CN1212114C - 口服灯盏花素缓释制剂 - Google Patents
口服灯盏花素缓释制剂 Download PDFInfo
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- CN1212114C CN1212114C CN 01117620 CN01117620A CN1212114C CN 1212114 C CN1212114 C CN 1212114C CN 01117620 CN01117620 CN 01117620 CN 01117620 A CN01117620 A CN 01117620A CN 1212114 C CN1212114 C CN 1212114C
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Images
Abstract
本发明涉及一种用于治疗心脑血管疾病的特殊剂型的药物。本发明所述的灯盏花素缓释制剂，其特征在于含灯盏花素的增溶组合物10-70%、阻滞剂5-70%以及余量的药用辅料。本发明具有药物释放性能良好，血药浓度平稳的特点，可以不同的释药机制延长作用时间、减少用药次数、降低副作用。
Description
本发明涉及一种用于治疗心脑血管疾病的特殊剂型的药物。
中国专利申请CN1053609A(申请号9010045.0)公开了一种“灯盏花素制剂原料药的提取工艺”，此工艺是将灯盏花全株粗粉，经乙醇浸提，将醇提液减压浓缩，放出浓缩物，热水提取后，加酸沉淀，除酸除杂质，并进行灯盏花素粗品精制，得到灯盏花素精品。
灯盏花素(Brevescapine)是从菊科植物短葶飞蓬(Erigeron Breviscapus(Vant.)Hand.-Mazz.)中提取出来的，其原植物始载于《滇南本草》，原名灯盏花(又叫灯盏细辛)。灯盏花素为黄色粉末，可溶于硷水，微溶于甲醇，不溶于水、氯仿等，具弱酸性。灯盏花素是以灯盏乙素为主，并含少量灯盏甲素的混合物，其主要成份为灯盏乙素(Scutellarin)，约占95％，其学名为4′，5，6-三羟基黄酮-7-葡萄糖醛酸苷。经药理研究证明，灯盏花素具有扩张脑血管，降低脑血管阻力，增加脑血流量，改善微循环，提高血脑屏障通透性，增强机体巨噬细胞吞噬免疫作用，对抗垂体后叶素所至脑缺血缺氧，并能对抗由二磷酸腺苷(ADP)引起的血小板凝聚作用。灯盏花素在临床上广泛用于治疗脑血栓、脑梗塞以及类型未定的中风后瘫痪等症。
目前，临床上应用的灯盏花素制剂有针剂、粉针剂颗粒剂和普通片剂，针剂、粉针剂主要用于脑血管病急性期的治疗，颗粒剂和普通片剂主要用于脑血管病恢复期、后遗症期的治疗及其脑血管病的预防。
众所周知，一个药物的制剂质量会极大地影响该药的临床应用价值，无论何种制剂，其进入体内后血浓一定要在治疗窗范围内才能发挥正常的治疗作用，低了无效，高了产生毒副反应。经研究发现，灯盏花素溶解性能差，为水不溶解、油不溶解性药物，灯盏花素在有机溶剂中的溶解度也很小。其在正己烷及氯仿中基本不溶，水中的溶解度为14mg/L，在乙醇中的溶解度为5.8g/L，为一特殊难溶性药物。灯盏花素在乙酸乙酯-水中的油/水分配系数P＝0.073，在正辛醇-水中的油/水分配系数P＝0.063。不仅如此，灯盏花素还是一弱酸性药物，在肠道由于解离而使吸收变差，因此灯盏花素的生物利用度低，其绝对生物利用度(＝AUCpo/AUCiv*100％)仅为16.2％。灯盏花素口服生物半衰期短(约2小时左右)，其普通颗粒剂和普通片剂的生物利用度低，有效血浓维持时间短，而其适应症脑血管病为慢性疾病，治愈难度大，其恢复期和后遗症期治疗周期长。因此临床上须采用大剂量多次给药才能达到治疗目的，不仅造成血药浓度“峰谷”波动现象，而且给病人带来很大的麻烦，同时由于存在易漏服和夜间服药间隔时间过长而不能维持有效的血药浓度和发挥持续的治疗效果，出现疗效上的盲区，在临床疗效方面有不稳定现象。
本发明的目的旨在克服现有技术的不足，提供一种以不同的释药机制延长作用时间、减少用药次数、降低副作用和提高制剂的生物利用度的口服灯盏花素缓释制剂。
本发明所述的口服灯盏花粉素缓释制剂，其特征在于含重量百分比的灯盏花素的增溶组合物10-80％、阻滞剂5-70％以及余量的药用辅料。
本发明所述的灯盏花素的增溶组合物可以是灯盏花素—大豆卵磷脂(或卵磷脂)复合物、灯盏花素的固体分散体、灯盏花素的环糊精包合物、灯盏花素的微粉化粉末或者灯盏花素与增溶剂的组合物，可以是其中的任意一种，也可以是所述几种任意比例的组合。
本发明所述的药用辅料包括乳化剂、PH调节剂、填充剂、润湿剂、助流剂和润滑剂。
所述制剂中灯盏花素增溶组合物的含量为重量百分比10％-80％，以30％-70％为佳，阻滞剂的含量为重量百分比5％-70％，以15％-50％为佳，乳化剂的含量为重量百分比1％-30％，PH调节剂的含量为重量百分比6％-50％。
所述的阻滞剂可以是羟丙基甲基纤维素(HPMC如HPMC K4M，HPMC K100，HPMC E50，HPMC E5，HPMC E4M，HPMC K15M，HPMC K50M，HPMC K100M等)，乙基纤维素(EC如EC 7，EC 10，EC 20等)，Carbopol(如Carbopol 934p及其钠盐，Carbopol 971p等)，羧甲基纤维素钠(CMC-Na)，羟乙基甲基纤维素(HEMC)，甲基纤维素(MC)，羟乙基纤维素(HEC)，羟丙基纤维素(HPC)，脂肪酸及脂肪酸酯(如油酸、油醇、硬脂酸、硬脂醇、胆酸、中链三甘油酯、单硬脂酸甘油酯等)等中的一种或几种。
制备固体分散体所用的辅料可以是聚乙二醇(PEG如PEG4000，PEG6000等)，聚乙烯吡咯烷酮(PVP如PVP-K30等)，低黏度羟丙基甲基纤维素(低黏度HPMC如HPMC-E50 HPMC-E5等)，Poloxamer 188(Pluronic F68等)，表面活性剂等中的一种或几种。
制备环糊精包合物所用的辅料可以是β-环糊精，羟丙基β-环糊精，羟乙基β-环糊精，甲基环糊精中的一种或几种。
增溶剂可以是药用表面活性剂Tween(如Tween-80)、十二烷基硫酸钠、Cremophor RH40、Poloxamer等和PH调节剂。
PH调节剂可以是氨基酸盐、邻苯二甲酸盐、磷酸盐(如Na2HPO4、NaH2PO4等)、柠檬酸盐、醋酸及醋酸盐、酒石酸盐等一种或一种以上弱酸性或弱碱性缓冲物。
乳化剂可以是表面活性剂(如Tween-80、十二烷基硫酸钠、Tween-85、Mrij 35、Migyol 30、Tagat TO、Migyol 812等)，大豆卵磷脂，油酸及油酸盐、油醇、胆酸及胆酸盐等中的一种或几种。
填充剂、润湿剂、助流剂和润滑剂为常规制剂生产用药用辅料。
本发明所述的灯盏花素的增溶组合物可以采用以下方法制备：
(一)、将灯盏花素采用微粉化粉碎。
(二)、采用熔融法或溶剂法或溶剂熔融法等固体分散体制备方法制备灯盏花素固体分散体。
(三)、采用饱和溶液法或冷冻干燥法或喷雾干燥法等包合物制备方法制备灯盏花素环糊精包合物。
(四)、在灯盏花素中加入按比例的增溶剂搅拌使之混合均匀。
(五)、将灯盏花素和大豆卵磷脂分散于非质子性溶剂中，制备灯盏花素—大豆卵磷脂复合物。
本发明制备的灯盏花素缓释制剂为口服缓释剂型，其质量控制的指标主要是生物利用度和生物效应。本发明产品只要工艺一致的条件下，一定的阻滞材料对药物的释放度有较好的重现性。
本发明产品释放度的质量标准是根据灯盏花素的理化性质、药理作用、最低有效浓度、出现毒副作用的最低血浓度、临床要求的起效时间和药效延续时间等制订出释放度标准，以保证临床用药的安全有效。本发明产品的稳定性也符合要求。
用本发明产品进行动物试验，经试验证明本发明产品体内过程符合二室模型，AUC为18.4884(ug/ml)*hr而普通制剂的AUC为9.3167(ug/ml)*hr，本发明产品比普通制剂生物利用度高近一倍，血药浓度的峰值维持在有效血药浓度范围内，较为平稳，血药浓度波动系数小。可由以下动物实验结果证实：
动物试验：普通家兔(禁食过夜，不禁水)12只，雌雄各半，体重2.32±0.25kg，随机均分为2组，按60mg/kg体重分别灌胃完整制剂：灯盏花素缓释片剂1片(含灯盏乙素60mg)或普通片3片(每片含灯盏乙素20mg，共60mg)，灌胃后灌水50mL。分别于灌胃后0.25、0.5、1.0、2.0、3.0、6.0、7.0、12.0、24.0、48.0h采取耳静脉血1mL。血样加1％肝素抗凝，分离血浆后-20℃保存至测定。两次交叉灌胃的时间为1周。
提取血浆中灯盏乙素，用高压液相色谱法进行试验动物体内血药浓度测定，绘制血药浓度-时间曲线，见图1。
利用3p87程序，双室模型拟合药物动力学参数。结果见表1。
本发明所述的灯盏花粉素缓释制剂具有以下特点：
(一)采用固体分散技术和缓控释技术来增加制剂中灯盏花素的生物利用度，延长其有效血浓维持时间，避免频繁给药所造成的血药浓度“峰谷”波动现象，使血药浓度平稳，药物在病变组织的浓度相对增加和稳定，提高疗效、时效及患者的顺应性，从而达到安全有效又方便治疗的目的。
(二)具有药物释放性能良好，血药浓度平稳的特点，可以不同的释药机制延长作用时间、减少用药次数、降低副作用。
(三)具有药物吸收良好，制剂生物得用度高的特点。
(四)具有产品稳定性好，工艺重现性高及机械化程度高的特点。并可用常规的生产设备和工艺制备，机械化程度高、产量大、成本低且便于运输保存。
图1为本发明所述制剂血药浓度曲线图。
表1为本发明所述制剂(SRT)和常规制剂(CT)动力学参数表。
图中：
为灯盏花素缓释片剂(STR)，
为灯盏花素普通制剂(CT)，(n＝6)。
下面是本发明的实施例，但本发明的内容并不局限于此。
实施例1：
组 份 含量(重量百分比)
灯盏花素-HPMC E50固体分散体 70.0％
HPMC K4M 10.0％
乳 糖 18.0％
硬脂酸镁 1％
95％乙醇 适量
制备方法：制备灯盏花素-HPMC E50固体分散体：按比例在灯盏花素(50.0％)中加入Tween-80(10.0％)、适量95％乙醇，混匀后分散于熔融的HPMC E50内，采用溶剂熔融法制成灯盏花素-HPMC E50固体分散体。在灯盏花素-HPMC E50固体分散体加入阻滞剂等药用辅料，按一定工艺处理后，混合均匀，加入适量95％乙醇制备软材，制粒，60℃以下干燥，整粒，取颗粒检查合格后，加入适量硬脂酸镁，混合均匀后压片。质量检查合格后分装，贴签，包装即得灯盏花素缓释片剂。
实施例2：
组 份 含量(重量百分比)
灯盏花素-Tween-80增溶剂组合物 10.0％
HPMC E50(或E5) 50.0％
HPMC K4M 5.0％
乳 糖 30.0％
硬脂酸镁 1.0％
95％乙醇 适量
制备方法：制备灯盏花素的增溶剂组合物：按比例在灯盏花素中加入Tween-80(增溶剂)混匀即得。在灯盏花素的增溶组合物加入阻滞剂(HPMC E50 HPMCK4M)等药用辅料，按一定工艺处理后，混合均匀，加入适量95％乙醇制备软材，制粒，60℃以下干燥，整粒，取颗粒检查合格后，加入硬脂酸镁，混合均匀后压片(也可按一定工艺处理后，加入阻滞剂及填充剂、助流剂、润滑剂等药用辅料，混合均匀后直接压片)。质量检查合格后分装，贴签，包装即得灯盏花素缓释片剂。
实施例3：
组 份 含量(重量百分比)
灯盏花素-β-环糊精包合物 80.0％
HPMC E50(或E5) 10.0％
HPMC K4M 8.0％
十二烷基硫酸钠 1.0％
硬脂酸镁 1.0％
95％乙醇 适量
制备方法：制备灯盏花素-β-环糊精包合物：按比例在灯盏花素中加入十二烷基硫酸钠、适量乙醇后，分散于β-环糊精β-环糊精内，采用饱和溶液法制成环糊精包合物。在灯盏花素-β-环糊精包合物中加入阻滞剂(HPMC E50 HPMC K4M)等药用辅料，按一定工艺处理后，混合均匀，加入适量95％乙醇制备软材，制粒，60℃以下干燥，整粒，取颗粒检查合格后，加入硬脂酸镁，混合均匀后压片(也可按一定工艺处理后，加入阻滞剂及填充剂、助流剂、润滑剂等药用辅料，混合均匀后直接压片)。质量检查合格后分装，贴签，包装即得灯盏花素缓释片剂。
实施例4：
组 份 含量(重量百分比)
灯盏花素-大豆卵磷脂复合物 40.0％
HPMC E50(或E5) 15.0％
EC 10(EC 20) 10.0％
Na2HPO4(PH调节剂) 25.0％
NaH2PO4(PH调节剂) 3.5％
硬脂酸镁 2％
95％乙醇 适量
制备方法：制备灯盏花素—大豆卵磷脂复合物：按比例将灯盏花素和大豆卵磷脂分散于非质了了性溶剂中制成。在灯盏花素的增溶组合物中加入阻滞剂(HPMCE50、EC 10或EC 20)如丙酮及药用辅料，按一定工艺处理后，混合均匀，加入适量95％乙醇制备软材，制粒，60℃以下干燥，整粒，取颗粒检查合格后，加入硬脂酸镁，混合均匀后压片(也可按一定工艺处理后，加入阻滞剂及填充剂、助流剂、润滑剂等药用辅料，混合均匀后直接压片)。质量检查合格后分装，贴签，包装即得灯盏花素缓释片剂。
实施例5：
组 份 含量(重量百分比)
灯盏花素增溶剂组合物 65.0％
HPMC E50(或E5) 20.0％
乳 糖 14.0％
硬脂酸镁 1.0％
制备方法：制备灯盏花素的增剂溶组合物：按比例在灯盏花素乙醇溶液中加入Mrij 35、Tween-80、大豆卵磷脂，混合均匀后加入油酸(或胆酸、硬脂酸)、油醇(或硬脂醇、中链三甘油酯、单硬脂酸甘油酯)，制备成灯盏花素的增溶组合物。在灯盏花素的增溶组合物加入阻滞剂HPMC E50(或E5)等，按一定工艺处理后，填充胶囊，制成缓释胶囊。质量检查合格后分装，贴签，包装即得灯盏花素缓释胶囊。
实施例6：
组 份 含量(重量百分比)
灯盏花素增溶剂组合物 70.0％
HPMC E5(或E50) 15.0％
Carbopol-934p 15.0％
制备方法：制备灯盏花素的增溶剂组合物：按比例在灯盏花素乙醇溶液中加入Mrij 35、Tween-80、大豆卵磷脂，混合均匀后加入油酸(或胆酸、硬脂酸)、油醇(或硬脂醇、中链三甘油酯、单硬脂酸甘油酯)、Poloxamer，制备成灯盏花素的增溶组合物。在灯盏花素的增溶组合物加入阻滞剂HPMC E50(或E5)、Carbopol-934p等，按一定工艺处理后，压丸，制成缓释胶丸。质量检查合格后分装，贴签，包装即得灯盏花素缓释胶丸。
实施例7：
组 份 含量(重量百分比)
灯盏花素的微粉化粉末 30.0％
HPMC E50(或E5) 50.0％
HPMC K4M 5.0％
微晶纤维素 10.0％
95％乙醇 适量
硬脂酸镁 1.0％
制备方法：制备灯盏花素的微粉化粉末：将灯盏花素置于气沉粉碎机中粉碎成微粉化粉末，细为小于5μ。在灯盏花素的微粉化粉末中加入阻滞剂(HPMC E50HPMC K4M)及药用辅料，按一定工艺处理后，混合均匀，加入适量95％乙醇制备软材，制粒，60℃以下干燥，整粒，取颗粒检查合格后，加入硬脂酸镁，混合均匀后压片(也可按一定工艺处理后，加入阻滞剂、填充剂、助流剂、润滑剂等药用辅料，混合均匀后直接压片)。质量检查合格后分装，贴签，包装即得灯盏花素缓释片剂。
| 参 数 | 单 位 | SRT | CT |
| A | ug/ml | -0.3138 | -0.2756 |
| Alpha | l/hr | 3.2164 | 3.4994 |
| B | ug/ml | 0.4104 | 0.1286 |
| Beta | l/hr | 0.0404 | 0.0148 |
| Ka | l/hr | 0.0229 | 0.2080 |
| V/f(c) | (mg)/(ug/ml) | 1.3745 | 13.3891 |
| t1/2 alpha | hr | 0.2155 | 0.1981 |
| t1/2 beta | hr | 77.4799 | 46.8203 |
| k21 | l/hr | -0.006 | 0.1077 |
| k10 | l/hr | 2.3610 | 0.4810 |
| k12 | l/hr | 0.8569 | 2.9255 |
| AUC | (ug/ml)*hr | 18.4884 | 9.3167 |
| CL(s) | mg/hr/(ug/ml) | 3.2453 | 6.4401 |
| T(peak) | hr | 1.6200 | 1.0800 |
| C(max) | ug/ml | 0.2998 | 0.2377 |
| t1/2 ka | l/hr | 30.2108 | 3.3326 |
表1
Claims (2)
1、一种口服灯盏花素缓释制剂，其特征在于由以下重量百分比的成分组成：灯盏花素的增溶组合物10-80％、阻滞剂5-70％以及余量的药用辅料，所述的灯盏花素的增溶组合物是灯盏花素-大豆卵磷脂复合物、灯盏花素的固体分散体、灯盏花素的环糊精包合物、灯盏花素的微粉化粉末、灯盏花素与增溶剂的组合物，所述的阻滞剂是羟丙基甲基纤维素、乙基纤维素、聚羧乙稀Carbopol、羟乙基甲基纤维素。
2、按照权利要求1所述的口服灯盏花素缓释制剂，其特征在于所述的阻滞剂的重量百分比为15-50％。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7745991B2 (en) | 1999-10-12 | 2010-06-29 | Semiconductor Energy Laboratory Co., Ltd. | Electro-optical device having an EL layer over a plurality of pixels |
| US7777409B2 (en) | 2001-08-01 | 2010-08-17 | Semiconductor Energy Laboratory Co., Ltd. | Semiconductor device including a flexible support |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100542528C (zh) * | 2003-10-23 | 2009-09-23 | 中国医学科学院药物研究所 | 双环醇微粉化及口服控释制剂 |
| CN107213132B (zh) * | 2017-05-26 | 2021-02-02 | 合肥华方医药科技有限公司 | 一种灯盏花素渗透泵控释片及其制备方法 |
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2001
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7745991B2 (en) | 1999-10-12 | 2010-06-29 | Semiconductor Energy Laboratory Co., Ltd. | Electro-optical device having an EL layer over a plurality of pixels |
| US7777409B2 (en) | 2001-08-01 | 2010-08-17 | Semiconductor Energy Laboratory Co., Ltd. | Semiconductor device including a flexible support |
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| CN1383817A (zh) | 2002-12-11 |
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