# Patent

## Title
Ceramide emulsions

## Abstract

A process for the production of a stabilized ceramide emulsion by adding one or more ceramides of Formula (2) to one or more sphingosines of Formula (1), and then adding an acidic compound and water to form one or more sphingosine salts, wherein the sphingosine salts emulsify the ceramides to form the emulsion.

## Background
FIELD OF INVENTION
The present invention relates to a ceramide emulsion (an emulsion of ceramides) which has a good storage stability and is excellent in a rough skin-improving effect and a skin barrier property and which has a high safety, and to a process for production of the same.
BACKGROUND OF THE INVENTION
A horny layer that forms the outermost layer of the skin has the functions of inhibiting penetration of substances from the outside and volatilization of moisture from the inside of the skin and of maintaining a flexibility and a smooth appearance of the skin by virtue of moisture held by the horny layer itself. The horny layer is constituted from horny cells, and a lipid called a horny intercellular lipid (hereinafter referred to as a horny ICL) forms a stratified structure between the spaces of the horny cells to fill up the spaces between the horny cells.
A ceramide accounting for about 50% of this horny ICL attracts attentions as an active ingredient for the skin reduced in moisture such as rough skin, dry skin or aged skin. Further, it is also known that the state of a horny layer reduced in a performance can be improved by externally supplementing a ceramide as a component for improving a horny layer performance (J. Invest. Dermatol., 84: 282 (1985) and J. Invest. Dermatol., 87: 758 (1986).
However, ceramides, including natural ceramides, are substances having a very high melting point and a strong crystallinity. Accordingly, a large amount of an oil and a surfactant has to be used in order to prepare a stable skin external preparation. As a result thereof, the properties of a skin external composition containing ceramides have been restricted, and therefore the use feeling has inevitably been further reduced.
SUMMARY OF THE INVENTION
The present inventors have found that emulsification of ceramides with sphingosines and a specific acid makes it possible to stably maintain the ceramides without crystallization to provide an emulsion of ceramides which is excellent in a storage stability.
The present invention provides a ceramide emulsion containing (A) sphingosines represented by Formula (1), (B) an acidic compound selected from inorganic acids and organic acids having a molecular weight of 200 or less and (C) ceramides represented by Formula (2) and not containing an acrylic acid polymer or a phospholipid, and a process for production thereof:




wherein R1 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 4 to 30 carbon atoms which may be (is optionally) substituted with a hydroxyl group, a carbonyl group or an amino group; Y represents a methylene group, a methine group or an oxygen atom; X1, X2 and X3 each represent independently a hydrogen atom, a hydroxyl group or an acetoxy group, and X4 represents a hydrogen atom, an acetyl group or a glyceryl group or, together with an adjacent oxygen atom, forms an oxo group, wherein when Y is a methine group, one of X1 and X2 is a hydrogen atom, and the other is not present, and when X4 forms an oxo group, X3 is not present; R2 and R3 each represent independently a hydrogen atom, a hydroxyl group, a hydroxymethyl group or an acetoxymethyl group; groups “R”s each are independently a hydrogen atom or an amidino group or each represents independently a linear or branched, saturated or unsaturated hydrocarbon group having in total 1 to 8 carbon atoms which may have a substituent selected from a hydroxyl group, a hydroxyalkoxy group, an alkoxy group and an acetoxy group; “a” represents a number of 2 or 3; and a bond represented by a “broken line and solid line” represents a single bond or a double bond;





wherein R7 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 4 to 30 carbon atoms which may be substituted with a hydroxyl group, a carbonyl group or an amino group; Z represents a methylene group, a methine group or an oxygen atom; X5, X6 and X7 each represent independently a hydrogen atom, a hydroxyl group or an acetoxy group, and X4 represents a hydrogen atom, an acetyl group or a glyceryl group or, together with an adjacent oxygen atom, forms an oxo group, wherein when Z is a methine group, one of X5 and X6 is a hydrogen atom, and the other is not present, and when X4 forms an oxo group, X7 is not present; R8 and R9 each represent independently a hydrogen atom, a hydroxyl group, a hydroxymethyl group or an acetoxymethyl group; R10 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 5 to 60 carbon atoms which may be substituted with a hydroxyl group, a carbonyl group or an amino group and which may have an ether bond, an ester bond or an amide bond in a principal chain; R11 represents a hydrogen atom or a linear or branched, saturated or unsaturated hydrocarbon group having in total 1 to 8 carbon atoms which may have a substituent selected from a hydroxyl group, a hydroxyalkoxy group, an alkoxy group and an acetoxy group; and a bond represented by a “broken line and solid line” represents a single bond or a double bond.



DETAILED DESCRIPTION OF THE INVENTION
The sphingosines of the component (A) used in the present invention are represented by Formula (1) described above, and R1 in the formula is a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 4 to 30 carbon atoms which may be substituted with a hydroxyl group, a carbonyl group or an amino group, preferably having 7 to 22 carbon atoms which may be substituted with a hydroxyl group. More preferably, R1 is a linear or branched alkyl group having 10 to 20 carbon atoms, or a linear or branched alkyl group having 10 to 20 carbon atoms and having a hydroxyl group at a Y side end, and when R1 is a branched alkyl group, the branched alkyl group is preferably methyl-branched. Preferred R1 are tridecyl, tetradecyl, pentadecyl, hexadecyl, 1-hydroxytridecyl, 1-hydroxypentadecyl, isohexadecyl and isostearyl groups.
Y represents any of a methylene group (CH2), a methine group (CH) and an oxygen atom.
X1, X2 and X3 each represent independently a hydrogen atom, a hydroxyl group or an acetoxy group, and X4 represents a hydrogen atom, an acetyl group, a glyceryl group or a substituent forming an oxo group together with an adjacent oxygen atom. Preferred is a case in which zero to one of X1, X2 and X3 is a hydroxyl group and the remainder is a hydrogen atom and X4 is a hydrogen atom. When Y is a methine group, only one of X1 and X2 is a hydrogen atom, and the other is not present. When X4 forms an oxo group, X3 is not present.
R2 and R3 each represent independently a hydrogen atom, a hydroxyl group, a hydroxymethyl group or an acetoxymethyl group, and R3 is preferably a hydrogen atom.
Further, “a” represents a number of 2 or 3. When a is 2, R represents R4 and R5, and when a is 3, R represents R4, R5 and R6.
R4, R5 and R6 each are independently a hydrogen atom or an amidino group or each represent independently a linear or branched, saturated or unsaturated hydrocarbon group having in total 1 to 8 carbon atoms which may have a substituent selected from a hydroxyl group, a hydroxyalkoxy group, an alkoxy group and an acetoxy group. In this respect, the hydroxyalkoxy group which can be a substituent of the hydrocarbon group is preferably a linear or branched hydroxyalkoxy group having 1 to 7 carbon atoms. Also, the alkoxy group is preferably a linear or branched alkoxy group having 1 to 7 carbon atoms. R4, R5 and R6 include, for example, a hydrogen atom; linear or branched alkyl groups such as methyl, ethyl, propyl, 2-ethylhexyl and isopropyl; alkenyl groups such as vinyl and allyl; an amidino group; and hydrocarbon groups having in total 1 to 8 carbon atoms which have 1 to 6 substituents selected from hydroxy, hydroxyalkyl and alkoxy groups such as hydroxymethyl, 2-hydroxyethyl, 1,1-dimethyl-2-hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxy-3-methoxypropyl, 2,3,4,5,6-pentahydroxyhexyl, 1,1-bis(hydroxymethyl)ethyl, 2-(2-hydroxyethoxy)ethyl, 2-methoxyethyl, 1-methyl-2-hydroxyethyl, 3-hydroxypropyl, 3-methoxypropyl and 1,1-bis(hydroxymethyl)-2-hydroxyethyl.
Preferably, R4, R5 and R6 are a hydrogen atom, a methyl group and an alkyl group which may have 1 to 3 substituents selected from hydroxy groups and hydroxyalkoxy groups such as 2-hydroxyethyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-bis(hydroxymethyl)ethyl or 2-(2-hydroxyethoxy)ethyl.
The sphingosines of the component (A) preferably include natural sphingosines or natural type sphingosines represented by the following Formula (3) and derivatives thereof (hereinafter referred to as natural type sphingosines):




wherein R12 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 7 to 19 carbon atoms which may be substituted with a hydroxyl group; Y1 represents a methylene group or a methine group; X8, X9 and X10 each represent independently a hydrogen atom, a hydroxyl group or an acetoxy group, and X11 represents a hydrogen atom or, together with an adjacent oxygen atom, forms an oxo group, wherein when Y1 is a methine group, one of X8 and X9 represents a hydrogen atom, and the other is not present, and when X11 forms an oxo group, X10 is not present; R13 represents a hydroxymethyl group or an acetoxymethyl group; groups “R1”s each are independently a hydrogen atom or an amidino group or each represent independently a linear or branched, saturated or unsaturated hydrocarbon group having in total 1 to 4 carbon atoms which may have a substituent selected from a hydroxyl group, a hydroxyalkoxy group, an alkoxy group and an acetoxy group; “a” represents a number of 2 or 3; and a bond represented by a “broken line and solid line” represents a single bond or a double bond.

In this respect, R12 is preferably a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 7 to 19 carbon atoms, more preferably a linear, saturated or unsaturated hydrocarbon group having 13 to 15 carbon atoms.
Preferably, “a” is preferably 2, and the groups “R1”s each are independently a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.
The natural type sphingosines represented by Formula (3) specifically include, natural sphingosines, dihydrosphingosine, phytosphingosine, sphingadienine, dehydrosphingosine, dehydrophytosphingosine and N-alkyl products thereof (for example, N-methyl products).
Either the optically active compounds of a natural type (D(+) compound) or the optically active compounds of a non-natural type (L(−) compound) may be used as these sphingosines, or a mixture of the natural type and the non-natural type may be used. The steric configuration of the compounds described above may be either the steric configuration of the natural type or the steric configuration of the non-natural type or may be a mixture thereof.
Preferred are PHYTOSPHINGOSINE (INCI dictionary; 8th Edition) and compounds represented by the following formulas:







(in the formulas, m represents a number of from 5 to 17, and l represents a number of from 1 to 13).

They may be either extracts obtained from the natural products or synthetic compounds, and commercially available products can be used.
Commercially available natural type sphingosines include, for example, D-Sphingosine (4-Sphingosine) (SIGMA-ALDRICH Co., Ltd.), DS-phytosphingosine (DOOSAN Co., Ltd.) and phytosphingosine (Cosmo Ferm Co., Ltd.).
Further, another type of the sphingosines represented by Formula (1) in the present invention includes a pseudo type (hereinafter referred to as a pseudo type sphingosine) having a structure represented by the following Formula (4):




wherein R17 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 10 to 22 carbon atoms which may be substituted with a hydroxyl group; X4 represents a hydrogen atom, an acetyl group or a glyceryl group; groups “R2”s each represent independently a hydrogen atom or an amidino group or represent a linear or branched, saturated or unsaturated hydrocarbon group having in total 1 to 8 carbon atoms which may have a substituent selected from a hydroxyl group, a hydroxyalkoxy group, an alkoxy group and an acetoxy group; and a represents a number of 2 or 3.

In this respect, R17 is preferably an iso-branched alkyl group having 14 to 20 carbon atoms, more preferably isostearyl group. The isostearyl group is still more preferably an isostearyl group in a compound obtained by using as a raw material, isostearyl alcohol originating in a by-product obtained in producing dimer acids using fatty acids originating in animal and vegetable oils.
Further, when a is 2, R2 represents R18 and R19, and when a is 3, R2 represents R18, R19 and R20.
R18, R19 and R20 include, for example, a hydrogen atom; linear or branched alkyl groups such as methyl, ethyl, propyl, 2-ethylhexyl and isopropyl; alkenyl groups such as vinyl and allyl; an amidino group; and alkyl groups having in total 1 to 8 carbon atoms which have one or more substituents selected from hydroxy, hydroxyalkoxy and alkoxy groups such as hydroxymethyl, 2-hydroxyethyl, 1,1-dimethyl-2-hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxy-3-methoxypropyl, 2,3,4,5,6-pentahydroxyhexyl, 1,1-bis(hydroxymethyl)ethyl, 2-(2-hydroxyethoxy)ethyl, 2-methoxyethyl, 1-methyl-2-hydroxyethyl, 3-hydroxypropyl, 3-methoxypropyl and 1,1-bis(hydroxymethyl)-2-hydroxyethyl.
Of these, preferred are secondary amines in which one of R18 and R19 is a hydrogen atom and the other is 2-hydroxyethyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-bis(hydroxymethyl)ethyl or 2-(2-hydroxyethoxy)ethyl.
The pseudo type sphingosines are preferably those in which R17 is isostearyl, X4 is a hydrogen atom, R18 is a hydrogen atom and R19 is an alkyl group having 1 to 3 substituents selected from hydroxy and hydroxyalkoxy groups such as 2-hydroxyethyl, 1,1-bis(hydroxymethyl)ethyl, 1,1-dimethyl-2-hydroxyethyl and 2-(2-hydroxyethoxy)ethyl.
Specific examples of the pseudo type sphingosines include those represented by the following formulas:




Two or more of the component (A) may be used in combination. A content of the component (A) in the emulsion of the present invention is preferably 0.001 to 10% by weight, more preferably 0.005 to 3% by weight and even more preferably 0.01 to 1.5% by weight.
The acidic compound used as the component (B) in the present invention is selected from inorganic acids and organic acids having a molecular weight of 200 or less. Among them, the inorganic acid includes, for example, phosphoric acid, hydrochloric acid, nitric acid, sulfuric acid, perchloric acid and carbonic acid, with phosphoric acid and hydrochloric acid being more preferred.
The organic acid includes monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid and valeric acid; dicarboxylic acids such as succinic acid, phthalic acid, fumaric acid, oxalic acid, malonic acid and glutaric acid; oxycarboxylic acids such as glycolic acid, citric acid, lactic acid, pyruvic acid, malic acid and tartaric acid; and amino acids such as glutamic acid and aspartic acid.
The component (B) is preferably phosphoric acid, hydrochloric acid, succinic acid, citric acid, lactic acid, glutamic acid and aspartic acid, and lactic acid, glutamic acid and aspartic acid are more preferred.
Two or more of the component (B) may be used in combination. A content of the component (B) in the emulsion of the present invention is preferably 0.001 to 10% by weight, more preferably 0.005 to 3% by weight and even more preferably 0.01 to 1.5% by weight.
In order to cationize the amine of the component (A), the component (B) is added preferably in an amount of 0.3 mole or more, more preferably 0.5 to 5 mole and even more preferably 1 to 3 mole per mole of the component (A). For example, an aqueous solution prepared by mixing the component (A) with the component (B) in an equivalent mole has preferably a pH of from 2 to 6 at 25° C. (measured, for example, by means of HORIBA pH METER F-22 after correcting with a phthalate standard solution).
The ceramides used as the component (C) in the present invention is represented by Formula (2) described above, and R7 in the formula is a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 4 to 30 carbon atoms which may be substituted with a hydroxyl group, a carbonyl group or an amino group, preferably having 7 to 22 carbon atoms which may be substituted with a hydroxyl group.
Z represents any of a methylene group, a methine group and an oxygen atom.
X5, X6 and X7 each represent independently a hydrogen atom, a hydroxyl group or an acetoxy group. It is preferred that zero to one group of X5, X6 and X7 is a hydroxyl group and that the remainder is a hydrogen atom. When Z is a methine group, only one of X5 and X6 is a hydrogen atom, and the other is not present. X4 is preferably a hydrogen atom or a glyceryl group.
R8 and R9 represent a hydrogen atom, a hydroxyl group, a hydroxymethyl group or an acetoxymethyl group. Preferred R8 is a hydrogen atom or a hydroxymethyl group, and preferred R9 is a hydrogen atom.
R10 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 5 to 60 carbon atoms which may be substituted with a hydroxyl group, a carbonyl group or an amino group and which may have an ether bond, an ester bond or an amide bond in a principal chain. Preferably, R10 includes a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 5 to 35 carbon atoms which may be substituted with a hydroxyl group or an amino group or a group obtained by subjecting a linear, branched or cyclic, saturated or unsaturated fatty acid having 8 to 22 carbon atoms which may be substituted with a hydroxyl group to ester bonding or amide bonding to the ω-position of the above hydrocarbon group. The fatty acid to be bonded is preferably isostearic acid, 12-hydroxystearic acid or linoleic acid.
R11 represents a hydrogen atom or is a linear or branched, saturated or unsaturated hydrocarbon group having in total 1 to 8 carbon atoms which may have a substituent selected from a hydroxyl group, a hydroxyalkoxy group, an alkoxy group and an acetoxy group. Among them, preferred is a hydrogen atom or a hydrocarbon group having in total 1 to 8 carbon atoms which may be substituted with 1 to 3 groups selected from a hydroxyl group, a hydroxyalkoxy group and an alkoxy group. The hydroxyalkoxy group and the alkoxy group have preferably 1 to 7 carbon atoms.
The ceramides as the component (C) are preferably ceramides represented by the following Formula (5) or (6). (I) Natural ceramides or natural type ceramides and derivatives thereof represented by Formula (5) (hereinafter described as natural type ceramides):




wherein R21 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 7 to 19 carbon atoms which may be substituted with a hydroxyl group; Z1 represents a methylene group or a methine group; X12, X13 and X14 each represent independently a hydrogen atom, a hydroxyl group or an acetoxy group; X15 represents a hydrogen atom or, together with an adjacent oxygen atom, forms an oxo group, wherein when Z1 is a methine group, one of X12 and X13 is a hydrogen atom, and the other is not present, and when X15 forms an oxo group, X14 is not present; R22 represents a hydroxymethyl group or an acetoxymethyl group; R23 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R24 is a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 5 to 30 carbon atoms which may be substituted with a hydroxyl group or represents a group obtained by subjecting a linear or branched, saturated or unsaturated fatty acid having 8 to 22 carbon atoms which may be substituted with a hydroxyl group to ester bonding to the ω-terminal of the above hydrocarbon group; and a bond represented by a “broken line and solid line” represents a single bond or a double bond.

Preferable is the compound in which R21 is a linear alkyl group having 7 to 19 carbon atoms, more preferably 13 to 15 carbon atoms; Z1 is a methine group; one of X12 and X13 is a hydrogen atom; and R24 is a linear alkyl group having 9 to 27 carbon atoms which may be substituted with a hydroxyl group or a linear alkyl group having 9 to 27 carbon atoms to which linoleic acid is ester-bonded. Preferably, X15 represents a hydrogen atom or forms an oxo group together with an oxygen atom. R24 is more preferably tricocyl, 1-hydroxypentadecyl, 1-hydroxytricocyl, heptadecyl, 1-hydroxyundecyl or nonacocyl in which linoleic acid is ester-bonded to the ω-position.
The specific examples of the natural type ceramides include sphingosine, dihydrosphingosine, phytosphingosine and ceramides Type 1 to 7 obtained by converting sphingadienes to corresponding amides (for example, ceramides of pigs and human beings described in FIG. 2 of J. Lipid Res., 24: 759 (1983) and FIG. 4 of J. Lipid Res., 35: 2069 (1994)).







Further, N-alkyl products thereof (for example, N-methyl product) are included therein. They may be either extracts obtained from the natural products or the synthetic compounds, and commercially available products can be used.
Either the optically active compounds of a natural type (D(−) compound) or the optically active compounds of a non-natural type (L(+) compound) may be used for these sphingosines, or a mixture of the natural type and the non-natural type may be used. The steric configuration of the compounds described above may be either the steric configuration of the natural type or the steric configuration of the non-natural type other than the above type or may be a mixture thereof. Preferred are CERAMIDE 1, CERAMIDE 2, CERAMIDE 3, CERAMIDE 5 and CERAMIDE 6II (INCI dictionary; 8th Edition) and compounds represented by the formulas shown below.
The commercially available products of the natural type ceramides include Ceramide I, Ceramide III, Ceramide IIIA, Ceramide IIIB, Ceramide IIIC and Ceramide VI (all manufactured by Cosmo Ferm Co., Ltd.), Ceramide TIC-001 (manufactured by Takasago International Corp.), CERAMIDE II (manufactured by Quest International Co., Ltd.), DS-Ceramide VI, DS-CLA-Phytoceramide, C6-Phytoceramide, DS-Ceramide Y3S (manufactured by DOOSAN Co., Ltd.) and







(II) Pseudo type ceramides represented by the following Formula (6):





wherein R25 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 10 to 22 carbon atoms which may be substituted with a hydroxyl group; X4 represents a hydrogen atom, an acetyl group or a glyceryl group; R26 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 5 to 22 carbon atoms which may be substituted with a hydroxyl group or an amino group or a group obtained by subjecting a linear or branched, saturated or unsaturated fatty acid having 8 to 22 carbon atoms which may be substituted with a hydroxyl group to ester bonding to the ω-terminal of the above hydrocarbon group; and R27 represents a hydrogen atom or an alkyl group having in total 1 to 8 carbon atoms which may be substituted with a hydroxyl group, a hydroxyalkoxy group, an alkoxy group or an acetoxy group.

R26 is preferably nonyl, tridecyl, pentadecyl, undecyl in which linoleic acid is ester-bonded to the ω-position, pentadecyl in which linoleic acid is ester-bonded to the ω-position, pentadecyl in which 12-hydroxystearic acid is ester-bonded to the ω-position or undecyl in which methyl-branched isostearic acid is amide-bonded to the ω-position. The hydroxy alkoxy group or the alkoxy group as R27 has preferably 1 to 8 carbon atoms.
Preferred are the pseudo type ceramides represented by Formula (6) in which R25 is hexadecyl, X4 is a hydrogen atom, R26 is pentadecyl and R27 is hydroxyethyl; R25 is hexadecyl, X4 is a hydrogen atom, R26 is nonyl and R27 is hydroxyethyl; or R25 is hexadecyl, X4 is glyceryl, R26 is tridecyl, R27 is 3-methoxypropyl. More preferred is the compound of Formula (6) in which R25 is hexadecyl, X4 is a hydrogen atom, R26 is pentadecyl and R27 is hydroxyethyl.
Two or more of the component (C) may be used in combination. A content of the component (C) in the emulsion of the present invention is preferably 50% by weight or less, more preferably 0.01 to 50% by weight and even more preferably 0.01 to 20% by weight.
In the emulsion of the present invention, a weight proportion ((A)+(B))/(C) of the contents of the components (A), (B) and (C) is preferably 0.0001 or more, more preferably 0.0001 to 1000, even more preferably 0.001 to 100, and still more preferably 0.01 to 10 in terms of the stability.
The ceramide emulsion of the present invention contains neither phospholipid (lecithin) nor an acrylic acid polymer (carboxyl vinyl polymer) in terms of the storage stability.
The ceramide emulsion of the present invention contains water in addition to (A) the sphingosines, (B) the acidic compound and (C) the ceramides. A content of water is preferably 0.1 to 99.99% by weight, more preferably 10 to 99.9% by weight. The whole amount of water may be added in an emulsifying step or only a part thereof may be added in the emulsifying step, and the remaining amount may be added later when cooled down to room temperature.
The ceramide emulsion of the present invention is produced by adding (B) the acidic compound to (A) the sphingosines in emulsifying the ceramides to form the salts of the sphingosines (hereinafter referred to as a sphingosine salt). In this case, a process for producing the ceramides emulsion may be any of (1) a process in which the acidic compound forming a salt with the sphingosines is added to a preliminary mixture of the sphingosines and the ceramides, (2) a process in which the sphingosines are mixed with the acidic compound forming a salt with a sphingosine to form a salt and the ceramides are then added thereto, and (3) a process in which the three components, sphingosines, the acidic compound forming a salt with a sphingosine and the ceramides, are added at the same time. Further, a component isolated as a sphingosine salt may be mixed with the ceramides.
In the present invention, if either the sphingosine or the acidic compound forming a salt with a sphingosine is not present during emulsifying for ceramides, the emulsification can not be achieved. If the emulsification is carried out in the absence of any of the essential components described above and the above short component is added thereafter, the emulsion of the present invention is not obtained.
If both of the sphingosines and the ceramides are solid during emulsification, they can be molten by heating or dissolved in a solvent such as an oil or an alcohol to carry out emulsification. All of the sphingosines and the ceramides which are the raw materials and the sphingosine salts which are reaction products with the acidic compound are preferably liquid.
An emulsifying temperature in producing the ceramides emulsion of the present invention may be any temperature as long as the sphingosines or the ceramides are neither crystallized nor deposited during an emulsifying operation, and it is preferably 120° C. or lower, more preferably 95° C. or lower in terms of an easiness in the work.
In the emulsification, stirring is carried out preferably at 20 to 1000 r/min, more preferably 200 to 1000 r/min and even more preferably 200 to 800 r/min by means of a propeller or the like. Further, it is preferable to conduct additional stirring at 1500 to 10000 r/min, more preferably 4500 to 9000 r/min by means of a homomixer. The emulsifying time is preferably 1 to 20 minutes, more preferably 5 to 20 minutes. When the emulsification is carried out under heating, the emulsion is preferably cooled down to room temperature at a cooling rate of 0.1 to 20° C./min, more preferably 0.1 to 10° C./min, even more preferably 0.1 to 5° C./min.
In producing the ceramide emulsion of the present invention, further addition of a lower alcohol having 1 to 4 carbon atoms and/or a polyhydric alcohol (hereinafter referred to as alcohols) enhances the storage stability and therefore is preferred.
The lower alcohol includes ethyl alcohol. The polyhydric alcohol includes glycerin, sorbitol, propylene glycol, dipropylene glycol, 1,3-butanediol, polyoxyethylene methyl glucoside and polyethylene glycol, and glycerin, 1,3-butanediol, polyoxyethylene methyl glucoside and polyethylene glycol are preferred.
The emulsion is produced preferably by adding the whole amount or a part of these alcohols in the emulsifying step.
Two or more kinds of the alcohols may be used in combination. The alcohols are preferably contained in the emulsion in a proportion of 50% by weight or less, more preferably 0.01 to 20% by weight.
The ceramide emulsion thus produced stays in a transparent, translucent or opaque state. In this case, the terms “transparent” and “translucent” mean that a turbidity (kaoline standard: a turbidity of refined kaoline 1 mg/l liter of water is set to a turbidity of 1 ppm) measured by means of an integrating sphere photoelectric scattering photometer is 1 to 1500 ppm. When a weight ratio ((A)+(B))/(C) of (A) the sphingosines, (B) the acidic compound and (C) the ceramides is 0.2 or more, a transparent or translucent emulsion is obtained, and when it is less than 0.2, an opaque emulsion is obtained. The emulsion is suitably produced so that the oil drop of the emulsion has an average particle diameter in a range of from 3 nm to 200 μm according to the appearance and the uses, and it is preferably 5 nm to 50 μm, more preferably 5 nm to 10 μm in terms of an appearance and a stability of the emulsion. The average particle diameter is measured by means of a dynamic light scattering type particle size distribution measuring apparatus (HORIBA LB-500) or a laser diffraction/scattering type particle size distribution measuring apparatus (HORIBA LA-920).
The ceramide emulsion of the present invention is preferably used as a skin external preparation, for example, a cosmetic, a medicine, a bathing agent, a clean wiping agent or a scalp care agent, and it is more preferably used as a cosmetic. The cosmetic includes skin cosmetics such as a translucent lotion, a translucent emulsion, a moisturizing essence, a whitening essence, a moisturizing emulsion, a moisturizing cream, and the like.
In the case of the skin external preparation, the specific combination of the components (A), (B) and (C) is preferably to combine the component (C) of Formula (5) with the component (A) of Formula (3), or combine the component (C) of Formula (6) with the component (A) of Formula (4). It is more preferred in terms of the stability and the effect to use a compound obtained by substituting a hydrogen atom for COR10 bonded to a nitrogen atom in the compound of Formula (2) of the component (C) as the compound of Formula (1) of the component (A).
Further, when the ceramide emulsion is used as a skin external preparation, further containing a higher alcohol, a fluorine oil or silicone into the skin external preparation is preferred, because it enhances the emulsion stability and the use feeling.
The higher alcohol includes stearyl alcohol, cetyl alcohol, isostearyl alcohol, acetic acid lanolin alcohol, acetic acid polyoxyethylene lanolin alcohol, hydrogenated lanolin alcohol, setostearyl alcohol, batyl alcohol, behenyl alcohol and lanolin alcohol. Of these, stearyl alcohol, cetyl alcohol, batyl alcohol and behenyl alcohol are preferred.
Two or more of these higher alcohols may be used in combination. A content of the higher alcohol in the skin external preparation is preferably 10% by weight or less, more preferably 0.01 to 5% by weight.
The fluorine oil includes a compound represented by the following Formula (7):

R28—O—(CH2)nRf  (7)

wherein R28 represents a linear or branched alkyl group having 2 to 30 carbon atoms; n represents an integer of 1 or 2; and Rf represents a linear or branched fuluorocarbon group having 3 to 20 carbon atoms which may have a hydrogen atom at a terminal carbon atom.

In Formula (7), R28 is preferably an alkyl group having 6 to 18 carbon atoms and is more preferably hexyl, octyl, decyl and dodecyl.
The group represented by Rf is preferably a fluorine-substituted alkyl group having a chain length of 6 to 12 carbon atoms. It includes, for example, linear or branched perfluoropropyl, perfluorobutyl, perfluoropentyl, perfluorohexyl, perfluoroheptyl, perfluorooctyl, perfluorononyl, perfluorodecyl, perfluoroundecyl, 1,1,2,2,3,3,4,4-octafluorobutyl, 1,1,2,2,3,3,4,4,5,5-decafluoropentyl, 1,1,2,2,3,3,4,4,5,5,6,6-dodecafluorohexyl, 1,1,2,2,3,3,4,4,5,5,6,6,7,7-tetradecafluoroheptyl and 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-hexadecafluorooctyl. Of these, preferred are perfluorohexyl, perfluorooctyl, perfluoroundecyl, 1,1,2,2,3,3,4,4,5,5,6,6-dodecafluorohexyl and 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-hexadecafluorooctyl.
Two or more of the fluorine base oil preparation may be used in combination. A content of the fluorine base oil preparation in the skin external solution is preferably 50% by weight or less, more preferably 0.01 to 10% by weight.
The silicone includes cyclic dimethylpolysiloxanes, chain dimethylpolysiloxanes, high molecular dimethylpolysiloxanes and methylphenylpolysiloxanes, as well as modified silicones such as amino-modified silicones, alkyl-modified silicones, polyether-modified silicones, alcohol-modified silicones and fluorine-modified silicones.
Two or more of the silicone may be used in combination. A content of the silicone in the skin external preparation is preferably 50% by weight or less, more preferably 0.01 to 10% by weight.
In addition to the above components, components used for conventional skin external preparations can suitably be used for the skin external preparation. They include, for example, moisturizers such as glycine betaine, xylitol, trehalose, urea, neutral amino acid and basic amino acid; water-soluble thickeners such as xanthane gum, hydroxyethyl cellulose, methyl cellulose and hydroxypropyl guar gum; oils such as squalane, liquid paraffin, isotridecyl isononanoate, cholesterol, phytosterol, higher fatty acids and cholesteryl isostearate; drug action agents such as allantoin and tocopherol acetate; cationic surfactants such as dimethyldistearylammonium chloride; nonionic surfactants such as polyoxyethylene-hardened castor oil and polyoxyethylene alkyl ethers; organic powders such as cellulose power, nylon powder, cross-linking type silicone powder, cross-linking type methylpolysiloxane powder, porous cellulose powder and porous nylon powder; inorganic powders such as anhydrous silica, zinc oxide and titanium oxide; refrigerants such as menthol and camphor; vegetable extracts; pH buffer agents; antioxidants; UV absorbers; antiseptic agents; perfumes; fungicides; and coloring matters.
In the present invention, a viscosity of the emulsion is influenced by the contents of solid lipids such as ceramides and the other components, the production process and the like. That is, the emulsion of the present invention may be not only a creamy emulsion having a high viscosity but also an emulsion having a low viscosity. For example, even if the viscosity is 1 to 20000 mPa·s at 25° C., deposition of crystals and separation of the emulsion do not occur, and the stability is good. In general, an emulsion having a low viscosity is liable to cause separation by creaming, but according to the present invention, the emulsion having suitable use feeling, spreading and appearance can be obtained in a viscosity falling in a range of 1 to 20000 mPa·s at 25° C.
EXAMPLES
Compounds Used
Pseudo type sphingosine (i); sphingosine of Formula (4), in which R17 is isostearyl; X4 is a hydrogen atom; a is 2; R19 is 1,1-dimethyl-2-hydroxyethyl; and R18 is a hydrogen atom.
Pseudo type sphingosine (ii); sphingosine of Formula (4), in which R17 is isostearyl; X4 is a hydrogen atom; a is 2; R18 is 2-hydroxyethyl; and R19 is a hydrogen atom.
Pseudo type sphingosine (iii); sphingosine of Formula (4), in which R17 is isostearyl; X4 is a hydrogen atom; a is 2; R18 is 2-(2-hydroxyethoxy)ethyl; and R19 is a hydrogen atom.
Pseudo type sphingosine (iv); sphingosine of Formula (4), in which R17 is isostearyl; X4 is a hydrogen atom; a is 2; R18 is 1,1-bis(hydroxymethyl)ethyl; and R19 is a hydrogen atom.
Pseudo type ceramides (i); ceramides of Formula (6), in which R25 is hexadecyl; X4 is a hydrogen atom; R26 is pentadecyl; and R27 is hydroxyethyl.
Pseudo type ceramides (ii); ceramides of Formula (6), in which R25 is hexadecyl; X4 is a hydrogen atom; R26 is nonyl; and R27 is hydroxyethyl.
Example 1
A 100 mL emulsifying bath was charged with 1.0 g of phytosphingosine (melting point: 102 to 107° C., manufactured by Cosmo Ferm Co., Ltd.) to melt it by heating on an oil bath set to 110° C., and 1.0 g of ceramide 2 (melting point: 99 to 105° C., manufactured by Sederma Co., Ltd.) heated in advance to 120° C. was added thereto and the resulting mixture was stirred at 300 r/min for 10 minutes. Then, a mixed solution of 0.2 g of phosphoric acid and 10 g of water was added in one minute while heating the emulsifying bath so that the ceramide was not deposited, and the solution was stirred and emulsified. The emulsion was cooled down to 25° C. at a cooling rate of 1° C./min, and 87.8 g of water was added during cooling to produce a ceramide emulsion.
Example 2
A ceramide emulsion was produced in the same manner and using the same composition as in Example 1 except that the mixed solution of phosphoric acid and water was added before adding ceramide 2.
Example 3
The addition order was changed as described below using the same composition as in Example 1 to produce a ceramide emulsion. Water (10 g) was added to the sphingosine, and the mixture was heated to dissolve the sphingosine. The resulting solution was mixed under stirring with the ceramide 2 which had been molten by heating, and then phosphoric acid was added thereto. The resulting mixture was stirred and emulsified. The remaining amount of water was added in a cooling step.
Example 4
A ceramide emulsion was produced in the same manner as in Example 1 except that an amount of water added to phosphoric acid was changed to 97.8 g (whole amount).
Example 5
A ceramide emulsion was produced in the same manner and using the same composition as in Example 1 except that the ceramides and phosphoric acid were mixed with the sphingosine at the same time and dissolved.
Example 6
A ceramide emulsion was produced in the same manner as in Example 1 except that in Example 1, phosphoric acid was mixed with the sphingosine at the same time and dissolved.
Example 7
A ceramide emulsion was produced in the same manner as in Example 1 except that in Example 1, the sphingosine, the ceramides, phosphoric acid and 10 g of water were mixed at the same time and dissolved.
Example 8
A ceramide emulsion was produced in the same manner as in Example 1 except that in Example 1, the sphingosine and the ceramides were mixed at the same time and dissolved.
Example 9
A ceramide emulsion was produced in the same manner as in Example 1 except that 10 g of glycerin was further added to the sphingosine, the ceramides, phosphoric acid and 10 g of water in the procedure of Example 7, and they were mixed and dissolved at the same time. Incidentally, an amount of water finally added was reduced by the portion of 10 g of glycerin added.
Example 10
A 100 mL emulsifying bath was charged with 1.0 g of phytosphingosine (melting point: 102 to 107° C., manufactured by Cosmo Ferm Co., Ltd.) to melt it by heating on an oil bath set to 110° C., and a mixture of 1.0 g of ceramide 2 heated in advance to 120° C., 1 g of stearyl alcohol, 4 g of dimethylpolysiloxane and 10 g of glycerin was added thereto and stirred at 80° C. at 300 r/min for 10 minutes. Then, a mixed solution of 0.5 g of lactic acid and 10 g of water was added thereto in one minute while heating the emulsifying bath so that crystal was not deposited, and the resulting mixture was stirred and emulsified. Further, the emulsion was stirred at 80° C. at 9000 r/min for 2 minutes by means of a homomixer. Then, the emulsion was cooled down to 25° C. at a cooling rate of 1° C./min, and 72.5 g of water was added during cooling to produce a ceramide emulsion.
Example 11
A ceramide emulsion was produced in the same manner as in Example 10, except that phytosphingosine, ceramide 2, stearyl alcohol, dimethylpolysiloxane and glycerin were mixed and dissolved at the same time in the emulsifying bath.
Example 12
A 100 mL emulsifying bath was charged with 1.0 g of phytosphingosine, 1.0 g of ceramide 2, 1.0 g of stearyl alcohol and 10 g of glycerin to melt them by heating on an oil bath set to 110° C. Then, a mixed solution of 0.5 g of lactic acid and 10 g of water was added thereto in one minute while heating the emulsifying bath so that crystal was not deposited and stirred at 80° C. at 300 r/min for 10 minutes, and 4 g of dimethylpolysiloxane heated in advance to 80° C. was added thereto to emulsify the resulting mixture. Further, the emulsion was stirred at 80° C. at 9000 r/min for 2 minutes by means of a homomixer and then cooled down to 25° C. at a cooling rate of 1° C./min, and 72.5 g of water was added thereto during cooling to produce a ceramide emulsion.
Example 13
Pseudo type sphingosine (ii) (melting point: 45° C.) (1.0 g) was molten by heating to 80° C., and 1.0 g of pseudo type ceramide (i) (melting point: 75° C.) heated in advance to 80° C. was added thereto. The mixture was stirred at 80° C. at 300 r/min for 10 minutes, and then a mixed solution of 0.5 g of L-glutamic acid and 10 g of water was added thereto in one minute while maintaining the emulsifying bath at a temperature of 80° C. and the resulting mixture was stirred to emulsify the mixture. The emulsion was cooled down to 25° C. at a cooling rate of 1° C./min, and 87.5 g of water was added thereto during cooling to produce a ceramide emulsion.
Example 14
Pseudo type sphingosine (ii) (melting point: 45° C.) (1.0 g) was molten by heating to 80° C., and 10.0 g of pseudo type ceramide (i) (melting point: 75° C.) heated in advance to 80° C. was added thereto. The mixture was stirred at 80° C. at 300 r/min for 10 minutes, and then a mixed solution of 0.5 g of L-glutamic acid and 10 g of water was added thereto in one minute while maintaining the emulsifying bath at a temperature of 80° C. and the resulting mixture was stirred to emulsify the mixture. Further, the emulsion was stirred at 80° C. at 9000 r/min for 2 minutes by means of a homomixer and then cooled down to 25° C. at a cooling rate of 1° C./min, and 78.5 g of water was added thereto during cooling to produce a ceramide emulsion.
Example 15
Pseudo type sphingosine (ii) (melting point: 45° C.) (0.1 g) and glycerin (10 g) were molten, and an oil phase component obtained by mixing 5.0 g of pseudo type ceramide (i) (melting point: 75° C.) heated in advance to 80° C., 0.5 g of stearyl alcohol, 0.75 g of cetyl alcohol and 4 g of squalane was added thereto. The mixture was stirred at 80° C. at 300 r/min for 10 minutes, and then a mixed solution of 0.1 g of L-glutamic acid and 10 g of water was added thereto in one minute while maintaining the emulsifying bath at a temperature of 80° C. and the resulting mixture was stirred to emulsify the mixture. Further, the emulsion was stirred at 80° C. at 9000 r/min for 2 minutes by means of a homomixer and then cooled down to 25° C. at a cooling rate of 1° C./min, and 79.55 g of water was added thereto during cooling to produce a ceramide emulsion.
Comparative Example 1
A ceramide emulsion was produced in the same manner as in Example 1 except that phosphoric acid was not used.
Comparative Example 2
Phytosphingosine (1.0 g) was heated and molten in the same manner as in Comparative Example 1, and then 1.0 g of molten ceramide 2 was added thereto and the mixture was stirred at 300 r/min for 10 minutes. The temperature of the emulsifying bath was lowered to 25° C. which was not higher than the melting point of ceramide 2 at a cooling rate of 1° C./min, and then a mixed solution of 0.2 g of phosphoric acid and 87.8 g of water was added thereto to produce a ceramide emulsion.
Comparative Example 3
A ceramide emulsion was produced in the same manner as in Example 1 except that 1 g of lecithin (Egg Yolk Lecithin PL-100P, average molecular weight: 788, manufactured by Kewpie Co., Ltd.) was added together with ceramide 2.
Comparative Example 4
A ceramide emulsion was produced in the same manner as in Example 1 except that 0.2 g of Carbopol 981 (average molecular weight: 1,250,000, manufactured by Goodrich Co., Ltd.) was added together with the remaining amount of water.
Comparative Example 5
A ceramide emulsion was produced in the same manner as in Example 1 except that phytosphingosine was not used. That is, a 100 mL emulsifying bath was charged with 1.0 g of ceramide 2 (manufactured by Sederma Co., Ltd.) to melt it by heating on an oil bath set to 120° C. Then, a mixed solution of 0.2 g of phosphoric acid and 10 g of water was added thereto in one minute while heating the emulsifying bath so that the ceramide was not deposited, and the resulting mixture was stirred and emulsified. The emulsion was cooled down to 25° C. at a cooling rate of 1° C./min, and 88.8 g of water was added thereto during cooling to produce a ceramide emulsion.
The ceramides emulsions prepared in Examples 1 to 15 were left standing still at −5° C., 25° C. and 50° C. for one week to find that ceramides were observed to be neither separated nor deposited in all cases and that they were excellent in emulsion stability. In contrast thereto, ceramides of Comparative Examples 1, 2, 4 and 5 were observed to be separated immediately after production, and stable emulsion systems were not obtained. The emulsion in which ceramides were not separated was obtained in Comparative Example 3, but when it was left standing still at 25° C. for one day, ceramides were coagulated and separated.
Examples 16 to 36
Skin external preparations having compositions shown in Tables 1 to 4 were produced and evaluated for stability.
Production Process
Examples 16 to 19
The components (A) and (C) and the components (7) to (9) were heated to 80 to 120° C. while stirring and molten to prepare oil phases. An aqueous phase obtained by dissolving the component (B) in a part of water of the component (13) by heating was added to the oil phases while stirring (300 r/min). After addition, the resulting mixtures were stirred, if necessary, by means of a homomixer (9000 r/min) and cooled down to 20 to 40° C., and then the components (10) to (13) were added thereto and mixed to obtain skin external preparations.
Examples 20 to 25
The components (A) and (C) and the components (11) to (15) were heated to 80 to 120° C. while stirring and molten to prepare oil phases. Aqueous phases obtained by dissolving the component (B) in a part of water of the component (18) by heating were added to the oil phases while stirring (300 r/min). After addition, the resulting mixtures were stirred, if necessary, by means of the homomixer (9000 r/min) and cooled down to 20 to 40° C., and then the components (16) to (18) were added thereto and mixed to obtain skin external preparations.
Examples 26 to 32
The components (A) and (C) and the components (13) to (23) were heated to 80 to 120° C. while stirring and molten to prepare oil phases. Aqueous phases obtained by dissolving the component (B) in a part of water of the component (31) by heating were added to the oil phases while stirring (300 r/min). After addition, the resulting mixtures were stirred, if necessary, by means of the homomixer (9000 r/min) and cooled down to 20 to 40° C., and then the components (24) to (31) were added and mixed to obtain skin external preparations.
Examples 33 to 36
The components (A) and (C), the components (10) to (15) and (17) were heated to 80 to 120° C. while stirring and molten to prepare oil phases. Aqueous phases obtained by dissolving the component (B) in a part of water of the component (32) by heating were added to the oil phases while stirring (300 r/min). The resulting mixtures were then stirred, if necessary, by means of the homomixer (9000 r/min) and cooled down to 20 to 40° C., and then the components (16) and (18) to (32) were added thereto and mixed to obtain skin external preparations.
Evaluation of Stability:
The appearance was observed with naked eyes after the preparations were left standing still at 50° C., room temperature (25° C.) and −5° C. for one week and judged according to the following criteria:

    ◯: the stability was good at all temperatures, and neither separation of the emulsion nor deposition was observed.
    x: the emulsion was instable at any temperatures, and separation of the emulsion or deposition of crystal was observed.











TABLE 1









Example












16
17
18
19









Transparent or translucent



emulsion composition of


Components (% by weight)
20000 mPa · s or less















A
(1) Phytosphingosine
0.2
0.2
0.2




(manufactured by



Cosmo Ferm Co., Ltd.)



(2) Pseudo type sphingosine (i)



0.2


B
(3) L-glutamic acid
0.06
0.06
0.06
0.06


C
(4) Pseudo type ceramides (i)
1


1



(5) Ceramide TIC-001


1



(manufactured by Takasago



International Corp.)



(6) Ceramide type 2

1



(manufactured by



Sederma Co., Ltd.)


Others
(7) Perfluorohexylethyl-1,3-methyl


0.02



butyl ether (compound described



in Japanese Patent Application



Laid-Open No. 322563/1999)



(8) Glycerin
5
5
4
9



(9) Polyethylene glycol



1



(10) 55% ethyl alcohol


1



(11) Polyoxyethylene (20) -



0.2



hardened castor oil



(12) Methylparabene



0.2










(13) Water
Balance








Appearance
Translucent











Stability
◯
◯
◯
◯


pH
4.5
4.5
4.5
4.5


















TABLE 2









Example














20
21
22
23
24
25









Emulsion composition of


Components (% by weight)
20000 mPa · s or less 

















A
(1) Phytosphingosine (manufactured
0.4
0.1



0.1



by Cosmo Ferm Co., Ltd.)



(2) Sphingosine (Formula (6))


0.1



(3) Pseudo type sphingosine (i)



0.1



(4) Pseudo type sphingosine (ii)




0.1


B
(5) Succinic acid


0.03
0.03



(6) Phosphoric acid
0.08



(7) L-glutamic acid

0.04


0.04
0.04


C
(8) Pseudo type ceramides (i)
3
4
4
4
4



(9) Ceramide type 1 (manufactured
0.1



by Cosmo Ferm Co., Ltd.)



(10) Ceramide type 2 (manufactured





4



by Sederma Co., Ltd.)


Others
(11) Stearyl alcohol

0.5
0.5
0.5
0.5
0.5



(12) Cetyl alcohol

0.5
0.5
0.5
0.5
0.5



(13) Perfluorohexylethyl-1,3-methyl

2
2
2
2
2



butyl ether (compound described in



Japanese Patent Application Laid-



Open No. 322563/1999)



(14) Squalane

2
2
2
2
2



(15) Glycerin
9
18
20
20
18
20



(16) Polyethylene glycol

2


2



(17) 55% ethyl alcohol
1










(18) Water
Balance








Appearance
Opaque













Stability
◯
◯
◯
◯
◯
◯


pH
4.2
4.5
4.8
4.8
4.5
4.5


















TABLE 3









Example















26
27
28
29
30
31
32










Emulsion
Emulsion



composition
composition



of 20000 mPa ·
of 20000


Component (% by weight)
s or less
mPa · s or more


















A
(1) Phytosphingosine (manufactured by Cosmo Ferm





0.2




Co., Ltd.)



(2) Pseudo type sphingosine (i)






0.2



(3) Pseudo type sphingosine (ii)
0.1
0.1
0.1
0.05
0.2


B
(4) 1N-hydrochloric acid




0.6



(5) L-aspartic acid
0.02
0.02



(6) L-glutamic acid
0.02
0.02
0.04
0.04

0.06
0.06


C
(7) Pseudo type ceramides (i)




10
5



(8) Pseudo type ceramides (ii)






5



(9) Ceramide type 1 (manufactured by Cosmo Ferm Co.,





1
1



Ltd.)



(10) Ceramide type 2 (manufactured by Sederma Co.,


4
4


4



Ltd.)



(11) Ceramide type 3 (manufactured by Cosmo Ferm
4




4



Co., Ltd.)



(12) Ceramide type 6 (manufactured by Cosmo Ferm

4



Co., Ltd.)


Others
(13) Stearyl alcohol
0.4
0.4
0.5
1
1
0.5
0.5



(14) Cetyl alcohol
0.5
0.5
0.5
1
1
1
1



(15) Batyl alcohol
0.1
0.1



(16) Behenyl alcohol



0.1

0.5
0.5



(17) Perfluorohexylethyl-1,3-methyl butyl ether
2
2
2


4
4



(compound described in Japanese Patent Application



Laid-Open No. 322563/1999)



(18) Perfluoropolyether (FOMBLIN HCO4: manufactured



4
3



by Montefroth Co., Ltd.



(19) Methylpolysiloxane (KF96, 1 cs)




1

2



(20) Cholesterol


0.5


1



(21) Cholesteryl isostearate



2
4
4



(22) Squalane
2
2
2

4
2
4



(23) Glycerin
20
20
20
10
20
10
10



(24) Polyethylene glycol




3
3



(25) 55% ethyl alcohol



5



(26) Polyoxyethylene (20) octyl dodecyl ether



3



(27) Polyoxyethylene (20) lauryl ether sodium






0.1



sulfate



(28) Methyl cellulose



0.5

0.5



(29) Guar gum




0.5

0.5



(30) Methylparabene


0.2



0.2










(31) Water
Balance








Appearance
Opaque














Stability
◯
◯
◯
◯
◯
◯
◯


pH
4.5
4.5
4.5
4.8
4.0
4.8
4.8


















TABLE 4









Example












33
34
35
36









Emulsion composition of


Component (% by weight)
20000 mPa · s or less















A
(1) Pseudo type sphingosine (ii)
0.1
0.05





(2) Pseudo type sphingosine (iii)


0.01



(3) Pseudo type sphingosine (iv)


0.05
0.08


B
(4) L-glutamic acid

0.04

0.02



(5) L-aspartic acid
0.05



(6) Lactic acid


0.06
0.03


C
(7) Pseudo type ceramides (i)

4
3
3



(8) Ceramide type 2 (manufactured by Sederma Co., Ltd.)
4



(9) Ceramide TIC-001 (manufactured by Takasago International Corp.)


0.01
0.01


Others
(10) Stearyl alcohol
0.5
0.5
0.5
0.5



(11) Cetyl alcohol
0.5
0.75
0.75
0.75



(12) Methylpolysiloxane (KF-96A (10 cs): manufactured by Shin-etsu
4
5
5
5



Chemical Ind. Co., Ltd.)



(13) Methylpolysiloxane (KF-96A (1000 cs): manufactured by Shin-etsu

1
1
1



Chemical Ind. Co., Ltd.)



(14) Glycerin
10
20
20
20



(15) Polyethylene glycol (PEG1540: manufactured by Sanyo Kasei Ind. Co.,

3
3
3



Ltd.)



(16) Hydroxypropyl methyl cellulose (Metolose 60SH4000: manufactured by

0.3
0.3
0.3



Shin-etsu Chemical Ind. Co., Ltd.)



(17) Cedrol

0.05
0.05
0.05



(18) Japanese linden extract (Falcolex Bodaiju: manufactured by Ichimaru

0.1

0.05



Falcos Co., Ltd.



(19) Fucuceae extract (Falcolex Hibamata: manufactured by Ichimaru



0.05



Falcos Co., Ltd.)



(20) Witch hazel extract (Hamamerisu Liquid: manufactured by Ichimaru


0.2



Falcos Co., Ltd.)



(21) Althaea officinalis root extract (Falcolex Arutea: manufactured by

0.1



Ichimaru Falcos Co., Ltd.)



(22) Citron extract (Citron Extract: manufactured by Maruzen Seiyaku

0.1



Co., Ltd.)



(23) Sanguisorba officinalis extract (Ju Extract: manufactured by



0.2



Maruzen Seiyaku Co., Ltd.)



(24) Tea extract (Green Tea Liquid: manufactured by Ichimaru Falcos Co.,

0.1



Ltd.)



(25) Phellodendri Cortex extract (Oubaku Liquid: manufactured by Ichimaru


0.03



Falcos Co., Ltd.)



(26) Royal jelly extract (Royal Jelly Extract: manufactured by Maruzen


0.5



Seiyaku Co., Ltd.)



(27) Glycine betaine (Amino Coat: manufactured by Asahi Kasei Co., Ltd.)



3



(28) dl-α-Tocopherol acetate (manufactured by Riken Vitamin Co., Ltd.)

0.1

0.1



(29) Eucalyptus extract (Falcolex Yukari: manufactured by Ichimaru


0.1
0.5



Falcos Co., Ltd.)



(30) Thujopsis dolabrata extract (Asunaro Liquid: manufactured by


0.5
1



Ichimaru Falcos Co., Ltd.)



(31) Methylparabene

0.2
0.2
0.2










(32) Water
Balance








Appearance
Opaque











Stability
◯
◯
◯
◯


pH
4.5
4.8
4.8
4.8









All of the skin external preparations of the present invention were excellent in stability.
INDUSTRIAL APPLICABILITY
The ceramide emulsions of the present invention are not separated and deposited even if surfactants are not used, and they are excellent in storage stability. The emulsions having transparent to opaque appearance can readily be obtained by controlling the components.

## Claims

1. A process for production of a ceramide emulsion comprising:
adding (C) one or more ceramides to (A) one or more sphingosines, and then
adding (B) an acidic compound and water thereby forming one or more sphingosine salts;

wherein
said one or more sphingosine salts emulsify said (C) one or more ceramides thereby forming said ceramide emulsion;
said (A) one or more sphingosines being represented by Formula (1):





wherein R1 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 4 to 30 carbon atoms which is optionally substituted with a hydroxyl group, a carbonyl group or an amino group; Y represents a methylene group, a methine group or an oxygen atom; X1, X2 and X3 each represent independently a hydrogen atom, a hydroxyl group or an acetoxy group, and X4 represents a hydrogen atom, an acetyl group or a glyceryl group or, together with an adjacent oxygen atom, forms an oxo group, wherein when Y is a methine group, either one of X1 and X2 is a hydrogen atom, and the other is not present, and when X4 forms an oxo group, X3 is not present; R2 and R3 each represent independently a hydrogen atom, a hydroxyl group, a hydroxymethyl group or an acetoxymethyl group; groups “R”s each are independently a hydrogen atom or an amidino group or each represent independently a linear or branched, saturated or unsaturated hydrocarbon group having in total 1 to 8 carbon atoms which optionally have a substituent selected from a hydroxyl group, a hydroxyalkoxy group, an alkoxy group and an acetoxy group; “a” represents a number of 2 or 3; and a bond represented by a “broken line and solid line” represents a single bond or a double bond;
said (B) acidic compound being selected from inorganic acids and organic acids having a molecular weight of 200 or less; and
said (C) one or more ceramides being represented by Formula (2):





wherein R7 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 4 to 30 carbon atoms which is optionally substituted with a hydroxyl group, a carbonyl group or an amino group; Z represents a methylene group, a methine group or an oxygen atom; X5, X6 and X7 each represent independently a hydrogen atom, a hydroxyl group or an acetoxy group, and X4 represents a hydrogen atom, an acetyl group or a glyceryl group or, together with an adjacent oxygen atom, forms an oxo group, wherein when Z is a methine group, one of X5 and X6 is a hydrogen atom, and the other is not present, and when X4 forms an oxo group, X7 is not present; R8 and R9 each represent independently a hydrogen atom, a hydroxyl group, a hydroxymethyl group or an acetoxymethyl group; R10 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 5 to 60 carbon atoms which is optionally substituted with a hydroxyl group, a carbonyl group or an amino group and which optionally have an ether bond, an ester bond or an amide bond in a principal chain; R11 represents a hydrogen atom or a linear or branched, saturated or unsaturated hydrocarbon group having in total 1 to 8 carbon atoms which optionally have a substituent selected from a hydroxyl group, a hydroxyalkoxy group, an alkoxy group and an acetoxy group; and a bond represented by a “broken line and solid line” represents a single bond or a double bond.

2. The process according to claim 1, wherein (B) the acidic compound is at least one selected from the group consisting of phosphoric acid, hydrochloric acid, succinic acid, citric acid, lactic acid, glutamic acid and aspartic acid.

3. The process according to claim 1, wherein (B) the acidic compound is present in an amount of from 0.001 to 10% by weight.

4. The process according to claim 1, wherein (C) the one or more ceramides is present in an amount of from 0.01 to 50% by weight.

5. The process according to claim 1, wherein a weight proportion of ((A)+(B))/(C) of (A) is 0.0001 to 1000.

6. The process according to claim 1, wherein emulsification is carried out at a temperature of 120° C. or lower.

7. The process according to claim 1, wherein emulsification is carried out with stirring at 20 to 10000 r/min.

8. The process according to claim 6, wherein after emulsification is carried out at a temperature of 120° C. or lower, the emulsion is cooled to room temperature at a cooling rate of 0.1 to 20° C./min.

9. The process according to claim 1, wherein the ceramide emulsion further comprises at least one selected from the group consisting of a lower alcohol having 1 to 4 carbon atoms and a polyhydric alcohol.

10. The process according to claim 1, wherein the ceramide emulsion further comprises a higher alcohol, a fluorine oil or a silicone oil, said higher alcohol being at least one selected from the group consisting of stearyl alcohol, cetyl alcohol, isostearyl alcohol, acetic acid lanolin alcohol, acetic acid polyoxyethylene lanolin alcohol, hydrogenated lanolin alcohol, setostearyl alcohol, batyl alcohol, behenyl alcohol and lanolin alcohol.

11. The process according to claim 1, wherein the ceramide emulsion has a viscosity of 1 to 20000 mPa·s at 25° C.