CN106214662A - 一种聚合电解质载药微粒的制备方法 - Google Patents
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Abstract
本发明公开了一种聚合电解质载药微粒的制备方法，其特征在于：以海藻酸钠溶液为分散相、以Span 85和Tween 85为混合乳化剂、以液体石蜡为连续相，经均质乳化、交联固化、载药、静电包衣，即获得聚合电解质载药微粒。本发明的制备工艺简单、成本低，对设备要求低、适于大批量制备；且本发明所得载药微粒大小均匀、表面圆滑，适于干燥、真空包装保存，其载药量和包封率高，性能稳定。
Description
技术领域
本发明涉及一种聚合电解质载药微粒的制备方法，属于载体制备技术领域。
背景技术
药物传递系统(Drug Delivery Systems,DDS)亦称给药系统，是现代药剂学研究的热门领域。DDS的研发综合利用了物理学、化学、生物学、生物医学、高分子科学、材料科学等多学科的理论和技术。载体制备技术与材料开发利用是DDS的研究核心。传统技术如前体药物技术、骨架技术、包衣技术、胶囊技术等制备的药物载体，因突释、溶剂残留、药物渗漏等问题亟待革新。随着现代药剂学的快速发展，物理、化学及工程技术等手段被用于载体的构建，微粒技术应运而生。在微纳米超细技术的推动下，微粒载体由宏观的颗粒逐渐向微观的微纳颗粒发展，推动了缓控释药物微载体的变革。微粒(0.1～100μm)是缓控释制剂的常用载体，具有不受胃肠道食物输送节律影响和释药规律重现性好等优点。传统的微粒制备技术有物理化学法，如复合凝聚法、复相乳液法等；物理机械法，如喷雾干燥法、超临界流体法等。近年来，一些新型的微粒制备方法不断涌现，如层层自组装法、微流控乳化法、膜乳化法等。
材料开发与高效利用是DDS研究的另一关键问题。无毒、良好的生物可降解性及生物相容性是载体材料选择的基本要求。近年来，生物质材料如纤维素、壳聚糖、海藻酸等受到了科学家的高度关注。张俐娜院士等(2015)研究发现甲壳素具有很高的生物活性，以其制备的水凝胶、微球等性能稳定，可以作为一种潜在的生物医学材料。目前，利用壳聚糖、海藻酸等材料制备的聚合电解质复合物(Polyelectrolyte Complexes,PEC)受到研究者的较多关注。由PEC形成的新型复合膜材料常被用于DDS载体研究，其具有靶向性、缓控释等给药特性，在多肽和蛋白类药物载体设计领域有着潜在的应用。PEC复合膜制备技术简单、设备低廉，作为一种潜在的载体制备材料受到研究者的普遍关注。然而，目前有关PEC微粒载体鲜有报道。
发明内容
本发明旨在提供一种高效、低廉、简便的聚合电解质载药微粒的制备方法，所要解决的技术问题是通过均质乳化、交联固化、载药、静电包衣等手段得到粒径均一且载药量、包封率高的微粒小球。
本发明解决技术问题采用如下技术方案：
本发明聚合电解质载药微粒的制备方法，其特点在于：以海藻酸钠溶液为分散相、以Span85和Tween 85为混合乳化剂、以液体石蜡为连续相，经均质乳化、交联固化、载药、静电包衣，即获得聚合电解质载药微粒。具体包括如下步骤：
(1)分散相的制备
将海藻酸钠溶入蒸馏水中，搅拌均匀并排除气泡，获得10mL浓度为0.02～0.03g/mL海藻酸钠溶液，作为分散相；
(2)连续相的制备
按体积比1:0.4～3将Span 85和Tween 85混匀，取3～4mL加入100mL的液体石蜡中，搅拌均匀，作为连续相；
(3)均质乳化
将步骤(1)配制的分散相倒入步骤(2)配制的连续相中，以3000rpm的搅拌速率均质乳化5～15min，得均质乳化液；
(4)交联固化
向均质乳化液中加入20mL 0.06g/mL CaCl2与0.025g/mL NaCl的混合溶液，以3000rpm的搅拌速率固化反应20～30min，得固化反应液；
(5)洗涤
向固化反应液中加入50mL石油醚，低速搅拌1h，然后倒入分液漏斗中静置20～30min；分离微粒并用蒸馏水洗涤、低速离心回收；
(6)载药
用蒸馏水配制20mL、1mg/mL的小分子晶体类药物溶液，倒入装有步骤(5)所得微粒的烧杯中，低速搅拌30min，获得含药物的平衡溶液；
(7)静电包衣
向所述含药物的平衡溶液中加入氯化壳聚糖溶液，使氯化壳聚糖的终浓度为0.005～0.015g/mL，保持低速搅拌，包衣30～90min；
(8)保存
包衣反应结束后，低速离心回收载药微粒，蒸馏水快速洗涤，-20℃冷冻后，置于冷冻干燥机中干燥，收集获得干燥的载药微粒。
优选的，所述小分子晶体类药物为5-氟尿嘧啶(5-FU)。
本发明所得载药微粒的载药量和包封率的测定方法：用蒸馏水配制0.1mol/L的HCl溶液200mL备用；称取0.005g载药微粒，倒入研磨器中，加入1mL HCl溶液(0.1mol/L)研磨充分，并加HCl溶液(0.1mol/L)定容至5mL，用0.22μm水系滤膜过滤待测。以高效液相色谱(HPLC)法绘制相应药物(如5-FU)含量的标准检测曲线，测量并计算载药量和包封率。
经测定，本发明所得载药微粒的最终载药量达到70％、包封率达到75％以上。且经扫描电镜观察显示，微粒大小均匀、表面圆滑。
本发明的有益效果体现在：
(1)本发明提供的聚合电解质载药微粒的制备工艺简单、成本低，所选材料绿色环保，整个操作过程在常温、常压下进行，对设备要求低、环境负荷小，可以进一步工艺放大，适于大批量制备。
(2)本发明制备得到的载药微粒大小均匀、表面圆滑，适于干燥、真空包装保存，其载药量和包封率高，性能稳定，可以作为一种缓控释药物传递系统设计的潜在载体。
(3)本发明的载药微粒不仅可应用于保健食品领域，也可应用于医药领域。
附图说明
图1为实施例1所得载药微粒的扫描电镜(SEM)图。
具体实施方式
下面的实施例可以使本领域技术人员更全面的理解本发明，但不以任何方式限制本发明。
实施例1
本实施例按如下步骤制备聚合电解质载药微粒：
(1)分散相的制备
将海藻酸钠溶入蒸馏水中，搅拌均匀并排除气泡，获得10mL浓度为0.02g/mL海藻酸钠(NaAlg)溶液，作为分散相；
(2)连续相的制备
按体积比7:3将Span 85和Tween 85混匀，取3mL加入100mL的液体石蜡中，搅拌均匀，作为连续相；
(3)均质乳化
将步骤(1)配制的分散相倒入步骤(2)配制的连续相中，以3000rpm的搅拌速率均质乳化5min，得均质乳化液；
(4)交联固化
向均质乳化液中加入20mL 0.06g/mL CaCl2与0.025g/mL NaCl的混合溶液，以3000rpm的搅拌速率固化反应20min，得固化反应液；
(5)洗涤
向固化反应液中加入50mL石油醚，低速搅拌1h，然后倒入分液漏斗中静置20min；分离微粒并用蒸馏水快速洗涤、低速离心回收；
(6)载药
用蒸馏水配制20mL、1mg/mL 5-氟尿嘧啶(5-FU)溶液，倒入装有步骤(5)所得微粒的烧杯中，低速搅拌30min，获得含5-FU的平衡溶液；
(7)静电包衣
向含药物的平衡溶液中加入氯化壳聚糖溶液，使氯化壳聚糖的终浓度为0.005g/mL，保持低速搅拌，包衣30min；
(8)保存
包衣反应结束后，低速离心回收载药微粒，蒸馏水快速洗涤，-20℃冷冻后，置于冷冻干燥机中干燥，收集获得干燥的载药微粒。
经测定，本实施例所得载药微粒的最终载药量达到71.62％，包封率为76.75％。
如图1所示，经扫描电镜表征，本实施例所得载药微粒大小均匀，表面圆滑。
实施例2
本实施例按如下步骤制备聚合电解质载药微粒：
(1)分散相的制备
将海藻酸钠溶入蒸馏水中，搅拌均匀并排除气泡，获得10mL浓度为0.02g/mL海藻酸钠(NaAlg)溶液，作为分散相；
(2)连续相的制备
按体积比5:5将Span 85和Tween 85混匀，取3mL加入100mL的液体石蜡中，搅拌均匀，作为连续相；
(3)均质乳化
将步骤(1)配制的分散相倒入步骤(2)配制的连续相中，以3000rpm的搅拌速率均质乳化10min，得均质乳化液；
(4)交联固化
向均质乳化液中加入20mL 0.06g/mL CaCl2与0.025g/mL NaCl的混合溶液，以3000rpm的搅拌速率固化反应30min，得固化反应液；
(5)洗涤
向固化反应液中加入50mL石油醚，低速搅拌1h，然后倒入分液漏斗中静置20min；分离微粒并用蒸馏水快速洗涤、低速离心回收；
(6)载药
用蒸馏水配制20mL、1mg/mL 5-氟尿嘧啶(5-FU)溶液，倒入装有步骤(5)所得微粒的烧杯中，低速搅拌30min，获得含5-FU的平衡溶液；
(7)静电包衣
向含药物的平衡溶液中加入氯化壳聚糖溶液，使氯化壳聚糖的终浓度为0.005g/mL，保持低速搅拌，包衣30min；
(8)保存
包衣反应结束后，低速离心回收载药微粒，蒸馏水快速洗涤，-20℃冷冻后，置于冷冻干燥机中干燥，收集获得干燥的载药微粒。
经测定，本实施例所得载药微粒的最终载药量达到72.33％，包封率为77.43％。
经扫描电镜表征，本实施例所得载药微粒大小均匀，表面圆滑。
实施例3
本实施例按如下步骤制备聚合电解质载药微粒：
(1)分散相的制备
将海藻酸钠溶入蒸馏水中，搅拌均匀并排除气泡，获得10mL浓度为0.03g/mL海藻酸钠(NaAlg)溶液，作为分散相；
(2)连续相的制备
按体积比1:3将Span 85和Tween 85混匀，取4mL加入100mL的液体石蜡中，搅拌均匀，作为连续相；
(3)均质乳化
将步骤(1)配制的分散相倒入步骤(2)配制的连续相中，以3000rpm的搅拌速率均质乳化15min，得均质乳化液；
(4)交联固化
向均质乳化液中加入20mL 0.06g/mL CaCl2与0.025g/mL NaCl的混合溶液，以3000rpm的搅拌速率固化反应30min，得固化反应液；
(5)洗涤
向固化反应液中加入50mL石油醚，低速搅拌1h，然后倒入分液漏斗中静置30min；分离微粒并用蒸馏水快速洗涤、低速离心回收；
(6)载药
用蒸馏水配制20mL、1mg/mL 5-氟尿嘧啶(5-FU)溶液，倒入装有步骤(5)所得微粒的烧杯中，低速搅拌30min，获得含5-FU的平衡溶液；
(7)静电包衣
向含药物的平衡溶液中加入氯化壳聚糖溶液，使氯化壳聚糖的终浓度为0.005g/mL，保持低速搅拌，包衣60min；
(8)保存
包衣反应结束后，低速离心回收载药微粒，蒸馏水快速洗涤，-20℃冷冻后，置于冷冻干燥机中干燥，收集获得干燥的载药微粒。
经测定，本实施例所得载药微粒的最终载药量达到74.51％，包封率为78.57％。
经扫描电镜表征，本实施例所得载药微粒大小均匀，表面圆滑。
Claims (3)
1.一种聚合电解质载药微粒的制备方法，其特征在于：以海藻酸钠溶液为分散相、以Span 85和Tween 85为混合乳化剂、以液体石蜡为连续相，经均质乳化、交联固化、载药、静电包衣，即获得聚合电解质载药微粒。
2.根据权利要求1所述的聚合电解质载药微粒的制备方法，其特征在于包括如下步骤：
(1)分散相的制备
将海藻酸钠溶入蒸馏水中，搅拌均匀并排除气泡，获得10mL浓度为0.02～0.03g/mL海藻酸钠溶液，作为分散相；
(2)连续相的制备
按体积比1:0.4～3将Span 85和Tween 85混匀，取3～4mL加入100mL的液体石蜡中，搅拌均匀，作为连续相；
(3)均质乳化
将步骤(1)配制的分散相倒入步骤(2)配制的连续相中，以3000rpm的搅拌速率均质乳化5～15min，得均质乳化液；
(4)交联固化
向均质乳化液中加入20mL 0.06g/mL CaCl2与0.025g/mL NaCl的混合溶液，以3000rpm的搅拌速率固化反应20～30min，得固化反应液；
(5)洗涤
向固化反应液中加入50mL石油醚，低速搅拌1h，然后倒入分液漏斗中静置20～30min；分离微粒并用蒸馏水洗涤、低速离心回收；
(6)载药
用蒸馏水配制20mL、1mg/mL的小分子晶体类药物溶液，倒入装有步骤(5)所得微粒的烧杯中，低速搅拌30min，获得含药物的平衡溶液；
(7)静电包衣
向所述含药物的平衡溶液中加入氯化壳聚糖溶液，使氯化壳聚糖的终浓度为0.005～0.015g/mL，保持低速搅拌，包衣30～90min；
(8)保存
包衣反应结束后，低速离心回收载药微粒，蒸馏水快速洗涤，-20℃冷冻后，置于冷冻干燥机中干燥，收集获得干燥的载药微粒。
3.根据权利要求2所述的聚合电解质载药微粒的制备方法，其特征在于：所述小分子晶体类药物为5-氟尿嘧啶。
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