Supramolecular tranexamic acid glycolic acid ion salt and its preparation method and application

Abstract

The present application provides a supramolecular tranexamic acid glycolic acid ion salt and its preparation method and application, which belongs to the technical field of cosmetic compounds. The supramolecular tranexamic acid glycolic acid ion salt has a structural formula as shown in Formula I. Transamic acid and glycolic acid are reacted to form a supramolecular salt. While maintaining the efficacy of tranexamic acid, the skin permeability of tranexamic acid can be effectively improved, and the irritation to the skin is low.

Description

Technical Field

[0001] The present application relates to the technical field of cosmetic compounds, and in particular to a supramolecular tranexamic acid glycolate ion salt and a preparation method and application thereof. Background Art

[0002] Tranexamic acid (TA), also known as tranexamic acid, is a commonly used whitening agent in cosmetics. It has a fading effect on freckles, age spots, and chloasma. It achieves the effect of removing spots and whitening skin mainly by inhibiting prostaglandins (PGE2) to prevent the formation of melanin, inhibiting tyrosinase and melanocyte activity to restore the formed melanin, preventing melanin aggregation, and blocking the diffusion pathway.

[0003] Transdermal administration is a common and direct way to solve the problem of skin pigmentation. However, conventional topical preparations of tranexamic acid are difficult to penetrate the stratum corneum, have low bioavailability, and have certain irritation, which limits their application. Therefore, it is necessary to develop a supramolecular tranexamic acid with high bioavailability and low irritation to solve the existing drawbacks of tranexamic acid. Summary of the invention

[0004] The purpose of the present application is to provide a supramolecular tranexamic acid glycolic acid ion salt and its preparation method and application, which can effectively improve the skin permeability of glycolic acid while better maintaining the efficacy of glycolic acid and has low irritation to the skin.

[0005] The embodiment of the present application is implemented as follows:

[0006] In a first aspect, the present application provides a supramolecular tranexamic acid glycolate ion salt having a structural formula as shown in Formula I;

[0007]

[0008] In a second aspect, an embodiment of the present application provides a method for preparing a supramolecular tranexamic acid glycolate ion salt as provided in the embodiment of the first aspect, which comprises reacting tranexamic acid and glycolic acid to obtain a supramolecular tranexamic acid glycolate ion salt as shown in Formula I.

[0009] In a third aspect, an embodiment of the present application provides a use of a supramolecular tranexamic acid glycolate ion salt as provided in an embodiment of the first aspect as a raw material in the preparation of cosmetics.

[0010] The supramolecular tranexamic acid glycolate ion salt provided in the embodiments of the present application and its preparation method and application have the following beneficial effects:

[0011] In the present application, tranexamic acid and glycolic acid are used as precursors, and a supramolecular tranexamic acid glycolic acid ion salt as shown in Formula I is obtained through an ionization salt-forming reaction. The supramolecular tranexamic acid glycolic acid ion salt can better maintain the efficacy of tranexamic acid; at the same time, it can effectively improve the skin permeability of glycolic acid and improve the bioavailability of tranexamic acid; moreover, it has low irritation to the skin, thereby enhancing the application effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0013] Figure 1 It is a schematic flow chart of a method for preparing a supramolecular tranexamic acid glycolate ion salt provided by an embodiment of the present invention;

[0014] Figure 2 is the thermogravimetric analysis curve of the supramolecular tranexamic acid glycolic acid ion salt, tranexamic acid monomer, and glycolic acid monomer in Example 1;

[0015] Figure 3 is the hydrogen NMR spectrum of the supramolecular tranexamic acid glycolate ion salt in Example 1;

[0016] Figure 4 is a schematic diagram of the molecular structure of the supramolecular tranexamic acid glycolate ion salt in Example 1;

[0017] Figure 5 is a statistical chart of the penetration efficiency of test example 1;

[0018] Figure 6 is a graph of cell viability of melanoma cells (B16) in Test Example 4;

[0019] Figure 7 is a graph showing the inhibitory effect of Test Example 4 on melanin synthesis in melanocytes;

[0020] Figure 8 is a graph showing the inhibitory effect of Test Example 4 on melanocyte tyrosinase activity;

[0021] Fig. 9 is the effect diagram of Test Example 4 on tyrosinase activity;

[0022] Fig.10 is a graph of macrophage viability of Test Example 5;

[0023] Fig.11 is a graph showing the change trend of IL-6 content in Test Example 5;

[0024] Fig.12 This is a trend chart of the change in TNF-α content in Test Example 5. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments of the present application will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0026] It should be noted that “and / or” in this application, such as “Feature 1 and / or Feature 2”, refers to the three situations of “Feature 1” alone, “Feature 2” alone, or “Feature 1” plus “Feature 2”.

[0027] In addition, in the description of the present application, unless otherwise specified, the meaning of "multiple" in "one or more" refers to more than two types; the meanings of "above" and "below" include the number itself; the range of "value a ~ value b" includes the two end values ​​"a" and "b", and the "unit" in "value a ~ value b + unit of measurement" represents the "unit of measurement" of both "value a" and "value b".

[0028] The technical solution of the present application will be described in detail below in conjunction with specific implementation methods.

[0029] In a first aspect, the present application provides a supramolecular tranexamic acid glycolate ion salt having a structural formula as shown in Formula I;

[0030]

[0031] In some possible embodiments, the supramolecular tranexamic acid glycolate ion salt includes a tranexamic acid structure and a glycolic acid structure in a molar ratio (i.e., a ratio of the amount of substance) of 1:3 to 3:1. In this embodiment, the tranexamic acid structure and the glycolic acid structure have a suitable ratio of the amount of substance, so that the supramolecular tranexamic acid glycolate ion salt can have a better penetration effect.

[0032] As an example, the molar ratio of the tranexamic acid structure to the glycolic acid structure is, for example but not limited to, any one of 1:3, 1:2, 1:1, 2:3, 2:1, 3:2 and 3:1, or a range between any two of them.

[0033] In a second aspect, an embodiment of the present application provides a method for preparing a supramolecular tranexamic acid glycolate ion salt as provided in the embodiment of the first aspect, which comprises reacting tranexamic acid and glycolic acid to obtain a supramolecular tranexamic acid glycolate ion salt as shown in Formula I.

[0034] See also Figure 1 As an example, the step of reacting tranexamic acid and glycolic acid to obtain a supramolecular tranexamic acid glycolic acid ion salt as shown in Formula I comprises the following operations:

[0035] In a protective gas atmosphere, tranexamic acid and glycolic acid are added to water, reacted for a predetermined time, and then ultrasonicated and stirred to obtain a supramolecular tranexamic acid glycolic acid ion salt solution.

[0036] The supramolecular tranexamic acid glycolic acid ion salt solution is crystallized, filtered and dried to obtain the supramolecular tranexamic acid glycolic acid ion salt.

[0037] The protective gas atmosphere refers to an anti-oxidation protective atmosphere, which is, for example, an atmosphere of one or more inert gases including helium, argon, nitrogen, carbon dioxide, etc.

[0038] The usage ratio of tranexamic acid and glycolic acid can refer to the molar ratio of tranexamic acid structure and glycolic acid structure in the supramolecular tranexamic acid glycolic acid ion salt, that is, as an example, the molar ratio of tranexamic acid and glycolic acid is 1:3 to 3:1.

[0039] In order to ensure the purity of the product, as an example, tranexamic acid and glycolic acid are added into deionized water to react to obtain a supramolecular tranexamic acid glycolic acid ion salt solution.

[0040] In order to allow tranexamic acid and glycolic acid to undergo a more complete ionization and salt-forming reaction, optionally, the predetermined time is 12 h to 48 h. The predetermined time for the ionization and salt-forming reaction is, for example but not limited to, any one of 12 h, 18 h, 24 h, 30 h, 36 h, 42 h and 48 h, or a range between any two of them.

[0041] In order to achieve a better ultrasonic effect, optionally, during the ultrasonic process, at least one of the following conditions (a1) to (a5) is met.

[0042] (a1) The temperature of the ultrasonic field is 40°C to 90°C, for example but not limited to any one of 40°C, 50°C, 60°C, 70°C, 80°C and 90°C, or a range between any two of them.

[0043] (a2) The ultrasonic frequency is 10 kHz to 50 kHz, for example but not limited to any one of 10 kHz, 20 kHz, 30 kHz, 40 kHz and 50 kHz, or a range between any two of them.

[0044] (a3) The ultrasonic power is 600W to 5000W, for example but not limited to any one of 600W, 1000W, 1500W, 2000W, 2500W, 3000W, 3500W and 4000W, or a range between any two of them.

[0045] (a4) The ultrasonic time is 6 h to 12 h, for example but not limited to any one of 6 h, 7 h, 8 h, 9 h, 10 h, 11 h and 12 h, or a range between any two of them.

[0046] (a5) Ultrasound is performed for 2s to 10s every 1s to 5s interval, wherein the time of the ultrasound interval is, for example but not limited to, any one of 1s, 2s, 3s, 4s and 5s, or a range between any two of them, and the ultrasound time between two intervals is, for example but not limited to, any one of 2s, 3s, 4s, 5s, 6s, 7s, 8s, 9s and 10s, or a range between any two of them.

[0047] In order to achieve a better stirring effect, optionally, during the stirring process, the following conditions (b1) and / or (b2) are met.

[0048] (b1) The stirring rate is 20 rad / min to 250 rad / min, for example but not limited to any one of 20 rad / min, 30 rad / min, 50 rad / min, 100 rad / min, 150 rad / min, 200 rad / min and 250 rad / min, or a range between any two of them.

[0049] (b2) The stirring time is 12 h to 48 h, for example but not limited to any one of 12 h, 18 h, 24 h, 30 h, 36 h, 42 h and 48 h, or a range between any two of them.

[0050] In the present application, the crystallization method is not limited, as long as the supramolecular tranexamic acid glycolate ion salt obtained by the reaction can be effectively crystallized and separated from the salt solution. Optionally, during the crystallization process, a concentration crystallization and / or a cooling crystallization method is adopted. For example, a concentration crystallization or a cooling crystallization method can be adopted separately, or a crystallization method of first concentrating and then cooling can be adopted.

[0051] In order to achieve efficient drying without destroying the supramolecular tranexamic acid glycolate ion salt, the drying temperature is optionally 50°C to 90°C, for example but not limited to any one of 50°C, 60°C, 70°C, 80°C and 90°C or a range between any two thereof. The drying time depends on the degree of drying, and can be optionally 36h to 60h, for example but not limited to any one of 36h, 42h, 48h, 54h and 60h or a range between any two thereof.

[0052] In a third aspect, an embodiment of the present application provides a use of a supramolecular tranexamic acid glycolate ion salt as provided in an embodiment of the first aspect as a raw material in the preparation of cosmetics.

[0053] As an example, cosmetics are, for example but not limited to, products used to achieve one or more of the following target functions, such as whitening, fading freckles, fading age spots, fading chloasma, etc.

[0054] The technical solution of the present application will be described below in conjunction with specific embodiments and test examples.

[0055] 1. Examples and Comparative Examples

[0056] Example 1

[0057] A supramolecular tranexamic acid glycolate ion salt, the preparation method of which is as follows:

[0058] In an inert gas atmosphere, 0.10 mol of tranexamic acid and 0.10 mol of glycolic acid were added to deionized water, and the reaction time was 24 hours. Under the condition of 70°C, the ultrasonic frequency was 30kHz, the ultrasonic power was 2000W, the ultrasonic time was 10 hours, and the interval time was 5 seconds for every 3 seconds of ultrasonication. The stirring time was 24 hours, and the stirring rate was 50 rad / min, and a supramolecular tranexamic acid glycolic acid ion salt solution was obtained. Under vacuum conditions, the obtained supramolecular tranexamic acid glycolic acid ion salt solution was concentrated and crystallized; it was dried in a vacuum drying oven for 24 hours at a drying temperature of 60°C to obtain a supramolecular tranexamic acid glycolic acid ion salt.

[0059] Example 2

[0060] A supramolecular tranexamic acid glycolate ion salt, the preparation method of which is as follows:

[0061] In an inert gas atmosphere, 0.10 mol of tranexamic acid and 0.10 mol of glycolic acid were added to deionized water, and the reaction time was 12 hours. Under the condition of 40°C, the ultrasonic frequency was 10kHz, the ultrasonic power was 600W, the ultrasonic time was 6 hours, and the intermittent time was 5 seconds per 3 seconds. The stirring time was 12 hours and the stirring rate was 20 rad / min to obtain a supramolecular tranexamic acid glycolic acid ion salt solution. Under vacuum conditions, the obtained supramolecular tranexamic acid glycolic acid ion salt solution was concentrated and crystallized; it was dried in a vacuum drying oven for 12 hours at a drying temperature of 50°C to obtain a supramolecular tranexamic acid glycolic acid ion salt.

[0062] Example 3

[0063] A supramolecular tranexamic acid glycolate ion salt, the preparation method of which is as follows:

[0064] In an inert gas atmosphere, 0.10 mol of tranexamic acid and 0.10 mol of glycolic acid were added to deionized water, and the reaction time was 48 hours. Under the condition of 90°C, the ultrasonic frequency was 50kHz, the ultrasonic power was 4000W, the ultrasonic time was 12 hours, and the intermittent time was 5 seconds per 3 seconds of ultrasonication. The stirring time was 48 hours, and the stirring rate was 250rad / min, and a supramolecular tranexamic acid glycolic acid ion salt solution was obtained. Under vacuum conditions, the obtained supramolecular tranexamic acid glycolic acid ion salt solution was concentrated and crystallized; it was dried in a vacuum drying oven for 48 hours at a drying temperature of 90°C to obtain a supramolecular tranexamic acid glycolic acid ion salt.

[0065] Example 4

[0066] A supramolecular tranexamic acid glycolate ion salt, which is different from Example 1 in that:

[0067] The molar ratio of tranexamic acid to glycolic acid is 3:1.

[0068] Example 5

[0069] A supramolecular tranexamic acid glycolate ion salt, which is different from Example 1 in that:

[0070] The molar ratio of tranexamic acid to glycolic acid is 1:3.

[0071] Example 6

[0072] A supramolecular tranexamic acid glycolate ion salt, which is different from Example 1 in that:

[0073] The molar ratio of tranexamic acid to glycolic acid is 5:1.

[0074] Example 7

[0075] A supramolecular tranexamic acid glycolate ion salt, which is different from Example 1 in that:

[0076] The molar ratio of tranexamic acid to glycolic acid is 1:5.

[0077] Comparative Example 1

[0078] A supramolecular ionic salt, which is different from Example 1 in that:

[0079] The supramolecular tranexamic acid citrate ion salt was prepared by replacing glycolic acid with the same amount of citric acid.

[0080] 2. Material performance test

[0081] (1) The thermal decomposition behavior of supramolecular tranexamic acid glycolic acid ion salt, tranexamic acid monomer, and glycolic acid monomer at a heating rate of 5.0 K / min was studied by thermogravimetric technology. Figure 2 shown.

[0082] like Figure 2 As shown in the figure, the supramolecular tranexamic acid glycolic acid ion salt begins to undergo thermal cracking at around 160°C, indicating that it is stable at room temperature. The thermal cracking of tranexamic acid and glycolic acid occurs at around 77°C and 214°C, respectively, that is, the melting point of the supramolecular tranexamic acid glycolic acid ion salt is lower than that of the tranexamic acid monomer, indicating that the ion salt is effectively formed.

[0083] (2) Figure 3 As shown, the H NMR spectrum data of the supramolecular tranexamic acid glycolate ion salt prepared in this embodiment are: 1H NMR (400 MHz, D2O) δ 3.91 (2H), 2.78-2.76 (2H), 2.21-2.16 (1H), 1.89 (2H), 1.75 (2H), 1.54 (2H), 1.26 (2H), 1.01-0.93 (2H).

[0084] (3) Figure 4 As shown, the supramolecular tranexamic acid glycolic acid crystals obtained in Example 5 were subjected to X-ray single crystal diffraction test, and the specific test parameters were: SuperNova, Dual, Cu at zero, AtlasS2 diffractometer, temperature of 169.99(10)K, and structural analysis using Olex2 and ShelXL.

[0085] The X-ray single crystal diffraction test results of supramolecular tranexamic acid glycolic acid crystals are shown in Table 1:

[0086] Table 1. Single crystal data of supramolecular tranexamic acid glycolate ion salt

[0087]

[0088]

[0089] Atomic coordinates of supramolecular tranexamic acid glycolic acid (×10 4 ) and isotropic atomic displacement parameters The analysis data are shown in Table 2. U(eq) is defined as the orthogonal U ij One third of the tensor's trace.

[0090] Table 2. Atomic coordinates and isotropic atomic displacement parameters of supramolecular tranexamic acid glycolate ion salt

[0091] atom x y z U(eq) O1 2048.5(16) 5892.9(13) 8230.4(6) 54.8(4) O2 382.6(14) 7117.0(11) 8484.2(6) 47.3(3) N1 669.2(13) 8351.7(11) 5103.6(6) 28.5(3) C1 1276.1(17) 6787.1(14) 8121.4(8) 33.1(4) C2 1601.5(16) 7315.8(13) 7495.7(8) 32.2(4) C3 1100(2) 8534.9(14) 7448.3(8) 41.9(4) C4 1482(2) 9025.3(14) 6810.5(8) 40.4(4) C5 900.6(15) 8327.0(12) 6271.2(7) 28.1(3) C6 1381.9(17) 7099.8(13) 6327.7(7) 30.7(3) C7 976.4(17) 6604.9(12) 6964.5(7) 30.8(3) C8 1348.5(15) 8875.7(13) 5659.7(7) 30.7(3) O3 1658.6(10) 4955.7(8) 9289.2(5) 28.0(3) O4 2381.9(11) 3402.8(9) 9775.9(5) 31.7(3) O5 5115.9(11) 3728.1(11) 9396.2(6) 39.9(3) C9 2609.0(14) 4261.6(12) 9462.5(6) 23.1(3) C10 4104.3(15) 4570.0(14) 9272.2(7) 32.1(4)

[0092] The anisotropic atomic displacement parameter analysis data of the supramolecular tranexamic acid glycolate ion salt are shown in Table 3, where the anisotropic atomic displacement factor power is expressed as: -2π 2 [h 2 a* 2 U 11 +2hka*b*U 12 +…].

[0093] Table 3. Anisotropic atomic displacement parameters of supramolecular tranexamic acid glycolate ion salt

[0094]

[0095]

[0096] The bond length analysis data of each chemical bond of the supramolecular tranexamic acid glycolate ion salt are shown in Table 4.

[0097] Table 4. Bond lengths of supramolecular tranexamic acid glycolate ion salt

[0098]

[0099] The analysis data of the chemical bond angles (°) of the supramolecular tranexamic acid glycolate ion salt are shown in Table 5.

[0100] Table 5. Bond angles of supramolecular tranexamic acid glycolate ion salt

[0101]

[0102]

[0103] The torsion angles of the chemical bonds of the supramolecular tranexamic acid glycolate ion salt are shown in Table 6.

[0104] Table 6. Chemical bond torsion angles of supramolecular tranexamic acid glycolate ion salt

[0105]

[0106]

[0107] Hydrogen Atom Coordinates of Supramolecular Tranexamic Acid Glycolate Ion Salt and the isotropic atomic displacement parameters (°)Analysis data are shown in Table 7.

[0108] Table 7. Hydrogen atom coordinates and isotropic atomic displacements of supramolecular tranexamic acid glycolate ion salt

[0109] atom x y z U(eq) H1 1876.92 5652.42 8582.25 82 H1A 834.71 8774.31 4767.1 34 H1B -256.11 8302.72 5166.82 34 H1C 1022.34 7664.42 5043.97 34 H2 2628.12 7315.99 7444.64 39 H3A 1537.2 8980.89 7775.97 50 H3B 86.94 8565.01 7506.43 50 H4A 1113.72 9787.01 6781.24 49 H4B 2499.56 9066.43 6774.05 49 H5 -130.92 8343.62 6293.99 34 H6A 2396.56 7060.93 6275.98 37 H6B 951.14 6656.23 5997.54 37 H7A -42.07 6586.46 7003.23 37 H7B 1322.98 5836.98 6995.26 37 H8A 1108.53 9670.83 5672.37 37 H8B 2363.97 8816.6 5617.72 37 H5A 5045.28 3223.32 9135.58 60 H10A 4114.46 4734.46 8827.35 39 H10B 4375.77 5253.12 9491.26 39

[0110] 3. Application Test Examples

[0111] Test Example 1

[0112] The supramolecular tranexamic acid glycolic acid ion salt prepared in Example 1 was formulated into a 10wt% supramolecular tranexamic acid glycolic acid solution, and a 4.92wt% glycolic acid solution was prepared according to the amount of glycolic acid and the like for comparison. The above solutions were tested for transdermal effect. The specific test method was as follows: based on the tranexamic acid content, the supramolecular tranexamic acid glycolic acid ion salt prepared in Example 1 was formulated into a supramolecular tranexamic acid glycolic acid solution containing 6.6wt% tranexamic acid, and a 10wt% tranexamic acid solution was prepared. The above solutions were tested for transdermal effect. The specific test method was as follows:

[0113] I. Use the back skin of a suckling pig, carefully peel off the subcutaneous fat layer and connective tissue, rinse it with saline, and place it in saline for later use.

[0114] II. Transdermal experiment using Franz cell method. The exposed mouse skin area in the diffusion cell of Franz diffusion device is 3.14cm 2 , the volume of the receiving chamber is 7.5mL.

[0115] III. Take 400 μL of the supramolecular tranexamic acid glycolic acid solution and the glycolic acid solution of equal amount prepared above respectively, as the test solution, and place them on the exposed skin surface in the diffusion cell. Add 7.5 mL of physiological saline receiving solution to the receiving cell, and place it in a constant temperature water bath at 32±1℃ with a stirring speed of 300 rad / min.

[0116] IV. Subcutaneous sample collection: Take 1 mL of the receptor solution every 2 hours and place it in a 2.0 mL EP tube for sample collection.

[0117] V. Treatment of the unpenetrated part of the skin: After 2h (sample) penetration, wash the surface of the suckling pig skin with physiological saline solution repeatedly, wash 3 times, and adjust the volume to 2.0mL.

[0118] VI. Treatment of the residual part in the skin: After 2h (sample) penetration, cut the suckling pig skin into pieces and place them in a 2.0mL EP tube, dilute to 2.0mL with physiological saline, and ultrasonicate for 30 minutes.

[0119] VII. Filter through a 0.22 μm microporous membrane and perform high performance liquid chromatography (HPLC) detection.

[0120] The calculation of diffusion percentage is as follows:

[0121]

[0122] Wherein, P: diffusion percentage; V: volume of receiving liquid in the receiving chamber, 7.5 mL; V0: volume of each sampling, 1.0 mL; Ci: drug concentration in the receiving liquid from the 1st to the n-1st sampling; Cn: sample concentration measured at the nth sampling point; P0: initial loading amount of the sample in the diffusion chamber.

[0123] Figure 5 is a statistical chart of the penetration effect, from Figure 5 It can be seen that the permeability of ordinary tranexamic acid after 2 hours of transdermal absorption test is 1.08%, and the permeability of supramolecular tranexamic acid glycolate ion salt after 2 hours is 2.23%.

[0124] The supramolecular ionic salts of Examples 1 to 7 and Comparative Example 1 were respectively formulated into supramolecular ionic salt solutions with a tranexamic acid content of 6.6 wt%, and were named supramolecular tranexamic acid glycolic acid solution 1, supramolecular tranexamic acid glycolic acid solution 2, supramolecular tranexamic acid glycolic acid solution 3, supramolecular tranexamic acid glycolic acid solution 4, supramolecular tranexamic acid glycolic acid solution 5, supramolecular tranexamic acid glycolic acid solution 6, supramolecular tranexamic acid glycolic acid solution 7 and supramolecular tranexamic acid citric acid solution 1, and transdermal effect tests were carried out according to the above method. The test results are shown in Table 8.

[0125] Table 8. Penetration effect statistics

[0126] substance Permeability Supramolecular tranexamic acid glycolic acid solution 1 2.23％ Supramolecular tranexamic acid glycolic acid solution 2 1.85％ Supramolecular tranexamic acid glycolic acid solution 3 2.01％ Supramolecular tranexamic acid glycolic acid solution 4 1.88％ Supramolecular tranexamic acid glycolic acid solution 5 1.76％ Supramolecular tranexamic acid glycolic acid solution 6 1.01％ Supramolecular tranexamic acid glycolic acid solution 7 0.97％ Supramolecular tranexamic acid citric acid solution 1 0.59％

[0127] Combined with the comparison of Examples 1 to 5 and Comparative Example 1, and the comparison of Example 1 and Examples 6 and 7, it can be seen that when the molar ratio of tranexamic acid to glycolic acid is in the range of 1:3 to 3:1, the prepared supramolecular tranexamic acid / glycolic acid has a better penetration effect, and the penetration effect is poor when the ratio is exceeded. This indicates that a specific ratio of tranexamic acid and glycolic acid can improve the penetration effect, and this effect is stronger than that of ionic salts made from other ligands, such as supramolecular tranexamic acid citrate ion salt.

[0128] Test Example 2

[0129] Example 1 was prepared into a 3 wt % aqueous solution and subjected to a human skin closed patch test to detect safety.

[0130] Establishment of skin irritation model: 33 subjects aged 20 to 60 years with healthy skin were selected. The closed patch test method was used. 0.020g to 0.025g of the test substance was placed in the patch test equipment and applied to the curved side of the subject's forearm with a low-allergenic tape. The test substance was removed after 24 hours, and the skin reaction was observed 0.5, 24, and 48 hours after removal. The results were recorded according to the skin reaction grading standard of "Safety Technical Specifications for Cosmetics" (2015 edition).

[0131] The results of the human skin occlusive patch test of supramolecular tranexamic acid glycolate ion salt are shown in Table 9. No adverse reaction was observed in any of the 33 subjects.

[0132] Table 9. Summary of cosmetics human skin patch test results

[0133]

[0134] Test Example 3

[0135] Example 1 was prepared into a 3 wt % aqueous solution, and tranexamic acid was converted into a 2.02 wt % tranexamic acid solution according to the amount of the same substance, and the chicken embryo chorioallantoic membrane test of cosmetic eye irritation / corrosiveness was conducted for comparison. The test method is as follows:

[0136] Preparation of CAM: 9-day-old chicken embryos were candled and the eggshell of the air chamber was peeled off with dental serrated curved forceps to expose the white egg membrane. Care was taken not to damage the integrity of the egg membrane. A drop of 0.9wt% sodium chloride solution was dropped on the egg membrane to moisten it, and the inner membrane was removed with forceps while ensuring that the vascular membrane was not damaged.

[0137] Pre-experimental test: Take 2 chicken embryos for the test and check the reactivity of this batch of chicken embryos within 5 minutes.

[0138] Endpoint evaluation method: Take 0.3mL or 0.3g of the test substance and apply it to the CAM, ensuring that at least 50% of the CAM surface is covered by the test substance. After 3 minutes of action, gently rinse the test substance on the CAM with normal saline, and observe the degree of change of each toxic effect about 30 seconds after rinsing.

[0139] Reaction evaluation method: Take 0.3mL or 0.3g of the test substance and apply it to the CAM, ensuring that at least 50% of the CAM surface is covered by the test substance. Observe the CAM reaction and record the time of occurrence of each toxic effect within 5 minutes of action.

[0140] Six chicken embryos were placed for each sample, and one chicken embryo was set as a negative control and one as a positive control.

[0141] Irritation score (IS): For experiments conducted using the reaction time method, the irritation score (IS) was calculated using formula (2) and the result was rounded to two decimal places:

[0142]

[0143] Wherein, secH (bleeding time): the average time when bleeding starts to occur on the CAM membrane, in seconds (s); secL (vascular lysis time): the average time when vascular lysis starts to occur on the CAM membrane, in seconds (s); secC (coagulation time): the average time when coagulation starts to occur on the CAM membrane, in seconds (s).

[0144] As shown in Table 10, the eye irritation of the test substances was classified according to the calculated IS values.

[0145] Table 10. Irritation classification

[0146] Stimulus score Irritation classification IS<1 Non-irritating 1≤IS<5 Mild irritation 5≤IS<10 Moderate irritation IS ≥ 10 Strong irritant / corrosive

[0147] The test results are shown in Table 11.

[0148] Table 11. Irritation rating and results

[0149]

[0150] According to Table 11, at the same detection concentration of tranexamic acid, the supramolecular tranexamic acid glycolic acid solution is non-irritating, while the tranexamic acid solution is slightly irritating. The experiment proves that the supramolecular tranexamic acid glycolic acid ion salt can reduce the irritation to the skin.

[0151] Test Example 4

[0152] According to T / SHRH027-2019 "In vitro test of B16 cell melanin synthesis inhibition experiment" and T-SHRH015-2018 "Cosmetics-Tyrosinase activity inhibition test method", based on melanoma cells (B16) cytotoxicity detection, the maximum safe dosage of Example 1 on melanoma cells was determined, and the melanin content, tyrosinase activity, and tyrosinase inhibition rate were tested within the safe concentration.

[0153] The results of the cytotoxicity test are shown in Table 12:

[0154] Table 12. Cytotoxicity test results

[0155]

[0156] The cell relative viability graph was drawn with the eight selected sample concentrations as the horizontal axis and the cell relative viability values ​​as the vertical axis (see Figure 6According to the cytotoxicity results, the samples showed no melanoma cell toxicity within the concentration range of 0.002% (m / V).

[0157] The results of the cell melanin synthesis inhibition test are shown in Table 13:

[0158] Table 13. Analysis of the results of cell melanin synthesis inhibition rate

[0159]

[0160] Note: When using t-test method for statistical analysis, the significance of PC group and sample group compared with BC group is indicated by *, p-value < 0.05 is indicated by *, and p-value < 0.01 is indicated by **.

[0161] The results of cell tyrosinase activity inhibition are shown in Table 14:

[0162] Table 14. Cellular tyrosinase activity inhibition test results

[0163]

[0164] The results of the in vitro tyrosinase inhibition test are shown in Table 15:

[0165] Table 15. Analysis of in vitro tyrosinase inhibition test results

[0166]

[0167]

[0168] The results of the cell melanin synthesis inhibition test are as follows Figure 7 As shown, the melanin synthesis inhibition rate of the supramolecular tranexamic acid glycolic acid solution in cells treated with 0.0006%, 0.0012%, and 0.002% (m / V) samples was increased and had a statistically significant difference compared with the blank control (p<0.05), indicating that it has the effect of inhibiting the cell melanin synthesis ability.

[0169] The results of cell tyrosinase activity inhibition test are as follows Figure 8 As shown, the inhibition rate of cell tyrosinase activity treated with 0.0006%, 0.0012%, and 0.002% (m / V) supramolecular tranexamic acid glycolic acid solution increased and was statistically different from that of the blank control (p<0.05), indicating that it has the effect of inhibiting cell tyrosinase activity.

[0170] like Fig. 9 As shown, the inhibition rate of supramolecular tranexamic acid glycolic acid solution on tyrosinase was above 90% at the concentration of 1.25-10% (m / V), which was statistically different from the blank control group (p<0.01), indicating that it had the effect of inhibiting tyrosinase activity.

[0171] Test Example 5

[0172] Based on the detection of cytotoxicity on macrophages (RAW264.7), the maximum safe dosage of Example 1 on macrophages was determined, and the soothing efficacy was evaluated within the safe concentration.

[0173] The results of the cytotoxicity test are shown in Table 16, and the cell viability graph is shown in Fig.10 .

[0174] Table 16. Cytotoxicity test results

[0175]

[0176] The results of IL-6 content detection are shown in Table 17, and the change trend is as follows Fig.11 shown.

[0177] Table 17. IL-6 data summary

[0178] Sample name Average concentration (pg / mL) SD BC 45.11 5.06 NC 1080.44 163.13 PC 515.03 51.04 Supramolecular Tranexamic Acid Glycolic Acid - 0.156% 1021.47 141.87 Supramolecular Tranexamic Acid Glycolic Acid - 0.313% 1002.69 2.80 Supramolecular Tranexamic Acid Glycolic Acid - 0.625% 922.00 270.58

[0179] The results of TNF-α content detection are shown in Table 18, and the change trend is as follows Fig.12 shown.

[0180] Table 18. TNF-α data summary

[0181] Sample name Average concentration (pg / mL) SD BC 539.16 8.99 NC 22954.13 2606.94 PC 20999.64 2562.19 Supramolecular Tranexamic Acid Glycolic Acid - 0.156% 22516.66 1443.78 Supramolecular Tranexamic Acid Glycolic Acid - 0.313% 22848.99 218.76 Supramolecular Tranexamic Acid Glycolic Acid - 0.625% 20330.54 448.28

[0182] According to the above data, based on the LPS-stimulated macrophage anti-inflammatory model, compared with the NC group, the secretion of macrophage inflammatory mediators TNF-α and IL-6 tended to decrease when the sample was administered at concentrations of 0.156%, 0.313% and 0.625% (m / V).

[0183] In summary, the present application uses tranexamic acid and glycolic acid as precursors, synthesizes supramolecular tranexamic acid glycolic acid ion salt through ionization salt-forming reaction, and separates and purifies the product through crystallization after the reaction. The obtained supramolecular tranexamic acid glycolic acid ion salt has significantly reduced irritation compared with tranexamic acid monomer, which can not only ensure the original efficacy of tranexamic acid, but also improve the permeability of the skin, greatly improve the bioavailability of tranexamic acid, and enhance the application effect.

[0184] The embodiments described above are part of the embodiments of the present application, rather than all of the embodiments. The detailed description of the embodiments of the present application is not intended to limit the scope of the present application for protection, but merely represents the selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present application.

Claims

1. A supramolecular tranexamic acid glycolate ion salt, characterized in that: It has a structural formula as shown in Formula I; the supramolecular tranexamic acid glycolate ion salt is an orthorhombic crystal system; (Formula I); The single crystal data of the supramolecular tranexamic acid glycolate ion salt are as follows: 。 2. A method for preparing the supramolecular tranexamic acid glycolate ion salt as claimed in claim 1, characterized in that: The method comprises reacting tranexamic acid and glycolic acid to obtain a supramolecular tranexamic acid glycolic acid ion salt as shown in formula I; In a protective gas atmosphere, the tranexamic acid and glycolic acid are added to water, reacted for a predetermined time, and then subjected to ultrasound and stirring to obtain a supramolecular tranexamic acid glycolic acid ion salt solution; Crystallizing, filtering and drying the supramolecular tranexamic acid glycolic acid ion salt solution to obtain the supramolecular tranexamic acid glycolic acid ion salt; During the ultrasonic process, the temperature of the ultrasonic field is 40° C. to 90° C., the ultrasonic frequency is 10 kHz to 50 kHz, and the ultrasonic power is 600 W to 4000 W.

3. The preparation method according to claim 2, characterized in that: The scheduled time is 12h~48h.

4. The preparation method according to claim 2, characterized in that: During the ultrasonic process, at least one of the following conditions (a1) to (a2) is satisfied; (a1) Ultrasonication time is 6h~12h; (a2) Ultrasound for 2s to 10s every 1s to 5s.

5. The preparation method according to claim 2, characterized in that: During the stirring process, the following conditions (b1) and / or (b2) are met; (b1) Stirring rate is 20 rad / min~250 rad / min; (b2) Stirring time is 12h~48h.

6. The preparation method according to claim 2, characterized in that: During the crystallization process, concentration crystallization and / or cooling crystallization are adopted.

7. The preparation method according to claim 2, characterized in that: During the drying process, the drying temperature is 50℃~90℃.

8. Use of the supramolecular tranexamic acid glycolate ion salt as claimed in claim 1 as a raw material in the preparation of cosmetics.

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