CN107823177B - 一种传递5-氟尿嘧啶微球的制备方法 - Google Patents
一种传递5-氟尿嘧啶微球的制备方法 Download PDFInfo
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Abstract
本发明公开了一种传递5‑氟尿嘧啶微球的制备方法,包括:丁二酸酐改性、海藻酸钠微球的制备、海藻酸钠‑壳聚糖微球的制备、海藻酸钠‑壳聚糖‑卡拉胶微球的制备。有益效果为:在海藻酸钠微球表面包裹两层多糖层,形成LBL结构,制备得到的核壳式多层微球表面空隙减少,并且传递的活性成分能够经过酸性胃液,到达结肠,达到一定的靶向治疗效果;海藻酸钠‑壳聚糖‑卡拉胶微球体系在pH为7.4左右的结肠弱碱性环境中表现出极高的敏感性,其在30分钟的溶胀比可以达到20以上,在结肠位置具有很好的靶向溶胀选择性,这种选择性使得海藻酸钠‑壳聚糖‑卡拉胶微球有望作为特殊制剂结肠靶向给药的载体,具有较高的市场前景。
Description
技术领域
本发明涉及传递介质的微球的制备领域,尤其是涉及一种传递5-氟尿嘧啶微球的制备方法。
技术背景
口服制剂是目前最常见,最有效的治疗途径,但对某些制剂来说,口服制剂具有许多缺点,如这些制剂的活性成分会在酸性胃液或体内酶液介质中分解,从而失去治疗效果。近年来,控释载物体系的研究,在医学领域具有显著增长,这些系统旨在改善疗法,减少副作用,增加制剂的预期治疗效果。许多文献已发表了运用相应的材料和方法,制备控释载物运载系统,但不幸的是,大多方法采用有害原材料,制备方法复杂,不具有实际应用价值。应用于传送系统的材料,研究最多的目前是一类pH敏感的聚电解质水凝胶,因为他们大部分属于天然多糖,具有无毒性,生物降解性,生物相容性,吸水溶胀性比较好,这些水凝胶被作为受控释材料,进入胃肠道后,在不同pH下,释放效率不同,达到我们所需的缓释靶向治疗作用。
海藻酸钠是从褐藻类的海带或马尾藻中提取碘和甘露醇之后的副产物,其分子由β-D-甘露糖醛酸和α-L-古洛糖醛酸按1→4键连接而成,是一种天然多糖,具有制剂辅料所需的稳定性、溶解性、粘性和安全性,海藻酸钠已经在食品工业得到了广泛应用;壳聚糖又称脱乙酰甲壳素,是由自然界广泛存在的几丁质经过脱乙酰作用得到的,化学名称为聚葡萄糖胺(1-4)-2-氨基-B-D葡萄糖,这种天然高分子的生物官能性和相容性、血液相容性、安全性、微生物降解性等优良性能被各行各业广泛关注,在食品、化工、化妆品、水处理、金属提取及回收、生化和生物医学工程等诸多领域的应用研究取得了重大进展;卡拉胶,又称为麒麟菜胶、石花菜胶、鹿角菜胶、角叉菜胶,因为卡拉胶是从麒麟菜、石花菜、鹿角菜等红藻类海草中提炼出来的亲水性胶体,它的化学结构是由半乳糖及脱水半乳糖所组成的多糖类硫酸酯的钙、钾、钠、铵盐,广泛用于制造果冻,冰淇淋,糕点,软糖,罐头,肉制品,八宝粥,银耳燕窝,羹类食品,凉拌食品等等。
关于海藻酸钠载有活性成分的微球技术有很多方法,现有技术如授权公众号为CN102885710 B的中国发明专利,公开了一种载有活性成分的海藻酸钠/壳聚糖/胶原复合微球及其制备方法,该发明方法以胶原、海藻酸钠、壳聚糖为载体材料制备负载多种化妆品活性成分的微球,具有微球表面光滑圆整,单分散性好,粒径分布均一等优点,但是该发明方法中的将海藻酸钠/壳聚糖/胶原复合微球溶胀的溶酶为丁二醇和透明质酸的水溶液,对溶酶的pH值有严苛的要求,限制了应用范围,其制备过程中涉及了多种二价阳离子如Co2+,Zn2 +,Mn2+,Ni2+,会对化妆品活性成分造成影响,而且其制备过程较为繁琐,工艺不易控,难易规模化应用。
发明内容
本方法的目的在于提供一种传递5-氟尿嘧啶微球的制备方法,制备方法简单易控,传递活性成分的微球对环境pH值敏感,其在特定碱性环境下溶胀响应速度较快,能够迅速释放活性成分。
本发明针对背景技术中提到的问题,采取的技术方案为:一种传递5-氟尿嘧啶微球的制备方法,包括:丁二酸酐改性、海藻酸钠微球的制备、海藻酸钠-壳聚糖微球的制备、海藻酸钠-壳聚糖-卡拉胶微球的制备,具体包括以下步骤:
丁二酸酐改性:称取壳聚糖2.0-2.2份置于容器中,加入150-160份蒸馏水,在室温下搅拌30-45分钟使其充分溶胀;称取0.5-0.55份丁二酸酐和0.4-0.5份碳酸钠,混合均匀为四份,每隔25-30分钟往三口容器中加入一份,随后反应2.5-3小时;将反应液以1.0-1.2mol/L的氢氧化钠溶液调节pH至9.5-10,离心除去未反应的壳聚糖,上清液用蒸馏水透析24-36小时,最后真空冷冻干燥得到白色产物丁二酰化壳聚糖;通过丁二酸酐锈蚀壳聚糖使其含有羧基基团,不仅可以提高壳聚糖在中性和碱性水溶液中的溶解性,而且会使壳聚糖带有负电荷,表面带有负电荷的凝胶微球可以有效的避免其在血液中的聚集,使其具有更长的血液循环,进而增强活性载物在患病组织的积累;
海藻酸钠微球的制备:在持续高速搅拌下,将10-12份海藻酸钠缓慢加入到60-65份span80溶液中,加入0.08-0.11份成孔剂,10-20分钟后滴加2-2.5份吐温-80溶液,继续乳化5-8分钟后,滴加1.0-1.2份交联剂,交联凝胶化形成海藻酸钠微球,搅拌固化10-15分钟后,加入8-10份无水乙醇分离微球;静置一段时间后离心分离微球,用无水乙醇、蒸馏水依次洗涤得海藻酸钠微球;该制备工艺条件下,微球的分散性和球形度较好,表面光滑,圆整均匀,微球粒径范围较窄,多为30-80μm;添加了适量的成孔剂,可以在微球内部及表面形成孔洞结构,有利于溶剂分子更快的进入微球中,提高了溶胀响应效率;
海藻酸钠-壳聚糖微球的制备:将0.045-0.050份5-氟尿嘧啶溶于30-40份壳聚糖醋酸水溶液中,在搅拌条件下加入0.5-0.6份海藻酸钠核心微球,400-500r/min高速搅拌10-15分钟,5000-6000r/min转速下离心3-5分钟,用无水乙醇、蒸馏水依次洗涤得海藻酸钠-壳聚糖微球;以5-氟尿嘧啶作为模型活性成分被封装到海藻酸盐微球中,形成一个海藻酸钠-Ca2+复合体,为进一步的包覆做准备;微球外壁是由海藻酸钠与壳聚糖反应得到的具有高强度的网状结构,且各层之间由于正负电荷吸引的作用,具有较大的分子链堆积密度,核心的活性成分向外释放速率较慢,释放时间较长;
海藻酸钠-壳聚糖-卡拉胶微球的制备:取0.5-0.6份卡拉胶以3-5份乙醇浸润,加入30-40份蒸馏水充分搅拌溶解,得轻微粘性、轻微乳白色的卡拉胶溶液,在搅拌条件下,将海藻酸钠-壳聚糖微球加入卡拉胶溶液中,400-500r/min高速搅拌10-15分钟,5000-6000r/min转速下离心5-8分钟,然后用无水乙醇、蒸馏水依次洗涤得海藻酸钠-壳聚糖-卡拉胶三重包覆载物微球;为了克服海藻酸盐微球多孔性和释放活性成分时出现爆破释放等缺点,采用正负离子相互作用,羧基与氨基,磺酸基与氨基形成聚合电解质的机理,在海藻酸钠微球表面包裹两层多糖层,形成LBL结构,制备得到的核壳式多层微球表面空隙减少,有效增加了活性成分释放速度,并且活性成分能够经过酸性胃液,到达结肠,达到一定的靶向治疗效果。
作为优选,所用的span80溶液为2.0-2.2%span80异辛烷溶液。
作为优选,所用的成孔剂为3-甲氧基苯乙酮。
作为优选,所用的吐温-80溶液为浓度为4.0-4.5%的吐温-80水溶液。
作为优选,所用的交联剂为0.5-0.6g/mL的CaCl2水溶液。
作为优选,所用的壳聚糖醋酸水溶液中醋酸的含量为20-21g/L,壳聚糖的含量为15-16g/L。
与现有技术相比,本发明的优点在于:1)采用正负离子相互作用,羧基与氨基,磺酸基与氨基形成聚合电解质的机理,在海藻酸钠微球表面包裹两层多糖层,形成LBL结构,制备得到的核壳式多层微球表面空隙减少,并且传递的活性成分能够经过酸性胃液,到达结肠,达到一定的靶向治疗效果;2)以3-甲氧基苯乙酮作为成孔剂,使海藻酸钠-壳聚糖-卡拉胶微球具有较高的pH敏感性,微球体系在细胞外液环境(pH值6.8左右)与胃液环境(pH值1.4左右)中溶胀比较小,30分钟的溶胀比也仅为1.5左右,微球体系在胃液环境中具有较好的稳定性,可以有效的保证微球中的活性成分不会溶出;3)海藻酸钠-壳聚糖-卡拉胶微球体系在pH为7.4左右的结肠液弱碱性环境中表现出极高的敏感性,其在30分钟的溶胀比可以达到20以上,在结肠位置具有很好的靶向溶胀选择性,这种选择性使得海藻酸钠-壳聚糖-卡拉胶微球有望作为特殊制剂结肠靶向给药的载体,具有较高的市场前景。
具体实施方式
下面通过实施例对本发明方案作进一步说明:
实施例1:
一种传递5-氟尿嘧啶微球的制备方法,包括以下步骤:
1)海藻酸钠微球的制备:在持续高速搅拌下,将10份海藻酸钠缓慢加入到60份2.0%的span80异辛烷溶液中,加入0.08份3-甲氧基苯乙酮,10分钟后滴加2份4.0%的吐温-80水溶液,继续乳化5分钟后,滴加1.0份0.5g/mL的CaCl2水溶液,交联凝胶化形成海藻酸钠微球,搅拌固化10分钟后,加入8份无水乙醇分离微球;静置一段时间后离心分离微球,用无水乙醇、蒸馏水依次洗涤得海藻酸钠微球;该制备工艺条件下,微球的分散性和球形度较好,表面光滑,圆整均匀,微球粒径范围较窄,多为30-80μm;
2)将0.045份5-氟尿嘧啶溶于30份壳聚糖醋酸水溶液中,在搅拌条件下加入0.5份海藻酸钠核心微球,400r/min高速搅拌10分钟,5000r/min转速下离心3分钟,用无水乙醇、蒸馏水依次洗涤得海藻酸钠-壳聚糖微球;以5-氟尿嘧啶作为模型活性成分被封装到海藻酸盐微球中,形成一个海藻酸钠-Ca2+复合体,为进一步的包覆做准备;
3)取0.5份卡拉胶以3份乙醇浸润,加入30份蒸馏水充分搅拌溶解,得轻微粘性、轻微乳白色的卡拉胶溶液,在搅拌条件下,将海藻酸钠-壳聚糖微球加入卡拉胶溶液中,400r/min高速搅拌10分钟,5000r/min转速下离心5分钟,然后用无水乙醇、蒸馏水依次洗涤得海藻酸钠-壳聚糖-卡拉胶三重包覆载物微球。
实施例2:
一种传递5-氟尿嘧啶微球的制备方法,包括以下步骤:
1)丁二酸酐改性:称取壳聚糖2.2份置于容器中,加入160份蒸馏水,在室温下搅拌30-45分钟使其充分溶胀;称取0.55份丁二酸酐和0.5份碳酸钠,混合均匀为四份,每隔30分钟往三口容器中加入一份,随后反应3小时;将反应液以1.2mol/L的氢氧化钠溶液调节pH至10,离心除去未反应的壳聚糖,上清液用蒸馏水透析36小时,最后真空冷冻干燥得到白色产物丁二酰化壳聚糖;
2)海藻酸钠微球的制备:在持续高速搅拌下,将12份海藻酸钠缓慢加入到65份2.2%的span80异辛烷溶液中,20分钟后滴加2.5份4.5%的吐温-80水溶液,继续乳化8分钟后,滴加1.2份0.6g/mL的CaCl2水溶液,交联凝胶化形成海藻酸钠微球,搅拌固化15分钟后,加入10份无水乙醇分离微球;静置一段时间后离心分离微球,用无水乙醇、蒸馏水依次洗涤得海藻酸钠微球;该制备工艺条件下,微球的分散性和球形度较好,表面光滑,圆整均匀,微球粒径范围较窄,多为30-80μm;
3)海藻酸钠-壳聚糖微球的制备:将0.050份5-氟尿嘧啶溶于40份壳聚糖醋酸水溶液中,在搅拌条件下加入0.55份海藻酸钠核心微球,500r/min高速搅拌15分钟,6000r/min转速下离心5分钟,用无水乙醇、蒸馏水依次洗涤得海藻酸钠-壳聚糖微球;以5-氟尿嘧啶作为模型活性成分被封装到海藻酸盐微球中,形成一个海藻酸钠-Ca2+复合体,为进一步的包覆做准备;
4)海藻酸钠-壳聚糖-卡拉胶微球的制备:取0.6份卡拉胶以5份乙醇浸润,加入40份蒸馏水充分搅拌溶解,得轻微粘性、轻微乳白色的卡拉胶溶液,在搅拌条件下,将海藻酸钠-壳聚糖微球加入卡拉胶溶液中,500r/min高速搅拌15分钟,6000r/min转速下离心8分钟,然后用无水乙醇、蒸馏水依次洗涤得海藻酸钠-壳聚糖-卡拉胶三重包覆载物微球;为了克服海藻酸盐微球多孔性和释放活性成分时出现爆破释放等缺点,采用正负离子相互作用,羧基与氨基,磺酸基与氨基形成聚合电解质的机理,在海藻酸钠微球表面包裹两层多糖层,形成LBL结构,制备得到的核壳式多层微球表面空隙减少,有效增加了活性成分释放速度,并且活性成分能够经过酸性胃液,到达结肠,达到一定的靶向治疗效果。
实施例3:
一种传递5-氟尿嘧啶微球的制备方法,包括:丁二酸酐改性、海藻酸钠微球的制备、海藻酸钠-壳聚糖微球的制备、海藻酸钠-壳聚糖-卡拉胶微球的制备,具体包括以下步骤:
丁二酸酐改性:称取壳聚糖2.0份置于容器中,加入160份蒸馏水,在室温下搅拌30分钟使其充分溶胀;称取0.5份丁二酸酐和0.5份碳酸钠,混合均匀为四份,每隔30分钟往三口容器中加入一份,随后反应2.5小时;将反应液以1.2mol/L的氢氧化钠溶液调节pH至9.8,离心除去未反应的壳聚糖,上清液用蒸馏水透析36小时,最后真空冷冻干燥得到白色产物丁二酰化壳聚糖;通过丁二酸酐锈蚀壳聚糖使其含有羧基基团,不仅可以提高壳聚糖在中性和碱性水溶液中的溶解性,而且会使壳聚糖带有负电荷,表面带有负电荷的凝胶微球可以有效的避免其在血液中的聚集,使其具有更长的血液循环,进而增强活性载物在患病组织的积累;
海藻酸钠微球的制备:在持续高速搅拌下,将12份海藻酸钠缓慢加入到60份2.0%的span80异辛烷溶液中,加入0.08份3-甲氧基苯乙酮、0.02份D-(+)-麻黄碱、0.06份D-(-)-麻黄碱,15分钟后滴加2.4份4.2%的吐温-80水溶液,继续乳化6分钟后,滴加1.0份0.6g/mL的CaCl2水溶液,交联凝胶化形成海藻酸钠微球,搅拌固化15分钟后,加入10份无水乙醇分离微球;静置一段时间后离心分离微球,用无水乙醇、蒸馏水依次洗涤得海藻酸钠微球;该制备工艺条件下,微球的分散性和球形度较好,表面光滑,圆整均匀,微球粒径范围较窄,多为30-80μm;添加了适量的成孔剂,可以在微球内部及表面形成孔洞结构,有利于溶剂分子更快的进入微球中,提高了溶胀响应效率;
海藻酸钠-壳聚糖微球的制备:将0.050份5-氟尿嘧啶溶于40份壳聚糖醋酸水溶液中,在搅拌条件下加入0.6份海藻酸钠核心微球,400r/min高速搅拌15分钟,5000r/min转速下离心5分钟,用无水乙醇、蒸馏水依次洗涤得海藻酸钠-壳聚糖微球;以5-氟尿嘧啶作为模型活性成分被封装到海藻酸盐微球中,形成一个海藻酸钠-Ca2+复合体,为进一步的包覆做准备;微球外壁是由海藻酸钠与壳聚糖反应得到的具有高强度的网状结构,且各层之间由于正负电荷吸引的作用,具有较大的分子链堆积密度,核心的活性成分向外释放速率较慢,释放时间较长;
海藻酸钠-壳聚糖-卡拉胶微球的制备:取0.6份卡拉胶以5份乙醇浸润,加入35份蒸馏水充分搅拌溶解,得轻微粘性、轻微乳白色的卡拉胶溶液,在搅拌条件下,将海藻酸钠-壳聚糖微球加入卡拉胶溶液中,400r/min高速搅拌10分钟,6000r/min转速下离心6分钟,然后用无水乙醇、蒸馏水依次洗涤得海藻酸钠-壳聚糖-卡拉胶三重包覆载物微球;为了克服海藻酸盐微球多孔性和释放活性成分时出现爆破释放等缺点,采用正负离子相互作用,羧基与氨基,磺酸基与氨基形成聚合电解质的机理,在海藻酸钠微球表面包裹两层多糖层,形成LBL结构,制备得到的核壳式多层微球表面空隙减少,有效增加了活性成分释放速度,并且活性成分能够经过酸性胃液,到达结肠,达到一定的靶向治疗效果。
将实施例1-3中的干态海藻酸钠-壳聚糖-卡拉胶微球分别置于pH=1.4(胃液环境)、pH=6.8(细胞外液环境)与pH=7.4(肠液环境),测量其30分钟时的溶胀比SR如表1所示:
表1.浸泡30分钟时的干态海藻酸钠-壳聚糖-卡拉胶微球的溶胀比
浸泡环境 | 实施例1 | 实施例2 | 实施例3 |
pH=1.4的SR | 2.5 | 1.5 | 1.3 |
pH=6.8的SR | 4.6 | 1.8 | 1.5 |
pH=7.4的SR | 17.5 | 20.1 | 23.4 |
由表1可以看出,海藻酸钠-壳聚糖-卡拉胶微球在pH=1.2(模拟胃液环境)与pH=6.7(去离子水环境)环境下的溶胀比均较低,微球体系在胃液环境中具有较好的稳定性,可以有效的保证微球中的活性成分不会溶出;同时当海藻酸钠-壳聚糖-卡拉胶微球处于pH=7.4的结肠液环境下,则具有较高的溶胀比,微球体系溶胀后,内部包覆的活性成分被释放出来发挥功效,具有较高的靶向释放特性,同时海藻酸钠、壳聚糖、卡拉胶也可以被人体吸收降解,完全无毒副物质残留;特别地,在实施例1中,没有对壳聚糖进行改性操作,导致体系LBL结构的牢固强度降低,使其在低pH值环境下也发生了一定程度的溶胀,导致其包覆活性成分的外泄;在实施例2中,海藻酸钠微球的制备步骤中没有添加成孔剂,导致微球体系在30分钟时的溶胀比相对较低,会影响微球核包覆活性成分的释放,降低其释放速度。因此在实施例3中,对壳聚糖进行丁二酸酐改性有利于增强壳聚糖的极性,进而增强羧基与氨基、磺酸基与氨基的相互作用,增强微球体系的强度,增强海藻酸钠-壳聚糖-卡拉胶微球体系的靶向特性;在制备海藻酸钠微球的步骤中加入了3-甲氧基苯乙酮作为成孔剂,同时加入了D-(+)-麻黄碱、D-(-)-麻黄碱的混合物,麻黄碱与3-甲氧基苯乙酮产生协同作用,可以使海藻酸钠-壳聚糖-卡拉胶微球体系在特定的靶向环境(pH=7.35-7.5)下具有较高的溶胀比与较快的溶胀速度,进一步提高活性成分靶向释放的精准度与时效性,具有较好的应用前景。
本发明的操作步骤中的常规操作为本领域技术人员所熟知,在此不进行赘述。
以上所述的实施例对本发明的技术方案进行了详细说明,应理解的是以上所述仅为本发明的具体实施例,并不用于限制本发明,凡在本发明的原则范围内所做的任何修改、补充或类似方式替代等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种传递5-氟尿嘧啶微球的制备方法,其特征在于:包括以下步骤:
1)丁二酸酐改性:以间歇加料法用丁二酸酐对壳聚糖进行优化改性,制得丁二酰化壳聚糖;
2)海藻酸钠微球的制备:在海藻酸钠的span80溶液中加入成孔剂、吐温-80溶液、交联剂,交联凝胶化形成海藻酸钠微球;
3)海藻酸钠-壳聚糖微球的制备:在丁二酰化壳聚糖醋酸水溶液中加入5-氟尿嘧啶、步骤2)制得的海藻酸钠微球,制备海藻酸钠-壳聚糖微球;
4)海藻酸钠-壳聚糖-卡拉胶微球的制备:将步骤3 )的藻酸钠-壳聚糖微球与卡拉胶的溶液复配形成海藻酸钠-壳聚糖-卡拉胶三重包覆载物微球;海藻酸钠-壳聚糖-卡拉胶微球中的5-氟尿嘧啶、海藻酸钠、壳聚糖与卡拉胶的质量比为4.5-5.0:50-60:45-64:50-60。
2.根据权利要求1所述的一种传递5-氟尿嘧啶微球的制备方法,其特征在于:所述的丁二酸酐改性步骤为:称取壳聚糖2.0-2.2份置于容器中,加入150-160份蒸馏水,在室温下搅拌30-45分钟使其充分溶胀;称取0.5-0.55份丁二酸酐和0.4-0.5份碳酸钠,混合均匀为四份,每隔25-30分钟往三口容器中加入一份,随后反应2.5-3小时;将反应液以1.0-1.2mol/L的氢氧化钠溶液调节pH至9.5-10,离心除去未反应的壳聚糖,上清液用蒸馏水透析24-36小时,最后真空冷冻干燥得到白色产物丁二酰化壳聚糖。
3.根据权利要求1所述的一种传递5-氟尿嘧啶微球的制备方法,其特征在于:所述的海藻酸钠微球的制备步骤为:在持续高速搅拌下,将10-12份海藻酸钠缓慢加入到60-65份span80溶液中,加入0.08-0.11份成孔剂,10-20分钟后滴加2.0-2.5份吐温-80溶液,继续乳化5-8分钟后,滴加1.0-1.2份交联剂,交联凝胶化形成海藻酸钠微球,搅拌固化10-15分钟后,加入8-10份无水乙醇分离微球;静置一段时间后离心分离微球,用无水乙醇、蒸馏水依次洗涤得海藻酸钠微球。
4.根据权利要求3所述的一种传递5-氟尿嘧啶微球的制备方法,其特征在于:所述的海藻酸钠微球的制备步骤中的成孔剂3-甲氧基苯乙酮。
5.根据权利要求3所述的一种传递5-氟尿嘧啶微球的制备方法,其特征在于:所述的海藻酸钠微球的制备步骤中的span80溶液为2.0-2.2%span80异辛烷溶液,吐温-80溶液为浓度为4.0-4.5%的吐温-80水溶液,交联剂为0.5-0.6g/mL的CaCl2水溶液。
6.根据权利要求1所述的一种传递5-氟尿嘧啶微球的制备方法,其特征在于:所述的海藻酸钠-壳聚糖微球的制备步骤为:将0.045-0.050份5-氟尿嘧啶溶于30-40份壳聚糖醋酸水溶液中,在搅拌条件下加入0.5-0.6份海藻酸钠核心微球,400-500r/min高速搅拌10-15分钟,5000-6000r/min转速下离心3-5分钟,用无水乙醇、蒸馏水依次洗涤得海藻酸钠-壳聚糖微球。
7.根据权利要求6所述的一种传递5-氟尿嘧啶微球的制备方法,其特征在于:所述的海藻酸钠-壳聚糖微球的制备步骤中的壳聚糖醋酸水溶液中醋酸的含量为20-21g/L,壳聚糖的含量为15-16g/L。
8.根据权利要求1所述的一种传递5-氟尿嘧啶微球的制备方法,其特征在于:所述的海藻酸钠-壳聚糖-卡拉胶微球的制备步骤为:取0.5-0.6份卡拉胶以3-5份乙醇浸润,加入30-40份蒸馏水充分搅拌溶解,得轻微粘性、轻微乳白色的卡拉胶溶液,在搅拌条件下,将海藻酸钠-壳聚糖微球加入卡拉胶溶液中,400-500r/min高速搅拌10-15分钟,5000-6000r/min转速下离心5-8分钟,然后用无水乙醇、蒸馏水依次洗涤得海藻酸钠-壳聚糖-卡拉胶三重包覆载物微球。
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