Tranexamic acid-tyrosinase inhibitor hybrid conjugate as well as preparation method and application thereof

Abstract

The invention discloses a tranexamic acid-tyrosinase inhibitor hybrid conjugate as well as a preparation method and application thereof, belongs to the technical field of cosmetics and biological medicines, and particularly relates to a tranexamic acid-tyrosinase inhibitor hybrid conjugate shown in a formula (I) and a skin composition taking the compound as an active component. According to the hybrid conjugate, tranexamic acid and a tyrosinase inhibitor are integrated into a single-structure molecule through an ester bond, so that the transdermal efficiency can be improved and the transdermal dynamic difference limitation of a traditional compound preparation can be broken through by adjusting the hydrophilic-hydrophobic balance of the compound; and plasmin activity can be inhibited through cooperation of tranexamic acid, so that melanin generation signal transmission capability and tyrosinase inhibition capability of tyrosinase inhibitor specificity are reduced, and efficient and mild multi-channel whitening and spot fading are realized. As a whitening active matter, the tranexamic acid-tyrosinase inhibitor hybrid conjugate disclosed by the invention has a great application prospect in the aspects of whitening and freckle removing effects.

Description

Technical Field

[0001] This invention belongs to the fields of cosmetics and biomedicine, specifically relating to a tranexamic acid-tyrosinase inhibitor hybrid conjugate, its preparation method, and its application in skin whitening and spot removal or in inhibiting melanin production. Background Technology

[0002] Current mainstream active ingredients in whitening skincare products, including phenylethyl resorcinol, arbutin, vitamin C derivatives, and niacinamide, generally suffer from low transdermal efficiency and limited mechanisms of action. Although the biological pathways of melanin production (such as tyrosinase activation, oxidative stress, and inflammatory signal transduction) have been well elucidated, existing ingredients struggle to achieve multi-target synergistic inhibition, resulting in suboptimal spot-fading efficacy. Furthermore, plant extracts and peptides have remained at technological bottlenecks due to high concentration requirements and poor stability. The market urgently needs to develop novel whitening active ingredients that combine highly efficient transdermal absorption with multi-pathway synergistic mechanisms to meet continuously evolving consumer demands.

[0003] Tranexamic acid, a skin-whitening ingredient derived from the medical field, has demonstrated its dual efficacy in fading dark spots and reducing inflammation through some commercially available products. Ultraviolet (UV) radiation induces keratinocytes to release prostaglandins (PGE2), thereby activating melanin production signals. Tranexamic acid can effectively inhibit plasminogen activation and reduce PGE2 release, thus blocking melanin synthesis at its source. However, this molecule has extremely strong hydrophilic properties (LogP = -2.24), resulting in a transdermal absorption rate of less than 5%, which prevents it from effectively penetrating the stratum corneum to target the basal layer of the skin. This structural defect severely limits its clinical efficacy and has become a core obstacle to its industrial application.

[0004] Tyrosinase is a key enzyme in melanin production by melanocytes, and it is produced exclusively by melanocytes. Therefore, tyrosinase inhibitors, by directly inhibiting the catalytic activity of tyrosinase, have become the most prominent and effective intervention for reducing melanin production. Tyrosinase inhibitors such as hydroquinone derivatives, arbutin, kojic acid, azelaic acid, L-ascorbic acid, ellagic acid, and tranexamic acid have been used as whitening agents in most cosmetics on the market, improving skin condition by whitening and fading dark spots. However, the tyrosinase inhibitors currently used in commercially available products generally suffer from multiple limitations, including hydrophilic-hydrophobic imbalance, low transdermal efficiency, and a single mechanism of action.

[0005] Molecular hybrid theory offers innovative solutions to the aforementioned technical bottlenecks through chemical bond recombination and energy level matching optimization. Guided by this theory, hydrophilic tranexamic acid residues can be hybridized with tyrosinase inhibitors via ester bonds through the targeted assembly of functional modules, reconstructing the molecular spatial conformation and regulating the hydrophilic-hydrophobic balance to improve transdermal efficiency. The novel hybrid conjugates rapidly degrade into tranexamic acid and tyrosinase inhibitor prototype molecules within the skin. This integrates the ability of tranexamic acid to inhibit plasmin activity and thus reduce melanin production signal transduction with the specific tyrosinase inhibitor's action, creating a synergistic system with a clearly defined in vivo metabolic pathway. Furthermore, its synthetic process is highly controllable, significantly reducing development risks and accelerating industrialization. This theory lays the methodological foundation for creating "high-penetration, multi-pathway, low-risk" skin-whitening active ingredients, possessing significant value in filling a technological gap in the industry. Summary of the Invention

[0006] The purpose of this invention is to provide a highly efficient tranexamic acid-tyrosinase inhibitor hybrid conjugate with skin whitening effects, and also relates to the preparation method of the above-mentioned compound and its application in the field of skin whitening and spot removal or in inhibiting melanin production.

[0007] Tranexamic acid-tyrosinase inhibitor hybrid conjugates were constructed using molecular hybridization techniques. Chemically, the carboxyl group of tranexamic acid is bonded to the hydroxyl group of the tyrosinase inhibitor via an easily degradable ester bond. The resulting hybrid conjugate exhibits better hydrophilicity-hydrophobicity balance and higher transdermal absorption efficiency compared to tranexamic acid or the tyrosinase inhibitor alone. In terms of synergistic function, the tranexamic acid-tyrosinase inhibitor hybrid conjugate can be degraded by endogenous enzymes into tranexamic acid and the tyrosinase inhibitor during transdermal absorption. This integrates the ability of tranexamic acid to inhibit plasmin activity and thus reduce melanin production signal transduction with the specific tyrosinase inhibitor's action, creating a synergistic system.

[0008] The tranexamic acid-tyrosinase inhibitor hybrid conjugate provided by this invention has not been reported in the field of skin whitening and freckle removal technology, and has significant innovation.

[0009] To achieve the above objectives, the present invention provides the following solution: One of the technical solutions of this invention: This invention discloses a tranexamic acid-tyrosinase inhibitor hybrid conjugate designed based on molecular hybridization theory, or its pharmaceutically or cosmetically acceptable salt, ester, solvate, or stereoisomer. This hybrid conjugate uses an ester bond (-C(=O)-O-) formed between the carboxyl group of tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) and the hydroxyl group of the tyrosinase inhibitor as the connecting unit. It has the structure shown in general formula (I):

[0010] TI stands for the molecular residue of a tyrosinase inhibitor.

[0011] The aforementioned tyrosinase inhibitors are compound molecules that have tyrosinase inhibitory activity and contain hydroxyl groups.

[0012] Furthermore, the tyrosinase inhibitors include, but are not limited to, the following compounds: 4-butylresorcinol, 4-hexylresorcinol, phenylethylresorcinol, dimethoxytolylresorcinol, isobutyramidothiazolylresorcinol, hydroquinone, kojic acid, arbutin, arbutin decanter, glycyrrhizin, catechin, quercetin, ascorbic acid, hexyl ascorbate, ellagic acid, morin, resveratrol, perillol, and trans-p-hydroxycinnamic acid.

[0013] The above compounds are prepared by reacting tranexamic acid or its reactive derivatives with a hydroxyl-containing tyrosinase inhibitor in an inert organic solvent and connecting them by ester bonds to obtain the corresponding heteropolymer conjugates.

[0014] The reactive derivatives of tranexamic acid are those in which the carboxyl group is activated, including its acyl chloride, acid anhydride, or active ester forms.

[0015] The acyl chloride is prepared by reacting tranexamic acid with a chlorinating reagent, wherein the chlorinating reagent is selected from at least one of thionyl chloride and oxalyl chloride.

[0016] The inert organic solvent is selected from at least one of dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, ethyl acetate, acetone, toluene, benzene, pyridine, 2,6-dimethylpyridine, or a mixture thereof.

[0017] The reaction temperature is from -20°C to the reflux temperature of the solvent, preferably from 0°C to 50°C.

[0018] The above synthesis method also includes a post-processing step, which includes washing, extraction, drying and concentration; and / or a purification step, which can be selected according to the properties and purity requirements of the target analyte, including recrystallization, column chromatography (such as silica gel column chromatography, ion exchange column chromatography, affinity chromatography, etc.), preparative high performance liquid chromatography, as well as extraction, distillation (including vacuum distillation and steam distillation), dialysis, ultrafiltration and other methods, or a combination of multiple techniques to achieve efficient purification.

[0019] The second technical solution of the present invention: the obtained free base form of the hybrid coupling reacts with a pharmaceutically or cosmetically acceptable acid to form the corresponding salt form.

[0020] The acid is selected from any one of lactic acid, malic acid, citric acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, succinic acid, benzenesulfonic acid, and acetic acid.

[0021] The third technical solution of the present invention provides a skin composition, the active ingredient of which includes a tranexamic acid-tyrosinase inhibitor hybrid conjugate or a combination thereof prepared by reacting the above-mentioned tranexamic acid with any tyrosinase inhibitor.

[0022] Furthermore, the composition for skin use also includes a solvent. The solvent includes one or more of the following: phosphate buffer solution, sterile water, physiological saline, dimethyl sulfoxide, propylene glycol, polyethylene glycol, glycerin, and vegetable oil.

[0023] Furthermore, the skin composition also includes at least one cosmetically or pharmaceutically acceptable excipient; the excipient includes, but is not limited to, moisturizers (such as hyaluronic acid, panthenol), keratinizers (such as glycolic acid, salicylic acid), antioxidants (such as pure vitamin C, ferulic acid), thickeners (such as carbomer), preservatives (such as phenoxyethanol), etc.

[0024] The skin composition can be prepared into various dosage forms such as creams, ointments, foams, lotions, serums, films, lotions, essences, gels, cosmetic coatings, facial cleansers, patches, and masks.

[0025] Furthermore, the tranexamic acid-tyrosinase inhibitor hybrid conjugate is present in the skin composition at a mass concentration of 0.01 wt%-20 wt%, preferably 0.1 wt%-5 wt%.

[0026] The fourth technical solution of the present invention provides the use of a tranexamic acid-tyrosinase inhibitor hybrid conjugate or a combination thereof, or a pharmaceutically or cosmetically acceptable salt, ester, solvate or stereoisomer thereof, prepared by reacting the above-mentioned tranexamic acid with any tyrosinase inhibitor, in the preparation of tyrosinase inhibitors.

[0027] The fifth technical solution of the present invention provides the use of a tranexamic acid-tyrosinase inhibitor hybrid conjugate or a combination thereof, or a pharmaceutically or cosmetically acceptable salt, ester, solvate or stereoisomer thereof, as an active ingredient in the preparation of a topical skin preparation, wherein the preparation is used to prevent, treat, reduce or lighten skin pigmentation.

[0028] Furthermore, the skin pigmentation includes, but is not limited to, melasma, pregnancy spots, freckles, sun spots, post-inflammatory hyperpigmentation, and age spots.

[0029] The sixth technical solution of the present invention provides the use of a tranexamic acid-tyrosinase inhibitor hybrid conjugate or a combination thereof, or a pharmaceutically or cosmetically acceptable salt, ester, solvate or stereoisomer thereof, as an active ingredient in the preparation of skin whitening and spot-removing products, obtained by reacting the above-mentioned tranexamic acid with any tyrosinase inhibitor.

[0030] The seventh technical solution of the present invention provides the use of a tranexamic acid-tyrosinase inhibitor hybrid conjugate or a combination thereof, or a pharmaceutically or cosmetically acceptable salt, ester, solvate or stereoisomer thereof, as an active ingredient in the preparation of a product that inhibits melanin production, obtained by reacting the above-mentioned tranexamic acid with any tyrosinase inhibitor.

[0031] Optionally, in the above applications of the present invention, the formulation / product dosage form includes any one of cream, ointment, foam, emulsion, serum, film, lotion, essence, gel, cosmetic coating, facial cleanser, patch, and mask.

[0032] Compared with the prior art, the beneficial effects of the present invention include, but are not limited to: 1. This invention, for the first time, designs a tranexamic acid-tyrosinase inhibitor hybrid conjugate based on molecular hybrid theory. Tranexamic acid or its reactive derivatives react with a hydroxyl-containing tyrosinase inhibitor in an inert organic solvent to obtain a hybrid conjugate linked by ester bonds. This synthetic process is simple, highly efficient, and generally applicable to tyrosinase inhibitor molecules containing hydroxyl groups. 2. This invention also discovers for the first time that the tranexamic acid-tyrosinase inhibitor hybrid conjugate designed based on molecular hybrid theory can efficiently inhibit tyrosinase activity, effectively inhibit melanin production, and has whitening and skin-lightening effects. 3. The tranexamic acid-tyrosinase inhibitor hybrid conjugate of this invention has a more suitable hydrophilic-hydrophobic balance, high transdermal penetration efficiency, and can degrade into the prototype molecules of tranexamic acid and tyrosinase inhibitor within skin tissue, synergistically exerting whitening and skin-lightening effects. 4. Compared to existing whitening ingredients, the tranexamic acid-tyrosinase inhibitor hybrid conjugate disclosed in this invention has superior or approximately equivalent activity and safety, providing a new raw material option for whitening products. 5. The present invention also provides a skin composition comprising an effective amount of a tranexamic acid-tyrosinase inhibitor heteropolymer conjugate and pharmaceutically or cosmetically acceptable excipients. Attached Figure Description

[0033] Figures 1-2 : 1H NMR and mass spectra of tranexamic acid-4-butylresorcinol hybrid conjugate; Figures 3-4: 1H NMR and mass spectra of the tranexamic acid-4-hexylresorcinol hybrid conjugate; Figures 5-6 : T1 NMR and mass spectra of the tranexamic acid-phenylethyl resorcinol hybrid coupling compound; Figures 7-8 : T1N NMR and mass spectra of tranexamic acid-kojic acid hybrid couplings; Figures 9-10 : T1N NMR and mass spectra of tranexamic acid-ascorbic acid hybrid conjugate; Figures 11-12 : T1N NMR and mass spectra of the tranexamic acid-hexyl ascorbate hybrid conjugate; Figures 13-14 : T1N NMR and mass spectra of the tranexamic acid-arbutin succinate hybrid conjugate; Figure 15 The inhibitory activity of tranexamic acid-tyrosinase inhibitor hybrid conjugate on melanin production in B16F10 cells; Figure 16 Tranexamic acid-tyrosinase inhibitor hybrid conjugates inhibit tyrosinase activity in B16F10 cells; Figure 17 Mass spectrum of metabolites of tranexamic acid-4-butylresorcinol hybrid conjugate in mouse skin tissue. Detailed Implementation

[0034] Unless otherwise stated, all technical and scientific terms have the meanings conventionally understood by one of ordinary skill in the art to which this invention pertains. In the embodiments, experimental methods not specified are conventional methods, and materials and reagents not specified in origin are commercially available; the purchase method does not affect the achievement of the technical effect. All components in the embodiments of this invention are expressed as a percentage by mass.

[0035] It should be understood that the terms "comprising," "including," "having," and "containing" used in this article are all open-ended terms, meaning that they include but are not limited to the listed elements. The term "or" is an inclusive statement, which is valid if any of the following conditions are met: A exists but B does not exist; A does not exist but B exists; or A and B exist simultaneously.

[0036] Certain parts of this document use terms such as "a," "an," "an," and "the," or similar terms to describe the components and technical features of the present invention. Such descriptions are for convenience only and to provide a general meaning for the technical features of the present invention. Therefore, unless otherwise specified, such descriptions should be understood to include one or at least one, and the singular also includes the plural.

[0037] The following definitions apply throughout the text: Skin whitening refers to the application of topical preparations, medical aesthetic interventions, or oral active ingredients to the skin. Following application, the skin's core quantitative indicators (such as the L value in the CIE Lab color space, where a higher value indicates a lighter skin tone) are measured using professional skin color measurement instruments (such as spectrophotometers and skin colorimeters) under standardized conditions (same light source, same measurement site, same measurement angle, constant temperature and humidity environment, and avoidance of direct ultraviolet radiation for more than 1 hour). The improvement is at least 5% (preferably >10%, ideally >20%) compared to the baseline value before intervention. This change must be statistically significant (excluding random errors through t-tests and other analyses) and clinically / application-related (visible to the naked eye or associated with effects such as fading of pigmentation or improvement of uneven skin tone). Applicable areas include human skin tissues such as the face, neck, chest, arms, back, legs, and scalp, as well as animal skin tissues (such as the back and ear skin of laboratory mice and rabbits, used for in vitro / in vivo efficacy evaluation of whitening active ingredients).

[0038] Hydroxyl group: refers to the -OH group.

[0039] Pharmacologically or cosmetically acceptable salts: These are salts that are not highly toxic to the skin and can be prepared from organic bases, inorganic bases, organic acids, or inorganic acids, including single salts or mixed salts.

[0040] Pharmaceutical or cosmetic acceptable excipients include non-toxic inert carriers, excipients, dispersants, thickeners, and diluents required for topical dosage forms such as creams, ointments, lotions, emulsions, masks, gels, solid foundations, and emulsified foundations. The core characteristic is that they do not affect the active ingredients and are conducive to skin absorption.

[0041] Pharmaceutical or cosmetic effective dose: refers to the amount of compound used that can achieve the expected therapeutic or cosmetic effect, as determined through in vitro / animal experiments.

[0042] The technical solution of the present invention will be further described below with reference to the embodiments.

[0043] Example 1

[0044] The synthesis route of the compound tranexamic acid chloride of this invention is as follows:

[0045] Reaction steps: Tranexamic acid (50 g, 0.32 mol) was added to a 1000 mL three-necked flask, and 500 mL of dichloromethane was added as a solvent. The reaction system was cooled in an ice bath for 30 min. Thionyl chloride (27.7 mL, 0.38 mol) was slowly added with stirring. After the addition was complete, the mixture was brought to room temperature and the reaction was continued for 12 h. The solvent was removed by rotary evaporation under reduced pressure to obtain tranexamic acid acyl chloride solid.

[0046] Example 2

[0047] Synthesis of the tranexamic acid-4-butylresorcinol heterocouple of this invention, synthetic route:

[0048] Reaction Procedure: Tranexamic acid acyl chloride (6.31 g, 0.036 mol) and 4-butylresorcinol (5 g, 0.030 mol) were placed in 80 mL of dichloromethane / ethyl acetate mixed solvent and reacted for 24 h at 30 °C. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by reversed-phase column chromatography to obtain the tranexamic acid-4-butylresorcinol heterocouple.

[0049] 1 H NMR (600 MHz, DMSO) δ 9.55 (d, J = 53.8 Hz, 1H), 7.95 (s, 3H), 7.03 (dd, J = 8.3, 5.4 Hz, 1H), 6.65 - 6.32 (m, 1H), 2.68 (d, J = 6.9 Hz, 2H), 2.36 - 2.26 (m, 2H), 2.09 (td, J = 15.1, 8.3 Hz, 2H), 1.94 - 1.79 (m,2H), 1.60 (dtt, J = 11.5, 6.8, 3.7 Hz, 1H), 1.52 - 1.37 (m, 5H), 1.31 - 1.21(m, 2H), 1.06 (pd, J = 13.0, 3.5 Hz, 2H), 0.90 - 0.81 (m, 3H). Figure 1 MS(ESI) m / z: [M+H] + calcd for C 18 H 27 NO3: 305.2, founded 306.3. Figure 2 .

[0050] Example 3

[0051] Synthesis of the tranexamic acid-4-hexylresorcinol heterocouple of this invention, synthetic route:

[0052] Reaction Procedure: Tranexamic acid acyl chloride (6.31 g, 0.036 mol) and 4-hexylresorcinol (5 g, 0.026 mol) were placed in 80 mL of dichloromethane / ethyl acetate mixed solvent and reacted for 24 h at 30 °C. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by reverse-phase column chromatography to obtain the tranexamic acid-4-hexylresorcinol heterocouple.

[0053] 1 H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 8.10 - 7.74 (m, 3H), 7.03 (d,J = 8.1 Hz, 1H), 6.61 - 6.31 (m, 2H), 2.68 (d,J = 6.8 Hz, 2H), 2.48 (d, J =7.6 Hz, 2H), 2.08 (dd, J = 13.7, 3.6 Hz, 2H), 1.94 - 1.81 (m, 2H), 1.68 -1.35 (m, 5H), 1.34 - 1.22 (m, 6H), 1.06 (qd, J = 13.1, 3.5 Hz, 2H), 0.87 (d,J = 6.1 Hz, 3H). Figure 3 MS(ESI) m / z: [M+H] + calcd for C 20 H 31 NO3: 333.2, founded 334.2. Figure 4 .

[0054] Example 4

[0055] Synthesis of the tranexamic acid-phenylethyl resorcinol heterocouple of the present invention, synthetic route:

[0056] Reaction Procedure: Tranexamic acid acyl chloride (6.31 g, 0.036 mol) and phenylethyl resorcinol (5 g, 0.023 mol) were placed in 80 mL of dichloromethane / ethyl acetate mixed solvent and reacted for 24 h at 30 °C. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by reversed-phase column chromatography to obtain the tranexamic acid-phenylethyl resorcinol heterocouple.

[0057] 1H NMR (400 MHz, DMSO) δ 9.78 (s, 1H), 8.00 (s, 3H), 7.33 - 7.01 (m,6H), 6.61 - 6.39 (m, 2H), 4.42 (q, J = 7.2 Hz, 1H), 2.57 - 2.40 (m, 3H), 2.07(dd, J = 13.6, 3.6 Hz, 2H), 1.95 - 1.79 (m, 2H), 1.69 - 1.48 (m, 4H), 1.40(qd, J = 13.0, 3.4 Hz, 2H), 1.05 (qd, J = 13.0, 3.5 Hz, 2H). Figure 5 MS(ESI) m / z:[M+H] + calcd for C 22 H 27 NO3: 353.2, founded 354.2. Figure 6 .

[0058] Example 5

[0059] Synthesis of the tranexamic acid-kojic acid heterocouple of this invention, synthetic route:

[0060] Reaction steps: Tranexamic acid acyl chloride (7.39 g, 0.042 mol) and kojic acid (5 g, 0.035 mol) were placed in 80 mL of acetonitrile and reacted for 24 h at 50 °C. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the tranexamic acid-kojic acid heterocouple.

[0061] 1 H NMR (600 MHz, DMSO) δ 8.47 (s, 1H), 8.05 (d, J = 13.9 Hz, 3H), 6.49 - 6.31 (m, 1H), 4.39 - 4.27 (m, 2H), 2.64 (dp, J = 18.1, 6.0 Hz, 3H), 2.06 (dd, J = 13.8, 3.6 Hz, 2H), 1.88 (dt, J = 13.7, 7.7 Hz, 2H), 1.60 (ttt,J = 11.1, 7.3, 3.6 Hz, 1H), 1.41 (qd, J = 13.1, 3.4 Hz, 2H), 1.06 (qd, J =13.1, 3.5 Hz, 2H). Figure 7 MS(ESI) m / z: [M+H] + calcd for C 14 H 19 NO5: 281.1, founded 282.1. Figure 8 .

[0062] Example 6

[0063] Synthesis of the tranexamic acid-ascorbic acid hybrid conjugate of this invention, synthetic route:

[0064] Reaction steps: Tranexamic acid acyl chloride (7.39 g, 0.042 mol) and ascorbic acid (5 g, 0.028 mol) were placed in 80 mL of acetonitrile and reacted for 24 h at 50 °C. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product, which was then purified by silica gel column chromatography to obtain the tranexamic acid-kojic acid heterocouple.

[0065] 1 H NMR (600 MHz, DMSO) δ 11.36 - 10.96 (m, 2H), 8.06 - 7.99 (m, 3H), 5.38 (ddd, J = 8.5, 4.1, 2.0 Hz, 1H), 4.35 (dd, J = 11.7, 4.0 Hz, 1H), 4.22(dd, J = 11.7, 8.4 Hz, 1H), 4.13 - 4.01 (m, 2H), 3.48 - 3.40 (m, 2H), 2.33 -2.12 (m, 1H), 2.00 - 1.86 (m, 1H), 1.81 (qd, J = 10.8, 3.7 Hz, 2H), 1.54(tdq, J = 14.8, 7.4, 3.6 Hz, 2H), 1.24 (ddt, J = 20.4, 10.9, 3.3 Hz, 2H), 0.99 - 0.94 (m, 2H). Figure 9 MS(ESI) m / z: [M+Na] + calcd for C 14 H 21 NO7: 315.1, founded 338.2. Figure 10 .

[0066] Example 7

[0067] Synthesis of the tranexamic acid-hexyl ascorbate heterocouple of this invention, synthetic route:

[0068] Reaction Procedure: Ascorbic acid (8.456 g, 48 mmol) was added to a mixed solvent of N,N-dimethylformamide (50 mL) and dichloromethane (10 mL) under ice bath conditions. Hexanoyl chloride (6.504 g, 48 mmol) was slowly added dropwise with stirring in an ice bath. After the addition was complete, the temperature was raised to 25 °C and the reaction continued for 12 h. After the reaction was complete, 150 mL of ethyl acetate and 250 mL of distilled water were added to the mixture for extraction. The aqueous layer was extracted again with 150 mL of ethyl acetate, and the organic layers were combined. The mixture was washed with saturated brine until no ascorbic acid residue was found (TLC monitoring). Anhydrous sodium sulfate was added, and the mixture was allowed to stand for 30 min. The organic solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by column chromatography. The column packing material was silica gel, and the eluent was a petroleum ether / ethyl acetate system. The eluent was evaporated under reduced pressure to obtain hexyl ascorbate.

[0069] Tranexamic acid acyl chloride (1.316 g, 7.5 mmol) and hexyl ascorbate (1.51 g, 5 mmol) were added to 30 mL of dichloromethane. The reaction was carried out under magnetic stirring at 25 °C for 12 h. The organic solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by column chromatography using silica gel as the packing material and a dichloromethane / methanol system as the eluent. The eluent was then evaporated under reduced pressure to obtain the tranexamic acid-hexyl ascorbate heterocouple.

[0070] 1 H-NMR (600 MHz, DMSO) δ 8.75 (s, 1H), 8.02 (s, 3H), 5.44 - 5.34 (m,1H), 4.99 (d, J = 2.3 Hz, 1H), 4.35 (dd, J = 12.0, 4.0 Hz, 1H), 4.20 (dd, J =11.6, 8.7 Hz, 1H), 2.63 (d, J = 7.0 Hz, 2H), 2.34 - 2.09 (m, 1H), 2.00 - 1.72(m, 4H), 1.52 (dt, J = 22.3, 8.1 Hz, 3H), 1.38 - 1.12 (m, 6H), 1.10 - 0.93 (m, 2H), 0.86 (t, J = 7.1 Hz, 3H). Figure 11 MS (ESI) m / z: [M+H] + calcd for C 20 H31 NO8:413.20, founded 414.1. Figure 12 .

[0071] Example 8

[0072] Synthesis of the tranexamic acid-arbutin decyl ester heterocouple of this invention, synthetic route:

[0073] Reaction steps: Arbutin (5 g, 0.018 mol) was dissolved in 20 mL of N,N-dimethylformamide, and decanoyl chloride (4.2 g, 0.022 mol) was added under ice bath conditions. The reaction was carried out at 25 °C for 12 h. After the reaction, purified water and ethyl acetate were added for extraction, followed by washing with saturated brine and drying with anhydrous sodium sulfate. The ethyl acetate layer was collected, and the solvent was removed by rotary evaporation under reduced pressure to obtain decanoyl arbutin. Tranexamic acid chloride (2.55 g, 0.15 mol) and decanoyl arbutin (5 g, 0.012 mol) were placed in 80 mL of dichloromethane / ethyl acetate mixed solvent and reacted for 12 h at 30 °C. After the reaction, the solvent was removed by distillation under reduced pressure to obtain the crude product, which was then purified by reverse column chromatography to obtain the tranexamic acid-decanoyl arbutin heteroconjugate.

[0074] 1 H-NMR (600 MHz, DMSO) δ 6.89 - 6.57 (m, 4H), 5.49 (d, J = 68.3 Hz,1H), 4.98 - 4.84 (m, 1H), 4.40 - 4.25 (m, 1H), 4.17 - 3.90 (m, 1H), 3.66(dddd, J = 16.9, 12.0, 6.1, 2.4 Hz, 1H), 3.29 - 3.21 (m, 2H), 2.70 - 2.58 (m,2H), 2.06 - 1.88 (m, 2H), 1.87 - 1.73 (m, 2H), 1.53 (tq, J = 15.0, 7.4 Hz, 4H), 1.39 - 1.11 (m, 19H), 1.06 - 0.94 (m, 2H), 0.87 - 0.78 (m, 3H). Figure 13 MS (ESI) m / z: [M+H] + calcd for C 30 H 47 NO9: 565.33, founded 566.4. Figure 14 .

[0075] Example 9

[0076] ACD percepta software predicts the physicochemical properties of tranexamic acid-tyrosinase inhibitor heterozygous conjugates.

[0077] The compounds were imported into ACD percepta to obtain predicted values ​​for their physicochemical properties. The specific prediction results are shown in Table 1. Log D is the logarithm of the distribution coefficient, an important parameter for measuring the lipophilicity or hydrophilicity of a compound. A larger Log D value indicates stronger lipophilicity; a smaller Log D value indicates stronger hydrophilicity.

[0078] Table 1. Log D values ​​of compounds under different pH conditions

[0079] The physicochemical property prediction results are shown in Table 1. The tranexamic acid-tyrosinase inhibitor hybrid conjugate has a more suitable hydrophilic-hydrophobic balance, which is beneficial to improving the solubility of the compound in commonly used cosmetic solvents and can also improve the transdermal efficiency of the compound.

[0080] Example 10

[0081] Effect of tranexamic acid-tyrosinase inhibitor heterozygous conjugate on B16F10 cell viability assay: Using mouse melanoma cells (B16F10) as a model, the cytotoxicity of heterozygous conjugates was determined using the CCK-8 assay. Representative examples included tranexamic acid-4-butylresorcinol heterozygous conjugate, tranexamic acid-4-hexylresorcinol heterozygous conjugate, tranexamic acid-phenylethylresorcinol heterozygous conjugate, tranexamic acid-kojic acid heterozygous conjugate, tranexamic acid-ascorbic acid heterozygous conjugate, tranexamic acid-hexyl ascorbate heterozygous conjugate, and tranexamic acid-arbutin succinate heterozygous conjugate. Tranexamic acid and kojic acid were used as control examples. When B16F10 cells reached the logarithmic growth phase, they were cultured at a density of 1×10⁶ cells / year. 4 Cells were seeded per well in a 96-well plate and incubated overnight. After cell attachment, sample solution (compound concentration 100 μmol / L) was added. Cells were incubated for 24 h, and then cell viability was determined according to the standard method in the CCK-8 manufacturer's manual. The relevant measurement data are shown in Table 2.

[0082] Table 2 Cell viability results

[0083] The results are shown in Table 2. Tranexamic acid, kojic acid, tranexamic acid-4-butylresorcinol hybrid conjugate, tranexamic acid-4-hexylresorcinol hybrid conjugate, tranexamic acid-phenylethylresorcinol hybrid conjugate, tranexamic acid-kojic acid hybrid conjugate, tranexamic acid-ascorbic acid hybrid conjugate, tranexamic acid-hexyl ascorbate hybrid conjugate, and tranexamic acid-arbutin succinate hybrid conjugate did not show significant cytotoxicity at the tested concentration of 100 μmol / L, and the cell viability was higher than 90% in all cases.

[0084] Example 11

[0085] Efficacy test of tranexamic acid-tyrosinase inhibitor heterozygous conjugate in inhibiting melanin production in B16F10 cells: The inhibitory activity of heterozygous conjugates on melanin production in B16F10 cells was determined using the NaOH lysis method. Representative examples included tranexamic acid-4-butylresorcinol heterozygous conjugate, tranexamic acid-4-hexylresorcinol heterozygous conjugate, tranexamic acid-phenylethylresorcinol heterozygous conjugate, tranexamic acid-kojic acid heterozygous conjugate, tranexamic acid-hexyl ascorbate heterozygous conjugate, and tranexamic acid-arbutin succinate heterozygous conjugate. Tranexamic acid and kojic acid served as control examples. B16F10 cells were seeded in 12-well plates and incubated overnight. After cell adhesion, 200 nM melanocyte-stimulating hormone (α-MSH) was added as an inducer to induce melanin expression. Simultaneously, different concentrations of sample solutions were added, and co-incubation was continued for 48 h. The group receiving only α-MSH served as the control group. After culture, cells were washed with PBS, and then lysed thoroughly with 1 mol / L NaOH solution containing 10% DMSO. Cell lysates were collected and incubated at 80°C for 1 h to fully release and dissolve melanin. The sample solution was centrifuged at 12000 g for 15 min, and the supernatant was collected. The supernatant was spotted onto 96-well plates, and absorbance was measured at 405 nm using a microplate reader. Experimental results are expressed as relative melanin content (%). The formula for calculating relative melanin content is: Relative melanin content (%) = A 实验组 / A 对照组 ×100. The relevant measurement data are shown in Tables 3-1 and 3-2.

[0086] Table 3-1 Results of relative melanin content

[0087] Table 3-2 Results of relative melanin content

[0088] From Tables 3-1, 3-2 and Figure 15It is known that the various hybrid conjugates of the present invention have a superior melanin production inhibition effect at the cellular level compared to existing whitening ingredients.

[0089] Example 12

[0090] Efficacy test of tranexamic acid-tyrosinase inhibitor hybrid conjugate in inhibiting tyrosinase activity in B16F10 cells: Tyrosinase catalyzes the production of dopachrome from L-DOPA, and the product exhibits a characteristic absorption peak at 475 nm. Tyrosinase activity can be characterized by changes in absorbance. Representative examples include tranexamic acid-4-butylresorcinol hybrid conjugates, tranexamic acid-4-hexylresorcinol hybrid conjugates, tranexamic acid-phenylethylresorcinol hybrid conjugates, tranexamic acid-kojic acid hybrid conjugates, tranexamic acid-ascorbic acid hybrid conjugates, tranexamic acid-hexyl ascorbate hybrid conjugates, and tranexamic acid-arbutin oleate hybrid conjugates. Tranexamic acid and kojic acid served as control examples. B16F10 cells were seeded in 12-well plates and incubated overnight. After cell adhesion, 200 nM melanocyte-stimulating hormone (α-MSH) was added as an inducer to induce melanin expression. Simultaneously, different concentrations of sample solutions were added, and co-incubation continued for 48 h. The group receiving only α-MSH served as the control group. After culture, cells were washed with PBS, and 1% Triton X-100 was added, followed by lysis at room temperature for 30 min. The lysate was collected and centrifuged at 12000 g for 15 min, and the supernatant was collected. Protein concentration in the supernatant was determined using the BCA method, and all samples were adjusted to the same concentration and spotted into 96-well plates. An equal volume of levodopa solution (5 mM) was added, mixed, and incubated at 37°C for 1 h. The absorbance at 475 nm was measured using a microplate reader. An equal volume of PBS solution mixed with levodopa served as a blank control. Experimental results are expressed as relative inhibition rate of tyrosinase (%). The formula for calculating the relative inhibition rate of tyrosinase (%) is: Relative inhibition rate of tyrosinase (%) = 100 - (A... 实验组 -A 空白组 ) / (A 对照组 -A 空白组 () × 100. The relevant measurement data are shown in Tables 4-1 and 4-2.

[0091] Table 4-1 Results of relative inhibition rate of tyrosinase

[0092] Table 4-2 Results of relative inhibition rate of tyrosinase

[0093] From Tables 4-1, 4-2 and Figure 16 It is known that the various hybrid conjugates of the present invention have a superior or equivalent tyrosinase activity inhibition effect at the cellular level compared to existing whitening ingredients.

[0094] Example 13

[0095] Transdermal penetration efficiency test of tranexamic acid-4-butylresorcinol hybrid coupling compound: Using isolated Panamanian pig skin as a skin model, the transdermal permeation efficiency of the heterozygous conjugate was determined using the Franz diffusion cell method. Pig skin was cut into appropriately sized circles, and after integrity was verified by an electrical resistivity meter, it was fixed in a Franz diffusion cell. 1 mL of 500 μM PBS solution of either tranexamic acid or tranexamic acid-4-butylresorcinol heterozygous conjugate was added to the supply chamber. 15 mL of PBS was used as the receiving solution. Transdermal permeation was performed under constant temperature at 32℃ and continuous stirring at 600 rpm. After 24 h, a suitable sample was taken from the supply chamber, diluted with methanol, and the remaining sample volume was detected by LC-MS to calculate the cumulative transdermal permeation rate (%). The formula for calculating the cumulative transdermal permeation rate (%) is: Cumulative transdermal permeation rate (%) = (Initial sample volume - Remaining sample volume) / Initial sample volume × 100.

[0096] Testing conditions: The chromatographic conditions were as follows: Waters ACQUITY UPLC HSS T3 reversed-phase column, flow rate of 0.3 mL / min, column temperature of 40℃, mobile phase of 0.1% formic acid / acetonitrile, and injection volume of 5 μL.

[0097] Mass spectrometry conditions: A TSQ Vantage triple quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source was used. Tranexamic acid and tranexamic acid-4-butylresorcinol hybrid conjugates were detected in positive ion mode using selected reaction monitoring. The ion source spray voltage was 3500 V, the sheath gas was 40 Arb, the auxiliary gas was 10 Arb, the ion transfer tube temperature was 350 °C, the nebulizer temperature was 350 °C, the Q1 / Q3 resolution was 0.7 FWHM, and the collision gas pressure was 1.5 mTorr.

[0098] The relevant measurement data are shown in Table 5.

[0099] Table 5. Transdermal penetration efficiency test results

[0100] As shown in Table 5, the hybrid couplings of this invention can significantly improve the transdermal penetration ability of the compounds by adjusting the hydrophilicity-hydrophobicity balance of the structure. Tranexamic acid-4-butylresorcinol hybrid couplings can achieve highly efficient transdermal penetration without the aid of penetration enhancers, which not only improves the whitening and spot-fading effects but also lays the foundation for the preparation of additive-free cosmetics.

[0101] Example 14

[0102] Identification of metabolites of tranexamic acid-4-butylresorcinol heterocouple in skin tissue: The metabolites of the heterozygous conjugate in the skin were investigated using mouse skin tissue homogenate. Healthy female C57 mice were deeply anesthetized and euthanized using an isoflurane anesthesia system. Immediately afterward, dorsal skin was rapidly harvested, and the surface was rinsed with saline to remove blood. The harvested skin was immediately immersed in liquid nitrogen and ground into powder. An appropriate amount of PBS was added to suspend the powder. The skin tissue suspension was transferred to a glass homogenizer, and the homogenate was repeatedly aspirated and aspirated under ice bath conditions. After homogenization, the homogenate was centrifuged at 12000 g for 15 min, and the supernatant was collected, yielding the enzymatically active skin tissue homogenate. The homogenate was aliquoted and cryopreserved in liquid nitrogen for later use.

[0103] Skin tissue homogenate was reconstituted at 37°C, and tranexamic acid-4-butylresorcinol was added and incubated at 37°C for 1 hour. After incubation, 3-5 times the sample volume of methanol was added to precipitate the protein. The sample solution was centrifuged at 16000 g for 20 minutes. The supernatant was collected, and the metabolites of tranexamic acid-4-butylresorcinol hybrid conjugate in skin tissue were analyzed by mass spectrometry.

[0104] The mass spectrometry conditions were as follows: an Agilent liquid chromatography-G6475A triple quadrupole mass spectrometer was used, equipped with an electrospray ionization source (ESI), positive ion mode was used, selected reaction monitoring was used, the ion source spray voltage was 4000 V, the sheath gas flow rate was 11 L / min, the drying gas temperature was 300 °C, and the sheath gas temperature was 250 °C.

[0105] Depend on Figure 17 Mass spectrometry data show that the tranexamic acid-4-butylresorcinol hybrid conjugate of the present invention can be hydrolyzed into tranexamic acid and 4-butylresorcinol in skin tissue according to the design concept. This lays the material basis for the hybrid conjugate to synergistically exert whitening and spot-fading effects in the skin.

[0106] Example 15

[0107] Whitening and spot-fading serum prepared with tranexamic acid-tyrosinase inhibitor hybrid conjugate as active ingredient and its preparation method: The components and mass percentages of the whitening and spot-fading essence are shown in Table 6.

[0108] Table 6. Components and Proportions of Whitening and Spot-Fading Essence

[0109] The active ingredients described in this embodiment are: tranexamic acid-4-butylresorcinol hybrid coupling compound, tranexamic acid-4-hexylresorcinol hybrid coupling compound, tranexamic acid-phenylethylresorcinol hybrid coupling compound, and tranexamic acid-kojic acid hybrid coupling compound.

[0110] The active ingredients in the control examples were tranexamic acid and kojic acid.

[0111] The preparation methods for the above embodiments and control examples are as follows: S1. Add hydroxyethyl cellulose and the prescribed amount of water to the main pot, homogenize and disperse evenly at room temperature, and keep warm at 50℃~60℃ for 30 min; S2. Once the material in the main pot has cooled to room temperature, add the active ingredient and propylene glycol, and stir to mix evenly; S3. Add arginine to adjust the pH to 6.0, then add phenoxyethanol; S4. Discharge the product to obtain a whitening and spot-fading essence containing various active ingredients.

[0112] Example 16

[0113] The animal safety of the whitening and spot-fading essence prepared in Example 15 was evaluated: Test samples: serums of each active ingredient in Example 15 and serums of the active ingredients in the control example.

[0114] Skin irritation test: Rabbits were randomly divided into groups of three. The fur on the backs of the rabbits was shaved, covering an area of ​​3 cm × 3 cm. 0.5 g of the test sample was applied to one side of the skin, covering an area of ​​2.5 cm × 2.5 cm. The other side of the skin was left untreated and served as a blank control. The test sample was applied once daily, with the fur shaved and any residue cleaned with warm water before application, for 14 consecutive days. One hour after each application, scores were calculated according to the "Cosmetic Safety Technical Specifications" (2015 edition) (hereinafter referred to as the Specifications). Both sides of the skin were treated in the same way. The average score for each animal per day was calculated using the formula, and the skin irritation intensity was determined according to page 492 of the Specifications.

[0115] Table 7 Skin Irritation Response Scores

[0116] Table 8. Repeated skin irritation test on rabbits

[0117] Multiple skin irritation tests on rabbits showed that the whitening and spot-fading essences containing various heterozygous conjugates were non-irritating and had a high safety profile.

[0118] Acute eye irritation test in rabbits: After acclimatizing to the animal facility for 3 days according to standard feeding procedures, the animals' eyes were examined using sodium fluorescein. Animals without eye irritation symptoms and with intact corneal and conjunctival structures were selected as test subjects. Three rabbits were randomly selected from each group. 0.1 mL of the test sample was instilled into the left conjunctival cyst, and the upper and lower eyelids were manually and passively closed for 1 second. The right eye was left untreated and served as a blank control. After 30 seconds, both eyes were rinsed with physiological saline, and then examined and scored according to the Cosmetic Safety Technical Specification P107 (Table 9-11). The results of the rabbit eye irritation test are shown in Tables 12-17.

[0119] Table 9 Corneal Irritation Response Scoring

[0120] Table 10 Iris Stimulation Response Scores

[0121] Table 11 Conjunctival Irritation Response Scoring

[0122] Table 12 Results of rabbit eye irritation test

[0123] Table 13 Results of rabbit eye irritation test

[0124] Table 14 Results of rabbit eye irritation test

[0125] Table 15 Results of rabbit eye irritation test

[0126] Table 16 Results of rabbit eye irritation test

[0127] Table 17 Results of rabbit eye irritation test

[0128] The results of acute eye irritation experiments on rabbits showed that the whitening and spot-fading essences containing various heterozygous conjugates had no obvious irritation and were highly safe.

[0129] Skin patch test: This invention evaluates the irritation of cosmetics using the 2015 "Cosmetic Safety Technical Specifications" as a reference standard. The test method is a skin patch test, which verifies the biosafety of the examples and control examples.

[0130] Test samples: serums of the active ingredients of each hybrid conjugate in Example 15 and serums of the active ingredients of the control examples.

[0131] Experimental Methods: Sixty participants aged 16–65 years were randomly assigned to each experimental group (n=10). All participants met the eligibility criteria. The test sample (0.020 g–0.025 g) was placed in the patch applicator chamber. An equal volume of physiological saline was added to the control well. The patch applicator was placed on the back or flexural side of the anterior wall of the participant, gently pressed to ensure even application to the skin surface, and secured with hypoallergenic tape for 24 hours. The patch applicator was removed, and skin reaction was observed according to the table criteria after 0.5 hours, once the pressure marks disappeared. If the result was negative, observations were repeated at 24 and 48 hours, and the results were recorded.

[0132] Table 18 Grading Criteria for Skin Reaction in Skin Occlusive Patch Tests

[0133] Table 19 Results of Skin Patch Test

[0134] Human skin patch test results showed that no adverse skin reactions occurred during the test period for any of the heterocouples and the control, indicating that the whitening and spot-fading essences of each heterocouple are gentle and non-irritating to the skin and have a high safety profile.

[0135] It is particularly noteworthy that the compositions of the present invention can also be formulated into other dosage forms of cosmetics, such as creams, ointments, foams, lotions, films, lotions, foundations, serums, gels, cosmetic coatings, facial cleansers, patches, and masks, etc. The effects of other dosage forms of cosmetic or pharmaceutical compositions are the same as those demonstrated in the examples.

Claims

1. A tranexamic acid-tyrosinase inhibitor heterozygous conjugate or its pharmaceutically or cosmetically acceptable salt, ester, solvate, or stereoisomer, characterized in that, It has the structure shown in general formula (I): ； Wherein, TI represents the molecular residue of a tyrosinase inhibitor; the tyrosinase inhibitor is a compound molecule that has tyrosinase inhibitory activity and has a hydroxyl group.

2. The tranexamic acid-tyrosinase inhibitor heterozygous conjugate or its pharmaceutically or cosmetically acceptable salt, ester, solvate, or stereoisomer according to claim 1, characterized in that, The tyrosinase inhibitors include, but are not limited to, the following compounds: 4-butylresorcinol, 4-hexylresorcinol, phenylethylresorcinol, dimethoxytolylresorcinol, isobutyramidothiazolylresorcinol, hydroquinone, kojic acid, arbutin, arbutin decanter, glycyrrhizin, catechin, quercetin, ascorbic acid, hexyl ascorbate, ellagic acid, morin, resveratrol, perillol, and trans-p-hydroxycinnamic acid; Pharmaceutically or cosmetically acceptable salts refer to the corresponding salt forms formed by the reaction of a tranexamic acid-tyrosinase inhibitor heterocouple in its free base form with a pharmaceutically or cosmetically acceptable acid; the acid used is selected from any one of lactic acid, malic acid, citric acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, succinic acid, benzenesulfonic acid, and acetic acid.

3. A method for preparing the tranexamic acid-tyrosinase inhibitor heterozygous conjugate according to claim 1 or 2, characterized in that, Includes the following: Tranexamic acid or its reactive derivatives are reacted with hydroxyl-containing tyrosinase inhibitors in an inert organic solvent, and the corresponding heteropolymers are obtained by ester bonding.

4. The preparation method according to claim 3, characterized in that, The reactive derivative of tranexamic acid is in the form of acyl chloride, acid anhydride, or active ester; wherein the acyl chloride is prepared by reacting tranexamic acid with a chlorinating agent, and the chlorinating agent is selected from at least one of thionyl chloride and oxalyl chloride; The inert organic solvent is selected from at least one of dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, ethyl acetate, acetone, toluene, benzene, pyridine, 2,6-dimethylpyridine, or a mixture thereof; The reaction temperature is from -20℃ to the reflux temperature of the solvent; The preparation method further includes a post-processing step, which includes washing, extraction, drying and concentration; and / or a purification step, which includes recrystallization, column chromatography, preparative high-performance liquid chromatography, as well as extraction, distillation, dialysis, ultrafiltration, or a combination of multiple techniques.

5. A skin composition, characterized in that, The active ingredient includes a tranexamic acid-tyrosinase inhibitor hybrid conjugate or a combination thereof prepared by reacting tranexamic acid as described in claim 1 or 2 with any tyrosinase inhibitor.

6. A skin composition according to claim 5, characterized in that, The composition for skin use also includes a solvent selected from one or more of the following: phosphate buffer solution, sterile water, physiological saline, dimethyl sulfoxide, propylene glycol, polyethylene glycol, glycerin, and vegetable oil. And / or the ingredients of the skin composition further include at least one cosmetically or pharmaceutically acceptable excipient, including but not limited to moisturizers, keratolytic agents, antioxidants, thickeners, and preservatives; The skin composition can be prepared into creams, ointments, foams, lotions, serums, films, lotions, essences, gels, cosmetic coatings, cleansers, patches, and mask formulations; The tranexamic acid-tyrosinase inhibitor hybrid conjugate is present in a concentration of 0.01 wt% to 20 wt% in the skin composition.

7. Use of a tranexamic acid-tyrosinase inhibitor heteropolymer conjugate of claim 1 or 2, or a pharmaceutically or cosmetically acceptable salt, ester, solvate, or stereoisomer thereof, in the preparation of a tyrosinase inhibitor.

8. The use of a tranexamic acid-tyrosinase inhibitor heteropolymer conjugate as described in claim 1 or 2, or a pharmaceutically or cosmetically acceptable salt, ester, solvate, or stereoisomer thereof, as an active ingredient in the preparation of topical skin formulations, characterized in that, The formulation is used to prevent, treat, reduce or lighten skin pigmentation; the skin pigmentation includes, but is not limited to, melasma, pregnancy spots, freckles, sun spots, post-inflammatory hyperpigmentation, and age spots.

9. Use of a tranexamic acid-tyrosinase inhibitor heteropolymer conjugate as described in claim 1 or 2, or a pharmaceutically or cosmetically acceptable salt, ester, solvate, or stereoisomer thereof, as an active ingredient in the preparation of skin whitening and spot-removing products, and in the preparation of products that inhibit melanin production.

10. The use according to any one of claims 7-9, characterized in that, Product formulations include creams, ointments, foams, lotions, serums, films, lotions, essences, gels, cosmetic coatings, cleansers, sheets, and masks.

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