KR101133770B1 - Manufacturing method of methyl 5-aminolevulinate hydrochloride and cosmetic omposition for skin external application for improvement of pimpled skin, manufacturing method thereof - Google Patents

Abstract

The present invention relates to a method for preparing methyl 5-aminolevulinate hydrochloride, and an external cosmetic composition for improving acne and skin using the same, and a method for preparing the same, more particularly 5-amino having an effect on acne and skin improvement. A method for preparing a salt of methyl 5-aminolevulinate, a derivative of 5-aminolevulinic acid, which is a derivative having a lipophilic group introduced to enhance skin absorption of levulinic acid, and a salt of methyl 5-aminolevulinate. The present invention relates to a cosmetic composition for external use of the skin which can be usefully used for photodynamic therapy and a method for producing the same.

In the method for preparing a salt of methyl 5-aminolevulinate of the present invention, methanol and thionyl chloride are reacted with 5-aminolevulinic acid hydrochloride, followed by addition of diethyl ether, followed by vacuum drying.

Aminolevulinic acid, aminolevulinate, salts, hydrochloride, photodynamics, acne, skin

Description

Manufacturing method of methyl 5-aminolevulinate hydrochloride and cosmetic omposition for skin external application for improvement of pimpled skin, manufacturing method

The present invention relates to a method for preparing methyl 5-aminolevulinate hydrochloride, and an external cosmetic composition for improving acne and skin using the same, and a method for preparing the same, more particularly 5-amino having an effect on acne and skin improvement. A method for preparing a salt of methyl 5-aminolevulinate, a derivative of 5-aminolevulinic acid, which is a derivative having a lipophilic group introduced to enhance skin absorption of levulinic acid, and a salt of methyl 5-aminolevulinate. The present invention relates to a cosmetic composition for external use of the skin which can be usefully used for photodynamic therapy and a method for producing the same.

The skin is the outermost part of our body that accepts and reacts sensitively to all stimuli from the outside and responds to everything from the outside, including light, temperature and humidity, wind, invisible air components and physical and chemical stimuli. Is the skin. This important organ, the skin, is composed of lipids and the skin surface is covered with a sebaceous membrane, which has lipophilic properties and constitutes a solid skin barrier.

Conventionally, external skin preparations have been developed for the purpose of improving various skin diseases. Recently, optical treatment with 5-aminolevulinic acid (hereinafter abbreviated as 5-ALA) has been used for various skin diseases such as UV keratosis, psoriasis, warts, and skin cancer, and Bowen's disease and superficial basal cell carcinoma. There are reports of the effect. 5-ALA is also used as a precursor for photosensitive materials used in photodynamic therapy (PDT).

When 5-ALA is absorbed into the skin through application or patching, 5-ALA transferred into the cell is a practical photosensitizer used in photodynamic therapy called protoporphyrin IX (PpIX) through the biosynthesis process of porphyrin. Is switched.

At this time, when 5-ALA is administered from the outside, excessive heme is generated in the human body, and PpIX is accumulated in cells by inhibiting an enzyme converting PpIX to heme. PpIX is a very effective light sensitizer that produces generator oxygen by reacting with surrounding oxygen by light and energy of a specific wavelength. The generator oxygen produced can damage the stomach and diseases by causing cell membrane injury and cell death. 5-ALA is also absorbed and converted more quickly in abnormal cells or tissues than in normal cells or tissues.

However, since 5-ALA has high hydrophilicity and weak hydrophobicity, it does not easily pass through barriers such as the stratum corneum and cell wall of the skin, so it takes a long time to accumulate 5-ALA in the cell or does not have the desired therapeutic effect. have.

For this reason, there is a method of effectively delivering 5-ALA into cells, using 5-ALA as a derivative such as methyl ester or butyl ester. This method has a much lower hydrophilicity than carboxylic acid, so it is very effective to pass through obstacles such as the stratum corneum and cell wall of the lipid layer, but these compounds have a long time to synthesize and have a low yield.

The present invention has been made to improve the above-mentioned problems, and the effect of methyl 5-aminolevulinate hydrochloride, which is a 5-ALA derivative having a methyl group, can effectively deliver 5-ALA into skin cells while shortening the synthesis time and improving the yield. The purpose is to provide a manufacturing method.

Another object of the present invention is to prepare a skin external cosmetic composition having a creamy formulation that can be used in photodynamic therapy for acne and skin improvement by mixing methyl 5-aminolevulinate hydrochloride in a base capable of maintaining viscosity and its preparation To provide a way.

Method for preparing methyl 5-aminolevulinate hydrochloride of the present invention for achieving the above object is to react methyl 5-aminolevulinate hydrochloride with methanol, thionyl chloride, and then add diethyl ether and then vacuum-dried methyl It is characterized by preparing 5-aminolevulinate hydrochloride (Methyl 5-aminolevulinate Hydrochloride).

And the external skin cosmetic composition for acne and skin improvement of the present invention for achieving the above object is characterized in that it comprises methyl 5-aminolevulinate hydrochloride of the formula (1) as an active ingredient.

The content of the methyl 5-aminolevulinate hydrochloride is characterized in that 9 to 15% by weight of the total weight of the cosmetic composition.

The methyl 5-aminolevulinate hydrochloride is contained in a base composed of a carrier or an excipient together with water, and is formed in any one of a formulation selected from cream, ointment, and lotion.

The base is formed by mixing the first material, the second material, the third material, the fourth material, the fifth material, the sixth material, the seventh material, and the eighth material, and the first material is water or allantoin. ), Butylene glycol, glycerin, PEG / PPG-17 / 6 copolymer, the second material is sodium hyaiuronate, and the third material is PEG-100 Stearate, Cetostearyl Alcohol, Stearic Acid, Glyceryl Stearate, PEG-4 Olivate, Propyl paraben, Methyl paraben paraben, Hydrogenated Camellia Oil, Hydrogenated Lanolin, Squalane, Butylene Glycol Dicaprylate / Dicaprate, Dimethicone, Toco Peryl acetate (Tocopheryl Acetate), the fourth The quality is polyacrylamide, the fifth substance is natto gum, green tea extract, beta-glucan, and the sixth substance is DMDM hydantoin, water, The seventh substance is triethanolamine, water, and the eighth substance is a fragrance.

And in order to achieve the above object of the present invention, a method for preparing an external cosmetic composition for improving acne and skin according to the present invention is reacted with 5-aminolevulinic acid hydrochloride to methanol, thionyl chloride, and then diethyl ether is added, followed by vacuum. Drying to obtain methyl 5-aminolevulinate hydrochloride;

A second step of heating and mixing a first material made of water, allantoin, butylene glycol, glycerin, and PEG / PPG-17 / 6 copolymer to 80 ° C .; A third step of adding and mixing a second substance of sodium hyaiuronate to the mixture of the second step; PEG-100 Stearate, Cetostearyl Alcohol, Stearic Acid, Glyceryl Stearate, PEG-4 Olivate, Propyl paraben, Methyl Paraben (Methyl paraben), Hydrogenated Camellia Oil, Hydrogenated Lanolin, Squalane, Butylene Glycol Dicaprylate / Dicaprate, Dimethicone ), A fourth step of adding a third material consisting of Tocopheryl Acetate to the mixture of the third step and then mixed at 75 ℃ emulsifying; Adding a fourth material of polyacrylamide to the mixture of the fourth step and then mixing at 50 ° C .; A fifth substance consisting of natto gum, green tea extract and beta-glucan, and a sixth substance consisting of DMDM hydantoin and water were sequentially added to the mixture of the fifth step at 5 minute intervals. A sixth step of mixing at 50 ° C. while adding; A seventh step of adding the methyl 5-aminolevulinate hydrochloride and water to the mixture of the sixth step and mixing at 50 ° C; An eighth step of adding triethanolamine, a seventh substance made of water, and an eighth substance, which is a fragrance, at 50 ° C. while sequentially adding the eighth substance, which is a fragrance, at a 5-minute interval; And a ninth step of aging the mixture of the eighth step at 50 ° C., characterized in that it is formed into a creamy formulation.

The first material is 31.490% by weight, the second material is 2.000% by weight, the third material is 14.750% by weight, the fourth material is 1.050% by weight, and the fifth material with respect to the total weight of the cosmetic composition. Is 5.010% by weight, the sixth material is 1.700% by weight, the methyl 5-aminolevulinate hydrochloride is 13.000% by weight, water is 27.000% by weight, the seventh material is 3.800% by weight, 8, the material is characterized in that 0.200% by weight.

As described above, according to the present invention, methyl-aminolevulinate hydrochloride is prepared by reacting 5-aminolevulinic acid hydrochloride with methanol and thionyl chloride, followed by diethyl ether, and then vacuum drying to shorten the synthesis time. Yield can be improved.

In addition, since it is prepared from the ALA derivative having a methyl group it can be seen that the high skin permeability of MAL is effective for skin improvement. In particular, in photodynamic therapy, the present invention is superior to conventional 5-ALA in skin permeability and is effective in acne and skin improvement by the effective production of the photosensitive agent PpIX produced thereby.

Hereinafter, a method for preparing methyl 5-aminolevulinate hydrochloride according to a preferred embodiment of the present invention, an external skin cosmetic composition for improving acne and skin using the same, and a method for preparing the same will be described in detail with reference to the accompanying drawings. .

Methyl 5-aminolevulinate hydrochloride according to an embodiment of the present invention is a manufacturing method of 5-aminolevulinic acid hydrochloride (5-aminolevulinic acid hydrochloride, HCl? H ₂ N-CH _2- Methanol and thionyl chloride are added to CO-CH ₂ -CH ₂ -COOH), followed by stirring for esterification. After confirming the esterification reaction, diethyl ether is added to recrystallize the reactants to remove excess methanol and diethyl ether, and the product is dried in vacuo to prepare methyl 5-aminolevulinate hydrochloride.

The prepared methyl 5-aminolevulinate hydrochloride can be represented by the formula HCl? H ₂ N-CH ₂ -CO-CH ₂ -CH ₂ -COOCH ₃ . Or it may be represented by the following formula.

According to the preparation method of the invention described above, the synthesis time is shortened and a high yield can be obtained as compared with the conventional synthesis method. It is possible to shorten the synthesis time and increase the yield because the reaction proceeds by converting the esterification reaction into a form having a leaving group which is good for nucleophilic attack of alcohol group when inducing esterification reaction by using cationyl chloride as a catalyst during the esterification reaction. Can be.

In the method for preparing the external cosmetic composition for skin of the present invention, methyl 5-aminolevulinate hydrochloride is prepared, and then, any one selected from creams, ointments, and lotions is contained in a base composed of a pharmaceutically acceptable carrier or excipient with water. It is formed into the formulation of.

The methyl 5-aminolevulinate hydrochloride is contained in an amount of 9 to 15% by weight, preferably 11 to 13% by weight based on the total weight of the cosmetic composition. If the content is less than 9% by weight, the scale of PpIX (Protoporphyrin IX) is somewhat insufficient when it is applied to the skin, which is insufficient for the improvement effect, and when the content is added more than 15% by weight, it is used for photodynamic therapy. When done, side effects such as erythema and sunburn can occur.

The base is formed by mixing the first material, the second material, the third material, the fourth material, the fifth material, the sixth material, the seventh material, and the eighth material. The first material is water, allantoin, butylene glycol, glycerin, PEG / PPG-17 / 6 copolymer, and the second material is sodium hyaluronate. hyaiuronate). The first and second substances play a role in wound healing, inflammation relief and sedation, and moisturizing agents.

The third material is PEG-100 stearate, cetostearyl alcohol, stearic acid, stearic acid, glyceryl stearate, PEG-4 olivate, propyl paraben ( Propyl paraben, Methyl paraben, Hydrogenated Camellia Oil, Hydrogenated lanolin, Squalane, Butylene glycol Dicaprylate / Dicaprate Dimethicone, Tocopheryl Acetate. The third material acts as an emulsifier and preservative, stabilizer, softening effect, moisture barrier formation, skin drying and itching and atopic skin improvement, antioxidant, moisturizing.

The fourth substance is polyacrylamide, the fifth substance is natto gum, green tea extract, beta-glucan, and the sixth substance is DMDM hydantoin, water. The seventh substance is triethanolamine, water, and the eighth substance is perfume. The fourth to eighth substances serve to strengthen skin elasticity, inhibit harmful oxygen activity, strengthen immunity, and regulate PH.

The composition ratio of the cosmetic composition of the present invention is 31.490 to 38.96% by weight of the first material, 2.000% by weight of the second material, 14.750% by weight of the third material, 0.680 to 1.050% by weight of the fourth material The fifth material is 5.010% by weight, the sixth material is 1.700% by weight, the methyl 5-aminolevulinate hydrochloride is 9.000 to 15.000% by weight, the water is 22.000 to 27.000% by weight, and the seventh material is 3.700 To 3.800% by weight and the eighth material is 0.200% by weight.

 The cosmetic composition of the present invention has a creamy formulation in which the viscosity is adjusted to 4,000 ± 500 CPS as a base.

Hereinafter, the present invention will be described through examples. However, the following examples are only for illustrating the present invention in detail, and the scope of the present invention is not limited to the following examples.

Example 1

1 g (5.96 mmol) of 5-aminolevulinic acid hydrochloride was added to a flask completely dehydrated at room temperature (25 ° C.), and methanol was stirred for 10 ml (excess) using a pipette. After methanol, 0.4 ml of thionyl chloride was added dropwise. The thionyl chloride was dropped dropwise because of the exotherm when thionyl chloride was added. At this time, the change in temperature was observed and maintained at 0 ° C. After thionyl chloride was added, the temperature was raised to 70 ° C and stirred for 3 hours. After the end of stirring, the progress of esterification was confirmed by H-NMR and TLC. To recrystallize the ester reactant, 25 ml of diethyl ether was added and then added at -20 ° C. for 6 hours or more. After removing the excess methanol and diethyl ether, the product was dried under vacuum at 25 to 30 ° C. to obtain methyl 5-aminolevuli. Nate hydrochloride (hereinafter referred to as m-ALA) was prepared. The structure was confirmed by H-NMR in DMSO, and the result can be confirmed in FIG. 1. (1H-NMR in DMSO; δ8.4 s 2H, NH 2; δ3.9 s 2H, -NCH ₂ ; δ3.6 s 3H, OCH ₃ ; δ2.8 t 2H, OCCH ₂ ; δ2.5 t 2H, CH ₂ CO ₂ )

Example 2

31.490 wt% of the first material was heated to 80 ° C. and stirred at a low speed of 20 rpm for 5 minutes to dissolve and mix the raw materials. And it stirred and mixed at the low speed of 20 rpm for 5 minutes which added 2.000 weight% of 2nd materials.

After mixing the first material and the second material, 14.45% by weight of the third material except for tocopheryl acetate was added to raise the temperature to 75 ° C., and mixed for 5 minutes to emulsify. At this time, the mixture was stirred at a high speed of 2500 rpm initially and a low speed of 20 rpm later. The temperature was maintained at 75 ° C. upon stirring, and 0.300% by weight of tocopheryl acetate was mixed immediately before emulsification.

After mixing the third material, the fourth material was added and then stirred at a high speed of 2000 rpm for 10 minutes. The fifth material, the sixth material, methyl 5-aminolevulinate hydrochloride and water, the seventh material, and the eighth material were sequentially added and mixed at intervals of five minutes while stirring was continued. Mixing of the fifth material, the sixth material, the methyl 5-aminolevulinate hydrochloride and water of Example 1 with the seventh material, and the eighth material was carried out while maintaining 50 ° C for cooling. After the mixture was filtered and aged at 30 ° C. for 24 hours. And finally, a light pale yellow cosmetic composition having a creamy formulation having a viscosity of 4,000 ± 500 CPS was prepared.

The composition and content of the cosmetic composition are summarized in Table 1 below.

division Raw material name ingredient Content (% by weight)
First substance (31.49 wt%)


Water 22.480 Allantoin Allantoin present in conifer bark, rice and wheat germ oil 0.010 1.3-B.G Butylene glycol 4.000 Glycerin glycerin 3.000 KONLUP DR-701C PEG / PPG-17 / 6 copolymer 2.000 Second material (2% by weight) Na Hyaluronate 1% Sodium hyaluronate 2.000





Third substance (14.75 wt%)





Arlacel # 165 PEG-100 Stearate 1,000 FA68 / 50F
(Lanett-o) Cetostearyl alcohol 1.600 Stearic acid Stearic acid 0.500 GMS-105 Glyceryl stearate 1.100 Olivem 700 PEG-4 oleate 2.200 Danisol p Profile paraben 0.050 Danisol M Methyl paraben 0.200 Phytodown HS Hydrogenated Cured Camellia Oil 0.500 Crodalan SWL Hydrogenated lanolin 0.500 Dermofell BGC Butylene Glycol Dicaprylate / Dicaprate 2.000 Squalane Squalene 4.500 Silicone # 200f (100cs) Dimethicone 0.300 V-E Acetate Tocopheryl acetate 0.300 4th substance (1.05 wt%) Sepigel 305 Polyacrylamide 1.050
5th substance (5.01 weight%)
Soypol Extract NATO sword 4.000 Green tea extract Green tea extract 0.010 Yeast beta-glucan Beta Glucan 1,000 6th substance (1.7% by weight)
Glydant-2000 DMDM Hydantoin 0.200 Water 1.500 7th substance (3.8% by weight)
T.E.A Triethanolamine 0.800 Water 3.000 8th substance (0.2 wt%) PF (TUNW410121) Spices 0.200 m-ALA (13% by weight) 13.000 Water (27% by weight) 27.000

<Experimental Example 1>

Compared with the conventional 5-ALA prepared m-ALA prepared in Example 1, the degree of production of PpIX, a photosensitive material, was confirmed in cells.

Normal and abnormal cells were added every 2 to 3 days in a 5% CO ₂ incuvator at 37 ° C with 10% getal bovin serum (FBS) and 1% antibiotics (penicillin / streptomycin) in minimum essential medium (MEM) medium. It was used while subculture.

In addition, 5-ALA and m-ALA was dissolved in phosphate buffer solution (PBS) to make a 5mg / ml stock solution was used. For treatment of 5-ALA, first add MEM medium to the cultured cells, mix well, adjust the cell number to 1.5 × 10 ⁶ cells / well, add 3 ml of each prepared cell to the 6-well microtiter plate, and prepare 5 -ALA and m-ALA was added at a concentration of 0, 50, 10, 200, 400, 800μm / ml and then incubated at 37 ℃, 5% CO ₂ for 24 hours.

Normal and abnormal cells were treated with 5-ALA and m-ALA to detect PpIX generated in and out of cells as follows. First, PpIX accumulated in the cells was treated with 5-ALA and m-ALA for 24 hours, and then cultured for 24 hours, and then, the supernatant of each well was collected and transferred to a tube. . PpIX accumulated in the cells were removed from the medium and washed with PBS two or three times for the remaining cells, and 2 ml of trypsin / EDTA was added to each well and left at 37 ° C. for 1 hour. When the cells were completely broken, 2 ml of a 1: 1 mixture of nethanol and 0.9 M perchloric acid was added. The solution was collected and centrifuged at 2000 rpm for 10 minutes to obtain a supernatant.

Analysis of PpIX-generated fluorescence intensity in and out of cells produced by 5-ALA and m-ALA measured in the fluorometer was shown in Figures 2 to 5 using Mathematica 5program.

FIG. 2 is a graph showing the degree of accumulation of PpIX depending on the concentration of m-ALA in the normal and abnormal cells (HepG2). The degree of PpIX production according to the concentration of 5-ALA in abnormal cells (HepG2) is a graph showing the degree of accumulation outside and inside the cell.

Referring to Figures 2 and 3, the production of PpIX in both m-ALA and 5-ALA accumulated more in the cell than in the extracellular.

4 is a graph showing the degree of accumulation of PpIX depending on the concentration of 5-ALA and m-ALA in the normal cells (extracellular and intracellular), and FIG. 5 is 5 in abnormal cells (HepG2). The degree of PpIX production according to the concentration of -ALA and m-ALA is a graph showing the degree of accumulation outside and inside the cell.

4 and 5, it was shown that m-ALA produced more PpIX in cells than 5-ALA in both normal and abnormal cells. This is because 5-ALA is a hydrophilic substance and has a problem of efficiency in penetrating through cell membranes, whereas m-ALA is likely to be more easily infiltrated into cell membranes due to increased lipophilic properties.

In view of the above results, it was confirmed that the use of m-ALA rather than the conventional 5-ALA increases the absorption of the skin and effectively accumulate the photosensitizers on the skin surface and sebaceous glands. Therefore, m-ALA is expected to have a better effect on acne and skin improvement than 5-ALA. It is also expected to have effects such as skin protection and alleviation of inflammation caused by various ingredients in the base.

<Experimental Example 2>

P. acnes, an acne bacterium, was cultured in BBLTMAcinomyBroth (BD, MD, USA) culture medium, followed by centrifugation of the cultured P. acnes bacteria, and then the culture solution was removed. The precipitate was extracted using a solution of 1M HCl dissolved in a methanol-water mixture having a volume of 1: 1 and left for a certain time, and then the solution was centrifuged again to prepare a solution for a sample of the solution layer. Ultraviolet absorption spectrum and fluorescence spectrum were measured using the prepared sample and are shown in FIG. 6.

In FIG. 6, A is a graph showing an excitation index at 400 to 405 nm, and B is a graph showing an excitation index at 405 to 420 nm. Referring to Figure 6, it can be seen that the most effective expression in the range of 400 to 420nm.

<Experimental Example 3>

P.acne bacteria cultured in the third experimental example was irradiated with light having a wavelength of 420 nm and the degree of destruction of P. acne bacteria was shown in the photographs of FIGS. 8 and 9.

Figure 7 is a photograph of the control without irradiating light, Figure 8 is a photograph irradiated with light of 1.2J / cm ² intensity, Figure 9 is 2.5J / cm ² This photo shows the light of the century.

7 to 9, the number of strains in FIG. 7 is 8 × 10 ⁹ CFU / ml, FIG. 8 is 3.69 × 10 ⁹ CFU / ml, and FIG. 9 is 2.55 × 10 ⁹ CFU / ml. From this, when the light of 420nm wavelength irradiation of acne bacteria can be seen that there is a significant difference compared to the control group. Therefore, when the cosmetic composition of the present invention is applied to the skin after irradiation with light having a wavelength of 400 to 420nm it is expected that the effect can be further increased.

In the above, the present invention has been described with reference to one embodiment, which is merely exemplary, and it will be understood by those skilled in the art that various modifications and equivalent embodiments are possible.

Therefore, the true scope of protection of the present invention should be defined only by the appended claims.

1 is a graph showing the result of H-NMR confirming the methyl 5-aminolevulinate hydrochloride prepared in Example 1,

FIG. 2 is a graph showing the degree of accumulation of PpIX depending on the concentration of m-ALA in the normal cells (Chang) and abnormal cells (HepG2).

3 is a graph showing the degree of accumulation of PpIX with the concentration of 5-ALA in the normal and abnormal cells (HepG2) outside and inside the cells.

Figure 4 is a graph showing the degree of accumulation of the outside of the cell and the degree of PpIX production in accordance with the concentration of 5-ALA and m-ALA in normal cells (Chang),

5 is a graph showing the degree of accumulation of PpIX in the abnormal cells (HepG2) according to the concentrations of 5-ALA and m-ALA, outside the cells and inside the cells,

6 is a graph showing the excitation index when the light is irradiated to the acne bacteria,

7 is a photograph showing a control group not irradiated with light on acne bacteria,

8 is a photograph irradiated with light of 1.2J / cm ² century,

9 is ^2.5 J / cm ² This photo shows the light of the century.

Claims (7)

Methyl 5-aminolevulinate hydrochloride represented by the following Chemical Formula 1 was prepared by reacting 5-aminolevulinic acid hydrochloride with methanol and thionyl chloride, and then adding diethyl ether followed by vacuum drying. Method for producing methyl 5-aminolevulinate hydrochloride, characterized in that.

delete delete delete It contains methyl 5-aminolevulinate hydrochloride prepared by the method of claim 1 as an active ingredient, The methyl 5-aminolevulinate hydrochloride is contained in a base consisting of a carrier or an excipient together with water to form a formulation selected from cream, ointment, and lotion, The base is formed by mixing the first material, second material, third material, fourth material, fifth material, sixth material, seventh material, and eighth material, The first substance is water, allantoin, butylene glycol, glycerin, PEG / PPG-17 / 6 copolymer, The second material is sodium hyaiuronate, The third substance is PEG-100 stearate, cetostearyl alcohol, stearic acid, stearic acid, glyceryl stearate, PEG-4 olivate, propyl paraben ( Propyl paraben, Methyl paraben, Hydrogenated Camellia Oil, Hydrogenated lanolin, Squalane, Butylene glycol Dicaprylate / Dicaprate , Dimethicone, Tocopheryl Acetate, The fourth material is polyacrylamide, The fifth substance is natto gum, green tea extract, beta glucan (β-glucan), The sixth substance is DMDM Hydantoin, water, The seventh substance is triethanolamine, water, The eighth substance is a fragrance cosmetic composition for improving skin and acne, characterized in that the fragrance. Methyl 5-aminolevulinate hydrochloride represented by the following Chemical Formula 2 is obtained by reacting 5-aminolevulinic acid hydrochloride with methanol and thionyl chloride, and then adding diethyl ether followed by vacuum drying. A first step of doing;

A second step of heating and mixing a first material made of water, allantoin, butylene glycol, glycerin, and PEG / PPG-17 / 6 copolymer to 80 ° C .; A third step of adding and mixing a second substance of sodium hyaiuronate to the mixture of the second step; PEG-100 Stearate, Cetostearyl Alcohol, Stearic Acid, Glyceryl Stearate, PEG-4 Olivate, Propyl paraben, Methyl Paraben (Methyl paraben), Hydrogenated Camellia Oil, Hydrogenated lanolin, Squalane, Butylene glycol Dicaprylate / Dicaprate, Dimethicone ), A fourth step of adding a third material consisting of Tocopheryl Acetate to the mixture of the third step and then mixed at 75 ℃ emulsifying; Adding a fourth material of polyacrylamide to the mixture of the fourth step and then mixing at 50 ° C .; A fifth substance consisting of natto gum, green tea extract and beta-glucan, and a sixth substance consisting of DMDM hydantoin and water were sequentially added to the mixture of the fifth step at 5 minute intervals. A sixth step of mixing at 50 ° C. while adding; A seventh step of adding the methyl 5-aminolevulinate hydrochloride and water to the mixture of the sixth step and mixing at 50 ° C; An eighth step of adding triethanolamine, a seventh substance made of water, and an eighth substance, which is a fragrance, at 50 ° C. while sequentially adding the eighth substance, which is a fragrance, at a 5-minute interval; And a ninth step of aging at 50 ° C. after filtering the mixture of the eighth step; and comprising a creamy formulation, wherein the external cosmetic composition for acne and skin improvement is formed. The method of claim 6, wherein the first material is 31.490% by weight, the second material is 2.000% by weight, the third material is 14.750% by weight, and the fourth material is 1.050% by weight based on the total weight of the cosmetic composition. Wherein the fifth material is 5.010% by weight, the sixth material is 1.700% by weight, the methyl 5-aminolevulinate hydrochloride is 13.000% by weight, the water is 27.000% by weight, and the seventh material is 3.800 Wt%, wherein the eighth substance is 0.200 wt%, the method for preparing an external cosmetic composition for skin for acne and skin improvement.

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