A pamaquin co-crystal, amorphous substance, preparation method and application thereof

Abstract

The present application belongs to the technical field of medicine or cosmetics, and particularly relates to a cinnamic acid co-crystal, amorphous substance, and a preparation method and application thereof. The cinnamic acid co-crystal and amorphous substance are selected from co-crystals of cinnamic acid and the following substances: serine, arbutin, kojic acid, citric acid, aspartic acid, octanoyl glycine; or a combination of at least two of the co-crystals; or amorphous substances of cinnamic acid and the following substances: epigallocatechin gallate, syringic acid, chlorogenic acid; or a combination of at least two of the amorphous substances; or a combination of at least two of the co-crystals and amorphous substances. The present application provides the above cinnamic acid co-crystal or amorphous substance or a combination of multiple substances, which can significantly improve the in-vitro cumulative permeation amount of cinnamic acid, so that cinnamic acid is efficiently delivered to deep skin and efficiently exerts the whitening and freckle-removing effects of cinnamic acid.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical or cosmetic technology, specifically relating to a tranexamic acid eutectic, amorphous compound, its preparation method, and its application. Background Technology

[0002] Tranexamic acid is a commonly used antifibrinolytic hemostatic agent in clinical practice. In recent years, it has been widely used to treat pigmentation disorders such as melasma because it can interfere with the interaction between melanocytes and keratinocytes by inhibiting the plasminogen-plasminogen system. However, the tranexamic acid molecule contains both hydrophilic carboxyl and amino groups and a hydrophobic carbon chain backbone, resulting in a lipid-water partition coefficient (Log P) of approximately -0.3, exhibiting strong hydrophilicity. This property makes it difficult for it to effectively penetrate the stratum corneum barrier of the skin, which is mainly composed of lipids. When applied to topical formulations, its transdermal absorption rate is low, and its bioavailability is limited.

[0003] To improve the transdermal properties of tranexamic acid, various strategies have been explored, such as preparing it as supramolecular complexes, cyclodextrin inclusion complexes, or forming cocrystals with other organic acids. For example, it has been reported to cocrystallize tranexamic acid with ferulic acid, azelaic acid, etc., to adjust its solubility or melting point. However, the types of cocrystals reported are limited, and the improvement in the transdermal properties of tranexamic acid is still insufficient to meet the desired whitening and other efficacy requirements, especially lacking cocrystals or novel solid forms that can significantly increase its permeability to the epidermis and dermis.

[0004] Therefore, developing more types of novel tranexamic acid eutectic or amorphous solid forms with higher transdermal absorption promotion effects has important application value. Summary of the Invention

[0005] This invention aims to provide a series of novel tranexamic acid eutectic or amorphous materials that can significantly increase the cumulative transdermal permeation of tranexamic acid in vitro, solving the problem of low transdermal absorption rate of tranexamic acid in the prior art. The tranexamic acid eutectic or amorphous materials have the function of improving the transdermal absorption rate of tranexamic acid; the transdermal absorption rate includes the transdermal absorption rate of the epidermis and / or dermis.

[0006] In one aspect, the present invention provides tranexamic acid cocrystals, including cocrystals formed by tranexamic acid with the following substances: serine, arbutin, kojic acid, citric acid, aspartic acid, capryloylglycine; or combinations of these cocrystals.

[0007] Furthermore, the cocrystals formed by tranexamic acid with serine, arbutin, kojic acid, citric acid, aspartic acid, and capryloylglycine are, in order, tranexamic acid-serine cocrystal, tranexamic acid-arbutin cocrystal, tranexamic acid-kojic acid cocrystal, tranexamic acid-citric acid cocrystal, tranexamic acid-aspartic acid cocrystal, and tranexamic acid-capryloylglycine cocrystal.

[0008] Furthermore, in the tranexamic acid-serine cocrystal, the molar ratio of tranexamic acid to serine is 1:1.5-2.5, preferably 1:1.5, 1:2, or 1:2.5.

[0009] Furthermore, in the tranexamic acid-arbutin cocrystal, the molar ratio of tranexamic acid to arbutin is 1:2-3, preferably 1:2, 1:2.5, or 1:3.

[0010] Furthermore, in the tranexamic acid-kojic acid eutectic, the molar ratio of tranexamic acid to kojic acid is 1:1.5-2.5, preferably 1:2.

[0011] Furthermore, in the tranexamic acid-citric acid eutectic, the molar ratio of tranexamic acid to citric acid is 1:0.5-1, preferably 1:0.5 (2:1) or 1:1.

[0012] Furthermore, in the tranexamic acid-aspartic acid cocrystal, the molar ratio of tranexamic acid to aspartic acid is 1:0.5-1.5, preferably 1:1.

[0013] Furthermore, in the tranexamic acid-caprylyl glycine cocrystal, the molar ratio of tranexamic acid to caprylyl glycine is 1:1-2, preferably 1:1 or 1:2.

[0014] On the other hand, the present invention also provides a method for preparing the above-mentioned eutectic, comprising preparing the raw materials in a solvent (40-60% ethanol solution by volume) according to a certain molar ratio.

[0015] Furthermore, the preparation method of the above-mentioned eutectic includes: adding tranexamic acid, serine, arbutin, kojic acid, citric acid, aspartic acid or capryloylglycine to a solvent (40-60% ethanol solution by volume), heating and stirring, removing the solvent, and obtaining the product.

[0016] Furthermore, the preparation method of the above-mentioned cocrystals includes adding tranexamic acid and serine, arbutin, kojic acid, citric acid, aspartic acid or capryloylglycine in a certain molar ratio to a solvent with a volume concentration of 40-60% ethanol solution, heating and stirring at 50-70°C, and then removing the solvent to obtain a solid product, namely tranexamic acid-serine cocrystal, tranexamic acid-arbutin cocrystal, tranexamic acid-kojic acid cocrystal, tranexamic acid-citric acid cocrystal, tranexamic acid-aspartic acid cocrystal, and tranexamic acid-capryloylglycine cocrystal.

[0017] Furthermore, the stirring speed is 50-800 rpm; the stirring time is 30-120 min.

[0018] Furthermore, cooling and evaporating the solvent includes cooling to 30-40°C to remove the solvent (e.g., by convection), removing the solvent under reduced pressure, or removing the solvent by drying.

[0019] On the other hand, the present invention provides tranexamic acid amorphous products, including amorphous products formed by tranexamic acid and at least one of the following substances: epigallocatechin gallate (EGCG), syringic acid, chlorogenic acid; or combinations of these amorphous products.

[0020] Furthermore, the amorphous products formed by tranexamic acid with epigallocatechin gallate (EGCG), syringic acid, and chlorogenic acid are, in order, tranexamic acid-EGCG amorphous product, tranexamic acid-syringic acid amorphous product, and tranexamic acid-chlorogenic acid amorphous product.

[0021] Furthermore, in the tranexamic acid-EGCG amorphous compound, the molar ratio of tranexamic acid to EGCG is 1:1-3, preferably 1:1, 1:2, or 1:3.

[0022] Furthermore, in the tranexamic acid-syringic acid amorphous compound, the molar ratio of tranexamic acid to syringic acid is 1:0.5-1.5, preferably 1:1.

[0023] Furthermore, in the tranexamic acid-chlorogenic acid amorphous compound, the molar ratio of tranexamic acid to chlorogenic acid is 1:0.5-1, preferably 1:0.5 (2:1).

[0024] On the other hand, the present invention also provides a method for preparing the above-mentioned amorphous material, which includes preparing the material by mixing raw materials in a solvent (40-60% ethanol solution by volume) at a certain molar ratio.

[0025] Furthermore, the preparation method of the above amorphous product includes: adding tranexamic acid, epigallocatechin gallate (EGCG), syringic acid, and chlorogenic acid to a solvent (40-60% ethanol solution by volume), heating and stirring, removing the solvent, and obtaining the product.

[0026] Furthermore, the above-mentioned method for preparing amorphous products includes adding tranexamic acid, epigallocatechin gallate (EGCG), syringic acid, and chlorogenic acid in a certain molar ratio to a solvent with a volume concentration of 40-60% ethanol solution, heating and stirring at 50-70°C, and then removing the solvent to obtain solid products, namely tranexamic acid-EGCG amorphous products, tranexamic acid-syringic acid amorphous products, and tranexamic acid-chlorogenic acid amorphous products.

[0027] Furthermore, the stirring speed is 50-800 rpm; the stirring time is 30-120 min.

[0028] Furthermore, cooling and evaporating the solvent includes cooling to 30-40°C to remove the solvent (e.g., by convection), or reducing pressure to remove the solvent, or drying to remove the solvent.

[0029] Furthermore, a tranexamic acid eutectic or amorphous product is selected from tranexamic acid eutectic with the following substances: serine, arbutin, kojic acid, citric acid, aspartic acid, capryloylglycine; or a combination of at least two of the eutectic products; or an amorphous product formed by tranexamic acid with the following substances: epigallocatechin gallate, syringic acid, chlorogenic acid; or a combination of at least two of the amorphous products; or a combination of the eutectic product and at least two of the amorphous products.

[0030] The present invention provides the above-mentioned tranexamic acid eutectic or amorphous or a combination thereof, which can significantly improve the in vitro transdermal cumulative permeation of tranexamic acid, enabling tranexamic acid to be efficiently delivered to the deep skin and effectively exert its whitening and spot-removing effects.

[0031] On the other hand, the present invention also provides the application of the tranexamic acid eutectic amorphous compound in the preparation of skin formulations, wherein the skin formulations include the tranexamic acid eutectic amorphous compound, Rhodiola rosea extract, tea extract, kale extract, Saururus chinensis extract, and excipients; the excipients include polyols and water.

[0032] Furthermore, the skin preparation comprises, by weight percentage: 0.001-1% of the aforementioned tranexamic acid cocrystal and amorphous material, 0.1-2.5% of Rhodiola rosea extract, 0.1-2.5% of tea extract, 0.1-2.5% of kale extract, 0.1-2.5% of Saururus chinensis extract, and the balance excipients. The cocrystal and amorphous material impart excellent whitening and spot-removing effects to the skin preparation, while the Rhodiola rosea extract, tea extract, kale extract, and Saururus chinensis extract enhance the whitening function of the preparation. The kale extract and Saururus chinensis extract exhibit a synergistic effect, enhancing whitening. Furthermore, optimizing the weight ratio of kale extract to Saururus chinensis extract to 1:0.8-1.3 further improves the whitening and spot-removing effects.

[0033] Among the aforementioned skin preparations, Rhodiola rosea extract is obtained by mixing Rhodiola rosea with water to form a pulp, adding ethanol, heating to extract, filtering, concentrating, and freeze-drying. Tea leaf extract is obtained by mixing tea leaves with water to form a pulp, heating to extract, filtering, concentrating, and freeze-drying. Kale extract is obtained by mixing kale with water to form a pulp, adding ethanol, heating to extract, filtering, ultrafiltration, concentrating, and freeze-drying. Saururus chinensis extract is obtained by mixing Saururus chinensis with water to form a pulp, adding ethanol, heating to extract, filtering, ultrafiltration, concentrating, and freeze-drying.

[0034] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0035] This invention provides a series of novel tranexamic acid eutectic or amorphous compounds, which are eutectic or novel solid forms that can significantly increase the cumulative transdermal permeation of tranexamic acid in vitro, solving the problem of low transdermal absorption rate of tranexamic acid in existing technologies. The tranexamic acid eutectic and amorphous compounds have the function of enhancing the transdermal absorption rate of tranexamic acid; the transdermal absorption rate includes the transdermal absorption rate of the epidermis and / or dermis, enabling tranexamic acid to be efficiently delivered to the deep layers of the skin, effectively exerting its whitening and spot-removing effects.

[0036] The tranexamic acid-serine cocrystal, tranexamic acid-kojic acid cocrystal, tranexamic acid-citric acid cocrystal, tranexamic acid-aspartic acid cocrystal, tranexamic acid-EGCG amorphous compound, tranexamic acid-syringic acid amorphous compound, and tranexamic acid-chlorogenic acid amorphous compound prepared by this invention can effectively increase the transdermal absorption of tranexamic acid compared to using tranexamic acid alone for transdermal absorption. The cocrystals and amorphous compounds formed by the above substances with tranexamic acid significantly increase the permeation of tranexamic acid in the epidermis and dermis, thereby enhancing the efficacy. Among them, the tranexamic acid-citric acid cocrystal exhibits the best effect in promoting the transdermal absorption of tranexamic acid, followed by the tranexamic acid-chlorogenic acid amorphous compound. The proportions of the two compounds that promote the permeation of tranexamic acid in the epidermis and dermis are 109% and 137%, and 97% and 126%, respectively.

[0037] The tranexamic acid-EGCG amorphous compound prepared by this invention can significantly increase the transdermal permeability of both tranexamic acid and EGCG; the increase in tranexamic acid permeability to the epidermis and dermis is 65% and 74%, respectively; and the increase in EGCG permeability to the epidermis and dermis is 139% and 181%, respectively. Furthermore, the tranexamic acid-arbutin cocrystal prepared by this invention can significantly increase the transdermal permeability of arbutin; the increase in arbutin permeability to the epidermis and dermis is 123% and 108%, respectively.

[0038] This invention applies the prepared tranexamic acid eutectic and amorphous products to the preparation of skin formulations, and further adds active ingredients such as Rhodiola rosea extract, tea extract, kale extract, and Saururus chinensis extract. The prepared kale extract and Saururus chinensis extract have a certain synergistic effect in whitening. The combination of the two in a weight ratio of 1:0.8-1.3 has a better effect, and the optimal weight ratio is 1:1. Attached Figure Description

[0039] Figure 1 XRD pattern of tranexamic acid-serine cocrystal.

[0040] Figure 2XRD pattern of tranexamic acid-arbutin cocrystal.

[0041] Figure 3 XRD pattern of tranexamic acid-kojic acid eutectic.

[0042] Figure 4 XRD pattern of tranexamic acid-citric acid eutectic.

[0043] Figure 5 XRD pattern of tranexamic acid-aspartic acid cocrystal.

[0044] Figure 6 XRD pattern of tranexamic acid-octanoylglycine cocrystal.

[0045] Figure 7 XRD pattern of tranexamic acid-EGCG amorphous compound.

[0046] Figure 8 XRD pattern of tranexamic acid-syringic acid amorphous compound.

[0047] Figure 9 XRD pattern of tranexamic acid-chlorogenic acid amorphous compound. Detailed Implementation

[0048] The specific embodiments of the present invention will now be described in detail.

[0049] Example 1: Preparation of Tranexamic Acid-Serine Cocrystal

[0050] Take 0.157 g of tranexamic acid and dissolve it with L-serine in 10 mL of a mixed solvent consisting of ethanol and water in a volume ratio of 1:1, respectively, at molar ratios of 1:1.5, 1:2, and 1:2.5. Stir at 65 °C and 300 rpm for 30 min, and then remove the solvent under reduced pressure at 40 °C to obtain a solid product.

[0051] Detected by X-ray powder diffraction (XRD) (see...) Figure 1 The products obtained by applying molar ratios of 1:1.5, 1:2, and 1:2.5 showed new characteristic diffraction peaks, proving that a eutectic was formed.

[0052] Example 2: Preparation of Tranexamic Acid-Arbutin Cocrystal

[0053] Take 0.0785 g of tranexamic acid and arbutin in molar ratios of 1:1.5, 1:2, 1:2.5, and 1:3 respectively, and dissolve them in 10 mL of a mixed solvent consisting of ethanol and water in a volume ratio of 1:1. Stir at 65 °C and 300 rpm for 30 min, and then remove the solvent under reduced pressure at 40 °C to obtain a solid product.

[0054] Detected by X-ray powder diffraction (XRD) (see...) Figure 2 The products obtained with molar ratios of 1:2, 1:2.5, and 1:3 showed new characteristic diffraction peaks, proving that a eutectic was formed; while the solid product obtained with a molar ratio of 1:1.5 did not form a eutectic.

[0055] Example 3: Preparation of Tranexamic Acid-Kojic Acid Eutectic

[0056] Take 0.157 g of tranexamic acid and kojic acid in a molar ratio of 1:2 and 2:1, dissolve them in 12 mL of a mixed solvent consisting of ethanol and water in a volume ratio of 5:7, stir at 65 °C and 300 rpm for 30 min, and then remove the solvent under reduced pressure at 40 °C to obtain a solid product.

[0057] Detected by X-ray powder diffraction (XRD) (see...) Figure 3 The product obtained with a molar ratio of 1:2 showed new characteristic diffraction peaks, proving that a eutectic was formed; while the solid product obtained with a molar ratio of 2:1 did not form a eutectic.

[0058] Example 4: Preparation of Tranexamic Acid-Citrate Eutectic

[0059] Take 0.157 g of tranexamic acid and citric acid in molar ratios of 1:1 and 2:1 respectively, and dissolve them in 10 mL of a mixed solvent consisting of ethanol and water in a volume ratio of 1:1. Stir at 65 °C and 300 rpm for 30 min, and then remove the solvent under reduced pressure at 40 °C to obtain a solid product.

[0060] Detected by X-ray powder diffraction (XRD) (see...) Figure 4 The products obtained at molar ratios of 1:1 and 2:1 showed new characteristic diffraction peaks, proving that a eutectic was formed.

[0061] Example 5: Preparation of Tranexamic Acid-Aspartic Acid Cocrystal

[0062] Take 0.157 g of tranexamic acid and aspartic acid in a molar ratio of 1:1, dissolve them in 10 mL of a mixed solvent consisting of ethanol and water in a volume ratio of 1:1, stir at 65 °C and 300 rpm for 30 min, and then remove the solvent under reduced pressure at 40 °C to obtain a solid product.

[0063] Detected by X-ray powder diffraction (XRD) (see...) Figure 5 The product obtained at a molar ratio of 1:1 showed new characteristic diffraction peaks, proving that a eutectic was formed.

[0064] Example 6: Preparation of Tranexamic Acid-Octayl Glycine Cocrystal

[0065] Take 0.157 g of tranexamic acid and dissolve it with capryloylglycine in 10 mL of a mixed solvent consisting of ethanol and water in a volume ratio of 1:1. Stir at 65 °C and 300 rpm for 30 min, and then remove the solvent under reduced pressure at 40 °C to obtain a solid product.

[0066] Detected by X-ray powder diffraction (XRD) (see...) Figure 6 The products obtained at molar ratios of 1:1 and 1:2 showed new characteristic diffraction peaks, proving that a eutectic was formed.

[0067] Example 7: Preparation of Tranexamic Acid-EGCG Amorphous Compound

[0068] Take 0.157 g of tranexamic acid and EGCG in molar ratios of 1:1, 1:2, and 1:3, dissolve them in 10 mL of a mixed solvent consisting of ethanol and water in a volume ratio of 1:1, stir at 65 °C and 300 rpm for 30 min, and then remove the solvent under reduced pressure at 40 °C to obtain a solid sample.

[0069] Detected by X-ray powder diffraction (XRD) (see...) Figure 7 The products obtained by using molar ratios of 1:1, 1:2, and 1:3 did not have sharp diffraction peaks, but rather diffuse, amorphous broad peaks, proving that an amorphous substance was formed.

[0070] Example 8: Preparation of Tranexamic Acid-Syringic Acid Amorphous Compound

[0071] Take 0.157 g of tranexamic acid and syringic acid in a molar ratio of 1:1, dissolve them in 10 mL of a mixed solvent consisting of ethanol and water in a volume ratio of 1:1, stir at 65 °C and 300 rpm for 30 min, and then remove the solvent under reduced pressure at 40 °C to obtain a solid sample.

[0072] Detected by X-ray powder diffraction (XRD) (see...) Figure 8 The product obtained at a molar ratio of 1:1 did not have sharp diffraction peaks, but rather diffuse, amorphous broad peaks, proving that an amorphous substance was formed.

[0073] Example 9: Preparation of Tranexamic Acid-Chlorogenic Acid Amorphous Compound

[0074] Take 0.157 g of tranexamic acid and chlorogenic acid in a molar ratio of 1:2 and 2:1, dissolve them in 10 mL of a mixed solvent consisting of ethanol and water in a volume ratio of 1:1, stir at 65 °C and 300 rpm for 30 min, and then remove the solvent under reduced pressure at 40 °C to obtain a solid sample.

[0075] Detected by X-ray powder diffraction (XRD) (see...) Figure 9 The product obtained at a molar ratio of 2:1 did not have sharp diffraction peaks, but rather diffuse, amorphous broad peaks, proving that an amorphous substance was formed.

[0076] Comparative Example 1

[0077] The raw materials from Examples 1-9 were physically mixed, specifically, tranexamic acid was weighed and mixed with L-serine, arbutin, kojic acid, citric acid, aspartic acid, capryloylglycine, EGCG, syringic acid, or chlorogenic acid according to the molar ratios described in Examples 1-9, and then ground evenly in a mortar to obtain physically mixed samples. XRD analysis of the physically mixed samples showed no new characteristic peaks or diffuse amorphous broad peaks, indicating that no eutectic or amorphous substances were formed.

[0078] Example 10

[0079] Transdermal testing was performed on the eutectic and amorphous products in the above embodiments.

[0080] 1. Testing the transdermal absorption rate of tranexamic acid.

[0081] Experimental model: Select piglet back skin with uniform thickness and no damage, remove subcutaneous fat, and pretreat with PBS buffer for 30 minutes.

[0082] Transdermal assay method: The Franz diffusion cell method was used. The treated pigskin was fixed between the supply and receiving cells, with the stratum corneum facing the supply cell. 7 mL of PBS buffer (pH 7.4) was injected into the receiving cell and maintained at a constant temperature of (37±0.5)℃ with magnetic stirring at 300 rpm. 2 mL of the test sample (tranexamic acid mass fraction was fixed at 0.5% in all test samples) was added to the supply cell, and the supply cell was sealed with plastic wrap to prevent solvent evaporation. The transdermal assay lasted for 8 hours.

[0083] Determination of drug content in skin: After the experiment, pig skin was removed, and residual samples were wiped off. The stratum corneum (the first 21 layers, discarding the first layer) was removed using tape stripping, followed by separation of the viable epidermis and dermis. Each layer of tissue was minced, 2 mL of isopropanol was added, and the mixture was sonicated for 30 minutes, centrifuged at 5000 rpm for 30 minutes. The supernatant was filtered through a 0.22 μm filter membrane, and the tranexamic acid content was determined by high-performance liquid chromatography (HPLC), as shown in Table 1.

[0084] Table 1: Transdermal Transfusion Rate of Tranexamic Acid

[0085] After converting the permeation rates in Table 1, the percentage increase in permeation rate of tranexamic acid was calculated when eutectic and amorphous materials were compared to tranexamic acid alone. The results are shown in Table 2.

[0086] Table 2: Percentage of Increase in Transmission Amount

[0087] According to the test results in Table 1-2, when the amount of sample to be tested is fixed and the mass fraction of tranexamic acid in all samples is fixed at the same value, the following compounds show similar properties: tranexamic acid-serine cocrystal, tranexamic acid-arbutin cocrystal, tranexamic acid-kojic acid cocrystal, tranexamic acid-citric acid cocrystal, tranexamic acid-aspartic acid cocrystal, tranexamic acid-caprylyl glycine cocrystal, tranexamic acid-EGCG amorphous compound, tranexamic acid-syringic acid amorphous compound, and tranexamic acid-chlorogenic acid amorphous compound. Compared to using tranexamic acid alone for transdermal absorption, all of these substances can effectively increase the transdermal absorption of tranexamic acid. The cocrystals and amorphous compounds formed by the above substances and tranexamic acid significantly increase the permeation of tranexamic acid in the epidermis and dermis, thereby improving efficacy. Among them, the tranexamic acid-citric acid cocrystal showed the best effect in promoting the transdermal absorption of tranexamic acid, with a 109% and 137% increase in the permeation of tranexamic acid in the epidermis and dermis, respectively.

[0088] 2. Testing the transdermal absorption rates of EGCG and arbutin.

[0089] Using the same experimental method described above, the effects of tranexamic acid-EGCG (molar ratio 1:1) amorphous material and tranexamic acid-arbutin (molar ratio 1:2) cocrystal on the transdermal behavior of EGCG and arbutin were tested. The mass fraction of EGCG and arbutin in all test samples was fixed at 0.5%. The proportion of increased permeation of EGCG and arbutin by the cocrystal and amorphous material compared to EGCG and arbutin alone was calculated. The results are shown in Tables 3 and 4.

[0090] Table 3: Increase in EGCG transdermal absorption and permeation rate

[0091] According to the test results in Table 1-3, the tranexamic acid-EGCG amorphous compound can significantly increase the transdermal permeability of both tranexamic acid and EGCG; the proportion of increased transdermal and dermal permeability of tranexamic acid is 65% and 74%, respectively; and the proportion of increased transdermal and dermal permeability of EGCG is 139% and 181%, respectively.

[0092] Table 4: Increase in transdermal and permeation rates of arbutin

[0093] According to the test results in Tables 1-2 and 4, the tranexamic acid-arbutin cocrystal can significantly increase the transdermal permeability of both tranexamic acid and arbutin; the proportion of increased permeability of arbutin to the epidermis and dermis is 123% and 108%, respectively.

[0094] Example 11

[0095] Rhodiola rosea extract: Take the whole plant of Rhodiola rosea, add water at a weight ratio of 1:10 and mix. Add 0.2 times the weight of water and ethanol, heat to 45°C, stir at 80 rpm for 5 hours, then filter, concentrate under reduced pressure to remove ethanol and freeze dry to constant weight.

[0096] Tea extract: Take the leaves of tea (CAMELLIA SINENSIS) tree, add water at a weight ratio of 1:12 to make a pulp, heat to 40℃, stir at 100rpm for 5.5 hours, then filter, concentrate under reduced pressure and freeze dry to constant weight to obtain the extract.

[0097] Kale extract: Take the leaves of kale (BRASSICA OLERACEA ACEPHALA), add water at a weight ratio of 1:10 and blend. Add 0.4 times the weight of water and ethanol, heat to 50℃, and extract by stirring at 100 rpm for 2.5 hours. Then filter, and ultrafilter through an ultrafiltration membrane with a molecular weight cutoff of 1000 Da. Take the ultrafiltrate, concentrate under reduced pressure to remove ethanol, and freeze dry to constant weight to obtain the extract.

[0098] Saururus Chinesesis extract: Take the leaves of Saururus Chinesesis, add water at a weight ratio of 1:10 and slurry, add 0.4 times the weight of water and ethanol, heat to 50℃, stir at 120 rpm for 3 hours, then filter, and ultrafilter through an ultrafiltration membrane with a molecular weight cutoff of 1000 Da. Take the ultrafiltrate, concentrate under reduced pressure to remove ethanol and freeze dry to constant weight to obtain the extract.

[0099] Test samples were prepared according to the weight percentages in Table 5.

[0100] Table 5: Ingredients of Test Samples

[0101] The B16-F10 skin melanoma cells from CRL-6475 mice in logarithmic growth phase were divided into 2×10⁻⁶ cells. 5Cells were seeded in 24-well plates using DMEM medium, 1 mL per well, and incubated at 37°C and 5% CO2 for 24 hours. The supernatant was discarded. For the control group, 1 mL of fresh DMEM medium was added, while for the sample groups, 1 mL of fresh DMEM medium containing 0.5 mg / mL or 0.1 mg / mL of the sample was added. The cells were incubated at 37°C and 5% CO2 for 24 hours. The supernatant was discarded, and the cells were washed with PBS, digested with 0.25% trypsin, and 1 mL of medium was added to collect the cells. The collected cell solution was centrifuged at 1500 rpm for 12 min and discarded. The supernatant was washed with PBS and the PBS washing solution was discarded. Then, 1.0 mL of 1.0 mol / L sodium hydroxide solution was added, and the mixture was incubated in a water bath at 80 °C for 1 h. After centrifugation at 2500 rpm for 12 min, the supernatant was transferred to a 96-well plate with a volume of 200 μL per well. The absorbance of the supernatant in the plate was measured at 405 nm. The above steps were repeated three times. The melanin inhibition rate was then calculated based on the absorbance. The formula for calculating the melanin inhibition rate is 1 - [absorbance of sample group / absorbance of blank group × 100%]. The higher the inhibition rate, the stronger the whitening effect. The results are shown in Table 6.

[0102] Table 6: Melanin Inhibition Rate

[0103] Based on the melanin inhibition rate experimental results in Table 6, the following clear conclusions can be drawn: the melanin inhibition rate of all eight tested samples showed a significant concentration dependence, with the inhibition rate at 0.5 mg / mL generally higher than that at 0.1 mg / mL. Among them, samples 1-2, 1-3, and 1-4 had the highest inhibition rates, reaching 56.91%, 58.05%, and 59.37% respectively at a concentration of 0.5 mg / mL, while sample 1-1 had the lowest inhibition rate, at only 27.43%. Analysis of the formulation composition in Table 5 revealed that sample 1-1, containing only Rhodiola rosea extract and tea extract but lacking kale extract and Saururus chinensis extract, exhibited the worst whitening effect. Samples 1-2, 1-3, and 1-4, containing both kale and Saururus chinensis extracts in a ratio of 1:0.8-1.3, showed the best whitening activity. Samples 1-7 and 1-8, with a ratio outside this range, showed the next best whitening effect. Samples 1-5 (lacking kale extract) and 1-6 (lacking Saururus chinensis extract), containing only one of the extracts, showed lower whitening effects than samples 1-2 to 1-4 and 1-7 to 1-8. This result indicates a significant synergistic effect between kale extract and Saururus chinensis extract in whitening, with a better whitening effect when combined in a weight ratio of 1:0.8-1.3, and the optimal weight ratio of the two in the formulation is approximately 1:1.

[0104] Skin preparations were prepared based on the above raw materials:

[0105] Skin preparation 2-1: by weight percentage, 0.08% tranexamic acid-EGCG (molar ratio 1:1) amorphous matter, 0.3% Rhodiola rosea extract, 0.4% tea leaf extract, 0.7% kale extract, 0.75% Saururus chinensis extract and balance excipients; the excipients consist of 1,3-butanediol and water in a weight ratio of 1:10.

[0106] Skin preparation 2-2: by weight percentage, 0.07% tranexamic acid-arbutin (molar ratio 1:2) cocrystal, 0.35% Rhodiola rosea extract, 0.48% tea extract, 0.75% kale extract, 0.8% Saururus chinensis extract and balance excipients; the excipients consist of 1,3-butanediol and water in a weight ratio of 1:8.

[0107] Skin formulation 2-3: by weight percentage, 0.04% tranexamic acid-citric acid (molar ratio 1:1) cocrystal, 0.06% tranexamic acid-chlorogenic acid (molar ratio 2:1) amorphous, 0.2% Rhodiola rosea extract, 0.35% tea leaf extract, 0.8% kale extract, 0.9% Saururus chinensis extract and balance excipients; excipients consist of 1,3-butanediol, glycerin and water in a weight ratio of 1:1:18.

[0108] The preparation methods of the above skin preparations 2-1 to 2-3 are as follows: Polyol and water are mixed by stirring at 80 rpm at room temperature for 5 minutes; cocrystal, amorphous material, Rhodiola rosea extract, tea extract, kale extract, and Saururus chinensis extract are added; the mixture is stirred at 80 rpm at room temperature for 8 minutes; the remaining water is added; and stirring is continued for 6 minutes to obtain the skin preparation.

[0109] The embodiments described above are merely examples of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. A tranexamic acid eutectic amorphous compound, characterized in that, Selected from cocrystals formed by tranexamic acid and the following substances: serine, arbutin, kojic acid, citric acid, and aspartic acid; Alternatively, a combination of at least two of the eutectic compounds; Alternatively, tranexamic acid forms amorphous compounds with the following substances: epigallocatechin gallate, syringic acid, and chlorogenic acid; Or, a combination of at least two of the amorphous materials; Alternatively, the combination of at least two of the eutectic and amorphous materials.

2. The tranexamic acid eutectic amorphous material according to claim 1, characterized in that, The tranexamic acid eutectic and amorphous products have the function of improving the transdermal absorption rate of tranexamic acid.

3. The tranexamic acid eutectic amorphous material according to claim 2, characterized in that, Transdermal absorption rate includes the transdermal absorption rate of the epidermis and / or dermis.

4. The tranexamic acid eutectic amorphous material according to claim 1, characterized in that, The molar ratio of tranexamic acid to serine is 1:1.5-2.5; And / or, the molar ratio of tranexamic acid to arbutin is 1:2-3; And / or, the molar ratio of tranexamic acid to kojic acid is 1:1.5-2.5; And / or, the molar ratio of tranexamic acid to citric acid is 1:0.5-1; And / or, the molar ratio of tranexamic acid to aspartic acid is 1:0.5-1.5; And / or, the molar ratio of tranexamic acid to epigallocatechin gallate is 1:1-3; And / or, the molar ratio of tranexamic acid to syringic acid is 1:0.5-1.5; And / or, the molar ratio of tranexamic acid to chlorogenic acid is 1:0.5-1.

5. A tranexamic acid eutectic amorphous material according to claim 1, characterized in that, The molar ratio of tranexamic acid to serine is 1:1.5, 1:2, or 1:2.5; And / or, the molar ratio of tranexamic acid to arbutin is 1:2, 1:2.5 or 1:3; And / or, the molar ratio of tranexamic acid to kojic acid is 1:2; And / or, the molar ratio of tranexamic acid to citric acid is 2:1 or 1:1; And / or, the molar ratio of tranexamic acid to aspartic acid is 1:1; And / or, the molar ratio of tranexamic acid to epigallocatechin gallate is 1:1, 1:2 or 1:3; And / or, the molar ratio of tranexamic acid to syringic acid is 1:1; And / or, the molar ratio of tranexamic acid to chlorogenic acid is 2:

1.

6. A method for preparing a tranexamic acid eutectic amorphous compound according to any one of claims 1-5, characterized in that, include: Tranexamic acid, along with serine, arbutin, kojic acid, citric acid, aspartic acid, epigallocatechin gallate, syringic acid, or chlorogenic acid, is added to a solvent, heated and stirred, and the solvent is removed to obtain the final product.

7. The preparation method according to claim 6, characterized in that, The solvent is an ethanol solution with a volume concentration of 40-60%.

8. The preparation method according to claim 6, characterized in that, Heating and stirring: heat and stir at 50-70℃ for 30-120 minutes.

9. The application of a tranexamic acid eutectic amorphous material according to any one of claims 1-5 in the preparation of skin formulations, characterized in that, The skin preparation comprises a tranexamic acid eutectic or amorphous compound as described in any one of claims 1-5, Rhodiola rosea extract, tea extract, kale extract, Saururus chinensis extract, and excipients; the excipients include polyols and water.

10. The application according to claim 9, characterized in that, The skin preparation is composed of the following by weight percentage: 0.001-1% of a tranexamic acid eutectic or amorphous compound as described in any one of claims 1-5, 0.1-2.5% of Rhodiola rosea extract, 0.1-2.5% of tea extract, 0.1-2.5% of kale extract, 0.1-2.5% of Saururus chinensis extract, and the balance of excipients.

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