WO2025092781A1 - 一种姜黄素左旋肉碱共晶及其制备方法和用途 - Google Patents

一种姜黄素左旋肉碱共晶及其制备方法和用途 Download PDF

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WO2025092781A1
WO2025092781A1 PCT/CN2024/128358 CN2024128358W WO2025092781A1 WO 2025092781 A1 WO2025092781 A1 WO 2025092781A1 CN 2024128358 W CN2024128358 W CN 2024128358W WO 2025092781 A1 WO2025092781 A1 WO 2025092781A1
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curcumin
carnitine
cocrystal
crystal
solvent
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French (fr)
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梅雪锋
王浩
张奇
戴文娟
陆鹂烨
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Cocrystal Health Industry Zhejiang Co Ltd
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Cocrystal Health Industry Zhejiang Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the technical field of pharmaceutical co-crystals, and in particular to a curcumin-L-carnitine co-crystal and a preparation method thereof, as well as products containing the curcumin-L-carnitine co-crystal and uses thereof.
  • Curcumin is a natural polyphenol compound extracted from turmeric, a plant of the ginger family. In recent years, a large number of studies have shown that it has a wide range of pharmacological activities, including anti-inflammatory, antioxidant, lipid-regulating, antiviral, anti-infective, anti-tumor, anti-coagulation, anti-liver fibrosis, and anti-atherosclerosis. Curcumin is a natural pigment with bright color, strong coloring power, good antioxidant properties, safety and non-toxicity, and rich nutritional value. It is widely used in food, health products, cosmetics, medicine, tobacco, and animal feed. Curcumin is a food additive approved by the Food and Agriculture Organization of the United Nations Codex Alimentarius Commission (FAO/WHO-1995). It is the first natural pigment allowed to be used in food in my country's "Hygiene Standards for the Use of Food Additives".
  • curcumin is a fat-soluble pigment.
  • curcumin has certain defects, such as poor solubility, low absorption rate, fast metabolism, short half-life, etc. These problems lead to its low bioavailability, limiting its application in the field of food and medicine.
  • the method for improving the solubility and bioavailability of curcumin is mainly through the preparation of new drug dosage forms, such as microemulsions, microspheres, solid dispersions, liposomes, phospholipid complexes, micellar nanoparticles, cyclodextrin inclusion compounds and dripping pills.
  • curcumin product that is convenient to use, high in content, chemically stable, simple in preparation process, and low in cost is a goal that people are constantly pursuing.
  • the present invention adds edible L-carnitine as a ligand to form a stable co-crystal with curcumin, thereby changing the intermolecular interaction and spatial arrangement of curcumin molecules at the molecular level, increasing the dissolution performance of curcumin, and further improving its bioavailability.
  • one of the objects of the present invention is to provide a curcumin-L-carnitine cocrystal.
  • the second object of the present invention is to provide a method for preparing the curcumin-L-carnitine cocrystal.
  • the third object of the present invention is to provide a product comprising the above-mentioned curcumin-L-carnitine cocrystal, wherein the product is selected from health products, foods, cosmetics, medicines, pharmaceutical excipients and feeds.
  • the fourth object of the present invention is to provide a use of the above-mentioned curcumin L-carnitine cocrystal in preparing products.
  • the products are selected from health products, foods, cosmetics, medicines, pharmaceutical excipients and feeds.
  • the present invention provides a curcumin-L-carnitine cocrystal, wherein the stoichiometric ratio of curcumin to L-carnitine in the cocrystal is 1:1.
  • the X-ray powder diffraction pattern of the curcumin L-carnitine cocrystal has characteristic peaks at 2 ⁇ angles of 5.0° ⁇ 0.2°, 6.4° ⁇ 0.2°, 13.1° ⁇ 0.2°, 16.8° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 23.9° ⁇ 0.2°; in particular, the X-ray powder diffraction pattern of the curcumin L-carnitine cocrystal has characteristic peaks at 2 ⁇ angles of 18.2° ⁇ 0.2°, 18.6° ⁇ 0.2°, 22.1° ⁇ 0.2°, 22.6 ° ⁇ 0.2°; more particularly, it also has characteristic peaks at 2 ⁇ angles of 9.0° ⁇ 0.2°, 15.0° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.2° ⁇ 0.2°, 18.6° ⁇ 0.2°, 22.1° ⁇ 0.2°, 22.6° ⁇ 0.2°, and 27.9° ⁇ 0.2°; preferably, the curcumin and L-carnitine co-crystal has an X-ray powder diffraction pattern substantially as shown in Figure
  • the differential scanning calorimetry analysis spectrum of the Curcumin L-carnitine co-crystal has a characteristic endothermic peak at 161 ⁇ 2° C.; preferably, the Curcumin L-carnitine co-crystal has a differential scanning calorimetry analysis spectrum substantially as shown in FIG. 3 .
  • the infrared spectrum of the Curcumin-L-carnitine cocrystal has characteristic peaks at 3032cm -1 ⁇ 2cm -1 , 2980cm -1 ⁇ 2cm -1 , and 2556cm -1 ⁇ 2cm -1 ; in particular, it also has characteristic peaks at 3069cm -1 ⁇ 2cm -1 , 2831cm -1 ⁇ 2cm -1 , 1563cm -1 ⁇ 2cm -1 , 1515cm -1 ⁇ 2cm -1 , 1286cm -1 ⁇ 2cm -1 , 1240cm -1 ⁇ 2cm -1 , and 1120cm -1 ⁇ 2cm -1 ; preferably, it has an infrared spectrum substantially as shown in Figure 4 .
  • the present invention provides a method for preparing the curcumin L-carnitine cocrystal, wherein the method is selected from one of the following methods:
  • Method 1 Recrystallize curcumin and L-carnitine in a solvent at a stoichiometric ratio of 1:1-1:2, and separate and dry the precipitate to obtain curcumin L-carnitine cocrystal;
  • Method 2 Curcumin and L-carnitine in a stoichiometric ratio of 1:1 are ball-milled in a solvent, and the resulting crystals are dried to obtain curcumin-L-carnitine cocrystals.
  • the solvent is selected from a solvent that has a certain solubility in the raw material and does not cause deterioration of the raw material.
  • the solvents are each independently selected from one or more of water, alcohols, ketones, esters, alkanes, aromatic hydrocarbons and halogenated alkanes; more preferably, the solvents are each independently selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl tert-butyl ether, n-hexane and n-heptane.
  • the mass and volume ratio of curcumin to L-carnitine to solvent is: 1 g: (3-20) mL,
  • the preferred dosage ratio is 1g:(4-15)mL.
  • the recrystallization temperature is 10-70°C, preferably 20-40°C, for example 20°C, 25°C, 30°C, 35°C, 40°C;
  • the recrystallization time is 1-36h, preferably 10-24h, for example 6h, 10h, 12h, 16h, 18h, 20h, 24h.
  • the crystals can be separated by any separation method that does not adversely affect the co-crystal, for example, the crystals and the solvent can be separated by filtration, centrifugation, etc.
  • the mass ratio of curcumin to L-carnitine and the volume of the solvent is 1 g:(0.1-5) mL, preferably 1 g:(0.5-2) mL.
  • the ball milling time is 10 min-180 min, preferably 30 min-60 min, for example 30 min, 40 min, 50 min, 60 min.
  • the crystallization drying method can be any drying method that has no adverse effect on the eutectic, for example, vacuum drying, boiling drying or forced air drying, preferably vacuum drying, and the drying time can be 3-36h, preferably 6-18h, for example 6h, 8h, 12h, 16h, 18h, 22h, 24h, 28h, 32h, 36h.
  • the preparation method of the present invention is simple to operate, the crystallization process is easy to control, the crystallinity is high, and the reproducibility is good, and the curcumin L-carnitine cocrystal can be stably obtained.
  • the present invention provides a curcumin product comprising the curcumin-L-carnitine cocrystal, wherein the product is selected from the group consisting of health products, foods, cosmetics, medicines, pharmaceutical excipients and feeds.
  • the present invention provides a use of the curcumin-L-carnitine cocrystal in the preparation of a curcumin product, wherein the product is selected from the group consisting of health products, foods, cosmetics, medicines, pharmaceutical excipients and feeds.
  • the product may also contain other suitable raw materials required for the product, for example, food may contain food ingredients and edible food additives acceptable to food, such as sweeteners, flavoring agents, preservatives, fragrances, colorants, etc.; cosmetics may contain cosmetic main ingredients and additives acceptable to cosmetics, such as solvents, fragrances, preservatives, flavors, colorants, etc.; medicines may contain medicinal active ingredients and pharmaceutically acceptable auxiliary materials, such as carriers, diluents, adjuvants, colorants, etc.; feed may contain feed ingredients, such as soybean meal, hay, etc., and feed auxiliary materials acceptable to feed, such as sweeteners, flavoring agents, preservatives, fragrances, colorants, etc., but the present invention is not limited to this.
  • food may contain food ingredients and edible food additives acceptable to food, such as sweeteners, flavoring agents, preservatives, fragrances, colorants, etc.
  • cosmetics may contain cosmetic main ingredients and additives acceptable to cosmetics, such as solvents, fragrances, preservative
  • the above product is prepared by adding the curcumin L-carnitine co-crystal of the present invention. Except for adding the curcumin L-carnitine co-crystal of the present invention, the preparation method of the product can be prepared according to its conventional method.
  • the numerical ranges throughout the application documents include any sub-ranges therein and any numerical values incremented by the smallest sub-unit of a given value therein. Unless otherwise expressly stated, the numerical values throughout the application documents represent approximate measurements or limitations of the range of embodiments including slight deviations from a given value and having approximately the values mentioned and having the exact values mentioned. Except for the working examples provided at the end of the detailed description, all numerical values of parameters (e.g., quantities or conditions) in this application document (including the appended claims) should be understood to be modified by the term "about” in all cases, regardless of whether "about” actually appears before the numerical value.
  • “About” means that the numerical value described allows for slight imprecision (some close to precision in the value; approximately or reasonably close to the value; approximately). If the imprecision provided by “about” is not understood in this art with this common meaning, the “about” used herein at least represents the changes that can be produced by the common methods of measuring and using these parameters. For example, “about” can include a variation of less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, or less than or equal to 0.5%, and in some aspects, a variation of less than or equal to 0.1%.
  • the terms “comprising”, “including”, “having”, “containing” or any other similar terms throughout the application documents are open-ended terms, which indicate that a co-crystal or article may include, in addition to the elements listed herein, other elements that are not explicitly listed but are generally inherent to the co-crystal or article.
  • the terms “comprising”, “including”, “having”, “containing” should be interpreted as specifically disclosed and also include closed or semi-closed conjunctions such as “consisting of” and “consisting essentially of”. "Consisting essentially of” means that the elements listed herein account for more than 95%, more than 97%, or in some aspects, more than 99% of the co-crystal or article.
  • the present invention provides a stable curcumin-L-carnitine cocrystal. Compared with the curcumin crystal itself, the cocrystal increases the solubility and dissolution performance of curcumin, so that its absorption and bioavailability are significantly improved, which can further broaden the application scope of curcumin, improve the use effect of curcumin, and reduce the dosage and use cost of curcumin. Therefore, it has strong practical application value.
  • curcumin L-carnitine cocrystals of the present invention is simple, has good reproducibility, and has the advantages of low cost, environmental friendliness and easy control.
  • FIG1 is a single crystal structure diagram of the curcumin L-carnitine cocrystal prepared in Example 1 of the present invention.
  • FIG2 is an X-ray powder diffraction (XRPD) pattern of curcumin-L-carnitine cocrystal prepared in Example 1 of the present invention
  • FIG4 is an infrared spectrum (IR) of the curcumin-L-carnitine cocrystal prepared in Example 1 of the present invention.
  • FIG5 is an infrared spectrum (IR) of commercially available curcumin crystals in Example 1 of the present invention.
  • FIG6 is a comparison diagram of the dissolution curves of the commercially available curcumin crystals in the test example and the curcumin L-carnitine co-crystals prepared in Example 3 in a pH 2.0 buffer solution;
  • FIG7 is a comparison of the dissolution curves of the commercially available curcumin crystals in the test example and the curcumin L-carnitine co-crystals prepared in Example 3 in a pH 4.5 buffer solution;
  • FIG8 is a comparison diagram of the drug-time curves of the commercially available curcumin crystals in Test Example 2 and the curcumin L-carnitine co-crystals prepared in Example 3.
  • the present invention uses L-carnitine as a ligand to form a stable cocrystal with curcumin. It can be seen from the following single crystal structure that the interaction and arrangement between the curcumin molecules in the curcumin crystal and the curcumin L-carnitine cocrystal are completely different.
  • the curcumin molecules form a two-dimensional network structure through the hydrogen bonding between the phenolic hydroxyl group and the carbonyl group; in the curcumin L-carnitine cocrystal, the curcumin molecules use L-carnitine molecules as a medium to form a one-dimensional chain structure through the hydrogen bonding between the phenolic hydroxyl group and the carboxylate group and the hydroxyl group and the carboxylate group.
  • the X-ray powder diffraction pattern in the present invention is obtained using a Bruker D8 Advanced model X-ray eutectic diffractometer, which uses Cu-K ⁇ irradiation
  • the scanning range was from 3° to 40° in the 2 ⁇ interval, and the scanning speed was 5°/min.
  • X-ray single crystal data were collected by a Bruker D8 Venture single crystal X-ray diffractometer equipped with a Mo-K ⁇ X-ray target.
  • the test temperature is 170K
  • the voltage is 50kV
  • the current is 30mA.
  • Differential scanning calorimetry was performed using a TADSC Q2000 instrument with a heating rate of 10 K/min.
  • Thermo Scientific Nicolet 6700 was used as the Fourier transform infrared spectrometer.
  • the ball mill adopts Jingxin JX-2G planetary ball mill.
  • Liquid chromatography was performed using Agilent 1260 Infinity HPLC.
  • L-carnitine purity 99%, purchased from Aladdin Reagent Co., Ltd.;
  • Curcumin (crystal) purity 98%, purchased from Aladdin Reagent Co., Ltd.;
  • Ethanol purity 99%, purchased from Sinopharm Chemical Reagent Co., Ltd.;
  • Ethyl acetate purity 99%, purchased from Sinopharm Chemical Reagent Co., Ltd.;
  • the curcumin-L-carnitine cocrystal and the raw material curcumin crystals and L-carnitine were characterized by X-ray powder diffraction (XRPD), respectively; and the curcumin-L-carnitine cocrystal was subjected to differential scanning calorimetry (DSC) and infrared (IR) spectroscopy analysis, and the results are shown in Table 1-3 and Figure 2-5, respectively.
  • curcumin-L-carnitine cocrystal has a completely different XRPD spectrum from curcumin and L-carnitine themselves.
  • the curcumin-L-carnitine cocrystal has characteristic peaks at 2 ⁇ angles of 5.0° ⁇ 0.2°, 6.4° ⁇ 0.2°, 13.1° ⁇ 0.2°, 16.8° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 23.9° ⁇ 0.2°.
  • the curcumin-L-carnitine cocrystal has a completely different infrared spectrum from that of curcumin itself.
  • the infrared characteristic peak of the phenolic hydroxyl group of curcumin red-shifts from 3508 cm -1 to 3165 cm -1 , indicating that there is a strong hydrogen bond between curcumin and L-carnitine in the cocrystal.
  • the cocrystal was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results were basically consistent with Figures 2 to 4.
  • the co-crystal was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results were basically consistent with Figures 2 to 4.
  • the co-crystal was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results were basically consistent with Figures 2 to 4.
  • the powder was analyzed by X-ray powder diffraction (XRPD) and found to have no co-crystals.
  • the powder was analyzed by X-ray powder diffraction (XRPD) and found to have no co-crystals.
  • the powder was analyzed by X-ray powder diffraction (XRPD) and found to have no co-crystals.
  • the powder was analyzed by X-ray powder diffraction (XRPD) and found to have no co-crystals.
  • curcumin L-carnitine co-crystals described above and below have a significantly improved dissolution rate compared to curcumin crystals themselves; a representative study was conducted using commercially available curcumin crystals and the curcumin L-carnitine co-crystals obtained in Example 3.
  • the powder dissolution difference of commercially available curcumin and the curcumin L-carnitine cocrystal obtained in Example 3 was compared.
  • the powder dissolution experiment was carried out in buffer solutions of pH 2.0 and pH 4.5 (with 0.5% Tween 80), the experimental temperature was 37°C, and the rotation speed was 50rpm.
  • the commercially available curcumin crystals and the curcumin L-carnitine cocrystal powder obtained in Example 3 were passed through a 100 mesh sieve to eliminate the effect of particle size on dissolution. Samples equivalent to 10 mg of curcumin were weighed and placed in the sample tank of the dissolution instrument, stirred, and samples were taken at 3, 5, 10, 15, 20, 30, 45, 60, 90 and 120 minutes, and the concentration was detected using HPLC.
  • the curcumin co-crystals disclosed in the present invention have better solubility and dissolution rate.
  • the curcumin L-carnitine co-crystals of the present invention have better bioavailability, and the maximum blood concentration of curcumin in rats administered with the co-crystals reaches 10.7 times that of commercially available curcumin crystals.

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Abstract

本发明涉及一种姜黄素左旋肉碱共晶及其制备方法和用途。本发明所述姜黄素左旋肉碱共晶中姜黄素与左旋肉碱的化学计量比为1:1，属于单斜晶系。相比姜黄素，本发明通过加入左旋肉碱作为配体与姜黄素形成共晶，从分子水平改变姜黄素分子的分子间相互作用和空间排列方式，增加姜黄素的溶解溶出性能，进而改善其生物利用度。并且该姜黄素左旋肉碱共晶的制备方法简单，容易控制，重现性好。

Description

一种姜黄素左旋肉碱共晶及其制备方法和用途 技术领域
本发明涉及药物共晶技术领域，具体而言，涉及一种姜黄素左旋肉碱共晶及其制备方法，以及包含所述姜黄素左旋肉碱共晶的产品和它们的用途。
背景技术
姜黄素(curcumin)是从姜科植物姜黄中提取的一种天然多酚类化合物。近些年来，大量研究表明其具有抗炎、抗氧化、调脂、抗病毒、抗感染、抗肿瘤、抗凝、抗肝纤维化、抗动脉粥样硬化等广泛的药理活性。姜黄素是一种天然色素，色泽鲜艳，着色力强，抗氧化性好，安全无毒害，具有丰富的营养价值，被广泛应用于食品、保健品、化妆品、医药、烟草和动禽类饲料等多个领域。姜黄素是联合国粮农组织食品法典委员会批准的食品添加剂(FAO/WHO-1995)，是我国《食品添加剂使用卫生标准》中最早颁布的，允许在食品中使用的天然色素。
然而姜黄素属脂溶性色素，在实际应用中发现，姜黄素存在一定缺陷，如溶解度差，吸收率低、代谢快、半衰期短等，这些问题导致了其生物利用度较低，限制了其在食品和药品领域中的应用。目前用于改善姜黄素的溶解度和生物利用度的方法主要是通过制备新的药物剂型，如微乳、微球、固体分散体、脂质体、磷脂复合物、胶束纳米粒、环糊精包合物及滴丸。但是，微球、纳米粒、固体分散体、脂质体等需要大量的载体辅料；微乳制剂含有大量表面活性剂具有潜在的毒性；制备磷脂复合物时需要在一定温度下药物与磷脂进行复合反应并除去溶剂，这样可能引起姜黄素的降解。因此，寻求一种使用便利、含量较高、化学稳定、且制备工艺简单、成本低廉的姜黄素产品是人们不断追求的目标。
发明内容
为了提高姜黄素产品的吸收和生物利用度，本发明通过加入可食用的左旋肉碱作为配体，与姜黄素形成稳定的共晶，从而从分子水平改变姜黄素分子的分子间相互作用和空间排列方式，增加姜黄素的溶解溶出性能，进而改善其生物利用度。
鉴于此，本发明的目的之一在于提供一种姜黄素左旋肉碱共晶。
本发明的目的之二在于提供所述姜黄素左旋肉碱共晶的制备方法。
本发明的目的之三在于提供一种产品，其包含上述的姜黄素左旋肉碱共晶，所述产品为选自保健品、食品、化妆品、药品、药用辅料和饲料。
本发明的目的之四在于提供一种上述的姜黄素左旋肉碱共晶在制备产品中的用途，所 述产品为选自保健品、食品、化妆品、药品、药用辅料和饲料。
为了实现上述目的，本申请采用如下技术方案：
本发明一方面，提供了一种姜黄素左旋肉碱共晶，所述共晶中姜黄素与左旋肉碱的化学计量比为1:1。
所述的姜黄素左旋肉碱共晶属于单斜晶系，晶胞参数为 α＝90°，β＝101.063(2)°，γ＝90°。
在一些实施方式中，所述的姜黄素左旋肉碱共晶的X-射线粉末衍射图谱在2θ角度为5.0°±0.2°，6.4°±0.2°，13.1°±0.2°，16.8°±0.2°，20.3°±0.2°，23.9°±0.2°处具有特征峰；特别地，还在2θ角度为18.2°±0.2°，18.6°±0.2°，22.1°±0.2°，22.6°±0.2°处具有特征峰；更特别地，还在2θ角度为9.0°±0.2°，15.0°±0.2°，15.7°±0.2°，18.2°±0.2°，18.6°±0.2°，22.1°±0.2°，22.6°±0.2°，27.9°±0.2°处具有特征峰；优选地，所述姜黄素与左旋肉碱共晶具有基本上如图2所示的X-射线粉末衍射图谱。
在一些实施方式中，所述姜黄素左旋肉碱共晶的差示扫描量热分析谱图在161±2℃处有特征吸热峰；优选地，所述姜黄素左旋肉碱共晶具有基本如图3所示的差示扫描量热分析图谱。
在一些实施方式中，所述姜黄素左旋肉碱共晶的红外图谱在3032cm-1±2cm-1，2980cm-1±2cm-1，2556cm-1±2cm-1处具有特征峰；特别地，还在3069cm-1±2cm-1，2831cm-1±2cm-1，1563cm-1±2cm-1，1515cm-1±2cm-1，1286cm-1±2cm-1，1240cm-1±2cm-1，1120cm-1±2cm-1处具有特征峰；优选地，具有基本如图4所示的红外图谱。
第二方面，本发明提供了所述姜黄素左旋肉碱共晶的制备方法，所述方法选自以下方法之一：
方法一：将化学计量比为1:1-1:2的姜黄素与左旋肉碱在溶剂中重结晶，沉淀经分离干燥后得到姜黄素左旋肉碱共晶；
方法二：将化学计量比为1:1的姜黄素与左旋肉碱在溶剂中球磨，得到的晶体经干燥后得到姜黄素左旋肉碱共晶。
上述方法一和方法二中，所述溶剂选自对原料有一定溶解度且不对原料造成变质的溶剂。优选地，所述溶剂各自独立地为选自水、醇类、酮类、酯类、烷烃、芳香烃和卤代烷烃中的一种或多种；更优选地，所述溶剂各自独立地为选自甲醇、乙醇、异丙醇、乙酸乙酯、乙酸异丙酯、丙酮、甲乙酮、甲基叔丁基醚、正己烷、正庚烷中的一种或多种。
根据上述方法一：
在一些实施方式中，姜黄素与左旋肉碱的质量和与溶剂体积的用量比为：1g:(3-20)mL， 优选用量比为1g:(4-15)mL。
在一些实施方式中，所述重结晶的温度为10-70℃，优选为20-40℃，例如20℃、25℃、30℃、35℃、40℃；重结晶的时间为1-36h，优选为10-24h，例如6h、10h、12h、16h、18h、20h、24h。
在一些实施方式中，分离结晶的方式可以采用对共晶无不利影响的任何分离方式，例如可以使用过滤、离心等方式分离结晶和溶剂。
根据上述方法二：
在一些实施方式中，姜黄素与左旋肉碱的质量和与溶剂体积的用量比为1g:(0.1-5)mL，优选用量比为1g:(0.5-2)mL。
在一些实施方式中，球磨的时间为10min-180min，优选为30min-60min，例如30min、40min、50min、60min。
上述方法一和方法二中，结晶干燥的方法可以采用对共晶无不利影响的任何干燥方法，例如可以采用真空干燥、沸腾干燥或鼓风干燥，优选为真空干燥，干燥时间可以为3-36h，优选为6-18h，例如6h、8h、12h、16h、18h、22h、24h、28h、32h、36h。
本发明涉及的制备方法操作简单，结晶过程容易控制，结晶度高，且重现性好，可稳定获得姜黄素左旋肉碱共晶。
第三方面，本发明提供了一种姜黄素产品，其包含所述姜黄素左旋肉碱共晶，所述产品选自保健品、食品、化妆品、药品、药用辅料和饲料。
第四方面，本发明提供了所述姜黄素左旋肉碱共晶在制备姜黄素产品中的用途，所述产品选自保健品、食品、化妆品、药品、药用辅料和饲料。
所述产品中还可以包含该产品所需的其他适合原料，例如食品中可以包含食品主料以及食品上可接受的可食用的食品添加剂，例如甜味剂、风味剂、防腐剂、香味剂、着色剂等；化妆品中可以包含化妆品上可接受的化妆品主料和添加剂，例如溶剂、香味剂、防腐剂、香精、着色剂等；药品中可以包含药用活性成分以及药学上可接受的辅料，例如载体、稀释剂、佐剂、着色剂等；饲料中可以包含饲料主料，例如豆粕、干草等，以及饲料中可以接受的饲料辅料，例如甜味剂、风味剂、防腐剂、香味剂、着色剂等，但是本发明不限于此。
上述产品是通过添加本发明的姜黄素左旋肉碱共晶而制备的。除了添加本发明的姜黄素左旋肉碱共晶之外，所述产品的制备方法可以按照其常规方法制备。
在上文中已经详细地描述了本发明，但是上述实施方式本质上仅是例示性，且并不欲限制本发明。此外，本文并不受前述现有技术或发明内容或以下实施例中所描述的任何理 论的限制。
除非另有明确说明，在整个申请文件中的数值范围包括其中的任何子范围和以其中给定值的最小子单位递增的任何数值。除非另有明确说明，在整个申请文件中的数值表示对包括与给定值的微小偏差以及具有大约所提及的值以及具有所提及的精确值的实施方案的范围的近似度量或限制。除了在详细描述最后提供的工作实施例之外，本申请文件(包括所附权利要求)中的参数(例如，数量或条件)的所有数值在所有情况下都应被理解为被术语“约”修饰，不管“约”是否实际出现在该数值之前。“约”表示所述的数值允许稍微不精确(在该值上有一些接近精确；大约或合理地接近该值；近似)。如果“约”提供的不精确性在本领域中没有以这个普通含义来理解，则本文所用的“约”至少表示可以通过测量和使用这些参数的普通方法产生的变化。例如，“约”可以包括小于或等于10％，小于或等于5％，小于或等于4％，小于或等于3％，小于或等于2％，小于或等于1％或者小于或等于0.5％的变化，并且在某些方面，小于或等于0.1％的变化。
除非另有明确说明，在整个申请文件中的用语“包含”、“包括”、“具有”、“含有”或其他任何类似用语均属于开放性用语，其表示一共晶或制品除了包括本文所列出的这些要素以外，还可包括未明确列出但却是共晶或制品通常固有的其他要素。此外，在本文中，用语“包含”、“包括”、“具有”、“含有”的解读应视为已具体公开并同时涵盖“由…所组成”及“基本上由…所组成”等封闭式或半封闭式连接词。“基本上由…所组成”表示本文所列出的这些要素占该共晶或制品的95％以上，97％以上，或者在某些方面，99％以上。
有益效果
(1)本发明提供一种稳定的姜黄素左旋肉碱共晶，相比于姜黄素晶体本身，该共晶增加了姜黄素的溶解溶出性能，使得其吸收和生物利用度具有显著的提升，可以进一步拓宽姜黄素的应用范围，提高姜黄素的使用效果，降低姜黄素的用量和使用成本，因此，具有很强的现实应用价值。
(2)本发明姜黄素左旋肉碱共晶制备方法简单，重现性好，具有成本低、环境友好和容易控制的优势。
附图说明
图1是本发明实施例1制备的姜黄素左旋肉碱共晶的单晶结构图；
图2是本发明实施例1制备的姜黄素左旋肉碱共晶的X-射线粉末衍射(XRPD)图；
图3是本发明实施例1制备的姜黄素左旋肉碱共晶的差示扫描量热分析(DSC)图；
图4是本发明实施例1制备的姜黄素左旋肉碱共晶的红外光谱(IR)图；
图5是本发明实施例1中市售的姜黄素晶体的红外光谱(IR)图；
图6是测试实施例中市售姜黄素晶体与实施例3制备的姜黄素左旋肉碱共晶在pH 2.0缓冲溶液中的溶出曲线比较图；
图7是测试实施例中市售姜黄素晶体与实施例3制备的姜黄素左旋肉碱共晶在pH 4.5缓冲溶液中的溶出曲线比较图；
图8是测试实施例2中市售姜黄素晶体与实施例3制备的姜黄素左旋肉碱共晶的药时曲线比较图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明以左旋肉碱为配体，与姜黄素形成稳定的共晶。从以下单晶结构可以看出，姜黄素晶体和姜黄素左旋肉碱共晶中的姜黄素分子之间的相互作用和排列方式完全不同。在姜黄素晶体中，姜黄素分子之间通过酚羟基与羰基之间的氢键作用形成一个二维网状结构；在姜黄素左旋肉碱共晶中，姜黄素分子之间以左旋肉碱分子为介质，通过酚羟基与羧酸根基团以及羟基与羧酸根基团之间的氢键作用形成一维链状结构。
本发明中X-射线粉末衍射图谱是采用Bruker D8 Advanced型号的X射线共晶衍射仪得到，该仪器采用Cu-Kα照射扫描范围在2θ区间自3°至40°，扫描速度为5°/分钟。
X-射线单晶数据由Bruker D8 Venture型号X-射线单晶衍射仪收集，仪器配置Mo-KαX-射线靶测试温度为170K，电压为50kV，电流为30mA。
差示扫描量热法采用TADSC Q2000设备，加热速度为10K/min。
傅里叶变换红外光谱仪采用Thermo Scientific Nicolet 6700。
球磨采用净信JX-2G行星式球磨仪。
液相色谱采用Agilent 1260Infinity HPLC。
以下实施例采用的试剂及来源信息如下：
左旋肉碱：纯度99％，购自阿拉丁试剂有限公司；
姜黄素(晶体)：纯度98％，购自阿拉丁试剂有限公司；
乙醇：纯度99％，购自国药集团化学试剂有限公司；
乙酸乙酯：纯度99％，购自国药集团化学试剂有限公司；
甲醇：纯度99％，购自国药集团化学试剂有限公司。
实施例1
将1.61克左旋肉碱与3.69克姜黄素加入到60毫升乙醇溶剂中，于30℃下搅拌混悬12小时，过滤得红色固体，真空干燥过夜获得姜黄素左旋肉碱共晶。
将此姜黄素左旋肉碱共晶和原料姜黄素晶体及左旋肉碱分别通过X-射线粉末衍射(XRPD)进行表征；并对姜黄素左旋肉碱共晶进行差示扫描量热分析(DSC)和红外(IR)光谱分析，结果分别如表1-3，图2-5所示。
由表1-3、图2可知，姜黄素左旋肉碱共晶与姜黄素、左旋肉碱本身具有完全不同的XRPD谱图，姜黄素左旋肉碱共晶在2θ角度为5.0°±0.2°，6.4°±0.2°，13.1°±0.2°，16.8°±0.2°，20.3°±0.2°，23.9°±0.2°处具有特征峰。
由图4-5可知，姜黄素左旋肉碱共晶与姜黄素本身具有完全不同的红外谱图。在姜黄素左旋肉碱共晶的红外谱图中，姜黄素酚羟基的红外特征峰由3508cm-1红移至3165cm-1处，说明共晶中姜黄素与左旋肉碱之间具有很强的氢键作用。
表1.姜黄素左旋肉碱共晶的XRPD数据

表2.市售姜黄素的XRPD数据
表3.左旋肉碱XRPD数据
实施例2
将1.61克左旋肉碱与3.69克姜黄素加入到60毫升乙酸乙酯溶剂中，于30℃下搅拌混悬12小时，过滤得红色固体，真空干燥过夜获得姜黄素左旋肉碱共晶。
此共晶通过X-射线粉末衍射(XRPD)、差示扫描量热分析(DSC)和红外(IR)光谱分析法表征。结果与图2-图4基本一致。
实施例3
将0.161克左旋肉碱与0.369克姜黄素加入到球磨罐中，加入1毫升乙醇，于室温下球磨0.5小时，并将固体于真空干燥箱中常温干燥12小时，获得姜黄素左旋肉碱共晶。
此共晶通过X-射线粉末衍射(XRPD)、差示扫描量热分析(DSC)和红外(IR)光谱分析表征。结果与图2-图4基本一致。
实施例4
将0.161克左旋肉碱与0.369克姜黄素加入到球磨罐中，加入1毫升甲醇，于室温下球磨0.5小时，并将固体于真空干燥箱中常温干燥12小时，获得姜黄素左旋肉碱共晶。
此共晶通过X-射线粉末衍射(XRPD)、差示扫描量热分析(DSC)和红外(IR)光谱分析表征。结果与图2-图4基本一致。
对比例1
将0.131克亮氨酸与0.369克姜黄素加入到球磨罐中，加入1毫升甲醇或乙醇，球磨0.5小时，并将固体于真空干燥箱中常温干燥12小时，获得黄色粉末。
此粉末通X-射线粉末衍射(XRPD)检测发现未形成共晶。
对比例2
将0.131克异亮氨酸与0.369克姜黄素加入到球磨罐中，加入1毫升甲醇或乙醇，球磨0.5小时，并将固体于真空干燥箱中常温干燥12小时，获得黄色粉末。
此粉末通X-射线粉末衍射(XRPD)检测发现未形成共晶。
对比例3
将0.139克甲硫氨酸与0.369克姜黄素加入到球磨罐中，加入1毫升甲醇或乙醇，球磨0.5小时，并将固体于真空干燥箱中常温干燥12小时，获得黄色粉末。
此粉末通X-射线粉末衍射(XRPD)检测发现未形成共晶。
对比例4
将0.119克苏氨酸与0.369克姜黄素加入到球磨罐中，加入1毫升甲醇或乙醇，球磨0.5小时，并将固体于真空干燥箱中常温干燥12小时，获得黄色粉末。
此粉末通X-射线粉末衍射(XRPD)检测发现未形成共晶。
测试实施例1.溶出度测试
本领域人员能够证明上下文中所述的姜黄素左旋肉碱共晶与姜黄素晶体本身相比，溶出速率有显著的提高；代表性研究采用市售姜黄素晶体和实施例3得到的姜黄素左旋肉碱共晶进行。
对市售的姜黄素和实施例3得到的姜黄素左旋肉碱共晶进行粉末溶出差异的比较。粉末溶出实验是在pH2.0和pH4.5的缓冲液中进行的(加0.5％吐温80)，实验温度为37℃，转速为50rpm。将姜黄素市售晶体和实施例3得到姜黄素左旋肉碱共晶粉末过100目筛，消除粒径大小对溶出的影响。分别称取相当于10mg姜黄素的样品置于溶出仪的样品槽中，搅拌，于第3，5，10，15，20，30，45，60，90和120分钟时取样，使用HPLC检测浓度。结果如图6、7所示。在pH2.0的缓冲溶液中，3分钟时，共晶的溶出达到姜黄素本身的7倍左右；在pH4.5的缓冲溶液中，3分钟时，共晶的溶出达到姜黄素本身的8倍左右。
如上述结果所示，与常规市售的姜黄素晶体相比，本发明所公开的姜黄素共晶具有更优异的溶解性和溶出速率。
测试实施例2.生物利用度测试
本领域技术人员能够证明上下文中所述的姜黄素左旋肉碱共晶与市售姜黄素晶体相比，生物利用度有明显提高；代表性研究采用市售姜黄素晶体和实施例3得到姜黄素左旋肉碱共晶进行。
对市售的姜黄素和实施例3得到的姜黄素左旋肉碱共晶进行生物利用度差异的比较。 使用雄性SD大鼠(体重200-300克)在喂养良好的条件下进行试验。共12只大鼠，平均分为2组，每组6只。姜黄素市售晶体和实施例3得到的共晶均匀分散在大豆油中，以混悬液的形式灌胃给药。给药剂量为以姜黄素计200毫克/公斤。给药后20分钟，40分钟，1小时，1.5小时，2.5小时，4小时，6小时，8小时经眼眶静脉丛采血，1mL/时间点。采血后0.5h内离心分离血浆，离心条件10000转/分钟，5分钟，获得血浆。精密移取100微升血浆，加入50微升酶缓冲液，37℃保温60min，然后加入0.45ml甲醇(0.2％醋酸)，振荡10min，14000rpm离心3min，取上清液进行液相检测。结果如表4和图8所示。
表4.姜黄素市售晶体和姜黄素左旋肉碱共晶的药代动力学参数
如上述结果所示，与常规市售的姜黄素晶体相比，本发明姜黄素左旋肉碱共晶具有更优异的生物利用度，共晶给药的大鼠的姜黄素最大血药浓度达到市售姜黄素晶体的10.7倍。

Claims (10)

  1. 一种姜黄素左旋肉碱共晶，所述共晶中姜黄素与左旋肉碱的化学计量比为1:1。
  2. 根据权利要求1所述的姜黄素左旋肉碱共晶，其特征在于，所述姜黄素左旋肉碱共晶属于单斜晶系，晶胞参数为α＝90°，β＝101.063(2)°，γ＝90°。
  3. 根据权利要求1所述的姜黄素左旋肉碱共晶，其特征在于，所述姜黄素左旋肉碱共晶的X-射线粉末衍射图谱在2θ角度为5.0°±0.2°，6.4°±0.2°，13.1°±0.2°，16.8°±0.2°，20.3°±0.2°，23.9°±0.2°处具有特征峰；
    优选地，所述的姜黄素左旋肉碱共晶的X-射线粉末衍射图谱还在2θ角度为18.2°±0.2°，18.6°±0.2°，22.1°±0.2°，22.6°±0.2°处具有特征峰；
    更优选地，所述姜黄素与左旋肉碱共晶具有基本上如图2所示的X-射线粉末衍射图谱。
  4. 根据权利要求1所述的姜黄素左旋肉碱共晶，其特征在于，所述姜黄素左旋肉碱共晶的差示扫描量热分析谱图在161±2℃处有特征吸热峰；
    优选地，所述姜黄素左旋肉碱共晶具有基本如图3所示的差示扫描量热分析图谱。
  5. 根据权利要求1所述的姜黄素左旋肉碱共晶，其特征在于，所述姜黄素左旋肉碱共晶的红外图谱在3032cm-1±2cm-1，2980cm-1±2cm-1，2556cm-1±2cm-1处具有特征峰；
    特别地，所述姜黄素左旋肉碱共晶的红外图谱还在3069cm-1±2cm-1，2831cm-1±2cm-1，1563cm-1±2cm-1，1515cm-1±2cm-1，1286cm-1±2cm-1，1240cm-1±2cm-1，1120cm-1±2cm-1处具有特征峰；
    优选地，所述姜黄素左旋肉碱共晶具有基本如图4所示的红外图谱。
  6. 权利要求1-5任一项所述姜黄素左旋肉碱共晶的制备方法，所述方法选自以下方法之一：
    方法一：将化学计量比为1:1-1:2的姜黄素与左旋肉碱在溶剂中重结晶，沉淀经分离干燥后得到姜黄素左旋肉碱共晶；
    方法二：将化学计量比为1:1的姜黄素与左旋肉碱在溶剂中球磨，得到的晶体经干燥后得到姜黄素左旋肉碱共晶。
  7. 根据权利要求6所述的姜黄素左旋肉碱共晶的制备方法，其特征在于，上述方法一和方法二中，所述溶剂各自独立地为选自水、醇类、酮类、酯类、烷烃、芳香烃和卤代烷烃中的一种或多种；
    优选地，所述溶剂各自独立地为选自甲醇、乙醇、异丙醇、乙酸乙酯、乙酸异丙酯、丙酮、甲乙酮、甲基叔丁基醚、正己烷、正庚烷中的一种或多种；和/或
    所述结晶干燥的方法采用真空干燥、沸腾干燥或鼓风干燥，优选为真空干燥，干燥时间为3～36h，优选为6～18h。
  8. 根据权利要求6所述的姜黄素左旋肉碱共晶的制备方法，其特征在于，
    方法一中：
    姜黄素与左旋肉碱的质量和与溶剂体积的用量比为：1g:(3-20)mL，优选用量比为1g:(4-15)mL；和/或
    所述重结晶的温度为10-70℃，优选为20-40℃；重结晶的时间为1-36h，优选为10-24h。
    方法二中：
    姜黄素与左旋肉碱的质量和与溶剂体积的用量比为1g:(0.1-5)mL，优选用量比为1g:(0.5-2)mL。
  9. 一种姜黄素产品，其包含权利要求1-5任一项所述姜黄素左旋肉碱共晶或权利要求6-8任一项所述制备方法制备得到的姜黄素左旋肉碱共晶，所述产品选自保健品、食品、化妆品、药品、药用辅料和饲料。
  10. 根据权利要求1-5任一项所述姜黄素左旋肉碱共晶，或者权利要求6-8任一项所述制备方法制备得到的姜黄素左旋肉碱共晶在制备姜黄素产品中的用途，所述产品选自保健品、食品、化妆品、药品、药用辅料和饲料。
PCT/CN2024/128358 2023-11-02 2024-10-30 一种姜黄素左旋肉碱共晶及其制备方法和用途 Pending WO2025092781A1 (zh)

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