5-氟尿嘧啶—丝素蛋白—壳聚糖微囊制备的研究
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摘要
5-氟尿嘧啶(5-Fluorouracil,5-FU)属于抗代谢抗肿瘤药,临床上主要用于治疗乳腺癌,大肠癌,肝癌和脑癌。由于5-FU在体内代谢速度快,因此只能通过不断给药,维持体内5-FU浓度从而提高药物的治疗能力,但5-FU浓度过高会产生一系列不良反应。因此通过改变该药物制剂形式,延长药物的有效作用时间、降低药物用量以提高用药安全性具有现实意义。本文主要探讨了5-FU-丝素蛋白-壳聚糖微囊的制备工艺、相关性能和缓释效果,为5-FU微囊的制备提供一定的理论基础。
本实验采用5-FU为包封药物,丝素蛋白和壳聚糖为囊材,液体石蜡为连续相(油相),醋酸溶液为分散相(水相),利用复凝聚法制备5-FU-丝素蛋白-壳聚糖微囊。在制备过程中,首先考虑不同因素对微囊成囊的影响,以确定制备工艺参数。经过单因素和正交实验,发现影响微囊成囊的主要因素有丝素蛋白溶液浓度、乳化剂用量、交联剂用量和水油比。最佳优化制备条件为:丝素溶液浓度3%,乳化剂用量2 ml,戊二醛用量2 ml,水油比1:5,即液体石蜡用量50 ml。通过扫描电镜和激光粒度分布仪的检测结果表明,优化条件下制得的微囊球形圆整,表面光滑,无裂痕,平均粒径为48.98μm,粒度呈正态分布。
对优化条件下制备的5-FU-丝素蛋白-壳聚糖微囊进行性能检测:傅立叶红外光谱的检测表明,囊材丝素蛋白分子和壳聚糖分子之间具有强相互作用,5-FU与丝素蛋白和壳聚糖之间可以形成很强的分子间相互作用力,药物包埋效果较好;5-FU用量,交联剂用量,乳化剂用量对微囊的包封率和载药量均有影响,其中5-FU用量对微囊包封率的影响较大。微囊的回收率实验表明,平均回收率为97.25%,说明微囊的囊材不干扰5-FU的测定;动态透析法检测包药微囊的缓释性能,结果表明,药物微囊化后,释药的速度较药粉明显下降,证明5-FU-丝素蛋白-壳聚糖微囊具有一定的缓释效果,并且缓释效果比由单凝聚法制备的5-FU-壳聚糖微囊更加显著,符合实验的目的和要求。
本实验研究发现,丝素蛋白和壳聚糖可以形成良好的双层囊材包裹5-FU,制备包药微囊,通过对制备条件的优化,制备出的微胶囊圆整光滑,粒度分布均匀并具有较好的缓释功能。
5-Fluorouracil (5-FU) is an anticancer agent that is widely used in the clinical treatment of several solid cancers, such as breast, colorectal, liver and brain cancer. Because of its high rate of metabolism in the body, the maintenance of a high serum concentration improves its therapeutic activity, but this requires its continuous administration. However, concentration above a certain limit produces a series of toxic effects. Via changing the medicine preparation form to prolong medicine’s effective time and play down medicine dosage have realistic significance. This paper discussed the preparation and the property of 5-FU loaded microcapsules with cross linked chitosan and silk fibroin, as well as drug in microcapsule releasing capability. The results give certain theory-base for the microcapsule preparation of 5-FU.
In the emulsion system, liquid proffin as continuous phase, Span as emulsifier, glutaradehyde as crosslinking agent, the silk fibroin-chitosan microcapsule with 5-FU wrapped in is prepared. Microcapsules are prepared using complex coacervation method. In order to get optimized preparation parameters, different factors are selected to evaluation the influence of different formulation in the preparation of microcapsule. By the single-factor and the orthogonal test, the concentration of silk fibroin, emulsifier concentration, glutaraldehyde amount and ratio of oil phase and water phase have done the most important effect to the formulation of microcapsules. Optimize experiment receive the furthest fit technical parameters: the concentration of silk fibroin is 3%, emulsifier concentration is 2ml, glutaraldehyde amount is 2ml, ratio of H2O / Oil (V:V) is 1:5. Under the optimum conditions, microcapsules are in good shape and approximatively global, the mean diameter is about 48.98μm.
Through testing the microcapsule’s property, the results indicate that: silk fibroin and chitosan are cross linked by strong coactions, 5-FU is firmly embedded in capsule wall material; the concentration of 5-FU, glutaradehyde and emulsifier has done some effect on encapsulation efficiency and drug contents, 5-FU concentration is the most important influencing factor of the total; the mean recovery rate of microcapsules is 97.25%; the experiment of releasing drug explains that 5-FU-silk fibroin and chitosan microcapsules possess more obvious sustained releasing property than 5-FU and 5-FU-chitosan microcapsules, which are accord with the test request. Silk fibroin and chitosan are profitable capsule wall material to embed 5-FU.
Through optimizing preparation conditions, microcapsules are in good shape and approximatively global, particle size is uniform. Microcapsules may prove better sustained release of drugs.
本实验采用5-FU为包封药物,丝素蛋白和壳聚糖为囊材,液体石蜡为连续相(油相),醋酸溶液为分散相(水相),利用复凝聚法制备5-FU-丝素蛋白-壳聚糖微囊。在制备过程中,首先考虑不同因素对微囊成囊的影响,以确定制备工艺参数。经过单因素和正交实验,发现影响微囊成囊的主要因素有丝素蛋白溶液浓度、乳化剂用量、交联剂用量和水油比。最佳优化制备条件为:丝素溶液浓度3%,乳化剂用量2 ml,戊二醛用量2 ml,水油比1:5,即液体石蜡用量50 ml。通过扫描电镜和激光粒度分布仪的检测结果表明,优化条件下制得的微囊球形圆整,表面光滑,无裂痕,平均粒径为48.98μm,粒度呈正态分布。
对优化条件下制备的5-FU-丝素蛋白-壳聚糖微囊进行性能检测:傅立叶红外光谱的检测表明,囊材丝素蛋白分子和壳聚糖分子之间具有强相互作用,5-FU与丝素蛋白和壳聚糖之间可以形成很强的分子间相互作用力,药物包埋效果较好;5-FU用量,交联剂用量,乳化剂用量对微囊的包封率和载药量均有影响,其中5-FU用量对微囊包封率的影响较大。微囊的回收率实验表明,平均回收率为97.25%,说明微囊的囊材不干扰5-FU的测定;动态透析法检测包药微囊的缓释性能,结果表明,药物微囊化后,释药的速度较药粉明显下降,证明5-FU-丝素蛋白-壳聚糖微囊具有一定的缓释效果,并且缓释效果比由单凝聚法制备的5-FU-壳聚糖微囊更加显著,符合实验的目的和要求。
本实验研究发现,丝素蛋白和壳聚糖可以形成良好的双层囊材包裹5-FU,制备包药微囊,通过对制备条件的优化,制备出的微胶囊圆整光滑,粒度分布均匀并具有较好的缓释功能。
5-Fluorouracil (5-FU) is an anticancer agent that is widely used in the clinical treatment of several solid cancers, such as breast, colorectal, liver and brain cancer. Because of its high rate of metabolism in the body, the maintenance of a high serum concentration improves its therapeutic activity, but this requires its continuous administration. However, concentration above a certain limit produces a series of toxic effects. Via changing the medicine preparation form to prolong medicine’s effective time and play down medicine dosage have realistic significance. This paper discussed the preparation and the property of 5-FU loaded microcapsules with cross linked chitosan and silk fibroin, as well as drug in microcapsule releasing capability. The results give certain theory-base for the microcapsule preparation of 5-FU.
In the emulsion system, liquid proffin as continuous phase, Span as emulsifier, glutaradehyde as crosslinking agent, the silk fibroin-chitosan microcapsule with 5-FU wrapped in is prepared. Microcapsules are prepared using complex coacervation method. In order to get optimized preparation parameters, different factors are selected to evaluation the influence of different formulation in the preparation of microcapsule. By the single-factor and the orthogonal test, the concentration of silk fibroin, emulsifier concentration, glutaraldehyde amount and ratio of oil phase and water phase have done the most important effect to the formulation of microcapsules. Optimize experiment receive the furthest fit technical parameters: the concentration of silk fibroin is 3%, emulsifier concentration is 2ml, glutaraldehyde amount is 2ml, ratio of H2O / Oil (V:V) is 1:5. Under the optimum conditions, microcapsules are in good shape and approximatively global, the mean diameter is about 48.98μm.
Through testing the microcapsule’s property, the results indicate that: silk fibroin and chitosan are cross linked by strong coactions, 5-FU is firmly embedded in capsule wall material; the concentration of 5-FU, glutaradehyde and emulsifier has done some effect on encapsulation efficiency and drug contents, 5-FU concentration is the most important influencing factor of the total; the mean recovery rate of microcapsules is 97.25%; the experiment of releasing drug explains that 5-FU-silk fibroin and chitosan microcapsules possess more obvious sustained releasing property than 5-FU and 5-FU-chitosan microcapsules, which are accord with the test request. Silk fibroin and chitosan are profitable capsule wall material to embed 5-FU.
Through optimizing preparation conditions, microcapsules are in good shape and approximatively global, particle size is uniform. Microcapsules may prove better sustained release of drugs.
引文
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