WO2008050844A1

WO2008050844A1 - Composition for external application to skin and skin regeneration promoter

Info

Publication number: WO2008050844A1
Application number: PCT/JP2007/070844
Authority: WO
Inventors: Rie Igarashi; Yoko Yamaguchi
Original assignee: Taisho Pharmaceutical Co., Ltd.; Nanoegg Research Laboratories, Inc.
Priority date: 2006-10-27
Filing date: 2007-10-25
Publication date: 2008-05-02
Also published as: JP2010001218A; TW200824717A

Abstract

Disclosed is a composition for external application to the skin, which comprises retinoic acid, has an excellent skin regeneration-promoting activity, has little adverse side-effects, and shows an excellent stability when prepared into a pharmaceutical preparation. The composition comprises: a lyotropic liquid crystal; and a microparticle of a bivalent metal salt of an inorganic acid having retinoic acid included therein, which is incorporated in the lyotropic liquid crystal. Examples of the microparticle of a bivalent metal salt of an inorganic acid include a magnesium carbonate microparticle, a calcium carbonate microparticle and a zinc carboante microparticle.

Description

Specification

External composition for skin and skin regeneration promoter

Technical field

[0001] The present invention relates to an external composition for skin containing retinoic acid that exhibits an excellent action for promoting skin regeneration, has few side effects, and has excellent formulation stability.

Background art

[0002] It is a well-known fact to those skilled in the art that retinoic acid, a physiologically active substance of vitamin A necessary for skin regeneration, is effective in preventing and treating spot wrinkles acne. However, since retinoic acid has an acid moiety in its molecular structure, it has the property that it is difficult to penetrate into the stratum corneum, and it also causes reactive dermatitis such as redness, pain, and itching as a side effect. It is a fact well known to those skilled in the art that there is a problem that it is difficult to use as an active ingredient of a topical skin preparation. Therefore, the present inventors have encapsulated retinoic acid in nanometer-order fine particles made of divalent metal inorganic acid salts such as magnesium carbonate calcium carbonate, thereby causing problems such as low skin permeability. A method has been proposed that improves the side effect problem and increases the utility value of the topical skin preparation as an active ingredient (Patent Document 1). Patent Document 1: JP 2004-161739 A

Disclosure of the invention

Problems to be solved by the invention

[0003] The above-described method is worthy of attention as a NANOEGG (registered trademark) technique advocated by the present inventors, which has led to a certain evaluation by those skilled in the art. However, there is a demand for a topical skin preparation that is superior in terms of drug efficacy and side effects, and has excellent formulation stability.

Accordingly, an object of the present invention is to provide an external composition for skin containing retinoic acid which exhibits an excellent action for promoting skin regeneration, has few side effects, and is excellent in formulation stability.

Means for solving the problem

[0004] As a result of intensive studies in view of the above points, the present inventors have encapsulated retinoic acid. By blending divalent metal inorganic acid salt fine particles with lyotropic liquid crystals, retinoic acid exhibits excellent skin regeneration promoting effects while having fewer side effects. Also, the resulting composition is superior in formulation stability. I found it.

[0005] The composition for external use of the skin of the present invention based on the above knowledge is obtained by blending divalent metal inorganic acid salt fine particles encapsulating retinoic acid in lyotropic liquid crystal as described in claim 1. It is characterized by that.

The external composition for skin according to claim 2 is characterized in that in the external composition for skin according to claim 1, the divalent metal is at least one selected from magnesium, calcium and zinc.

The external composition for skin according to claim 3 is characterized in that in the external composition for skin according to claim 1, the divalent metal inorganic acid salt is a divalent metal carbonate.

Moreover, the skin regeneration-promoting agent of the present invention comprises the composition for external use of the skin according to claim 1 as described in claim 4.

The invention's effect

[0006] According to the present invention, it is possible to provide an external skin composition containing retinoic acid that exhibits an excellent skin regeneration promoting action, has few side effects, and has excellent formulation stability.

[0007] FIG. 1 is a graph showing the results of a pharmacological test in Examples.

FIG. 2 is a graph showing the results of formulation stability test 1.

FIG. 3 is a graph showing the results of formulation stability test 2 in the same manner.

BEST MODE FOR CARRYING OUT THE INVENTION

[0008] The external composition for skin of the present invention is characterized in that divalent metal inorganic acid salt fine particles encapsulating retinoic acid are blended in a lyotropic liquid crystal. In the present invention, the divalent metal inorganic acid salt fine particles encapsulating retinoic acid are known per se (see, for example, Patent Document 1 if necessary). Examples of retinoic acid include all-trans retinoic acid, 9 cis-retinoic acid, 11 cis-retinoic acid, 13 cis-retinoic acid and the like. Divalent metal inorganic acid salts include magnesium carbonate and calcium carbonate. Examples include umya zinc carbonate. Preparation of divalent metal inorganic acid salt fine particles with a diameter of 10 to about 10 OOOnm encapsulated in retinoic acid, for example, by dispersing retinoic acid in a polar organic solvent such as alcohol and adding water containing alkali (preferable Water is purified water (the same applies hereinafter), and water, polyhydric alcohols such as glycerin, and surfactants such as nonionic surfactants are sequentially added to the mixed micelles. This can be done by adding an aqueous solution of divalent metal chloride such as magnesium chloride or calcium chloride or zinc chloride, and then adding an aqueous solution such as sodium bicarbonate or sodium carbonate. The amount of each component used to prepare the divalent metal inorganic acid salt fine particles encapsulating retinoic acid is 2 to 4 parts by weight of a polar organic solvent and 1% by weight of water containing an alkali (for example, 2 ~ 5% sodium hydroxide aqueous solution) 3-5 parts by weight, surfactant 3-40 parts by weight, polyvalent vinylol 3 ~; 100 parts by weight, water 10-300 parts by weight, 1 ~; 10M divalent metal salt An aqueous solution of a compound of 0.3 to;! By weight, 0.1 to 1; an aqueous solution of 1M sodium hydrogen carbonate or sodium carbonate, etc. from 0.3 to;

In the present invention, a lyotropic liquid crystal is a coexisting system of a surfactant (an amphiphilic molecule having a hydrophilic part and a hydrophobic (lipophilic) part in the molecule) and water. It means that the liquid crystal state (a state in which the liquid crystal-like fluidity is maintained while maintaining a certain regularity in the molecular arrangement like a crystal) is formed by the mixing ratio and temperature of both. In principle, when lyotropic liquid crystal is used, water is added to a solid-state surfactant having a crystalline structure in which hydrophobic parts (hydrophobic groups such as alkyl groups) are directed to each other. The part loses regularity due to thermal motion and becomes a liquid state, but this time the hydrophilic part acts by hydrogen bonding and maintains a long period to take an association structure (hexagonal structure, lamellar structure, etc.) It can be understood (if necessary, see “Toshiyuki Suzuki, Liquid Crystal, Vol. 2, 194–201, 1998”).

[0010] The lyotropic liquid crystal can be prepared by mixing a surfactant and water as constituents thereof at a predetermined temperature and mixing them at a predetermined ratio. If necessary, the operation may be performed when the components are heated temporarily before or after mixing.

[0011] In the coexistence system with water, the surfactant which is a constituent component of the lyotropic liquid crystal has a liquid crystal state (especially a periodic structure with a surface interval of 10 nm to 800 nm) depending on the mixing ratio with water and the temperature. Any non-ionic type, anionic type, cationic type or amphoteric type of surfactant may be used as long as it can form (desired). In addition, naturally occurring surfactants such as lecithin (eg, egg yolk lecithin and soybean lecithin) and saponin may be used. Further, it may be hydrogenated lecithin in which hydrogen is added to natural lecithin in order to enhance stability against oxidation. A single surfactant may be used alone, or a plurality of surfactants may be used in combination.

[0012] Examples of the nonionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene alkyl phenol ether, alkyl darcoside, polyoxyethylene fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, and polyoxyethylene sorbitan fatty acid. Examples include esters, fatty acid alkanolamides, and polyoxyethylene hydrogenated castor oil. Anionic surfactants include soap (fatty acid sodium and potassium salts), alkylbenzene sulfonate (sodium salt, etc.), higher alcohol sulfates (sodium salt, etc.), polyoxyethylene alkyl ether sulfates. (Sodium salt, etc.), α-sulfo fatty acid ester, α-olefin sulfonate (sodium salt, etc.), monoalkyl phosphate ester salt (sodium salt, etc.), alkane sulfonate (sodium salt, etc.) . Cationic surfactants include alkyltrimethylammonium salts (such as chloride), dialkyldimethylammonium salts (such as chloride), alkyldimethylbenzylammonium salts (such as chloride), and amine salts (acetate and hydrochloride). Etc.). Examples of amphoteric surfactants include alkylamino fatty acid salts (such as sodium salts), alkylbetaines, and alkylamine oxides.

[0013] As water that is a constituent of the lyotropic liquid crystal, for example, purified water can be used. Water may contain a polar organic solvent such as ethanol or isopropanol that is compatible with water.

[0014] The lyotropic liquid crystal may contain an oil component in addition to the surfactant and water. By containing oil, the liquid crystal structure approximates to the lamellar structure formed by intercellular lipids in the stratum corneum, making it easier to cause phase transition of intercellular lipid structures when applied to the skin surface. Excellent transdermal absorption for active ingredients. Examples of oils include wheat germ oil, corn oil, castor oil, castor oil and soybean oil, vegetable oils such as silicone oil, isopropyl myristate, glyceryl trioctanoate, diethylene glycol monopropylene pentaerythritol, and the like. Examples include ester oils such as pentaerythritinoretetraoctanoate, and hydrocarbon oils such as squalene and squalene and liquid paraffin and polybutene. A single oil component may be used alone, or a plurality of types may be used in combination.

[0015] The lyotropic liquid crystal may contain a polyhydric alcohol. Inclusion of polyhydric alcohol can facilitate the formation of liquid crystal structure (expansion of phase region) and stabilization. Examples of the polyhydric alcohol include polyalkylene glycols such as polyethylene glycol and polyalkylene glycol, glycerin, propylene glycol, 1,3-propanediol, 2 butene 1,4 dianol, pentane 1,5 diol, and 2,2 dimethylolpropane. 1,3 diol, 3 methylpentane 1,5 diol, pentane 1,2 diol, 2,2,4-trimethylpentane 1,3-diol, 2-methylpropane 1,3-diol monoole, hexylene glycolanol, Examples include 1,3-butylene glycol, dipropylene glycol, diethylene glycol, and triethylene glycol. A single polyhydric alcohol may be used alone, or a plurality of polyhydric alcohols may be mixed and used.

[0016] The lyotropic liquid crystal may contain cholesterol or the like as an auxiliary surfactant. By including an auxiliary surfactant, even when a wide variety of surfactants are used, it is possible to reduce the curvature of the interface film, thereby facilitating the formation and stabilization of the liquid crystal structure.

[0017] The external composition for skin of the present invention can be produced, for example, by adding divalent metal inorganic acid salt fine particles encapsulating retinoic acid in the process of preparing lyotropic liquid crystals. Among the components used to prepare divalent metal inorganic acid salt fine particles encapsulating retinoic acid, at least part of the surfactant, polyhydric alcohol and water are divalent metal inorganic encapsulated with retinoic acid. It is thought that after adding fine salt particles to lyotropic liquid crystal, it functions as a constituent of lyotropic liquid crystal. Therefore, the amount of each component used to prepare the lyotropic liquid crystal is composed of divalent metal inorganic acid salt fine particles encapsulating retinoic acid. It is desirable to capture the proportion of the lyotropic liquid crystal after it has been applied. According to the perception, the proportion of the surfactant in the lyotropic liquid crystal is preferably 5 to 80% by weight, more preferably 7 to 70% by weight. More preferably, it is 10 to 65% by weight (including the amount used for preparing retinoic acid-encapsulated divalent metal inorganic acid salt fine particles). The proportion of water in the lyotropic liquid crystal is preferably 5 to 80% by weight, more preferably 10 to 60% by weight, and even more preferably 13 to 50% by weight (preparing retinoic acid-encapsulated divalent metal inorganic acid salt fine particles Usage amount to include). The proportion of oil in the lyotropic liquid crystal is preferably 1% to 80% by weight, more preferably 5% to 70%, and even more preferably 10% to 65%. The proportion of polyhydric alcohol in the lyotropic liquid crystal is preferably 1 to 55% by weight, more preferably 3 to 52% by weight, and even more preferably 5 to 50% by weight (retinoic acid encapsulated divalent metal inorganic acid salt fine particles Including the amount used to prepare). The proportion of the auxiliary surfactant in the lyotropic liquid crystal is preferably 0.01 to 10% by weight. When preparing a lyotropic liquid crystal, when using lecithin as a surfactant and a co-surfactant, the former and the latter are used in a weight ratio of 10: 3 to 10: 5, Each bimolecular film constituting the lyotropic liquid crystal containing the divalent metal inorganic acid salt fine particles has a flat structure, whereby a lyotropic liquid crystal having a stable laminated structure can be obtained.

[0018] The content of retinoic acid in the composition for external use of the present invention is desirably 0.00;! To 1% by weight.

[0019] In addition to the above-mentioned components, the composition for external use of the present invention contains, for example, an antioxidant such as dibutylhydroxytoluene in an amount of 0.001 to;% by weight, methyl paraoxybenzoate and paraoxybenzoic acid. It is desirable to contain 0.01 to 0.3% by weight of a preservative such as propyl and 0.;! To 2% by weight of a thickener such as cetanol.

[0020] When the composition for external use of the present invention is applied to the surface of the skin, retinoic acid effectively promotes differentiation and proliferation of keratinocytes (keratinocytes) to promote skin regeneration, while having side effects. It is useful for the prevention and treatment of stains, wrinkles, and acne because of its low onset of reactive dermatitis and excellent formulation stability.

Example

[0021] Hereinafter, the present invention will be described in detail with reference to examples. The present invention is not limited to the following description. This is not something that can be interpreted.

Example 1: Production of composition for external use of skin of the present invention (Part 1)

The composition for external use of the skin of the present invention comprising 5 types of formulations shown in Table 1 below was produced.

[0023] [Table 1]

[0024] (Process 1)

Divalent metal inorganic acid salt fine particles encapsulating retinoic acid (all-trans retinoic acid) were prepared as follows.

Retinoic acid was weighed into a beaker, ethanol and then 4% aqueous sodium hydroxide solution were added to uniformly dissolve the retinoic acid. Subsequently, purified water was added and stirred for about 10 minutes, then glycerin and polyoxyethylene hydrogenated castor oil 60 were added and stirred for about 1 hour. Then, 2.5M aqueous magnesium chloride solution (prepared using magnesium chloride hexahydrate) was added and stirring was continued for about 10 minutes. Finally, 0.5M aqueous sodium hydrogen carbonate solution was added and stirred for about 10 minutes to obtain an aqueous solution containing magnesium carbonate fine particles (nanoparticles) having a diameter of 10 nm to lOOOnm encapsulated with retinoic acid.

[0025] (Step 2) In a beaker, squalene, hydrogenated soybean phospholipid, polyoxyethylene hydrogenated castor oil 60 and cholesterol were weighed and heated to about 80 ° C. to dissolve them. In some cases, cetanol was added here and dissolved together. After cooling this to 60 ° C or lower, glycerin was added and stirred until uniform. Furthermore, an aqueous solution containing retinoic acid-encapsulated magnesium carbonate fine particles prepared in Step 1 and purified water (formulations 1 to 3) are added and stirred well to form a lyotropic liquid crystal containing retinoic acid-encapsulated magnesium carbonate fine particles. The composition for external use of the skin of the present invention was obtained. All operations in Step 1 and Step 2 were performed under light shielding. Dibutylhydroxytoluene was added in Step 2, and methyl noroxybenzoate and propyl parabenzoate were added at! /, Either of Step 1 or Step 2.

Example 2 Production of External Composition for Skin of the Present Invention (Part 2)

In accordance with Example 1, a composition for external use of the skin of the present invention comprising two kinds of formulations shown in Table 2 below was produced.

[0027] [Table 2]

[0028] Pharmacological test 1:

(experimental method) The back skin of a mouse (ddY, male, 5 weeks old, purchased from SLC Japan) is shaved with Norican (2 cm x 2 cm, 1 location), and the sample to be tested is applied to the relevant area once a day 4 The effect of retinoic acid on promoting skin regeneration was evaluated by thickening (n = 6) by applying it daily (30 mg / site) and measuring the thickness of the epidermis one day later. The control group was the same as described above except that no sample was applied. In addition, scoring was performed by observation with an optical microscope for four inflammatory findings (skin formation, deposition of eosinophilic substances in the epidermis, inflammatory cell infiltration into the dermis, peeling of the epidermis). For each item, scoring was performed in three stages: 0, mild findings: 1, moderate findings: 2, and compared to the control group (score total was 0 minimum) The maximum is 8, n = 6) _{0 The} test samples are as follows.

• A lyotropic liquid crystal composition containing the formulation shown in Table 3 below and containing no retinoic acid (Comparative formulation 1)

• Skin preparation composition for formulation 2 of Example 1

• Formulation 3 topical skin composition

• A lyotropic liquid crystal composition containing the formulation shown in Table 4 below and containing no retinoic acid (Comparative formulation 2)

• The composition for external use of skin of Formula 6 of Example 2

• Formula 7 topical skin composition

• Cream preparation containing retinoic acid with the formulation shown in Table 5 below (Comparative Formula 3) [Table 3]

Comparative prescription 1

All-trans retinoic acid

Ethanol 0.150

4¾ NaOH aqueous solution 0.191

Water 8.35

Bihikuzole

Glycerin 2.99

E xylene-hardened castor oil 60 0.98

2.5 MgCI _₂ - 6H ₂ 0 0.033

0.5M NaHC0 ₃ 0.033

Skullan 15.0

Hydrogenated soybean phospholipid 9.57

Cholesterol 3.83

; School crystal y chillhi'loxytoluene 0.037

E xylene-hardened castor oil 60 4.22

Glycerin 43.58

Wed 10.92

A Methyl laoxybenzoate 0.1

Additive A Laoxybenzoate A □ Pil 0.02

Cetanol

Total amount (g) 100.0

[0030] The lyotropic liquid crystal composition containing no retinoic acid having the formulation shown in Table 3 above (Comparative formulation 1) was prepared by weighing ethanol, 4% aqueous sodium hydroxide, and purified water (vehicle) into a beaker. Then add glycerin and polyoxyethylene hydrogenated castor oil 60, stir for about 1 hour, then add 2.5M aqueous magnesium chloride solution (prepared using magnesium chloride hexahydrate) and add about Stirring was continued for 10 minutes, and finally, an aqueous solution obtained by adding 0.5 M aqueous sodium hydrogen carbonate solution and stirring for about 10 minutes was used as the retinoin prepared in Step 1 of Example 1 in Step 2 of Example 1. It was obtained in the same manner as in Step 2 of Example 1, except that it was added instead of the solution containing the acid-encapsulated magnesium carbonate fine particles.

[0031] [Table 4] Comparative prescription 2

All-trans-retinoic acid-ethanol 0.300

1 N NaOH aqueous solution 0.382

Water 1 6.70

Biyle y Tilhuman 'Roxytoluene 0.074

Glycerin 5.98

E xylene-hardened castor oil 60 1.96

2.5 MgCI _₂ - 6H ₂ 0 0.066

0.5M NaHC0 ₃ 0.066

Skullan 15.0

Hydrogenated soybean phospholipid 8.93

Cholesterol 4.45

Liquid crystal

E xylene ethylene hard castor oil 60 13.04

Glycerin 32.80

Water 0.10

A Methyl Raokiji benzoate 0.1

Additive

A Laoxybenzoic acid pill 0.02

Total amount) 100

[0032] A lyotropic liquid crystal composition containing no retinoic acid having the formulation shown in Table 4 above (Comparative Formula 2) was obtained in the same manner as Comparative Formula 1.

[0033] [Table 5]

[0034] It should be noted that a cream preparation containing retinoic acid having the formulation shown in Table 5 above (Comparative Treatment 3) is used in a beaker with retinoic acid, medium chain fatty acid triglyceride, benzyl alcohol, cetanol, stearic acid, stearyl alcohol. , Polyoxyethylene stearyl ether , Dibutylhydroxytoluene, methyl noroxybenzoate, and noroxybenzoic acid pills were weighed and heated to about 80 ° C, and water that had been heated to about 80 ° C was gradually added. It was added and emulsified, and further, 2% xanthan gum and EDTA ′ 2Na were added with stirring, and the mixture was cooled with stirring.

[0035] (Experimental result)

Figure 1 shows. As is clear from FIG. 1, the composition for external use of the present invention (formulation 2, formulation 3, method 6, formulation 7) has a thickening thickness of retinoic acid based on the skin regeneration promoting action of retinoic acid. Although it is thicker than the lyotropic liquid crystal composition (Comparative Formulation 1 and Comparative Formula 2), it has an inflammation score that is much lower than that of the cream formulation containing retinoic acid (Comparative Formula 3). It has been found that it has excellent side effects and few side effects.

[0036] Formulation stability test 1:

In order to confirm the storage stability of retinoic acid for the composition for external use of the formulation 2 in Example 1, the content (%) relative to the starting content (%) after storage at 25 ° C, 40 ° C and 50 ° C was determined. Asked. The result is shown in figure 2. As is clear from FIG. 2, the composition for external use of the skin of the present invention has a retinoic acid content of 1 month at 50 ° C, 3 months at 40 ° C, and 12 months at 25 ° C. Almost no solution occurred, and it was remarkable that the drug product had excellent stability.

[0037] On the other hand, against the retinoic acid magnesium carbonate particulates plastibase formulation and hydrophilic ointment and macrogol formulation was formulated as the content of retinoic acid is 0.05 by weight ^_0/0, the same stability and the When the test was conducted, 3 weeks after the start of the test, all the preparations showed that the content of retinoic acid relative to the start was less than 90%, indicating that the preparation stability was poor. Each formulation was prepared as follows.

[0038] (Plastic base preparation containing retinoic acid-encapsulated magnesium carbonate fine particles)

In the same manner as in Step 1 of Example 1, an aqueous solution containing retinoic acid-encapsulated magnesium carbonate fine particles having the formulation shown in Table 6 below was obtained, and this was added to a plastibase so that the retinoic acid content was 0.05% by weight. It was obtained by blending.

[0039] [Table 6] All-trans-retinoin 酉 0.102

Ethanol 0.40

1 N NaOH aqueous solution 0.39

Wed 17.00

Nano-particle Shi'fu Chiru-Hide Phytol Toluene 0.075

Glycerin 6.29

Polyoxyethylene octyl chloride "Silether 2.00

2.5 MgCI _₂ - 6H ₂ 0 0.0667

0.5M NaHC0 ₃ 0.0333

Total amount (g) 26.36

[0040] (Retinoic acid-encapsulated magnesium carbonate fine particle-containing hydrophilic ointment formulation)

An aqueous solution containing retinoic acid-encapsulated magnesium carbonate fine particles having the formulation shown in Table 6 above was added during the preparation process of the hydrophilic ointment base to obtain a formulation having the formulation shown in Table 7 below.

[0041] [Table 7]

[0042] (Macrogol formulation containing retinoic acid-encapsulated magnesium carbonate fine particles)

An aqueous solution containing retinoic acid-encapsulated magnesium carbonate fine particles having the formulation shown in Table 6 above was blended with Macrogol so that the retinoic acid content was 0.05% by weight.

[0043] Formulation stability test 2:

An aqueous solution containing retinoic acid-encapsulated magnesium carbonate fine particles prepared to obtain the skin external composition of Formula 1 of Example 1 and the skin external composition of Formula 3 of Example 1 has a retinoic acid content of 0.10% by weight. Composition mixed with petrolatum (Comparative Example 1), retinoy In order to confirm the storage stability of retinoic acid for three types of compositions (Comparative Example 2), which was formulated with petrolatum so that the acid content was 0.10% by weight, The content (%) at the beginning of storage after storage was determined. The results are shown in Figure 3. As is apparent from FIG. 3, the composition for external use of the present invention showed little degradation of retinoic acid even after 2 months from the start of the test, and was found to have excellent formulation stability.

Example 3 Production of External Composition for Skin of the Present Invention (Part 3)

According to Example 1, a composition for external use of the skin of the present invention comprising the two types of formulations shown in Table 8 below was produced.

[0045] [Table 8]

[0046] Formulation stability test 3:

In order to confirm the storage stability of the retinoic acid for the external preparation compositions of Formulation 8 and Formulation 9 of Example 3, the content (%) at the start after storage at 50 ° C. was determined. The results are shown in Table 9. As is clear from Table 9, the composition for external use of the present invention has a content at the start of 90% or more even after 4 weeks from the start of the test, regardless of the content of retinoic acid. It is the power that is superior in nature.

[0047] [Table 9] Content at start /%

At the start of the test 1 week later 2 weeks later 4 weeks later

Formula 8 100.0 97.5 99.8 93.0

Formula 9 100.0 97.7 99.7 93.5 Industrial applicability

INDUSTRIAL APPLICABILITY The present invention has industrial applicability in that it can provide an external skin composition containing retinoic acid that exhibits an excellent action for promoting skin regeneration, has few side effects, and has excellent formulation stability. Have

Claims

The scope of the claims

[1] A composition for external use on skin, comprising divalent metal inorganic acid salt fine particles encapsulating retinoic acid in a lyotropic liquid crystal.

[2] The external composition for skin according to claim 1, wherein the divalent metal is at least one selected from magnesium, calcium and zinc.

[3] The external composition for skin according to claim 1, wherein the divalent metal inorganic acid salt is a divalent metal carbonate.

[4] A skin regeneration-promoting agent comprising the composition for external use according to claim 1.