基于壳聚糖与环糊精纳米给药系统的研究
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摘要
基于壳聚糖(chitosan, CS)与环糊精(cyclodextrin, CD)这两种生物材料的纳米(nanoparticle, NP)给药系统的研究,包括物理混合环糊精/壳聚糖及其衍生物(β-CD/CS)与环糊精固载壳聚糖聚合物(CD-g-CS)的纳米给药系统。本课题比较系统地研究了β-CD/CS与CD-g-CS纳米给药系统,为其进一步开发提供了实验数据。
以三聚磷酸钠(sodium tripolyphosphate, TPP)为交联剂,CS为载体材料,通过离子凝胶法制备CS NP,利用单因素法优化制备条件。以β-CD、羟丙基-β-CD、磺丁基-β-CD、二甲基-β-CD与CS为基础材料,制备β-CD/CS纳米粒,以粒径、电位等为评价指标,优化制备条件。得到球形良好,均一分散,粒径在157-576 nm范围内可控,zeta电位为+28.72-42.90 mv,稳定性良好的β-CD/CS NP。采用光学显微镜、透射电镜、激光粒度、红外、元素分析等方法对纳米粒进行表征,阐明β-CD/CS NP形成机制。实验结果表明,β-CD及其衍生物的加入有效地提高了NP的稳定性,且对NP的形成影响不大,β-CD/CS纳米给药系统有望包裹不同种类的难溶性药物成为一种有前途的药物载体。
采用化学合成手段制备CD-g-CS聚合物,以β-CD与对甲苯磺酰氯反应得到活化的β-CD衍生物(6-OTs-β-CD),与CS反应得到一系列不同CD取代度(DSCD=9.6%,14%,20%)的新型CD-g-CS生物材料,采用核磁,红外,x衍射等对其结构进行表征。以新型CD-g-CS为载体材料,采用离子凝胶法制备新型CD-g-CS NP。通过单因素法优化制备条件,制备得到粒径可控在202-589 nm范围内,zeta电位为+23.0～43.0mv球形特征,表面光滑圆整,均一分散度好的一系列CD-g-CS NP。实验结果表明,不同DSCD的CD-g-CS NP的最佳制备工艺不同。选用难溶性药物酮洛芬(ketoprofen,KTP)为模型,采用不同DSCD的CD-g-CS聚合物为载体材料,制备包载KTP的三种CD-g-CS NP,测定了载药率和包封率。体外释放结果表明,在不同PBS (pH=4.0,6.8,7.4)释放介质中,CD-g-CS纳米给药系统的释放速率存在着pH敏感性,这可能与CS分子上固载的CD取代度有关。
Chitosan (CS) is used as a bioadhesive polymer since the CS has non-toxic, biodegradable, biocompatible, mucoadhesion and ability to transiently open the tight junctions of the intestinal barrier properties. Cyclodextrin (CD) can form inclusion complexes with a variety of drugs, which can increase solubility, improve chemical and physical stability and/or enhance oral absorption of the drug. According to the advantages of both CD and CS, incorporatting CD into CS nanoparticle (NP) and grafting CD molecules onto CS (CD-g-CS) may lead to a carrier that possesses the cumulative effects of inclusion, size specificity and transport properties of CD and mucoadhesive properties of CS. In this study, we systematically investigated the process ofβ-CD/CS and CD-g-CS NPs. And the physicochemical properties of these nanoparticles were characterized. Ketoprofen (KTP) is as a model drug, and drug release from KTP-loaded CD-g-CS NP in vitro was further investigated.
The CS nanoparticles were obtained via ionic gelation method using TPP, which possessed spherical morphology, uniform size (157～576 nm), positive zeta potential (28.72～42.90 mv). With the similar conditions and methods, we obtained theβ-CD/CS nanoparticles, CS/HP-β-CD NPs, CS/SB-β-CD NPs and CS/DM-β-CD NPs,which also possessed spherical morphology demonstrated by TEM. The results indicated that the presence ofβ-CD derivatives had no critical impact in the NPs formation process. However, in all the series prepared, the mean diameter of the NPs varied accordingly to the concentration of CDs added during the preparation process. The results from IR studies and element alanalysis, suggest that CS is the major compound on the surface of the NPs, while CD are strongly associated with the NP matrix. Finally, in vitro stability studies indicated that the presence of CDs in the NP structure can prevent the aggregation of this nanometric carrier system in simulated intestinal fluid.
Chitosan bearing pendant cyclodextrin (CD-g-CS) was prepared with CS and 6-OTs-β-CD, which was prepared withβ-CD and TsCl. CD-g-CS NPs were obtained via ionic gelation method using TPP, which possessed spherical morphology, uniform size (202 ～589 nm), positive zeta potential (+23.0～43.0 mv). This study demonstrates that systematic design and modulation of the surface charge, particle size of CD-g-CS NPs can be readily achieved with the right control of critical processing parameters. Drug release in vitro from KTP-loaded CD-g-CS NP was further investigated. The release study indicated this CD-g-CS NPs had controlled-release effect and the degree of drug release from KTP-loaded CD-g-CS NPs was depended on the DS of CD-g-CS and pH of release medium.
以三聚磷酸钠(sodium tripolyphosphate, TPP)为交联剂,CS为载体材料,通过离子凝胶法制备CS NP,利用单因素法优化制备条件。以β-CD、羟丙基-β-CD、磺丁基-β-CD、二甲基-β-CD与CS为基础材料,制备β-CD/CS纳米粒,以粒径、电位等为评价指标,优化制备条件。得到球形良好,均一分散,粒径在157-576 nm范围内可控,zeta电位为+28.72-42.90 mv,稳定性良好的β-CD/CS NP。采用光学显微镜、透射电镜、激光粒度、红外、元素分析等方法对纳米粒进行表征,阐明β-CD/CS NP形成机制。实验结果表明,β-CD及其衍生物的加入有效地提高了NP的稳定性,且对NP的形成影响不大,β-CD/CS纳米给药系统有望包裹不同种类的难溶性药物成为一种有前途的药物载体。
采用化学合成手段制备CD-g-CS聚合物,以β-CD与对甲苯磺酰氯反应得到活化的β-CD衍生物(6-OTs-β-CD),与CS反应得到一系列不同CD取代度(DSCD=9.6%,14%,20%)的新型CD-g-CS生物材料,采用核磁,红外,x衍射等对其结构进行表征。以新型CD-g-CS为载体材料,采用离子凝胶法制备新型CD-g-CS NP。通过单因素法优化制备条件,制备得到粒径可控在202-589 nm范围内,zeta电位为+23.0～43.0mv球形特征,表面光滑圆整,均一分散度好的一系列CD-g-CS NP。实验结果表明,不同DSCD的CD-g-CS NP的最佳制备工艺不同。选用难溶性药物酮洛芬(ketoprofen,KTP)为模型,采用不同DSCD的CD-g-CS聚合物为载体材料,制备包载KTP的三种CD-g-CS NP,测定了载药率和包封率。体外释放结果表明,在不同PBS (pH=4.0,6.8,7.4)释放介质中,CD-g-CS纳米给药系统的释放速率存在着pH敏感性,这可能与CS分子上固载的CD取代度有关。
Chitosan (CS) is used as a bioadhesive polymer since the CS has non-toxic, biodegradable, biocompatible, mucoadhesion and ability to transiently open the tight junctions of the intestinal barrier properties. Cyclodextrin (CD) can form inclusion complexes with a variety of drugs, which can increase solubility, improve chemical and physical stability and/or enhance oral absorption of the drug. According to the advantages of both CD and CS, incorporatting CD into CS nanoparticle (NP) and grafting CD molecules onto CS (CD-g-CS) may lead to a carrier that possesses the cumulative effects of inclusion, size specificity and transport properties of CD and mucoadhesive properties of CS. In this study, we systematically investigated the process ofβ-CD/CS and CD-g-CS NPs. And the physicochemical properties of these nanoparticles were characterized. Ketoprofen (KTP) is as a model drug, and drug release from KTP-loaded CD-g-CS NP in vitro was further investigated.
The CS nanoparticles were obtained via ionic gelation method using TPP, which possessed spherical morphology, uniform size (157～576 nm), positive zeta potential (28.72～42.90 mv). With the similar conditions and methods, we obtained theβ-CD/CS nanoparticles, CS/HP-β-CD NPs, CS/SB-β-CD NPs and CS/DM-β-CD NPs,which also possessed spherical morphology demonstrated by TEM. The results indicated that the presence ofβ-CD derivatives had no critical impact in the NPs formation process. However, in all the series prepared, the mean diameter of the NPs varied accordingly to the concentration of CDs added during the preparation process. The results from IR studies and element alanalysis, suggest that CS is the major compound on the surface of the NPs, while CD are strongly associated with the NP matrix. Finally, in vitro stability studies indicated that the presence of CDs in the NP structure can prevent the aggregation of this nanometric carrier system in simulated intestinal fluid.
Chitosan bearing pendant cyclodextrin (CD-g-CS) was prepared with CS and 6-OTs-β-CD, which was prepared withβ-CD and TsCl. CD-g-CS NPs were obtained via ionic gelation method using TPP, which possessed spherical morphology, uniform size (202 ～589 nm), positive zeta potential (+23.0～43.0 mv). This study demonstrates that systematic design and modulation of the surface charge, particle size of CD-g-CS NPs can be readily achieved with the right control of critical processing parameters. Drug release in vitro from KTP-loaded CD-g-CS NP was further investigated. The release study indicated this CD-g-CS NPs had controlled-release effect and the degree of drug release from KTP-loaded CD-g-CS NPs was depended on the DS of CD-g-CS and pH of release medium.
引文
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