CN110668932A - 一种共晶体及制备方法、包含共晶体的药物组合物及用途 - Google Patents

一种共晶体及制备方法、包含共晶体的药物组合物及用途 Download PDF

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CN110668932A
CN110668932A CN201910852708.2A CN201910852708A CN110668932A CN 110668932 A CN110668932 A CN 110668932A CN 201910852708 A CN201910852708 A CN 201910852708A CN 110668932 A CN110668932 A CN 110668932A
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刘湖
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Abstract

本发明公开了一种共晶体及制备方法、包含共晶体的药物组合物及用途。共晶体由姜黄素的氢化产物与有机酸类化合物、葡甲胺、2‑羟基苯乙酮、4‑胺基苯酚、(异)烟酰胺、甘露醇、或山梨醇中的任意一种制备而成，制备得到的该共晶体可以制备用于治疗癌症、消除炎症、治疗创伤、预防或治疗老年痴呆、防治骨质疏松和/或促进骨愈合、降血脂、治疗脂肪肝以及伴有高血脂症、糖尿病的相关代谢性综合征疾病或美容美白的药物。在实际应用中，发现姜黄素的氢化产物在共晶体药物中的生物利用度得到了明显提高，极大地扩展了其临床应用。

Description

一种共晶体及制备方法、包含共晶体的药物组合物及用途
技术领域
本发明涉及医药技术领域，尤其涉及一种共晶体及制备方法、包含共晶体的药物组合物及用途。
背景技术
姜黄素是姜黄中的主要成分，具有抗氧化、抗肿瘤、降血脂、降血糖、抗溃疡、保护肝脏、抗心肌缺血、抗抑郁、抗菌、消炎、抗病毒和抗真菌等作用，可用于治疗癌症、糖尿病、冠心病、关节炎、阿尔茨海默氏病(早老性痴呆)以及其他慢性疾病。
四氢姜黄素、四氢去甲氧基姜黄素、四氢双去甲氧基姜黄素是姜黄素的氢化产物，具有类似姜黄素的药理作用，研究已发现其具有较强的抗癌活性、抗氧化、自由基清除、降血糖、降血脂等多种药理活性，另外还发现四氢姜黄素对代谢综合征、肥胖型2型糖尿病、高血压以及胰岛素抵抗综合征等相关疾病均有较好治疗效。大量的实验结果表明，其生物活性均优于姜黄素。
但是，在实际应用中，发现四氢姜黄素(SHCUR)及其衍生物四氢去甲氧基姜黄素(SHDMCUR)和四氢双去甲氧基姜黄素(SHDDMCUR)的生物利用度非常低，极大地限制了其临床应用。
发明内容
本发明的目的在于提供一种共晶体及制备方法、包含共晶体的药物组合物及用途，从而解决现有技术中存在的前述问题。
为了实现上述目的，本发明采用的技术方案如下：
本发明一方面提供了一种共晶体，由原料A和B制备而成，其中，A的化学结构式为：
Figure BDA0002197334390000011
R1和R2为H或OCH3，
B为有机酸类化合物、葡甲胺、2-羟基苯乙酮、4-胺基苯酚、(异)烟酰胺、甘露醇、或山梨醇中的任意一种。
优选地，所述有机酸类化合物选自长链脂肪酸类化合物、苯甲酸衍生物类化合物、有机二酸类化合物和氨基酸类化合物。
优选地，所述长链脂肪酸类化合物选自辛酸、癸酸和月桂酸中的任意一种。
优选地，所述苯甲酸衍生物类化合物选自苯甲酸、邻羟基苯甲酸、对羟基苯甲酸、间羟基苯甲酸、邻苯二甲酸、间苯二甲酸、对苯二甲酸和均苯三甲酸中的任意一种。
优选地，所述有机二酸类化合物选自草酸、丁二酸、戊二酸、己二酸、富马酸和马来酸中的任意一种。
优选地，所述氨基酸类化合物选自丙氨酸、精氨酸、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、组氨酸、异亮氨酸、甘氨酸、天冬酰胺、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸中的任意一种。
本发明另一方面提供了一种共晶体的制备方法，包括
按照1:1～2:1的摩尔比混合原料A和B，并加入去离子水，搅拌均匀后，升温至60～80℃，搅拌反应1～3h；
反应完毕后过滤反应液，得到滤液；
滤液在室温放置60～72h，析出共晶体。
本发明第三方面提供了一种包含共晶体的药物组合物，由上述共晶体以及药学可接受的添加剂制备而成。
优选地，所述药物组合物的剂型为冻干粉、片剂、含片、胶囊及软胶囊剂、颗粒剂、糖浆剂、微丸剂、微球剂、丹剂、水剂、口服液和膏剂中的任意一种。
本发明第四方面提供了一种共晶体在制备用于治疗癌症、消除炎症、治疗创伤、预防或治疗老年痴呆、防治骨质疏松和/或促进骨愈合、降血脂、治疗脂肪肝以及伴有高血脂症、糖尿病的相关代谢性综合征疾病或美容美白药物中的用途。
本发明的有益效果是：本发明提供的共晶体及制备方法、包含共晶体的药物组合物及用途，其中，共晶体由姜黄素的氢化产物与有机酸类化合物、葡甲胺、2-羟基苯乙酮、4-胺基苯酚、(异)烟酰胺、甘露醇、或山梨醇中的任意一种制备而成，制备得到的该共晶体可以制备用于治疗癌症、消除炎症、治疗创伤、预防或治疗老年痴呆、防治骨质疏松和/或促进骨愈合、降血脂、治疗脂肪肝以及伴有高血脂症、糖尿病的相关代谢性综合征疾病或美容美白的药物。在实际应用中，发现姜黄素的氢化产物在共晶体药物中的生物利用度得到了明显提高，极大地扩展了其临床应用。
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方式仅仅用以解释本发明，并不用于限定本发明。
实施例一
本发明提供了一种共晶体，由原料A和B制备而成，其中，A的化学结构式为：
Figure BDA0002197334390000031
如果R1＝R2＝OCH3，则原料A为四氢姜黄素；如果R1＝H，R2＝OCH3，则原料A为四氢去甲氧姜黄素；如果R1＝R2＝H，则原料A为四氢双去甲氧姜黄素。
原料B可以为长链脂肪酸类化合物、苯甲酸衍生物类化合物、有机二酸类化合物和氨基酸类化合物中的任意一种。
其中，所述长链脂肪酸类化合物包括辛酸、癸酸和月桂酸中的任意一种。
所述苯甲酸衍生物类化合物包括苯甲酸、邻羟基苯甲酸、对羟基苯甲酸、间羟基苯甲酸、邻苯二甲酸、间苯二甲酸、对苯二甲酸和均苯三甲酸中的任意一种。
所述有机二酸类化合物包括草酸、丁二酸、戊二酸、己二酸、富马酸和马来酸中的任意一种。
所述氨基酸类化合物包括丙氨酸、精氨酸、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、组氨酸、异亮氨酸、甘氨酸、天冬酰胺、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸中的任意一种。
在制备过程中，按照1:1～2:1的摩尔比混合原料A和B，并加入去离子水，搅拌均匀后，升温至60～80℃，搅拌反应1～3h；
反应完毕后过滤反应液，得到滤液；
滤液在室温放置60～72h，析出共晶体。
利用上述的原料A和B按照上述方法制备得到的各共晶体，其缩写形式及X-射线粉末衍射图谱中的特征峰如表1所示。
表1各共晶体的缩写及X-射线粉末衍射图谱中的特征峰
Figure BDA0002197334390000041
Figure BDA0002197334390000051
Figure BDA0002197334390000061
Figure BDA0002197334390000071
实施例二
利用实施例一制备得到的共晶体以及药学可接受的添加剂制备得到共晶药物，该共晶药物的剂型可以为冻干粉、片剂、含片、胶囊及软胶囊剂、颗粒剂、糖浆剂、微丸剂、微球剂、丹剂、水剂、口服液和膏剂中的任意一种。
实施例一制备得到的共晶体可以用于制备治疗癌症、消除炎症、治疗创伤、预防或治疗老年痴呆、防治骨质疏松和/或促进骨愈合、降血脂、治疗脂肪肝以及伴有高血脂症、糖尿病的相关代谢性综合征疾病或美容美白药物。
本实施例中，对含有共晶体的药物功能进行实验。
实验例1---体内抗肿瘤实验
动物肿瘤模型的建立：C57小鼠(18-22g)，将人胃癌SGC-7901细胞、人肝癌Bet-7402细胞、人肺癌H460细胞复苏，分别在小鼠腋窝皮下接种，肿瘤生长达到直径2cm左右时，将小鼠颈椎去臼处死。
取出瘤块，按每克肿瘤组织3mL生理盐水的比例，制成肿瘤细胞匀浆，用匀浆给昆明小鼠腋窝皮下接种，每鼠接种0.2mL。
将动物随机分组、称重，每组12只老鼠，设阴性对照组、紫杉醇阳性对照组，SHCUR组、SHDMCUR组、SHDDCUR组及药物共晶组。分别用含有效成分2mg/Kg的药物给动物灌喂，每天2次，连续15-20天。颈椎去臼处死动物，分别称体重、瘤重；计算肿瘤抑制率，并将各组结果进行统计学处理。
肿瘤抑瘤率＝(阴性组瘤重-治疗组瘤重)/阴性组瘤重×100％，
各组数据均以均数±标准差
Figure BDA0002197334390000081
表示，用Student t检验。
测定得到各组肿瘤重量(g)和抑瘤率％，如表2所示。
表2各组肿瘤重量(g)和抑瘤率％
Figure BDA0002197334390000101
Figure BDA0002197334390000111
注：数据分析软件为SPSS，以均值±SD表示各组平均瘤重。根据T检验结果，*P<0.05为显著，**P<0.01为极显著性差异。
数据显示紫杉醇阳性对照组、SHCUR组、SHDMCUR组、SHDDCUR组及药物共晶组具有较好的抑制肿瘤的效果，肿瘤明显减小，低于阴性对照组，且药物共晶组优于SHCUR组、SHDMCUR组、SHDDCUR组的抑菌效果。所以本发明提供的共晶体药物在小鼠肿瘤体内试验中表现出较强的肿瘤抑制作用。
实验例2---抗紫外线损伤实验
实验动物：ICR清洁级雄性小鼠，质量(20±2)g。
试验前2天用8％硫化钠去动物背部被毛，暴露面积4cm×3cm。将小鼠随机分为阳性对照组、空白对照组、模型组和试验组，其中，试验组包括SHCUR组、SHDMCUR组、SHDDMCUR组和药物共晶组。阳性对照组涂抹市售防晒霜，空白对照组和模型组涂抹不加入有效成分制成的润肤霜，SHCUR组涂抹加入四氢姜黄素(SHCUR)的润肤霜、SHDMCUR组涂抹加入四氢去甲氧基姜黄素(SHDMCUR)的润肤霜、SHDDMCUR组涂抹加入四氢双去甲氧基姜黄素(SHDDMCUR)的润肤霜，药物共晶组涂抹加入本发明提供的共晶药物的水溶液。
给药量，背部给0.3g，每只耳朵给0.1g，每天2次，共涂抹3天。除空白组外，小鼠水平固定，与紫外灯垂直距离15cm，照射6小时，造成皮损小鼠模型。
皮损小鼠模型连续照射紫外线40h，处死小鼠，称量小鼠体质量并记录，再分别取两耳及背部9mm直径的圆形耳片和皮片，精确称量其耳质量和皮质量，计算耳指数和皮指数，其中耳指数＝耳质量/体质量、皮指数＝皮质量/体质量。
测得结果如表3所示。
表3小鼠耳指数、皮指数试验结果
Figure BDA0002197334390000131
Figure BDA0002197334390000141
注:模型组与空白对照组比较，△△P＜0.01；试验组、阳性对照组与模型组比较，**＜0.01，*P＜0.05。
数据显示本发明提供的共晶药物样品对小鼠紫外防护效果基本优于市售防晒霜，也优于含有SHCUR、SHDMCUR、SHDDMCUR的样品对小鼠的紫外防护效果，说明本发明提供的共晶药物样品在小鼠试验中可以起到明显的紫外线防护作用，另外，本发明提供的共晶药物在紫外防护的用途中提高了四氢姜黄素、四氢去甲氧基姜黄素、四氢双去甲氧基姜黄素的生物利用度。
实验例3--抑制黑色素细胞中酪氨酸酶活力实验
实验样品：本发明提供的市售美白凝胶、SHCUR、SHDMCUR、SHDDMCUR、共晶体样品，各1g加40mL蒸馏水稀释备用
96孔板中接种B16黑色素细胞，每孔100μL，置培养箱培育24小时后，添加实验样品，3天后弃去上清液，用PBS冲洗两遍，然后每孔加90μL含体积分数为1％的TritonX-100的PBS，在冰浴中超声破碎，每孔再加10μL 10mmol/L左旋多巴，在37℃下孵育60分钟，于475nm处比色，测各孔吸光度值。
黑色素细胞中酪氨酸酶抑制率：
K％＝(1-药物组平均吸光度值÷对照组平均吸光度值)×100％。
实验结果如表4所示。
表4小鼠黑色素细胞中酪氨酸酶抑制率
Figure BDA0002197334390000151
Figure BDA0002197334390000161
Figure BDA0002197334390000171
Figure BDA0002197334390000181
注:P＞0.05表示差异性不显著；0.01＜P＜0.05表示差异性显著；P＜0.01表示差异性极其显著。
表4中的数据显示，本发明提供的共晶化合物样品有较强的抑制酪氨酸酶的活力，与市售美白凝胶相比，美白效果有显著性差异。且本发明提供的共晶化合物样品对酪氨酸酶的活力抑制效果优于SHCUR、SHDMCUR、SHDDMCUR对照组，说明在共晶体中，SHCUR、SHDMCUR、SHDDMCUR的生物利用度得到了显著提高。
实验例4---对代谢综合征模型大鼠脂肪细胞因子的影响实验
SD大鼠，每组12只，对照组喂以普通标准饲料，造模组大鼠喂以高糖高脂高盐饲料，连续喂养12周。造模成功标准：①符合肥胖成模标准；②符合甘油三酯(TG)水平升高、高密度脂蛋白(HDL-C)水平下降、高血压及胰岛素抵抗指数(HOMA-IR)升高4项中的任意2项，成功建立代谢综合征模型。
将造模成功大鼠随机分为模型组、SHCUR组、SHDMCUR组、SHDDMCUR组及药物共晶组，均继续喂以高糖高脂高盐饲料，模型组给予0.5％羧甲基纤维素钠溶液10mL/kg，日1次，灌胃；给药给予SHCUR组、SHDMCUR组、SHDDMCUR组及药物共晶组10mL/kg，日1次，灌胃；各组大鼠均连续给药8周。
各组大鼠体质量、Lee's指数及SBP数据如表5所示，各组大鼠血清TG、HDL-C、LDL-C水平数据如表6所示。
表5体质量、Lee's指数及SBP数据
Figure BDA0002197334390000182
Figure BDA0002197334390000191
Figure BDA0002197334390000201
表5中各组大鼠体质量、Lee's指数及SBP的数据显示，与对照组比较，模型组大鼠的数据均较高，SHCUR组、SHDMCUR组、SHDDMCUR组及药物共晶组的数据结果较低，差异有统计学意义(P<0.05)。另外，药物共晶组优于SHCUR组、SHDMCUR组、SHDDMCUR组，说明在共晶体中，SHCUR、SHDMCUR、SHDDMCUR的生物利用度得到了显著提高，能够对代谢综合征模型大鼠脂肪细胞因子带来更加显著的影响。。
表6血清TG、HDL-C、LDL-C水平
Figure BDA0002197334390000211
Figure BDA0002197334390000231
表6中的数据显示，与对照组比较，模型组、SHCUR组、SHDMCUR组、SHDDMCUR组的大鼠血清TG、LDL-C水平较高，血清HDL-C水平较低，差异有统计学意义(P<0.05)。与模型组比较，SHCUR组、SHDMCUR组、SHDDMCUR组及药物共晶组的大鼠血清TG、LDL-C水平较低。
实验例5---致肝损伤副作用实验
昆明小鼠，18～22g，雌雄各半，每组12只。灌胃给药，分为正常空白对照组、辛伐他汀阳性对照组和给药组，其中给药组包括SHCUR组、SHDMCUR组、SHDDMCUR组及本发明提供的共晶药物组，正常对照组每日0.5％的CMCNa按0.2ml/10g灌胃，辛伐他汀和给药组的剂量为0.012g/kg。给药2周后，禁食15小时后眼底静脉采血，分离血清，测定ALT、AST活性，测定结果如表7所示。
表7对ALT、AST活性影响的测定结果
Figure BDA0002197334390000241
Figure BDA0002197334390000251
注：*P<0.05
表7中ALT和ASL的测定结果显示，与正常组比较，辛伐他汀组有明显的升高，P<0.05，有显著差异，说明具有显著性的肝损伤作用，而SHCUR组、SHDMCUR组、SHDDMCUR组及本发明提供的共晶药物的ALT和ASL的测定结果与正常对照组相近，没有明显肝损伤作用，没有明显差异，相对安全。
通过采用本发明公开的上述技术方案，得到了如下有益的效果：本发明提供的共晶体及制备方法、包含共晶体的药物组合物及用途，其中，共晶体由姜黄素的氢化产物与有机酸类化合物、葡甲胺、2-羟基苯乙酮、4-胺基苯酚、(异)烟酰胺、甘露醇、或山梨醇中的任意一种制备而成，制备得到的该共晶体可以制备用于治疗癌症、消除炎症、治疗创伤、预防或治疗老年痴呆、防治骨质疏松和/或促进骨愈合、降血脂、治疗脂肪肝以及伴有高血脂症、糖尿病的相关代谢性综合征疾病或美容美白的药物。在实际应用中，发现姜黄素的氢化产物在共晶体药物中的生物利用度得到了明显提高，极大地扩展了其临床应用。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视本发明的保护范围。

Claims (10)

1.一种共晶体，由原料A和B制备而成，其中，A的化学结构式为：
Figure FDA0002197334380000011
R1和R2为H或OCH3，
B为有机酸类化合物、葡甲胺、2-羟基苯乙酮、4-胺基苯酚、(异)烟酰胺、甘露醇、或山梨醇中的任意一种。
2.根据权利要求1所述的共晶体，其特征在于，所述有机酸类化合物选自长链脂肪酸类化合物、苯甲酸衍生物类化合物、有机二酸类化合物和氨基酸类化合物。
3.根据权利要求2所述的共晶体，其特征在于，所述长链脂肪酸类化合物选自辛酸、癸酸和月桂酸中的任意一种。
4.根据权利要求2所述的共晶体，其特征在于，所述苯甲酸衍生物类化合物选自苯甲酸、邻羟基苯甲酸、对羟基苯甲酸、间羟基苯甲酸、邻苯二甲酸、间苯二甲酸、对苯二甲酸和均苯三甲酸中的任意一种。
5.根据权利要求2所述的共晶体，其特征在于，所述有机二酸类化合物选自草酸、丁二酸、戊二酸、己二酸、富马酸和马来酸中的任意一种。
6.根据权利要求2所述的共晶体，其特征在于，所述氨基酸类化合物选自丙氨酸、精氨酸、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、组氨酸、异亮氨酸、甘氨酸、天冬酰胺、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸中的任意一种。
7.如权利要求1-6任一项所述的共晶体的制备方法，其特征在于，包括
按照1:1～2:1的摩尔比混合原料A和B，并加入去离子水，搅拌均匀后，升温至60～80℃，搅拌反应1～3h；
反应完毕后过滤反应液，得到滤液；
滤液在室温放置60～72h，析出共晶体。
8.一种包含共晶体的药物组合物，由权利要求1-6任一项所述的共晶体以及药学可接受的添加剂制备而成。
9.根据权利要求8所述的包含共晶体的药物组合物，其特征在于，所述药物组合物的剂型为冻干粉、片剂、含片、胶囊及软胶囊剂、颗粒剂、糖浆剂、微丸剂、微球剂、丹剂、水剂、口服液和膏剂中的任意一种。
10.如权利要求1-6任一项所述的共晶体在制备用于治疗癌症、消除炎症、治疗创伤、预防或治疗老年痴呆、防治骨质疏松和/或促进骨愈合、降血脂、治疗脂肪肝以及伴有高血脂症、糖尿病的相关代谢性综合征疾病或美容美白药物中的用途。
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