WO2007077770A1 - Glycoside d’alkylresorcinol, son procede de production et son utilisation - Google Patents

Glycoside d’alkylresorcinol, son procede de production et son utilisation Download PDF

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Publication number
WO2007077770A1
WO2007077770A1 PCT/JP2006/325658 JP2006325658W WO2007077770A1 WO 2007077770 A1 WO2007077770 A1 WO 2007077770A1 JP 2006325658 W JP2006325658 W JP 2006325658W WO 2007077770 A1 WO2007077770 A1 WO 2007077770A1
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Prior art keywords
group
glycoside
alkylresorcinol
acid
butylresorcinol
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PCT/JP2006/325658
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English (en)
Japanese (ja)
Inventor
Takashi Shibuya
Ayashi Noguchi
Satoru Takayama
Yasuo Suemoto
Makoto Takeuchi
Masayuki Nakano
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Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo
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Priority to JP2007552917A priority Critical patent/JP5244400B2/ja
Publication of WO2007077770A1 publication Critical patent/WO2007077770A1/fr

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    • 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
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/602—Glycosides, e.g. rutin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides

Definitions

  • Alkylresorcinol glycoside its production method and use
  • the present invention relates to a novel 4-alkylresorcinol glycoside, a process for producing the same, and uses thereof. More specifically, 4-alkylresorcinol or a derivative thereof (excluding glycosides, hereinafter referred to as 4 alkylresorcinol in the present specification). And its derivatives (excluding glycosides) are sometimes referred to as “4 alkylresorcinols.”) 4 alkylresorcinol glycosides having one or two glycosyl groups bonded thereto, and The present invention relates to a production method and a composition containing the 4-alkylresorcinol glycoside.
  • 4 Alkylresorcinols prevent and improve skin pigmentation (Japanese Patent Laid-Open No. 2001-206813), whitening (Japanese Patent Laid-Open No. 2002-179516), and wrinkle suppression (Japanese Patent Laid-Open No. 2001-302506) ), And can be used as a component of an external composition for skin, and has antibacterial activity against bacteria that are involved in the development and deterioration of acne (Patent No. 2875374).
  • 4 n-butylresorcinol has already been used as an active ingredient in quasi-drugs for topical skin preparations.
  • alkylresorcinols generally have a number of problems, such as low solubility in water, difficult to handle, poor stability after dissolution, and irritation. Are inconvenient when used as pharmaceuticals, quasi-drugs, cosmetics, etc., and the development of methods for using these in stabilized, water-solubilized and low-stimulated derivatives is desired.
  • Japanese Patent Publication No. 7-36759 and Japanese Patent Application Laid-Open No. 2001-46096 propose a method for producing a glycoside using a glycosyltransferase.
  • JP-A-2002-179516 describes a whitening composition containing an alkylresorcinol derivative.
  • there has been no development of effective means for solving the drawbacks that have been an obstacle to the use of these alkylresorcinols and all of the above patent documents describe alkylresorcinol glycosides. Descriptions about the body are not allowed.
  • the present invention eliminates the drawbacks of alkylresorcinols, has excellent water solubility and stability, is substantially tasteless, odorless, has no irritation and has no fear of toxicity, and has physiological activity in vivo. It is an object of the present invention to provide an alkylresorcinol derivative that can sufficiently exhibit the above.
  • alkylresorcinol glycosides are water-soluble, stable, virtually tasteless, odorless, and less irritating.
  • alkylresorcinol glycosides are water-soluble, stable, virtually tasteless, odorless, and less irritating.
  • alkylresorcinol glycosides in large quantities at low cost by an organic synthesis method or an enzymatic method, particularly an enzyme method using glycosyltransferase, was found, and further, this alkylresorcinol glycoside was contained.
  • the caulked composition was established and the present invention was completed.
  • the alkyl resorcinol glycoside of the present invention is more stable than alkyl resorcinols, exhibits high water solubility, is odorless, odorless, less irritating, and less toxic. It is easily hydrolyzed in the body and exhibits the original physiological activity of alkylresorcinols. Further, the alkylresorcinol glycoside of the present invention can be blended at a high concentration in a composition such as a pharmaceutical, a quasi-drug, or a cosmetic, and the whitening effect of alkylresorcinols is a therapeutic effect against anti-sensitive diseases. It is possible to produce an excellent composition.
  • the method for producing an alkylresorcinol glycoside of the present invention is to produce an alkylresorcinol glycoside from an alkylresorcinol and, in particular, an inexpensive partial decomposition product of starch at a low cost in large quantities. Can do.
  • FIG. 1 is a diagram showing a UV absorption spectrum of a 4 n-butylresorcinol glycoside of the present invention.
  • FIG. 2 is a diagram showing an elution pattern of HPLC (using a CAPCELLPAK C18 AG120 column) of a 4-n-ptylresorcinol glycoside-containing preparation of the present invention prepared by a glycosyltransferase reaction using a glycosyltransferase.
  • FIG. 3 Reaction product of the present invention a (3—0—a D darcobilanosyl 4-n-butylresorcinol) and reaction product b (1-0-a-D-darcobilanosyl-4-n-butylresorcinol)
  • a 0—a D darcobilanosyl 4-n-butylresorcinol
  • reaction product b 1-0-a-D-darcobilanosyl-4-n-butylresorcinol
  • FIG. 4 is a diagram showing a 1 H-NMR ⁇ vector of a reaction product a (3-O-a-D-darcobilanosyl 4-n-butylresorcinol) of the present invention.
  • FIG. 5 Reaction product of the present invention a (3—0—a D darcoviranosyl 4-n-butyl methacrylate It is a figure which shows the C-NMR ⁇ vector of solcinol).
  • FIG. 6 is a diagram showing a H—H COZY spectrum of a reaction product a (3-0-a D darcoviranosyl-4-n-butylresorcinol) of the present invention.
  • FIG. 7 shows a C—H COZY spectrum of the reaction product a (3-0-a D darcoviranosyl-4-n-butylresorcinol) of the present invention.
  • FIG. 8 is a diagram showing a 1 H-NMR ⁇ vector of a reaction product b (1-0-a D darcobilanosyl-4-n-butylresorcinol) of the present invention.
  • FIG. 9 is a diagram showing a 13 C-NMR ⁇ vector of the reaction product b (1-0-a D darcobilanosyl-4-n-butylresorcinol) of the present invention.
  • FIG. 10 is a diagram showing a H—H COZY spectrum of a reaction product b (1-0-a D darcoviranosyl-4-n-butylresorcinol) of the present invention.
  • FIG. 11 is a diagram showing a C—H COZY spectrum of the reaction product b of the present invention (l—O—a—D-darcoviranosyl 4-n-butylresorcinol).
  • FIG. 12 is a diagram showing a remote C—H COZY spectrum of a reaction product b (1-0-a D darcoviranosyl-4-n-butylresorcinol) of the present invention.
  • FIG. 13 is an enlarged view of a part of the remote C—H COZY spectrum of the reaction product b (l—0—a D—Dalcoviranosyl 4-n-butylresorcinol) in FIG.
  • the 4 alkylresorcinol glycoside referred to in the present invention is a 4-alkylresorcinol glycoside having a glycosyl group bonded to either R or R of the 4 alkylresorcinol represented by the following general formula 1.
  • It may be a resorcinol glycoside, or in two places of the glycosyl basic forces R and R,
  • It may be a 4-alkylresorcinol glycoside bonded to each other, or a mixture of two or more of these glycosides.
  • R and R each independently represent a hydrogen atom or a glycosyl group
  • At least one of R is a glycosyl group, and R is a cyclic structure having 3 to 20 carbon atoms or
  • the 4-alkylresorcinol glycoside of the present invention may have a cyclic or branched structure in which the alkyl group has a carbon number of 3 to 20, preferably 4 to 18 substituted with an alkyl group, It may have 1 to 20 unsubstituted linear structures.
  • the cyclic structure is not limited to an aliphatic group such as an alkyl group or an alkenyl group.
  • an aromatic group such as a phenyl group is included as long as the portion directly bonded to resorcinol is an alkyl group. To do. Further, when such an aromatic cyclic substituent exists, the carbon number is counted including the carbon number of the aromatic substituent.
  • alkyl group having a cyclic or branched structure examples include a cyclopentyl group, a cyclohexyl group, a 2-phenylethyl group, an isooctyl group, an amyl group, an isoamyl group, an isobutyl group, a tertiary butyl group, and a 1-methylpropyl group.
  • Preferred examples include a group, 2-methylhexyl group or isostearyl group. Of these, preferred are those having a cyclic alkyl group, those having a branched alkyl group that is preferred by a less toxic cyclopropyl group, a good balance between effect and toxicity, and 1 methylpropyl.
  • Group or 1-methylbutyl group is preferred ⁇ .
  • the 1-ethylpropyl group or 1-isopropyl 2-methylpropyl group is preferable in that the effect of the present invention is remarkable, and it is preferable because the stability can be improved.
  • alkyl group having an unsubstituted linear structure examples include, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group. Group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group and eicosyl group. Of these, those having an alkyl group having 1 to 7 carbon atoms are particularly desirable butyl groups, which are desirable from the standpoint of their anti-inflammatory activity and their anti-inflammatory activity.
  • one or more of the hydrogen atoms of the alkyl group contains an oxygen atom such as a hydrocarbon group other than a methyl group, a carboxyl group, or a ketone group.
  • an oxygen atom such as a hydrocarbon group other than a methyl group, a carboxyl group, or a ketone group.
  • 4-alkylresorcinol glycosides in the presence of optical isomers, as long as they have the physiological activity of 4-alkylresorcinols such as antibacterial action and whitening action, One of them or a mixture of both may be used.
  • the glycosyl group bonded to the two hydroxyl groups of the alkylresorcinol of the 4 alkylresorcinol glycoside of the present invention is any one that can be bonded to the 4 alkylresorcinol by a synthesis method or an enzymatic method.
  • darcosyl group galactosyl group, fructosyl group, arabinosyl group, maltosyl group, isomaltosyl group, selbiosyl group, rabuinosyl group, gentiobiosyl group, codibiosyl group, laminaribiosyl group, -gerovosyl group, sambubiosyl group, neohebrosyl group
  • Examples of one or two types of forces selected from a peridosyl group, a cellotriosyl group, a glycerol group, or a gentiotriosyl group can be given.
  • a darcosyl group or a dalcosyl group desired by a malto-oligosyl group such as a maltosyl group is particularly desirable.
  • the 4 alkylresorcinol glycosides of the present invention were produced by combining methods such as organic synthesis methods, fermentation methods, enzymatic methods, and the like, which are not limited to the origins and production methods, and appropriate combinations thereof. It may be a thing. Specifically, an organic synthesis method in which acylyl sucrose is condensed with 4-alkylresorcinol in the presence of a peracid-silver catalyst and an enzyme method using a glycosyltransferase can be preferably exemplified.
  • the enzyme method in which a glycosyltransferase is allowed to act on a system containing 4-alkylresorcinols and ⁇ -glycosyl compounds is inexpensive in large quantities from 4 alkylresorcinols and inexpensive starches and partial hydrolysates thereof. Since an alkyl resorcinol glycoside can be produced, it is economical and can be advantageously used industrially.
  • alcohol and tertiary butyl alcohol are condensed with resorcinol at 200-300 ° C, 4-cyclopentylresorcinol, 4-cyclohexylresorcinol, 4 isooctylresorcinol, 4-amylresorcinol, 4-isoamylresorcinol, 4- Isobutyl resorcino , 4-tert-butyl resorcinol and the like can be obtained.
  • the introduction of another alkyl group having a branch at the 1-position can also be obtained by conducting a Grignard reaction using 4-isobutyrylresorcinol or the like as a starting material and, if necessary, a catalytic reduction reaction using palladium as a catalyst.
  • the 4-alkylresorcinol thus obtained tends to be less stable in storage than linear alkyl-substituted resorcinols such as 4 n-butylresorcinol. An example is shown below.
  • Table 1 shows the results of preparing 0.5% aqueous solutions of various 4 alkylresorcinols, storing them at 40 ° C for 1 month, and quantifying 4 alkylresorcinols by HPLC.
  • HPLC conditions were as follows: Column: ODS 4.6 mm x 150 mm, Column temperature: 40 ° C, Detection: UV 230 nm absorption, Mobile phase: 25% Acetonitrile—15 mM Tetraptylamonium bromide added 15 mM phosphate buffer ( pH 6.5), flow rate: lml / min. The quantitative value after storage was divided by the quantitative value immediately after production and multiplied by 100 to obtain the residual rate.
  • a glycosyltransferase used for the production of a glycoside comprises a 4-alkylresorcinol and a glycosyl compound.
  • a glycosyltransferase used for the production of a glycoside comprises a 4-alkylresorcinol and a glycosyl compound.
  • ⁇ -darcosidase belongs to an enzyme derived from an animal or plant tissue such as pig liver, buckwheat seed, or the like in the genus Mucor or Penicillium.
  • Enzymes derived from cultures obtained by culturing microorganisms such as fungi or yeasts belonging to the genus Saccharomyces in a nutrient medium are cyclomaltodextrin glucanotransferases, such as the genus Bacillus, the genus Klebsiella, etc.
  • Enzymes derived from bacterial cultures that belong to OC amylase belong to the genus Bacillus And known enzymes having transglycosylation activity such as enzymes derived from mold cultures belonging to the genus Aspergillus or the like. These glycosyltransferases do not necessarily need to be purified and used. Usually, the object of the present invention can be achieved with a crude enzyme such as a culture solution of these microorganisms or a concentrated solution thereof.
  • these enzymes may be used after being purified by various known methods, or may be used after being immobilized on a carrier.
  • Commercially available glycosyltransferases can also be used.
  • the amount of enzyme is selected so that the reaction is completed within about 5 to 80 hours of economic point.
  • a method of performing an enzyme reaction in a batch system or a continuous system can be appropriately selected.
  • the glycosyl compound used in the present invention is not particularly limited as long as it becomes a substrate for the enzyme when a 4-alkylresorcinol glycoside is produced using glycosyltransferase.
  • amylose, dextrin Preferred examples include starch partial hydrolysates such as cyclodextrin and maltooligosaccharide, and OC darcosyl compounds such as liquefied starch and gelatinized starch.
  • glycosyl compounds suitable for each enzyme may be selected depending on the sugar transferase used.
  • the concentration of the glycosyl compound in the reaction solution during the transglycosylation reaction is not particularly limited, but is usually 0.1% by mass or more (hereinafter referred to as mass% unless otherwise specified in the present specification). Is expressed as “%”), and 0.1% to 70% is desirable, and 0.1% to 50% of the solution is particularly desirable.
  • the liquid containing 4 alkylresorcinols at the time of the reaction should contain 4 alkylresorcinols in as high a concentration as possible.
  • 4 alkylresorcinols are suspended.
  • a concentration of about 0.005% or more is used, and a solution of about 0.01% to 10.0% is particularly desirable.
  • glycosyltransferase it is desirable to allow glycosyltransferase to act in a state where the charged concentration of 4 alkylresorcinols is increased.
  • 4-alkylresorcinols When the reaction is carried out in suspension, about 0.1% to 2.0% suspension of 4 alkylresorcinols containing a suitable amount of glycosyl compound and 4 alkylresorcinol-rich solution with a pH of about 4 0 to 7.0, and as high as possible at which glycosyltransferase can act, specifically about 20 ° C to 90 ° C.
  • 4-alkylresorcinol Suspended 4-alkylresorcinols gradually dissolve as the compounds are converted to 4-alkylresorcinol glycosides, and at the same time, 4-alkylresorcinol glycosides are easily produced at high concentrations.
  • alkylresorcinols in the alkaline solution are liable to be decomposed. Therefore, in order to prevent this, it is desirable to keep them as dark and anaerobic as possible. If necessary, acid-detergents such as L-ascorbic acid and erythorbic acid can coexist.
  • a liquid containing a high amount of alkylresorcinols containing about 0.5% to 10.0% alkylresorcinols and an appropriate amount of ⁇ -glycosyl compound is about 7.5 to 10%.
  • the temperature is maintained at about 50 ° C. to 80 ° C. and a glycosyltransferase is allowed to act on this, an alkyl resorcinol glycoside is easily produced at a high concentration.
  • alkylresorcinols for example, strong alkaline aqueous solutions such as caustic soda aqueous solution, caustic potash aqueous solution, sodium carbonate aqueous solution, hydroxide-calcium water, ammonia water, etc.
  • alkyl resorcinol compound solution dissolved in a high concentration, with an acidic aqueous solution [rho Eta Since it is easy to cause precipitation of alkylresorcinols, before the pH adjustment, a-glycosyl compounds and a small amount of alkylresorcinol glycosides can coexist to suppress the precipitation of alkylresorcinols. Initiating the reaction can also be carried out advantageously.
  • the liquid containing a high amount of the alkylresorcinols is mutually combined with water.
  • a soluble organic solvent for example, a lower alcohol such as methanol, ethanol, n propanol, isopropanol, n-butanol, and acetonitrile acetone, and a lower ketone can be appropriately selected.
  • the relatively high-molecular alkylresorcinol glycoside produced by the transglycosylation reaction may be used as it is or after purification with a porous synthetic adsorbent as necessary.
  • 2. 1. 3 or partial hydrolysis with an amylase such as j8-amylase (EC 3.2.1. 2) to reduce the number of a-darcosyl groups in a-glycosylalkylresorcinols Can do.
  • darcoamylase when darcoamylase is allowed to act, it can hydrolyze higher molecular weight compounds than ⁇ -maltosyl-4 alkylresorcinols to produce glucose and accumulatively produce ⁇ -darcosyl-4 alkylresorcinols.
  • a high molecular weight compound higher than one maltotriosyl-4 alkylresorcinol is hydrolyzed to form maltose, and mainly ⁇ -darcosyl-4-alkylresorcinol. Mixtures with ⁇ -maltosyl 4 alkylresorcinols can be accumulated.
  • the 4-alkylresorcinol glycoside that can be obtained by the method for producing a glycoside by the enzymatic method of the present invention is different in the binding mode of the darcosyl group to the hydroxyl group of 4-alkylresorcinol, which is in the 1- or 3-position.
  • Three types are obtained: those in which a glycosyl group is introduced into any of the hydroxyl groups, and those in which a glycosyl group is introduced in both the 1- and 3-positions.
  • the number of monosaccharides constituting each glycosyl group is not particularly limited. However, in terms of ease of production and ease of handling, it is usually desirable to have 1 to 6 monosaccharides. And one or two is particularly desirable.
  • reaction solution Obtained by the production method of the present invention
  • the reaction solution is left as it is, partially purified, highly purified, and Sarasako separates these three types of glycosides individually and mixes the fractions. It is also optional to filter and concentrate syrup or dry and powder it into the composition for external use of the present invention by a conventional method.
  • the method for purifying these 4 alkylresorcinol glycosides is not particularly limited as long as it can increase the purity of the 4 alkylresorcinol glycosides.
  • the 4 alkylresorcinol glycosides and impurities such as ⁇ - glycosyl compounds may be separated and purified using the difference in adsorptivity by the adsorbent.
  • the 4 alkylresorcinols that have been glycosylated are not necessarily removed because they are physiologically active themselves.
  • 4 alkylresorcinols are possible. It is desirable to increase the purity of resorcinol glycosides.
  • the porous synthetic adsorbent is a porous, wide, adsorbing surface area and nonionic styrene-dibutylbenzene polymer, phenol-formalin rosin, talile.
  • Synthetic resin such as salt resin and meta acrylate resin.
  • reaction solution in which the 4-alkylresorcinol glycoside of the present invention is produced is passed through, for example, a column filled with the porous synthetic adsorbent as described above, the 4-alkylresorcinol glycoside and the relatively A small amount of unreacted 4 alkylresorcinols are adsorbed on the porous synthetic adsorbent, whereas the majority of the glycosyl compounds that coexist in large amounts flow out without being adsorbed.
  • the reaction solution is heated to remove insoluble matter, or the aluminate cate Treatment with magnesium acid, magnesium aluminate, etc.
  • purification methods such as adsorption removal and treatment with strong acidic ion exchange resin (H type), medium basic or weak basic ion exchange resin (OH type), etc. This is also optional.
  • the 4-alkylresorcinol glycoside selectively adsorbed on the porous synthetic adsorbent column and the relatively small amount of the unreacted 4-alkylresorcinol were washed with dilute alkali or water. Thereafter, if a relatively small amount of an organic solvent or a mixed solution of an organic solvent and water, for example, methanol water, ethanol water, or the like is passed through, first, the 4 alkylresorcinol glycoside is eluted, and the amount of liquid passing is increased. If the organic solvent concentration is increased, unreacted 4 alkylresorcinols will be eluted.
  • an organic solvent or a mixed solution of an organic solvent and water for example, methanol water, ethanol water, or the like
  • the porous synthetic adsorbent can be used repeatedly. enable.
  • This eluate containing a high content of 4 alkylresorcinol glycosides is distilled, and after first distilling off the organic solvent and concentrating to an appropriate concentration, a syrup-like product containing 4 alkylresorcinol glycosides as the main component. Is obtained. Furthermore, by drying and pulverizing this by a method such as freeze-drying or spray-drying, a powdered product mainly comprising 4 alkylresorcinol glycosides can be obtained.
  • the purification using the porous synthetic adsorbent of the present invention has a feature that it is possible to simultaneously remove impurities such as water-soluble salts contained in the enzyme reaction solution, which is not only the glycosyl compound.
  • All of the 4 alkylresorcinol glycosides obtained by the synthesis method or enzymatic method as described above are stable and have higher water solubility than the 4 alkylresorcinols themselves.
  • it since it maintains its own physiological activity, it has excellent antibacterial and whitening effects.
  • the expression of this physiological activity is due to the glycosyl power of 4 alkylresorcinol on the skin surface or in the skin, where the glycoside is decomposed into 4 alkylresorcinols and sugar, and the function of 4 alkylresorcinol is exerted. It is thought.
  • a mixture of three types of 4 alkylresorcinol glycosides, which differ in the mode of attachment of the glycosyl group to the hydroxyl group of 4 alkylresorcinol, can be isolated as is, individually isolated, or individually What was isolated can be combined and the composition of this invention can be manufactured. Preferably, only the hydroxyl group at the 1-position is glycosylated.
  • these 4 alkyl resorcinol glycosides can be treated with an alkali, converted into a salt, and contained as a salt in the composition.
  • Preferred salts include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium and magnesium, organic amine salts such as ammonium salt, triethanolamine salt, and triethylamine salt, and lysine.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium and magnesium
  • organic amine salts such as ammonium salt, triethanolamine salt, and triethylamine salt
  • Preferred examples include basic amino acid salts such as salts and arginine salts.
  • the term “whitening” is used to mean not only a positive effect of whitening the skin but also a preventive effect of suppressing skin blackening. For example, it includes not only the effect of improving pigmentation such as stains and buckwheat but also the effect of suppressing pigmentation.
  • the amount of the 4-alkylresorcinol glycoside or a salt thereof in the composition of the present invention is an amount that exhibits the physiological functions of the 4-alkylresorcinol glycoside such as antibacterial, whitening, and antioxidant.
  • the limit is usually used at 0.001% to 10%, 0.05% to 5% is preferred 0.1% to 2% is more preferred 0.05 to 1% is particularly desirable That's right. If it is within the range, 4 alkylresorcinol glycosides can be easily blended, and excellent effects, especially whitening, has an antioxidant effect.
  • the composition containing the 4 alkylresorcinol glycoside of the present invention refers to pharmaceuticals, quasi drugs, cosmetics, miscellaneous goods and the like.
  • 4 alkylresorcinol glycosides have excellent antibacterial action, whitening action, antioxidant action, etc., and therefore can be advantageously blended in a composition for external use for whitening purposes.
  • cosmetics especially quasi drugs.
  • quasi-drugs it is safer and more effective to display the effect, precautions for use and quasi-drugs, and clarify the usage. It is preferable for the performance.
  • Such a medicinal effect may be determined according to the characteristics of the active ingredient blended in the external preparation for skin.
  • the 4-alkylresorcinol glycoside which is an essential component of this external preparation for skin, has a whitening action based on a melanin production inhibitory action and an anti-inflammatory action. It is also possible to display a whitening effect based on the action and an anti-inflammatory action.
  • components that are usually used in formulations such as cosmetics, quasi-drugs, and pharmaceuticals, that is, water (purification) Water, hot spring water, deep sea water, etc.), alcohols, oils, surfactants, metal soaps, gelling agents, powders, water-soluble polymers, carbohydrates, film-forming agents, resins, UV protection agents, inclusions Compound, Antibacterial agent, Preservative, Fragrance, Dye, Deodorant, Salt, PH adjuster, Coolant, Animal or microbial extract, Plant extract, Blood circulation promoter, Anti-inflammatory agent, Astringent, Anti Seborrheic agents, whitening agents, active oxygen scavengers, cell activators, moisturizers, chelating agents, keratolytic agents, enzymes, hormones, vitamins, minerals, etc. can be included. Specific examples thereof include the following components.
  • Alcohol is used for the purpose of dissolution, refreshing feeling, antiseptic, moisturizing and the like.
  • Alcohols include lower alcohols such as ethanol and isopropanol, and glycerin, diglycerin, polyglycerin, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, pentylene glycol, and polyethylene glycol.
  • polyalcohols such as isopentyldiol
  • sugar alcohols such as sorbitol, maltitol, maltotriitol, maltotetriitol, and maltopentitol.
  • the oil agent is used as a component of the base material for the purpose of improving usability or feeling of use. Any of those used in normal cosmetics can be used. For example, whether it is a natural oil or a synthetic oil, or whether it is a solid, semi-solid, or liquid. It doesn't matter about the properties. As oils, hydrocarbons, waxes, fatty acids, higher alcohols, ester oils, silicone oils, fluorine oils, etc. can be used. .
  • ester oils such as cetyl triethyl 2-ethylhexylate, pentaerythritol tetra-2-ethylhexylate, corn oil, olive oil, rapeseed oil, cottonseed oil, coconut oil, palm oil, Liquid lanolin, hydrogenated coconut oil, hydrogenated oil, mole, hydrogenated castor oil
  • Olive oil castor oil, jojoba oil, mink oil, virgin demian nut oil, apricot oil, persic oil, safflower oil, castor oil, apogad oil, meadowweed oil, camellia oil, almond oil
  • Oils derived from plants and animals such as sesame oil, sesame oil, borage oil, shea butter; waxes such as beeswax, carnauba wax, candelilla wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax, gay wax; pristane, Hydrocarbons such as ozokerite, liquid paraffin, squalane, ⁇ serine, ceresin, and microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, and undecylenic acid ; Higher alcohols such as cetyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, otatildodecanol, myristyl alcohol, cetosteryl alcohol; cetyl isooctanoate, isopropyl myristate, Hexyldec
  • Red 202 whose surface may be treated May be raked red 202, red 228, red 226, yellow 4, blue 404, yellow 5, red 505, red 230, red 223, orange 201, red 213, yellow 204, yellow Organic dyes such as Color No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204; organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer, etc.
  • Vitamin B such as vitamin B12, Vitamin B15 or its derivative
  • Vitamin B such as vitamin B12, Vitamin B15 or its derivative
  • ⁇ -tocopherol, ⁇ -Tocopherol, y-tocopherol vitamin E such as vitamin E acetate, vitamin D, vitamin H, pantothenic acid, pantethine, pyro-quinoline quinone, vitamin P such as vitamin P and their derivatives, etc. Preferred examples can be given.
  • Usable UV protection agents include para-aminobenzoic acid UV absorbers, anthranilic acid UV absorbers, salicylic acid UV absorbers, cinnamic acid UV absorbers, benzophenone UV absorbers, and sugar UV absorbers. An agent can be mentioned.
  • paraaminobenzoic acid and its ester octyl salicylate, homomethyl salicylate, methyl 2,5 diisopropylcinnamate, cinoxalate, diparamethoxyketic acid mono-2-ethyl hexyl hexylate, dihydroxydimethoxybenzophenol
  • Non-dihydroxydimethoxybenzophenone sodium disulfonate dihydroxybenzophenone, 1- (3,4 dimethoxyphenol) -1,4 dimethyl-1,3-pentanedione, dimethico-ethyl benzomalonic acid and its esters, dimethoxybenzylidene Dioxoimidazolidine 2-ethylhexyl propionate, tetrahydroxybenzophenone, 2, 4, 6 tris "one (2-ethylhexyloxycarboxyl) -lino" 1, 3, 5 triazine, trimethoxy key Methyl bis (trimethyl bis
  • Water-soluble polymers and carbohydrates are used for stabilizing the system, for improving usability or feeling of use, and for obtaining a moisturizing effect.
  • water-soluble polymers that can be used include plant polymers such as pullulan, carrageenan, pectin, agar, locust bean gum, cellulose polymers such as methylcellulose, carboxymethylcellulose, and hydroxypropylcellulose, and sodium alginate.
  • Examples include bulge polymers such as alginic acid polymers and carboxyvinyl polymers.
  • saccharide examples include maltose, manoletotriose, manoletotetraose, trenosulose, a saccharide derivative of trehalose, and a cyclic saccharide such as a cyclic tetrasaccharide.
  • antiseptic and antibacterial agent examples include benzoic acid, sodium benzoate, paraoxybenzoic acid ester, benzalkonium chloride, phenoxyethanol, isopropylmethylphenol and the like.
  • the 4-alkylresorcinol glycoside of the present invention has an excellent whitening effect alone.
  • the composition of the present invention may be used in combination with a conventionally known whitening agent.
  • the whitening agent is used for the purpose of preventing skin darkening caused by sunburn and the like, and spots and freckles caused by pigmentation.
  • whitening agents that can be used include arbutin, linoleic acid, 5,5'-dipropylbisphenol-2,2'-diol, vitamin C and its derivatives, vitamin E and its derivatives, glycyrrhizic acid and Its derivatives, tranexamic acid and its derivatives, tetrahydrotalcuminoids, placenta extract, indigo extract, ripe mitsu extract, licorice extract, age extract, argon extract, seaweed extract, cucumber extract, cuckoo extract , Gokahi extract, rice bran extract, wheat germ extract, saicin extract, hawthorn extract, sunpens extract, shirayuri extract, peonies extract, sempukuka extract, soybean extract, tea extract, molasses Extract, Beechlen extract, Grape extract, Hop extract, Maikai extract, Mokka extract, Yukinoshita extract, Yokui Down extract, mention may be made of royal jelly extract or the like.
  • Anti-inflammatory agents are used for the purpose of suppressing inflammation such as hot flashes and erythema on the skin after sunburn.
  • Anti-inflammatory agents include io and its derivatives, glycyrrhizic acid and its derivatives, Lithyl retinoic acid and its derivatives, salty lepocalcun, aloe extract,retea extract, ashtapa extract, al-force extract, indigo extract, inchinko extract, nettle extract, obata extract, hypericum extract, force mitre Examples include extract, licorice extract, kingfish force extract, tareson extract, comfrey extract, salvia extract, sicon extract, perilla extract, birch extract, gentian extract and the like.
  • the cell activator is used for the purpose of improving rough skin.
  • the cell activator that can be used in the composition of the present invention include power fin, chicken crown extract, shell extract, shell extract, royal jelly, silk protein and its degradation product, or derivatives thereof, ratatopherin or Degradation products, mucopolysaccharides such as chondroitin sulfate and hyaluronic acid or their salts, collagen, yeast extract, lactic acid bacteria extract, bifidobacteria extract, fermentation metabolic extract, yew extract, barley extract, senpri extract Organic acid such as glycerin, citric acid, malic acid, tartaric acid and succinic acid, and derivatives thereof.
  • the active oxygen scavenger is used for the purpose of suppressing oxidative damage such as suppression of lipid peroxide production.
  • active oxygen scavengers include superoxide dismutase, mannitol, taercetin, catechin and its derivatives, rutin and its derivatives, bopi extract, coconut extract, melissa extract, rakan extract, retinol and carotenoid Vitamin A and its derivatives, vitamin B and its derivatives such as thiamine, riboflavin, pyridoxine and nicotinic acid, vitamin C and its derivatives, vitamin P and its derivatives such as rutin, hesperidin and naringin, vitamin E such as tocopherol And its derivatives, dibutylhydroxytoluene, butylhydroxyl-sol and the like.
  • moisturizing agents include proteins such as elastin and keratin or derivatives thereof, hydrolysates and salts thereof, amino acids such as glycine, serine, aspartic acid, glutamic acid, arginine and theanine and derivatives thereof, sorbitol, Erythritol, trehalose and its derivatives, inositol, glucose, maltose, sucrose and its derivatives, dextrin, cyclodextrin, cyclic tetrasaccharide and their derivatives, saccharides such as honey, D panthenol and its derivatives, urea, phospholipid, Ceramide, Oren extract, Shobu extract, Zi extract, Senkiyu extract, Zeaoi extract, Tachijiakousou extract Products, dokudami extract, hamamelis extract, bodaiju extract, marronnier extract, quince extract and the like.
  • proteins such as elastin and keratin or derivatives thereof, hydroly
  • the form of the composition for external use of the skin of the present invention is not particularly limited.
  • lotion, essence, milky lotion, cream, lotion, knock, cosmetic liquid, cleaning agent, makeup cosmetics, hair care cosmetics, bath preparations examples thereof include dispersions, ointments, liquids, aerosols, patches, poultices, and replenishers.
  • the purpose of use is generally known for external preparations for skin, such as basic skin care and makeup, and can be applied to other uses.
  • Particularly preferred is an emulsified essence preparation or cream preparation that can fully utilize the effects of the present invention.
  • the production method is not particularly limited, and can be produced by conventional methods.
  • the medium was removed from each bottle, washed with PBS (phosphate buffered saline), treated with trypsin, and the cells were detached from the culture bottle to obtain cell suspensions.
  • the cell suspension was centrifuged to collect cells. The number of cells obtained and the degree of melanin pigmentation were observed and visually observed according to the following criteria to evaluate cytotoxicity and melanin production inhibitory action. The results are shown in Table 3.
  • glycoside which is the compound of the present invention, has the same melanogenesis inhibitory action as aglycone. It can also be seen that cytotoxicity is reduced by glycosides.
  • 4-n-Butylresorcinol was prepared based on the method described in Example 1 of GB 1,581,428. 4 g of 4-n-butylresorcinol and 80 g of a-cyclodextrin (hereinafter sometimes abbreviated as “ ⁇ -CD”) were dissolved in 800 mL of 50 mM acetate buffer (pH 5.5, containing 2 mM CaCl). Later, Bacillus stearothermophile
  • reaction product After stopping the reaction by heating at 100 ° C for 10 minutes, the column (7 « ⁇ ⁇ X 39cm, 1) packed with porous synthetic adsorbent (Mitsubishi Kasei Co., Ltd., trade name“ Diaion HP-20 ”) 5L). The column was washed with water, and 35% ethanol was passed through to elute the fraction adsorbed on the column. The obtained fraction was concentrated to dryness, suspended and dissolved in 96% ethanol, and then insoluble carbohydrates were removed. After the solvent in the supernatant is distilled off, the sample is dissolved again in water, freeze-dried, and a powder sample containing a reaction product by glycosyltransferase (hereinafter sometimes abbreviated as “reaction product”). 3.
  • reaction product a powder sample containing a reaction product by glycosyltransferase
  • Tube Lens Offset — 10. 0V
  • reaction product a reaction product a
  • reaction product b reaction product b
  • the glucose residue is in the pyranose type, and the chemical shift of anomeric carbon to chemical shift ⁇ 97.
  • reaction product a is chemically 3—O—a—D—Curcopyranosyl 4-N-butylresorcinol represented by Formula 1 and l—O—a D darcobilanosyl 4-n-butylresorcinol where reaction product b is represented by Formula 2 Tells you that you have
  • the mass of these reaction products corresponds to the molecular weight of butylresorcinol in which two molecules of glucose are bound to butylresorcinol, and, as shown in Chemical Formula 1, 4 n-butylresorcinol by glycosyltransferase is used.
  • 4 n-butyl resorcinol used in Example 7 10 mg
  • 4 n-butylresorcinol used in Example 7 used as a substrate for preparing glycosides in Example 7, and D-ODS in Experiment 1 — 5 — L-O-a-D-Darcopyranosyl— 4— n-butylresorcinol (reaction product b) 10 mg, prepared by column chromatography using S5, and 3— 0— ⁇ — D Darcoviranosyl 4 — ⁇ —Butyl resorcinol (reaction product a) 10 mg each, each with deionized water, stirred for 2 to 3 minutes with a vortex mixer and left to stand until insoluble matter is no longer visible. was determined as the solubility of each compound. The results are shown in Table 6.
  • Freeze-dried powder containing the reaction product prepared in Example 7 (1 O—a D darcopyranosyl 4-n-butylresorcinol and 3-O—a-D-darcopyranosyl 4-n Contains a small amount of 4-n-butylresorcinol glycoside in which two or more darcosyl residues are bonded to butylresorcinol: hereinafter referred to as “4-n-butylresorcinol glycoside-containing powder”), 1 -0- a D Dalcoviranosi luo 4— n-Butyl resorcinol and 3-O— a—D—Darcopyranosyl 4— n— Butyl resorcinol 4 n butyl resorcinol glycoside preparations and 4 n used in Example 7 A test for confirming the whitening effect using butyl resorcinol was conducted as follows.
  • mice B16 melanoma cells were cultured, and after removing the culture supernatant, either 4-n-butylresorcinol or three types of 4-n-butylresorcinol glycoside preparations were added. Then, 4 n-butylresorcinol or 4 n-butylresorcinol glycoside was added to a medium prepared so as to have the concentrations shown in Table 7, and further cultured for 72 hours. The cells are collected, packed in a glass tube and observed for color tone, and the degree of whitening based on the melanin production inhibitory action is determined according to the following criteria. The results are shown in Table 7.
  • whitening effect was similarly determined using kojic acid (2.5 mM) used as a skin whitening agent as a skin whitening agent.
  • a portion of the collected cells is stained with a dye that stains only living cells (Alamable I), and the percentage of viable cells stained with the dye that is incorporated into all cells is determined. It is shown in Table 7 as (%).
  • the concentration of 4 n-butylresorcinol glycoside in the powder containing 4 n-butylresorcinol glycoside used in the following experiment was calculated based on the molar extinction coefficient of resorcinol at 280 nm.
  • a test for confirming the whitening effect of 4n butylresorcinol glycoside was performed as follows. That is, in the same manner as in Test Example 2, mouse B16 melanoma cells were cultured for 24 hours, the culture supernatant was removed, and a medium containing each test sample to the concentration shown in Table 8 was added. The culture was further continued for 72 hours. Cells are collected, packed in a single tube, and the color tone is observed. The degree of whitening effect based on the melanin production inhibitory effect is determined according to the following criteria, and the results are shown in Table 8.
  • 4-n-butylresorcinol glycoside-containing powder preparation is composed of L-ascorbic acid sodium salt, potassium 4-methoxysalicylate, kojic acid, arbutin, tranexamic acid, ellagic acid, A synergistic whitening effect was observed when used in combination with linoleic acid, power mitre extract, and tetrahydrocurcumin.
  • TSA value thiobarbituric acid value
  • 4-n-Butylresorcinol was prepared based on the method described in Example 1 of GB 1,581,428. After dissolving 20 g of 4-n-butylresorcinol in 800 mL of 50 mM acetate buffer (pH 5.5), 400 g of dextrin (Matsuya Chemical Co., Ltd., trade name “Pinedetas #l”) was added and stirred. Thereafter, acetate buffer was added to make up a total volume of 4000 mL.
  • reaction product a and reaction product b were subjected to MS analysis and NMR analysis in the same manner as in Test Example 3.
  • reaction product a was 3-O-a- It was confirmed that D-darcopyrano silu 4-n-butylresorcinol and reaction product b was l-O- ⁇ -D-darcobilanosyl 4- ⁇ -butylresorcinol.
  • the amount produced was smaller than that of reaction product a and reaction product b, 1, 3-O-a-D-darcoviranosyl 4-n -Production of a substance corresponding to butylresorcinol was confirmed.
  • Freeze-dried powder containing 4 n-ptylresorcinol glycoside prepared in Example 7 Sample, reaction product a and reaction product b prepared by column chromatography using D-ODS-5 S5 in Example 7 3 parts by mass (freeze-dried sample is 3 parts by mass as 4 n-butyl resorcinol glycoside), 5 parts by mass of ethanol, 5 parts by mass of glycerol and 87 parts by mass of purified water as a base And a test solution was prepared. Apply any of these solutions to the inside of the upper arm of 5 volunteers each (15 people in total) in the range of lcm x 1cm 3 times a day for 3 consecutive days, and then the skin condition at the site of application for 1 week Was observed.
  • Example 7 4-n-methylresorcinol, 4-n-ethylresorcino 1-nore, 4-n-hexenoresolezonoresinore, 4-n-heptinorezonoresinole, 4-n-octylresorcinol, 4-n-decylresorcinol and 4-n eicosylresorcinol 5g and dextrin lOOg were used for the transglycosylation reaction, and the reaction solution was filled with a porous synthetic adsorbent (Mitsubishi Kasei Co., Ltd., trade name “Diaion HP-20”) as in Experiment 1.
  • the saccharides were purified using a column prepared by removing 96% ethanol-precipitated saccharides and freeze-dried to prepare these alkylresorcinol glycoside powder preparations (purity: 85% to 91%).
  • lotion cosmetics 1 to 18 which are skin external preparations of the present invention were prepared according to the following formulation. That is, the formulation components were stirred and dissolved at 80 ° C. and stirred and cooled to obtain a lotion. What are these lotions This also had an excellent whitening effect.
  • the combination of each component of the example showing the composition containing the glycoside of the present invention shown below is the ratio of each component to the total mass of the cosmetic (
  • a lotion was prepared by the conventional method using the following formulation.
  • This product was an excellent cosmetic product that, when applied to the skin, whitens the skin and gives the skin a moisturizing effect.
  • this product contains 4-n-butylresorcinol glycoside, the storage stability was also good.
  • a two-layer lotion was prepared by a conventional method using the following formulation.
  • This product was an excellent cosmetic product that, when applied to the skin, whitens the skin and gives the skin wrinkles.
  • this product contained 3-O-a-D monodalcopyranosyl 4-n-butyl resorcinol, the storage stability was also good.
  • An emulsion was prepared by a conventional method using the following formulation.
  • This product was an excellent cosmetic product that, when applied to the skin, whitens the skin and gives wrinkles to the skin.
  • this product contains 1 -0-a D-darcobilanosyl 4-n-butylresorcinol, which is free from starch generation and browning, and thus has good storage stability.
  • An emulsion was prepared by a conventional method using the following formulation.
  • This product was an excellent cosmetic product that, when applied to the skin, whitens the skin and gives wrinkles to the skin. In addition, this product does not show browning, etc., if starch is generated, and 3—O—a—D—Dalcobilanosyl-4— Because it contains n-butylresorcinol! /, storage stability was also good.
  • the composition of the present invention can be used in various applications such as cosmetics, quasi drugs, and external medicines. Among them, it is particularly useful as a cosmetic because it has excellent anti-acid effect and Z or whitening effect.
  • the 4-n-alkylresorcinol glycoside of the present invention is highly water-soluble and has an excellent action and effect, it can be used for various uses, preferably as an external skin whitening composition.

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Abstract

La présente invention concerne un dérivé 4-alkylrésorcinol dans lequel des défauts inhérents à un 4-alkylrésorcinol sont surmontés et lequel est excellent en termes d’hydrosolubilité et de stabilité, n’ayant pratiquement aucun goût et aucune odeur, n'étant pas irritant, n’ayant aucun problème en ce qui concerne la toxicité, et pouvant exprimer son activité physiologique dans un corps vivant d'une manière satisfaisante. Ainsi, la présente invention concerne un glycoside de 4-alkylrésorcinol ayant un groupe glycosyle lié à un ou aux deux groupes hydroxyle dans un 4-alkylrésorcinol.
PCT/JP2006/325658 2005-12-26 2006-12-22 Glycoside d’alkylresorcinol, son procede de production et son utilisation WO2007077770A1 (fr)

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TWI414317B (zh) * 2008-05-29 2013-11-11 Shiseido Co Ltd 皮膚外用劑
EP4046619A1 (fr) * 2008-07-21 2022-08-24 Unigen, Inc. Famille de composés permettant le blanchiment (éclaircissement) de la peau
JP2010150240A (ja) * 2008-11-20 2010-07-08 Oppen Keshohin Kk ニゲロオリゴ糖を有効成分とする皮膚外用剤、抗炎症剤、美白剤および化粧料
CN115554180A (zh) * 2022-10-24 2023-01-03 陕西畅想制药有限公司 一种4-丁基间苯二酚超分子囊泡聚集体及其制备方法和化妆品组合物
CN115554180B (zh) * 2022-10-24 2023-09-22 陕西畅想制药有限公司 一种4-丁基间苯二酚超分子囊泡聚集体及其制备方法和化妆品组合物
CN116217754A (zh) * 2023-01-31 2023-06-06 上海贤鼎生物科技有限公司 一种4-烷基间苯二酚环糊精衍生物超分子及其制备方法和在制备化妆品中的应用

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