CN102793672A - 壳聚糖修饰的醋甲唑胺固体脂质纳米粒及其制备方法 - Google Patents
壳聚糖修饰的醋甲唑胺固体脂质纳米粒及其制备方法 Download PDFInfo
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Abstract
本发明提供了一种可滴眼用的壳聚糖修饰的醋甲唑胺固体脂质纳米粒及其可供工业化的制备方法。该一种壳聚糖修饰的醋甲唑胺固体脂质纳米粒,其特征在于,按制备30ml纳米粒溶液计,所述的纳米粒含有醋甲唑胺5mg,脂质材料25~150mg,磷脂25~150mg,壳聚糖5~100mg,非磷脂的表面活性剂50~250mg和助表面活性剂50~250mg。本发明制备的壳聚糖修饰的醋甲唑胺固体脂质纳米粒粒径较小,药物包封率较高,较未经壳聚糖修饰的固体脂质纳米粒,表面所带的正电荷能提高该制剂稳定性及角膜渗透性,从而提高药物生物利用度,在治疗青光眼方面有巨大的临床运用潜力。
Description
一、技术领域
本发明属于药物制剂领域,涉及一种抗青光眼药物的新剂型—壳聚糖修饰的固体脂质纳米粒。
二、背景技术
醋甲唑胺(Methazolamide,MTZ)是一种碳酸酐酶抑制剂(carbonic anhydrase inhibitor,CAI),治疗青光眼已有40多年历史,具有显著的降眼压作用。碳酸酐酶是一种含锌金属酶,它在睫状上皮细胞中催化CO2和H2O,最终生成HCO3 -,透过腔膜分泌于房水。由于溶液要保持电中性,因此Na+向房水分泌增加,同时又带动Cl-向房水迁移,从而在房水形成高渗透压,促进H2O向房水方向运动,以保持房水的离子平衡。应用醋甲唑胺原理主要是通过抑制碳酸酐酶的活性,使HCO3 -的生成减少从而减少HCO3 -、Na+、Cl-和H2O进入房水,使房水生成减少,起到降低眼内压作用。
临床上常通过口服醋甲唑胺片剂降低眼内压,此给药途径非常有效,但由于其对非眼组织碳酸酐酶的抑制,会产生许多全身的不良反应,如多尿、胃肠不适、代谢性酸中毒、肾结石、再生障碍性贫血等。为了避免全身用药副作用,增加眼部药物的生物利用度,近年来其他剂型已进入研究阶段。文献报道,已成功研制出醋甲唑胺无机盐纳米粒、醋甲唑胺脂质体及醋甲唑胺凝胶剂。这几种制剂虽有良好的降眼压效果,但无机盐在眼部的聚集,对眼部有一定的损伤;脂质体的缺点是载药量低,稳定性差,无菌脂质体的大工业生产成本高,技术上有难度;而传统的凝胶剂因为热压灭菌会对凝胶结构造成不可逆的破坏,所以需在制备凝胶之前对所用的原料、试剂进行灭菌并在生产过程中保持严格的无菌操作,此外凝胶剂作为半固体制剂给药剂量不准确的特点也使其应用受到限制。因此针对现有剂型存在的不足,研究醋甲唑胺局部给药的新剂型显得非常必要。
固体脂质纳米粒(solid lipid nanoparticles,SLNs)是以固态的天然或合成的生理相容的高熔点脂质材料为载体,将药物包裹于类脂核中或吸附于纳米粒表面形成粒径为50-1000nm的固体胶粒给药体系。SLNs既具备聚合物纳米粒物理稳定性高、避免药物的降解或泄漏以及良好的靶向性的优势,又兼具了脂质体、乳剂毒性低、能大规模生产的优点,可以控制药物释放和具有良好的靶向性等,是一种很有发展前景的药物载体。
壳聚糖(Chitosan,CS),又名脱乙酰甲壳素,可溶性甲壳素,是甲壳素脱去乙酰基的衍生物。它是自然界中存在的唯一荷正电的碱性多糖,具有无毒,良好的生物相容性,低免疫排斥反应,生物粘附性及跨细胞膜转导能力等一系列特性,适合作为缓控释载体的修饰材料。
三、发明内容
发明目的
本发明的目的是提供一种壳聚糖修饰的醋甲唑胺固体脂质纳米粒及其制备方法。制得的壳聚糖修饰的固体脂质纳米粒能包载脂溶性的醋甲唑胺,提高眼部生物利用度。这是因为经壳聚糖修饰的固体脂质纳米粒表面荷正电,与带负电的角膜能紧密结合,同时壳聚糖具有渗透促进作用,可以提高醋甲唑胺角膜渗透能力,提高药物的眼部生物利用度,壳聚糖修饰的固体脂质纳米粒具有一定的缓释作用。
技术方案
一种壳聚糖修饰的醋甲唑胺固体脂质纳米粒,其特征在于,所述的纳米粒含有醋甲唑胺5mg,脂质材料25~150mg,磷脂25~150mg,壳聚糖5~100mg,非磷脂的表面活性剂50~250mg和助表面活性剂50~250mg;该纳米粒粒径为100~500nm。
所述的脂质材料为C14~C30的脂肪酸或C14~C30脂肪酸脂,包括而不局限于单硬脂酸甘油酯、硬脂酸、山嵛酸甘油酯、甘油棕榈酸硬脂酸酯、乙酸丁脂、三肉豆蔻酸甘油酯、三硬脂酸甘油酯中的至少一种。
壳聚糖粘均分子量范围为2000~80000Da。
非磷脂的表面活性剂包括吐温、司盘、卖泽、苄泽、泊洛沙姆、聚氧乙烯蓖麻油中至少一种;助表面活性剂包括乙醇、PEG-400、异丙醇和1,2-丙二醇中的至少一种。
所述的壳聚糖修饰的醋甲唑胺固体脂质纳米粒的制备方法,其特征在于由如下步骤实现:
A、取5mg醋甲唑胺,25~150mg脂质材料及25~150mg磷脂溶于70℃乙醇中构成有机相;
B、取含50~250mg的表面活性剂和50~250mg的助表面活性剂水溶液构成内水相;
C、将有机相缓慢滴入磁力搅拌下的70℃内水相中,继续搅拌使有机溶媒完全蒸发,得到初乳(约5ml);在磁力搅拌下,将所得的初乳快速倾倒入为初乳体积5倍0-4℃的连续相中,该连续相为pH4~6醋酸缓冲溶液,含有5~100mg壳聚糖及5%v/v甘露醇,继续搅拌固化1~2h,恢复到室温,过0.45μm的微孔滤膜,即得壳聚糖修饰的醋甲唑胺固体脂质纳米粒。
有益效果
本发明的壳聚糖修饰的醋甲唑胺固体脂质纳米粒,结合了壳聚糖和固体脂质纳米粒的优势。未经壳聚糖修饰的固体脂质纳米粒荷负电,与壳聚糖通过物理静电吸附作用,使经壳聚糖修饰的固体脂质纳米粒(CS-SLNs)荷正电,而角膜带负电,有助于促进CS-SLNs与角膜的特异性结合,从而延长该制剂在角膜的滞留时间,壳聚糖的生物粘附性也有利于CS-SLNs在角膜的滞留,同时,壳聚糖具有渗透促进剂的作用,有利于提高角膜对该制剂的摄取率,增强药物对青光眼的治疗效果。CS-SLNs滴眼给药,眼内无异物感,不影响眼部正常的生理功能。该制剂使减少给药剂量、减少给药频率、提高眼部生物利用度、降低不良反应成为现实,治疗青光眼具有潜在的临床运用价值。
乳化蒸发-低温固化法制备壳聚糖修饰的醋甲唑胺固体脂质纳米粒是在高温下,将脂质材料和磷脂溶于有机溶剂中,滴加到同温含有表面活性剂和助表面活性剂溶液中形成初乳。然后将初乳倾倒到置冰水浴中的含壳聚糖和甘露醇的醋酸溶液中,形成壳聚糖修饰的醋甲唑胺固体脂质纳米粒,该处方中加入的磷脂,不仅可显著增加药物的包封率,还可减小纳米粒的粒径,这可能是由于脂质材料在固化时形成的晶格对药物有一定的排斥作用,而磷脂可溶于固体脂质中形成分子型的固体分散体,使脂质材料不能形成完整的晶格,增加其不规则性,提高对药物的容纳性能,以增加对药物的包封;同时,磷脂具有乳化剂的作用,适量的磷脂使制备的纳米粒粒径变小。该制备方法简单,重复性好,制得的纳米粒粒径较小,分布均一,荷正电。与未经壳聚糖修饰的醋甲唑胺固体脂质纳米粒相比,该纳米粒稳定性高,角膜渗透能力强,药效显著增强,并且药效略优于市售药派立明(AZOPT),无刺激性,在治疗青光眼方面有巨大的临床运用潜力。
四、附图说明
图1.按实施例1~9制备的壳聚糖修饰的醋甲唑胺固体脂质纳米粒的透射电镜照片,其中A,B,C,D,E,F,G,H和I分别代表按实施例1~9制备的MTZ-CS-SLNs的透射电镜图;
图2.按实施例1~9制备的壳聚糖修饰的醋甲唑胺固体脂质纳米粒的释放曲线(n=3),其中A,B,C,D,E,F,G,H和I分别代表按实施例1~9制备的MTZ-CS-SLNs的释放曲线;
图3.按实施例1~9制备的壳聚糖修饰的醋甲唑胺固体脂质纳米粒的角膜渗透曲线(n=3);其中A,B,C,D,E,F,G,H和I分别代表按实施例1~9制备的MTZ-CS-SLNs的角膜渗透曲线;
图4.按实施例1~9制备的壳聚糖修饰的醋甲唑胺固体脂质纳米粒的降眼压效果(n=6);其中A,B,C,D,E,F,G,H和I分别代表按实施例1~9制备的MTZ-CS-SLNs的降眼压效果;
图5.按实施例1~9制备的壳聚糖修饰的醋甲唑胺固体脂质纳米粒连续给药后的兔眼病理切片;其中A,B,C,D,E,F,G和H分别代表给予生理盐水及按实施例1~9制备的MTZ-CS-SLNs后兔眼的虹膜病理切片照片。A',B′,C′,D′,E′,F′,G′和H′分别代表给予生理盐水及按实施例1~9制备的MTZ-CS-SLNs后兔眼的视网膜病理切片照片。
具体实施方式
本发明所用药用辅料为市售符合药典标准,如单硬脂酸甘油酯(GMS,上海试四赫维化工有限公司);磷脂(Lipoid S100,德国Lipoid公司);硬脂酸(SA,上海凌峰化学试剂有限公司);山嵛酸甘油酯(888ATO,法国Gattefosse公司);甘油棕榈酸硬脂酸酯(ATO5,嘉法狮(上海)贸易有限公司);三肉豆蔻酸甘油酯(Dynasan114,沙索(中国)化学有限公司);三硬脂酸甘油酯(Dynasan118沙索(中国)化学有限公司);壳聚糖(Chitosan,济南海得贝海洋生物工程有限公司)。
实施例1
取醋甲唑胺5mg、单硬脂酸甘油酯(GMS)100mg、磷脂75mg,加入5mL无水乙醇,70℃加热溶解,构成有机相。另取含150mg Tween80和150mg PEG400的溶液15mL构成内水相。玻璃注射器吸取有机相,通过5#针头,将有机相缓慢滴入1200rpm搅拌下的同温度的内水相中,继续搅拌使有机溶媒完全蒸发,得到初乳(约5mL);在1000rpm搅拌下,将所得的初乳快速倾倒入为初乳体积5倍的连续相(0-4℃)中,该连续相为pH4醋酸溶液,含有5%(w/v)甘露醇和2.5mg/mL壳聚糖。搅拌继续固化2h,恢复到室温,过0.45μm的微孔滤膜,即得壳聚糖修饰的固体脂质纳米粒,测定包封率、粒径和Zeta电位分别为69.2%,248.3nm和+33.1mV。
实施例2
取醋甲唑胺5mg、单硬脂酸甘油酯(GMS)150mg、磷脂150mg,加入5mL无水乙醇,70℃加热溶解,构成有机相。另取含250mg Tween80和250mg PEG400的溶液15mL构成内水相。玻璃注射器吸取有机相,通过5#针头,将有机相缓慢滴入1200rpm搅拌下的同温度的内水相中,继续搅拌使有机溶媒完全蒸发,得到初乳(约5mL);在1000rpm搅拌下,将所得的初乳快速倾倒入为初乳体积10倍的连续相中(0-4℃)中,该连续相为pH4醋酸溶液,含有5%(w/v)甘露醇和2mg/mL壳聚糖。搅拌继续固化2h,恢复到室温,过0.45μm的微孔滤膜,即得壳聚糖修饰的固体脂质纳米粒,测定包封率、粒径和Zeta电位分别为84.6%,438.9nm和+49.5mV。
实施例3
取醋甲唑胺5mg、单硬脂酸甘油酯(GMS)25mg、磷脂25mg,加入5mL无水乙醇,70℃加热溶解,构成有机相。另取含50mg Tween80和50mg PEG400的溶液15mL构成内水相。玻璃注射器吸取有机相,通过5#针头,将有机相缓慢滴入1200rpm搅拌下的同温度的内水相中,继续搅拌使有机溶媒完全蒸发,得到初乳(约5mL);在1000rpm搅拌下,将所得的初乳快速倾倒入为初乳5倍体积的连续相中(0-4℃)中,该连续相为pH6醋酸溶液,含有5%(w/v)甘露醇和0.2mg/mL壳聚糖。搅拌继续固化2h,恢复到室温,过0.45μm的微孔滤膜,即得壳聚糖修饰的固体脂质纳米粒,测定包封率、粒径和Zeta电位分别为57.4%,178.1nm和+13.4mV。
实施例4
取醋甲唑胺5mg、单硬脂酸甘油酯(GMS)75mg、磷脂75mg,加入5mL无水乙醇,70℃加热溶解,构成有机相。另取含100mg Tween80和100mg PEG400的溶液15mL构成内水相。玻璃注射器吸取有机相,通过5#针头,将有机相缓慢滴入1200rpm搅拌下的同温度的内水相中,继续搅拌使有机溶媒完全蒸发,得到初乳(约5mL);在1000rpm搅拌下,将所得的初乳快速倾倒入为初乳体积5倍的连续相中(0-4℃)中,该连续相为pH5醋酸溶液,含有5%(w/v)甘露醇和1.5mg/mL壳聚糖。搅拌继续固化2h,恢复到室温,过0.45μm的微孔滤膜,即得壳聚糖修饰的固体脂质纳米粒,测定包封率、粒径和Zeta电位分别为66.3%,235.3nm和+26.7mV。
实施例5
取醋甲唑胺5mg、甘油棕榈酸硬脂酸酯(GMS)100mg、山嵛酸甘油酯50mg、磷脂150mg,加入5mL无水乙醇,70℃加热溶解,构成有机相。另取含150mg Tween80和150mg PEG400的溶液15mL构成内水相。玻璃注射器吸取有机相,通过5#针头,将有机相缓慢滴入1200rpm搅拌下的同温度的内水相中,继续搅拌使有机溶媒完全蒸发,得到初乳(约5mL);在1000rpm搅拌下,将所得的初乳快速倾倒入为初乳体积5倍的连续相中(0-4℃)中,该连续相为pH4醋酸溶液,含有5%(w/v)甘露醇和4mg/mL壳聚糖。搅拌继续固化2h,恢复到室温,过0.45μm的微孔滤膜,即得壳聚糖修饰的固体脂质纳米粒,测定包封率、粒径和Zeta电位分别为79.8%,369.3nm和+23.9mV。
实施例6
取醋甲唑胺5mg、山嵛酸甘油酯150mg,磷脂25mg加入5mL无水乙醇,70℃加热溶解,构成有机相。另取含50mgTween80和50mgPEG400的溶液15mL构成内水相。玻璃注射器吸取有机相,通过5#针头,将有机相缓慢滴入1200rpm搅拌下的同温度的内水相中,继续搅拌使有机溶媒完全蒸发,得到初乳(约5mL);在1000rpm搅拌下,将所得的初乳快速倾倒入为初乳体积5倍的连续相中(0-4℃)中,该连续相为pH6醋酸溶液,含有5%(w/v)甘露醇和0.2mg/mL壳聚糖。搅拌继续固化2h,恢复到室温,过0.45μm的微孔滤膜,即得壳聚糖修饰的固体脂质纳米粒,测定包封率、粒径和Zeta电位分别为67.3%,454.2nm和+13.8mV。
实施例7
取醋甲唑胺5mg、山嵛酸甘油酯75mg,磷脂75mg加入5mL无水乙醇,70℃加热溶解,构成有机相。另取含50mg泊洛沙姆和50mg PEG400的溶液15mL构成内水相。玻璃注射器吸取有机相,通过5#针头,将有机相缓慢滴入1200rpm搅拌下的同温度的内水相中,继续搅拌使有机溶媒完全蒸发,得到初乳(约5mL);在1000rpm搅拌下,将所得的初乳快速倾倒入为初乳体积5倍的连续相中(0-4℃)中,该连续相为pH4醋酸溶液,含有5%(w/v)甘露醇和2.5mg/mL壳聚糖。搅拌继续固化2h,恢复到室温,过0.45μm的微孔滤膜,即得壳聚糖修饰的固体脂质纳米粒,测定包封率、粒径和Zeta电位分别为68.1%,289.2nm和+31.7mV。
实施例8
取醋甲唑胺5mg、山嵛酸甘油酯25mg,磷脂25mg加入5mL无水乙醇,70℃加热溶解,构成有机相。另取含50mg泊洛沙姆和50mg异丙醇的溶液15mL构成内水相。玻璃注射器吸取有机相,通过5#针头,将有机相缓慢滴入1200rpm搅拌下的同温度的内水相中,继续搅拌使有机溶媒完全蒸发,得到初乳(约5mL);在1000rpm搅拌下,将所得的初乳快速倾倒入为初乳体积5倍的连续相中(0-4℃)中,该连续相为pH4醋酸溶液,含有5%(w/v)甘露醇和0.5mg/mL壳聚糖。搅拌继续固化2h,恢复到室温,过0.45μm的微孔滤膜,即得壳聚糖修饰的固体脂质纳米粒,测定包封率、粒径和Zeta电位分别为56.1%,179.8nm和+18.31mV。
实施例9
取醋甲唑胺5mg、甘油棕榈酸硬脂酸酯75mg,磷脂75mg加入5mL无水乙醇,70℃加热溶解,构成有机相。另取含150mg泊洛沙姆和150mg PEG400的溶液15mL构成内水相。玻璃注射器吸取有机相,通过5#针头,将有机相缓慢滴入1200rpm搅拌下的同温度的内水相中,继续搅拌使有机溶媒完全蒸发,得到初乳(约5mL);在1000rpm搅拌下,将所得的初乳快速倾倒入为初乳体积5倍的连续相中(0-4℃)中,该连续相为pH4醋酸溶液,含有5%(w/v)甘露醇和1.5mg/mL壳聚糖。搅拌继续固化2h,恢复到室温,过0.45μm的微孔滤膜,即得壳聚糖修饰的固体脂质纳米粒,测定包封率、粒径和Zeta电位分别为71.2%,211.7nm和+35.34mV。
实施例10
单次给药刺激性实验
实验前先观察并记录每只家兔角膜、虹膜及结膜情况,已有病变或炎症者,剔除不用。将家兔随机分成9组,每组6只,每组家兔右眼结膜囊内用微量加样器分别滴入样品MTZ-CS-SLNs(按实施例1~9制备的样品)50μL,作为实验组,左眼滴入生理盐水作为对照组。刺激性试验前,样品需先从冰箱中取出放置冷却至室温,若低温滴入家兔眼中会引起流泪反射,加快药物从眼部表面清除。给药后使家兔眼睛轻轻闭合30s,观察给药后8h眼部组织的反应情况,按表1的Draize眼部刺激试验评分标准对角膜、虹膜、结膜分别进行评分,每只家兔眼刺激反应总积分等于每只家兔眼角膜、虹膜、结膜的刺激反应分值之和,并自身进行比较。然后按表2的评价标准,判断实施例1~9制备的MTZ-CS-SLNs眼刺激性,结果见表3。
表1眼刺激反应评分标准
表2眼刺激性评价标准
表3醋甲唑胺自不同处方单次给药角膜刺激性实验
实施例11
壳聚糖修饰的醋甲唑胺固体脂质纳米粒连续给药后对兔眼的刺激性评价
A.给药方案:选取无眼睛刺激症状、角膜缺陷和结膜损伤的家兔,将家兔随机分成9组,每组8只,雌雄各半,进行给药后兔眼病理切片考察。每组家兔右眼给予MTZ-CS-SLNs,反复轻合眼睑约10秒,使药物与眼睛充分接触,左眼同法给予生理盐水作为参比。每日给药3次,连续14天。试验结束后,放血处死所有动物,取出左右眼睛,用10%甲醛固定,进行石蜡包埋切片,切片厚约4-5μm,HE染色,进行病理组织学检查。
B.病理组织切片结果见图5。图片为分别给予生理盐水saline和MTZ-CS-SLNs(按实施例1~9制备的样品)兔眼虹膜(iris)和视网膜(retina)的病理切片照片。与阴性对照(saline)对比,可见试验组(按实施例1~9制备的样品)对兔眼虹膜和视网膜无影响,未引起病理组织改变,即MTZ-CS-SLNs对兔眼无明显刺激反应。
Claims (7)
1.一种壳聚糖修饰的醋甲唑胺固体脂质纳米粒,其特征在于所述的纳米粒含有醋甲唑胺5mg,脂质材料25~150mg,磷脂25~150mg,壳聚糖5~100mg,非磷脂的表面活性剂50~250mg和助表面活性剂50~250mg。
2.根据权利要求1所述的一种壳聚糖修饰的醋甲唑胺固体脂质纳米粒,其特征在于,该纳米粒粒径为100~500nm。
3.根据权利要求1所述的壳聚糖修饰的醋甲唑胺固体脂质纳米粒,其特征在于所述的脂质材料为C14~C30的脂肪酸或C14~C30脂肪酸脂。
4.根据权利要求3所述的壳聚糖修饰的醋甲唑胺固体脂质纳米粒,其特征在于所述的脂质材料为单硬脂酸甘油酯、硬脂酸、山嵛酸甘油酯、甘油棕榈酸硬脂酸酯、乙酸丁脂、三肉豆蔻酸甘油酯、三硬脂酸甘油酯中的至少一种。
5.根据权利要求1所述的壳聚糖修饰的醋甲唑胺固体脂质纳米粒,其特征在于壳聚糖粘均分子量范围为2000~80000Da。
6.根据权利要求1所述的壳聚糖修饰的醋甲唑胺固体脂质纳米粒,其特征在于非磷脂的表面活性剂包括吐温、司盘、卖泽、苄泽、泊洛沙姆、聚氧乙烯蓖麻油中至少一种;助表面活性剂包括乙醇、PEG-400、异丙醇和1,2-丙二醇中至少一种。
7.根据权利要求1所述的壳聚糖修饰的醋甲唑胺固体脂质纳米粒的制备方法,其特征在于由如下步骤实现:
A、取5mg醋甲唑胺,25~150mg脂质材料及25~150mg磷脂溶于70℃乙醇中构成有机相;
B、取含50~250mg的表面活性剂和50~250mg的助表面活性剂水溶液构成内水相;
C、将有机相缓慢滴入磁力搅拌下的70℃内水相中,继续搅拌使有机溶媒完全蒸发,得到初乳;在磁力搅拌下,将所得的初乳快速倾倒入为初乳体积5倍0-4℃的连续相中,该连续相为pH4~6醋酸缓冲溶液,含有5~100mg壳聚糖及5%v/v的甘露醇,继续搅拌固化1~2h,恢复到室温,过0.45μm的微孔滤膜,即得壳聚糖修饰的醋甲唑胺固体脂质纳米粒。
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