WO2022222844A1 - 一种离子液体及其制备方法和应用 - Google Patents

一种离子液体及其制备方法和应用 Download PDF

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WO2022222844A1
WO2022222844A1 PCT/CN2022/086902 CN2022086902W WO2022222844A1 WO 2022222844 A1 WO2022222844 A1 WO 2022222844A1 CN 2022086902 W CN2022086902 W CN 2022086902W WO 2022222844 A1 WO2022222844 A1 WO 2022222844A1
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ionic liquid
choline
compound
preparation
retinoic acid
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French (fr)
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戚建平
武喜营
吴伟
胡弢
卢懿
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Nanjing Indetek Laboratory Co Ltd
Fudan University
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Nanjing Indetek Laboratory Co Ltd
Fudan University
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    • 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
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41—Amines
    • A61K8/416—Quaternary ammonium compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • 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
    • C07C215/40—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 with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use
    • 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 ionic liquids, and in particular relates to an ionic liquid and a preparation method and application thereof.
  • Vitamin A and its metabolites have important roles in the human body and are currently widely used in the treatment of various diseases.
  • retinoic acid molecular formula: C 20 H 28 O 2
  • Retinoic acid is mainly used for the treatment of acne vulgaris, 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.
  • Isotretinoin an isomer of tretinoin, can be taken orally to treat severe acne, especially for nodular cystic acne, and also for pityriasis rubra pilaris and other diseases.
  • Vitamin A and its similar derivatives are fat-soluble and insoluble in water, so their dissolution in formulations and in vivo dissolution are poor.
  • the commonly used clinical preparations are creams. Because the solubility of tretinoin is extremely poor, it is made by suspending tretinoin in a cream base. Due to the extremely poor solubility of retinoic acid, its release from the matrix is limited, and its pharmacological effects are also hindered. However, in oral administration, retinoic acid or isotretinoin is directly made into ordinary tablets. Due to poor dissolution in the body, its bioavailability is extremely low, and it cannot exert a good therapeutic effect.
  • the present invention provides an ionic liquid, the ionic liquid is composed of anion A - and cation B + ;
  • the anion is selected from the following structures:
  • the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 6 ', R 7 ', R 8 ', R 9 ', R 10 ', R 11 ', R 12 ' are the same or different from each other independently selected from H, OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; preferably independently of each other from H, methyl, methoxy.
  • the anion is selected from the following structures:
  • the anion may be provided by a vitamin A compound; preferably, the vitamin A compound may be selected from retinoic acid, isotretinoin, retinol and/or retinal.
  • the cation is selected from quaternary ammonium ions; the cation is further preferably a choline cation (choline compound acts as a cation donor).
  • the cation is provided by a choline compound; preferably, the choline compound is selected from choline, glycerophosphorylcholine, betaine, choline chloride, choline hydroxide or Other physiologically acceptable salts of choline.
  • the cation is selected from the following structures:
  • the other physiologically acceptable salts may be selected from inorganic acid salts such as carbonates, bicarbonates, hydrobromides, phosphates, sulfates, nitrates, perchlorates ; and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, adipate, alginate, ascorbate, aspartate Carboxylate, Benzenesulfonate, Benzoate, Bisulfate, Borate, Butyrate, Camphorate, Camphorsulfonate, Cyclopentane Propionate, Digluconate, Dodecane Alkyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydriodate , 2-hydroxy-ethanesul
  • organic acid salts such as
  • the choline compound is preferably choline bicarbonate.
  • the molar ratio of cations to anions is (1.1-10):1, preferably (1.5-5):1, for example 2:1, 3:1, 4:1, 5:1 , 6:1, 7:1.
  • the ionic liquid is [A ⁇ ][B + ] x , which may be selected from 1-10, eg, 1, 2, 3, 4, 5, 6, 7.
  • the ionic liquid is obtained by reacting the vitamin A compound and the choline compound.
  • the molar ratio of the choline compound and the vitamin A compound is (1.1-10):1, preferably (1.5-5):1, such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1.
  • the [A - ][B + ] x has the following structure:
  • the ionic liquid is a viscous liquid.
  • the present invention also provides the preparation method of the ionic liquid, which comprises the following steps: obtaining by reacting a retinoic acid compound and a choline compound.
  • the preparation method of the ionic liquid includes the following steps: obtained by reacting the retinoic acid compound and the choline compound; preferably, the reaction may be a metathesis reaction or a melting reaction.
  • the molar ratio of the choline compound and the retinoic acid compound is (1.1-10):1, preferably (1.5-5):1, such as 2:1, 3:1, 4:1 , 5:1, 6:1, 7:1.
  • the reaction may be carried out in a solvent.
  • the solvent is a solvent capable of dissolving vitamin A substances and having volatility, for example, the solvent is selected from a volatile organic solvent or a mixed solvent of the volatile organic solvent and water.
  • the volatile organic solvent may be selected from one, two or three of ethanol, methanol and acetone.
  • the volume percentage of water does not exceed 50%.
  • the reaction is carried out at 10-60°C, for example at 20-40°C, preferably at room temperature (25°C).
  • the reaction time is 15-40 h, such as 20-30 h, exemplarily 24 h, 25 h, 35 h.
  • the preparation method further includes removing the solvent, eg, removing the volatile organic solvent, after the reaction is completed.
  • the solvent can be removed, for example, by means known in the art, such as by rotary evaporation.
  • the preparation method further comprises freeze-drying the reactant after removing the solvent.
  • the present invention also provides a composition comprising the ionic liquid.
  • the present invention further provides the application of the ionic liquid or the composition in preparations, including but not limited to pharmaceutical preparations, cosmetics, care products, and cosmetic products.
  • the formulation can be applied topically through the skin, for example, selected from creams, patches, ointments, cream formulations, gels and sprays, etc., or can be administered orally (ie oral formulation) administration, for example, selected from tablets, granules, capsules, oral liquids, pills, suspensions, dropping pills and the like.
  • the formulation further includes a physiologically acceptable carrier (eg, a material having biocompatibility), such as optionally including surfactants, excipients, humectants, emulsification enhancers, suspending agents, for regulating penetration Pressed salts or buffers, colorants, flavors, stabilizers, bactericides, preservatives or other conventional supplements.
  • the administration route of the formulation includes but is not limited to gastrointestinal administration or parenteral administration; wherein, the gastrointestinal administration may be oral administration; the parenteral administration Enteral administration may be transdermal administration or the like.
  • the invention combines retinoic acid compounds and choline substances to form an ionic liquid with good safety, and can have the characteristics of good solubility and high permeability without adding additional transdermal adjuvants, etc., and can also significantly improve oral administration. Utilization. Therefore, the ionic liquid of the present invention has significant advantages in formulation application, overcomes the limitation in the field of formulation application of retinoic acid compounds in the prior art, and can be widely and effectively used in various formulations.
  • Figure 1 shows the H NMR spectra of tretinoin ionic liquids with different molar ratios of raw materials: A represents 4:1[Ch][Tre], B represents 3:1[Ch][Tre], and C represents 2:1[Ch] ][Tre].
  • Figure 2 shows the peak assignment of the 1H NMR spectrum of the retinoic acid ionic liquid [Ch][Tre] with a molar ratio of 2:1.
  • Figure 3 shows the FT-IR spectra of tretinoin ionic liquid [Ch][Tre] (molar ratio of 2:1), tretinoin and choline bicarbonate.
  • Figure 4 shows the NOSEY spectrum of the retinoic acid ionic liquid and the related force analysis.
  • Figure 5 shows the penetration amount of different transdermal agents in each layer of skin.
  • Figure 6 is the plasma concentration-time curve after oral administration of retinoic acid ionic liquid and retinoic acid suspension.
  • [Tre][Ch] or [Ch][Tre] indicates a structure formed by anions derived from retinoic acid and choline cations, in which the anion and cation moieties can be in different ratios ([Tre] indicates an anion moiety, [ Ch] indicates a cationic moiety).
  • Retinoic acid and choline bicarbonate were dissolved in ethanol solvent according to the molar ratio of 1:1, 1:2, 1:3 and 1:4 respectively, reacted at room temperature for 24h, the ethanol was removed by rotary evaporation, and freeze-dried to obtain the product .
  • the results showed that the products prepared from tretinoin and choline bicarbonate in a molar ratio of 1:1 were solid, and the other molar ratios were viscous liquids.
  • the introduction of the conjugated system delocalizes the electrons of the acid fragments, which leads to the increase of the electron cloud density of the choline fragment -OH, and the blue-shift of the infrared absorption, that is, the wave number of the absorption becomes larger.
  • the 1 H- 1 H NOESY spectrum (Fig. 4) reveals the spatial proximity relationship between all protons and protons in the molecule.
  • the relevant horizontal and vertical coordinates are the hydrogen spectrum, and the diagonal is itself.
  • [Tre][Ch] (molar ratio 1:2) was assigned 19 correlation peaks.
  • blue is the intra-ion
  • red is the interaction between the ions in the system
  • the NOESY signal of the ionic liquid is distributed asymmetrically, possibly due to the measurement evaluating the average interaction within the solvent rather than a specific ion, which may imply that the relaxation is not symmetric.
  • the molar ratio of tretinoin and tretinoin ionic liquid ([Tre][Ch](respectively according to the structure of 1:2, 1:3, 1:4 can be recorded as 2:1[Ch][Tre], 3 :1[Ch][Tre], 4:1[Ch][Tre], or 2[Ch][Tre], 3[Ch][Tre], 4[Ch][Tre])) respectively placed in the bright light (4500 ⁇ 500LX) for 15 days, and the stability of each sample was tested at 5, 10, and 15 days respectively.
  • 20%-2[Ch][Tre], 40%-2[Ch][Tre], 60%-2[Ch][Tre], 80%-2[Ch][Tre], 100%-2[ Ch][Tre] retinoic acid ionic liquid is used as a transdermal agent, of which 20%-2[Ch][Tre], 40%-2[Ch][Tre], 60%-2[Ch][Tre], The 80%-2[Ch][Tre] retinoic acid ionic liquid is obtained by diluting with water.
  • the abdominal skin of 2-week-old domestic pigs was fixed in a standard Franz diffusion cell (FDC, effective diffusion area: 1.77 cm 2 , Shanghai Kaikai Technology Trading Co., Ltd., China), with the stratum corneum facing the supply cell.
  • the receiver solution was sonicated phosphate buffered saline (PBS, pH 7.4) with 1% BSA, stirred (300 rpm) at 37°C. After equilibration, 200 mg of each formulation was placed in a supply cell in contact with the skin. Throughout the experiment, the equipment was covered with aluminum foil to protect from light.
  • the skin was removed from the FDC, washed with ethanol and distilled water in turn, to remove the residual formula, and wiped with a tampon.
  • the skin was transected into the stratum corneum (SC), epidermis (Epidermis) and dermis (Dermis) using a cryostat (Leica, Mainz, Germany) with 650 ⁇ L MeOH/H 2 O (1:1) and 100 ⁇ L snake, respectively
  • the skin was soaked overnight in a solvent consisting of Osthole, Ost solution (226 ⁇ L g/mL in MeOH) for quantitative analysis. Centrifuge at 10,000 g for 5 min, and measure the supernatant by HPLC.
  • HPLC test conditions are as follows:
  • Analytical HPLC was Agilent Technologies 1100HPLC system (Agilent, Santa Clara, USA); chromatographic column: Agilent Eclipse XDB-C18 (5 ⁇ m, 4.6 mm ⁇ 150 mm); mobile phase: methanol-water-glacial acetic acid (361:39:1.3, v/v/v); elution flow rate: 1.0 mL/min; detection wavelength: 350 nm; injection volume: 20 ⁇ L. Internal standard: osthole.
  • the transdermal transport of retinoic acid was calculated according to the following formula:
  • Q is the percentage of transdermal absorption
  • P a is the amount of drug in the receiving pool
  • P d is the amount of drug in the supply pool.
  • the 2[Ch][Tre] retinoic acid ionic liquid was orally administered to the rats, once orally, and the single oral dose was 2 mg/kg.
  • the SD male rats were randomly divided into two groups with the same number, the rats were fasted overnight before the experiment, and they drank water freely. At 100, 130, 190, 250, 370, and 490 min, 0.5 mL of blood was collected from the orbit, placed in a centrifuge tube treated with heparin sodium, and centrifuged at 4000 r/min for 15 min to separate plasma.
  • HPLC test conditions are as follows:
  • Analytical HPLC was Agilent Technologies 1260 HPLC system (Agilent, Santa Clara, USA); chromatographic column: InertSustain C18 (5 ⁇ m, 4.6mm ⁇ 150mm); mobile phase: methanol-2% glacial acetic acid (88/10, v/v) ; Elution flow rate: 1.0 mL/min; Detection wavelength: 350 nm; Column temperature: 25°C; Injection volume: 30 ⁇ L. Internal standard: Acitretin.

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Abstract

本发明公开一种离子液体及其制备方法和应用。所述离子液体由维生素A类化合物和胆碱类化合物制备得到，具有溶解度好和渗透性高的特点，同时还能显著改善口服利用度，具有显著的制剂应用优势，可广泛有效地应用于各类制剂中。

Description

一种离子液体及其制备方法和应用
本申请要求享有2021年4月22日向中国国家知识产权局提交的申请号为2021104385889，名称为“一种离子液体及其制备方法和应用”的发明专利申请的优先权。该申请的全文以引用的方式并入本文。
技术领域
本发明属于离子液体领域，具体涉及一种离子液体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C 20H 28O 2)，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、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酸的异构体异维A酸口服可治疗重度痤疮，尤其适用于结节囊肿型痤疮，亦可用于毛发红糠疹等疾病。
维生素A及其类似衍生物具有脂溶性，不溶于水，因此在制剂中的溶解以及体内的溶出均较差。以维A酸和异维A酸为例，临床常用的制剂为乳膏剂。由于维A酸的溶解度极差，因此采取将维A酸混悬于乳膏基质中制成。由于维A酸的溶解度极差，限制了其从基质中的释放，也阻碍了其药理作用的发挥。而在口服给药中，将维A酸或异维A酸直接制成普通片剂，由于体内溶出较差，其生物利用度极低，无法发挥较好的治疗作用。目前有报道采用固体分散体、包合技术、以及纳米乳技术等提高维A酸的口服生物利用度，但是这些技术本身的缺陷限制 了维A酸制剂的发展。如固体分散体的老化性能、包合技术的结构限制以及纳米乳中表面活性剂的安全性问题等。
发明内容
为了改善上述技术问题，本发明提供一种离子液体，所述离子液体由阴离子A -和阳离子B +组成；
根据本发明的实施方案，所述阴离子选自如下结构：
Figure PCTCN2022086902-appb-000001
根据本发明的实施方案，所述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 1’、R 2’、R 3’、R 4’、R 5’、R 6’、R 7’、R 8’、R 9’、R 10’、R 11’、R 12’相同或不同，彼此独立地选自H，OH，卤素，C 1-C 6烷基、C 1-C 6烷氧基；优选地，彼此独立地选自H，甲基，甲氧基。
优选地，所述阴离子选自如下结构：
Figure PCTCN2022086902-appb-000002
根据本发明的实施方案，所述阴离子可以由维生素A类化合物提供；优选地，所述维生素A类化合物可以选自维A酸、异维A酸、视黄醇和/或视黄醛。
根据本发明的实施方案，所述阳离子选自季铵类离子；所述阳离子进一步优 选为胆碱类阳离子(胆碱类化合物作为阳离子供体)。
根据本发明的实施方案，所述阳离子由胆碱类化合物提供；优选地，所述胆碱类化合物选自胆碱、甘油磷酰胆碱、甜菜碱、氯化胆碱、氢氧化胆碱或胆碱的其它生理学上可接受的盐。
优选地，所述阳离子选自如下结构：
Figure PCTCN2022086902-appb-000003
根据本发明的实施方案，所述其它生理学上可接受的盐可以选自无机酸盐，例如碳酸盐、碳酸氢盐、氢溴酸盐、磷酸盐、硫酸盐、硝酸盐、高氯酸盐；以及有机酸盐，例如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂烷硫酸盐、苹果酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、油酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。
根据本发明的实施方案，所述胆碱类化合物优选为胆碱碳酸氢盐。
在一些实施方案中，所述阳离子与阴离子的摩尔比为(1.1-10):1，优选为(1.5-5):1，例如为2:1、3:1、4:1、5:1、6:1、7:1。
在一些实施方案中，所述离子液体为[A -][B +] x，所述x可以选自1-10，例如为1，2，3，4，5，6，7。
根据本发明的实施方案，所述离子液体由所述维生素A类化合物和胆碱类化合物反应得到。
优选地，所述胆碱类化合物和维生素A类化合物的摩尔比为(1.1-10):1，优选为(1.5-5):1，例如为2:1、3:1、4:1、5:1、6:1、7:1。
根据本发明示例性的实施方案，所述[A -][B +] x为如下结构：
Figure PCTCN2022086902-appb-000004
根据本发明的实施方案，所述离子液体为粘稠液体。
本发明还提供所述离子液体的制备方法，包括如下步骤：由维A酸类化合物和胆碱类化合物反应得到。
根据本发明的实施方案，所述离子液体的制备方法包括如下步骤：由所述维A酸类化合物和胆碱类化合物反应得到；优选地，所述反应可以为复分解反应或熔融反应。
优选地，所述胆碱类化合物和维A酸类化合物的摩尔比为(1.1-10):1，优选为(1.5-5):1，例如为2:1、3:1、4:1、5:1、6:1、7:1。
根据本发明的实施方案，所述反应可以在溶剂中进行。例如，所述溶剂为能够溶解维生素A类物质、并具有挥发性的溶剂，例如所述溶剂选自挥发性有机溶剂、或者所述挥发性有机溶剂和水的混合溶剂。
优选地，所述挥发性有机溶剂可以选自乙醇、甲醇和丙酮中的一种、两种或三种。
优选地，所述挥发性有机溶剂和水的混合溶剂中，水的体积百分比不超过50％。
根据本发明的实施方案，所述反应在10-60℃下进行，例如为20-40℃下进行，优选为室温下(25℃)进行。
根据本发明的实施方案，所述反应的时间为15-40h，例如20-30h，示例性为24h、25h、35h。
根据本发明的实施方案，所述制备方法还包括反应完成后，除去所述溶剂，例如除去所述挥发性有机溶剂。例如可以采用本领域已知方式，比如为旋转蒸发除去所述溶剂。
根据本发明的实施方案，所述制备方法还包括将除去所述溶剂后的反应物冷冻干燥。
本发明还提供一种组合物，所述组合物含有所述离子液体。
本发明进一步提供所述离子液体或所述组合物在制剂中的应用，所述制剂包括但不限于药物制剂、化妆品、护理品、美容品。
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
本发明将维A酸类化合物与胆碱类物质结合形成安全性好的离子液体，且无需添加额外的透皮辅助剂等即能具有溶解度好和渗透性高的特点，同时还能显著改善口服利用度。因此，本发明的离子液体具有显著的制剂应用优势，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，可广泛有效地应用于各类制剂中。
附图说明
图1为不同原料摩尔比的维A酸离子液体的核磁共振氢谱：A代表4:1[Ch][Tre]，B代表3:1[Ch][Tre]，C代表2:1[Ch][Tre]。
图2为摩尔比为2:1的维A酸离子液体[Ch][Tre]的核磁共振氢谱峰归属。
图3为维A酸离子液体[Ch][Tre](摩尔比为2:1)、维A酸(Tretinoin)和胆碱碳酸氢盐(Choline bicarbonate)的FT-IR图谱。
图4为维A酸离子液体的NOSEY谱图及相关作用力分析。
图5为不同透皮剂在各层皮肤中的渗透量。
图6为维A酸离子液体和维A酸混悬液口服给药后血药浓度-时间曲线。
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。
下述实施例中的百分含量“％”代表质量百分含量。
[Tre][Ch]或[Ch][Tre]示意源自维A酸的阴离子与胆碱阳离子形成的结构，该结构中，阴离子与阳离子部分可以按不同比例([Tre]示意阴离子部分，[Ch]示意阳离子部分)。
实施例1 维A酸离子液体的合成
将维A酸与胆碱碳酸氢盐分别按照摩尔比1:1、1:2、1:3、1:4溶解于乙醇溶剂中，室温下反应24h，旋转蒸发将乙醇除去，冷冻干燥得产物。结果表明，维A酸与胆碱碳酸氢盐按照摩尔比1:1制备的产物是固体，其余摩尔比得到的产物均为粘稠液体。
通过核磁共振结果(图1和图2)证明按原料摩尔比为1:2、1:3和1:4制备的结构为维A酸离子液体([Tre][Ch])。
1H-NMR(DMSO-d6):δ6.56(dd,1H,H-11,J＝15.2,12.0Hz),6.23(d,1H,H-8,J＝15.2Hz),6.15(d,1H,H-12,J＝12.0Hz),6.11(d,2H,H-7/10,J＝12.0Hz),5.67(s,1H,H-14),3.83(t,J＝4.8Hz,2H,H-3'),3.42(t,J＝4.8Hz,2H,H-2'),3.12(s,3CH 3-N),2.05(s,CH 3-9),1.99(t,J＝5.2Hz,2H,H-4),1.90(s,CH 3-13),1.67(s,CH 3-3),1.57(m,2H,H-5),1.43(m,2H,H-6),1.00(s,2CH 3-1).
1.体外表征
(1)FT-IR
分别研究碳酸氢胆碱、维A酸和维A酸离子液体(摩尔比为1:2)的FT-IR，对比三种物质的红外图谱，说明维A酸离子液体中存在氢键相互作用(图3)。与维A酸相比，2:1[Ch][Tre]离子液体中在1657cm ＝1处出现新的吸收峰，是由羧酸的不对称伸缩振动引起的。O-H峰变宽说明分子间相互作用力发生变化；向低波数的移动(红移)，说明了分子间氢键作用力的形成。与胆碱碳酸氢盐相比共轭体系中的电子离域化，原来的单键也具有部分双键的性质，而原来的双键或三键中的电子密度降低，键长增大，红外吸收发生红移，即吸收的波数变小或者说吸收的波的频率降低，所以C＝O(从1674移动至1657cm -1)。但共轭体系的引入，使得酸的片段电子离域化，导致胆碱片段-OH电子云密度增大，红外吸收发生蓝移，即吸收的波数变大。
(2)NOESY
1H- 1H NOESY谱(图4)揭示了分子内所有质子与质子间在空间的相互接近关系，两个H距离小于5埃时，相关横纵坐标都是氢谱，对角线是自身质子信号相关峰，除自身信号相关峰及杂质信号外，[Tre][Ch](摩尔比1:2)归属了19个相关峰。分子示意图所示，蓝色为离子内的，红色为此体系出现的离子间的相互作用，红色有11个相关峰。离子液体的NOESY信号呈非对称分布，可能是由于测量评估的是溶剂内部的平均相互作用，而不是特定的离子，这可能意味着弛豫不是对称的。
2.维A酸离子液体的溶解性及稳定性
(1)溶解性
利用水稀释，[Tre][Ch](摩尔比1:2)维A酸离子液体，研究其水溶性及可吸湿性。
实验表明离子液体浓度在14％以下时，维A酸离子液体被破坏，有不溶物析出。当维A酸离子液体浓度超过14％后，维A酸离子液体可完全溶解于水中。
(2)稳定性
将维A酸、维A酸离子液体([Tre][Ch](摩尔比分别按1:2，1:3，1:4的结构，可记为2:1[Ch][Tre]、3:1[Ch][Tre]、4:1[Ch][Tre]，或2[Ch][Tre]、3[Ch][Tre]、4[Ch][Tre]))分别放置于强光(4500±500LX)下15天，分别在5、10、15天检测各样品的稳定性。
实验结果证明三种维A酸离子液体在光照下的稳定性与维A酸本身无显著差异，表明维A酸离子液体的形成并不会降低维A酸的稳定性。
实施例2 透皮剂及体外渗透实验
以20％-2[Ch][Tre]、40％-2[Ch][Tre]、60％-2[Ch][Tre]、80％-2[Ch][Tre]、100％-2[Ch][Tre]的维A酸离子液体作为透皮剂，其中20％-2[Ch][Tre]、40％-2[Ch][Tre]、60％-2[Ch][Tre]、80％-2[Ch][Tre]的维A酸离子液体为加水稀释得到。
透皮剂的体外渗透实验：
取2周龄家猪腹部皮肤固定于标准Franz扩散池(FDC，有效扩散面积:1.77cm 2，上海凯凯科技贸易有限公司，中国)，角质层朝向供给池。接收液为1％BSA的超声磷酸盐缓冲盐水(PBS,pH 7.4)，于37℃搅拌(300rpm)。平衡后，将200mg各制剂置于供给池中与皮肤接触。整个实验过程中，设备上覆盖铝箔以避光。给药6h后，将皮肤从FDC中取出，依次用乙醇和蒸馏水清洗，去除残留的配方，并用卫生棉条擦拭。用冷冻切片机(Leica,Mainz,Germany)将皮肤横切为角质层(SC)、表皮层(Epidermis)和真皮层(Dermis)，分别用650μL MeOH/H 2O(1:1)和100μL蛇床子素(Osthole,Ost)溶液(MeOH中226μLg/mL)组成的 溶剂浸泡皮肤过夜，用于定量分析。10000g离心5min，HPLC测定上清。
HPLC测试条件如下：
分析型HPLC为Agilent Technologies 1100HPLC system(Agilent,Santa Clara,USA)；色谱柱：Agilent Eclipse XDB-C18(5μm,4.6mm×150mm)；流动相：甲醇-水-冰醋酸(361:39:1.3,v/v/v)；洗脱流速：1.0mL/min；检测波长：350nm；进样体积：20μL。内标：蛇床子素。
根据下式计算维A酸的经皮转运量：
Q＝P a/P d
式中，Q为透皮吸收百分率，P a为接受池中药物的量，P d为供给池中药物的量。
通过体外皮肤渗透实验研究上述各组透皮剂在皮肤中的穿透能力，其中20％-2[Ch][Tre]可使维A酸渗透穿过皮肤，在接受池中可检测到维A酸；其他组在接受池中均检测不到维A酸，在皮肤各层中维A酸的量如图5所示：透皮剂20％-2[Ch][Tre]组对真皮层的渗透性增强能力最佳，其次为40％-2[Ch][Tre]、60％-2[Ch][Tre]、80％-2[Ch][Tre]和100％-2[Ch][Tre]；值得注意的是，20％-2[Ch][Tre]组与其他组在表皮和真皮中的差异显著(p<0.0001)。
另外以市售乳膏(水包油型基质，迪维)为基质，加入维A酸使其质量含量达20％，混悬于基质中，透皮实验后其在各层皮肤中维A酸的量均处于定量限(37ng/ml)以下。
实施例3 维A酸离子液体口服
将2[Ch][Tre]维A酸离子液体口服给予大鼠，口服次数一次，单次口服剂量为2mg/kg，同时以维A酸混悬液(将40mg维A酸加入100mL 0.5％CMC-Na溶液中，研磨至分散均匀，得到维A酸混悬液)作为对照口服灌胃给予大鼠，给药次数和剂量与维A酸离子液体相同。
取SD雄性大鼠随机分成数量相同的两组，大鼠实验前禁食过夜，自由饮水， 将各制剂分别按照上述用量口服灌胃给药，分别于给药后10，30，50，70，100，130，190，250，370，490min经眼眶取血0.5mL，置于肝素钠处理的离心管中，4000r/min离心15min，分离血浆。精密吸取空白血浆样品100μL于1.5mL的EP管中，准确加入20μL阿维A酸(Acitren,Atr)内标溶液涡旋1min混匀，随后加入200μL乙腈，涡旋5min充分混匀，再以14000rpm离心10min分离上清，最后取30μL上清液，经HPLC进样。
HPLC测试条件如下：
分析型HPLC为Agilent Technologies 1260 HPLC system(Agilent,Santa Clara,USA)；色谱柱：InertSustain C18(5μm,4.6mm×150mm)；流动相：甲醇-2％冰醋酸(88/10，v/v)；洗脱流速：1.0mL/min；检测波长：350nm；柱温：25℃；进样体积：30μL。内标：阿维A酸。
如图6结果表明，维A酸离子液体给药后，维A酸的生物利用度为混悬液的3.61倍，达峰浓度为混悬液的2.87倍。通过离子液体技术大大促进了维A酸的口服生物利用度。
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. 一种离子液体，其特征在于，所述离子液体由阴离子和阳离子组成；
    所述阴离子选自如下结构：
    Figure PCTCN2022086902-appb-100001
    所述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 1’、R 2’、R 3’、R 4’、R 5’、R 6’、R 7’、R 8’、R 9’、R 10’、R 11’、R 12’相同或不同，彼此独立地选自H，OH，卤素，C 1-C 6烷基、C 1-C 6烷氧基；优选地，彼此独立地选自H，甲基，甲氧基。
  2. 根据权利要求1所述的离子液体，其特征在于，所述阳离子选自季铵类离子；所述阳离子进一步优选为胆碱类阳离子；
    优选地，所述阳离子由胆碱类化合物提供，所述胆碱类化合物选自胆碱、甘油磷酸胆碱、甜菜碱、氯化胆碱、氢氧化胆碱或胆碱的其它生理学上可接受的盐。
    优选地，所述胆碱的其它生理学上可接受的盐选自碳酸盐和/或碳酸氢盐。
  3. 根据权利要求1或2所述的离子液体，其特征在于，所述阴离子选自如下结构：
    Figure PCTCN2022086902-appb-100002
    所述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 1’、R 2’、R 3’、R 4’、R 5’、R 6’、R 7’、R 8’、R 9’、R 10’、R 11’、R 12’相同或不同，彼此独立地选自H，卤素，C 1-C 6烷基、C 1-C 6烷氧基；优选地，彼此独立地选自H，甲基，甲氧基。
    优选地，所述阴离子选自如下结构：
    Figure PCTCN2022086902-appb-100003
    优选地，所述阴离子由维生素A类化合物提供；优选地，所述维生素A类化合物可以选自维A酸、异维A酸、视黄醇和/或视黄醛。
  4. 根据权利要求1-3任一项所述的离子液体，其特征在于，所述阳离子与阴离子的摩尔比为(1.1-10):1；
    优选地，所述离子液体由所述维生素A类化合物和胆碱类化合物反应得到。
    优选地，所述胆碱类化合物和维生素A类化合物的摩尔比为(1.1-10):1。
  5. 权利要求1-4任一项所述离子液体的制备方法，其特征在于，所述制备方法包括如下步骤：由维A酸类化合物和胆碱类化合物反应得到。
  6. 根据权利要求5所述的制备方法，其特征在于，所述胆碱类化合物和维A酸类化合物的摩尔比为(1.1-10):1。
  7. 一种组合物，其特征在于，所述组合物含有权利要求1-4任一项所述的离 子液体。
  8. 权利要求1-4任一项所述的离子液体或权利要求7所述组合物在制剂中的应用。
  9. 根据权利要求8所述的应用，其特征在于，所述制剂包括但不限于药物制剂、化妆品、护理品、美容品。
  10. 根据权利要求8或9所述的应用，其特征在于，所述制剂可通过皮肤，局部施用，也可通过口服方式施用；优选地，所述制剂进一步包括生理学上可接受的载体。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4727064A (en) * 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
US4857525A (en) * 1987-05-06 1989-08-15 L'oreal Quaternary ammonium retinoates, their use in cosmetics and in dermopharmacy
CN1854120A (zh) * 2004-12-06 2006-11-01 河北师范大学 无毒离子液体、制备方法及其应用
CN101260051A (zh) * 2008-04-24 2008-09-10 中国科学院过程工程研究所 一种可生物降解的胆碱类离子液体
CN102126968A (zh) * 2011-01-11 2011-07-20 中国科学院过程工程研究所 碱性离子液体及其制备、应用
CN105315164A (zh) * 2014-08-01 2016-02-10 中国科学院大连化学物理研究所 一类环境友好的胆碱离子液体及其制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1202817C (zh) * 2001-04-17 2005-05-25 刘文江 速释维a酸固体分散体
EP3290026A1 (en) * 2016-09-06 2018-03-07 Athenion AG Method for solubilizing poorly water-soluble dietary supplements and pharmaceutically active agents
CN110623859A (zh) * 2019-10-25 2019-12-31 广州市博之越精细化工有限公司 一种羟丙基环糊精包合视黄醇的制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4727064A (en) * 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
US4857525A (en) * 1987-05-06 1989-08-15 L'oreal Quaternary ammonium retinoates, their use in cosmetics and in dermopharmacy
CN1854120A (zh) * 2004-12-06 2006-11-01 河北师范大学 无毒离子液体、制备方法及其应用
CN101260051A (zh) * 2008-04-24 2008-09-10 中国科学院过程工程研究所 一种可生物降解的胆碱类离子液体
CN102126968A (zh) * 2011-01-11 2011-07-20 中国科学院过程工程研究所 碱性离子液体及其制备、应用
CN105315164A (zh) * 2014-08-01 2016-02-10 中国科学院大连化学物理研究所 一类环境友好的胆碱离子液体及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PITHA, J. ET AL.: "Hydroxypropyl-β-Cyclodextrin: Preparation and Characterization Effects on Solubility of Drugs", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 29, no. 1, 31 March 1986 (1986-03-31), XP025502232, ISSN: 0378-5173, DOI: 10.1016/0378-5173(86)90201-2 *

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