CN115192529B - 一种溶剂法制备的阿苯达唑固体分散体组合物及其制备方法 - Google Patents
一种溶剂法制备的阿苯达唑固体分散体组合物及其制备方法 Download PDFInfo
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- CN115192529B CN115192529B CN202210814563.9A CN202210814563A CN115192529B CN 115192529 B CN115192529 B CN 115192529B CN 202210814563 A CN202210814563 A CN 202210814563A CN 115192529 B CN115192529 B CN 115192529B
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- albendazole
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Abstract
本发明公开了一种溶剂法制备的阿苯达唑固体分散体及其制法,涉及难溶性药物纳米制剂领域。为阿苯达唑缓释固体分散体及速释固体分散体的组合,阿苯达唑缓释固体分散体各组分的质量比为阿苯达唑:亲水性高分子聚合物:缓释骨架材料:表面活性剂=1:1‑10:1‑5:0.2‑2;阿苯达唑速释固体分散体各组分的质量比为阿苯达唑:亲水性高分子聚合物:抑晶成分:表面活性剂=1:1‑7:0.5‑3:0.2‑2;本制剂通过使用亲水性高分子聚合物和缓释骨架材料,利用多释药机理开发既能增加药物溶解度又可以避免其在胃肠道快速释药造成吸收差异,提高阿苯达唑的溶解度以及增加大鼠体内生物利用度。
Description
技术领域
本发明涉及药物制剂领域,涉及一种溶剂法制备的阿苯达唑固体分散体组合物及其制备方法。
背景技术
阿苯达唑(albendazole),又称丙硫咪唑,属于苯并咪唑类药物,广泛用于治疗蛲虫、蛔虫、绦虫、包虫等寄生虫感染,是世界卫生组织(WHO)推荐的首选驱虫药(杨海山,朱吉海,赵玲莉,等.阿苯达唑葡聚糖纳米颗粒大鼠体内药动学和小鼠肝脏靶向性研究[J].中国医院药学杂志,2022,42(04):408-415.)。阿苯达唑在法国、非洲、拉丁美洲、中东以及亚洲70多个国家用于治疗各种蠕虫病。研究证明阿苯达唑与虫体作用过程中可抑制虫体摄取葡萄糖致使虫体内源性糖元耗竭;并且抑制延胡素酸还原酶,阻碍三磷酸腺苷产生,致使虫体因能源耗竭而逐渐死亡。本品在所有动物体内代谢的主要途径是经过亚砜与砜,从胃肠道内吸收,在肝内代谢成为有活力的亚砜,然后渗出回到胃肠道内。阿苯达唑口服后95%肝不吸收,有利于药物在肠内直接与线虫的成虫作用。24小时内由粪便排出,吸收的5%在肝内迅速代谢为有活力的亚砜,并在48小时内通过肾脏排出,在体内无蓄积作用。
固体分散体(Solid Dispersion,SD)是药物的一种存在形式,具体指药物在合适的载体材料中以分子、微晶、胶体或非晶态均匀高度分散(司俊仁,叶小强,李新月等.固体分散体的发展及制备工艺研究进展[J].吉林医药学院学报,2015,36(04):300-303.)。作为一种制剂中间体,固体分散体很大程度地改善了难溶性药物的溶出并提高了药物的生物利用度。大量研究表明,固体分散体可通过以下机制增强难溶性药物的溶解度及溶出速率:①减小药物的粒径;②药物从晶态转变为无定形态;③形成固态溶液;④减少药物的再聚集和结块等。此外,固体分散体通常采用亲水性载体,使得药物的润湿性增强,与介质接触时更易分散,药物的溶解度与溶出速率增加。(L.M.d.Mohac,A.V.Keating,M.d.F.Pina,etal.Engineering of Nanofibrous Amorphous and Crystalline Solid Dispersions forOral Drug Delivery[J].Pharmaceutics,2018,11(1):7.)
阿苯达唑为白色或类白色粉末;无臭。在丙酮或三氯甲烷中微溶,在乙醇中几乎不溶,在水中不溶;在冰醋酸中溶解。其在体内迅速代谢为亚砜、砜醇和2-胺砜醇。阿苯达唑单剂量的急性毒性极低,现有制剂主要为固体制剂,由于其水中溶解度极低,口服生物利用度较差,因此口服剂量较高。目前研究发现阿苯达唑在体内吸收本身就具有较大个体差异以及多变的生物利用度现象(Pettarin M,Bolger M B,Chronowska M,et al.A combined invitro in-silico approach to predict the oral bioavailability of borderlineBCS Class II/IV weak base Albendazole and its main metabolite AlbendazoleSulfoxide[J].European journal of pharmaceutical sciences:official journal ofthe European Federation for Pharmaceutical Sciences,2020,155(2):105552.)。阿苯达唑在胃酸及肠液中的溶解度相差900倍以上,快速进入小肠会产生大量沉淀造成吸收差异(Raval M K,Vaghela P D,Vachhani A N,et al.Role of excipients in thecrystallization of Albendazole[J].Advanced Powder Technology,2015,26(4):1102-1115.)普通的增溶技术可能由于药物快速进入小肠导致药物结晶发生溶解度的显著变化,反而可能不利于药物的吸收。阿苯达唑为多晶型药物,有ABZ-I和ABZ-II两种晶型,现有研究往往采用单一的增溶载体提高阿苯达唑溶解度,目前制得的阿苯达唑产品存在生物利用度低、药物溶解度不理想等问题。因此本品的开发主要考虑采用固体分散技术,将亲水性高分子聚合物、缓释骨架材料的缓释作用、表面活性剂或抑晶成分等的抑晶作用相结合,通过不同释药速度的阿苯达唑固体分散体的组合,利用多释药机理开发既能增加药物溶解度又可以避免其在胃肠道快速释药造成吸收差异的高生物利用度制剂。
发明内容
本发明的目的在于提供一种以溶剂法制备的阿苯达唑固体分散体组合物,该组合物以阿苯达唑缓释固体分散体与速释固体分散体混合而成。以亲水性高分子聚合物、缓释骨架材料、表面活性剂、抑晶成分为载体,在提高阿苯达唑的溶解度的基础上,利用载体材料的抑晶作用及多释药机理调节其体内外释药特性,从而达到提高阿苯达唑生物利用度的目的。
本发明的另一目的是提供这种阿苯达唑固体分散体组合物的制备方法。以亲水性高分子聚合物,缓释骨架材料、表面活性剂以及抑晶成分为载体,利用溶剂法制备上述制剂,并研究两种释药特性的阿苯达唑固体分散体的混合比例。
为实现上述目的,本发明采用的技术方案如下:
一种溶剂法制备的阿苯达唑固体分散体组合物,所述组合物包括阿苯达唑缓释固体分散体和阿苯达唑速释固体分散体,所述阿苯达唑缓释固体分散体由亲水性高分子聚合物、缓释骨架材料以及表面活性剂为载体制备所得,其中各组分的质量比为阿苯达唑:亲水性高分子聚合物:缓释骨架材料:表面活性剂=1:1-10:1-5:0.2-2;所述阿苯达唑速释固体分散体由亲水性高分子聚合物、抑晶成分以及表面活性剂为载体制备所得,其中各组分的质量比为阿苯达唑:亲水性高分子聚合物:抑晶成分:表面活性剂=1:1-7:0.5-3:0.2-2;阿苯达唑缓释固体分散体与阿苯达唑速释固体分散体的质量比为1:0-1:3。
一种溶剂法制备的阿苯达唑固体分散体组合物,按照下述步骤进行:
(1)阿苯达唑溶解于一定体积无水乙醇中,超声5-20min使均匀,得到A溶液;亲水性高分子聚合物,缓释骨架材料以及表面活性剂溶解于一定体积无水乙醇,超声5-20min使均匀,得到B溶液。其中,溶液间的体积比例A:B等于1:1-5。
(2)上述A溶液分散到B溶液中,超声20-40min使混合均匀,得到总有机相。
(3)上述总有机相倒入100mL圆底烧瓶中,使用旋转蒸发仪(水浴40℃,转速60rpm/min)将大部分有机溶剂除去,再将样品放至表面皿中并放至真空干燥机,40℃干燥12h可得阿苯达唑固体分散体。
进一步的,所述的亲水性高分子聚合物为聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)、聚乙烯吡咯烷酮K12(PVP K12)、聚乙烯吡咯烷酮K 30S(PVPK30S)、共聚维酮VA64(PVPVA64)等。
进一步的,所述的缓释骨架材料可为羟丙基甲基纤维素E5(HPMC E5)、羟丙基甲基纤维素E15(HPMC E15)、羟丙基甲基纤维素E10M(HPMC E10M)等。
进一步的,所述的表面活性剂可为十二烷基硫酸钠(SDS)、月桂醇聚氧乙烯醚硫酸钠、或卵磷脂。
进一步的,所述的抑晶成分可为柠檬酸或酒石酸等。
进一步的,所述的阿苯达唑缓释固体分散体比例为阿苯达唑:亲水性高分子聚合物:缓释骨架材料:表面活性剂=1:1-10:1-5:0.2-2。
进一步的,所述的阿苯达唑缓释固体分散体比例阿苯达唑:亲水性高分子聚合物:抑晶成分:表面活性剂=1:1-7:0.5-3:0.2-2。
进一步的,所述的阿苯达唑固体分散体组合物为阿苯达唑缓释与速释固体分散体按照质量比1:0-1:3混合而成。
进一步的,所述的组合物可灌装于胶囊中制成胶囊剂或压制成片剂。
一种阿苯达唑固体分散体组合物制备方法,所述方法包括以下步骤:
将阿苯达唑溶解于无水乙醇中,超声处理使均匀;将亲水性高分子聚合物、缓释骨架材料和表面活性剂溶解于无水乙醇中,超声处理使均匀;将两种溶液混合,超声处理使充分分散;将混合溶液使用旋转蒸发仪除去部分有机溶剂,真空干燥并研磨后得到阿苯达唑缓释固体分散体;
将阿苯达唑溶解于无水乙醇中,超声处理使均匀;将亲水性高分子聚合物、抑晶成分和表面活性剂溶解于无水乙醇中,超声处理使均匀;将两种溶液混合,超声处理使充分分散;将混合溶液使用旋转蒸发仪除去部分有机溶剂,真空干燥并研磨后得到阿苯达唑速释固体分散体;
将阿苯达唑缓释固体分散体与阿苯达唑速释固体分散体按1:0-1:3的质量比均匀混合。
进一步的,旋转蒸发仪的参数为水浴35~45℃,转速55~65rpm/min。
进一步的,真空干燥的温度为35~45℃,干燥时间为10~14h。
进一步的,每次超声处理的时间为18~22min。
有益效果
本发明具有以下的有益效果:
1、本发明提供了一种高生物利用度的阿苯达唑固体分散体组合物及其制备方法,以亲水性高分子聚合物,缓释骨架材料、表面活性剂以及抑晶成分为载体,利用溶剂法制得的阿苯达唑固体分散体呈干燥白色粉末状。
2、本发明针对阿苯达唑的水难溶性问题,制备具有不同释药特征的缓释与速释固体分散体体系。体外实验研究表明,与阿苯达唑原料药相比,两种固体分散体均显著提高了药物溶出速度,其中阿苯达唑速释固体分散体在0.1mol/L盐酸溶液中30min的释放达42.28%,阿苯达唑缓释固体分散体在0.1mol/L盐酸溶液中2h释放29.15%,6h释药达31.53%,具有明显的缓释特征。
3、本发明通过使用亲水性高分子聚合物和缓释骨架材料,利用多释药机理开发既能增加药物溶解度又可以避免其在胃肠道快速释药造成吸收差异,提高阿苯达唑的溶解度以及增加大鼠体内生物利用度。结果表明:与市售片剂组相比,该阿苯达唑固体分散体组合物的体内生物利用度显著提高。药动学参数显示固体分散体组的血药浓度曲线下面积为3448.54hng/mL;与市售片剂相比,阿苯达唑固体分散体组合物的相对生物利用度高达243.79%,说明阿苯达唑固体分散体组合物显著提高阿苯达唑的体内生物利用度。
附图说明
图1为阿苯达唑速释固体分散体体外释放曲线图;
图2为阿苯达唑缓释固体分散体体外释放曲线图;
图3为阿苯达唑缓释固体分散体大鼠体内生物利用度药时曲线图;
图4为阿苯达唑固体分散体组合物大鼠体内生物利用度药时曲线图;
图5为阿苯达唑固体分散体XRD图谱。
具体实施方式
以下所列实施例有助于本领域技术人员更好地理解本发明,但不以任何方式限制本发明。
以下实施例所用主要仪器和材料
实验材料:
阿苯达唑(华中药业股份有限公司);聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(BASF,德国);共聚维酮VA64(BASF,德国);聚乙烯吡咯烷酮K12(BASF,德国);聚乙烯吡咯烷酮K 30S(BASF,德国);卵磷脂(国药集团化学试剂有限公司);月桂醇聚氧乙烯醚硫酸钠(国药集团化学试剂有限公司);十二烷基硫酸钠(国药集团化学试剂有限公司);甲醇(HPLC级)(美国,天地);乙腈(HPLC级)(美国,天地);乙酸乙酯(阿拉丁);阿苯达唑片(史克肠虫清,批号BR3B,根据说明书本品为类白色薄膜衣片,辅料为乳糖、淀粉、聚乙烯吡咯烷酮、羧甲基淀粉钠、糖精钠、硬脂酸镁、微晶纤维素、十二烷基硫酸钠、羟丙基甲基纤维素)
实验仪器:
高效液相色谱(SHIMADZU(岛津),日本);电子天平(赛多利斯,德国SartoriusBSA124S-CW);90Plus PALS激光粒度仪(美国Brookhaven公司);MS-H-S加热磁力搅拌器(北京大龙兴创实验仪器有限公司);XH-2800快速混匀器(江苏金怡仪器科技有限公司);数控超声波清洗器(昆山市超声仪器有限公司);恒温振荡器(江苏金坛市中大仪器厂);JEM-7001F扫描电镜(日本电子株式会社JEOL);DF-101S集热式恒温加热磁力搅拌器(上海予申仪器有限公司);QB-128旋转培养混合器(江苏海门其林贝尔仪器制造有限公司);高速冷冻离心机(德国Heraeus公司)
实施例1阿苯达唑速释固体分散体的制备
(1)精密称取阿苯达唑100mg溶解于20mL无水乙醇中,超声20min使均匀。精密称取聚乙烯吡咯烷酮K 30S 300mg,柠檬酸150mg和十二烷基硫酸钠50mg溶解于20mL的无水乙醇中,超声20min使均匀。将阿苯达唑溶液分散到含聚乙烯吡咯烷酮K 30S,柠檬酸和十二烷基硫酸钠的溶液中,超声20min使充分分散。
(2)再将此溶液倒入100mL圆底烧瓶中,使用旋转蒸发仪(水浴40℃,转速60rpm/min)将大部分有机溶剂除去,再将样品放至表面皿中并放至真空干燥机,40℃干燥12h可得阿苯达唑固体分散体。将其研磨过80目筛。
实施例2阿苯达唑速释固体分散体的制备
(1)精密称取阿苯达唑100mg溶解于20mL无水乙醇中,超声20min使均匀。精密称取聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物300mg,柠檬酸150mg和十二烷基硫酸钠50mg溶解于20mL的无水乙醇中,超声20min使均匀。将阿苯达唑溶液分散到含聚乙烯吡咯烷酮K 30S,柠檬酸和十二烷基硫酸钠的溶液中,超声20min使充分分散。
(2)再将此溶液倒入100mL圆底烧瓶中,使用旋转蒸发仪(水浴40℃,转速60rpm/min)将大部分有机溶剂除去,再将样品放至表面皿中并放至真空干燥机,40℃干燥12h可得阿苯达唑固体分散体。将其研磨过80目筛。
实施例3阿苯达唑缓释固体分散体的制备
(1)精密称取阿苯达唑100mg溶解于20mL无水乙醇中,超声20min使均匀。精密称取聚乙烯吡咯烷酮K 30S 500mg,羟丙基甲基纤维素E5 150mg和十二烷基硫酸钠50mg溶解于20mL的无水乙醇中,超声20min使均匀。将阿苯达唑溶液分散到含聚乙烯吡咯烷酮K 30S,羟丙基甲基纤维素E5和十二烷基硫酸钠的溶液中,超声20min使充分分散。
(2)再将此溶液倒入100mL圆底烧瓶中,使用旋转蒸发仪(水浴40℃,转速60rpm/min)将大部分有机溶剂除去,再将样品放至表面皿中并放至真空干燥机,40℃干燥12h可得阿苯达唑固体分散体。将其研磨过80目筛。
实施例4阿苯达唑缓释固体分散体的制备
(1)精密称取阿苯达唑100mg溶解于20mL无水乙醇中,超声20min使均匀。精密称取聚乙烯吡咯烷酮K 30S 300mg,羟丙基甲基纤维素E5 50mg和十二烷基硫酸钠150mg溶解于20mL的无水乙醇中,超声20min使均匀。将阿苯达唑溶液分散到含聚乙烯吡咯烷酮K 30S,羟丙基甲基纤维素E5和十二烷基硫酸钠的溶液中,超声20min使充分分散。
(2)再将此溶液倒入100mL圆底烧瓶中,使用旋转蒸发仪(水浴40℃,转速60rpm/min)将大部分有机溶剂除去,再将样品放至表面皿中并放至真空干燥机,40℃干燥12h可得阿苯达唑固体分散体。将其研磨过80目筛。
实施例5阿苯达唑固体分散体组合物的制备
(1)精密称取阿苯达唑100mg溶解于20mL无水乙醇中,超声20min使均匀。精密称取聚乙烯吡咯烷酮K 30S 500mg,羟丙基甲基纤维素E5 50mg和十二烷基硫酸钠150mg溶解于20mL的无水乙醇中,超声20min使均匀。将阿苯达唑溶液分散到含聚乙烯吡咯烷酮K 30S,羟丙基甲基纤维素E5和十二烷基硫酸钠的溶液中,超声20min使充分分散。再将此溶液倒入100mL圆底烧瓶中,使用旋转蒸发仪(水浴40℃,转速60rpm/min)将大部分有机溶剂除去,再将样品放至表面皿中并放至真空干燥机,40℃干燥12h可得阿苯达唑固体分散体。将其研磨过80目筛,得阿苯达唑缓释固体分散体。
(2)精密称取阿苯达唑100mg溶解于20mL无水乙醇中,超声20min使均匀。精密称取聚乙烯吡咯烷酮K 30S 500mg,柠檬酸150mg和十二烷基硫酸钠50mg溶解于20mL的无水乙醇中,超声20min使均匀。将阿苯达唑溶液分散到含聚乙烯吡咯烷酮K 30S,柠檬酸和十二烷基硫酸钠的溶液中,超声20min使充分分散。再将此溶液倒入100mL圆底烧瓶中,使用旋转蒸发仪(水浴40℃,转速60rpm/min)将大部分有机溶剂除去,再将样品放至表面皿中并放至真空干燥机,40℃干燥12h可得阿苯达唑固体分散体。将其研磨过80目筛,得阿苯达唑速释固体分散体。
(3)将阿苯达唑缓释固体分散体与阿苯达唑速释固体分散体按1:1的比例均匀混合,得到阿苯达唑固体分散体组合物。
实施例6阿苯达唑固体分散体组合物的制备
(1)精密称取阿苯达唑100mg溶解于20mL无水乙醇中,超声20min使均匀。精密称取聚乙烯吡咯烷酮K 30S 500mg,羟丙基甲基纤维素E5 50mg和十二烷基硫酸钠150mg溶解于20mL的无水乙醇中,超声20min使均匀。将阿苯达唑溶液分散到含聚乙烯吡咯烷酮K 30S,羟丙基甲基纤维素E5和十二烷基硫酸钠的溶液中,超声20min使充分分散。再将此溶液倒入100mL圆底烧瓶中,使用旋转蒸发仪(水浴40℃,转速60rpm/min)将大部分有机溶剂除去,再将样品放至表面皿中并放至真空干燥机,40℃干燥12h可得阿苯达唑固体分散体。将其研磨过80目筛,得阿苯达唑缓释固体分散体。
(2)精密称取阿苯达唑100mg溶解于20mL无水乙醇中,超声20min使均匀。精密称取聚乙烯吡咯烷酮K 30S 500mg,柠檬酸150mg和十二烷基硫酸钠50mg溶解于20mL的无水乙醇中,超声20min使均匀。将阿苯达唑溶液分散到含聚乙烯吡咯烷酮K 30S,柠檬酸和十二烷基硫酸钠的溶液中,超声20min使充分分散。再将此溶液倒入100mL圆底烧瓶中,使用旋转蒸发仪(水浴40℃,转速60rpm/min)将大部分有机溶剂除去,再将样品放至表面皿中并放至真空干燥机,40℃干燥12h可得阿苯达唑固体分散体。将其研磨过80目筛,得阿苯达唑速释固体分散体。
(3)将阿苯达唑缓释固体分散体与阿苯达唑速释固体分散体按1:2的比例均匀混合,得到阿苯达唑固体分散体组合物。
实施例7实施例1及实施例3所制备的阿苯达唑固体分散体体外释药实验
精密称取70.0mg实施例1下制备的阿苯达唑速释固体分散体与70.0mg实施例3下制备的阿苯达唑缓释固体分散体,投入到超声脱气处理的0.1mol/L的盐酸180mL为释放介质,恒温37±0.5℃,转速100r min,从样品进入介质开始计时,分别于5,15,30,45,60,90,120,180,240,360min,定时取样5mL,用0.45MCE混合纤维素酯水系针头式微孔滤膜,弃去初滤液,同时补加同温介质5mL,用紫外分光光度法在295nm处测吸光度,代入标准曲线,计算药物浓度求不同时间的累积溶出百分率.绝对累计溶出百分率=Ci×180/W0(W0为投药量).以时间为横坐标,以累积释放百分率为纵坐标,绘制阿苯达唑固体分散体释放曲线,其结果如图1与图2所示。由图1可以看出,阿苯达唑固体分散体在药典规定的介质中高溶出度成功解决了阿苯达唑原料药难溶性的问题,说明溶剂法制备的阿苯达唑固体分散体符合处方设计目的。图2可以看出阿苯达唑缓释固体分散体在0.1mol/L盐酸溶液中2h释放29.15%,6h释药达31.53%,具有明显的缓释特征。
实施例8实施例3所制备的阿苯达唑缓释固体分散体体内生物利用度初步评价
对实施例3制备所得的阿苯达唑缓释固体分散体的体内生物利用度进行评价,进行大鼠体内药动学研究,考察大鼠分别口服阿苯达唑缓释固体分散体和阿苯达唑市售片剂的血药浓度随时间变化的关系。以眼眶取血的方式收集经灌胃给药后的大鼠血样,经系列处理后评价阿苯达唑固体分散体的口服生物利用度和体内药物动力学特征。
(1)动物给药
SPF级SD大鼠,雄性,体重200±10g,6只,由江苏大学实验动物中心提供,实验动物生产许可证号:SYXK苏2018-0053。实验前置动物于实验室适应环境3天,室温20-25℃,标准饲料喂养,自由饮水,未禁食。按照70mg/kg·BW的给药剂量精密称量阿苯达唑缓释固体分散体和阿苯达唑片,并均匀溶于10mL超纯水。实验过程中每只大鼠的灌胃剂量为2.0mL,在0.5、1、2、4、6、8、10、12、24h八个时间点分别取0.5mL血样。
(2)样品处理
大鼠眼眶取血0.5mL,加入到含20μL肝素钠1.5mL EP管中,静置处理30min后用离心机在3700rpm/min条件下离心10min,上清即血浆。取血浆200μL,置于1.5mL离心管中,依次加入磷酸盐缓冲液200μL,内标溶液250μL,醋酸乙酯250μL,涡旋混合震荡2min,12000rpm/min进行离心10min,取上层有机层转移至另一干净的离心管中,于第一管内再加醋酸乙酯250μL,12000rpm/min进行离心10min,取上层有机层与前液合并,70℃氮气水浴挥干,残余物用100μL乙腈溶解,20μL进样。
(3)结果
为考察阿苯达唑市售片剂及阿苯达唑缓释固体分散体经SD大鼠口服给药后的药动学参数,使用BAPP 2.3软件拟合非隔室模型药动学参数,所得结果见表一。
表1药动学参数拟合(n=3)
根据表1,阿苯达唑缓释固体分散体的半衰期为7.18h,相较于原料药T1/2的35.54h,制剂的半衰期减少约5倍,说明制剂进入体内可被迅速吸收。阿苯达唑缓释固体分散体的平均驻留时间为6.90h,也明显低于市售制剂的16.00h,也说明了制剂的增溶作用较好,进入机体后迅速被吸收。另外,阿苯达唑缓释固体分散体的药时曲线下面积AUC为4002.0h·ng·mL-1,阿苯达唑市售片剂的AUC为1414.57h·ng·mL-1,制剂的AUC明显高于原料药。根据相对生物利用度公式(Fr=(AUCT×DR)/(AUCR×DT),T为受试制剂、R为参比制剂)计算得到制剂的相对生物利用度高达282.91%,结合图3,阿苯达唑缓释固体分散体的血药浓度随时间的增加逐步上升再逐步下降,且阿苯达唑缓释固体分散体的Tmax较市售片剂晚2h,说明阿苯达唑固体分散体中缓释骨架材料在生物利用度研究中发挥了延缓递送作用。说明溶剂法制备的阿苯达唑缓释固体分散体极大程度上提高了阿苯达唑的口服生物利用度,促进了阿苯达唑进入机体后的迅速吸收。
实施例9实施例5所制备的阿苯达唑固体分散体组合物体内生物利用度初步评价
对实施例5制备所得的阿苯达唑固体分散体组合物的体内生物利用度进行评价,进行大鼠体内药动学研究,考察大鼠分别口服阿苯达唑固体分散体组合物和阿苯达唑市售片剂的血药浓度随时间变化的关系。以眼眶取血的方式收集经灌胃给药后的大鼠血样,经系列处理后评价阿苯达唑固体分散体组合物的口服生物利用度和体内药物动力学特征。
(1)动物给药
SPF级SD大鼠,雄性,体重200±10g,6只,由江苏大学实验动物中心提供,实验动物生产许可证号:SYXK苏2018-0053。实验前置动物于实验室适应环境3天,室温20-25℃,标准饲料喂养,自由饮水,未禁食。按照70mg/kg·BW的给药剂量精密称量阿苯达唑固体分散体组合物和阿苯达唑片,并均匀溶于10mL超纯水。实验过程中每只大鼠的灌胃剂量为2.0mL,在0.5、1、2、4、6、8、10、12、24h八个时间点分别取0.5mL血样。
(2)样品处理
大鼠眼眶取血0.5mL,加入到含20μL肝素钠1.5mL EP管中,静置处理30min后用离心机在3700rpm/min条件下离心10min,上清即血浆。取血浆200μL,置于1.5mL离心管中,依次加入磷酸盐缓冲液200μL,内标溶液250μL,醋酸乙酯250μL,涡旋混合震荡2min,12000rpm/min进行离心10min,取上层有机层转移至另一干净的离心管中,于第一管内再加醋酸乙酯250μL,12000rpm/min进行离心10min,取上层有机层与前液合并,70℃氮气水浴挥干,残余物用100μL乙腈溶解,20μL进样。
(3)结果
为考察阿苯达唑市售片剂及阿苯达唑固体分散体组合物经SD大鼠口服给药后的药动学参数,使用BAPP 2.3软件计算非隔室模型药动学参数,所得结果见表二。
表2药动学参数拟合(n=3)
根据表2,阿苯达唑市售片剂和阿苯达唑固体分散体组合物的达峰时间相同,均为6h,阿苯达唑固体分散体组合物的半衰期为55.74h,相较于原料药T1/2的35.54h,制剂的半衰期增加了约1.5倍,说明制剂进入体内有缓释作用,这与缓释骨架材料性质有关。阿苯达唑固体分散体组合物的平均驻留时间为5.64h,也明显低于市售制剂的16.00h,也说明了制剂的增溶作用较好,进入机体后迅速被吸收。另外,阿苯达唑固体分散体组合物的药时曲线下面积AUC为3448.54h·ng·mL-1,阿苯达唑市售片剂的AUC为1414.57h·ng·mL-1,制剂的AUC明显高于原料药。根据相对生物利用度公式(Fr=(AUCT×DR)/(AUCR×DT),T为受试制剂、R为参比制剂)计算得到制剂的相对生物利用度高达243.79%,结合图4,阿苯达唑固体分散体组合物的血药浓度随时间的增加逐步上升再逐步下降,且阿苯达唑固体分散体组合物的Tmax较市售片剂一致,说明阿苯达唑固体分散体组合物中缓释骨架材料和亲水性高分子聚合物在生物利用度研究中共同发挥增加生物利用度的作用。说明溶剂法制备的阿苯达唑固体分散体组合物极大程度上提高了阿苯达唑的口服生物利用度,促进了阿苯达唑进入机体后的迅速吸收。
实施例10聚维酮K30单一载体阿苯达唑固体分散体体内生物利用度比较研究
(1)制备方法:精密称取阿苯达唑200mg溶于50mL无水乙醇,超声30min,再加入聚乙烯吡咯烷酮K 30S 1000mg超声1h,使用旋转蒸发仪30min,使部分有机溶液挥发,仍是溶液状态将其至表面皿中并放至真空干燥机,常温干燥过夜可得聚维酮K30单一载体阿苯达唑固体分散体。将样品刮下,研磨过80目筛网。
(2)动物实验与样品处理参考实施例8
(3)结果
与实施例3及实施例5相比,聚维酮K30单一载体阿苯达唑固体分散体大鼠相对生物利用度为84.11%,如表3所示,说明相比于采用单一增溶载体,本发明的阿苯达唑缓释固体分散体及阿苯达唑固体分散体组合物均有显著的生物利用度优势。
通过调节阿苯达唑固体分散体组合物中缓释固体分散体和速释固体分散体的比例,可以调节药物释放速度,以便灵活的进行生物利用度的控制。
实施例11实施例1及实施例3所制备的阿苯达唑固体分散体X-射线衍射分析
精密称取阿苯达唑原料药、实施例1制备阿苯达唑速释固体分散体缓释样品以及实施例3制备阿苯达唑缓释固体分散体缓释样品100mg。测试条件为步进的测定方式,扫描范围10-90°,速度10°/min,其结果如下图5所示,阿苯达唑固体分散体特征峰与阿苯达唑原料药一致说明其保持了药物的晶体性质。阿苯达唑固体分散体中特征峰显著降低,体现了载体的包覆效应。
Claims (8)
1. 一种溶剂法制备的阿苯达唑固体分散体组合物,其特征在于:所述组合物包括阿苯达唑缓释固体分散体和阿苯达唑速释固体分散体,所述阿苯达唑缓释固体分散体由亲水性高分子聚合物、缓释骨架材料以及表面活性剂为载体制备所得,其中各组分的质量比为阿苯达唑:亲水性高分子聚合物:缓释骨架材料:表面活性剂=1: 1-10 : 1-5 : 0.2-2;所述阿苯达唑速释固体分散体由亲水性高分子聚合物、抑晶成分以及表面活性剂为载体制备所得,其中各组分的质量比为阿苯达唑:亲水性高分子聚合物:抑晶成分:表面活性剂=1: 1-7 :0.5-3 : 0.2-2;阿苯达唑缓释固体分散体与阿苯达唑速释固体分散体的质量比为1: 0-1:3;
所述缓释骨架材料为羟丙基甲基纤维素E5、羟丙基甲基纤维素E15或羟丙基甲基纤维素E10M;所述抑晶成分为柠檬酸或酒石酸。
2. 根据权利要求1所述的溶剂法制备的阿苯达唑固体分散体组合物,其特征在于,所述亲水性高分子聚合物为聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、聚乙烯吡咯烷酮K 12、聚乙烯吡咯烷酮K 30S或共聚维酮VA64。
3.根据权利要求1所述的溶剂法制备的阿苯达唑固体分散体组合物,其特征在于,所述表面活性剂为十二烷基硫酸钠、月桂醇聚氧乙烯醚硫酸钠或卵磷脂。
4.根据权利要求1所述的溶剂法制备的阿苯达唑固体分散体组合物,其特征在于,所述组合物灌装于胶囊中制成胶囊剂或压制成片剂。
5.根据权利要求1所述的阿苯达唑固体分散体组合物制备方法,其特征在于,所述方法包括以下步骤:
将阿苯达唑溶解于无水乙醇中,超声处理使均匀;将亲水性高分子聚合物、缓释骨架材料和表面活性剂溶解于无水乙醇中,超声处理使均匀;将两种溶液混合,超声处理使充分分散;将混合溶液使用旋转蒸发仪除去部分有机溶剂,真空干燥并研磨后得到阿苯达唑缓释固体分散体;
将阿苯达唑溶解于无水乙醇中,超声处理使均匀;将亲水性高分子聚合物、抑晶成分和表面活性剂溶解于无水乙醇中,超声处理使均匀;将两种溶液混合,超声处理使充分分散;将混合溶液使用旋转蒸发仪除去部分有机溶剂,真空干燥并研磨后得到阿苯达唑速释固体分散体;
将阿苯达唑缓释固体分散体与阿苯达唑速释固体分散体按1: 0-1: 3的质量比均匀混合。
6. 根据权利要求5所述的阿苯达唑固体分散体组合物制备方法,其特征在于,旋转蒸发仪的参数为水浴35~45℃,转速55~65 rpm/min。
7.根据权利要求5所述的阿苯达唑固体分散体组合物制备方法,其特征在于,真空干燥的温度为35~45℃,干燥时间为10~14h。
8.根据权利要求5所述的阿苯达唑固体分散体组合物制备方法,其特征在于,每次超声处理的时间为18~22min。
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