CN108938566A - 细辛脑自乳化系统 - Google Patents
细辛脑自乳化系统 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明涉及药物制剂领域，提供了一种细辛脑自乳化系统。所述细辛脑自乳化系统由细辛脑、油相、表面活性剂和助表面活性剂组成，其中细辛脑与自乳化系统的质量比小于1∶2，油相质量比为10％～70％，表面活性剂质量比为30％～80％，助表面活性剂质量比为0～30％。本发明的细辛脑自乳化系统口服后可在体内自发形成粒径10～100nm的水包油型纳米乳，可明显提高药物溶出速率，增加稳定性，改善药物生物利用度。
Description
技术领域
本发明涉及药物制剂领域，具体涉及细辛脑自乳化系统及其制备方法。
背景技术
细辛脑(Asarone，ARE)又名α-细辛脑或α-细辛醚，化学名称为2，4，5-三甲氧基-1-丙烯基苯，主要存在于石菖蒲等植物的挥发油中。细辛脑在乙酸乙酯、氯仿或乙醚中易溶，在乙醇或石油醚中溶解，但是在水中难溶。研究证实，细辛脑具有止咳、祛痰、平喘、镇静、解痉以及抗惊厥作用，对肺炎双球菌、金黄色葡萄球菌和大肠杆菌的生长也具有抑制作用。
目前上市的细辛脑制剂主要包括注射液、片剂和胶囊剂，临床上主要用于肺炎、哮喘、癫痫大发作等疾病治疗。由于在水中难溶，细辛脑的口服固体制剂存在溶出困难、生物利用度低的问题，细辛脑的注射液因使用聚山梨酯80而存在安全性问题。为解决细辛脑临床用药的安全性与有效性问题，本发明运用自乳化技术开发细辛脑的自乳化系统，为细辛脑高效口服制剂的开发提供基础技术支持。
自乳化药物传递系统(Self-Emulsifying Drug Delivery System，SEDDS)由油相、表面活性剂和助表面活性剂构成，其基本特征是在胃肠道内或在环境温度(一般为体温37℃)及温和搅拌的条件下能够自发形粒径10～200nm的水包油型纳米乳，均匀、快速分布并增加药物溶解度。载有细辛脑的自乳化系统尚未见报道。细辛脑自乳化体系在胃肠液环境下，可自乳化形成纳米乳，有利于提高药物溶出度和胃肠道渗透性。此外，自乳化系统可刺激机体产生脂蛋白和乳糜微粒，促进脂溶性药物经肠道淋巴系统的吸收，克服了肝首过效应。
发明内容
本发明提供了一种细辛脑自乳化系统及其制备方法，旨在提高细辛脑的溶出度，增加其在胃肠道内的稳定性，克服肝首过效应，从而解决细辛脑口服生物利用度低的问题。
本发明的上述目的通过以下技术方案实现：一种细辛脑自乳化系统及其制备方法，其特征在于，细辛脑与自乳化系统的质量比小于1∶2，优选1∶2.5～20。
本发明中，所述自乳化系统包括油相、表面活性剂和助表面活性剂，各组分的质量百分比为：油相10％～70％，表面活性剂30％～80％，助表面活性剂0～30％。
本发明中，所述的油相选自油酸、肉豆蔻酸异丙酯、中链甘油三酯、亚油酸甘油酯、油酸聚乙二醇甘油酯、单椰子油甘油酯中的一种或多种，优选中链甘油三酯、油酸聚乙二醇甘油酯。
本发明中，所述的表面活性剂选自聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、聚山梨酯80、辛酸癸酸聚乙二醇甘油酯、15-羟基硬脂酸聚乙二醇酯中的一种或多种，优选聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油。
本发明中，所述的助表面活性剂选自乙醇、丙二醇、异丙醇、二乙二醇单乙基醚、聚乙二醇400，优选二乙二醇单乙基醚。
本发明所述的细辛脑自乳化系统制备方法，包括如下步骤：
(1)将油相、表面活性剂和助表面活性剂混合均匀；
(2)将细辛脑加入步骤(1)所得混合液中，搅拌、涡旋振荡或超声至药物完全溶解，即得细辛脑自乳化系统。
本发明中，所述细辛脑自乳化系统分散于水中形成的纳米乳粒径在10～100nm，更优选小于50nm，最优选小于30nm。
本发明所述的细辛脑自乳化系统，可直接灌装于胶囊中，制成胶囊剂，或加入固体辅料进一步加工制备颗粒剂、丸剂或片剂等。
本发明的优点在于：
(1)自乳化体系可解决传统乳剂热力学稳定性较差、贮存体积大、粒径较大等问题。
(2)细辛脑自乳化体系能够提高药物的溶出度，增加药物在胃肠道内的稳定性，避免肝首过效应，提高药物生物膜渗透性，显著改善其口服生物利用度。
(3)细辛脑自乳化体系制备方法简单，材料安全，无需特殊设备，成本较低，适于工业化大生产。
附图说明
图1自乳化系统三元相图。
图2细辛脑自乳化系统稀释100倍时的粒径分布图。
图3细辛脑原料药、细辛脑自乳化系统的溶出曲线。
具体实施方式
下面通过具体实施例对本发明进一步阐述，但需要指出的是，以下实施例不构成对本发明的任何限制。
实施例1：自乳化系统各组分比例的确定
选择油酸聚乙二醇甘油酯为油相，聚氧乙烯氢化蓖麻油为表面活性剂，二乙二醇单乙基醚为助表面活性剂。称取不同比例各组分并混合均匀，加入100倍量蒸馏水轻摇至乳化完全。根据溶液澄明度情况与各组分比例绘制三元相图，曲线连接部分为可自乳化形成纳米乳区域，其中油相含量5％～30％，表面活性剂含量46％～70％，助表面活性剂含量6％～25％，见附图1。
实施例2：细辛脑自乳化系统的制备、稀释倍数影响与稀释介质影响研究
精密称取1.35g油酸聚乙二醇甘油酯、5.4g聚氧乙烯氢化蓖麻油及2.25g二乙二醇单乙基醚，混合均匀，另取3g细辛脑加入上述混合液中，搅拌1～2h，至药物完全溶解，即得细辛脑自乳化系统。
取适量该细辛脑自乳化系统，加入100倍量蒸馏水轻摇至乳化完全，形成的纳米乳粒径为25.1nm，PDI为0.119，见附图2。
细辛脑自乳化系统经蒸馏水500～2500倍稀释后粒径分别为25.0、24.0、23.2、26.4和23.7nm，稀释倍数对细辛脑自乳化系统乳化后的粒径基本无影响；PDI分别为0.205、0.253、0.267、0.326和0.441，由于激光粒度仪检测结果受样品粒子数影响，稀释倍数越大单位体积内粒子数越少，PDI越大。
细辛脑自乳化系统经蒸馏水、pH1.2盐酸溶液、pH4.0醋酸盐缓冲液和pH6.8磷酸盐缓冲液稀释后粒径分别为25.0、24.6、23.8和26.4nm，PDI分别为0.205、0.168、0.222和0.249，稀释介质对细辛脑自乳化系统乳化后的粒径与PDI基本无影响。
稀释倍数影响研究：
取适量细辛脑自乳化系统，分别加入500、1000、1500、2000和2500倍量蒸馏水，轻摇至乳化完全，采用激光粒度仪测定粒径与PDI。
稀释介质影响研究：
取适量细辛脑自乳化系统，分别加入500倍量蒸馏水、pH1.2盐酸溶液、pH4.0醋酸盐缓冲液和pH6.8磷酸盐缓冲液，轻摇至乳化完全，采用激光粒度仪测定粒径与PDI。
实施例3：细辛脑自乳化系统的体外溶出度研究
将细辛脑原料药与本发明实施例1的细辛脑自乳化系统进行溶出度对比实验，不同时间点的样品经含量测定并计算溶出度。结果显示本发明的细辛脑自乳化系统的溶出速率明显高于细辛脑原料药，见附图3。
溶出度测定：
取适量样品(含细辛脑30mg)，照溶出度测定法(中国药典2015版四部通则0931第二法)，以蒸馏水1000ml为溶出介质，转速为75r/min，依法操作，经5、10、15、20、30、45、60分钟时，取溶液5ml(同时补加5ml溶出介质)，0.22μm滤膜过滤，取续滤液作为供试品溶液，测定细辛脑浓度，计算溶出量。
Claims (7)
1.细辛脑自乳化系统，其特征在于，所述细辛脑自乳化系统包括细辛脑和自乳化系统，细辛脑与自乳化系统的质量比小于1∶2；所述自乳化系统包括油相、表面活性剂和助表面活性剂，各组分的质量百分比为：油相10％～70％，表面活性剂30％～80％，助表面活性剂0～30％。
2.根据权利要求1所述的细辛脑自乳化系统，其特征在于，所述油相选自油酸、肉豆蔻酸异丙酯、中链甘油三酯、亚油酸甘油酯、油酸聚乙二醇甘油酯、单椰子油甘油酯中的一种或多种。
3.根据权利要求1所述的细辛脑自乳化系统，其特征在于，所述表面活性剂选自聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、聚山梨酯80、辛酸癸酸聚乙二醇甘油酯、15-羟基硬脂酸聚乙二醇酯中的一种或多种。
4.根据权利要求1所述的细辛脑自乳化系统，其特征在于，所述助表面活性剂选自乙醇、丙二醇、异丙醇、二乙二醇单乙基醚、聚乙二醇400。
5.根据权利要求1所述的细辛脑自乳化系统制备方法，其特征在于，包括如下步骤：
(1)将油相、表面活性剂和助表面活性剂混合均匀；
(2)将细辛脑加入步骤(1)所得混合液中，搅拌、涡旋振荡或超声至药物完全溶解，即得细辛脑自乳化系统。
6.根据权利要求1所述的细辛脑自乳化系统，其特征在于，分散于水中形成的纳米乳粒径在10～100nm。
7.根据权利要求1所述的细辛脑自乳化系统，其特征在于，可进一步装入软胶囊、硬胶囊制备胶囊剂，或加入固体辅料制备颗粒剂、丸剂或片剂等。
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