JP2010001218A - Composition for skin external use and skin regeneration promoter - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composition for skin external use, containing retinoic acid which exhibits an excellent skin regeneration-promoting action, little produces side effects, and is excellent in preparation stability. <P>SOLUTION: Provided is a composition for skin external use, characterized in that divalent metal inorganic acid salt fine particles containing retinoic acid sealed therein is compounded with a lyotropic liquid crystal. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a composition for external use of skin containing retinoic acid which exhibits an excellent action for promoting skin regeneration, has few side effects, and is excellent in formulation stability.

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 spots, wrinkles and acne. However, since retinoic acid has an acid moiety in its molecular structure, it has the property of being difficult to permeate into the skin stratum corneum, and also has the problem of developing 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 it is difficult to use as an active ingredient of an external preparation for skin. Therefore, the present inventors encapsulate retinoic acid in nanometer-order microparticles made of divalent metal inorganic acid salts such as magnesium carbonate and calcium carbonate, thereby causing problems of low skin permeability and side effects. Has proposed a method of improving the use value as an active ingredient of an external preparation for skin (Patent Document 1).
JP 2004-161739 A

The above-mentioned method is worthy of attention that has led to a certain evaluation from those skilled in the art as the NANOEGG (registered trademark) technology proposed by the present inventors. However, an external preparation for skin that is superior in terms of medicinal effects and side effects and has excellent formulation stability is desired.
Accordingly, an object of the present invention is to provide an external composition for skin containing retinoic acid that exhibits an excellent action for promoting skin regeneration, has few side effects, and is excellent in formulation stability.

  As a result of diligent research in view of the above points, the present inventors have blended divalent metal inorganic acid salt fine particles encapsulating retinoic acid into lyotropic liquid crystal, whereby retinoic acid has an excellent skin regeneration promoting action. It has been found that while exhibiting, there are few side effects, and the resulting composition is excellent in formulation stability.

The external composition for skin of the present invention based on the above knowledge is characterized in that, as described in claim 1, divalent metal inorganic acid salt fine particles encapsulating retinoic acid are blended in lyotropic liquid crystal. To do.
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 promoter of this invention consists of the composition for external use of the skin of Claim 1 as described in Claim 4.

  ADVANTAGE OF THE INVENTION According to this invention, the composition for external use of skin which contains the retinoic acid which shows the outstanding skin reproduction | regeneration promotion effect, has few side effects, and was excellent in formulation stability can be provided.

  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 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. Examples of the divalent metal inorganic acid salt include magnesium carbonate, calcium carbonate, and zinc carbonate. Preparation of the divalent metal inorganic acid salt fine particles having a diameter of about 10 to 1000 nm in which retinoic acid is encapsulated is prepared, for example, by dispersing retinoic acid in a polar organic solvent such as alcohol, and water containing alkali (preferable water is This is dissolved in purified water (the same shall apply hereinafter), and water, polyhydric alcohols such as glycerin, and surfactants such as nonionic surfactants are sequentially added to the mixed micelles. It can be carried out by adding an aqueous solution of a divalent metal chloride such as calcium or zinc chloride and further adding an aqueous solution of sodium hydrogen carbonate or sodium carbonate. The amount of each component used for preparing 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 alkali (for example, 2 ~ 5% sodium hydroxide aqueous solution) 3-5 parts by weight, surfactant 3-40 parts by weight, polyhydric alcohol 3-100 parts by weight, water 10-300 parts by weight, 1-10M divalent metal chloride aqueous solution. Examples are 0.3 to 1 part by weight, and 0.3 to 1 part by weight of an aqueous solution of 0.1 to 1M sodium bicarbonate or sodium carbonate.

  In the present invention, a lyotropic liquid crystal is a mixture of a surfactant (an amphiphilic molecule having a hydrophilic part and a hydrophobic (lipophilic) part in the molecule) and water in a coexisting system. It means a liquid crystal state (a state having fluidity like a liquid while maintaining a certain regularity in its molecular arrangement like a crystal) depending on the ratio and temperature. In principle, when lyotropic liquid crystal is added water in a predetermined temperature range to a solid-state surfactant having a crystalline structure in which hydrophobic portions (hydrophobic groups such as alkyl groups) face each other, The part loses regularity due to thermal motion and becomes a liquid state, but this time it is understood that the hydrophilic part acts by hydrogen bonding and maintains a long period to take an association structure (hexagonal structure, lamellar structure, etc.) (See "Toshiyuki Suzuki, Liquid Crystal, Vol. 2, pages 194-201, 1998" if necessary).

  The lyotropic liquid crystal can be prepared by mixing a surfactant and water as constituent components at a predetermined ratio at a predetermined temperature. If necessary, an operation of temporarily heating the constituent components before mixing or after mixing may be performed.

  The surfactant which is a constituent component of the lyotropic liquid crystal can form 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 in a coexistence system with water. If it is, it will not be restrict | limited especially, Any type of surfactant of nonionic type, anionic type, cationic type, amphoteric type may be sufficient, and lecithin (egg yolk lecithin, soybean lecithin, etc.) ) And naturally occurring surfactants such as saponins. Further, it may be hydrogenated lecithin obtained by adding hydrogen to natural lecithin in order to enhance stability against oxidation. A single surfactant may be used alone, or a plurality of surfactants may be mixed and used.

  Examples of the nonionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene alkylphenol ether, alkyl glucoside, polyoxyethylene fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, fatty acid alkanol. Amides, polyoxyethylene hydrogenated castor oil, etc. are mentioned. Anionic surfactants include soap (fatty acid sodium and potassium salts), alkylbenzene sulfonate (sodium salt, etc.), higher alcohol sulfate (sodium salt), polyoxyethylene alkyl ether sulfate (sodium) Salt), α-sulfo fatty acid ester, α-olefin sulfonate (sodium salt, etc.), monoalkyl phosphate ester salt (sodium salt, etc.), alkane sulfonate (sodium salt, etc.) and the like. Examples of the cationic surfactant include alkyltrimethylammonium salts (such as chloride), dialkyldimethylammonium salts (such as chloride), alkyldimethylbenzylammonium salts (such as chloride), and amine salts (such as acetate and hydrochloride). . Examples of amphoteric surfactants include alkylamino fatty acid salts (such as sodium salts), alkylbetaines, and alkylamine oxides.

  For example, purified water can be used as the water that is a constituent of the lyotropic liquid crystal. The water may contain a polar organic solvent such as ethanol or isopropanol that is compatible with water.

  The lyotropic liquid crystal may contain an oil component in addition to the surfactant and water. By including oil, the liquid crystal structure approximates to the lamellar structure formed by intercellular lipids in the stratum corneum, making it easier to cause a phase transition of the intercellular lipid structure when applied to the skin surface. It exerts a transdermal absorption promoting effect on the active ingredient. Examples of oils include vegetable oils such as wheat germ oil, corn oil, sunflower oil, castor oil and soybean oil, silicone oil, isopropyl myristate, glyceryl trioctanoate, diethylene glycol monopropylene pentaerythritol ether and pentaerythrityl tetraocta. Examples include ester oils such as noate, hydrocarbon oils such as squalane and squalene, liquid paraffin, and polybutene. A single oil component may be used alone, or a plurality of oil components may be mixed and used.

  The lyotropic liquid crystal may contain a polyhydric alcohol. By including a polyhydric alcohol, it is possible to facilitate formation of the liquid crystal structure (expansion of the 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-diol, pentane-1,5-diol, 2,2-dimethylpropane-1,3-diol, 3-methylpentane-1,5-diol, pentane-1,2-diol, 2,2,4-trimethylpentane-1,3-diol, 2-methyl Examples include propane-1,3-diol, hexylene glycol, 1,3-butylene glycol, dipropylene glycol, diethylene glycol, and triethylene glycol. A single polyhydric alcohol may be used alone, or a plurality of types may be mixed and used.

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

  The composition for external use of the 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 a lyotropic liquid crystal. Among the components used for preparing the 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 considered that the acid salt fine particles function as a constituent component of the lyotropic liquid crystal after being mixed with the lyotropic liquid crystal. Therefore, the amount of each component used for preparing the lyotropic liquid crystal is preferably understood as the proportion of the lyotropic liquid crystal after blending the divalent metal inorganic acid salt fine particles encapsulating retinoic acid. For example, the proportion of the surfactant in the lyotropic liquid crystal is desirably 5 to 80% by weight, more desirably 7 to 70% by weight, and further desirably 10 to 65% by weight (preparing retinoic acid-encapsulated divalent metal inorganic acid salt fine particles. Use amount to include). The proportion of water in the lyotropic liquid crystal is desirably 5 to 80% by weight, more desirably 10 to 60% by weight, and further desirably 13 to 50% by weight (use for preparing retinoic acid-encapsulated divalent metal inorganic acid salt fine particles. Including quantity). The proportion of oil in the lyotropic liquid crystal is preferably 1% to 80% by weight, more preferably 5% to 70% by weight, and still more preferably 10% to 65% by weight. The proportion of the polyhydric alcohol in the lyotropic liquid crystal is desirably 1 to 55% by weight, more desirably 3 to 52% by weight, and further desirably 5 to 50% by weight (for preparing retinoic acid-encapsulated divalent metal inorganic acid salt fine particles. Use amount). 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 an auxiliary 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 in which the metal inorganic acid salt fine particles are blended has a flat structure, whereby a lyotropic liquid crystal having a stable laminated structure can be obtained.

  In addition, as for content of retinoic acid in the composition for external use of skin of this invention, 0.001-1 weight% is desirable.

  In addition to the above components, the composition for external use of the present invention contains, for example, 0.001 to 1% by weight of an antioxidant such as dibutylhydroxytoluene, and antiseptics such as methyl paraoxybenzoate and propyl parahydroxybenzoate. It is desirable to contain 0.01 to 0.3% by weight of the agent and 0.1 to 2% by weight of a viscous agent such as cetanol.

  The composition for external use of the skin of the present invention is applied to the surface of the skin, so that retinoic acid effectively promotes the differentiation and proliferation of keratinocytes (keratinocytes) and promotes skin regeneration while reacting as a side effect. It is useful for the prevention and treatment of stains, wrinkles and acne because it has few onset of dermatitis and has excellent formulation stability.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is limited to the following description and is not interpreted at all.

Example 1: Production of composition for external use of skin of the present invention (Part 1)
The composition for external use of skin of this invention which consists of 5 types of prescription shown in following Table 1 was manufactured.

(Process 1)
Divalent metal inorganic acid salt fine particles in which retinoic acid (all-trans-retinoic acid) was encapsulated 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. Thereafter, a 2.5 M aqueous magnesium chloride solution (prepared using magnesium chloride hexahydrate) was added and stirring was continued for about 10 minutes. Finally, a 0.5 M sodium hydrogen carbonate aqueous 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 1000 nm in which retinoic acid was encapsulated.

(Process 2)
Squalane, hydrogenated soybean phospholipid, polyoxyethylene hydrogenated castor oil 60 and cholesterol were weighed into a beaker and heated to about 80 ° C. to dissolve them. In some cases, cetanol was added here and dissolved together. After cooling this to 60 degrees C or less, glycerol was added and it stirred until it became uniform. Further, 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. In addition, operation of the process 1 and the process 2 was performed under light shielding. Dibutylhydroxytoluene was added in step 2, and methyl paraoxybenzoate and propyl paraoxybenzoate were added in either step 1 or step 2.

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

Pharmacological test 1:
(experimental method)
The back skin of a mouse (ddY, male, 5 weeks old, purchased from Japan SLC Co., Ltd.) was shaved with a clipper (2 cm × 2 cm, 1 location), and a sample to be tested was once a day for 4 days. By applying (30 mg / site) and measuring the thickness of the epidermis one day later, the skin regeneration promoting action of retinoic acid was evaluated by thickening thickness (n = 6). The control group was the same as the above except that no sample was applied. In addition, scoring was performed by observation with an optical microscope for four inflammatory findings (scab formation, deposition of eosinophilic substances in the epidermis, inflammatory cell infiltration into the dermis, and peeling of the epidermis). For each item, scoring was performed in three stages, with no findings: 0, mild findings: 1, moderate findings: 2, and compared with the control group (score total is 0 for the minimum and maximum for the total) 8, n = 6). The test samples are as follows.
A lyotropic liquid crystal composition containing no retinoic acid having the formulation shown in Table 3 below (Comparative Formula 1)
-Composition for external use of skin of Formula 2 of Example 1-Composition for external use of skin of Formula 3-Lyotropic liquid crystal composition containing no formulation as shown in Table 4 below (Comparative Formula 2)
-Composition for external use of skin of formulation 6 of Example 2-Composition for external use of skin of formulation 7,-Cream preparation containing retinoic acid comprising the formulation shown in Table 5 below (Comparative formulation 3)

  The lyotropic liquid crystal composition (Comparative Formula 1) containing no retinoic acid having the formulation shown in Table 3 above was weighed with ethanol, 4% aqueous sodium hydroxide and purified water (vehicle content) in a beaker, and then glycerin. And polyoxyethylene hydrogenated castor oil 60 and stirred for about 1 hour, and then 2.5M magnesium chloride aqueous solution (prepared using magnesium chloride hexahydrate) was added and stirred for about 10 minutes. Continuing, finally, an aqueous solution obtained by adding a 0.5 M aqueous sodium hydrogen carbonate solution and stirring for about 10 minutes was used to obtain retinoic acid-encapsulated magnesium carbonate fine particles 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.

  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.

  The cream preparation containing retinoic acid having the formulation shown in Table 5 (Comparative formulation 3) was used in a beaker with retinoic acid, medium chain fatty acid triglyceride, benzyl alcohol, cetanol, stearic acid, stearyl alcohol, polyoxyethylene stearyl. Ether, dibutylhydroxytoluene, methyl paraoxybenzoate, propyl paraoxybenzoate are weighed and heated to about 80 ° C., and water previously heated to about 80 ° C. is gradually added to emulsify, Further, 2% xanthan gum and EDTA · 2Na were added with stirring, and the mixture was cooled while stirring.

(Experimental result)
As shown in FIG. As is clear from FIG. 1, the composition for external use of skin (Formulation 2, Formula 3, Formula 6, Formula 7) of the present invention has a thickening thickness that does not contain retinoic acid based on the skin regeneration promoting action of retinoic acid. Despite being thicker than the lyotropic liquid crystal composition (Comparative Formula 1 and Comparative Formula 2), the inflammation score is much lower than that of the cream formulation containing retinoic acid (Comparative Formula 3), and the skin regeneration promoting action is excellent. It was found that there were few side effects.

Formulation stability test 1:
In order to confirm the storage stability of the retinoic acid of the composition for external skin of Formulation 2 of Example 1, the content (%) at the start after storage at 25 ° C., 40 ° C., and 50 ° C. was determined. The results are shown in FIG. As is apparent from FIG. 2, the external composition for skin of the present invention was found to be excellent in preparation stability, with little or no degradation of retinoic acid even after 1 month from the start of the test.

  On the other hand, the same stability test as described above was performed on the plastibase preparation, the hydrophilic ointment preparation and the macrogol preparation in which the retinoic acid-encapsulated magnesium carbonate fine particles were mixed so that the content of retinoic acid was 0.05% by weight When 3 weeks passed from the start of the test, it was found that all the preparations had a retinoic acid content at the start of less than 90%, and the preparation stability was inferior. Each formulation was prepared as follows.

(Plastic base formulation 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 made into a plasti base so that the content of retinoic acid was 0.05% by weight. Obtained by blending.

(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.

(Macrogol formulation containing retinoic acid-encapsulated magnesium carbonate fine particles)
It was obtained by blending macrogol with an aqueous solution containing retinoic acid-encapsulated magnesium carbonate fine particles having the formulation shown in Table 6 so that the content of retinoic acid was 0.05% by weight.

Formulation stability test 2:
An aqueous solution containing retinoic acid-encapsulated magnesium carbonate fine particles prepared to obtain the external composition for skin of Formula 3 in Example 1 and the external composition for skin of Formula 3 in Example 1 has a retinoic acid content of 0.10% by weight. For three types of compositions, a composition formulated in petrolatum (Comparative Example 1) and a composition blended in petrolatum so that the content of retinoic acid is 0.10 wt% (Comparative Example 2), In order to confirm the storage stability of the retinoic acid, the content at the start (%) after storage at 40 ° C. was determined. The results are shown in FIG. As is clear from FIG. 3, it was found that the composition for external use of the present invention hardly decomposes retinoic acid even after 2 months from the start of the test and is excellent in preparation stability.

  INDUSTRIAL APPLICABILITY The present invention has industrial applicability in that it can 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. .

It is a graph which shows the result of the pharmacological test in an Example. 3 is a graph showing the results of Formulation Stability Test 1; 3 is a graph showing the results of Formulation Stability Test 2;

Claims (4)

  A composition for external use on the skin, wherein divalent metal inorganic acid salt fine particles encapsulating retinoic acid are blended in a lyotropic liquid crystal.   The skin external composition according to claim 1, wherein the divalent metal is at least one selected from magnesium, calcium and zinc.   The external composition for skin according to claim 1, wherein the divalent metal inorganic acid salt is a divalent metal carbonate.   A skin regeneration promoter comprising the composition for external use of the skin according to claim 1.

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