CN105997875A - 一种明显提高难溶性药物生物利用度的油包水型纳米乳及其制备方法 - Google Patents
一种明显提高难溶性药物生物利用度的油包水型纳米乳及其制备方法 Download PDFInfo
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- CN105997875A CN105997875A CN201610575083.6A CN201610575083A CN105997875A CN 105997875 A CN105997875 A CN 105997875A CN 201610575083 A CN201610575083 A CN 201610575083A CN 105997875 A CN105997875 A CN 105997875A
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- cyclodextrin
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- insoluble drug
- emulsion
- phosphatide complexes
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Abstract
本发明属于药物制剂领域。本发明涉及一种明显提高难溶性药物生物利用度的油包水型纳米乳及其制备方法。本发明制备得到的油包水型纳米乳可以实现改善难溶性药物的溶解度,促进难溶性药物的吸收,显著增加难溶性药物的生物利用度。
Description
技术领域
本发明属于医药制剂领域,涉及一种明显提高难溶性药物生物利用度的油包水型纳米乳及其制备方法。
背景技术
制药行业从药物发现到临床的应用,最后一个环节是药物制剂。许多药物由于脂溶性强,水溶性低,体内吸收差,生利用度低,限制了药物在临床的广泛应用,因此需要将药物制备成一定的药物制剂,从而增加药物的溶解度,促进药物在体内的吸收,增加药物的生物利用度,提高药物的疗效。
纳米乳是由水、油、表面活性剂、助表面活性剂等自发形成的一种新型的药物载体,它具有以下优点:毒性小、安全性高、制备简单,能显著提高难溶于水药物的溶解性,提高药物的生物利用度。磷脂复合物是药物和磷脂分子通过电荷迁移作用而形成的较为稳定的化合物或络合物,它能够改变药物的溶解性能,增强在胃肠道中的吸收,延长药物作用时间,降低药物不良反应,提高药物的生物利用度。环糊精是一种安全性高、无毒副作用的药物辅料,其包合物能够增加难溶性药物的水溶性、提高药物的生物利用度、降低药物的毒副作用。
本专利首次同时采用环糊精包合物技术、磷脂复合物技术、纳米乳技术制备了一种明显提高难溶性药物生物利用度的油包水型纳米乳,即一种难溶性药物环糊精磷脂复合物的油包水型纳米乳,较游离难溶性药物、采用单一技术制备的制剂(难溶性药物环糊精包合物、难溶性药物磷脂复合物、难溶性药物纳米乳)具有更高的生物利用度,由药代动力学参数可知:它的药时曲线下面积(AUC)显著大于3个单一制剂(难溶性药物环糊精包合物、难溶性药物磷脂复合物、难溶性药物纳米乳)AUC的加和,表明同时采用环糊精包合物技术、磷脂复合物技术、纳米乳技术制备的一种难溶性药物环糊精磷脂复合物的油包水型纳米乳,能够显著提高难溶性药物溶解度、生物利用度、疗效,为难溶性药物提供一种可供选择的新型载药系统,具有重要意义。
经查询专利及文献,目前尚未见同时采用环糊精包合物技术、磷脂复合物技术、纳米乳技术增加任何药物(包括1种药物,2种药物或2种以上的药物)的生物利用度的研究报道,亦尚未见同时采用环糊精包合技术和纳米乳技术增加任何药物生物利用度的研究报道,当然,更未见同时采用环糊精包合物技术、磷脂复合物技术、纳米乳技术增加难溶性药物的生物利用度。目前,通常仅见采用单一技术增加药物的生物利用度,比如姜黄素包合物、厚朴酚磷脂复合物、水飞蓟素纳米乳、葛根素纳米乳等;同时采用两种技术提高药物的生物利用,仅见本研究团队的文献报道:文献(Hu J,et al.,Improved absorption and invivo kinetic characteristics of nanoemulsions containing evodiamine-phospholipid nanocomplex.Int J Nanomedicine.2014,9:4411-20)报道同时采用磷脂复合物技术和纳米乳技术可以提高难溶性药物的生物利用度,文献(罗见春,等.姜黄素羟丙基-β-环糊精磷脂复合物在大鼠体内药代动力学研究.中药材.2015,38(3):572-5)报道同时采用环糊精包合物技术和磷脂复合物技术可以提高难溶性药物的生物利用度。目前尚未见同时采用环糊精包合物技术、磷脂复合物技术、纳米乳技术增加任何药物(包括1种药物,2种药物或2种以上的药物)生物利用度的研究报道,当然,更未见同时采用环糊精包合物合技术、磷脂复合物技术、纳米乳技术增加难溶性药物生物利用度的研究报道,即:目前尚无一种或多种难溶性药物环糊精磷脂复合物的油包水型纳米乳的任何研究报道。
发明内容
本发明所要解决的技术问题是提供一种明显提高难溶性药物生物利用度的油包水型纳米乳及其制备方法。本发明制备得到的油包水型纳米改善了难溶性药物的溶解度,促进了药物在体内的吸收,显著增加了药物的生物利用度,提高了药物的疗效。本发明提供的一种明显提高难溶性药物生物利用度的油包水型纳米乳的制备工艺简单,成本较低,制备得到的水包油型纳米乳的稳定性高,易于控制,易于工业化生产。
本发明提供的一种明显提高难溶性药物生物利用度的油包水型纳米乳,其特征在于该制剂为难溶性药物环糊精磷脂复合物的纳米乳:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
难溶性药物 0.5-6份,
环糊精 1.5-46.6份,
磷脂 1-20份,
纳米乳,包括以下各组分,各组分重量份比例为:
本发明提供的一种明显提高难溶性药物生物利用度的油包水型纳米乳的制备方法如下:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于有机溶剂(乙醇、二氯甲烷、三氯甲烷中的一种或几种)中,40-60℃恒温磁力搅拌条件下反应1-4小时后,旋转蒸发除去有机溶剂,真空干燥除去残留的有机溶剂,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在30-60℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得到油包水型纳米乳。
本发明所述的一种明显提高难溶性药物生物利用度的油包水型纳米乳,所述的难溶性药物为以下(1)至(9)所列药物的一种或几种的混合物:(1)抗肿瘤药物:姜黄素、吴茱萸碱、卡莫司汀、小檗碱、甲氨蝶呤、青蒿素、白藜芦醇、紫杉醇、羟喜树碱、葫芦素B、胡椒碱、顺铂、卡铂、多柔比星、甲氨蝶呤;(2)抗心血管疾病药物:环维黄杨星D、川芎嗪、灯盏花素、葛根素、黄芪苷、银杏酮酯、盐酸胺碘酮、吡罗昔康、硝苯地平、替米沙坦、普罗帕酮、奎尼丁;(3)抗炎药物:白头翁、穿心莲内酯、黄芩素、布洛芬、酮替芬、奈普生、槲皮素、木犀草素、芒果苷、吲哚美辛、塞来昔布、丙酸氯倍他索、酮替芬、齐墩果酸、水飞蓟素、水飞蓟宾;(4)抗菌药物:厚朴酚、小檗碱、丹参酮、氟苯尼考、盐酸布替萘芬、头孢克肟、环吡酮胺、异烟肼、利福平、吡嗪酰胺、伊曲康唑、氟哌酸、肉桂酮、氧氟沙星、左旋氧氟沙星、司帕沙星、诺氟沙星、磺胺甲氧哒嗪、恩诺沙星、妥曲珠利;(5)降血脂药物:非诺贝特、考来烯胺、普罗布考、吡罗昔康;(6)抗精神病药物:伊潘立酮、利培酮、奥氮平、舒必利;(7)镇痛、镇静药物:延胡索乙素、左旋延胡索乙素;(8)抗氧化药物:维生素E;(9)免疫抑制剂:环孢素A。
因本发明涉及的难溶性药物内容较多,故以下内容以1种药物(环维黄杨星D)、2种药物(复方姜黄素与吴茱萸碱混合物)为例来进行说明。
以环维黄杨星D为例,用本发明制得的环维黄杨星D羟丙基-β-环糊精磷脂复合物的油包水型纳米乳进行药代动力学研究,大鼠口服给药后体内药动学考察结果表明,相对于环维黄杨星D、环维黄杨星D羟丙基-β-环糊精包合物、环维黄杨星D磷脂复合物、环维黄杨星D纳米乳、环维黄杨星D羟丙基-β-环糊精磷脂复合物、环维黄杨星D羟丙基-β-环糊精包合物纳米乳、环维黄杨星D磷脂复合物纳米乳,环维黄杨星D羟丙基-β-环糊精磷脂复合物的油包水型纳米乳的曲线下面积增大,半衰期延长,峰浓度增大,在体内的生物利用度显著增大。环维黄杨星D羟丙基-β-环糊精磷脂复合物的油包水型纳米乳曲线下面积AUC(μg/L*h)为(8118.79±1031.36)(μg/L*h),分别是环维黄杨星D(657.95±82.93)(μg/L*h)、环维黄杨星D羟丙基-β-环糊精包合物(1743.55±216.63)(μg/L*h)、环维黄杨星D磷脂复合物(1953.94±670.12)(μg/L*h)、环维黄杨星D纳米乳(1525.50±132.37)(μg/L*h)、环维黄杨星D羟丙基-β-环糊精磷脂复合物(3016.70±476.14)(μg/L*h)、环维黄杨星D羟丙基-β-环糊精包合物纳米乳(3204.11±940.74)(μg/L*h)、环维黄杨星D磷脂复合物纳米乳(3513.94±739.47)(μg/L*h)的1233%、465%、415%、532%、269%、253%、231%,其生物利用度显著提高。同时环维黄杨星D羟丙基-β-环糊精磷脂复合物的油包水型纳米乳AUC显著大于环维黄杨星D的3个单一制剂(环维黄杨星D羟丙基-β-环糊精包合物、环维黄杨星D磷脂复合物、环维黄杨星D纳米乳)AUC的加和,表明同时采用环糊精包合物合技术、磷脂复合物技术、纳米乳技术制备的一种难溶性药物环糊精磷脂复合物的油包水型纳米乳,能够显著提高难溶性药物溶解度,增加药物的生物利用度,提高药物疗效。
以姜黄素与吴茱萸碱混合物为例,用本发明对制得的复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物的油包水型纳米乳进行药代动力学研究,大鼠口服给药后体内药动学考察结果表明,相对于复方姜黄素/吴茱萸碱、复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物、复方姜黄素/吴茱萸碱磷脂复合物、复方姜黄素/吴茱萸碱纳米乳、复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物、复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物纳米乳、复方姜黄素/吴茱萸碱磷脂复合物纳米乳,复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物的油包水型纳米乳的曲线下面积增大,半衰期延长,峰浓度增大,在体内的生物利用度显著增大。复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物的油包水型纳米乳中吴茱萸碱曲线下面积AUC为(19543.45±1764.42)(μg/L*h),分别是复方姜黄素/吴茱萸碱中吴茱萸碱(1389.61±39.61)(μg/L*h)、复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物中吴茱萸碱(2516.47±103.35)(μg/L*h)、复方姜黄素/吴茱萸碱磷脂复合物中吴茱萸碱(2619.63±83.93)(μg/L*h)、复方姜黄素/吴茱萸碱纳米乳中吴茱萸碱(2973.19±147.81)(μg/L*h)、复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复物中吴茱萸碱(3212.31±88.40)(μg/L*h)、复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物纳米乳中吴茱萸碱(4862.05.39±237.46)(μg/L*h)、复方姜黄素/吴茱萸碱磷脂复合物纳米乳中吴茱萸碱(5846.11±174.54)(μg/L*h)的1406%、776%、746%、657%、608%、401%、334%,其生物利用度显著提高。同时复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物的油包水型纳米乳的AUC显著大于复方姜黄素/吴茱萸碱的3个单一制剂(复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物、复方姜黄素/吴茱萸碱磷脂复合物、复方姜黄素/吴茱萸碱纳米乳)AUC的加和,表明同时采用环糊精包合物合技术、磷脂复合物技术、纳米乳技术制备的一种难溶性药物环糊精磷脂复合物的油包水型纳米乳,能够显著提高难溶性药物溶解度,增加药物的生物利用度,提高药物的疗效。
以上实例说明:同时采用环糊精包合物合技术、磷脂复合物技术、纳米乳技术制备得到的环维黄杨星D羟丙基-β-环糊精磷脂复合物的油包水型纳米乳、复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物的油包水型纳米乳,分别较游离药物(环维黄杨星D、复方姜黄素/吴茱萸碱)、采用1种技术制备的制剂(环维黄杨星D羟丙基-β-环糊精包合物、环维黄杨星D磷脂复合物、环维黄杨星D纳米乳、复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物、复方姜黄素/吴茱萸碱磷脂复合物、复方姜黄素/吴茱萸碱纳米乳)、采用2种技术制备的制剂(环维黄杨星D羟丙基-β-环糊精磷脂复合物、环维黄杨星D羟丙基-β-环糊精包合物纳米乳、环维黄杨星D磷脂复合物纳米乳、复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物、复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物纳米乳、复方姜黄素/吴茱萸碱磷脂复合物纳米乳)具有更高的生物利用度,体现出了同时采用3种技术(环糊精包合物合技术、磷脂复合物技术、纳米乳技术)制备的油包水型纳米乳对提高难溶性药物溶解度、生物利用度和疗效的优势。
本专利首次报道了同时采用环糊精包合物合技术、磷脂复合物技术、纳米乳技术增加难溶性药物的生物利用度。本发明首次同时采用3种技术(环糊精包合物合技术、磷脂复合物技术、纳米乳技术)制备了复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物的油包水型纳米乳、环维黄杨星D羟丙基-β-环糊精磷脂复合物的油包水型纳米乳、姜黄素羟丙基-β-环糊精磷脂复合物的油包水型纳米乳、吴茱萸碱羟丙基-β-环糊精磷脂复合物的油包水型纳米乳,显著增加了药物的溶解度,提高了药物的生物利用度。同时,姜黄素羟丙基-β-环糊精磷脂复合物的油包水型纳米乳的AUC(3410.20±154.10)(μg/L*h)显著大于其单一制剂,亦大于罗见春课题组制备的姜黄素羟丙基-β-环糊精磷脂复合物的AUC(1126.20±323.24)(μg/L*h);吴茱萸碱羟丙基-β-环糊精磷脂复合物的油包水型纳米乳的AUC(8833.06±177.80)(μg/L*h)显著大于单一制剂,亦大于胡江波课题组制备的吴茱萸碱磷脂复合物的油包水型纳米乳AUC(6368.57±2705.75)(μg/L*h)。分析原因可能如下:(1)环糊精能够提高药物在水中的溶解度,进一步增加药物的生物利用度;(2)磷脂是细胞膜的组成成分,将磷脂作为药物载体可以促进药物的吸收,增加药物在肠道的渗透系数和吸收速率常数,从而增加药物的生物利用度;(3)纳米乳能够增加难溶性药物的溶解度,促进药物吸收,其具体的吸收机制还需要进一步的研究。本专利首次同时采用环糊精包合物合技术、磷脂复合物技术、纳米乳技术制备的油包水型纳米乳,即:一种难溶性药物环糊精磷脂复合物的油包水型纳米乳,为难溶性药物提供了一种较好的新型载药系统,具有重要意义。
附图说明
图1为本发明制得的环维黄杨星D、环维黄杨星D羟丙基-β-环糊精包合物、环维黄杨星D磷脂复合物、环维黄杨星D纳米乳、环维黄杨星D羟丙基-β-环糊精磷脂复合物、环维黄杨星D羟丙基-β-环糊精包合物纳米乳、环维黄杨星D磷脂复合物纳米乳、油包水型环维黄杨星D羟丙基-β-环糊精磷脂复合物纳米乳的大鼠口服给药后体内药物浓度-时间曲线图(以下简称药时曲线图)。纵坐标为药物浓度,横坐标为时间。
大鼠口服灌胃给药环维黄杨星D、环维黄杨星D羟丙基-β-环糊精包合物、环维黄杨星D磷脂复合物、环维黄杨星D纳米乳、环维黄杨星D羟丙基-β-环糊精磷脂复合物、环维黄杨星D羟丙基-β-环糊精包合物纳米乳、环维黄杨星D磷脂复合物纳米乳、环维黄杨星D羟丙基-β-环糊精磷脂复合物的油包水型纳米乳(给药剂量均为相当于环维黄杨星D60mg/kg)。分别于给药后不同时间眼眶后静脉丛取血,置于肝素化试管中,混匀,离心(6000r/min)10min,分离上层血浆,于-20℃冰箱中保存备用。血浆样品处理方法为:分别吸取待测血浆样品150μL,加入二氯甲烷1mL,旋涡振荡5min,6000r·min-1离心10min,收集下层溶液,加入1-萘基异氰酸酯溶液50μL,40℃反应60min,氮气吹干,加150μL甲醇溶解,1200r·min-1离心10min,取上清液进样测定。测定得到药时曲线,药动学参数表明,相对于环维黄杨星D、环维黄杨星D羟丙基-β-环糊精包合物、环维黄杨星D磷脂复合物、环维黄杨星D纳米乳、环维黄杨星D羟丙基-β-环糊精磷脂复合物、环维黄杨星D羟丙基-β-环糊精包合物纳米乳、环维黄杨星D磷脂复合物纳米乳,环维黄杨星D羟丙基-β-环糊精磷脂复合物的油包水型纳米乳的曲线下面积增大,半衰期延长,峰浓度增大,在体内的生物利用度明显增加。环维黄杨星D羟丙基-β-环糊精磷脂复合物的油包水型纳米乳的生物利用度分别是环维黄杨星D、环维黄杨星D羟丙基-β-环糊精包合物、环维黄杨星D磷脂复合物、环维黄杨星D纳米乳、环维黄杨星D羟丙基-β-环糊精磷脂复合物、环维黄杨星D羟丙基-β-环糊精包合物纳米乳、环维黄杨星D磷脂复合物纳米乳的1233%、465%、415%、532%、269%、253%、231%。
图2为本发明制得的复方姜黄素/吴茱萸碱中吴茱萸碱、复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物中吴茱萸碱、复方姜黄素/吴茱萸碱磷脂复合物中吴茱萸碱、复方姜黄素/吴茱萸碱纳米乳中吴茱萸碱、复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物中吴茱萸碱、复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物纳米乳中吴茱萸碱、复方姜黄素/吴茱萸碱磷脂复合物纳米乳中吴茱萸碱、复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物的油包水型纳米乳中吴茱萸碱的大鼠口服给药后体内药时曲线图。纵坐标为药物浓度,横坐标为时间。
大鼠口服灌胃给药复方姜黄素/吴茱萸碱、复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物、复方姜黄素/吴茱萸碱磷脂复合物、复方姜黄素/吴茱萸碱纳米乳、复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物、复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物纳米乳、复方姜黄素/吴茱萸碱磷脂复合物纳米乳、复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物的油包水型纳米乳(给药剂量均为相当于姜黄素50mg/kg、吴茱萸碱100mg/kg)。分别于给药后不同时间眼眶后静脉丛取血,置于肝素化试管中,混匀,离心(6000r/min)10min,分离上层血浆,于-20℃冰箱中保存备用。血浆样品处理方法为:分别吸取待测血浆样品200μL,涡旋30s,加入甲醇800μL,涡旋30s,(涡旋1min后静置30s,再涡旋1min,重复3次),12000r/min离心10min,吸取上清液,氮气吹干挥去甲醇,再用甲醇复溶至150μL,取100μL进样检测。结果代入回归方程计算血药浓度,得到药时曲线。大鼠口服给药后体内药动学考察结果表明,相对于复方姜黄素/吴茱萸碱、复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物、复方姜黄素/吴茱萸碱纳米乳,油包水型复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物纳米乳的曲线下面积增大,峰浓度增大,在体内的生物利用度明显增加。复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物的油包水型纳米乳中吴茱萸碱的生物利用度是分别是复方姜黄素/吴茱萸碱中吴茱萸碱、复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物中吴茱萸碱、复方姜黄素/吴茱萸碱磷脂复合物中吴茱萸碱、复方姜黄素/吴茱萸碱纳米乳中吴茱萸碱、复方姜黄素/吴茱萸碱羟丙基-β-环糊精磷脂复合物中吴茱萸碱、复方姜黄素/吴茱萸碱羟丙基-β-环糊精包合物纳米乳中吴茱萸碱、复方姜黄素/吴茱萸碱磷脂复合物纳米乳中吴茱萸碱的1406%、776%、746%、657%、608%、401%、334%。
具体实施方式
为了进一步说明本发明及其优点,给出了下列特定的实施例,应理解这些实施例仅有于具体说明而不是作为本发明范围的限制。
实施例1:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
姜黄素与吴茱萸碱 3.9份(姜黄素0.6份+吴茱萸碱3.3份),
羟丙基-γ-环糊精 45.3份,
甘油磷脂 10.3份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于二氯甲烷中,60℃恒温磁力搅拌条件下反应2小时后,旋转蒸发除去二氯甲烷,真空干燥除去残留的二氯甲烷,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在30℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例2:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
环维黄杨星D 5.3份,
磺丁基-α-环糊精 6.7份,
肌醇磷脂 7.5份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于三氯甲烷中,40℃恒温磁力搅拌条件下反应4小时后,旋转蒸发除去三氯甲烷,真空干燥除去残留的三氯甲烷,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在60℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例3:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
姜黄素 3.5份,
羟丙基-β-环糊精 13.1份,
大豆卵磷脂 7份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于乙醇中,60℃恒温磁力搅拌条件下反应3.5小时后,旋转蒸发除去乙醇,真空干燥除去残留的乙醇,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在40℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例4:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
姜黄素与胡椒碱 1.7份(姜黄素1.1份+胡椒碱0.6份),
甲基-β-环糊精 29.1份,
磷脂酸 17.5份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于三氯甲烷中,60℃恒温磁力搅拌条件下反应1.5小时后,旋转蒸发除去三氯甲烷,真空干燥除去残留的三氯甲烷,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在50℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例5:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
小檗碱 2.7份,
羟丙基-α-环糊精 36.7份,
磷脂酰乙醇胺 11.9份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于乙醇中,60℃恒温磁力搅拌条件下反应1小时后,旋转蒸发除去乙醇,真空干燥除去残留的乙醇,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在30℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例6:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
异烟肼、利福平、吡嗪酰胺 6份(异烟肼2份+利福平2份+比嗪酰胺2份),
磺丁基-γ-环糊精 10.3份,
甘油磷脂 17.9份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于二氯甲烷中,40℃恒温磁力搅拌条件下反应3小时后,旋转蒸发除去二氯甲烷,真空干燥除去残留的二氯甲烷,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在50℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例7:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
姜黄素与吴茱萸碱 1.3份(姜黄素0.8份+吴茱萸碱0.5份),
羟丙基-α-环糊精 37.9份,
丝氨酸磷脂 19.5份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于乙醇中,50℃恒温磁力搅拌条件下反应2.5小时后,旋转蒸发除去乙醇,真空干燥除去残留的乙醇,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在40℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例8:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
环维黄杨星D 2.2份,
羟丙基-β-环糊精 17.1份,
大豆卵磷脂 5.8份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于乙醇中,50℃恒温磁力搅拌条件下反应2小时后,旋转蒸发除去乙醇,真空干燥除去残留的乙醇,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在50℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例9:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
丹参酮 5.6份,
磺丁基-γ-环糊精 21.6份,
肌醇磷脂 20份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于乙醇中,40℃恒温磁力搅拌条件下反应4小时后,旋转蒸发除去乙醇,真空干燥除去残留的乙醇,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在40℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例10:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
姜黄素与胡椒碱 3.7份(姜黄素3.2份+胡椒碱0.5份),
磺丁基-α-环糊精 3.8份,
大豆卵磷脂与甘油磷脂 8.4份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于三氯甲烷中,60℃恒温磁力搅拌条件下反应2.5小时后,旋转蒸发除去三氯甲烷,真空干燥除去残留的三氯甲烷,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在40℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例11:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
槲皮素 2.5份,
羧甲基-β-环糊精 1.5份,
甘油磷脂 9.4份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于三氯甲烷中,50℃恒温磁力搅拌条件下反应3.5小时后,旋转蒸发除去三氯甲烷,真空干燥除去残留的三氯甲烷,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在60℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例12:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
0.8份(姜黄素0.4份+吴茱萸碱0.2份+
姜黄素、吴茱萸碱、胡椒碱
胡椒碱0.2份),
羟丙基-α-环糊精 23.5份,
1,2-二油酰基卵磷脂 4.1份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于二氯甲烷中,60℃恒温磁力搅拌条件下反应3小时后,旋转蒸发除去二氯甲烷,真空干燥除去残留的二氯甲烷,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在40℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例13:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
白藜芦醇与吴茱萸碱 4.5份(白藜芦醇2.3份+吴茱萸碱2.2份),
羟丙基-β-环糊精 19.3份,
大豆卵磷脂 11份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于二氯甲烷中,40℃恒温磁力搅拌条件下反应4小时后,旋转蒸发除去二氯甲烷,真空干燥除去残留的二氯甲烷,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在60℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例14:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
水飞蓟宾 4.9份,
磺丁基-γ-环糊精 25.3份,
磷脂酸 16.3份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于乙醇中,60℃恒温磁力搅拌条件下反应3小时后,旋转蒸发除去乙醇,真空干燥除去残留的乙醇,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在40℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例15:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
姜黄素 1.3份,
羟丙基-α-环糊精 38.5份,
脑磷脂 8.7份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于乙醇中,50℃恒温磁力搅拌条件下反应3小时后,旋转蒸发除去乙醇,真空干燥除去残留的乙醇,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在30℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例16:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
姜黄素与吴茱萸碱 2.9份(姜黄素2份+吴茱萸碱0.9份),
磺丁基-γ-环糊精 8.8份,
磷脂酰胆碱 4.7份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于二氯甲烷中,40℃恒温磁力搅拌条件下反应3.5小时后,旋转蒸发除去二氯甲烷,真空干燥除去残留的二氯甲烷,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在50℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例17:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
白藜芦醇 3.1份,
羟丙基-γ-环糊精 42份,
丝氨酸磷脂 2.3份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于二氯甲烷中,60℃恒温磁力搅拌条件下反应2小时后,旋转蒸发除去二氯甲烷,真空干燥除去残留的二氯甲烷,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在60℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例18:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
4.1份(姜黄素0.5份+吴茱萸碱2.5
姜黄素、吴茱萸碱、胡椒碱
份+胡椒碱1.1份),
羟丙基-β-环糊精 32.8份,
大豆卵磷脂 10.3份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于三氯甲烷中,50℃恒温磁力搅拌条件下反应2.5小时后,旋转蒸发除去三氯甲烷,真空干燥除去残留的三氯甲烷,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在50℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例19:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
姜黄素与胡椒碱 5.8份(姜黄素2.9份+胡椒碱2.9份),
羧甲基-β-环糊精 23.5份,
1,2-二油酰基卵磷脂 3.1份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于乙醇中,60℃恒温磁力搅拌条件下反应1.5小时后,旋转蒸发除去乙醇,真空干燥除去残留的乙醇,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在30℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
实施例20:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
环维黄杨星D 0.5份,
甲基-β-环糊精 28.1份,
肌醇磷脂 18份,
纳米乳,包括以下各组分,各组分重量份比例为:
制备方法包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于乙醇中,50℃恒温磁力搅拌条件下反应4小时后,旋转蒸发除去乙醇,真空干燥除去残留的乙醇,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物在50℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得透明的液体,即得油包水型纳米乳。
Claims (8)
1.一种明显提高难溶性药物生物利用度的油包水型纳米乳,其特征在于,该制剂为难溶性药物环糊精磷脂复合物的纳米乳:
难溶性药物环糊精磷脂复合物,包括以下各组分,各组分重量份比例为:
难溶性药物 0.5-6份,
环糊精 1.5-46.6份,
磷脂 1-20份,
纳米乳,包括以下各组分,各组分重量份比例为:
2.根据权利要求1所述的一种明显提高难溶性药物生物利用度的油包水型纳米乳,其特征在于,所述的难溶性药物为以下(1)至(9)所列药物的一种或几种的混合物:
(1)抗肿瘤药物:姜黄素、吴茱萸碱、卡莫司汀、小檗碱、甲氨蝶呤、青蒿素、白藜芦醇、紫杉醇、羟喜树碱、葫芦素B、胡椒碱、顺铂、卡铂、多柔比星、甲氨蝶呤;
(2)抗心血管疾病药物:环维黄杨星D、川芎嗪、灯盏花素、葛根素、黄芪苷、银杏酮酯、盐酸胺碘酮、吡罗昔康、硝苯地平、替米沙坦、普罗帕酮、奎尼丁;
(3)抗炎药物:白头翁、穿心莲内酯、黄芩素、布洛芬、酮替芬、奈普生、槲皮素、木犀草素、芒果苷、吲哚美辛、塞来昔布、丙酸氯倍他索、酮替芬、齐墩果酸、水飞蓟素、水飞蓟宾;
(4)抗菌药物:厚朴酚、小檗碱、丹参酮、氟苯尼考、盐酸布替萘芬、头孢克肟、环吡酮胺、异烟肼、利福平、吡嗪酰胺、伊曲康唑、氟哌酸、肉桂酮、氧氟沙星、左旋氧氟沙星、司帕沙星、诺氟沙星、磺胺甲氧哒嗪、恩诺沙星、妥曲珠利;
(5)降血脂药物:非诺贝特、考来烯胺、普罗布考、吡罗昔康;
(6)抗精神病药物:伊潘立酮、利培酮、奥氮平、舒必利;
(7)镇痛、镇静药物:延胡索乙素、左旋延胡索乙素;
(8)抗氧化药物:维生素E;(9)免疫抑制剂:环孢素A。
3.根据权利要求1所述的一种明显提高难溶性药物生物利用度的油包水型纳米乳,其特征在于,所述的环糊精为环糊精及其衍生物中的一种或几种,环糊精及其衍生物为:
(1)α-环糊精类:α-环糊精、羟丙基-α-环糊精、磺丁基-α-环糊精;
(2)β-环糊精类:β-环糊精、羟丙基-β-环糊精、甲基-β-环糊精、三乙酰基-β-环糊精、2,6-二甲氧基-β-环糊精、磺丁基-β-环糊精、羟丁基-β-环糊精、羟乙基-β-环糊精、羧甲基-β-环糊精、6-(2-葡萄糖基胺基)-β-环糊精、低聚乳酸基-β-环糊精;
(3)γ-环糊精类:γ-环糊精、羟丙基-γ-环糊精、磺丁基-γ-环糊精。
4.根据权利要求1所述的一种明显提高难溶性药物生物利用度的油包水型纳米乳,其特征在于,所述的磷脂为:大豆卵磷脂、脑磷脂、磷脂酰胆碱、肌醇磷脂、磷脂酸、磷脂酰乙醇胺、1,2-二油酰基卵磷脂、甘油磷脂、丝氨酸磷脂中的一种或几种。
5.根据权利要求1所述的一种明显提高难溶性药物生物利用度的油包水型纳米乳,其特征在于,所述的油相为:油酸乙酯、单辛酸甘油酯、乙酸乙酯、单硬脂酸甘油酯、月桂酸甘油酯、硬脂酸甘油酯、乙二醇、丙三醇、石蜡、杏仁油中的一种或几种。
6.根据权利要求1所述的一种明显提高难溶性药物生物利用度的油包水型纳米乳,其特征在于,所述的表面活性剂为:聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、蓖麻油、司盘、吐温、单硬脂酸甘油酯、十二烷基硫酸钠、泊洛沙姆、聚乙烯醇、聚乙烯吡咯烷酮中的一种或几种。
7.根据权利要求1所述的一种明显提高难溶性药物生物利用度的油包水型纳米乳,其特征在于,所述的助表面活性剂为:聚乙二醇400、乙醇、1,2-丙二醇、正丁醇、乙二醇、丙三醇、十二烷基硫酸钠、十二烷基磺酸钠、十四烷基硫酸钠、十八烷基硫酸钠、十八烷基磺酸钠、硬脂酸钾、月桂酸蔗糖酯、吐温、司盘中的一种或几种。
8.根据权利要求1所述的一种明显提高难溶性药物生物利用度的油包水型纳米乳的制备方法,其特征在于,包括下列步骤:(1)难溶性药物环糊精磷脂复合物的制备:取处方量的难溶性药物、环糊精、磷脂,溶解于有机溶剂(乙醇、二氯甲烷、三氯甲烷中的一种或几种)中,40-60℃恒温磁力搅拌条件下反应1-4小时后,旋转蒸发除去有机溶剂,真空干燥除去残留的有机溶剂,即得难溶性药物环糊精磷脂复合物;(2)纳米乳的制备:取处方量的油相、表面活性剂、助表面活性剂与(1)中制备的难溶性药物环糊精磷脂复合物,在30-60℃恒温磁力搅拌条件下充分溶解,将蒸馏水作为水相,然后在搅拌的同时加入处方量的蒸馏水得到油包水型纳米乳。
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