WO2017076169A1 - 黄芩素咖啡因共晶、其制备方法、药物组合物及其应用 - Google Patents

黄芩素咖啡因共晶、其制备方法、药物组合物及其应用 Download PDF

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WO2017076169A1
WO2017076169A1 PCT/CN2016/102618 CN2016102618W WO2017076169A1 WO 2017076169 A1 WO2017076169 A1 WO 2017076169A1 CN 2016102618 W CN2016102618 W CN 2016102618W WO 2017076169 A1 WO2017076169 A1 WO 2017076169A1
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baicalein
caffeine
eutectic
crystal
baicalin
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PCT/CN2016/102618
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English (en)
French (fr)
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朱理平
梅雪锋
王建荣
朱冰清
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诸城市浩天药业有限公司
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/12—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1, 3, and 7, e.g. caffeine
    • 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 invention relates to the technical field of medicinal chemistry and crystallization technology, in particular to a baicalein caffeine eutectic, a preparation method thereof, a pharmaceutical composition and application thereof.
  • Baicalein 5,6,7-trihydroxyflavone
  • chemical structure is as follows:
  • baicalein As a flavonoid compound, baicalein has various pharmacological effects such as antibacterial, antiviral, liver-protecting, choleretic, diuretic, anti-cancer, etc. Currently, it is mainly used for antibacterial, anti-inflammatory and anti-infective in clinical practice. However, due to the poor water solubility of baicalein, poor oral absorption has greatly limited its clinical application.
  • Co-crystallization of drugs refers to the active pharmaceutical ingredient (API) and other physiologically acceptable acids, bases, salts, nonionic compounds, hydrogen bonding, ⁇ - ⁇ stacking, van der Waals forces and other non-covalent The bonds are connected and combined in the same crystal lattice.
  • API active pharmaceutical ingredient
  • Co-crystals have a greater advantage in the development of some drugs than other solid forms such as polymorphs and salts.
  • the solubility difference of different crystal forms is usually not more than 2 times compared with polymorphs, and the solubility of co-crystals can vary by several tens of times.
  • salt formation requires that the compound have at least one ionization center, while the components in the drug co-crystal may be neutral molecules, and there are many potential molecules for co-crystallization with the API.
  • These substances may include food additives, preservatives, pharmaceutical excipients, minerals, vitamins, amino acids and other active molecules, and may even be other APIs. Therefore, for baicalein without an ionization center, co-crystal is an ideal solid form.
  • One of the objects of the present invention is to provide a high dissolution rate of baicalein, which can improve bioavailability.
  • the baicalin caffeine eutectic.
  • Baicalein caffeine eutectic which has X-ray powder diffraction at diffraction angles 2 ⁇ of 3.55, 6.20, 7.09, 9.53, 10.62, 12.43, 14.46, 16.60, 17.76, 18.96 degrees. Characteristic peak with an error of ⁇ 0.2 degrees.
  • the differential scanning calorimetry spectrum of the baicalein caffeine has a characteristic melting peak at 208.2 ⁇ 0.2 °C.
  • the infrared spectrum of the baicalin caffeine eutectic is at least 3320 cm -1 , 3115 cm -1 , 1699 cm -1 , 1644 cm -1 , 1588 cm -1 , 1553 cm -1 , 1474 cm -1 , 1450 cm -1 , 1421cm -1 , 1366cm -1 , 1328cm -1 , 1273cm -1 , 1239cm -1 , 1187cm -1 , 1166cm -1 , 1101cm -1 , 1073cm -1 , 1033cm -1 , 896cm -1 , 857cm -1 , 798cm - 1, 763cm -1, 684cm -1, 614cm -1, 578cm -1, with characteristic peaks at 489cm -1.
  • the Raman spectrum of the baicalin caffeine eutectic is at least 1666 cm -1 , 1618 cm -1 , 1605 cm -1 , 1582 cm -1 , 1508 cm -1 , 1459 cm -1 , 1334 cm -1 , 1256 cm -1 . There are characteristic peaks at 1006 cm -1 , 623 cm -1 , 559 cm -1 , and 491 cm -1 .
  • thermogravimetric analysis profile of the baicalein caffeine eutectic lost 97% at 315.0 °C.
  • the xanthophyll caffeine eutectic molecule has a molar ratio of baicalein to caffeine of 2:1.
  • the second object of the present invention is to provide a simple and easy-to-reproduce method for preparing a baicalein co-crystal.
  • the preparation method comprises the following steps:
  • step (c) comprises:
  • step (a) the baicalein and caffeine molar ratio 4:1 to 1:4 are dissolved in the organic solvent.
  • step (a) the baicalein and caffeine are dissolved in the organic solvent by a molar ratio of 2:1.
  • the organic solvent is removed by slow volatilization to form a baicalein caffeine eutectic.
  • the crystallization treatment comprises adding a seed crystal to the baicalein caffeine solution.
  • the organic solvent is one or more of methanol, ethanol, isopropanol, n-propanol, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, methyl ethyl ketone, toluene, chloroform, dichloromethane, and water. mixture.
  • a third object of the present invention is to provide a pharmaceutical composition comprising the above-described baicalein caffeine eutectic and a pharmaceutically acceptable carrier.
  • the fourth object of the present invention is to provide a drug for preventing and treating nervous system diseases, preventing cardiovascular and cerebrovascular diseases, inflammation and immune system diseases, metabolic diseases, senile diseases, and bacterial and viral infection diseases by providing baicalin caffeine eutectic. Application in .
  • the invention provides a baicalin caffeine eutectic, the preparation method thereof is simple in operation, the crystallization process is easy to control, the reproducibility is good, and the dissolution rate and the high bioavailability of the baicalein itself are significantly improved.
  • the invention finds that there are differences in absorption between the two solid forms of baicalein and baicalein in the living body, wherein the plasma concentration of the eutectic is greater than that of the baicalein raw material itself, and has a strong practical application value.
  • Example 1 is an X-ray powder diffraction (XRPD) pattern of the baicalein caffeine eutectic provided in Example 1.
  • XRPD X-ray powder diffraction
  • thermogravimetric analysis (TG) chart of the baicalein caffeine eutectic provided in Example 1.
  • DSC differential scanning calorimetry
  • IR infrared spectrum
  • Figure 5 is a Raman spectrum of the baicalein caffeine eutectic provided in Example 1.
  • Figure 6 is a graph showing the powder dissolution rate of baicalein itself and baicalein caffeine eutectic.
  • Figure 7 is a graph showing the concentration of drug in blood at different times after oral administration (121 mg/kg) of baicalein rats.
  • baicalein 0.1mmol
  • caffeine 0.05mmol
  • baicalein 0.1 mmol
  • caffeine 0.05 mmol
  • baicalein 0.1 mmol
  • caffeine 0.05 mmol
  • baicalein 0.1 mmol
  • caffeine 0.05 mmol
  • baicalein 0.025 mmol
  • caffeine 0.1 mmol
  • ethanol 2 ml
  • acetonitrile 2 ml
  • the invention provides a baicalein caffeine eutectic by X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), differential scanning calorimetry (DSC), infrared (IR) and Raman (Raman) Characterization by solid state methods.
  • XRPD X-ray powder diffraction
  • TG thermogravimetric analysis
  • DSC differential scanning calorimetry
  • IR infrared
  • Raman Raman Characterization by solid state methods.
  • the weight loss analysis of the baicalein eutectic solid sample prepared in Example 1 was carried out by using the German TG20F3 type thermogravimetric analyzer with a nitrogen atmosphere at a heating rate of 10 deg/min. The analysis results are shown in Figure 2.
  • Example 3 The xanthine caffeine eutectic solid sample prepared in Example 1 was subjected to differential scanning calorimetry, which was detected by a DSC 8500 differential calorimeter from Elmer, USA, and the atmosphere was nitrogen, and the heating rate was 10 degrees Celsius. /minute. The analysis results are shown in Figure 3.
  • the infrared spectroscopy analysis of the baicalein eutectic solid sample prepared in Example 1 was carried out at room temperature using a Nicolet-Magna FT-IR 750 infrared spectroscopy analyzer of the United States, and the detection range was 4000-350 cm. -1 wave number. The analysis results are shown in Figure 4.
  • the flavonoids of the baicalein eutectic solid sample prepared in Example 1 were subjected to Raman spectroscopy, which was detected at room temperature by a DXR micro Raman spectrometer of American Thermoelectric Corporation, and the detection range was: 3500-50 cm -1 Raman shift.
  • the analysis results are shown in Figure 5.
  • Test sample source baicalein caffeine eutectic was prepared by the method provided by the present invention; baicalein raw material was purchased from Shanghai Boyle Chemical Co., Ltd., and the purity was more than 99%.
  • Dissolution medium 0.5% Tween aqueous solution with pH 2.0
  • Dissolution temperature 37 degrees Celsius
  • Figure 6 The dissolution rate of baicalein caffeine and the powder of lutein itself.
  • the baicalein co-crystal provided by the present invention has better dissolution performance than baicale itself, and its maximum dissolution concentration is more than three times that of the baicalein raw material itself.
  • baicalein The raw material of baicalein, the physical mixture of baicalein and caffeine, and the absorption characteristics and blood concentration characteristics of baicalein caffeine eutectic in vivo:
  • Rat arterial blood was drawn at different time points after administration to determine the content of baicalein.
  • the results show that the drug concentration in the blood and the peak concentration are different under the same dosage of oral administration of the baicalein drug substance and the eutectic, wherein the plasma concentration of the eutectic is significantly higher than that of the raw material powder and The blood concentration of the physical mixture.
  • the pharmaceutical composition comprises a baicalein caffeine eutectic and a pharmaceutically acceptable carrier, the acceptable carrier comprising a diluent, a binder, a wetting agent, a disintegrant, a lubricant, a glidant .
  • the diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, and the like.
  • the wetting agent can be water, ethanol, isopropanol or the like.
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, Ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, and the like.
  • the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium hydrogencarbonate and citric acid, Polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, and the like.
  • Lubricants and glidants can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
  • the pharmaceutical composition is mixed with several carriers to prepare different dosage forms such as tablets, capsules and granules, and tablets, capsules, granules, etc. of the pharmaceutical composition.
  • the preparation method of the dosage form is the same as the preparation method of the dosage forms such as tablets, capsules, granules and the like which are conventional in the art.
  • the baicalein raw material itself has a role in preparing a medicament for preventing and treating diseases of the nervous system, cardiovascular and cerebrovascular diseases, inflammation, immune system diseases, metabolic diseases, senile diseases, and bacterial and viral infection diseases
  • the present invention provides a flavonoid coffee The application of the eutectic in the preparation of a medicament for preventing and treating diseases of the nervous system, cardiovascular and cerebrovascular diseases, inflammation, immune system diseases, metabolic diseases, senile diseases, and bacterial and viral infections will not be described herein.

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Abstract

本发明提供了一种黄芩素咖啡因共晶、其制备方法、药物组合物及其应用。本发明的黄芩素咖啡因共晶具有优良的溶出速率和生物利用度。本发明提供的黄芩素咖啡因共晶的制备方法简单，容易控制，重现性好，可以稳定获得目标共晶。

Description

黄芩素咖啡因共晶、其制备方法、药物组合物及其应用 技术领域
本发明涉及药物化学及结晶工艺技术领域，尤其涉及黄芩素咖啡因共晶、其制备方法、药物组合物及其应用。
背景技术
黄芩素(Baicalein)的化学名为：5,6,7-三羟基黄酮，其化学结构式如下：
Figure PCTCN2016102618-appb-000001
黄芩素作为黄酮类化合物，具有抗菌、抗病毒、保肝、利胆、利尿、抗癌等多种药理作用，目前，在临床上主要用于抗菌消炎和抗感染。但由于黄芩素水溶性很差，口服吸收差，大大限制了它的临床应用。
药物共结晶是指药物活性成分(API，active pharmaceutical ingredient)分子与其他生理上可接受的酸，碱，盐，非离子化合物分子以氢键，π-π堆积作用，范德华力和其他非共价键相连而结合在同一晶格中。
与多晶型及盐类等其他固体形态相比，共结晶在一些药物的研发过程中有着更大的优势。首先，与多晶型相比，不同晶型的溶解度差异通常不会超过2倍，而共结晶的溶解度变化可达几十倍。其次，与盐类相比，成盐要求化合物至少有一个离子化的中心，而药物共结晶中的各个组份可以是中性分子，而潜在的用来和API形成共结晶的分子也很多，这些物质可能包括食品添加剂，防腐剂，药用辅料，矿物质，维生素，氨基酸以及其他活性分子，甚至可以是其他的API。因此，对于没有离子化中心的黄芩素来说，共结晶是一种较为理想的固体形态。
迄今为止，在专利CN 103848803A中报道了黄芩素和烟酰胺的一种共结晶，共结晶的溶解度相比黄芩素本身提高了2倍左右。我们通过研究发现了一种黄芩素的新的共结晶：黄芩素咖啡因的共结晶。
发明内容
本发明的目的之一在于：提供了一种黄芩素溶出速率高，可提高生物利用度 的黄芩素咖啡因共晶。
为实现上述目的，本发明的技术方案为：
黄芩素咖啡因共晶，所述黄芩素咖啡因共晶在X-射线粉末衍射下，在衍射角2θ为3.55、6.20、7.09、9.53、10.62、12.43、14.46、16.60、17.76、18.96度处具有特征峰，误差为±0.2度。
作为一种改进，所述黄芩素咖啡因共晶的差示扫描量热分析图谱在208.2±0.2℃处有特征熔融峰。
作为一种改进，所述黄芩素咖啡因共晶的红外图谱至少在3320cm-1、3115cm-1、1699cm-1、1644cm-1、1588cm-1、1553cm-1、1474cm-1、1450cm-1、1421cm-1、1366cm-1、1328cm-1、1273cm-1、1239cm-1、1187cm-1、1166cm-1、1101cm-1、1073cm-1、1033cm-1、896cm-1、857cm-1、798cm-1、763cm-1、684cm-1、614cm-1、578cm-1、489cm-1处具有特征峰。
作为一种改进，所述黄芩素咖啡因共晶的拉曼图谱至少在1666cm-1、1618cm-1、1605cm-1、1582cm-1、1508cm-1、1459cm-1、1334cm-1、1256cm-1、1006cm-1、623cm-1、559cm-1、491cm-1处具有特征峰。
作为一种改进，所述黄芩素咖啡因共晶的热失重分析图谱在315.0℃处失重97％。
作为一种改进，所述黄芩素咖啡因共晶为单斜晶系，空间群为P21/c，晶胞参数为：
Figure PCTCN2016102618-appb-000002
α＝90°；β＝90.320(8)°；γ＝90°，晶胞体积为
Figure PCTCN2016102618-appb-000003
作为一种改进，所述黄芩素咖啡因共晶分子中，黄芩素和咖啡因的摩尔比为2：1。
本发明的目的之二在于：提供一种简单易行、重现性好的黄芩素咖啡因共晶的制备方法。
所述制备方法包括以下步骤：
(a).将黄芩素和咖啡因溶解于有机溶剂中，形成黄芩素咖啡因溶液；
(b).对所述黄芩素咖啡因溶液进行结晶处理，形成黄芩素咖啡因的共结晶溶液体系；
(c).从所述共结晶溶液体系中分离得到黄芩素咖啡因共晶。
作为一种改进，所述步骤(c)包括：
(c1)对所述共结晶溶液体系进行过滤，获得黄芩素咖啡因共晶；和/或
(c2)对所述共结晶溶液体系进行离心，获得黄芩素咖啡因共晶；和/或
(c3)对所述共结晶溶液体系进行加热，蒸发去除所述有机溶剂，获得黄芩素咖啡因共晶。
作为一种改进，步骤(a)中，将所述黄芩素和咖啡因按摩尔比4:1-1:4溶解于所述有机溶剂中。
优选的，步骤(a)中，所述黄芩素和咖啡因按摩尔比2:1溶解于所述有机溶剂中。
作为一种改进，步骤(b)中，通过缓慢挥发去除所述有机溶剂，从而形成黄芩素咖啡因共晶。
作为一种改进，步骤(b)中，所述的结晶处理包括向所述黄芩素咖啡因溶液中添加晶种。
作为一种改进，所述有机溶剂为甲醇、乙醇、异丙醇、正丙醇、丙酮、四氢呋喃、乙腈、乙酸乙酯、甲乙酮、甲苯、氯仿、二氯甲烷、水中的一种或两种以上的混合物。
本发明的目的之三在于：提供一种药物组合物，所述药物组合物包含上述黄芩素咖啡因共晶以及药学上可接受的载体。
本发明的目的之四在于：提供黄芩素咖啡因共晶在制备防治神经系统疾病、防治心脑血管系统疾病、炎症及免疫系统疾病、代谢性疾病、老年性疾病及细菌和病毒感染疾病的药物中的应用。
由于采用了上述技术方案，本发明的有益效果是：
本发明提供的黄芩素咖啡因共晶，其制备方法操作简单，结晶过程易于控制，重现性好，且较黄芩素本身具有较显著提高的溶出速率和较高的生物利用度。本发明发现黄芩素本身和黄芩素共晶两种固体形态在生物体内存在吸收差异，其中共晶的血药浓度大于黄芩素原料本身，具有很强的现实应用价值。
附图说明
图1是实施例1提供的黄芩素咖啡因共晶的X-射线粉末衍射(XRPD)图。
图2是实施例1提供的黄芩素咖啡因共晶的热失重分析(TG)图。
图3是实施例1提供的黄芩素咖啡因共晶的差示扫描量热分析(DSC)图。
图4是实施例1提供的黄芩素咖啡因共晶的红外光谱(IR)图。
图5是实施例1提供的黄芩素咖啡因共晶的拉曼光谱(Raman)图。
图6是黄芩素本身以及黄芩素咖啡因共晶的粉末溶出速率曲线图。
图7是黄芩素大鼠口服(121mg/kg)后不同时间血液中药物浓度曲线图。
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。
实施例1
黄芩素咖啡因共晶(No.1)
将黄芩素(0.1mmol)和咖啡因(0.05mmol)按化学计量比2:1加入到丙酮(3毫升)和水(1毫升)的混合溶液中，完全溶解后，再在室温条件下缓慢挥发，得到黄芩素咖啡因共晶。
实施例2
黄芩素咖啡因共晶(No.2)
将黄芩素(0.1mmol)和咖啡因(0.05mmol)按化学计量比2:1加入到甲乙酮(3毫升)和水(1毫升)的混合溶液中，完全溶解后，再在室温条件下缓慢挥发，得到黄芩素咖啡因共晶。
实施例3
黄芩素咖啡因共晶(No.3)
将黄芩素(0.1mmol)和咖啡因(0.05mmol)按化学计量比2:1加入到四氢呋喃(2毫升)和乙腈(2毫升)的混合溶液中，完全溶解后，再在室温条件下缓慢挥发，得到黄芩素咖啡因共晶。
实施例4
黄芩素咖啡因共晶(No.4)
将黄芩素(0.1mmol)和咖啡因(0.05mmol)按化学计量比2:1加入到甲醇(2毫升)和乙腈(2毫升)的混合溶液中，完全溶解后，再在室温条件下缓慢挥发，得到黄芩素咖啡因共晶。
实施例5
黄芩素咖啡因共晶(No.5)
将黄芩素(0.1mmol)和咖啡因(0.05mmol)按化学计量比2:1加入到甲醇(4毫升)的混合溶液中，完全溶解后，再在室温条件下缓慢挥发，得到黄芩素咖啡因共晶。
实施例6
黄芩素咖啡因共晶(No.6)
将黄芩素(0.1mmol)和咖啡因(0.05mmol)按化学计量比2:1加入到甲醇(4毫升)的混合溶液中，完全溶解后，再在4℃条件下缓慢挥发，得到黄芩素咖啡因共晶。
实施例7
黄芩素咖啡因共晶(No.7)
将黄芩素(0.1mmol)和咖啡因(0.05mmol)按化学计量比2:1加入到甲醇(2毫升)和乙腈(2毫升)的混合溶液中，完全溶解后，再在4℃条件下缓慢挥发，得到黄芩素咖啡因共晶。
实施例8
黄芩素咖啡因共晶(No.8)
将黄芩素(0.1mmol)和咖啡因(0.025mmol)按化学计量比4:1加入到丙酮(3毫升)和水(1毫升)的混合溶液中，完全溶解后，再在室温条件下缓慢挥发，得到黄芩素咖啡因共晶。
实施例9
黄芩素咖啡因共晶(No.9)
将黄芩素(0.025mmol)和咖啡因(0.1mmol)按化学计量比1:4加入到乙醇(2毫升)和乙腈(2毫升)的混合溶液中，完全溶解后，再在室温条件下缓慢挥发，得到黄芩素咖啡因共晶。
本发明提供的一种黄芩素咖啡因共晶，通过X-射线粉末衍射(XRPD)、热失重分析(TG)、差示扫描量热分析(DSC)、红外(IR)以及拉曼(Raman)等固态方法表征。
对实施例1制得的黄芩素咖啡因共晶固体样品进行X-射线粉末衍射分析，其采用德国布鲁克仪器有限公司Bruker D8advance型的衍射仪，采用Cu–K射线
Figure PCTCN2016102618-appb-000004
Figure PCTCN2016102618-appb-000005
电压为40千伏，电流为40毫安，步径：0.02度，每步用时0.1秒。其分析结果见图1。
对实施例1制得的黄芩素咖啡因共晶固体样品进行热失重分析，其采用德国耐驰科学仪器有限公司TG20F3型热重分析仪，气氛为氮气，升温速率为10度/分钟。其分析结果见图2。
对实施例1制得的黄芩素咖啡因共晶固体样品进行差示扫描量热分析，其采用美国铂金埃尔默公司的DSC 8500差示量热仪检测，气氛为氮气，加热速度为10摄氏度/分钟。其分析结果见图3。
对实施例1制得的黄芩素咖啡因共晶固体样品进行红外光谱分析，其采用美国尼高力公司的Nicolet-Magna FT-IR 750红外光谱分析仪于室温检测，检测范围为：4000-350cm-1波数。其分析结果见图4。
对实施例1制得的黄芩素咖啡因共晶固体样品进行拉曼光谱分析，其采用美国热电公司的DXR显微拉曼光谱仪于室温检测，检测范围为：3500-50cm-1拉曼位移。其分析结果见图5。
实施例10
黄芩素咖啡因共晶与黄芩素本身的溶出速率比较
受试样品来源：黄芩素咖啡因共晶由本发明提供的方法制备；黄芩素原料购买于上海波以尔化工有限公司，纯度大于99％。
实验方法：将黄芩素咖啡因共晶，以及黄芩素与原料本身研磨后过100目筛，准确称量5毫克黄芩素，及具有相应含量的黄芩素共结晶7毫克，分别溶于15毫升溶出介质中，每隔一段时间取0.2毫升溶液，经水相微孔滤膜过滤，用高效液相监测各个时间点的溶液浓度，最终得到原料及共晶的粉末溶出速率曲线。
溶出条件：仪器：微量溶出仪
溶出介质：pH 2.0的0.5％的吐温水溶液
搅拌速度：75转数/分钟
溶出温度：37摄氏度
取样时间：5,10,15,20,30,40,60,80,100,120,150,180分钟
液相条件：仪器：安捷伦1260
流动相：甲醇：0.05％磷酸水溶液＝70:30
柱温：30摄氏度
流速：1毫升/分钟
实验结果：
图6：黄芩素咖啡因共晶以及黄芩素本身的粉末溶出速率。
显然，本发明提供的黄芩素咖啡因共晶比黄芩素本身具有更好的溶出性能，且其最大溶出浓度超过黄芩素原料本身的3倍以上。
实施例11
黄芩素原料、黄芩素和咖啡因的物理混合物、以及黄芩素咖啡因共晶在体内的吸收特征和血药浓度特征：
对清洁级大鼠胃内分别给予黄芩素固体原料药粉末、黄芩素和咖啡因的物理混合物粉末、黄芩素咖啡因共晶粉末的悬浮液(12mg/mL)，给药剂量为121mg/kg，在给药后不同时间点内抽取大鼠动脉血测定黄芩素含量。如图7所示，结果证明：黄芩素原料药与共晶在口服同样剂量的条件下，血液中的药物浓度和达到高峰浓度的时间不同，其中共晶的血药浓度明显高于原料药粉末以及物理混合物的血药浓度。
所述药物组合物的配方包含黄芩素咖啡因共晶以及药学上可接受的载体，所述可接受的载体包括稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、助流剂。
稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等。
润湿剂可以是水、乙醇、异丙醇等。
粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羟甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等。
崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等。
润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
根据药物组合物的剂型选用不同的载体进行组合，药物组合物与几种载体混合后可制成片剂、胶囊、颗粒剂等不同的剂型，该药物组合物的片剂、胶囊、颗粒剂等剂型的制备方法与本领域常规的片剂、胶囊剂、颗粒剂等剂型的制备方法相同。
由于黄芩素原料本身具有制备防治神经系统疾病、心脑血管系统疾病、炎症、免疫系统疾病、代谢性疾病、老年性疾病及细菌和病毒感染疾病的药物中的作用，本发明提供的黄芩素咖啡因共晶在制备防治神经系统疾病、心脑血管系统疾病、炎症、免疫系统疾病、代谢性疾病、老年性疾病及细菌和病毒感染疾病的药物中的应用在此不再赘述。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (12)

  1. 一种黄芩素咖啡因共晶，其特征在于，所述黄芩素咖啡因共晶具有3个或3个以上选自下组的特征衍射峰：3.55、6.20、7.09、9.53、10.62、12.43、14.46、16.60、17.76、18.96，误差为±0.2度。
  2. 如权利要求1所述的黄芩素咖啡因共晶，其特征在于，所述黄芩素咖啡因共晶的X-射线粉末衍射图基本如图1所示。
  3. 如权利要求1所述的黄芩素咖啡因共晶，其特征在于，所述黄芩素咖啡因共晶的差示扫描量热分析图谱在208.2±0.2℃有特征熔融峰。
  4. 如权利要求1所述的黄芩素咖啡因共晶，其特征在于，所述黄芩素咖啡因共晶的红外图谱至少在3320cm-1、3115cm-1、1699cm-1、1644cm-1、1588cm-1、1553cm-1、1474cm-1、1450cm-1、1421cm-1、1366cm-1、1328cm-1、1273cm-1、1239cm-1、1187cm-1、1166cm-1、1101cm-1、1073cm-1、1033cm-1、896cm-1、857cm-1、798cm-1、763cm-1、684cm-1、614cm-1、578cm-1、489cm-1处具有特征峰。
  5. 如权利要求1所述的黄芩素咖啡因共晶，其特征在于，所述黄芩素咖啡因共晶的拉曼图谱至少在1666cm-1、1618cm-1、1605cm-1、1582cm-1、1508cm-1、1459cm-1、1334cm-1、1256cm-1、1006cm-1、623cm-1、559cm-1、491cm-1处具有特征峰。
  6. 如权利要求1所述的黄芩素咖啡因共晶，其特征在于，所述黄芩素咖啡因共晶具有选自下组的一个或多个特征：
    (1)所述黄芩素咖啡因共晶的热失重分析图谱在加热至315.0℃失重97％；
    (2)所述黄芩素咖啡因共晶为单斜晶系，空间群为P21/c，晶胞参数为：
    Figure PCTCN2016102618-appb-100001
    α＝90°；β＝90.320(8)°；γ＝90°，晶胞体积为
    Figure PCTCN2016102618-appb-100002
    (3)所述黄芩素咖啡因共晶的热失重分析图基本如图2所示；
    (4)所述黄芩素咖啡因共晶的差示扫描量热分析图基本如图3所示；
    (5)所述黄芩素咖啡因共晶的红外光谱图基本如图4所示；和/或
    (6)所述黄芩素咖啡因共晶的拉曼光谱基本如图5所示。
  7. 如权利要求1-6任一项所述的黄芩素咖啡因共晶的制备方法，其特征在于，包括如下步骤：
    a.将黄芩素和咖啡因溶解于溶剂中，形成黄芩素咖啡因溶液，其中，所述溶剂选自下组：甲醇、乙醇、异丙醇、正丙醇、丙酮、四氢呋喃、乙腈、乙酸乙酯、 甲乙酮、甲苯、氯仿、二氯甲烷、水、或其组合；
    b.对所述黄芩素咖啡因溶液进行结晶处理，形成黄芩素咖啡因的共结晶溶液体系；
    c.从所述共结晶溶液体系中分离得到黄芩素咖啡因共晶。
  8. 如权利要求7所述的制备方法，其特征在于，所述步骤(c)包括：
    (c1)对所述共结晶溶液体系进行过滤，获得黄芩素咖啡因共晶；和/或
    (c2)对所述共结晶溶液体系进行离心，获得黄芩素咖啡因共晶；和/或
    (c3)对所述共结晶溶液体系进行加热，蒸发去除所述有机溶剂，获得黄芩素咖啡因共晶。
  9. 如权利要求7所述的制备方法，其特征在于，所述步骤(a)中，所述黄芩素和咖啡因的摩尔比为4:1-1:4。
  10. 如权利要求7所述的制备方法，其特征在于，步骤(b)中，所述的结晶处理包括向所述黄芩素咖啡因溶液中添加晶种。
  11. 一种药物组合物，其特征在于，所述药物组合物包括权利要求1-6任一项所述的黄芩素咖啡因共晶以及药学上可接受的载体。
  12. 如权利要求1-6任一项所述的黄芩素咖啡因共晶在制备防治神经系统疾病、心脑血管系统疾病、炎症、免疫系统疾病、代谢性疾病、老年性疾病及细菌和病毒感染疾病的药物中的应用。
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