Compositions containing tretinoin, and methods for preparing and using the same

Abstract

The present invention relates to a composition containing tretinoin, its preparation method, and its use. The composition comprises (a) a tretinoin-alcoholamine compound complex, (b) a gel matrix, and (c) an oil phase component. The composition has good ingredient compatibility, comfort in use, stability, safety, and skin permeability, and therefore has broad medicinal prospects.

Description

[Technical Field]

[0001] This application claims priority to a prior application bearing patent application number 202211543235.6 and entitled "Composition containing tretinoin, and its preparation method and use," filed with the State Intellectual Property Office of China on December 2, 2022. The application is incorporated herein by reference in its entirety.

[0002] The present invention belongs to the field of medicinal chemistry, and specifically relates to a composition containing tretinoin and its preparation method and use. [Background technology]

[0003] Vitamin A and its metabolites play important roles in the human body and are currently widely used to treat various diseases. For example, tretinoin (molecular formula C), an intermediate product of vitamin A metabolism in the body, is 20 H 28 O2) primarily affects bone growth and promotes metabolic processes such as epithelial cell proliferation, differentiation, and keratolysis. Tretinoin is primarily used to treat diseases such as acne vulgaris, hyperpigmentation, skin photoaging, psoriasis, ichthyosis, lichen planus, pityriasis rubra pilaris, follicular keratosis, squamous cell carcinoma, and melanoma. Oral administration of tretinoin can also be used to treat acute promyelocytic leukemia.

[0004] Tretinoin is lipid-soluble and practically insoluble in water, resulting in low solubility in formulations and low dissolution in the body, limiting its medicinal use. Furthermore, due to the barrier function of the stratum corneum, conventional topical tretinoin formulations only allow a small amount of the active ingredient to penetrate the barrier during use, making it difficult to maintain an effective therapeutic concentration. However, increasing the amount of tretinoin used can cause significant skin irritation, resulting in inflammatory symptoms such as varying degrees of redness, stinging, and edema. Given the promising application prospects of tretinoin in the treatment of skin diseases, it is necessary to develop a medicinal form suitable for use in skin diseases.

[0005] Research has shown that a complex of tretinoin and an alcoholamine compound is liquid at room temperature and has good water solubility / water dilution resistance and skin penetration effects. Based on the discovery of this complex, it is expected that further development of tretinoin formulations with good medicinal properties will be possible. Summary of the Invention

[0006] In order to improve the technical problems existing in the prior art, in a first aspect, the present invention provides: (a) a tretinoin alcoholamine compound complex; (b) a gel substrate; (c) an oil phase component. According to an embodiment of the present invention, the complex comprises tretinoin and an alcoholamine compound.

[0007] In some embodiments, the composition comprises: (a) a tretinoin alcoholamine compound complex; (b) a gel substrate; (c) an oil phase component; (d) an emulsifier.

[0008] According to an embodiment of the present invention, the (c) oil phase component is selected from one or more of (c1) an oily substrate, (c2) a co-solvent, and (c3) a penetration enhancer.

[0009] According to an embodiment of the present invention, the composition further comprises (e) water.

[0010] In some embodiments, the composition comprises: (a) a tretinoin alcoholamine compound complex; (b) a gel substrate; (d) an emulsifier.

[0011] In some embodiments, the composition comprises: (a) a tretinoin alcoholamine compound complex; (b) a gel substrate; (c2) a co-solvent; (c3) a penetration enhancer; (d) an emulsifier.

[0012] In some embodiments, the composition comprises: (a) a tretinoin alcoholamine compound complex; (b) a gel substrate; (c1) an oily substrate; (c2) a co-solvent; (d) an emulsifier.

[0013] In some embodiments, the composition comprises: (a) a tretinoin alcoholamine compound complex; (b) a gel substrate; (c2) a co-solvent; (c3) a penetration enhancer.

[0014] In some embodiments, the composition comprises: (a) a tretinoin alcoholamine compound complex; (b) a gel substrate; (c3) a penetration enhancer.

[0015] According to an embodiment of the invention, the gel matrix is ​​selected from carbomers, such as Carbopol 980, Carbopol ETD2020.

[0016] According to an embodiment of the present invention, the co-solvent is selected from alcohols, and the alcohols are preferably one or more of glycerin, ethanol, propylene glycol, and benzyl alcohol.

[0017] According to embodiments of the invention, the emulsifier is selected from one or more of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, Span 20, Span 60, Span 80, polyoxyethylene castor oil derivatives, poloxamer, Triton, polyethylene glycol glyceryl caprylate decanoate, polyethylene glycol stearate, polyoxyethylene-8 beeswax, and lauroyl polyoxyethylene glyceryl. In some embodiments, the emulsifier is selected from polyethylene glycol (32) stearate and lauroyl polyoxyethylene (6) glyceryl, and in some embodiments, the polyoxyethylene castor oil derivative is selected from polyoxyethylene castor oil or polyoxyethylene hydrogenated castor oil, such as polyoxyethylene 35 castor oil, polyoxyethylene 40 castor oil, polyoxyethylene 54 hydrogenated castor oil, and polyoxyethylene 100 hydrogenated castor oil.

[0018] According to an embodiment of the present invention, the oleaginous substrate is selected from one or more of octadecanol, hexadecanol, stearic acid, and fatty acid esters, and the fatty acid esters are selected from one or more of isopropyl myristate, medium chain triglycerides, glyceryl monooleate, glyceryl monolinoleate, propylene glycol dicaprylate decanoate, polyoxyethylene glyceryl oleoyl, myristyl myristate, isopropyl palmitate, isopropyl linoleate, dodecanol benzoate, isostearyl isostearate, fatty acid lactic acid esters, decyl oleate, and octyl palmitate.

[0019] According to an embodiment of the invention, the penetration enhancer is selected from one or more of glyceryl monocaprylate, laurocapram, diethylene glycol monoethyl ether, polyglycerol fatty acid esters, propylene glycol monocaprylate, polyethylene glycol glyceryl caprylate decanoate.

[0020] According to an embodiment of the invention, the composition further comprises one or more of an antioxidant, a preservative, a pH adjuster, a metal ion complexing agent, and a rheology adjuster.

[0021] According to an embodiment of the present invention, the antioxidant is selected from one or more of dibutylhydroxytoluene, butylhydroxyanisole, vitamin C, vitamin E, and sodium metabisulfite; the preservative is selected from one or more of benzyl alcohol, phenoxyethanol, sodium benzoate, methylparaben, ethylparaben, propylparaben, sodium methylparaben, and sodium propylparaben; the pH adjuster is selected from one or more of triethanolamine and sodium hydroxide; and the rheology modifier is selected from one or more of Pemulen™ TR-1 NF polymer, Pemulen™ TR-2 NF polymer, Carbopol® 1342 NF polymer, and Carbopol® 5984 EP polymer.

[0022] According to an embodiment of the present invention, the metal ion complexing agent is selected from one or more of ethylenediaminetetraacetic acid (EDTA), disodium ethylenediaminetetraacetic acid (EDTA-2Na), tetrasodium ethylenediaminetetraacetic acid (EDTA-4Na), disodium nitrilotriacetate, sodium tripolyphosphate, sodium hexametaphosphate, and tetrapotassium pyrophosphate, and is preferably selected from EDTA or EDTA-2Na.

[0023] According to an embodiment of the present invention, the pH value of the composition is 4 to 7, for example, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, preferably 5.0 to 6.0.

[0024] In some embodiments, the composition comprises: (a) a tretinoin alcoholamine compound complex; (b) a gel substrate; (c1) an oily substrate selected from one or more of octadecanol and isopropyl myristate; (c2) a co-solvent selected from one or more of glycerin, ethanol, and benzyl alcohol; (d) an emulsifier selected from polysorbate 80.

[0025] The composition optionally further comprises one or more of Pemulen™ TR-1 NF, dibutylhydroxytoluene.

[0026] In some embodiments, the composition comprises: (a) a tretinoin alcoholamine compound complex; (b) a gel substrate; (c2) a cosolvent selected from propylene glycol; (c3) a penetration enhancer selected from laurocapram.

[0027] The composition optionally further comprises one or more of dibutylhydroxytoluene, sodium methylparaben, sodium propylparaben.

[0028] According to an embodiment of the present invention, the component (a) is present in an amount of 0.01% to 5% (w / w) of the total amount of the composition, for example, 0.01, 0.05, 0.10, 0.11, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 100, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 1 In some embodiments, component (a) comprises 0.01-0.5% (w / w) of the total composition.

[0029] According to an embodiment of the present invention, the component (b) is present in an amount of 0.01% to 5% (w / w) of the total amount of the composition, for example, 0.01, 0.05, 0.10, 0.11, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0. In some embodiments, component (b) comprises 0.1-2.0% (w / w) of the total composition.

[0030] According to an embodiment of the present invention, the component (c) is present in an amount of 0.5% to 70.0% (w / w) of the total amount of the composition, for example, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0% (w / w). In some embodiments, the component (c) comprises 1.0 to 35.0% (w / w) of the total amount of the composition.

[0031] According to an embodiment of the present invention, the component (c1) is present in an amount of 4.0% to 60.0% (w / w) of the total amount of the composition, for example, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20. In some embodiments, component (c1) comprises 5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, or 50.0% (w / w) of the total composition. In some embodiments, component (c1) comprises 4.0 to 30.0% (w / w) of the total composition. In some embodiments, when component (c1) is selected from two or more oleaginous substrates, each oleaginous substrate accounts for 4.0% to 20.0% (w / w) of the total weight of the composition, e.g., 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0% (w / w).

[0032] According to an embodiment of the present invention, the component (c2) is present in an amount of 0.5% to 25.0% (w / w) of the total amount of the composition, for example, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0 , 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0% (w / w). In some embodiments, component (c2) comprises 1.0 to 20.0% (w / w) of the total amount of the composition, and in some embodiments, when component (c2) is selected from two or more co-solvents, each co-solvent comprises 1.0% to 20.0% (w / w) of the total amount of the composition, for example, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5. Occupy 0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0% (w / w).

[0033] According to an embodiment of the present invention, the component (c3) is present in an amount of 0.5% to 30.0% (w / w) of the total amount of the composition, for example, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0 , 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0% (w / w). In some embodiments, component (c3) comprises 1.0 to 25.0% (w / w) of the total composition.

[0034] According to an embodiment of the present invention, the component (d) is present in an amount of 0.5% to 30.0% (w / w) of the total amount of the composition, for example, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, In some embodiments, component (d) comprises 1.0 to 20.0% (w / w) of the total composition.

[0035] According to an embodiment of the present invention, the antioxidant is present in an amount of 0.01% to 5% (w / w) of the total amount of the composition, for example, 0.01, 0.05, 0.10, 0.11, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 10 ... In some embodiments, the antioxidant comprises 0.01-0.5% (w / w) of the total composition.

[0036] According to an embodiment of the present invention, the preservative is present in an amount of 0.01% to 5% (w / w) of the total amount of the composition, for example, 0.01, 0.05, 0.10, 0.11, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0. In some embodiments, the preservative comprises 0.01-0.2% (w / w) of the total composition.

[0037] According to an embodiment of the present invention, the rheology modifier is present in an amount of 0.01% to 5% (w / w) of the total amount of the composition, for example, 0.01, 0.05, 0.10, 0.11, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26 , 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0% (w / w) of the total composition. In some embodiments, the rheology modifier comprises 0.01 to 0.5% (w / w) of the total composition.

[0038] According to an embodiment of the present invention, the metal ion complexing agent is present in an amount of 0.01% to 2.0% (w / w) of the total amount of the composition, for example, 0.01, 0.05, 0.10, 0.11, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83 In some embodiments, the metal ion complexing agent comprises 0.01 to 0.5% (w / w) of the total composition.

[0039] According to an embodiment of the present invention, the alcoholamine compound is selected from the following formula I:

[0040] [ka] In the formula, X is C 1-6Preferably, R1 and R2 are independently selected from the group consisting of H, C ... 1-6 Alkyl, C 1-6 alkyl-OH.

[0041] [ka]

[0042] According to an embodiment of the present invention, the amine represented by formula I is selected from diethanolamine, triethanolamine, monoethanolamine (2-hydroxyethylamine), N-methyldiethanolamine, n-propanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, n-butanolamine, dibutanolamine, and isobutanolamine.

[0043] According to an embodiment of the present invention, the molar ratio of the alcoholamine compound to tretinoin 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, more preferably (1-5):1.

[0044] According to an embodiment of the present invention, the complex is in a liquid form at room temperature. In the complex, the tretinoin may be present partially or entirely in anionic form, and the alcoholamine compound may be present partially or entirely in cationic form. In some embodiments, in the complex, a portion of the tretinoin is present in molecular form, and / or a portion of the alcoholamine compound is present in molecular form.

[0045] In some embodiments, in the complex, tretinoin is selected from the group consisting of the following: - ] exists in the form.

[0046] [ka]

[0047] In some embodiments, in the complex, the alcoholamine compound is represented by the following formula II: + ] exists in the form.

[0048] [ka]

[0049] In the formula II, X' is C 1-6 Preferably, R1 and R2 are independently selected from the group consisting of H, C ... 1-6 Alkyl, C 1-6 alkyl-OH.

[0050] [ka]

[0051] According to an embodiment of the present invention, the compound represented by formula II is selected from the group consisting of 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.

[0052] In some embodiments, the complex comprises [A - ][B + ] x wherein x can be selected from 1 to 10, for example, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, and 7.

[0053] According to an embodiment of the present invention, the complex is prepared by reacting tretinoin with the alcoholamine compound.

[0054] According to an embodiment of the present invention, in the preparation method, the molar ratio of the alcoholamine compound to tretinoin 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, more preferably (1-5):1.

[0055] According to an embodiment of the present invention, the reaction reagent of the reaction may be water, an organic solvent, or a mixture of an organic solvent and water, and the organic solvent is selected from one or a combination of two or more of ethanol, methanol, and acetone. Preferably, the organic solvent is ethanol.

[0056] According to an embodiment of the present invention, the volume ratio of the organic solvent to water in the mixed solvent is 5:95 to 95:5. Preferably, the volume ratio of the organic solvent to water in the mixed solvent is 40:60 to 95:5.

[0057] According to an embodiment of the present invention, the reaction can be carried out by dry grinding.

[0058] According to an embodiment of the present invention, the ratio of the total amount of tretinoin to the reaction reagent used is 1 g:5 to 150 mL, and preferably 1 g:5 to 20 mL.

[0059] According to an embodiment of the present invention, the preparation method comprises: Step (1) of adding a reaction reagent to the tretinoin and stirring to mix; Step (2) of adding a reaction reagent to the alcoholamine compound and stirring to dilute; and step (3) adding the diluted solution obtained in step (2) to the mixture obtained in step (1).

[0060] According to an embodiment of the present invention, in step (1), the ratio of the amount of tretinoin to the reaction reagent used is 1 g:5 to 100 mL, preferably 1 g:5 to 20 mL, and in step (2), the ratio of the amount of alcoholamine compound to the reaction reagent used is 1 g:0.5 to 50 mL, preferably 1 g:0.5 to 5 mL, and more preferably 1 g:0.5 to 1 mL.

[0061] According to an embodiment of the present invention, the preparation method further includes the step of removing the reaction reagent and vacuum drying after the reaction is completed.

[0062] In a third aspect, the present invention provides a method for preparing the composition, comprising: The method includes the steps of mixing and stirring the components (a), (b), and (c) to homogeneity, and optionally adding other auxiliary ingredients during the mixing process.

[0063] In a fourth aspect, the present invention provides the use of said composition in the preparation of a formulation, including but not limited to a pharmaceutical formulation, a cosmetic product, a care product or a beauty product.

[0064] Preferably, the pharmaceutical preparation can be used to treat skin diseases such as acne, hyperpigmentation, photoaging of the skin, psoriasis, ichthyosis, lichen planus, pityriasis rubra pilaris, follicular keratosis, squamous cell carcinoma and melanoma.

[0065] According to an embodiment of the present invention, the formulation may be applied topically through the skin, for example, selected from creams, patches, ointments, ointment formulations, latex formulations, gels, sprays, etc., or may be applied orally (i.e., oral formulations), for example, selected from tablets, granules, capsules, oral liquid formulations, pills, suspensions, drop pills, etc. The formulation may further contain a physiologically acceptable carrier (e.g., a biocompatible material), and may optionally contain, for example, surfactants, excipients, humectants, emulsifiers, suspending agents, salts or buffers for adjusting osmotic pressure, colorants, flavorings, stabilizers, bactericides, preservatives, or other conventional auxiliary agents. Preferably, the formulation is an ointment formulation, latex formulation, or gel formulation.

[0066] According to an embodiment of the present invention, the route of administration of the formulation includes, but is not limited to, gastrointestinal administration or non-gastrointestinal administration, wherein the gastrointestinal administration may be oral administration, and the non-gastrointestinal administration may be transdermal administration, etc. [Effects of the Invention]

[0067] The composition containing the tretinoin and alcoholamine compound complex of the present invention has good formulation properties such as component compatibility, comfort in use, stability, safety, and skin permeability, and therefore has broad medicinal prospects. [Brief explanation of the drawings]

[0068] [Figure 1] 1 is a HNMR spectrum of tretinoin. [Figure 2] 1 is a HNMR spectrum of diethanolamine. [Figure 3] 1H NMR spectrum of complex 2[DEA][RA]. [Figure 4] IR spectra of tretinoin, diethanolamine, and complex 2 [DEA] [RA]. [Figure 5] IR spectra of tretinoin-diethanolamine complexes with different molar ratios ([RA]:[DEA]=1:2, 1:2.5, 1:3, 1:4). [Figure 6] Raman spectra of tretinoin, diethanolamine, and complex 2 [DEA][RA]. [Figure 7] DVS of Complex 2 [DEA] [RA]. [Figure 8] PLM photographs of complex 2 [DEA] [RA] before and after DVS. [Figure 9] DSC of complex 2 [DEA] [RA]. [Figure 10] mDSC of complex 2[DEA][RA]. [Figure 11] Properties of complex 2 [DEA] [RA] with different water contents. [Figure 12] This is the liquid nitrogen freezing test process for Complex 2 [DEA] [RA]. [Figure 13] 1H NMR spectrum of complex 2.5[DEA][RA]. [Figure 14] 1H NMR spectrum of complex 3[DEA][RA]. [Figure 15] Figure 15(a) shows that 7[TEA][RA] cannot form a complex (solid precipitate, cloudy state), while Figure 15(b) shows that 8[TEA][RA] can form a complex (reddish-brown clear liquid). [Figure 16] 1 shows the results of a skin permeation test of the formulation of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0069] The technical solutions of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are only intended to exemplify and explain the present invention and should not be construed as limiting the scope of protection of the present invention. Any technology realized based on the above content of the present invention is included in the scope of protection of the present invention.

[0070] Unless otherwise specified, all materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0071] [Table 1]

[0072] Unless otherwise specified, the percentages "%" in the following examples represent percentages by mass.

[0073] Example 1 Preparation of Tretinoin-Diethanolamine Complex 1.1 Raw materials and reagents: tretinoin (RA) (AR, Shanghai Al Ding Biochemical Technology Co., Ltd.), diethanolamine (DEA) (AR, China National Pharmaceutical Group Chemical Reagents Co., Ltd.), ethanol (AR, China National Pharmaceutical Group Chemical Reagents Co., Ltd.).

[0074] [Table 2]

[0075] (1) Tretinoin was weighed according to the prescribed amount and placed in a round-bottom flask. Ethanol was added and the mixture was stirred. The tretinoin did not dissolve completely and remained in a suspended state. The round-bottom flask was wrapped in aluminum foil to protect it from light.

[0076] (2) Diethanolamine was weighed according to the prescribed amount, placed in a container wrapped in aluminum foil, and diluted with ethanol by stirring.

[0077] The diethanolamine diluted solution obtained in step (2) was added dropwise to the mixed solution obtained in step (1), and the mixture was stirred while being added dropwise. The container was washed with about 5 ml of ethanol, which was then added all at once to the flask and stirred.

[0078] After all additions were complete, the solution should be red-orange and clear and was allowed to stir for 4 h.

[0079] The solvent was removed using a rotary evaporator at a vacuum level of -0.095 MPa. A programmed temperature ramp was used to prevent the ethanol from splashing. Rotational evaporation was continued at 45°C for 1 hour, followed by heating to 50°C and rotary evaporation for 1 hour, and then heating to 60°C and rotary evaporation for 2 hours. A reddish-brown viscous liquid was obtained, which was siphoned off while still hot and then vacuum dried in a vacuum oven at 60°C for 48 hours. The resulting sample was sealed and stored in a dark place.

[0080] [Table 3]

[0081] process: The prescribed amount of tretinoin was weighed and placed in a round-bottom flask, and ethanol / water was added and stirred to mix. The tretinoin did not dissolve completely and remained in a suspension state. The round-bottom flask was wrapped in aluminum foil to protect from light.

[0082] Diethanolamine was weighed according to the prescribed amount, placed in a container wrapped in aluminum foil, and diluted with ethanol / water by stirring.

[0083] The diluted diethanolamine solution was added dropwise to the round-bottom flask containing the tretinoin mixture, stirring as it was added dropwise. The container was rinsed with approximately 5 mL of ethanol / water, which was then added all at once to the flask and stirred. After all additions were complete, the solution should be reddish-orange and clear. Stirring was continued for 4 hours. The solvent was removed using a rotary evaporator. A reddish-brown viscous liquid was obtained, which was siphoned off while hot and then vacuum dried in a vacuum oven at 60°C for 48 hours. The resulting sample was sealed and stored away from light.

[0084] [Table 4]

[0085] process: Diethanolamine was weighed according to the prescribed amount and placed in a round-bottom flask, which was then wrapped in aluminum foil to shield it from light.

[0086] The prescribed amount of water was added to a round-bottom flask and stirred until homogenous. The prescribed amount of tretinoin was weighed out, and the powder was carefully added to the flask in portions, stirring as it was added. The solution was stirred until clear, after which stirring was continued for 4 hours. The solvent was removed using a rotary evaporator. A reddish-brown viscous liquid was obtained, which was siphoned off while hot and then vacuum dried in a vacuum oven at 60°C for 48 hours. The resulting sample was sealed and stored away from light.

[0087] [Table 5]

[0088] process: The test process was carefully protected from light. Tretinoin was weighed according to the prescribed amount and placed in a crucible, followed by the prescribed amount of diethanolamine. The two substances were carefully mixed homogeneously using a fine grinding pestle. The crucible was heated in an electric heating jacket and maintained at a temperature of 60-80°C. The mixture was stirred and ground until a reddish-brown viscous liquid was obtained. The mixture was transferred to a light-blocking container while still hot, cooled, and then sealed and stored.

[0089] 1.3 Preparation of tretinoin-diethanolamine complexes with different ratios Referring to the preparation process in 1.2.1, complexes were prepared using different ratios of tretinoin and diethanolamine (shown in the table below). The results show that tretinoin and diethanolamine can form a complex (a reddish-brown, transparent liquid at room temperature) at molar ratios ranging from 2:1 to 10:1.

[0090] [Table 6]

[0091] Characterization of 1.4 Tretinoin Diethanolamine Complex Experimental Objective: Through the detection and analysis of the nuclear magnetic resonance hydrogen spectrum, infrared spectrum, and Raman spectrum of the original material and the tretinoin-diethanolamine complex, we were able to determine that the substance formed between tretinoin and diethanolamine is not a simple physical mixture, but rather an intermolecular interaction involving ionic and hydrogen bonds, which constitutes the chemical basis for the special physicochemical properties of the tretinoin complex.

[0092] 1.4.1H Nuclear Magnetic Resonance Spectroscopy (HNMR) Nuclear magnetic resonance hydrogen spectroscopy was performed on tretinoin, diethanolamine, and the prepared tretinoin-diethanolamine complex (2[DEA][RA]), as shown in Figures 1 to 3 and the table below.

[0093] [Table 7]

[0094] The HNMR spectra of 2[DEA][RA] showed the disappearance of the active hydrogen of tretinoin, indicating that tretinoin interacted with diethanolamine. The chemical shift of the ortho hydrogen atom of the carboxyl group of tretinoin shifted upfield from 7.02 to 6.78, indicating that tretinoin acted as a proton donor in the complex, resulting in an anion and a charge center at the carboxy oxygen atom. The chemical shifts of the two pairs of methylene hydrogens of diethanolamine shifted downfield from 2.58 to 2.76 and 3.46 to 3.56, respectively, indicating that diethanolamine acted as a proton acceptor in the complex, i.e., the lone pair on the N atom bonded with a free proton, resulting in a cationization and a charge center at the N atom.

[0095] Figures 13 and 14 show the HNMR spectra of complexes 2.5[DEA][RA] and 3[DEA][RA], respectively, which show characteristic chemical shift changes similar to those seen in 2[DEA][RA]. This indicates that the same intermolecular interactions occur between tretinoin and higher ratios of diethanolamine, allowing the formation of stable liquid complexes at room temperature.

[0096] 1.4.2 Infrared Spectrum (IR) IR identification was performed on tretinoin, diethanolamine, and the prepared 2[DEA][RA] (shown in Figure 4). The results showed that compared with diethanolamine, the peak shift of diethanolamine in 2[DEA][RA] was not obvious, and compared with tretinoin, the characteristic frequency of the C=O double bond of tretinoin in 2[DEA][RA] (1681.57 cm) was shifted. -1 ) shifts to lower wavenumbers, indicating that there is an interaction between the tretinoin and diethanolamine molecules.

[0097] The complexes with different ratios were prepared according to the molar ratios of RA:DEA = 1:2, 1:2.5, 1:3, and 1:4. The infrared spectra of the complexes with different ratios were consistent (shown in Figure 5), and all of them had the characteristic frequency of the C=O double bond (1682 cm -1 ) shifts to lower wavenumbers, indicating that an interaction occurs between the tretinoin and diethanolamine molecules.

[0098] 1.4.3 Raman spectrum Raman spectrum identification was performed for tretinoin, diethanolamine, and the prepared 2[DEA][RA] (shown in Figure 6). The results showed that the Raman spectrum of 2[DEA][RA] was obviously different from that of diethanolamine, and the difference was observed when compared with tretinoin, with the characteristic frequency of the C=C double bond (1574.72 cm -1 ) is 1589.19 cm -1 and shifts to higher wavenumbers, indicating that tretinoin interacts with diethanolamine.

[0099] Example 2 Preparation of Tretinoin Triethanolamine Complex Referring to the preparation process in 1.2 of Example 1, diethanolamine was replaced with triethanolamine, and complexes were prepared using different ratios of tretinoin and triethanolamine (shown in the table below). The results show that complexes were formed between tretinoin and triethanolamine at molar ratios of 1:8, 1:9, and 1:10, but it was difficult to form a liquid complex at room temperature at molar ratios of 1: (1-7) (see Figure 15).

[0100] [Table 8]

[0101] Example 3: Study on general physicochemical properties of tretinoin alcoholamine complex The following physicochemical properties of 2[DEA][RA] prepared according to 1.2.1 were investigated.

[0102] 3.1 Water and residual solvents Using a Karl Fischer moisture tester, three batches of 2[DEA][RA] were detected, and the results showed that the moisture and residual solvent in the prepared complexes could be easily removed.

[0103] [Table 9]

[0104] 3.2 Dynamic Ventilation (DVS) The DVS results showed that 2[DEA][RA] was hygroscopic to some extent (see Figure 7). The PLM results showed that 2[DEA][RA] before and after DVS did not contain any crystalline particles, indicating that the complex had a low risk of precipitating tretinoin at ambient humidity and could stably maintain its liquid form (see Figure 8).

[0105] 3.3 Differential scanning calorimetry (DSC) The DSC results showed that 2[DEA][RA] had no exothermic or endothermic signals in the temperature range of -25°C to 40°C (see Figure 9), indicating that the complex did not have a freezing point in this temperature range. The mDSC results showed that the glass transition temperature of the complex was not observed in the temperature range of -25°C to 25°C. This indicates that the complex can maintain a stable liquid form without the risk of solidification or precipitation in this temperature range (see Figure 10).

[0106] Example 4 Water solubility / water dilution resistance of tretinoin complex 4.1 Experimental Objectives The entry on tretinoin in Part II of the 2020 edition of the Chinese Pharmacopoeia states that tretinoin is extremely insoluble in water. According to literature, the solubility of tretinoin in water is only 1.06*10 -6 mol / L (Ascenso A, Guedes R, Bernardino R, et al. Complexation and full characterization of the tretinoin and dimethyl-β-cyclodextrin complex. AAPS PharmSciTech. 2011;12(2):553-563. doi:10.1208 / s12249-011-9612-3). The poor solubility of tretinoin poses significant challenges in the formulation process. However, the tretinoin complex has some water solubility, which is advantageous for formulation preparation.

[0107] 4.2 Testing process 2[DEA][RA] and different proportions of water were accurately weighed and vortex-mixed. The properties of the complexes with different water contents were observed. After the water content exceeded 90%, water was added in small amounts multiple times using a microsyringe until the solution became cloudy, and the vortex-mixing was continued. The limiting water content of the complex was then calculated by weighing.

[0108] 4.3 Results and Discussion As shown in Figure 11, 2[DEA][RA] was compatible with water over the water content range of 0 to 91.4% (w / w) (liquids in bottles with a water content of 90% or less were clear and transparent). When the water content was too high (>91.4%), hydrogen bonding in the water destroyed the complex, resulting in the precipitation of solid tretinoin (bottles with a water content of 91.4% were cloudy). The water dilution resistance of complexes with other molar ratios was tested, and the test results are shown in the table below. As the DEA ratio increased, the water dilution resistance of the tretinoin-diethanolamine complex increased.

[0109] [Table 10]

[0110] Example 5 Induced crystallization test of tretinoin complex 5.1 Test Objectives In the practice of chemical synthesis, compounds often form amorphous crystals or supercooled liquids during recrystallization, often appearing in a glassy or transparent oily state. This is similar to the properties of the complexes described in the present invention. However, this state is not stable and can be transformed into a stable crystalline state by changes in external conditions or the induction of seed crystals. Therefore, to rule out this possibility and further demonstrate that the complexes prepared according to the present invention have a stable liquid form, a series of induction challenge tests were conducted, and various crystallization-promoting methods, such as volatilization tests, stirring tests, and temperature-reducing tests, were used to attempt to obtain a solid form of the complex. If a solid form could not be obtained, the liquid form of the resulting complex was considered to be its stable form.

[0111] 5.2 Volatilization test The complexes were investigated in different solvent systems, with or without polymer, at different temperatures to determine whether solid forms of the material would form after the solvent had completely evaporated. The polymer was added to the system to add "nuclei" to compare the effects of the presence or absence of nuclei, and different temperatures affected the rate of solvent evaporation and the crystallization behavior of the material.

[0112] Approximately 80 mg of 2[DEA][RA] was dissolved in the corresponding solvent to obtain a clear solution, which was then divided into four equal parts. Polymers were used as the "crystallization nuclei," with either no polymer added or Polymer B or Polymer C added, and the samples were then allowed to evaporate at 5°C and 50°C for approximately four days. The samples were then observed, and no solid substances were observed except for the added polymers. The results are shown in the table below.

[0113] [Table 11]

[0114] Polymer B: A mixture of five polymers, namely PCL polycaprolactone, PEG polyethylene glycol, PMMA polymethyl methacrylate, SA stearyl acrylate, and HEC hydroxyethyl cellulose, mixed in equal mass ratios.

[0115] Polymer C: A mixture of four polymers, polystyrene, polytetrafluoroethylene, polytribromostyrene, and polyvinyl stearate, mixed in equal mass ratios.

[0116] 5.3 Stirring test At room temperature (~22°C), 0.3 mL of the corresponding solvent was added to approximately 20 mg of 2[DEA][RA], and after stirring at the corresponding temperature for 3 days, either a clear solution was obtained or the formation of oil was observed, and no solid substance was obtained, and the results are shown in the table below.

[0117] [Table 12]

[0118] 5.4 Temperature drop test Approximately 40 mg of 2[DEA][RA] was dissolved in the corresponding solvent at 50°C to obtain a clear solution, which was then divided into two equal parts, cooled according to the corresponding procedure, and equilibrated at low temperature for 3 days, but no solid substance was obtained in either case. The results are shown in the table below.

[0119] [Table 13]

[0120] 50°C → 5°C: The resulting clear solution was equilibrated at 50°C for 30 min, then cooled to 5°C over 450 min, and equilibrated at 5°C for 3 days.

[0121] 50°C → -20°C: The clear solution obtained at 50°C was quickly transferred to -20°C and equilibrated at -20°C for 3 days.

[0122] *: Melted immediately after removal.

[0123] 5.5 Liquid nitrogen freezing test Approximately 50 mg of 2[DEA][RA] was scooped onto a weighing spoon, and the spoon and sample were placed in liquid nitrogen (it was a reddish-brown, transparent liquid before freezing). After freezing for approximately 1 minute, the sample was removed and a reddish-brown, transparent solid (hard and brittle) was obtained. However, after reheating (to room temperature: approximately 22°C), the sample quickly melted (returning to a reddish-brown, transparent liquid), and no solid substance was observed. The test process is shown in Figure 12.

[0124] 5.6 Antisolvent addition test A corresponding volume of good solvent was added to an appropriate amount of 2[DEA][RA] to obtain a clear solution. If two corresponding antisolvents were used, the clear solution was divided into two. The antisolvent was gradually added to the clear solution with stirring at room temperature (~22°C) until a solid precipitated (the maximum volume of antisolvent added was 1.5 mL). When a solid precipitated, the addition of the antisolvent was stopped and the mixture was stirred at room temperature for approximately 4 days. Either a clear solution was obtained, or oil formation was observed, but no solid substance was obtained. The results are shown in the table below.

[0125] [Table 14]

[0126] 5.7 Summary of induced crystallization tests Using the tretinoin-diethanolamine complex as the starting material, a total of 49 induced crystallization experiments (including evaporation, stirring, cooling, antisolvent addition, and liquid nitrogen freezing) were performed. The reaction solvents included a variety of single solvents and binary solvent combinations. The reaction temperatures ranged from -20°C to 50°C (the temperature for the liquid nitrogen freezing experiment was -196°C). No solid material was obtained in any of the experiments. The results indicate that the tretinoin-diethanolamine complex is difficult to exist in solid form; that is, the liquid form is its stable form at room temperature.

[0127] Example 6 Study on the formulation of a composition containing a tretinoin alcoholamine complex 6.1 Study on the solubility of tretinoin alcoholamine complex in different solvent systems

[0128] [Table 15]

[0129] Tests have shown that the tretinoin alcoholamine complex has low solubility in the above oily media, therefore further research into suitable formulation systems is required.

[0130] [Table 16]

[0131] Approximately 80% of the prescribed amount of water was taken and heated to 85-90°C. PVA was weighed and added to the water. The mixture was heated in a water bath at 85°C and stirred until uniformly dispersed and swollen. The prescribed amounts of glycerin and benzyl alcohol were added, and water was added until the prescribed amount was reached. The mixture was cooled to room temperature, frozen at -20°C for 4 hours, removed, and thawed at room temperature. The freeze-thaw process was repeated twice to obtain the desired product.

[0132] [Table 17]

[0133] Approximately 80% of the prescribed amount of water was taken and heated to approximately 40°C. H-HPC was weighed and added to the water, and stirred at room temperature until uniformly dispersed and swollen. The prescribed amounts of glycerin and benzyl alcohol were then added, and water was added until the prescribed amount was reached, and the mixture was stirred uniformly to obtain the desired product.

[0134] [Table 18]

[0135] HPMC was weighed out and added to approximately 80% of the prescribed amount of water, and stirred at room temperature until uniformly dispersed and swollen. The prescribed amounts of glycerin and benzyl alcohol were then added, and water was added until the prescribed amount was reached, and the mixture was stirred uniformly.

[0136] [Table 19]

[0137] Each material was weighed, added to water, and stirred at room temperature until uniformly dispersed, and then homogenized with a high-shear homogenizer at 10,000 rpm for 1 minute to obtain the dispersion.

[0138] [Table 20]

[0139] Triethanolamine was dissolved in water, PVP K30 was added and stirred to disperse uniformly, benzyl alcohol, propylene glycol, and glycerin were added and stirred to mix uniformly, polycarbophil was sieved through a 35 mesh sieve and added to the system, stirred to disperse uniformly, and homogenized with a high-shear homogenizer at 1000 rpm for 2 minutes to obtain the desired dispersion.

[0140] [Table 21]

[0141] Polyethylene glycol 400 and polyethylene glycol 3350 were placed in a 250 ml beaker, placed in a water bath at 60°C, and stirred at 100 rpm to dissolve and mix. The raw materials were weighed out in the dark and added to the substrate solution, followed by continued stirring to dissolve. The temperature was lowered in a 40°C water bath and a vacuum was applied. The temperature was then lowered to approximately 40°C. The mixture was homogenized in a homogenizer at 3000 rpm for 5 minutes. The mixture was then naturally cooled to give a solution.

[0142] [Table 22]

[0143] Carbopol 980 was weighed out and added to approximately 60% of the prescribed amount of water, and stirred at room temperature until uniformly dispersed. The prescribed amounts of glycerin and benzyl alcohol were added and stirred uniformly. An appropriate amount of triethanolamine was added, and the pH was adjusted to 5.0-5.5 to cause gelation. Purified water was then added until the prescribed amount was reached, and stirring was continued for 20 minutes using an anchor stirrer.

[0144] [Table 23]

[0145] Carbopol ETD2020 was weighed out and added to approximately 60% of the prescribed amount of water, and stirred at room temperature until uniformly dispersed. The prescribed amounts of ethanol, glycerin, and benzyl alcohol were then added and stirred uniformly. An appropriate amount of triethanolamine was added, and the pH was adjusted to 5.0-5.5 to cause gelation. Purified water was then added until the prescribed amount was reached, and stirring was continued for 20 minutes using an anchor stirrer.

[0146] [Table 24]

[0147] Based on the above comparison, carbomer is preferred as the semi-solid matrix material.

[0148] [Table 25]

[0149] When 0.17% (0.1% with RA) of the 2[DEA][RA] complex was added to a Carbopol 980 gel matrix, the reddish-brown tretinoin complex precipitated as a yellow solid, i.e., was destroyed by the water in the matrix.

[0150] Due to the limited dosage of tretinoin, the tretinoin complex was destroyed in the high-water content gel matrix, resulting in precipitation of tretinoin. Therefore, the high-water content Carbopol 980 gel matrix was incompatible with the tretinoin complex. Particulate tretinoin was not favorable for transdermal absorption. Therefore, other auxiliary materials had to be added to the formulation to promote compatibility with the complex, avoid tretinoin precipitation, and form a stable semi-solid formulation.

[0151] 6.4 Semi-solid preparations containing tretinoin alcoholamine complex 6.4.1 Lactation:

[0152] [Table 26]

[0153] [Table 27]

[0154] Formulation 1-2 plaster process: Polyoxyethylene 54 hydrogenated castor oil is heated to 60°C to melt, cooled to 40°C, other oil phase raw materials and auxiliary materials are added and mixed to dissolve, the aqueous phase materials are mixed, Carbopol is added to disperse uniformly, the two phases are mixed, and homogenized in a homogenizer at 1000 rpm for 2 minutes, an appropriate amount of NaOH is added to adjust the pH to 5.0-5.5, and the product is filled into an aluminum-plastic composite tube.

[0155] [Table 28]

[0156] [Table 29]

[0157] Formulation 3-4 Latex Process: Each auxiliary ingredient in the aqueous phase was weighed according to the prescribed amounts and mixed uniformly. The resulting solution was placed in a 40°C water bath and kept warm for use. 2[DEA][RA] and ethanol were weighed according to the prescribed amounts and mixed together. Isopropyl myristate and benzyl alcohol (or phenoxyethanol) were weighed and added to the oil phase, and the mixture was mixed uniformly. Octadecanol and dibutylhydroxytoluene were weighed and added to the oil phase. The mixture was heated in a 60°C water bath to dissolve, then cooled to 40°C. While maintaining the water bath at 40°C, the oil phase was added to the aqueous phase and homogenized using a high-shear homogenizer for 3 minutes. An appropriate amount of triethanolamine was added to adjust the pH to 5.0-5.5, and the mixture was mechanically stirred (four-blade or anchor type) until an opaque semi-solid latex was formed. The product was then filled into an aluminum-plastic composite tube.

[0158] [Table 30]

[0159] [Table 31]

[0160] [Table 32]

[0161] [Table 33]

[0162] [Table 34]

[0163] [Table 35]

[0164] [Table 36]

[0165] [Table 37]

[0166] [Table 38]

[0167] [Table 39]

[0168] Gel process for Formulas 5 to 14: 60% of the formulation's volume of water was weighed out, and the preservative was added and stirred to dissolve. Carbomer was added and stirred at 200 rpm for 5 minutes to disperse uniformly. The mixture was then stirred at 50 rpm for 50 minutes to hydrate the carbomer. The oil phase auxiliary material, 2[DEA][RA], was added and mixed to form a uniform oil phase. The water phase was added to the oil phase and homogenized at 5000 rpm for 3 minutes using a high-shear homogenizer. An appropriate amount of NaOH was added to adjust the pH to 5.0-5.5, and the mixture was mechanically stirred at low speed for 30 minutes to form a uniform gel. The resulting product was then filled into aluminum-plastic composite tubes.

[0169] [Table 40]

[0170] Formulation 15 Latex Process: Each auxiliary ingredient in the aqueous phase was weighed according to the prescribed amounts and mixed uniformly. The solution was placed in a 40°C water bath and kept warm for use. Tretinoin and ethanol were weighed according to the prescribed amounts and mixed together. Isopropyl myristate and benzyl alcohol were weighed and added, and mixed uniformly. Octadecanol and dibutylhydroxytoluene were weighed and added to the oil phase. The mixture was heated in a 60°C water bath until dissolved, and then cooled to 40°C. While maintaining the water bath at 40°C, the oil phase was added to the aqueous phase and homogenized using a high-shear homogenizer for 3 minutes. An appropriate amount of triethanolamine was added, and the pH was adjusted to 5.0-5.5. The mixture was mechanically stirred (four-blade or anchor type) until an opaque semi-solid latex was formed. The product was then filled into an aluminum-plastic composite tube.

[0171] [Table 41]

[0172] Formula 16 Gel Process: 60% of the formulation's water volume was weighed out, and preservatives and other auxiliary ingredients were added and stirred to dissolve. Carbomer was added and stirred at 200 rpm for 5 minutes to uniformly disperse it, followed by 50 minutes at a slow speed of 50 rpm to hydrate the carbomer. Tretinoin was added to the oil phase auxiliary ingredients and mixed uniformly to form a uniform oil phase. The water phase was added to the oil phase and homogenized at 5000 rpm for 3 minutes using a high-shear homogenizer. An appropriate amount of NaOH was added to adjust the pH to 5.0-5.5, and mechanical stirring was continued at a slow speed for 30 minutes to form a uniform gel. The product was then filled into aluminum-plastic composite tubes.

[0173] [Table 42]

[0174] [Table 43]

[0175] The results showed that the formulations of the present invention (Formulations 4 and 5) had a significant penetration-enhancing effect. Among them, the skin retention amount of the 2[DEA][RA] latex formulation (Formulation 4) was 11.8 times that of the tretinoin latex formulation (Formulation 15), and the skin retention amount of the 2[DEA][RA] gel formulation (Formulation 5) was 11.9 times that of the tretinoin gel formulation (Formulation 16). Compared with the commercially available formulations, the skin retention amounts of Formulas 4 and 5 were 4.9 to 10.5 times that of the commercially available formulations (see Figure 16).

[0176] 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 principle of the present invention should be included within the protection scope of the present invention.

Claims

1. 1. A composition comprising: (a) a tretinoin alcoholamine compound complex; (b) a gel matrix; (c) an oil phase component; The complex is a composition comprising tretinoin and an alcoholamine compound.

2. The alcohol amine compound is selected from the following formula I: 【Chemistry 1】 In the formula, X is C １－６ and preferably —CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ - and is selected from the following formula 2, R １ , R ２ are each independently H, C １－６ Alkyl, C １－６ alkyl-OH; 【Chemistry 2】 Preferably, said formula I is selected from diethanolamine, triethanolamine, monoethanolamine (2-hydroxyethylamine), N-methyldiethanolamine, n-propanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, n-butanolamine, dibutanolamine, isobutanolamine; More preferably, the composition according to claim 1, wherein the molar ratio of the alcoholamine compound to tretinoin is (1-100):

1.

3. The composition according to claim 1 or 2, wherein the (c) oil phase component is selected from one or more of (c1) an oily substrate, (c2) a co-solvent, and (c3) a penetration enhancer.

4. The composition comprises: Formulation 1: (a) Tretinoin alcoholamine compound complex (b) Gel substrate (d) emulsifier Formulation 2: (a) Tretinoin alcoholamine compound complex (b) Gel substrate (c2) Co-solvent (c3) penetration enhancer (d) emulsifier Formulation 3: (a) Tretinoin alcoholamine compound complex (b) Gel substrate (c1) Oily substrate (c2) Co-solvent (d) emulsifier Formulation 4: (a) Tretinoin alcoholamine compound complex (b) Gel substrate (c2) Co-solvent (c3) penetration enhancer Formulation 5: (a) Tretinoin alcoholamine compound complex (b) Gel substrate The composition according to any one of claims 1 to 3, characterized in that (c3) a penetration enhancer is selected from compounds 1 to 5.

5. the gel matrix is ​​selected from carbomers, e.g. Carbopol 980, Carbopol ETD2020; The co-solvent is preferably selected from alcohols, and the alcohols are preferably one or more of glycerin, ethanol, propylene glycol, and benzyl alcohol; the emulsifier is selected from one or more of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, span 20, span 60, span 80, polyoxyethylene castor oil derivatives, poloxamer, triton, polyethylene glycol glyceryl caprylate decanoate, polyethylene glycol stearate, polyoxyethylene-8 beeswax, lauroyl polyoxyethylene glyceryl; The oily substrate is selected from one or more of octadecanol, hexadecanol, stearic acid, and fatty acid esters; 5. The composition of claim 1, wherein the penetration enhancer is selected from one or more of glyceryl monocaprylate, laurocapram, diethylene glycol monoethyl ether, polyglycerol fatty acid esters, propylene glycol monocaprylate, and polyethylene glycol glyceryl caprylate decanoate.

6. The composition according to any one of claims 1 to 5, further comprising one or more of an antioxidant, a preservative, a pH adjuster, a metal ion complexing agent, and a rheology adjuster.

7. the antioxidant is selected from one or more of dibutylhydroxytoluene, butylhydroxyanisole, vitamin C, vitamin E, and sodium metabisulfite; The preservative is selected from one or more of benzyl alcohol, phenoxyethanol, sodium benzoate, methylparaben, ethylparaben, propylparaben, sodium methylparaben, and sodium propylparaben; the pH adjuster is selected from one or more of triethanolamine and sodium hydroxide; the rheology modifier is selected from one or more of Pemulen™ TR-1 NF polymer, Pemulen™ TR-2 NF polymer, Carbopol® 1342 NF polymer, Carbopol® 5984 EP polymer; the metal ion complexing agent is selected from one or more of ethylenediaminetetraacetic acid (EDTA), disodium ethylenediaminetetraacetic acid (EDTA-2Na), tetrasodium ethylenediaminetetraacetic acid (EDTA-4Na), disodium nitrilotriacetate, sodium tripolyphosphate, sodium hexametaphosphate, and tetrapotassium pyrophosphate; 7. The composition according to claim 6, wherein the pH value of the composition is preferably between 4 and 7.

8. said component (a) comprising 0.01% to 5% (w / w) of the total amount of the composition; said component (b) comprising 0.01% to 5% (w / w) of the total amount of the composition; said component (c) comprising 0.5% to 70.0% (w / w) of the total amount of the composition; The composition according to any one of claims 1 to 7, characterized in that component (d) accounts for 0.5% to 30.0% (w / w) of the total amount of the composition.

9. said component (c1) accounts for 4.0 to 30.0% (w / w) of the total amount of the composition; said component (c2) accounts for 0.5% to 25.0% (w / w) of the total amount of the composition; 8. The composition according to claim 1, wherein component (c3) accounts for 0.5% to 30.0% (w / w) of the total amount of the composition.

10. the formulation is selected from pharmaceutical formulations, cosmetics, care products, beauty products, Use of the composition according to any one of claims 1 to 9 in the manufacture of a preparation, characterized in that the pharmaceutical preparation can be used to treat skin diseases such as acne, hyperpigmentation, photoaging of the skin, psoriasis, ichthyosis, lichen planus, pityriasis rubra pilaris, follicular keratosis, squamous cell carcinoma and melanoma.

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