Supramolecular 4-methoxysalicylic acid tranexamic acid ion salt and preparation method and application thereof

Abstract

The present application provides a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt and its preparation method and application, which belongs to the technical field of compounds for medicine and cosmetics. The supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided by the present application can not only effectively solve the problem of poor percutaneous permeability of potassium 4-methoxysalicylate, but also effectively reduce the toxic and side effects and irritation of potassium 4-methoxysalicylate and tranexamic acid when used alone, greatly expanding its application range; in addition, there is a synergistic effect between the 4-methoxysalicylic acid structure and the tranexamic acid structure in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt, compared with the use of potassium 4-methoxysalicylate or tranexamic acid alone, it can effectively enhance the whitening effect, brightening effect, spot-lightening effect, yellowing effect, fading acne scar effect and transdermal effect; therefore, it can be applied to the preparation of drugs, cosmetics and skin care products with effects such as whitening, spot-lightening and fading acne scar.

Description

Technical Field

[0001] The present application relates to the technical field of compounds for medicine and cosmetics, and in particular to a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt and a preparation method and application thereof. Background Art

[0002] Potassium 4-methoxysalicylate (4MSK) is a medicinal whitening ingredient that can coordinate keratin metabolism, correct abnormal epidermal hyperplasia, and promote melanin excretion. It regulates the imbalance of proliferation and differentiation of keratinocytes and promotes the release of melanin, thereby achieving the effect of smoothing and whitening the skin. However, the high water solubility of 4MSK makes it difficult to penetrate the stratum corneum (SC) and pass to the epidermis, resulting in certain challenges for conventional 4MSK topical preparations in penetrating the stratum corneum barrier. The low percutaneous permeability restricts the bioavailability of 4MSK to a certain extent. In addition, 4MSK has a certain irritation, which also limits its application dose in the product.

[0003] Tranexamic acid, also known as tranexamic acid, is a synthetic lysine analog. Tranexamic acid not only has the effect of resisting secondary fibrinolysis, but also inhibits the activation of plasminogen, thereby effectively alleviating ultraviolet radiation-induced melanin production and new blood vessel formation. In addition, tranexamic acid can also inhibit the production of prostaglandins and reduce the activity of melanocyte tyrosinase, thereby achieving the effect of whitening and lightening spots. In the actual application of tranexamic acid, transdermal administration is the main way to use tranexamic acid products. However, topical tranexamic acid may cause adverse reactions such as local erythema, skin irritation, dryness and desquamation. Summary of the invention

[0004] The purpose of the present application is to provide a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt and its preparation method and application, which aims to reduce the toxic side effects and irritation of potassium 4-methoxysalicylate and tranexamic acid, and synergistically exert the freckle removal effect, whitening effect, brightening effect, yellow removal effect, acne scar fading effect and skin penetration effect of potassium 4-methoxysalicylate and tranexamic acid.

[0005] In the first aspect, the present application provides a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt, wherein the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is a compound shown in the following structural formula, or the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is a hydrate of a compound shown in the following structural formula:

[0006]

[0007] The present application constructs a 4-methoxysalicylic acid structure and a tranexamic acid structure to form a novel compound supramolecular 4-methoxysalicylic acid tranexamic acid ion salt; in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt, the 4-methoxysalicylic acid anion and the tranexamic acid cation are tightly bound by ionic bonds, which is beneficial to improving the stability of the 4-methoxysalicylic acid structure and the tranexamic acid structure in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt in the solid phase and the liquid phase, and can effectively solve the problem of poor transdermal permeability of potassium 4-methoxysalicylate. In addition, the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt can effectively reduce the toxic side effects and irritation of potassium 4-methoxysalicylic acid and tranexamic acid when used alone, greatly expanding its application range; the 4-methoxysalicylic acid structure and the tranexamic acid structure in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt have a synergistic effect, and compared with the use of potassium 4-methoxysalicylic acid or tranexamic acid alone, it can effectively enhance the whitening effect, brightening effect, spot removal effect, yellowing effect, acne scar reduction and transdermal effect.

[0008] In combination with the first aspect, in an optional embodiment of the present application, the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is an orthorhombic crystal system.

[0009] In a second aspect, the present application provides a method for preparing the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided in the first aspect, the preparation method comprising: sequentially heating, stirring and ultrasonically treating a liquid phase containing 4-methoxysalicylic acid, tranexamic acid and an organic solvent to obtain a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution; and crystallizing the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution.

[0010] In the preparation method of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided by the present application, 4-methoxysalicylic acid and tranexamic acid are reacted, the hydrogen atom of 4-methoxysalicylic acid is transferred to tranexamic acid, proton transfer occurs, and then the 4-methoxysalicylic acid structure and the tranexamic acid structure are constructed to form a new type of compound supramolecular 4-methoxysalicylic acid tranexamic acid ion salt; the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt can not only effectively solve the problem of poor transdermal permeability of potassium 4-methoxysalicylate, but also effectively reduce the toxic side effects and irritation of potassium 4-methoxysalicylate and tranexamic acid when used alone, greatly expanding its application range; in addition, the 4-methoxysalicylic acid structure and the tranexamic acid structure in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt have a synergistic effect, compared with the use of potassium 4-methoxysalicylic acid or tranexamic acid alone, it can effectively enhance the whitening effect, brightening effect, spot lightening effect, yellowing effect, acne scar lightening and transdermal effect.

[0011] In combination with the second aspect, in an optional embodiment of the present application, the molar ratio of 4-methoxysalicylic acid to tranexamic acid is (3-1):(1-3).

[0012] In the above technical solution, the above ratio is conducive to the full reaction of 4-methoxysalicylic acid and tranexamic acid, which is conducive to improving the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0013] In combination with the second aspect, in an optional embodiment of the present application, the temperature of the heating and stirring treatment is 80 to 110° C.; or / and the time of the heating and stirring treatment is 10 to 25 hours.

[0014] In the above technical scheme, under the above heating and stirring treatment conditions, 4-methoxysalicylic acid and tranexamic acid can be fully combined, which is beneficial to improve the conversion rate of the reaction between 4-methoxysalicylic acid and tranexamic acid, and further helps to improve the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0015] In combination with the second aspect, in an optional embodiment of the present application, the temperature of the ultrasonic treatment is 40-60°C; or / and, the ultrasonic frequency of the ultrasonic treatment is 20-60kHz; or / and, the ultrasonic power of the ultrasonic treatment is 280-320W; or / and, the time of the ultrasonic treatment is 4-8h.

[0016] In the above technical scheme, under the above ultrasonic treatment conditions, 4-methoxysalicylic acid and tranexamic acid are further fully combined, the reaction is more thorough, and the conversion rate of the reaction between 4-methoxysalicylic acid and tranexamic acid is further improved, thereby further improving the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0017] In combination with the second aspect, in an optional embodiment of the present application, the temperature of the crystallization treatment is ≤0°C; or / and the crystallization treatment is carried out under vacuum conditions.

[0018] In the above technical scheme, under the above crystallization treatment conditions, the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution can be fully crystallized to precipitate crystals, which is beneficial to improve the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0019] In combination with the second aspect, in an optional embodiment of the present application, the method for preparing the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution also includes: after ultrasonic treatment, concentrating the system after ultrasonic treatment; or / and, the method for preparing the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt also includes: after crystallization treatment, filtering, washing and drying the system after crystallization treatment in sequence.

[0020] In combination with the second aspect, in an optional embodiment of the present application, the organic solvent includes at least one of methanol, ethanol, isopropanol, N-methylpyrrolidone, tetrahydrofuran, benzene, toluene, petroleum ether, n-hexane, acetone, dioxane, N,N-dimethyldiamide, ethyl acetate and acetonitrile; or / and, the preparation process of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is carried out under an inert gas atmosphere.

[0021] Optionally, the inert gas includes at least one of nitrogen, helium, neon and argon.

[0022] In a third aspect, the present application provides a use of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided in the first aspect in the preparation of medicines, cosmetics or skin care products.

[0023] The supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided by the present application can not only effectively solve the problem of poor transdermal permeability of potassium 4-methoxysalicylate, but also effectively reduce the toxic side effects and irritation of potassium 4-methoxysalicylate and tranexamic acid when used alone, greatly expanding its application range; in addition, the 4-methoxysalicylic acid structure and the tranexamic acid structure in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt have a synergistic effect, and compared with the use of potassium 4-methoxysalicylic acid or tranexamic acid alone, it can effectively enhance the whitening effect, brightening effect, spot-lightening effect, yellowing effect, acne scar fading and transdermal effect; therefore, it can be used to prepare drugs, cosmetics and skin care products with whitening, spot-lightening, acne scar fading and other effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] 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.

[0025] Figure 1 This is a flow chart of the preparation method of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided in this application.

[0026] Figure 2 This is a molecular structure diagram of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt prepared in Example 1.

[0027] Figure 3 This is the H NMR spectrum of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt prepared in Example 1.

[0028] Figure 4 This is a comparison result of the rate of change of the facial brightness L value of the subjects in Experimental Example 6.

[0029] Figure 5 This is a comparison result of the change rate of erythema E value on the face of the subjects in Experimental Example 6.

[0030] Figure 6 This is a comparison of the change rates of melanin M values ​​on the faces of the subjects in Experimental Example 6.

[0031] Figure 7 This is a comparison result of the change rate of ITA° values ​​on the faces of the subjects in Experimental Example 6. DETAILED DESCRIPTION

[0032] The present application provides a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt, wherein the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is a compound represented by the following structural formula (Formula I), or the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is a hydrate of a compound represented by the following structural formula (Formula I):

[0033]

[0034] In the present application, the Bonded by ionic bonds.

[0035] In the present application, the chemical formula of formula I is C 16 H 23 NO6; the chemical formula of the hydrate of formula I is C 16 H 23 NO6·nH2O, wherein n is a natural number, and the present application does not limit the specific value of n.

[0036] The present application constructs a 4-methoxysalicylic acid structure and a tranexamic acid structure to form a novel compound supramolecular 4-methoxysalicylic acid tranexamic acid ion salt; in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt, the 4-methoxysalicylic acid anion and the tranexamic acid cation are tightly bound by ionic bonds, which is beneficial to improving the stability of the 4-methoxysalicylic acid structure and the tranexamic acid structure in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt in the solid phase and the liquid phase. Therefore, the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt has strong chemical stability.

[0037] The supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided by the present application can not only effectively solve the problem of poor transdermal permeability of potassium 4-methoxysalicylate, but also effectively reduce the toxic side effects and irritation of potassium 4-methoxysalicylate and tranexamic acid when used alone, has good cell and biocompatibility, high solubility and high safety, can reduce irritation and discomfort to the human body, and greatly expands its application range; in addition, the 4-methoxysalicylic acid structure and the tranexamic acid structure in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt have a synergistic effect, compared with the use of potassium 4-methoxysalicylate or tranexamic acid alone, it can improve the bioavailability of potassium 4-methoxysalicylic acid and tranexamic acid, has high permeability, can effectively reduce the formation of melanin, and can effectively enhance the whitening effect, brightening effect, spot lightening effect, yellowing effect, acne scar lightening and transdermal effect.

[0038] In the present application, the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is a hydrate of formula I, and the chemical formula of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is C 16 H 23 NO6·H2O (i.e. C 16 H 25 NO7).

[0039] In the present application, the supramolecular 4-methoxysalicylic acid tranexamic acid salt is an orthorhombic crystal system.

[0040] As an example, the supramolecular 4-methoxysalicylic acid tranexamic acid salt has a space group of P212121 and a unit cell parameter of α = 90°, β = 90°, γ = 90°, Z (the number of units in the unit cell) = 4, and the unit cell volume is

[0041] The present application provides a method for preparing the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided above, and the preparation method comprises: subjecting a liquid phase containing 4-methoxysalicylic acid, tranexamic acid and an organic solvent to heating, stirring and ultrasonic treatment in sequence to obtain a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution; and subjecting the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution to crystallization treatment.

[0042] In the preparation method of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided by the present application, 4-methoxysalicylic acid and tranexamic acid are reacted, the hydrogen atom of 4-methoxysalicylic acid is transferred to tranexamic acid, proton transfer occurs, and then the 4-methoxysalicylic acid structure and the tranexamic acid structure are constructed to form a new type of compound supramolecular 4-methoxysalicylic acid tranexamic acid ion salt; the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt can not only effectively solve the problem of poor transdermal permeability of potassium 4-methoxysalicylate, but also effectively reduce the toxic side effects and irritation of potassium 4-methoxysalicylate and tranexamic acid when used alone, greatly expanding its application range; in addition, the 4-methoxysalicylic acid structure and the tranexamic acid structure in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt have a synergistic effect, compared with the use of potassium 4-methoxysalicylic acid or tranexamic acid alone, it can effectively enhance the whitening effect, brightening effect, spot lightening effect, yellowing effect, acne scar lightening and transdermal effect.

[0043] In addition, the preparation method of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided in the present application is simple and easy, and can improve the preparation efficiency of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0044] Figure 1 For the preparation process flow chart of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided in this application, please refer to Figure 1 The preparation method of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt comprises the following steps:

[0045] S110, sequentially subjecting the liquid phase containing 4-methoxysalicylic acid, tranexamic acid and an organic solvent to a heating and stirring treatment and an ultrasonic treatment to obtain a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution.

[0046] In some optional embodiments of the present application, the molar ratio of 4-methoxysalicylic acid to tranexamic acid is (3-1):(1-3); under the above ratio, it is beneficial to allow the reaction to proceed fully, and thus it is beneficial to improve the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0047] As an example, the molar ratio of 4-methoxysalicylic acid to tranexamic acid can be any value among 1:3, 1:2, 1:1, 2:1 and 3:1, or a range value therebetween.

[0048] Further, in some optional embodiments of the present application, the molar ratio of 4-methoxysalicylic acid to tranexamic acid is 1: 1. Under the above ratio, it is more conducive to fully reacting 4-methoxysalicylic acid with tranexamic acid, and thus more conducive to improving the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0049] In some optional embodiments of the present application, the organic solvent includes at least one of methanol, ethanol, isopropanol, N-methylpyrrolidone, tetrahydrofuran, benzene, toluene, petroleum ether, n-hexane, acetone, dioxane, N,N-dimethyldiamide, ethyl acetate and acetonitrile.

[0050] Illustratively, the organic solvent is selected from ethanol.

[0051] In some optional embodiments of the present application, the temperature of the heating and stirring treatment is 80-110°C; the temperature of the heating and stirring treatment within the above temperature range is conducive to the full combination of 4-methoxysalicylic acid and tranexamic acid, and the reaction is more thorough, which is conducive to improving the conversion rate of the reaction of 4-methoxysalicylic acid and tranexamic acid, and further helps to improve the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0052] As an example, the temperature of the heating and stirring treatment can be any value among 80°C, 85°C, 90°C, 95°C, 100°C, 105°C and 110°C, or a range between any two values.

[0053] In some optional embodiments of the present application, the heating and stirring treatment adopts oil bath heating.

[0054] In some optional embodiments of the present application, the heating and stirring treatment time is 10 to 25 hours; the heating and stirring treatment time within the above time range is conducive to the full combination of 4-methoxysalicylic acid and tranexamic acid, a more thorough reaction, and is conducive to improving the conversion rate of the reaction of 4-methoxysalicylic acid and tranexamic acid, thereby helping to improve the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0055] As an example, the time for the heating and stirring treatment can be any value among 10 h, 12 h, 14 h, 18 h, 20 h, 22 h and 25 h, or a range value between any two of them.

[0056] In the present application, ultrasonic treatment can accelerate the reaction rate of 4-methoxysalicylic acid and tranexamic acid, so that the 4-methoxysalicylic acid anion and the tranexamic acid cation are effectively combined through ionic bonds.

[0057] In some optional embodiments of the present application, the temperature of the ultrasonic treatment is 40 to 60° C. At the above ultrasonic treatment temperature, 4-methoxysalicylic acid and tranexamic acid are further fully combined, the reaction is more thorough, and the conversion rate of the reaction of 4-methoxysalicylic acid and tranexamic acid is further improved, thereby further improving the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0058] As an example, the temperature of the ultrasonic treatment may be any one of 40° C., 45° C., 50° C., 55° C. and 60° C. or any range therebetween.

[0059] In some optional embodiments of the present application, the ultrasonic frequency of the ultrasonic treatment is 20 to 60 kHz. Under the ultrasonic frequency of the above ultrasonic treatment, 4-methoxysalicylic acid and tranexamic acid are further fully combined, the reaction is more thorough, and it is beneficial to further improve the conversion rate of the reaction of 4-methoxysalicylic acid and tranexamic acid, and further help to further improve the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0060] As an example, the ultrasonic frequency of the ultrasonic treatment can be any value among 20 kHz, 25 kHz, 30 kHz, 35 kHz, 40 kHz, 45 kHz, 50 kHz, 55 kHz, and 60 kHz, or any range therebetween.

[0061] In some optional embodiments of the present application, the ultrasonic power of the ultrasonic treatment is 280 to 320 W; under the ultrasonic power of the above-mentioned ultrasonic treatment, 4-methoxysalicylic acid and tranexamic acid are further fully combined, the reaction is more thorough, and it is beneficial to further improve the conversion rate of the reaction of 4-methoxysalicylic acid and tranexamic acid, and further help to further improve the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0062] As an example, the ultrasonic power of the ultrasonic treatment can be any value among 280W, 285W, 290W, 295W, 300W, 305W, 310W, 315W and 320W, or a range between any two values.

[0063] In some optional embodiments of the present application, the ultrasonic treatment time is 4 to 8 hours; the above ultrasonic treatment time is conducive to further full combination of 4-methoxysalicylic acid and tranexamic acid, a more thorough reaction, and further improvement of the conversion rate of the reaction of 4-methoxysalicylic acid and tranexamic acid, thereby further improving the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0064] As an example, the ultrasonic treatment time can be any value among 4 h, 5 h, 6 h, 7 h and 8 h, or a range between any two values.

[0065] In some optional embodiments of the present application, the method for preparing the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution further comprises: after the ultrasonic treatment, concentrating the system after the ultrasonic treatment. The above method facilitates the subsequent crystallization treatment and facilitates the precipitation of crystals.

[0066] As an example, the concentration process may be carried out by a reduced pressure concentration method.

[0067] In some optional embodiments of the present application, the system after ultrasonic treatment is concentrated to obtain a supersaturated supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution; the above method is more convenient for the subsequent rapid precipitation of crystals.

[0068] In some optional embodiments of the present application, the preparation process of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution is carried out under an inert gas atmosphere; the inert gas atmosphere is beneficial to avoid oxidation of 4-methoxysalicylic acid and tranexamic acid during the reaction, and is beneficial to avoid destruction of the biological activities of 4-methoxysalicylic acid and tranexamic acid, thereby improving the yield and purity of the prepared supramolecular 4-methoxysalicylic acid tranexamic acid ion salt, and is also beneficial to fully exerting the whitening effect, brightening effect, spot removal effect, yellowing effect, acne scar reduction and transdermal effect.

[0069] Furthermore, the inert gas includes at least one of nitrogen, helium, neon and argon.

[0070] In some optional embodiments of the present application, the preparation method of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution includes: dissolving 4-methoxysalicylic acid in the aforementioned organic solvent to obtain a first system, and dissolving tranexamic acid in the aforementioned organic solvent to obtain a second system; then, adding the first system drop by drop into the second system or adding the second system drop by drop into the first system to obtain the aforementioned "liquid phase containing 4-methoxysalicylic acid, tranexamic acid and organic solvent".

[0071] S120, subjecting the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution to crystallization treatment.

[0072] In some optional embodiments of the present application, the crystallization treatment adopts a temperature-lowering crystallization method.

[0073] Furthermore, the temperature of the crystallization treatment is ≤0°C; at the above crystallization temperature, the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution can be fully crystallized to precipitate crystals, which is beneficial to improving the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0074] As an example, the temperature of the crystallization treatment is -20°C.

[0075] In some optional embodiments of the present application, the crystallization treatment is carried out under vacuum conditions; under the above-mentioned crystallization treatment conditions, the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution can be fully crystallized to precipitate crystals, which is beneficial to improve the yield and purity of the obtained supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0076] In some optional embodiments of the present application, the method for preparing supramolecular 4-methoxysalicylic acid tranexamic acid ion salt further comprises: after the crystallization treatment, filtering, washing and drying the system after the crystallization treatment in sequence.

[0077] As an example, the system after the crystallization treatment can be washed with at least one of methanol, ethanol, isopropanol, N-methylpyrrolidone, tetrahydrofuran, benzene, toluene, petroleum ether, n-hexane, acetone, dioxane, N,N-dimethyldiamide, ethyl acetate and acetonitrile.

[0078] In some optional embodiments of the present application, the preparation process of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is carried out under an inert gas atmosphere; the inert gas atmosphere is beneficial to avoid oxidation of 4-methoxysalicylic acid and tranexamic acid during the reaction, and is beneficial to avoid destruction of the biological activities of 4-methoxysalicylic acid and tranexamic acid, thereby improving the yield and purity of the prepared supramolecular 4-methoxysalicylic acid tranexamic acid ion salt, and is also beneficial to fully exerting the whitening effect, brightening effect, spot removal effect, yellowing effect, acne scar reduction and transdermal effect.

[0079] Furthermore, the inert gas includes at least one of nitrogen, helium, neon and argon.

[0080] The present application provides an application of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt in the preparation of medicines, cosmetics or skin care products.

[0081] The supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided by the present application can not only effectively solve the problem of poor transdermal permeability of potassium 4-methoxysalicylate, but also effectively reduce the toxic side effects and irritation of potassium 4-methoxysalicylate and tranexamic acid when used alone, greatly expanding its application range; in addition, the 4-methoxysalicylic acid structure and the tranexamic acid structure in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt have a synergistic effect, and compared with the use of potassium 4-methoxysalicylic acid or tranexamic acid alone, it can effectively enhance the whitening effect, brightening effect, spot-lightening effect, yellowing effect, acne scar fading and transdermal effect; therefore, it can be used to prepare drugs, cosmetics and skin care products with whitening, spot-lightening, acne scar fading and other effects.

[0082] In some optional embodiments of the present application, the aforementioned medicines, cosmetics and skin care products may include an aqueous solution of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt; as an example, the aqueous solution of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt can be prepared by mixing deionized water and supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0083] 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.

[0084] Example 1

[0085] This embodiment provides a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt, and the preparation method thereof comprises the following steps:

[0086] 1 mol of 4-methoxysalicylic acid and 1 mol of tranexamic acid were dispersed in ethanol solution to obtain 4-methoxysalicylic acid ethanol dispersion and tranexamic acid ethanol dispersion, respectively. The 4-methoxysalicylic acid ethanol dispersion was slowly added dropwise to the tranexamic acid ethanol dispersion to obtain a mixed solution. The mixed solution was placed in a reactor, stirred in an 80°C oil bath under argon atmosphere for 24 hours, and then ultrasonically reacted for 5 hours under the conditions of ultrasonic input power of 300W, ultrasonic frequency of 40kHz, and ultrasonic temperature of 40°C. As the reaction proceeded, argon was slowly added to ensure that the temperature and pressure in the reactor were kept constant, and then the reaction solution was concentrated under reduced pressure to obtain a supersaturated solution. The supersaturated solution was placed at -20°C for low-temperature crystallization treatment, and the precipitated ion salt compound was filtered, washed 3 times with frozen ethanol solvent, and dried in a vacuum drying oven at 60°C to obtain a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0087] Example 2

[0088] This embodiment provides a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt, and the preparation method thereof comprises the following steps:

[0089] 1 mol of 4-methoxysalicylic acid and 1 mol of tranexamic acid were dispersed in ethanol solution to obtain 4-methoxysalicylic acid ethanol dispersion and tranexamic acid ethanol dispersion, respectively. The 4-methoxysalicylic acid ethanol dispersion was slowly added dropwise to the tranexamic acid ethanol dispersion to obtain a mixed solution. The mixed solution was placed in a reactor, stirred in an 80°C oil bath under argon atmosphere for 12 hours, and then ultrasonically reacted for 5 hours under the conditions of ultrasonic input power of 300W, ultrasonic frequency of 40kHz, and ultrasonic temperature of 50°C. As the reaction proceeded, argon was slowly added to ensure that the temperature and pressure in the reactor were kept constant, and then the reaction solution was concentrated under reduced pressure to obtain a supersaturated solution. The supersaturated solution was placed at -20°C for low-temperature crystallization treatment, and the precipitated ion salt compound was filtered, washed 3 times with frozen ethanol solvent, and dried in a vacuum drying oven at 60°C to obtain a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0090] Example 3

[0091] This embodiment provides a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt, and the preparation method thereof comprises the following steps:

[0092] 1 mol of 4-methoxysalicylic acid and 2 mol of tranexamic acid were dispersed in ethanol solution to obtain 4-methoxysalicylic acid ethanol dispersion and tranexamic acid ethanol dispersion, respectively. The 4-methoxysalicylic acid ethanol dispersion was slowly added dropwise to the tranexamic acid ethanol dispersion to obtain a mixed solution. The mixed solution was placed in a reactor, stirred in an oil bath at 90°C for 12 hours under the protection of argon atmosphere, and then ultrasonically reacted for 5 hours under the conditions of ultrasonic input power of 300W, ultrasonic frequency of 40kHz, and ultrasonic temperature of 50°C. As the reaction proceeded, argon was slowly added to ensure that the temperature and pressure in the reactor were kept constant, and then the reaction solution was concentrated under reduced pressure to obtain a supersaturated solution. The supersaturated solution was placed at -20°C for low-temperature crystallization treatment, and the precipitated ion salt compound was filtered, washed 3 times with frozen ethanol solvent, and dried in a vacuum drying oven at 60°C to obtain a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt.

[0093] Comparative Example 1

[0094] This comparative example is potassium 4-methoxysalicylate.

[0095] Comparative Example 2

[0096] This comparative example is tranexamic acid.

[0097] Comparative Example 3

[0098] This comparative example is a mixture of potassium 4-methoxysalicylate and tranexamic acid in a molar ratio of 1:1.

[0099] Experimental Example 1

[0100] The melting point of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt obtained in Example 1 was tested, and its melting point was 185-190° C., which met the conditions of ion salt.

[0101] The supramolecular 4-methoxysalicylic acid tranexamic acid salt obtained in Example 1 was subjected to X-ray single crystal diffraction test using an X-ray diffractometer (SuperNova, Dual, Mo at zero, AtlasS2 diffractometer). The test temperature was 170.00(10)K. The structural analysis was performed using Olex2 and ShelXL. The molecular structure of the supramolecular 4-methoxysalicylic acid tranexamic acid salt obtained in Example 1 is shown in FIG. Figure 2As shown, the X-ray single crystal test results of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt prepared in Example 1 are shown in Table 1.

[0102] Table 1 Single crystal data of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt prepared in Example 1

[0103]

[0104]

[0105] Atomic coordinates of the single crystal of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt prepared in Example 1 (×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.

[0106] Table 2 Atomic coordinates and isotropic atomic displacement parameters of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt single crystal obtained in Example 1

[0107]

[0108]

[0109] The anisotropic atomic displacement parameter analysis data of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt single crystal prepared in Example 1 are shown in Table 3, wherein the anisotropic atomic displacement factor power is expressed as: 2π2[h2a*2U11+2hka*b*U12+…].

[0110] Table 3 Anisotropic atomic displacement parameters of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt single crystal prepared in Example 1

[0111]

[0112] The chemical bond length analysis data of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt single crystal prepared in Example 1 are shown in Table 4.

[0113] Table 4 The chemical bond lengths of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt single crystal prepared in Example 1

[0114]

[0115] The chemical bond angle analysis data of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt single crystal prepared in Example 1 are shown in Table 5.

[0116] Table 5 Chemical bond angles of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt single crystal prepared in Example 1

[0117] atom atom atom Bond angle / ° C6 C1 C2 109.5(3) C8 C1 C2 112.9(3) C8 C1 C6 110.1(3) C3 C2 C1 110.3(3) C4 C3 C2 111.8(3) C5 C4 C3 110.9(3) C7 C4 C3 109.5(3) C7 C4 C5 111.5(3) C4 C5 C6 111.3(4)

[0118] atom atom atom Bond angle / ° C5 C6 C1 111.9(3) O1 C7 O2 122.4(4) O1 C7 C4 124.7(4) O2 C7 C4 112.8(4) N1 C8 C1 111.7(3) C13 O7 C16 117.1(3) O4 C9 O5 121.4(3) O4 C9 C10 121.5(4) O5 C9 C10 117.1(3) C11 C10 C9 120.8(3) C11 C10 C15 117.2(3) C15 C10 C9 122.0(3) O6 C11 C10 119.8(3) O6 C11 C12 118.1(4) C12 C11 C10 122.0(4) C11 C12 C13 118.8(4) O7 C13 C12 123.4(3) O7 C13 C14 116.0(3) C14 C13 C12 120.7(3) C15 C14 C13 119.6(4) C14 C15 C10 121.8(3)

[0119] The hydrogen bond analysis data of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt single crystal prepared in Example 1 are shown in Table 6.

[0120] Table 6 Hydrogen bonding of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt single crystal prepared in Example 1

[0121]

[0122] The chemical bond torsion angle analysis data of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt single crystal prepared in Example 1 are shown in Table 7.

[0123] Table 7 Chemical bond torsion angles of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt single crystal obtained in Example 1

[0124] A B C D Angle / ° C1 C2 C3 C4 -57.5(4) C2 C1 C6 C5 -57.4(4) C2 C1 C8 N1 57.5(5) C2 C3 C4 C5 55.1(5) C2 C3 C4 C7 178.5(3) C3 C4 C5 C6 -53.6(5) C3 C4 C7 O1 -124.5(5) C3 C4 C7 O2 56.2(5) C4 C5 C6 C1 55.7(5) C5 C4 C7 O1 -1.4(6) C5 C4 C7 O2 179.3(4) C6 C1 C2 C3 57.7(4) C6 C1 C8 N1 -179.8(3) C7 C4 C5 C6 -175.9(3) C8 C1 C2 C3 -179.3(3) C8 C1 C6 C5 178.0(4) O4 C9 C10 C11 -178.4(4) O4 C9 C10 C15 1.1(6) O5 C9 C10 C11 2.0(5) O5 C9 C10 C15 -178.5(4) O6 C11 C12 C13 -179.5(4) O7 C13 C14 C15 179.5(4) C9 C10 C11 O6 -0.8(6) C9 C10 C11 C12 179.5(4) C9 C10 C15 C14 180.0(4) C10 C11 C12 C13 0.2(6) C11 C10 C15 C14 -0.5(6) C11 C12 C13 O7 -180.0(4) C11 C12 C13 C14 0.2(6) C12 C13 C14 C15 -0.6(6) C13 C14 C15 C10 0.8(6) C15 C10 C11 O6 179.6(3) C15 C10 C11 C12 0.0(6) C16 O7 C13 C12 4.8(6) C16 O7 C13 C14 -175.4(4)

[0125] Hydrogen atom coordinates of the single crystal of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt prepared in Example 1 and the isotropic atomic displacement parameters The analysis data are shown in Table 8.

[0126] Table 8 Hydrogen atom coordinates and isotropic atomic displacement parameters of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt single crystal obtained in Example 1

[0127] atom x y z U(eq) H2 5121.8 4823.05 4817.97 82 H1A 5489.19 6872.59 -283.78 53 H1B 6556.85 6312.65 310.22 53 H1C 5738.72 7300.69 542.85 53 H1 5381.51 5087.33 1263.07 38 H2A 6030.52 6720.46 1842.34 40 H2B 4103.77 6871.84 2101.41 40 H3A 6288.88 5288.39 2723.58 40 H3B 5655.51 6267.42 3231.27 40 H4 2868.76 5657.34 3205.97 39 H5A 2123.19 4092.65 2589.9 47 H5B 4031.2 3880.3 2328.02 47 H6A 1943.8 5500.3 1693.99 45 H6B 2554.82 4508.61 1195.27 45 H8A 3805.24 5606.94 129.66 46 H8B 3165.86 6614.07 600.58 46 H3C 5714.98 3842.19 5864.86 56 H3D 6400.54 4793.61 6067.57 56 H6 3315.74 828.99 7689.34 63 H12 4046.85 1737.14 9561.2 43 H14 6085.23 4420.6 8740.87 38 H15 5704.63 3873.26 7417.89 38 H16A 5628.09 2176.45 10629.32 61 H16B 3821.76 2706.25 10726.96 61 H16C 5405.4 3157.62 11208.88 61

[0128] The supramolecular 4-methoxysalicylic acid tranexamic acid ion salt prepared in Example 1 was characterized by H NMR spectrum. The H NMR spectrum is shown in FIG. Figure 3 shown.

[0129] Figure 3 The NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.61(d,J=8.3Hz,1H),6.49–6.15(m,2H),3.71(s,3H),2.68(d,J=6.9Hz,2H),2.13(tt,J=12.1,3.6Hz,1H),1.90(dd,J= 13.6, 3.6Hz, 2H), 1.81 (dd, J = 13.5, 3.6Hz, 2H), 1.54 ( dqd, J = 11.3, 7.3, 3.4Hz, 1H), 1.26 ( qd, J = 13.2, 3.4Hz, 2H), 0.96 ( qd, J = 13.1, 3.5Hz, 2H).

[0130] from Figure 3 It can be seen that the 3 hydrogen atoms on the phenol ring of 4-methoxysalicylic acid and the methoxy group on the benzene ring are substituted, the hydrogen atom on N of tranexamic acid, the 2 methines and 4 methylenes on the six-membered ring and the methylene signal on the side chain; the rest are a small amount of residual deuterated reagent peaks, and no obvious impurity peaks are seen. It shows that in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt prepared in Example 1, 4-methoxysalicylic acid and tranexamic acid exist in a molecular ratio of 1:1, and its purity exceeds 98%.

[0131] Experimental Example 2 Cytotoxicity Detection

[0132] The steps for cytotoxicity assay are as follows:

[0133] (1) Prepare samples of different concentrations

[0134] Test sample 1: The supramolecular 4-methoxysalicylic acid tranexamic acid ion salt obtained in Example 1 was dissolved in Gibco cell culture medium and prepared into different concentrations. The concentrations of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt in the liquid phase were 0.0195 mg / mL, 0.0391 mg / mL, 0.0781 mg / mL, 0.1563 mg / mL, 0.3125 mg / mL and 0.625 mg / mL, respectively.

[0135] Test sample 2: The tranexamic acid of comparative example 2 was dissolved in Gibco cell culture medium and prepared into different concentrations. The concentrations of tranexamic acid in the liquid phase were 0.0195 mg / mL, 0.0391 mg / mL, 0.0781 mg / mL, 0.1563 mg / mL, 0.3125 mg / mL and 0.625 mg / mL, respectively.

[0136] Test sample 3: The potassium 4-methoxysalicylate of comparative example 1 was dissolved in Gibco cell culture medium and prepared into different concentrations. The concentrations of potassium 4-methoxysalicylate in the liquid phase were 0.0195 mg / mL, 0.0391 mg / mL, 0.0781 mg / mL, 0.1563 mg / mL, 0.3125 mg / mL and 0.625 mg / mL, respectively.

[0137] (2) Cell inoculation

[0138] Human melanocytes were seeded at 1×10 4 The cells were seeded at a seeding density of 10 cells / well in a 96-plate incubator (37° C., 5% CO 2 , 95% RH) and incubated overnight.

[0139] (3) Administration

[0140] When the cell plating rate in the 96-well plate reaches 40% to 60%, the drug is administered; after the drug administration, the 96-well plate is placed in an incubator (37° C., 5% CO 2 , 95% RH) for culture.

[0141] Among them, 200 μL of cell culture medium was added to each well of the blank control group; 200 μL of cell culture medium containing 10wt% DMSO was added to each well of the positive control group; 200 μL of different concentrations of test sample 1, test sample 2 and test sample 3 were added to each well of the test sample group; the zeroing well was not inoculated with cells, and only 200 μL of cell culture medium was added. Three replicate wells were set for each different concentration of each test sample.

[0142] (4) Detection

[0143] After the cells were incubated for 24 h, the supernatant was discarded, MTT working solution (0.5 mg / mL) was added, and the cells were incubated at 37° C. in the dark for 4 h. After the incubation, the supernatant was discarded, 150 μL of DMSO was added to each well, and the OD value was read at 490 nm.

[0144] Wherein, cell viability (%) = [(OD of dosing well - OD of zero-adjusting well) / (OD of blank control well - OD of zero-adjusting well)] × 100%; wherein, the dosing well is the positive control group or the sample group to be tested.

[0145] The cytotoxicity results of the test sample 1 at different concentrations are shown in Table 9.

[0146] Table 9 Cytotoxicity of different concentrations of the test sample 1

[0147]

[0148]

[0149] The cytotoxicity results of the test sample 2 at different concentrations are shown in Table 10.

[0150] Table 10 Cytotoxicity of different concentrations of the test sample 2

[0151]

[0152] The cytotoxicity results of the test sample 3 at different concentrations are shown in Table 11.

[0153] Table 11 Cytotoxicity of different concentrations of the test sample 3

[0154]

[0155] It can be seen from Tables 9 to 11 that the cytotoxicity of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt of Example 1 is lower than that of potassium 4-methoxysalicylate of Comparative Example 1 and tranexamic acid of Comparative Example 2, indicating that the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt of Example 1 is more suitable for use on the skin.

[0156] Experimental Example 3: Melanin Content Detection

[0157] The steps for melanin content detection are as follows:

[0158] (1) Liquid preparation grouping

[0159] Blank control (BC): Gibco cell culture medium.

[0160] Positive control (PC): glabridin was dissolved in the cell culture medium. The concentration of glabridin in the positive control medium was 125 μg / mL.

[0161] Test sample 1: The supramolecular 4-methoxysalicylic acid tranexamic acid ion salt obtained in Example 1 was dissolved in the cell culture medium. The concentrations of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt in the test sample 1 were 0.078 mg / mL, 0.156 mg / mL and 0.313 mg / mL, respectively.

[0162] Test sample 2: The tranexamic acid of comparative example 2 was dissolved in the cell culture medium. The concentrations of tranexamic acid in the test sample 2 were 0.078 mg / mL, 0.156 mg / mL and 0.313 mg / mL, respectively.

[0163] Test sample 3: The potassium 4-methoxysalicylate of comparative example 1 was dissolved in the cell culture medium. The concentrations of potassium 4-methoxysalicylate in the test sample 3 were 0.078 mg / mL, 0.103 mg / mL and 0.156 mg / mL, respectively.

[0164] (2) Cell inoculation

[0165] 2.2×105 The cells were seeded at a density of 1 melanocyte / well into a 6-well plate and incubated overnight in an incubator (37° C., 5% CO 2 , 95% RH).

[0166] (3) Administration

[0167] When the cell plating rate in the 6-well plate reaches 40% to 60%, the cells are divided into groups for administration. The dosage per well is 2 mL, and each group has 3 replicate wells. The cells are cultured in an incubator (37°C, 5% CO2, 95% RH) for 72 hours.

[0168] (4) Sample collection

[0169] After the culture was completed, the remaining culture medium in the well was discarded, and 700 μL of 0.25% trypsin was added to each well to digest the melanocytes at 37°C for 1 to 2 minutes. The cells were collected into a 1.5 mL centrifuge tube and centrifuged at 10,000 r / min for 10 minutes, and the supernatant was discarded. 200 μL of distilled water, 500 μL of anhydrous ethanol and 500 μL of ether were added to each tube and mixed evenly. After standing at room temperature for 30 minutes, the tube was centrifuged at 10,000 r / min for 10 minutes.

[0170] (5) Dissolution

[0171] The supernatant was discarded, and 1 mL of 1 mol / L NaOH aqueous solution containing 10 wt% (volume fraction) DMSO was added to obtain each group of test samples. Each group of test samples and melanin standard solutions of different concentrations were heated in a 80°C water bath for 30 min.

[0172] (6) Reading

[0173] Take 200 μL of suspension from each tube of sample into a 96-well plate, set up 2 replicate wells, and measure the absorbance value on an enzyme-linked immunosorbent assay reader at a wavelength of 405 nm.

[0174] According to the concentration and absorbance value of the standard, a melanin content-absorbance standard curve was drawn, and the sample OD value was substituted into the standard curve to calculate the melanin content. Statistical analysis was performed, and the results are shown in Table 12.

[0175] Table 12 Cell melanin synthesis inhibition rate results

[0176]

[0177] As can be seen from Table 12, compared with the BC group, the melanin content of the PC group decreased significantly (P<0.0001), indicating that this experiment is effective. Compared with the BC group, the melanin content of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt of Example 1 decreased significantly and the effect was significantly better than 4-methoxysalicylic acid potassium and tranexamic acid, indicating that the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt has better whitening and spot-lightening effects.

[0178] Experimental Example 4: Transdermal Effect Test

[0179] The steps of transdermal effect testing are as follows:

[0180] (1) The dorsal skin of GF Kunming mice was used, and the subcutaneous fat layer and connective tissue were carefully peeled off, rinsed with saline, and placed in saline for later use.

[0181] (2) The Franz cell method was used for transdermal experiments. The exposed mouse skin area in the diffusion cell of the Franz diffusion device was 1.13 cm 2 , the volume of the receiving chamber is 15mL.

[0182] (3) 1.0 mL of the test solution was applied to the skin surface, 15 mL of commercially available PBS buffered saline solution (pH ≈ 7.4) was added to the receiving pool, and the pool was placed in a 32°C constant temperature water bath with a stirring speed of 350 rad / min; wherein the samples obtained in Experimental Examples 1 to 2 and Comparative Examples 1 to 3 were dissolved in the aqueous solution to obtain a test solution with a concentration of 3 wt%.

[0183] (4) Subcutaneous permeability test: 2 mL of receiving solution was collected at different time points, and triplicate samples were collected at each time point. 2 mL of receiving solution was immediately added to the receiving chamber after sampling. The receiving solutions collected at different time points were filtered through a 0.22 μm microporous filter membrane, and the concentration of the receiving solution was measured by liquid phase detection.

[0184] The results of the transdermal effect test are shown in Table 13.

[0185] Table 13 Transdermal effect test results

[0186]

[0187] It can be seen from Table 13 that the transdermal effect of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt of Example 1 is significantly better than that of potassium 4-methoxysalicylate of Comparative Example 1, tranexamic acid of Comparative Example 2, and the mixture of potassium 4-methoxysalicylate and tranexamic acid of Comparative Example 3, indicating that the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt has a better transdermal effect.

[0188] Experimental Example 5 Patch Test

[0189] The steps for patch testing are as follows:

[0190] (1) Select qualified patch test equipment and use the closed patch test method. Place 0.020g to 0.025g of the test substance in the patch test equipment and apply it to the curved side of the subject's forearm with a hypoallergenic tape.

[0191] The supramolecular 4-methoxysalicylic acid tranexamic acid ion salt of Example 1 was dissolved in deionized water to form a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt aqueous solution with a concentration of 3 wt %.

[0192] (2) After 24 hours, remove the test substance and observe the skin reaction at 0.5 h, 24 h, and 48 h after removal. Record the results according to the skin reaction grading standard in the Technical Specification for Safety of Cosmetics (2015 edition) (as shown in Table 14).

[0193] Table 14 Skin closure patch test skin reaction grading standard

[0194]

[0195]

[0196] The patch test statistical results are shown in Table 15.

[0197] Table 15 Patch test results

[0198]

[0199] As can be seen from Table 15, the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt of Example 1 was configured into a 3wt% aqueous solution for a human skin occlusive patch test, and no adverse skin reaction occurred in 40 people, indicating that the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt has low irritation and high safety.

[0200] Experimental Example 6 Whitening and Spot Lightening Effect Test

[0201] (1) Subject screening criteria

[0202] Volunteers aged between 18 and 60 who meet the experimental requirements, with epidermal pigmentation or no epidermal pigmentation in the forearm test area, measured 5 times at different locations in the intended test area with a tristimulus colorimeter, and with an average ITA° value between 10 and 41. The subject information is shown in Table 16.

[0203] Table 16 Subjects

[0204]

[0205] (2) Whitening and spot-lightening effect test environment

[0206] The whitening and spot-lightening effect tests were completed in the laboratory with a test temperature of 20-22°C and a relative humidity of 40%-60%.

[0207] (3) Requirements during the test

[0208] It is prohibited to use preparations that may affect the whitening and freckle removal test on the test area.

[0209] The subjects are prohibited from taking any preparations that may affect the whitening and freckle removal test by drip, injection, oral administration or other forms of intake.

[0210] The subjects mainly engaged in indoor activities to avoid long-term exposure to light.

[0211] (4) Configuration of the sample to be tested

[0212] The supramolecular 4-methoxysalicylic acid tranexamic acid ion salt of Experimental Example 1 was formulated into an essence according to the essence formula (as shown in Table 17).

[0213] Table 17 Essence formula

[0214]

[0215] (5) Method of applying the sample to be tested

[0216] Every morning and evening, apply 1.5mL of product evenly on face.

[0217] (6) Detect skin data

[0218] Immediately (i.e., day 0), 7 days, 14 days, 21 days, and 24 days after a single use of the test sample, a skin color measuring instrument (XJJC-EQ-029) and a facial scanner (XJJC-EQ-030) were used to collect the subjects' skin color and facial data before using the product.

[0219] (7) Statistical methods

[0220] Statistical analysis software was used for statistical analysis of the data. Measurement data were expressed as mean ± standard deviation, and normal distribution test was performed to meet the normal distribution requirements. Paired t test was used for comparison before and after, otherwise two related sample rank sum test was used: before and after comparison of graded data, two related sample rank sum test was used: independent sample t test or rank sum test was used for comparison between test area and control area: at the same time, the regression coefficient (slope k value) of each parameter changing with time was calculated, and the significance level was P < 0.05.

[0221] The comparison results of the change rate of the subject's facial brightness L value are as follows: Figure 4 As shown. Figure 4 It can be seen that after 7 days of using the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt essence, the face brightness L value of the subjects increased, and the growth rate was higher than that of the blank essence group (the facial area without essence), indicating that the use of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt essence can brighten the skin after 7 days.

[0222] The comparison results of the change rate of the erythema E value of the subjects' faces are as follows Figure 5 As shown. Figure 5 It can be seen that after using the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt essence for 14 days, the E value of facial erythema of the subjects decreased and the reduction rate was higher than that of the blank essence group (the facial area without essence application), indicating that the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt essence can play the effect of fading erythema after 14 days.

[0223] The comparison results of the change rate of melanin M value on the face of the subjects are as follows Figure 6 As shown. Figure 6 It can be seen that after using the essence of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt for 7 days, the melanin M value of the subjects' faces decreased and the decrease rate was higher than that of the blank essence group (the facial area without essence application), indicating that the essence of supramolecular 4-methoxysalicylic acid tranexamic acid ion salt can have the effect of lightening melanin after 7 days.

[0224] The comparison results of the change rate of ITA° values ​​on the subjects' faces are as follows: Figure 7 As shown. Figure 7 It can be seen that after using the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt essence for 7 days, the ITA° value of the subject's face continued to rise, and the growth rate was much higher than that of the blank essence group (the facial area without essence applied), indicating that the use of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt essence can have a whitening effect on the skin after 7 days.

[0225] Experimental Example 7 Clinical Test for Treatment of Chloasma

[0226] The clinically tested steps for treating melasma are as follows:

[0227] (1) Screening of subjects

[0228] First, a preliminary diagnosis of chloasma was performed on the 40 volunteers recruited. The qualified subjects filled in the informed consent form. The subjects rested for 30 minutes in an environment with a temperature of 21±1℃ and a relative humidity of 50±10%RH.

[0229] Then use the VISIA skin image analyzer to scan the facial skin. It uses the Mirror medical imaging system to group the skin of different age groups, circular facial photography technology and a small magnifying glass tool to quantitatively analyze redness, pores, and UV reflective spots, accurately diagnose subtle skin problems, and provide a clear qualitative analysis report.

[0230] (2) Apply the sample

[0231] According to the cream formula in Table 18, a cream was prepared using the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt of Example 1 (referred to as the experimental group cream).

[0232] Table 18 Cream formula

[0233]

[0234]

[0235] The subjects were treated with cream. A commercially available chloasma-removing cream (referred to as the control group cream) was applied on half of their face, and the experimental group cream was applied on the other half of their face.

[0236] After 7, 14 and 28 days of daily application of the cream, the subjects were revisited (the subjects were not allowed to wash their faces within 48±4 hours before the visit), the facial skin condition was photographed, the facial condition was scored, and the subjects filled in the questionnaire.

[0237] Requirements after applying the cream are as follows:

[0238] Do not squeeze or rub the skin on your face, otherwise it will cause damage to the surface of the facial skin and cause infection.

[0239] Avoid exposing facial skin to excessive ultraviolet rays.

[0240] Avoid eating spicy food, smoking, drinking, etc.

[0241] The statistical results of the questionnaire survey on the treatment of melasma are shown in Table 19.

[0242] Table 19 Statistical results of questionnaire survey on treatment of chloasma

[0243]

[0244]

[0245] As can be seen from Table 19, the cream prepared with the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt of Example 1 (i.e., the experimental group cream) has the effect of treating chloasma, and is significantly better than a certain competitive product on the market for removing chloasma cream (i.e., the experimental group cream); indicating that the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt has a good effect on removing chloasma.

[0246] In summary, the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt provided by the present application can not only effectively solve the problem of poor transdermal permeability of potassium 4-methoxysalicylate, but also effectively reduce the toxic side effects and irritation of potassium 4-methoxysalicylate and tranexamic acid when used alone, greatly expanding its application range; in addition, the 4-methoxysalicylic acid structure and the tranexamic acid structure in the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt have a synergistic effect, and compared with the use of potassium 4-methoxysalicylic acid or tranexamic acid alone, it can effectively enhance the whitening effect, brightening effect, spot removal effect, yellowing effect, acne scar fading and transdermal effect; therefore, it can be used to prepare drugs, cosmetics and skin care products with whitening, spot fading, acne scar fading and other effects.

[0247] 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 making creative work are within the scope of protection of the present application.

Claims

1. A method for preparing a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt, characterized in that: The supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is a hydrate of a compound represented by the following structural formula: The chemical formula of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is C 16 H 25 NO7; The supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is an orthorhombic crystal system; The preparation method comprises the following steps: The liquid phase containing 4-methoxysalicylic acid, tranexamic acid and an organic solvent is subjected to heating and stirring treatment and ultrasonic treatment in sequence to obtain a supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution; The organic solvent comprises at least one of methanol, ethanol and isopropanol; subjecting the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution to a crystallization treatment; The molar ratio of the 4-methoxysalicylic acid to the tranexamic acid is 1:1; The temperature of the heating and stirring treatment is 80-110°C; The ultrasonic power of the ultrasonic treatment is 280~320W; The ultrasonic frequency of the ultrasonic treatment is 20-60 kHz.

2. The preparation method according to claim 1, characterized in that: The heating and stirring treatment time is 10 to 25 hours.

3. The preparation method according to claim 1, characterized in that: The temperature of the ultrasonic treatment is 40-60°C; Or / and, the ultrasonic treatment time is 4 to 8 hours.

4. The preparation method according to claim 1, characterized in that: The temperature of the crystallization treatment is ≤ 0°C; Or / and, the crystallization treatment is carried out under vacuum conditions.

5. The preparation method according to claim 1, characterized in that: The method for preparing the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt solution further comprises: after the ultrasonic treatment, concentrating the system after the ultrasonic treatment; Or / and, the preparation method of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt further comprises: after the crystallization treatment, filtering, washing and drying the system after the crystallization treatment in sequence.

6. The preparation method according to claim 1, characterized in that: The preparation process of the supramolecular 4-methoxysalicylic acid tranexamic acid ion salt is carried out under an inert gas atmosphere.

7. The preparation method according to claim 6, characterized in that: The inert gas includes at least one of nitrogen, helium, neon and argon.

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