JP5306725B2 - Topical skin preparation - Google Patents

Description

  The present invention relates to an external preparation for skin having excellent solubility, excellent stability, excellent usability, low skin irritation and the like of ceramide as a compounding component.

Ceramide is an important component of intercellular lipid and is known to have an excellent skin protecting action. However, ceramide 2 and plant ceramide are difficult to dissolve in both hydrophilic and lipophilic solvents, and it is difficult to stably and uniformly disperse or dissolve them in the composition, and their use has been limited.
Gels with high-pressure dispersion of glycosphingolipid and glycerin and / or diglycerin or gels with high-pressure dispersion of glycosphingolipid and glycerin and / or diglycerin or oil-soluble component in glycosphingolipid and glycerin and / or diglycerin There is a disclosure of an emulsified composition in which water and a water-soluble component are mixed with stirring after high-pressure dispersion (Patent Document 1). It is disclosed that the composition is excellent in stability, does not cause separation and the like, increases the commercial value of cosmetics and the like, and the emulsion composition has a fine particle size and is also excellent in terms of functionality.

There is disclosed a topical skin preparation characterized by high-pressure emulsification treatment of a surfactant such as an oil-soluble active ingredient, an oil, a polyhydric alcohol and a plant sphingolipid, and mixing and stirring in water and a water-soluble component (patent) Reference 2). It is disclosed that the external preparation for skin is safe and extremely stable in the preparation and excellent in skin absorption of the active ingredient.
(A) ceramide, (b) glycerin, esterified product of fatty acid having 8 to 30 carbon atoms and aliphatic saturated dibasic acid, (c) polyglycerin fatty acid ester, (d) oil, and (e) many There is a disclosure of a ceramide-containing emulsion composition characterized by emulsifying a mixture containing a monohydric alcohol at a pressure of 500 to 2000 kg / cm ² (Patent Document 3). It is disclosed that the composition is a ceramide-containing emulsified composition that can be used for cosmetics and the like that suppress the precipitation of ceramide crystals and require a wide range of functionality.
(A) There is a disclosure of cosmetics characterized by containing an oil-soluble N-long chain acyl acidic amino acid ester (aminoceramide) and glycine betaine (Patent Document 4). It is disclosed that the cosmetics have no stickiness, feel excellent, and have a high moisturizing effect.

However, the external preparation for skin containing (1) ceramide 2, (2) plant ceramide, (3) aminoceramide, (4) trimethylglycine and (5) hydroxyproline, which is a feature of the present invention, and excellent skin protection thereof There is no disclosure or suggestion of action.
JP 2000-128760 A JP 2002-338499 A JP 2007-31381 A Japanese Patent Laid-Open No. 7-258019

  The object of the present invention is excellent in solubility of ceramide, excellent in stability of ceramide, excellent in stability of composition, excellent in moisturizing property, excellent in feeling of use, high in safety, low in irritation to skin, An object of the present invention is to provide a skin external preparation that solves at least one of the problems such as excellent skin protection action and high usefulness for dry skin sites such as atopic dermatitis patients.

  The present inventors have excellent solubility of ceramide, excellent stability of ceramide, excellent stability of the composition, excellent moisture retention, excellent usability, high safety, low irritation to the skin, As a result of intensive studies on topical skin preparations that solve at least one of the problems such as excellent skin protection action and high usefulness for dry skin sites such as atopic dermatitis patients, ceramide 2, plant ceramide, It was confirmed that an external preparation for skin containing aminoceramide, trimethylglycine and hydroxyproline solved at least one of the above problems, and the present invention was completed.

That is, the present invention
(1) A skin external preparation containing ceramide 2, plant ceramide, aminoceramide, trimethylglycine and hydroxyproline.
In particular,
(2) The external preparation for skin according to the above (1), wherein ceramide 2 is octadecanoylaminooctadecanediol,
(3) The external preparation for skin according to the above (1) or (2), wherein the plant ceramide is glycosphingo glycolipid.
(4) The external preparation for skin according to any one of the above (1) to (3), wherein the aminoceramide is dilauroyl glutamate (phytosteryl octyldodecyl),
(5) The skin external application according to any one of the above (1) to (4), wherein the ceramide 2 is octadecanoylaminooctadecanediol, the plant ceramide is glycosphingo glycolipid, and the aminoceramide is dilauroyl glutamate (phytosteryl octyldodecyl). Agent,
(6) The skin external preparation according to any one of the above (1) to (5), wherein the hydroxyproline is L-hydroxyproline,

(7) The skin external preparation according to any one of (1) to (6), further comprising tocopherol acetate and / or dipotassium glycyrrhizinate,
(8) The skin external preparation according to any one of the above (1) to (7), wherein the skin external preparation is a moisturizing gel,
(9) The external preparation for skin according to any one of (1) to (8) above, which is produced by an emulsification method.
(10) A skin external preparation containing ceramide 2, plant ceramide, and aminoceramide. (11) Improved dispersibility and / or stability of ceramide used to improve and / or stabilize dispersibility of dilauroyl glutamate di (phytosteryl octyldodecyl), preferably ceramide 2 and / or plant ceramide Method.
In the composition of the external preparation for skin, “%” indicates “% by mass” unless otherwise specified.

  The skin external preparation of the present invention achieves excellent ceramide solubility and stability by combining amino ceramide with ceramide 2 and plant ceramide, without blending a synthetic surfactant, and has an excellent composition. Stability, high safety, etc. were obtained. Furthermore, by combining trimethylglycine and hydroxyproline, in addition to excellent skin protective action, excellent moisturizing properties, excellent feeling of use, low skin irritation, atopic dermatitis patients such as dry skin sites High usability was achieved.

As the ceramide 2 used in the present invention, a commercially available product can be used. It is a white powder and has almost no odor. For example, optically active ceramide 2 (Ceramide TIC-001) manufactured by Takasago International Corporation can be used. Preferred is octadecanoylaminooctadecanediol, and more preferred is (2S, 3R) -2-octadecanoylaminooctadecane-1,3-diol. The amount of ceramide 2 in the total amount of the external preparation for skin is 0.001 to 0.5.
% Is preferable, 0.01 to 0.2% is more preferable, and 0.02 to 0.1% is most preferable.

  As the plant ceramide used in the present invention, a commercially available product can be used, and rice glycosphingoglycolipid is preferable. Comenukasphingoglycolipid is a pale yellow to tan powder with a slightly unique smell. For example, a quasi-drug material standard can be used. The amount of plant ceramide in the total amount of the external preparation for skin is preferably 0.001 to 0.5%, more preferably 0.005 to 0.2%, and most preferably 0.01 to 0.1%.

  The aminoceramide used in the present invention may be a commercially available one, preferably dilauroyl glutamate (phytosteryl octyldodecyl), more preferably N-lauroyl-L-glutamate di (phytosteryl 2-octyldodecyl). . N-lauroyl-L-glutamate di (phytosteryl 2-octyldodecyl) is a pale yellow liquid with a slightly unique odor. For example, a quasi-drug material standard can be used. The compounding amount of aminoceramide in the total amount of the external preparation for skin is preferably 0.01 to 10%, more preferably 0.05 to 5%, and most preferably 0.1 to 1%. Dilauroyl glutamate (phytosteryl octyldodecyl) has an effect of improving and / or stabilizing dispersibility of ceramide 2 and plant ceramide.

  The combination of the three ceramides used in the present invention, that is, ceramide 2, plant ceramide, and aminoceramide, is preferably 1 to 10: 1 to 5:10 to 100, and 5: 3: 50. More preferably. A more specific combination of the three components is preferably a combination of octadecanoylaminooctadecane diol, rice bran glycosphingolipid and lauroyl glutamate (phytosteryl / octyldodecyl), and these are preferably in the above-mentioned blending ratio. Examples of the amount of ceramide in the total amount of the external preparation for skin include 0.012 to 11%, preferably 0.065 to 5.4%, and 0.13 to 1.2%. More specifically, more specifically, octadecanoylaminooctadecanediol, rice bran glycosphingolipid, and lauroylglutamate di (phytosteryl octyldodecyl) are 0.01 to 0.2% and 0.01 to 0.1, respectively. %, 0.1 to 1% is preferable, and 0.05%, 0.03%, and 0.5% of the above three components are most preferable.

Commercially available trimethylglycine (also known as betaine), which is an amino acid-based moisturizing component used in the present invention, can be used. Trimethylglycine is a white crystalline powder with a slightly unique odor. For example, a quasi-drug material standard can be used. The amount of trimethylglycine in the total amount of the external preparation for skin is preferably 0.1 to 20%, more preferably 0.5 to 15%, and most preferably 1 to 10%.
Hydroxyproline (also known as oxyproline), which is another amino acid-based moisturizing component used in the present invention, can be commercially available, and is preferably L-hydroxyproline. L-hydroxyproline is a white crystalline powder with no odor. For example, a quasi-drug material standard can be used. The content of hydroxyproline in the total amount of the external preparation for skin is preferably 0.01 to 5%, more preferably 0.02 to 2%, and most preferably 0.05 to 1%.

  In the external preparation for skin of the present invention, various components that can be usually blended in the external preparation for skin within the range in which the object of the present invention is not impaired, or for further improving the effect of the present invention or for other purposes. Can be blended. Examples of such other components include anti-inflammatory agents, blood circulation promoters, moisturizers, oily bases, plant extracts, solvents, emulsifiers, thickeners, pH adjusters, preservatives, sugars, and antioxidants. , Solubilizers, fragrances, other components, and mixtures thereof. These may be used alone or in combination of two or more.

  Examples of the anti-inflammatory agent include glycyrrhizic acid, glycyrrhetinic acid, allantoin, guaiazulene, derivatives thereof and salts thereof, or a mixture thereof, and dipotassium glycyrrhizinate is preferable. Examples of the blood circulation promoter include tocopherol acetate. Examples of the humectant include mucopolysaccharides and salts thereof such as hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin and keratan sulfate; proteins such as collagen, elastin and keratin, derivatives thereof and salts thereof; NMF components such as amino acids, sodium lactate, sodium pyrrolidone carboxylate; polyols such as concentrated glycerin, BG (also known as 1,3-butylene glycol), propylene glycol; 1,2-pentanediol, 1,2-octanediol, etc. Alkanediol (preferably 1,2-pentanediol and / or 1,2-octanediol); methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer liquid (Lipidure®), or a mixture thereof It is. Examples of the oily base include vegetable oils such as avocado oil, castor oil, olive oil, cacao oil, coconut oil, coconut oil, tree wax, jojoba oil, grape seed oil; squalane (preferably vegetable squalane), fluid Hydrocarbons such as paraffin, microcrystalline wax, ceresin wax, paraffin wax, petrolatum; higher alcohols such as cetanol, stearyl alcohol, hexyl decanol, octyldodecanol; silicones such as methylpolysiloxane, decamethylcyclopentasiloxane, or These mixtures etc. are mentioned. Examples of plant extracts include chamomile extract, soybean extract, ginkgo biloba extract, rosemary extract, buckwheat extract, comfrey extract, litchi extract, etc. Tuberose polysaccharide solution-BG), or a mixture thereof.

Examples of solvents include water and ethanol. Examples of the emulsifier include hydrogenated soybean phospholipid and egg yolk lecithin. Examples of the thickener include xanthan gum, carboxyvinyl polymer, carrageenan, guar gum, and hydroxyethyl cellulose. Examples of the pH adjuster include any non-toxic acid and base such as Na hydroxide. Examples of the preservative include benzoate, sorbate, dehydroacetate, p-hydroxybenzoate, benzethonium chloride, phenoxyethanol, chlorhexidine gluconate, and the like. Examples of the sugar include glucose, sorbitol, and maltose. Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, ascorbic acid, vitamins E, or a mixture thereof. Examples of the solubilizer include any non-toxic surfactant.

The external preparation for skin of the present invention includes pharmaceuticals, quasi drugs and cosmetics, preferably quasi drugs.
The external preparation for skin of the present invention can be in various forms, and examples thereof include creams and gels. Gels are preferred and moisturizing gels are most preferred.
In order to prepare the external preparation for skin of the present invention, the above-mentioned various raw material components can be obtained by emulsification by a known emulsification method. Specifically, for example, a new cosmetic handbook (issued October 30, 2006, representative Shigeru Sekine, editor Hiroaki Tamura et al., Published by Nikko Chemicals Co., Ltd.) III. Cosmetic formulation technology It can be prepared by the emulsification methods described in Tables 1 and 1 and Tables 1 and 2 of emulsification. Further, as another example of the emulsification method, for example, a method described in JP-A No. 2002-338499, a method described in JP-A No. 2007-31381, and the like can be mentioned. Can be used.

  EXAMPLES Hereinafter, although an Example and a test example demonstrate this invention further in detail, this invention is not limited to these.

Example 1
Each component shown in Table 1 was mixed, a composition (moisturizing gel) was produced by an emulsification method, and filled in a container.
The composition of Example 1 is a finely emulsified composition exhibiting a slightly bluish translucent white gel. In addition, the composition of Example 1 was precipitated, separated, etc. in a stability test carried out under conditions of 45 ° C. for 6 months, 0 ° C. for 6 months, and 40 ° C. and humidity of 75% for 6 months in a state filled in a plastic container. The stability of the product was confirmed.
In addition, No. The same composition (Comparative Example 1) as in Example 1 except that 5 was not included, and a uniform fine emulsion composition could not be obtained by the same production method as in Example 1. In insoluble matter was precipitated.

Test example 1
The first study was conducted on 19 patients aged 8 to 35 years (average 19.2 years) (2 males, 17 females; atopic dermatitis 7 cases, psoriasis 9 cases, hand eczema 3 cases) It was.
The second study was conducted on 10 patients (5 males, 5 females; 9 atopic dermatitis, 1 xeroderma) who were 13 to 32 years old (average 25.5 years old).
For the above 29 cases, the composition of Example 1 (moisturizing gel) was simply applied 2 to 3 times a day every day and always applied after bathing, and a test for 4 weeks was conducted in principle. Observations were made by a dermatologist at the start of the study, 2 weeks after the start and 4 weeks after the start.
Table 2 shows the degree of improvement by symptom in a total of 29 cases in the first and second tests. Each item had a high improvement rate.

In addition, Table 3 shows the effectiveness of each of the 29 cases in the first and second tests for each disease. A wide range of effects was observed, ranging from moderate atopic dermatitis to mild psoriasis.

No side effects were observed in all 29 cases in the first and second tests.
In addition, Table 4 shows the results of the usability evaluation for all 29 subjects examined after the test. It was confirmed that the composition of Example 1 had excellent functionality.

In the first test, the test was conducted mainly on a dry site without inflammation of a patient with dry skin disease. Since the clinical symptoms were improved, the stratum corneum water content was increased, and the transepidermal water transpiration amount was decreased, the composition of Example 1 of the present invention was effective in improving the skin barrier function and moisturizing function. it is conceivable that. The usefulness is very useful 37% (7/19 cases), useful 58% (11/19 cases), slightly useful 5% (1/19 cases), and more than useful is 95% (18/19 cases). It was an example.
In the second test, the test was performed mainly on mild inflammatory symptoms of atopic dermatitis patients. In addition to the significant improvement in the items of the first study, some cases showed a decrease in nucleated cells, and other stratum corneum showed an improvement trend. Usefulness is very useful 20% (2/10 cases), useful 60% (6/10 cases), slightly useful 10% (1/10 cases), and no usefulness 10% (1/10 cases) More than useful was 80% (8/10 cases).
From the above results, the composition of Example 1 can be expected to improve the overall stratum corneum function by continuous use and to restore normal skin.

Test example 2
A stinging (skin irritation) test of the composition of Example 1 of the present invention was performed on 15 subjects. The average score was 2.5, confirming that the composition of Example 1 of the present invention was hypoallergenic.

Test example 3
A patch test (48-hour closed patch test) of the composition of Example 1 of the present invention was performed on 120 healthy persons. After 48 hours, 2 cases were found (±), and the skin irritation index calculated from this result was 0.8, confirming that the composition of Example 1 was extremely hypoallergenic.

Test example 4
Skin surface horny layer of 10 healthy persons (6 men, 4 women, 23 to 57 years old (average 32 years old)) about the composition of Example 1 of the present invention and a commercially available moisturizing skin external preparation A moisture retention evaluation test was conducted by measuring the amount of moisture. Specifically, each subject wiped the inner part of the forearm with 70% ethanol and then acclimated for 15 minutes in a constant temperature and humidity chamber (room temperature 22 ° C., humidity 45%). The moisture content of the test site (before use) was measured, and each test specimen (composition of Example 1, commercially available product A (containing ceramide and sodium hyaluronate), commercially available product B (containing xylitol and glycerin), and commercially available product C ( Urea blended) and commercial product D (Na hyaluronic acid, maltitol blended)) were applied to the inner side of the forearm, and 120 minutes later, conductance (conductivity μS) was measured using SKICON 200 (IBS) (measured three times). Averaged). As a control, the conductance was measured in the same manner for the test sample uncoated portion. The results are shown in FIG. As is apparent from FIG. 1, it was confirmed that Example 1 has excellent moisture retention.

6 is a graph showing the results of a moisture retention evaluation test of Test Example 4.

Claims (9)

It is a skin external preparation containing the following components, and the blending ratio of (1) ceramide 2: (2) plant ceramide: (3) aminoceramide is 1-10: 1 to 5: 10-100, Skin external preparation .
(1) Ceramide 2
(2) Plant ceramide (3) Aminoceramide (4) Trimethylglycine (5) Hydroxyproline (1) The amount of ceramide 2 in the total amount of the external preparation for skin is 0.001 to 0.5%, (2) The amount of plant ceramide is 0.001 to 0.5%, (3) The amount of aminoceramide The external preparation for skin according to claim 1, wherein is 0.01 to 10%. The external preparation for skin according to claim 1 or 2, wherein ceramide 2 is octadecanoylaminooctadecanediol. The external preparation for skin according to any one of claims 1 to 3 , wherein the plant ceramide is a rice bran glycosphingolipid. The skin external preparation according to any one of claims 1 to 4 , wherein the aminoceramide is dilauroyl glutamate (phytosteryl octyldodecyl). The skin external preparation according to any one of claims 1 to 5 , wherein ceramide 2 is octadecanoylaminooctadecanediol, plant ceramide is glycosphingoglycolipid, and aminoceramide is dilauroyl glutamate (phytosteryl octyldodecyl). Hydroxyproline is L-hydroxyproline, The skin external preparation of any one of Claims 1-6 . The skin external preparation according to any one of claims 1 to 7 , wherein the skin external preparation is a moisturizing gel. The skin external preparation according to any one of claims 1 to 8 , which is produced by an emulsification method.