CN109568294B - 两性离子纳米聚合物胶囊的可控制备方法 - Google Patents
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Abstract
一种两性离子纳米聚合物胶囊的可控制备方法,按照如下步骤进行:(1)以吐温80和司盘80为助乳化剂,加正己烷配制油相;将药物或生物活性物质、核芯材料、两性离子单体、双亲性大分子RAFT试剂、交联剂、水溶性引发剂混合成水相;将水相加入油相中混合均匀,经超声粉碎机剪切制得细乳液,然后加入四甲基乙二胺;将所得细乳液在25~50℃进行RAFT活性自由基细乳液聚合反应,反应6~10小时后冷却,制得胶囊溶液;(2)将胶囊溶液离心得到凝胶状的纳米聚合物,冷冻干燥,将获得的粉末状纳米聚合物超声分散在PBS缓冲溶液中,再离心分离得到两性离子纳米聚合物胶囊。本发明所述方法在提高纳米胶囊生物相容性和抗蛋白污染性能的同时实现了对纳米胶囊结构的调控。
Description
(一)技术领域
本发明涉及一种两性离子纳米聚合物胶囊的可控制备方法,以及其用于包埋药物及生物活性物质等的应用。
(二)背景技术
药物缓释剂是指用药后能在较长时间内持续释放药物来达到长效作用的制剂。该类药物主要特点有:
一、给药次数少:对半衰期短的或需要频繁给药的药物,可以减少服药次数以提高患者服药的顺应性,使用方便。
二、血药浓度波动较小:使血药浓度平稳,避免峰谷现象,有利于降低药物的毒副作用。
三、使用剂量小:使用药物总剂量减少,用最小剂量达到最大药效。
在上市和开发的各种缓释制剂主要研究方向有:口服缓释、透皮给药、靶向给药。目前缓释制剂的形式主要有微胶囊、微球、微粒、纳米微胶球和膜等。
纳米胶囊是指尺度上介于1-1000nm,具有核壳结构的包裹体。由于纳米胶囊颗粒小,易于分散和悬浮在水中形成外观清澈透明胶体溶液,具有比普通微胶囊更大的比表面积,因此更易于表面修饰,从而在许多领域得到了广泛的应用。纳米胶囊在医药领域主要用于包覆药物和生物活性物质等。由于纳米胶囊尺寸减小,其活性物质对组织的附着力增加,生物利用率提高;纳米胶囊还能透过毛细血管,穿过粘膜上皮层渗透进入到组织(如肝脏)中,被组织中的细胞吞噬、吸收,从而将包裹的生物活性物质有效地输送到体内的靶细胞处,使芯材对靶细胞具有精确的靶向性。包裹药物的纳米胶囊溶液可用于静脉注射,其极小的粒径不会造成血管阻塞。用于肌肉注射时可使药物集中在注射部位发挥药效,而且有保护药物、降低药物释放浓度、易于控制等优点。
利用纳米胶囊包埋药物或生物活性物质是制备缓释胶囊的一种新途径,近年来备受关注。国内外学者已报道选用有机(聚合物、脂质体和树状大分子)和无机(二氧化硅、量子点(quantum dots(QD))等纳米胶囊来包埋药物或生物活性物质,主要采用层层自组装方法(layer-by-layer,LBL)、再沉淀-包覆法(encapsulation–reprecipitation)和反向细乳液聚合法制备纳米胶囊用作药物缓释纳米胶囊。这些方法在固定药物或生物活性物质的同时均可保持其分子结构、化学性质和生物活性,其中LBL法利用活性成分的胶体颗粒(如胶乳或细胞)作为组装模板,交替吸附带有相反电荷的物质,通过静电引力相互吸引并在模板颗粒表面聚合或沉积,层层自组装形成二维或三维的具有核壳结构的粒子,可对壳层进行一定的调控和修饰,但制备过程繁琐,不适合用于制备直径小于200nm的具有中空结构的纳米胶囊;再沉淀-包覆法利用生物活性物质的的亲水性及其在基质和溶剂中的溶解性不同来制备纳米胶囊,制备过程简单,但粒子结构难以精确调控;传统反向细乳液聚合法制作方法简单,能制备粒径分布在50-500nm的纳米胶囊,但是存在中空率低、生物相容性差的问题。
综上所述,众多学者在制备包埋药物或生物活性物质的纳米胶囊方面做了大量研究工作,并提出了多种制备方法,但存在其核壳结构和表面形态难以精确调控的问题,限制了其进一步应用。本发明利用生物相容性好的两性离子为壳层单体,采用可控聚合的方法制备两性离子纳米聚合物胶囊,并用其作为载体来包埋药物或生物活性物质,从而解决传统纳米胶囊结构难调控、抗蛋白污染性能差的问题;可实现对两性离子纳米聚合物胶囊进行表面及内部结构调控,同时提高其生物相容性,并通过温度、盐的浓度的改变实现所包埋药物或生物活性物质的可控缓释。
(三)发明内容
本发明旨在解决传统缓释纳米胶囊的结构难以调控、抗蛋白污染性能差、生物相容性差的问题,提供一种两性离子纳米聚合物胶囊的可控制备方法,在提高纳米胶囊生物相容性和抗蛋白污染性能的同时实现对纳米胶囊结构的调控。
本发明采用的技术方案是:
一种两性离子纳米聚合物胶囊的可控制备方法,所述方法按照如下步骤进行:
(1)以吐温80和司盘80为助乳化剂,加正己烷配制助乳化剂质量分数为2~7%(优选3~7%)的油相;
将药物或生物活性物质、核芯材料、两性离子单体、双亲性大分子RAFT试剂、交联剂、水溶性引发剂按质量比1:5-15:3-7:0.05-0.15:0.03-0.15:0.1-0.2(优选1:10:4.9-5.0:0.1:0.04-0.10:0.1-0.15)混合成水相;
将水相加入油相中,使水相、油相的质量比为1:4~10(优选1:4~6),两相混合均匀,经超声粉碎机剪切制得细乳液,然后加入四甲基乙二胺,使药物或生物活性物质与四甲基乙二胺的质量用量之比为1:0.2-0.3,优选1:0.25-0.30;
将所得细乳液在25~50℃条件下进行RAFT活性自由基细乳液聚合反应,反应6~10小时后冷却,制得两性离子纳米聚合物胶囊溶液;
所述两性离子单体为甲基丙烯酸羧基甜菜碱、甲基丙烯酸磺酸基甜菜碱、羟基磺丙基甜菜碱或磷酸酯基甜菜碱,优选甲基丙烯酸磺酸基甜菜碱;
所述的交联剂为N,N-亚甲基双丙烯酰胺或二甲基丙烯酸乙二醇酯,优选N,N-亚甲基双丙烯酰胺;
所述的水溶性引发剂为过硫酸铵;
所述的核心材料为pH=6.86~8.6PBS溶液、Tris-HCl缓冲液、硼酸缓冲溶液或柠檬酸缓冲溶液,优选pH=8.4的PBS溶液;
所述的药物为亲水性药物,所述的生物活性物质为对温度或pH敏感的生物活性物质;
(2)将步骤(1)得到的两性离子纳米聚合物胶囊溶液在离心机中离心得到凝胶状的纳米聚合物,冷冻干燥得到粉末状纳米聚合物,将获得的粉末状纳米聚合物超声分散在pH=6.86~8.6的PBS缓冲溶液(优选pH=6.86的PBS缓冲溶液)中,所得分散液离心分离得到两性离子纳米聚合物胶囊。
进一步,步骤(1)中,所述的药物为盐酸多柔比星或β-羟乙基茶碱。
进一步,步骤(1)中,所述的生物活性物质为牛血清蛋白或蛋白酶。
进一步,步骤(2)中,将胶囊溶液在离心机中于10000rpm条件下离心得到凝胶状的纳米聚合物。
进一步,步骤(2)中,所得分散液在100kd Millipore超滤离心管中10000rpm条件下离心分离得到两性离子纳米聚合物胶囊。
本发明制得的两性离子纳米聚合物胶囊的核心部分为含缓冲溶剂的去离子水和药物或生物活性物质,壳层为两性离子单体和交联剂聚合后形成的交联的聚合物,平均粒径为50~300nm,并且可以通过离心、冷冻干燥的方式将两性离子纳米聚合物胶囊分散在水相中,以备后续应用。
本发明中,所述双亲性大分子RAFT试剂通过如下方法制备:4,4-偶氮-二(4-氰基戊酸)和十二烷基-3-氰基戊酸三硫酯溶于二氧六环溶剂中,再加入亲水性单体和亲油性单体混合均匀,在70~90℃条件下聚合反应8~9小时,减压蒸除溶剂制得双亲性大分子RAFT试剂,所述亲水性单体为丙烯酸或甲基丙烯酸,所述亲油性单体为苯乙烯或甲基丙烯酸甲酯;所述亲水性单体、亲油性单体、4,4-偶氮-二(4-氰基戊酸)、十二烷基-3-氰基戊酸三硫酯的质量比为1:0.5~2:0.01~0.1:0.1~0.7,优选1:0.7~1:0.03~0.05:0.4~0.6,最优选1:0.75:0.375:0.5;所述亲水性单体与二氧六环溶剂的质量比通常为1:4~16,优选1:14~16。
本发明中,两性离子单体可通过文献报道的方法进行制备。
本发明的技术优势在于:
1)应用反向RAFT细乳液聚合法将药物或生物活性物质包埋到两性离子纳米聚合物胶囊中,可精确调控含药物或生物活性物质的纳米聚合物胶囊的核壳结构和表面形态,从而实现了药物或生物活性物质的有效包埋并进行结构调控。
2)以两性离子为单体,可精确调控纳米聚合物胶囊的表面官能团,实现纳米胶囊抗蛋白污染能力和生物相容性的提升,并对温度刺激做出响应。
(四)附图说明
图1是实施例4两性离子纳米聚合物胶囊的扫描电镜图(左)和透射电镜图(右);
图2是实施例15所制备的两性离子纳米聚合物胶囊在不同温度下的粒径响应;
图3是实施例15所制备的两性离子纳米聚合物胶囊在10℃、40℃溶液中的蛋白释放曲线;
图4是实施例15制备的两性离子纳米聚合物胶囊的抗蛋白污染性能测试曲线。
(五)具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此。
所有实施例所用双亲性大分子RAFT试剂由以下方法制得:将4克的甲基丙烯酸、3克的甲基丙烯酸甲酯、0.15克的4,4-偶氮-二(4-氰基戊酸)和2克的十二烷基-3-腈基戊酸三硫酯溶于60克的二氧六环溶剂中,在80℃条件下聚合8小时,减压蒸除溶剂制得双亲性大分子RAFT试剂。
实施例1:
制备甲基丙烯酸磺酸基甜菜碱两性离子单体,具体步骤如下:
将15.70g甲基丙烯酸二甲氨乙酯溶于34.54g丙酮溶剂中,再缓慢滴入24.4g质量分数为50%的1,3-丙烷磺酸内酯的丙酮溶液,50℃条件下磁力搅拌开环反应18h。产物减压抽滤,并用丙酮和乙腈的混合溶液不断洗涤,50℃下真空干燥8h制得甲基丙烯酸磺酸基甜菜碱。
实施例2a-2d:
实施例2a-2d与实施例1的方法相同,不同之处为甲基丙烯酸二甲氨乙酯用量分别为16.49g(实施例2a)、17.27g(实施例2b)、18.06g(实施例2c)、18.84克(实施例2d),对甲基丙烯酸磺酸基甜菜碱产率进行调控。发现随着甲基丙烯酸二甲氨乙酯用量的增加,甲基丙烯酸磺酸基甜菜碱产率逐渐增加至不变。甲基丙烯酸二甲氨乙酯用量为17.27克时甲基丙烯酸磺酸基甜菜碱产率约为84.89%。
实施例3:
制备甲基丙烯酸羧基甜菜碱两性离子单体,具体步骤如下:
将15.70g甲基丙烯酸二甲氨乙酯溶于34.54g丙酮溶剂中,再缓慢滴入14.4g质量分数为50%的β-丙内酯的丙酮溶液,50℃条件下磁力搅拌开环反应18h。产物减压抽滤,并用丙酮和去离子水的混合溶液不断洗涤,50℃下真空干燥8h制得甲基丙烯酸羧基甜菜碱。
实施例4:
制备包埋盐酸多柔比星的两性离子纳米聚合物胶囊,具体步骤如下:
将0.25克吐温80、0.75克司盘80与13.2克正己烷配制成溶液作为油相,加入由1.7g磷酸缓冲盐溶液(pH=8.4)、0.17g盐酸多柔比星、0.017g双亲性大分子RAFT试剂、0.837g实施例制备的甲基丙烯酸磺酸基甜菜碱、0.008g N,N-亚甲基双丙烯酰胺、0.023g过硫酸铵组成的水相并混合均匀,经超声粉碎6分钟制得细乳液,再加入0.047g四甲基乙二胺。将细乳液在25℃条件下进行RAFT活性自由基细乳液聚合反应,反应6小时后冷却。
产物在离心机中10000rpm条件下得到凝胶状的纳米聚合物,取一定量的该纳米聚合物胶囊的颗粒物冷冻干燥12h得到粉末状纳米聚合物。将获得的粉末状纳米聚合物超声分散在pH=6.86的PBS缓冲溶液中,在100kdMillipore超滤离心管中10000rpm条件下离心分离30min得到包埋盐酸多柔比星的两性离子纳米聚合物胶囊。
实施例5
制备包埋β-羟乙基茶碱的两性离子纳米聚合物胶囊,具体步骤如下:
将0.25克吐温80、0.75克司盘80与13.2克正己烷配制成溶液作为油相,加入由1.7g混合磷酸缓冲溶液、0.17gβ-羟乙基茶碱、0.017g双亲性大分子RAFT试剂、0.837g实施例制备的甲基丙烯酸磺酸基甜菜碱、0.008gN,N-亚甲基双丙烯酰胺、0.023g过硫酸铵组成的水相并混合均匀,经超声粉碎6分钟制得细乳液,再加入0.047g四甲基乙二胺。将细乳液在25℃条件下进行RAFT活性自由基细乳液聚合反应,反应6小时后冷却。
产物在离心机中10000rpm条件下得到凝胶状的纳米聚合物,取一定量的该纳米聚合物胶囊的颗粒物冷冻干燥12h得到粉末状纳米聚合物。将获得的粉末状纳米聚合物超声分散在pH=6.86的PBS缓冲溶液中,在100kdMillipore超滤离心管中10000rpm条件下离心分离30min得到包埋有β-羟乙基茶碱的两性离子纳米聚合物胶囊。
实施例6
制备包埋牛血清蛋白的两性离子纳米聚合物胶囊,具体步骤如下:
将0.25克吐温80、0.75克司盘80与13.2克正己烷配制成溶液作为油相,加入由1.7g混合磷酸缓冲溶液、0.17g牛血清蛋白、0.017g双亲性大分子RAFT试剂、0.837g实施例制备的甲基丙烯酸磺酸基甜菜碱、0.008g N,N-亚甲基双丙烯酰胺、0.023g过硫酸铵组成的水相并混合均匀,经超声粉碎6分钟制得细乳液,再加入0.047g四甲基乙二胺。将细乳液在25℃条件下进行RAFT活性自由基细乳液聚合反应,反应6小时后冷却。
产物在离心机中10000rpm条件下得到凝胶状的纳米聚合物,取一定量的该纳米聚合物胶囊的颗粒物冷冻干燥12h得到粉末状纳米聚合物。将获得的粉末状纳米聚合物超声分散在pH=6.86的PBS缓冲溶液中,在100kdMillipore超滤离心管中10000rpm条件下离心分离30min得到包埋有牛血清蛋白的两性离子纳米聚合物胶囊。
实施例7-12
本实施例7-12与实施例6的方法相同,不同之处为N,N-亚甲基双丙烯酰胺用量分别为0.017g、0.033g、0.050g、0.067g、0.084g、0.168g,对该聚合物胶囊的表面形貌进行调控。发现随着交联剂用量的增多,合成的纳米聚合物胶囊形貌规整度增加、粒径相近,纳米聚合物粒子由最初的不规则形状最终变为完整的球形结构并且具有相似的粒径。
实施例13
制备助乳化剂(吐温80和司班80)用量为2%的包埋有牛血清蛋白的两性离子纳米聚合物胶囊,平均粒径为129.2nm,具体步骤如下:
将0.066克吐温80、0.198克司盘80与13.2克正己烷配制成溶液作为油相,加入由1.7g混合磷酸缓冲溶液、0.17g牛血清蛋白、0.017g双亲性大分子RAFT试剂、0.837g实施例制备的甲基丙烯酸磺酸基甜菜碱、0.050gN,N-亚甲基双丙烯酰胺、0.023g过硫酸铵组成的水相并混合均匀,经超声粉碎6分钟制得细乳液,再加入0.047g四甲基乙二胺。将细乳液在25℃条件下进行RAFT活性自由基细乳液聚合反应,反应6小时后冷却。
产物在离心机中10000rpm条件下得到凝胶状的纳米聚合物,取一定量的该纳米聚合物胶囊的颗粒物冷冻干燥12h得到粉末状纳米聚合物。将获得的粉末状纳米聚合物超声分散在pH=6.86的PBS缓冲溶液中,在100kdMillipore超滤离心管中10000rpm条件下离心分离30min得到包埋牛血清蛋白的两性离子纳米聚合物胶囊。
实施例14-17
实施例14-17与实施例13的方法相同,不同之处为助乳化剂用量分别为0.396g、0.528g、0.660g、0.792g,对该聚合物胶囊的粒径进行调控。发现相对应的两性离子纳米聚合物胶囊平均粒径分别为175.0nm、178.8nm、173.1nm、178.1nm,说明通过调节助乳化剂用量成功实现对两性离子纳米聚合物胶囊粒径可控调节。
实施例18-21
实施例18-21与实施例6的方法相同,不同之处为反应时间分别为7、8、9、10小时,考察了反应时间对单体转化率的影响,发现相对应的单体转化率为54.73%、66.55%、73.43%、86.3%,随着反应时间的增加,单体转化率逐渐增加,纳米聚合物粒子形状逐渐由不规整转变为规整的球形结构,反应时间为10h时单体最终转化率约为86.3%。
对比例1-3
对比例1-3与实施例6所述方法相同,不同之处为在包埋牛血清蛋白的两性离子纳米聚合物胶囊的水溶液制备过程中,在其它条件不变的情况下,分别用四氢呋喃、丙酮、二氧六环三种有机物良溶剂洗涤纳米聚合物胶囊以进行筛选组成油相的有机溶剂。发现在溶剂用量一样的条件下,四氢呋喃、丙酮、二氧六环会与纳米聚合物胶囊壳层发生化学键作用,使纳米聚合物胶囊壳层塌陷。正己烷为制备纳米聚合物胶囊的连续相,极性低且对乳化剂溶解度大,故选择正己烷最佳。
实施例22:实施例15所制备的两性离子纳米聚合物胶囊在不同温度下的粒径响应
取实施例15产物两性离子纳米胶囊溶液,用正己烷稀释到0.1wt‰,使用仪器为ZS90型激光粒度仪,设置散射光角度90°,粘度为0.09Ns·m-2,折光系数为1.43的条件下,调节温度20-50℃,分别测试粒径大小绘制成曲线,见图2。
实施例23:实施例15所制备的两性离子纳米聚合物胶囊在10℃、40℃溶液中的蛋白释放曲线
取实施例15制备的0.264g冷冻干燥后的两性离子纳米胶囊粉末平均分成2份,磁力搅拌分别分散在15g 10℃PBS溶液(1mmol/L、pH=8.4)、40℃PBS溶液(1mmol/L、pH=8.4)中。每隔24h取样0.5g,离心分离后取上层清液测吸光度,根据标准曲线换算出清液中BSA浓度绘制成曲线,见图3。
实施例24:实施例15制备的两性离子纳米聚合物胶囊的抗蛋白污染性能测试曲线
取实施例15制备的0.132g冷冻干燥后的两性离子纳米胶囊粉末分散在15g牛血清白蛋白溶液(质量分数为10wt%,pH=6.86)中,每隔30min测量一次,连续测量10h,将粒径测试结果绘制成曲线,见图4。
Claims (12)
1.一种两性离子纳米聚合物胶囊的可控制备方法,所述方法包括如下制备步骤:
(1)以吐温80和司盘80为助乳化剂,加正己烷配制助乳化剂质量分数为2~7%的油相;
将药物或生物活性物质、核心 材料、两性离子单体、双亲性大分子RAFT试剂、交联剂、水溶性引发剂按质量比1:5-15:3-7:0.05-0.15:0.03-0.15:0.1-0.2混合成水相;
将水相加入油相中,使水相与油相的质量比为1:4~10,两相混合均匀,经超声粉碎机剪切制得细乳液,然后加入四甲基乙二胺,使药物或生物活性物质与四甲基乙二胺的质量用量之比为1:0.2-0.3;
将所得细乳液在25~50℃条件下进行RAFT活性自由基细乳液聚合反应,反应6~10小时后冷却,制得两性离子纳米聚合物胶囊溶液;
所述两性离子单体为甲基丙烯酸羧基甜菜碱、甲基丙烯酸磺酸基甜菜碱、羟基磺丙基甜菜碱或磷酸酯基甜菜碱;
所述的交联剂为N,N-亚甲基双丙烯酰胺或二甲基丙烯酸乙二醇酯;
所述的水溶性引发剂为过硫酸铵;
所述的核心材料为pH=6.86~8.6PBS溶液、Tris-HCl缓冲液、硼酸缓冲溶液或柠檬酸缓冲溶液;
所述的药物为亲水性药物,所述的生物活性物质为对温度或pH敏感的生物活性物质;
(2)将步骤(1)得到的两性离子纳米聚合物胶囊溶液在离心机中离心得到凝胶状的纳米聚合物,冷冻干燥得到粉末状纳米聚合物,将获得的粉末状纳米聚合物超声分散在pH=6.86~8.6的PBS缓冲溶液中,所得分散液离心分离得到两性离子纳米聚合物胶囊。
2.如权利要求1所述的两性离子纳米聚合物胶囊的可控制备方法,其特征在于:步骤(1)中,所述的药物为盐酸多柔比星或β-羟乙基茶碱。
3.如权利要求1所述的两性离子纳米聚合物胶囊的可控制备方法,其特征在于:步骤(1)中,所述的生物活性物质为牛血清蛋白或蛋白酶。
4.如权利要求1~3之一所述的两性离子纳米聚合物胶囊的可控制备方法,其特征在于:所述双亲性大分子RAFT试剂通过如下方法制备:4,4-偶氮-二(4-氰基戊酸)和十二烷基-3-氰基戊酸三硫酯溶于二氧六环溶剂中,再加入亲水性单体和亲油性单体混合均匀,在70~90℃条件下聚合反应8~9小时,减压蒸除溶剂制得双亲性大分子RAFT试剂,所述亲水性单体为丙烯酸或甲基丙烯酸,所述亲油性单体为苯乙烯或甲基丙烯酸甲酯;所述亲水性单体、亲油性单体、4,4-偶氮-二(4-氰基戊酸)、十二烷基-3-氰基戊酸三硫酯的质量比为1:0.5~2:0.01~0.1:0.1~0.7。
5.如权利要求4所述的两性离子纳米聚合物胶囊的可控制备方法,其特征在于:所述亲水性单体、亲油性单体、4,4-偶氮-二(4-氰基戊酸)、十二烷基-3-氰基戊酸三硫酯的质量比为1:0.7~1:0.03~0.05:0.4~0.6。
6.如权利要求4所述的两性离子纳米聚合物胶囊的可控制备方法,其特征在于:所述亲水性单体、亲油性单体、4,4-偶氮-二(4-氰基戊酸)、十二烷基-3-氰基戊酸三硫酯的质量比为1:0.75:0.375:0.5。
7.如权利要求1~3之一所述的两性离子纳米聚合物胶囊的可控制备方法,其特征在于:步骤(1)中,所述两性离子单体为甲基丙烯酸磺酸基甜菜碱。
8.如权利要求1~3之一所述的两性离子纳米聚合物胶囊的可控制备方法,其特征在于:步骤(1)中,所述的交联剂为N,N-亚甲基双丙烯酰胺。
9.如权利要求1~3之一所述的两性离子纳米聚合物胶囊的可控制备方法,其特征在于:步骤(1)中,所述的核心材料为pH=8.4的PBS溶液。
10.如权利要求4所述的两性离子纳米聚合物胶囊的可控制备方法,其特征在于:步骤(1)中,所述两性离子单体为甲基丙烯酸磺酸基甜菜碱,所述的交联剂为N,N-亚甲基双丙烯酰胺,所述的核心材料为pH=8.4的PBS溶液。
11.如权利要求1~3之一所述的两性离子纳米聚合物胶囊的可控制备方法,其特征在于:步骤(1)中,使油相中助乳化剂质量分数为3~7%,使水相与油相的质量比为1:4~6。
12.如权利要求1~3之一所述的两性离子纳米聚合物胶囊的可控制备方法,其特征在于:步骤(1)中,所述药物或生物活性物质、核心 材料、两性离子单体、双亲性大分子RAFT试剂、交联剂、水溶性引发剂的质量比为1:10:4.9-5.0:0.1:0.04-0.10:0.1-0.15。
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