论文总字数：26799字

摘 要

随着现代生活水平的提高，全球肾脏病的发病率也在不断提高。据调查，目前患有各种肾病的患者比例已达全球人口的10％。未来十年内慢性肾脏疾病（CKD）将增加超过17％，并且继发性甲状旁腺功能亢进症（Secondary Hyperparathyroidism, SHPT）是由CKD引发的，其发病率也很高。盐酸西那卡塞（Cinacalcet Hydrochlorde ，CLC，分子式C₂₂H₂₂F₃N·HCL）是第一个获得FDA批准的拟钙剂。研究表明CLC可以有效治疗慢性肾脏病透析引起的SHPT。近年来，人们将CLC作为治疗SHPT的新选择和重要方向。然而，由于CLC的水溶性与溶出速率不理想，体内代谢迅速以及生物利用度低，这些都严重阻碍了其临床应用。作为一种新型的药物给药系统，纳米乳不但可以增加难溶性药物的溶解度，也能增加药物的稳定性和生物利用度。纳米乳剂热力学稳定，长期储存后不易分层，不易破乳。因此，它可以作为不溶性药物的理想载体。

本课题在制备纳米乳时，选择油酸为油相、op-10为乳化剂、PEG-200为助乳化剂。将盐酸西那卡塞均匀的分散在乳液中，增加了药物的溶解度，同时也提高了生物利用度。本课题的主要研究内容与研究结果如下：

1. 建立了盐酸西那卡塞的体外分析方法，采用高效液相色谱法（HPLC）进行测定。结果表明：空白辅料等对盐酸西那卡塞的测定无干扰，回收率达99.76%，线性关系及精密度好（RSDlt;2.0%），方法准确度高。
2. 使用油酸为油相、op-10为乳化剂、PEG-200为助乳化剂制备出盐酸西那卡塞纳米乳。并考察了油相、乳化剂、助乳化剂各相在处方中的百分含量，来研究其对纳米乳形成的影响。最终确定了最佳处方为：油酸—op-10—PEG-200—水=6% : 28% : 9.33% : 56.67%，药物含量为0.25%。另外还对制备的纳米乳进行了一系列的质量研究。结果表明：纳米乳平均粒径为24.1±3.8nm，多分散指数（PDI）为0.261±0.032；Zeta平均值绝对值均大于20，表明制备的纳米乳有很好的稳定性；透射电镜观察外观呈规则圆形。长期及加速实验证明纳米乳的稳定性很好，且通过测定，盐酸西那卡塞在纳米乳中的溶解度也得到很大提升。

本研究表明，纳米乳作为一种新型药物载体，对水溶性差的药物盐酸西那卡塞，不但能够提高药物的溶解度，还能增加药物在体内的血药浓度，提高药物的生物利用度。本研究的结果也为盐酸西那卡塞纳米乳的临床应用提供了一定的科学依据。

关键词: 盐酸西那卡塞 纳米乳 生物利用度

Abstract

With the improvement of modern living standards, the incidence of global kidney disease is also increasing. According to the survey, the proportion of patients suffering from various kidney diseases has reached 10% of the global population. Chronic kidney disease (CKD) will increase by more than 17% over the next decade, and Secondary Hyperparathyroidism (SHPT) is a common complication of CKD and its incidence is also high. Cinacalcet Hydrochloride (CLC, Molecular Formula C₂₂H₂₂F₃N·HCl) is the first Calcium Calcium approved by the FDA. Studies have shown that CLC can effectively treat SHPT caused by dialysis in chronic kidney disease. In recent years, people have used CLC as a new choice and important direction for the treatment of SHPT. However, due to the poor solubility and dissolution rate of CLC, rapid metabolism in vivo and low bioavailability, these have seriously hindered its clinical application. As a novel drug delivery system, nanoemulsions can increase the solubility of poorly soluble drugs and increase drug stability and bioavailability. Nanoemulsions are thermodynamically stable, difficult to delaminate after long-term storage, and difficult to break. Therefore, it can be used as an ideal carrier for insoluble drugs.

In the preparation of nanoemulsion, this topic chooses oleic acid as oil phase, op-10 as emulsifier and PEG-200 as coemulsifier. Cinacalcet hydrochloride is evenly dispersed in the emulsion, which increases the solubility of the drug and also increases the bioavailability.The main research contents and research results of this topic are as follows:

(1) An in vitro method for the determination of cinacalcet hydrochloride was established and determined by high performance liquid chromatography (HPLC). The results showed that blank excipients had no interference with the determination of cinacalcer hydrochloride, the recovery rate was 99.76%, the linear relationship and precision were good (RSDlt;2.0%), and the accuracy of the method was high.

(2) Cinacalse hydrochloride nanoemulsion was prepared using oleic acid as the oil phase, op-10 as the emulsifier, and PEG-200 as the coemulsifier. The percentage of oil phase, emulsifier, and co-emulsifier phases in the formulation was examined to investigate its effect on nanoemulsion formation. The best prescription was finally determined: oleic acid-op-10-PEG-200-water=6%: 28%: 9.33%: 56.67%, and the drug content was 0.25%. In addition, a series of quality studies were conducted on the prepared nanoemulsions. The results indicated that the average grain diameter of nanoemulsion was 24.1±3.8 nm, the polydispersity index (PDI) was 0.261±0.032, and the absolute value of Zeta mean was more than 20, indicating that the prepared nanoemulsion had good stability; the appearance was observed by transmission electron microscope. Regularly round. Long-term and accelerated experiments have demonstrated that the stability of nanoemulsions is very good, and by measuring, the solubility of cinacalc hydrochloride in nanoemulsions has also been greatly improved.

This study shows that nanoemulsion, as a novel drug carrier, can not only improve drug solubility, but also increase the blood drug concentration in the body and improve the bioavailability of the drug when the water-soluble drug cinacalcet is poor. The results of this study also provide a scientific basis for the clinical application of cinacalcet hydrochloride nanoemulsion.

Key words: Cinacalse hydrochloride; Nanoemulsion; Bioavailability

目录

摘要 I

Abstract III

第一章 文献综述

1.1研究背景

1.2 盐酸西那卡塞简介

1.2.1 盐酸西那卡塞的性质及应用

1.2.2 盐酸西那卡塞的药理作用

1.2.3 盐酸西那卡塞的作用机制

1.3 纳米乳给药系统简述

1.3.1 纳米乳的发展及应用

1.3.2纳米乳的构成

1.3.3纳米乳的制备方法

1.4 立题依据以及主要研究内容

1.4.1 立题依据

1.4.2主要研究内容

第二章 盐酸西那卡塞体外分析方法的建立

2.1 引言

2.2 实验部分

2.2.1 实验材料与仪器

2.2.2 盐酸西那卡塞最大吸收波长的确定

2.2.3 盐酸西那卡塞体外分析方法的建立

2.3 结果与讨论

2.3.1 盐酸西那卡塞最大吸收波长的确定

2.3.2 CLC体外分析方法的建立

2.4 本章小结

第三章 盐酸西那卡塞纳米乳的制备、表征及质量评价

3.1 引言

3.2 实验部分

3.2.1 实验材料与仪器

3.2.2 筛选纳米乳处方

3.2.3 伪三元相图法处方优化

3.2.4 纳米乳的制备

3.2.5 纳米乳的表征

3.2.6 纳米乳的质量评价

3.3 实验结果与讨论

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