WO2024012400A1 - 一种维a酸醇胺类复合物及其制备方法和应用 - Google Patents

一种维a酸醇胺类复合物及其制备方法和应用 Download PDF

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WO2024012400A1
WO2024012400A1 PCT/CN2023/106535 CN2023106535W WO2024012400A1 WO 2024012400 A1 WO2024012400 A1 WO 2024012400A1 CN 2023106535 W CN2023106535 W CN 2023106535W WO 2024012400 A1 WO2024012400 A1 WO 2024012400A1
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retinoic acid
complex
compound
cation
preparation
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PCT/CN2023/106535
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English (en)
French (fr)
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刘振云
胡弢
鲁西强
戚建平
吴伟
武余波
陈磊
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南京毓浠医药技术有限公司
复旦大学
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Publication of WO2024012400A1 publication Critical patent/WO2024012400A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/12—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic the nitrogen atom of the amino group being further bound to hydrocarbon groups substituted by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a retinoic acid olamine complex and its preparation method and application.
  • Vitamin A and its metabolites play important roles in the human body and are currently widely used to treat various diseases.
  • retinoic acid molecular formula: C 20 H 28 O 2
  • Retinoic acid is mainly used to treat acne vulgaris, hyperpigmentation, skin photoaging, psoriasis, ichthyosis, lichen planus, pityriasis rubra pilaris, keratosis pilaris, squamous cell carcinoma and melanoma.
  • Oral retinoic acid can also be used to treat acute promyelocytic leukemia.
  • Retinoic acid is fat-soluble and almost insoluble in water. Therefore, its dissolution in the preparation and dissolution in the body are poor, which limits the medicinal use of its preparations.
  • due to the barrier function of the skin's stratum corneum when conventional tretinoin topical preparations are used, only a small amount of ingredients can penetrate the barrier and exert their effect, making it difficult to maintain an effective therapeutic concentration.
  • the dosage of tretinoin is increased, it will cause greater Skin irritation, such as varying degrees of redness, stinging, edema and other inflammatory symptoms.
  • retinoic acid In view of the good application prospects of retinoic acid in the treatment of skin diseases, it is necessary to develop it into a medicinal form suitable for skin diseases.
  • the present invention provides a retinoic acid-alcoholamine compound, which is composed of retinoic acid and an alkanolamine compound.
  • the alcoholamine compound is selected from the following formula I:
  • _ _ _ _ _ R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 alkyl-OH.
  • the formula I is selected from diethanolamine, triethanolamine, monoethanolamine (2-hydroxyethylamine), N-methyldiethanolamine, n-propanolamine, isopropanolamine, and diisopropanol Amine, triisopropanolamine, n-butanolamine, dibutanolamine, isobutanolamine.
  • the molar ratio of the alcoholamine compound to retinoic 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, more preferably (1-5):1.
  • the complex is in liquid form at room temperature.
  • the retinoic acid may exist partially or entirely in anionic form, and the alcoholamine compound may exist partially or entirely in cationic form.
  • part of the retinoic acid exists in a molecular form and/or part of the alcoholamine compounds exists in a molecular form.
  • tretinoin in the complex, is present in the form [A - ] as follows:
  • the alcoholamine compound in the complex, exists in the form [B + ] shown in the following formula II:
  • X' is selected from a C 1-6 alkyl group, preferably, is selected from -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - and R 1 ', R 2 ' are each independently selected from H, C 1-6 alkyl, C 1-6 alkyl-OH.
  • the formula II is selected from the group consisting of diethanol ammonium cation, triethanol ammonium cation, monoethanol ammonium cation (i.e. 2-hydroxyethylammonium cation), N-methyl diethanol ammonium cation, n-propylammonium cation Cations, isopropylammonium cation, diisopropylammonium cation, triisopropylammonium cation, n-butylammonium cation, dibutylammonium cation, isobutylammonium cation.
  • the complex is [A - ][B + ] x , and 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.
  • the present invention provides a method for preparing the complex, which includes the following steps: obtaining it by reacting retinoic acid and the alcoholamine compound.
  • the molar ratio of the alcoholamine compound and retinoic 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, more preferably (1-5):1.
  • the reaction reagent can be water or an organic solvent or a mixed solvent of an organic solvent and water.
  • the organic solvent is selected from one or more of ethanol, methanol and acetone. combination.
  • the organic solvent is ethanol.
  • the volume ratio of organic solvent and water in the mixed solvent is 5:95 to 95:5.
  • the volume ratio of organic solvent and water is 40:60-95:5.
  • the reaction may be carried out by dry grinding.
  • the total dosage ratio of the retinoic acid and the reaction reagent is 1g:5-150mL, preferably 1g:5-20mL.
  • the preparation method includes the following steps:
  • step (3) Add the diluent obtained in step (2) to the mixed solution obtained in step (1).
  • the dosage ratio of the retinoic acid and the reaction reagent is 1g:5-100mL, preferably 1g:5-20mL; in the step (2), The dosage ratio of the alcoholamine compound and the reaction reagent is 1g:0.5-50mL, preferably 1g:0.5-5mL, and more preferably 1g:0.5-1mL.
  • the preparation method further includes the steps of removing the reaction reagent and vacuum drying after the reaction is completed.
  • the present invention also provides a composition containing the retinoic acid olamine complex.
  • the present invention provides the use of the retinoic acid olamine complex or the composition in preparing preparations, including but not limited to pharmaceutical preparations, cosmetics, care products, and beauty products.
  • the pharmaceutical preparation is used in the treatment of skin diseases and non-skin tumors.
  • the pharmaceutical preparation is used to treat skin diseases, for example, it can be used to treat acne, hyperpigmentation, skin photoaging, psoriasis, ichthyosis, lichen planus, pityriasis rubra pilaris, keratosis pilaris, and scale. diseases such as ovarian cancer and melanoma.
  • the pharmaceutical preparation is used for the treatment of non-cutaneous tumors, for example, for the treatment of acute promyelocytic leukemia, and can also be used for the treatment of gastric cancer, lung cancer, ovarian cancer, cervical cancer, neuroblastoma, Glioma etc.
  • the preparation can be applied topically through the skin, for example, selected from creams, patches, ointments, cream preparations, gels and sprays, etc., or can be administered orally (i.e., oral Preparation) administration, for example, selected from tablets, granules, capsules, oral liquid preparations, pills, suspensions, dropping pills, etc.
  • the preparation further includes a physiologically acceptable carrier (for example, a biocompatible material), for example, optionally including surfactants, excipients, humectants, emulsification accelerators, suspending agents, for regulating penetration. Pressed salts or buffers, colorants, flavors, stabilizers, bactericides, preservatives or other conventional supplements.
  • the administration route of the preparation includes but is not limited to gastrointestinal administration or parenteral administration; wherein the gastrointestinal administration can be oral administration; the parenteral administration Intestinal administration can be transdermal administration, etc.
  • retinoic acid and alcoholamine compounds can form a complex in liquid form at room temperature, which has good water solubility/water dilution resistance and skin penetration effect, overcoming the existing technology of retinoic acid compounds. It has broad medicinal prospects despite limitations in the application field of preparations.
  • the preparation method used in this study is simple and easy to implement, without harsh reaction conditions, easy for quality control and scale-up production; in addition, the solvent used can be recycled and reused, which is in line with the concept of green chemistry.
  • Figure 1 shows the HNMR spectrum of retinoic acid.
  • Figure 2 shows the HNMR spectrum of diethanolamine.
  • FIG. 3 shows the HNMR spectrum of complex 2[DEA][RA].
  • Figure 4 shows the IR spectra of retinoic acid, diethanolamine, and complex 2[DEA][RA].
  • Figure 6 shows the Raman spectra of retinoic acid, diethanolamine, and complex 2[DEA][RA].
  • Figure 7 shows the DVS of complex 2[DEA][RA].
  • Figure 8 shows the PLM photos before and after DVS of compound 2[DEA][RA].
  • Figure 9 is the DSC of complex 2[DEA][RA].
  • Figure 10 shows complex 2[DEA][RA]mDSC.
  • Figure 11 shows the properties of compound 2[DEA][RA] with different water contents.
  • Figure 12 shows the liquid nitrogen freezing test process of compound 2[DEA][RA].
  • Figure 13 is the HNMR spectrum of complex 2.5[DEA][RA].
  • Figure 14 is the HNMR spectrum of complex 3[DEA][RA]
  • Figure 15(a) shows that 7[TEA][RA] cannot form a complex (solid precipitates and the state is turbid); (b) shows that 8[TEA][RA] can form a complex (red-brown transparent liquid)
  • step (2) Add the diethanolamine dilution obtained in step (2) dropwise to the mixed solution obtained in step (1), stirring while adding; clean the container with about 5 ml of ethanol, and add it to the flask together with stirring.
  • Retinoic acid, diethanolamine and the prepared retinoic acid-diethanolamine complex (2[DEA][RA]) were identified by hydrogen nuclear magnetic resonance spectroscopy, as shown in Figures 1 to 3 and the following table:
  • Both pairs of methylene hydrogens of diethanolamine have chemical shifts that move to the lower field, which are 2.58 ⁇ 2.76, 3.46 ⁇ 3.56 respectively; indicating that diethanolamine acts as a proton acceptor in the complex system, that is, the lone pair of electrons on the N atom is combined The free proton is cationized, and the charge center is the N atom.
  • Figures 13 and 14 show the HNMR spectra of complexes 2.5[DEA][RA] and 3[DEA][RA] respectively, which also show the same characteristic chemical shift changes as 2[DEA][RA]. It can be seen that the same intermolecular interaction occurs between tretinoin and a higher proportion of diethanolamine, and a liquid complex that is stable at room temperature can also be formed.
  • DVS results show (see Figure 7) that 2[DEA][RA] has certain hygroscopicity.
  • the PLM results show that there are no crystal particles in 2[DEA][RA] before and after DVS, indicating that the compound has a low risk of precipitating retinoic acid in ambient humidity and can stably maintain its liquid form.
  • the DSC results show that 2[DEA][RA] has no exothermic or endothermic signals in the range of -25°C to 40°C, indicating that the composite has no freezing point in this temperature range.
  • the mDSC results showed that the glass transition temperature of the composite was not observed in the range of -25°C to 25°C. It shows that the compound can maintain a stable liquid form within this temperature range without the risk of solidification and precipitation.
  • 2[DEA][RA] is miscible with water in the ratio range of water content 0 to 91.4% (w/w) (in bottles with water content ⁇ 90% The liquid is clear and transparent).
  • the water ratio is too high (>91.4%)
  • the hydrogen bonds in the water will destroy the complex system and precipitate the retinoic acid solid (a bottle with a water content of 91.4% will be turbid).
  • the water dilution resistance of the complexes with other molar proportions was tested. The test results are shown in the table below. As the DEA ratio increases, the water dilution resistance of the retinoic acid diethanolamine complex increases.
  • the compound prepared by the present invention has a stable liquid form
  • a series of induction challenge tests are planned to be carried out, through various means of promoting crystallization such as volatilization tests, stirring tests, cooling tests, etc., in order to The solid form of the compound is obtained; if the solid form cannot be obtained, the liquid form of the obtained compound can be considered as its stable form.
  • Polymer B a mixture composed of five polymers, PCL polycaprolactone, PEG polyethylene glycol, PMMA polymethyl methacrylate, SA stearyl acrylate, and HEC hydroxyethyl cellulose, in equal mass ratios.
  • Polymer C a mixture composed of four polymers, polystyrene, polytetrafluoroethylene, polytribromostyrene, and polyvinyl stearate, in equal mass ratios.
  • retinoic acid diethanolamine complex Starting from the retinoic acid diethanolamine complex, a total of 49 induced crystallization experiments (including volatilization, stirring, cooling and anti-solvent addition, and liquid nitrogen freezing) were conducted.
  • the reaction solvents covered different types of single solvents or binary solvent combinations.
  • the reaction temperature ranges from -20°C to 50°C (liquid nitrogen freezing experimental temperature is -196°C). None of the experiments resulted in solid form.
  • the results show that the retinoic acid diethanolamine complex is difficult to exist in solid form, that is, the liquid form is its stable form at room temperature.
  • Test preparation Prepare the sample and receiving solution in advance; prepare pig skin of appropriate size, preferably skin with fewer pores, and weigh the skin so that the weight difference is less than 0.05g;
  • Test Administer about 0.5ml. The cream should be applied evenly and fully contact with the skin; the actual dosage is measured by a balance;
  • Retinoic acid was not detected in the receiving fluid.
  • the amount of retinoic acid retained in the skin was measured. The results are as follows:
  • Retinoic acid skin retention (transmittance per unit area ⁇ g/cm 2 )

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Abstract

本发明涉及一种维A酸醇胺类复合物，所述复合物由维A酸与醇胺类化合物组成，在常温下为液态形式，具有良好的水溶性/抗水稀释能力以及皮肤渗透效果，克服了现有技术中维A酸类化合物在制剂应用领域的限制，具有广泛的药用前景。

Description

一种维A酸醇胺类复合物及其制备方法和应用
本申请要求2022年7月11日向中国国家知识产权局提交的，专利申请号为202210853741.9，发明名称为“一种维A酸醇胺类复合物及其制备方法和应用”的在先申请的优先权。所述申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于药物化学领域，具体涉及一种维A酸醇胺类复合物及其制备方法和应用。
背景技术
维生素A及其代谢产物在人体内均具有重要的作用，目前被广泛用于治疗各种疾病。如维生素A的体内代谢中间产物维A酸(分子式为C20H28O2)，主要影响骨的生长和促进上皮细胞增生、分化、角质溶解等代谢作用。维A酸主要用于治疗寻常痤疮、色素过度沉着、皮肤光老化、银屑病、鱼鳞病、扁平苔癣、毛发红糠疹、毛囊角化病、鳞状细胞癌及黑色素瘤等疾病。口服维A酸还可用于治疗急性早幼粒细胞白血病。
维A酸具有脂溶性，几乎不溶于水，因此在制剂中的溶解以及体内的溶出均较差，使得其制剂药用受到一定限制。此外，由于皮肤角质层的屏障功能，常规维A酸外用制剂在使用时，仅少量成分可以透过屏障发挥作用，难以维持有效治疗浓度；但若增加维A酸用量，则会带来较大的皮肤刺激性，比如出现不同程度的发红、刺痛、水肿等炎症症状。鉴于维A酸在皮肤类疾病的治疗领域具有较好的应用前景，有必要将其开发为适合于皮肤类疾病应用的药用形式。
发明内容
为了改善现有技术存在的技术问题，第一方面，本发明提供一种维A酸醇胺类复合物，所述复合物由维A酸与醇胺类化合物组成。
根据本发明的实施方案，所述醇胺类化合物选自如下式I：
其中，X选自C1-6的烷基，优选的，选自-CH2-CH2-、-CH2-CH2-CH2-和R1、R2各自独立地选自H，C1-6烷基，C1-6烷基-OH。
根据本发明的实施方案，所述式I选自二乙醇胺、三乙醇胺，单乙醇胺(2-羟基乙胺)，N-甲基二乙醇胺，正丙醇胺，异丙醇胺、二异丙醇胺，三异丙醇胺、正丁醇胺、二丁醇胺、异丁醇胺。
根据本发明的实施方案，所述醇胺类化合物与维A酸的摩尔比为(1-100):1，例如为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，更优选为(1-5):1。
根据本发明的实施方案，所述复合物在室温下为液体形式。所述复合物中，所述维A酸可以部分或全部以阴离子形式存在，所述醇胺类化合物可以部分或全部以阳离子形式存在。在一些实施方式中，所述复合物中，部分所述维A酸以分子形式存在和/或部分所述醇胺类化合物以分子形式存在。
在一些实施方式中，所述复合物中，维A酸以如以下[A-]形式存在：
在一些实施方式中，所述复合物中，醇胺类化合物如以下式II所示[B+]形式存在：
所述式II中，X’选自C1-6的烷基，优选的，选自-CH2-CH2-、-CH2-CH2-CH2-和R1’、R2’各自独立地选自H，C1-6烷基，C1-6烷基-OH。
根据本发明的实施方案，所述式II选自二乙醇铵阳离子、三乙醇铵阳离子，单乙醇铵阳离子(即2-羟基乙铵阳离子)，N-甲基二乙醇铵阳离子，正丙醇铵阳离子，异丙醇铵阳离子、二异丙醇铵阳离子，三异丙醇铵阳离子、正丁醇铵阳离子、二丁醇铵阳离子、异丁醇铵阳离子。
在一些实施方案中，所述复合物为[A-][B+]x，所述x可以选自1-10，例如为1，1.5，2，2.5，3，3.5，4，4.5，5，5.5，6，6.5，7。
第二方面，本发明提供一种所述复合物的制备方法，包括如下步骤：由维A酸和所述醇胺类化合物反应得到。
根据本发明的实施方案，所述醇胺类化合物和维A酸的摩尔比为(1-100):1，例如为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，更优选为(1-5):1。
根据本发明的实施方案，所述反应的反应试剂可以为水或有机溶剂或有机溶剂和水的混合溶剂中进行，所述有机溶剂选自乙醇、甲醇和丙酮中的一种或两种以上的组合。优选的，所述有机溶剂为乙醇。
根据本发明的实施方案，所述混合溶剂中有机溶剂和水的体积比为5:95～95:5。优选的，所述混合溶剂中，有机溶剂和水的体积比为40:60～95:5。
根据本发明的实施方案，所述反应可以通过干法研磨的方式进行。
根据本发明的实施方案，所述维A酸与所述反应试剂总的用量比例为1g：5-150mL，优选为1g：5-20mL。
根据本发明的实施方案，所述制备方法包括如下步骤：
(1)向所述维A酸中加入反应试剂中搅拌混合；
(2)向醇胺类化合物中加入反应试剂搅拌稀释；
(3)将步骤(2)所得稀释液加入步骤(1)所得混合液。
根据本发明的实施方案，所述步骤(1)中，所述维A酸与反应试剂的用量比例为1g：5-100mL，优选的为1g：5-20mL；所述步骤(2)中，所述醇胺化合物与反应试剂的用量比例为1g：0.5-50mL，优选的为1g：0.5-5mL，更优选的为1g：0.5-1mL。
根据本发明的实施方案，所述制备方法还包括反应完成后，除去所述反应试剂、真空干燥的步骤。
第三方面，本发明还提供一种组合物，所述组合物含有所述维A酸醇胺类复合物。
第四方面，本发明提供所述维A酸醇胺类复合物或所述组合物在制备制剂中的应用，所述制剂包括但不限于药物制剂、化妆品、护理品、美容品。
所述药物制剂应用于皮肤类疾病和非皮肤类肿瘤的治疗。优选的，所述药物制剂应用于治疗皮肤类疾病，例如可用于治疗痤疮、色素过度沉着、皮肤光老化、银屑病、鱼鳞病、扁平苔癣、毛发红糠疹、毛囊角化病、鳞状细胞癌及黑色素瘤等疾病。在一些实施方式中，所述药物制剂应用于非皮肤类肿瘤的治疗，例如用于治疗急性早幼粒细胞白血病，还可以用于治疗胃癌、肺癌、卵巢癌、宫颈癌、成神经细胞癌、胶质瘤等。
根据本发明的实施方案，所述制剂可通过皮肤，局部施用，例如选自霜剂、贴剂、软膏剂、乳膏制剂、凝胶剂和喷雾剂等，也可通过口服方式(即为口服制剂)施用，例如选自片剂、颗粒剂、胶囊、口服液体制剂、丸剂、混悬剂、滴丸等。所述制剂进一步包括生理学上可接受的载体(例如具有生物相容性的材料)，例如任选地包括表面活性剂、赋形剂、保湿剂、乳化促进剂、助悬剂、用于调节渗透压的盐或缓冲剂、着色剂、香精、稳定剂、杀菌剂、防腐剂或其它常规补充剂。
根据本发明的实施方案，所述制剂的给药途径包括但不限于胃肠道给药或非胃肠道给药；其中，所述胃肠道给药可以为口服给药；所述非胃肠道给药可以为透皮给药等。
本发明的有益效果
本发明意外地发现，维A酸与醇胺类化合物可以形成常温下液态形式的复合物，具有良好的水溶性/抗水稀释能力以及皮肤渗透效果，克服了现有技术中维A酸类化合物在制剂应用领域的限制，具有广泛的药用前景。本研究所采用的制备方法简便易行，无苛刻反应条件，易于质量控制以及放大生产；此外，所用溶剂可回收重复利用，符合绿色化学理念。
附图说明
图1为维A酸HNMR图谱。
图2为二乙醇胺HNMR图谱。
图3为复合物2[DEA][RA]HNMR图谱。
图4为维A酸、二乙醇胺、复合物2[DEA][RA]的IR图谱。
图5为不同摩尔比的维A酸二乙醇胺复合物([RA]：[DEA]＝1:2、1:2.5、1:3、1:4)的IR图谱。
图6为维A酸、二乙醇胺、复合物2[DEA][RA]拉曼光谱。
图7为复合物2[DEA][RA]的DVS。
图8为复合物2[DEA][RA]DVS前后PLM照片。
图9为复合物2[DEA][RA]的DSC。
图10为复合物2[DEA][RA]mDSC。
图11为不同含水量复合物2[DEA][RA]性状。
图12为复合物2[DEA][RA]液氮冷冻试验过程。
图13为复合物2.5[DEA][RA]的HNMR图谱。
图14为复合物3[DEA][RA]的HNMR图谱
图15(a)示意7[TEA][RA]无法形成复合物(固体析出，状态浑浊)；(b)示意8[TEA][RA]可以形成复合物(红棕色透明液体)
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
仪器和检测条件：
除非另有说明，下述实施例中的百分含量“％”代表质量百分含量。
实施例1维A酸-二乙醇胺复合物的制备
1.1原料和试剂：维A酸(RA)(AR，上海阿拉丁生化科技股份有限公司)、二乙醇胺(DEA)(AR，国药集团化学试剂有限公司)、乙醇(AR，国药集团化学试剂有限公司)。
1.2维A酸-二乙醇胺复合物制备工艺
1.2.1制备方法一
处方
(1)按处方量称量维A酸置于圆底烧瓶中，加入乙醇搅拌混合；维A酸无法完全溶解，呈悬浊态；将圆底烧瓶包裹铝箔遮光。
(2)按处方量称量二乙醇胺，置于铝箔包裹的容器中，加入乙醇搅拌稀释。
将步骤(2)所得二乙醇胺稀释液滴加至步骤(1)所得混合液中，边加边搅拌；并用约5ml乙醇清洗容器，一并加入烧瓶中搅拌。
全部滴加完毕后，溶液应呈橙红色澄清状态；继续搅拌4h。
使用旋转蒸发仪去除溶剂：真空度(表显)：-0.095Mpa；采用程序升温以防止乙醇暴沸飞溅；45℃旋蒸1h，升至50℃继续旋蒸1h，升至60℃继续旋蒸2h。得到红棕色粘稠液体，趁热吸出后，于真空干燥箱中60℃继续真空干燥48h。所得样品密封遮光保存。
1.2.2制备方法二
处方：
工艺：
按处方量称量维A酸置于圆底烧瓶中，加入乙醇/水搅拌混合；维A酸无法完全溶解，呈悬浊态；将圆底烧瓶包裹铝箔遮光。
按处方量称量二乙醇胺，置于铝箔包裹的容器中，加入乙醇/水搅拌稀释。
将二乙醇胺稀释溶液滴加至上述装有维A酸混合液的圆底烧瓶中，边加边搅拌；并用约5ml乙醇/水清洗容器，一并加入烧瓶中搅拌。全部滴加完毕后，溶液应呈橙红色澄清状态；继续搅拌4h。使用旋转蒸发仪去除溶剂。得到红棕色粘稠液体，趁热吸出后，于真空干燥箱中60℃继续真空干燥48h。所得样品密封遮光保存。
1.2.3制备方法三
处方：
工艺：
按处方量称量二乙醇胺置于圆底烧瓶中，将圆底烧瓶包裹铝箔遮光。
向圆底烧瓶中，加入处方量水，搅拌至均匀。称量处方量维A酸，将粉末小心地分次加入至烧瓶中，边加边搅拌。搅拌至溶液澄清后，继续搅拌4h。使用旋转蒸发仪去除溶剂。得到红棕色粘稠液体，趁热吸出后，于真空干燥箱中60℃继续真空干燥48h。所得样品密封遮光保存。
1.2.4制备方法四
处方：
工艺：
试验过程应注意避光。按处方量称量维A酸置于坩埚中；然后加入处方量的二乙醇胺。用一个较细的研磨杵小心的将两种物质混合均匀。将坩埚置于电热套中加热，维持温度在60～80℃。继续搅拌研磨，至呈红棕色粘稠液体。趁热转移至避光容器中，冷却后密封保存。
1.3不同比例的维A酸二乙醇胺复合物的制备
参照1.2.1的制备工艺，采用不同比例的维A酸和二乙醇胺(如下表所示)制备复合物，结果表明，维A酸与二乙醇胺按照摩尔比例2:1～10:1均可形成复合物(室温下均为红棕色澄明液体)。
表A-1不同比例的维A酸和二乙醇胺形成的复合物
1.4维A酸二乙醇胺复合物的表征
实验目的：通过对原始物料以及维A酸二乙醇胺复合物核磁共振氢谱、红外光谱以及拉曼光谱的检测分析，可以判断维A酸与二乙醇胺之间所形成的物质并非简单的物理混合物，而是于分子间发生相互作用，存在离子键与氢键，这构成了维A酸复合物特殊理化性质的化学基础。
1.4.1核磁共振氢谱(HNMR)
对维A酸、二乙醇胺以及制备得到的维A酸二乙醇胺复合物(2[DEA][RA])进行核磁共振氢谱鉴定，如图1至图3以及下表所示：
表A-2特征氢原子化学位移情况
结果显示，2[DEA][RA]的HNMR中，维A酸的活泼氢消失，说明维A酸与二乙醇胺发生了相互作用。维A酸羧基邻位氢原子化学位移向高场移动，由7.02→6.78，表明维A酸在复合物体系中作为质子供体，发生阴离子化，电荷中心为羧基氧原子。二乙醇胺的两对亚甲基氢均出现化学位移向低场移动，分别为2.58→2.76、3.46→3.56；表明二乙醇胺在复合物体系中作为质子受体，即N原子上孤对电子结合了游离的质子，发生阳离子化，电荷中心为N原子。
图13-图14分别为复合物2.5[DEA][RA]和3[DEA][RA]的HNMR图谱，也出现与2[DEA][RA]同样的特征化学位移改变。由此可知，维A酸与更高比例的二乙醇胺之间也发生了相同的分子间相互作用，亦可形成室温下稳定的液态复合物。
1.4.2红外光谱(IR)
对维A酸、二乙醇胺以及制备得到的2[DEA][RA]进行IR鉴定(如图4所示)，结果显示：与二乙醇胺相比，2[DEA][RA]中二乙醇胺的峰偏移不明显；与维A酸相比，2[DEA][RA]中维A酸的C＝O双键特征频率(1681.57cm-1)向低波数处移动；说明维A酸与二乙醇胺分子间存在相互作用。
按摩尔比RA：DEA＝1:2、1:2.5、1:3、1:4，制备不同比例的复合物；不同比例复合物红外图谱一致(如图5所示)，均显示C＝O双键特征频率(1682cm-1)向低波数移动，说明维A酸与二乙醇胺分子间发生相互作用。
1.4.3拉曼光谱
对维A酸、二乙醇胺以及制备得到的2[DEA][RA]进行拉曼光谱鉴定(如图6所示)，结果显示：2[DEA][RA]的拉曼谱图与二乙醇胺的拉曼谱图明显不同，与维A酸相比可看出区别，C＝C双键特征频率(1574.72cm-1)向高波数处移动至1589.19cm-1，说明维A酸与二乙醇胺发生相互作用。
实施例2维A酸三乙醇胺复合物的制备
参照实施例1中1.2的制备工艺，替换二乙醇胺为三乙醇胺，并采用不同比例的维A酸和三乙醇胺(如下表所示)制备复合物，结果表明，维A酸与三乙醇胺在摩尔比例为1:8、1:9、1:10时形成复合物，而在摩尔比例为1:(1～7)时，难以形成室温下液体形式的复合物(参见图15)。
表B-1不同配体比例的维A酸三乙醇胺复合物
实施例3维A酸醇胺类复合物一般理化性质研究
针对根据1.2.1制备得到的2[DEA][RA]进行如下理化性质研究：
3.1水分与残留溶剂
使用卡尔费休水分测试仪对三个批次的2[DEA][RA]进行检测，由结果可知，所制备的复合物中水分与残留溶剂易于去除。
表C-1维A酸复合物含水量
3.2动态吸湿(DVS)
DVS结果显示(参见图7)2[DEA][RA]具有一定的引湿性。而PLM结果(参见图8)显示DVS前后的2[DEA][RA]中均不含晶体颗粒，说明复合物在环境湿度中析出维A酸的风险较低，可以稳定地保持其液态形式。
3.3差示扫描量热(DSC)
DSC结果(参见图9)显示2[DEA][RA]在-25℃～40℃范围内无放热或吸热信号，说明复合物在该温度范围内无凝固点。mDSC结果(参见图10)显示，在-25℃～25℃范围内未观察到复合物的玻璃化转变温度。说明复合物在该温度范围内，无固化析出的风险，可以保持稳定的液态形式。
实施例4维A酸复合物水溶性/抗水稀释能力
4.1实验目的
《中国药典》2020版二部，维A酸项下显示，维A酸在水中极难溶解。查阅文献可知，维A酸水中 溶解度仅1.06*10-6mol/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)。维A酸的难溶特性，给制剂工艺带来极大挑战。而维A酸复合物具有一定的水溶性，从而有利于制剂的制备。
4.2试验过程
精确称量2[DEA][RA]与不同比例水，涡旋混合，观察不同含水量复合物的性状；在超过90％含水量后，使用微量注射器，少量多次继续加入水进行涡旋混合，直至溶液出现浑浊，称量计算得到复合物的极限含水量。
4.3结果与讨论
如图11所示，2[DEA][RA]，在含水量0～91.4％(w/w)的比例范围内，2[DEA][RA]与水互溶(含水量≤90％的瓶中液体澄清透明)。当水分比例过高(>91.4％)时，水中氢键占将复合物体系破坏，析出维A酸固体(含水量91.4％的瓶子呈浑浊态)。测试其他摩尔比例的复合物的抗水稀释能力，试验结果如下表所示，随DEA比例提高，维A酸二乙醇胺复合物抗水稀释能力增加。
表D-1不同比例维A酸二乙醇胺复合物抗水稀释能力
实施例5维A酸复合物的诱导结晶试验
5.1试验目的
化学合成工艺的实践中，常常遇到化合物在重结晶过程，形成无定形晶态或者过冷液体，其外观形态亦表现为玻璃态或者澄明油状。这与本发明所述复合物的性状相似。但这种状态并不稳定，在外部条件改变或在晶种引导下，即向其稳定结晶态转变。因此，为了排除这种可能，进一步表明本发明所制备的复合物具有稳定的液体形态，拟进行一系列诱导挑战试验，通过诸如挥发试验、搅拌试验、降温试验等多种促进结晶的手段，以期得到复合物的固体形态；若无法得到固体形态，则可以认为所得到的复合物的液体形式为其稳定形态。
5.2挥发试验
考察不同溶剂体系下，复合物在有无聚合物以及不同温度下，溶剂挥发完全后有无固态物质产生。其中，添加聚合物是为了向体系中加入“晶核”，以比较有无晶核的影响；而不同温度则会影响溶剂的挥发速度以及物质的结晶行为。
将约80mg 2[DEA][RA]溶于相应溶剂中得到澄清溶液，将澄清溶液均分为4份；其中，利用聚合物作为“晶核”，不加聚合物或加入聚合物B或加入聚合物C后置于5℃与50℃挥发约4天，观察样品状态，除外加的聚合物外，未观察到固体形态物质，结果如下表所示。
表E-1挥发试验结果

聚合物B：由PCL聚己内酯、PEG聚乙二醇、PMMA聚甲基丙烯酸甲酯、SA丙烯酸十八酯、HEC羟乙
基纤维素五种聚合物等质量比组成的混合物。
聚合物C：由聚苯乙烯、聚四氟乙烯、聚三溴苯乙烯、聚硬脂酸乙烯酯四种聚合物等质量比组成的混合物。
5.3搅拌试验
在室温(～22℃)下将0.3mL相应溶剂加入约20mg的2[DEA][RA]中，于相应温度下搅拌3天后，得到澄清溶液或观察到成油现象，未得到固体形态物质，结果如下表所示：
表E-2搅拌试验结果

5.4降温试验
将约40mg的2[DEA][RA]于50℃溶于相应溶剂中，得到澄清溶液后均分为2份，按相应程序降温，并在低温平衡3天，均未得到固体形态物质，结果如下表所示：
表E-3降温试验结果

50℃→5℃：将得到的澄清溶液在50℃平衡30min，再经过450min降温至5℃，在5℃平衡3天。
50℃→-20℃：将在50℃得到的澄清溶液迅速移至-20℃，在-20℃平衡3天。
*：取出后立刻融化。
5.5液氮冷冻试验
用称量勺挖取约50mg的2[DEA][RA]，勺子连同样品放入液氮中(冷冻前为红棕色透明液体)，冷冻约1min后取出，得到红棕色透明固体(硬且脆)，但复温(室温：～22℃)后样品立刻融化(恢复为红棕色透明液体)，未见有固体形态物质，试验过程如图12所示。
5.6反溶剂添加试验
将相应体积的正溶剂加入适量2[DEA][RA]中，得到澄清溶液。若对应的反溶剂有2种，则将澄清溶 液分为2份。在室温(～22℃)下，向澄清溶液中边搅拌边缓慢加入反溶剂，直至析出固体(最大反溶剂添加体积为1.5mL)，若析出固体则停止添加反溶剂，在室温搅拌约4天，得到澄清溶液或观察到成油现象，均未得到固体形态物质，结果如下表所示。
表E-4反溶剂添加试验
5.7诱导结晶试验总结
以维A酸二乙醇胺复合物为起始，共进行49个诱导结晶实验(包含挥发、搅拌、降温与反溶剂添加、液氮冷冻)，反应溶剂涵盖不同类别的单一溶剂或二元溶剂组合，反应温度涵盖-20℃到50℃(液氮冷冻实验温度为-196℃)。所有实验均未得到固体形态物质。结果表明，维A酸二乙醇胺复合物很难以固体形式存在，即常温下液体形式是其稳定的形态。
实施例6维A酸复合物促渗效果的考察
6.1不同浓度维A酸二乙醇胺复合物促渗效果比较
将2[DEA][RA]与不同量的水混合后分别配成含10％、20％以及40％(w/w)的复合物溶液，通过体外透皮实验研究维A酸的皮肤渗透效果，结果表明随着含水量的增加，其皮肤渗透效果增加。
表F-1不同浓度2[DEA][RA]透皮比较
6.2复合物透皮试验
6.2.1复合物溶液的制备
称取一定量复合物2[DEA][RA]在纯化水中溶解(使得复合物在水溶液中的浓度为10％(w/w))，搅 拌至呈均一状态，涡旋3min使样品混合均匀即得。以维A酸计，所制备复合物水溶液浓度为5.88％(w/w)。
6.2.2维A酸乳膏的制备
按照如下处方工艺制备o/w基质20g备用。
工艺：
按照处方称量水相物料，混合均匀备用；按照处方称量油相物料，加热至80℃使成为熔融状态并混合均匀；趁热加入水相，使用高速剪切分散乳化机20000rpm均质2min，使形成淡黄色乳状液；放冷至室温即得。
6.2.3透皮试验基本信息

*：给药前皮肤需要置于扩散池上平衡1h，并测定TEWL值；
**：给药时，应保证乳膏涂抹均匀，与皮肤充分接触，避免气泡；
***：实际给药量由天平称量得到。
6.2.4试验过程：
(1)试验准备：提前配制好样品、接收液备用；备好合适尺寸的猪皮，优选毛孔较少的皮肤，并对皮肤称重，重量差异小于0.05g；
(2)皮肤平衡：组装Franz扩散池，小心地将皮肤固定好；加入接收液，排空气泡，确保接收液与皮肤下 表面充分接触；待扩散仪温度达到预设温度后，皮肤平衡1h；测定TEWL值，应小于20g/m2h；
(3)试验：给药约0.5ml，乳膏应涂抹均匀，与皮肤充分接触；实际给药量由天平称量得到；
(4)取样：6h后试验结束，收集接收液与皮肤，并进行处理。
6.2.5样品处理
(1)接收液：
透皮试验结束后，吸取接收液1.5ml；12000rpm离心15min，上清液进HPLC检测。
(2)皮肤提取液：
透皮试验结束后，无尘纸擦拭去除皮肤表面样品，并用不少于5ml的PBS冲洗表面；小心取下皮肤，置于滤纸上吸干两面水分；使用胶带沾皮肤上表面6次，以沾除角质层；然后用棉球蘸取乙醇仔细擦拭皮肤上表面。
剪除皮肤四周压边后，将皮肤剪碎，置于5ml离心管中；加入甲醇1ml，使皮肤碎片充分浸没；超声提取60min；超声结束后，吸取提取液0.8ml，12000rpm离心15min，上清液进HPLC检测。
6.2.6试验结果
(1)透皮试验HPLC检测结果
接收液中未检出维A酸。测定皮肤中滞留的维A酸量，结果如下：
维A酸皮肤滞留量(单位面积透过量μg/cm2)
如上表所示，2[DEA][RA]水溶液组的皮肤滞留量显著高于RA乳膏组，说明2[DEA][RA]具有明显的促渗作用。
(2)透皮试验后皮肤染色情况(沾除角质层并乙醇擦拭)
在透皮试验结束后，清洗皮肤表面，使用胶带沾除角质层，并使用乙醇进行擦拭，以尽可能地去除残留在皮肤表面的样品。试验结果显示，相比于RA乳膏组，2[DEA][RA]水溶液组的皮肤被明显染色，出现维A酸的特征黄色。说明2[DEA][RA]显著的提高了维A酸的透皮效果。需要说明的是，维A酸制剂实际使用的浓度(0.025％、0.05％、0.1％)远低于该实验样品的浓度(5.88％)，因此不必担心实际使用时会出现皮肤染色的副作用。该实验选取较高浓度样品进行的目的是为了满足HPLC定量限要求，以及更容易地验证2[DEA][RA]的促渗作用。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种维A酸醇胺类复合物，其特征在于，所述复合物由维A酸与醇胺类化合物组成。
  2. 根据权利要求1所述的复合物，其特征在于，所述醇胺类化合物选自如下式I：
    其中，X选自C1-6的烷基，优选的，选自-CH2-CH2-、-CH2-CH2-CH2-和R1、R2各自独立地选自H，C1-6烷基，C1-6烷基-OH；优选的，所述式I选自二乙醇胺、三乙醇胺，单乙醇胺(2-羟基乙胺)，N-甲基二乙醇胺，正丙醇胺，异丙醇胺、二异丙醇胺，三异丙醇胺、正丁醇胺、二丁醇胺、异丁醇胺。
  3. 根据权利要求1所述的复合物，其特征在于，所述醇胺类化合物与维A酸的摩尔比为(1-100):1，例如为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，更优选为(1-5):1。
  4. 根据权利要求1所述的复合物，其特征在于，所述复合物在室温下为液体形式。
  5. 根据权利要求1所述的复合物，其特征在于，所述复合物中，所述维A酸可以部分或全部以阴离子形式存在，所述醇胺类化合物可以部分或全部以阳离子形式存在。
  6. 根据权利要求5所述的复合物，其特征在于，所述维A酸以如以下[A-]形式存在：
  7. 根据权利要求5所述的复合物，其特征在于，所述醇胺类化合物如以下式II所示[B+]形式存在：
    所述式II中，X’选自C1-6的烷基，优选的，选自-CH2-CH2-、-CH2-CH2-CH2-和R1’、R2’各自独立地选自H，C1-6烷基，C1-6烷基-OH；
    优选的，所述式II选自二乙醇铵阳离子、三乙醇铵阳离子，单乙醇铵阳离子，N-甲基二乙醇铵阳离子， 正丙醇铵阳离子，异丙醇铵阳离子、二异丙醇铵阳离子，三异丙醇铵阳离子、正丁醇铵阳离子、二丁醇铵阳离子、异丁醇铵阳离子。
  8. 根据权利要求1-7任一项所述复合物的制备方法，包括如下步骤：
    由维A酸和所述醇胺类化合物反应得到；优选的，所述醇胺类化合物和维A酸的摩尔比为(1-100):1。
  9. 一种组合物，其特征在于，所述组合物含有权利要求1-7任一项所述维A酸醇胺类复合物。
  10. 根据权利要求1-7任一项所述维A酸醇胺类复合物或权利要求9所述组合物在制备治疗皮肤类疾病和非皮肤类肿瘤的药物制剂中的应用，优选的，所述药物制剂用于皮肤类疾病的治疗。
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