CN110898232A - 基于烷氨基环糊精的功能性载体在包载阿魏酸中的应用 - Google Patents
基于烷氨基环糊精的功能性载体在包载阿魏酸中的应用 Download PDFInfo
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- CN110898232A CN110898232A CN201911293243.8A CN201911293243A CN110898232A CN 110898232 A CN110898232 A CN 110898232A CN 201911293243 A CN201911293243 A CN 201911293243A CN 110898232 A CN110898232 A CN 110898232A
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- cyclodextrin
- ferulic acid
- alkylamino
- polymer
- mono
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Abstract
本发明公开了一类基于烷氨基环糊精的功能性载体在包载阿魏酸中的应用。一方面设计以烷氨基修饰的β‑环糊精作为主体,用以制备阿魏酸包合物,另一方面设计了连有线性聚合物分子的烷氨基环糊精高分子聚合物,用以负载阿魏酸。采用本发明的载体包载的阿魏酸水溶性较阿魏酸单体有了显著提高,热稳定也有所改善,为开发新型的水溶性阿魏酸材料及拓展阿魏酸在食品医药领域的应用提供了一定的理论参考。
Description
技术领域
本发明属于食品医药技术领域,具体涉及一种基于烷氨基环糊精的功能性载体在包载阿魏酸中的应用。
背景技术
天然抗氧化剂阿魏酸具有很多重要的生理功能,如降血脂、增强免疫力、抗菌抗病毒等。但由于其水溶性低、稳定性差等原因,很难被有效利用,因此如何改善阿魏酸的理化性质,提高其生物利用度是当前的研究热点。
环糊精是一类天然的包合材料,由于具有疏水性的空腔结构,能包埋许多具有特定分子结构和大小的难溶性物质,从而使物质的理化特性得以改善,达到缓释增溶等效果。但是一些天然环糊精如β-环糊精存在水溶性差、包合能力有限等问题,使得其应用受到限制。因此,有越来越多的研究关注于环糊精的结构修饰及功能性环糊精衍生物的开发利用。环糊精分子中众多的羟基基团为其结构优化提供了多个化学修饰位点。一些常见的环糊精衍生物如磺丁基-β-环糊精(SBE-β-CD)和羟丙基环糊精(HP-β-CD)能有效提高药物的水溶性和稳定性,降低肾毒性和溶血效应,在口服制剂、注射剂、鼻腔给药制剂等方面已有较好的应用(Cutrignelli et al.2014;Ma et al.1999)。
专利CN101485447A公开了一种阿魏酸环糊精包合物的制备方法,但是该包合物采用的环糊精分子为α-环糊精、β-环糊精、γ-环糊精、羟丙基环糊精、葡萄基环糊精中的任一种,包合能力有限,使得其应用受到限制。
发明内容
针对上述现有技术的不足,本发明提供了一种阿魏酸/烷氨基环糊精包合物及其制备方法和应用,通过采用烷氨基环糊精包合阿魏酸,进一步提高其水溶性,更加稳定。
为了实现上述发明目的,本发明采用以下技术方案:
一种阿魏酸/烷氨基环糊精包合物,阿魏酸与烷氨基环糊精衍生物的摩尔比为1-10:1。
进一步地,所述烷氨基环糊精衍生物为单取代环糊精衍生物、双取代环糊精衍生物或多取代环糊精衍生物。
进一步地,所述烷氨基环糊精衍生物的环糊精母体为α-环糊精、β-环糊精或γ-环糊精。
进一步地,所述烷氨基环糊精衍生物为单-6-脱氧-氨基-β-环糊精、单-6-脱氧-乙二胺-β-环糊精或单-6-脱氧-己二胺-β-环糊精。
上述阿魏酸/烷氨基环糊精包合物的制备方法,具体为:在20℃-30℃条件下,将烷氨基环糊精衍生物与阿魏酸在水中混合、反应,除去溶剂即可得到阿魏酸/烷氨基环糊精包合物。
上述阿魏酸/烷氨基环糊精包合物在制备药物、食品添加剂中的应用。
一种两亲性环糊精聚合物,其特征在于:所述聚合物如式Ⅰ所示:
式中,m:n=2~5:1~3,R为烷氨基环糊精衍生物。
进一步地,所述烷氨基环糊精衍生物为单-6-脱氧-氨基-β-环糊精、单-6-脱氧-乙二胺-β-环糊精或单-6-脱氧-己二胺-β-环糊精。
一种烷氨基环糊精聚合物胶束,由上述两亲性环糊精聚合物在水溶液中自组装形成,所述胶束包载有阿魏酸;
上述烷氨基环糊精聚合物胶束在制备药物或食品添加剂中的应用。
有益效果:
1、本发明通过化学法对β-环糊精进行结构修饰,合成得到三种含有不同烷基链长的烷氨基环糊精,并以这三种烷氨基环糊精为主体,制得了阿魏酸包合物。该包合物的水溶性较阿魏酸单体有了显著提高,热稳定也有所改善,为开发新型的水溶性阿魏酸材料及拓展阿魏酸在食品医药领域的应用提供了一定的理论参考。
2、本发明以MAA和mPEGMA为单体,通过自由基共聚反应制备得到了链状聚合物PA,然后通过酰胺化反应,将三种烷氨基环糊精分别接枝到聚合物PA分子链中,得到了三种两亲性的线型聚合物NH-CD-PA、EDA-CD-PA和HDA-CD-PA。采用线型聚合物包载阿魏酸,制得的载药胶束在pH5.5的弱酸性环境中对阿魏酸有较高的累积释放量,表明聚合物HDA-CD-PA具有一定的pH响应性,可有效包载疏水性药物并控制其体外释放,具有进一步开发利用的价值。
附图说明
图1为实施例1中阿魏酸(A)、NH-β-CD(B)及其包合物(C)的红外光谱图。
图2为实施例1中阿魏酸(A)、EDA-β-CD(B)及其包合物(C)的红外光谱图。
图3为实施例1中阿魏酸(A)、HDA-β-CD(B)及其包合物FA/HDA-β-CD(C)的红外光谱图。
图4为实施例1中阿魏酸(A)、NH-β-CD(B)及其包合物(C)的1H NMR图。
图5为实施例1中阿魏酸(A)、EDA-β-CD(B)及其包合物(C)的1H NMR图。
图6为实施例1中阿魏酸(A)、HDA-β-CD(B)及其包合物(C)的1H NMR图。
图7为实施例1中阿魏酸(A)、NH-β-CD(B)及其包合物FA/NH-β-CD(C)的XRD图谱。
图8为实施例1中阿魏酸(A)、EDA-β-CD(B)以及FA/EDA-β-CD包合物(C)的XRD图谱。
图9为实施例1中阿魏酸(A)、HDA-β-CD(B)及其包合物FA/HDA-β-CD(C)的XRD图谱。
图10为实施例2中MAA(A)、mPEGMA(B)、PA(C)、NH-CD-PA(D)、EDA-CD-PA(E)以及HDA-CD-PA(F)的红外光谱图。
图11为实施例2中载药聚合物胶束及阿魏酸/聚合物物理混合物的XRD图谱:FA/NH-CD-PA(A)、FA与NH-CD-PA的物理混合物(B)、FA/EDA-CD-PA(C)、FA与EDA-CD-PA的物理混合物(D)、FA/HDA-CD-PA(E)、FA与HDA-CD-PA的物理混合物(F)及FA(G)。
图12为实施例中载药胶束FA@H-PA在pH=5.5和pH=7.4的PBS中的体外释放情况。
具体实施方式
烷氨基环糊精是指环糊精分子中的羟基被胺基官能团选择性取代的一类环糊精衍生物,属于环糊精的离子化衍生物。除了其空腔的包埋作用之外,烷氨基环糊精还可以通过胺基取代基的静电吸附、氢键作用与客体分子结合。另外,胺基的引入会对环糊精的空腔结构和形状产生一定影响,从而影响其对客体分子的包结性能(Choi et al.2017)。近年来,以环糊精胺类衍生物作为包合主体的研究逐渐受到了人们的关注。Yang等人(2013)研究了β-环糊精、SBE-β-CD、HP-β-CD及烷氨基环糊精EDA-β-CD对芒果苷的包合行为,结果表明EDA-β-CD对芒果苷的包合常数最大。Song等人(2019)用一系列不同脂肪胺取代的环糊精衍生物对膳食性黄酮白杨素进行包载,研究发现这些胺基取代的环糊精衍生物均对白杨素有较好的包结性能,有效改善其水溶性和稳定性,且白杨素与烷氨基环糊精形成包合物以后,体外抗氧化活性及细胞毒性显著增强,表明烷氨基环糊精作为一种性能优异的载体材料,在功能食品、生物医药等领域具有潜在的应用价值。
天然抗氧化剂阿魏酸(FA)具有很多重要的生理功能,如降血脂、增强免疫力、抗菌抗病毒等。但由于其水溶性低、稳定性差等原因,很难被有效利用,因此如何改善阿魏酸的理化性质,提高其生物利用度是当前的研究热点。目前,以烷氨基环糊精作包合材料负载阿魏酸的相关研究还未见报道,基于此,本发明一方面设计以烷氨基修饰的β-环糊精作为主体,用以制备阿魏酸包合物,另一方面设计了连有线性聚合物分子的烷氨基环糊精,用以负载阿魏酸。
具体地,在本发明的下述实施例中,分别采用了6-位不同烷氨基修饰的β-环糊精,单-6-脱氧-氨基-β-环糊精、单-6-脱氧-乙二胺-β-环糊精或单-6-脱氧-己二胺-β-环糊精。
同时,以聚乙二醇单甲醚甲基丙烯酸酯(mPEGMA)和甲基丙烯酸(MAA)为单体材料,通过自由基共聚反应合成了一种线性聚合物分子PA。再通过酰胺化反应将三种烷氨基环糊精分别接枝到PA分子中,得到了三个系列(NH-CD-PA,EDA-CD-PA,HAD-CD-PA)的两亲性环糊精聚合物。利用两亲性聚合物在水中的自组装行为协同环糊精空腔的包合作用对阿魏酸进行负载。
以下实施例进一步说明本发明的内容,但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。实施例中未注明具体条件的实验方法及未说明配方的试剂均为按照本领域常规条件。
实施例1
三种阿魏酸/烷氨基环糊精包合物的制备
1、阿魏酸和单-6-脱氧-氨基-β-环糊精-的包合物(FA/NH-β-CD)
(1)单-6-脱氧-氨基-β-环糊精(NH-β-CD)的制备
准确称取单(6-氧-6-对甲苯磺酰基)-β-环糊精(Mono-6-OTs-β-CD)(4g,3.14mmol)和NaN3(1.02mg,15.7mmol),溶于30mL无水DMF中,在氮气保护下反应体系加热至75℃反应24h,待反应结束体系温度降至室温后,将反应液倒入大量丙酮中搅拌得到白色固体,收集粗产物溶于少量水中,再次滴加至大量丙酮中得到沉淀物,如此操作重复2~3次,将最终收集到的沉淀干燥,即可得到纯净的中间体Mono-6-N3-β-CD,产率约为87%。1H NMR(500MHz,D2O):5.77(s,14H,2,3-OH of CD),4.83-4.86(7H,1-H of CD),4.13-4.37(m,6H,6-OH of CD),3.35-3.85(m,42H,H-2,3,4,5,6 of CD);ESI-MS m/z 1182.36[M+Na]+(Anal.Calcd for C42H69N3O34,1159.38)。
准确称取Mono-6-N3-β-CD(1.5g,1.29mmol)和Ph3P(0.7g,2.67mmol),溶于15mL无水DMF中,在氮气保护下于室温搅拌1h。随后向反应液中滴加5mL浓氨水,此时不断有白色沉淀生成。反应体系继续在室温下搅拌8h,然后将反应液倒入大量丙酮中,收集沉淀并溶于少量水中,过SephadexG-25凝胶柱,得到纯品产物,收率约为90%。1H NMR(500MHz,D2O):4.97(s,7H,H-l of CD),3.47-3.55(m,14H,H-2,4 of CD),3.77-3.90(m,26H,H-3,5,6 of CD),3.10-3.16(m,2H);ESI-MS m/z 1134.36[M+H]+(Anal.Calcd for C42H71NO34,1133.39)。
(2)FA/NH-β-CD的制备
采用冻干法制备阿魏酸和烷氨基环糊精的包合物,阿魏酸与烷氨基环糊精的投料摩尔比分别为1:1、3:1和5:1。
以投料比3:1为例,具体的制备方法如下:将0.1mM的烷氨基环糊精溶于20mL蒸馏水中,再加入0.3mM的阿魏酸,反应体系置于室温下避光搅拌24h,之后用0.45μm微孔滤膜滤掉不溶物,将滤液冻干,即得到相应的阿魏酸/烷氨基环糊精的固体包合物。
同理可制得阿魏酸与烷氨基环糊精投料摩尔比分别为1:1和5:1的包合物。
2、阿魏酸和单-6-脱氧-乙二胺基-β-环糊精包合物(FA/EDA-β-CD)
(1)单-6-脱氧-乙二胺基-β-环糊精(EDA-β-CD)的制备
将Mono-6-OTs-β-CD(2.5g,3.10mmol)分散于溶于15mL乙二胺中,反应体系升温至70℃,氮气保护下反应8h。待反应完毕冷却至室温后,减压旋蒸除去大量的乙二胺溶液,剩余物滴入大量的丙酮中,产生白色沉淀。收集白色沉淀并溶于少量水中,过SephadexG-25凝胶柱,得到纯品产物,收率约为64%。1H NMR(500MHz,D2O):4.98(s,7H,H-1 of CD),3.7-3.9(m,26H,H-3,5,6 of CD),3.4-3.6(m,14H,H-2,4of CD),2.8-3.0(m,4H,-CH2-CH2-);ESI-MSm/z 1177.44[M+H]+(Anal.Calcd for C44H76N2O34,1176.43)。
(2)FA/EDA-β-CD的制备
采用冻干法制备阿魏酸和烷氨基环糊精的包合物,阿魏酸与烷氨基环糊精的投料摩尔比分别为1:1、3:1和5:1。
具体制备方法同FA/NH-β-CD包合物。
3、阿魏酸和单-6-脱氧-己二胺基-β-环糊精包合物(FA/HDA-β-CD)
(1)单-6-脱氧-己二胺基-β-环糊精(HDA-β-CD)的制备
将Mono-6-OTs-β-CD(2g,1.55mmol)和己二胺(8g,68.85mmol)溶于15mL无水DMF中,反应体系升温至80℃,氮气保护下反应18h。待反应完毕冷却至室温后,将反应液倒入大量丙酮中,得到白色沉淀,收集沉淀并溶于少量水中,过SephadexG-25凝胶柱,得到纯品产物,收率约为67%。1H NMR(500MHz,D2O):ESI-MS m/z 1233.51[M+H]+(Anal.Calcd forC48H84N2O34,1232.49)。
(2)FA/HDA-β-CD的制备
采用冻干法制备阿魏酸和烷氨基环糊精的包合物,阿魏酸与烷氨基环糊精的投料摩尔比分别为1:1、3:1和5:1。
具体制备方法同FA/NH-β-CD包合物。
下面对上述包合物进行结构表征和理化性质分析。
1、红外光谱的测定(FTIR)
用KBr压片法对阿魏酸、烷氨基环糊精以及阿魏酸/烷氨基环糊精包合物进行红外光谱扫描。扫描范围在4000cm-1–400cm-1,扫描速度为4mm/s。
图1是阿魏酸单体(FA)、NH-β-CD及其包合物FA/NH-β-CD的红外光谱图。从图中可以看出,阿魏酸在3437cm-1和3020-2843cm-1处的吸收被掩盖,阿魏酸芳环骨架在1618cm-1、1603cm-1和1433cm-1处的伸缩振动峰消失,在1514cm-1处的吸收峰明显减弱,另外,阿魏酸指纹区的吸收峰850cm-1和804cm-1消失,说明阿魏酸分子中的芳环部分通过包合作用进入到NH-β-CD的空腔,从而证明了FA/NH-β-CD包合物的形成。
图2分别为阿魏酸、EDA-β-CD及其包合物的红外光谱图,由图可知,当阿魏酸与EDA-β-CD形成包合物后,其芳环骨架C=C所对应的1618cm-1、1603cm-1和1433cm-1的伸缩振动峰消失,在1514cm-1处的吸收峰明显减弱,另外,芳环指纹区对应的吸收峰850cm-1和804cm-1消失,说明阿魏酸所处的化学环境发生了而改变,由此判断阿魏酸与EDA-β-CD形成了包合物。
图3为阿魏酸、HDA-β-CD及二者包合物的红外光谱图,由图可知,对FA/HDA-β-CD包合物来说,阿魏酸芳环骨架在1618cm-1、1603cm-1和1433cm-1处的伸缩振动峰消失,在1514cm-1处的吸收峰明显减弱,且芳环指纹区的吸收峰850cm-1和804cm-1消失,说明阿魏酸所处的化学环境发生了而改变,由此证明阿魏酸与EDA-β-CD之间包合物的形成。
2、核磁表征(NMR)
1H NMR表征:以D2O作溶剂,分别对阿魏酸、烷氨基环糊精以及阿魏酸/烷氨基环糊精包合物的结构进行表征。
图4是阿魏酸、NH-β-CD及其包合物的1H NMR谱图。从图中可以看到,FA/NH-β-CD包合物的1H NMR图中既包含阿魏酸的质子信号(6ppm-8ppm),又有NH-β-CD的质子信号(2.5ppm-4ppm),说明包合物制备成功。
同理,对包合前后EDA-β-CD和阿魏酸的1H NMR谱(图5)进行分析,表明EDA-β-CD与阿魏酸之间形成了1:1的包合物。对包合前后HDA-β-CD和阿魏酸的1H NMR谱(图6)进行分析,表明HDA-β-CD与阿魏酸之间形成了1:1的包合物。
3、X-射线粉末衍射分析(XRD)
用X-射线粉末衍射仪对阿魏酸、烷氨基环糊精以及阿魏酸/烷氨基环糊精包合物的晶体结构进行检测。将样品研磨后的粉末置于圆形样品槽内,设置仪器参数为:电压为40kV,扫描速率为0.1°/min,扫描范围为2θ=5°~70°。
图7是阿魏酸、NH-β-CD及其包合物的粉末X射线衍射图谱,可以看出,阿魏酸在2θ=9°,10.5°,12.8°,15.6°,17.4°,26.5°和29.5°处有明显而强烈的晶体衍射峰,表明阿魏酸具有晶体结构。NH-β-CD也呈现典型的晶体结构,在2θ=10.5°、12.3°、16.9°、19.4°、20.8°等处出现其特征衍射峰。而在形成包合物以后,几乎没有任何衍射峰的出现,表明包合作用生成了新的物相,即FA/NH-β-CD为无定形结构。
同理,从阿魏酸、EDA-β-CD及其包合物的XRD衍射图谱(图8)可以看出,包合物FA/EDA-β-CD为无定形结构。从阿魏酸、HDA-β-CD及其包合物的XRD衍射图谱(图9)可以看出,包合物FA/HDA-β-CD为无定形结构。
4、水溶性的测定
采用紫外分光光度法测定三种阿魏酸/烷氨基环糊精包合物的水溶性。将过量的阿魏酸/烷氨基环糊精包合物溶于5mL蒸馏水中,直至出现浑浊,用0.45μm的微孔滤膜过滤除去不溶物,得到包合物的饱和溶液。将饱和溶液稀释至适当倍数后检测其310nm处的紫外吸光值,根据阿魏酸标准曲线和稀释倍数计算得到包合物的溶解度。
用紫外分光光度法对三种阿魏酸/烷氨基环糊精包合物的水溶性进行了测定,以阿魏酸单体和包合物FA/β-CD作为对照。从下表可以看出,在三种烷氨基环糊精NH-β-CD,EDA-β-CD及HDA-β-CD的作用下,阿魏酸的溶解度分别提升至161.77mmol/L、316.69mmol/L和509.45mmol/L(以阿魏酸计),较阿魏酸单体(2.34mmol/L)的溶解度有了显著的改善,且水溶性的提高与烷氨基环糊精6-位取代上的氨基个数和碳链长度呈正相关。除了利用疏水性空腔的包埋作用,烷氨基环糊精还可以在水溶液中发生质子化,与弱酸性的阿魏酸通过静电吸附等作用结合从而大大改善其水溶性。
实施例2
三种烷氨基环糊精聚合物对阿魏酸的包载
1、聚合物poly(mPEGMA-co-MAA)的制备(PA)
采用自由基共聚法合成了甲基丙烯酸(MAA)和甲氧基聚乙二醇甲基丙烯酸酯(MPEGMA)的二元共聚物poly(mPEGMA-co-MAA)。合成路线如下所示:
具体为:0.4g的mPEGMA和0.4g的MAA溶解于4mL无水乙醇作为油相;0.0274g(NH4)2S2O8及0.0274g NaHSO3溶解于4mL蒸馏水中作为水相。将油相和水相分别加入到圆底烧瓶中,反应体系在氮气下进行,于37℃水浴下搅拌反应14h。待反应结束后,反应液置于透析袋中(MWCO:8000~14000)透析24h。透析结束后冻干即得到聚合物PA。
2、烷氨基环糊精聚合物的制备
以聚合物PA作为主链结构,通过酰胺化反应将三种不同的烷氨基环糊精通过酰胺键连接到PA分子上,分别得到了侧基是三种烷氨基环糊精的线性聚合物分子。
(1)聚合物NH-CD-poly(mPEGMA-co-MAA)的制备(NH-CD-PA)
取50mg聚合物PA溶于12mL的无水DMF,在冰浴条件下加入EDCI(0.324mM,186mg)和HOBT(0.324mM,37.3mg),搅拌半小时,使聚合物上的羧基活化,然后加入NH-β-CD(0.41mM,459.3mg),反应体系在氮气氛围中、室温条件下持续搅拌24h。待反应结束后,将反应液置于透析袋(MWCO:8000~14000)中用蒸馏水透析24h,冻干透析液即得到聚合物NH-CD-PA的固态粉末。
(2)聚合物EDA-CD-poly(mPEGMA-co-MAA)EDA-CD-PA的制备(EDA-CD-PA)
取50mg聚合物PA于含有12mL无水DMF的圆底烧瓶中,在冰浴条件下加入EDCI(0.324mM,186mg)和HOBT(0.324mM,37.3mg),搅拌半小时,使聚合物上的羧基活化,然后加入EDA-β-CD(0.41mM,477mg),反应体系在氮气氛围中、室温条件下持续搅拌24h。待反应结束后,将反应液置于透析袋(MWCO:8000~14000)中用蒸馏水透析24h,冻干透析液即得到聚合物EDA-CD-PA的固态粉末。
(3)聚合物HDA-CD-poly(mPEGMA-co-MAA)EDA-CD-PA的制备(HDA-CD-PA)
取50mg聚合物poly(mPEGMA-co-MAA)于含有12ml无水DMF的圆底烧瓶中,在冰浴条件下加入EDCI(0.324mM,186mg)和HOBT(0.324mM,37.3mg),搅拌半小时,对聚合物上的羧基进行活化,然后加入HDA-β-CD(0.41mM,499.4mg)反应体系在氮气氛围中、室温条件下持续搅拌24h。待反应结束后,将反应液置于透析袋中(MWCO:8000~14000)用蒸馏水透析24h,冻干透析液即得到聚合物HDA-CD-PA的固态粉末。
3、烷氨基环糊精聚合物对阿魏酸的包载
用透析法制备三种烷氨基环糊精聚合物的胶束溶液。具体方法如下:准确称取8mg的烷氨基环糊精聚合物和一定质量的阿魏酸,加入少量DMSO超声溶解,再逐滴加至8mL蒸馏水中,边搅拌边滴加,滴加完毕后再继续搅拌1h。将含有聚合物和阿魏酸的DMSO溶液置于透析袋(MWCO:8000~14000)中透析24h,得到的透析液即为聚合物载药胶束溶液。
下面对上述包合物进行结构表征和理化性质分析。
1、聚合物的红外表征
用KBr压片法对聚合物PA、NH-CD-PA、EDA-CD-PA以及HAD-CD-PA进行红外光谱扫描。扫描范围在4000cm-1-400cm-1,扫描速度为4mm/s。
如图10所示,1638cm-1左右的C=C伸缩振动峰消失,在2874cm-1和1730cm-1附近分别保留着C-H伸缩振动峰和C=O伸缩振动峰,表明单体单体MAA和mPEGMA之间发生了聚合反应,得到了PA。对于三种烷氨基环糊精聚合物,出现了表征环糊精骨架结构及酰胺键的红外特征峰,充分证明了烷氨基环糊精分子与聚合物PA发生了酰胺化反应。
2、载药率及包封率测定
称取不同投料比的聚合物载药胶束冻干粉,加入1mL甲醇中,超声15min使包载的阿魏酸充分释放溶解,然后将溶液过0.45μm有机相微孔滤膜,滤液经甲醇适当稀释后,测定310nm处的吸光度值,根据阿魏酸在甲醇中的标准曲线及稀释倍数计算载药胶束中阿魏酸的含量。然后分别根据公式(1)和(2)分别计算载药率(DL%)和包封率(EE%)。
由上表可知,三种聚合物载药胶束的DL均随阿魏酸投料量的增加而增加,胶束FA@N-PA在投料比为6/8时载药量达到最大,为6.9%。FA@H-PA在投料比为4/8、6/8时也具有较高载药量,分别为5.2%和5.9%。对包封率的数据进行分析,发现EDA-CD-PA和HDA-CD-PA的IE随投料比的增加有所降低。综合上述对胶束粒径大小、载药率和包封率的分析结果发现,聚合物HDA-CD-PA在投料比为4/8时制备的载药胶束FA@H-PA粒径大小适宜(在100nm左右),具有较高的载药率(5.2%)和包封率(10.7%),可以作为负载阿魏酸的潜在载体材料。
3、载药胶束的XRD检测
称取一定质量的载药胶束冻干粉,将样品置于制样架内成平板状,放入X射线衍射仪中对其晶体结构进行测定。测定条件:电压为40kV,扫描速率为0.1°/min,扫描范围为2θ=5°~70°。
从图11可以看出,三种载药聚合物的XRD谱线中没有晶体峰的出现,表明其均为无定形结构。而在阿魏酸与聚合物的物理混合物的图谱中,明显看到2θ=9.1°、12.9°、15.7°及26.6°等处有阿魏酸的特征晶体衍射峰,这一结果表明阿魏酸以无定型或无规晶型的状态存在于聚合物中,也证明了载药胶束的形成。
4、载药胶束体外释药行为考察
采用透析法考察不同pH值的透析介质中载药胶束的体外释放行为。精确称取一定质量的载药胶束冻干粉,用蒸馏水溶解,将溶液转移至透析袋(MWCO:3500)中,并置于20mLpH=7.4或者pH=5.5的磷酸盐缓冲溶液(PBS,10mM)中,每隔一段时间,吸取3mL透析介质,于310nm处测定透析液的吸光度值,同时补充等体积的新鲜PBS。根据公式(3)计pH=7.4或者pH=5.5的磷酸盐缓冲溶液(PBS,10mM)中,每隔一段时间,吸取3mL透析介质,于310nm处测定透析液的吸光度值,同时补充等体积的新鲜PBS。根据公式(3)计算累积释放率(Cumulativerelease),绘制体外释放曲线。
Cn为第n个时间点所取样品的浓度;Vn为释放介质总体积;Ci和Vi分别为第i个时间点所取样品的浓度及取样体积(Co及Vo均为0);W和LC%分别为载药胶束的质量及载药率。
如图12所示,两种pH条件下,载药胶束均在初期阶段对阿魏酸有较快的释放,经历约10h以后,释放速度减慢,并逐渐趋于平缓。药物在初始阶段短暂而快速的释放可能是由于吸附在胶束表面的游离阿魏酸在水中快速扩散,以及胶束疏水内核解体导致的阿魏酸释放。缓慢释放阶段主要是通过主-客体相互作用结合于环糊精空腔中的阿魏酸在水溶液中的分离及扩散。
此外,不同pH条件下的载药胶束对阿魏酸的最终释放量有显著的差异。在pH=7.4的释放介质中,48h内阿魏酸的释放量仅为55%左右,而在pH=5.5条件下阿魏酸的释放量达到80%,这表明所合成的烷氨基环糊精聚合物材料具有pH响应性,使得载药胶束进入体内之后,在正常组织中释药较少,而在肿瘤部位(pH呈酸性)释放较多的阿魏酸,从而能有效发挥阿魏酸对肿瘤细胞的抑制作用。
Claims (10)
1.一种阿魏酸/烷氨基环糊精包合物,其特征在于:阿魏酸与烷氨基环糊精衍生物的摩尔比为1-10:1。
2.根据权利要求1所述的包合物,其特征在于:所述烷氨基环糊精衍生物为单取代环糊精衍生物、双取代环糊精衍生物或多取代环糊精衍生物。
3.根据权利要求2所述的包合物,其特征在于:所述烷氨基环糊精衍生物的环糊精母体为α-环糊精、β-环糊精或γ-环糊精。
4.根据权利要求3所述的包合物,其特征在于:所述烷氨基环糊精衍生物为单-6-脱氧-氨基-β-环糊精、单-6-脱氧-乙二胺-β-环糊精或单-6-脱氧-己二胺-β-环糊精。
5.权利要求1所述的包合物的制备方法,其特征在于:在20℃-30℃条件下,将烷氨基环糊精衍生物与阿魏酸在水中混合、反应,除去溶剂即可得到阿魏酸/烷氨基环糊精包合物。
6.权利要求1所述的阿魏酸/烷氨基环糊精包合物在制备药物或食品添加剂中的应用。
8.根据权利要求7所述的环糊精聚合物,其特征在于:所述烷氨基环糊精衍生物为单-6-脱氧-氨基-β-环糊精、单-6-脱氧-乙二胺-β-环糊精或单-6-脱氧-己二胺-β-环糊精。
9.一种烷氨基环糊精聚合物胶束,其特征在于:由权利要求7所述的两亲性环糊精聚合物在水溶液中自组装形成,所述胶束包载有阿魏酸。
10.权利要求9所述的胶束在制备药物或食品添加剂中的应用。
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