CN104755071A - External preparation for skin - Google Patents

Abstract

Provided is an external preparation for the skin. The external preparation comprises an emulsion containing glycyrrhetinic acid; at least one substance selected from the group consisting of astaxanthin and astaxanthin derivatives; and a preservative that has an I/O value of 1.5 or less, and that either does not have an alkyl group or has a linear or branched alkyl group having an alkyl chain length of 5 or less. The external preparation either does not comprise ethanol or comprises 1 mass% or less of ethanol.

Description

Skin preparations for extenal use

Technical field

The present invention relates to a kind of skin preparations for extenal use.

Background technology

To be the biosynthetic C of parent material with Squalene ₃₀compound be called triterpene.Triterpenoid is roughly divided into the triterpenoids such as dammarane system, hopance system, Radix Ononis hircinae methane series, lanostane system, olive methane series, cycloartane system according to the bonding pattern of ring.

In triterpenoid, known to being coupled in skin preparations for extenal use the triterpenoid of olive methane series of the main constituent as plant extract playing antiinflammatory, moisturizing, whitening, the function such as crease-resistant, antibacterial.Wherein, knownly 5 rings are belonged to and the triterpenoid that substituent group has an olive methane series of carboxyl has as the useful especially function of cosmetic preparation (Tanaka believe Shou, ト リ テ Le ペ Application and び ト リ テ Le ペ Application system サ Port ニ Application, natural goods chemistry change Order the 6th edition, Nan Jiangtang (1985), p130 ~ p140).

Belong to 5 rings as such and there is the triterpenoid of the olive methane series of carboxyl, known enoxolone etc.Enoxolone is extensively matched with in the various compositionss such as scalp compositions (Japanese Unexamined Patent Publication 2008-201767 publication) as the oil-soluble medicament with antiphlogistic effects.

On the other hand, known is that the carotenoid such as the phylloxanthin of representative have anti-dandruff effect and antipruritic effect with astaxanthin.Known particularly astaxanthin has excellent hair growth promoting and educates sends out effect (with reference to Japanese Unexamined Patent Publication 2009-179628 publication and Japanese Unexamined Patent Publication 2008-273874 publication).

Summary of the invention

Invent problem to be solved

Although enoxolone is excellent in suppression coarse skin etc. is functional, it is slightly solubility to water, and dissolubility in oil is also low.Therefore, enoxolone was be coupled in skin preparations for extenal use after ethanol solubilising with q.s in the past always.But, owing to also there is the user of a part to alcohol sensible, therefore expect that there is the skin preparations for extenal use without ethanol composition.

The present inventors have found that as not using ethanol, the enoxolone of desired amount being coupled to one of countermeasure in skin preparations for extenal use is use the emulsion comprising enoxolone.But the skin preparations for extenal use not containing ethanol has the tendency that anti-corrosive properties are deteriorated.On the other hand, obtain following cognition: when in order to improve anti-corrosive properties in skin preparations for extenal use, coordinate antiseptic time, the stability of emulsion can be damaged because the kind of antiseptic is different.

The present invention completes in view of the foregoing, and problem of the present invention is to provide a kind of skin preparations for extenal use suppressing coarse skin, anti-corrosive properties and emulsion excellent in stability.

For solving the means of problem

Means for solving above-mentioned problem are as follows.

[1] a kind of skin preparations for extenal use, it contains: comprise the emulsion of enoxolone, be selected from the group that is made up of astaxanthin and astaxanthin derivatives at least one and I/O value be less than 1.5 and do not there is alkyl or there is the antiseptic that alkyl chain length is the straight or branched alkyl of less than 5

The content of described skin preparations for extenal use not containing ethanol or ethanol is below 1 quality %.

[2] skin preparations for extenal use Gen Ju [1], wherein, the emulsion comprising enoxolone contains the emulsifying agent comprising phospholipid.

[3] according to [1] or the skin preparations for extenal use described in [2], wherein, the emulsion comprising enoxolone contains N-acyl amino acid monoester.

[4] according to the skin preparations for extenal use according to any one of [1] ~ [3], wherein, the emulsion comprising enoxolone contains N-Hamposyl L isopropyl ester.

[5] according to the skin preparations for extenal use according to any one of [1] ~ [4], wherein, I/O value is less than 1.5 and does not have alkyl or have alkyl chain length is at least one antiseptic that the antiseptic of the straight or branched alkyl of less than 5 comprises in the group being selected from and being made up of phenyl phenol, parabens and butyl carbamic acid iodopropynyl ester.

[6] according to the skin preparations for extenal use according to any one of [1] ~ [5], the at least one be selected from the group that is made up of astaxanthin and astaxanthin derivatives contains with emulsion form by it, and described emulsion contains at least one in the group being selected from and being made up of astaxanthin and astaxanthin derivatives and comprises the emulsifying agent of phospholipid.

[7] according to the skin preparations for extenal use according to any one of [1] ~ [6], wherein, the content of enoxolone is 0.0001 quality % ~ 0.5 quality %.

[8] according to the skin preparations for extenal use according to any one of [1] ~ [7], it is scalp cosmetic preparation.

Invention effect

According to the present invention, the skin preparations for extenal use suppressing coarse skin, anti-corrosive properties and emulsion excellent in stability can be provided.

Detailed description of the invention

In the present invention, represent using the numerical value described in " ~ " front and back as minima and maximum and the scope be included with the numerical range that " ~ " represents.

In this description, about the amount of each composition in compositions, exist multiple when belonging to the material of each composition in the composition, as long as no special instructions, then refer to the total amount of this many kinds of substance existed in compositions.

In the present invention, " aqueous phase ", regardless of the kind of solvent, uses as the term relative with " oil phase ".

In this description, " operation " this term not only refers to independently operation, even if when cannot distinguish clearly with other operations, as long as can reach the object that this operation expects, is then also contained in this term.

Emulsion in the present invention is preferably the oil-in-water emulsion (O/W type emulsion) containing the oil phase be made up of the Unctuous compositions comprising oil components and the aqueous phase be made up of the waterborne compositions comprising water composition.Emulsion in the present invention as described later, is obtained by mixing preferably by by the waterborne compositions comprising water composition and the Unctuous compositions emulsifying comprising oil components.

The mean diameter of the emulsion in the present invention refers to the volume average particle size of emulsion.

The mean diameter of the emulsion in the present invention is obtained by known methods such as ultramicroscope, centrifugal settling method, liquid exclusion chromatography, laser light scattering diffraction approach, dynamic light scattering methods.From the simplicity of precision and mensuration, the mean diameter of the emulsion in the present invention preferably uses dynamic light scattering determination.

As the commercially available determinator employing dynamic light scattering method, particle diameter Analyzer FPAR-1000 (Otsuka Electronics Co., Ltd. of dense system can be listed), Nano Trak UPA (Nikkiso Company Limited), Nanosizer (Malvern Inc.) etc.Particle diameter in the present invention adopts the value using Nano TrakUPA to measure at 25 DEG C.

About the mean diameter of emulsion, specifically, the sample as determination object do not diluted and directly stock solution measured, obtaining meso-position radius (d=50).

In addition, the mean diameter of emulsion except the composition of compositions, by the ratio of stirring condition (shearing force, temperature, pressure), oil phase and the aqueous phase in manufacture method etc. because usually regulating.

Below, each element in skin preparations for extenal use of the present invention is described in detail.

In addition, below, required composition contained in skin preparations for extenal use of the present invention and any composition are described, then the relevant issues of the preparation being applicable to emulsion of the present invention are described.

[skin preparations for extenal use]

Skin preparations for extenal use of the present invention contain comprise enoxolone emulsion, be selected from least one in the group that is made up of astaxanthin and astaxanthin derivatives and I/O value is less than 1.5 and does not have alkyl or have the antiseptic that alkyl chain length is the straight or branched alkyl of less than 5, it is the skin preparations for extenal use in fact not containing ethanol.

In the following description, suitably I/O value being less than 1.5 and not having alkyl or have alkyl chain length is that the antiseptic of the straight or branched alkyl of less than 5 is called " specific antiseptic ".In addition, in the present invention, sometimes also the group be made up of astaxanthin and astaxanthin derivatives " astaxanthin class " this term is carried out general name.

According to the present invention, by combination containing comprising the emulsion of enoxolone and specific antiseptic, and the content not containing ethanol or ethanol is below 1 quality %, can provides and there is excellent inhibition and the skin preparations for extenal use of anti-corrosive properties and emulsion excellent in stability to coarse skin.

Skin preparations for extenal use of the present invention, by being contained with the form of emulsion by enoxolone, stably contains enoxolone with can not using ethanol in system.In addition, skin preparations for extenal use of the present invention, by containing both enoxolone and astaxanthin class, can suppress the inflammation of skin synergistically.Therefore, according to the present invention, the skin preparations for extenal use with the excellent coarse skin effect of suppression can be provided.

In addition, the specific antiseptic in the present invention, while suppressing the emulsion breakdown of emulsion containing enoxolone etc., effectively maintaining the stability of emulsion, can also improve the anti-corrosive properties of skin preparations for extenal use.Namely, the present inventors infer, use there is hydrophilic portion and hydrophobic portion and with the breakdown of emulsion to emulsion that can significantly occur during the antiseptic that the structure of emulsifying agent is close to be caused by antiseptic, this is the surface that the hydrophobic portion had due to antiseptic is adsorbed on the emulsion of the oil components comprising enoxolone etc., thus emulsion is condensed.On the other hand the present inventors infer, in skin preparations for extenal use of the present invention, by optionally containing having ad hoc structure and the low specific antiseptic of polarity, can realize taking into account of the stabilisation of antiseptic and emulsion.

In addition, skin preparations for extenal use of the present invention, due in fact not containing ethanol, therefore can also use being included in the user of alcohol sensible in object.

The content of skin preparations for extenal use of the present invention not containing ethanol or ethanol is below 1 quality %.When skin preparations for extenal use contains ethanol, the content of ethanol is preferably below 0.5 quality % relative to the gross mass of skin preparations for extenal use, is more preferably below 0.1 quality %.

The ethanol contained in skin preparations for extenal use is more than reducing enoxolone and astaxanthin class during 1 quality % and with the inflammation inhibitory effect brought.

Skin preparations for extenal use of the present invention is not preferably containing ethanol.

< enoxolone >

Skin preparations for extenal use of the present invention contains enoxolone.

Enoxolone (Glycyrrhetinic acid) is the one in 5 ring triterpenoids of the olive methane series being hydrolyzed and being obtained by the composition contained by the root to such as Radix Glycyrrhizae and glycyrrhizic acid (glycyrrhizic acid).Enoxolone expects in cosmetic field, have antiinflammatory action, antioxidation, aging resistance effect, can be coupled in cosmetics for the purpose of defying age nursing etc. or medicine part outer article etc.

In addition, enoxolone has significant effect to acute or chronic scytitis, there will be a known the effects such as antiphlogistic effects, anti-allergic effects, anti-bacteria (Staphylococcus aureus, diphtheria corynebacterium, Salmonella etc.) growth.In addition, enoxolone is excellent in the effects such as mitigation scytitis, the suppression of suppression sebum secretion, is used in a lot of skin-care products, lipstick etc.In addition, enoxolone owing to also there is Anti-hair loss effect, suppressing the effect such as the dandruff or pruritus, therefore also by a large amount of in scalp care goods.

Enoxolone can be extract or its refining thing in natural goods source, also can be the composite of synthesizing according to known synthetic method.Enoxolone can also obtain with commercially available product form, as the example of commercially available product, can list Maruzen Pharmaceuticals Co., Ltd.'s system, the β enoxolone that Alps medicine, gold can be made.

1 kind, each goods can be used alone by enoxolone, also two or more can be combinationally used.

Enoxolone contains in skin preparations for extenal use of the present invention with the form of emulsion.

Comprise the emulsion of enoxolone preferably containing emulsifying agent.From the view point of stability, comprise the emulsion of enoxolone more preferably containing the emulsifying agent comprising phospholipid.The details of the emulsifying agent preferably used in the present invention is described below.

As the content of the enoxolone in skin preparations for extenal use of the present invention, from the view point of the coarse skin effect of suppression obtaining enoxolone and be expected to, be preferably 0.0001 quality % ~ 0.5 quality %, be more preferably 0.001 quality % ~ 0.3 quality %, more preferably 0.005 quality % ~ 0.2 quality %.

When the content of enoxolone is more than 0.0001 quality %, such as there is the tendency fully obtaining the effect that enoxolone such as suppressing coarse skin effect (antiphlogistic effects) is expected to, when for below 0.5 quality %, there is the tendency being easy to suppress enoxolone to be separated out.

< astaxanthin and astaxanthin derivatives >

Skin preparations for extenal use of the present invention contains at least one in the group (astaxanthin class) being selected from and being made up of astaxanthin and astaxanthin derivatives.Astaxanthin derivatives comprises the ester etc. of astaxanthin.

The composition that astaxanthin apoplexy due to endogenous wind comprises can a kind be used alone, also two or more can be combinationally used.

Astaxanthin class can also contain in skin preparations for extenal use of the present invention as the composition in the extract being separated from the natural goods containing astaxanthin class or extracting and astaxanthin-containing oil.Astaxanthin class also can be the material suitably refined the extract being separated from natural goods or extracting as required and obtain.In addition, astaxanthin class also can be composite.

Astaxanthin class except obtain from natural goodses such as plant, algae, shell-fish and antibacterials, as long as obtained by conventional method, can use any one.

As the astaxanthin class of natural goods, such as phaffiafhodozyma (Phaffiarhodozyma), Haematococcus Pluvialis (Haematococcus algae), maritime antibacterial, krill etc. can be listed.In addition, as astaxanthin class, the extract etc. obtained from the culture of natural goods can be listed, from the angle of quality and productivity ratio, the extract (also referred to as Haematococcus Pluvialis extract) particularly preferably extracted from Haematococcus Pluvialis and the pigment in krill source.

In addition, in the present invention, as astaxanthin class, extensively commercially available Haematococcus Pluvialis extract can also be used.As Haematococcus Pluvialis extract, such as, can obtain with forms such as the BioAstin SCE7 of the AstaREAL Oil 50F of ASTOTS-S, ASTOTS-2.5O, ASTOTS-5O, ASTOTS-10O etc. of Wu Tianzhi device Co., Ltd., Fuji Chemical Industry Co., Ltd, AstaREAL Oil 5F etc., enzyme chemistry Co., Ltd. of Japan.As krill extract, Astax ST etc. can be obtained.

Operate when manufacturing from the view point of compositions, being preferably 0.001 quality % ~ 50 quality % in the content of the pure composition of pigment, being more preferably 0.01 quality % ~ 25 quality % of the astaxanthin class in the present invention in spendable krill extract or Haematococcus Pluvialis extract.

In skin preparations for extenal use of the present invention, astaxanthin class to contain by the form of the solubilisings such as solubilizing agent, also can contain with the form of the emulsion comprising astaxanthin class.From the view point of percutaneous permeability, astaxanthin class preferably contains in skin preparations for extenal use of the present invention with the form of emulsion.

The emulsion comprising astaxanthin class preferably contains emulsifying agent, from the view point of the stability of astaxanthin class, more preferably containing the emulsifying agent comprising phospholipid.The details of the emulsifying agent preferably used in the present invention is described below.

About the content being selected from least one in the group be made up of astaxanthin and derivant thereof in skin preparations for extenal use of the present invention, from the view point of the antiphlogistic effects obtaining astaxanthin or derivatives thereof and be expected to, be preferably 0.000001 quality % ~ 0.01 quality %, be more preferably 0.00001 quality % ~ 0.0075 quality %, more preferably 0.0001 quality % ~ 0.005 quality %.

The specific antiseptic > of <

Skin preparations for extenal use of the present invention contains I/O value and is less than 1.5 and does not have alkyl or have the antiseptic (specific antiseptic) that alkyl chain length is the straight or branched alkyl of less than 5.

The compound needs of specific antiseptic are used as: (1) I/O value is less than 1.5, (2) are do not have alkyl or have molecular structure that alkyl chain length is the straight or branched alkyl of less than 5 and (3) have anti-corrosive properties in the present invention.

Only otherwise damage effect of the present invention, skin preparations for extenal use of the present invention containing other antiseptic except specific antiseptic except, more preferably only can also contain specific antiseptic.

Here, I/O value refers to the parameter as representing the index of the yardstick of the hydrophilic and hydrophobic shown in compound with Organic group and the ratio of inorganic nature group.I represents inorganic nature, O represents Organic, and I/O value is larger then represents that inorganic nature is higher.About I/O value, in " having Machine concept figure " (first Tian Shansheng work, three is published altogether, 1984), there is the explanation of its details.

The anti-corrosive properties obtained by antiseptic are depended on as the hydrophilic and hydrophobic shown in the character contributing to the position of anti-corrosive properties of the compound of antiseptic and this compound, and the basis considering these is determined the requirement of antiseptic.

The hydrophilic of the antiseptic of I/O value more than 1.5 is high, in order to utilize such antiseptic to obtain anti-corrosive properties, needs the antiseptic coordinating more.Being engaged in the skin preparations for extenal use of the emulsion comprised containing enoxolone of the antiseptic of I/O value more than 1.5, produces viscosity owing to coordinating antiseptic in a large number, then need to reduce I/O to keep efficiency of preservation with a small amount of antiseptic.When for the antiseptic of I/O value below 1.5, even if use level also can play anti-corrosive properties less.

On the other hand, even the antiseptic of I/O value below 1.5, also there is the antiseptic making to make in the skin preparations for extenal use comprising the emulsion containing enoxolone emulsion bad stability because of its molecular structure, but when be not there is alkyl or there is alkyl chain length be the antiseptic of straight or branched alkyl of less than 5 time, emulsion is maintained with having good stability.

The I/O value that specific antiseptic has is less than 1.5, is preferably less than 1.4, is more preferably less than 1.3.

Specific antiseptic does not have alkyl or has the antiseptic that alkyl chain length is the straight or branched alkyl of less than 5, also can be the antiseptic further with aromatic group (such as phenyl).

As specific antiseptic, when be I/O value be less than 1.5 and not there is alkyl or there is alkyl chain length be the compound of straight or branched alkyl of less than 5 time, can use without particular limitation.

Specific antiseptic can a kind be used alone, also two or more can be combinationally used.

The Suitable examples of specific antiseptic comprises at least one antiseptic in the group being selected from and being made up of phenyl phenol, parabens and butyl carbamic acid iodopropynyl ester.

As specific antiseptic, from the view point of anti-corrosive properties, preferably two or more being selected from the group that is made up of phenyl phenol, parabens and butyl carbamic acid iodopropynyl ester is combinationally used.

As the example of parabens, comprise methyl parabens (methyl parahydroxybenzoate), ethyl p-Hydroxybenzoate (ethylparaben) or propyl p-hydroxybenzoate (propyl p-hydroxybenzoate) etc.

The content of the specific antiseptic in skin preparations for extenal use of the present invention suitably can set on the basis considering the molecular structure of the compound being used as specific antiseptic, physical property.Below, the content of the specific compound that the present invention is preferably suitable for is shown, but the kind of specific antiseptic in the present invention and content thereof are not limited to these.

When using phenyl phenol, the content of phenyl phenol is preferably 0.001 quality % ~ 1 quality % relative to the gross mass of skin preparations for extenal use, is more preferably 0.001 quality % ~ 0.7 quality %, more preferably 0.001 quality % ~ 0.5 quality %.

When using methyl parabens, the content of methyl parabens is preferably 0.001 quality % ~ 0.5 quality % relative to the gross mass of skin preparations for extenal use, is more preferably 0.001 quality % ~ 0.3 quality %, more preferably 0.001 quality % ~ 0.2 quality %.

When using ethyl p-Hydroxybenzoate, the content of ethyl p-Hydroxybenzoate is preferably 0.001 quality % ~ 0.5 quality % relative to the gross mass of skin preparations for extenal use, is more preferably 0.001 quality % ~ 0.3 quality %, more preferably 0.001 quality % ~ 0.2 quality %.

When using butyl carbamic acid iodopropynyl ester, the content of butyl carbamic acid iodopropynyl ester is preferably 0.0001 quality % ~ 0.02 quality % relative to the gross mass of skin preparations for extenal use, is more preferably 0.001 quality % ~ 0.015 quality %, more preferably 0.002 quality % ~ 0.01 quality %.

In the present invention, whether the compound as antiseptic has anti-corrosive properties is by judging based on the conventional method of minimal inhibitory concentration (Minimum Inhibitory Concentration:MIC).

Here, minimal inhibitory concentration (Minimum Inhibitory Concentration:MIC) refers to the minimum (quality %) of the antiseptic needed for propagation suppressing specific bacteria.MIC value is less, and the antiseptic effect of this compound is stronger, and this numerical value is larger on the contrary, represent meet some special datum antiseptic effect then needs add in large quantities.

MIC is obtained by " the microbial limit test method(s) " in the ordinary test method in " Pharmacopeia of Japan the 15 corrects (Heisei 18 years) ".As microbial limit test method(s), there is membrane filter method, agar plate mixes interpretation of the law, agar plate surface semar technique and fluid medium stage dilution method.As the MIC in the present invention, use the value obtained by fluid medium stage dilution method.

The example of the MIC (escherichia coli) shown in specific antiseptic He other antiseptic is below shown.

Methyl parabens (methyl parahydroxybenzoate) (MIC:0.2 quality %)

Phenyl phenol (MIC:0.4 quality %)

Ethyl p-Hydroxybenzoate (ethylparaben) (MIC:0.1 quality %)

Butyl carbamic acid iodopropynyl ester (MIC:0.01 quality %)

Sensiva SC50 (MIC:0.2 quality %)

Caprylyl glycol (MIC:0.2 quality %)

Penta glycol (MIC:2.65 quality %)

<N-acyl amino acid monoester >

Skin preparations for extenal use of the present invention is preferably containing N-acyl amino acid monoester.N-acyl amino acid monoester is in comprising in the emulsion of enoxolone preferably containing in oil phase contained by skin preparations for extenal use of the present invention.

N-acyl amino acid monoester can be synthesized by the chemical reaction of acyl group, neutral amino acid and the alcohols forming esteratic site.In addition, as the synthetic method of N-acyl amino acid monoester, the method described in paragraph [0047] ~ [0053] of Japanese Unexamined Patent Publication 11-246841 publication can be listed.

As acyl group; preferably having carbon number is the saturated of the straight or branched of 6 ~ 22 or unsaturated hydrocarbons, such as, be the acyl group that can derive from capric acid, lauric acid, myristic acid, Palmic acid, stearic acid, behenic acid, linoleic acid, linolenic acid, oleic acid, isostearic acid, 2 ethyl hexanoic acid, coco-nut oil fatty acid, tallow fatty acids, solidification tallow fatty acids etc.

As preferred acyl group, caproyl, lauroyl, myristyl, palmityl, stearyl, mountain Yu acyl group, cocoyl etc. can be listed.

As neutral amino acid, glycine, alanine, beta Alanine, aminobutyric acid, alanine, sarcosine, N-methyl-Beta-alanine etc. can be listed, preferred glycine, alanine, valine, leucine, isoleucine, serine, threonine, proline, beta Alanine, aminobutyric acid, sarcosine and N-methyl-Beta-alanine, particularly preferably sarcosine, alanine, glycine and N-methyl-Beta-alanine.In addition, these aminoacid can be optically active bodies also can be raceme.

As forming the alcohols of esteratic site, can list carbon number be 1 ~ 40 straight or branched, carbon number be the cyclic alcohol etc. of 3 ~ 30.

Be the straight or branched of 1 ~ 40 as carbon number, can list such as carbon number be 1 ~ 5 lower alcohol, carbon number be the higher alcohol etc. of 6 ~ 20.

From the deliquescent viewpoint of enoxolone in oil phase, as the alcohols forming esteratic site, having carbon number in preferred molecule is the branched-chain or straight-chain alkyl of 1 ~ 10 or the alcohols of alkenyl, more preferably has the alcohols of alkyl in molecule.

Be the cyclic alcohol of 3 ~ 30 as carbon number, such as ring propanol, cyclobutanol, cyclopentanol, Hexalin etc. can be listed.

In addition, in addition to the foregoing, as the alcohols forming esteratic site, also the sterols etc. such as cholesterol, beta-cholestanol, plant sterol can be listed.

As the alcohols forming esteratic site, such as methanol, ethanol, propanol, isopropyl alcohol, butanols, the tert-butyl alcohol, isobutanol, 3-methyl-1-butanol, 2-methyl-1-butene alcohol, amylalcohol, hexanol, Hexalin, capryl alcohol, 2-ethyl-hexanol, decanol, fusel wet goods can be listed.

Wherein, there is the alcohols that carbon number is the branched-chain or straight-chain alkyl of 2 ~ 8, most preferably isopropyl alcohol in preferred molecule.

As the combination of the alcohols of acyl group, neutral amino acid and formation esteratic site used during synthesis N-acyl amino acid monoester, the combination such as " lauroyl, sarcosine and isopropyl alcohol ", " myristoyl, beta Alanine and plant sterol " or " caproyl, glycine and isobutanol " can be listed.

Wherein, from the deliquescent viewpoint of enoxolone, the combination of preferred lauroyl, sarcosine base and isopropyl alcohol.

In addition, the N-acyl amino acid monoester in the present invention, except basis can be synthesized by above-mentioned known synthetic method, can also use commercially available product.As the example of commercially available product, the myristoyl methylaminopropionic cetyl ester (trade name AMITER MA-HD) etc. of the N-Hamposyl L isopropyl ester (trade name Eldew SL-205) of Ajinomoto Co., Ltd., N-myristoyl-N-methyl beta Alanine plant sterol base-decyl myristyl ester (trade name EldewAPS307), Japanese Emulsion can be listed.

As N-acyl amino acid monoester, preferably have the aminoacid be selected from the group that is made up of sarcosine, alanine, glycine and N-methyl-Beta-alanine carried out N-caproyl, N-lauroyl, N-myristyl, N-are palmitoylated, N-stearyl, N-mountain Yu acyl group or N-cocoyl and the part-structure obtained and above-mentioned aminoacid is had carry out esterified with alkyl and the side chain obtained or straight chain, carbon number are the ester of the part-structure of the alkyl chain length of 2 ~ 8.

In above-mentioned N-acyl amino acid monoester, more preferably N-Hamposyl L isopropyl ester in the present invention.

These N-acyl amino acid monoesters can a kind be used alone or be two kinds or more.

N-acyl amino acid monoester is the composition that the enough high concentrations needed for Function that enoxolone can be made to be expected to dissolve enoxolone.From this viewpoint, the emulsion comprising enoxolone in the present invention preferably contains N-acyl amino acid monoester, more preferably containing N-Hamposyl L isopropyl ester.

The content of the N-acyl amino acid monoester in skin preparations for extenal use of the present invention is preferably counted 2 times amount ~ 200 times amount with quality criteria relative to the gross mass of enoxolone, is more preferably 5 times amount ~ 100 times amount, more preferably 10 times amount ~ 50 times amount.When the content of N-acyl amino acid monoester is relative to when the gross mass of enoxolone is in the scope counting 2 times amount ~ 200 times amount with quality criteria, comprise having good stability of the emulsion of enoxolone, therefore preferably.

< emulsifying agent >

Skin preparations for extenal use of the present invention is preferably containing emulsifying agent.

During the preparation of emulsion in the present invention, emulsifying agent can be added in any one of aqueous phase composition and oil phase composition according to the characteristic of each emulsifying agent.

As emulsifying agent, as long as any one in nonionic surfactant and ionic surfactant.In addition, as one of the optimal way of the emulsifying agent in the present invention, the emulsifying agent comprising phospholipid can be listed.

(nonionic surfactant)

As the example of nonionic surfactant, polyglyceryl fatty acid ester, fatty acid glyceride, organic acid mono-glyceride, polyglycerol fatty acid ether, methyl glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxy-propylene, polyoxyethylene sterol, polyoxyethylene solidification Oleum Ricini, polyglycereol condensation ricinoleate ester, sorbitan fatty acid esters, sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid esters etc. can be listed.Wherein, preferably sucrose fatty acid ester and polyglyceryl fatty acid ester.

The total amount of nonionic surfactant is preferably below 20 quality % relative to the gross mass of emulsion, is more preferably 2 quality % ~ 15 quality %, more preferably 5 quality % ~ 10 quality %.

Polyglyceryl fatty acid ester

Polyglyceryl fatty acid ester is from the view point of emulsifying capacity, and HLB is preferably 10 ~ 16, is more preferably 11 ~ 15.

Here, HLB value, with the equilbristat of the hydrophilic-hydrophobic used in common surfactant field, can use normally used calculating formula, such as river above formula etc.In the present invention, river above formula is as follows.

HLB＝7+11.7log(M _w/M ₀)

Here, M _wthe molecular weight of hydrophilic group, M ₀it is the molecular weight of hydrophobic group.

In addition, the numerical value of the middle HLB value recorded such as catalogue can be used.

In addition, from above formula, utilize the additivity of HLB, the emulsifying agent of any HLB value can be obtained.

As the preferred example of polyglyceryl fatty acid ester, six monomyristins, six glyceryl monolaurates, SY-Glyster MO 750, SY-Glyster MSW 750, ten glycerol monoisostearate, ten glycerol monopalmitate, ten monomyristins, DECAGLYCERYL MONOLAURATE, decaglycerinmonolinoleate Decaglycerin monolinoleate, ten glycerol diisopstearates etc. can be listed.Wherein, preferred SY-Glyster MO 750, SY-Glyster MSW 750, ten glycerol monoisostearate, ten glycerol monopalmitate, ten monomyristins, particularly preferably SY-Glyster MO 750, SY-Glyster MSW 750, ten glycerol monoisostearate.

In addition, as polyglyceryl fatty acid ester, commercially available product can also be used.As the example of commercially available product, isostearic acid polyglycerin ester-10 (HLB=12) (daylight Chemicals system), polyglyceryl oleate-10 (HLB=12) (daylight Chemicals system), myristic acid polyglycerin ester-10 (HLB=14), polyglycerol stearate-10 (HLB=12), myristic acid polyglycerin ester-6 (HLB=11) etc. can be listed.

These polyglyceryl fatty acid esters one can be used alone or used by multiple combination.

Sucrose fatty acid ester

As the preferred example of sucrose fatty acid ester, Sucrose myristate, sucrose palmitate, sucrose stearate, sucrose oleate sucrose erucate etc. can be listed.

In addition, as sucrose fatty acid ester, commercially available product can also be used.

These sucrose fatty acid ester one can be used alone or used by multiple combination.

(ionic surfactant)

As ionic surfactant, can be any one in anion surfactant, cationic surfactant and amphoteric surfactant.

As the example of ionic surfactant, alkylsulfonate, alkyl sulfate, MAP, soap etc. can be listed.As salt, sodium chloride, sodium citrate, sodium ascorbate etc. can be used.These ionic surfactants one can be used alone or used by multiple combination.

In addition, these ionic surfactants can combinationally use with arbitrary proportion relative to the gross mass of the emulsion contained by the present invention.

(comprising the emulsifying agent of phospholipid)

As one of the optimal way of the emulsifying agent in the present invention, the emulsifying agent comprising phospholipid can be listed.As the emulsifying agent comprising phospholipid, preferably lecithin.

Lecithin is the emulsifying agent oil phase composition comprising N-acyl amino acid monoester being demonstrated to good emulsifying capacity, particularly preferably as emulsifying agent when using N-acyl amino acid monoester in the present invention.

In this description, lecithin refers to the lipid mixture being main constituent with various phospholipid being not limited to phosphatidylcholine (PC).As lipid, the glycerol lecithin such as such as phosphatidic acid, phosphatidyl glycerol, phosphatidylinositols, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl methylethanolamine, phosphatidylcholine, Phosphatidylserine, two phosphatidic acid, cardiolipin (cuorin) can be listed; The sheath lecithin etc. such as sphingomyelins.

Lecithin is due to its safety and make the emulsifying capacity forming emulsion in oil dispersion to water, through being often used as food, emulsifying agent used for cosmetic.In addition, in pharmaceuticals, to utilize from skin, mucosa through the osmosis of absorbing material, be also used to the material of pharmaceutical liposome, intravenous lipid emulsion, hemorrhoid or treating for skin disease medicine etc.For food or cosmetic preparation purposes, mainly from the view point of cost, use soybean lecithin more.

In addition, lecithin is the one of phosphoglyceride, is present in natural all vegeto-animal cells, is the main composition composition of organism film.

As the lecithin that spendable natural object is originated, can list with the lecithin etc. of the lecithin in the lecithin of soybean-source, the egg yolk source plant and animal material that is representative.

Soybean lecithin by by dry for the dregs of fat of by-product in soybean oil refining step, refine and manufacture.Content of phospholipid be the pasty state lecithin of less than 70% due to cheap in the thick oil of Semen sojae atricolor of about 30%, in field of food, therefore particularly use this content of phospholipid to be the lecithin of the pasty state of less than 70%.

In recent years, from the physiologically active of phospholipid self, demand to the more emulsifying agent of height, apply the technology such as highly purified, fractional distillation, modification, thus make performance, various lecithin groups that function is different.

Highly purified lecithin carries out removing oil, powdered and the lecithin obtained with acetone equal solvent from above-mentioned pasty state lecithin, and usual lecithin content can reach more than 90%.

As the example of this highly purified lecithin, commercially available has Phospholipon 20 (Lipoid company), レ シ オ Application P (reason grinds Vitamin), SLP White (Tsuji liquefaction), EMULMETIK 300 (Lucas Meyer Cosmetics company) etc.

Except common refined lecithin, can also use mainly improve phosphatidylcholine (PC) content fractionated lecithins, carry out single stranded by enzymolysis and the modified lecithin such as enzymolysis (haemolysis) lecithin obtained or the hydrolecithin that carries out hydrogenation treatment and obtain.

Fractionated lecithins is operated by the operation, distillation etc. that make use of the poor solubility in various solvent from above-mentioned highly purified lecithin and improves the lecithin of specific content of phospholipid, the commercially available lecithin being improved PC content usually.

As the example of fractionated lecithins that improve PC content, commercially available have Phospholipon 50 (PC45%), Phospholipon 85G (PC80%), Phospholipon 90G (PC94%) (above, Lipoid Inc.), EMULMETIK 900 (PC50%), EMULMETIK 930 (PC95%) (above by Lucas Meyer Cosmetics Inc.), SLP-PC70, SLP-PC90 (Yi Shang You Tsuji liquefaction system) etc.

As modified lecithin, roughly distinguish ground words, have hydrolecithin and enzymolysis lecithin.

Wherein, hydrolecithin be in order to improve oxidation, the fatty acid polyenoic acid in lecithin structure is carried out hydrogenation treatment by light stability, be transformed to satisfied fatty acid and the lecithin obtained.This lecithin can be preferred for cosmetic preparation, pharmaceuticals.

As the example of hydrolecithin, have EMULMETIK 320 (Lucas Meyer Cosmetics Inc.), SLP White H (Tsuji liquefaction system) etc.The example of the lecithin obtained as carrying out hydrogenation treatment on the basis that improve PC content, commercially available have EMULMETIK 950 (Lucas MeyerCosmetics Inc.), SLP-PC92H (Tsuji liquefaction system), Phospholipon 90H (Lipoid Inc.) etc.

On the other hand, as enzymolysis lecithin, para-linkage can be listed in the ester bond enzyme of the fatty acid of 2 of glycerol and carry out selectivity decomposition and the lecithin obtained, in order to be called as LYSOLECITHIN SUNLECITHIN A with common lecithin Qu Do.LYSOLECITHIN SUNLECITHIN A is compared with the lecithin before enzymolysis processing, and water solublity improves, usual emulsifying capacity also improves.This enzymolysis processing is carried out initial pasty state lecithin usually, then carries out highly purified to it, but also can carry out enzymolysis processing to fractionated lecithins.Representatively LYSOLECITHIN SUNLECITHIN A, can list SLP White Lyso (Tsuji liquefaction system).

In addition, as the enzyme-treated lecithin different from LYSOLECITHIN SUNLECITHIN A, be manufactured with the lecithin decomposed by the ester bond between phosphoric acid and alkali.By carrying out this process, except lixiviating from phospholipid, show strong anionic property by being formed as phosphatidic acid form.As the example of such enzyme-treated lecithin, commercially available have PA Nagase, lysophosphatide Nagase H (by Nagase ChemiteX Co., Ltd. system) etc.

In above-mentioned lecithin, arbitrary lecithin can be used, but from the view point of maintaining the storage stability of emulsion compositions, preferably soya lecithin, wherein, more preferably highly purified lecithin, fractionated lecithins.

In addition, commercially available product can also be used.As the example of commercially available product, SLP-White (Tsuji liquefaction system can be listed), EMULMETIK 900 (Lucas Meyer system), Phospholipon 50 (Lipoid system), レ シ オ Application P (reason grinds Vitamin system) etc.

Lecithin one can be used alone or used by multiple combination.

The content comprising the emulsifying agent of phospholipid is preferably 0.01 quality % ~ 30 quality % relative to the gross mass of emulsion, is more preferably 0.1 quality % ~ 20 quality %, more preferably 0.5 quality % ~ 10 quality %.

As emulsifying agent, preferably sucrose fatty acid ester, polyglyceryl fatty acid ester or lecithin.

Mentioned emulsifier can one be used alone according to purposes, also multiple combination can be used.

< plant sterol, cholesterol, plant sterol ester and cholesteryl ester >

Skin preparations for extenal use of the present invention preferably comprises at least one oil components (hereinafter appropriately referred to as " specific oil components ") in the compound group being selected from and being made up of plant sterol, cholesterol, plant sterol ester and cholesteryl ester.

Specific oil components is preferably containing in the oil phase of the emulsion contained by skin preparations for extenal use.

Plant sterol is the one of sterol, is the water-fast composition of the white solid being also referred to as plant sterol.As natural goods, there is various plants sterol.Such as cupreol, campesterol, stigmasterol, brassicasterol etc. can be listed.

Plant sterol can be any one in natural goods and composite, mainly can obtain from plant etc.Specifically, by from middle organic solvent extraction such as wood pulps, refine and obtain.

In addition, plant sterol can also use commercially available product.As the example of commercially available product, the plant sterol (trade name) of TAMA BIOCHEMICAL Inc. can be listed; The Generol 122N (trade name) etc. of Henkel Japan Inc..

These plant sterols can one be used alone, and also multiple combination can be used.

Cholesterol (CAS registration number 57-88-5) is the one of sterol, is the water-fast composition of white or yellowish solid.

Cholesterol can be any one in natural goods and composite, mainly can obtain from the fat of higher mammal.Specifically, can obtain by refining from lanoline.

In addition, cholesterol can also use commercially available product.As the example of commercially available product, the reason that can list Li Yan Vitamin Inc. grinds cholesterol (trade name); Japan refines the cholesterol (trade name) etc. of Inc..

Plant sterol ester obtains by the esterification of fatty acid and plant sterol.

As fatty acid, the fatty acid that total carbon atom number is 6 ~ 30 can be listed.Be the fatty acid of 6 ~ 30 as total carbon atom number, specifically, caproic acid, sad, capric acid, lauric acid, Palmic acid, myristic acid, stearic acid, arachidic acid, behenic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid can be listed.Also can for extract the mixture obtained from the natural goodses such as lanoceric acid, macadimia nut fatty acid.In addition, the amino acid derivativges such as the hydroxy fatty acids such as hydroxy stearic acid, N-lauroyl glutamate can also be listed.Wherein, from the view point of raising emulsion stability, preferred isostearic acid or N-lauroyl glutamate.

As plant sterol ester, preferred isostearic acid plant sterol ester, N-lauroyl glutamate two (plant sterol ester/octyldodecyl), hydroxy stearic acid plant sterol ester etc.

These plant sterol esters can one be used alone, and also multiple combination can be used.

Cholesteryl ester obtains by the esterification of fatty acid and cholesterol.

As fatty acid, the fatty acid that total carbon atom number is 6 ~ 30 can be listed.Be the fatty acid of 6 ~ 30 as total carbon atom number, specifically, caproic acid, sad, capric acid, lauric acid, Palmic acid, myristic acid, stearic acid, arachidic acid, behenic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid etc. can be listed.Can be from the natural goodses such as lanoceric acid or macadimia nut fatty acid, extract the fatty acid contained by mixture obtained.In addition, as fatty acid, the amino acid derivativges such as the hydroxy fatty acids such as hydroxy stearic acid, N-lauroyl glutamate also can be listed.Wherein, from the view point of raising emulsion stability, as fatty acid, preferred isostearic acid or lauroyl glutamate.

As cholesteryl ester, preferred cholesterol isostearate, N-lauroyl glutamate two (cholesteryl ester/octyldodecyl), hydroxy stearic acid cholesteryl ester, lanolin fatty acid cholesteryl ester, macadimia nut fatty acid cholesterol ester etc.

These cholesteryl esters can one be used alone, and also multiple combination can be used.

The specific oil components be selected from the group be made up of plant sterol, cholesterol, plant sterol ester and cholesteryl ester can one be used alone as required, also multiple combination can be used.

From the view point of raising emulsion stability, the content of specific oil components is preferably 1 quality % ~ 70 quality % relative to the gross mass of oil components, is more preferably 2 quality % ~ 30 quality %, more preferably 2 quality % ~ 25 quality %.

Other compositions of < >

Skin preparations for extenal use as required can containing other compositions any except above-mentioned each composition.

From the view point of the stability improving astaxanthin class, skin preparations for extenal use can contain antioxidant.As antioxidant, ascorbic acid compound, dibenzylatiooluene, tocopherol compound etc. can be listed.From the angle of stability significantly improving astaxanthin class, as antioxidant, be more preferably selected from least one in ascorbic acid compound.

As ascorbic acid compound, such as ascorbic acid, sodium ascorbate, Magnesium ascorbate, ascorbic acid magnesium sulfate, ascorbic acid sodium sulfate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbic acid glucoside, ascorbyl palmitate can be listed.

As tocopherol compound, the compound in the compound group that is selected from and combined by tocopherol and derivant thereof can being listed and being selected from the compound group that is made up of the rare phenol of fertility three and derivant thereof.The compound being selected from these compound groups can one be used alone, and also multiple combination can be used.In addition, can also use and will be selected from the compound combination use of the compound group be made up of tocopherol and derivant thereof and the compound group be made up of the rare phenol of fertility three and derivant thereof respectively.

As the compound group be made up of tocopherol and derivant thereof, comprise dl-alpha-tocopherol, dl-betatocopherol, dl-Gamma-Tocopherol, dl-Delta-Tocopherol, acetic acid dl-alpha-tocopherol, nicotinic acid-dl-alpha-tocopherol, linoleic acid-dl-alpha-tocopherol, succinic acid dl-alpha-tocopherol etc.Wherein, more preferably dl-alpha-tocopherol, dl-betatocopherol, dl-Gamma-Tocopherol, dl-Delta-Tocopherol and their mixture (mixed tocopherol).In addition, as Tocopheryl derivatives, preferably use carboxylate, the particularly acetate of these tocopherols.

As the compound group be made up of the rare phenol of fertility three and derivant thereof, comprise the rare phenol of α-fertility three, the rare phenol of β-fertility three, the rare phenol of γ-fertility three, the rare phenol of δ-fertility three etc. and give birth to the derivative compound group of three rare phenol from these.In addition, as the rare amphyl of fertility three, these are preferably used to give birth to the acetate of three rare phenol.

As the content of the antioxidant in skin preparations for extenal use, can be 0.0001 quality % ~ 5 quality % relative to the gross mass of skin preparations for extenal use, be preferably 0.001 quality % ~ 3 quality %.

Skin preparations for extenal use can contain functional oil components.Functional oil components can be the oil components that the functional oil components that can expect as various physiologically active is known.In addition, functional oil components also can be used as the solubilizing agent for carotenoid such as astaxanthin classes.

As the object lesson of functional oil components, the ceramide types such as such as natural type ceramide type, sugar-modified ceramide can be listed; Olive oil, Oleum Camelliae, macadimia nut oil, Oleum Ricini, Cortex cocois radicis wet goods oils; The ubiquinone classes such as coenzyme Q10; ω-3 oils such as EPA, DHA, linolenic acid; The hydrocarbon such as Liquid Paraffin, paraffin, vaseline, ceresine, microwax, squalane; The waxes such as Brazil wax, candelilla wax, Cera Flava, lanoline; The esters such as isopropyl myristate, myristic acid 2-octyldodecyl, 2 ethyl hexanoic acid cetyl ester, the different stearyl ester of malic acid two; The fatty acids such as Palmic acid, stearic acid, isostearic acid; The higher alcohols such as hexadecanol, stearyl alcohol, isooctadecanol, 2-octyldodecanol; The silicone oil such as methyl polysiloxane, methyl phenyl silicone; The fatty acid ester of glycerol etc.; The fatsoluble vitamiies such as retinoid, vitamin D class; Deng.

Skin preparations for extenal use can contain from expecting to play the various extracts obtained the natural goods of various living body functional.As so various extracts, such as Radix Ginseng extract can be listed, Radix Gentianae extract, Aloe extract-1, arnica montana extract, Herba Lamii albi extract, Holland's mustard extract, Cortex Mori extract burdock extract, ocean Caulis Hederae Sinensis extract, Bulbus Allii extract, pine extract, Herba Rosmarini Officinalis extract, ononis spinosa extract, Anthemis nobilis extract, Althaea officinalis L. extract, ononis spinosa extract, milfoil extract, Folium paulowniae extract, Herba Apii graveolentis extract, Thymi Serpylli Herba extract-2, Pericarpium Zanthoxyli extract, coltsfoot extract, Flos lupuli (Flos Humuli Lupuli) extract, Pericarpium Citri Reticulatae extract, Herba melissae axillaris extract, sage extract, eucalyptus extracts, roxburgh engelhardtia extractive, Herba Hyperici Erecti extract, camomile extract, Herba Equiseti Arvinsis extract, Pericarpium Zanthoxyli extract, Radix Paeoniae Alba extract, Folium Eriobotryae fermented product etc.

In addition, skin preparations for extenal use can also containing niacin amide acetic acid DL-alpha-tocopherol pantothenic acid alcohol ethylether nicotinic acid benzyl ester β-enoxolone l-menthol etc. as the living body functional composition had except extract.

Except mentioned component, skin preparations for extenal use of the present invention can also suitably containing the adding ingredient usually used in the skin preparations for extenal use of skin preparations for extenal use, particularly scalp according to its form.

As other adding ingredients, the polyhydric alcohol such as such as 1,3-PD can be listed; Monosaccharide or the polysaccharide such as k-carrageenin, locust bean gum, guar gum, hydroxypropyl guar gum, xanthan gum, POLY-karaya, tamarind seed polysaccharide, arabic gum, tragakanta, hyaluronic acid, hyaluronate sodium, chondroitin sulfate sodium sulfate, cyclodextrin; The sugar alcohols such as Sorbitol, mannitol, maltose alcohol, lactose, maltotriose alcohol, xylitol; The vitamin B1 compounds such as thiamine; The vitamin B2 compounds such as riboflavin; The vitamin b 3 compound such as nicotinic acid, niacin amide; The vitamin B complexes such as vitamin B12 compound, folic acid such as vitamin B7 compound, cobalamine such as vitamin B6 compound, biotin such as vitamin B5 compound, pyridoxol such as nicotinic acid, pantothenic acid, pantothenic acid alcohol ethylether; The water soluble vitamins compounds such as gamma oryzanol, orotic acid, glucuronolactone, glucuronamide, Semen Coicis; The inorganic salt such as sodium chloride, sodium sulfate; Casein, albumin, methylated collagen, hydrolytic collagen, water solublity collagen, the albumen of gelatin equimolecular quantity more than 5000; Aminoacid and their derivants such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, cystine, methionine, lysine, oxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, hydroxyproline, acetyl group hydroxyproline; The synthesis macromolecule of the acid of CVP Carbopol ETD2050, polyacrylic acid sodium, polyvinyl alcohol, Polyethylene Glycol, ethylene oxide/propylene oxide block copolymer etc.; The water-soluble cellulose derivatives such as hydroxy ethyl cellulose/methylcellulose; Flavonoid class (catechin, anthocyanidin, flavone, isoflavone, flavane, flavanone, rutin), phenolic acids (chlorogenic acid, ellagic acid, gallic acid, propyl gallate), lignin compound, curcumin compound, coumarin compound, comprise the hydroxystilbene etc. of pterostilbene etc.Skin preparations for extenal use, according to its function, can also add other adding ingredients as such as functional components, excipient, viscosity modifier, radical scavenger etc.

In addition, in the present invention, such as can also and other additives usually used according to its purposes with various active ingredient, pH adjusting agent, pH buffer agent, UV absorbent, spice, coloring agent etc.

[manufacture method of skin preparations for extenal use]

There is no particular limitation for the manufacture method of skin preparations for extenal use of the present invention, preferably manufactures comprising the combination of the emulsion of enoxolone, astaxanthin class, specific antiseptic and other desired compositions.

In skin preparations for extenal use of the present invention, enoxolone contains with the emulsion form comprising enoxolone.

The emulsion comprising enoxolone is prepared with the waterborne compositions emulsifying mixing comprising water composition preferably by the Unctuous compositions making enoxolone be dissolved in preparation in the soluble oil components of enoxolone.The preparation method of the emulsion that the present invention is preferably suitable for is described below.

From the view point of enoxolone to the permeability of skin, the turbidity of skin preparations for extenal use and emulsion stability, the particle diameter containing the emulsified particle in the emulsion of enoxolone is preferably below 500nm, is more preferably below 200nm, more preferably below 150nm.

The assay method of the particle diameter of emulsion and the details of determinator are as described above.

The emulsion comprising enoxolone prepared in the manufacture method of skin preparations for extenal use can be prepared containing the emulsion form in the skin preparations for extenal use of the present invention of final form by making the enoxolone of the desired amount that can obtain the effect expected containing enoxolone make.The preferred content of enoxolone contained in skin preparations for extenal use of the present invention as described above.

As the method made containing astaxanthin class in skin preparations for extenal use of the present invention, can list (1) utilizes solubilizing agent etc. make astaxanthin class solubilising and containing the method in skin preparations for extenal use, the emulsion of (2) preparation containing astaxanthin class, make this emulsion contain the method in skin preparations for extenal use.

Emulsion containing astaxanthin class is prepared preferably through by the Unctuous compositions of preparation in make astaxanthin class be dissolved in oil components that astaxanthin class dissolves and the waterborne compositions emulsifying mixing that comprises water composition.The preparation method of the emulsion that the present invention is preferably suitable for is described below.

The emulsion comprising astaxanthin class can be the emulsion prepared respectively with the emulsion comprising enoxolone, also can be when preparation comprises the emulsion of enoxolone, use the emulsion of both enoxolone and astaxanthin class and preparation.

From the view point of permeability, the turbidity of skin preparations for extenal use, the emulsion stability of astaxanthin class to skin, the particle diameter of the emulsified particle in the emulsion containing astaxanthin class is preferably below 500nm, is more preferably below 200nm, more preferably below 150nm.

The assay method of the particle diameter of emulsion and the details of determinator are as described above.

From the view point of obtaining the effect be expected to containing astaxanthin or derivatives thereof, comprise the gross mass of content relative to this emulsion of the astaxanthin or derivatives thereof in the emulsion of astaxanthin or derivatives thereof, be preferably 0.0001 quality % ~ 10 quality %, be more preferably 0.001 quality % ~ 5 quality %, more preferably 0.005 quality % ~ 3 quality %.

Method containing specific antiseptic in skin preparations for extenal use of the present invention is not particularly limited, method, (ii) preparation of directly adding specific antiseptic can be listed in such as (i) skin preparations for extenal use after the production when comprising the emulsion of enoxolone, in aqueous phase composition, add the method etc. of specific antiseptic.

Skin preparations for extenal use of the present invention comprises the emulsion of enoxolone and comprise the emulsion of astaxanthin class more particularly by preparation respectively, then these emulsions and specific antiseptic and other any compositions is combined to prepare.

Below, the manufacture method of the emulsion that the present invention is preferably suitable for is described.Containing comprising the emulsion of enoxolone and comprising the emulsion of astaxanthin class in emulsion in below illustrating.

Be applicable to emulsion of the present invention to manufacture according to known method.

Below, the preferable production process being applicable to emulsion of the present invention is described in detail.

Be applicable to emulsion of the present invention to be manufactured by the Unctuous compositions of the oil components comprising regulation is mixed with waterborne compositions, emulsifying etc.

When manufacture comprises the emulsion of enoxolone, Unctuous compositions at least containing enoxolone, in addition, can also contain N-acyl amino acid monoester, emulsifying agent, specific oil components and desired arbitrary oil components.

When manufacture comprises the emulsion of astaxanthin class, Unctuous compositions at least containing astaxanthin class, in addition, can also contain emulsifying agent and desired arbitrary oil components.

Below, the example of the preferable production process being applicable to emulsion of the present invention is shown.But the manufacture method of the emulsion in the present invention is not limited to following method.

First, preferably by the mixing of the oil components of regulation, be heated to 60 DEG C ~ 90 DEG C and be prepared into uniform Unctuous compositions.This Unctuous compositions can also contain other oil components as required.

Then, prepared Unctuous compositions is added to while stirring in the waterborne compositions of the water composition containing regulation being heated to 40 DEG C ~ 90 DEG C and mix.

The blending ratio (quality) of Unctuous compositions now and waterborne compositions is not particularly limited, and is preferably 0.1/99.9 ~ 50/50, is more preferably 0.5/99.5 ~ 30/70, more preferably 1/99 ~ 20/80 in Unctuous compositions/waterborne compositions ratio (quality %).

By making Unctuous compositions/waterborne compositions ratio be more than 0.1/99.9, because the effective ingredient amounts such as enoxolone can not reduce, there is the tendency that can not produce emulsion problem in practical use, therefore preferably.In addition, by making Unctuous compositions/waterborne compositions ratio be less than 50/50, there is emulsifier concentration can not stability that is thinning, emulsion the tendency that can not be deteriorated, therefore preferably.

Unctuous compositions is mixed with waterborne compositions, emulsifying time, preferably Unctuous compositions and waterborne compositions are mixed to get thick emulsion, then carry out miniaturization by fine emulsifying means.

As means Unctuous compositions and waterborne compositions being mixed to get thick emulsion, commercially available any mixed media can be used.Such as the mix and blends such as aqueous medium magnetic stirring apparatus, home-use blender, paddle mixer, impeller mixer can be prepared uniform thick emulsion.

In addition, more preferably with mixer means, the i.e. Homomixer, distributing blender, super blender (Ultramixer) etc. with Strong shear power, Unctuous compositions is mixed with waterborne compositions.

In addition, in order to improve the effect of thick emulsifying, on the basis of these mixer meanses, also preferably utilize ultrasonic.

As giving ultrasonic means, preferably use ultrasound homogenizer.As the example of ultrasound homogenizer, ultrasound homogenizer US-600, US-1200T, RUS-1200T, MUS-1200T (doing made by the smart mechanism of Japan of Co., Ltd. above), Ultrasound Processor UIP2000, UIP-4000, UIP-8000, Ultrasound ProcessorUIP-16000 (above by Hielscher Inc.) etc. can be listed.

These high-power ultrasonic irradiation units can with the frequency usage of below 25kHz, preferably 15kHz ~ 20kHz.

In addition, as other mixed medias, can also use do not have from outside mixing part, only need low-energy static mixer, microchannel, micro-mixer etc.

Temperature in this thick emulsifying can be implemented under the arbitrary temp of less than 90 DEG C more than 20 DEG C, but can list and preferably process at the temperature of less than 80 DEG C more than 40 DEG C.

Then, the thick emulsion fine emulsifying means miniaturization will obtained.

As the means of miniaturization, preferably use high pressure homogenizer.High pressure homogenizer, owing to can give the shearing force larger than alr mode, therefore can carry out miniaturization, and commercially available have various device.

High pressure homogenizer is roughly divided into the homogenizing valve-type high pressure homogenizer of the chamber profile high pressure homogenizer with fixing press section and the aperture type controlling extruding.As the example of the former chamber profile high pressure homogenizer, Microfluidizer (Micro fluidics Inc.), Nanomizer (Jitian's machinery industrial Co., Ltd. system), Star Burst (Co., Ltd. Sugino Machine system) etc. can be listed.As the homogenizing valve-type high pressure homogenizer of the latter, Gaulin type homogenizer (APV Inc.), Lanier type homogenizer (Lanier Inc.), high pressure homogenizer (Niro Soavi Inc.), homogenizer (three and Machinery Co., Ltd.'s system), high pressure homogenizer (Izumi Food Machinery Co., Ltd. system), supertension homogenizer (Ika Inc.) etc. can be listed.

High pressure homogenizer possesses very narrow chamber portion or press section in stream, by forcibly carrying liquid with pump to narrow stream, very large pressure differential is produced in the front and back of press section, with this pressure differential for driving-energy, liquid moves in narrow pipeline with the speed that can be equal to velocity of sound, thus and produce large shearing force between stream wall, this power becomes dispersion force.

Institute's applied pressure and the shearing force produced have proportionate relationship, more apply the shear energy of high pressure then for disperseing higher.But known shearing force is not be all used to dispersion, having is more the tendency that high pressure, energy efficiency more reduce, the ratio that changes heat into more increases, and therefore high pressure also exists limit.

In the manufacture of the emulsion in the present invention, from the view point of dispersibility (miniaturization), pressure is preferably made to be more than 100MPa, to be more preferably more than 150MPa.About on high-tension side limit, in commercially available device, rise and resistance to pressure from the view point of temperature, be preferably below 300MPa.

When carrying out miniaturization by fine emulsifying means, the number of times carrying out HIGH PRESSURE TREATMENT can be 1 time, but in order to improve the uniformity of liquid entirety, preferably carries out the HIGH PRESSURE TREATMENT of more than 2 times, more preferably carries out the HIGH PRESSURE TREATMENT of 2 times ~ 5 times.

Good pressure distribution temperature before treatment is preferably set to 20 DEG C ~ 80 DEG C, is more preferably 40 DEG C ~ 70 DEG C.Preferably carry out rapidly cooling, being reduced to set point of temperature with cooling way after firm good pressure distribution process.As chiller, arbitrary commercially available heat exchanger can be used.

As the pH of skin preparations for extenal use of the present invention, from the view point of improve both enoxolone and astaxanthin class stability, from the view point of emulsion stability, preferred pH is more than 5 and less than 8.

PH regulates by the addition regulating various pH adjusting agents etc. and have the composition of pH regulator ability.

Skin preparations for extenal use of the present invention is particularly preferably used as scalp cosmetic preparation.When skin preparations for extenal use of the present invention is made scalp cosmetic preparation, except mentioned component, can also further coordinating example as emollient, inorganic agent, lubricant, wetting agent, educate and send out an agent, hair growth promoter, natural on-off cycles of hair growth agent, anti-achromotrichia, antibiotic, antibacterial, antiinflammatory, anti-allergic agent, antidotal agent, spice, pigment agent, Antiperspiration agent, creeping chill agent, clear Cool agent, warming agent etc.

Embodiment

Below, by embodiment, the present invention is described further particularly, as long as but be no more than purport of the present invention, the present invention is not limited to following embodiment.

" preparation of enoxolone emulsion "

By β enoxolone (ball is apt to pharmacy system) 0.54g, high-purity soybean lecithin (Tsuji liquefaction system; SLP-White) 2.00g, N-Hamposyl L isopropyl ester (Ajinomoto system; Eldew SL-205) 11.02g, oleyl alcohol 1.84g, decyl myristyl alcohol (KOKYU ALCOHOL KOGYO system; RISONOL 24SP) 1.84g, lauroyl glutamate two (plant sterol ester/octyldodecyl) (Ajinomoto system; Eldew PS-203) 3.67g mixing, dissolve while stir limit at 70 DEG C, it can be used as Unctuous compositions A.

On the other hand, by isostearic acid polyglycerin ester-10 (daylight Chemicals system; Decaglyn 1-ISV, HLB=12) 6.13g is dissolved in the mixed liquor of glycerol (with light pure pharmaceutical worker industry system) 48.00g and Milli-Q water 24.97g at 70 DEG C, makes waterborne compositions A.

By the waterborne compositions A that as above prepares and Unctuous compositions A TK Homomixer (PRIME-MIX system) at 60 DEG C with the thick emulsifying of the rotating speed of 500rpm 15 minutes.This thick emulsion supertension dispersal device Star Burst Mini machine (Sugino Machine system) limit is remained on 60 DEG C of limits makes it by 2 times under pressure is 200MPa, prepares fine emulsion (the enoxolone emulsion of oil-in-water type).

The sample NanoTrak UPA (day machine dress system) fine emulsion Purified Water after just preparing being diluted to 50 times carries out the mensuration of emulsion mean diameter, obtains its volume average particle size (Mv).The volume average particle size (Mv) of emulsion is 80 μm.

" preparation of astaxanthin emulsion "

Following compositions limit heating edge at 70 DEG C is dissolved 1 hour, obtains waterborne compositions B.

Following compositions limit heating edge at 70 DEG C is dissolved 1 hour, obtains Unctuous compositions B.

Krill extracts astaxanthin liquid 15.0g

(astaxanthin class containing ratio is 5 quality %, goods name: Astax ST, イ タ ノ Shi Yan Co., Ltd. system)

Mixed tocopherol

(Li Yan Vitamin Co., Ltd. system, reason grinds E oil 800) 4.4g

Lecithin

(Li Yan Vitamin Co., Ltd. system, goods name: レ シ オ Application P, soybean-source) 1.9g

Waterborne compositions B obtained above is used homogenizer (machine name: HP93 under the state remaining 70 DEG C, (strain) SMT Inc.) stir (10000rpm), Unctuous compositions B is added in waterborne compositions B, obtains preparing emulsion.

Then, the preparation emulsion obtained is cooled to about 40 DEG C, under the pressure of 200MPa, carries out high-pressure emulsification with ア Le テ ィ マ イ ザ ー HJP-25005 (Sugino Machine society of Co., Ltd. system).Then, filter with the microstrainer that average pore size is 1 μm, prepare astaxanthin emulsion (astaxanthin class containing ratio: 0.3 quality %).

The astaxanthin emulsion Milli-Q water obtained is diluted to 1 quality %, with particle diameter AnalyzerFPAR-1000 (Otsuka Electronics Co., Ltd.) measure the mean diameter of emulsion.The mean diameter of emulsion is 58nm (meso-position radius (d=50)).

[embodiment 1 ~ 5, comparative example 1 ~ 8]

According to the kind of gradation composition with reach the kind shown in table 1 containing ratio and containing the mode of ratio, enoxolone emulsion, astaxanthin emulsion, antiseptic and other compositions are mixed, obtains the skin preparations for extenal use of embodiment 1 ~ embodiment 5, comparative example 1 ~ comparative example 8.

In table 1, the content of each composition represents quality % (total amount is 100 quality %).

[evaluation]

Using a part for each skin preparations for extenal use of embodiment 1 ~ embodiment 5 obtained above and comparative example 1 ~ comparative example 8 as sample for evaluation, for following evaluation.Each evaluation result is shown in table 1.

(1) with the coarse skin restoration evaluation that SDS carries out

In order to the inflammation inhibitory effect that the skin preparations for extenal use confirmed containing enoxolone brings, with sodium lauryl sulphate (SDS), patch test evaluation is implemented to coarse skin model.

According to the condition of coarse skin model, the SDS solution of 0.5 quality % is coated the predetermined portion of upper wrist, then place 1 hour, carry out closed patch test.

Then, at the position identical with the position being coated with SDS solution, use any one sample for evaluation in the skin preparations for extenal use of water (contrast), embodiment 1 ~ 5 and comparative example 1 ~ 8, implement 24 hours closed patch tests.The inflammatory conditions at visualization test position, evaluates the recovery of coarse skin with SDS.

Metewand is: by with the position being coated with water with degree the sample that reddens be evaluated as " C ", the sample slightly reddened be evaluated as " B ", red residual sample will do not had completely to be evaluated as " A ".

(2) anti-corrosive properties

The provocative test carried out of preservation test according to day office is implemented to each sample for evaluation.

Evaluating by adding two kinds of funguses (yeast and aspergillus niger) in each sample for evaluation, making it reach 10 ⁶individual.

By 2 weeks interior funguses 10 ²individual following sample is evaluated as " A ", will will be 10 ³individual above sample is evaluated as " B ", will is being evaluated as " C " of peer-level with initial bacterium number.

(3) emulsion stability

In order to utilize emulsion change of size evaluating skin external preparation contained by the stability of emulsion, the turbidity evaluation of implementation evaluation sample.

Turbidity evaluation is carried out as follows: by each sample for evaluation keeping at 50 DEG C 1 week, by the optical concentration (OD) (1cm cuvette, transmission measurement) of each sample turbidity after keeping under UV visible spectrophotometer mensuration 625nm.

The sample of turbidity more than 0.5 is evaluated as " C ", by turbidity more than 0.3 and be less than 0.5 sample be evaluated as " B ", be that the sample of less than 0.3 is evaluated as " A " by turbidity.

From the known following content of the result shown in table 1.

The known effect containing both enoxolone and astaxanthin class and the skin preparations for extenal use of the embodiment 1 ~ 5 of specific antiseptic with the coarse skin recovery making SDS cause.

Clear in addition, the skin preparations for extenal use of embodiment 1 ~ 5 is by combination containing being selected from as two or more in the methyl parabens of specific antiseptic, phenyl phenol, ethyl p-Hydroxybenzoate, butyl carbamic acid iodopropynyl ester, and anti-corrosive properties also fully and be not deteriorated containing the emulsion of enoxolone and the stability of astaxanthin emulsion.

Clear on the other hand, the anti-corrosive properties of the skin preparations for extenal use of the comparative example 1 not containing antiseptic are poor, and the performance as skin preparations for extenal use is insufficient.

Knownly to coordinate in the skin preparations for extenal use of the comparative example 2 of the ethanol sending out in agent amount corresponding to the amount of alcohol (before and after 50 quality %) that coordinates with educating in the past, even if do not add antiseptic, also give anti-corrosive properties, but coarse skin recovery effects has been insufficient.Insufficient to the coarse skin preventing effectiveness of the skin preparations for extenal use having coordinated the comparative example 3 of the ethanol fewer than comparative example 2 amount, the anti-corrosive properties of the comparative example 4 that amount of alcohol is few in addition reduce.These result display, a small amount of ethanol coordinated also can affect the suppression of coarse skin.

Clear in addition, along with the use level of ethanol increases, the stability of emulsion is also deteriorated.

Employ the comparative example 5 (containing Sensiva SC50 and caprylyl glycol) of the antiseptic except specific antiseptic and comparative example 6 (containing caprylyl glycol and penta glycol) although skin preparations for extenal use impart anti-corrosive properties, the bad stability of emulsion.

In addition we know, the coarse skin recovery effects of the skin preparations for extenal use of the skin preparations for extenal use of the comparative example 7 not containing enoxolone, the comparative example 8 not containing astaxanthin class is insufficient.

[embodiment 6]

According to following prescription, prepare daily hair treatment.Following numerical value refers to the quality % relative to prescription gross mass.In addition, about enoxolone emulsion and astaxanthin emulsion, obtained by said method.

Confirm by carrying out above-mentioned evaluation, the daily hair treatment of embodiment 6 has the coarse skin recovery effects of sufficient scalp, can not damage the stability of the emulsion containing enoxolone and the emulsion containing astaxanthin and have sufficient antiseptic effect.

Known by above result, in order to by making enoxolone and astaxanthin class and being used for playing coarse skin recovery effects and not giving skin preparations for extenal use with anti-corrosive properties with damaging the stability of emulsion, to need containing specific antiseptic and in fact not containing ethanol.

In addition we know, when skin preparations for extenal use of the present invention is applied to scalp cosmetic preparation, the stable effect that both enoxolone and astaxanthin class are brought can be expected.

The disclosure of the Japan Patent Japanese publication 2013-248315 that the Japanese patent application 2013-008703 and 2013 of application on January 21st, 2013 applies for 29, on November is by referring to including in this description.

The all documents recorded in this description, patent application and technical standard and specifically and record respectively each document, patent application and technical standard time equal extent by referring to including in this description.

Claims (8)

1. a skin preparations for extenal use, it contains: comprise the emulsion of enoxolone, be selected from the group that is made up of astaxanthin and astaxanthin derivatives at least one and I/O value be less than 1.5 and do not there is alkyl or there is the antiseptic that alkyl chain length is the straight or branched alkyl of less than 5

The content of described skin preparations for extenal use not containing ethanol or ethanol is below 1 quality %.

2. skin preparations for extenal use according to claim 1, wherein, the emulsion comprising enoxolone contains the emulsifying agent comprising phospholipid.

3. skin preparations for extenal use according to claim 1 and 2, wherein, the emulsion comprising enoxolone contains N-acyl amino acid monoester.

4. the skin preparations for extenal use according to any one of claims 1 to 3, wherein, the emulsion comprising enoxolone contains N-Hamposyl L isopropyl ester.

5. the skin preparations for extenal use according to any one of Claims 1 to 4, wherein, I/O value is less than 1.5 and does not have alkyl or have alkyl chain length is at least one antiseptic that the antiseptic of the straight or branched alkyl of less than 5 comprises in the group being selected from and being made up of phenyl phenol, parabens and butyl carbamic acid iodopropynyl ester.

6. the skin preparations for extenal use according to any one of Claims 1 to 5, the at least one be selected from the group that is made up of astaxanthin and astaxanthin derivatives contains with emulsion form by it, and described emulsion contains at least one in the group being selected from and being made up of astaxanthin and astaxanthin derivatives and comprises the emulsifying agent of phospholipid.

7. the skin preparations for extenal use according to any one of claim 1 ~ 6, wherein, the content of enoxolone is 0.0001 quality % ~ 0.5 quality %.

8. the skin preparations for extenal use according to any one of claim 1 ~ 7, it is scalp cosmetic preparation.