CN116687869B - 一种双载体的氟比洛芬酯纳米载药材料及其制备方法 - Google Patents
一种双载体的氟比洛芬酯纳米载药材料及其制备方法 Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
本发明公开了一种双载体的氟比洛芬酯纳米载药材料及其制备方法,按以下步骤进行制备:S1:用己二酸二酰肼对透明质酸进行化学修饰,制备固体粉末HA‑ADH;S2:制备HA‑PLGA;S3:制备双载体的氟比洛芬酯纳米载药材料:称取氟比洛芬酯溶于无水乙醇中,再加入步骤S2制得的HA‑PLGA、吐温80和二氯甲烷搅拌20min;再加入l1.5wt%的聚乙烯醇溶液,冰浴,200W超声20min后继续搅拌8h,透析后冻干得到双载体的氟比洛芬酯纳米载药材料,为固体粉末状。本发明制得的双载体的氟比洛芬酯纳米载药材料具备良好的稳定性,且毒副作用较低。
Description
技术领域
本发明涉及纳米复合材料技术领域,特别涉及一种双载体的氟比洛芬酯纳米载药材料及其制备方法。
背景技术
氟比洛芬酯(Flurbiprofen axetil),是氟比洛芬的前体药物,用于手术后及各种癌症的镇痛。氟比洛芬酯注射液是一种非甾体类靶向镇痛药,通过在脊髓和外周抑制环氧化酶(COX)减少***素的合成,降低手术创伤引起的痛觉过敏状态。脂微球制剂药效更强,起效更迅速,持续时间更长,且不易引起胃黏膜损伤等不良反应。其用于术后镇痛,优点在于没有中枢抑制作用,不影响处于麻醉状态患者的苏醒,可在术后立即使用。
现有的氟比洛芬酯在应用时,受到存储条件的影响,稳定性和安全性无法得到保证。由于氟比洛芬酯为酯类化合物,在存放过程中易水解生成杂质氟比洛芬,从而导致有效成分含量降低,杂质含量上升,影响其有效性和安全性。另外,氟比洛芬酯注射液在使用中存在一些难以避免的毒副作用,且不良反应发生几率较大,如:注射部位疼痛及皮下出血;循环***血压上升、心悸;皮肤偶见瘙痒、皮疹等过敏反应;消化***出现恶心呕吐、转氨酶升高、腹泻、胃肠道溃疡出血等,这是氟比洛芬酯类药物亟需改进的一大问题。
聚乳酸-羟基乙酸共聚物(poly(lactic-co-glycolic acid),PLGA)由两种单体--乳酸和羟基乙酸随机聚合而成,是一种可降解的功能高分子有机化合物,具有良好的生物相容性、无毒、良好的成囊和成膜的性能,被广泛应用于制药、医用工程材料和现代化工业领域。PLGA的降解产物是乳酸和羟基乙酸,同时也是人代谢途径的副产物,所以当它应用在医药和生物材料中时不会有毒副作用。
透明质酸(HA)是细胞外基质中广泛存在的蛋白多糖成分,具有良好的生物相容性,有望成为理想的缓释、控释药物载体材料。透明质酸是一种酸性粘多糖,以其独特的分子结构和理化性质在机体内显示出多种重要的生理功能,如润滑关节,调节血管壁的通透性,调节蛋白质,水电解质扩散及运转,促进创伤愈合等。
聚乙烯醇(PVA)是一种用途相当广泛的水溶性高分子聚合物。PVA具有独特的强力粘接性、皮膜柔韧性、平滑性、耐油性、耐溶剂性、保护胶体性、气体阻绝性、而磨性以及经特殊处理具有的耐水性,还被大量用于生产涂料、粘合剂、纸品加工剂、乳化剂、分散剂薄膜等产品。应用范围遍及纺织、食品、医药、建筑、木材加工、造纸、印刷、农业、钢铁、高分子化工等行业。
发明内容
为了克服现有技术的不足,本发明目的是提供一种双载体的氟比洛芬酯纳米载药材料的制备方法,该制备方法工艺简单,且制得的双载体的氟比洛芬酯纳米载药材料相比氟比洛芬酯原药毒副作用较低。
为了达到上述目的,本发明采用以下技术方案:
本发明提供一种双载体的氟比洛芬酯纳米载药材料的制备方法,包括以下步骤:
S1:用己二酸二酰肼对透明质酸进行化学修饰,制备固体粉末HA-ADH;
S2:制备HA-PLGA:将聚乳酸-羟基乙酸共聚物溶于二甲基亚砜、1,2-二氯乙烷和N-羟基丁二酰亚胺的混合溶液中充分搅拌,然后加入步骤S1制得的HA-ADH搅拌12h,待反应停止后透析得到HA-PLGA;
S3:制备双载体的氟比洛芬酯纳米载药材料:称取氟比洛芬酯溶于无水乙醇中,再加入步骤S2制得的HA-PLGA、吐温80和二氯甲烷搅拌20min;再加入l1.5wt%的聚乙烯醇溶液,冰浴,200W超声20min后继续搅拌8h,透析后冻干得到双载体的氟比洛芬酯纳米载药材料,为固体粉末状。
相比于现有技术,本发明通过制备双载体的纳米包载材料对氟比洛芬酯进行包覆,提高了氟比洛芬酯的稳定性,且制得的双载体的氟比洛芬酯纳米载药材料在细胞实验、迁移实验和荧光实验中均表现出较低的毒性,使其应用范围有望得到拓展。
进一步地,步骤S1包括以下步骤:
S11:称取透明质酸溶解于去离子水中,再加入己二酸二酰肼在室温下搅拌10min;
S12:待反应停止后,用50%的盐酸溶液调节混合溶液pH值至4.8,再加入乙醇溶液混合搅拌10min;
S13:称取1,2-二氯乙烷加入混合溶液中,并通过50%的盐酸溶液保持混合溶液pH值为4.8,反应2h;反应停止之后用20%的NaOH溶液将混合溶液pH值提升至7;
S14:将混合溶液透析后冻干得到固体粉末HA-ADH。
优选地,步骤S1中,透明质酸、去离子水、己二酸二酰肼、乙醇溶液、1,2-二氯乙烷的用量比为100mg:20mL:10mmol:20mL:1mmol。
优选地,步骤S2中,聚乳酸-羟基乙酸共聚物、二甲基亚砜、1,2-二氯乙烷、N-羟基丁二酰亚胺和HA-ADH的用量比为200mg:5mL:15μm:15μm:5mg;步骤S3中,氟比洛芬酯、无水乙醇、吐温80、二氯甲烷和聚乙烯醇溶液的用量比为200g:10mL:11.3μL:6.25mL:33mL。
优选地,各个步骤中的搅拌速度均为300r/min。
优选地,步骤S14中,透析步骤为:采用截留分子量为7000的透析带透析3天,第一天采用100mM的NaCl溶液透析,第二天采用体积百分比浓度为25%的乙醇溶液透析,第三天采用纯水透析。
优选地,步骤S2和步骤S3的透析均采用截留分子量为7000的透析带纯水透析3天。
本发明还提供如上所述制备方法制备得到的双载体的氟比洛芬酯纳米载药材料。
进一步地,所述双载体的氟比洛芬酯纳米载药材料载药率为33.86%。
与现有技术相比,本发明具有以下有益效果:通过PLGA和HA双载体,并以PVA作为修饰物,使制得的双载体的氟比洛芬酯纳米载药材料具备良好的稳定性,对储存条件要求较低;同时由于双载体和修饰物材料的协同作用,氟比洛芬酯纳米载药材料的毒性相比于氟比洛芬酯纯药也大幅降低,对患者更为友好,在镇痛的同时不会增加更多的痛苦和风险,也有利于氟比洛芬酯应用范围的拓展。
附图说明
图1为本发明的双载体的氟比洛芬酯纳米载药材料合成原理示意图;
图2为实施例1制得的双载体的氟比洛芬酯纳米载药材料的TEM图;
图3为实施例1制得的双载体的氟比洛芬酯纳米载药材料的SEM图;
图4为实施例1制得的双载体的氟比洛芬酯纳米载药材料的电位曲线图;
图5为测试例2的细胞毒性实验空载组测试结果柱状图;
图6为测试例2的细胞毒性实验材料组测试结果柱状图;
图7为测试例2的细胞毒性实验纯药组测试结果柱状图;
图8为测试例3得到的荧光图;
图9为测试例4得到的迁移实验显微镜图像;
图10为测试例4得到的迁移实验数据柱状图。
以下结合附图与具体实施例对本发明作进一步说明。
具体实施方式
以下实施例所用到的原料及试剂来源信息如表1所示:
表1原料及试剂来源
下面通过具体实施例以及附图对本发明作进一步阐释,但是本发明的技术方案不以具体实施例为限。
实施例1氟比洛芬酯纳米载药材料的制备
S1:制备固体粉末HA-ADH:称量100mgHA于50ml烧杯中,加入去离子水20mL使其完全溶解,再加入10mmolADH在室温300r/min的速度下搅拌10min。停止反应后用50%盐酸调节pH至4.8,再加入20ml乙醇(50%v/v)混合搅拌30min。称量1mmolEDC直接加入溶液,并通过加入盐酸保持和pH为4.8,反应2h。反应停之后用20%NaOH将溶液PH提升至7。反应溶液用透析带(MWCO为7000)透析3天,第一天100mM NaCl溶液,第二天25%(v/v)乙醇溶液,第三天纯水透析。再将溶液-80℃冷冻干燥得固体粉末HA-ADH。
S2:制备HA-PLGA:称量200mgPLGA于100mL烧杯中,加入5mlDMSO,15umolEDC和15umolNHS充分搅拌,溶液中加入5mgHA-ADH搅拌12h,反应停之后,溶液用透析带(MWCO为7000)纯水透析3天,得到HA-PLGA。
S3:制备氟比洛芬酯纳米载药材料:称量200mg氟比洛芬酯于100ml烧杯中,10mL无水乙醇使其完全溶解,再加入HA-PLGA,11.3μL吐温80和6.25mL二氯甲烷(DCM)搅拌20min。再加入33ml1.5wt%PVA溶液,冰浴200w超声20min,后继续搅拌过夜。7000Mv纯水透析,-80℃冷冻干燥得固体粉末。
请参阅图1,本发明采用PLGA和HA作为双载体,并采用PVA作为修饰物,使制得的双载体的氟比洛芬酯纳米载药材料具备良好的稳定性。同时由于双载体和修饰物材料的协同作用,氟比洛芬酯纳米载药材料的毒性相比于氟比洛芬酯纯药也大幅降低,对患者更为友好,在镇痛的同时不会增加患者更多的痛苦和风险,也有利于氟比洛芬酯应用范围的拓展。
测试例1双载体的氟比洛芬酯纳米载药材料的表征
采用负染制样方法对实施例1制得的双载体的氟比洛芬酯纳米载药材料进行制样并在透射电子显微镜下观察:将样品稀释至1mg/mL,取10uL滴于铜网上静置10min后吸走多余样品,再滴10uL醋酸双氧铀染液滴于原铜网,静置1min后吸走多余染液,晾干即可上镜观察。
请参阅图2,其为实施例1制得的双载体的氟比洛芬酯纳米载药材料的TEM图。从图中可以看出,制得的双载体的氟比洛芬酯纳米载药材料颗粒均匀,分散度好,粒径约为300nm,达到纳米载药材料标准。
ZETA电位测定:取约1mg样品,置于5mL离心管中,加入2mL水,超声分散5min。取1mL上层溶液,缓慢加入样品池中,避免样品池内出现气泡。采用马尔文激光粒度仪ZS90进行测试,仪器预热30min;启动测试软件,选择Zeta测试程序,选择水为溶剂,25℃下预热30s后测定,每个样品平行测定3次。
请参阅图3,经测定,实施例1制得的双载体的氟比洛芬酯纳米载药材料电位均值为-30.6mV,处于相对稳定的区间内,且主要带负电。可见制得的双载体的氟比洛芬酯纳米载药材料稳定性较好,且与细胞结合效果良好。
扫描电镜观察:将冷藏保存的样品取出,超声10min后滴在硅片上自然干燥,干燥后粘贴在样品台后喷金,最后进电镜观察。
请参阅图4,可以观察到在扫描电镜下,实施例1制得的双载体的氟比洛芬酯纳米载药材料形态大致为棒状。
测试例2双载体的氟比洛芬酯纳米载药材料对HaCaT细胞的毒性测定
采用CCK-8检测增殖法,使用细胞计数试剂盒(CCK-8;美仑)测定双载体的氟比洛芬酯纳米载药材料,先取100微升细胞悬液(5X104细胞/毫升;Hacat细胞的来源:尚恩生物,货号:SNL-163,细胞培养方法:10%FBS+DMEM(货号:MA0212-Dec-28H))接种于96孔板,分别加入3种药物:第1组空载组(即PLGA+HA+PVA):不同浓度的空载;第2组纳米材料组:不同浓度的PLGA+HA+PVA+氟比洛芬酯;第3组纯药组:不同浓度的氟比洛芬酯;其中,空载组浓度与纳米材料组一致,纳米材料组和纯药组浓度以含氟比洛芬酯量计算,即相同浓度下的纳米材料组和纯药组是指二者含氟比洛芬酯的量相同。在37℃条件下分别培养24h、48h、72h,然后每孔加入CCK-8试剂(10微升),得到的混合物在37℃条件下培养50分钟。记录混合物在450nm处的吸光度并计数细胞活力。
结果如图5~7所示,可以看出,空载组对HaCaT细胞几乎无抑制作用,24h时250~500ug/ml的浓度和72h时125~500ug/ml的浓度的纳米材料组的对细胞抑制作用强于空载组,但对细胞均无明显抑制作用;而24h时62~500ug/ml的浓度的纯药对细胞的抑制作用强于空载组和材料组,且对细胞有明显抑制作用。可见,24h和72h时空载组和纳米材料组均几乎无细胞毒性,而纯药组在24h时有明显细胞毒性,72h时则几乎无细胞毒性,原因可能是氟比洛芬酯纯药在24小时左右就完成分解了。综合三组的情况可以看出,双载体的氟比洛芬酯纳米载药材料相比氟比洛芬酯对HaCaT细胞的毒性更为微弱,安全性较强;且其作用时间相比氟比洛芬酯纯药较长,具备一定的缓释性能。
测试例3双载体的氟比洛芬酯纳米载药材料对HaCaT细胞的荧光测试
采用以下步骤进行荧光测试:
第一天,铺板:6孔板20万个/孔,HaCaT;
第二天,给药:分组:①空白组;②纳米材料组:PLGA+HA+PVA+氟比洛芬酯;浓度:139.2μg/mL;③纯药组:氟比洛芬酯;浓度:47.13μg/mL
第三天,分别用PI、AM染色观察荧光:(1)吸去培养基;(2)PBS洗2-3次;(3)加入染液15min;(4)PBS洗2-3次;(5)观察拍照。试剂盒为碧云天-Calcein/PI细胞活性与细胞毒性检测试剂盒(货号:MA0361)。
如图8所示,空白组与材料组细胞存活率无显著性差异;而纯药组相比空白组和材料组细胞存活率较低,表明该纳米材料在139.2μg/mL浓度下细胞毒性不强,而氟比洛芬酯纯药则有较强的细胞毒性。
测试例4双载体的氟比洛芬酯纳米载药材料对HaCaT细胞的迁移实验
进一步采用以下方法进行迁移实验:具体步骤为:
第一天铺板:6孔板30万/孔,HaCaT;
第二天:加药:
分组:
①空白组:DMEM;
②纳米材料组:PLGA+HA+PVA+氟比洛芬酯
浓度:139.2μg/mL(浓度选择是按照CCK8数据作散点图,根据回归线方程选取细胞活力百分之80时的给药浓度,请参阅图6);
③纯药组:氟比洛芬酯
浓度:47.13μg/mL(浓度选择是根据纳米药物给药浓度的氟比洛芬酯载药量(请参阅测试例5,载药率为33.86%),使纯药组和材料组含氟比洛芬酯的量一致)。
结果如图9和图10所示,可以看出,该浓度下材料组抑制细胞迁移效果不明显,而纯药组抑制细胞迁移较明显。可见,相比于氟比洛芬酯纯药,双载体的氟比洛芬酯纳米载药材料对HaCaT细胞的抑制作用较弱,毒性较低,安全性较高。
测试例5双载体的氟比洛芬酯纳米载药材料载药率测试
采用高效液相法对实施例1制得的氟比洛芬酯纳米载药材料进行载药率测试,实验条件为:
仪器:岛津LC-20AD
色谱柱:Ultimate Plus-C18 4.6*150mm 5um
磷酸缓冲液:1mol/L磷酸二氢钠溶液1.3ml与0.5mol/L磷酸氢二钠32.5ml,用水稀释至1000ml,调PH=8.00
流动相:乙腈-0.3%乙酸水=65-35
流速:1.0ml/min
柱温:30
检测波长:254nm
进样量:5uL
样品配置:
对照溶液:精密称取对照品(氟比洛芬酯纯药)适量,加DMSO溶解稀释至各浓度(20,40,60,80,100ug/ml)
样品溶液:精密称取实施例1制得的双载体的氟比洛芬酯纳米载药材料2.0mg,加1.0ml二氯甲烷,超声30min,精密移取200ul上述溶液,加800ul甲醇,摇匀,过膜,即得。
表2载药率测试数据表
经过测试,如表2所示,双载体的氟比洛芬酯纳米载药材料的载药率为33.86%,达到较高水平。
相比于现有技术,本发明通过采用PLGA和HA双载体,并采用PVA作为修饰物,对氟比洛芬酯进行包覆,使制得的双载体的氟比洛芬酯纳米载药材料具备良好的稳定性,对储存条件的要求较低。同时由于双载体和修饰物材料的协同作用,氟比洛芬酯纳米载药材料的毒性相比于氟比洛芬酯纯药也有明显降低,对患者更为友好,在镇痛的同时不会增加更多的痛苦和风险,也有利于氟比洛芬酯应用范围的拓展。此外,在细胞毒性实验中还可以看出制得的双载体的氟比洛芬酯纳米载药材料具有一定的缓释性能,这也为其进一步拓宽应用范围提供了可能性。
本发明并不局限于上述实施方式,如果对本发明的各种改动或变型不脱离本发明的精神和范围,倘若这些改动和变型属于本发明的权利要求和等同技术范围之内,则本发明也意图包含这些改动和变动。
Claims (6)
1.一种双载体的氟比洛芬酯纳米载药材料的制备方法,其特征在于,包括以下步骤:
S1:用己二酸二酰肼对透明质酸进行化学修饰,制备固体粉末HA-ADH;
S2:制备HA-PLGA:将聚乳酸-羟基乙酸共聚物溶于二甲基亚砜、1,2-二氯乙烷和N-羟基丁二酰亚胺的混合溶液中充分搅拌,然后加入步骤S1制得的HA-ADH搅拌12h,待反应停止后透析得到HA-PLGA;
S3:制备双载体的氟比洛芬酯纳米载药材料:称取氟比洛芬酯溶于无水乙醇中,再加入步骤S2制得的HA-PLGA、吐温80和二氯甲烷搅拌20min;再加入1.5wt%的聚乙烯醇溶液,冰浴,200W超声20min后继续搅拌8h,透析后冻干得到双载体的氟比洛芬酯纳米载药材料,为固体粉末状;
步骤S1包括以下步骤:
S11:称取透明质酸溶解于去离子水中,再加入己二酸二酰肼在室温下搅拌10min;
S12:待反应停止后,用50%的盐酸溶液调节混合溶液pH值至4.8,再加入乙醇溶液混合搅拌10min;
S13:称取1,2-二氯乙烷加入混合溶液中,并通过50%的盐酸溶液保持混合溶液pH值为4.8,反应2h;反应停止之后用20%的NaOH溶液将混合溶液pH值提升至7;
S14:将混合溶液透析后冻干得到固体粉末HA-ADH;
步骤S1中,透明质酸、去离子水、己二酸二酰肼、乙醇溶液、1,2-二氯乙烷的用量比为100mg:20mL:10mmol:20mL:1mmol;
步骤S2中,聚乳酸-羟基乙酸共聚物、二甲基亚砜、1,2-二氯乙烷、N-羟基丁二酰亚胺和HA-ADH的用量比为200mg:5mL:15μmol:15μmol:5mg;步骤S3中,氟比洛芬酯、无水乙醇、吐温80、二氯甲烷和聚乙烯醇溶液的用量比为200mg:10mL: 11.3μL:6.25 mL: 33mL。
2.根据权利要求1所述的双载体的氟比洛芬酯纳米载药材料的制备方法,其特征在于:搅拌速度均为300r/min。
3.根据权利要求1所述的双载体的氟比洛芬酯纳米载药材料的制备方法,其特征在于:步骤S14中,透析步骤为:采用截留分子量为7000的透析袋透析3天,第一天采用100mM的NaCl溶液透析,第二天采用体积百分比浓度为25%的乙醇溶液透析,第三天采用纯水透析。
4.根据权利要求1所述的双载体的氟比洛芬酯纳米载药材料的制备方法,其特征在于:步骤S2和步骤S3的透析均采用截留分子量为7000的透析袋纯水透析3天。
5.一种根据权利要求1~4任一项所述的制备方法制得的双载体的氟比洛芬酯纳米载药材料。
6.根据权利要求5所述双载体的氟比洛芬酯纳米载药材料,其特征在于:所述双载体的氟比洛芬酯纳米载药材料载药率为33.86%。
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