WO2016038193A1

WO2016038193A1 - Emulsion comprising oil phase dispersed in outer phase having bicontinuous structure and method for producing the same

Info

Publication number: WO2016038193A1
Application number: PCT/EP2015/070845
Authority: WO
Inventors: Masayoshi Miyamoto; Tomomi Kuromiya
Original assignee: Chanel Parfums Beaute
Priority date: 2014-09-12
Filing date: 2015-09-11
Publication date: 2016-03-17
Also published as: JP6290050B2; JP2016056151A

Abstract

The present invention provides an emulsion obtained by dispersing a physiologically acceptable salt of a tranexamate ester whose solubility in water and oil is low in a stable state in a composition. An emulsion comprising an oil phase dispersed in an outer phase having a bicontinuous structure, wherein the outer phase contains A) a physiologically acceptable salt of a tranexamate ester; B) an amphiphilic substance selected from combinations of a linear or branched, saturated or unsaturated alcohol having 12 to 22 carbon atoms and an alkyl glyceryl ether, which is a mono- or diether of a linear or branched, saturated or unsaturated alcohol having 8 to 22 carbon atoms and glycerin; C) an oil; and D) water; the oil phase as a dispersed phase contains E) an oil; and the total content of ingredients constituting the outer phase is 55 to 95 mass% and the total content of ingredients constituting the dispersed phase is 5 to 4 mass% based on the total mass of the emulsion.

Description

EMULSION COMPRISING OIL PHASE DISPERSED IN OUTER PHASE HAVING BICONTINUOUS STRUCTURE AND METHOD FOR PRODUCING

THE SAME [Technical Field]

[0001]

The present invention relates to an emulsion comprising an oil phase dispersed in an outer phase having a bicontinuous structure and a method for producing the same. The present invention also relates to the cosmetic use of the emulsion and a cosmetic method for inhibiting pigmentation of and/or whitening the skin.

[Background Art]

[0002]

A tranexamate ester or a salt thereof has been known to exhibit a whitening effect, and it has been used as a whitening ingredient in compositions for external use. For example, Japanese Patent Laid-Open No. 04-46144 describes an anti- pigmentation agent for external use using a tranexamate ester as an active ingredient. Japanese Patent Laid-Open No. 2003-306419 exemplifies tranexamic acid and derivatives thereof as whitening ingredients to be usable with coenzyme Q10.

Japanese Patent Laid-Open No. 2004-107262 exemplifies a cetyl tranexamate ester as an oil-soluble whitening agent to be usable with an L-ascorbic acid tetra-branched fatty acid ester derivative.

However, a problem of a tranexamate ester or a salt thereof is that it is sparingly soluble in water and oil and this is likely to cause aggregates in a

formulation, and thus it is difficult to disperse it in a formulation in a stable state. [Summary of Invention]

[0004]

Under the circumstances, a method for dispersing a tranexamate ester or a salt thereof in a stable state in a composition is demanded.

[0005]

The present inventors have conducted intensive studies to solve the problem mentioned above and consequently have succeeded in dispersing a physiologically acceptable salt of a tranexamate ester (hereinafter also referred to as a "tranexamate ester salt") at a nano level in an aqueous medium by an ordinary mixing operation by mixing the tranexamate ester salt, an amphiphilic substance and an oil at a specific quantitative ratio in the medium (Japanese Patent No. 5570442).

As a result of further study, the present inventors have found that a composition having a bicontinuous structure in which the water phase and the oil phase are each three-dimensionally continuous can be obtained by mixing a tranexamate ester salt, a specific amphiphilic substance, an oil and water, and thus the tranexamate ester salt can be dispersed in a stable state in the composition.

Furthermore, the present inventors have found that an extremely stable milky or creamy emulsion comprising an oil phase dispersed in an outer phase having a bicontinuous structure can be obtained by adding an oil to this composition. While not being bound by any theory, it is considered that this emulsion comprises a bicontinuous structure, which is an outer phase and is constituted of a robust self- assembled structure, and thus can inhibit coalescing and destabilizing factors such as Ostwald ripening phenomenon observed in common emulsions, thereby enhancing the stability. In addition, there is an advantage that emollient properties, which were not sufficient in a composition merely having a bicontinuous structure, can be improved by taking a form of an emulsion, and thus the feeling of cosmetic products can be improved. The present invention has been completed based on these findings. [0006]

That is, the present invention relates to an emulsion and a method for producing the same, as described below. The present invention also relates to the cosmetic use of the emulsion and to a cosmetic method for inhibiting pigmentation of and/or whitening the skin.

[0007]

The present invention relates to an emulsion comprising an oil phase dispersed in an outer phase having a bicontinuous structure, wherein

the outer phase contains

A) a physiologically acceptable salt of a tranexamate ester;

B) an amphiphilic substance selected from combinations of a linear or branched, saturated or unsaturated alcohol having 12 to 22 carbon atoms and an alkyl glyceryl ether, which is a mono- or diether of a linear or branched, saturated or unsaturated alcohol having 8 to 22 carbon atoms and glycerin;

C) an oil; and

D) water, a water-soluble organic solvent or a mixture thereof;

and the oil phase (as dispersed phase) contains

E) an oil;

and wherein the total content of ingredients constituting the outer phase is 55 to 95 mass and the total content of ingredients constituting the dispersed phase is 5 to 45 mass based on the total mass of the emulsion.

Preferably according to the invention, the tranexamate ester is represented by the following formula (1):

wherein R represents a linear or branched, saturated or unsaturated hydrocarbon group having 1 to 22 carbon atoms, which may be substituted by a substituent selected from a hydroxy group and an amino group.

More preferably, the physiologically acceptable salt of a tranexamate ester is cetyl tranexamate hydrochloride.

Preferably, the amphiphilic substance is a combination of cetyl alcohol and at least one compound selected from the group consisting of chimyl alcohol and batyl alcohol.

Preferably, the content of ingredient A is 0.5 to 10 mass , the content of ingredient B is 0.5 to 10 mass , the content of ingredient C is 1 to 25 mass and the total content of ingredients A, B and C is 5 to 50 mass based on the total mass of the emulsion.

Preferably, the outer phase of the emulsion of the invention further contains a pH regulator. Such a pH regulator may be selected from Lewis bases.

The present invention also relates to a method for producing the emulsion according to the present invention, comprising the steps of:

preparing an oil phase containing

A) a physiologically acceptable salt of a tranexamate ester;

B) an amphiphilic substance selected from combinations of a linear or branched, saturated or unsaturated alcohol having 12 to 22 carbon atoms and an alkyl glyceryl ether, which is a mono- or diether of a linear or branched, saturated or unsaturated alcohol having 8 to 22 carbon atoms and glycerin; and

C) an oil;

adding the oil phase to a water phase containing

D) water, a water-soluble organic solvent or a mixture thereof

to form an outer phase having a bicontinuous structure; and

adding an oil phase containing E) an oil

to the outer phase to form a dispersed phase.

The present invention also relates to a composition for external use containing the emulsion according to the invention.

The present invention also relates to the cosmetic use of the emulsion according to the invention, for inhibiting pigmentation of and/or whitening the skin, and/or for reducing an aging spot or pigmentation.

The present invention also relates to a cosmetic method for inhibiting pigmentation of and/or whitening the skin, the method comprising topical application, to the skin, of the emulsion according to the invention.

[0008]

According to the present invention, a milky or creamy emulsion comprising a tranexamate ester salt can be obtained. The emulsion of the present invention can be used for inhibiting pigmentation of and/or whitening the skin, and/or for reducing an aging spot or pigmentation.

According to the present invention, it is possible to disperse a tranexamate ester salt in a stable state in the emulsion, and thus the tranexamate ester salt easily penetrates the skin when applied to the skin, and a whitening effect of the

tranexamate ester salt is expected to be enhanced thereby.

[0009]

The description of the drawings is as follows:

Fig. 1 shows the cryo SEM observation results (micrographs) for the composition of Reference Example 1. Fig. 1(a) is an observation result with magnification of 12,000 and Fig. 1(b) is an observation result with magnification of 35,000.

Fig. 2 shows the cryo SEM observation results (micrographs) for the composition of Example 3. Figs. 2(a) and 2(b) show the cryo SEM observation results before FIB processing. Fig. 2(a) is an observation result with magnification of 64 and Fig. 2(b) is an observation result with magnification of 650. Figs. 2(c) and 2(d) show the cryo SEM observation results after FIB processing. Fig. 2(c) is an observation result with magnification of 5,000 and Fig. 2(d) is an observation result with magnification of 12,000.

Fig. 3 shows the results (graph) of the thermal analysis by DSC for the compositions obtained in Reference Example 1 and Examples 1 to 4. In the figure, (a), (b), (c), (d) and (e) illustrate the measurement results of the compositions of Reference Example 1, Example 1, Example 2, Example 3 and Example 4, respectively.

[0010]

In the following, the emulsion, the method for producing the same and the use of the emulsion according to the present invention will be described in detail.

[0011]

The emulsion of the present invention is an emulsion comprising an oil phase dispersed in an outer phase having a bicontinuous structure, wherein the outer phase contains

A) a physiologically acceptable salt of a tranexamate ester;

C) an oil; and

D) water, a water-soluble organic solvent or a mixture thereof;

and the oil phase (as dispersed phase) contains

E) an oil;

and the total content of ingredients constituting the outer phase is 55 to 95 mass and the total content of ingredients constituting the dispersed phase is 5 to 45 mass based on the total mass of the emulsion. [0012]

As described above, the emulsion of the present invention comprises an oil phase dispersed in an outer phase having a bicontinuous structure. In the emulsion of the present invention, the outer phase contains A) a tranexamate ester salt, B) an amphiphilic substance, C) an oil and D) water, a water-soluble organic solvent or a mixture thereof. In the emulsion of the present invention, a bicontinuous structure is formed by adding D) water, a water-soluble organic solvent or a mixture thereof, to a mixture containing A) the tranexamate ester salt, B) the amphiphilic substance and C) the oil. Here, the "bicontinuous structure" refers to a state in which the water phase and the oil phase are each continuous three-dimensionally, and the water and oil phases coexist without phase separation of each phase. Specifically, the term means that an infinite aggregate such as a liquid crystal (LC) phase, a bicontinuous microemulsion (BME), a bicontinuous cc-gel (BAG) and/or a sponge (L3) phase is formed. An example of such a bicontinuous structure is exemplified in Figures 2C and D.

The fact that the outer phase has a bicontinuous structure can be confirmed, for example, by adding an oil- soluble dye and a water-soluble dye to allow both of them to diffuse into the outer phase. Besides, a liquid crystal (LC) phase exhibiting anisotropy can be confirmed by observing birefringence with a polarized light microscopy. Meanwhile, a bicontinuous microemulsion (BME), bicontinuous cc-gel (BAG), and sponge (L3) phase can be confirmed by observing the flow birefringence. Here, the "flow birefringence" refers to a birefringence showing phenomenon in which, when an isotropic gel-like structure is made to flow by shaking and the like, the structure is oriented in the direction of the flow.

The emulsion of the present invention is obtained by dispersing an oil phase containing E) an oil in the obtained outer phase having a bicontinuous structure. In the following, each ingredient will be described. [0013]

A) Tranexamate ester salt

It is preferable that the tranexamate ester used in the present invention is represented by the following formula (1):

wherein R represents a cyclic or acyclic, linear or branched, saturated or unsaturated hydrocarbon group having 1 to 22 carbon atoms, which may be substituted by a substituent selected from a hydroxyl group and an amino group.

[0014]

In Formula (1), R represents a cyclic or acyclic, linear or branched, saturated or unsaturated hydrocarbon group having 1 to 22 carbon atoms, in which a hydrogen atom contained therein may be replaced by a substituent selected from a hydroxyl group and an amino group.

The hydrocarbon group may be acyclic or cyclic. In the case where the hydrocarbon group is acyclic, it may be a linear or branched chain. Examples of the hydrocarbon group include: an alkyl group, an alkenyl group, an alkynyl group, an alkyldienyl group, an aryl group, an alkylaryl group, an arylalkyl group, a cycloalkyl group, a cycloalkenyl group, and a cycloalkylalkyl group. Among them, an alkyl group is preferable. The number of carbon atoms is preferably 8 to 20, and especially preferably 12 to 18.

[0015]

There are no particular restrictions on the number of substituents on the hydrocarbon group. In the case where the hydrocarbon group has 2 or more substituents, the substituents may be either hydroxyl groups or amino groups, or both of hydroxyl group(s) and amino group(s).

[0016]

Specific examples of the tranexamate ester represented by Formula (1) include lauryl tranexamate, myristyl tranexamate, cetyl tranexamate and stearyl tranexamate. Among them, cetyl tranexamate is especially preferable.

[0017]

There are no particular restrictions on a physiologically acceptable tranexamate ester salt to be used in the present invention, as long as the object of the present invention is not impeded. Preferable examples of the tranexamate ester salt to be used in the present invention include a mineral acid salt, such as hydrochloride, phosphate, sulfate, bromate, and nitrate; an organic acid salt, such as oxalate, lactate, and citrate; and carbonate of a tranexamate ester. Among them, a hydrochloride is preferred.

[0018]

Among others, a tranexamate ester salt to be used in the present invention is preferably selected from the group consisting of cetyl tranexamate hydrochloride, cetyl tranexamate phosphate, cetyl tranexamate sulfate, cetyl tranexamate bromate, cetyl tranexamate nitrate, cetyl tranexamate oxalate, cetyl tranexamate lactate, cetyl tranexamate citrate, and cetyl tranexamate carbonate. Cetyl tranexamate

hydrochloride is especially preferable.

The tranexamate ester salts may be used singly or in combinations of two or more.

[0019]

The content of the tranexamate ester salt (ingredient A) in the emulsion of the present invention is preferably 0.5 to 10 mass , more preferably 1 to 6 mass and still more preferably 2 to 4 mass based on the total mass of the emulsion. [0020]

B) Amphiphilic substance

The amphiphilic substance used in the present invention is selected from combinations of a linear or branched, saturated or unsaturated alcohol having 12 to 22 carbon atoms and an alkyl glyceryl ether, which is a mono- or diether of a linear or branched, saturated or unsaturated alcohol having 8 to 22 carbon atoms and glycerin. In the present invention, the outer phase can form a bicontinuous structure thanks to the amphiphilic substance.

[0021]

The alcohol is not particularly limited as long as it has a linear or branched, saturated or unsaturated alkyl group having 12 to 22 carbon atoms. The number of carbon atoms of the alkyl group is preferably 14 to 20, more preferably 16 to 18.

Specifically, lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol, cetostearyl alcohol, 2-decyltetradecanol, lanolin alcohol, cholesterol, phytosterol, hexyl dodecanol, isostearyl alcohol, octyldodecanol and the like are preferably used. Among these, linear and saturated alcohols are preferred; lauryl alcohol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol and oleyl alcohol are more preferred; cetyl alcohol, cetostearyl alcohol and stearyl alcohol are still more preferred; and cetyl alcohol is particularly preferred.

[0022]

The alkyl glyceryl ether, which is a mono- or diether of a linear or branched, saturated or unsaturated alcohol having carbon 8 to 22 atoms and glycerin, is not particularly limited as long as it is a mono- or diether of an alcohol mentioned above and glycerin, and a monoether of a linear and saturated alcohol and glycerin is particularly preferred. The number of carbon atoms of the alkyl group is preferably 14 to 20, and more preferably 16 to 18. Examples of the alkyl glyceryl ether include glyceryl monostearyl ether (batyl alcohol), glyceryl monocetyl ether (chimyl alcohol), monooleyl glyceryl ether (selachyl alcohol), monobehenyl glyceryl ether, mono-2-ethylhexyl glyceryl ether, monoisostearyl glyceryl ether, monocapryl glyceryl ether, monoisodecyl glyceryl ether, monoisostearyl diglyceryl ether, and glycerin mono-2-ethylhexyl ether.

Among these, monostearyl glyceryl ether (batyl alcohol), glyceryl monocetyl ether (chimyl alcohol), and monooleyl glyceryl ether (selachyl alcohol) are preferred.

[0023]

The linear or branched, saturated or unsaturated alcohol having carbon 12 to 22 atoms and the alkyl glyceryl ethers, which are mono- or diethers of a linear or branched, saturated or unsaturated alcohol having 8 to 22 carbon atoms and glycerin may each be used singly or in combinations of two or more. The amphiphilic substance as ingredient B is preferably a combination of cetyl alcohol and at least one selected from the group consisting of chimyl alcohol and batyl alcohol. Among these, a combination of cetyl alcohol and chimyl alcohol or a combination of cetyl alcohol and batyl alcohol is preferably used. The mixing ratio of the alcohol and the alkyl glyceryl ether is preferably 1 :9 to 9: 1, more preferably 1 :6 to 6: 1, still more preferably 1 :3 to 3: 1 as a mass basis.

[0024]

The content of the amphiphilic substance (ingredient B) in the emulsion of the present invention is preferably 0.5 to 10 mass , more preferably 1 to 6 mass , still more preferably 2 to 4 mass in total based on the total mass of the emulsion.

[0025]

C) Oil

The oil for use in the present invention is not limited as long as it is a material having a property of not dissolving or being difficult to dissolve in water and being easy to dissolve in oil. Examples of the oil for use as ingredient C in the present invention preferably include low viscosity liquid oils/fats, solid oils/fats, waxes, hydrocarbon oils, synthetic ester oils, silicone oils and silicone elastomers that are commonly used in compositions for external use.

[0026]

Examples of the liquid oil/fat (oil/fat which is liquid at room temperature

(25°C)) include avocado oil, camellia oil, turtle oil, macadamia nut oil, corn oil, mink oil, olive oil, rapeseed oil, yolk oil, sesame oil, persic oil, wheat germ oil, camellia kissi oil, castor oil, linseed oil, safflower oil, cottonseed oil, perilla oil, soybean oil, peanut oil, tea seed oil, Torreya seed oil, rice bran oil, Chinese tung oil, Japanese tung oil, jojoba oil, germ oil, and triglycerin.

Examples of the solid oil/fat (oil/fat which is solid at room temperature (25°C)) include cacao butter, coconut oil, horse tallow, hardened coconut oil, palm oil, palm kernel oil, Japan tallow kernel oil, hardened oil, Japan tallow, and hardened castor oil.

[0027]

Examples of the wax include bees wax, candelilla wax, cotton wax, carnauba wax, bayberry wax, Chinese insect wax, montan wax, bran wax, lanolin, kapok wax, acetylated lanolin, liquid lanolin, sugar cane wax, lanolin fatty acid isopropyl ester, hexyl laurate, reduction lanolin, jojoba wax, hard lanolin, shellac wax, POE lanolin alcohol ether, POE lanolin alcohol acetate, POE cholesterol ether, lanolin fatty acid polyethylene glycol, and POE hydrogenated lanolin alcohol ether.

[0028]

Examples of the hydrocarbon oil include liquid paraffin, ozokerite, squalane, pristane, paraffin, ceresin, squalene, vaseline, microcrystalline wax, hydrogenated polydecene, and isododecane.

[0029] Examples of the synthetic ester oil include tripropylene glycol

dineopentanoate, isononyl isononanoate, isotridecyl isononanoate, isopropyl myristate, cetyl octanoate, cetyl isooctanoate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, hexyldecyl dimethyloctanoate, cetyl lactate, myristyl lactate, acetylated lanolin, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearate, ethylene glycol di-2-ethylhexanoate, dipentaerythritol fatty acid ester, N-alkylglycol monoisostearate, neopentyl glycol dicaprylate, diisostearyl malate, glyceryl di-2- heptylundecanoate, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, pentaerythritol tetra-2-ethylhexanoate, glyceryl tri-2-ethylhexanoate, glyceryl trioctanoate, glyceryl triisopalmitate, trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, 2-ethylhexyl palmitate, glyceryl trimyristate, glyceride tri-2- heptylundecanoate, castor oil fatty acid methyl ester, oleyl oleate, acetoglyceride, 2- heptylundecyl palmitate, diisobutyl adipate, N-lauroyl-L-glutamic acid-2- octyldodecyl ester, di-2-heptylundecyl adipate, ethyl laurate, di-2-ethylhexyl sebacate, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, 2-hexyldecyl adipate, diisopropyl sebacate, 2-ethylhexyl succinate, triethyl citrate, bis- behenyl/isostearyl/phytosteryl dimer dilinoleyl dimer dilinoleate,

phytosteryl/behenyl/octyldodecyl/isostearyl lauroyl glutamate, caprylic/capric triglyceride, and triethylhexanoin.

[0030]

Examples of the silicone oil include a chain polysiloxane, such as

dimethicone (dimethylpolysiloxane), methyl trimethicone, methylphenylpolysiloxane and diphenylpolysiloxane; a cyclic polysiloxane, such as octamethyl

cyclotetrasiloxane, decamethyl cyclopentasiloxane and dodecamethyl

cyclohexasiloxane; a silicone resin forming a 3D net structure; a silicone rubber; and various modified polysiloxanes, such as amino-modified polysiloxane, polyether- modified polysiloxane, alkyl-modified polysiloxane and fluorine-modified polysiloxane.

[0031]

Examples of silicone elastomers include non-emulsifying organopolysiloxane elastomers and emulsifying organosiloxane elastomers. Examples of the non- emulsifying organopolysiloxane elastomers include dimethicone/vinyl dimethicone crosspolymers and lauryl dimethicone/vinyl dimethicone crosspolymers.

[0032]

The dimethicone/vinyl dimethicone crosspolymers include products commercially available from DOW CORNING (Midland, Michigan) under the trade names of, for example, DC 9040 and DC 9045; products commercially available from MOMENTIVE under the trade name of SFE 839 and the Velvasil series products; products commercially available from Shin-Etsu Chemical Co., Ltd. under the trade names of, for example, KSG-15, KSG-16, and KSG-18

([dimethicone/phenyl vinyl dimethicone crosspolymer]); and Gransil (TM) series products from GRANT INDUSTRIES, Inc.

[0033]

The lauryl dimethicone/vinyl dimethicone crosspolymers include products commercially available from Shin-Etsu Chemical Co., Ltd. under the trade names of, for example, KSG-31, KSG-32, KSG-41, KSG-42, KSG-43, and KSG-44.

[0034]

Examples of the emulsifying organosiloxane elastomers include

polyalkoxylated silicone elastomers and polyglycerolated silicone elastomers.

[0035]

The polyalkoxylated silicone elastomers include products commercially available from DOW CORNING under the trade names of, for example, DC9010 and DC9011; and products commercially available from Shin-Etsu Chemical Co., Ltd. under the trade names of, for example, KSG-20, KSG-21, KSG-30, KSG-31, KSG-32, KSG-33, KSG-210, KSG-310, KSG-320, KSG-330, KSG-340, and X- 226146.

[0036]

The polyglycerolated silicone elastomers include products commercially available from Shin-Etsu Chemical Co., Ltd. under the trade names of, for example, KSG-710, KSG-810, KSG-820, KSG-830, KSG-840, KSG-31, KSG-32, KSG-41, KSG-42, KSG-43, and KSG-44. In addition, examples of silicone elastomers into which 2 types of branches, i.e., a silicone chain and an alkyl chain have been introduced include products commercially available from Shin-Etsu Chemical Co., Ltd. under the trade names of, for example, KSG-042Z, KSG-045Z, KSG-320Z, KSG-350Z, KSG-820Z, and KSG-850Z.

[0037]

Silicone elastomers comprising a polyalkyl ether group as pendant or cross- linked may also be used. Particularly suitable silicone elastomers comprising a polyalkyl ether group include compounds with an International Nomenclature of Cosmetic Ingredients (INCI) name: bis-vinyldimethicone/bis-isobutyl PPG-20 crosspolymer, bis-vinyldimethicone/PPG-20 crosspolymer, dimethicone/bis-isobutyl PPG-20 crosspolymer, dimethicone/PPG-20 crosspolymer, and dimethicone/bis- secbutyl PPG-20 crosspolymer. Such cross-linked elastomers are available from

DOW CORNING under the experimental compound names of, for example, SOEB-1, SOEB-2, SOEB-3 and SOEB-4, and under the proposed commercial name of, for example, DC EL-8052 IH Si Organic Elastomer Blend. The elastomer particles are supplied pre-swollen in the respective solvents, isododecane (for SOEB- 1 and -2), isohexadecane (for SOEB-3), and isodecyl neopentanoate (for SOEB-4).

[0038]

These oils may be used singly or in combinations of two or more. [0039]

The content of the oil (ingredient C) in the emulsion of the present invention is preferably 1 to 25 mass , more preferably 4 to 12 mass , still more preferably 6 to 10 mass based on the total mass of the emulsion.

[0040]

D) Water, a water-soluble organic solvent or a mixture thereof

In the emulsion of the present invention, water, a water-soluble organic solvent or a mixture thereof is used as ingredient D.

The water-soluble organic solvent is not particularly limited and examples thereof preferably include those commonly used in compositions for external use. Examples thereof include lower alcohols (preferably, alcohols having 1 to 5 carbon atoms) such as methanol, ethanol, propanol, and isopropanol; and polyhydric alcohols such as ethylene glycol, 1,3-butylene glycol, propylene glycol, dipropylene glycol, isoprene glycol, polyethylene glycol, polyoxyethylene methylglucoside, glycerin and diglycerin. These water-soluble organic solvents can be used singly or in combinations of two or more.

[0041]

The content of water, water-soluble organic solvent or mixture thereof

(ingredient D) is the remainder of the emulsion of the present invention. For example, the content of the water, water-soluble organic solvent or mixture thereof is preferably 30 to 90 mass , more preferably 40 to 80 mass , still more preferably 50 to 70 mass in total based on the total mass of the emulsion. Among these, the content of the water-soluble organic solvent is preferably 0.5 to 10 mass , more preferably 1 to 6 mass , still more preferably 2 to 4 mass . The outer phase tends to be likely to form a bicontinuous structure when the water-soluble organic solvent is contained in the above-mentioned range.

[0042] In one embodiment of the present invention, it is preferred that the content of ingredient A be 0.5 to 10 mass , the content of ingredient B be 0.5 to 10 mass , the content of ingredient C be 1 to 25 mass and the total content of ingredients A, B and C be 5 to 45 mass based on the total mass of the emulsion. The total content of ingredients A, B and C is preferably 8 to 30 mass , more preferably 10 to 20 mass . If the content of ingredients A, B, and C is within the above-mentioned range, the outer phase is likely to form a more stable bicontinuous structure.

[0043]

In the emulsion of the present invention, the bicontinuous structure which the outer phase has is also maintained when the ingredients constituting the oil phase containing an oil (ingredient E) are added in a predetermined quantitative ratio. In the emulsion of the present invention, the oil phase containing an oil (ingredient E) is dispersed in the outer phase to form a dispersed phase and exist stably without causing phase separation.

[0044]

E) Oil

The oil (ingredient E) constituting the oil phase to be dispersed in the outer phase having a bicontinuous structure is not particularly limited as long as it is a material having a property of not dissolving or being difficult to dissolve in water and being easy to dissolve in oil. Examples of the oil for use as ingredient E in the present invention preferably include low viscosity liquid oils/fats, solid oils/fats, waxes, hydrocarbon oils, synthetic ester oils, silicone oils and silicone elastomers that are commonly used in compositions for external use. Specific examples include the same as those exemplified as an oil (ingredient C).

[0045]

Besides, for example, oils such as methoxycinnamic acid derivatives, diphenylacrylic acid derivatives, salicylic acid derivatives, para-aminobenzoic acid derivatives, triazine derivatives, benzophenone derivatives, benzalmalonate derivatives, anthranilic derivatives, imidazoline derivatives, 4,4-diarylbutadiene derivatives, phenylbenzimidazole derivatives, and perfluoropolyether derivatives can be used.

Specific examples include octyl methoxycinnamate, 2-ethylhexyl p- methoxycinnamate, homosalate, octyl salicylate, oxybenzone, 4-t-butyl-4'-methoxy dibenzoylmethane, octyltriazone, methylene-bis-benzotriazolyl

tetramethylbutylphenol, 2-hydroxy-4-methoxybenzophenone, benzophenone- dihydroxy-dimethoxy, dihydroxybenzophenone, tetrahydroxybenzophenone, diethylaminohydroxybenzoyl hexyl benzoate, 2-cyano-3,3-diphenyl acrylic acid-2'- ethylhexyl ester, polysilicone- 15, drometrizole polysiloxane, phenyl benzimidazole sulfonic acid, and polyperfluoromethylisopropyl ether.

[0046]

The oil (ingredient E) usable in the present invention can be selected arbitrarily from a nonpolar oil (such as squalene) to a highly polar oil (such as octyl methoxycinnamate, diethylamino hydroxy-benzoyl hexyl benzoate).

These oils may be used singly or in combinations of two or more.

[0047]

The content of the oil (ingredient E) in the emulsion of the present invention is preferably 5 to 45 mass , more preferably 10 to 35 mass , still more preferably 15 to 25 mass based on the total mass of the emulsion.

[0048]

As described above, the emulsion of the present invention enables a tranexamate ester salt (ingredient A) to be formulated in a stable state without phase separation, and thus the tranexamate ester salt is likely to penetrate the skin.

Accordingly, it is considered that the whitening effect thereof can be maximized. In addition, since the emulsion of the present invention can increase the amount of an oil contained while having the tranexamate ester salt dispersed in a stable state, the emulsion of the present invention can impart emollient properties. As mentioned in the Background Art section, the solubility of a tranexamate ester salt in water and oil is low, and it has been considered until now that it is very difficult to increase the amount of an oil contained while having the tranexamate ester salt dispersed in a stable state. In order to cope with the problems of the conventional art described above, the present invention has adopted a completely new concept of firstly allowing a tranexamate ester salt to be dispersed (or dissolved) in a stable state by forming an outer phase having a bicontinuous structure, and then dispersing the oil phase in the thus obtained outer phase and thereby succeeded in increasing the amount of an oil contained while having the tranexamate ester salt dispersed in a stable state and thus overcome the problems of the conventional art.

[0049]

In the emulsion of the present invention, the content of the ingredients constituting the outer phase is 55 to 95 mass , preferably 60 to 87 mass , more preferably 65 to 90 mass , still more preferably 75 to 85 mass in total based on the total mass of the emulsion.

The amount of the ingredients constituting the oil phase as a dispersed phase contained is 5 to 45 mass , preferably 7 to 40 mass , more preferably 10 to 35 mass , still more preferably 15 to 25 mass in total based on the total mass of the emulsion.

Although it depends on the kind of ingredients which constitute the dispersed phase, there is a tendency that the viscosity of the emulsion becomes higher as the amount of the ingredients constituting the dispersed phase increases. The mixing ratio of the outer phase and the dispersed phase may be appropriately selected depending on the use.

[0050] According to a preferred embodiment of the present invention, the peak observed by differential scanning calorimetry (DSC) attributable to the melting or phase transition is small (or substantially not observed) for the emulsion of the present invention. This means that the tranexamate ester salt (ingredient A), which is inherently solid, is present in an almost liquid state in the emulsion of the present invention. In one embodiment of the present invention, unlike conventional compositions wherein a tranexamate ester salt is dispersed in a solid state (gel-like state), it is considered that the permeability into the skin of the tranexamate ester salt increases since the tranexamate ester salt (ingredient A) is present in an almost liquid state and thus the whitening effect thereof is expected to be further enhanced.

[0051]

The emulsion of the present invention has a structure comprising an oil phase dispersed in an outer phase having a bicontinuous structure. According to a preferred embodiment of the present invention, the emulsion of the present invention can maintain the above-mentioned structure in a thermodynamically stable state without phase separation in a wide temperature range (for example, in the range of -20 to 70°C, preferably - 10 to 50°C).

[0052]

The pH value of the emulsion of the present invention is not particularly limited, but a weakly acidic range with higher affinity to the skin (pH5.0 to 5.5) is preferable. The pH regulator usable in the emulsion of the present invention is not particularly limited as long as it is commonly used in typical compositions for external use. Inter alia, Lewis bases represented by nicotinic acid amide do not achieve the increase in the pH value by the donation of hydroxide ions but achieves the increase in the pH value by the donation of electron pairs. Accordingly, the addition of Lewis base to the emulsion of the present invention does not affect the water solubility of the tranexamate ester salt (ingredient A). Therefore, it is possible to raise the pH value to any value without precipitating the tranexamate ester salt as crystals, and therefore, Lewis bases are preferably used.

Examples of the Lewis base include nitrogen-containing basic compounds or salts thereof, carboxylic acids, and alcohols. Among these, use of nitrogen- containing basic compound is preferable.

Specific examples of the nitrogen-containing basic compounds include amine compounds such as triethylamine, tri-n-propylamine, tri-i-propylamine, tri-n- butylamine, tri-n-hexylamine, triethanolamine, triphenylamine, aniline, N,N- dimethylaniline, 2-methylaniline, 3-methylaniline, 4-methylaniline, 4-nitroaniline, 1- naphthylamine, 2-naphthylamine, diphenylamine, ethylenediamine, tetramethylene diamine, hexamethylene diamine, pyrrolidine, and piperidine;

imidazole compounds such as imidazole, 4-methylimidazole, 4-methyl-2- phenylimidazole, and thiabendazole;

pyridine compounds such as pyridine, 2-methylpyridine, 4-ethylpyridine, 2- hydroxypyridine, 4-hydroxypyridine, 2-phenylpyridine, 4-phenylpyridine, nicotinic acid, nicotinic acid amide (niacinamide), quinoline, and acridine; and

other nitrogen-containing heterocyclic compounds such as purine, 1,3,5- triazine, triphenyl- l,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, and urazole.

The Lewis bases may be used singly or in combinations of two or more. Even pH regulators other than Lewis bases, for example, ionic bases represented by sodium hydroxide and arginine, hardly affect the tranexamate ester salt by the hydroxide ions if they are in low concentrations, and it is possible to raise the pH to any value without precipitating the tranexamate ester salt as crystals.

The amount of the pH regulator used is not limited as long as it may adjust the pH of the emulsion of the present invention in a desired range and it may be appropriately determined depending on the type of pH regulator.

[0053] The emulsion of the present invention can, as required, optionally contain ingredients in addition to the above to such an extent that the ingredients do not impair the object and effects of the present invention. For example, ingredient(s) which can be contained in compositions for external use such as drugs, quasi drugs or cosmetic products can be contained. The optional ingredients may be incorporated into the emulsion of the present invention by containing them in the dispersed phase or the outer phase. Those skilled in the art can determine appropriately whether they should be contained in either of the outer phase or the dispersed phase according to the type of the optional ingredient.

[0054]

As the optional ingredient(s) usable in the present invention, for example, powder ingredient(s), surfactant(s), cosurfactant(s), moisturizer(s), film agent(s), thickener(s), gelatinizer(s), inorganic mineral(s), sequestering agent(s), polyhydric alcohol(s), monosaccharide(s), oligosaccharide(s), amino acid(s), plant extract(s), organic amine(s), polymer emulsion(s), antioxidant(s), oxidization prevention assistant(s), skin nutritional supplement(s), vitamin(s), bloodstream accelerant(s), sterilizer(s), antiphlogistic (antiinflammation) agent(s), cell (skin) activation agent(s), keratolytic agent(s), tonic(s), astrictive(s), whitening agent(s), UV absorber(s), fading inhibitor(s), preservative(s), buffer(s) and/or fragrance(s) can be appropriately contained as needed. These optional ingredients can be appropriately selected depending on the formulation form and usage, etc. to be aimed at.

[0055]

Examples of the powder ingredients include inorganic powders (for example, talc, kaolin, mica, sericite, muscovite, phlogopite, synthetic mica, deep red mica, biotite, vermiculite, magnesium carbonate, calcium carbonate, aluminum silicate, barium silicate, calcium silicate, magnesium silicate, strontium silicate, tungstic acid metal salt, silica, zeolite, barium sulfate, magnesium sulfate, burnt calcium sulfate (plaster), calcium phosphate, fluorine apatite, hydroxyapatite, ceramic powders, metallic soaps (for example, zinc myristate, calcium palmitate, aluminum stearate, magnesium stearate), boron nitride); organic powders (for example, polyamide resin powder (nylon powder), polyethylene powder, polymethyl methacrylate powder, polystyrene powder, co-polymer resin powder of styrene and acrylic acid, benzoguanamine resin powder, polytetrafluoroethylene powder, cellulose powder); metallic powder pigments (for example, aluminum powder, copper powder), organic pigments such as zirconium, barium or aluminum lakes; and natural pigments (for example, chlorophyll, β-carotene). Here, the powder ingredients may be subjected to a hydrophobic treatment.

[0056]

The surfactants may include anionic surfactants, cationic surfactants, ampholytic surfactants, lipophilic nonionic surfactants and hydrophilic nonionic surfactants.

[0057]

Examples of the anionic surfactant include fatty acid soaps (for example, sodium laurate and sodium palmitate); higher alkyl sulfate salts (for example, sodium lauryl sulfate and potassium lauryl sulfate); alkylether sulfate salts (for example, triethanolamine POE-lauryl sulfate and POE-sodium lauryl sulfate); N-acyl sarcosine acids (for example, sodium lauroylsarcosinate); higher fatty acid amide sulfonates (for example, sodium N-myristoyl-N-methyl taurate, sodium cocoyl methyl tauride and sodium lauryl methyltauride); phosphate salts (sodium POE-oleyl ether phosphate, a POE-stearyl ether phosphoric acid, etc.); sulfosuccinates (for example, sodium di-2-ethylhexylsulfosuccinate, sodium monolauroyl monoethanolamide polyoxyethylene sulfosuccinate and sodium lauryl polypropylene glycol

sulfo succinate); alkyl benzenesulfonates (for example, linear sodium

dodecylbenzenesulfonate, linear triethanolamine dodecylbenzenesulfonate and a linear dodecylbenzenesulfonic acid); higher fatty acid ester sulfate salts (for example, sodium cocomonoglyceride sulfate); N-acyl glutamates (for example, monosodium N-lauroyl glutamate, disodium N-stearoyl glutamate and monosodium N-myristoyl- L-glutamate); sulfated oils (for example, Turkey red oil); POE-alkylether carboxylic acids; POE-alkylallylether carboxylates; cc-olefin sulfonates; higher fatty acid ester sulfonates; secondary alcohol sulfate ester salts; higher fatty acid alkylolamide sulfate ester salts; sodium lauroyl monoethanolamide succinates; ditriethanolamine N-palmitoyl aspartate; and sodium casein.

[0058]

Examples of the cationic surfactant include alkyltrimethylammonium salts

(for example, stearyltrimethylammonium chloride and lauryltrimethylammonium chloride); alkylpyridinium salts (for example, cetylpyridinium chloride); a chloride distearyldimethylammonium dialkyldimethylammonium salt; poly(N,N'-dimethyl- 3,5-methylene piperidinium) chloride; alkyl quaternary ammonium salts;

alkyldimethylbenzylammonium salts; alkylisoquinolinium salts; dialkylmorpholium salts; POE-alkylamine; alkylamine salts; polyamine fatty acid derivatives;

amylalcohol fatty acid derivatives; benzalkonium chloride; and benzethonium chloride.

[0059]

Examples of the ampholytic surfactant include imidazoline-based ampholytic surfactants (for example, sodium 2-undecyl-N,N,N-(hydroxyethylcarboxymethyl)-2- imidazoline; and a 2-cocoyl-2-imidazolinium hydroxide- 1-carboxyethyloxy disodium salt); and betaine-based surfactants (for example, 2-heptadecyl-N- carboxymethyl-N-hydroxyethyl imidazolinium betaine, lauryldimethylamino acetate betaine, alkyl betaine, amide betaine, and sulfobetaine).

[0060] Examples of the lipophilic nonionic surfactant include sorbitan fatty acid esters, such as sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, diglycerol sorbitan penta-2-ethylhexylate and diglycerol sorbitan tetra-2- ethylhexylate; glyceryl polyglyceryl fatty acids, such as glyceryl mono-cottonseed oil fatty acid, glyceryl monoerucate, glyceryl sesquioleate, glyceryl monostearate, glyceryl , '-oleate pyroglutamate, and glyceryl monostearate malate; propylene glycol fatty acid esters such as monostearate propylene glycol; a hydrogenated castor oil derivative; a glycerin alkyl ether; and steareth-2.

[0061]

Examples of the hydrophilic nonionic surfactant include POE- sorbitan fatty acid esters, such as POE-sorbitan monooleate, POE-sorbitan monostearate, POE- sorbitan monooleate and POE-sorbitan tetraoleate; POE sorbitol fatty acid esters, such as POE-sorbitol monolaurate, POE-sorbitol monooleate, POE-sorbitol pentaoleate and POE-sorbitol monostearate; POE-glycerin fatty acid esters, such as POE-glycerin monostearate, POE-glycerin monoisostearate and POE-glycerin triisostearate; POE-fatty acid esters, such as POE-monooleate, POE-distearate, POE- monodioleate and ethylene glycol distearate; POE-alkyl ethers, such as POE-lauryl ether, POE-oleyl ether, POE-stearyl ether, POE-behenyl ether, POE-2-octyldodecyl ether and POE-cholestanol ether; Pluronic type surfactants (e.g., Pluronic); POE- POP-alkyl ethers, such as POE-POP-cetyl ether, POE-POP-2-decyltetradecyl ether, POE-POP-monobutyl ether, POE-POP-hydrogenated lanolin and POE-POP-glycerin ether; and steareth-21.

[0062]

The water-soluble polymer may be used as the thickener. Examples of the water-soluble polymer include natural polymers such as Arabian gum, carrageenan, karaya gum, tragacanth gum, quince seed (marmelo), casein, dextrin, gelatine, sodium pectate, sodium alginate, locust bean gum, guar gum, tara gum, Tamarind gum, glucomannan, xylan, mannan, xanthan gum, agar, pectin, fucoidan, galactomannan, curdlan, gellan gum, fucogel, casein, collagen, starch, sodium hyaluronate and Alcasealan (Alcaligenes Polysaccharides), semi- synthetic polymers such as methylcellulose, ethylcellulose, sodium carboxymethylcellulose,

hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, methylhydroxypropylcellulose, hydroxypropylmethylcellulose stearoyl ester, propylene glycol alginate and cellulose dialkyldimethylammonium sulfate, and synthetic polymers such as PVA (polyvinyl alcohol), PVM (polyvinyl methyl ether), PVP (polyvinylpyrrolidone), polyethylene oxide, sodium polyacrylate, carboxyvinyl polymer, acrylate/Cio-30 alkyl acrylate crosspolymer, and sodium polyacrylate.

Among them, a water-soluble polymer selected from the group consisting of nonionic and cationic water-soluble polymers, which are compatible with the tranexamate ester salt, is preferable. Especially, the water-soluble polymer selected from the group consisting of locust bean gum, guar gum, tara gum, Tamarind gum and hydroxypropylmethylcellulose stearoyl ester is preferable. More preferably, nonionic associative thickeners can be mentioned. Addition of an only small amount of a non-ionic associative thickener which would not affect the feeling can impart thickening properties sufficient to maintain a bicontinuous structure.

Specific examples thereof include polyoxyethylene distearates such as distearate

PEG- 150 and distearate PEG-250 and hydrophobically modified polyether urethanes such as (PEG-240/decyltetradeceth-20/HDI)copolymer.

[0063]

Clay minerals may also be used as the thickener. Examples of the clay minerals include one which can provide thickening properties to the water phase such as bentonite, hectorite, magnesium aluminum silicate (veegum) and laponite, and one which can provide thickening properties to the oil phase such as organically- modified clay minerals.

[0064]

Examples of the metal sequestering agent include l-hydroxyethane- 1,1- diphosphonic acid; tetrasodium l-hydroxyethane- l,l-diphosphonate salt; disodium edetate; trisodium edetate; tetrasodium edetate; sodium citrate; sodium

polyphosphate; sodium metaphosphate; gluconic acid; phosphoric acid; citric acid; ascorbic acid; succinic acid; edetic acid; and trisodium ethylenediaminehydroxyethyl triacetate.

[0065]

Examples of the polyhydric alcohol include a dihydric alcohol, such as ethylene glycol, propylene glycol, pentylene glycol, trimethylene glycol, 1,2- butylene glycol, 1,3-butylene glycol, tetramethylene glycol, 2,3-butylene glycol, pentamethylene glycol, 2-butene-l,4-diol, hexylene glycol and octylene glycol; a trihydric alcohol, such as glycerin and trimethylolpropane; a tetrahydric alcohol such as pentaerythritol (e.g., 1,2,6-hexanetriol); a pentahydric alcohol such as xylitol; a hexahydric alcohol, such as sorbitol and mannitol; a polyhydric alcohol polymer, such as diethylene glycol, dipropylene glycol, triethylene glycol, polypropylene glycol and tetraethylene glycol; dihydric alcohol alkyl ethers, such as ethylene glycol monomethyl ether and ethylene glycol monoethyl ether; dihydric alcohol alkyl ethers, such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether and diethylene glycol monobutyl ether; a dihydric alcohol ether ester, such as ethylene glycol monomethyl ether acetate and ethylene glycol monoethyl ether acetate; a glycerol monoalkyl ether, such as chimyl alcohol, selachyl alcohol and batyl alcohol; and a sugar alcohol, such as sorbitol, maltitol, maltotriose, mannitol, sucrose, erythritol, glucose, fructose, starch sugar, maltose, xylitose, and a reduced alcohol of a starch sugar. [0066]

Examples of the monosaccharide include a triose, such as D-glyceryl aldehyde and dihydroxyacetone; a tetrose, such as D-erythrose, D-erythrulose, D- threose and erythritol; a pentose, such as L-arabinose, D-xylose, L-lyxose, D- arabinose, D-ribose, D-ribulose, D-xylulose and L-xylulose; a hexose, such as D- glucose, D-talose, D-psicose, D-galactose, D-fructose, L-galactose, L-mannose and D-tagatose; a heptose, such as aldoheptose and heprose; an octose such as octurose; a deoxy sugar, such as 2-deoxy-D-ribose, 6-deoxy-L-galactose and 6-deoxy-L- mannose; an amino sugar, such as D-glucosamine, D-galactosamine, sialic acid, amino uronic acid and muramic acid; and an uronic acid, such as D-glucuronic acid, D-mannuronic acid, L-guluronic acid, D-galacturonic acid and L-iduronic acid.

[0067]

Examples of the oligosaccharide include sucrose, lactose, maltose, trehalose, cellobiose, gentiobiose, umbilicin, raffinose, gentianose, maltotriose, melezitose, planteose, unbelliferose, stachyose, and verbascose.

[0068]

Examples of the amino acid include a neutral amino acid, such as threonine and cysteine; and a basic amino acid such as hydroxylysine. Further, as an amino acid derivative, for example, sodium acyl sarcosinate (sodium lauroyl sarcosinate), acyl glutamate, sodium acyl β-alanine, glutathione, and pyrrolidone carboxylic acid may be exemplified.

[0069]

Examples of the organic amine include monoethanolamine, diethanolamine, triethanolamine, morpholine, triisopropanolamine, 2-amino-2-methyl-l,3- propanediol, and 2-amino-2-methyl- 1-propanol.

[0070] Examples of the polymer emulsion include an acrylic resin emulsion, a poly(ethyl acrylate) emulsion, an acrylic resin solution, a poly(alkyl acrylate) emulsion, a poly(vinyl acetate) resin emulsion, and a natural rubber latex.

[0071]

Examples of the vitamins include vitamins A, B_{1 ;} B₂, B₆, C and E and derivatives thereof, pantothenic acid and derivatives thereof and biotin.

[0072]

Examples of the antioxidants include ascorbic acid and derivatives thereof such as ascorbyl palmitate, ascorbyl tetraisopalmitate, ascorbyl glucoside, magnesium ascorbyl phosphate, sodium ascorbyl phosphate and ascorbyl sorbate; tocopherol and derivatives thereof, such as tocopheryl acetate, tocopheryl sorbate, and other esters of tocopherol; dibutyl hydroxytoluene (BHT) and butylated hydroxyanisole (BHA); gallic acid ester; phosphoric acid; citric acid; maleic acid; malonic acid; succinic acid; fumaric acid; cephalin; a hexametaphosphate; phytic acid; ethylenediaminetetraacetic acid; and plant extracts, for instance from Chondrus crispus, Rhodiola, Thermus thermophilus, mate leaves, oak wood, kayu rapet bark, sakura leaves and ylang ylang leaves.

[0073]

Examples of the moisturizing agent include polyethylene glycol; propylene glycol; dipropylene glycol; glycerin; 1,3-butylene glycol; xylitol; sorbitol; maltitol; mucopolysaccharides such as chondroitin sulfuric acid; hyaluronic acid; sodium hyaluronate; sodium acetyl hyaluronate; mucoitinsulfuric acid; caronic acid; atelo- collagen; cholesteryl- 12-hydroxystearate; a bile salt; a main ingredient of NMF (natural moisturizing factor), such as a pyrrolidone carboxylic acid salt and a lactic acid salt; amino acids such as urea, cysteine and serine; short-chain soluble collagen; a diglycerin (EO) PO addition product; homo- or copolymers of 2- methacryloyloxyethylphosphorylcholine commercially available from NOF Corporation under the names of, for example, Lipidure HM and Lipidure PBM; panthenol; allantoin; PEG/PPG/Polybutylene Glycol-8/5/3 Glycerin commercially available from NOF Corporation under the trade name of Wilbride S 753;

trimethylglycine commercially available from Asahi Kasei Chemicals Corporation under the trade name of AMINOCOAT; and various plant extracts such as Castanea sativa extracts, hydrolyzed hazelnut proteins, Polianthes tuberosa polysaccharides, Argania spinosa kernel oil, and an extract of pearl containing conchiolin

commercially available from Maruzen Pharmaceuticals Co., Ltd. under the trade name of Pearl Extract (R).

[0074]

Examples of the skin softener include glyceryl polymethacrylate and methyl gluceth-20.

[0075]

Examples of the antiaging agent include acyl amino acids (specifically for example, products commercially available from SEDERMA, S.A.S. under the trade names of Maxilip, Matrixyl L 3000 and Biopeptide CL, and a product commercially available from SEPPIC under the trade name of Sepilift); Pisum sativum extracts; hydrolyzed soy proteins; methylsilanol mannuronate; hydrolyzed cucurbita pepo seedcake; and Scenedesmus extracts.

[0076]

Examples of the anti-pollution agents include Moringa pterygosperma seed extracts (specifically, such as a product commercially available from LSN under the trade name of Purisoft); and Shea butter extracts (specifically, for example, products commercially available from SILAB under the trade name of Detoxyl, and a blend of an ivy extract, phytic acid and a sunflower seed extract (for example, a product commercially available from SEDERMA, S.A.S. under the trade name of

OSMOPUR)). [0077]

Examples of the keratolytic agents include cc-hydroxy acids (specifically, for example, glycolic, lactic, citric, malic, mandelic and tartaric acids), β-hydroxy acids (specifically, for example, salicylic acid), esters thereof (specifically, C_12-13 alkyl lactate), and plant extracts containing these hydroxy acids (specifically, for example, Hibiscus sabdriffa extracts).

[0078]

Examples of the anti-inflammatory agents include bisabolol, allantoin, tranexamic acid, zinc oxide, sulfur oxide and derivatives thereof, chondroitin sulfate, and glycyrrhizinic acid and derivatives thereof (for example, glycyrrhizinates).

[0079]

The emulsion of the present invention may also contain at least one whitening agent to block the synthesis of structural proteins such as the melanocyte-specific protein Pmell7 involved in the mechanism of melanogenesis (stage I). Examples of such a whitening agent include the ferulic acid-containing cytovector (water, glycol, lecithin, ferulic acid, and hydroxyethylcellulose) commercially available from BASF under the trade name of Cytovector (R).

[0080]

Furthermore, the emulsion of the present invention may contain at least one peptide as described in WO2009/010356.

[0081]

Furthermore, the emulsion of the present invention may include a whitening agent having an inhibitory effect on melanin synthesis, on nanophthalmia-related transcription factor expression, on an anti-tyrosinase activity and/or on endothelin-1 synthesis. Examples of such a whitening agent include a Glycyrrhiza glabra extract commercially available from Maruzen Pharmaceuticals Co., Ltd. under the trade name of Licorice extract (R). [0082]

Furthermore, the emulsion of the present invention may include whitening agents having an antioxidant action as well, such as vitamin C compounds, which include ascorbate salts, ascorbyl esters of fatty acids or of sorbic acid, and other ascorbic acid derivatives. Specific examples include ascorbyl phosphates

(magnesium ascorbyl phosphate, sodium ascorbyl phosphate, and the like), and saccharide esters of ascorbic acid (ascorbyl-2-glucoside, 2-O-CC-D-glucopyranosyl L- ascorbate, β-Ο-β-D-galactopyranosyl L-ascorbate, and the like). Active agents of this type are commercially available from DKSH under the trade name of Ascorbyl glucoside (R).

[0083]

Furthermore, the emulsion of the present invention may include other whitening agents. Examples of the other whitening agents include pigmentation inhibiting agents such as plant extracts (e.g., Narcissus tazetta extracts), cetyl tranexamate (Nikko Chemicals Co., Ltd; trade name: NIKKOL TXC), arbutin, kojic acid, ellagic acid, cysteine, 4-thioresorcin, resorcinol or rucinol or derivatives thereof, glycyrrhizinic acid and hydroquinone- -glucoside.

[0084]

Furthermore, the emulsion of the present invention may also include organic and/or inorganic sunscreens.

Examples of the organic sunscreens include dibenzoylmethane derivatives such as butyl methoxydibenzoylmethane (for example, a product commercially available from HOFFMANN LA ROCHE under the trade name of Parsol 1789); cinnamic acid derivatives such as octyl methoxycinnamate (for example, a product commercially available from HOFFMANN LA ROCHE under the trade name of Parsol MCX); salicylates; para-aminobenzoic acids; β,β'-diphenylacrylate

derivatives; benzophenone derivatives; benzylidenecamphor derivatives such as terephtalylidene dicamphor sulphonic acid; phenylbenzimidazole derivatives;

triazine derivatives; phenylbenzotriazole derivatives; and anthranilic acid derivatives, all of which may be coated or encapsulated.

Examples of the inorganic sunscreens include pigments and nanopigments formed from coated or uncoated metal oxides. Examples of the nanopigments include titanium oxide, iron oxide, zinc oxide, zirconium oxide and cerium oxide nanopigments, which are all well-known as UV photoprotective agents.

[0085]

Examples of the antiseptic agent include p-oxybenzoate ester (e.g., methylparaben and propylparaben) and phenoxyethanol.

[0086]

In addition, as an optional ingredient to be used in the emulsion of the present invention, those mentioned in the International Cosmetic Ingredient Dictionary and Handbook, 13th Edition, 2010, published by the Personal Care Products Council, can be used.

The amounts of these optional ingredients contained are not particularly limited as long as the optional ingredients are in a range which does not impair the object of the present invention.

[0087]

The emulsion of the present invention can be produced by a method comprising the steps of:

preparing an oil phase containing

A) a physiologically acceptable salt of a tranexamate ester;

B) an amphiphilic substance selected from combinations of a linear or branched, saturated or unsaturated alcohol having 12 to 22 carbon atoms and an alkyl glyceryl ether, which is a mono- or diether of a linear or branched, saturated or unsaturated alcohol having 8 to 22 carbon atoms and glycerin; and C) an oil;

adding the oil phase to a water phase containing

D) water, a water-soluble organic solvent or a mixture thereof

to form an outer phase having a bicontinuous structure; and

adding an oil phase containing

E) an oil

to the outer phase to form a dispersed phase.

In the following, each of the steps will be described.

[0088]

First, an oil phase containing ingredients A, B and C is prepared. A preferred amount of each ingredient contained is as described previously, and it is preferred that the content of ingredient A be 0.5 to 10 mass , the content of ingredient B be 0.5 to 10 mass , the content of ingredient C be 1 to 25 mass , and the total content of ingredients A, B and C be 5 to 45 mass based on the total mass of the emulsion.

The oil phase is preferably completely dissolved by heating. The heating temperature is preferably in the range of 65 to 95 °C, more preferably in the range of

75 to 90°C and particularly preferably in the range of 80 to 85°C.

[0089]

Then, the obtained oil phase is added to the water phase containing ingredient D. At this time, a small amount (about 4 to 8 mass based on the total mass of the emulsion) of ingredient D which makes up the water phase is preferably mixed in advance in the oil phase. Although not being bound by any theory, it is considered that the oil-soluble moiety (lipophilic moiety of the oil, tranexamate ester salt and amphiphilic substance) and the water-soluble moiety (hydrophilic moiety of the aqueous medium, tranexamate ester salt and amphiphilic substance) can be oriented to some extent by mixing a small amount of a water phase ingredient in advance in the oil phase, which can promote the formation of a bicontinuous structure upon addition of the oil phase to the water phase.

[0090]

Before the oil phase is added to the water phase, the oil phase and the water phase are preferably heated separately to maintain a dissolved state. The heating temperature is preferably in the range of 65 to 95°C, more preferably in the range of 75 to 90°C and particularly preferably in the range of 80 to 85°C. Note that although it is stated that "the oil phase is added to the water phase", the water phase may be added to the oil phase as long as it is possible to uniformly mix the oil phase and the water phase.

[0091]

After mixing the water phase and the oil phase, it is possible to form the outer phase having a bicontinuous structure by cooling the mixture to below 30°C while stirring. Cooling method is not particularly limited, and for example, it may be natural cooling or ice-cooling.

As described above, according to the method of the present invention, it is possible to form an outer phase having a bicontinuous structure by an ordinary stirring operation without using a special device.

Water-soluble or oil-soluble optional ingredients may be added respectively to the water phase and the oil phase in advance under the condition that they do not inhibit the stability of the composition.

[0092]

Then, the oil phase containing an oil (ingredient E) is added to the outer phase having a bicontinuous structure obtained in the above step to form a dispersed phase.

A preferred amount of the ingredients constituting the dispersed phase contained is the same as described previously, and it is preferably 5 to 45 mass , more preferably 10 to 35 mass , and still more preferably 15 to 25 mass based on the total mass of the emulsion.

Optional ingredients may be added along with the oil (ingredient E) to the oil phase under the condition that they do not inhibit the stability of the emulsion and the object of the present invention.

[0093]

Preferably, prior to the addition of the oil phase containing the oil (ingredient E) to the outer phase, each of the outer phase and the oil phase is maintained in the range of 20 to 35°C. After mixing the outer phase and the oil phase, sufficient stirring can provide a milky to creamy emulsion.

[0094]

It is possible to produce an emulsion of the present invention in the manner described above. According to the present invention, it is possible to obtain an emulsion comprising an oil phase dispersed in an outer phase having a bicontinuous structure by an ordinary stirring operation without using a special device.

[0095]

The emulsion of the present invention contains a tranexamate ester salt

(ingredient A) having a whitening effect, and thus, it is possible to achieve the effect of inhibiting pigmentation of and/or whitening the skin by topical application to the skin. That is, the present invention provides a cosmetic method for inhibiting pigmentation of and/or whitening the skin by topically applying to the skin the emulsion according to the present invention.

According to a preferred embodiment of the present invention, by using the emulsion of the present invention as a composition for external use such as cosmetics (such as a milky lotion and a cream in particular), it is possible to obtain effects of inhibiting pigmentation of and/or whitening the skin, for reducing an aging spot or pigmentation. [0096]

The emulsion of the present invention can be preferably used as a

composition for external use such as drugs, quasi drugs and cosmetic products. The product form of the composition for external use is arbitrarily selectable. For example, the composition is applicable to facial cosmetic materials, such as a facial cleanser, a face lotion, an essence liquid, a milky lotion, a cream and a pack; makeup cosmetic materials, such as a foundation, a lipstick and an eye shadow; body cosmetic materials; perfumeries; body cleansers; and ointments, etc. It can be preferably used as a whitening essence, a whitening cream, and a whitening pack especially.

[Examples]

[0097]

In the following, the present invention will be described by way of Examples and Comparative Examples but the present invention is not limited to these

Examples. Note that unless stated otherwise, the composition ratio is based on the mass ratio (mass ).

[0098]

Preparation and evaluation of physical properties of compositions (outer phase) having a bicontinuous structure

Compositions having a bicontinuous structure containing a tranexamate ester salt in the compositions shown in Table 1 were prepared as follows. Stirring was manually conducted with a stirring rod.

1) Dipropylene glycol (3 mass ) and purified water (3 mass ) (part of ingredient D) were mixed to the oil phase ingredient containing ingredients A, B and C, and these ingredients were completely dissolved by heating at 85±5°C while stirring. 2) Then, the remaining part of the water phase ingredients D were heated at 85±5°C, and the mixture obtained in the above 1) was added slowly thereto while thoroughly stirring, and the whole was homogenized.

3) Then, the mixture obtained in the above 2) was cooled to 25±5°C or lower while stirring to obtain a composition in a liquid state having a transparent to translucent appearance.

[0099]

The compositions obtained in the above 3) were tested for the following items at room temperature (25±5°C) and the results are shown in Table 1.

[0100]

(1) Diffusion of dyes

The fact that the sample has a bicontinuous structure can be confirmed by adding an oil-soluble dye and a water-soluble dye and observing the respective dyes diffused into the solution.

An oil (squalane) containing an oil-soluble dye (Red No. 225) and water containing a water-soluble dye (Blue No. 1) were added dropwise to the surface of the sample and the formation of a bicontinuous phase was confirmed with diffusion of each dye. If the oil-soluble dye is diffused, it indicates that the continuous phase is an oil phase, whereas if the water-soluble dye is diffused, it indicates that the continuous phase is a water phase. It can be said that the sample has a bicontinuous structure in which the oil phase and the water phase are present continuously when both the oil-soluble dye and the water-soluble dye were added dropwise at the same time, and diffusion of both was observed.

The case was evaluated as "A" where both the water-soluble dye and the oil- soluble dye were diffused, and the case was evaluated as "C" where only one of the water-soluble dye and the oil-soluble dye was diffused.

[0101] (2) Flow birefringence

The flow birefringence refers to a phenomenon showing a birefringence in which, when an isotropic gel-like structure is made to flow by shaking and the like, the structure is oriented in the direction of the flow, and the fact that the sample has flow birefringence can be confirmed by light transmitted through the orthogonal polarizing plates.

A transparent glass tube bottle containing the sample was sandwiched between the orthogonal polarizing plates and the sample was shaken from side to side by hand while irradiating the light from the back of a polarizing plate. It can be said that flow birefringence was shown if the following phenomenon was observed while the sample was shaken: the sample temporarily showed anisotropy to thereby cause birefringence resulting in passage of light. The case was evaluated as "A" where flow birefringence was shown, and the case was evaluated as "C" where flow birefringence was not shown.

[0102]

(3) State (transparency) immediately after sample preparation

The sample was fully dispensed into a 50mL transparent glass tube bottle and the transparency was visually evaluated. The sample which enabled characters on a printed material to be read clearly through the tube bottle was evaluated as "A: very high"; the sample which had a transparent to translucent appearance and enabled said characters to be read was evaluated as "B high"; and the sample which did not enable said characters on the printed material to be read was evaluated as "C: cloudy". Here, samples with separation or precipitated crystals were excluded from the evaluation (designated as D in Table 1).

[0103]

[Table 1] Table 1 Composition and evaluation of physical properties of outer pha:

: Diffusion of dyes Both water-soluble and oil-soluble dyes diffuse

Only one of water-soluble and oil-soluble dyes diffuses

^• : Flow birefringence Shown

Not shown

*** : State (transparency)

immediately after sample A Very high

preparation

B High

C Cloudy

D Separation or precipitation of crystals

[0104]

As shown in Table 1, it could be confirmed that the compositions comprising ingredients A, B, C and D (Reference Examples 1 to 7) had a bicontinuous structure. On the other hand, if any of the ingredients lacks, the compositions did not form a bicontinuous structure. Besides, compositions comprising only one of the alkyl glyceryl ether and alcohol as ingredient B did not form a bicontinuous structure.

[0105]

The composition of Reference Example 1 was subjected to freeze- sectional observation using cryo-focused ion beam scanning electron microscopy (cryo FIB- SEM) (manufactured by FEI Co., Model [HeliosNanoLab 650]). First, the composition of Reference Example 1 was instantaneously frozen by liquid nitrogen, and then it was introduced into an FIB-SEM apparatus and subjected to cryo FIB processing and cryo SEM observation. The cryo SEM observation results are shown in Figs. 1(a) and 1(b). Fig. 1 (a) is an observation result with magnification of 12,000 and Fig. 1(b) is an observation result with magnification of 35,000. From the observation results of Figs. 1(a) and 1 (b), it could be clearly confirmed that the water phase and the oil phase are each continuous three-dimensionally to form a bicontinuous structure in the composition of Reference Example 1.

[0106]

Preparation and evaluation of physical properties of Emulsions

Emulsions containing a tranexamate ester salt in the compositions shown in Table 2 were prepared as follows. Stirring was manually conducted with a stirring rod.

3) Then, the mixture obtained in the above 2) was naturally cooled to 25±5°C or lower with stirring to obtain a composition in a liquid state having a transparent to translucent appearance.

4) Then, ingredient E, which is an arbitrary oil maintained at room temperature (25±5°C) was added to the composition obtained in the above 3) in the quantitative ratio described in Table 2 while thoroughly stirring to obtain an emulsion. The obtained emulsions were evaluated with regard to the stability as described below. The results are shown in Table 2.

[0107]

(4) Stability of samples

The sample was fully dispensed into a 200 mL transparent glass tube bottle, allowed to stand still at room temperature (25±5°C) and at 40°C each for one month and the appearance was visually evaluated. The sample maintaining the initial state was evaluated as "A: stable", and the sample with separation and precipitated crystals was evaluated as "C: separation".

[0108]

Except for using the compositions shown in Table 2, emulsions containing a tranexamate ester salt were prepared in the same manner as in Examples, and the physical properties were evaluated. The results are shown in Table 2.

[0109]

[Table 2] Table 2 Composition and Evaluation of physical properties of emulsion

* : Stability at room

A Stable temperature for one month

C Separation

** : Stability at 40°C for

A Stable one month

C Separation

[0110]

As shown in Table 2, the emulsion of the present invention maintained the initial state without phase separation even after allowed to stand still at room temperature and at 40°C for one month. It could be confirmed from this that even after addition of the oil phase containing ingredient E to the outer phase having a bicontinuous structure, the emulsion of the present invention could maintain a bicontinuous structure to form a structure in which the oil phase was dispersed in the outer phase having a bicontinuous structure and that stability of the structure thereof was very high.

On the other hand, a sufficient stability was not obtained when the mixing ratio of ingredient E (oil) which is a constituent of the dispersed phase exceeded the range defined in the present invention (5 to 45 mass based on the total mass of the emulsion).

[0111]

The composition of Example 3 was subjected to freeze- sectional observation using cryo-focused ion beam scanning electron microscopy (cryo FIB-SEM) (manufactured by FEI Co., Model [HeliosNanoLab 650]). First, the composition of Example 3 was instantaneously frozen by liquid nitrogen, and then it was introduced into an FIB-SEM apparatus and subjected to cryo FIB processing and cryo SEM observation. The cryo SEM observation results before FIB processing are shown in Figs. 2(a) and 2(b). Fig. 2(a) is an observation result with magnification of 64 and Fig. 2(b) is an observation result with magnification of 650. The cryo SEM observation results after FIB processing are shown in Figs. 2(c) and 2(d). Fig. 2(c) is an observation result with magnification of 5,000 and Fig. 2(d) is an observation result with magnification of 12,000. From the observation result of Fig. 2(d), it could be clearly confirmed that the outer phase maintained a bicontinuous structure in the composition of Example 3. [0112]

(5) Differential Scanning Calorimetry (DSC)

Each of the compositions obtained in Reference Example 1 and Examples 1 to 4 was subjected to thermal analysis by DSC (equipment: DSC822 manufactured by METTLER Corp., heating rate: 2°C/min). The results of these are shown in Fig. 3. In the figure, (a), (b), (c), (d) and (e) illustrate the measurement results of the compositions of Reference Example 1, Example 1, Example 2, Example 3 and Example 4, respectively.

As is clear from Fig. 3, it was found that as the amount of the ingredient E contained increases, the peak projected below seen around 20 to 40°C becomes smaller. This indicates that the crystallinity of the solid ingredients of the

composition is weakened as the amount of ingredient E contained increases, and the solid ingredients approaches from the solid state to the liquid state. As shown here, according to one embodiment of the present invention, the solid ingredients contained in the emulsion can be made into a state close to a liquid state by suitably adjusting the amount of the ingredient E contained, and the tranexamate ester salt, which is inherently in a solid state, can be dispersed in the emulsion in a state close to a liquid state. It is considered that through this phenomenon, the tranexamate ester salt, which is a whitening ingredient, easily penetrates into the skin and the whitening effect of the emulsion is further enhanced.

[Industrial Applicability]

[0113]

The emulsion of the present invention is preferably used as a composition for external use such as drugs, quasi drugs and cosmetic products. According to a preferred embodiment of the present invention, it is possible to achieve the effect of inhibiting pigmentation of and/or whitening the skin by topically applying a composition of the present invention to the skin.

Claims

1. An emulsion comprising an oil phase dispersed in an outer phase having a bicontinuous structure, wherein

the outer phase contains

A) a physiologically acceptable salt of a tranexamate ester;

C) an oil; and

D) water, a water-soluble organic solvent or a mixture thereof;

and the oil phase contains

E) an oil;

2. The emulsion according to claim 1, wherein the tranexamate ester is represented by the following formula (1):

[Formula 3]

( 1 ) wherein R represents a linear or branched, saturated or unsaturated hydrocarbon group having 1 to 22 carbon atoms, which may be substituted by a substituent selected from a hydroxy group and an amino group.

3. The emulsion according to claim 1 or 2, wherein the physiologically acceptable salt of a tranexamate ester comprises cetyl tranexamate hydrochloride.

4. The emulsion according to any one of claims 1 to 3, wherein the amphiphilic substance is a combination of cetyl alcohol and at least one compound selected from the group consisting of chimyl alcohol and batyl alcohol.

5. The emulsion according to any one of claims 1 to 4, wherein the content of ingredient A is 0.5 to 10 mass , the content of ingredient B is 0.5 to 10 mass , the content of ingredient C is 1 to 25 mass and the total content of ingredients A, B and C is 5 to 50 mass based on the total mass of the emulsion.

6. The emulsion according to any one of claims 1 to 5, wherein the outer phase further contains a pH regulator.

7. The emulsion according to claim 6, wherein the pH regulator is selected from Lewis bases.

8. A method for producing the emulsion according to any one of claims 1 to 7, comprising the steps of:

preparing an oil phase containing

A) a physiologically acceptable salt of a tranexamate ester; B) an amphiphilic substance selected from combinations of a linear or branched, saturated or unsaturated alcohol having 12 to 22 carbon atoms and an alkyl glyceryl ether, which is a mono- or diether of a linear or branched, saturated or unsaturated alcohol having 8 to 22 carbon atoms and glycerin; and

C) an oil;

adding the oil phase to a water phase containing

D) water, a water-soluble organic solvent or a mixture thereof

to form an outer phase having a bicontinuous structure; and

adding an oil phase containing

E) an oil

to the outer phase to form a dispersed phase.

9. A composition for external use containing the emulsion according to any one of claims 1 to 7.

10. Cosmetic use of the emulsion according to any one of claims 1 to 7, for inhibiting pigmentation of and/or whitening the skin, and/or for reducing an aging spot or pigmentation.

11. A cosmetic method for inhibiting pigmentation of and/or whitening the skin, comprising topical application, to the skin, of the emulsion according to any one of claims 1 to 7.