CN112294974A - 具有多级缓控释作用的载药微粒及其制备方法 - Google Patents
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Abstract
本发明提供一种具有多级缓控释作用的载药微粒,所述载药微粒由药物微球和介孔二氧化硅纳米粒子结合而成;所述药物微球为水包油双乳化液微球,所述药物微球中含有第一活性因子;所述介孔二氧化硅纳米粒子上结合有第二活性因子和第三活性因子。本发明提供的载药微粒与现有技术中的脂质体相比,具有较好的稳定性,可负载多种药物或生物大分子,且可实现控制不同药物及生物大分子的给药时间,达到精确控制药物释放,以实现不同药物最大生物利用度的要求。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种具有多级缓控释作用的载药微粒及其制备方法。
背景技术
将微球作为药物的载体,以微颗粒的形式进入体内,这将打破传统的药物给药方式,彻底改变药物的剂型。无论是口服,还是静脉给药,都能改进药物的一些固有缺点,以满足临床治疗日益增加的用药需求。与传统的药剂相比,这类高分子载体系统可大大减少服药次数,屏蔽药物的刺激性气味、延长药物的活性、控制药物释放剂量、提高药物疗效,因此比一般药物制剂具有明显的优越性。是药物制剂发展的一个新方向。
脂质体是一种常用的纳米载体,大小约为80300 nm。它们是球形的,由磷脂和类固醇组成。它们可以通过将脂质分散在水性介质中自发制备。药物可被包封在脂质体内,随后通过改变pH、渗透梯度和周围环境等参数从药物中释放出来。不同的表面修饰也提高了脂质体的半衰期。例如,加入聚乙二醇( PEG )通过阻止吞噬体的识别来增加脂质体的半衰期。同样,也加入了聚乙二醇-磷脂酰乙醇胺( PEG-PE )缀合物。PEG-PE缀合物无毒,可用于将纳米载体特异性靶向线粒体.
申请号为CN201610010573.1的专利提供了一种共载柔红霉素和藤黄酸CdTe量子点纳米载药体系的制备方法,实现了集逆转多药耐药药物与化疗药物协同作用/纳米载药可控缓释,PH敏感靶向肿瘤等多种优势为一体,从而减少化疗药物使用量,降低化疗毒副作用增强化疗疗效。申请号为CN201710071053.6的专利提供了一种共载化学抗肿瘤药物和anti-Fas抗体的纳米载药体系的制备方法,实现与肿瘤微环境中MMPs响应,程序性,持续性地在肿瘤组织中释放抗体及小分子抗肿瘤药物,增强药物的肿瘤靶向性及抗肿瘤效果,集纳米载药可控释放,被动靶向,主动靶向,酶响应性与免疫治疗-化学药物治疗等多种优势于一体。但是现有技术的多药载药系统仅能做到可同时负载多种药物的要求,部分系统可通过连接靶向分子起到靶向给药的目的,但在疾病治疗过程中很多药物是需要分不同时间进行协同作用,现有技术的多药载体系统无法达到不同时间释放药物的要求,从而无法使多种药物协同作用最大化,影响治疗效果。
发明内容
本发明的目的在于,针对现有技术存在的问题,提供一种具有多级缓控释作用的载药微粒及其制备方法。
本发明的目的是通过以下技术方案来实现的:
一方面,提供一种具有多级缓控释作用的载药微粒,所述载药微粒由药物微球和介孔二氧化硅纳米粒子结合而成;所述药物微球为水包油双乳化液微球,所述药物微球中含有第一活性因子;所述介孔二氧化硅纳米粒子上结合有第二活性因子和第三活性因子。
优选地,所述第一活性因子选自B淋巴细胞趋化因子-1或IL-17抗体,所述第二活性因子选自IL-1或CCL3,所述第三活性因子选自TNF-α或IFN-γ。应当理解,第一活性因子、第二活性因子或第三活性因子可以根据具体的疾病选择不同的活性因子,不仅仅限于此处列举的B淋巴细胞趋化因子-1、IL-17抗体、IL-1、CCL3、TNF-α或IFN-γ,此处仅用于举例说明,以便容易理解本发明的构思。
优选地,所述药物微球选自B淋巴细胞趋化因子-1微球或IL-17抗体微球。
优选地,所述药物微球的结构为:
由聚乙烯醇水溶液构成的外层;
包裹于所述外层内部的油层,所述油层由聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物和聚乳酸-羟基乙酸共聚物的混合物组成;
包裹于所述油层内部的第一活性因子水溶液层。
优选地,所述聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物由以下方法制备而成:
(2)在引发剂参与下,在第三有机介质中,使甲基丙烯酸羟乙基酯-聚乳酸共聚物与丙烯酸发生聚合反应,生成聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物,具有如式Ⅱ所示的结构式:
优选地,所述甲基丙烯酸羟乙基酯与L-丙交酯的摩尔比为1:20。
优选地,所述催化剂选自异辛酸亚锡;以甲基丙烯酸羟乙基酯的摩尔含量为1计算,所述异辛酸亚锡的摩尔含量为0.2。
优选地,步骤(1)中,所述聚合反应的条件为:在氮气保护下,加热至甲基丙烯酸羟乙基酯与L-丙交酯完全融化,然后在140度加热2小时。
优选地,,所述引发剂选自偶氮二异丁腈。
优选地,所述第一有机介质选自二氧六环。
优选地,甲基丙烯酸羟乙基酯-聚乳酸共聚物、丙烯酸和引发剂的摩尔比为5:50:1。
优选地,所述介孔二氧化硅纳米粒子为经过氨基和硫醇共功能化的介孔二氧化硅纳米粒子。
另一方面,提供上述的载药微粒的制备方法,包含以下步骤:
(1)在缩合反应条件下,使介孔二氧化硅纳米粒子与药物微球在蒸馏水中接触,获得药物微球-介孔二氧化硅纳米粒子连接体;所述介孔二氧化硅纳米粒子为氨基和硫醇共功能化介孔二氧化硅纳米粒子。
(2)将药物微球-介孔二氧化硅纳米粒子连接体分散于含聚(乙二醇)二甲基丙烯酸酯和2,2-二甲氧基-2-苯乙酮的蒸馏水中,在紫外线照射下搅拌30分钟,然后用蒸馏水清洗形成聚乙二醇改性的药物微球-介孔二氧化硅纳米粒子连接体;
(3)将所述聚乙二醇改性的药物微球-介孔二氧化硅纳米粒子连接体在含有环氧乙烷-聚乙二醇的蒸馏水中于室温下搅拌12小时;过滤、冷冻干燥获得所述聚乙二醇/环氧乙烷-聚乙二醇共修饰的药物微球-介孔二氧化硅纳米粒子连接体颗粒;
(4)将所述聚乙二醇/环氧乙烷-聚乙二醇共修饰的药物微球-介孔二氧化硅纳米粒子连接体颗粒在蒸馏水中与第二活性因子接触,获得结合第二活性因子的聚乙二醇/环氧乙烷-聚乙二醇共修饰的药物微球-介孔二氧化硅纳米粒子连接体颗粒 ;将所述结合第二活性因子的聚乙二醇/环氧乙烷-聚乙二醇共修饰的药物微球-介孔二氧化硅纳米粒子连接体颗粒在蒸馏水中,与第三活性因子接触,搅拌、过滤、洗涤、冷冻干燥得到所述载药微粒。
优选地,步骤(1)中,所述缩合反应条件为:在1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺作用下室温搅拌,所述1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺的质量比为71:22。
优选地,所述氨基和硫醇共功能化介孔二氧化硅纳米粒子由以下方法制备而成:
将介孔二氧化硅纳米粒子分散于第一有机介质中,超声处理20分钟,获得悬浮液;将3-三甲氧基硅丙硫醇和(3-氨基丙基)三甲氧基硅烷加入所述悬浮液中,室温搅拌12小时,过滤,洗涤后,在40℃的真空烘箱中干燥,获得氨基和硫醇共功能化介孔二氧化硅纳米粒子;
优选地,所述药物微球由以下方法制备而成:将50 mg聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物和50 mg聚乳酸-羟基乙酸共聚物溶解于第二有机介质中,然后加入到100微升含有1mg B淋巴细胞趋化因子-1的水溶液中,利用超声乳化形成形成油包水乳液,将所述油包水(w/o)乳液逐渐加入到聚乙烯醇溶液中,经搅拌或超声处理形成水包油(w/o/w)双乳化液,在室温下搅拌蒸发掉第二有机介质,离心收集具有包埋孔的微球,得到的微球用蒸馏水清洗后并冻干,获得所述药物微球。
优选地,所述药物微球由以下方法制备而成:将75 mg聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸和75 mg 聚乳酸-羟基乙酸共聚物溶解于第二有机介质中,然后加入到100微升含有3mg IL-17抗体的水溶液,利用超声乳化形成形成油包水乳液,将所述油包水(w/o)乳液逐渐加入到聚乙烯醇溶液中,经搅拌或超声处理形成水包油(w/o/w)双乳化液,在室温下搅拌蒸发掉第二有机介质,离心收集具有包埋孔的微球,得到的微球用蒸馏水清洗后并冻干,获得所述药物微球。
优选地,所述聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物由以下方法制备而成:
(2)在引发剂参与下,在第三有机介质中,使甲基丙烯酸羟乙基酯-聚乳酸共聚物与丙烯酸发生聚合反应,生成聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物;具有如式Ⅱ所示的结构式:
优选地,所述甲基丙烯酸羟乙基酯与L-丙交酯的摩尔比为1:20。
优选地,所述催化剂选自异辛酸亚锡;以甲基丙烯酸羟乙基酯的摩尔含量为1计算,所述异辛酸亚锡的摩尔含量为0.2。
优选地,步骤(1)中,所述聚合反应的条件为:在氮气保护下,加热至甲基丙烯酸羟乙基酯与L-丙交酯完全融化,然后在140度加热2小时。
优选地,所述引发剂选自偶氮二异丁腈。
优选地,所述第一有机介质选自乙醇。
优选地,所述第二有机介质选自二氯甲烷。
优选地,所述第三有机介质选自二氧六环。
优选地,甲基丙烯酸羟乙基酯-聚乳酸共聚物、丙烯酸和引发剂的摩尔比为5:50:1。
优选地,所述第一活性因子选自B淋巴细胞趋化因子-1或IL-17抗体,所述第二活性因子选自IL-1或CCL3,所述第三活性因子选自TNF-α或IFN-γ。
相对于现有技术,本发明的有益效果在于:
本发明的具有多级缓控释作用的载药微粒与现有技术中的脂质体相比,具有较好的稳定性,可负载多种药物或生物大分子,且可实现控制不同药物及生物大分子的给药时间,达到精确控制药物释放,以实现不同药物最大生物利用度的要求。
本发明的具有多级缓控释作用的载药微粒可通过连接不同的细胞因子,从而靶向到病灶部位,并只在病灶部位分时段释放不同药物,实现主动靶向治疗的目的,达到最大化药物利用度及精准治疗调控的目的。
本发明静脉给药系统,以PLGA与丙烯酸-甲基丙烯酸羟-丙交酯聚合体,具有毒性低,防止敏感药物的水解,可组合式给药,控制药物释放等优点。本发明的组合式结构静脉给药系统与脂质体相比,具有较好的稳定性,可负载多种药物或生物大分子,且可实现控制不同药物及生物大分子的给药时间,可达到精确控制药物释放,以实现不同药物最大生物利用度的要求。
本发明的药物微球的主要成分LLA、甲基丙烯酸羟乙基酯、异辛酸亚锡、AA单体、偶氮二异丁腈,均为低毒性产品安全性高,所形成微球密封性好,且可包裹亲水亲油等多种药物。
本发明利用EO-PEG-EO和PEGMEMA对二氧化硅纳米粒子进行了改性,可连接含有C00H-的靶向细胞因子,然后通过吸收法吸附细胞因子在二氧化硅纳米粒子的微孔中,其所制备的纳米粒子可通过连接合适的靶向细胞因子驱使纳米粒子向病灶区域主动迁移并结合,然后通过释放纳米粒子上吸附的细胞因子2对疾病进行精准治疗。
本发明将药物微球与二氧化硅纳米粒子进行连接,可达到多种药物共同负载的目的,而且微球与纳米粒子上的药物在体内的释放可实现分阶段释放的要求,纳米粒子上设计靶向细胞因子,可迁移病灶区域,其在此设计下,可根据疾病治疗的要求,合理设计药物的包装,释放顺序及释放量,达到药物的最大利用度。
附图说明
图1为本发明实施例中具有多级缓控释作用的载药微粒的结构示意图;
图2为本发明实施例中共载IL-17抗体,CCL3,IFN-γ的载药微粒的电镜图;
图3为本发明实施例中具有多级缓控释作用的载药微粒中IFN-γ随时间释放的比例;
图4为本发明实施例中具有多级缓控释作用的载药微粒中IL-17抗体随时间释放的比例。
具体实施例
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
试剂说明:
B淋巴细胞趋化因子-1采购自赛业生物,产品编号:HECXP- 1301;
IL-17抗体采购自赛业生物,产品编号:HETNP-0101;
IL-1采购自北京同立海源生物科技有限公司,产品编号:TL-109;
CCL3采购自北京百奥莱博科技有限公司,产品编号:JN0292;
TNF-α或IFN-γ采购自北京同立海源生物科技有限公司,产品编号:TL-105;
L-丙交酯采购自Sigma-Aldrich Inc,产品编号:L09031;
M-甲基丙烯酸羟乙基酯采购自Sigma-Aldrich Inc,产品编号:B24260;
N-异辛酸亚锡采购自Sigma-Aldrich Inc,产品编号:B23612;
甲基丙烯酸羟乙基酯-聚乳酸、丙烯酸、偶氮二异丁腈采购自Sigma Aldrich;
其他未特别说明来源的试剂均采购自Sigma Aldrich。
实施例1
参考图1,图1为本实施例中具有多级缓控释作用的载药微粒的结构示意图;本实施例提供一种具有多级缓控释作用的载药微粒,所述载药微粒由药物微球和介孔二氧化硅纳米粒子结合而成;所述药物微球为水包油双乳化液微球,所述药物微球中含有第一活性因子;所述介孔二氧化硅纳米粒子上结合有第二活性因子和第三活性因子。
在一些实施例中,所述第一活性因子选自B淋巴细胞趋化因子-1或IL-17抗体,所述第二活性因子选自IL-1或CCL3,所述第三活性因子选自TNF-α或IFN-γ。
在一些实施例中,所述药物微球的结构为:
由聚乙烯醇水溶液构成的外层;
包裹于所述外层内部的油层,所述油层由丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物和聚乳酸-羟基乙酸共聚物的混合物组成;
包裹于所述油层内部的第一活性因子水溶液层。
在一些实施例中,所述聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物由以下方法制备而成:
取L-丙交酯(40 mmol,5.760 g)、甲基丙烯酸羟乙基酯(2 mmol,0.26 g)和异辛酸亚锡(0.4mmol,0.162g)在50ml圆底烧瓶中搅拌并加氮净化,获得混合物,在氮气保护下,将混合物加热至120度,使其完全熔化后,在140度下聚合2小时,将聚合产物溶于20毫升氯仿,在100毫升冷甲醇中沉淀,然后真空干燥,获得甲基丙烯酸羟乙基酯-聚乳酸;
取甲基丙烯酸羟乙基酯-聚乳酸(0.3 mmol,0.771 g),丙烯酸(3mmol,0.216 g)和偶氮二异丁腈(0.06 mmol,9.8 mg)添加到二氧六环(5 ml)中并搅拌直到溶解,聚合反应于70度下持续24小时,聚合后的原产品经氯仿至甲醇反复沉淀3次,真空干燥40小时,获得聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物。
在一些实施例中,所述介孔二氧化硅纳米粒子为经过氨基和硫醇共功能化的介孔二氧化硅纳米粒子。
实施例2
本实施例提供一种载药微粒的制备方法,包含以下步骤:
(1)取71毫克EDC.HCl和22毫克N-羟基琥珀酰亚胺,加入3ml蒸馏水中,然后再加入20mg氨基和硫醇共功能化介孔二氧化硅纳米粒子和1mgB淋巴细胞趋化因子-1微球,获得悬浮液,将悬浮液在室温下搅拌24小时,然后用蒸馏水清洗,收集微球后,冷冻干燥后获得B淋巴细胞趋化因子-1微球-二氧化硅纳米粒子连接体;
(2)将100mgB淋巴细胞趋化因子-1微球-介孔二氧化硅纳米粒子连接体分散于20ml含1毫升聚(乙二醇)二甲基丙烯酸酯和30毫克2,2-二甲氧基-2-苯乙酮的蒸馏水中,获得悬浮液,将悬浮液在365nm的紫外线照射下搅拌30分钟,然后用蒸馏水清洗三次形成聚乙二醇改性的B淋巴细胞趋化因子-1微球-介孔二氧化硅纳米粒子连接体;
(3)将所述聚乙二醇改性的B淋巴细胞趋化因子-1微球-介孔二氧化硅纳米粒子连接体在含有800微升环氧乙烷-聚乙二醇的20毫升蒸馏水中重新分散,室温下搅拌12小时,过滤、冷冻干燥获得聚乙二醇/环氧乙烷-聚乙二醇共修饰的B淋巴细胞趋化因子-1微球-介孔二氧化硅纳米粒子连接体颗粒。
(4)将制备好的聚乙二醇/环氧乙烷-聚乙二醇共修饰的B淋巴细胞趋化因子-1微球-介孔二氧化硅纳米粒子连接体颗粒分散于20 ml含有IL-1的蒸馏水,在室温下搅拌12小时;用3次蒸馏水洗涤去除未结合的IL-1 ,将其分散在蒸馏水中,然后通过吸收法增加TNF-α;将混合物在室温下搅拌24小时,所得固体进行过滤,用蒸馏水清洗,然后冷冻干燥得到共载B淋巴细胞趋化因子-1, IL-1,TNF-α的载药微球。
在一些实施例中,所述氨基和硫醇共功能化介孔二氧化硅纳米粒子由以下方法制备而成:
将介孔二氧化硅纳米粒子分散于乙醇中中,超声处理20分钟,获得悬浮液;将3-三甲氧基硅丙硫醇和(3-氨基丙基)三甲氧基硅烷加入所述悬浮液中,室温搅拌12小时,过滤,洗涤后,在40℃的真空烘箱中干燥,获得氨基和硫醇共功能化介孔二氧化硅纳米粒子;
在一些实施例中,所述药物微球由以下方法制备而成:将50 mg聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物和50 mg聚乳酸-羟基乙酸共聚物溶解于第二有机介质中,然后加入到100微升含有1mg B淋巴细胞趋化因子-1的水溶液中,利用超声乳化形成形成油包水乳液,将所述油包水(w/o)乳液逐渐加入到聚乙烯醇溶液中,经搅拌或超声处理形成水包油(w/o/w)双乳化液,在室温下搅拌蒸发掉第二有机介质,离心收集具有包埋孔的微球,得到的微球用蒸馏水清洗后并冻干,获得所述药物微球。
在一些实施例中,所述聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物由以下方法制备而成:将甲基丙烯酸羟乙基酯-聚乳酸(0.3 mmol,0.771 g),丙烯酸(3mmol,0.216 g)和偶氮二异丁腈(0.06 mmol,9.8 mg)添加到5 ml二氧六环中并搅拌直到溶解,于70度下聚合反应24小时,聚合后的原产品经氯仿至甲醇反复沉淀3次纯化,并最后真空干燥40小时,获得聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物,具有如式Ⅱ所示的结构式:
在一些实施例中,所述甲基丙烯酸羟乙基酯-聚乳酸由以下方法制备而成:
取L-丙交酯(40 mmol,5.760 g)、甲基丙烯酸羟乙基酯(2 mmol,0.26 g)和异辛酸亚锡
(0.4mmol,0.162g)在50ml圆底烧瓶中搅拌并加氮净化,在氮气保护下,将混合物加热至120
度,使其完全熔化,在140度下聚合反应2小时,将聚合产物溶于20毫升氯仿,在100毫升冷甲
醇中沉淀,然后真空干燥,获得甲基丙烯酸羟乙基酯-聚乳酸,具有如式I所示的结构式:
实施例3
本实施例提供一种的载药微粒的制备方法,包含以下步骤:
(1)取71毫克EDC.HCl和22毫克N-羟基琥珀酰亚胺,加入3ml蒸馏水中,然后再加入20mg氨基和硫醇共功能化介孔二氧化硅纳米粒子和1mg IL-17抗体微球,获得悬浮液,将悬浮液在室温下搅拌24小时,然后用蒸馏水清洗,收集微球后,冷冻干燥后获得IL-17抗体微球-二氧化硅纳米粒子连接体;
(2)将100mgIL-17抗体微球-介孔二氧化硅纳米粒子连接体分散于20ml含1毫升聚(乙二醇)二甲基丙烯酸酯和30毫克2,2-二甲氧基-2-苯乙酮的蒸馏水中,获得悬浮液,将悬浮液在365nm的紫外线照射下搅拌30分钟,然后用蒸馏水清洗三次形成聚乙二醇改性的IL-17抗体微球-介孔二氧化硅纳米粒子连接体;
(3)将所述聚乙二醇改性的IL-17抗体微球-介孔二氧化硅纳米粒子连接体在含有800微升环氧乙烷-聚乙二醇的20毫升蒸馏水中重新分散,室温下搅拌12小时,过滤、冷冻干燥获得聚乙二醇/环氧乙烷-聚乙二醇共修饰的IL-17抗体微球-介孔二氧化硅纳米粒子连接体颗粒。
(4)将制备好的聚乙二醇/环氧乙烷-聚乙二醇共修饰的IL-17抗体微球-介孔二氧化硅纳米粒子连接体颗粒分散于20 ml含有CCL3的蒸馏水,在室温下搅拌12小时;用3次蒸馏水洗涤去除未结合的CCL3 ,将其分散在蒸馏水中,然后通过吸收法增加IFN-γ;将混合物在室温下搅拌24小时,所得固体进行过滤,用蒸馏水清洗,然后冷冻干燥得到共载IL-17抗体, CCL3,IFN-γ的载药微球,图2为共载IL-17抗体,CCL3,IFN-γ的载药系统电镜图;
图3显示了共载IL-17抗体,CCL3,IFN-γ的载药系统中IFN-γ随时间释放的比例;
图4显示了共载IL-17抗体,CCL3,IFN-γ中IL-17抗体随时间释放的比例。
在一些实施例中,所述氨基和硫醇共功能化介孔二氧化硅纳米粒子由以下方法制备而成:
将介孔二氧化硅纳米粒子分散于乙醇中中,超声处理20分钟,获得悬浮液;将3-三甲氧基硅丙硫醇和(3-氨基丙基)三甲氧基硅烷加入所述悬浮液中,室温搅拌12小时,过滤,洗涤后,在40℃的真空烘箱中干燥,获得氨基和硫醇共功能化介孔二氧化硅纳米粒子;
在一些实施例中,所述药物微球由以下方法制备而成:100微升含有3mg IL-17抗体的水溶液加入含有15 %(质量分数)聚合物(75 mg聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸和75 mg 聚乳酸-羟基乙酸共聚物)二氯甲烷中在冰浴上利用超声波仪(15W的输出功率持续20s)进行乳化形成油包水(w/o)乳液。将w/o乳液逐渐加入10ml 1 %(质量分数)聚乙烯醇溶液经搅拌或超声处理形成水包油(w/o/w)双乳化液。将溶液在室温下搅拌3h以蒸发二氯甲烷,离心收集具有包埋孔的微球。得到的微球用蒸馏水清洗三次并冻干。
在一些实施例中,所述聚丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物由以下方法制备而成:将甲基丙烯酸羟乙基酯-聚乳酸(0.3 mmol,0.771 g),丙烯酸(3mmol,0.216 g)和偶氮二异丁腈(0.06 mmol,9.8 mg)添加到5 ml二氧六环中并搅拌直到溶解,于70度下聚合反应24小时,,聚合后的原产品经氯仿至甲醇反复沉淀3次纯化,并最后真空干燥40小时。
在一些实施例中,所述甲基丙烯酸羟乙基酯-聚乳酸由以下方法制备而成:
取L-丙交酯(40 mmol,5.760 g)、甲基丙烯酸羟乙基酯(2 mmol,0.26 g)和异辛酸亚锡(0.4mmol,0.162g)在50ml圆底烧瓶中搅拌并加氮净化,在氮气保护下,将混合物加热至120度,使其完全熔化,在140度下聚合反应2小时,将聚合产物溶于20毫升氯仿,在100毫升冷甲醇中沉淀,然后真空干燥,获得甲基丙烯酸羟乙基酯-聚乳酸。
以上所述,仅为本申请的具体实施方式,但本申请的保护范围并不局限于此,任何在本申请揭露的技术范围内的变化或替换,都应涵盖在本申请的保护范围之内。因此,本申请的保护范围应以所述权利要求的保护范围为准。
Claims (10)
1.具有多级缓控释作用的载药微粒,其特征在于,所述载药微粒由药物微球和介孔二氧化硅纳米粒子结合而成;所述药物微球为水包油双乳化液微球,所述药物微球中含有第一活性因子;所述介孔二氧化硅纳米粒子上结合有第二活性因子和第三活性因子。
2.根据权利要求1所述的载药微粒,其特征在于,所述第一活性因子选自B淋巴细胞趋化因子-1或IL-17抗体,所述第二活性因子选自IL-1或CCL3,所述第三活性因子选自TNF-α或IFN-γ。
3.根据权利要求1所述的载药微粒,其特征在于,所述药物微球选自B淋巴细胞趋化因子-1微球或IL-17抗体微球。
4.根据权利要求1所述的载药微粒,其特征在于,所述药物微球的结构为:
由聚乙烯醇水溶液构成的外层;
包裹于所述外层内部的油层,所述油层由丙烯酸-甲基丙烯酸羟乙基酯-聚乳酸共聚物和聚乳酸-羟基乙酸共聚物的混合物组成;
包裹于所述油层内部的第一活性因子水溶液层。
6.根据权利要求5所述的载药微粒,其特征在于,所述甲基丙烯酸羟乙基酯与L-丙交酯的摩尔比为1:20;甲基丙烯酸羟乙基酯-聚乳酸共聚物、丙烯酸和引发剂的摩尔比为5:50:1。
7.根据权利要求5所述的载药微粒,其特征在于,所述催化剂选自异辛酸亚锡;以甲基丙烯酸羟乙基酯的摩尔含量为1计算,所述异辛酸亚锡的摩尔含量为0.2。
8.根据权利要求5所述的载药微粒,其特征在于,步骤(1)中,所述聚合反应的条件为:在氮气保护下,加热至甲基丙烯酸羟乙基酯与L-丙交酯完全融化,然后在140度加热2小时。
9.根据权利要求5所述的载药微粒,其特征在于,所述引发剂选自偶氮二异丁腈;所述第一有机介质选自二氧六环。
10.根据权利要求5所述的载药微粒,其特征在于,其特征在于,所述介孔二氧化硅纳米粒子为经过氨基和硫醇共功能化的介孔二氧化硅纳米粒子。
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US20170065523A1 (en) * | 2015-09-09 | 2017-03-09 | Board Of Regents, The University Of Texas System | Multifunctional nanoparticle systems and methods for cancer diagnosis and combination therapy |
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US20170065523A1 (en) * | 2015-09-09 | 2017-03-09 | Board Of Regents, The University Of Texas System | Multifunctional nanoparticle systems and methods for cancer diagnosis and combination therapy |
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