Compound composition comprising tranexamic acid and tretinoin

Abstract

Disclosed are a composition and a formulation. The composition comprises tranexamic acid and a tretinoin alcohol amine or tretinoin fatty amine compound. After the composition is prepared into the formulation, the solubility of tretinoin can be improved, the loss of tretinoin in the formulation process is reduced, the content uniformity of the formulation is improved, and the stability of the formulation is improved. The composition can significantly increase the intradermal retention amount of tretinoin and tranexamic acid, and meanwhile, the cross-skin permeation amount of tranexamic acid is not significantly increased. In the treatment of pigmentation and chloasma, the composition and the formulation can significantly improve the curative effect and avoid aggravating toxic and side effects.

Description

A compound composition containing tranexamic acid and tretinoin

[0001] This application requires the following:

[0002] Priority to the prior application, patent application number 202311464036.0, filed with the State Intellectual Property Office of China on November 6, 2023, entitled “A compound composition containing tranexamic acid and tretinoin”;

[0003] The entire content of this prior application is incorporated into this application by reference. Technical Field

[0004] The present invention relates to the field of preparations, and in particular to a compound composition containing tranexamic acid and tretinoin. Background Art

[0005] The skin, the largest organ in the human body, serves as the primary barrier between the body and the external environment. It is often exposed to a complex external environment and is attacked by a variety of harmful factors (such as heat and cold stimulation, ultraviolet rays, bacteria, and viruses). Therefore, skin-related abnormalities or diseases often have diverse causes, complex pathogenesis, and diverse clinical symptoms.

[0006] Topical preparations are one of the main drugs for the treatment of dermatological diseases. In order to cope with the complexity of dermatological diseases, multiple drugs are often used in combination to develop compound preparations. Due to the differences in physical and chemical properties between different drugs, the formulation and process design of compound preparations has become very challenging. For example, when two drugs with different solubility characteristics are designed into a compound preparation, their key quality attributes such as compatibility and content uniformity are prone to problems, so special attention needs to be paid to the corresponding formulation and process parameters. Penetration enhancement technology is often used in topical preparations to improve drug bioavailability, but the differences in physical and chemical properties between different drugs make the penetration enhancement means "lose sight of one thing while focusing on another", and it is impossible to promote the transdermal absorption of multiple drugs at the same time.

[0007] Retinoin can be used to treat a variety of skin diseases, improve skin texture, and reduce spots and pigmentation. It is a poorly soluble drug, with some fat solubility but very poor water solubility.

[0008] Tranexamic acid (TA) can inhibit melanin production and alleviate various spots and pigmentation. It has good water solubility but poor fat solubility.

[0009] Summary of the Invention

[0010] In order to improve the above technical problems, the present invention provides a composition comprising a complex of tranexamic acid and vitamin A acid, and a preparation method and application thereof.

[0011] The present invention provides a composition comprising the following components:

[0012] (1) tranexamic acid or a pharmaceutically acceptable salt thereof;

[0013] (2) Vitamin A acid alcohol amine complex or vitamin A acid fatty amine complex.

[0014] According to an embodiment of the present invention, the vitamin A acid alcoholamine complex consists of vitamin A acid and an alcoholamine compound.

[0015] According to an embodiment of the present invention, the vitamin A acid fatty amine complex consists of vitamin A acid and a fatty amine compound.

[0016] According to an embodiment of the present invention, the fatty amine compound is selected from C1-20 alkylamine compounds, preferably C1-10 alkylamine compounds, such as C9, C8, C7, C6, C5, C4, C3, C2, C1 alkylamine compounds; for example, ethylamine, diethylamine, triethylamine, monomethylamine, dimethylamine, trimethylamine, monopropylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, 1,2-dimethylpropylamine, 1,2-propylenediamine, etc.

[0017] According to an embodiment of the present invention, the vitamin A acid fatty amine complex consists of vitamin A acid and triethylamine.

[0018] According to an embodiment of the present invention, in the vitamin A acid fatty amine complex, the molar ratio of the fatty amine compound to vitamin A acid is (1-100):1, for example, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, (1-10):1, and more preferably (1-5):1.

[0019] According to an embodiment of the present invention, the mass ratio of component (1) (calculated as tranexamic acid) to component (2) (calculated as vitamin A acid) is 0.01-100:0.0001-10, preferably 0.05-50:0.0005-5, further preferably 0.1-10:0.001-1, for example, 2.5-7.5 (for example, 2.5, 5, 7.5):0.01-0.1 (for example, 0.01, 0.025, 0.05, 0.1).

[0020] According to an embodiment of the present invention, (2) in the vitamin A acid alcoholamine complex, the molar ratio of the alcoholamine compound to vitamin A acid is (1-100):1, for example, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, (1-10):1, and more preferably (1-5):1.

[0021] According to an embodiment of the present invention, the alcoholamine compound is selected from the following formula I:

[0022] Wherein, X is selected from C 1-6 Alkyl (alkylene); preferably, selected from -CH2-CH2-, -CH2-CH2-CH2- and

[0023] Indicates the group attachment site;

[0024] R1 and R2 are each independently selected from H, C 1-6 Alkyl, C 1-6 Alkyl-OH.

[0025] According to an embodiment of the present invention, the formula I is selected from diethanolamine, triethanolamine, monoethanolamine (2-hydroxyethylamine), N-methyldiethanolamine, n-propanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, n-butanolamine, dibutanolamine, and isobutanolamine.

[0026] According to an embodiment of the present invention, the complex is in liquid form at room temperature. In the complex, the vitamin A acid may be partially or entirely present in anionic form, and the alcoholamine compound may be partially or entirely present in cationic form.

[0027] According to an embodiment of the present invention, in the complex, part of the vitamin A acid exists in molecular form and / or part of the alcoholamine compound exists in molecular form.

[0028] According to an embodiment of the present invention, in the complex, vitamin A acid is as follows [A - ] exists in the form of:

[0029] According to an embodiment of the present invention, in the composite, the alcoholamine compound is as shown in the following formula II [B + ] exists in the form of:

[0030] In the formula II, X' is selected from C 1-6 Alkyl (alkylene), preferably, selected from -CH2-CH2-, -CH2-CH2-CH2- and

[0031] Indicates the group attachment site;

[0032] R1', R2' are each independently selected from H, C 1-6 Alkyl, C 1-6Alkyl-OH.

[0033] According to an embodiment of the present invention, the formula II is selected from diethanolammonium cation, triethanolammonium cation, monoethanolammonium cation (i.e., 2-hydroxyethylammonium cation), N-methyldiethanolammonium cation, n-propanolammonium cation, isopropanolammonium cation, diisopropanolammonium cation, triisopropanolammonium cation, n-butanolammonium cation, dibutanolammonium cation, and isobutanolammonium cation.

[0034] According to an embodiment of the present invention, the complex is x[B + ][A - ], wherein x can be selected from 1-10, for example, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7.

[0035] According to an embodiment of the present invention, pharmaceutically acceptable salts of tranexamic acid include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, zinc salts, iron salts, ammonium salts, salts with basic amino acids such as arginine, lysine, histidine, and ornithine, and salts with amines such as monoethanolamine, diethanolamine, and triethanolamine. Among them, sodium salts, potassium salts, triethanolamine salts, and arginine salts are preferred, and sodium salts are more preferred.

[0036] According to an embodiment of the present invention, in the composition, components (1) and (2) are each administered in the form of a pharmaceutical composition.

[0037] According to an embodiment of the present invention, in the composition, components (1) and (2) can be administered simultaneously, sequentially or intermittently.

[0038] According to an embodiment of the present invention, the administration route of the composition includes but is not limited to gastrointestinal administration or parenteral administration; wherein, the gastrointestinal administration can be oral administration; the parenteral administration can be transdermal administration (such as skin application administration), etc.

[0039] According to an embodiment of the present invention, the composition can improve the transdermal performance of vitamin A acid (for example, increase the intradermal retention amount without significantly increasing the skin permeation amount).

[0040] According to an embodiment of the present invention, the composition can improve the transdermal performance of component (1) (tranexamic acid) (eg, increase the intradermal retention amount without significantly increasing the skin permeation amount).

[0041] According to an embodiment of the present invention, the composition includes but is not limited to pharmaceutical preparations, cosmetics, care products, and beauty products.

[0042] According to an embodiment of the present invention, the composition can be applied through the skin or topically, for example, selected from creams, patches, ointments, cream preparations, latexes, gels and sprays, etc., and can also be administered orally (i.e., oral preparations), for example, selected from tablets, granules, capsules, oral liquid preparations, pills, suspensions, dripping pills, etc. Preferably, the composition is a cream, latex, emulsion, or gel preparation.

[0043] According to an embodiment of the present invention, in the composition, the content of component (1) (calculated as tranexamic acid) is 0.01%-20%, preferably 0.1%-15%, further preferably 1%-10%, for example 2.5%-7.5%, for example 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%.

[0044] According to an embodiment of the present invention, in the composition, the content of component (2) (calculated as vitamin A acid) is 0.001%-2%, preferably 0.01%-1%, and further preferably 0.01%-0.5%, for example 0.01%, 0.025%, 0.05%, 0.08%, 0.1%, 0.2%, 0.3%.

[0045] According to an embodiment of the present invention, the specification of the composition is 1g / stick to 20g / stick, for example, 3g / stick, 5g / stick, 10g / stick, 15g / stick.

[0046] According to an embodiment of the present invention, the composition optionally further comprises:

[0047] (3) Gel matrix.

[0048] According to an embodiment of the present invention, the gel matrix is ​​selected from carbomer, such as Carbopol 980 and Carbopol ETD2020.

[0049] According to an embodiment of the present invention, the content of the gel matrix is ​​0.01%-10%, preferably 0.05%-5%, for example 0.1%, 0.15%, 0.2%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%.

[0050] According to an embodiment of the present invention, the composition optionally further comprises:

[0051] (4) Penetration enhancers.

[0052] According to an embodiment of the present invention, the penetration enhancer is selected from one, two or more of monocaprylic acid glyceryl, Transcutol P, isopropyl myristate, laurocaprylate, diethylene glycol monoethyl ether, polyglycerol fatty acid ester, propylene glycol monocaprylate, and caprylic acid polyethylene glycol glyceride.

[0053] According to an embodiment of the present invention, the content of the penetration enhancer is 0.01%-20%, preferably 0.1%-15%, such as 0.5%, 1%, 2%, 3%, 4%, 10%, 12.57%, 13%.

[0054] According to an embodiment of the present invention, the composition optionally further comprises:

[0055] (5) Preservatives.

[0056] According to an embodiment of the present invention, the preservative is selected from one, two or more of benzoic acid, phenoxyethanol, sodium benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate.

[0057] According to an embodiment of the present invention, the content of preservatives is 0.001%-2%, preferably 0.005%-1%, for example 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.08%, 0.1%, 0.2%, 0.3%, 0.5%, 0.8%.

[0058] According to an embodiment of the present invention, the composition optionally further comprises:

[0059] (6) Antioxidants.

[0060] According to an embodiment of the present invention, the antioxidant is selected from one, two or more of butylated hydroxyanisole (BHA), butylated hydroxytoluene, butylated hydroxyanisole, vitamin C (ascorbic acid), vitamin E, and sodium metabisulfite.

[0061] According to an embodiment of the present invention, the content of the antioxidant is 0.001%-2%, preferably 0.01%-1%, such as 0.1%, 0.2%, 0.3%.

[0062] According to an embodiment of the present invention, the composition optionally further comprises:

[0063] (7) Cosolvent.

[0064] According to an embodiment of the present invention, the cosolvent is selected from alcohols, and the alcohols are preferably one, two or more of glycerol, propylene glycol, 1,2-pentanediol, ethanol and benzyl alcohol.

[0065] According to an embodiment of the present invention, the content of the cosolvent is 0.5%-30%, preferably 1%-20%, for example 1%, 2.0%, 2.5%, 5.0%, 10%, 13.5%, 14%, 15%, 16%, 17%, 18%.

[0066] According to an embodiment of the present invention, the composition optionally further comprises:

[0067] (8) Emulsifier.

[0068] According to an embodiment of the present invention, the emulsifier is selected from one, two or more of Pemulen TR-1NF, Emulium Delta MB, Tween (e.g., Tween 20, Tween 40, Tween 60, Tween 80), Span (e.g., Span 20, Span 60, Span 80), polyoxyethylene castor oil derivatives, poloxamer, Triton, caprylic / capric macrogol glycerides, polyethylene glycol stearate, polyoxyethylene-8 beeswax, and lauroyl polyoxyethylene glycerides.

[0069] In some embodiments, polyethylene glycol stearate, such as polyethylene glycol (32) stearate. In some embodiments, lauroyl polyoxyethylene glyceride, such as lauroyl polyoxyethylene (6) glyceride.

[0070] In some embodiments, the polyoxyethylene castor oil derivative is selected from polyoxyethylene castor oil or polyoxyethylene hydrogenated castor oil, for example, selected from polyoxyethylene 35 castor oil, polyoxyethylene 40 castor oil, polyoxyethylene 54 hydrogenated castor oil, and polyoxyethylene 100 hydrogenated castor oil.

[0071] According to an embodiment of the present invention, the content of the emulsifier is 0.1%-30%, preferably 0.2%-20%, such as 0.2%, 0.3%, 2%, 5%, 8%, 10%, 15%.

[0072] According to an embodiment of the present invention, the composition optionally further comprises:

[0073] (9) Oily matrix.

[0074] According to an embodiment of the present invention, the oily matrix is ​​selected from one or more of long-chain fatty alcohols, long-chain fatty acids, fatty acid esters, and oils. Preferably, the long-chain fatty alcohol is selected from hexadecanol and stearyl alcohol; preferably, the long-chain fatty acid is selected from stearic acid; preferably, the fatty acid ester is selected from isopropyl myristate, medium-chain triglycerides, monoolein, monolinolein, propylene glycol dicaprylate, oleoyl polyoxyethylene glyceride, myristyl myristate, isopropyl palmitate, isopropyl linoleate, lauryl benzoate, isostearyl isostearate, fatty acid lactate, decyl oleate, and one or more of octyl palmitate. Preferably, the oil is selected from jojoba oil, soybean oil, linseed oil, and the like, with jojoba oil being further preferred.

[0075] According to an embodiment of the present invention, the content of the oily base is 0.5%-20%, preferably 1.0%-15%, such as 1.5%, 2.0%, 5%, 6%, 8%, 10%, 12%.

[0076] According to an embodiment of the present invention, the composition optionally further comprises:

[0077] (10) Rheology regulator.

[0078] According to an embodiment of the present invention, the rheology modifier is selected from xanthan gum.

[0079] According to an embodiment of the present invention, the content of the rheology modifier is 0.01%-0.5%, preferably 0.1%-0.3%, such as 0.15%.

[0080] According to an embodiment of the present invention, the composition optionally further comprises any one or more of a metal ion complexing agent, an emulsifier, and a texture regulator.

[0081] According to an embodiment of the present invention, the co-emulsifier is selected from propylene glycol monocaprylate.

[0082] According to an embodiment of the present invention, the content of the co-emulsifier is 0.1%-5%, preferably 1%-3%, for example 2.0%.

[0083] According to an embodiment of the present invention, the texture modifier is selected from cyclopentasiloxane.

[0084] According to an embodiment of the present invention, the content of the texture modifier is 1%-5%, for example 3.0%.

[0085] According to an embodiment of the present invention, the metal ion complexing agent is selected from one, two or more of ethylenediaminetetraacetic acid (EDTA), disodium ethylenediaminetetraacetate (EDTA-2Na), tetrasodium ethylenediaminetetraacetate (EDTA-4Na), disodium nitrilotriacetate, sodium tripolyphosphate, sodium hexametaphosphate, and tetrapotassium pyrophosphate, preferably EDTA or EDTA-2Na.

[0086] According to an embodiment of the present invention, the composition optionally further includes other physiologically acceptable carriers (e.g., biocompatible materials), for example, optionally including surfactants, excipients, humectants, emulsifying promoters, suspending agents, salts or buffers for regulating osmotic pressure, colorants, flavors, stabilizers, bactericides or other conventional supplements.

[0087] According to an embodiment of the present invention, the composition comprises the following components:

[0088] 2.5%-7.5% (e.g., 2.5%, 5%, 7.5%) tranexamic acid;

[0089] 0.01%-1% (e.g., 0.01%, 0.025%, 0.05%, 0.1%) of a vitamin A alcoholamine complex or a vitamin A fatty amine complex (e.g., vitamin A diethanolamine, vitamin A triethanolamine, vitamin A triethylamine) calculated as vitamin A acid;

[0090] 0.05%-5% (e.g., 0.1%, 0.15%, 0.2%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%) of a gel base (e.g., Carbopol 980 and / or Carbopol ETD2020);

[0091] Optionally, 0.1%-15% (e.g., 0.5%, 1%, 2%, 3%, 4%, 10%, 12.57%, 13%) of a penetration enhancer (e.g., one, two or more of monocaprylin, Transcutol P, isopropyl myristate, laurocaprylate, diethylene glycol monoethyl ether, polyglycerol fatty acid esters, propylene glycol monocaprylate, and caprylic acid polyethylene glycol glyceride);

[0092] Optionally, 0.005%-1% (e.g., 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.08%, 0.1%, 0.2%, 0.3%, 0.5%, 0.8%) of a preservative (e.g., one, two or more of benzoic acid, phenoxyethanol, sodium benzoate, methylparaben, ethylparaben, propylparaben, sodium methylparaben, and sodium propylparaben);

[0093] Optionally, 0.01%-1% (e.g., 0.1%, 0.2%, 0.3%) of an antioxidant (e.g., one, two or more of butylated hydroxyanisole, butylated hydroxytoluene, butylated hydroxyanisole, vitamin C, vitamin E, and sodium metabisulfite);

[0094] Optionally, 1%-20% (e.g., 1%, 2.0%, 2.5%, 5.0%, 10%, 13.5%, 14%, 15%, 16%, 17%, 18%) of a cosolvent (e.g., one, two or more of glycerol, propylene glycol, 1,2-pentanediol, ethanol, benzyl alcohol);

[0095] Optionally, 0.2%-20% (e.g., 0.2%, 0.3%, 2%, 5%, 8%, 10%, 15%) of an emulsifier (e.g., one, two or more of Pemulen TR-1NF, Emulium Delta MB, Tween, Span, polyoxyethylene castor oil derivatives, poloxamer, Triton, caprylic / capric macrogol glycerides, macrogol stearate, polyoxyethylene-8 beeswax, and lauroyl polyoxyethylene glycerides);

[0096] Optionally, 1.0%-15% (e.g., 1.5%, 2.0%, 5%, 6%, 8%, 10%, 12%) of an oily base (e.g., one, two or more of octadecanol, cetyl alcohol, stearic acid, and fatty acid esters);

[0097] Optionally, 0.1%-0.3% (e.g., 0.15%) of a rheology modifier (e.g., xanthan gum);

[0098] Optionally, 1%-3% (e.g., 2.0%) of a co-emulsifier (e.g., propylene glycol monocaprylate);

[0099] Optionally, 1%-5% (e.g., 3.0%) of a texturizing agent (e.g., cyclopentasiloxane);

[0100] The balance is water.

[0101] According to an embodiment of the present invention, the composition comprises the following components:

[0102] Vitamin A acid alcoholamine complexes or vitamin A acid fatty amine complexes such as vitamin A diethanolamine, vitamin A triethanolamine, and vitamin A triethylamine.

[0103] According to an embodiment of the present invention, the composition is a cream.

[0104] According to an embodiment of the present invention, the composition comprises the following components:

[0105] Vitamin A acid alcoholamine complexes or vitamin A acid fatty amine complexes such as vitamin A diethanolamine, vitamin A triethanolamine, and vitamin A triethylamine.

[0106] According to an embodiment of the present invention, the composition is a latex.

[0107] According to an embodiment of the present invention, the composition comprises the following components:

[0108] Vitamin A acid alcoholamine complexes or vitamin A acid fatty amine complexes such as vitamin A diethanolamine, vitamin A triethanolamine, vitamin A triethylamine;

[0109] Penetration enhancers such as one or more of laurocaprylate, monocaprylin, Trancutol P, and isopropyl myristate;

[0110] Antioxidants such as one or more of butylated hydroxytoluene, butylated hydroxyanisole, sodium metabisulfite, and ascorbic acid;

[0111] Preservatives such as one or more of sodium methylparaben, sodium propylparaben, methylparaben, propylparaben, butylated hydroxytoluene, and phenoxyethanol.

[0112] According to an embodiment of the present invention, the composition is a gel.

[0113] According to an embodiment of the present invention, the composition comprises the following components:

[0114] Vitamin A acid alcoholamine complexes or vitamin A acid fatty amine complexes such as vitamin A diethanolamine, vitamin A triethanolamine, and vitamin A triethylamine.

[0115] According to an embodiment of the present invention, the composition is an emulsion.

[0116] The present invention also provides use of the above-mentioned composition in preparing medicines for preventing and / or treating skin diseases.

[0117] According to an embodiment of the present invention, the skin disease is selected from melasma and pigmentation.

[0118] The present invention also provides a method for preventing and / or treating skin diseases, which comprises administering a therapeutically effective amount of the composition to a patient suffering from the skin disease.

[0119] According to an embodiment of the present invention, the skin disease is selected from melasma and pigmentation.

[0120] The present invention also provides a method for preparing the above composition, which comprises the following steps:

[0121] 1) preparing an aqueous phase containing tranexamic acid;

[0122] 2) preparing an oil phase comprising a vitamin A alcohol amine complex or a vitamin A acid fatty amine complex;

[0123] 3) Mixing: adding the water phase to the oil phase, emulsifying and homogenizing, and thus obtaining the composition.

[0124] According to an embodiment of the present invention, the aqueous phase further comprises a gel matrix.

[0125] According to an embodiment of the present invention, the aqueous phase optionally further comprises one or more of a penetration enhancer, a preservative, an antioxidant, a solubilizer, an emulsifier, an oily base, a rheology regulator, an emulsifier co-, and a texture regulator.

[0126] According to an embodiment of the present invention, the oil phase optionally further includes one or more of a penetration enhancer, a preservative, an antioxidant, a solubilizer, an emulsifier, an oily matrix, a rheology regulator, an emulsifier, and a texture regulator.

[0127] The present invention also provides a method for preparing the above composition, which comprises the following steps:

[0128] 1) preparing an aqueous phase: adding tranexamic acid, a preservative, and a gel matrix to a certain amount of water and stirring to obtain an aqueous phase;

[0129] 2) preparing an oil phase: mixing and stirring the vitamin A acid alcohol amine complex or the vitamin A acid fatty amine complex, a penetration enhancer, an antioxidant, a cosolvent, etc. to obtain an oil phase;

[0130] 3) Mixing: adding the water phase to the oil phase, emulsifying and homogenizing, and thus obtaining the composition.

[0131] According to an embodiment of the present invention, the preparation method specifically comprises the following steps:

[0132] 1) Dissolve the preservative in a certain amount of water, add the gel matrix, stir at high speed to make it evenly dispersed, and stir at low speed to make it hydrated;

[0133] 2) adding an aqueous solution of tranexamic acid, continuing to stir and mix uniformly to gel the gel matrix to obtain an aqueous phase;

[0134] 3) mixing and stirring the vitamin A acid alcohol amine complex or the vitamin A acid fatty amine complex, a penetration enhancer, an antioxidant, and a solvent to obtain an oil phase;

[0135] 4) adding the aqueous phase in step 2) to the oil phase in step 3), and performing emulsification and homogenization treatment to obtain the composition; preferably, the composition is a gel;

[0136] According to an embodiment of the present invention, the preparation method specifically comprises the following steps:

[0137] 1) dissolving the gel matrix in water, stirring, and degassing to prepare a uniform, bubble-free gel matrix phase;

[0138] 2) Add the preservative to a certain amount of water, dissolve it, then add tranexamic acid and disperse it evenly;

[0139] 3) adding the tranexamic acid solution in step 2) to the gel matrix phase in step 1) to obtain a gel;

[0140] 4) mixing the vitamin A acid alcohol amine complex or the vitamin A acid fatty amine complex, an antioxidant, a penetration enhancer, and a certain amount of a solvent to obtain an oil phase;

[0141] 5) adding the oil phase in step 4) to the gel in step 3), and performing emulsification and homogenization treatment to obtain the composition.

[0142] According to an embodiment of the present invention, the preparation method further comprises the steps of washing the container with water or a co-solvent and mixing the washing liquids. Beneficial effects

[0143] The present invention provides a composition comprising tranexamic acid and a retinoic acid alcoholamine complex. The composition can increase the solubility of retinoic acid, reduce retinoic acid loss during the formulation process, improve the content uniformity of the formulation, and enhance the stability of the formulation. Furthermore, the composition can significantly increase the intradermal retention of retinoic acid and tranexamic acid without significantly increasing the transdermal permeation of tranexamic acid. Furthermore, the composition of the present invention has lower irritation, lower toxic side effects, and lower allergenicity.

[0144] The composition provided by the present invention can significantly improve the therapeutic effect and avoid aggravating toxic side effects in the treatment of pigmentation and chloasma. BRIEF DESCRIPTION OF THE DRAWINGS

[0145] Figure 1 is a comparison of the skin color of the guinea pig's back before and after treatment with the tranexamic acid / vitamin A acid adduct compound preparation.

[0146] Figure 2 is a comparison of skin sections from the dosing area and non-dosing area on the back of guinea pigs treated with tranexamic acid / vitamin A acid adduct compound preparation.

[0147] FIG3 is a hydrogen nuclear magnetic resonance spectrum of 8[TEA][RA].

[0148] FIG4 is a hydrogen nuclear magnetic resonance spectrum of 2[Et3N][RA].

[0149] FIG5 shows the prepared melasma model.

[0150] Figure 6 shows the therapeutic effect of the compound preparation on chloasma.

[0151] Figure 7 shows typical sections of the compound preparation for the treatment of melasma. DETAILED DESCRIPTION

[0152] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0153] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0154] Tranexamic acid was purchased from Yantai Wanrun Pharmaceutical Co., Ltd. Carbopol 980 (Carbomer 980), Carbopol ETD2020 (Carbomer ETD2020), and Pemulen TR-1NF were purchased from Lubrizol. Sodium metabisulfite was purchased from Hunan Erkang Pharmaceutical Co., Ltd. Sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, butylated hydroxytoluene, and BHA butylated hydroxyanisole were purchased from Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd. Vitamin A acid (retinoic acid) and isopropyl myristate were purchased from Shanghai MacLean Biochemical Technology Co., Ltd. Monocaprylic acid glyceryl was purchased from Aiminsdi (China) Co., Ltd. Polyoxyethylene 54 hydrogenated castor oil was purchased from Nanjing Well Pharmaceutical Technology Co., Ltd. Glycerin, lauric nitrogen Ketone, propylene glycol, and 1,2-pentanediol were purchased from Shandong Ruisheng Pharmaceutical Excipients Co., Ltd. Tween 80 was purchased from Sigma. Ethanol, stearyl alcohol, benzyl alcohol, diethanolamine (DEA) (AR), and phenoxyethanol were purchased from Sinopharm Chemical Reagent Co., Ltd. Xanthan gum was purchased from Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd. Transcutol P, Emulium Delta MB, medium-chain triglycerides, and propylene glycol monocaprylate were purchased from Gattefossé. Jojoba oil was purchased from Adamas. Cyclopentasiloxane was purchased from Shanghai Fangdeng Chemical Co., Ltd. Commercially available tretinoin ointment (0.05%, 20 g) was purchased from Guangdong Xiangshantang Pharmaceutical Co., Ltd. Commercially available hydroquinone cream (2%, 20 g) was purchased from Guangdong Renrenkang Pharmaceutical Co., Ltd.

[0155] Carbopol 980, Carbopol ETD2020: Carbomer 980, Carbopol ETD2020.

[0156] Transcutol P: Diethylene glycol monoethyl ether.

[0157] Pemulen TR-1 NF: Carbomer Copolymer Type B, a high molecular weight copolymer of acrylic acid and C10-C30 alkyl acrylates crosslinked with pentaerythritol allyl ether.

[0158] Emulium Delta MB: Cetyl Alcohol (and) Glyceryl Stearate (and) PEG-75 Stearate (and) Ceteth-20 (and) Steareth-20.

[0159] Example 1 Preparation of Tranexamic Acid / Vitamin A Acid Common Compound Preparation

[0160] 1.1 Preparation 1: Tranexamic acid / vitamin A acid compound ointment

[0161] prescription:

[0162] Process: Polyoxyethylene 54 hydrogenated castor oil is heated to 60°C and melted, cooled to 40°C, and the remaining oil phase raw materials and auxiliary materials are added and mixed and dissolved; tranexamic acid is dissolved in about 40% water; the remaining aqueous phase auxiliary materials are mixed with the remaining water, and Carbopol 980 is added and evenly dispersed; the tranexamic acid aqueous solution and the aqueous phase auxiliary materials are mixed and mechanically stirred for 30 minutes to obtain an aqueous phase; the two phases are mixed and homogenized using a homogenizer at 1000 rpm for 2 minutes; mechanically stirred (four-blade or anchor type) for 30 minutes to mix evenly, and then filled into aluminum-plastic composite tubes.

[0163] 1.2. Preparation 2: Tranexamic acid / vitamin A acid common compound latex

[0164] prescription:

[0165] Process: Weigh all excipients according to the prescribed amount; dissolve tranexamic acid in approximately 40% water; after the remaining aqueous phase materials are mixed thoroughly, add the tranexamic acid solution and mechanically stir for 30 minutes to mix thoroughly, allowing the carbomer ETD2020 to gel; the resulting aqueous phase is kept warm in a 40°C water bath until ready for use. Weigh tretinoin and ethanol according to the prescribed amount and mix them. Weigh and add isopropyl myristate and benzyl alcohol and mix thoroughly. Weigh octadecyl alcohol and butylated hydroxytoluene and add them to the oil phase, then heat in a 60°C water bath to dissolve, then cool to 40°C. Maintaining the 40°C water bath, add the oil phase to the aqueous phase and homogenize using a high shear homogenizer for 3 minutes; mechanically stir (four-blade or anchor type) until a semisolid latex forms. After cooling, fill the mixture into aluminum-plastic composite tubes.

[0166] 1.3. Preparation 3: Tranexamic acid / retinoic acid regular compound gel

[0167] prescription:

[0168] Process: Weigh all excipients according to the prescribed amount; dissolve tranexamic acid in approximately 40% water; dissolve the preservatives (sodium methylparaben and sodium propylparaben) in the remaining water. Add Carbopol 980 and stir at 200 rpm for 5 minutes to evenly disperse. Stir at 50 rpm for 50 minutes to hydrate the carbomer. Add the tranexamic acid solution and mechanically stir for 30 minutes to mix thoroughly and gel the carbomer. Mix and stir the oil phase excipients to form a uniform oil phase. Add the aqueous phase to the oil phase and homogenize at 5000 rpm in a high shear homogenizer for 3 minutes. Stir mechanically at low speed for 30 minutes to form a uniform gel. Fill into aluminum-plastic composite tubes.

[0169] 1.4. Formulation 4: Tranexamic acid / vitamin A acid common compound emulsion

[0170] prescription:

[0171] Process: Weigh all excipients, disperse xanthan gum and carbomer 980 in glycerol and Transcutol P, add part of the water, and stir in a water bath at 80°C to mix thoroughly; dissolve tranexamic acid in the remaining water, then mix it into the aqueous phase, mechanically stir to mix thoroughly and gel the carbomer 980; mix the ingredients in the oil phase and keep it warm to 80°C; add the oil phase to the aqueous phase and homogenize at 8000rpm for 3 minutes; cool to 40-50°C, add phenoxyethanol, and mechanically stir for 30 minutes to mix thoroughly; then dispense into aluminum tubes.

[0172] Example 2 Preparation of Tranexamic Acid / Vitamin A Acid Diethanolamine Adduct Compound

[0173] 2.1. Preparation of Vitamin A Acid Adducts

[0174] Materials and reagents: Vitamin A acid (RA) (AR, Shanghai Aladdin Biochemical Technology Co., Ltd.), diethanolamine (DEA) (AR, Sinopharm Chemical Reagent Co., Ltd.), ethanol (AR, Sinopharm Chemical Reagent Co., Ltd.).

[0175] prescription:

[0176] The molar ratio of diethanolamine (DEA) to retinoic acid (RA) is 2:1.

[0177] Process:

[0178] (1) Weigh vitamin A acid according to the prescribed amount and place it in a round-bottom flask. Add ethanol and stir to mix. The vitamin A acid cannot be completely dissolved and remains in a suspended state. Wrap the round-bottom flask with aluminum foil to block light.

[0179] (2) Weigh diethanolamine according to the prescribed amount, place it in a container wrapped in aluminum foil, and add ethanol to stir and dilute it.

[0180] The diethanolamine diluted solution obtained in step (2) was added dropwise to the mixed solution obtained in step (1) while stirring; and the container was rinsed with about 5 mL of ethanol and added to the flask together with stirring.

[0181] After all the additions are complete, the solution should be orange-red and clear; continue stirring for 4 hours.

[0182] The solvent was removed using a rotary evaporator and the resulting sample was sealed and stored in a light-shielded environment.

[0183] For hydrogen nuclear magnetic resonance spectrum, infrared spectrum, and Raman spectrum data of vitamin A acid diethanolamine complex (2[DEA][RA]), please refer to patent application CN202210853741.9. The vitamin A acid adduct in preparations 5-9 below is vitamin A acid diethanolamine complex (2[DEA][RA]).

[0184] 2.2 Formulation 5: Tranexamic acid / vitamin A acid adduct compound ointment

[0185] Process: Polyoxyethylene 54 hydrogenated castor oil is heated to 60°C and melted, cooled to 40°C, and the remaining oil phase raw materials and auxiliary materials are added and mixed and dissolved; tranexamic acid is dissolved in about 40% water; the remaining aqueous phase auxiliary materials are mixed with the remaining water, and Carbopol 980 is added and evenly dispersed; the tranexamic acid aqueous solution and the aqueous phase auxiliary materials are mixed and mechanically stirred for 30 minutes to obtain an aqueous phase; the two phases are mixed and homogenized using a homogenizer at 1000 rpm for 2 minutes; mechanically stirred (four-blade or anchor type) for 30 minutes to mix evenly, and then filled into aluminum-plastic composite tubes.

[0186] 2.3 Formulation 6: Tranexamic acid / vitamin A acid adduct compound latex

[0187] prescription:

[0188] Process: Weigh all excipients according to the prescribed amount; dissolve tranexamic acid in approximately 40% water; after the remaining aqueous phase materials are mixed thoroughly, add the tranexamic acid solution and mechanically stir for 30 minutes to mix thoroughly, allowing the carbomer ETD2020 to gel; the resulting aqueous phase is kept warm in a 40°C water bath until ready for use. Weigh the vitamin A acid adduct and ethanol according to the prescribed amount and mix them. Weigh and add isopropyl myristate and benzyl alcohol and mix thoroughly. Weigh octadecyl alcohol and butylated hydroxytoluene and add them to the oil phase, then heat in a 60°C water bath to dissolve, then cool to 40°C. Maintaining the 40°C water bath, add the oil phase to the aqueous phase and homogenize with a high shear homogenizer for 3 minutes; mechanically stir (four-blade or anchor type) to mix until a semisolid latex forms. After cooling, fill the mixture into aluminum-plastic composite tubes.

[0189] 2.4 Formulation 7: Tranexamic acid / vitamin A acid adduct compound gel

[0190] prescription:

[0191] Process: Weigh all excipients according to the prescribed amount; dissolve tranexamic acid in approximately 40% water; dissolve the preservative in the remaining water, then add Carbomer 980 and stir at 200 rpm for 5 minutes to evenly disperse. Stir at 50 rpm for 50 minutes to hydrate the carbomer. Add the tranexamic acid solution and mechanically stir for 30 minutes to mix thoroughly and gel the carbomer. Add the oil phase excipients and stir to form a uniform oil phase. Add the aqueous phase to the oil phase and homogenize at 5000 rpm in a high shear homogenizer for 3 minutes. Stir mechanically at low speed for 30 minutes to form a uniform gel. Fill into aluminum-plastic composite tubes.

[0192] 2.5 Formulation 8: Tranexamic acid / vitamin A acid adduct compound emulsion

[0193] prescription:

[0194] Process: Weigh all excipients, disperse xanthan gum and carbomer 980 in glycerol and Transcutol P, add part of the water, and stir in a water bath at 80°C to mix thoroughly; dissolve tranexamic acid in the remaining water, then mix it into the aqueous phase, mechanically stir to mix thoroughly and gel the carbomer 980; mix the ingredients in the oil phase and keep it warm to 80°C; add the oil phase to the aqueous phase and homogenize at 8000rpm for 3 minutes; cool to 40-50°C, add phenoxyethanol, and mechanically stir for 30 minutes to mix thoroughly; then dispense into aluminum tubes.

[0195] Example 3 Comparison of IVPT (in vitro transdermal) tests of formulations 1-8

[0196] 3.1 IVPT test method

[0197] Methods: An IVPT test was conducted on ex vivo skin from Bama miniature pigs (aged ≤ 3 months) using a Franz diffusion cell. Receiving fluid was collected at different time points (1h, 2h, 4h, and 6h). After the test, the skin was cleaned and then the tissue was broken into pieces to obtain an intradermal retained extract. The obtained samples were analyzed using UPLC-MS to determine the contents of tranexamic acid and retinoic acid in the samples.

[0198] Example 4 Comparison of content and content uniformity of preparations 1-8

[0199] The content of vitamin A acid in the preparation is low, and it will be adsorbed by the container or stirring paddle during mixing, which will have a great impact on the content; at the same time, its low content is also prone to uneven content.

[0200] Three samples were randomly taken from each preparation, their content was tested, and the RSD% of the intra-batch content was calculated.

[0201] Table 2 Content and content uniformity of different compound preparations

[0202] From the content and content uniformity results in Table 2, it can be seen that the content of vitamin A acid in the four common tranexamic acid and vitamin A acid compound preparations is low and the content uniformity is poor; however, by first preparing vitamin A acid into an adduct and then preparing the compound preparation with tranexamic acid, the loss of vitamin A acid due to transfer and adsorption during the preparation process is reduced, the content of the resulting preparation is significantly increased, and the content uniformity is also significantly improved.

[0203] Example 5 Comparison of drug distribution status of formulations 1-8

[0204] Microscopic observation of Preparations 1-8 revealed that in the standard compound preparations, some tretinoin was dispersed as solid particles, such as needle-shaped crystals. In the adduct compound preparations, however, tretinoin was primarily dispersed as oil droplets. This suggests that the distribution of tretinoin in the adduct compound preparations is more uniform and stable.

[0205] Example 6 Scale-up Production of a Compound Gel of Tranexamic Acid and Vitamin A Acid Diethanolamine Complex (Preparation 9)

[0206] 6.1 Scale-up production recipe

[0207] 6.2 Scale-up production process:

[0208] Weigh the raw materials and excipients according to the prescribed dosage. Add approximately 20% water to the water tank and stir at 30 rpm. While stirring, add Carbomer 980 powder and stir for 10 minutes. Continue to increase the stirring speed to 60 rpm and stir for 1 hour. Set the negative pressure to -0.08 MPa. Use the vacuum to draw the carbomer solution into the main pot for approximately 3 minutes. Rinse the container with approximately 10% purified water and stir. Stir at a negative pressure of -0.08 MPa. Degas the mixture in the main pot at 25 rpm for 30 minutes to obtain a uniform, bubble-free carbomer phase.

[0209] Add the prescribed amount of laurocapram, vitamin A acid adduct and butylated hydroxytoluene to a beaker and dissolve the laurocapram under magnetic stirring. Then add the solution to 10% propylene glycol and stir to mix.

[0210] Add sodium methylparaben and sodium propylparaben to about 40% water and stir at 400 rpm to dissolve. After dissolution, add the prescribed amount of tranexamic acid while stirring until it is completely dispersed.

[0211] Add the tranexamic acid solution to the carbomer phase, and use the remaining water to rinse the tranexamic acid phase container before adding it to the carbomer phase. Set the emulsification homogenization tank to a negative pressure of -0.08 MPa, a stirring speed of 50 rpm, and an auxiliary stirring speed of 200 rpm for approximately 1 hour, until the material in the tank becomes a clear, transparent gel free of white foreign matter.

[0212] Add the vitamin A acid adduct phase solution to the aqueous phase mixture. Rinse the vitamin A acid adduct phase container with 5% propylene glycol and add the solution to the mixture. Set the emulsification homogenization tank to a negative pressure of -0.08 MPa, a stirring speed of 50 rpm, and an auxiliary stirring speed of 200 rpm for approximately 120 minutes.

[0213] 6.3 Assay and Content Uniformity of Scale-Up Batch

[0214] Table 3 Uniformity of vitamin A acid content in scaled-up batches

[0215] Table 4 Amplified batch tranexamic acid content uniformity

[0216] Table 5 Uniformity in the container of scaled-up batches of vitamin A acid and tranexamic acid

[0217] As shown in Table 3-5, the compound gel of tranexamic acid and vitamin A acid prepared by the 5kg scale-up process has a uniform distribution of vitamin A acid and tranexamic acid in the preparation tank.

[0218] 6.4 Related substances in scale-up batches

[0219] Table 6 Related substances of vitamin A acid in amplified batch

[0220] Table 7 Related substances of tranexamic acid in amplified batches

[0221] As shown in Tables 6-7, the compound gel of tranexamic acid and vitamin A acid complex prepared by the 5kg scale-up process has a total impurity content within a controllable range, various indicators meet the quality standards, and has good stability.

[0222] 6.5 Scale-up batch stability accelerated test data (30℃±2℃ / 65%RH±5%RH)

[0223] Table 8 Results of scaled-up batch accelerated test

[0224] The results of the accelerated test show that after the prepared adduct compound preparation was placed at an accelerated temperature for 3 months, all indicators met the quality standards and the stability was good.

[0225] Example 7 Whitening Effect Test of Adduct Compound Preparation 7

[0226] Male guinea pigs weighing 300-350 g were selected as model animals to investigate the effect of a compound preparation of tranexamic acid and retinoic acid adduct (preparation 7) on melanin in brown-skinned guinea pigs.

[0227] 7.1 Test plan

[0228] Grouping: Guinea pigs were adapted to feeding for 7 days. The day before grouping, hair removal cream was used to remove hair from the back. The area of ​​hair removal was 3*3cm. 2 During the experiment, hair removal was performed according to the hair growth. Forty guinea pigs were randomly divided into five groups, with eight in each group. The drug information for each group is shown in Table 9.

[0229] Table 9 Drug grouping in efficacy test

[0230] Drug administration: Each guinea pig was treated with the drug evenly applied to the hair removal area once daily for 4 weeks. A thin layer of drug was evenly applied to each group, covering the hair removal area. The residual drug was washed off 12 hours after each administration.

[0231] Symptom observation: Observe and record the skin condition of the administration area before each administration to observe whether there is skin irritation.

[0232] Skin color card detection: After the animals are grouped, the skin color card is used to detect and record the skin color of the dosing area of ​​each animal. During the dosing period, the skin color card is used to detect and record the skin color of the dosing area every week until the end of dosing, and the skin color difference before and after dosing is compared between each group.

[0233] Skin color and dermoscopy: Before and four weeks after administration, skin color was tested using a skin colorimeter.

[0234] Fotana-Masson staining of skin sections: Four weeks after administration, paraffin sections of skin were taken from the administration area and non-administration area on the back of guinea pigs, and then Fotana-Masson staining was performed to evaluate the changes in melanin.

[0235] 7.2 Test results

[0236] 7.2.1 Skin color card test

[0237] Table 10 Comparison of the mean values ​​of skin color card readings of animals in each group before and after administration

[0238] The lower the color card reading, the whiter the skin. The mean skin color card values ​​of each group before and after administration are shown in Table 10: The adduct compound gel has a more obvious effect of reducing melanin, which is higher than that of commercially available vitamin A acid cream and the positive control drug hydroquinone.

[0239] 7.2.2 Skin color detection

[0240] Table 11 Animal L in each group ＊ Mean ± SD

[0241] Use colorimeter to detect L * The value is used to evaluate the drug effect, L * The value represents the balance of black and white in the skin, which is mainly affected by melanin. The larger the L value, the whiter the skin color. As shown in Table 11, the L values ​​of the animals in each group after administration were * The values ​​all increased, indicating that the skin color became lighter to varying degrees. Among them, the adduct compound gel showed a stronger effect in reducing melanin, which was higher than the positive control commercial hydroquinone group.

[0242] As shown in Figure 1, the skin color of guinea pigs became significantly whiter before and after treatment with the tranexamic acid / vitamin A acid adduct compound preparation.

[0243] As shown in Figure 2, the melanin in the epidermis was significantly reduced before and after treatment with the tranexamic acid / vitamin A acid adduct compound preparation.

[0244] Example 8 Verification of the Penetration-Enhancing Effect of Adducts

[0245] 8.1 Formulation 10: Adduct-free Compound Gel (ligand diethanolamine is added to the formulation as an excipient)

[0246] Process: Weigh all excipients according to the prescribed amount; dissolve tranexamic acid in approximately 40% water; dissolve the preservatives (sodium methylparaben and sodium propylparaben) in the remaining water. Add Carbomer 980 and stir at 200 rpm for 5 minutes to evenly disperse. Stir at 50 rpm for 50 minutes to hydrate the carbomer. Add the tranexamic acid solution and mechanically stir for 30 minutes to mix thoroughly and gel the carbomer. Add the oil phase excipients and mix thoroughly to form a uniform oil phase. Add the aqueous phase to the oil phase and homogenize at 5000 rpm in a high shear homogenizer for 3 minutes. Stir mechanically at low speed for 30 minutes to form a uniform gel. Fill into aluminum-plastic composite tubes.

[0247] 8.2 IVPT trial

[0248] 8.2.1 IVPT test method

[0249] Methods: An IVPT test was conducted on ex vivo skin from Bama miniature pigs (aged ≤ 3 months) using a Franz diffusion cell. Receiving fluid was collected at different time points (1h, 2h, 4h, and 6h). After the test, the skin was cleaned and then the tissue was broken into pieces to obtain an intradermal retained extract. The obtained samples were analyzed using UPLC-MS to determine the contents of tranexamic acid and retinoic acid in the samples.

[0250] 8.2.2 IVPT test results

[0251] Table 12 IVPT test results of different compound preparations ND- means not detected; NA means not applicable (the commercially available control preparation is a single-ingredient vitamin A acid preparation that does not contain tranexamic acid and is therefore not applicable).

[0252] The results, as shown in Table 12, show that the retinoic acid adduct / tranexamic acid compound gel (Formulation 7) exhibited better transdermal penetration than the compound gel without the adduct (Formulation 10) and the commercially available tretinoin ointment. This suggests that tretinoin must first form an adduct with the ligand diethanolamine before it can exert its permeation-enhancing effect.

[0253] Example 9 Other types of vitamin A acid complex-vitamin A acid triethanolamine complex preparations

[0254] 9.1 Preparation of Vitamin A Acid Triethanolamine Complex

[0255] Materials and reagents: Vitamin A acid (RA) (AR, Shanghai Aladdin Biochemical Technology Co., Ltd.), triethanolamine (TEA) (AR, Sinopharm Chemical Reagent Co., Ltd.), ethanol (AR, Sinopharm Chemical Reagent Co., Ltd.).

[0256] prescription:

[0257] The molar ratio of triethanolamine (TEA) to retinoic acid (RA) is 8:1 (abbreviated as 8[TEA][RA]).

[0258] Process:

[0259] (1) Weigh vitamin A acid according to the prescribed amount and place it in a round-bottom flask. Add ethanol and stir to mix. The vitamin A acid cannot be completely dissolved and remains in a suspended state. Wrap the round-bottom flask with aluminum foil to block light.

[0260] (2) Weigh triethanolamine according to the prescribed amount, place it in a container wrapped in aluminum foil, and add ethanol to stir and dilute it.

[0261] The triethanolamine diluted solution obtained in step (2) was added dropwise to the mixed solution obtained in step (1) while stirring; and the container was rinsed with about 5 mL of ethanol and added to the flask together with stirring.

[0262] After all the additions are complete, the solution should be orange-red and clear; continue stirring for 4 hours.

[0263] The solvent was removed using a rotary evaporator, and the resulting sample was sealed and stored in the dark.

[0264] 8[TEA][RA] H NMR data:

[0265] 1 H NMR (400MHz, DMSO-d6) δ6.98 (dd, J=15.1, 11.4Hz, 1H), 6.38 (d, J=15.1Hz, 1H ), 6.26-6.15(m, 2H), 5.77(s, 1H), 4.45(s, 24H), 3.41(td, J=6.1, 0.9Hz, 48H ), 2.55 (td, J=6.1, 0.9Hz, 48H), 2.26 (d, J=1.0Hz, 3H), 1.99 (d, J=12.7Hz, 5H ), 1.69 (s, 3H), 1.63-1.52 (m, 2H), 1.48-1.40 (m, 2H), 1.01 (d, J=0.8Hz, 6H).

[0266] The H NMR spectrum is shown in FIG3 . From the spectrum, it is observed that the active hydrogen of the carboxyl group of vitamin A acid disappears, and the chemical shift and peak shape of the hydroxyl hydrogen of triethanolamine change, indicating that vitamin A acid interacts with triethanolamine to form a complex.

[0267] 9.2 Preparation of Tranexamic Acid / Vitamin A Triethanolamine Adduct Compound Gel (Preparation 11)

[0268] prescription:

[0269] Process: Weigh all excipients according to the prescribed amount; dissolve tranexamic acid in approximately 40% water; dissolve sodium methylparaben and sodium propylparaben in the remaining water. Add Carbopol 980 and stir at 200 rpm for 5 minutes to evenly disperse. Stir at 50 rpm for 50 minutes to hydrate the carbomer. Add the tranexamic acid solution and mechanically stir for 30 minutes to mix thoroughly and gel the carbomer. Add the oil phase excipients and stir to form a uniform oil phase. Add the aqueous phase to the oil phase and homogenize at 5000 rpm in a high shear homogenizer for 3 minutes. Stir mechanically at low speed for 30 minutes to form a uniform gel. Fill into aluminum-plastic composite tubes.

[0270] 9.3 Test of Content and Content Uniformity of Tranexamic Acid / Vitamin A Triethanolamine Adduct Compound Gel

[0271] Six tubes of tranexamic acid / vitamin A triethanolamine adduct compound gel were randomly selected and tested for content and content uniformity.

[0272] Table 13 Tranexamic acid / vitamin A acid triethanolamine adduct compound gel content and content uniformity

[0273] The results in Table 13 show that the contents and content uniformity of the two drugs in the obtained preparations meet the standards.

[0274] 9.4 IVPT Trial of Tranexamic Acid / Vitamin A Triethanolamine Adduct Compound Gel

[0275] Methods: An IVPT test was conducted on ex vivo skin from Bama miniature pigs (aged ≤ 3 months) using a Franz diffusion cell. Receiving fluid was collected at different time points (1h, 2h, 4h, and 6h). After the test, the skin was cleaned and then the tissue was broken into pieces to obtain an intradermal retained extract. The obtained samples were analyzed using UPLC-MS to determine the contents of tranexamic acid and retinoic acid in the samples.

[0276] Table 14 Tranexamic acid / vitamin A acid triethanolamine adduct compound gel IVPT test results

[0277] As shown in Table 14, compared with Preparation 3-ordinary compound gel, Preparation 11-TEA adduct compound gel also has a penetration-enhancing effect.

[0278] Example 10 Other types of vitamin A acid complexes-vitamin A acid triethylamine complexes

[0279] 10.1 Preparation of Vitamin A Acid Triethylamine Complex

[0280] Materials and reagents: Vitamin A acid (RA) (AR, Shanghai Aladdin Biochemical Technology Co., Ltd.), triethylamine (AR, Sinopharm Chemical Reagent Co., Ltd.).

[0281] prescription:

[0282] The molar ratio of triethylamine to retinoic acid (RA) is 2:1 (may be abbreviated as 2[Et3N][RA]).

[0283] Process:

[0284] Weigh vitamin A acid according to the prescribed amount and place it in a flask, then wrap it in aluminum foil to protect it from light. Add the prescribed amount of triethylamine, sonicate for 30 minutes until the solution becomes clear, and continue stirring for 4 hours to obtain a clear orange-yellow liquid.

[0285] 2[Et3N][RA] H NMR data:

[0286] 1 H NMR (400MHz, DMSO-d6) δ6.96 (dd, J=15.1, 11.4Hz, 1H), 6.37 (d, J=15.0Hz, 1H), 6.29-6.18 (m, 2H), 6.15 (d, J=16.1Hz, 1H), 5.77 (s, 1H), 2.57-2.52 (m, 12H), 2.32-2.21 (m, 3H), 1.99 (d, J=13.7Hz, 5H), 1.68 (s, 3H), 1.63-1.52 (m, 2H), 1.52-1.40 (m, 2H), 1.05-0.93 (m, 24H).

[0287] The H NMR spectrum is shown in FIG4 . From the spectrum, it is observed that the active hydrogen of the carboxyl group of vitamin A acid disappears and the chemical shift of the methylene hydrogen of triethylamine moves to the low field, indicating that vitamin A acid interacts with triethylamine to form a complex.

[0288] 10.2 Preparation of Tranexamic Acid / Vitamin A Triethylamine Adduct Compound Gel (Preparation 12)

[0289] prescription:

[0290] Process: Weigh all excipients according to the prescribed amount; dissolve tranexamic acid in approximately 40% water; dissolve sodium methylparaben and sodium propylparaben in the remaining water. Add Carbopol 980 and stir at 200 rpm for 5 minutes to evenly disperse. Stir at 50 rpm for 50 minutes to hydrate the carbomer. Add the tranexamic acid solution and mechanically stir for 30 minutes to mix thoroughly and gel the carbomer. Add the oil phase excipients and stir to form a uniform oil phase. Add the aqueous phase to the oil phase and homogenize at 5000 rpm in a high shear homogenizer for 3 minutes. Stir mechanically at low speed for 30 minutes to form a uniform gel. Fill into aluminum-plastic composite tubes.

[0291] 10.3 Test of Content and Content Uniformity of Tranexamic Acid / Triethylamine Vitamin A Adduct Compound Gel

[0292] Six tubes of tranexamic acid / vitamin A triethylamine adduct compound gel were randomly selected and tested for content and content uniformity.

[0293] Table 15 Tranexamic acid / vitamin A acid triethylamine adduct compound gel content and content uniformity

[0294] The results in Table 15 show that the contents and content uniformity of the two drugs in the obtained preparations meet the standards.

[0295] 10.4 IVPT Test of Tranexamic Acid / Triethylamine Vitamin A Adduct Compound Gel

[0296] Methods: An IVPT test was conducted on ex vivo skin from Bama miniature pigs (aged ≤ 3 months) using a Franz diffusion cell. Receiving fluid was collected at different time points (1h, 2h, 4h, and 6h). After the test, the skin was cleaned and then the tissue was broken into pieces to obtain an intradermal retained extract. The obtained samples were analyzed using UPLC-MS to determine the contents of tranexamic acid and retinoic acid in the samples.

[0297] Table 16 Tranexamic acid / vitamin A acid triethylamine adduct compound gel IVPT test results

[0298] As shown in Table 16, compared with preparation 3-ordinary compound gel, preparation 12-triethylamine adduct compound gel also has a penetration-enhancing effect, and its penetration-enhancing effect is slightly weaker than that of DEA adduct compound gel.

[0299] Example 11 Tranexamic acid / vitamin A acid diethanolamine adduct compound prescription

[0300] The present invention also prepared formulations 13-27 containing tranexamic acid and vitamin A acid adduct (vitamin A acid ethylene glycol amine complex (2[DEA][RA])) with different penetration enhancers, different solubilizers, different antioxidants, different preservatives, and different drug loading amounts.

[0301] 11.1 Different penetration enhancers

[0302] Preparation 13

[0303] Preparation 14

[0304] Preparation 15

[0305] 11.2 Different cosolvents

[0306] Preparation 16

[0307] Preparation 17

[0308] 11.3 Different Antioxidants

[0309] Preparation 18

[0310] Preparation 19

[0311] Preparation 20

[0312] 11.4 Different preservatives

[0313] Preparation 21

[0314] Preparation 22

[0315] Preparation 23

[0316] 11.5 Different drug loadings

[0317] Preparation 24

[0318] Preparation 25

[0319] Preparation 26

[0320] Preparation 27

[0321] Example 12: Therapeutic effect of the compound preparation of the example on chloasma

[0322] 12.1. Test system

[0323] 12.1.1. Experimental Animals

[0324] 12.1.1.1. Basic Animal Information

[0325] 12.1.1.2. Quarantine and Adaptation Period

[0326] Quarantine period: at least 3 days, during which the veterinarian will complete the animal quarantine.

[0327] Adaptation period: at least 2 days. Experimenters will conduct daily inspections during the adaptation period.

[0328] 12.1.1.3. Feeding and Environment

[0329] 12.1.2. Investigational Drugs

[0330] 12.2. Test content

[0331] 12.2.1. Animal Grouping and Treatment

[0332] Grouping: 45 animals were screened out of 50 animals and divided into 6 groups, G1 and G2 with 11 animals in each group, G3 with 5 animals in each group, and G4, G5, and G6 with 6 animals in each group.

[0333] Hair removal: The day before the experiment, the animals were treated with depilatory cream to remove hair from the animal's back skin in an area of ​​approximately 2*3 cm. Thereafter, hair removal was performed two to three times a week depending on the animal's hair growth rate.

[0334] Progesterone injection: Except for the animals in group G1, the other animals were given progesterone at a dose of 20 mg / kg intramuscularly every day, with the injections being given alternately into the two hind legs for 4 weeks.

[0335] Ultraviolet light irradiation: Except for the animals in group G1, the remaining animals were anesthetized with isoflurane, laid flat on a surgical pad, and their eyes were shielded with light-shielding paper. Then, an ultraviolet lamp with a wavelength of 280-320 nm (UVB light source) was used to illuminate the upper back of the animals. The light source was 12 cm ± 0.5 cm above the back of the animals. The exposure time was 4 minutes three times a week for 4 weeks.

[0336] 12.2.2. Confirmation of Melasma Model

[0337] After the first week of animal modeling, the backs of animals in group G3 were smeared with hydroquinone cream at 30 mg / cm 2 The remaining animals were not treated with any other treatment. After the third week of modeling, 5 mice were randomly selected from each of the G1 and G2 groups, as well as the G3 group, and euthanized.

[0338] Skin samples from the irradiated dorsal area of ​​mice were fixed with 10% formalin, embedded in paraffin, and stained with Fontana-Masson staining. The sections were scanned in their entirety using Halo software. Ten equally sized fields of view were randomly selected from each skin region within each image, and the melanin area in these ten selected fields was calculated and analyzed using the software.

[0339] As shown in Figure 5, melanin levels in the G2 group were significantly higher than those in the control group, and in the G3 group were also higher than those in the control group, but lower than those in the modeling group. This suggests that progesterone injection and UV irradiation resulted in abnormal melanin metabolism and pigmentation in mice, successfully establishing a chloasma model.

[0340] 12.2.3. Efficacy Test

[0341] Each group of animals began receiving medication according to the group design starting at week 4. Three weeks after dosing, the animals were euthanized, and the irradiated dorsal skin of the mice was fixed with 10% formalin, embedded in paraffin, and stained with Fontana-Masson staining. The sections were scanned in their entirety using Halo software. Ten equally sized fields of view were randomly selected from each image, and the melanin area in these ten selected fields was calculated and analyzed using the software.

[0342] The test results are shown in Figure 6. Compared with the modeling group, the adduct compound preparation group showed a significant effect in reducing pigmentation (p < 0.001). Hydroquinone is a first-line drug for treating chloasma. Compared with the hydroquinone group (positive control), the adduct compound preparation showed superior efficacy (p < 0.05). Compared with the retinoic acid monotherapy group, the adduct compound preparation showed superior efficacy (p < 0.05). Therefore, the compound preparation of the present invention has a good therapeutic effect on chloasma.

[0343] 12.2.4. Typical Slice Photos

[0344] Typical slice photos of each group are shown in Figure 7.

[0345] Example 13: Toxicity study of the adduct compound preparation after repeated administration for 4 weeks

[0346] 13.1. Test system

[0347] 13.1.1. Experimental Animals

[0348] 13.1.1.1. Basic Animal Information

[0349] 13.1.1.2. Quarantine and Adaptation Period

[0350] Quarantine period: During the period of stocking, veterinarians complete animal quarantine during the quarantine period.

[0351] Adaptation period: 8 days (including the day of grouping). Experimenters conducted general observations once a day during the adaptation period.

[0352] 13.1.1.3. Rearing and Environment

[0353] 13.1.2. Test drugs in each group

[0354] 13.2. Test content

[0355] Forty Bama miniature pigs were randomly divided into four groups (10 pigs per group, half male and half female). The drug was applied to the skin on both sides of the spine. The intended surface area of ​​the animal to be applied was approximately 10% of the total body surface area. The drug volume of the negative control group, vehicle control group, adduct compound group, and commercial control group was 15 mg / cm 2 The dosing frequency is once daily for 4 consecutive weeks (28 doses in total), followed by a 4-week recovery period. The specific dosing schedule is detailed in the table below.

[0356] Toxicity assessment endpoints for this study included death / moribundity, general observations, observations for irritation at the administration site, body weight, food intake, ophthalmological examination, body temperature, electrocardiogram (lead II), hematology / coagulation / serum biochemistry tests, and urinalysis. At the end of the dosing period (D29) and the recovery period (D59), all animals scheduled for dissection underwent gross anatomical examinations, organ weights and coefficients, and histopathological examinations. Blood samples were collected at various time points before and after the first and final doses for toxicokinetic studies.

[0357] 13.3. Test results and conclusions

[0358] 13.3.1 Summary of Irritation and Pathology

[0359] During the experiment, no obvious toxic changes related to the administration of the test article were observed in the animals' body weight, food intake, body temperature, electrocardiogram, ophthalmological examination, hematology / coagulation / serum biochemical index tests, urine analysis and organ weight.

[0360] General observations showed mild to mild irritation of the dorsal skin in 4 / 10 animals in the vehicle control group and 4 / 10 animals in the test article group, respectively; mild irritation of the dorsal skin was also observed in 5 / 10 animals in the commercially available control group. These findings resolved by the end of the recovery period.

[0361] Gross autopsy revealed no gross abnormalities related to the test article or the commercial control at the administration site at the end of the dosing period. Mild skin lesions were observed in some animals in the test article group, and mild to moderate skin lesions were also observed in some animals in the commercial control group. No gross abnormalities related to the test article were observed at the end of the recovery period.

[0362] Histopathological examination showed that histopathological changes related to the test article or the commercial control were observed at the administration site, with mild to mild lesions observed in the test article group and mild to moderate crusting, moderate erosions / ulcers, and moderate dermal fibrosis observed in the commercial control group.

[0363] Irritation observations and pathological results at the administration sites of the above test samples showed that the irritation of the above test samples of various specifications was lower than that of the commercially available reference product (0.05% tretinoin cream) and no new changes were observed. It is believed that the risk of local toxic side effects in the above test sample groups is lower than that of existing therapeutic drugs.

[0364] Example 14: Study on the sensitization of adduct compound preparation

[0365] 14.1. Test system

[0366] 14.1.1. Experimental Animals

[0367] 14.1.1.1. Basic Animal Information

[0368] 14.1.1.2. Quarantine and Adaptation Period

[0369] Quarantine period: 3 days, during which the veterinarian will complete the animal quarantine.

[0370] Acclimation period: 2 days (including the day of grouping). Experimenters conducted cage-side observation once a day during the acclimation period and completed a detailed clinical observation before grouping.

[0371] 14.1.1.3. Rearing and Environment

[0372] 14.1.2. Drug Information

[0373] 14.2. Test content

[0374] Fifty guinea pigs were randomly divided into five groups. Specific group information is shown in the table below.

[0375] The drug was administered by skin application, with sensitization administered on days 1, 8, and 15 (D(Day) 1, D8, and D15). Challenges were conducted on days 14 (D29) and 21 (D36) after the last sensitization administration.

[0376] During the experiment, death and moribund conditions were observed once a day, and body weight was measured once on D-1 (before grouping), D15 (last sensitization), D31 (end of observation 48 hours after the first challenge), and D38 (end of observation 48 hours after the second challenge). Generally, the animals were observed once 1 hour and 24 hours after sensitization administration (after cleaning the administration site), and skin allergic reactions were observed immediately, 24 hours, and 48 hours after challenge (after cleaning the administration site).

[0377] 14.3. Test results and conclusions

[0378] During the trial, no deaths or near-deaths related to the test article or control article were observed in any group of animals. Compared to the negative control group, no significant differences were observed in the body weights of male and female animals in the low- and high-dose test article groups, as well as the commercially available control group. In the positive control group, male animals showed slow weight gain on Days 15, 31, and 38, while no significant differences were observed in the body weights of female animals.

[0379] In the negative control group, no erythema or edema was observed on the skin after either the initial or re-challenge administration. In the positive control group, erythema or edema was observed on the skin after both the initial and re-challenge administration. The allergic reaction rate was 100%, indicating a strong sensitization intensity. This test system is established.

[0380] During the sensitization phase, 1 / 20 animals in the test article group developed skin erythema 24 hours after the second sensitization dose, and 2 / 20 and 6 / 20 animals developed skin erythema 1 and 24 hours after the third sensitization dose, respectively. This skin erythema is related to the specific effects of retinoic acid in the test article. During the challenge phase, no skin erythema, edema, or other abnormal reactions were observed in the test article group within 48 hours after the first and second challenges. This indicates that the test article was negative in the guinea pig Buehler test, indicating that the adduct combination preparation is non-allergenic.

[0381] During the sensitization period, the number of animals in the commercially available control group that developed skin erythema 1 hour and 24 hours after the second sensitization administration was 5 / 10 and 3 / 10, respectively, and the number of animals that developed skin erythema 1 hour and 24 hours after the third sensitization administration was 6 / 10 and 5 / 10, respectively. During the provocation period, no erythema or edema reaction occurred after the first provocation administration, and the number of animals that developed skin erythema immediately after the second provocation, 2 / 10 and 1 / 10, respectively, 24 hours after the provocation and 48 hours after the provocation. The incidence rate of allergic reaction was 20%, and the sensitization intensity was mild.

[0382] In summary, under the conditions of this study, the adduct combination formulation was negative in the Buehler test when administered transdermally to guinea pigs; the commercially available tretinoin cream (0.05%) was mildly sensitizing. Therefore, the adduct combination formulation is considered non-sensitizing and poses a lower safety risk of allergic reactions than existing therapeutic agents.

[0383] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A composition comprising the following components: (1) tranexamic acid or a pharmaceutically acceptable salt thereof; (2) Vitamin A acid alcohol amine complex or vitamin A acid fatty amine complex; The vitamin A acid alcoholamine complex is composed of vitamin A acid and alcoholamine compounds; The vitamin A acid fatty amine complex consists of vitamin A acid and fatty amine compounds.

2. The composition according to claim 1, characterized in that The fatty amine compound is selected from C1-20 alkylamine compounds; Preferably, the vitamin A acid fatty amine complex consists of vitamin A acid and triethylamine; Preferably, in the vitamin A acid fatty amine complex, the molar ratio of the fatty amine compound to vitamin A acid is (1-100):1; Preferably, the mass ratio of component (1) (calculated as tranexamic acid) to component (2) (calculated as vitamin A acid) is 0.01-100:0.0001-10.

3. The composition according to claim 1, characterized in that (2) In the vitamin A acid alcoholamine complex, the molar ratio of the alcoholamine compound to vitamin A acid is (1-100):1; Preferably, the alcoholamine compound is selected from the following formula I: Wherein, X is selected from C 1-6 an alkyl (alkylene) group; Indicates the group attachment site; R1 and R2 are each independently selected from H, C 1-6 Alkyl, C 1-6 Alkyl-OH.

4. The composition according to any one of claims 1 to 3, characterized in that In the composition, components (1) and (2) are each administered in the form of a pharmaceutical composition; Preferably, in the composition, components (1) and (2) can be administered simultaneously, sequentially or intermittently; Preferably, the administration route of the composition includes, but is not limited to, enteral administration or parenteral administration; Preferably, the composition includes but is not limited to pharmaceutical preparations, cosmetics, care products, and beauty products; Preferably, the composition is administrable topically through the skin.

5. The composition according to any one of claims 1 to 4, characterized in that In the composition, the content of component (1) (calculated as tranexamic acid) is 0.01%-20%; Preferably, in the composition, the content of component (2) (calculated as vitamin A acid) is 0.001%-2%; Preferably, the specification of the composition is 1g / stick to 20g / stick; Preferably, the composition further comprises: (3) gel matrix; Preferably, the gel matrix is ​​selected from carbomer; preferably, the content of the gel matrix is ​​0.01%-10%; Preferably, the composition further comprises: (4) penetration enhancers; Preferably, the penetration enhancer is selected from one, two or more of monocaprylic acid glyceryl, Transcutol P, isopropyl myristate, laurocaprylate, diethylene glycol monoethyl ether, polyglycerol fatty acid ester, propylene glycol monocaprylate, and caprylic acid caprylic acid polyethylene glycol glyceride; preferably, the content of the penetration enhancer is 0.01%-20%; Preferably, the composition further comprises: (5) Preservatives; Preferably, the preservative is selected from one, two or more of benzoic acid, phenoxyethanol, sodium benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium methyl parahydroxybenzoate, and sodium propyl parahydroxybenzoate; preferably, the preservative The content is 0.001%-2%; Preferably, the composition further comprises: (6) Antioxidants; Preferably, the antioxidant is selected from one, two or more of butylated hydroxyanisole (BHA), butylated hydroxytoluene, butylated hydroxyanisole, vitamin C (ascorbic acid), vitamin E, and sodium metabisulfite; preferably, the content of the antioxidant is 0.001%-2%; Preferably, the composition further comprises: (7) cosolvent; Preferably, the cosolvent is selected from alcohols, and the alcohol is preferably one, two or more of glycerol, propylene glycol, 1,2-pentanediol, ethanol, and benzyl alcohol; preferably, the content of the cosolvent is 0.5%-30%; Preferably, the composition further comprises: (8) Emulsifier; Preferably, the emulsifier is selected from one or more of Pemulen TR-1 NF, Emulium Delta MB, Tween, Span, polyoxyethylene castor oil derivatives, poloxamer, Triton, caprylic capric acid macrogol glyceride, macrogol stearate, polyoxyethylene-8 beeswax, and lauroyl polyoxyethylene glyceride; Preferably, the content of the emulsifier is 0.1%-30%; Preferably, the composition further comprises: (9) Oily matrix; Preferably, the oily matrix is ​​selected from one or more of long-chain fatty alcohols, long-chain fatty acids, fatty acid esters, and oils; preferably, the long-chain fatty alcohol is selected from hexadecanol and stearyl alcohol; preferably, the long-chain fatty acid is selected from stearic acid; preferably, the fatty acid ester is selected from one or more of isopropyl myristate, medium-chain triglycerides, monoolein, monolinolein, propylene glycol dicaprylate, oleoyl polyoxyethylene glyceride, myristyl myristate, isopropyl palmitate, isopropyl linoleate, dodecanol benzoate, isostearyl isostearate, fatty acid lactate, decyl oleate, and octyl palmitate; preferably, the content of the oily matrix is ​​0.5%-20%; Preferably, the composition further comprises: (10) Rheology modifier; Preferably, the rheology modifier is selected from xanthan gum; preferably, the content of the rheology modifier is 0.01%-0.5%; Preferably, the composition further comprises any one or more of a metal ion complexing agent, an emulsifier, and a texture regulator; preferably, the emulsifier is selected from propylene glycol monocaprylate; preferably, the content of the emulsifier is 0.1%-5%; preferably, the texture regulator is selected from cyclopentasiloxane; preferably, the content of the texture regulator is 1%-5%; preferably, the metal ion complexing agent is selected from one or more of ethylenediaminetetraacetic acid (EDTA), disodium ethylenediaminetetraacetate (EDTA-2Na), tetrasodium ethylenediaminetetraacetate (EDTA-4Na), disodium nitrilotriacetate, sodium tripolyphosphate, sodium hexametaphosphate, and tetrapotassium pyrophosphate; Preferably, the composition further comprises other physiologically acceptable carriers.

6. The composition according to any one of claims 1 to 5, characterized in that The composition comprises the following components: 2.5%-7.5% tranexamic acid; 0.01% to 1% of vitamin A acid alcoholamine complex or vitamin A acid fatty amine complex calculated as vitamin A acid; 0.05%-5% gel matrix; Optionally, 0.1%-15% of a penetration enhancer; Optionally, 0.005%-1% preservative; Optionally, 0.01%-1% antioxidant; Optionally, 1%-20% of a co-solvent; Optionally, 0.2%-20% of an emulsifier; Optionally, 1.0%-15% of an oily base; Optionally, 0.1%-0.3% rheology modifier; Optionally, 1%-3% of a co-emulsifier; Optionally, 1%-5% of a texture modifier; The balance is water.

7. The composition according to any one of claims 1 to 6, characterized in that The composition comprises the following components: Vitamin A acid alcohol amine complexes or vitamin A acid fatty amine complexes such as vitamin A acid diethanolamine, vitamin A acid triethanolamine, vitamin A acid triethylamine; Preferably, the composition comprises the following components: Vitamin A acid alcohol amine complexes or vitamin A acid fatty amine complexes such as vitamin A acid diethanolamine, vitamin A acid triethanolamine, vitamin A acid triethylamine; Preferably, the composition comprises the following components: Vitamin A acid alcohol amine complexes or vitamin A acid fatty amine complexes such as vitamin A acid diethanolamine, vitamin A acid triethanolamine, vitamin A acid triethylamine; Preferably, the composition comprises the following components: Vitamin A acid alcohol amine complexes or vitamin A acid fatty amine complexes such as vitamin A acid diethanolamine, vitamin A acid triethanolamine, and vitamin A acid triethylamine.

8. Use of the composition according to any one of claims 1 to 7 in the preparation of a medicament for preventing and / or treating skin diseases; Preferably, the skin disease is selected from chloasma and pigmentation.

9. A method for preventing and / or treating skin diseases, comprising administering an effective amount of the composition according to any one of claims 1 to 7 to a patient suffering from the skin diseases; Preferably, the skin disease is selected from chloasma and pigmentation.

10. A method for preparing the composition according to any one of claims 1 to 7, comprising the following steps: 1) preparing an aqueous phase comprising tranexamic acid; 2) preparing an oil phase comprising a vitamin A alcohol amine complex or a vitamin A acid fatty amine complex; 3) Mixing: adding the water phase into the oil phase, emulsifying and homogenizing, and obtaining the composition.

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