阿霉素—壳聚糖微囊的制备、表征及其药效学研究

发布时间：2018-04-09 04:21

  本文选题：阿霉素　切入点：壳聚糖　出处：《新乡医学院》2014年硕士论文

【摘要】：背景微胶囊技术已经在许多领域得到了广泛应用,可以掩盖药物的不良气味及口味、提高药物的稳定性、减少药物对胃的刺激、包裹生物活性物质等。常用的微囊化方法有物理化学法、物理机械法、化学法等。本课题选用壳聚糖为囊材、阿霉素为模型药物。壳聚糖不仅来源广泛,天然无毒,还具有优良的成膜性能,具备控制胆固醇、预防和控制高血压、抑制细菌活性、抗肿瘤等特性。阿霉素为广谱抗肿瘤药,具有强烈的细胞毒性作用,抑制RNA能力最强,在肿瘤内科治疗中发挥着重要的作用,但因其毒性大,患者耐受性差,而将其微囊化后不仅可以降低毒性,而且可以提高药物的稳定性及生物利用度。 目的本课题拟通过制备壳聚糖载阿霉素微囊,研究其体外释放机理及药效学,为以壳聚糖为载体的药物微囊化的基础应用研究提供理论支持和实验基础。 方法本课题首先采用高效液相色谱法建立了阿霉素的含量测定方法,通过Minitab对实验进行响应曲面设计和优化,运用单凝聚法制备了壳聚糖载阿霉素微囊。对每批所制微囊的外观形貌和粒径分布进行表征；通过所建立的含量分析方法,计算其载药量和包封率；通过体外释放实验测定累积释放率。研究过程中,通过对壳聚糖载药微囊成囊及体外释放机理的研究,以评估各种相关因素的影响；以荷有H22肝癌细胞小鼠为肿瘤模型对载药微囊进行药效学的初步研究。 结果1.采用高效液相色谱法建立了阿霉素的含量测定方法,经方法学验证,表明阿霉素在1.01-50.4μg·ml-1浓度范围内具有良好的线性关系。 2.阿霉素-壳聚糖微囊制备优化条件为壳聚糖质量浓度0.2%、芯壁比2：3、表面活性剂含量7%及温度45℃；微囊的平均粒径为12.51±1.26μm,跨距为0.65；平均载药量(%)20.6±0.21,包封率(%)90.73±0.40。微囊质量均符合中国药典2010年版微囊制备的参数要求。 3.实验结果表明,壳聚糖的性质、微囊的粒径、交联剂的用量、缓释介质环境等因素对于微囊的体外释放产生不同的影响。 4.实验结果表明,ADM微囊化后抑瘤效果更优,不仅延长了ADM作用时间,同时降低了其相对的脾和胸腺毒性,从而实现了长效、低毒的治疗目的。 结论本课题以ADM为模型药物,CS为囊材,所制得微囊拥有良好的缓释特性,并且可在显著提高抑瘤率的同时,降低ADM的毒副作用。
[Abstract]:Background Microencapsulation technology has been widely used in many fields, which can cover up the bad smell and taste of drugs, improve the stability of drugs, reduce the irritation of stomach, encapsulate bioactive substances and so on.The commonly used microencapsulation methods include physicochemical method, physico-mechanical method, chemical method and so on.Chitosan was selected as capsule material and adriamycin as model drug.Chitosan not only has a wide range of sources, natural non-toxic, but also has excellent film forming properties, such as cholesterol control, prevention and control of hypertension, inhibition of bacterial activity, anti-tumor and other characteristics.Adriamycin is a broad-spectrum antitumor drug with strong cytotoxicity and the strongest ability to inhibit RNA, which plays an important role in the treatment of oncology.Microencapsulation can not only reduce the toxicity, but also improve the stability and bioavailability of the drug.Objective to prepare chitosan-loaded doxorubicin microcapsules and study their release mechanism and pharmacodynamics in vitro to provide theoretical and experimental basis for the basic application of chitosan-based drug microencapsulation.Methods A method for the determination of adriamycin was established by high performance liquid chromatography (HPLC). The response surface of the experiment was designed and optimized by Minitab. Chitosan loaded doxorubicin microcapsules were prepared by single agglomeration method.The appearance and particle size distribution of each batch of microcapsules were characterized, the drug loading and encapsulation efficiency were calculated by the established method, and the cumulative release rate was determined by in vitro release experiment.In order to evaluate the influence of various related factors, the pharmacodynamics of drug loaded microcapsules in mice bearing H22 was studied by studying the mechanism of microencapsulation and in vitro release mechanism of chitosan loaded microcapsules.Result 1.A method for the determination of adriamycin was established by HPLC. The method was verified that the linear range of adriamycin was 1.01-50.4 渭 g ml-1.2.The optimum conditions for preparation of doxorubicin chitosan microcapsules were as follows: chitosan concentration 0.2, core / wall ratio 2: 3, surfactant content 7% and temperature 45 鈩，

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