CN111760031B - 他汀和维生素d组合物及其制备方法与用途 - Google Patents
他汀和维生素d组合物及其制备方法与用途 Download PDFInfo
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- CN111760031B CN111760031B CN202010697511.9A CN202010697511A CN111760031B CN 111760031 B CN111760031 B CN 111760031B CN 202010697511 A CN202010697511 A CN 202010697511A CN 111760031 B CN111760031 B CN 111760031B
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Abstract
本发明公开了一种组合物,包括:以他汀药物和维生素D为活性成分,其中,二者的物料比例为他汀组合物1‑80mg,维生素D 1000‑50000单位。本发明还公开了所述的固体自微乳的制备方法以及用途。本发明能够补足维生素D协同他汀类药物的使用,降低和缓解他汀类药物的相关毒副作用,对于推进他汀类药物最大程度降低低密度脂蛋白水平以及预防心血管疾病的重建具有重要的现实意义。
Description
技术领域
本发明涉及药物。更具体地说,本发明涉及一种他汀和维生素D组合物及其制备方法与用途。
背景技术
高血脂症是指血脂水平过高,可直接引起一些严重危害人体健康的疾病,如动脉粥样硬化、冠心病、胰腺炎等。高脂血症的临床表现主要是脂质在真皮内沉积所引起的黄色瘤和脂质在血管内皮沉积所引起的动脉硬化。血脂异常者往往伴有多种心血管危险因素。血脂水平和下降会使得心血管疾病的发生率和死亡率随着血清总胆固醇和LDL胆固醇水平的下降而降低。
他汀类药物为一线降脂药,在临床应用较为广泛。他汀类药物为HMG-CoA还原酶选择性抑制剂,通过抑制HMG-CoA还原酶和胆固醇在肝脏的生物合成而降低血浆胆固醇和脂蛋白水平,并能通过增加肝细胞表面低密度脂蛋白(LDL)受体数目而增加LDL的摄取和分解代谢,他汀类药物也能减少LDL的生成和其颗粒数。
他汀类药物的临床不良反应主要表现为恶心、腹痛、腹胀、便秘、消化不良和肝功能异常,尤其是肌痛、肌肉异常和肝肾损伤等。他汀类药物存在肌肉毒性,特别是可能导致横纹肌溶解症。
对于长时间服用他汀类药物的患者,如何保障用药安全有效是一个重要的临床问题。
发明内容
本发明的一个目的是解决至少上述问题,并提供至少后面将说明的优点。
本发明还有一个目的是提供一种他汀和维生素D组合物及其制备方法与用途,其能够补足维生素D协同他汀类药物的使用,降低和缓解他汀类药物的相关毒副作用,对于推进他汀类药物最大程度降低低密度脂蛋白水平以及预防心血管疾病的重建具有重要的现实意义。
为了实现根据本发明的这些目的和其它优点,提供了一种组合物,包括:以他汀药物和维生素D为活性成分,其中,二者的物料比例为他汀组合物1-80mg,维生素D1000-50000单位。
优选的是,还包括:油相、表面活性剂、助表面活性剂、固体吸附剂,其中,三者的重量比1:1-2:1-3:2-3。
优选的是,他汀药物包括洛伐他汀、普伐他汀、辛伐他汀、氟伐他汀、阿托伐他汀、瑞舒伐他汀或匹伐他汀。
优选的是,维生素D包括维生素D2和/或维生素D3。
优选的是,所述油相为Capryol 90、椰子油、玉米油、葡萄籽油、月见草油、CapmulMCM、油酸乙酯、葵花油、蓖麻油中任意一种或者其中的组合,所述表面活性剂为吐温-(20、60、80)、十聚甘油单月桂酸脂、辛酸/癸酸聚乙二醇甘油酯、聚氧乙酸硬脂酸、鲸蜡硬脂醇和山梨坦橄榄油酸酯、Cremophor EL、Solutol HS、Labrasol中任意一种或者其中的组合,所述助表面活性剂为聚甘油蓖麻醇酯、鲸蜡基聚乙二醇/聚丙二醇、聚乙二醇-二聚羟基硬脂酸酯、乙醇、PEG-400、PEG-600、Transcutol P中任意一种或者其中的组合。
优选的是,所述固体吸附剂为无水碳酸钙、硅酸镁铝、二氧化硅、阿拉伯树胶、柠檬酸异丙醇酯或甘露醇。
所述的固体自微乳的制备方法,包括:
将上述物料比例的他汀药物与维生素D混合加入油相搅拌溶解,形成油相体系;
将表面活性剂和助表面活性剂在50-70℃恒温下混合搅拌,加入到油相体系得到液态自微乳;
室温下,向液态自微乳加入固体吸附剂,得到固体自微乳制剂。
所述的组合物在制备抑制他汀药物毒副作用的药物的用途。
优选的是,所述用途包括他汀引起的肌痛、肌酸激酶升高、肝损伤、肾损伤。
本发明至少包括以下有益效果:
第一、本发明通过提高血清中维生素D的含量协同他汀类药物的使用,可降低和缓解他汀类药物的相关毒副作用,例如肌痛、肌酸激酶升高、肌肉异常和肝肾损伤等,改善他汀类药物的应用与其相关性肌肉不良反应的高风险关系,从而影响他汀类药物使用效果,即使是对两种及两种以上他汀类药物不能耐受的患者,补足血清维生素D后,能够重建他汀类药物的治疗,同时伴有LDL-C的明显降低,对于推进他汀类药物最大程度降低LDL-C水平以及预防心血管疾病的重建具有重要的现实意义。
第二、本发明他汀药物和维生素D组合物的固体自微乳,由他汀药物与维生素D混合后加入油相搅拌溶解,形成油相体系,表面活性剂和助表面活性剂在50-70℃恒温下混合搅拌,加入到油相中得到液态自微乳,室温下向自微乳体系中加入固体吸附剂,得到分散性佳、载药能力强,外观和质量良好的他汀药物和维生素D组合物的固体自微乳,可制备成自微乳化微丸、微球、软胶囊、胶囊和片剂等或缓控释制剂,在胃肠蠕动提供的作用力下和胃肠液相互作用进而发生自乳化,所形成的液滴粒径细小均一,药物存在于其中溶解度得到明显提高,体内吸收及生物利用度显著增加,可显著提高他汀类药物溶出度及生物利用度,减少他汀类药物的服用量,有效增加维生素D的吸收,降低毒副作用,提高用药者的依从性。
本发明的其它优点、目标和特征将部分通过下面的说明体现,部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
具体实施方式
下面结合实例对本发明做进一步的详细说明,以令本领域技术人员参照说明书文字能够据以实施。
应当理解,本文所使用的诸如“具有”、“包含”以及“包括”术语并不配出一个或多个其它元件或其组合的存在或添加。
需要说明的是,下述实施方案中所述实验方法,如无特殊说明,均为常规方法,所述试剂和材料,如无特殊说明,均可从商业途径获得。
一种实施方式为:
组合物,包括:以他汀组合物和维生素D为活性成分,其中,二者的物料比例为他汀组合物1-80mg,维生素D 1000-50000单位。
其中,他汀组合物包括洛伐他汀、普伐他汀、辛伐他汀、氟伐他汀、阿托伐他汀、瑞舒伐他汀或匹伐他汀;维生素D包括维生素D2和/或维生素D3。
另一种实施方式为:组合物,包括:以他汀组合物和维生素D为活性成分,还包括:油相、表面活性剂、助表面活性剂、固体吸附剂,其中,二者的物料比例为他汀组合物1-80mg,维生素D 1000-50000单位,油相、表面活性剂、助表面活性剂、固体吸附剂的重量比1:1-2:1-3:2-3。
由他汀药物与维生素D混合后加入油相搅拌溶解,形成油相体系,表面活性剂和助表面活性剂在50-70℃恒温下混合搅拌,加入到油相中得到液态自微乳,室温下向自微乳体系中加入固体吸附剂,得到分散性佳、载药能力强,外观和质量良好的他汀药物和维生素D组合物的固体自微乳,可制备成自微乳化微丸、微球、软胶囊、胶囊和片剂等或缓控释制剂。他汀药物和维生素D组合物的固体自微乳制剂可显著提高他汀类药物溶出度及生物利用度,减少他汀类药物的服用量,有效增加维生素D的吸收,降低毒副作用,提高用药者的依从性。提高液体自微乳的稳定性,增加剂型的多样性,提高患者的顺应性,使之更好的应用于临床。本研究的目的就是将连翘苷元开发成固体自微乳制剂。
其中,他汀组合物包括洛伐他汀、普伐他汀、辛伐他汀、氟伐他汀、阿托伐他汀、瑞舒伐他汀或匹伐他汀;维生素D包括维生素D2和/或维生素D3;所述油相为Capryol 90、椰子油、玉米油、葡萄籽油、月见草油、Capmul MCM、油酸乙酯、葵花油、蓖麻油中任意一种或者其中的组合,所述表面活性剂为吐温-(20、60、80)、十聚甘油单月桂酸脂、辛酸/癸酸聚乙二醇甘油酯、聚氧乙酸硬脂酸、鲸蜡硬脂醇和山梨坦橄榄油酸酯、CremophorEL、Solutol HS、Labrasol中任意一种或者其中的组合,所述助表面活性剂为聚甘油蓖麻醇酯、鲸蜡基聚乙二醇/聚丙二醇、聚乙二醇-二聚羟基硬脂酸酯、乙醇、PEG-400、PEG-600、Transcutol P中任意一种或者其中的组合,所述固体吸附剂为无水碳酸钙、硅酸镁铝、二氧化硅、阿拉伯树胶、柠檬酸异丙醇酯或甘露醇。
<实例1>
组合物,制备成分散片;
将羧甲基纤维素钠溶于适量的蒸馏水中搅拌至胶状。称取处方量的他汀和维生素D3组合物、淀粉进行混合,加入羧甲基纤维素钠溶液混合制备软材,用挤压的方法将制的软材过筛,然后在30℃烘箱里烘干,将干燥颗粒过筛并加入羧甲基淀粉钠混合后,加入滑石粉混合均匀,用压片机进行手动压片制得他汀和维生素D3组合物固体分散片。
他汀适量×1000,维生素D3 2000单位×1000,羧甲基纤维素钠0.5g,滑石粉0.3g,淀粉12.7g,水适量,制成1000片。
每颗分散片含他汀类药物和维生素D3用量比例:
匹伐他汀(PIT,Pitavastatin)1mg;维生素D3 2000单位。
<实例2>
组合物,制备成胶囊;
称取处方量的他汀和维生素D2组合物,微晶纤维素、交联羧甲基纤维素,混合均匀30分钟,加入适量2%羟丙甲纤维素水溶液制软材,过24目筛制粒,于60℃干燥,干颗粒过24目筛整粒,加入处方量的滑石粉混合均匀,测定中间体含量,计算装量,用2#胶囊灌装。
他汀适量×1000,维生素D2 5000单位×1000,微晶纤维素14g,交联羧甲基纤维素5g,滑石粉1g,羟丙甲纤维素溶液(2%)适量,制成1000粒。
每粒胶囊含他汀类药物和维生素D2用量比例:
辛伐他汀(SIM,Simvastatin)10mg;维生素D2 5000单位。
<实例3>
组合物,制备成软胶囊;
他汀类药物和维生素D2、维生素D3混合,加精炼食用植物油(在0℃左右脱去固体脂肪),超声溶解,灭菌后制成软胶囊。
(1)化胶:按明胶:甘油:纯化水=1:0.3:1的量称取,和总量的0.2%的山梨酸钾;明胶先用约80%水浸泡使其充分溶胀后;将剩余纯化水与甘油混合,置化胶罐中加热至70℃,加入明胶液,搅拌20min,加入山梨酸钾,抽真空将胶内的空气排净后,保温55℃静置3小时备用。
(2)压丸:明胶盒加热至55℃,打开伴热带。缓慢打开压缩空气,控制化胶罐内压力不大于0.04Mpa,温度保持在80~90℃之间压制胶片,将制成合格的胶片及他汀类药物和维生素D2、维生素D3混合药液通过全自动软胶囊机压制成软胶囊;
(3)药丸经过定型、干燥、擦丸、检丸,将合格的软胶囊丸放入洁净干燥的容器中。
每粒软胶囊含他汀类药物和维生素D2、维生素D3用量比例:
阿托伐他汀(ATO,Atorvastatin)5mg;维生素D2 1000单位;维生素D3 1000单位。
<实例4>
组合物,制备成固体自微乳;
他汀药物与维生素D3混合加入油相搅拌溶解,形成油相体系;表面活性剂和助表面活性剂在50-70℃恒温下混合搅拌,加入到油相中得到液态自微乳;他汀类药物与维生素D3组合物的自微乳灭菌后,室温下,向自微乳体系中加入固体吸附剂,得到固体自微乳,干燥粉碎,制备成片剂;Capmul MCM作为油相:吐温-80作为表面活性剂:Transcutol P作为助表面活性剂:阿拉伯胶作为吸附剂=1:1.5:2:1.5。
他汀适量×1000,维生素D3 2000单位×1000,微晶纤维素14g,交联羧甲基纤维素5g,滑石粉1g,羟丙甲纤维素溶液(2%)适量,制成1000粒。
每粒胶囊含他汀类药物和维生素D3用量比例:
洛伐他汀(LOV,Lovastain)20mg;维生素D3 2000单位。
1.粒径分布测定和微观形态观察:取少量实例4制备得到的固体自微乳加蒸馏水稀释,取少量涂覆到200目铜网上,浸泡到5%磷钨酸溶液中复染10min取出,自然晾干,在透射电子显微镜下观察形成的微乳液滴外观形态和粒径大小。取上述溶液加入蒸馏水稀释,使用Zetasizernano S90动态光散射仪测定粒径分布和多分散系数,使用Zetasizer2000HAS激光多普勒电泳仪测定Zeta电位。固体自微乳的药物剂型形状呈规则球形,平均粒径为39.8±12.8nm,PdI值为0.165±0.02,Zeta电位为-23.7±1.4mV。固体自微乳的粒径较小,均小于50nm,分散指数也比较小,分布均匀,相差不大,带负电荷量比较大,有利于纳米微粒更加稳定。
2.抑制他汀药物毒副作用:
a.使用8周龄C57雄性小鼠,将其随机分为空白对照组、模型对照组、他汀组、实例1分散片组、实例2胶囊组、实例3软胶囊组以及实例4固体自微乳组,其中除空白对照组给予正常饲料喂养以外,其他组给予高脂饲料喂养进行高脂动物造模,连续喂养6周,抽血化验TC、TG、HDL-C、LDL-C水平,造模成功后,除空白对照组以外,各组他汀给药量为每天一个制剂单位,每组10只,具体为:匹伐他汀组、实例1分散片组用药量为1mg/kg/天,辛伐他汀组、实例2胶囊组用药量为10mg/kg/天,阿托伐他汀组、实例3软胶囊组用药量为5mg/kg/天,洛伐他汀组、实例4固体自微乳组用药量为20mg/kg/天。每组小鼠均灌胃给药,连续给药28天。使用测力计(DFEⅡ,Chatillon,美国)进行小鼠肌力(四肢和前肢握力)测试,每次测量重复三次,每次测量间隔2分钟,记录握力值。然后眼球取血,获得小鼠血清后检测小鼠血清中肌酸激酶水平(肌酸激酶检测试剂盒,南京建成生物工程研究所),结果如表1所示。
表1
#P<0.05vs.模型对照组;*P<0.05vs.他汀组;**P<0.01vs.他汀组;
与空白对照组相比,他汀组小鼠四肢握力与前肢握力显著下降,表明肌力显著受损。而联合维生素D给药之后,肌力显著改善,不同剂型的改善程度不同。其中,实例4固体自微乳组改善小鼠肌力最为显著。另外,当肌细胞受损,肌酸激酶释放入血,因此血清中肌酸激酶水平增加。检测小鼠血清中肌酸激酶含量,结果显示,与空白对照组相比,辛伐他汀组小鼠血清中肌酸激酶含量显著增加,表明他汀组小鼠肌细胞受损;而联合维生素D给药之后,小鼠血清中肌酸激酶含量明显下降,不同剂型中实例4固体自微乳组小鼠血清中肌酸激酶含量最低。上述结果表明,他汀联合维生素D给药可缓解高剂量他汀导致的他汀相关肌病,并且二者组合物的不同剂型改善他汀肌病的程度不同,其中固体自微乳效果最佳。
b.使用8周龄C57雄性小鼠,将其随机分为空白对照组、模型对照组、他汀组、实例1分散片组、实例2胶囊组、实例3软胶囊组以及实例4固体自微乳组,其中除空白对照组给予正常饲料喂养以外,其他组给予高脂饲料喂养进行高脂动物造模,连续喂养6周,抽血化验TC、TG、HDL-C、LDL-C水平,造模成功后,除空白对照组外,各组他汀给药量为每天一个制剂单位,每组10只,具体为:匹伐他汀组、实例1分散片组用药量为1mg/kg/天,辛伐他汀组、实例2胶囊组用药量为10mg/kg/天,阿托伐他汀组、实例3软胶囊组用药量为5mg/kg/天,洛伐他汀组、实例4固体自微乳组用药量为20mg/kg/天。每组小鼠均灌胃给药,连续给药56天。然后静脉采血,测定BUN、UA、ALT、AST水平,然后称重,记录体重,处死,取左肾清洗并吸干表面水分,称重,计算肾脏指数,肾脏指数=左肾重量/体重,收集尿液,测量计算Ccr,结果如表2-3所示。
表2
组别 | ALT(U/L) | AST(U/L) |
空白对照组 | 46.21±0.28 | 91.26±0.80 |
模型对照组 | 60.23±0.58<sup>&</sup> | 141.31±0.17<sup>&</sup> |
匹伐他汀组 | 56.32±0.12 | 118.35±0.32# |
辛伐他汀组 | 56.29±0.11# | 118.25±0.29# |
阿托伐他汀组 | 56.38±0.18 | 118.28±0.34# |
洛伐他汀组 | 56.31±0.13# | 118.31±0.31# |
实例1片剂组 | 51.59±0.04* | 102.24±0.56* |
实例2胶囊组 | 50.57±0.74* | 103.43±0.61* |
实例3软胶囊组 | 50.24±0.42* | 102.50±0.45* |
实例4固体自微乳组 | 49.25±0.26* | 99.62±0.73* |
&P<0.05vs.空白对照组;#P<0.05vs.模型对照组;*P<0.05vs.他汀组;
与空白对照组相比,模型对照组小鼠肝功能明显损伤。而联合维生素D给药之后,谷丙转氨酶、谷草转氨酶水平明显降低,且优于他汀组。上述结果表明,他汀联合维生素D给药可有效缓解高脂饮食造成的肝损伤,并且二者组合物的不同剂型改善的程度不同,其中固体自微乳效果最佳。
表3
&P<0.05vs.空白对照组;#P<0.05vs.模型对照组;*P<0.05vs.他汀组;
与空白对照组相比,模型对照组小鼠Ccr明显降低,BUN、UA、肾脏指数明显升高。而联合维生素D给药之后,肾功能、肾脏指数明显改善,且优于他汀组。上述结果表明,他汀联合维生素D给药可缓解高脂饮食导致的肾损伤,并且二者组合物的不同剂型改善肾损伤的程度不同,其中固体自微乳效果最佳。
3.使用8周龄C57雄性小鼠,将其随机分为空白对照组、模型对照组、洛伐他汀组、实例4固体自微乳组高剂量组、实例4固体自微乳组中剂量组、实例4固体自微乳组低剂量组,其中除空白对照组给予正常饲料喂养以外,其他组给予高脂饲料喂养进行高脂动物造模,连续喂养6周,抽血化验TC、TG、HDL-C、LDL-C水平,造模成功后,他汀组给药量为每天一个制剂单位,具体为:洛伐他汀组用药量为20mg/kg/天,实例4固体自微乳组高剂量组给药量为20mg/kg/天、实例4固体自微乳组中剂量组给药量为15mg/kg/天、实例4固体自微乳组低剂量组给药量为10mg/kg/天,每组10只。每组小鼠均灌胃给药,连续给药56天。然后静脉采血,测定TC、TG、HDL-C、LDL-C水平,收集尿液,测量计算结果如表4所示。
表4
&P<0.05vs.空白对照组;#P<0.05vs.模型对照组;
与空白对照组相比,洛伐他汀组小鼠与实例4中剂量组效果接近,上述结果表明,洛伐他汀联合维生素D给药可在较小剂量达到较优的TC、TG、HDL-C、LDL-C水平。
这里说明的设备数量和处理规模是用来简化本发明的说明的。对本发明的应用、修改和变化对本领域的技术人员来说是显而易见的。
尽管本发明的实施方案已公开如上,但其并不仅仅限于说明书和实施方式中所列运用,它完全可以被适用于各种适合本发明的领域,对于熟悉本领域的人员而言,可容易地实现另外的修改,因此在不背离权利要求及等同范围所限定的一般概念下,本发明并不限于特定的细节和这里示出与描述的实例。
Claims (3)
1.固体自微乳制剂在制备抑制他汀药物毒副作用的药物的用途,其特征在于,所述用途包括他汀引起的肝损伤、肾损伤,包括:
固体自微乳制剂的制备方法为:
备料,组合物包括:以他汀药物和维生素D为活性成分,其中,二者的物料比例为他汀组合物1-80mg,维生素D 1000-50000单位;组合物还包括:油相、表面活性剂、助表面活性剂、固体吸附剂,其中,四 者的重量比1:1-2:1-3:2-3;
将上述物料比例的他汀药物与维生素D混合加入油相搅拌溶解,形成油相体系;
将表面活性剂和助表面活性剂在50-70℃恒温下混合搅拌,加入到油相体系得到液态自微乳;
室温下,向液态自微乳加入固体吸附剂,得到固体自微乳制剂;
所述油相为Capryol 90、椰子油、玉米油、葡萄籽油、月见草油、Capmul MCM、油酸乙酯、葵花油、蓖麻油中任意一种或者其中的组合,所述表面活性剂为吐温-(20、60、80)、十聚甘油单月桂酸脂、辛酸/癸酸聚乙二醇甘油酯、聚氧乙酸硬脂酸、鲸蜡硬脂醇和山梨坦橄榄油酸酯、Cremophor EL、Solutol HS、Labrasol中任意一种或者其中的组合,所述助表面活性剂为聚甘油蓖麻醇酯、鲸蜡基聚乙二醇/聚丙二醇、聚乙二醇-二聚羟基硬脂酸酯、乙醇、PEG-400、PEG-600、Transcutol P中任意一种或者其中的组合;
所述固体吸附剂为无水碳酸钙、硅酸镁铝、二氧化硅、阿拉伯树胶、柠檬酸异丙醇酯或甘露醇。
2.如权利要求1所述的用途,其特征在于,他汀药物包括洛伐他汀、普伐他汀、辛伐他汀、氟伐他汀、阿托伐他汀、瑞舒伐他汀或匹伐他汀。
3.如权利要求1所述的用途,其特征在于,维生素D包括维生素D2和/或维生素D3。
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