载硝苯地平壳聚糖缓释微球的制备
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摘要
硝苯地平(Nifedipine)是目前临床治疗高血压和心绞痛的首选药物之一。但因该药具有结晶度高、难溶于水和对光敏感等特点,且非缓释的普通制剂的不良反应发生率较高,所以如何提高硝苯地平制剂的稳定性,改善其疗效已成为国内外十分重视的课题。壳聚糖(Chitosan)作为优良的天然聚阳离子材料,具有可生物降解性、生物相容性、无毒性及良好的缓释性能。因此,本文选用壳聚糖微球作为硝苯地平的口服载体来达到长效缓释,降低药物毒副作用的目的。
本文探讨了乳化交联法制备壳聚糖微球的条件,通过正交实验和单因素考察得到了制备的较佳条件。较佳制备条件为:一定浓度的壳聚糖溶液20ml,油相为含有4%Span-80的石蜡30ml,搅拌速度为350rpm,戊二醛的加入量按氨基与醛基摩尔比1:1算得,交联时间为30min。
为了改善壳聚糖浓度较低时微球的外观形貌,还采用预交联的方法对乳化交联制备过程进行了改进。通过正交实验、单因素考察和对比实验确定了改进后的较佳制备条件:一定浓度的壳聚糖溶液20ml,油相为含有6%Span-80的石蜡30ml,搅拌速度为350rpm,戊二醛的加入量按氨基与醛基摩尔比1:1算得,预先加入的交联剂用量为交联剂总用量的5%,加入交联剂预交联后,超声分散5min,乳化后,加入剩余交联剂交联固化,交联时间为30min。实验表明,采用改进后的方法制得的微球形貌更为规整,粒径更为均一。
选用含有0.5%SDS的溶液作为载药微球的释放体系,并测定了硝苯地平在该体系中的稳定性。建立了基于此体系的硝苯地平的检测分析方法。
应用以上两种方法制备了载硝苯地平壳聚糖微球,观察了制得微球的外观形貌,考察了壳聚糖微球对于药物的包埋率和载药量,绘制了载药微球的体外释放曲线。通过以上实验表明:采用改进方法制备的微球成球性能好,无粘连,在药物的包埋率、载药量和缓释效果方面都有一定的提高。当壳聚糖浓度为1.0%时,制得的载药微球综合性能最佳,药物包埋率能够达到32.1%,载药量为8.5%,体外释放实验12h释放率44.2%,48h释放率88.5%。对比与传统乳化交联法,包埋率提高了约3%,载药量提高了约1%,48h释药率提高约12%。
Nifedipine is most commonly used as the antianginal and antihypertensive medicine. However, it has high crystallization, poor solubilization and photosensitive property, and the rate of adverse effects of its normal reagent is high, so stable and sustained release nifedipine formulations have attracted much attention. Chitosan is a biodegradable natural polymer with great potential for pharmaceutical applications due to its degradability, biocompatibility, and nontoxicity. Chitosan as the carrier can not only improve the solubilization of poorly soluble drugs, but also control the release of drugs Therefore, in this paper, nifedipine-loaded chitosan microspheres were prepared to enhance the stability and reduce the adverse effect of nifedipine.
The conditions of the preparation of chitosan microspheres using emulsion-crosslinking method were investigated by the orthogonal and single factor experiments. The optimal preparation conditions were as follows: chitosan solution with certain concentration, 20ml; liquid paraffin containing 4% Span-80, 30ml; glutaraldehyde, the ratio of amino and aldehyde is 1:1; stirring speed, 350 rpm; reaction time, 30 min.
Pre-crosslinking method, which is an improvement of the emulsion-crosslinking method, was then developed to prepare the chitosan microspheres. The optimum conditions were as follows: chitosan solution of certain concentration, 20ml; liquid paraffin with 6% Span-80 content emulsion-crosslinking method, 30ml; stirring speed, 350 rpm; glutaraldehyde, the ratio of amino and aldehyde is 1:1. In this experiment, 5% of glutaraldehyde was used as pre-crosslinking agent. After ultrasonic dispersed 5 min, to the solution was added the residual crosslinking agent and reacted for 30 min. Results showed that the microspheres made by pre-crosslinking had good appearance and uniform size.
The methods of detection and analysis of were established and 0.5% SDS solution was selected to determine the amount of nifedipine released from the microspheres, in which the solubility of nifedipine was detected.
Finally, nifedipine-loaded chitosan microspheres were prepared, and their particle size, appearance, entrapment efficiency, drug loading and in vitro release were also studied. Results indicated that, compared with the emulsion-crosslinking method, the microspheres prepared by the pre-crosslinking method had better performance in balling property, entrapment efficiency, drug loading and in vitro release. When the concentration of the chitosan was 1.0%, the entrapment efficiency was 32.1%, the drug loading was 8.5%, and the in vitro released drug content was 44.2% after 12h and 88.5% after 48h; and it means that the entrapment efficiency of the microspheres increased 3%, the drug loading increased 1%, and in vitro released drug content after 48h increased 12%.
本文探讨了乳化交联法制备壳聚糖微球的条件,通过正交实验和单因素考察得到了制备的较佳条件。较佳制备条件为:一定浓度的壳聚糖溶液20ml,油相为含有4%Span-80的石蜡30ml,搅拌速度为350rpm,戊二醛的加入量按氨基与醛基摩尔比1:1算得,交联时间为30min。
为了改善壳聚糖浓度较低时微球的外观形貌,还采用预交联的方法对乳化交联制备过程进行了改进。通过正交实验、单因素考察和对比实验确定了改进后的较佳制备条件:一定浓度的壳聚糖溶液20ml,油相为含有6%Span-80的石蜡30ml,搅拌速度为350rpm,戊二醛的加入量按氨基与醛基摩尔比1:1算得,预先加入的交联剂用量为交联剂总用量的5%,加入交联剂预交联后,超声分散5min,乳化后,加入剩余交联剂交联固化,交联时间为30min。实验表明,采用改进后的方法制得的微球形貌更为规整,粒径更为均一。
选用含有0.5%SDS的溶液作为载药微球的释放体系,并测定了硝苯地平在该体系中的稳定性。建立了基于此体系的硝苯地平的检测分析方法。
应用以上两种方法制备了载硝苯地平壳聚糖微球,观察了制得微球的外观形貌,考察了壳聚糖微球对于药物的包埋率和载药量,绘制了载药微球的体外释放曲线。通过以上实验表明:采用改进方法制备的微球成球性能好,无粘连,在药物的包埋率、载药量和缓释效果方面都有一定的提高。当壳聚糖浓度为1.0%时,制得的载药微球综合性能最佳,药物包埋率能够达到32.1%,载药量为8.5%,体外释放实验12h释放率44.2%,48h释放率88.5%。对比与传统乳化交联法,包埋率提高了约3%,载药量提高了约1%,48h释药率提高约12%。
Nifedipine is most commonly used as the antianginal and antihypertensive medicine. However, it has high crystallization, poor solubilization and photosensitive property, and the rate of adverse effects of its normal reagent is high, so stable and sustained release nifedipine formulations have attracted much attention. Chitosan is a biodegradable natural polymer with great potential for pharmaceutical applications due to its degradability, biocompatibility, and nontoxicity. Chitosan as the carrier can not only improve the solubilization of poorly soluble drugs, but also control the release of drugs Therefore, in this paper, nifedipine-loaded chitosan microspheres were prepared to enhance the stability and reduce the adverse effect of nifedipine.
The conditions of the preparation of chitosan microspheres using emulsion-crosslinking method were investigated by the orthogonal and single factor experiments. The optimal preparation conditions were as follows: chitosan solution with certain concentration, 20ml; liquid paraffin containing 4% Span-80, 30ml; glutaraldehyde, the ratio of amino and aldehyde is 1:1; stirring speed, 350 rpm; reaction time, 30 min.
Pre-crosslinking method, which is an improvement of the emulsion-crosslinking method, was then developed to prepare the chitosan microspheres. The optimum conditions were as follows: chitosan solution of certain concentration, 20ml; liquid paraffin with 6% Span-80 content emulsion-crosslinking method, 30ml; stirring speed, 350 rpm; glutaraldehyde, the ratio of amino and aldehyde is 1:1. In this experiment, 5% of glutaraldehyde was used as pre-crosslinking agent. After ultrasonic dispersed 5 min, to the solution was added the residual crosslinking agent and reacted for 30 min. Results showed that the microspheres made by pre-crosslinking had good appearance and uniform size.
The methods of detection and analysis of were established and 0.5% SDS solution was selected to determine the amount of nifedipine released from the microspheres, in which the solubility of nifedipine was detected.
Finally, nifedipine-loaded chitosan microspheres were prepared, and their particle size, appearance, entrapment efficiency, drug loading and in vitro release were also studied. Results indicated that, compared with the emulsion-crosslinking method, the microspheres prepared by the pre-crosslinking method had better performance in balling property, entrapment efficiency, drug loading and in vitro release. When the concentration of the chitosan was 1.0%, the entrapment efficiency was 32.1%, the drug loading was 8.5%, and the in vitro released drug content was 44.2% after 12h and 88.5% after 48h; and it means that the entrapment efficiency of the microspheres increased 3%, the drug loading increased 1%, and in vitro released drug content after 48h increased 12%.
引文
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