CN100391467C - 含有人参皂苷的纳米乳剂及其制备方法和用途 - Google Patents
含有人参皂苷的纳米乳剂及其制备方法和用途 Download PDFInfo
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Abstract
本发明提供了人参皂苷的纳米乳剂及其制备方法和用途。本发明提供的人参皂苷乳剂含有人参皂苷，水，油、调等渗剂和表面活性剂，还可以含有稳定剂。本发明提供的乳剂无致敏性，副作用小；且本发明提供的纳米乳剂油相中活性成分的含量较高，满足了临床药效所需的高浓度，同时该乳剂还可以改变皂苷在人体内的分布，提高药物的生物利用度，可以使人参皂苷在体内浓集于肿瘤部位，提高该化合物的抑瘤作用。
Description
发明领域
本发明涉及一种人参皂苷纳米乳剂及其制备方法用途。
背景技术
人参皂苷Rh2为人参中提取得到的单组分化合物，属于二醇组皂苷，它可以通过诱导分化或凋亡抑制肿瘤细胞的增殖与生长，但对正常组织毒性甚低，见[徐景达，长白山中医药研究与开发，1996，5(5)：48]。李氏研究发现人参皂苷Rh2对C6胶质瘤细胞有明显的增殖抑制和诱导凋亡作用，这种作用具有周期特异性。他认为Rh2是人参的天然活性成分，毒性低、分子量小，且为脂溶性，易通过血脑屏障，是一种潜在的化疗药，见[李殿友等，白求恩医科大学学报，2000，26(4)：342]。
由于人参皂苷Rh2为脂溶性，因此制备注射液需要大量使用有毒副作用的增溶剂，如使用聚氧乙烯蓖麻油类(Cremophor-EL)等表面活性剂，该类表面活性剂具有致敏性，大量使用后过敏反应的发生率较高，见[魏晓慧，等Chinese Journal of Pharmaceuticals 2001，32(4)：188-192]。鉴于此，本发明人提供了一种纳米乳剂。
发明内容
本发明提供了人参皂苷纳米乳剂，人参皂苷是指20(R)-人参皂苷-Rh2、20(S)-人参皂苷-Rh2或20(R，S)-人参皂苷-Rh2。
本发明还提供了人参皂苷纳米乳剂的制备方法。
本发明提供的人参皂苷纳米乳剂含有人参皂苷、油、水、表面活性剂和调等渗剂，其中人参皂苷∶油∶表面活性剂和调等渗剂的重量比为1∶1-50∶1-10∶1-10。
本发明所述的油是指生物可接受的物质，可以是植物油、动物油、精油、矿物油或合成油中的一种或几种。其中，植物油选自大豆油、玉米油、花生油、橄榄油、蓖麻油、棕榈油、椰子油、菜籽油、芝麻油或棉子油中的一种或几中；动物油选自鱼油、油酸、鯨蜡油、单、双、三甘油酯中的一种或几种；精油选自五味子油、沙棘油、桃仁油、杏仁油、红花油、茶油、月见草油、小麦胚芽油、紫苏油、山苍子油、鸦胆子油或莪术油中的一种或几种；矿物油选自脂肪烃、蜡基烃、芳香烃或石蜡油中的一种或几种；合成油选自亚油酸、共轭亚油酸、油酸乙酯、氢化蓖麻油、氢化花生油、氢化棉子油、亚油酸乙酯、共轭亚油酸乙酯、自乳化单硬脂酸酯、辛/癸酸甘油酯或甘油三乙酯中的一种或几种。优选为富含甘油三酯的油。
本发明所述的表面活性剂可以是两性表面活性剂或非离子表面活性剂中的一种或几种。两性表面活性剂选自豆磷脂、蛋黄磷脂、磷脂酰胆碱、磷脂酰乙醇胺、丝氨酸磷脂、肌醇磷脂、磷脂酸、脑磷脂或氢化磷脂中的一种或几种；非离子表面活性剂选自蔗糖脂肪酸酯类(如蔗糖酯)、司盘类、吐温类、聚氧乙烯脂肪酸酯类(如卖泽Myrij)、聚氧乙烯脂肪醇醚类(如卞泽Brij)类或泊洛沙姆类(如poloxamer)中的一种或几种。其优选为大豆磷脂、蛋黄磷脂、氢化磷脂或聚氧乙烯-聚氧丙稀嵌段聚合物(泊洛沙姆)中的一种或几种。
本发明所用的调等渗剂是甘油。
本发明提供的人参皂苷乳剂还可以加入稳定剂，如胆固醇、长链醇(C14-22)、油酸、亚油酸或其衍生物，其用量是人参皂苷的0-200倍。
本发明提供的人参皂苷乳剂制备方法为将人参皂苷加入至油中，混合，在表面活性剂的作用下，在水中形成分散相。其优选制备方法为将人参皂苷先溶解于醇溶液中，如果需要，可以将稳定剂如胆固醇、表面活性剂磷脂可加入到此醇溶液中，接着把该溶液加到油中并混合至澄明。用旋转蒸发或通氮气流蒸发除去醇。将溶于水相的表面活性剂如泊洛沙姆分散到水中，调等渗剂甘油可在制备过程中的任何时候加到水相中。在高速搅拌下把含有人参皂苷的油溶液加到水相中形成粗乳剂。所得的粗乳剂通过超声粉碎机、高压乳匀机进一步乳化，得放置稳定、粒度均匀、无毒的乳剂。
本发明提供的乳剂不含具有毒副作用的增溶剂，且所用的添加剂均为可降解和生物相容，因此该乳剂副作用降低，此外本发明提供的乳剂抑瘤作用提高，且还有利于工业化批量生产。
具体实施方式
实例1：人参皂苷乳剂的制备
将100mg 20(R)-人参皂苷-Rh2、2.0g豆磷脂、0.5g胆固醇用乙醇溶解后加入到10g精制大豆油中，混合至澄明，并通过旋转蒸发或通入氮气蒸发除去醇，得到含人参皂苷10mg/ml和50mg/ml胆固醇的大豆油溶液。将1.0g泊洛沙姆、2.5g甘油分散至注射用水中，在高速搅拌条件下，慢慢滴加含有人参皂苷的磷脂、胆固醇的油溶液到分散体系中，制成粗乳剂。将所得到的粗乳剂在压力100Mpa的条件下，通过乳匀机进一步乳化，乳化结束后可于115℃，30min灭菌，分装即得。
实例2：人参皂苷乳剂的制备
将500mg 20(S)-人参皂苷-Rh2、2g豆磷脂、4.5g油酸用乙醇溶解后加入到15g精制大豆油中，混合至澄明，并通过旋转蒸发或通入氮气蒸发除去醇，得到含人参皂苷50mg/ml和450mg/ml油酸的大豆油溶液。将甘2.5g甘油，3.0g泊洛沙姆加入至注射用水中，在高速搅拌条件下，慢慢滴加含有人参皂苷的磷脂、油酸的油溶液到分散体系中，制成粗乳剂。将所得到的粗乳剂在压力100Mpa的条件下，通过乳匀机进一步乳化，乳化结束后可以于115℃，30min灭菌，分装即得。
实例3：人参皂苷乳剂的制备
将200mg 20(R，S)-人参皂苷-Rh2、3.0g蛋黄磷脂、4.5g油酸用乙醇溶解后加入到15g精制大豆油中，混合至澄明，并通过旋转蒸发或通入氮气蒸发除去醇，得到含人参皂苷20mg/ml和450mg/ml油酸的大豆油溶液。将2.5g甘油加入至注射用水中，在高速搅拌条件下，慢慢滴加含有人参皂苷的磷脂、油酸的油溶液到分散体系中，制成粗乳剂。将所得到的粗乳剂在压力100Mpa的条件下，通过乳匀机进一步乳化，乳化后可于115℃，30min灭菌，分装即得。
试验例1人参皂苷Rh2乳剂对S180肉瘤体内增殖的影响：
人参皂苷乳剂按制备例方法制备，注射液按CN200410002110.8的实施例制备。
取已经传代一周生长状态良好的S180肿瘤传代小鼠，取腹水后，加入三倍体积的注射用生理盐水稀释，接种于80只昆明鼠腋下，每只0.2ml。接种第二天按体重随机分为8组，分别为模型对照组、阳性药组(环磷酰胺60mg/kg，接瘤后第二天单次给药)、人参皂苷Rh2乳剂高(50mg/kg)、中(25mg/kg)、低(12.5mg/kg)剂量组，和人参皂苷Rh2水针高(50mg/kg)、中(25mg/kg)、低(12.5mg/kg)剂量组。各组小鼠尾静脉给药(模型组给以等量生理盐水)，每天一次，给药10天。于末次给药后24小时处死动物，称体重，剥取瘤组织称重，计算抑瘤率。
结果表明，人参皂苷Rh2乳剂和水针剂50mg/kg和25mg/kg均能明显抑制体内S180肉瘤的生长肿瘤(P＜0.01)，乳剂组50mg/kg时的抑瘤作用明显优于水针剂组(P＜0.05)。
实验例2人参皂苷Rh2乳剂对H22肝癌体内增殖的影响：
取已经传代一周生长状态良好的H22肿瘤传代小鼠，取腹水后，加入三倍体积的注射用生理盐水稀释，接种于80只昆明鼠腋下，每只0.2ml。接种第二天按体重随机分为8组，分别为模型对照组、阳性药组(环磷酰胺60mg/kg，接瘤后第二天单次给药)、人参皂苷Rh2乳剂高(50mg/kg)、中(25mg/kg)、低(12.5mg/kg)剂量组，和人参皂苷Rh2水针高(50mg/kg)、中(25mg/kg)、低(12.5mg/kg)剂量组。各组小鼠尾静脉给药(模型组给以等量生理盐水)，每天一次，给药10天。于末次给药后24小时处死动物，称体重，剥取瘤组织称重，计算抑瘤率。
结果表明，人参皂苷Rh2乳剂和水针剂50mg/kg和25mg/kg均能明显抑制H22肝癌的体内增殖(P＜0.01)，乳剂组的抑瘤作用相对较强，50mg/kg时作用明显优于水针剂组(P＜0.05)。
实验例3人参皂苷Rh2乳剂对U14宫颈癌体内增殖的影响：
取已经传代一周生长状态良好的U14肿瘤传代小鼠，取腹水后，加入三倍体积的注射用生理盐水稀释，接种于80只昆明鼠腋下，每只0.2ml。接种第二天按体重随机分为8组，分别为模型对照组、阳性药组(环磷酰胺60mg/kg，接瘤后第二天单次给药)、人参皂苷Rh2乳剂高(50mg/kg)、中(25mg/kg)、低(12.5mg/kg)剂量组，和人参皂苷Rh2水针高(50mg/kg)、中(25mg/kg)、低(12.5mg/kg)剂量组。各组小鼠尾静脉给药(模型组给以等量生理盐水)，每天一次，给药10天。于末次给药后24小时处死动物，称体重，剥取瘤组织称重，计算抑瘤率。
结果表明，人参皂苷Rh2乳剂和水针剂50mg/kg和25mg/kg均能明显抑制U14宫颈癌的体内增殖(P＜0.01)，乳剂组50mg/kg的抑瘤作用明显优于水针剂组(P＜0.05)。
实验例3对ESC腹水癌小鼠生存期的作用比较：
取接种ESC腹水7天后小鼠的乳白色腹水，加入三倍体积生理盐水稀释，在无菌条件下给80只昆明鼠腹腔注射0.2ml(约500万细胞)，接种后次日随机分为8组，分别为模型对照组、阳性药组(环磷酰胺60mg/kg，接瘤后第二天单次给药)、人参皂苷Rh2乳剂高(50mg/kg)、中(25mg/kg)、低(12.5mg/kg)剂量组，和人参皂苷Rh2水针高(50mg/kg)、中(25mg/kg)、低(12.5mg/kg)剂量组。各组小鼠尾静脉给药(模型组给以等量生理盐水)，每天一次，给药10天。停药后观察小鼠生存状态，记录死亡时间，按生存天数计算生命延长率。
结果表明，人参皂苷Rh2乳剂和水针剂50mg/kg和25mg/kg均能明显延长ESC腹水癌小鼠的生存时间(P＜0.01)，乳剂组50mg/kg的生命生长作用明显优于水针剂组(P＜0.05)。
Claims (1)
1.一种含有人参皂苷的纳米乳剂，其组成为人参皂苷Rh2、油、表面活性剂、调等渗剂、稳定剂和水，其中人参皂苷Rh2∶油∶表面活性剂∶调等渗剂的重量比为1∶1-50∶1-10∶1-10；所述的人参皂苷Rh2为20(R)-人参皂苷Rh2、20(S)-人参皂苷Rh2或20(R，S)-人参皂苷Rh2；所述的油为豆油；所述的表面活性剂为大豆磷脂、蛋黄磷脂和泊洛沙姆中的两种或几种；所述的调等渗剂为甘油；所述的稳定剂为5-200倍人参皂苷Rh2重量的胆固醇，或9-200倍人参皂苷Rh2重量的油酸。
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| CN1225366A (zh) * | 1998-02-05 | 1999-08-11 | 大连天马制药有限公司 | 20(S)－人参皂甙－Rh2的制备方法,其药物组合物及应用 |
| CN1395961A (zh) * | 2002-08-02 | 2003-02-12 | 上海医药工业研究院 | 一枝黄花注射用脂肪乳剂及制备方法 |
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| CN1225366A (zh) * | 1998-02-05 | 1999-08-11 | 大连天马制药有限公司 | 20(S)－人参皂甙－Rh2的制备方法,其药物组合物及应用 |
| CN1395961A (zh) * | 2002-08-02 | 2003-02-12 | 上海医药工业研究院 | 一枝黄花注射用脂肪乳剂及制备方法 |
Non-Patent Citations (2)
| Title |
|---|
| 注射用乳剂与抗肿瘤的疗效. 国外医学.肿瘤学分册，第5期. 1979 |
| 注射用乳剂与抗肿瘤的疗效. 国外医学.肿瘤学分册，第5期. 1979 * |
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