CN101088523B - 黄芩天然活性成分的固体脂质纳米粒及其制备方法和制剂 - Google Patents
黄芩天然活性成分的固体脂质纳米粒及其制备方法和制剂 Download PDFInfo
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Abstract
本发明公开了一种黄芩天然活性成分的固体脂质纳米粒及其制剂制备方法。黄芩天然活性成分系指从中药黄芩中提取分离得到的黄芩素含量在50％以上的有效部位或黄芩素含量在90％以上的有效成分以及汉黄芩素含量在50％以上的有效部位或汉黄芩素含量在90％以上的有效成分。黄芩天然活性成分水溶性和脂溶性均较差，随着溶液pH值升高溶解度增加，但在碱性条件易发生化学降解。黄芩天然活性成分理化性质的不足使其无法制成注射给药制剂，口服后生物利用度较低。本发明通过固体脂质纳米粒技术，改善黄芩活性成分的亲水性和亲脂性，以期提高口服制剂生物利用度，或满足注射给药制剂及粘膜给药制剂设计要求。
Description
技术领域
本发明涉及一种黄芩天然活性成分的固体脂质纳米粒及其制剂。以脂质材料为载体制备黄芩天然活性成分的载药固体脂质纳米粒，可明显改善黄芩活性成分的溶解性和化学稳定性，满足不同给药途径制剂的设计要求，提高临床治疗效果。
背景技术
唇形科植物黄芩Scutellaria baicalensis Georgi的根有清热燥湿，泻火解毒，止血和安胎功能。黄芩的有效成分是黄酮类化合物，主要有黄芩苷(Baicalin)、黄芩素(Baicalein)、汉黄芩素(wogomin)、汉黄芩苷(Wogonoside)等四种成分。黄芩苷(黄芩素-7-0-葡萄糖醛酸苷)制剂临床上已用于呼吸道感染、急性扁桃体炎、咽炎、慢性阻塞性肺病、传染性肝炎、急慢性胃肠炎及细菌性痢疾、肾盂肾炎等的治疗。近年来研究发现，黄芩素同黄芩苷有相类似的药理作用，但抗菌抗病毒活性及抗菌谱均优于黄芩苷。
黄芩素分子中带有三个邻位的酚羟基，容易被氧化成为醌类化合物，化学性质不稳定。
黄芩素在中性及酸性条件下稳定性良好，但在pH<7.5时黄芩素溶解度极低，不能满足剂量要求；当pH≥8.5，药物溶解度增大，但在72小时后几乎全部发生降解，化学性质不稳定。
为将黄芩素制成注射给药制剂，CN1562147A公开了一种“黄芩提取物冻干粉针剂及其制备方法”，由黄芩提取物22～80％、碱性溶解剂11~75％、抗氧剂、络合剂1～12％和填充剂1～30％组成。基于黄芩素的溶解度和稳定性特征，该专利将pH值限定在7.45～8.0，这种要求难以满足产业化的要求。此外，制成的冻干粉在用生理盐水或葡萄糖注射液稀释时可能发生配伍变化，导致物理性质和化学性质的改变。
为改善黄芩素理化性质，有文献对其脂质体进行了研究。但脂质体存在包封率低、长期贮存易泄漏、不易产业化等缺陷，使产品开发和临床应用受到限制。
为制备稳定的注射给药制剂，满足临床用药需求，本发明人曾试图将黄芩素制成水包油(0/W)脂肪乳剂，以提高制剂载药量、提高长期贮存的稳定性。研究发现，黄芩素亲脂性较差，在大豆油中溶解度仅0.3mg/ml，中链油为1mg/ml，油酸、油酸乙酯、肉豆蔻酸异丙酯和棕榈酸异丙酯为0.5mg/ml。油相中较低的溶解度难以满足乳剂载药量的要求，同时乳剂在灭菌时药物易发生相转移，黄芩素由内油相迁移至外水相，随之出现破乳、分层和析出药物结晶的现象。
综上所述，黄芩素溶解度和稳定性不能满足注射剂制备的要求，通过控制pH值制备冻干粉针，或采用亚微乳技术制备脂肪乳剂均不能获得满意的结果。
上世纪90年代初，引入了一种新型纳米粒给药系统—固体脂质纳米粒(solidlipid nanoparticles，SLN)。SLN具有下述优点：(1)颗粒尺寸小，平均粒径在纳米尺度，可用于注射给药；(2)生理可接受，在制备过程中无有机溶剂、有毒聚合物单体等有毒残留物；(3)对亲脂性药物有足够的载药能力，通过工艺调整，还可以包封亲水性药物；(4)延长药物释放达数天至数周；(5)其水分散系可长期稳定达3年，通过冷冻干燥或喷雾干燥还可制成固体粉末；(6)有足以供应市场的大规模工业化生产方式；(7)价格相对较为低廉。近些年来，SLN吸引了国内外越来越多药物研究单位的注意。
为此，本发明采用固体脂质纳米粒技术对黄芩活性成分进行研究，以改善药物的溶解性和稳定性，提高生物有效性，满足不同给药途径制剂设计的要求。
发明内容
本发明的目的就是提供一种黄芩天然活性成分的固体脂质纳米粒，从而解决上述黄芩天然活性成分水溶性和脂溶性均较差，随着溶液pH值升高溶解度增加，但在碱性条件易发生化学降解的缺点，改善黄芩活性成分的亲水性和亲脂性，以期提高口服制剂生物利用度，或满足注射给药制剂及粘膜给药制剂设计要求。
本发明的另外一个目的是提供该黄芩天然活性成分的固体脂质纳米粒的制备方法。
本发明的又一个目的是提供含有黄芩天然活性成分的固体脂质纳米粒的制剂。
黄芩天然活性成分的固体脂质纳米粒，由黄芩天然活性成分、脂质材料、乳化剂和助乳化剂组成，其中黄芩天然活性成分与脂质材料的比例为1:1至1:99，粒径控制在500nm以下，黄芩天然活性成分系指由中药黄芩中提取分离得到的黄芩素含量在50％以上的有效部位或黄芩素含量在90％以上的有效成分以及汉黄芩素含量在50％以上的有效部位或汉黄芩素含量在90％以上的有效成分，所述的脂质材料包括三酰甘油酯，部分甘油酯，甾体类和蜡类，以及室温时为液态的脂质材粒。
本发明所述的固体脂质纳米粒，黄芩活性成分与脂质材料的比例为优选1:5至1:10，粒径控制在优选200nm以下。
本发明所述的固体脂质纳米粒的脂质材料可选自三酰甘油酯、部分甘油酯、甾体类(胆固醇等)和蜡类(如微晶石蜡，鲸酯蜡等)，亦可选用室温时为液态的脂质材粒。其中三酰甘油酯包括三硬脂酸，三棕榈酸，三月桂酸，三油酸等中、长链脂肪酸的甘油酯；部分甘油酯包括单硬脂酸甘油酯，含有单、二、三酰甘油酯的合成甘油酯；甾体类为胆固醇等，蜡类包括微晶石蜡和鲸酯蜡；或它们的混合物。乳化剂可选自离子型表面活性剂、非离子表面活性剂和天然表面活性剂；助乳化剂是刺激性小的聚乙二醇(PEG)类和聚氧烯烃整体共聚表面活性剂(泊洛沙姆类)。
除上述成分外，还可加入适量的稳定剂，包括油酸、PEG类、甘油、木糖醇、山梨醇(糖)醇和甘露醇。还可加入适量的抗氧剂、抑菌剂及络合剂。
本发明所述的固体脂质纳米粒的制备方法包括：
高压热乳匀法：将脂质材料加热至熔点以上使其熔融，加入黄芩活性成分制备共熔物；另将乳化稳定剂溶于水中，将同温度的水相与载药脂质共熔物混合，用高剪切混合设备制备初乳，再通过高压均质机乳化，即可得到粒径在200nm的载药脂质纳米粒混悬液，经无菌过滤后可制成注射液或冻干粉。
高压冷乳匀法：考虑到黄芩活性成分在高温状态下易发生降解，上述方法进行如下改进，即用干冰或液氮将载药脂质共熔液进行快速冷却，高的冷却速度有利于药物在脂质基材中的均匀分布，再对固态的含药脂质进行粉碎和研磨，然后分散于乳化剂溶液中形成初乳混悬液，初乳在低温下进行高压乳化，即得载药固体脂质纳米粒混悬液，经无菌过滤后可制成注射液或冻干粉。
溶剂乳化挥发法(或沉淀法)：将脂质材料溶解于二氯甲烷中，黄芩活性成分溶于乙酸乙酯中，两者混合制得有机相，另取乳化剂和助乳化剂溶于水中掉成水相，将有机相加入至水相中搅拌均匀，再移至高压均质机中进行乳化，减压蒸除有机溶剂，即得脂质纳米粒混悬液。经无菌过滤后可制成注射液或冻干粉。溶剂挥除不完全是限制该方法大规模生产的关键因素。
黄芩活性成分固体脂质纳米粒混悬液可经无菌过滤后制成小容量注射液、大容量输液或注射用冻干粉针，制成可供粘膜用的滴剂、喷雾剂及气雾剂，制成肺部吸入制剂。
黄芩活性成分固体脂质纳米粒混悬液经冷冻干燥后制成的粉末，再与合适的赋形剂混合，可制成各种口服制剂；还可溶于植物油中制成水包油亚微乳，再经灭菌或无菌过滤后制成注射液和粘膜给药制剂。
为进一步说明本发明方法的制备工艺和所体现的创新性，特列出以下实施例，但本发明的权利保护并不仅限于实施例描述的内容。
实施例1：载药固体脂质纳米粒混悬液的制备
取胆固醇84g，加热熔融，加入黄芩素有效成分12g，制备共熔物，用干冰进行快速冷却，固态物经粉碎和研磨，备用；另取失水山梨醇脂肪酸酯和泊洛沙姆适量，加入2000ml水中形成水相，将粉碎后的固态粉末分散于水相中形成初乳混悬液，再于15℃以下进行高压均质乳化，得载药固体脂质纳米粒混悬液。
实施例2：载药固体脂质纳米粒注射液制备
取实施例1制备的脂质纳米粒混悬液100ml，经0.45μm微孔滤膜过滤，取5ml分装于安瓶中，经121℃灭菌15分钟，即得胶体注射液，每支含黄芩素活性成分为30mg。
实施例3：载药固体脂质纳米粒注射用冻干粉针制备
取实施例1制备的脂质纳米粒混悬液100ml，加入甘露醇6g，搅拌使溶解，经0.22μm微孔滤膜过滤，取5-6ml分装于西林瓶中，-40℃预冻4小时，-25℃升华10小时去除水分，-10℃干燥5小时，20℃再干燥5小时，得注射用冻干粉针。每只西林瓶含黄芩素活性成分为30mg。
实施例4：载药固体脂质纳米粒鼻粉剂的制备
取实施例1制备的脂质纳米粒混悬液100ml，加入脱乙酰化壳聚糖0.5g，聚维酮2g，搅拌使溶解，-40℃预冻4小时，-25℃升华10小时去除水分，-10℃干燥5小时，20℃再干燥5小时，得冻干粉，分装即得。
实施例5：载药固体脂质纳米粒口服制剂制备
取实施例1制备的脂质纳米粒混悬液500ml，加入甘露醇5g搅拌使溶解，-40℃预冻4小时，-25℃升华10小时去除水分，-10℃干燥5小时，20℃再干燥5小时，得冻干粉，再加入乳糖和微晶纤维素，装入胶囊，即得。
实施例6：载药固体脂质纳米粒脂肪乳及其注射液制备
按实施例1制备方法制备载药固体脂质纳米粒混悬液，经冷冻干燥或喷雾干燥得固体脂质纳米粒粉末，黄芩素活性成分重量百分比为12.3％。取固体脂质粉末适量(相当于黄芩素有效成分1000mg)，卵磷脂12g，油酸2.4g，一同加入100g注射用大豆油中，加热到60℃，形成油相；另取甘油25g和Pluronic(F68)20g，加入约700-800ml水中，加热到60℃，形成水相。将油相缓慢加入到水相，加注射用水至1000ml，在60℃、16000r/min条件下高剪切乳化8min，迅速冷却制得初乳。将初乳用高压匀质机在650Mpa条件下乳化6次，即得均匀的类白色脂肪乳剂，载药量为1mg/ml。
取上述脂肪乳，经0.45μm微孔滤膜过滤，分装于小输液瓶中，每瓶装量100ml，在121℃下灭菌15min，得灭菌输液，每瓶含黄芩素活性成分100mg。
另取过滤后的脂肪乳，分装于小安瓶中，每瓶装量10ml，在121℃下灭菌15min，得灭菌小针剂，每瓶含黄芩素活性成分10mg。
实施例8：载药固体脂质纳米粒脂肪乳及其粘膜给药制剂制备
按实施例1制备方法制备载药固体脂质纳米粒混悬液，经冷冻干燥得固体脂质纳米粒粉末，黄芩素活性成分重量百分比为12.3％。取载药固体脂质粉末适量(相当于黄芩素有效成分1500mg)，卵磷脂20g，油酸3g，一同加入50g注射用大豆油中，加热到60℃，形成油相；另取甘油25g和Pluronic(F68)25g，加入约350-400ml水中，加热到60℃，形成水相。将油相缓慢加入到水相，加注射用水至500ml，在60℃、16000r/min条件下高剪切乳化8min，迅速冷却制得初乳。将初乳用高压匀质机在650Mpa条件下乳化6次，即得均匀的类白色脂肪乳剂，载药量为3mg/ml。
取上述脂肪乳，经0.22μm膜无菌过滤，分装于10ml带定量阀的喷雾瓶中，得无菌喷雾溶液，供鼻粘膜、口腔粘膜或呼吸道粘膜喷雾给药。
Claims (6)
1.一种黄芩天然活性成分的固体脂质纳米粒，由黄芩天然活性成分、脂质材料、乳化剂和助乳化剂组成，其中黄芩天然活性成分与脂质材料的比例为1∶5至1∶10，粒径控制在500nm以下，黄芩天然活性成分系指中药黄芩提取分离得到的黄芩素含量在90％以上的有效成分或汉黄芩素含量在90％以上的有效成分，所述的脂质材料为三酰甘油酯，部分甘油酯，甾体类和蜡类；所述的乳化剂为失水山梨醇脂肪酸酯，所述的助乳化剂是刺激性小的聚乙二醇类和聚氧烯烃整体共聚表面活性剂。
2.根据权利要求1所述的固体脂质纳米粒，其特征在于所述固体脂质纳米粒粒径控制在200nm以下。
3.根据权利要求1或2所述的固体脂质纳米粒，其特征在于，所述的三酰甘油酯为三硬脂酸，三棕榈酸，三月桂酸或三油酸中、长链脂肪酸的甘油酯；部分甘油酯为单硬脂酸甘油酯或含有单、二、三酰甘油的合成甘油酯；甾体类为胆固醇和蜡类为微晶石蜡或鲸酯蜡。
4.根据权利要求1或2所述的固体脂质纳米粒的制备方法，其特征在于将脂质材料溶解于二氯甲烷中，黄芩活性成分溶于乙酸乙酯中，两者混合制得有机相，另取乳化剂和助乳化剂溶于水中形成水相，将有机相加入至水相中搅拌均匀，再移至高压均质机中进行乳化，减压蒸除有机溶剂，即得脂质纳米粒混悬液。
5.含有权利要求1或2所述的固体脂质纳米粒的制剂，其特征在于制成注射药制剂，口服给药制剂，肺部吸入制剂，口腔粘膜或呼吸道粘膜给药制剂及外用制剂。
6.根据权利要求5所述的制剂，其特征在于，注射药系将载药固体脂质纳米粒制成胶体分散注射液、冻干粉针或输液；口服给药制剂系将载药固体脂质纳米粒制成片剂、胶囊、颗粒剂、丸剂；肺部吸入制剂系将载药固体脂质纳米粒制成干粉吸入剂、胶体分散吸入液或含抛射剂的气雾剂；口腔粘膜或呼吸道粘膜给药制剂系将载药固体脂质纳米粒制成干粉剂、胶体溶液剂、喷雾剂或气雾剂；外用制剂系将载药固体脂质纳米粒制成软膏剂、凝胶剂、胶体溶液剂、膜剂、乳剂。
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| CN110051654A (zh) * | 2019-04-19 | 2019-07-26 | 天津中医药大学 | N-三甲基壳聚糖修饰的黄芩素眼用脂质纳米粒制剂及其制备方法 |
| CN110227062B (zh) * | 2019-07-18 | 2022-08-30 | 泉州师范学院 | 一种黄芩苷脂质体软膏及其制备方法 |
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