CN113214207B - 橙皮素与甜菜碱共晶物a及制备方法和其组合物与用途 - Google Patents
橙皮素与甜菜碱共晶物a及制备方法和其组合物与用途 Download PDFInfo
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- CN113214207B CN113214207B CN202010080008.9A CN202010080008A CN113214207B CN 113214207 B CN113214207 B CN 113214207B CN 202010080008 A CN202010080008 A CN 202010080008A CN 113214207 B CN113214207 B CN 113214207B
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- betaine
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Abstract
本发明公开了橙皮素与甜菜碱共晶物A及制备方法和其组合物与用途，属于医药技术领域。具体而言，本发明公开了一种橙皮素与甜菜碱形成的共晶物A，该共晶物的分子式为(C16H14O6)·(C5H11NO2)；橙皮素与甜菜碱共晶物A的制备方法；橙皮素与甜菜碱共晶物A作为药物有效成分，在制备抗氧化、抗炎、心脑血管疾病、癫痫、肝肾损伤、抗肿瘤、神经疾病及治疗阿尔兹海默症疾病及并发症药物中的应用。
Description
技术领域
本发明涉及了一种橙皮素-甜菜碱形成的共晶物A；橙皮素与甜菜碱共晶物A的制备方法；橙皮素与甜菜碱共晶物A作为药物有效成分，在制备抗氧化、抗炎、心脑血管疾病、癫痫、肝肾损伤、抗肿瘤、神经疾病及治疗阿尔兹海默症疾病及并发症药物中的应用；属于医药技术领域。
背景技术
橙皮素(英文名：Hesperetin)是广泛存在于柑橘属植物果中的二氢黄酮类化合物，是橙皮苷的水解产物，结构式如a所示，能够起到抗肿瘤、抗氧化、抗炎症、防止动脉粥样硬化的作用[1-3]。
甜菜碱(英文名：Betaine)是从枸杞中提取的一种季铵型水溶性生物碱，具有多种良好的理化性状及生物学功能，被广泛地应用于制药、食品、添加剂等多个领域，结构式如b所示。甜菜碱能够具有抗炎、治疗心脑血管疾病、抗癫痫、改善肝肾损伤、抗肿瘤，还具有抑制神经疾病及治疗阿尔兹海默症等多种药理作用[4-11]。
关于橙皮素的多晶型研究：目前发现的橙皮素具有两种晶型状态[12-13],其中研究晶A型为含一分子水的橙皮素，晶B型为不含水晶型。这两种晶型物质与本发明在物质组成上存在本质差异，本专利使用的橙皮素原料药为晶B型。
综上所述，迄今没有见到橙皮素-甜菜碱形成共晶物的研究报道，在物质形态、组合比例、制备方法以及用途等方面，也未见与本发明相似或冲突研究内容。
发明内容
本发明是通过将橙皮素-甜菜碱制备成为具有特定非共价作用力的共晶物固体物质，从而形成有别于橙皮素和甜菜碱及二者简单联合应用的新物质，进而发现本发明的新共晶物固体物质在制备抗氧化、抗炎、心脑血管疾病、癫痫、肝肾损伤、抗肿瘤、神经疾病及治疗阿尔兹海默症等相关疾病及并发症的治疗中的特殊优势。
本发明要解决的技术问题：
本发明要解决的技术问题之一：提供橙皮素与甜菜碱共晶物A存在状态和表征方式。
本发明要解决的技术问题之二：提供橙皮素与甜菜碱共晶物A的制备方法。
本发明要解决的技术问题之三：提供使用橙皮素与甜菜碱共晶物A作为药物活性成分的药物组合物，其每次用药剂量在10-1000mg范围内。所述的药物组合物包括片剂、胶囊、丸剂、针剂、缓释或控释制剂药物。
本发明要解决的技术问题之四：是提供橙皮素与甜菜碱共晶物A治疗疾病过程中由于二者共晶物结合而提高生物体内血药浓度而发挥药物有效治疗作用。
本发明要解决的技术问题之五：是提供了使用橙皮素与甜菜碱共晶物A及其混合晶型固体物质作为药物有效成分的原料，在制备抗氧化、抗炎、心脑血管疾病、癫痫、肝肾损伤、抗肿瘤、神经疾病及治疗阿尔兹海默症疾病及并发症药物中的应用。
为解决上述技术问题，本发明采用如下技术方案：
1.橙皮素与甜菜碱共晶物A样品形态特征：
1.1本发明涉及的橙皮素与甜菜碱共晶物A，橙皮素-甜菜碱以非共价键相结合形成共晶物质，二者的摩尔比为1:1。
1.2本发明涉及的橙皮素与甜菜碱共晶物A，不含有结晶溶剂或结晶水成分，当使用粉末X射线衍射分析，采用CuKα辐射实验条件时，表现为衍射峰位置：2-Theta 值(°)或d值衍射峰相对强度峰高值(Height％)或峰面积值(Area％)具有如下特征峰值时的固体物质(表1，图1)。橙皮素-甜菜碱原料的物理混合物的粉末X 射线衍射图谱数据见图2、表2。橙皮素与甜菜碱共晶物A与橙皮素-甜菜碱原料的物理混合物的粉末X射线衍射图谱在衍射峰数量、衍射峰位置、衍射峰强度、衍射峰拓扑图形等方面均存在明显差异，表明橙皮素与甜菜碱共晶物A与橙皮素-甜菜碱原料的物理混合物既不相同也不等同。
表1橙皮素与甜菜碱共晶物A的粉末X射线衍射峰值
表2橙皮素-甜菜碱物理混合的粉末X射线衍射峰值
1.3本发明涉及的橙皮素与甜菜碱共晶物A，使用衰减全反射傅立叶红外光谱法进行分析时，在3056，2973，2846，2752，2619，2167，2015，1723，1711，1641， 1634，1607，1594，1533，1516，1488，1473，1459，1447，1434，1426，1397， 1388，1336，1305，1280，1269，1244，1221，1185，1176，1161，1133，1089， 1065，1025，1012，978，968，955，935，896，863，838，830，812，781，762， 744，713，658cm-1处存在红外光谱特征峰，其中红外光谱特征峰的允许偏差为±2 cm-1(图3)。
1.4根据权利要求1所述的橙皮素与甜菜碱共晶物A，其特征在于，使用差示扫描量热技术分析时，表现为在30～250℃范围内，升温速率为每分钟10℃时，其DSC 图谱中在187℃±3℃处存在1个吸热峰(图4)。橙皮素与甜菜碱共晶物A与橙皮素、甜菜碱的DSC图谱在吸/放热峰数量、位置等方面均存在明显差异，表明橙皮素与甜菜碱共晶物A与橙皮素及甜菜碱原料的既不相同也不等同(图5)。
2.橙皮素与甜菜碱共晶物A的制备方法特征：
2.1本发明所涉及的的橙皮素与甜菜碱共晶物A的制备方法，采用溶剂混悬法，将橙皮素与甜菜碱按摩尔比1:1混合，加入有机溶剂，室温，搅拌器的搅拌转速 20r/min～400r/min，搅拌1小时～96小时，所获得的混悬液通过溶剂蒸发干燥、过滤自然干燥或过滤真空干燥，制备获得橙皮素与甜菜碱共晶物A。所述的有机溶剂优选自甲醇、乙醇、乙酸乙酯、二氧六环、正丙醇、异丙醇中的任意一种或多种经不同配比组合制成的混合溶剂；保持橙皮素-甜菜碱总质量与有机溶剂固液比为1mg/ml～500mg/ml范围内。
2.2本发明的橙皮素与甜菜碱共晶物A的混合固体物质，是将上述方法制备获得的橙皮素与甜菜碱共晶物A成分，与其他化学物质按照任意非零比例和常规的方法进行混合。
3.含有橙皮素与甜菜碱共晶物A成分、给药剂量及药物制剂组合物特征：
3.1本发明涉及的药物组合物，含有有效剂量的橙皮素与甜菜碱共晶物A和药学上可接受的载体。
3.2本发明涉及的药物组合物，橙皮素与甜菜碱共晶物A的每日用药剂量在10 mg～1000mg范围内。
3.3本发明涉及的药物组合物，所述药物组合物的剂型是片剂、胶囊、丸剂、针剂、缓释制剂或控释制剂。
3.4本发明涉及的橙皮素与甜菜碱共晶物A在制备各种预防或治疗制备抗氧化、抗炎、心脑血管疾病、癫痫、肝肾损伤、抗肿瘤、神经疾病及治疗阿尔兹海默症等疾病及并发症药物中的应用。
本发明涉及以本发明橙皮素与甜菜碱共晶物A为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明橙皮素与甜菜碱共晶物A与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明橙皮素与甜菜碱共晶物A成分通常为10-90％重量范围内。
本发明橙皮素与甜菜碱共晶物A可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
本发明的给药剂型优选是固体剂型。固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等。
本发明橙皮素与甜菜碱共晶物A、本发明橙皮素与甜菜碱共晶物A的混合固体物质可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明橙皮素与甜菜碱共晶物A制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、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；湿润剂可以是水、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、羧甲基纤维素钠、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。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明橙皮素与甜菜碱共晶物A 与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明橙皮素与甜菜碱共晶物A先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明橙皮素与甜菜碱共晶物A成分片剂的各种稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明橙皮素与甜菜碱共晶物A的胶囊剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
4.含有橙皮素与甜菜碱共晶物A的用途：
本发明发现了橙皮素与甜菜碱共晶物A在制备和/或治疗抗氧化、抗炎、心脑血管疾病、癫痫、肝肾损伤、抗肿瘤、神经疾病及治疗阿尔兹海默症疾病及并发症药物中的应用。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明橙皮素与甜菜碱共晶物A的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明橙皮素与甜菜碱共晶物A可单独服用，或与其他治疗药物或对症药物合并使用。当本发明橙皮素与甜菜碱共晶物A与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明的技术方案具有如下有益技术效果：
本发明的橙皮素与甜菜碱共晶物A在安全性、稳定性、溶解性和生物活性等方面和现有技术中的橙皮素相比具有显著优势。
本发明的橙皮素与甜菜碱共晶物A不含任何结晶溶剂，具有良好的安全性成药优势。
本发明涉及的橙皮素与甜菜碱共晶物A，与橙皮素相比，具有预料不到的溶解性优势，具体体现在：在盐酸盐缓冲液(pH1.2)、醋酸盐缓冲液(pH4.5)、磷酸盐缓冲液(pH6.8)等溶出体系中表现出显著的溶解度与溶解速率优势(图6)。
本发明涉及的橙皮素与甜菜碱共晶物A，在高温(60℃)、光照(4500lx±500lx) 条件下均可以稳定存在，具有良好的稳定性成药优势(图7)。
附图说明
图1橙皮素与甜菜碱共晶物A的粉末X射线衍射图谱
图2橙皮素与甜菜碱共晶物A的物理混合物的粉末X射线衍射图谱
图3橙皮素与甜菜碱共晶物A的红外吸收光谱图
图4橙皮素与甜菜碱共晶物A的差示扫描量热图谱
图5橙皮素与甜菜碱共晶物A及原料的差示扫描量热图谱
图6橙皮素与甜菜碱共晶物A样品的溶出曲线图谱
图7橙皮素与甜菜碱共晶物A的稳定性图谱
具体实施方式
为更好说明本发明的技术方案，特给出以下实施例，但本发明并不仅限于此。
实施例1
橙皮素与甜菜碱共晶物A制备方法
取橙皮素与甜菜碱适量，二者摩尔比为1:1，室温下采用溶剂混悬法将样品加入适宜容器中，加入适量有机溶剂，于室温条件下搅拌适当时间，将所得的混悬液溶剂蒸发干燥、过滤自然干燥或过滤真空干燥，条件参数参见表3。对其进行粉末X射线衍射分析，其衍射图谱与图1一致，表明所得样品为橙皮素与甜菜碱共晶物A。
表3橙皮素与甜菜碱共晶物A制备方法1具体实例
实施例2
橙皮素-甜菜碱体外溶出释放特征
考察了橙皮素与甜菜碱共晶物A与原料药及橙皮素在pH值为1.2，pH值为 4.5，pH值为6.8的溶液系统中的溶解性特征。参照《普通口服固体制剂溶出度试验技术指导原则》进行实验测定，溶解百分含量采用用高效液相法，以外标法计算其溶解百分含量。以时间为横坐标，溶解百分含量为纵坐标分别绘制溶解曲线 (图6)。数据见表4。
检测条件：检测系统：Aligent 1200，色谱柱：Agilent Eclipse XDB-C18(4.6 ×150mm,5μm)；流动相：甲醇-水(70:30，v/v)；流速：1mL·min-1；柱温：30℃；检测波长：橙皮素：280nm；进样量：10μl。
表4溶出曲线数据
由实验数据可以看出，橙皮素与甜菜碱共晶物在盐酸盐缓冲溶液、醋酸盐缓冲液、磷酸盐缓冲液体系中的溶解行为均优于橙皮素，具体体现在橙皮素与甜菜碱共晶物具有更快速的溶解速率和更高的溶解量，易于更快速地吸收达到有效血药浓度，其吸收总量亦有明显增加，溶解量约为橙皮素的1.5倍，可以更好地实现药物的疾病治疗作用；橙皮素与甜菜碱共晶物的溶解性曲线具有稳定的释放平台，可保证在疾病治疗过程中保持稳定的血药浓度。
实施例3
橙皮素与甜菜碱共晶物A的稳定性优势
高温试验：将取橙皮素与甜菜碱共晶物A样品置开口洁净表面皿中，在60℃温度下放置10天，并于第0天、第5天和第10天取样。将上述取样点所得样品进行粉末X射线衍射分析，结果表明橙皮素与甜菜碱共晶物A在高温影响因素试验下稳定。
光照试验：将橙皮素与甜菜碱共晶物A样品置开口洁净表面皿中，放在装有日光灯的光照箱，于照度为4500lx±500lx的条件放置10天，并于第0天、第5天和第10 天取样。将上述取样点所得样品进行粉末X射线衍射分析，结果表明橙皮素与甜菜碱共晶物A在光照条件下稳定。(图7)
实施例4
组合药物制剂的制备方法1(片剂)：
一种组合药物片剂的制备方法，其特征是使用橙皮素与甜菜碱共晶物A纯品作为组合药物的原料药、使用几种赋形剂作为制备组合药物片剂的辅料成分，按照一定比例配比制成每片含药量在10～500mg的片剂样品，表5给出片剂配方比例：
表5橙皮素与甜菜碱共晶物A组合药物片剂的制备配方
将橙皮素与甜菜碱共晶物A物质纯品原料药制备成片剂制剂的方法是：将几种赋形剂与原料药混合均匀，直接压片；或辅料混合干法制粒再与原料药混合均匀后压片，即得。
组合药物制剂的制备方法2(片剂)：
一种组合药物片剂的制备方法，其特征是使用橙皮素与甜菜碱共晶物A纯品为组合药物的原料药、使用几种赋形剂作为制备组合药物片剂的辅料成分，按照一定比例配比制成每片含药量在10～500mg的片剂样品，表6给出片剂配方比例：
表6橙皮素与甜菜碱共晶物A组合药物片剂的制备配方
将橙皮素与甜菜碱共晶物A物质纯品原料药制备成片剂制剂的方法是：将几种赋形剂与原料药混合均匀，加入1％羟甲基纤维素钠溶液适量，制成软料，过筛制粒，湿粒烘干，过筛整粒，加入硬脂酸镁和滑石粉混合均匀，压片，即得。
组合药物制剂的制备方法3(胶囊)：
一种组合药物胶囊的制备方法，其特征是使用橙皮素与甜菜碱共晶物A物质纯品作为组合药物的原料药、使用几种赋形剂作为制备组合药物胶囊的辅料成分，按照一定比例配比制成每片含药量在10～500mg的胶囊样品，表7给出胶囊配方比例：
表7橙皮素与甜菜碱共晶物A组合药物胶囊制剂的原料药和辅料配方
将橙皮素与甜菜碱共晶物A原料药制备成片剂制剂的方法是：将几种赋形剂与原料药混合均匀，加入1％羟甲基纤维素钠溶液适量，制成湿粒烘干过筛整粒，加入硬脂酸镁混合均匀，插入胶囊制得；或不使用制粒步骤，而直接将橙皮素与甜菜碱共晶物A物质原料药与几种赋形剂辅料混合均匀，过筛后，直接装入胶囊制得。
实施例5
橙皮素与甜菜碱共晶物A组合药物的给药剂量1(片剂)：
使用橙皮素与甜菜碱共晶物A样品作为药物活性成分制备开发的药物组合物，其特征是使用橙皮素与甜菜碱共晶物A作为药物的活性成分，每日给药剂量为300mg，可分别制备成每日3次/每次1片100mg普通片剂，或每日1次/每次1 片300mg的片剂类。
橙皮素与甜菜碱共晶物A组合药物的给药剂量2(胶囊)：
使用橙皮素与甜菜碱共晶物A样品作为药物活性成分制备开发的药物组合物，其特征是使用橙皮素与甜菜碱共晶物A作为药物的活性成分，每日给药剂量为500mg，可分别制备成每日2次/每次1粒250mg胶囊，或每日1次/每次1粒 500mg胶囊。
需要说明的问题：本发明涉及的橙皮素与甜菜碱共晶物A药物组合物在有效成分的给药剂量上存在有许多因素影响，例如：用于预防和治疗的用途不同而造成每日用药剂量的不同；患病性质与患病严重程度不同而造成每日用药剂量的不同；患者性别、年龄、体表面积的不同，给药途径、给药次数、治疗目的不同而造成每日用药剂量的不同；此外，晶型样品间存在的吸收和血药浓度不同等，亦造成本发明在使用橙皮素与甜菜碱共晶物A成分的每日合适剂量范围为0.002-20mg/kg体重，优选为0.01-10mg/kg体重。使用时应根据实际的预防与治疗不同情况需求制定不同的橙皮素与甜菜碱共晶物A有效成分总剂量方案，并可分为多次或一次给药方式完成。
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Claims (14)
1.一种橙皮素与甜菜碱共晶物A，其特征在于，橙皮素与甜菜碱按照1:1摩尔比以非共价键形成共晶物A，当使用粉末X射线衍射分析采用CuKα辐射实验条件时，衍射峰位置：2-Theta值(°)或d值和衍射峰相对强度：峰高值(Height％)或峰面积值(Area％)具有如下特征：
2.根据权利要求1所述的橙皮素与甜菜碱共晶物A，其特征在于，使用衰减全反射傅立叶红外光谱法进行分析时，在3056，2973，2846，2752，2619，2167，2015，1723，1711，1641，1634，1607，1594，1533，1516，1488，1473，1459，1447，1434，1426，1397，1388，1336，1305，1280，1269，1244，1221，1185，1176，1161，1133，1089，1065，1025，1012，978，968，955，935，896，863，838，830，812，781，762，744，713，658cm-1处存在红外光谱特征峰，其中红外光谱特征峰的允许偏差为±2cm-1。
3.根据权利要求1所述的橙皮素与甜菜碱共晶物A，其特征在于，使用差示扫描量热技术分析时，表现为在30～250℃范围内，升温速率为每分钟10℃时，其DSC图谱中在187℃±3℃处存在1个吸热峰。
4.一种如权利要求1-3任一所述的橙皮素与甜菜碱共晶物A的制备方法，其特征在于，将橙皮素与甜菜碱按照1:1的摩尔比例投料，采用溶剂混悬的化学方法制备获得橙皮素与甜菜碱共晶物A。
5.根据权利要求4的制备方法，所述溶剂混悬法中溶剂的选自为甲醇、乙醇、乙酸乙酯、二氧六环、正丙醇、异丙醇中的一种或多种；搅拌器的搅拌转速20r/min～400r/min；搅拌时间为1小时～96小时，所获得的混悬液通过溶剂蒸发干燥、过滤自然干燥或过滤真空干燥制备获得橙皮素与甜菜碱共晶物A。
6.一种含有橙皮素与甜菜碱共晶物A的混合固体物质，其特征在于，含有权利要求1-3任一项所述的橙皮素与甜菜碱共晶物A的量为1-99.9％。
7.一种含有橙皮素与甜菜碱共晶物A的混合固体物质，其特征在于，含有权利要求1-3任一项所述的橙皮素与甜菜碱共晶物A的量为10-99.9％。
8.一种含有橙皮素与甜菜碱共晶物A的混合固体物质，其特征在于，含有权利要求1-3任一项所述的橙皮素与甜菜碱共晶物A的量为50-99.9％。
9.一种含有橙皮素与甜菜碱共晶物A的混合固体物质，其特征在于，含有权利要求1-3任一项所述的橙皮素与甜菜碱共晶物A的量为85-99.9％。
10.一种药物组合物，其特征在于，含有有效剂量的权利要求1-3中任一项的橙皮素与甜菜碱共晶物A和药学上可接受的载体。
11.一种药物组合物，其特征在于，含有有效剂量的权利要求6-9任一项所述的橙皮素与甜菜碱共晶物A的混合固体物质和药学上可接受的载体。
12.根据权利要求10或11的药物组合物，其特征在于，橙皮素与甜菜碱共晶物A的每日用药剂量在10mg～1000mg范围内。
13.根据权利要求10或11的药物组合物，其特征在于，所述药物组合物的剂型是片剂、胶囊、丸剂、粉针剂、缓释制剂或控释制剂。
14.权利要求1-3中任一项所述的橙皮素与甜菜碱共晶物A或权利要求10或11所述的药物组合为药物活性成分在制备抗氧化、抗炎、抗心脑血管疾病、抗癫痫、抗肝肾损伤、抗肿瘤、抗神经疾病及治疗阿尔兹海默症疾病及并发症药物中的应用。
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