Tranexamic acid ionic liquid, micro-capsule and preparation method and application of tranexamic acid ionic liquid

Abstract

The invention discloses tranexamic acid ionic liquid, a micro-capsule as well as a preparation method and application of the micro-capsule, and relates to the field of daily chemical products. The ionic liquid comprises a tranexamic acid hydrogen bond donor and a hydrogen bond receptor, and the hydrogen bond receptor comprises at least one of citric acid, glycolic acid and malic acid; the microcapsule is prepared by mixing and homogenizing grease, an emulsifier, tranexamic acid ionic liquid and water at a specific temperature. The tranexamic acid is used as a hydrogen bond donor to prepare the form of the ionic liquid, the solubility of the tranexamic acid is improved, meanwhile, the emulsifier, the grease and the water are combined to achieve the effect of the ionic liquid in water, whitening components can be promoted to efficiently permeate in the skin, the whitening effect is enhanced, meanwhile, irritation is reduced, the prepared micro-capsule is smaller in particle size, and the skin whitening effect is improved. Whitening active ingredients are high in storage and temperature-resistant stability, the encapsulation efficiency of the active ingredients is remarkably improved, the permeability, stability and safety of tranexamic acid are comprehensively improved, and the whitening effect is good.

Description

Technical Field

[0001] This invention relates to the field of daily chemical products, and in particular to a tranexamic acid ionic liquid, microcapsules, preparation method and application thereof. Background Technology

[0002] The stratum corneum, hydrolipidic protective layer, and cell membrane of the skin constitute its natural barrier. Once these barrier functions are damaged, the skin is prone to moisture loss, leading to dryness and dullness. Beyond basic hydration and moisturizing, whitening and brightening have become important demands in the skincare industry, and highly effective, safe, and stable whitening ingredients are increasingly attracting market attention. Tranexamic acid, as a commonly used whitening active ingredient, has the effect of inhibiting melanin production and improving dull skin tone. However, tranexamic acid has low transdermal absorption efficiency and poor stability under light and high temperature environments, easily degrading and affecting its whitening effect. Furthermore, tranexamic acid is highly polar and extremely water-soluble, easily escaping to the external aqueous phase in conventional water-in-oil or oil-in-water emulsion microcapsule systems, resulting in low encapsulation rates and easy drug leakage, making it difficult to achieve efficient sustained release and targeted encapsulation. At the same time, when used alone, tranexamic acid may cause some skin irritation, limiting its widespread application in cosmetics. Therefore, improving the solubility, stability, and transdermal absorption efficiency of tranexamic acid, and reducing its irritation, has become the key to expanding its application in whitening cosmetics.

[0003] Ionic liquids are stable mixtures formed by the physical interaction of two or more chemical substances, which remain liquid at room temperature. They are primarily formed through non-covalent interactions of functional groups between compounds, such as ionic bonds, intermolecular hydrogen bonds, and van der Waals forces. Compared to their precursors, ionic liquids retain their original chemical properties, but some physical characteristics change, such as melting point, viscosity, state, and vapor pressure. Substances formed through these non-covalent interactions are generally called supramolecular substances; therefore, ionic liquids are also known as supramolecular solvents or supramolecular ionic liquids. Supramolecular ionic liquids possess many excellent properties, exhibiting advantages such as low potential toxicity, high safety, and reasonable price in various fields, serving as a substitute for organic solvents. They also promote the dissolution and efficacy of substances, enhance the solubility of active ingredients, and improve their efficacy, making them widely used in cosmetics, health products, and food.

[0004] Ionic liquids can achieve maximum / optimal applications by selecting monomers with specific functional structures. Therefore, the selection of precursor monomers for ionic liquids is crucial, as choosing suitable monomers can produce synergistic effects. Tranexamic acid typically has whitening and anti-inflammatory effects. By selecting ligand monomers with specific structures, ionic liquids can be formed with tranexamic acid and applied to cosmetics, health foods, and other fields. Therefore, developing tranexamic acid ionic liquid synergistic products is of great significance. Summary of the Invention

[0005] This invention provides a tranexamic acid ionic liquid, microcapsules, preparation method, and application thereof. By preparing tranexamic acid as a hydrogen bond donor in the form of an ionic liquid, its lipid solubility is improved. At the same time, the nanostructured microcapsules increase the transdermal permeability and stability of tranexamic acid, ensuring that tranexamic acid is effectively absorbed while maintaining its physicochemical stability, thereby extending the whitening effect and service life of the product.

[0006] To address the aforementioned technical problems, one objective of this invention is to provide a tranexamic acid ionic liquid comprising a hydrogen bond donor and a hydrogen bond acceptor in a molar ratio of (1-10):(1-10), wherein the hydrogen bond donor is tranexamic acid and the hydrogen bond acceptor comprises at least one of citric acid, glycolic acid, and malic acid.

[0007] This application uses tranexamic acid as a hydrogen bond donor and utilizes specific hydrogen bond acceptors, along with a specific molar ratio of hydrogen bond donor to acceptor, to successfully obtain an ionic liquid form of tranexamic acid. By preparing tranexamic acid into an ionic liquid form, its lipid solubility is effectively improved. When subsequently encapsulating microcapsules with lipid wall materials, leakage of tranexamic acid due to its high water solubility can be reduced, thereby increasing the encapsulation rate of whitening active ingredients. Furthermore, the microcapsule structure enhances transdermal penetration, solving the problem of poor permeability limiting the application of tranexamic acid in cosmetics.

[0008] In some embodiments, the molar ratio of the hydrogen bond donor and the hydrogen bond acceptor is any one of or between any two of the following: 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1.

[0009] In some embodiments, when the hydrogen bond acceptor is glycolic acid, the molar ratio of the hydrogen bond donor to the hydrogen bond acceptor is (1-3):(1-10).

[0010] In some embodiments, when the hydrogen bond acceptor is citric acid and / or malic acid, the molar ratio of the hydrogen bond donor to the hydrogen bond acceptor is (1-10):(1-10).

[0011] In some embodiments, the molar ratio of the hydrogen bond donor to the hydrogen bond acceptor is (1-2):(1-4).

[0012] The molar ratio of hydrogen bond donors to hydrogen bond acceptors in this application affects the liquid morphology of the ionic liquid, thereby affecting the encapsulation and permeation-enhancing effects of the microcapsules. If the molar ratio of hydrogen bond donors to hydrogen bond acceptors is too small or too large, a viscous liquid will be formed, resulting in poor performance of the ionic liquid phase encapsulated in the microcapsules. This leads to a decrease in the permeation-enhancing effect of the ionic liquid encapsulated in the microcapsules, and a simultaneous decrease in the whitening effect and particle size stability of the microcapsules.

[0013] To solve the above-mentioned technical problems, the second objective of this invention is to provide a method for preparing tranexamic acid ionic liquid, comprising the following steps: mixing a hydrogen bond donor and a hydrogen bond acceptor, heating and stirring in a sealed water bath at 40-90 ℃ for 20-120 min, and cooling to room temperature to obtain the ionic liquid.

[0014] The present invention can prepare an ionic liquid by mixing the hydrogen bond donor and the hydrogen bond acceptor and controlling the reaction temperature and reaction time. If the temperature is too low or the time is too short, it is difficult to form an ionic liquid; if the temperature is too high or the time is too long, tranexamic acid is easily deactivated, resulting in a low content of whitening active ingredients.

[0015] In some embodiments, the stirring temperature is a range of any one or any two of 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, and 90 ℃.

[0016] In some embodiments, the stirring time is any one or a range between any two of 20 min, 30 min, 40 min, 50 min, 60 min, 70 min, 80 min, 90 min, 100 min, 110 min, and 120 min.

[0017] In some embodiments, the stirring temperature is 55-60 ℃. Preferably, ultrasonication, grinding, homogenizing shearing, high-pressure treatment and other methods can be used to help the solute dissolve fully.

[0018] To address the aforementioned technical problems, a third objective of this invention is to provide a method for preparing microcapsules containing tranexamic acid, comprising the following steps: S1. Mix the oil, emulsifier and the tranexamic acid ionic liquid, and stir evenly at a temperature of 70-75 ℃ to obtain phase A. Stir the water evenly to obtain phase B. S2. Under stirring conditions, phase A is added dropwise to phase B and stirred until homogeneous to obtain a mixture. The mixture is then homogenized at a temperature of 70-75 ℃ to obtain microcapsules.

[0019] This application describes the preparation of nanostructured microcapsules from tranexamic acid ionic liquid. Using ionic liquid, oils, and emulsifiers as the ionic liquid phase and water as the aqueous phase, microcapsules encapsulating the ionic liquid structure were successfully prepared, further improving the photostability of tranexamic acid. This microcapsule structure allows for more efficient penetration of whitening ingredients into the skin, exhibiting a penetration-enhancing effect. Simultaneously, it reduces the irritation of active whitening ingredients such as tranexamic acid, improving their safety. Furthermore, the smaller particle size of the microcapsules prepared from the ionic liquid enhances the stability of the whitening active ingredients, ensuring no discoloration and stable content. This guarantees effective absorption of tranexamic acid while maintaining its physicochemical stability, extending the product's shelf life. These microcapsules demonstrate good stability and permeability, and are highly effective and non-irritating for whitening.

[0020] In some embodiments, in S1, the A phase is stirred uniformly under conditions ranging from 70 ℃, 71 ℃, 72 ℃, 73 ℃, 74 ℃, 75 ℃, or between any two of these conditions.

[0021] In some embodiments, in S1, the A phase is stirred at a speed of 500-1300 rpm for 5-15 min at 70-75 °C.

[0022] In some embodiments, in S1, the stirring speed is any one or a range between any two of 500 rpm, 600 rpm, 700 rpm, 800 rpm, 900 rpm, 1000 rpm, 1100 rpm, 1200 rpm, and 1300 rpm.

[0023] In some embodiments, in S2, the mixture is homogenized under conditions ranging from 70°C, 71°C, 72°C, 73°C, 74°C, and 75°C, or between any two of these conditions.

[0024] In some embodiments, in S2, the mixture is homogenized at a pressure of 100-600 bar at 70-75 °C.

[0025] This invention utilizes a specific temperature to ensure uniform mixing of ionic liquid (IL), oil, and emulsifier. If the temperature is too low, the oil and ionic liquid components will not be completely emulsified, resulting in a reduction in the whitening effect of the microcapsules. If the temperature is too high, the oil and ionic liquid components will evaporate, reducing the effective ingredients in the microcapsules and also reducing their whitening effect.

[0026] In some embodiments, in S2, the homogenizing pressure is any one or a range between any two of 100 bar, 150 bar, 200 bar, 250 bar, 300 bar, 350 bar, 400 bar, 450 bar, 500 bar, 550 bar, and 600 bar, preferably 200-500 bar.

[0027] In some embodiments, the oil accounts for 1%-20% of the mass fraction of the microcapsules.

[0028] In some embodiments, the oil constitutes any one or a range between any two of the following: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20% of the microcapsule mass fraction.

[0029] In some embodiments, the emulsifier accounts for 2%-8% of the mass fraction of the microcapsules.

[0030] In some embodiments, the emulsifier comprises any one or a range between any two of 2%, 3%, 4%, 5%, 6%, 7%, and 8% of the microcapsule mass fraction.

[0031] In some embodiments, the tranexamic acid ionic liquid accounts for 1%-20% of the mass fraction of the microcapsules.

[0032] In some embodiments, the tranexamic acid ionic liquid comprises any one or a range between any two of the following: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20% of the mass fraction of the microcapsules.

[0033] The weight percentage of the ionic liquid in this application affects the high-efficiency whitening effect of the microcapsules. If the IL content is low, the encapsulation layer composed of IL in the microcapsules will be too small, which will lead to a poor whitening effect. If the IL content is too high, the internal structure or interface layer formed in the microcapsules will be too thick, which will hinder the release rate of the whitening active ingredients and make it difficult to reach the effective concentration within the target time, resulting in poor immediate whitening effect. At the same time, an excessively high IL content may cause unstable internal pressure or uneven particle size distribution in the microcapsule system, thereby affecting the long-term physical stability of the formulation.

[0034] In some embodiments, in S1, the oil includes at least one of olive oil, grapeseed oil, camellia oil, squalane, jojoba oil, shea butter, and meadowfoam seed oil.

[0035] In some embodiments, in S1, the oil comprises meadowfoam seed oil and squalane at a mass fraction of 0.1%-19% of the microcapsules.

[0036] In some embodiments, the emulsifier includes at least one selected from soybean lecithin, Tween 80, tococelen, polyglycerol-3-methylglucose distearate, PEG-40 hydrogenated castor oil, stearyl alcohol polyether-2, inulin lauryl carbamate, docosyl alcohol, polysorbate-60, PEG-15 glyceryl lauryl ester, and glyceryl stearate. The emulsifier in the microcapsule component of this invention is amphiphilic; its hydrophobic (ionic liquid-loving) end can contact ionic liquids, oils, or other ionic liquid phases, and encapsulate the ionic liquid phase internally; its hydrophilic end contacts water, ultimately forming microcapsules encapsulating the ionic liquid.

[0037] In some embodiments, the emulsifier comprises 0.8%-6% soybean lecithin and 0.8%-6% tococelen, which constitute 0.8%-6% of the microcapsule mass fraction.

[0038] In some embodiments, in S2, the mixture is homogenized 3-7 times.

[0039] To solve the above-mentioned technical problems, the fourth objective of this invention is to provide a microcapsule containing tranexamic acid prepared by the above-mentioned method for preparing microcapsules containing tranexamic acid.

[0040] In some embodiments, the particle size of the tranexamic acid-containing microcapsules is 80-300 nm.

[0041] In some embodiments, the particle size of the tranexamic acid-containing microcapsules is any one or a range between any two of 80 nm, 100 nm, 150 nm, 200 nm, 250 nm, and 300 nm.

[0042] To address the aforementioned technical problems, the fifth objective of this invention is to provide an application of microcapsules containing tranexamic acid in the field of skin whitening products.

[0043] To address the aforementioned technical problems, the sixth objective of this invention is to provide a skin whitening preparation comprising microcapsules containing tranexamic acid.

[0044] In some embodiments, the whitening formulation also includes excipients.

[0045] Compared with the prior art, the present invention has the following beneficial effects: 1. This application uses tranexamic acid as a hydrogen bond donor and utilizes specific hydrogen bond acceptors, along with a specific molar ratio of hydrogen bond donor to hydrogen bond acceptor, to prepare tranexamic acid into an ionic liquid form, effectively improving the lipophilicity and permeability of tranexamic acid. Subsequent preparation into microcapsules can improve the encapsulation rate of active ingredients. The microcapsule structure improves the permeability, stability, and safety of whitening active ingredients.

[0046] 2. The microcapsules of this application encapsulate ionic liquid to form an ionic liquid phase, which can promote the efficient penetration of whitening ingredients into the skin, thus enhancing the whitening effect. At the same time, it reduces the irritation of tranexamic acid. The microcapsules do not contain organic solvents, avoiding sensitization, with minimal toxic side effects, thus improving the safety of the microcapsules.

[0047] 3. This application encapsulates tranexamic acid ionic liquid in microcapsules, resulting in smaller particle size and higher stability of the whitening active ingredients. This achieves a high stability effect with minimal particle size change under long-term and high-temperature storage conditions, and good heat resistance. While achieving highly effective whitening, it is also more stable, safe, and non-irritating.

[0048] 4. This application utilizes tranexamic acid to form an ionic liquid by binding it to a specific hydrogen bond acceptor, effectively shielding the original strong polarity and high water solubility of tranexamic acid and significantly increasing its affinity for lipid wall materials. During microencapsulation, the active ingredient in ionic liquid form can be firmly encapsulated within the internal ionic liquid phase, greatly inhibiting the escape of the active ingredient from the external aqueous phase, achieving extremely high encapsulation efficiency and excellent drug loading stability. Attached Figure Description

[0049] Figure 1 This is a schematic diagram of the preparation process of the tranexamic acid ionic liquid in Example 2 of the present invention; Figure 2 This is a differential scanning calorimetry (DSC) spectrum of the tranexamic acid ionic liquid in Preparation Example 2 of the present invention (Note: EA - glycolic acid raw material; TA - tranexamic acid raw material; ILs - tranexamic acid ionic liquid in Preparation Example 2). Figure 3 The infrared spectrum of the tranexamic acid ionic liquid in Preparation Example 2 of this invention (Note: Tranexamic Acid - tranexamic acid raw material; Glycolic Acid - glycolic acid raw material; ILs - tranexamic acid ionic liquid in Preparation Example 2). Figure 4 This is an electron micrograph of the microcapsules containing tranexamic acid in Example 1 of the present invention; Figure 5 This is a particle size diagram of the microcapsules containing tranexamic acid in Example 1 of the present invention; Figure 6 This is a statistical chart showing the transdermal retention of microcapsules containing tranexamic acid in Example 1 and Comparative Example 3 of the present invention. Figure 7 These are representative photographs and quantitative statistical charts of melanin inhibition rates in zebrafish containing tranexamic acid microcapsules, as shown in Example 1 and Comparative Example 3 of this invention.

[0050] Figure 8 The graph shows the encapsulation efficiency test results of the microcapsules containing tranexamic acid in Example 1 and Comparative Examples 2 and 3 of this invention. Detailed Implementation

[0051] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0052] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0053] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0054] As used in this article: In these embodiments, unless otherwise specified, the portions and percentages are all by weight.

[0055] "And / or" is used to indicate that one or both of the described situations may occur, for example, A and / or B includes (A and B) and (A or B).

[0056] In the description of this invention, it should be understood that the terms "upper", "lower", "left", "right", "top", "bottom", etc., indicating orientation or positional relationship are only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of this invention.

[0057] To further illustrate the present invention, the following detailed description is provided in conjunction with embodiments, but these should not be construed as limiting the scope of protection of the present invention. Unless otherwise specified, the sources and types of raw materials used in the following embodiments and comparative examples are all commercially available, and the same raw materials were used in parallel experiments.

[0058] Preparation Examples 1-3 and Comparative Preparation Examples 1-4 A method for preparing a tranexamic acid ionic liquid includes the following steps: Tranexamic acid was used as a hydrogen bond co-donor. The hydrogen bond donor and hydrogen bond acceptor were mixed in a 1:1 molar ratio and placed in a container. The hydrogen bond donor and hydrogen bond acceptor are shown in Table 1 below. The container was placed in a 60 ℃ water bath, sealed, heated and stirred for 30 min, and then cooled to room temperature to obtain a solution. The appearance of the solution and the results of detecting whether an ionic liquid was formed are shown in Table 1 below.

[0059] Table 1 - Preparation methods and product appearance of tranexamic acid ionic liquids in the preparation examples and comparative preparation examples of this application. As shown in Table 1 and Figure 1 As shown, it can be seen that when tranexamic acid is used as a hydrogen bond donor in this application, only specific hydrogen bond acceptors such as citric acid, glycolic acid and malic acid can form ionic liquids with tranexamic acid, which is beneficial to improving the stability of tranexamic acid; other hydrogen bond acceptors will precipitate after mixing with tranexamic acid and cannot form ionic liquids.

[0060] Preparation Examples 4-10 and Comparative Preparation Examples 5-6 A method for preparing a tranexamic acid ionic liquid includes the following steps: Tranexamic acid was used as a hydrogen bond co-donor and glycolic acid as a hydrogen bond acceptor. The hydrogen bond donor and acceptor were mixed in a molar ratio of (1-4):(1-11) and placed in a container. The molar ratio of hydrogen bond donor and acceptor is shown in Table 2 below. The container was placed in a 60 ℃ water bath, sealed, heated and stirred for 30 min, and then cooled to room temperature to obtain a solution. The appearance of the solution and the results of detecting whether an ionic liquid was formed are shown in Table 2 below, and its appearance was evaluated.

[0061] Table 2 - Preparation methods and product appearance of tranexamic acid ionic liquids in the preparation examples and comparative preparation examples of this application. Preparation Examples 11-17 and Comparative Preparation Examples 7-8 A method for preparing a tranexamic acid ionic liquid includes the following steps: Tranexamic acid was used as a hydrogen bond co-donor and citric acid as a hydrogen bond acceptor. The hydrogen bond donor and acceptor were mixed in a molar ratio of (1-11):(1-11) and placed in a container. The molar ratio of hydrogen bond donor and acceptor is shown in Table 2 below. The container was placed in a 60 ℃ water bath, sealed, heated and stirred for 30 min, and then cooled to room temperature to obtain a solution. The appearance of the solution and the results of detecting whether an ionic liquid was formed are shown in Table 3 below, and its appearance was evaluated.

[0062] Table 3 - Preparation methods and product appearance of tranexamic acid ionic liquids in the preparation examples and comparative preparation examples of this application. Preparation Examples 18-24 and Comparative Preparation Examples 9-10 A method for preparing a tranexamic acid ionic liquid includes the following steps: Tranexamic acid was used as a hydrogen bond co-donor and malic acid as a hydrogen bond acceptor. The hydrogen bond donor and the hydrogen bond acceptor were mixed in a molar ratio of (1-11):(1-11) and placed in a container. The molar ratio of hydrogen bond donor and hydrogen bond acceptor is shown in Table 2 below. The container was placed in a 60 ℃ water bath, sealed, heated and stirred for 30 min, and then cooled to room temperature to obtain a solution. The appearance of the solution and the results of detecting whether an ionic liquid was formed are shown in Table 4 below, and its appearance was evaluated.

[0063] Table 4 - Preparation methods and product appearance of tranexamic acid ionic liquids in the preparation examples and comparative preparation examples of this application. As shown in Table 2, an ionic liquid (IL) can only be formed when the molar ratio of the hydrogen bond donor tranexamic acid to the hydrogen bond acceptor glycolic acid is within the range of (1-3):(1-10). Beyond this range, an ionic liquid cannot be formed and the liquid does not completely dissolve. Meanwhile, when the molar ratio of the hydrogen bond donor to the hydrogen bond acceptor is controlled within the range of (1-2):(1-4), the tranexamic acid ionic liquid formed has a better appearance and is a transparent, colorless, and homogeneous liquid.

[0064] As shown in Table 3-4, ionic liquids (ILs) can only be formed when the molar ratio of the hydrogen bond donor tranexamic acid to the hydrogen bond acceptor citric acid or malic acid is within the range of (1-10):(1-10). Beyond this range, ionic liquids cannot be formed and the liquids are not completely dissolved.

[0065] Examples 1-11 A method for preparing microcapsules containing tranexamic acid includes the following steps: S1. Mix meadowfoam seed oil, squalane, soybean lecithin, tococelenol, and tranexamic acid ionic liquid (IL), and stir evenly at 70 ℃ and 800 rpm to obtain phase A; S2. Stir the deionized water at a temperature of 70 ℃ and a rotation speed of 800 rpm until homogeneous to obtain phase B; S3. At a speed of 3000 rpm, phase A was added dropwise to phase B. After the addition was completed, the mixture was sheared at 3000 rpm for 4 min to obtain a mixture. The mixture was homogenized 4 times at a temperature of 70 ℃ and a pressure of 600 bar to obtain microcapsules. The components and their contents are shown in Table 5 below.

[0066] Table 5 - Components and mass fraction content in the microcapsules of Examples 1-11 of this application Example 12 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment and process parameters used in each step are the same as those in Example 1. The difference is that the stirring temperature in S1 is 75 °C and in S3, the mixture is homogenized 4 times at a temperature of 75 °C and a pressure of 600 bar.

[0067] Comparative Example 1 A method for preparing a mixed solution containing tranexamic acid, wherein each step and the reagents, equipment and process parameters used in each step are the same as in Example 1, except that the amount of meadowfoam seed oil, squalane, soybean lecithin and glyceryl stearate added is 0.

[0068] Comparative Example 2 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment and process parameters used in each step are the same as those in Example 1. The difference is that the tranexamic acid ionic liquid in Example 2 is prepared by replacing the tranexamic acid raw material with tranexamic acid, and the mass fraction of tranexamic acid is 5.4%.

[0069] Comparative Example 3 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment, and process parameters used in each step are the same as those in Example 1. The difference is that the tranexamic acid ionic liquid in Preparation Example 2 is prepared by replacing tranexamic acid and glycolic acid raw materials. The molar ratio of tranexamic acid to glycolic acid is 1:1. The total amount of tranexamic acid and glycolic acid is the same as that in Preparation Example 2. In S1, tranexamic acid and glycolic acid are added simultaneously with other components in phase A.

[0070] Comparative Example 4 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment, and process parameters used in each step are the same as those in Example 6. The difference is that the tranexamic acid ionic liquid in Preparation Example 1 is prepared by replacing tranexamic acid and citric acid raw materials. The molar ratio of tranexamic acid to citric acid is 1:1. The total amount of tranexamic acid and citric acid is the same as that in Preparation Example 1. In S1, tranexamic acid and citric acid are added simultaneously with other components in phase A.

[0071] Comparative Example 5 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment, and process parameters used in each step are the same as those in Example 7. The difference is that the tranexamic acid ionic liquid in Preparation Example 3 is prepared by replacing tranexamic acid and malic acid raw materials. The molar ratio of tranexamic acid to malic acid is 1:1. The total amount of tranexamic acid and malic acid is the same as that in Preparation Example 3. In S1, tranexamic acid and malic acid are added simultaneously with other components in phase A.

[0072] Comparative Example 6 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment, and process parameters used in each step are the same as those in Example 1. The difference is that the tranexamic acid ionic liquid in Preparation Example 2 is replaced by an equal amount of the tranexamic acid ionic liquid in Comparative Preparation Example 1.

[0073] Comparative Example 7 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment, and process parameters used in each step are the same as those in Example 1. The difference is that the tranexamic acid ionic liquid in Preparation Example 2 is replaced by an equal amount of the tranexamic acid ionic liquid in Comparative Preparation Example 2.

[0074] Comparative Example 8 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment, and process parameters used in each step are the same as those in Example 1. The difference is that the tranexamic acid ionic liquid in Preparation Example 2 is replaced by an equal amount of the tranexamic acid ionic liquid in Comparative Preparation Example 3.

[0075] Comparative Example 9 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment, and process parameters used in each step are the same as those in Example 1. The difference is that the tranexamic acid ionic liquid in Preparation Example 2 is replaced by an equal amount of the tranexamic acid ionic liquid in Comparative Preparation Example 4.

[0076] Comparative Example 10 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment, and process parameters used in each step are the same as those in Example 1. The difference is that the tranexamic acid ionic liquid in Preparation Example 2 is replaced by an equal amount of the tranexamic acid ionic liquid in Comparative Preparation Example 5.

[0077] Comparative Example 11 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment, and process parameters used in each step are the same as those in Example 1. The difference is that the tranexamic acid ionic liquid in Preparation Example 2 is replaced by an equal amount of the tranexamic acid ionic liquid in Comparative Preparation Example 6.

[0078] Comparative Example 12 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment and process parameters used in each step are the same as those in Example 1. The difference is that the stirring temperature in S1 is 80 °C and in S3, the mixture is homogenized 4 times at a temperature of 80 °C and a pressure of 600 bar.

[0079] Comparative Example 13 A method for preparing microcapsules containing tranexamic acid is provided. The steps, reagents, equipment and process parameters used in each step are the same as those in Example 1. The difference is that the stirring temperature in S1 is 65 °C and in S3, the mixture is homogenized 4 times at a temperature of 65 °C and a pressure of 600 bar.

[0080] Performance testing 1. Determination of Ionic Liquids: The formation of ionic liquids is determined by a combination of macroscopic phase observation, microscopic structure characterization, and thermodynamic analysis. First, the macroscopic phase is used as an initial screening standard. If the reaction system transforms into a homogeneous, transparent liquid without solid residue and does not separate into layers after prolonged standing at room temperature (25 °C), it is considered to have initially formed. Second, the microstructure is confirmed by FT-IR spectroscopy. The peak broadening and redshift in the 3000-3500 cm⁻¹ region confirm the construction of a dense hydrogen bond network, and the disappearance or smoothing of the sharp crystal characteristic peaks in the fingerprint region (500-1500 cm⁻¹) confirms the destruction of the raw material lattice structure and the transition to liquid disorder. Finally, DSC thermal analysis is used as a thermodynamic criterion. If the mixture no longer shows the characteristic endothermic melting peaks of the raw material, but instead exhibits a glass transition temperature (Tg) below room temperature or a single eutectic melting point (Tm < 100 °C), the successful construction of the ionic liquid system is finally confirmed.

[0081] (1) The formation of ionic liquids was characterized and verified by differential scanning calorimetry (DSC). The melting point of the ionic liquid sample and the melting points of the hydrogen bond donor and acceptor monomers were determined using a differential scanning calorimeter. Taking Preparation Example 2 as an example, the test conditions were set as follows: under a nitrogen protective atmosphere, the heating rate was 10 °C / min, and the test temperature range covered from -50 °C to 350 °C. The DSC curve of the ionic liquid obtained from Preparation Example 2 is shown below. Figure 2 As shown.

[0082] like Figure 2 As shown, the DSC curve of pure tranexamic acid (TA) exhibits its characteristic bulk thermal behavior, with a characteristic endothermic peak appearing around 300 °C. However, the DSC curve of the solution product from Preparation Example 2 of this invention completely fails to reflect the characteristic thermal signal of TA, and shows no phase transition signals such as crystallization or melting peaks within a wide temperature range of -50 °C to 350 °C, exhibiting the wide-temperature-range homogeneous liquid thermal behavior characteristic of ionic liquids. These differences in the DSC curves directly prove that an ionic bonding reaction occurred between tranexamic acid and glycolic acid in Preparation Example 2, successfully generating an ionic liquid.

[0083] (2) The infrared spectra of the ionic liquids prepared in the preparation examples and the comparative preparation examples were measured using a Fourier transform infrared spectrometer (IRSpirit, Shimadzu Corporation, Tokyo, Japan), and the infrared spectra of the hydrogen bond donors and hydrogen bond acceptors in the ionic liquids were measured simultaneously. Taking Preparation Example 2 as an example, the infrared spectrum of the tranexamic acid ionic liquid prepared therefrom is shown below. Figure 3 As shown, firstly, in the spectra of the raw materials tranexamic acid and glycolic acid, the 3000-3500 cm⁻¹... -1 The region primarily corresponds to the stretching vibrations of OH and NH. Comparison with the spectra of ionic liquids reveals an extremely broad and strong absorption band in this region. This significant peak broadening and shift are typical signals of strong hydrogen bond formation, indicating that a broad and complex intermolecular hydrogen bond network has formed between the amino / carboxyl groups of tranexamic acid and the hydroxy / carboxyl groups of glycolic acid. It is this strong hydrogen bond interaction that disrupts the original crystal lattice structure of the raw materials, driving the formation of the eutectic system.

[0084] Secondly, glycolic acid is at approximately 1700-1750 cm. -1 The peak exhibits a sharp C=O stretching vibration of carboxylic acid at 1500-1650 cm⁻¹. In ionic liquid spectra, this carbonyl peak still exists but has broadened significantly, and it overlaps with tranexamic acid in the 1500-1650 cm⁻¹ range. -1The characteristic peaks of amino / carboxylate groups in the region partially overlapped and merged. This further confirms that the carboxyl groups participated in proton transfer or hydrogen bond donor / acceptor interactions within the system, leading to a change in its chemical environment rather than a simple physical mixing.

[0085] Finally, the crystal structure disappeared (fingerprint region 500-1500 cm). -1 In the fingerprint region, tranexamic acid exhibits numerous sharp and highly separated characteristic peaks, a typical feature of its highly crystalline solid nature. However, in the ionic liquid spectrum, these sharp crystalline characteristic peaks mostly disappear or become smooth. This loss of spectral detail indicates that the long-range ordered crystal structure of the raw material has been completely destroyed, and the system has transformed into a disordered amorphous / liquid structure. In summary, this infrared spectroscopy confirms that the reaction between tranexamic acid and glycolic acid is not a simple physical mixture, but rather a successful disruption of the initial lattice energy of each component through the formation of a dense intermolecular hydrogen bond network, thereby forming a homogeneous and stable ionic liquid / eutectic solvent system at room temperature.

[0086] 2. Particle Size Stability: The appearance, particle size, and particle size stability of the microcapsules prepared in the examples and comparative examples were tested. The appearance of the microcapsules was observed visually; the microstructure of the microcapsules was observed using a scanning electron microscope. Taking Example 1 as an example, its electron microscope image is shown below. Figure 4 As shown; the particle size and particle size distribution of the microcapsules were determined using a particle size analyzer. Taking Example 1 as an example, its particle size distribution is shown in the figure. Figure 5 As shown in Table 6, each microcapsule was stored at room temperature and 45 ℃ for 3 months. The particle size of the microcapsules was tested before and after three months of storage.

[0087] 3. Retention rate of whitening active ingredients: The stability of the whitening active ingredient (tranexamic acid) content in the microcapsules prepared in the examples and comparative examples was tested. The tranexamic acid content in the microcapsule samples was determined by high performance liquid chromatography (HPLC). The test method is as follows: the standard tranexamic acid was diluted to a concentration of 1000 ppm; the microcapsule test sample was diluted to 0.1 μg / mL in the same way. A C18 column (150 mm × 4.6 mm; 5 μm) was selected, and the mobile phase was a methanol-water solution containing 0.23% sodium dodecyl sulfate (SDS), which included 40 wt% methanol. The flow rate was 0.9 mL / min. The retention rate of the whitening active ingredient of each microcapsule was tested after being placed at different temperatures (-15 ℃, 25 ℃, 45 ℃) for three months. The test results are shown in Table 6 below.

[0088] 4. Transdermal Retention of Whitening Active Ingredients: The permeability of the microcapsules prepared in the examples and comparative examples was tested. The test method is as follows: Fresh pigskin with uniform pretreatment thickness was fixed between a diffusion pool and a receiving pool, with the diffusion pool above the receiving pool; microcapsule test samples were added to the diffusion pool, and physiological saline was added to the receiving pool. The microcapsule samples were in contact with the surface layer of the pigskin, and the physiological saline was in contact with the inner layer of the pigskin. An electromagnetic stirrer and a constant temperature water bath were turned on in the diffusion pool. The diffusion test was carried out under the conditions of a stirring speed of 320 rpm and a temperature of 32 ℃. Pigskin samples were taken 4 hours after the start of the diffusion test, cut into pieces, left overnight, extracted, and the retention of whitening active ingredients (using tranexamic acid as the test object) in the pigskin of each microcapsule sample was measured. The test results are shown in Table 6 below. Figure 6 As shown.

[0089] Table 6 - Performance test results of microcapsules prepared in the embodiments and comparative examples of this application As shown in Table 6, the microcapsules of the embodiments retained more than 80% of their whitening active ingredients after being stored at different temperatures (-15 ℃, 25 ℃, 45 ℃) for 3 months, compared with before storage. In contrast, the microcapsules of Comparative Examples 1-4 retained between 50% and 70% of their whitening active ingredients after being stored at different temperatures (-15 ℃, 25 ℃, 45 ℃) for 3 months. This indicates that the microcapsules prepared in the embodiments of the present invention have good temperature resistance and storage stability, and the content of whitening active ingredients in the microcapsules is less affected by temperature, which can improve the storage period.

[0090] As shown in Table 6, the retention rate of the whitening active ingredient in the microcapsules prepared in the examples within the pigskin was 20 µg / cm³. 2 The whitening active ingredient in the microcapsules prepared in the comparative proportion was retained in pigskin at a concentration of 10 µg / cm³. 2 Furthermore, compared with the microcapsules of Comparative Example 3, the permeation-enhancing effect of the microcapsules prepared in Example 1 was increased by 4 times, indicating that the whitening active ingredients of the microcapsules prepared in this embodiment of the invention have a higher retention rate in pig skin and a better permeation-enhancing effect.

[0091] Compared to Example 1, Comparative Example 3 used a physical mixture of tranexamic acid and glycolic acid instead of an ionic liquid. The resulting microcapsules initially had a particle size exceeding 800 nm, and exhibited explosive growth in particle size (>5000 nm) after storage. This indicates that the ionic liquid in this application is not a simple acid-base coexistence, but rather forms a stable supramolecular network through hydrogen bond acceptor interactions. In Comparative Example 3, due to the lack of this supramolecular ionic liquid morphology, the highly polar tranexamic acid monomer could not be effectively encapsulated by the lipid wall material, and it caused disturbance to the oil-water interface, resulting in a loose and porous microcapsule interfacial membrane. During storage, due to the Ostwald ripening effect, the internal phase substances within small droplets easily migrated through the loose interfacial membrane to larger droplets, causing the system to rapidly coarsen and stratify. Simultaneously, the lack of an ionic liquid structure prevented the active ingredient from shielding its polarity through ion-pair effects, resulting in no improvement in its lipophilicity and difficulty in penetrating the stratum corneum barrier. Therefore, the intradermal retention of Comparative Example 3 was significantly lower than that of Example 1.

[0092] Compared to Example 1, the microcapsule preparation temperature of Comparative Example 12 was 80 °C, and that of Comparative Example 13 was 65 °C. Table 6 shows that there is a narrow and critical process window for microcapsule preparation temperature. At the excessively low temperature of Comparative Example 13, the lipid wall material (phospholipid / torcoxexyl) lacks fluidity and cannot rapidly spread to form a dense interfacial film during homogenization, resulting in incomplete mechanical encapsulation. At the excessively high temperature of Comparative Example 12, the excessively vigorous molecular thermal motion disrupts the weak interactions (hydrogen bonds / van der Waals forces) between the ionic liquid and the wall material, leading to phase separation or thermal instability during microcapsule self-assembly. In contrast, this application, within a suitable temperature range of 70-75 °C, exhibits both suitable rheological properties and thermodynamic stability, thus enabling the preparation of microcapsules with uniform particle size (approximately 150 nm), long-term storage stability, and excellent transdermal performance.

[0093] 5. Zebrafish Melanin Inhibition Experiment: The microcapsules prepared in Example 1 and Comparative Example 3 were subjected to a zebrafish melanin inhibition experiment to evaluate their whitening efficacy. The test method is as follows: Wild-type AB line zebrafish embryos with synchronized development were selected and cultured in embryo culture medium containing PTU (1-phenyl-2-thiourea, which inhibits endogenous melanin production) until 48 hpf (hours postfertilization). The test samples were prepared into drug solutions with a final concentration of 100 μg / mL. Each group consisted of 30 embryos. The positive control group was the whitening agent arbutin (100 μg / mL), and the blank control group was the embryo culture medium. After drug administration, zebrafish were cultured to 72 hpf. The distribution of melanin on the zebrafish surface was observed and photographed using a stereomicroscope. ImageJ software was used to quantitatively analyze the melanin area in the head and trunk regions of the zebrafish, and the melanin inhibition rate was calculated. Melanin was extracted using DMSO, and the absorbance at OD450 was measured to calculate the melanin inhibition rate. The calculation formula was: Melanin inhibition rate (%) = (Melanin area of ​​blank control group - Melanin area of ​​drug-treated group) / Melanin area of ​​blank control group × 100%. The experiment was repeated three times, and the test results are as follows. Figure 7 As shown in Table 7.

[0094] Table 7 - Experimental results of zebra melanin inhibition in Examples 1 and 3 of this application. As shown in Table 7, the relative melanin content in the blank control group was 100%; the melanin content in the zebrafish skin of the microcapsule administration group in Example 1 was significantly reduced, with an average relative melanin content of 85.87% and a melanin inhibition rate of 14.13%; the relative melanin content in the microcapsule administration group in Comparative Example 3 was an average of 69.40%, with a melanin inhibition rate of 30.60%. Compared with the blank control group, the melanin inhibition effect of the microcapsule group in Comparative Example 3 was more significant. Although the inhibition rate of the microcapsules in Example 1 was slightly lower than that in Comparative Example 3, combined with other effects such as transdermal retention, particle size, and stability advantages, it indicates that its overall whitening, penetration-promoting, and safety performance is better.

[0095] 6. Microcapsule Encapsulation Efficiency Determination: The encapsulation efficiency of the microcapsules containing tranexamic acid prepared in Example 1 and Comparative Examples 2-3 was tested to evaluate the loading capacity of the microcapsules for the active ingredient. The test method is as follows: The encapsulation efficiency of the microcapsules was determined by ultrafiltration centrifugation. An appropriate amount of the microcapsule test solution was placed in an ultrafiltration centrifuge tube (molecular weight cutoff 10 kDa), centrifuged at 4 ℃ and 10000 rpm for 30 min, and the lower supernatant was collected. The content of free tranexamic acid in the lower supernatant was determined by high performance liquid chromatography (HPLC). At the same time, an equal amount of the microcapsule test solution was taken, and an appropriate amount of anhydrous ethanol was added for ultrasonic demulsification. After complete demulsification, the total content of tranexamic acid in the microcapsule system was determined by HPLC. The encapsulation efficiency (EE, %) was calculated as follows: Encapsulation efficiency (%) = (1 - free tranexamic acid content / total tranexamic acid content) × 100%; each sample was measured in triplicate and the average value was taken. The test results are as follows. Figure 8 As shown in Table 8.

[0096] Table 8 - Encapsulation efficiency test results of microcapsules prepared in Example 1 and Comparative Examples 2-3 of this application As shown in Table 8, the encapsulation efficiency of the microcapsules (ILs-NPs) containing tranexamic acid-glycolic acid ionic liquid prepared in Example 1 of this invention reached 76.3±1.3%, significantly better than the 32.1±5.2% of Comparative Example 3 (which did not form an ionic liquid, but was only a physical mixture of tranexamic acid and glycolic acid). This indicates that by combining tranexamic acid as a hydrogen bond donor and hydrogen bond acceptor to form a supramolecular ionic liquid form, the strong polarity and high water solubility of tranexamic acid can be effectively reduced, significantly increasing its affinity with the microcapsule lipid wall materials (such as meadowfoam seed oil, squalane, and emulsifiers). During the self-assembly process of microcapsule preparation, the active ingredients in the ionic liquid form are more easily and effectively encapsulated in the internal ionic liquid phase, thereby achieving a high encapsulation efficiency. In contrast, the tranexamic acid in Comparative Examples 2-3, due to its lack of ionic liquid formation, high polarity and excessive water solubility, easily escapes into the external aqueous phase during emulsification and homogenization, resulting in extremely low encapsulation efficiency and making it difficult to achieve effective sustained release and permeation-encapsulation of microcapsules.

[0097] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above descriptions are merely specific embodiments of the present invention and are not intended to limit the scope of protection of the present invention. In particular, it should be noted that any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention for those skilled in the art.

Claims

1. A tranexamic acid ionic liquid, characterized in that, It includes a hydrogen bond donor and a hydrogen bond acceptor in a molar ratio of (1-10):(1-10), wherein the hydrogen bond donor is tranexamic acid and the hydrogen bond acceptor includes at least one of citric acid, glycolic acid and malic acid.

2. The tranexamic acid ionic liquid as described in claim 1, characterized in that, When the hydrogen bond acceptor is glycolic acid, the molar ratio of the hydrogen bond donor to the hydrogen bond acceptor is (1-3):(1-10). And / or, when the hydrogen bond acceptor is citric acid and / or malic acid, the molar ratio of the hydrogen bond donor to the hydrogen bond acceptor is (1-10):(1-10).

3. The tranexamic acid ionic liquid as described in claim 1, characterized in that, The molar ratio of the hydrogen bond donor to the hydrogen bond acceptor is (1-2):(1-4).

4. A method for preparing a tranexamic acid ionic liquid as described in any one of claims 1-3, characterized in that, Includes the following steps: After mixing the hydrogen bond donor and the hydrogen bond acceptor, the mixture is heated and stirred in a sealed water bath at 40-90 ℃ for 20-120 min, and then cooled to room temperature to obtain an ionic liquid.

5. A method for preparing microcapsules containing tranexamic acid, characterized in that, The method of using the tranexamic acid ionic liquid as described in any one of claims 1-3 includes the following steps: S1. Mix the oil, emulsifier and the tranexamic acid ionic liquid, and stir evenly at a temperature of 70-75 ℃ to obtain phase A. Stir the water evenly to obtain phase B. S2. Under stirring conditions, phase A is added dropwise to phase B and stirred until homogeneous to obtain a mixture. The mixture is then homogenized at a temperature of 70-75 ℃ to obtain microcapsules.

6. The method for preparing microcapsules containing tranexamic acid as described in claim 5, characterized in that, The oil constitutes 1%-20% of the mass fraction of the microcapsules; And / or, the emulsifier accounts for 2%-8% of the mass fraction of the microcapsules; And / or, the tranexamic acid ionic liquid accounts for 1%-20% of the mass fraction of the microcapsules.

7. The method for preparing microcapsules containing tranexamic acid as described in claim 5, characterized in that, In S1, the oil includes at least one of olive oil, grapeseed oil, camellia oil, squalane, jojoba oil, shea butter, and meadowfoam seed oil; And / or, the emulsifier includes at least one of soybean lecithin, Tween 80, tococelen, polyglycerol-3-methylglucose distearate, PEG-40 hydrogenated castor oil, stearyl alcohol polyether-2, inulin lauryl carbamate, docosyl alcohol, polysorbate-60, PEG-15 glyceryl lauryl ester, and glyceryl stearate.

8. A microcapsule containing tranexamic acid prepared by the method for preparing microcapsules containing tranexamic acid as described in any one of claims 5-7.

9. The application of the microcapsule containing tranexamic acid as described in claim 8 in the field of skin whitening products.

10. A skin whitening preparation, characterized in that, Including the tranexamic acid-containing microcapsules as described in claim 8.

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