimated that the ascorbic acid activity in the living body was lower than that of the derivative of the present invention.
  • Some vitamin C derivatives that are enzymatically hydrolyzed with ascorbic acid are known to have high collagen production in fibroblasts, which is higher than FGF (fibroblast growth factor). There are also reports.
  • the compound of the present invention has a higher stability than the existing vitamin C derivative and does not have a phosphoric diester structure having a low enzymatic hydrolysis action such as AA-2-P-Toc, AA-2- It was presumed to have higher ability to suppress melanin production and fibroblast proliferation than P-Toc.
  • the compound of the present invention has a promoting effect on fibroblast proliferation, but no inhibitory action was observed, and thus high safety was recognized.
  • Table 6 shows ⁇ for those improved by 30% or more, ⁇ for those improved by 10% or more but less than -30%, and ⁇ for those less than 10%.
  • the vitamin C derivative and vitamin C of the present invention were improved by 30% or more in all test items compared to the gel base group to which the same amount of the placebo gel base material and the control derivative were added. It was possible to confirm the effect of the vitamin C derivative of the present invention. The same analysis was performed on the redness area, the number of porphyrin spots, the number of pores, and the number of wrinkles using a facial image analyzer (VISIA and Roboscan analyzer). Yes, all of the control derivatives in Table 6 in the control section were X.
  • the compound of the present invention has a high clinical effect, is efficiently taken into cells and expresses vitamin C and vitamin E activity at a high rate, and a composition for external use such as cosmetics and external medicines, It increased the commercial value of human and animal radical disease therapeutic agents, cell growth promoting compositions and antioxidant compositions, and proved their usefulness and effectiveness.
  • the increase in acne, blemishes and wrinkles has also been reported to be due to the promotion of lipid peroxidation in the epidermis, which is a category of radical disease. Since it can be suppressed by an antioxidant composition such as vitamin E, it is considered that the use of the compound of the present invention resulted in good clinical results.
  • the cell lysate was measured for absorbance at 570 nm using an absorptiometer, and the cell growth rate was calculated.
  • the cell growth rate is expressed by the following formula, where the absorbance of cells treated with the sample is MTTs, and the absorbance of cells without added sample is expressed as MTTc.
  • Cell increase rate (%) ((MTTs / MTTc) -1) x 100
  • vitamin C and vitamin E are already known to reduce the temperature stress of cells, the present results show that the compound of the present invention is efficiently incorporated into cells and vitamin C and vitamin E at a high rate. It has been shown to exhibit activity, and external compositions such as cosmetics and external medicines, oral compositions such as food additives and feed additives, therapeutic agents for radical diseases for humans and animals, cell growth promoting compositions, It increased the commercial value as an antioxidant composition and proved its usefulness and effectiveness. .
  • Example A 1.0 g of a trade name “Dexon” manufactured by Davis & Greck, which is a suture made of a PGA polymer, was immersed in the 1% weight aqueous solution of the present invention shown in Table 8 and then taken out. It was. After air drying, a suture thread as an example of the water-absorbing polymer composition used in the present invention was obtained. For comparison, a compound that did not immerse the compound of the present invention and a compound containing the same amount of existing L-ascorbic acid-2-glucoside were used for comparison.
  • the back of a 10-week-old guinea pig was shaved, and a 2 cm long cut was made with a scalpel in a direction perpendicular to the midline of the back.
  • the wound was repaired by absorbing the water used in the present invention at five locations at regular intervals.
  • a strip of cutaneous tissue with a width of 1 cm was cut from the center of the incision to the left and right from the center of the incision under ether anesthesia, and the tensile strength (g / cm) of the incision using a rheometer was measured.
  • the tensile strength was greatly increased in the compound of the present invention. From these results, it was considered that the compound of the present invention showed a significant increase in the tensile strength, and thus the collagen synthesis was promoted well, the cell proliferation of the tissue was promoted, and the wound healing effect was expressed.
  • the wound healing effect by increasing the tensile strength of the tissue is recognized even when the compound of the present invention is administered orally, and can be expected to be highly effective as a food additive or a feed additive. Since it is known to enhance healing, the present results indicate that the compound of the present invention is efficiently taken into tissues and expresses vitamin C and vitamin E activities at a high rate.
  • the compound of the present invention is a composition for external use such as cosmetics and external medicines having wound healing effect by cell proliferation, oral composition such as food additives and feed additives, therapeutic agents for radical diseases for humans and animals, cells It increased the commercial value as a growth promoting composition and an antioxidant composition, and proved its usefulness and effectiveness. .
  • Example 8 A cell growth promoting composition having a wound healing effect by cell proliferation is shown below.
  • 0.1 parts by weight of each of the compounds of the present invention shown in Table 9 is 84 parts by weight of polybutylene succinate PBS (Bionore 1001, Showa High Polymer), polyethylene terephthalate PET (Dianite PA-). 500 parts by Mitsubishi Rayon) and 1 part by weight of ethylene glycidyl methacrylate copolymer E-GMA (reactive compatibilizer, Bondfast E, manufactured by Sumitomo Chemical Co., Ltd.), respectively.
  • polybutylene succinate PBS Bionore 1001, Showa High Polymer
  • polyethylene terephthalate PET Dianite PA-
  • E-GMA reactive compatibilizer, Bondfast E, manufactured by Sumitomo Chemical Co., Ltd.
  • Example 10 A cell growth promoting composition having a wound healing effect by cell proliferation is shown below.
  • 10% by weight of hydroxyapatite (HA) prepared by spray-drying to a particle size of about 50 ⁇ m in an aqueous solution containing 1% by weight of a sodium alginate aqueous solution and 1% by weight of the compound of the present invention described in Table 10 in the previous section.
  • This slurry was formed into a spherical shape by dropping 3 ⁇ l each into a 1% by weight calcium chloride aqueous solution.
  • the spherical HA molded as described above was dried at 60 ° C. for 12 hours and then sintered at 1250 ° C.
  • 1 was obtained by sterilizing an aqueous solution prepared by dissolving 10% by weight of each of the aqueous emulsified and dispersed preparations prepared in the above examples in ultrapure water by vacuum decompression of the porous spherical aggregate particles using a 0.2 ⁇ m membrane filter. 1 was added, and then freeze-dried to obtain porous spherical aggregate particles for bone repair, which is an example of the water-absorbing polymer composition of the present invention containing the compound of the present invention. It was.
  • the self-hardening calcium phosphate cement paste mixed with the aggregate particles so as to be 80 vol% is kneaded so that bubbles are taken into the paste, and CT data of the bone defect portion is obtained.
  • a calcium phosphate porous body having a bone defect site shape which is an example of the water-absorbent polymer composition used in the present invention, could be obtained.
  • macropores of about 100 ⁇ m and micropores of several microns were distributed.
  • the macropores are connected by micropores in the adjacent aggregate particles to form a communication hole network.
  • the healing speed is greatly improved in the compound of the present invention.
  • the compound of the present invention has increased the commercial value as a cell proliferation promoting composition having a wound healing effect by cell proliferation, and proved its usefulness and effectiveness.
  • Soybean oil was bottled, sealed and stored to obtain 12 types of soybean oil.
  • the obtained 12 kinds of soybean oil can be used as health food for preventing adult diseases.
  • This edible oil has a heat stress reducing effect, so it is not only for humans but also useful livestock such as cattle, horses, chickens, pigs, fish, shrimp, crab, abalone, silkworm, frogs, dogs, cats, It could also be used to increase the production of tropical fish, guinea pigs, mice, monkeys, earthworms, beer yeast, baker's yeast economic animals and economic microorganisms.
  • Example. Biscuit-type nutrition-enriched food and animal feed and its production method 100 kg of flour, 15 kg of margarine, 4.5 kg of flavoring additives, 7.0 kg of sugar, 2.3 kg of salt, 0.58 kg of edible soda, Carbon-ammonium salt 4 kg, citric acid 0.021 kg, starch 5 kg, and IP-AA-3-VE, AA-3-VE, IP-AA-2-VE, AA-2-VE, IP of the present invention -AA-3-dl- ⁇ -Toc, AA-3-dl- ⁇ -Toc, IP-AA-2-dl- ⁇ -Toc, AA-2-dl- ⁇ -Toc, IP-AA-3-d Add 0.01kg each of 12 kinds of compounds- ⁇ -Toc, AA-3-d- ⁇ -Toc, IP-AA-2-d- ⁇ -Toc, AA-2-d- ⁇ -Toc and mix well did. Subsequently, the mixture was shaken and formed into a biscuit shape, and then baked in an electric oven for 5 minutes to produce 12 types
  • scalp care cosmetics 12 types of scalp care cosmetics comprising the compounds of the present invention listed in Table 11 were prepared to have the following composition% weight of% weight: : About 10% isopropyl palmitate, about 3% (hereinafter weight percent) concentrated phosphatide with lecithin, about 3% bentonite clay, about 2% keratin hydrolysate, about 2% silicone wax, about An emulsified aqueous solution containing 0.5% ⁇ -tocopherol oil essence, about 0.5% fragrance, and 0.1% of each of the 12 compounds of the present invention listed in Table 11 and 1% surfactin, About 0.5% preservative, the rest being moisture.
  • the scalp care cosmetics containing the compound of the present invention made the skin healthy, promoted hair growth, revived hair and eliminated dandruff.
  • Vitamin C and vitamin E are known for their hair elongation effect.
  • the composition of the present invention was orally administered, the hair elongation was recognized in the same manner. Therefore, it was found that the composition was effective as an oral composition for hair elongation.
  • the results show that the compound of the present invention is efficiently taken into the skin tissue from the hair epidermis and expresses vitamin C and vitamin E activity at a high rate. Enhance the commercial value of oral compositions such as additives and feed additives, therapeutic agents for radical diseases for humans and animals, cell growth promoting compositions and antioxidant compositions, and prove their usefulness and effectiveness. It was a thing.
  • Vitamin C and vitamin E are known to prevent and treat sunburn.
  • many free radicals are produced in sunburn, and the oxidation of sebum on the skin is promoted, and these oxidized sebum becomes lipid oxides and damages cells.
  • the composition of the present invention was orally administered, it was found that the composition was also effective as an oral composition for tanning because it similarly showed prevention and treatment effects against sunburn.
  • Examples of external compositions such as cosmetics and external medicines are shown below.
  • Examples of water-soluble drugs and skin lotions shown below in% weight) 6% glycerin, 1% betaine, 1,3-butylene glycol: 5%, 0.5% phenoxyethanol, IP-AA-3-VE, AA-3-VE, IP-AA-2-VE, AA-2 of the present invention -VE, IP-AA-3-dl- ⁇ -Toc, AA-3-dl- ⁇ -Toc, IP-AA-2-dl- ⁇ -Toc, AA-2-dl- ⁇ -Toc, IP-AA Add 0.01% each of 12 compounds of -3-d- ⁇ -Toc, AA-3-d- ⁇ -Toc, IP-AA-2-d- ⁇ -Toc, AA-2-d- ⁇ -Toc Finally, purified water was added to make 100%.
  • emulsions and emulsions (1) Polyoxyethylene (10E.O.) sorbitan 1.0 monostearate: 0.5, (2) Polyoxyethylene (60E.O.) sorbit 0.5 tetraoleate : 0.5, (3) Glyceryl monostearate: 1.0, (4) F3: 0.1, (5) Behenyl alcohol: 0.5, (6) Squalane: 8.0, ( 7) Carboxyvinyl polymer: 0.1, (8) Phenoxyethanol: 0.5%, and IP-AA-3-VE, AA-3-VE, IP-AA-2-VE, AA-2-VE of the present invention , IP-AA-3-dl- ⁇ -Toc, AA-3-dl- ⁇ -Toc, IP-AA-2-dl- ⁇ -Toc, AA-2-dl- ⁇ -Toc, IP-AA-3 0.01% of each of 12 types of compounds, -d- ⁇ -Toc, AA-3-d- ⁇ -Toc, IP-AA-2-d-d
  • Example 18 Examples of external detergents, facial cleansers, body shampoos. (Prescription) (%) (1) stearic acid: 10.0, (2) palmitic acid: 8.0, (3) myristic acid: 12.0, (4) lauric acid: 4.0, (5) oleyl alcohol: 1.
  • Example 19 The lotion of the present invention of the above embodiment of the present invention and the lotion of the subject area obtained by removing the 12 compounds of the present invention from the lotion of the present invention were prepared, and the stability test was conducted at 40 ° C. for 6 months. went. In the evaluation of the stability test, the color change of the preparation, the occurrence of precipitation, and the generation of odor were evaluated with the following scores, and the average score was obtained and compared. The evaluation was performed by 10 men and women from 20 to 50 years old, and the average score was obtained.
  • test group injection solution composed of the 12 compounds of the present invention prepared in the examples and 0.1% of L-ascorbic acid-2-phosphate Na are blended.
  • target group injection solution the injection solution of the control group prepared by the production method
  • the effects of the therapeutic agent for radical disease of the present invention were compared and confirmed by the following experiment.
  • the rat was thoracotomized and the left anterior descending coronary artery was ligated for 15 minutes before resuming blood flow.
  • the test group injection solution which is the pharmaceutical composition of the present invention at 5 mg (total compound weight) / kg ⁇ body weight, was previously administered intravenously to the rat as a test group 24 hours before the coronary artery occlusion, and the control group injection solution was used as the control group.
  • the test group injection solution which is the pharmaceutical composition of the present invention at 5 mg (total compound weight) / kg ⁇ body weight, was previously administered intravenously to the rat as a test group 24 hours before the coronary artery occlusion, and the control group injection solution was used as the control group.
  • free radical radical-dependent chemiluminescence in peripheral blood after coronary artery occlusion was measured by chemiluminescence, and a significant increase in radicals was confirmed immediately after reperfusion.
  • the test group injection solution which is a free radical-related disease drug of the present invention of 5 mg (total compound weight) / kg ⁇ body weight of the present invention, was intravenously administered to the rat 24 hours before the rat coronary artery blockage in advance.
  • the injection solution was injected in the same manner as in the test group.
  • the blood amylase level in the control group was significantly higher than the level before blocking, and an individual having a maximum of 7000 U / dl was clearly observed.
  • the blood amylase level in the test group administered with 1100 U / dl at the maximum was slightly higher than that in the control group, although it was slightly higher than that in the control group. The effect on the therapeutic agent for radical disease of the present invention was proved.
  • the urinary protein level in the control group was significantly higher than the level before blocking, and the pathological condition of renal disease was clearly observed.
  • the urinary protein level in the test group administered with the urine was slightly higher than that in the control group compared to the normal state before blocking, but it was significantly lower than that in the control group. The effect on therapeutic drugs has been proven.
  • test for organ failure Systemic ischemia was applied for 5 minutes by the rat coronary occlusion model, and blood flow was resumed.
  • radical-dependent chemiluminescence in peripheral blood was measured by chemical luminescence manufactured by Showa Denko before the experiment, a significant radical increase was confirmed immediately after resumption of blood flow.
  • the test group injection solution of 5 mg (total compound weight) / kg ⁇ body weight of the present invention was intravenously administered to the rat in advance as a test group 24 hours before the rat coronary artery blockage, and only the target group injection solution as the control group was the same as the test group. Injected into.
  • oral compositions for animals are as follows: Corn 75% (% is weight percentage), soy flour (CP45%) 20%, calcium phosphate 1.5% and appropriate amount of inorganic mixture, yeast, ascorbic acid and vitamin E
  • the compound of the present invention was added to the composition containing the total vitamin mixture excluding the varieties so that the ratio of each of the compounds of the present invention was 100 ppm with respect to the composition, and the mixture was sufficiently stirred with a normal pelleter machine. It was molded by heating (maximum temperature of 100 ° C.) and dried (maximum temperature of 82 ° C.) to prepare an oral stress relieving composition of the present invention. This is hereinafter referred to as test zone feed.
  • This composition can be used for pets such as dogs and cats, ornamental fish such as tropical fish and goldfish, livestock such as pigs, cattle, horses and sheep, poultry such as chickens and quail, hamachi, thailand, pufferfish, flounder, It can be used as an oral composition typified by feed additives such as fish for aquaculture such as tuna, salmon, salmon, trout, salmon and salmon, shellfish such as shrimp and salmon, and shellfish, and feed.
  • feed additives such as fish for aquaculture such as tuna, salmon, salmon, trout, salmon and salmon, shellfish such as shrimp and salmon, and shellfish, and feed.
  • L-ascorbic acid-2-phosphates (Stay C manufactured by DSM Co.) marketed as a feed additive were used in the same manner as in the test plot feed.
  • a feed prepared by blending and production was prepared in the same manner as in Example 2. That is, corn 75% (% is the weight percentage), soybean flour (CP45%) 20%, calcium phosphate 1.5%, L-sodium ascorbate 0.5%, and a proper amount of inorganic mixture, yeast, and ascorbic acids A vitamin mixture was added, and the well-stirred one was heat-molded with an ordinary pelleter machine and dried to obtain a control feed.
  • thermoforming and drying of the feed were carried out to improve feed efficiency, reduce germs in the feed, and reduce livestock dust, but the conditions were about 70 degrees Celsius for the maximum product temperature in the pelleter.
  • Test preparation 5 of the present invention 100 30-day-old male pigs of Landrace x Yorkshire were divided into 10 groups of 10 each (2 groups of 20 heads of equal weight were set as 1 test group). A seed test was conducted. The test group feed was given to 10 groups of 1 test group, and the control group feed was fed to the other 10 groups. These pigs were raised with the same vitamin C-free commercial feed until 23 days of age except the lactation and weaning periods.
  • test group feed was mixed with the non-added general feed once every morning so that 0.02 mmol (total) of the compound of the present invention was orally administered per kg of body weight per day. .
  • Body weight was measured once a week to adjust the amount of feed contained.
  • the test group feed was fed and reared so that 0.02 mmol (total) of the existing L-ascorbic acid-2-phosphate was orally administered.
  • the pigs were moved to another piggery and reorganized in order to keep their weight at the same time. This movement and reorganization work causes stress on pigs, and problems such as a decrease in weight gain have been confirmed from past cases.
  • the enzyme activity was determined by spectroscopically measuring the change in absorbance of NADH at 30 ° C. at 340 nm.
  • the total amount of the enzyme reaction solution is 3.0 ml, and the overall configuration is as follows.
  • LDH and MDH 200 mM Tris buffer, 1.0 ml (final concentration, 67 mM), 5 mM NADH, 0.1 ml (0.17 mM), 30 mM KCl, 0.1 ml (1 mM), 30 mM 2-mercaptoethanol (2-ME), 0.1 ml, substrate (pyruvic acid for LDH; oxaloacetate for MDH) 0.3 ml (sufficient amount, 5-10 mM), water 1.3 ml and plasma preparation 0.1 ml Set to 3.0 ml.
  • AspAT 200 mM Tris buffer 1.0 ml, 5 mM NADH, 0.1 ml, 30 mM KCl, 0.1 ml, 30 mM 2-ME, 0.1 ml, 20 mM ⁇ -ketoglutarate 0.3 ml, auxiliary enzyme (MDH) 0.1 ml, 50 mM aspartic acid 0.3 ml, water 0.9 ml and plasma preparation 0.1 ml are added to make a total of 3.0 ml.
  • MDH auxiliary enzyme
  • Stress protein measurement method The molecular weight of the stress protein in plasma, the number of molecular species, and the abundance of each molecular species were mainly measured using a gel-stained electrophoretic diagram of SDS-PAGE gel. In particular, the abundance of each protein was determined by using a gel scanner to determine the relative ratio from the absorbance. Electrophoresis was performed within the range in which SDS-PAGE electrophoresis conditions were not changed depending on the type of plasma preparation from various animals, and they were compared with each other.
  • the average values of the LDH, MDH, AapAT, stress protein, and body weight increase rates in blood and the values of the respective target sections corresponding thereto were determined, and the ratios to the target sections of the present invention were determined by the following formulas, and the effects were compared.
  • the average values of LDH, MDH, AspAT, and stress-ptothein in the blood of the test group feed administration of the present invention were significantly decreased by 11.9% or more compared to that of the control group, confirming the effect of the present invention. did it.
  • the target group feed was prepared by the same manufacturing method and composition as described above. In the test section, the test group and the control group of cattle were transported over 500 km by truck at the start of the test, and then each feed was freely fed for 60 days.
  • test for dogs A pure beagle dog with an average weight of 8.7 kg, 6 females and 6 males, a total of 12 females, divided into 2 groups of 3 males and 3 females for the test group and the control group (3 males and 3 females).
  • the test group was fed with a free-feeding stress-reducing feed composition in which 1% by weight of the test group feed was added to general beagle dog feed.
  • the control group feed was added 1% by weight to a general beagle dog feed and was freely fed.
  • the test was carried out for 30 days in an open barn installed outdoors in the hot summer season.
  • the prescription for the control group was produced by the same production method after adding 1% by weight of the target group feed with the same composition.
  • non-liquid crystal emulsion paste A ′ containing 12 kinds of compounds of the present invention.
  • 0.1 g of each of the 12 kinds of compounds of the present invention described in Table 15 and 0.1 g of the surfactants of the surfactant group described below are mixed, and sodium cocoyl glutamate is added to make a total amount of 5 g with an electric mixer.
  • Mix well for 1 minute mix 0.1 g each of water-soluble substances in the water-soluble substance group, add glycerin to a total of 20 g, mix well for 3 minutes with an electric mixer, and make this mixture B.
  • 0.1 g of each lipid of the following lipid group is taken and heated to 80 ° C., 5 g of cholesterol is mixed and dissolved, and jojoba oil is added thereto to make a total mixture of 20 g of lipid.
  • each water-soluble substance in the water-soluble substance group was mixed, and further glycerin was added to make a total of 15 g, which was a water-soluble substance mixture.
  • 0.1 g of each lipid of the following lipid group was taken and heated to 80 ° C., 5 g of cholesterol was mixed and dissolved, and jojoba oil was added thereto to make a total mixture of 20 g of lipid.
  • 5 g of the surfactant mixture, 15 g of the water-soluble mixture and 20 g of the lipid mixture prepared above were put into an electric mixer at a time and mixed for 3 minutes to obtain a paste B ′ for non-liquid crystal emulsion for comparison.
  • Water-soluble substance group Glycerin, diglycerin, triglycerin, polyglycerin, methylbutanediol, butylene glycol, isoprene glycol, polyethylene glycol, pentanediol, hexanediol, propylene glycol, dipropylene glycol, polypropylene glycol, ethylene glycol, diethylene glycol, neopentyl glycol, polyethylene Glycol, sorbitol, xylitol, pyrrolidone carboxyl sodium, hy
  • the liquid crystal emulsion compositions A and B of the present invention obtained a maltase cross image peculiar to the liquid crystal structure, and this emulsion composition had a multilayer capsule structure (vesicle structure). It was confirmed to be a liquid crystal emulsion. On the other hand, no maltase cross image was observed in the non-liquid crystal emulsions A ′ and B ′. When these emulsified compositions were stored at 40 ° C.
  • Antioxidant Group D
  • Kojic acid arbutin, sodium ascorbate phosphate, magnesium ascorbate phosphate, methyl ascorbate, ethyl ascorbate, sodium ascorbate sulfate, glucoside ascorbate, sodium palmitate ascorbate phosphate, sodium tocopheryl phosphate , (Ascorbyl / tocopheryl) phosphate K, tocopheryl ascorbyl maleate, caprylyl glyceryl ascorbate, hexyl glyceryl ascorbate, myristyl glyceryl ascorbate, glyceryl ascorbate, bisglyceryl ascorbate, diglyceryl ascorbate, isostearyl ascorbyl lin Sodium acid, Ascorbyl stearate, Ascorbyl palmitate, Ascolic dipalmitate Bill, ellagic acid, resorcinol, butyl res
  • This pasty mixture is referred to as an existing emulsifier oil paste E.
  • 12 types of paste C for liquid crystal emulsions of the present invention paste C ′ for non-liquid crystal emulsions containing 12 types of compounds of the present invention and 7 types of pastes for liquid crystal emulsions containing existing derivatives D and 12 types of paste C for liquid crystal emulsion of the present invention, the same amount of the existing emulsifier oil paste E is added to double the amount and mixed well with an electric mixer for 20 minutes.
  • a paste F for liquid crystal emulsion was obtained.
  • Purified water is added to each of the 43 types of pastes of C, C ', D, and F to make 100g, and stirred for 10 minutes with an electric hand mixer so that bubbles do not form. I got a thing.
  • This emulsified composition was subjected to a microfluidizer treatment to obtain an emulsified composition having an average particle diameter of 500 nm. Further, it was sterilized with a membrane filter having a 45 ⁇ m hole and sealed in a sterile vial. When this emulsion composition was observed with a polarizing microscope, a maltase cross image peculiar to the liquid crystal structure was obtained, and it was confirmed that this emulsion composition had a multilayer capsule structure.
  • the emulsion preparation prepared with the paste for non-liquid crystal emulsion containing 12 kinds of the compounds of the present invention did not show a decrease in titer by HPLC, but it was severely separated into two layers and lost commercial value. It was.
  • the results are shown in Table 16 below.
  • X was marked when no o was recognized.
  • X was marked when the smell was greatly recognized, and ⁇ was marked otherwise.
  • X was marked if the emulsification was clearly separated, and ⁇ was marked otherwise.
  • the force value test by HPLC those that remained 90% or more were marked with ⁇ and others with X.
  • ⁇ was marked for all ⁇ , and X was marked otherwise.
  • the number of acne was measured twice at the start of the test and 29 days later using a facial image analyzer (VISIA and Roboscan analyzer).
  • the effect of moisturizing the face was measured using a skin moisture measuring device. was measured. Comparison was made on the improvement rate for how many percentages were improved from the time of each experimental start.
  • the number of subjects in one test area was 8. As a result, an average value was obtained for each test section, and when the acne improvement rate and the water increase rate were significantly improved by 10% or more, it was marked as “good”, and otherwise X was marked.
  • the results are shown in Table 17.
  • liquid crystal emulsions of the present invention were all good in clinical trials as compared with liquid crystal emulsions added with existing derivatives.
  • liquid crystal emulsion of the present invention to which the existing emulsion was added showed very high stability as compared with the case of not adding it.
  • a composition for external use that has a barrier function enhancing action, an ultraviolet ray-derived inflammation suppressing action, an anti-decubitus action, a low irritation and high safety, and includes cosmetics, quasi-drugs, pharmaceuticals, veterinary drugs, and aquatic animal drugs.

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CN107998146A (zh) * 2017-12-29 2018-05-08 武汉市天辰生物科技有限公司 一种高效水产养殖用抗应激制剂及制备方法
BE1025922B1 (fr) * 2017-11-21 2019-09-19 Shanghai Lofty Brand Man Co Ltd Crème contour des yeux anti-rides et procédé de préparation de celle-ci
CN113337029A (zh) * 2020-02-18 2021-09-03 长佳国际股份有限公司 Eva发泡复合材料及eva制品
US20230048204A1 (en) * 2021-08-12 2023-02-16 Jiayin BAO Skincare product and multi-dimensional ascorbic acid serum formulation therefor

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CN114788791A (zh) 2017-06-23 2022-07-26 宝洁公司 用于改善皮肤外观的组合物和方法
BR102017014319A2 (pt) * 2017-06-30 2019-01-15 Natura Cosmeticos Sa composição cosmética de correção de tom de pele, uso de uma composição cosmética e método de correção de tom de pele em ambiente urbano
CN112437657A (zh) 2018-07-03 2021-03-02 宝洁公司 处理皮肤状况的方法
CN115843238B (zh) 2020-06-01 2025-06-10 宝洁公司 改善维生素b3化合物渗透到皮肤中的方法
US10959933B1 (en) 2020-06-01 2021-03-30 The Procter & Gamble Company Low pH skin care composition and methods of using the same

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Publication number Priority date Publication date Assignee Title
BE1025922B1 (fr) * 2017-11-21 2019-09-19 Shanghai Lofty Brand Man Co Ltd Crème contour des yeux anti-rides et procédé de préparation de celle-ci
CN107998146A (zh) * 2017-12-29 2018-05-08 武汉市天辰生物科技有限公司 一种高效水产养殖用抗应激制剂及制备方法
CN113337029A (zh) * 2020-02-18 2021-09-03 长佳国际股份有限公司 Eva发泡复合材料及eva制品
US20230048204A1 (en) * 2021-08-12 2023-02-16 Jiayin BAO Skincare product and multi-dimensional ascorbic acid serum formulation therefor

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