JP2003146872A - Lipid dispersion composition and external preparation for skin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a lipid dispersion composition that has improved dispersibility of ceramide, particularly N,N'-bis(2-hydroxyethyl)-N,N'- biscetylmalonamide and to provide an external preparation for skin that includes the composition of which the applicability to the skin preparation is improved. SOLUTION: The lipid dispersion composition contains a ceramide compound represented by general formula [1], hydroxylated phospholipid and polyhydric alcohol. The external preparation of skin included the lipid dispersion composition wherein m1 and m2 are each 10-14 and n1 and n2 are each 1-3.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a lipid dispersion composition and a skin external preparation containing the same. More specifically, the present invention relates to ceramide analogue compounds, especially N, N'-bis
Lipid dispersion composition having improved dispersibility of (2-hydroxyethyl) -N, N'-biscetylmalonamide, and external preparation for skin containing the composition having improved applicability to external preparation for skin Regarding

[0002]

Ceramide is one of the important constituents of intercellular lipids in the epidermis, and plays an important role in the barrier function of protecting the living body from allergens, foreign bacteria, and desiccation. However, natural ceramide is very expensive, the concentration of the compound is suppressed, and there are cases in which sufficient effects are not exhibited. Therefore, various attempts have been made to develop synthetic ceramide-like compounds. Among them, at present, the formula [2]
Represented by N, N'-bis (2-hydroxyethyl) -N,
N′-biscetylmalonamide is said to be the best ceramide-like compound in terms of efficacy, safety and cost.

[Chemical 2] However, N, N'-bis (2-hydroxyethyl)-
N, N'-biscetylmalonamide, like other ceramides, still has the problem of dispersibility. Ceramides are useful substances for the skin, but due to poor solubility, dispersibility, etc., the compounding amount and application have been limited. Further, there is a problem with stability over time, and its solution has been awaited.

[0003]

SUMMARY OF THE INVENTION The present invention is directed to ceramide analog compounds, especially N, N'-bis (2-hydroxyethyl)-.
For the purpose of providing a lipid dispersion composition having improved dispersibility of N, N′-biscetylmalonamide, and a skin external preparation containing the composition having improved applicability to the skin external preparation. It was made.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventor has found that a ceramide-like compound can be obtained by blending a phosphoamide lipid with a polyhydric alcohol with a phosphoamide lipid. It has been found that the dispersibility of the compound can be improved and the amount of the ceramide-like compound compounded in the composition can be increased, and the present invention has been completed based on this finding. That is, the present invention provides (1) a lipid dispersion composition comprising a ceramide-like compound represented by the general formula [1], a hydroxylated phospholipid and a polyhydric alcohol,

[Chemical 3] (However, in the formula, m ₁ and m ₂ are 10 to 14, and n ₁
And n ₂ are 1 to 3. ), (2) The lipid dispersion according to item 1, wherein the ceramide-like compound represented by the general formula [1] is N, N′-bis (2-hydroxyethyl) -N, N′-biscetylmalonamide. The composition, (3) the polyhydric alcohol is isoprene glycol, 1,3-butanediol,
1,2-pentanediol, dipropylene glycol,
Glycerin, diglycerin, sorbitol or maltitol according to the first aspect of the lipid dispersion composition, (4) lysolecithin blended with the first, second or third aspect of the lipid dispersion composition, and (5) An external preparation for skin, which comprises the lipid dispersion composition according to item 1, item 2, item 3 or item 4. Furthermore, as a preferred embodiment of the present invention, the content of (6) the ceramide-like compound represented by the general formula [1] is 0.1 to 10% by weight.
And the content of the ceramide-like compound represented by the general formula [1] (7).
The skin external preparation described in the fifth item is 001 to 10% by weight.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The lipid dispersion composition of the present invention is a composition comprising a ceramide-like compound represented by the general formula [1], a hydroxylated phospholipid and a polyhydric alcohol.

[Chemical 4] However, in the general formula [1], m ₁ and m ₂ are 10 to ₁
4 and n ₁ and n ₂ are 1 to 3. Examples of the ceramide-like compound represented by the general formula [1] include N, N ′
-Bis (2-hydroxyethyl) -N, N'-bislauryl malonamide, N, N'-bis (3-hydroxypropyl)
-N, N'-bislauryl malonamide, N, N'-bis
(2-Hydroxyethyl) -N, N'-bismyristyl malonamide, N, N'-bis (3-hydroxypropyl)-
N, N'-bismyristyl malonamide, N, N'-bis
(2-Hydroxyethyl) -N, N'-biscetylmalonamide, N, N'-bis (3-hydroxypropyl) -N, N '
-Biscetyl malonamide and the like can be mentioned.
In the composition of the present invention, the ceramide-like compound represented by the general formula [1] can be used alone or in combination of two or more. Among these, N, N'-bis (2-hydroxyethyl)-
N, N'-biscetylmalonamide is excellent in efficacy and safety, and is advantageous in terms of price and stable supply, and thus can be particularly preferably used.

In the composition of the present invention, the compounding amount of the ceramide-like compound represented by the general formula [1] is preferably 0.1 to 10% by weight, more preferably 0.5 to 5% by weight. More preferable. The compounding amount of the ceramide-like compound is 0.
If it is less than 1% by weight, a large amount of the lipid dispersion composition may be required in the preparation. If the blending amount of the ceramide-like compound exceeds 10% by weight, the stability of the lipid dispersion composition may be impaired. In the composition of the present invention,
In addition to the ceramide-like compound, a glycosphingolipid can be added. Glycosphingolipids have 16 to 16 carbon atoms
It is a glycolipid containing sphingoid, which is 20 long-chain amino alcohols, and can be separated from animal cell membranes. By incorporating the glycosphingolipid, the stability of the lipid dispersion composition can be improved and the skin protecting function can be enhanced. The content of the glycosphingolipid is preferably 0.1 to 1% by weight, more preferably 0.3 to 0.7% by weight. In the composition of the present invention, lysolecithin can be added in addition to the ceramide-like compound. Lysolecithin is a compound obtained by removing one fatty acid group from lecithin and can be obtained by enzymatic hydrolysis of lecithin. In the composition of the present invention, either 1-acyl lysolecithin or 2-acyl lysolecithin can be used. By incorporating lysolecithin, lipid dispersion can be improved. The blending amount of lysolecithin is preferably 0.01 to 5% by weight, and more preferably 0.1 to 2% by weight.

The hydroxylated phospholipid used in the composition of the present invention is
It is a substance in which the unsaturated bond of the fatty acid portion of the phospholipid is hydroxylated, and can be obtained by subjecting the phospholipid to an oxidation treatment. As the phospholipid to be oxidized, both glycerophospholipid and sphingophospholipid can be used. The amount of the hydroxylated phospholipid in the composition of the present invention is not particularly limited, but is preferably 0.1 to 100 times the weight of the ceramide-like compound, and 0.2 to 2 times.
It is more preferably 0 times by weight, further preferably 0.4 to 5 times by weight. By incorporating the hydroxyphospholipid, the dispersibility or solubility of the ceramide-like compound in the polyhydric alcohol can be improved. Ordinary phospholipids that have not been oxidized, even if they have a similar structure, do not have such an effect of improving dispersibility or solubility. When the amount of the hydroxyphospholipid compounded is less than 0.1 times the weight of the ceramide-like compound, the effect of improving the dispersibility or solubility of the ceramide-like compound may be insufficient. When the amount of the hydroxyphospholipid compounded exceeds 100 times by weight that of the ceramide-like compound, the content of the ceramide-like compound becomes relatively small, and the effect as the lipid dispersion composition may be reduced.

The polyhydric alcohol used in the composition of the present invention is
It is a compound having two or more hydroxyl groups in the molecule. Examples of the polyhydric alcohol include ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol,
1,3-butanediol, 1,2-pentanediol, isoprene glycol, glycerin, diglycerin, triglycerin, tetraglycerin, pentaerythritol, xylitol, sorbitol, glucose, galactose, fructose, inositol, maltose, sucrose, maltitol, etc. Can be mentioned. Among these, isoprene glycol, 1,3-butanediol, 1,2-pentanediol, dipropylene glycol, glycerin, diglycerin, sorbitol and maltitol can be preferably used, and 1,2-pentanediol, Since 1,3-butanediol and isoprene glycol have antibacterial properties, they can be used particularly preferably. These polyhydric alcohols can be used individually by 1 type, or can also be used in combination of 2 or more type. In the composition of the present invention, the polyhydric alcohol content is preferably 0.1 to 300 times by weight, more preferably 5 to 150 times by weight, the total amount of the ceramide-like compound and the hydroxylated phospholipid. 1
It is more preferably 0 to 70 times by weight. When the amount of the polyhydric alcohol compounded is less than 0.1 weight times the total amount of the ceramide-like compound and the hydroxylated phospholipid, the stability of the lipid dispersion composition may be insufficient. If the amount of the polyhydric alcohol compounded exceeds 300 times by weight the total amount of the ceramide-like compound and the hydroxylated phospholipid, the content of the ceramide-like compound becomes relatively small, and the effect as a lipid dispersion composition may decrease. There is.

If desired, the composition of the present invention may contain phospholipids, lysophospholipids, sterols, vitamin E, other oil-soluble active ingredients and the like. The method for producing the lipid dispersion composition of the present invention is not particularly limited, for example, a ceramide-like compound and a hydroxyphospholipid can be mixed and heated, and the mixture can be added to the heated polyhydric alcohol while stirring, or The heated polyhydric alcohol can also be added to the mixture of heated ceramide-like compound and hydroxylated phospholipid. Among these, the method of adding the mixture of the ceramide-like compound and the hydroxylated phospholipid to the polyhydric alcohol is preferable. The external preparation for skin of the present invention contains a lipid dispersion composition containing the ceramide-like compound of the present invention, a phospholipid hydroxide and a polyhydric alcohol. In the external preparation for skin of the present invention, the content of the lipid dispersion composition of the present invention is not particularly limited, but the content of the ceramide-like compound is 0.00
It is preferable to contain 1 to 10 wt%, 0.01 to 5
It is more preferable that the content is wt%. The external preparation for skin of the present invention is manufactured into a dosage form such as cream, ointment, emulsion, lotion, solution, gel, powder or stick according to a conventional method, and is used as an external drug or quasi drug. It can be used as a product, cosmetics, etc.

[0010]

Examples Example 1 (lipid dispersion composition) As the component A, N, N'-bis (2-hydroxyethyl)-
1.0 part by weight of N, N'-biscetylmalonamide was mixed with 1.0 part by weight of hydroxylated phospholipid [NIKKOL Recinol SH50, manufactured by Nikko Chemicals Co., Ltd.]. Further, as the B component, 20.0 parts by weight of glycerin and 78.0 parts by weight of 1,2-pentanediol were mixed. Each of the component A and the component B was heated to 80 ° C., the component A was gradually added to the component B with stirring, and then the mixture was cooled to 30 ° C. with slow stirring to obtain a lipid dispersion composition. This lipid dispersion composition was diluted 10 times by weight with tap water. The diluent was clear. When the diluted solution was stored at 40 ° C. for 3 months, it became slightly cloudy. Example 2 (lipid dispersion composition) As the A component, N, N'-bis (2-hydroxyethyl)-
A mixture of 1.0 parts by weight of N, N'-biscetylmalonamide and 2.0 parts by weight of hydroxylated phospholipid [NIKKOL Recinol SH-50] (Nikko Chemicals Co., Ltd.) was used, and 50 parts of isoprene glycol was used as the B component. A lipid dispersion composition was prepared and evaluated in the same manner as in Example 1 except that a mixture of 0 parts by weight, sorbitol 30.0 parts by weight and maltitol 17.0 parts by weight was used. The 10-fold diluted solution of water was transparent immediately after preparation and after being stored at 40 ° C. for 3 months. Example 3 (lipid dispersion composition) As the A component, N, N'-bis (2-hydroxyethyl)-
N, N'-biscetylmalonamide 2.0 parts by weight, hydroxylated phospholipids [Nikko Chemicals Co., Ltd., NIKKOL Recinol WS-50] 0.5 parts by weight and hydroxylated phospholipids [Nikko Chemicals Co., Ltd., NIKKOL] Resinol SH50]
Example 1 except that 4.0 parts by weight of the mixture was used, and as the B component, a mixture of 40.0 parts by weight of glycerin, 40.0 parts by weight of 1,3-butanediol and 13.5 parts by weight of sorbitol was used. Similarly to the above, a lipid dispersion composition was prepared and evaluated. The 10-fold diluted solution of water was transparent immediately after preparation and after being stored at 40 ° C. for 3 months. Example 4 (Lipid dispersion composition) As the A component, N, N'-bis (2-hydroxyethyl)-
1.5 parts by weight of N, N'-biscetylmalonamide, hydroxylated phospholipid [Nikko Chemicals Co., Ltd., NIKKOL Recinol SH-50] 1.5 parts by weight, and lysophosphadylcholine [Kewpie Co., Ltd., LC-]. 100] Using 1.5 parts by weight of the mixture, as component B, 40.0 parts by weight of glycerin, 40.0 parts by weight of 1,3-butanediol, 10.0 parts by weight of diglycerin, 2.0 parts by weight of sorbitol and Example 1 except 3.5 parts by weight of maltitol were used.
Similarly to the above, a lipid dispersion composition was prepared and evaluated. The 10-fold diluted solution of water was transparent immediately after preparation and after being stored at 40 ° C. for 3 months. Example 5 (lipid dispersion composition) As the A component, N, N'-bis (2-hydroxyethyl)-
N, N'-biscetylmalonamide 3.0 parts by weight, glycosphingolipid [Yamakawa Trading Co., Ltd., bioceramide CH] 0.5
Parts by weight and hydroxylated phospholipid [Nikko Chemicals, NI
KKOL Recinol SH-50] 1.5 parts by weight of the mixture, and as component B, glycerin 30.0 parts by weight, 1,
In the same manner as in Example 1 except that a mixture of 40.0 parts by weight of 3-butanediol, 10.0 parts by weight of dipyropyrene glycol, 10.0 parts by weight of sorbitol and 5.0 parts by weight of maltitol was used. A lipid dispersion composition was prepared and evaluated. The 10-fold weight diluted solution of water was slightly turbid immediately after the adjustment, but it remained slightly turbid even after being stored at 40 ° C. for 3 months.

Comparative Example 1 (Lipid Dispersion Composition) A lipid dispersion composition was prepared and evaluated in the same manner as in Example 1 except that 1.0 part by weight of soybean lecithin was used instead of the hydroxylated phospholipid. I went. The 10-fold weight diluted solution of water was cloudy immediately after the adjustment, but after being stored at 40 ° C. for 3 months, separation occurred and the polyhydric alcohol layer became transparent,
A mixture of N, N'-bis (2-hydroxyethyl) -N, N'-biscetylmalonamide and soybean lecithin floated as droplets. Comparative Example 2 (Lipid Dispersion Composition) A lipid dispersion composition was prepared in the same manner as in Example 1 except that 98.0 parts by weight of water was used instead of the mixture of glycerin and 1,2-pentanediol. I tried. But,
Since the mixture of N, N′-bis (2-hydroxyethyl) -N, N′-biscetylmalonamide and hydroxylated phospholipid did not disperse in water and remained separated from the beginning, 40 ° C.
No storage test was conducted for 3 months. Comparative Example 3 (lipid dispersion composition) As the component A, N, N'-bis (2-hydroxyethyl)-
1.0 parts by weight of N, N'-biscetylmalonamide and a mixture of 20.0 parts by weight of glycerin and 79.0 parts by weight of 1,2-pentanediol as the B component were used. The mixture was heated to 0 ° C., component A was gradually added to component B with stirring, and then the mixture was cooled to 30 ° C. with slow stirring. Since the component A was not dispersed in the component B and remained separated from the beginning, the test of storing at 40 ° C. for 3 months was not performed. The results of Examples 1 to 5 and Comparative Examples 1 to 3 are shown in Table 1.

[0012]

[Table 1]

Example 6 (skin external preparation) 2.0 parts by weight of sodium ascorbate, 2 parts by weight of aqueous solution of carboxyvinyl polymer [Wiko Pure Chemical Industries, Ltd., Hibiswako 104] 2.0 parts by weight, 2% by weight xanthan gum Aqueous solution 1.0 parts by weight, triethanolamine 0.5 parts by weight, methyl paraoxybenzoate 0.2 parts by weight, purified water 89.3 parts by weight, the lipid dispersion composition obtained in Example 1.
0 parts by weight were mixed to obtain a cream. Example 7 (External skin preparation) As component A, polyoxyethylene (40 mol) stearic acid ester 2.0 parts by weight, glyceryl monostearate 5.0 parts by weight, squalane 8.0 parts by weight, tri-2-ethylhexane. Glyceryl acidate 8.0 parts by weight, cetanol 4.5
Parts by weight, 0.2 parts by weight of methyl polysiloxane (300 cSt) and 0.2 parts by weight of methyl paraoxybenzoate were mixed. As the component B, 5.0 parts by weight of a 1% by weight aqueous sodium hyaluronate solution, 7.0 parts by weight of 1,3-butanediol and 10.0 parts by weight of purified water were mixed. As the C component,
L-ascorbyl magnesium phosphate 3.0 parts by weight, sodium citrate 0.5 parts by weight, tetrasodium edetate 0.2 parts by weight, purified water 36.4 parts by weight and the lipid dispersion composition obtained in Example 2. 10.0 parts by weight were mixed. A component and B component are each heated to 80 ° C, B component is gradually added to A component with stirring, slowly cooled to 50 ° C with stirring, and C component heated to 50 ° C is gradually stirred with stirring. In addition to the above, cool to 30 ° C. with slower stirring,
Got the cream.

[0014]

The lipid dispersion composition of the present invention comprises a ceramide-like compound, a hydroxylated phospholipid and a polyhydric alcohol, and the ceramide-like compound is conventionally considered to have poor solubility or dispersibility. Can be stably mixed in a large amount. The external preparation for skin of the present invention, which contains a ceramide-like compound in a stable manner, has great effects on moisturizing the skin, preventing rough skin, and preventing aging.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 7/48 A61K 7/48 9/10 9/10 47/10 47/10 47/24 47/24 A61P 17/16 A61P 17/16 F term (reference) 4C076 AA16 BB31 CC18 DD38 DD63 FF16 4C083 AC022 AC072 AC111 AC121 AC122 AC131 AC132 AC482 AC532 AC542 AC641 AC642 AD041 AD042 AD092 AD152 AD352 AD571 AD572 AD642 CC01 CC02 CC05 A3A01A02C05 DD31 DD01 EE01A GA13 MA03 MA05 MA41 MA83 NA05 NA14 ZA89

Claims (5)

[Claims] 1. A lipid dispersion composition comprising a ceramide-like compound represented by the general formula [1], a hydroxylated phospholipid and a polyhydric alcohol. [Chemical 1] (However, in the formula, m ₁ and m ₂ are 10 to 14, and n ₁
And n ₂ are 1 to 3. ) 2. A ceramide-like compound represented by the general formula [1] is N, N'-bis (2-hydroxyethyl) -N, N'-.
The lipid dispersion composition according to claim 1, which is biscetylmalonamide. 3. The lipid dispersion composition according to claim 1, wherein the polyhydric alcohol is isoprene glycol, 1,3-butanediol, 1,2-pentanediol, dipropylene glycol, glycerin, diglycerin, sorbitol or maltitol. object. 4. The lipid dispersion composition according to claim 1, 2 or 3, which further comprises lysolecithin. 5. An external preparation for skin comprising the lipid dispersion composition according to claim 1, claim 2, claim 3 or claim 4.