CN103948568A - 一种静电喷雾技术制备载疏水性药物核壳结构微/纳米粒的方法 - Google Patents
一种静电喷雾技术制备载疏水性药物核壳结构微/纳米粒的方法 Download PDFInfo
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Abstract
本发明公开了一种静电喷雾技术制备载疏水性药物核壳结构微/纳米粒的方法,涉及药剂学领域,其作法是:将疏水性药物与脂溶性高分子材料共同溶解于有机溶剂后,乳化分散于含水溶性高分子材料的水性溶液中;再将所得水包油乳液置于微量推进器中,在高压静电场作用下进行静电喷雾,最终得到载疏水性药物核壳结构微/纳米粒。该制备方法操作简单,成本低,对环境友好,适合工业化生产。制备得到的载疏水性药物核壳结构微/纳米粒的粒径可控,具有组织器官靶向性;且核壳结构粒子有利于延长药物作用时间。
Description
技术领域
本发明涉及药剂学领域,尤其涉及一种静电喷雾技术制备载疏水性药物核壳结构微/纳米粒的方法。
背景技术
微/纳米粒子型药物携载系统主要用于提高难溶性药物的生物利用度的药物剂型。目前,常用的载药微/纳米粒制备技术包括熔融法、溶剂法、溶剂-熔融法、研磨法、溶剂喷雾干燥法、冷冻干燥法等等。现有的载药微/纳米粒子制备技术主要面临的问题是:(1)所制载药微/纳米粒稳定性不好,药物团聚现象严重;(2)常需要粉碎、过筛等步骤,过程复杂,影响因素多,所得载药微/纳米粒粒径分布广;(3)制备过程中常需加入一些非降解材料,如表面活性剂等;(4)有机溶剂残留较高,难以有效的移除,等等。这些问题限制了载药微/纳米粒的进一步广泛应用。静电喷雾技术,是一种利用高压静电场提供的电场力作为驱动力,对目标液体进行雾化,经收集、干燥后获得微/纳米粒的方法。这种方法简单、有效,可制备粒径从1 nm~100 μm的载药粒子。
发明内容
本发明的目的是提供一种静电喷雾技术制备载疏水性药物核壳结构微/纳米粒的方法。该方法适应性强,工艺简单、成本低廉、重复性好。制得的载疏水性药物核壳结构微/纳米粒具有核壳结构,疏水性药物与脂溶性高分子材料形成微/纳米粒的内核,水溶性高分子材料形成微/纳米粒的外壳。载疏水性药物核壳结构微/纳米粒对药物的包封率高、药物活性保持良好。可应用于靶向给药,并且通过调节核层或壳层的聚合物组成与分子量可对药物的释放进行控制和调节。
本发明解决其技术问题,所采用的技术方案是:一种静电喷雾技术制备载疏水性药物核壳结构微/纳米粒的方法,其步骤是:
A、将新藤黄酸和脂溶性高分子材料溶解于挥发性有机溶剂制成均一性溶液,新藤黄酸与脂溶性高分子材料的质量比在1︰999~1之间,溶液A粘度在1~105 mPa·s之间;
B、将水溶性高分子材料溶解于水中形成均一性溶液,溶液B粘度在1~105 mPa·s之间;
C、将A步的溶液分散于B步的溶液中形成乳液,A步溶液与B步溶液的比例在1︰99~1之间,再将乳液以高压静电喷雾法进行喷射、收集、干燥后得到载疏水性药物核壳结构微/纳米粒,高压静电喷雾装置喷嘴口径在0.05~5 mm之间、喷射速度在1 μL/min~1 mL/min之间、电压在0.5~30 kV之间、收集距离在1~50 cm之间。
与现有技术相比,本发明的有益效果是:
一、疏水性药物和脂溶性高分子材料溶解于挥发性有机溶剂制成均一性溶液,再分散于水溶性高分子材料的水溶液中形成水包油型乳液,采用乳液静电喷雾的方式,制备出以疏水性药物和脂溶性高分子材料为核层、水溶性高分子材料为壳层的载药微/纳米粒。疏水性药物绝大多数存在于粒子内部,在释放过程中壳层材料可保护内层的药物,避免酶、pH环境等对药物的降解和失活作用,延长药物的生物半衰期。实验测试证明,本发明制得的载疏水性药物核壳结构微/纳米粒中所包裹的药物在整个释放过程中均保持完整的结构与活性。并且药物的携载率高,实验测试证明,本发明制得的载药粒子的包封率可达95%以上;
二、本发明通过以水溶性高分子材料作为载药微/纳米粒的壳层使其在体液环境下有较好的分散性、不易团聚;与体液的亲和性高、细胞毒性小;可显著降低药物的早期突释。此外,水溶性高分子材料在体液中发生溶胀,可调节药物的溶解速率,延长药物作用时间,达到缓释的目的。因此,可通过采用不同种类、分子量的水溶性高分子材料作为壳层达到控制药物释放的目的;
三、本发明可通过调节核层与壳层高分子材料的种类、分子量、浓度调节所获载药微/纳米粒的粒径,制备的载疏水性药物核壳结构微/纳米粒的粒径从1 nm~100 μm可控,粒径分布窄,可达到心、肝、脾、肺、肾、脑、骨髓等部位靶向给药的目的;
四、本发明与普通载药粒子制备技术相比,应用该静电喷雾技术制备固体分散体具有独特优势:(1)溶剂挥发速度快;(2)工艺简单、适应性强、无需特殊设备、成本低廉、重复性好;(3)制备所得载药微/纳米粒具有完整的核壳结构,且粒径可在纳米到微米级可控、分布范围窄;(4)材料选择范围广,很有可能实现工业化生产。
上述A步中的疏水性药物为脂溶性镇静催眠药、抗癫痫药、抗精神失常药、中枢兴奋药、镇痛药、拟胆碱药、抗胆碱药、拟肾上腺素药、组胺H1受体拮抗剂、局部麻醉剂、离子通道药物、受体与递质相关药物、酶抑制剂、利尿药、调血脂药物、抗溃疡药、止吐药、促动力药、肝胆疾病辅助治疗药物、解热镇痛药、非甾体抗炎药、生物烷化剂、抗代谢药物、抗肿瘤抗生素、抗肿瘤植物药有效成分及其衍生物、β-内酰胺类抗生素、四环类抗生素、氨基糖甙类抗生素、大环内酯类抗生素、氯霉素类抗生素、喹诺酮类抗菌药、抗结核药、磺胺类药物及抗菌增效剂、抗真菌药、抗病毒药、抗寄生虫药、前列腺素、肽类激素、甾体激素、维生素、糖、苷、苯丙素、醌、黄酮、萜、挥发油、三萜及其苷、甾体及其苷、生物碱、氨基酸、多肽、脱氧核糖核酸、核糖核酸和反义寡核苷酸中的一种或一种以上的混合物。这些药物本身不具备靶向功能,同时在生理环境中半衰期短,生物相容性差,而通过本发明与脂溶性高分子材料共混并携载于具有水溶性高分子材料外壳的粒子中,可达到向特定器官靶向给药、长效缓释给药、延长药物生物半衰期的目的。
上述A步中的脂溶性高分子材料为脂溶性淀粉及其衍生物、脂溶性纤维素及其衍生物、脂溶性蛋白质、脂溶性多糖与杂多糖、丙烯酸类均聚物和共聚物、乙烯基类均聚物和共聚物、环氧乙烷类均聚物和共聚物、聚酯、聚氨基酸、偶氮聚合物、离子交换树脂的一种或一种以上的混合物。
以上的脂溶性高分子材料为现有成熟的药用高分子材料,用其制备载药粒子工艺简单、成本低廉、重复性好、安全性高。
上述B步中的水溶性高分子材料为水溶性淀粉及其衍生物、水溶性纤维素及其衍生物、水溶性蛋白质、水溶性多糖与杂多糖、水溶性丙烯酸类均聚物和共聚物、水溶性乙烯基类均聚物和共聚物、水溶性环氧乙烷类均聚物和共聚物、聚酯、聚氨基酸、偶氮聚合物、离子交换树脂中的一种或一种以上的混合物。
以上的水溶性高分子材料为现有成熟的药用高分子材料,用其制备载药粒子工艺简单、成本低廉、重复性好、安全性高。
附图说明
图1是本发明实施例一的方法制得的载疏水性药物核壳结构微/纳米粒新藤黄酸-聚乳酸/壳聚糖的扫描电镜观察图;图2是本发明实施例二的方法制得的载疏水性药物核壳结构微/纳米粒氟哌啶醇-聚丙烯树酯/羧甲基纤维素钠的扫描电镜观察图;图3是本发明实施例三的方法制得的载疏水性药物核壳结构微/纳米粒氟哌啶醇-聚丙烯树酯/羧甲基纤维素钠的扫描电镜观察图;图4是本发明实施例一的方法制得的载疏水性药物核壳结构微/纳米粒放线菌素D-聚氧乙烯/瓜尔豆胶的扫描电镜观察图;图5是本发明实施例一的方法制得的载疏水性药物核壳结构微/纳米粒新藤黄酸-聚乳酸/壳聚糖经尾静脉注射给药后的药物组织分布实验结果;图6是与实施例一等量的新藤黄酸直接溶解成液体后经尾静脉注射给药的药物组织分布对照实验结果。
具体实施方式
下面结合附图和具体实施方式对本发明作进一步的详细说明。
实施例一
A、将抗肿瘤植物药有效成分新藤黄酸与脂溶性高分子材料聚乳酸共同溶解于氯仿中形成均一性溶液,新藤黄酸与聚乳酸比例为1:250,溶液粘度为100 m·Ps;
B、将水溶性高分子材料壳聚糖溶解于水中形成均一性水相溶液,溶液粘度为100 m·Ps;
C、将A步溶液缓慢滴入B步溶液中,A步溶液与B步溶液的比例为1:25,形成水包油型乳液后以高压静电喷雾法进行喷射,喷嘴直径为0.4 mm,喷射速度为0.02 ml/min,电压为20 kV,收集距离为15 cm,收集干燥后得到载疏水性药物核壳结构微/纳米粒为新藤黄酸-聚乳酸/壳聚糖。
实施例二
本实施例与实施例一相同,所不同的仅仅是:步骤A中的疏水性药物为抗精神失常药氟哌啶醇,脂溶性高分子材料为聚丙烯树酯,氟哌啶醇与聚丙烯树酯比例为1:100,溶液粘度为200 m·Ps;步骤B中的水溶性高分子材料为羧甲基纤维素钠,溶液粘度为200 m·Ps;步骤C中A步溶液与B步溶液的比例为1:50,形成水包油型乳液后以高压静电喷雾法进行喷射,喷嘴直径为0.5 mm,喷射速度为0.05 ml/min,电压为18 kV,收集距离为17 cm,收集干燥后得到载疏水性药物核壳结构微/纳米粒为氟哌啶醇-聚丙烯树酯/羧甲基纤维素钠。
实施例三
本实施例与实施例一相同,所不同的仅仅是,步骤A中的疏水性药物为调血脂药洛伐他汀,脂溶性高分子材料为聚异丁烯,洛伐他汀与聚异丁烯比例为1:500,溶液粘度为1500 m·Ps;步骤B中的水溶性高分子材料为明胶,溶液粘度为1500 m·Ps;A步溶液与B步溶液的比例为1:100,形成水包油型乳液后以高压静电喷雾法进行喷射,喷嘴直径为0.7 mm,喷射速度为0.10 ml/min,电压为15 kV,收集距离为20 cm,收集干燥后得到载疏水性药物核壳结构微/纳米粒为洛伐他汀-聚异丁烯/明胶。
实施例四
本实施例与实施例一相同,所不同的仅仅是,步骤A中的疏水性药物为抗肿瘤抗生素放线菌素D,脂溶性高分子材料为聚氧乙烯,放线菌素D与聚氧乙烯比例为1:2000,溶液粘度为5000 m·Ps;步骤B中的水溶性高分子材料为明胶,,溶液粘度为5000 m·Ps;步骤B中的水溶性高分子材料为瓜尔豆胶;A步溶液与B步溶液的比例为1:200,形成水包油型乳液后以高压静电喷雾法进行喷射,喷嘴直径为0.9 mm,喷射速度为0.15 ml/min,电压为13 kV,收集距离为10 cm,收集干燥后得到载疏水性药物核壳结构微/纳米粒为放线菌素D-聚氧乙烯/瓜尔豆胶。
本发明方法中疏水性药物不局限于以上实施例中的举例,可以为镇静催眠药、抗癫痫药、抗精神失常药、中枢兴奋药、镇痛药、拟胆碱药、拟肾上腺素药、组胺H1受体拮抗剂、局部麻醉剂、离子通道药物、受体与递质相关药物、酶抑制剂、利尿药、调血脂药物、抗溃疡药、止吐药、促动力药、肝胆疾病辅助治疗药物、解热镇痛药、非甾体抗炎药、生物烷化剂、抗代谢药物、抗肿瘤抗生素、抗肿瘤植物药有效成分及其衍生物、β-内酰胺类抗生素、四环类抗生素、氨基糖甙类抗生素、大环内酯类抗生素、氯霉素类抗生素、喹诺酮类抗菌药、抗结核药、磺胺类药物及抗菌增效剂、抗真菌药、抗病毒药、抗寄生虫药、前列腺素、肽类激素、甾体激素、非甾体激素、蛋白同化激素、孕激素、抗孕激素、肾上腺皮质激素、维生素、糖、苷、苯丙素、醌、黄酮、萜、挥发油、三萜及其苷、甾体及其苷、生物碱、氨基酸、多肽、脱氧核糖核酸、核糖核酸和反义寡核苷酸中具有脂溶性的任意一种或一种以上的混合物。
本发明方法中的疏水性药物与水溶性或脂溶性高分子材料之间的比例也无特殊要求,只要疏水性药物的量足以产生疗效且不致于产生毒性即可。其数值能够根据现有疏水性药物的使用量确定。
由于脂溶性高分子材料可溶解于绝大多数的有机溶剂,因此,本发明方法A步中的溶剂不局限于以上实施例中所使用的溶剂,只要是能够溶解所选脂溶性高分子材料的有机溶剂均可。
本发明方法B步中的溶剂不局限于以上实施例中所使用的水,无论pH值与离子强度等,只要是能够溶解所选水溶性高分子材料的水相溶剂均可。
Claims (4)
1.一种静电喷雾技术制备载疏水性药物核壳结构微/纳米粒的方法,其特征在于包括如下步骤:
A、将疏水性药物和脂溶性高分子材料溶解于挥发性有机溶剂制成均一性溶液,疏水性药物与脂溶性高分子材料的质量比在1︰999~1之间,溶液A粘度在1~105 mPa·s之间;
B、将水溶性高分子材料溶解于水中形成均一性溶液,溶液B粘度在1~105 mPa·s之间;
C、将A步的溶液分散于B步的溶液中形成乳液,A步溶液与B步溶液的比例在1︰99~1之间,再将乳液以高压静电喷雾法进行喷射、收集、干燥后得到载疏水性药物核壳结构微/纳米粒,高压静电喷雾装置喷嘴口径在0.05~5 mm之间、喷射速度在1 μL/min~1 mL/min之间、电压在0.5~30 kV之间、收集距离在1~50 cm之间。
2.如权利要求1所述的一种静电喷雾技术制备载疏水性药物核壳结构微/纳米粒的方法,其特征在于:所述A步中的疏水性药物为脂溶性镇静催眠药、抗癫痫药、抗精神失常药、中枢兴奋药、镇痛药、拟胆碱药、抗胆碱药、拟肾上腺素药、组胺H1受体拮抗剂、局部麻醉剂、离子通道药物、受体与递质相关药物、酶抑制剂、利尿药、调血脂药物、抗溃疡药、止吐药、促动力药、肝胆疾病辅助治疗药物、解热镇痛药、非甾体抗炎药、生物烷化剂、抗代谢药物、抗肿瘤抗生素、抗肿瘤植物药有效成分及其衍生物、β-内酰胺类抗生素、四环类抗生素、氨基糖甙类抗生素、大环内酯类抗生素、氯霉素类抗生素、喹诺酮类抗菌药、抗结核药、磺胺类药物及抗菌增效剂、抗真菌药、抗病毒药、抗寄生虫药、前列腺素、肽类激素、甾体激素、维生素、糖、苷、苯丙素、醌、黄酮、萜、挥发油、三萜及其苷、甾体及其苷、生物碱、氨基酸、多肽、脱氧核糖核酸、核糖核酸和反义寡核苷酸中的一种或一种以上的混合物。
3.如权利要求1所述的一种静电喷雾技术制备载疏水性药物核壳结构微/纳米粒的方法,其特征在于:所述A步中的脂溶性高分子材料为淀粉及其衍生物、纤维素及其衍生物、蛋白质、多糖与杂多糖、丙烯酸类均聚物和共聚物、乙烯基类均聚物和共聚物、环氧乙烷类均聚物和共聚物、聚酯、聚氨基酸、偶氮聚合物、离子交换树脂的一种或一种以上的混合物。
4.如权利要求1所述的一种静电喷雾技术制备载疏水性药物核壳结构微/纳米粒的方法,其特征在于:所述B步中的水溶性高分子材料为淀粉及其衍生物、纤维素及其衍生物、蛋白质、多糖与杂多糖、丙烯酸类均聚物和共聚物、乙烯基类均聚物和共聚物、环氧乙烷类均聚物和共聚物、聚酯、聚氨基酸、偶氮聚合物、离子交换树脂中的一种或一种以上的混合物。
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CN108301068A (zh) * | 2017-12-29 | 2018-07-20 | 浙江大学 | 通过凝胶状水包油型乳液静电纺丝制备的具有核壳结构纳米纤维及方法 |
CN108301068B (zh) * | 2017-12-29 | 2020-07-17 | 浙江大学 | 通过凝胶状水包油型乳液静电纺丝制备的具有核壳结构纳米纤维及方法 |
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