CN105853378A - 白藜芦醇烟酸酯纳米结晶速释胶囊制剂及其制备工艺 - Google Patents

白藜芦醇烟酸酯纳米结晶速释胶囊制剂及其制备工艺 Download PDF

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CN105853378A
CN105853378A CN201610346682.0A CN201610346682A CN105853378A CN 105853378 A CN105853378 A CN 105853378A CN 201610346682 A CN201610346682 A CN 201610346682A CN 105853378 A CN105853378 A CN 105853378A
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trinocotinate
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王言才
王路路
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Qilu University of Technology
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Abstract

本发明属于药物制剂领域，涉及白藜芦醇烟酸酯纳米结晶速释胶囊制剂及其制备工艺。该制剂白藜芦醇烟酸酯与稳定剂组成，制成纳米混悬液后加入冷冻干燥剂并进行冷冻干燥，得白藜芦醇烟酸酯纳米结晶；进行胶囊灌装后得白藜芦醇烟酸酯纳米结晶胶囊。制备的纳米结晶粒径均匀，溶解度和溶出速率显著增加。本发明显著的优点是该纳米结晶可以增加白藜芦醇烟酸酯的溶解度，增加口服制剂的生物利用度。

Description

白藜芦醇烟酸酯纳米结晶速释胶囊制剂及其制备工艺
技术领域
本发明属于药物制剂领域，涉及白藜芦醇烟酸酯纳米结晶速释胶囊制剂及其制备工艺。
背景技术
白黎芦醇(Resverartol)，又称芪三酚，化学名为3,5,4’-三羟基-1,2-二苯乙烯，是含芩类结构的非黄酮类多酚化合物，广泛的存在于葡萄、虎杖、黎芦、决明子和花生等天然植物或果实中。有顺式和反式两种存在形式，还可以和糖形成糖苷，可在肠道中糖苷酶的作用下释放出白藜芦醇，天然植物中主要以反式白藜醇存在，其生理活性强于顺式异构体。目前为止至少己在21科、31属的72种植物中发现了白黎芦醇，它是植物在受到真菌感染、紫外照射或病理状况下产生的一种植物抗毒素，对植物本身起着保护作用。研究表明白藜芦醇具有防癌抗癌、降血脂、抗血小板聚集、激活Sirtuins抗衰老酶、抗氧化、抗自由基、抗过敏、抗菌消炎、抗骨质疏松、护肤增白等多种有益的生理活性。
但是白藜芦醇存在易氧化，t1/2时间短，水溶性稍差等缺点，极大地限制了其开发与使用。
烟酸又称维生素B5，俗称尼古丁酸，是吡啶类衍生物，水溶性强，它具有参与生物体内的氧化还原，促进新陈代谢，降低血浆甘油三酯及升高高密度脂蛋白的作用。由于白藜芦醇存在易氧化，体内代谢快，生物利用度低等不足，为了进一步提高白藜芦醇的稳定性、改善生物利用度。
根据药物设计拼合原理和其分子结构特点，通过酯键将其结构上的酚羟基与3个烟酸相偶联，将白藜芦醇和烟酸进行酯化合成白藜芦醇烟酸酯，可以有效保护白藜芦醇中酚羟基被氧化，延长t1/2。根据前药的原理，在体内可能通过水解过程而生成白藜芦醇及烟酸，而发挥相应的生物活性。
纳米结晶技术是改善难溶性药物功效的重要途径，可显著增加难溶性药物的溶解度与溶出速率，提高口服生物利用度，减小个体差异，且具备辅料用量少、毒副作用小等优点，是当今制药领域正大力发展的药物制剂新技术。本发明将该技术应用于白藜芦醇烟酸酯纳米结晶速释胶囊的制备，一方面是改善白藜芦醇的物理化学稳定性；另一方面是增加口服给药时的吸收速度与程度，通过速释功能达到快速起效。
发明内容
本发明针对白藜芦醇烟酸酯临床口服生物利用度差等问题，采用反溶剂法制备白藜芦醇烟酸酯纳米混悬剂，再将纳米混悬液冷冻干燥后制成纳米结晶，将冻干所得粉末灌装进胶囊所得。
白藜芦醇烟酸酯纳米结晶胶囊系以白藜芦醇烟酸酯为原料药制成的制剂具有降低血液粘稠度，抑制血小板凝结和血管舒张，预防心肌硬塞、脑栓塞，治疗乳腺癌，延缓衰老等功效。
为为实现上述目的，本发明的技术方案如下：
本发明的白藜芦醇烟酸酯纳米结晶制剂的原辅料组成如下，均为重量份：
白藜芦醇烟酸酯100份，稳定剂10～100份；
优先的，原辅料组成比例为：
白藜芦醇烟酸酯100份，稳定剂40～50份；
本发明的白藜芦醇烟酸酯纳米结晶制备过程如下：
首先，采用反溶剂法制备白藜芦醇烟酸酯纳米混悬剂。具体步骤为：将稳定剂按照上述比例加入100ml注射用水中，磁力搅拌并充分溶胀2h，将白藜芦醇烟酸酯按照上述比例溶解在药用甲醇中。然后，有机相按1：5的体积比快速注入水相中，进行超声15min，即得白藜芦醇烟酸酯纳米混悬剂。在所得纳米混悬剂中，按照重量：体积比=5:100的比例加入冷冻干燥剂，轻微搅拌促进溶解。随即以冷冻干燥的方法对所得纳米混悬剂进行干燥，以除去水分。冷冻干燥结束，收集粉末，即得白藜芦醇烟酸酯纳米结晶。
所获得的白藜芦醇烟酸酯纳米结晶经物相分析，粒径分布较窄，纳米结晶表面被稳定剂覆盖，外观基本一致，白藜芦醇烟酸酯的溶解度和溶出速率有了大幅度提高，且与原料药相比具有统计学意义。
将所得白藜芦醇烟酸酯纳米结晶按照20 mg每粒的剂量进行硬胶囊灌装，即可得白藜芦醇烟酸酯纳米结晶胶囊。稳定剂可以是十二烷基硫酸钠、羟丙基甲基纤维素、泊洛沙姆407、泊洛沙姆F68、PVP K30、卵磷脂、TPGS、吐温80中的一种或者多种；冷冻干燥剂可以是甘露醇、海藻糖、葡萄糖中的一种或者多种。
白藜芦醇烟酸酯纳米结晶胶囊用法用量为口服，一次40mg，一日3次。重症每次2～4粒，每日3次。轻症每次2粒，每日3次。症状减轻后减至每次1片，每日3次。
附图说明
图1：白藜芦醇烟酸酯纳米结晶粒径分布图。
具体实施方式
下面结合实施例对本发明作详细的阐述，但不限于这些具体记载的实施例。
实施例1：
称取20mg白藜芦醇烟酸酯溶于10ml甲醇中，分别称取40mg的泊洛沙姆407与羟丙基甲基纤维素溶于100ml蒸馏水中，溶胀2h。甲醇相以1:5的体积比快速注入水相中，超声15min中，即得白藜芦醇烟酸酯纳米混悬液。
将上述白藜芦醇烟酸酯纳米混悬液按照5％（w/v）比例加入冻干保护剂甘露醇，震荡溶解后分装至西林瓶，并迅速放入超低温冰箱，在-80℃温度下冷冻48小时，再取出迅速放入温度已降至-50℃的冻干机搁板上，盖上真空罩，开启真空泵开关，冻干48小时。在冻干结束时将冻干机翻填氮气，并自动进行压盖。冻干结束后即得白藜芦醇烟酸酯纳米结晶。
实施例2：
称取20mg白藜芦醇烟酸酯溶于10ml甲醇中，称取30mg的PVPK30与45mg十二烷基硫酸钠溶于100ml蒸馏水中，溶胀2h。甲醇相以1:5的体积比快速注入水相中，超声15min中，即得白藜芦醇烟酸酯纳米混悬液。
将上述白藜芦醇烟酸酯纳米混悬液按照5％（w/v）比例加入冻干保护剂海藻糖、葡萄糖，震荡溶解后分装至西林瓶，并迅速放入超低温冰箱，在-80℃温度下冷冻48小时，再取出迅速放入温度已降至-50℃的冻干机搁板上，盖上真空罩，开启真空泵开关，冻干48小时。在冻干结束时将冻干机翻填氮气，并自动进行压盖。冻干结束后即得白藜芦醇烟酸酯纳米结晶。

Claims (4)

1.白藜芦醇烟酸酯纳米结晶由白藜芦醇烟酸酯与少量稳定剂制成，稳定剂选自十二烷基硫酸钠、羟丙基甲基纤维素、泊洛沙姆407、泊洛沙姆F68、PVP K30、卵磷脂、TPGS、吐温80中的一种或者多种。
2.权利要求1所述白藜芦醇烟酸酯纳米结晶，其制备工艺特征在于采用反溶剂法和真空冷冻干燥法制备纳米结晶。
3.权利要求2所述真空冷冻干燥法所用冻干保护剂选自甘露醇、蔗糖、乳糖、半乳糖、海藻糖中的一种或多种。
4.权利要求3所述的冻干保护剂加入比例以重量比体积计为1%～10%。
CN201610346682.0A 2016-05-24 2016-05-24 白藜芦醇烟酸酯纳米结晶速释胶囊制剂及其制备工艺 Pending CN105853378A (zh)

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Publication number Priority date Publication date Assignee Title
US20210371446A1 (en) * 2018-10-16 2021-12-02 President And Fellows Of Harvard College Sirt1 activating compounds
CN113925831A (zh) * 2021-09-09 2022-01-14 山东大学 一种高稳定性的根皮素纳米混悬剂及其制备方法和微针
CN115350290A (zh) * 2022-10-19 2022-11-18 潍坊中医药产业技术研究院 基于tpgs修饰的白藜芦醇纳米晶脂质体的制备方法与应用

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刘凯: "白藜芦醇纳米混悬液的制备及固化", 《药学研究》 *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210371446A1 (en) * 2018-10-16 2021-12-02 President And Fellows Of Harvard College Sirt1 activating compounds
CN113925831A (zh) * 2021-09-09 2022-01-14 山东大学 一种高稳定性的根皮素纳米混悬剂及其制备方法和微针
CN113925831B (zh) * 2021-09-09 2022-10-14 山东大学 一种高稳定性的根皮素纳米混悬剂及其制备方法和微针
CN115350290A (zh) * 2022-10-19 2022-11-18 潍坊中医药产业技术研究院 基于tpgs修饰的白藜芦醇纳米晶脂质体的制备方法与应用
CN115350290B (zh) * 2022-10-19 2022-12-13 潍坊中医药产业技术研究院 基于tpgs修饰的白藜芦醇纳米晶脂质体的制备方法与应用

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