JP4095950B2 - Skin preparation - Google Patents

Description

  The present invention relates to an improvement in viscosity and high temperature stability in an external preparation for skin, particularly in a salt-type drug combination system.

In the field of topical skin preparations, thickeners are used to improve usability and stability. For example, carboxyvinyl polymer is widely used for base thickening of skin care preparations because it has a high thickening viscosity and is crushed freshly when applied to the skin.
However, it is known that the carboxyvinyl polymer has low salt resistance, and the viscosity is remarkably lowered when a high salt content is added. This is thought to be because the electrostatic repulsion between the negatively charged carboxyl groups that are ionized is shielded by the salt and decreases.

When a high concentration carbomer is blended to compensate for such a decrease in viscosity due to salt, stickiness and twist (polymer waste) are generated, and the feeling of use is impaired.
For this reason, for example, in whitening cosmetics where it is desired to highly blend an ascorbic acid derivative that is a salt-type whitening agent, it has been difficult to design a formulation mainly based on thickening with a carboxyvinyl polymer.
In order to solve such a problem, xanthan gum, which is a polysaccharide thickener, has been used in the past. There was a problem that it was slimy or caused a sticky feeling.

As described above, in the external preparation for skin mainly composed of a drug such as a salt-type whitening agent, there are many restrictions on the types and blending amounts of thickeners that can be used, and therefore, variations in the preparation are limited. In particular, there were few variations in preparations such as medium viscosity essence of 2,000 to 10,000 mPa · s.
In recent years, it has been reported that a hard and brittle gel formed using agar, gellan gum, or the like is mechanically pulverized, and the resulting microgel can function as a thickener with high salt resistance (Patent Literature). 1).
JP 2001-342125 A

However, since the above technique requires a pulverization process for microgel preparation, there is a problem that the process becomes complicated and the cost becomes high.
Therefore, in a composition containing a salt-type whitening agent, there has been a demand for a preparation that can be thickened by a simple method that does not require such a pulverization step and that has excellent stability and usability.
The present invention has been made in view of the above-mentioned problems of the prior art. The purpose of the present invention is to obtain a sufficient viscosity with a simple operation in a salt-type whitening agent blending system, and is excellent in stability over time and usability. It is to provide a skin external preparation.

As a result of intensive studies conducted by the present inventors in order to achieve the above-mentioned object, when a xanthan gum and guar gum are used in combination as a thickener in a salt whitening compounding system, the viscosity and the feeling of use are synergistically improved. There was found. And when both were used in the specific range, it also discovered that the thinning in high temperature storage property was suppressed remarkably, and came to complete this invention.

（式中、Ｒは炭素数１〜４のアルコキシ基である。）
本発明の皮膚外用剤において、キサンタンガムとグアガムとが重量比で５０：５０〜２０：８０であることが好適である。 That is, the external preparation for skin according to the present invention includes a salt-type whitening agent that is one or more salts selected from the group consisting of ascorbate, a salt of an ascorbic acid derivative, and a salt of alkoxysalicylic acid , xanthan gum, and guar gum. Blended ,
The ascorbic acid derivative is L-ascorbic acid monophosphate ester, L-ascorbic acid-2-sulfate ester, dl-α-tocopherol 2-L-ascorbic acid phosphate diester, L-ascorbic acid monostearate, L-ascorbine Acid monopalmitate, L-ascorbic acid monooleate, L-ascorbic acid distearate, L-ascorbic acid dipalmitate, L-ascorbic acid dioleate, L-ascorbic acid tristearate, L-ascorbic acid tripalmitate, L-ascorbic acid trioleate 2-O-α-D-glucopyranosyl-L-ascorbic acid, and 2-O-ethylascorbic acid,
The alkoxysalicylic acid is represented by the following general formula (I) .
Formula (I):

(In the formula, R is an alkoxy group having 1 to 4 carbon atoms.)
In the external preparation for skin of the present invention, it is preferable that xanthan gum and guar gum are 50:50 to 20:80 in weight ratio .

According to the present invention, in a skin external preparation containing a salt-type whitening agent, the combined use of xanthan gum and guar gum as a thickener synergistically improves the thickening and feeling of use, and also provides high temperature stability. Excellent formulations can be obtained.

In the present invention, the salt-type whitening agent means a whitening agent that is itself a salt type or is neutralized with an alkaline agent to form a salt . A whitening agent salt is used. The external preparation for skin of the present invention contains at least one selected from these.

  Ascorbic acid-based whitening agents include ascorbic acid-based compounds composed of ascorbic acid and its derivatives. As a specific example, ascorbic acid includes L-ascorbic acid. Ascorbic acid derivatives include, for example, ascorbic acid inorganic acid esters such as L-ascorbic acid monophosphate, L-ascorbic acid-2-sulfate, dl-α-tocopherol 2-L-ascorbic acid diester; L Ascorbic acid monostearate, L-ascorbic acid monopalmitate, ascorbic acid monoalkyl esters such as L-ascorbic acid monooleate; L-ascorbic acid distearate, L-ascorbic acid dipalmitate, ascorbic acid such as L-ascorbic acid dioleate Diesters; ascorbic acid triesters such as L-ascorbic acid tristearate, L-ascorbic acid tripalmitate, L-ascorbic acid trioleate; 2-O-α-D-glucopyranosyl-L-a Ascorbic acid glycosides such as Colvin acid; 2-O-ethyl-ethyl vitamin C such as ascorbic acid, and the like, Preferred examples of these include ascorbic acid-2-glucoside. Examples of salts of these ascorbic acid and ascorbic acid derivatives include alkali metal salts (Na salts, K salts, etc.), alkaline earth metal salts (Ca salts, Mg salts, etc.), ammonium salts, alkanolamine salts, amino acid salts, etc. In the present invention, an alkali metal salt is preferable.

（式中、Ｒは炭素数１〜４のアルコキシ基である。）
具体例としては、３−メトキシサリチル酸、３−エトキシサリチル酸、４−メトキシサリチル酸、４−エトキシサリチル酸、４−プロポキシサリチル酸、４−イソプロポキシサリチル酸、４−ブトキシサリチル酸、５−メトキシサリチル酸、５−エトキシサリチル酸、５−プロポシキサリチル酸、あるいはこれらの塩が挙げられる。塩はアルカリ金属塩（Ｎａ塩、Ｋ塩等）、アルカリ土類金属塩（Ｃａ塩、Ｍｇ塩等）、アンモニウム塩、アルカノールアミン塩、アミノ酸塩などが挙げられるが、本発明において好ましくはアルカリ金属塩である。 Examples of the alkoxysalicylic acid-based whitening agent include those represented by the following general formula (I) described in JP-A-6-40886.
Formula (I):

(In the formula, R is an alkoxy group having 1 to 4 carbon atoms .)
Specific examples include 3-methoxysalicylic acid, 3-ethoxysalicylic acid, 4-methoxysalicylic acid, 4-ethoxysalicylic acid, 4-propoxysalicylic acid, 4-isopropoxysalicylic acid, 4-butoxysalicylic acid, 5-methoxysalicylic acid, 5-ethoxysalicylic acid. , 5-proposixalicylic acid, or salts thereof. Examples of the salt include alkali metal salts (Na salt, K salt, etc.), alkaline earth metal salts (Ca salt, Mg salt, etc.), ammonium salts, alkanolamine salts, amino acid salts, etc. Salt.

In the present invention, the blending amount of the salt whitening agent is not particularly limited as long as it is a range usually blended in cosmetics and pharmaceuticals.
In addition, in the skin external preparation of this invention, the said salt type whitening agent may be mix | blended after making it into the form of a salt, and may be neutralized in a composition with an alkali agent. Such an alkali agent for neutralizing a salt-type drug is not particularly limited as long as it can form a salt. For example, metal hydroxides such as sodium hydroxide and potassium hydroxide; alkanolamines such as monoethanolamine, diethanolamine and triethanolamine; organic acid salts such as sodium citrate, potassium malate and sodium lactate, and amino acids such as lysine Etc. Of these, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are preferred.

The xanthan gum and guar gum used in the present invention are not particularly limited as long as they are usually used in the cosmetics and pharmaceutical fields.
By using xanthan gum and guar gum in combination, a higher viscosity is obtained than when each of them is used alone, and the usability when stretched on the skin is also improved. In addition, there is no significant decrease in viscosity due to a salt-type drug such as carboxyvinyl polymer.
In order to obtain such an effect, the ratio of xanthan gum and guar gum is preferably 90:10 to 10:90, and more preferably 20:80 to 80:20. When either xanthan gum or guar gum is excessive, a synergistic effect on thickening and feeling of use cannot be obtained sufficiently. Moreover, when xanthan gum and guar gum are used in the range of 50:50 to 20:80, particularly 45:55 to 30:70, a preparation having very high temperature stability can be obtained.

Although the mechanism of such a synergistic effect is not clear, it is considered that the thickening agent and the feeling of use are improved by the interaction of the thickeners in the medium and taking some composite structure.
In addition, xanthan gum and guar gum are stable in a wide pH range from acidic to basic, and a formulation design suitable for the optimum pH of the drug to be used is possible. For example, among drugs that are stable in a strongly acidic region having a pH of 5 or less, there are few thickeners that are applicable to external preparations for skin and have excellent acid resistance. Xanthan gum and guar gum are excellent in acid resistance, and can be suitably used also in these drug-containing skin external preparations that are stable in the low pH range.

Although the manufacturing method of the skin external preparation of this invention is not restrict | limited in particular, It is preferable to manufacture with the method including the following processes.
(A) Xanthan gum and guar gum are added to an aqueous medium containing water and dissolved at 70 to 80 ° C. to obtain a thickener aqueous solution.
(B) To the thickener aqueous solution of (A), a salt-type drug and, if necessary, an alkali agent and other components are preferably added under temperature conditions of 50 to 60 ° C., and mixed with stirring. If the temperature is too low, the gelation rate is fast, and it may take time to dissolve the drug uniformly. On the other hand, if the temperature is too high, thermal decomposition of a salt-type drug or the like may be caused.
(C) The mixed solution of (B) is allowed to cool or is stirred and cooled.
In addition, as long as there is no problem in particular, you may add another component to (A) aqueous solution.

In the present invention, components that can be usually blended in an external preparation for skin can be appropriately blended within a range that does not impair the effects of the present invention. Examples include oils, surfactants, humectants, preservatives, stabilizers, powders, pigments, fragrances, pH adjusters, chelating agents, other medicinal ingredients, and the like.
The dosage form of the external preparation for skin of the present invention is not particularly limited, and various dosage forms such as a solubilizing system, an emulsifying system, and a dispersing system can be used. Specific examples of the preparation include an aqueous gel, an O / W emulsified gel, an O / W emulsion, and an O / W cream.

Hereinafter, the present invention will be described in more detail with reference to specific examples, but these do not limit the present invention. The blending amount is mass% unless otherwise specified.
First, the test method used in the present invention will be described.

(viscosity)
Using a rotational viscometer manufactured by Shibaura Systems, the viscosity (mPa · s / 30 ° C.) after rotating the rotor for 1 minute was measured.

(PH)
The pH at 25 ± 2 ° C. was measured using a HORIBA pH meter and electrodes.

(Feeling of use)
An actual use test by 10 panelists evaluated the slime, smoothness and stickiness when applying cosmetics to the skin.
○: 5 or more respondents who did not feel slimy, smooth, or non-sticky △: 3-4 respondents who responded that they did not feel slimy, smooth, or non-sticky ×: Not slimy, smooth, or non-sticky 2 or less

Test Example 1 Synergistic Effect on Thickening First, the present inventors examined the interaction when a polysaccharide thickener was used in combination. The composition and production method of the sample are as follows.
(composition)
Thickener aqueous solution:
(1) Thickener [(a) + (b)] 0.5
(2) Dipropylene glycol 5
(3) Methylparaben 0.15
(4) Ion-exchange water Residual salt type chemicals:
(5) Ascorbic acid-2-glucoside (AA-2G) 2.0
(6) Na citrate 0.01
(7) Citric acid 0.09
(8) KOH 0.38
(9) Ion exchange water appropriate amount (production method)
In the case of no salt-form drug blending: (2) dissolved in (3) was added to (4) and mixed, then (1) was further added at 70 ° C., and after mixing, the mixture was allowed to cool.
In the case of a salt type drug formulation: (3) dissolved in (2) was added to (4) and mixed, and then (1) was further added at 70 ° C. and mixed well. The obtained thickener aqueous solution was allowed to cool to 50 ° C., and a solution in which (5) to (8) was dissolved in (9) was mixed and allowed to cool.

(Table 1)
――――――――――――――――――――――――――――――――――――
Sample thickener 1 2 3 4 5 6 7
――――――――――――――――――――――――――――――――――――
(1) Lambda carrageenan 0.5 0.25
(2) Locust bean gum 0.5 0.25 0.25
(3) Xanthan gum 0.5 0.25 0.25
(4) Guam gum 0.5 0.25
――――――――――――――――――――――――――――――――――――
viscosity
[Without AA-2G] 160 320 2000 80 130 18000 4600
[Composition with AA-2G] 80 270 2800 60 190 2500 3200
−――――――――――――――――――――――――――――――――――――

As can be seen from Table 1, the λ carrageenan / locust bean gum combined system has a low viscosity as a whole, and both λ carrageenan alone and locust bean gum alone, both with and without a salt-type drug. Viscosity higher than the case cannot be obtained.
In the xanthan gum / locust bean gum combination system, when the salt type drug is not added, the viscosity is remarkably higher than the case of each thickener alone, but when the salt type drug is added, the viscosity when the salt type drug is added is the same as the locust bean gum alone. In comparison, the effect on the viscosity of the salt-type drug is extremely significant.
On the other hand, the xanthan gum / guagum combination system has a higher viscosity than the case of each thickener alone, regardless of the presence or absence of the salt-type drug, and the change in viscosity due to the salt-type drug is not so large. It was.
Then, it examined by changing the compounding ratio of the xanthan gum / gua gum combination system of Table 1. The results are shown in Table 2.

(Table 2)
――――――――――――――――――――――――――――――――――――――
Sample Thickener 3 8 9 10 7 11 12 13 4
――――――――――――――――――――――――――――――――――――――
(1) Xanthan gum 0.5 0.45 0.4 0.3 0.25 0.2 0.1 0.05 0
(2) Guam gum 0 0.05 0.1 0.2 0.25 0.3 0.4 0.45 0.5
――――――――――――――――――――――――――――――――――――――
viscosity
[Without AA-2G] 2000 2000 2900 4000 4600 5900 5800 2400 80
[Composition with AA-2G] 2800 3200 3600 4300 3200 2300 2100 2000 60
−――――――――――――――――――――――――――――――――――――――

From Table 2, in order to use xanthan gum and guar gum in combination to synergistically improve thickening, the weight ratio of xanthan gum to guar gum is 90:10 to 10:90, and moreover, 80:20 to 20:80. It is preferable to do.
Test Example 2 Stability Samples of the xanthan gum / locust bean gum / salt type drug combination system and xanthan gum / guam gum / salt type drug combination system used in Test Example 1 were stored at 0 ° C., room temperature, and 50 ° C. for 1 month, respectively. The viscosities were compared.

(Table 3)
―――――――――――――――――――――――――――――――――――――――
Sample Thickener 14 6 9 10 7 11 12
―――――――――――――――――――――――――――――――――――――――
(1) Locust bean gum 0.3 0.25
(2) Xanthan gum 0.2 0.25 0.4 0.3 0.25 0.2 0.1
(3) Guam gum 0.1 0.2 0.25 0.3 0.4
―――――――――――――――――――――――――――――――――――――――
Viscosity Immediately after production 2300 2500 3600 4300 3200 2300 2100
0 ° C 2000 2500 3600 4300 3200 2300 2100
Room temperature 2000 2400 3600 4300 3200 2400 2100
50 ° C (aggregation) (aggregation) 2300 2800 2400 2300 1600
−――――――――――――――――――――――――――――――――――――――

As shown in Table 3, in the xanthan gum / locust bean gum combined system, agglomerates were formed by storage at 50 ° C.
On the other hand, in the xanthan gum / guam gum combined system, there was not much influence of the storage temperature at any blending ratio, and aggregates like the xanthan gum / locust bean gum system were not seen. Moreover, in the range of xanthan gum: gua gum of 50:50 to 20:80, and further 45:55 to 30:70, the high temperature stability of the viscosity was particularly high.

Test Example 3 Usability Furthermore, the usability of the xanthan gum / guam gum / salt-type drug combination system sample of Test Example 2 was examined.
(Table 4)
―――――――――――――――――――――――――――――――――――――――
Sample composition 3 8 9 10 11 12 13 4
―――――――――――――――――――――――――――――――――――――――
Thickener
(1) Xanthan gum 0.5 0.45 0.4 0.3 0.2 0.1 0.05 0
(2) Guam gum 0 0.05 0.1 0.2 0.3 0.4 0.45 0.5
―――――――――――――――――――――――――――――――――――――――
Smooth feeling × △ ○ ○ ○ ○ ○ ○
Sliminess △ △ ○ ○ ○ ○ △ ×
Stickiness △ △ ○ ○ ○ ○ △ ×
−――――――――――――――――――――――――――――――――――――――

  It can be seen from Table 4 that the combined use of xanthan gum and guar gum improves the smoothness and reduces the slimy feeling compared to the case where each is used alone. In order to obtain such an effect, the weight ratio of xanthan gum and guar gum is preferably 90:10 to 10:90, more preferably 80:20 to 20:80.

Formulation Example 1 O / W Essence (1) Ion Exchange Water Residue (2) Glycerin 2
(3) Dipropylene glycol 5
(4) Xanthan gum 0.2
(5) Guam gum 0.3
(6) Isostearic acid 0.3
(7) Stearic acid 0.2
(8) Behenic acid 0.3
(9) Self-emulsifying glyceryl monostearate 1.1
(10) POE glycerol monostearate 0.75
(11) α-olefin oligomer 2
(12) Glyceryl tri-2-ethylhexanoate 3.5
(13) Methyl polysiloxane (KF-96A, Shin-Etsu Chemical Co., Ltd.) 2
(14) Squalane 1
(15) Behenyl alcohol 0.5
(16) BHT 0.1
(17) Ascorbic acid-2-glucoside 2
(18) Citric acid 0.01
(19) Sodium citrate 0.09
(20) Paraben 0.3
(21) Edetate trisodium 0.1
(22) Methyl taurine sodium (for neutralizing AA-2G) 2.05

(Manufacturing method)
The components (1) to (5) were mixed to prepare an aqueous phase part. The components (6) to (15) were dissolved by heating at 80 to 90 ° C. to prepare oil phase parts. After mixing the two parts at 70 ° C., parts such as (17) to (22) drugs and (16) stabilizer were added, treated with an emulsifier, and then cooled to 30 ° C.
The O / W essence of Formulation Example 1 had a viscosity of 6,930 mPa · s / 30 ° C. and had good usability and stability.

Formulation Example 2 O / W Latex Ion Exchange Water Residual Glycerin 2
Dipropylene glycol 5
Xanthan gum 0.12
Guam gum 0.18
Isostearic acid POE glycerin 0.45
Glycerol monostearate0.7
Self-emulsifying propylene glycol stearate 0.4
Stearyl alcohol 0.5
Behenyl alcohol 0.7
Methyl polysiloxane (KF-96A, Shin-Etsu Chemical Co., Ltd.) 0.6
Hydrogenated palm oil 1
Cetyl 2-ethylhexanoate 1.2
α-olefin oligomer 1.2
Ascorbic acid-2-glucoside 2
Potassium hydroxide (for neutralizing AA-2G) 0.385
Citric acid 0.01
Sodium citrate 0.09
Edetate trisodium 0.1
BHT 0.1
Paraben 0.3
Fragrance 0.05

(Manufacturing method)
According to Formulation Example 1, aqueous components were mixed to prepare an aqueous phase part. The oil component was dissolved by heating at 80 to 90 ° C. to prepare an oil phase part. After mixing two parts at 70 degreeC, parts, such as a chemical | medical agent and a stabilizer, were added, and after processing with an emulsifier, this was cooled to 30 degreeC.
The O / W emulsion of Formulation Example 2 had a viscosity of 2,580 mPa · s / 30 ° C. and had good usability and stability.

Formulation Example 3 O / W Latex Ion Exchange Water Residual Glycerin 2
Dipropylene glycol 5
Xanthan gum 0.12
Guam gum 0.18
Isostearic acid POE glycerin 0.44
Glycerol monostearate 0.72
Self-emulsifying propylene glycol stearate 0.4
Stearyl alcohol 0.5
Behenyl alcohol 0.7
Methyl polysiloxane (KF-96A, Shin-Etsu Chemical Co., Ltd.) 0.6
Hydrogenated palm oil 1
Cetyl 2-ethylhexanoate 1.2
Meadow Foam Oil 1.0
α-olefin oligomer 1.0
Vitamin A acetate 1.5 million units 0.2
Potassium 4-methoxysalicylate 3
3-O-ethylascorbic acid 1
Citric acid 0.12
Sodium citrate 0.08
Edetate trisodium 0.1
BHT 0.1
Paraben 0.3
Fragrance 0.05

(Manufacturing method)
According to Formulation Example 1, aqueous components were mixed to prepare an aqueous phase part. The oil component was dissolved by heating at 80 to 90 ° C. to prepare an oil phase part. After mixing two parts at 70 degreeC, parts, such as a chemical | medical agent and a stabilizer, were added, and after processing with an emulsifier, this was cooled to 30 degreeC.
The O / W emulsion of Formulation Example 3 had a viscosity of 2,250 mPa · s / 30 ° C. and had good usability and stability.

Claims (3)

Formulating a salt-type whitening agent that is one or more salts selected from the group consisting of ascorbate, ascorbic acid derivative salt, and alkoxysalicylic acid salt , xanthan gum, and guar gum ,
The ascorbic acid derivative is L-ascorbic acid monophosphate ester, L-ascorbic acid-2-sulfate ester, dl-α-tocopherol 2-L-ascorbic acid phosphate diester, L-ascorbic acid monostearate, L-ascorbine Acid monopalmitate, L-ascorbic acid monooleate, L-ascorbic acid distearate, L-ascorbic acid dipalmitate, L-ascorbic acid dioleate, L-ascorbic acid tristearate, L-ascorbic acid tripalmitate, L-ascorbic acid trioleate 2-O-α-D-glucopyranosyl-L-ascorbic acid, and 2-O-ethylascorbic acid,
A skin external preparation, wherein the alkoxysalicylic acid is represented by the following general formula (I) .
Formula (I):

(In the formula, R is an alkoxy group having 1 to 4 carbon atoms.) The skin external preparation according to claim 1, wherein xanthan gum and guar gum are in a weight ratio of 50:50 to 20:80. The skin external preparation according to claim 1 or 2, wherein the skin external preparation has a viscosity of 2,000 to 10,000 mPa · s (30 ° C) .