Compositions for improving bioavailability of rare ginsenosides, methods of making and uses thereof

Abstract

The application belongs to the technical field of daily chemical products, and discloses a composition for improving bioavailability of rare ginsenosides, a preparation method and application. The composition comprises components: yeast / rice fermentation product filtrate, ethoxydiglycol, phospholipid and allantoin. The composition of the application is prepared by compounding yeast / rice fermentation product filtrate, ethoxydiglycol, phospholipid and allantoin, and through the multi-dimensional joint action of water combination, similar-soluble effect and structural change, the transdermal penetration rate of rare ginsenosides is significantly improved, and the utilization efficiency of the organism to rare ginsenosides is enhanced.

Description

Technical Field

[0001] This invention belongs to the field of daily chemical products technology, and specifically relates to a composition, preparation method and application for improving the bioavailability of rare ginsenosides. Background Technology

[0002] Ginsenosides are the medicinal material basis of ginseng, and more than 100 kinds of ginsenosides have been identified in ginseng. The main proto-ginsenosides include: Ra, Rb1, Rb2, Rb3, Rc, Rd, Re, Rf, Rg1, etc. Rare ginsenosides include: Rh2, Rg3, aPPD, Rk2, Rh3, aPPT, Rk1, Rg5, Rk3, Rh1, Rh3, Rh4, etc. Rare ginsenosides are secondary derivatives of ginsenosides; their content in natural plants is extremely low, less than one ten-thousandth, making them extremely precious.

[0003] Currently, although rare ginsenosides exist in various dosage forms, their molecular structure makes them difficult to absorb transdermally, resulting in low bioavailability. Therefore, research on their topical formulations has become a hot topic both domestically and internationally. The stratum corneum is the main barrier affecting the penetration of rare ginsenosides into the skin. It is composed of keratin-rich keratinocytes and intercellular lipids, with the lipids primarily consisting of a certain proportion of ceramides, cholesterol, and free fatty acids. The functional groups contained in lipids and proteins in the stratum corneum can generate new intermolecular interactions with active ingredient molecules or formulation excipients during transdermal penetration, thus affecting the penetration of the active ingredient. The skin barrier is a major factor limiting the therapeutic efficacy of transdermal ginsenoside administration formulations.

[0004] Therefore, how to improve the bioavailability of rare ginsenosides is a technical problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention proposes a composition, preparation method and application for improving the bioavailability of rare ginsenosides. This composition integrates hydration mechanism, like-soluble mechanism and structural change mechanism, with multiple dimensions working together to improve the transdermal penetration rate of rare ginsenosides and improve their bioavailability.

[0006] The main mechanisms that promote the transdermal penetration of active ingredients are as follows:

[0007] Hydration mechanism: When the hydration capacity of nitrogenous substances in keratinocytes is enhanced, the keratinocytes absorb water and swell. The originally densely packed cells change in density, increasing the gaps between cells, which helps to improve the permeability of water-soluble and polar active substances.

[0008] The "like dissolves like" mechanism mainly utilizes ester solvents similar to those in the skin to improve the transdermal absorption efficiency of active ingredients. However, since the active layer below the stratum corneum is a water-soluble channel, if the active ingredient can only dissolve in oil, it will not be conducive to the further delivery of the active ingredient to the basal layer. Therefore, this principle requires that the water-oil partition coefficient of the active ingredient be within a certain range in order to penetrate into the deep epidermis.

[0009] Structural change mechanism: This mainly utilizes the ability of penetration-enhancing ingredients to alter the orderly arrangement of lipids in the stratum corneum, allowing the lipids to fluidize and thus increasing the penetration rate of active ingredients. Commonly used chemical penetration enhancers, such as azone and surfactants, mostly utilize structural change mechanisms to improve the penetration of active ingredients, but the penetration effect needs further improvement and they also have a certain degree of irritation.

[0010] This invention combines yeast / rice fermentation product filtrate, ethoxydiethylene glycol, phospholipids, and allantoin, integrating hydration, like-solubility, and structural change mechanisms to enhance the transdermal permeability and bioavailability of rare ginsenosides. Specifically, the yeast / rice fermentation product filtrate is rich in amino acids and small peptides, which, when combined with allantoin, are nitrogen-containing substances. Hydration increases the intercellular spaces, thus improving permeability. The yeast / rice fermentation product filtrate also contains lipopolysaccharides, which, combined with phospholipids, enhance the dissolution of rare ginsenosides in the sebum, further enhancing the like-solubility effect. Ethoxydiethylene glycol can be used as a chemical penetration enhancer, working in conjunction with the small acid molecules in the yeast / rice fermentation product filtrate to better exert the structural change effect.

[0011] A first aspect of the present invention provides a composition comprising the components: yeast / rice fermentation product filtrate, ethoxydiethylene glycol, phospholipids, and allantoin.

[0012] In some embodiments of the present invention, the composition comprises the following components in weight percentages: 10-80% yeast / rice fermentation product filtrate, 10-50% ethoxydiethylene glycol, 0.05-5% phospholipids, and 0.05-5% allantoin. Further, the composition comprises the following components in weight percentages: 40-80% yeast / rice fermentation product filtrate, 15-40% ethoxydiethylene glycol, 0.5-2.5% phospholipids, and 0.1-2% allantoin. Even further, the composition comprises the following components in weight percentages: 62-67% yeast / rice fermentation product filtrate, 30-35% ethoxydiethylene glycol, 1.5-2.5% phospholipids, and 0.5-1.5% allantoin.

[0013] In some embodiments of the present invention, the phospholipids include soybean lecithin and / or lecithin.

[0014] A second aspect of the present invention provides a method for preparing the composition of the present invention, comprising the following steps:

[0015] The ethoxydiethylene glycol, the phospholipid, the allantoin, and the yeast / rice fermentation product filtrate are mixed and stirred to dissolve, thus obtaining the composition.

[0016] In some embodiments of the present invention, the preparation method of the composition of the present invention specifically includes the following steps:

[0017] The ethoxydiethylene glycol, the phospholipid, and the allantoin are mixed and dissolved by stirring at 60-90°C and 50-200 rpm to obtain a mixture.

[0018] The mixture is added to the yeast / rice fermentation product filtrate and stirred evenly at 60-90℃ and 50-200rpm to obtain the composition.

[0019] A third aspect of the present invention provides a composition for promoting the transdermal absorption of rare ginsenosides, including the composition described in the present invention.

[0020] A fourth aspect of the present invention provides a composition having anti-aging and anti-inflammatory properties, comprising rare ginsenosides and the composition described herein.

[0021] In some embodiments of the present invention, the rare ginsenosides include at least one of ginsenoside CK, ginsenoside C-Mx, and ginsenoside F2.

[0022] In some embodiments of the present invention, the rare ginsenosides are added in an amount of 1-10 wt% of the composition having anti-aging and anti-inflammatory effects. Further, the rare ginsenosides are added in an amount of 1-5 wt% of the composition having anti-aging and anti-inflammatory effects. Even further, the rare ginsenosides are added in an amount of 1-3 wt% of the composition having anti-aging and anti-inflammatory effects.

[0023] A fifth aspect of the present invention provides a cosmetic product comprising the anti-aging and anti-inflammatory composition described herein.

[0024] In some embodiments of the present invention, the amount of the anti-aging and anti-inflammatory composition added to the cosmetic is 0.01-10 wt%. Further, the amount of the anti-aging and anti-inflammatory composition added to the cosmetic is 0.1-10 wt%. Even further, the amount of the anti-aging and anti-inflammatory composition added to the cosmetic is 1-5 wt%.

[0025] In some embodiments of the present invention, the cosmetic also includes cosmetic-acceptable excipients.

[0026] In some embodiments of the present invention, the excipients include at least one of humectants, emulsifiers, thickeners, emollients, and preservatives.

[0027] In some embodiments of the present invention, the dosage form of the cosmetic includes one of the following: aqueous solution, emulsion, spray, cream, serum, or mask.

[0028] In some embodiments of the present invention, the cosmetic is a serum or lotion.

[0029] In some embodiments of the present invention, the essence comprises the following components: the anti-aging and anti-inflammatory composition of the present invention, glycerin, 1,3-butanediol, disodium EDTA, carbomer, β-glucan, 1,2-hexanediol, p-hydroxyacetophenone, and water.

[0030] In some embodiments of the present invention, the emulsion comprises the following components: the anti-aging and anti-inflammatory composition of the present invention, 1,3-butanediol, isononyl isononanoate, C12-20 alkyl glucoside, polydimethylsiloxane, cyclopentamethoxysiloxane, propylene glycol, 1,2-hexanediol, sodium polyacrylamide dimethyl taurate, p-hydroxyacetophenone, xanthan gum, and water.

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0032] The composition of this invention combines yeast / rice fermentation product filtrate, ethoxydiethylene glycol, phospholipids, and allantoin. Through the combined effects of hydration, like dissolves like, and structural changes, it significantly improves the transdermal permeability of rare ginsenosides and enhances the utilization efficiency of rare ginsenosides by organisms. Detailed Implementation

[0033] To enable those skilled in the art to more clearly understand the technical solutions described in this invention, the following embodiments are provided for illustration. It should be noted that the following embodiments do not constitute a limitation on the scope of protection claimed by this invention.

[0034] Unless otherwise specified, the raw materials, reagents or devices used in the following examples are available from conventional commercial sources or can be obtained by existing known methods.

[0035] Example 1

[0036] This embodiment provides a composition comprising the following components by weight percentage: 67% yeast / rice fermentation product filtrate, 30% ethoxydiethylene glycol, 2% soybean lecithin, and 1% allantoin.

[0037] The preparation method of the composition in this embodiment is as follows: Ethoxydiethylene glycol, soybean lecithin and allantoin are mixed and stirred at 70°C and 120 rpm to dissolve them, and then the mixture is added to the yeast / rice fermentation product filtrate and stirred evenly at 70°C and 120 rpm to obtain the composition.

[0038] Example 2

[0039] This embodiment provides a composition comprising the following components in weight percentages: 62% yeast / rice fermentation product filtrate, 35% ethoxydiethylene glycol, 1.5% soybean lecithin, and 1.5% allantoin.

[0040] The preparation method of the composition in this embodiment is as follows: Ethoxydiethylene glycol, soybean lecithin and allantoin are mixed and stirred at 70°C and 120 rpm to dissolve them, and then the mixture is added to the yeast / rice fermentation product filtrate and stirred evenly at 70°C and 120 rpm to obtain the composition.

[0041] Example 3

[0042] This embodiment provides a composition comprising the following components in weight percentage: 64% yeast / rice fermentation product filtrate, 33% ethoxydiethylene glycol, 2.5% soybean lecithin, and 0.5% allantoin.

[0043] The preparation method of the composition in this embodiment is as follows: Ethoxydiethylene glycol, soybean lecithin and allantoin are mixed and stirred at 70°C and 120 rpm to dissolve them, and then the mixture is added to the yeast / rice fermentation product filtrate and stirred evenly at 70°C and 120 rpm to obtain the composition.

[0044] Comparative Example 1

[0045] The composition provided in Comparative Example 1 differs from that in Example 1 in that ethoxydiethylene glycol is replaced with butanediol, while the other components, amounts, and preparation methods are the same as in Example 1.

[0046] Comparative Example 2

[0047] The composition provided in Comparative Example 2 differs from that in Example 1 in that soybean lecithin is replaced with β-cyclodextrin, while the other components, amounts, and preparation methods are the same as in Example 1.

[0048] Comparative Example 3

[0049] The composition provided in Comparative Example 3 differs from that in Example 1 in that allantoin is replaced with glucose, while the other components, amounts, and preparation methods are the same as in Example 1.

[0050] Comparative Example 4

[0051] The composition provided in Comparative Example 4 differs from that in Example 1 in that the yeast / rice fermentation product filtrate is replaced with deionized water, while the other components, amounts, and preparation methods are the same as in Example 1.

[0052] Comparative Example 5

[0053] The composition provided in Comparative Example 5 is a mixture of 5 wt% azone, 45 wt% glycerol and 50 wt% water.

[0054] Experimental Example 1: Evaluation of Red Blood Cell Hemolytic Activity

[0055] This test example uses the compositions of Examples 1-3 and the compositions of Comparative Examples 1-5 as samples to evaluate erythrocyte hemolysis. The basic principle of the erythrocyte hemolysis test is to evaluate the damage of chemicals to ocular tissue cells by measuring the amount of hemoglobin dissolved and the degree of denaturation. HD50 is the sample concentration at which 50% of erythrocytes undergo hemolysis, DI is the protein denaturation index, and L / D is the ratio of HD50 to DI. The evaluation criteria are shown in Table 1, and the evaluation results are shown in Table 2.

[0056] Table 1

[0057] L / D Classification L / D>100 Non-irritating 10<L / D≤100 Mild irritation 1<L / D≤10 Mild irritation 0.1<L / D≤1 Poisoning Irritant L / D≤0.1 Severe irritation

[0058] Table 2

[0059] sample Classification sample Classification Example 1 Non-irritating Comparative Example 2 Non-irritating Example 2 Non-irritating Comparative Example 3 Non-irritating Example 3 Non-irritating Comparative Example 4 Non-irritating Comparative Example 1 Non-irritating Comparative Example 5 Mild irritation

[0060] As shown in Table 2, except for Comparative Example 5 which is slightly irritating, the compositions of Examples 1-3 and Comparative Examples 1-4 are all non-irritating, indicating that these compositions use relatively mild components.

[0061] Application Example 1 and Application Comparative Examples 1-5

[0062] Take the ginsenoside CK, the composition of Example 1 and Comparative Examples 1-5, and prepare them according to Table 3 to obtain Application Example 1 containing ginsenoside CK and each composition, and Application Comparative Examples 1-5.

[0063] Table 3

[0064]

[0065] Application Example 2 and Application Comparative Examples 6-10

[0066] Take the composition of ginsenoside C-Mx, Example 1 and Comparative Examples 1-5, and prepare it according to Table 4 to obtain Application Example 2 containing ginsenoside C-Mx and each composition, and Application Comparative Examples 6-10.

[0067] Table 4

[0068]

[0069]

[0070] Application Example 3 and Application Comparative Examples 11-15

[0071] Take ginsenoside F2, the composition of Example 1 and Comparative Examples 1-5, and prepare them according to Table 5 to obtain Application Example 3 containing ginsenoside F2 and each composition, and Application Comparative Examples 11-15.

[0072] Table 5

[0073]

[0074]

[0075] Experimental Example 2: Permeability Test

[0076] This test example uses the compositions from Application Examples 1-3 and the compositions from Comparative Examples 1-15 as samples, and conducts experiments using a Franz vertical dual-chamber permeation diffusion cell. The effective permeation area is 1.77 cm². 2 The receiving chamber has a volume of 12 mL, and 30% ethanol PBS (v / v) buffer solution is used as the receiving solution.

[0077] The prepared isolated pig skin was placed between the two halves of the diffusion and receiving chambers of a Franz vertical diffusion cell and secured with clamps. With the stratum corneum facing upwards, 0.1 g of each sample was weighed and placed in the diffusion chamber. The receiving chamber was filled with receiving solution until the liquid surface just touched the skin. Air bubbles in the receiving medium were removed, and the chamber was heated in a constant-temperature water bath at (32±0.5)℃. A magnetic stirrer was turned on and stirred at 300 rpm. 0.9 mL of receiving solution was collected at 2, 4, 6, 8, and 12 hours. After each sampling, 0.9 mL of blank receiving solution at the same temperature was immediately added. The concentration of the analyte in the receiving solution at different time points was determined using the HLPC-DAD method. The data were processed according to the following formula to calculate the cumulative permeation (μg).

[0078] The formula for calculating cumulative permeability Q is: Q=[Cn×V+∑Ci×V0] / S (i=1···n-1);

[0079] Q: Cumulative permeation volume; V: Volume of receiving liquid in the receiving chamber; V0: Volume of each sample taken; Ci: Drug concentration in the receiving liquid from the first to the last sample taken; Cn: Sample concentration measured at the nth sampling point.

[0080] The test results are shown in Table 6.

[0081] Table 6

[0082]

[0083]

[0084]

[0085] The results in Table 6 show that, compared with Comparative Examples 1-15, the ginsenosides CK, C-Mx, and F2 in Application Examples 1-3 have higher cumulative permeation, indicating that the composition of the present invention can improve the transdermal absorption of the three rare ginsenosides.

[0086] Experimental Example 3: Assay of Human Type I Collagen and Matrix Metalloproteinases

[0087] This test example uses the compositions from Application Examples 1-3 and the compositions from Comparative Examples 1-15 as samples. Human skin fibroblasts (HDF) were cultured in 6-well plates at a rate of 2 × 10⁶ cells per well. 4 The cells were cultured at a density of 1% at 37°C with 5% CO2 for 24 hours. HDF was treated with the sample (1%) for 24 hours, then washed twice with PBS and cultured at 30 J / cm². 2 The sample was irradiated with UVB. Then, the PBS was removed, and the sample (1%) was incubated with HDF at 37°C with 5% CO2 for 24 hours. After incubation, the levels of human type I collagen (COL-I) and matrix metalloproteinase-1 (MMP-1) were determined according to the ELISA kit instructions.

[0088] Total RNA extract purification was performed according to the kit procedure. RNA concentration and purity (2 μL) were measured by the absorbance ratio at 260 / 280 nm, and the remaining RNA solution was stored at -80°C for reverse transcription. Total RNA was converted to first-strand complementary DNA (cDNA) using the following reverse transcription system: 4 μL 5x Prime Script RT Master MIX, 0.5 μg total RNA, and 20 μL RNase-free water for the reaction. cDNA was used for real-time PCR, and the reaction system contained 10 μL SYBR Premix EX Taq (2x), 1 μL forward primer (10 μM), 1 μL reverse primer (10 μM) (Table 7), and 8 μL cDNA, which was amplified in an AppliedBiosystems 7500 Fast Real-time PCR System v2.3 under the following conditions: 50.0°C for 3 min, 95.0°C for 5 min, followed by 40 cycles of 95.0°C for 10 s and 60.0°C for 30 s. The threshold cycle (Ct) was analyzed using instrument software, and the comparison of Ct methods (2) was performed. -ΔΔCtThe fold change in mRNA expression was calculated. The test results are shown in Table 8.

[0089] Table 7

[0090]

[0091] Table 8

[0092]

[0093] Table 8 shows that, compared to Comparative Examples 1-15, the compositions containing ginsenoside CK, ginsenoside C-Mx, and ginsenoside F2 provided in Examples 1-3 not only better increased the COL-I content in HDF but also reduced the MMP-1 content. Furthermore, the compositions containing rare ginsenosides provided in Examples 1-3 also increased the relative expression level of COL-I mRNA and decreased the relative expression level of MMP-1 mRNA in HDF. The increase in MMP-1 and the decrease in COL-I can cause skin aging and wrinkles, indicating that the rare ginsenosides in Examples 1-3 can exert a stronger anti-aging effect.

[0094] Experimental Example 4: Effects of UVB irradiation on the levels of IL-1β, IL-6, and TNF-α in HaCaT cells

[0095] This test example uses the compositions of Application Examples 1-3 and the compositions of Comparative Examples 1-15 as samples. Human epidermal keratinocytes were seeded into 6-well plates and incubated overnight at 37°C and 5% CO2. When the cell deposition rate in the 6-well plates reached 50%-60%, cell culture medium was added to the blank group without any other treatment; cell culture medium was added to the model group; and cell culture medium containing 1% (w / w) of the sample was added to the test sample group. After pretreatment for 1 hour, each group was irradiated with UVB (medium-wave ultraviolet light) for 40 minutes at a radiation intensity of 30 mJ / cm². 2 After treatment, the samples were incubated at 37℃ and 5% CO2 for another 24 hours. After incubation, the levels of IL-1β, IL-6, and TNF-α were determined according to the operating procedures of the Human IL-1β ELISA Kit (Beyotime), Human IL-6 ELISA Kit (Beyotime), and Human TNF-α ELISA Kit (Beyotime). The test results are shown in Table 9.

[0096] Table 9

[0097]

[0098]

[0099] Table 9 shows that, compared to Comparative Examples 1-15, the compositions provided in Examples 1-3, containing ginsenoside CK, ginsenoside C-Mx, and ginsenoside F2 respectively, were more effective in reducing the levels of inflammatory factors IL-1β, IL-6, and TNF-α produced by HaCaT cells after UVB irradiation. By applying the compositions of Examples 1-3, the three rare ginsenosides exhibited more prominent anti-inflammatory and soothing activities, and have the potential to improve aging caused by inflammatory factors.

[0100] Application Example 1

[0101] This application example provides an essence containing the composition of Application Example 1 above, the specific formula of which is shown in Table 10.

[0102] Table 10

[0103]

[0104]

[0105] Experiment 5: Evaluation of the Firming Efficacy of the Serum

[0106] Thirty volunteers, aged 20-45 years, with an equal number of men and women, were selected for the efficacy evaluation. The left side used the serum prepared in Application Example 1, while the right side used the serum prepared in the control group. The only difference between the control group and Application Example 1 was that the composition of Application Example 1 was replaced with the composition of Comparative Example 15.

[0107] Use the product three times a day, morning, noon, and evening. Apply 1g of the sample to the face each time and massage for 2 minutes. Complete the trial evaluation form based on sensory feedback. Data is collected at 7, 14, and 28 days of use. Volunteers evaluated the product's effects on skin elasticity (0-5 points) and firmness (0-5 points) during use, with a maximum score of 5 indicating significant effect and a minimum score of 0 indicating no effect. Test results are shown in Table 11, and the average score is used for statistical analysis.

[0108] Table 11

[0109]

[0110] The results in Table 11 show that volunteers believed that using the serum prepared in Application Example 1 significantly improved their skin elasticity and firmness, compared to using the serum prepared in the control group.

[0111] Application Example 2

[0112] This application example provides an emulsion containing the composition of Application Example 1 above, the specific formulation of which is shown in Table 12.

[0113] Table 12

[0114] Element Quality fraction (%) Deionized water margin 1,3-Butanediol 6.00 Application Example 1 3.00 Isononyl isononanoate 2.50 C12-20 alkyl glucoside 1.50 polydimethylsiloxane 1.50 Cyclopentadimethylsiloxane 1.00 Propylene glycol 1.00 1,2-Hexanediol 1.00 Sodium polyacrylamide dimethyl taurate 0.50 p-Hydroxyacetophenone 0.50 Xanthan Gum 0.12

[0115] Experimental Example 6: Evaluation of the Efficacy of Emulsion in Reducing Wrinkles

[0116] Thirty female volunteers aged 30-45 years were selected for the efficacy evaluation. The test samples included the lotion from Application Example 2, and a control lotion using the composition from Comparative Example 15 (comparative example 15) instead of the composition from Application Example 1. Before testing, photos were taken using a VISIA facial image analyzer to analyze the fine lines around the volunteers' eyes. After cleansing, volunteers used the corresponding group of samples, and photos were taken and analyzed again after 5 minutes to represent the immediate wrinkle-reducing effect of the product. Volunteers then used the test samples twice daily, 0.5g each time, for 28 consecutive days. Follow-up visits were conducted on days 7 and 28, with facial photos taken and analyzed to represent the long-term wrinkle-reducing effect of the sample. The same personnel performed the tests on the same volunteer. The rate of change in fine lines around the eyes was calculated using the built-in analysis system of the instrument, and the statistical results are shown in Table 13.

[0117] Table 13

[0118]

[0119]

[0120] The results in Table 13 indicate that volunteers reported significant improvement in fine lines around the eyes after using the lotion prepared in Application Example 2, with better results than the lotion prepared in the control group at different time points.

[0121] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the embodiments described. Those skilled in the art can make various equivalent modifications or substitutions without departing from the spirit of the present invention, and these equivalent modifications or substitutions are all included within the scope defined by the claims of this application.

Claims

1. A composition for improving the bioavailability of rare ginsenosides, characterized in that, The composition comprises the following components in weight percentage: 10-80% yeast / rice fermentation product filtrate, 10-50% ethoxydiethylene glycol, 0.05-5% phospholipids, and 0.05-5% allantoin.

2. The composition for improving the bioavailability of rare ginsenosides according to claim 1, characterized in that, The phospholipids include soybean lecithin and / or lecithin.

3. The method for preparing the composition for improving the bioavailability of rare ginsenosides according to claim 1 or 2, characterized in that, Includes the following steps: The ethoxydiethylene glycol, the phospholipid, the allantoin, and the yeast / rice fermentation product filtrate are mixed and stirred to dissolve, thus obtaining the composition.

4. The method for preparing the composition for improving the bioavailability of rare ginsenosides according to claim 3, characterized in that, The ethoxydiethylene glycol, the phospholipid, and the allantoin are mixed and dissolved by stirring at 60-90°C and 50-200 rpm to obtain a mixture. The mixture is added to the yeast / rice fermentation product filtrate and stirred evenly at 60-90℃ and 50-200rpm to obtain the composition.

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