CN105218500B - 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 PDFInfo
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- CN105218500B CN105218500B CN201510733116.0A CN201510733116A CN105218500B CN 105218500 B CN105218500 B CN 105218500B CN 201510733116 A CN201510733116 A CN 201510733116A CN 105218500 B CN105218500 B CN 105218500B
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Classifications
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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
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Abstract
本发明属于化学药物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。本发明运用X‑射线粉末衍射分析、热失重分析、差示扫描量热分析等手段对黄芩素咖啡因共晶进行了全面表征，发现黄芩素咖啡因共晶具有更加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
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：
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、盐及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℃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加热至315.0℃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α＝90°；β＝90.320(8)°；γ＝90°；晶胞体积为
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、丙酮、四氢呋喃、乙腈、乙酸乙酯、甲乙酮、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，所述药物组合物包括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咖啡因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
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
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
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
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
将黄芩素0.1mmol和咖啡因0.05mmol按化学计量比2:1加入到4毫升甲醇中，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
将黄芩素0.1mmol和咖啡因0.05mmol按化学计量比2:1加入到4毫升甲醇中，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
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
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
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 D8 advance型的衍射仪，采用Cu-Kα射线电压为40千伏，电流为40毫安，步径：0.02度，每步用时0.1秒。其分析结果见附图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摄氏度/分钟。其分析结果见附图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。其分析结果见附图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。其分析结果见附图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波数。其分析结果见附图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咖啡因共晶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/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曲线。
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 (9)
1.黄芩素咖啡因共晶，其特征在于，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。
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差示扫描量热分析图谱在208.2±0.2℃有特征熔融峰。
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。
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。
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热失重分析图谱在加热至315.0℃失重97％。
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为单斜晶系，空间群为P21/c，晶胞参数为： α＝90°；β＝90.320(8)°；γ＝90°；晶胞体积为
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.将黄芩素和咖啡因按摩尔比2:1溶解于有机溶剂中，形成黄芩素咖啡因溶液；所述有机溶剂为乙醇、四氢呋喃、乙腈、乙酸乙酯、甲乙酮或水中的一种或两种以上的混合物；
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。
8.一种药物组合物，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。
9.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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