Compound composition containing tranexamic acid and tretinoin

Abstract

The invention provides a novel composition and a preparation. The composition and the preparation comprise tranexamic acid and a vitamin A acid alcohol amine compound or a vitamin A acid fatty amine compound. After the composition is prepared into a preparation, the solubility of the vitamin A acid can be improved, the loss of the vitamin A acid in the preparation process is reduced, the content uniformity of the preparation is improved, and the stability of the preparation is improved; the composition can significantly increase the intradermal retention amount of vitamin A acid and tranexamic acid, and does not significantly increase the transdermal penetration amount of tranexamic acid. The composition and the preparation provided by the invention can significantly improve the curative effect and avoid aggravation of toxic and side effects in the treatment of hyperpigmentation and chloasma.

Description

Technical Field

[0001] The invention relates to the field of preparations, and in particular to a compound composition containing tranexamic acid and retinoic acid. Background Art

[0002] The skin is the largest organ of the human body and the main barrier between the body and the external environment. It is often exposed to a complex external environment and attacked by a variety of harmful factors (cold and hot stimulation, ultraviolet rays, bacteria, viruses, etc.). Therefore, skin-related abnormalities or diseases often have a variety of causes, complex pathogenesis, and diverse clinical symptoms.

[0003] 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. There are differences in the physical and chemical properties between different drugs, so the formulation and process design of compound preparations becomes 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 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.

[0004] Retinoin can be used to treat a variety of skin diseases, and can also improve skin texture and reduce spots and pigmentation. This drug is a poorly soluble drug, with a certain degree of fat solubility, but very poor water solubility.

[0005] Tranexamic acid (TA) can inhibit melanin production and relieve various spots and pigmentation. It has good water solubility but poor fat solubility. Summary of the invention

[0006] 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.

[0007] The present invention provides a composition comprising the following components:

[0008] (i) tranexamic acid or a pharmaceutically acceptable salt thereof;

[0009] (ii) Vitamin A acid alcohol amine complex or vitamin A acid fatty amine complex.

[0010] According to an embodiment of the present invention, the vitamin A acid alcoholamine complex consists of vitamin A acid and an alcoholamine compound.

[0011] 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.

[0012] 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.

[0013] According to an embodiment of the present invention, the vitamin A acid fatty amine complex consists of vitamin A acid and triethylamine.

[0014] 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.

[0015] According to an embodiment of the present invention, the mass ratio of component (i) (calculated as tranexamic acid) to component (ii) (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 (0.01, 0.025, 0.05, 0.1).

[0016] According to an embodiment of the present invention, in (ii) 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.

[0017] According to an embodiment of the present invention, the alcoholamine compound is selected from the following formula I:

[0018]

[0019] Wherein, X is selected from C 1-6 Alkyl (alkylene); preferably, selected from -CH 2 -CH 2 -、-CH 2 -CH2 -CH 2 -and Indicates the group attachment site;

[0020] R 1 , R 2 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkyl-OH.

[0021] 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.

[0022] 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 exist partially or entirely in anionic form, and the alcoholamine compound may exist partially or entirely in cationic form.

[0023] 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.

[0024] According to an embodiment of the present invention, in the complex, vitamin A acid is as follows [A - ] exists in the form of:

[0025]

[0026] According to an embodiment of the present invention, in the composite, the alcohol amine compound is as shown in the following formula II: + ] exists in the form of:

[0027]

[0028] In the formula II, X' is selected from C 1-6 The alkyl (alkylene) group is preferably selected from -CH 2 -CH 2 -、-CH 2 -CH 2 -CH 2 -and

[0029] Indicates the group attachment site;

[0030] R 1 ’ , R 2 ’ Each independently selected from H, C1-6 Alkyl, C 1-6 Alkyl-OH.

[0031] 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, isobutanolammonium cation.

[0032] 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.

[0033] 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, ornithine, and salts with amines such as monoethanolamine, diethanolamine, and triethanolamine, etc. Among them, sodium salts, potassium salts, triethanolamine salts, and arginine salts are preferred, and sodium salts are more preferred.

[0034] According to an embodiment of the present invention, in the composition, components (i) and (ii) are each administered in the form of a pharmaceutical composition.

[0035] According to an embodiment of the present invention, in the composition, components (i) and (ii) can be administered simultaneously, sequentially or intermittently.

[0036] 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 may be oral administration; the parenteral administration may be transdermal administration (e.g., skin application administration), etc.

[0037] 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).

[0038] According to an embodiment of the present invention, the composition can improve the transdermal performance of component (i) (tranexamic acid) (eg, increase the intradermal retention amount without significantly increasing the skin permeation amount).

[0039] According to an embodiment of the present invention, the composition includes but is not limited to pharmaceutical preparations, cosmetics, care products, and beauty products.

[0040] According to an embodiment of the present invention, the composition can be applied through the skin, topically, for example, selected from creams, patches, ointments, cream preparations, latexes, gels and sprays, etc., and can also be applied 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.

[0041] 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%, 5.0%, 7.5%.

[0042] 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%, 0.1%.

[0043] According to an embodiment of the present invention, the specification of the composition is 1 g / stick to 20 g / stick, for example, 10 g / stick.

[0044] According to an embodiment of the present invention, the composition further comprises:

[0045] (3) Gel matrix.

[0046] According to an embodiment of the present invention, the gel matrix is ​​selected from carbomer, such as Carbopol 980 and Carbopol ETD2020.

[0047] 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%.

[0048] According to an embodiment of the present invention, the composition further comprises:

[0049] (4) Permeation enhancers.

[0050] According to an embodiment of the present invention, the penetration enhancer is selected from the group consisting of monocaprylic glyceryl, Transcutol P, isopropyl myristate, lauryl nitrogen One, two or more of ketone, diethylene glycol monoethyl ether, polyglycerol fatty acid ester, propylene glycol monocaprylate, and caprylic acid caprylic acid polyethylene glycol glyceride.

[0051] 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%.

[0052] According to an embodiment of the present invention, the composition further comprises:

[0053] (5) Preservatives.

[0054] 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.

[0055] According to an embodiment of the present invention, the content of preservative 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%.

[0056] According to an embodiment of the present invention, the composition further comprises:

[0057] (6) Antioxidants.

[0058] 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.

[0059] 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%.

[0060] According to an embodiment of the present invention, the composition further comprises:

[0061] (7) Solvent aid.

[0062] According to an embodiment of the present invention, the co-solvent is selected from alcohols, and the alcohols are preferably one, two or more of glycerol, propylene glycol, 1,2-pentanediol, ethanol and benzyl alcohol.

[0063] According to an embodiment of the present invention, the content of the co-solvent is 0.5%-30%, preferably 1%-20%, for example 1%, 2.0%, 2.5%, 5.0%, 10%, 13.5%, 14%, 15%, 16%, 17%, 18%.

[0064] According to an embodiment of the present invention, the composition further comprises:

[0065] (8) Emulsifier.

[0066] According to an embodiment of the present invention, the emulsifier is selected from one 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 glyceride.

[0067] In some embodiments, polyethylene glycol stearate, such as polyethylene glycol (32) stearate. In some embodiments, lauroyl polyoxyethylene glyceride, such as lauroyl polyoxyethylene (6) glyceride.

[0068] 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, polyoxyethylene 100 hydrogenated castor oil.

[0069] According to an embodiment of the present invention, the content of the emulsifier is 0.1%-30%, preferably 0.2%-20%, for example 0.2%, 0.3%, 2%, 5%, 8%, 10%, 15%.

[0070] According to an embodiment of the present invention, the composition further comprises:

[0071] (9) Oily matrix

[0072] According to an embodiment of the present invention, the oleaginous 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 octadecyl 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, dodecanol 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, etc., and jojoba oil is further preferred.

[0073] According to an embodiment of the present invention, the content of the oily base is 0.5%-20%, preferably 1.0%-15%, for example 1.5%, 2.0%, 5%, 6%, 8%, 10%, 12%.

[0074] According to an embodiment of the present invention, the composition further comprises:

[0075] (10) Rheology regulator.

[0076] According to an embodiment of the present invention, the rheology modifier is selected from xanthan gum.

[0077] 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%.

[0078] According to an embodiment of the present invention, the composition further comprises any one or more of a metal ion complexing agent, an emulsifier, and a texture regulator.

[0079] According to an embodiment of the present invention, the co-emulsifier is selected from propylene glycol monocaprylate.

[0080] 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%.

[0081] According to an embodiment of the present invention, the texture modifier is selected from cyclopentasiloxane.

[0082] According to an embodiment of the present invention, the content of the texture modifier is 1%-5%, for example 3.0%.

[0083] According to an embodiment of the present invention, 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 EDTA or EDTA-2Na.

[0084] According to an embodiment of the present invention, the composition further includes other physiologically acceptable carriers (e.g., biocompatible materials), such as optionally including surfactants, excipients, humectants, emulsifying promoters, suspending agents, salts or buffers for regulating osmotic pressure, colorants, flavors, stabilizers, bactericides or other conventional supplements.

[0085] According to an embodiment of the present invention, the composition comprises the following components:

[0086] 2.5%-7.5% (e.g., 2.5%, 5%, 7.5%) tranexamic acid;

[0087] 0.01%-1% (e.g., 0.01%, 0.025%, 0.05%, 0.1%) of vitamin A acid alcoholamine complex or vitamin A acid fatty amine complex (e.g., vitamin A acid diethanolamine, vitamin A acid triethanolamine, vitamin A acid triethylamine) based on vitamin A acid;

[0088] 0.05%-5% (e.g., 0.1%, 0.15%, 0.2%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%) of a gel matrix (e.g., Carbopol 980 and / or Carbopol ETD2020);

[0089] Optionally, 0.1%-15% (e.g., 0.5%, 1%, 2%, 3%, 4%, 10%, 12.57%, 13%) of a penetration enhancer (e.g., monocaprylin, Transcutol P, isopropyl myristate, lauryl nitrogen One or more of ketone, diethylene glycol monoethyl ether, polyglycerol fatty acid ester, propylene glycol monocaprylate, caprylic acid caprylate polyethylene glycol glyceride);

[0090] 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 or more of benzoic acid, phenoxyethanol, sodium benzoate, methylparaben, ethylparaben, propylparaben, sodium methylparaben, sodium propylparaben);

[0091] Optionally, 0.01%-1% (e.g., 0.1%, 0.2%, 0.3%) antioxidant (e.g., one or more of butylated hydroxyanisole, butylated hydroxytoluene, butylated hydroxyanisole, vitamin C, vitamin E, sodium metabisulfite);

[0092] 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 or more of glycerol, propylene glycol, 1,2-pentanediol, ethanol, benzyl alcohol);

[0093] Optionally, 0.2%-20% (e.g., 0.2%, 0.3%, 2%, 5%, 8%, 10%, 15%) of an emulsifier (e.g., one 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);

[0094] Optionally, 1.0%-15% (e.g., 1.5%, 2.0%, 5%, 6%, 8%, 10%, 12%) of an oily base (e.g., one or more of octadecanol, hexadecanol, stearic acid, and fatty acid esters);

[0095] Optionally, 0.1%-0.3% (e.g., 0.15%) of a rheology modifier (e.g., xanthan gum);

[0096] Optionally, 1%-3% (e.g., 2.0%) of a co-emulsifier (e.g., propylene glycol monocaprylate);

[0097] Optionally, 1%-5% (e.g., 3.0%) of a texture modifier (e.g., cyclopentasiloxane);

[0098] The balance is water.

[0099] According to an embodiment of the present invention, the composition comprises the following components:

[0100]

[0101] The balance is water;

[0102] 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.

[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]

[0106] The balance is water;

[0107] 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.

[0108] According to an embodiment of the present invention, the composition is a latex.

[0109] According to an embodiment of the present invention, the composition comprises the following components:

[0110]

[0111] The balance is water;

[0112] 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;

[0113] Penetration enhancers such as lauryl nitrate One or more of caprylic acid, monocaprylic acid, trancutol P, isopropyl myristate;

[0114] Antioxidants such as one or more of butylated hydroxytoluene, butylated hydroxyanisole, sodium metabisulfite, and ascorbic acid;

[0115] Preservatives such as one or more of sodium methylparaben, sodium propylparaben, methylparaben, propylparaben, butylated hydroxytoluene, and phenoxyethanol.

[0116] According to an embodiment of the present invention, the composition is a gel.

[0117] According to an embodiment of the present invention, the composition comprises the following components:

[0118]

[0119] The balance is water;

[0120] 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.

[0121] According to an embodiment of the present invention, the composition is an emulsion.

[0122] The present invention provides the use of the above-mentioned composition in preparing medicines for preventing and / or treating skin diseases.

[0123] According to an embodiment of the present invention, the skin disease is selected from melasma and pigmentation.

[0124] The present invention provides a method for preventing and / or treating skin diseases, which comprises administering an effective amount of the above composition to a patient suffering from the skin diseases.

[0125] According to an embodiment of the present invention, the skin disease is selected from melasma and pigmentation.

[0126] The present invention also provides a method for preparing the above composition, which comprises the following steps:

[0127] 1) preparing an aqueous phase comprising tranexamic acid;

[0128] 2) preparing an oil phase comprising a vitamin A alcohol amine complex or a vitamin A acid fatty amine complex;

[0129] 3) Mixing: adding the water phase into the oil phase, emulsifying and homogenizing, and obtaining the composition.

[0130] According to an embodiment of the present invention, the aqueous phase further comprises a gel matrix.

[0131] According to an embodiment of the present invention, the aqueous 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.

[0132] 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 cosolvent, an emulsifier, an oily matrix, a rheology modifier, an emulsifier, and a texture modifier. The present invention also provides a method for preparing the above composition, the preparation method comprising the following steps:

[0133] 1) preparing an aqueous phase: adding tranexamic acid, a preservative, and a gel matrix into a certain amount of water, stirring, and obtaining an aqueous phase;

[0134] 2) preparing the 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;

[0135] 3) Mixing: adding the water phase into the oil phase, emulsifying and homogenizing, and obtaining the composition.

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

[0137] 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;

[0138] 2) adding tranexamic acid aqueous solution, continuing to stir and mix evenly, so that the gel matrix gels and obtains an aqueous phase;

[0139] 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;

[0140] 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;

[0141] According to an embodiment of the present invention, the preparation method specifically comprises the following steps:

[0142] 1) dissolving the gel matrix in water, stirring and degassing to prepare a uniform gel matrix phase without bubbles;

[0143] 2) adding a certain amount of preservative into water, adding tranexamic acid after dissolving, and dispersing evenly;

[0144] 3) adding the tranexamic acid solution in step 2) to the gel matrix phase in step 1) to obtain a gel;

[0145] 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;

[0146] 5) adding the oil phase in step 4) to the gel in step 3), and performing emulsification and homogenization treatment to obtain the composition.

[0147] 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.

[0148] Beneficial Effects

[0149] The present invention provides a novel composition, comprising tranexamic acid and a vitamin A acid alcoholamine complex. The composition can improve the solubility of vitamin A acid, reduce the loss of vitamin A acid in the preparation process, improve the content uniformity of the preparation, and improve the stability of the preparation; and the composition can significantly increase the intradermal retention of vitamin A acid and tranexamic acid, while not significantly increasing the transdermal permeation of tranexamic acid.

[0150] 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

[0151] Figure 1 This is a comparison of the skin color on the back of guinea pigs before and after treatment with the tranexamic acid / vitamin A acid adduct compound preparation.

[0152] Figure 2 This is a comparison of skin sections from the doping area and non-dosing area on the back of guinea pigs treated with tranexamic acid / vitamin A acid adduct combination preparation.

[0153] Figure 3 This is the H NMR spectrum of 8[TEA][RA].

[0154] Figure 4 =2[Et 3 NMR hydrogen spectrum of [RA].

[0155] Figure 5 The prepared melasma model.

[0156] Figure 6 It is the therapeutic effect of the compound preparation on chloasma.

[0157] Figure 7 This is a typical slice showing the compound preparation used to treat chloasma. DETAILED DESCRIPTION

[0158] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions 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 included in the scope that the present invention is intended to protect.

[0159] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0160] Tranexamic acid was purchased from Yantai Wanrun Pharmaceutical Co., Ltd. Carbopol 980, Carbopol ETD2020, and Pemulen TR-1NF were purchased from Lubrizol. Sodium metabisulfite was purchased from Hunan Erkang Pharmaceutical Co., Ltd. Methyl paraben, sodium propyl paraben, butylated hydroxytoluene, and BHA butylated hydroxyanisole were purchased from Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd. Vitamin A acid and isopropyl myristate were purchased from Shanghai MacLean Biochemical Technology Co., Ltd. Glyceryl monocaprylate 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, octadecyl alcohol (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 vitamin A acid 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.

[0161] Carbopol 980, Carbopol ETD2020: Carbopol 980, Carbopol ETD2020.

[0162] Transcutol P: diethylene glycol monoethyl ether.

[0163] Pemulen TR-1NF: Carbomer Copolymer Type B, a high molecular weight copolymer of acrylic acid and C10-C30 alkyl acrylates crosslinked with pentaerythritol allyl ether.

[0164] Emulium Delta MB: Cetyl Alcohol (and) Glyceryl Stearate (and) PEG-75 Stearate (and) Ceteth-20 (and) Steareth-20.

[0165] Example 1 Preparation of Tranexamic Acid / Vitamin A Acid Common Compound Preparation

[0166] 1.1 Preparation 1: Tranexamic acid / vitamin A acid common compound ointment

[0167] prescription:

[0168]

[0169] Process: Polyoxyethylene 54 hydrogenated castor oil is heated to 60°C to melt, cooled to 40°C, and the remaining oil phase raw materials and auxiliary materials are added to mix and dissolve; tranexamic acid is dissolved in about 40% of water; the remaining water phase auxiliary materials are mixed with the remaining water, and Carbopol 980 is added to disperse evenly; the tranexamic acid aqueous solution is mixed with the water phase auxiliary materials, and mechanically stirred for 30 minutes to obtain a water phase; the two phases are mixed and homogenized with a homogenizer at 1000 rpm for 2 minutes; mechanically stirred (four-blade or anchor type) for 30 minutes to mix evenly, and then filled with an aluminum-plastic composite tube to obtain the product.

[0170] 1.2. Preparation 2: Tranexamic acid / vitamin A acid common compound latex

[0171] prescription:

[0172]

[0173]

[0174] Process: Weigh each excipient according to the prescription amount; dissolve tranexamic acid in about 40% water; after the remaining aqueous phase materials are mixed evenly, add tranexamic acid solution, stir mechanically for 30 minutes to mix evenly, and gel the carbomer ETD2020; the resulting aqueous phase is placed in a 40°C water bath for insulation. Weigh retinoic acid and ethanol according to the prescription amount and mix the two. Weigh and add isopropyl myristate and benzyl alcohol and mix evenly. Weigh octadecyl alcohol and butylated hydroxytoluene and add them to the oil phase, then heat in a 60°C water bath to dissolve, and then cool to 40°C. Keep the water bath at 40°C, 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 semi-solid latex is formed. After cooling, fill it in an aluminum-plastic composite tube.

[0175] 1.3. Preparation 3: Tranexamic acid / vitamin A acid ordinary compound gel

[0176] prescription:

[0177]

[0178] Process: weigh each auxiliary material according to the prescription amount; dissolve tranexamic acid with about 40% water; dissolve the preservatives (sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate) in the remaining water, add Carbopol 980, stir at high speed of 200rpm for 5 minutes to make it evenly dispersed; stir at low speed of 50rpm for 50 minutes to hydrate the carbomer; add tranexamic acid solution, stir mechanically for 30 minutes to mix evenly, and gel the carbomer; mix and stir the oil phase auxiliary materials evenly to form a uniform oil phase. Add the water phase to the oil phase, and homogenize for 3 minutes with a high shear homogenizer at 5000rpm. Stir mechanically at low speed for 30 minutes to form a uniform gel. Fill it into an aluminum-plastic composite tube.

[0179] 1.4. Preparation 4: Tranexamic acid / vitamin A acid common compound emulsion

[0180] prescription:

[0181]

[0182] Process: Weigh all the auxiliary materials, disperse xanthan gum and carbomer 980 in glycerol and Transcutol P, add some water, and stir and mix in a water bath at 80°C; dissolve tranexamic acid in the remaining water, and then mix it into the water phase, stir mechanically to mix evenly and gel the carbomer 980; mix the ingredients in the oil phase and keep warm at 80°C; add the oil phase to the water phase and homogenize at 8000rpm for 3min; cool to 40-50°C, add phenoxyethanol; stir mechanically for 30min to mix evenly; and dispense into aluminum tubes.

[0183] Example 2 Preparation of tranexamic acid / vitamin A acid diethanolamine adduct compound preparation

[0184] 2.1. Preparation of Vitamin A Acid Adducts

[0185] Raw 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.).

[0186] prescription:

[0187] materials Dosage Solvents Solvent amount Retinol (RA) 6.0g Ethanol 30ml~60ml Diethanolamine (DEA) 4.2g Ethanol 5ml

[0188] The molar ratio of diethanolamine (DEA) to retinoic acid (RA) is 2:1.

[0189] Process:

[0190] (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 is in a suspended state; wrap the round-bottom flask with aluminum foil to block light.

[0191] (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.

[0192] The diethanolamine diluted solution obtained in step (2) is added dropwise to the mixed solution obtained in step (1) while stirring; and the container is cleaned with about 5 ml of ethanol, and the mixture is added to the flask and stirred.

[0193] After all the additions are complete, the solution should be orange-red and clear; continue stirring for 4 hours.

[0194] The solvent was removed by rotary evaporator and the obtained sample was sealed and stored in a light-proof manner.

[0195] For the nuclear magnetic resonance hydrogen spectrum, infrared spectrum, and Raman spectrum data of vitamin A acid diethanolamine complex (2[DEA][RA]), please refer to patent application CN202210853741.9.

[0196] 2.2 Preparation 5: Tranexamic acid / vitamin A acid adduct compound ointment

[0197]

[0198] Process: Polyoxyethylene 54 hydrogenated castor oil is heated to 60°C to melt, cooled to 40°C, and the remaining oil phase raw materials and auxiliary materials are added to mix and dissolve; tranexamic acid is dissolved in about 40% of water; the remaining water phase auxiliary materials are mixed with the remaining water, and Carbopol 980 is added to disperse evenly; the tranexamic acid aqueous solution is mixed with the water phase auxiliary materials, and mechanically stirred for 30 minutes to obtain a water phase; the two phases are mixed and homogenized with a homogenizer at 1000 rpm for 2 minutes; mechanically stirred (four-blade or anchor type) for 30 minutes to mix evenly, and then filled with an aluminum-plastic composite tube to obtain the product.

[0199] 2.3 Preparation 6: Tranexamic acid / vitamin A acid adduct compound latex

[0200] prescription:

[0201]

[0202]

[0203] Process: weigh each excipient according to the prescription amount; dissolve tranexamic acid in about 40% water; after the remaining aqueous phase materials are mixed evenly, add tranexamic acid solution, stir mechanically for 30 minutes to mix evenly, and gel the carbomer ETD2020; the resulting aqueous phase is placed in a 40°C water bath for insulation. Weigh vitamin A acid adduct and ethanol according to the prescription amount and mix the two. Weigh and add isopropyl myristate and benzyl alcohol and mix evenly. Weigh octadecyl alcohol and butylated hydroxytoluene and add them to the oil phase, then heat in a 60°C water bath to dissolve, and then cool to 40°C. Keep the water bath at 40°C, 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 semi-solid latex is formed. After cooling, fill it in an aluminum-plastic composite tube.

[0204] 2.4 Preparation 7: Tranexamic acid / vitamin A acid adduct compound gel

[0205] prescription:

[0206]

[0207] Process: weigh each auxiliary material according to the prescription amount; dissolve tranexamic acid with about 40% water; after the remaining water dissolves the preservative, add Carbomer 980, stir at high speed of 200rpm for 5 minutes to make it evenly dispersed; stir at low speed of 50rpm for 50 minutes to hydrate the Carbomer; add tranexamic acid solution, stir mechanically for 30 minutes to mix evenly, and gel the Carbomer; mix and stir the oil phase auxiliary materials evenly to form a uniform oil phase. Add the water phase to the oil phase, and homogenize for 3 minutes with a high shear homogenizer at 5000rpm. Stir mechanically at low speed for 30 minutes to form a uniform gel. Fill it into an aluminum-plastic composite tube.

[0208] 2.5 Preparation 8: Tranexamic acid / vitamin A acid adduct compound emulsion

[0209] prescription:

[0210]

[0211] Process: Weigh all the auxiliary materials, disperse xanthan gum and carbomer 980 in glycerol and Transcutol P, add some water, and stir and mix in a water bath at 80°C; dissolve tranexamic acid in the remaining water, and then mix it into the water phase, stir mechanically to mix evenly and gel the carbomer 980; mix the ingredients in the oil phase and keep warm at 80°C; add the oil phase to the water phase and homogenize at 8000rpm for 3min; cool to 40-50°C, add phenoxyethanol; stir mechanically for 30min to mix evenly; and dispense into aluminum tubes.

[0212] Example 3 Comparison of IVPT (in vitro transdermal) tests of formulations 1-8

[0213] 3.1 IVPT test method

[0214] The IVPT test was carried out on a Franz diffusion cell using ex vivo skin from Bama miniature pigs (age ≤ 3 months). The receiving solution was taken at different time points (1h, 2h, 4h, 6h), and after the test, the skin was cleaned and then the tissue was crushed to obtain the intradermal retention extract. The obtained samples were tested using UPLC-MS to obtain the contents of tranexamic acid and vitamin A acid in the samples.

[0215]

[0216] Example 4 Comparison of content and content uniformity of preparations 1-8

[0217] 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.

[0218] Three samples were randomly selected from each prescription, their contents were tested, and the RSD% of the content within the batch was calculated.

[0219] Table 2 Content and content uniformity of different compound preparations

[0220]

[0221] From the content and content uniformity results in Table 2, it can be seen that the contents of vitamin A acid in the four common compound preparations of tranexamic acid and vitamin A acid are all 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 caused by transfer and adsorption during the preparation of vitamin A acid is reduced, the content of the obtained preparation is significantly increased, and the content uniformity is also significantly improved.

[0222] Example 5 Comparison of drug distribution status of formulations 1-8

[0223] Preparations 1-8 were observed under a microscope. Under the microscope, in the common compound preparations, part of the vitamin A acid was dispersed in the preparations in the form of solid particles, such as needle-shaped crystals; while in the adduct compound preparations, the vitamin A acid was mainly dispersed in the preparations in the form of oil droplets. This shows that the distribution of the vitamin A acid in the adduct compound preparations is more uniform and stable.

[0224] Example 6 Scale-up production of a compound gel of tranexamic acid and vitamin A acid diethanolamine complex (preparation 9)

[0225] 6.1 Scale-up production recipe

[0226]

[0227] 6.2 Scale-up production process:

[0228] Weigh the raw materials and excipients according to the prescribed dosage. Add about 20% water to the water tank, stir at 30rpm, add Carbomer 980 powder while stirring, sprinkle it in and stir for 10 minutes. Continue to increase the stirring speed to 60rpm and stir for 1h. Set the negative pressure to -0.08Mpa, and use the vacuum to suck the Carbomer solution into the main pot for about 3 minutes. Use about 10% purified water to wash the container and stir, negative pressure -0.08Mpa, stir and degas in the main pot at 25rpm for 30 minutes to obtain a uniform and bubble-free Carbomer phase.

[0229] Add the prescribed amount of lauric nitrogen into the beaker. Ketone, vitamin A acid adduct and butylated hydroxytoluene were added to lauryl nitrogen The ketone was dissolved by magnetic stirring, and the solution was added to 10% propylene glycol and stirred to mix.

[0230] 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 to make it dispersed completely.

[0231] Add the tranexamic acid solution to the carbomer phase, and use the remaining water to wash the tranexamic acid phase container and add it to the carbomer phase. Set the negative pressure of the emulsification homogenization tank to -0.08Mpa, the stirring speed to 50rpm, the auxiliary stirring to 200rpm, and stir for about 1h until the material in the tank is clear and transparent and has no white foreign matter.

[0232] Add the vitamin A acid adduct phase solution to the aqueous phase mixed material, and use 5% propylene glycol to wash the vitamin A acid adduct phase container and add it to the mixed material. Set the negative pressure of the emulsification homogenization tank to -0.08Mpa, the stirring speed to 50rpm, the auxiliary stirring to 200rpm, and stir for about 120min.

[0233] 6.3 Scale-up batch content and content uniformity

[0234] Table 4 Uniformity of vitamin A acid content in enlarged batches

[0235]

[0236] Table 5 Uniformity of tranexamic acid content in amplified batches

[0237]

[0238] Table 6 Uniformity in the container of scaled-up batches of vitamin A acid and tranexamic acid

[0239] batch number Vitamin A acid content (%) Tranexamic acid content (%) On the container 105.8 104.8 in container 105.9 105.2 Under the container 107.0 105.8 NMT% (10%) 1.2 1.0

[0240] As can be seen from Tables 4-6, the tranexamic acid and vitamin A acid complex gel prepared by the 5kg scale-up process has a uniform distribution of vitamin A acid and tranexamic acid in the preparation tank.

[0241] 6.4 Related substances in scale-up batches

[0242] Table 7 Related substances of vitamin A acid in enlarged batches

[0243] name Isotretinoin % Maximum unknown single impurity % Total impurities% Scaling up the batch 0.113 0.052 0.659

[0244] Table 8 Related substances of tranexamic acid in enlarged batches

[0245] name Aminobenzoic acid% Maximum unknown single impurity % Total impurities% Scaling up the batch ND ND ND

[0246] It can be seen from Tables 7-8 that 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 have good stability.

[0247] 6.5 Data of accelerated stability test of scaled-up batches (30℃±2℃ / 65%RH±5%RH)

[0248] Table 9 Results of accelerated test of scaled-up batches

[0249]

[0250] 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 had good stability.

[0251] Example 7 Whitening effect test of adduct compound preparation 7

[0252] Male spotted guinea pigs were selected as model animals, with a body weight range of 300g-350g. The effect of a compound preparation of tranexamic acid and vitamin A acid adduct (preparation 7) on the skin melanin of brown-skinned guinea pigs was investigated.

[0253] 7.1 Experimental plan

[0254] Grouping: The guinea pigs were adaptively raised for 7 days. The day before grouping, the backs were depilated with depilatory cream. The depilatory area was 3*3cm 2 In the experiment, hair removal was performed according to the hair growth. 40 guinea pigs were randomly divided into 5 groups, 8 in each group; the drug conditions of each group are shown in Table 10.

[0255] Table 10 Drug grouping in efficacy test

[0256] serial number drug Dosage Specifications factory T1 Tranexamic acid / vitamin A acid adduct compound gel 5％ / 0.1％，10g / T2 Commercially available vitamin A acid ointment 0.05％，20g Guangdong Xiangshantang Pharmaceutical T3 Commercially available hydroquinone cream 2％，20g Guangdong Renrenkang Pharmaceutical T4 Blank Group Blank gel /

[0257] Drug administration: Each guinea pig was evenly smeared with the drug on the depilatory area, once a day, for 4 weeks. A thin layer of drug was evenly applied to each group, covering the depilatory area, and the residual drug was washed off 12 hours after each administration.

[0258] Symptom observation: Observe and record the skin condition of the administration area before each administration to observe whether there is skin irritation.

[0259] 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.

[0260] Skin colorimetry and dermoscopy: Before and four weeks after medication, skin colorimetry was performed using a skin colorimeter.

[0261] Fotana-Masson staining of skin sections: Four weeks after administration, paraffin sections of the 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.

[0262] 7.2 Test results

[0263] 7.2.1 Skin color card detection

[0264] Table 11 Comparison of the mean values ​​of skin color card readings of animals in each group before and after administration

[0265] Group D0 D28 ΔD T1: Adduct compound gel 23.33 19.33 -4.00 T2: Commercially available hydroquinone cream 11.00 10.50 -0.50 T3: Commercially available vitamin A cream 16.67 15.34 -1.33 T4: Blank control 20.75 20.00 -0.75

[0266] The lower the color card reading, the whiter the skin. The mean values ​​of the skin color cards of each group before and after administration are shown in Table 11: The adduct compound gel has a more obvious effect of reducing melanin, which is higher than the commercially available vitamin A acid cream and higher than the positive control drug hydroquinone.

[0267] 7.2.2 Skin color detection

[0268] Table 12 Animal L in each group * Mean ± SD

[0269] Group D0 D28 ΔL* T1: Adduct compound gel 26.55±6.69 43.43±1.28 16.88 T2: Commercially available hydroquinone cream 45.33±13.92 52.17±6.73 6.84 T3: Commercially available vitamin A cream 44.65±12.05 47.07±3.60 2.42 T4: Blank control 41.24±8.29 44.09±2.51 2.85

[0270] Use colorimeter to detect L * Value to evaluate drug effect, L * The value represents the balance of black and white of the skin, which is mainly affected by melanin. The larger the L value, the whiter the skin color. As shown in Table 12, 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 of reducing blackness, which was higher than the commercially available hydroquinone group of the positive control.

[0271] Depend on Figure 1 It can be seen that the skin color of guinea pigs became significantly whiter before and after treatment with the tranexamic acid / vitamin A acid adduct compound preparation.

[0272] Depend on Figure 2 It can be seen that: before and after the treatment with the tranexamic acid / vitamin A acid adduct compound preparation, the melanin in the epidermis was significantly reduced.

[0273] Example 8 Verification of the penetration-enhancing effect of adducts

[0274] 8.1 Formulation 10: Adduct-free compound gel (ligand diethanolamine is added to the formulation as an excipient)

[0275]

[0276] Process: weigh each auxiliary material according to the prescription amount; dissolve tranexamic acid with about 40% water; dissolve the preservatives (sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate) in the remaining water, add carbomer 980, stir at high speed of 200rpm for 5 minutes to make it evenly dispersed; stir at low speed of 50rpm for 50 minutes to hydrate the carbomer; add tranexamic acid solution, stir mechanically for 30 minutes to mix evenly, and gel the carbomer; add the oil phase auxiliary materials and mix and stir evenly to form a uniform oil phase. Add the water phase to the oil phase, and homogenize for 3 minutes with a high shear homogenizer at 5000rpm. Stir mechanically at low speed for 30 minutes to form a uniform gel. Fill it into an aluminum-plastic composite tube.

[0277] 8.2 IVPT trial

[0278] 8.2.1 IVPT test method

[0279] The IVPT test was carried out on a Franz diffusion cell using ex vivo skin from Bama miniature pigs (age ≤ 3 months). The receiving solution was taken at different time points (1h, 2h, 4h, 6h), and after the test, the skin was cleaned and then the tissue was crushed to obtain the intradermal retention extract. The obtained samples were tested using UPLC-MS to obtain the contents of tranexamic acid and vitamin A acid in the samples.

[0280] 8.2.2 IVPT test results

[0281] Table 13 IVPT test results of different compound preparations

[0282]

[0283] ND-means not detected;

[0284] The statement NA is not applicable (the commercially available control preparation is a single preparation of vitamin A acid, which does not contain tranexamic acid and is therefore not applicable).

[0285] The results are shown in Table 13. The transdermal penetration of the compound gel of vitamin A acid adduct / tranexamic acid (preparation 7) is better than that of the compound gel without adduct process (preparation 10) and the commercially available retinoic acid ointment. This indicates that vitamin A acid needs to form an adduct with the ligand diethanolamine before it can play a penetration-enhancing role.

[0286] Example 9 Other types of vitamin A acid complex-vitamin A acid triethanolamine complex preparations

[0287] 9.1 Preparation of Vitamin A Acid Triethanolamine Complex

[0288] Raw 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.).

[0289] prescription:

[0290] materials Dosage Solvents Solvent amount Retinol (RA) 6.0g Ethanol 30ml~60ml Triethanolamine (TEA) 23.87g Ethanol 10ml

[0291] The molar ratio of triethanolamine (TEA) to retinoic acid (RA) is 8:1 (abbreviated as 8[TEA][RA]).

[0292] Process:

[0293] (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 is in a suspended state; wrap the round-bottom flask with aluminum foil to block light.

[0294] (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.

[0295] The triethanolamine diluted solution obtained in step (2) is added dropwise to the mixed solution obtained in step (1) while stirring; and the container is cleaned with about 5 ml of ethanol, and the mixture is added to the flask and stirred.

[0296] After all the additions are complete, the solution should be orange-red and clear; continue stirring for 4 hours.

[0297] The solvent was removed using a rotary evaporator and the resulting sample was sealed and stored in a light-proof container.

[0298] 8[TEA][RA] H NMR spectrum data:

[0299] 1 H NMR (400 MHz, DMSO-d 6)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 .

[0300] H NMR spectra Figure 3 As shown, it was observed from the spectrum that the active hydrogen of the carboxyl group of vitamin A acid disappeared, and the chemical shift and peak shape of the hydroxyl hydrogen of triethanolamine changed, indicating that vitamin A acid interacted with triethanolamine to form a complex.

[0301] 9.2 Preparation of tranexamic acid / vitamin A acid triethanolamine adduct compound gel (preparation 11)

[0302] prescription:

[0303]

[0304] Process: weigh each auxiliary material according to the prescription amount; dissolve tranexamic acid with about 40% water; dissolve sodium methylparaben and sodium propylparaben in the remaining water, add Carbopol 980, stir at high speed of 200rpm for 5 minutes to make it dispersed evenly; stir at low speed of 50rpm for 50 minutes to hydrate the carbomer; add tranexamic acid solution, stir mechanically for 30 minutes to mix evenly, and gel the carbomer; mix and stir the oil phase auxiliary materials evenly to form a uniform oil phase. Add the water phase to the oil phase, and homogenize for 3 minutes with a high shear homogenizer at 5000rpm. Stir mechanically at low speed for 30 minutes to form a uniform gel. Fill it into an aluminum-plastic composite tube.

[0305] 9.3 Test of the content and uniformity of tranexamic acid / vitamin A acid triethanolamine adduct compound gel

[0306] Six tubes of tranexamic acid / vitamin A acid triethanolamine adduct compound gel were randomly selected to detect their content and content uniformity.

[0307] Table 14 Content and content uniformity of tranexamic acid / vitamin A acid triethanolamine adduct compound gel

[0308]

[0309] The results in Table 14 show that the contents and content uniformity of the two drugs in the obtained preparations meet the standards.

[0310] 9.4 IVPT Trial of Tranexamic Acid / Vitamin A Triethanolamine Adduct Compound Gel

[0311] The IVPT test was carried out on a Franz diffusion cell using ex vivo skin from Bama miniature pigs (age ≤ 3 months). The receiving solution was taken at different time points (1h, 2h, 4h, 6h), and after the test, the skin was cleaned and then the tissue was crushed to obtain the intradermal retention extract. The obtained samples were tested using UPLC-MS to obtain the contents of tranexamic acid and vitamin A acid in the samples.

[0312] Table 15 Tranexamic acid / vitamin A acid triethanolamine adduct compound gel IVPT test results

[0313]

[0314] It can be seen from Table 15 that compared with the ordinary compound gel of prescription 3, the TEA adduct compound gel of prescription 11 also has a permeation-enhancing effect.

[0315] Example 10 Other types of vitamin A acid complex-vitamin A acid triethylamine complex

[0316] 10.1 Preparation of Vitamin A Acid Triethylamine Complex

[0317] Raw materials and reagents: Vitamin A acid (RA) (AR, Shanghai Aladdin Biochemical Technology Co., Ltd.), triethylamine (AR, Sinopharm Chemical Reagent Co., Ltd.).

[0318] prescription:

[0319] materials Dosage Retinol (RA) 6.0g <![CDATA[Triethylamine (Et 3 N)]]> 4.05g

[0320] The molar ratio of triethylamine to vitamin A acid (RA) is 2:1 (abbreviated as 2[Et 3 N][RA]).

[0321] Process:

[0322] Weigh vitamin A acid according to the prescription amount and place it in a flask, wrap it with aluminum foil to protect it from light; add the prescription amount of triethylamine, sonicate for 30 minutes until the solution becomes clear, and continue stirring for 4 hours; a clear orange-yellow liquid is obtained.

[0323] 2[Et 3 NMR hydrogen spectrum data of [RA]:

[0324] 1 H NMR (400 MHz, DMSO-d 6)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).

[0325] H NMR spectra Figure 4 As shown, it was observed from the spectrum that the active hydrogen of the carboxyl group of vitamin A acid disappeared and the chemical shift of the methylene hydrogen of triethylamine moved to the low field, indicating that vitamin A acid and triethylamine interacted to form a complex. 10.2 Preparation of tranexamic acid / vitamin A acid triethylamine adduct composite gel (preparation 12)

[0326] prescription:

[0327]

[0328] Process: weigh each auxiliary material according to the prescription amount; dissolve tranexamic acid with about 40% water; dissolve sodium methylparaben and sodium propylparaben in the remaining water, add Carbopol 980, stir at high speed of 200rpm for 5 minutes to make it dispersed evenly; stir at low speed of 50rpm for 50 minutes to hydrate the carbomer; add tranexamic acid solution, stir mechanically for 30 minutes to mix evenly, and gel the carbomer; mix and stir the oil phase auxiliary materials evenly to form a uniform oil phase. Add the water phase to the oil phase, and homogenize for 3 minutes with a high shear homogenizer at 5000rpm. Stir mechanically at low speed for 30 minutes to form a uniform gel. Fill it into an aluminum-plastic composite tube.

[0329] 10.3 Test of the content and uniformity of tranexamic acid / triethylamine vitamin A adduct compound gel

[0330] Six tubes of tranexamic acid / vitamin A acid triethylamine adduct compound gel were randomly selected to detect their content and content uniformity.

[0331] Table 16 Content and content uniformity of tranexamic acid / vitamin A acid triethylamine adduct compound gel

[0332]

[0333]

[0334] The results in Table 16 show that the contents and content uniformity of the two drugs in the obtained preparations meet the standards.

[0335] 10.4 IVPT trial of tranexamic acid / triethylamine retinoic acid adduct compound gel

[0336] The IVPT test was carried out on a Franz diffusion cell using ex vivo skin from Bama miniature pigs (age ≤ 3 months). The receiving solution was taken at different time points (1h, 2h, 4h, 6h), and after the test, the skin was cleaned and then the tissue was crushed to obtain the intradermal retention extract. The obtained samples were tested using UPLC-MS to obtain the contents of tranexamic acid and vitamin A acid in the samples.

[0337] Table 17 Tranexamic acid / vitamin A acid triethylamine adduct compound gel IVPT test results

[0338]

[0339] It can be seen from Table 17 that compared with the ordinary compound gel of prescription 3, the triethylamine adduct compound gel of prescription 12 also has a penetration-enhancing effect, and its penetration-enhancing effect is slightly weaker than that of the DEA adduct compound gel.

[0340] Example 11 Tranexamic acid / vitamin A acid diethanolamine adduct compound prescription

[0341] The present invention also prepares preparations 13-27 containing tranexamic acid and vitamin A acid adduct (vitamin A acid ethylene glycol amine complex) with different penetration enhancers, different cosolvents, different antioxidants, different preservatives, and different drug loading amounts.

[0342] 11.1 Different penetration enhancers

[0343] Preparation 13

[0344]

[0345] Preparation 14

[0346]

[0347]

[0348] Preparation 15

[0349]

[0350] 11.2 Different co-solvent preparations 16

[0351]

[0352] Preparation 17

[0353]

[0354] 11.3 Different antioxidant preparations 18

[0355]

[0356] Preparation 19

[0357]

[0358]

[0359] Preparation 20

[0360]

[0361] 11.4 Preparations with different preservatives 21

[0362]

[0363] Preparation 22

[0364]

[0365]

[0366] Preparation 23

[0367]

[0368] 11.5 Preparations with different drug loadings 24

[0369]

[0370] Preparation 25

[0371]

[0372]

[0373] Preparation 26

[0374]

[0375] Preparation 27

[0376]

[0377] Example 12: Therapeutic effect of the compound preparation of the example on chloasma

[0378] 12.1. Test system

[0379] 12.1.1. Experimental Animals

[0380] 12.1.1.1. Basic information of animals

[0381]

[0382] 12.1.1.2. Quarantine and acclimatization period

[0383] Quarantine period: at least 3 days, during which the veterinarian will complete the animal quarantine.

[0384] Adaptation period: at least 2 days, during which the experimenters will conduct daily inspections.

[0385] 12.1.1.3. Feeding and environment

[0386]

[0387] 12.1.2. Investigational Drugs

[0388] name Specification Commercially available progesterone injection 20mg / ml Commercially available hydroquinone cream 2%, 10g / stick Commercially available tretinoin cream 0.1%, 10g / stick Blank Accessories 10g / stick Compound preparation (Preparation 24) RA0.1% / TA7.5%, 10g / piece

[0389] 12.2. Test content

[0390] 12.2.1. Animal grouping and treatment methods

[0391] Group Number of animals Give medication Dosage Dosage Dosing frequency G1: Control group 11 NA NA NA NA G2: Model Group 11 Blank Accessories 30mg / cm2 Skin application QD G3: Modeling control 5 Hydroquinone cream 30mg / cm2 Skin application QD G4: Positive control 6 Hydroquinone cream 30mg / cm2 Skin application QD G5: Retinoic acid alone 6 Retinoic acid cream 30mg / cm2 Skin application QD G6: Adduct compound 6 RA0.1% / TA7.5% 30mg / cm2 Skin application QD

[0392] Grouping: 45 animals were selected from 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.

[0393] Hair removal: The day before the experiment, the animals were treated with a hair removal cream to remove hair on the back of the animals in an area of ​​approximately 2*3 cm. Afterwards, hair removal was performed two to three times a week depending on the speed of hair growth.

[0394] Progesterone injection: Except for the animals in group G1, the other animals were given intramuscular injection of progesterone at a dose of 20 mg / kg every day, with injections alternately into the two hind legs, for 4 weeks.

[0395] 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 shading 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 was performed three times a week, each time for 4 min, for 4 weeks.

[0396] 12.2.2. Confirmation of Melasma Model

[0397] After the first week of animal modeling, the backs of animals in group G3 were smeared with hydroquinone cream at a dose of 30 mg / cm2 once a day. The remaining animals were not treated. After the third week of modeling, 5 mice were randomly selected from each of group G1 and G2, as well as group G3, and euthanized.

[0398] The skin of the irradiated back of the mouse was fixed with 10% formalin, embedded in paraffin, and stained with Fontana-Masson Staining. The slices were scanned in full using Halo software, and then 10 fields of view of equal size were randomly selected from the skin area of ​​each image. Finally, the melanin area of ​​the selected 10 areas was calculated and analyzed using the software.

[0399] like Figure 5 As shown, the melanin in the G2 group was significantly higher than that in the control group, and the melanin in the G3 group was also higher than that in the control group, but lower than that in the modeling group. This indicates that the injection of progesterone and ultraviolet irradiation caused abnormal melanin metabolism in mice and pigment deposition, and the chloasma model was successfully established.

[0400] 12.2.3. Efficacy test

[0401] Each group of animals began to receive medication according to the group design at the 4th week. After 3 weeks of medication, the experimental animals were euthanized, and the skin of the irradiated part of the back of the mice was fixed with 10% formalin, embedded in paraffin, and stained with Fontana-Masson Staining. The slices were scanned in full using Halo software, and then 10 fields of view of equal size were randomly selected from the skin area of ​​each picture. Finally, the melanin area of ​​the selected 10 regions was calculated and analyzed using the software.

[0402] The test results are as follows Figure 6 As shown, compared with the modeling group, the adduct compound preparation group significantly reduced the pigmentation effect (p<0.001); hydroquinone is a first-line drug for treating chloasma, and compared with the hydroquinone group (positive control), the adduct compound preparation has a superior effect (p<0.05); compared with the retinoic acid single preparation group, the adduct compound preparation has a superior effect (p<0.05). Therefore, the compound preparation of the present invention has a good therapeutic effect on chloasma.

[0403] 12.2.4. Typical slice photos

[0404] Typical slice photos of each group are shown in Figure 7 shown.

[0405] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A composition comprising the following components: (i) tranexamic acid or a pharmaceutically acceptable salt thereof; (ii) vitamin A acid alcohol amine complex or vitamin A acid fatty amine complex; Preferably, the vitamin A acid alcoholamine complex consists of vitamin A acid and alcoholamine compounds; Preferably, 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 C1-10 alkylamine compounds, such as C9, C8, C7, C6, C5, C4, C3, C2, C1 alkylamine compounds; such as ethylamine, diethylamine, triethylamine, monomethylamine, dimethylamine, trimethylamine, monopropylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, 1,2-dimethylpropylamine, 1,2-propylenediamine, etc.; 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, more preferably (1-5):1; Preferably, the mass ratio of component (i) (calculated as tranexamic acid) to component (ii) (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 2.5-7.5:0.01-0.

1.

3. The composition according to claim 1, characterized in that (ii) in the vitamin A acid alcoholamine complex, the molar ratio of the alcoholamine compound to vitamin A acid is (1-100):1, for example (1-10):1, more preferably (1-5):1; Preferably, the alcoholamine compound is selected from the following formula I: Wherein, X is selected from C 1-6 Alkyl (alkylene); preferably, selected from -CH2-CH2-, -CH2-CH2-CH2- and Indicates the group attachment site; R1 and R2 are each independently selected from H, C 1-6 Alkyl, C 1-6 Alkyl-OH; Preferably, the formula I is selected from diethanolamine, triethanolamine, monoethanolamine (2-hydroxyethylamine), N-methyldiethanolamine, n-propanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, n-butanolamine, dibutanolamine, isobutanolamine.

4. The composition according to any one of claims 1 to 3, characterized in that In the composition, components (i) and (ii) are each administered in the form of a pharmaceutical composition; Preferably, in the composition, components (i) and (ii) can be administered simultaneously, sequentially or intermittently; Preferably, the administration route of the composition includes, but is not limited to, gastrointestinal administration or parenteral administration; wherein the gastrointestinal administration may be oral administration; the parenteral administration may be transdermal administration (e.g., skin application administration), etc.; Preferably, the composition includes but is not limited to pharmaceutical preparations, cosmetics, care products, and beauty products; Preferably, 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 applied orally (i.e., oral preparations), for example, selected from tablets, granules, capsules, oral liquid preparations, pills, suspensions, pellets, etc.; preferably, the composition is a cream, latex, emulsion, or gel preparation.

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 0.1%-15%, more preferably 1%-10%, for example 2.5%-7.5%; Preferably, in the composition, the content of component (2) (calculated as vitamin A acid) is 0.001%-2%, preferably 0.01%-1%, and more preferably 0.01%-0.5%; Preferably, the specification of the composition is 1 g / stick to 20 g / stick, for example, 10 g / stick; Preferably, the composition further comprises: (3) gel matrix; Preferably, the gel matrix is ​​selected from carbomer, such as Carbopol 980, Carbopol ETD2020; Preferably, the content of the gel matrix is ​​0.01%-10%, preferably 0.05%-5%; Preferably, the composition further comprises: (4) penetration enhancers; Preferably, the penetration enhancer is selected from the group consisting of monocaprylic glyceryl, Transcutol P, isopropyl myristate, lauryl nitrogen One, two or more of ketone, diethylene glycol monoethyl ether, polyglycerol fatty acid ester, propylene glycol monocaprylate, caprylic acid caprylate polyethylene glycol glyceride; Preferably, the content of the penetration enhancer is 0.01%-20%, preferably 0.1%-15%; 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 content of preservative is 0.001%-2%, preferably 0.005%-1%; 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 antioxidant is 0.001%-2%, preferably 0.01%-1%; 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 1%-20%; Preferably, the composition further comprises: (8) Emulsifier; Preferably, the emulsifier is selected from one 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 acid macrogol glyceride, macrogol stearate, polyoxyethylene-8 beeswax, and lauroyl polyoxyethylene glyceride; Preferably, polyethylene glycol stearate such as polyethylene glycol (32) stearate; lauroyl polyoxyethylene glyceride such as lauroyl polyoxyethylene (6) glyceride; Preferably, 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, polyoxyethylene 100 hydrogenated castor oil; Preferably, the content of the emulsifier is 0.1%-30%, preferably 0.2%-20%; 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 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 oils are selected from jojoba oil, soybean oil, linseed oil, etc., and jojoba oil is further preferred; Preferably, the content of the oily base is 0.5%-20%, preferably 1.0%-15%; 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 0.1%-0.3%, for example 0.15%; Preferably, the composition further comprises any one or more of a metal ion complexing agent, an emulsifier, and a texture regulator; Preferably, the co-emulsifier is selected from propylene glycol monocaprylate; Preferably, the content of the co-emulsifier is 0.1%-5%, preferably 1%-3%, for example 2.0%; Preferably, the texture modifier is selected from cyclopentasiloxane; Preferably, the content of the texture modifier is 1%-5%, for example 3.0%; 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 EDTA or EDTA-2Na; Preferably, the composition further includes other physiologically acceptable carriers (e.g., biocompatible materials), such as optionally including surfactants, excipients, humectants, emulsifying promoters, suspending agents, salts or buffers for regulating osmotic pressure, colorants, flavors, stabilizers, bactericides or other conventional supplements.

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 (e.g., vitamin A acid diethanolamine, vitamin A acid triethanolamine, vitamin A acid triethylamine); 0.05%-5% gel base (e.g. Carbopol 980 and / or Carbopol ETD2020); Optionally, 0.1%-15% of a penetration enhancer (e.g., monocaprylin, Transcutol P, isopropyl myristate, lauryl nitrogen One or more of ketone, diethylene glycol monoethyl ether, polyglycerol fatty acid ester, propylene glycol monocaprylate, caprylic acid caprylate polyethylene glycol glyceride); Optionally, 0.005%-1% of a preservative (e.g., one or more of benzoic acid, phenoxyethanol, sodium benzoate, methylparaben, ethylparaben, propylparaben, sodium methylparaben, sodium propylparaben); Optionally, 0.01%-1% antioxidant (e.g., one or more of butylated hydroxyanisole, butylated hydroxytoluene, butylated hydroxyanisole, vitamin C, vitamin E, sodium metabisulfite); Optionally, 1%-20% of a cosolvent (e.g., one or more of glycerol, propylene glycol, 1,2-pentanediol, ethanol, benzyl alcohol); Optionally, 0.2%-20% of an emulsifier (e.g., one 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); Optionally, 1.0%-15% of an oily base (e.g., one or more of octadecanol, cetyl alcohol, stearic acid, and fatty acid esters); Optionally, 0.1%-0.3% (e.g., 0.15%) of a rheology modifier (e.g., xanthan gum); Optionally, 1%-3% (e.g., 2.0%) of a co-emulsifier (e.g., propylene glycol monocaprylate); Optionally, 1%-5% (e.g., 3.0%) of a texture modifier (e.g., cyclopentasiloxane); 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: The balance is water; 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 is a cream; Preferably, the composition comprises the following components: The balance is water; 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 is a latex; Preferably, the composition comprises the following components: The balance is water; 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; Penetration enhancers such as lauryl nitrate One or more of caprylic acid, monocaprylic acid, trancutol P, isopropyl myristate; Antioxidants such as one or more of butylated hydroxytoluene, butylated hydroxyanisole, sodium metabisulfite, and ascorbic acid; Preservatives such as one or more of sodium methylparaben, sodium propylparaben, methylparaben, propylparaben, butylated hydroxytoluene, and phenoxyethanol; Preferably, the composition is a gel; Preferably, the composition comprises the following components: The balance is water; 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 is an emulsion.

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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