CN106727422B - 一种聚对二氧环己酮为核的核-壳双层微球及其制备方法和应用 - Google Patents
一种聚对二氧环己酮为核的核-壳双层微球及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种聚对二氧环己酮为核的核‑壳双层微球及其制备方法和应用,属于生物医药技术领域,本发明提供了一种聚对二氧环己酮为核的核‑壳双层微球及其制备方法,该方法主要包括聚对二氧环己酮微球的制备及以该微球为核制备具有核‑壳结构的双层微球,该方法操作简单、重复性好、成本低,且制备过程对环境友好。制得的微球粒径大小相近、可控,安全可降解,组织相容性好,且降解缓慢,降解时间可根据壳材料的种类和核‑壳材料添加比例进行调控。该微球可广泛用于缓释或控释药物和生物活性物质、化妆品、软组织充填和修复等领域。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种聚对二氧环己酮为核的核-壳双层微球及其制备方法和应用。
背景技术
美国的Green B.X.和Wurster D.E.是微球技术的先驱,从1957年至今已有六十年的历史,最初是将微球技术用于制造压敏式炭复写纸,后逐渐拓展到了食品、药品、化妆品、感光材料及纺织等领域,随着科学技术的不断发展,人们对药品制剂的要求逐渐提高,微球作为一种新型控释、缓释给药体系(DDS)越来越多得到关注和广泛应用,药物经微球化、微囊化以后,可防止其在空气中氧化及分解,降低对人体脏器的刺激,通过缓释,可以减少药物用量并延长药效。然而,传统的单层微球制剂存在着一定缺点,例如,释放速率较快、药物突释等。现在,微球制备多集中在一些天然高分子材料、半合成高分子材料和合成高分子材料,如海藻酸钠、壳聚糖、透明质酸钠、CMC、HPMC、PLGA、PLA、PLLA、POE等。然而这些材料制备的微球,要么降解时间很快,要么降解时间很慢或无法降解。
因此,急需一种可以解决单层微球的突释与封包率低及不能调控缓释时间等问题的材料及其制备方法。
发明内容
有鉴于此,本发明的目的在于:(1)提供一种聚对二氧环己酮为核的核-壳双层微球的制备方法;(2)提供一种聚对二氧环己酮为核的核-壳双层微球;(3)提供一种聚对二氧环己酮为核的核-壳双层微球的应用。
为达到上述目的,本发明提供如下技术方案:
1、一种聚对二氧环己酮为核的核-壳双层微球的制备方法,包括如下步骤:
(1)将聚对二氧环己酮加入六氟异丙醇中至所述聚对二氧环己酮完全溶解,再加入溶剂A搅拌后,滴加到乳化剂中得混合溶液,所述混合溶液经分散、固化后,制得含有聚对二氧环己酮微球的乳化液;
(2)将步骤(1)中制得的乳化液进行负压蒸馏处理至所述乳化液中六氟异丙醇和溶剂A挥发,制得悬浮液;
(3)将步骤(2)中制得的悬浮液进行离心、洗涤、干燥后,制得聚对二氧环己酮微球;
(4)将物质B加入溶剂A中至所述物质B完全溶解,然后加入步骤(3)中制备的聚对二氧环己酮微球,搅拌后滴加到乳化剂中得混合溶液,所述混合溶液经分散、固化后,制得含有聚对二氧环己酮为核的核-壳双层微球的乳化液;
(5)将步骤(4)中制得的乳化液进行负压蒸馏处理至所述乳化液中溶剂A挥发,制得悬浮液;
(6)将步骤(5)中制得的悬浮液进行离心、洗涤、干燥后,制得聚对二氧环己酮为核的核-壳双层微球;
所述溶剂A为二氯甲烷,三氯甲烷或四氯化碳中的一种或几种;所述物质B为聚乳酸、聚左乳酸、聚乳酸-羟基乙酸共聚物、聚已内酯、聚羟基丁酸酯或3-羟基丁酸酯和3-羟基戊酸酯的共聚物中的一种或几种。
进一步,步骤(1)中,所述聚对二氧环己酮和六氟异丙醇的质量体积比(g/mL)为1~10:100;所述六氟异丙醇与溶剂A的体积比为1:1~3:1;所述乳化剂为聚乙烯醇水溶液或聚乙二醇水溶液中的一种,所述聚对二氧环己酮和所述乳化剂中溶质的质量比为2:1~1:2。
进一步,步骤(1)和步骤(4)中,所述分散、固化具体为室温下以4000~7000rpm均质搅拌至乳化完全后加入体积为所述混合溶液2~5倍的水固化微球,所述水的温度为1~5℃。
进一步,步骤(2)中,所述负压蒸馏处理为在55℃,0.06~0.09MPa条件下蒸馏30~60min。
进一步,步骤(3)中,所述离心为在4000rpm下离心3min;所述洗涤用洗涤剂是质量分数为70~75%的乙醇水溶液,所述乙醇水溶液和悬浮液的体积比为10:1~2:1;所述干燥为喷雾干燥,具体条件为100℃,功率为4kW,进料量为350~450mL/min。
进一步,步骤(4)中,所述物质B和溶剂A的质量体积比(g/mL)为1~10:100;所述乳化剂为聚乙烯醇水溶液或聚乙二醇水溶液中的一种,所述物质B和所述乳化剂中溶质的质量比为2:1~1:2。
进一步,步骤(5)中,所述负压蒸馏处理为在55~65℃,0.06~0.09MPa条件下蒸馏30~60min。
进一步,步骤(6)中,所述离心为在4000r/min下离心3min;所述洗涤用洗涤剂是质量分数为70~75%的乙醇水溶液,所述乙醇水溶液和悬浮液的体积比为10:1~2:1;所述干燥为喷雾干燥,具体条件为100~120℃,功率为4kW,进料量为350~450mL/min。
2、由所述的方法制备的聚对二氧环己酮为核的核-壳双层微球。
3、所述的聚对二氧环己酮为核的核-壳双层微球作为载药微球的应用。
本发明的有益效果在于:本发明提供了一种聚对二氧环己酮为核的核-壳双层微球及其制备方法,该方法操作简单、重复性好、成本低,且制备过程对环境友好。其中,所用的聚对二氧环己酮是一种具有良好水解性和极好的生物相容性、生物可吸收性的生物可降解材料。聚对二氧环己酮聚合物分子链中的酯键使其具有优异的生物降解性,醚键和CH2基团使其具有良好的柔韧性,于上个世纪70年代被美国食品及药品管理局(FDA)批准为医用可吸收手术缝合线的基体材料,以其为原料制得的微球粒径大小相近、可控,安全可降解,组织相容性好,且降解缓慢,降解时间可根据壳材料的种类和核-壳材料添加比例进行调控,解决了单层微球的突释与封包率低等问题。该微球不仅可用于DDS体系,更可以应用于生物组织工程领域,作为一种生物组织工程支架,细胞可在支架上生长、增殖,可以起到软组织局部充填和修复的作用,或直接用于局部靶组织栓塞治疗,另外,双层微球也可应用于化妆品领域,可载生物活性物质、刺激性气味成分等,进一步拓展了聚对二氧环己酮在医药及其他领域的应用。
附图说明
为了使本发明的目的、技术方案和有益效果更加清楚,本发明提供如下附图进行说明:
图1为实施例1中制备的聚对二氧环己酮为核的核-壳双层微球的扫描电镜图;
图2为实施例1中制备的聚对二氧环己酮为核的核-壳双层微球的荧光显微镜图;
图3为实施例1中所用原料聚对二氧环己酮的XRD图;
图4为实施例1中所用原料聚左乳酸的XRD图;
图5为实施例1中制备的聚对二氧环己酮为核的核-壳双层微球的XRD图;
图6为实施例5中制备的聚对二氧环己酮微球的粒径分布图;
图7为实施例5中制备的聚对二氧环己酮为核的核-壳双层微球的粒径分布图。
具体实施方式
下面将结合附图,对本发明的优选实施例进行详细的描述。
实施例1
(1)按聚对二氧环己酮和六氟异丙醇的质量体积比(g/mL)为8:100将聚对二氧环己酮加入六氟异丙醇中至所述聚对二氧环己酮完全溶解,再加入三氯甲烷搅拌后,滴加到聚乙烯醇水溶液中得混合溶液,此时,混合溶液中六氟异丙醇和三氯甲烷的体积比为2.5:1,聚对二氧环己酮和聚乙烯醇水溶液中聚乙烯醇的质量比为1:1,将所述混合溶液以6000rpm均质搅拌至乳化完全后加入体积为所述混合溶液2倍的水固化微球,所述水的温度为2℃,制得含有聚对二氧环己酮微球的乳化液;
(2)将步骤(1)中制得的乳化液在55℃,0.08MPa条件下蒸馏30min至所述乳化液中六氟异丙醇和三氯甲烷挥发,制得悬浮液;
(3)将步骤(2)中制得的悬浮液在4000rpm下离心3min后,用体积为所述悬浮液8倍的质量分数为75%的乙醇水溶液进行洗涤,然后在100℃,功率为4kW,进料量为400mL/min条件下进行喷雾干燥,制得聚对二氧环己酮微球;
(4)按聚左乳酸和三氯甲烷的质量体积比(g/mL)为8:100将聚左乳酸加入三氯甲烷中至所述聚左乳酸完全溶解,然后加入步骤(3)中制备的聚对二氧环己酮微球,搅拌后滴加到聚乙烯醇水溶液中得混合溶液,此时,混合溶液中聚左乳酸和聚乙烯醇水溶液中聚乙烯醇的质量比为1:1,将所述混合溶液以5000rpm均质搅拌至乳化完全后加入体积为所述混合溶液2倍的水固化微球,所述水的温度为2℃,制得含有聚对二氧环己酮为核的核-壳双层微球的乳化液;
(5)将步骤(4)中制得的乳化液在62℃,0.08MPa条件下蒸馏40min至所述乳化液中三氯甲烷挥发,制得悬浮液;
(6)将步骤(5)中制得的悬浮液在4000rpm下离心3min后,用体积为所述悬浮液8倍的质量分数为75%的乙醇水溶液进行洗涤,然后在100℃,功率为4kW,进料量为400mL/min条件下进行喷雾干燥,制得聚对二氧环己酮为核的核-壳双层微球。
实施例2
(1)按聚对二氧环己酮和六氟异丙醇的质量体积比(g/mL)为1:100将聚对二氧环己酮加入六氟异丙醇中至所述聚对二氧环己酮完全溶解,再加入二氯甲烷搅拌后,滴加到聚乙二醇水溶液中得混合溶液,此时,混合溶液中六氟异丙醇和二氯甲烷的体积比为1:1,聚对二氧环己酮和聚乙二醇水溶液中聚乙二醇的质量比为2:1,将所述混合溶液以4000rpm均质搅拌至乳化完全后加入体积为所述混合溶液3倍的水固化微球,所述水的温度为5℃,制得含有聚对二氧环己酮微球的乳化液;
(2)将步骤(1)中制得的乳化液在55℃,0.08MPa条件下蒸馏50min至所述乳化液中六氟异丙醇和二氯甲烷挥发,制得悬浮液;
(3)将步骤(2)中制得的悬浮液在4000rpm下离心3min后,用体积为所述悬浮液6倍的质量分数为70%的乙醇水溶液进行洗涤,然后在100℃,功率为4kW,进料量为450mL/min条件下进行喷雾干燥,制得聚对二氧环己酮微球;
(4)按3-羟基丁酸酯和3-羟基戊酸酯的共聚物与二氯甲烷的质量体积比(g/mL)为1:100将3-羟基丁酸酯和3-羟基戊酸酯的共聚物加入二氯甲烷中至所述3-羟基丁酸酯和3-羟基戊酸酯的共聚物完全溶解,然后加入步骤(3)中制备的聚对二氧环己酮微球,搅拌后滴加到聚乙二醇水溶液中得混合溶液,此时,混合溶液中3-羟基丁酸酯和3-羟基戊酸酯的共聚物和聚乙二醇水溶液中聚乙二醇的质量比为2:1,将所述混合溶液以4000rpm均质搅拌至乳化完全后加入体积为所述混合溶液3倍的水固化微球,所述水的温度为5℃,制得含有聚对二氧环己酮为核的核-壳双层微球的乳化液;
(5)将步骤(4)中制得的乳化液在55℃,0.05MPa条件下蒸馏50min至所述乳化液中二氯甲烷挥发,制得悬浮液;
(6)将步骤(5)中制得的悬浮液在4000rpm下离心3min后,用体积为所述悬浮液6倍的质量分数为70%的乙醇水溶液进行洗涤,然后在100℃,功率为4kW,进料量为450mL/min条件下进行喷雾干燥,制得聚对二氧环己酮为核的核-壳双层微球。
实施例3
(1)按聚对二氧环己酮和六氟异丙醇的质量体积比(g/mL)为4:100将聚对二氧环己酮加入六氟异丙醇中至所述聚对二氧环己酮完全溶解,再加入二氯甲烷搅拌后,滴加到聚乙烯醇水溶液中得混合溶液,此时,混合溶液中六氟异丙醇和二氯甲烷的体积比为1:1,聚对二氧环己酮和聚乙烯醇水溶液中聚乙烯醇的质量比为1:2,将所述混合溶液以7000rpm均质搅拌至乳化完全后加入体积为所述混合溶液4倍的水固化微球,所述水的温度为1℃,制得含有聚对二氧环己酮微球的乳化液;
(2)将步骤(1)中制得的乳化液在55℃,0.06MPa条件下蒸馏60min至所述乳化液中六氟异丙醇和二氯甲烷挥发,制得悬浮液;
(3)将步骤(2)中制得的悬浮液在4000rpm下离心3min后,用体积为所述悬浮液2倍的质量分数为75%的乙醇水溶液进行洗涤,然后在100℃,功率为4kW,进料量为380mL/min条件下进行喷雾干燥,制得聚对二氧环己酮微球;
(4)按聚已内酯和二氯甲烷的质量体积比(g/mL)为4:100将聚已内酯加入二氯甲烷中至所述聚已内酯完全溶解,然后加入步骤(3)中制备的聚对二氧环己酮微球,搅拌后滴加到聚乙烯醇水溶液中得混合溶液,此时,混合溶液中聚已内酯和聚乙烯醇水溶液中聚乙烯醇的质量比为1:2,将所述混合溶液以7000rpm均质搅拌至乳化完全后加入体积为所述混合溶液4倍的水固化微球,所述水的温度为1℃,制得含有聚对二氧环己酮为核的核-壳双层微球的乳化液;
(5)将步骤(4)中制得的乳化液在55℃,0.06MPa条件下蒸馏35min至所述乳化液中二氯甲烷挥发,制得悬浮液;
(6)将步骤(5)中制得的悬浮液在4000rpm下离心3min后,用体积为所述悬浮液2倍的质量分数为75%的乙醇水溶液进行洗涤,然后在110℃,功率为4kW,进料量为380mL/min条件下进行喷雾干燥,制得聚对二氧环己酮为核的核-壳双层微球。
实施例4
(1)按聚对二氧环己酮和六氟异丙醇的质量体积比(g/mL)为10:100将聚对二氧环己酮加入六氟异丙醇中至所述聚对二氧环己酮完全溶解,再加入四氯化碳搅拌后,滴加到聚乙二醇水溶液中得混合溶液,此时,混合溶液中六氟异丙醇和四氯化碳的体积比为3:1,聚对二氧环己酮和聚乙二醇水溶液中聚乙二醇的质量比为2:1,将所述混合溶液以5000rpm均质搅拌至乳化完全后加入体积为所述混合溶液2倍的水固化微球,所述水的温度为3℃,制得含有聚对二氧环己酮微球的乳化液;
(2)将步骤(1)中制得的乳化液在55℃,0.09MPa条件下蒸馏30min至所述乳化液中六氟异丙醇和四氯化碳挥发,制得悬浮液;
(3)将步骤(2)中制得的悬浮液在4000rpm下离心3min后,用体积为所述悬浮液4倍的质量分数为70%的乙醇水溶液进行洗涤,然后在100℃,功率为4kW,进料量为420mL/min条件下进行喷雾干燥,制得聚对二氧环己酮微球;
(4)按聚乳酸和四氯化碳的质量体积比(g/mL)为10:100将聚乳酸加入四氯化碳中至所述聚乳酸完全溶解,然后加入步骤(3)中制备的聚对二氧环己酮微球,搅拌后滴加到聚乙二醇水溶液中得混合溶液,此时,混合溶液中聚乳酸和聚乙二醇水溶液中聚乙二醇的质量比为2:1,将所述混合溶液以5000rpm均质搅拌至乳化完全后加入体积为所述混合溶液2倍的水固化微球,所述水的温度为3℃,制得含有聚对二氧环己酮为核的核-壳双层微球的乳化液;
(5)将步骤(4)中制得的乳化液在60℃,0.09MPa条件下蒸馏30min至所述乳化液中四氯化碳挥发,制得悬浮液;
(6)将步骤(5)中制得的悬浮液在4000rpm下离心3min后,用体积为所述悬浮液4倍的质量分数为70%的乙醇水溶液进行洗涤,然后在120℃,功率为4kW,进料量为420mL/min条件下进行喷雾干燥,制得聚对二氧环己酮为核的核-壳双层微球。
实施例5
(1)按聚对二氧环己酮和六氟异丙醇的质量体积比(g/mL)为5:100将聚对二氧环己酮加入六氟异丙醇中至所述聚对二氧环己酮完全溶解,再加入三氯甲烷搅拌后,滴加到聚乙二醇水溶液中得混合溶液,此时,混合溶液中六氟异丙醇和三氯甲烷的体积比为2.5:1,聚对二氧环己酮和聚乙二醇水溶液中聚乙二醇的质量比为1:1,将所述混合溶液以6000rpm均质搅拌至乳化完全后加入体积为所述混合溶液5倍的水固化微球,所述水的温度为4℃,制得含有聚对二氧环己酮微球的乳化液;
(2)将步骤(1)中制得的乳化液在55℃,0.07MPa条件下蒸馏40min至所述乳化液中六氟异丙醇和三氯甲烷挥发,制得悬浮液;
(3)将步骤(2)中制得的悬浮液在4000rpm下离心3min后,用体积为所述悬浮液10倍的质量分数为72%的乙醇水溶液进行洗涤,然后在100℃,功率为4kW,进料量为350mL/min条件下进行喷雾干燥,制得聚对二氧环己酮微球;
(4)按聚乳酸-羟基乙酸共聚物和三氯甲烷的质量体积比(g/mL)为5:100将聚乳酸-羟基乙酸共聚物加入三氯甲烷中至所述聚乳酸-羟基乙酸共聚物完全溶解,然后加入步骤(3)中制备的聚对二氧环己酮微球,搅拌后滴加到聚乙二醇水溶液中得混合溶液,此时,混合溶液中聚乳酸-羟基乙酸共聚物和聚乙二醇水溶液中聚乙二醇的质量比为1:1,将所述混合溶液以6000rpm均质搅拌至乳化完全后加入体积为所述混合溶液5倍的水固化微球,所述水的温度为4℃,制得含有聚对二氧环己酮为核的核-壳双层微球的乳化液;
(5)将步骤(4)中制得的乳化液在60℃,0.07MPa条件下蒸馏40min至所述乳化液中三氯甲烷挥发,制得悬浮液;
(6)将步骤(5)中制得的悬浮液在4000rpm下离心3min后,用体积为所述悬浮液10倍的质量分数为72%的乙醇水溶液进行洗涤,然后在120℃,功率为4kW,进料量为350mL/min条件下进行喷雾干燥,制得聚对二氧环己酮为核的核-壳双层微球。
图1、图2分别为实施例1中制备的聚对二氧环己酮为核的核-壳双层微球的扫描电镜图和荧光显微镜图,由图可知,所制备的微球呈核壳结构,外层材料对聚对二氧环己酮微球进行了完好的包覆。
图3为实施例1中所用原料聚对二氧环己酮的XRD图,图4为实施例1中所用原料聚左乳酸的XRD图,图5为实施例1中制备的聚对二氧环己酮为核的核-壳双层微球的XRD图,对比三幅图可知,所制备聚对二氧环己酮为核的核-壳双层微球中核材料聚对二氧环己酮和壳材料聚左乳酸依然保持原有材料的特征晶形,说明双层微球的核、壳材料依然保持着改材料原有的特性。
图6为实施例1中制备的聚对二氧环己酮微球的粒径分布图,由图可知,所制备出的聚对二氧环己酮微球的平均粒径为432nm。
图7为实施例1中制备的聚对二氧环己酮为核的核-壳双层微球的粒径分布图,由图可知,所制备出的聚对二氧环己酮为核的核-壳双层微球的平均粒径为642nm。
本发明中,在制备聚对二氧环己酮为核的核-壳双层微球过程中,聚对二氧环己酮微球和物质B的添加量可根据实际需求进行添加。
最后说明的是,以上优选实施例仅用以说明本发明的技术方案而非限制,尽管通过上述优选实施例已经对本发明进行了详细的描述,但本领域技术人员应当理解,可以在形式上和细节上对其作出各种各样的改变,而不偏离本发明权利要求书所限定的范围。
Claims (7)
1.一种聚对二氧环己酮为核的核-壳双层微球的制备方法,其特征在于,包括如下步骤:
(1)将聚对二氧环己酮加入六氟异丙醇中至所述聚对二氧环己酮完全溶解,再加入溶剂A搅拌后,滴加到乳化剂中得混合溶液,所述混合溶液经分散、固化后,制得含有聚对二氧环己酮微球的乳化液;所述聚对二氧环己酮和六氟异丙醇的质量体积比为1~10:100;所述六氟异丙醇与溶剂A的体积比为1:1~3:1;所述乳化剂为聚乙烯醇水溶液或聚乙二醇水溶液中的一种,所述聚对二氧环己酮和所述乳化剂中溶质的质量比为2:1~1:2;所述质量体积比的单位为g/mL;
(2)将步骤(1)中制得的乳化液进行负压蒸馏处理至所述乳化液中六氟异丙醇和溶剂A挥发,制得悬浮液;
(3)将步骤(2)中制得的悬浮液进行离心、洗涤、干燥后,制得聚对二氧环己酮微球;
(4)将物质B加入溶剂A中至所述物质B完全溶解,然后加入步骤(3)中制备的聚对二氧环己酮微球,搅拌后滴加到乳化剂中得混合溶液,所述混合溶液经分散、固化后,制得含有聚对二氧环己酮为核的核-壳双层微球的乳化液;所述物质B和溶剂A的质量体积比为1~10:100;所述乳化剂为聚乙烯醇水溶液或聚乙二醇水溶液中的一种,所述物质B和所述乳化剂中溶质的质量比为2:1~1:2;所述质量体积比的单位为g/mL;
(5)将步骤(4)中制得的乳化液进行负压蒸馏处理至所述乳化液中溶剂A挥发,制得悬浮液;
(6)将步骤(5)中制得的悬浮液进行离心、洗涤、干燥后,制得聚对二氧环己酮为核的核-壳双层微球;
步骤(1)和步骤(4)中,所述分散、固化具体为室温下以4000~7000rpm均质搅拌至乳化完全后加入体积为所述混合溶液2~5倍的水固化微球,所述水的温度为1~5℃;
所述溶剂A为二氯甲烷,三氯甲烷或四氯化碳中的一种或几种;所述物质B为聚乳酸、聚左乳酸、聚乳酸-羟基乙酸共聚物、聚已内酯、聚羟基丁酸酯或3-羟基丁酸酯和3-羟基戊酸酯的共聚物中的一种或几种。
2.如权利要求1所述的一种聚对二氧环己酮为核的核-壳双层微球的制备方法,其特征在于,步骤(2)中,所述负压蒸馏处理为在55℃,0.06~0.09MPa条件下蒸馏30~60min。
3.如权利要求1所述的一种聚对二氧环己酮为核的核-壳双层微球的制备方法,其特征在于,步骤(3)中,所述离心为在4000rpm下离心3min;所述洗涤用洗涤剂是质量分数为70~75%的乙醇水溶液,所述乙醇水溶液和悬浮液的体积比为10:1~2:1;所述干燥为喷雾干燥,具体条件为100℃,功率为4kW,进料量为350~450 mL /min。
4.如权利要求1所述的一种聚对二氧环己酮为核的核-壳双层微球的制备方法,其特征在于,步骤(5)中,所述负压蒸馏处理为在55~65℃,0.06~0.09MPa条件下蒸馏30~60min。
5.如权利要求1所述的一种聚对二氧环己酮为核的核-壳双层微球的制备方法,其特征在于,步骤(6)中,所述离心为在4000 r/min下离心3min;所述洗涤用洗涤剂是质量分数为70~75%的乙醇水溶液,所述乙醇水溶液和悬浮液的体积比为10:1~2:1;所述干燥为喷雾干燥,具体条件为100~120℃,功率为4kW,进料量为350~450 mL /min。
6.由权利要求1-5任一项所述的方法制备的聚对二氧环己酮为核的核-壳双层微球。
7.权利要求6所述的聚对二氧环己酮为核的核-壳双层微球在制备载药微球药物的应用。
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