药用辅料拉曼光谱库构建及其初步应用

发布时间：2019-07-10 12:14

【摘要】：近年来发生的“齐二药”事件、毒胶囊事件、以及大剂量采用吐温80等助溶剂所造成的不良反应等，深刻警示我们药用辅料再也不是无活性、无危害的辅助性材料。有毒辅料不仅严重危害着人民群众用药安全与身体健康，而且不法分子利用不合格辅料搅乱医药市场的正常发展。目前，国际市场由于新材料、新剂型的开发应用，辅料种类繁多，而国内市场药用辅料市场正处于初步上升期，生产水平不均衡导致药用辅料质量残差不齐，假冒伪劣现象时有发生。如何解决药用辅料在源头、流通过程中、生产时的定性问题对分析检测技术的能力提出了很大挑战。分析检测技术的推广有赖于分析检测技术的各项指标包括快速性、简便性、经济性以及准确性等。用于药用辅料大体分为三种分析方法：化学法、色谱法、光谱法等。其中，拉曼光谱技术具备简单、快速、灵敏、无需样品处理、特征丰富等独特优势，已有较为广泛的报道。本论文首先概述了质谱和光谱领域谱库应用核心算法，这些算法在建库领域应用较为成熟，借鉴意义很大。然后在准备建库的药用辅料相关基本信息收集完整的基础上，使用便携式拉曼光谱仪采集药用辅料拉曼光谱，经过剪切平滑基线纠正预处理后构建光谱库，对各辅料的特征峰做解析并绘制特征峰树状图，最后本文使用相似度算法和特征峰树状图相结合的方法对未知药用辅料样品做定性鉴别，并在辅料建库的基础上，对仿冒药及原研药做定性判别。第一部分概述。化学计量学应用数学和统计学、化学和计算机科学及其他学科的理论和方法，通过对化学数据的解析，最大限度地获取有用的化学信息。目前，在质谱和光谱建库领域，合适的计量学方法得到广泛应用。质谱谱库检索的应用已经成为蛋白质组学、植物代谢组学研究的可靠手段。光谱建库方法在如艺术品真假鉴别、司法鉴定、化学结构式推断方面有了广泛应用。这些领域的相关算法值得我们借鉴并用于药用辅料拉曼光谱建库和应用。拉曼光谱技术提供了快速、简单、灵敏且非破坏性的检测分析，用于药品分析中的研究报道日渐增多。本课题通过借鉴以上方法，建立了药用辅料的拉曼光谱库，目的是为药用辅料的的现场快检提供一种完整有效的解决方案。第二部分药用辅料拉曼光谱构建。随着国内对药用辅料市场监管力度加强，建立可靠的拉曼光谱数据库切实可行，目前，已有的拉曼光谱数据库如Satler，Thermo数据库，这些数据库价格昂贵、未作出结构解析、不适合国内药用辅料市场应用。本论文收集整理了正规来源的145个药用辅料，其中不同种类91个，收集名称、厂家、用途等相关信息。在采集拉曼光谱图后，经过预处理，对药用辅料的特征峰整理，并对拉曼光谱特征峰进行光谱解析，最终将药用辅料按结构整理归类为8类：多糖类、聚合物类、酯类及长链烃类、含羧基基团类、单糖二糖及多元醇类、氨基酸及其盐类、含硫无机盐、含磷无机盐类。根据特征峰所在拉曼光谱谱段及相对强度绘制这些种类特征峰树状图。第三部分药用辅料光谱库的初步应用。针对国内同种辅料厂家生产工艺不同、生产能力参次不齐、部分辅料命名不规范、辅料市场亟需加强管理等现状，本文考察了三种预处理方法，不同阈值及其结合相似度算法鉴别未知药用辅料，并考察哪种优势预处理方法与树状图相结合后结果较理想。其中一阶导数结合阈值0.9结果最佳，与树状图定性未知药用辅料。同时证明库内样品增多后，结果与库扩增前一致。同时，本研究以市场上出现的采用药典方法不能鉴别的仿冒药，应用相似度算法与特征峰树状图及主成分分析相结合的方法，以苯磺酸氨氯地平片为工具药，鉴别了其仿冒药与原研药。本论文使用拉曼光谱法构建药用辅料光谱库，用于药用辅料的快速定性鉴别，具有广阔的应用前景。首先总结质谱和光谱建库方法的应用领域与核心算法，在此基础上，研究搜集的145个药用辅料，其中包含了不同种类辅料91种，将药用辅料类型按照结构划分为8个种类。在光谱解析的基础上，根据特征峰绘制特征峰树状图，这对于后续药用辅料加入建库分类有提示作用，并建立了一套较为完整的药用辅料鉴别系统。同时本论文不仅仅是简单的归纳总结药用辅料，并且初步应用药用辅料库，，解决了现实应用中如何快速准确鉴别片剂原研药与仿冒药，为监管药用辅料及片剂质量贡献一份力量。
[Abstract]:In recent years, the "Qi Eryao" events, the toxic capsule events, and the adverse reactions caused by the large dosage of the co-solvent such as Tween 80 and the like have been deeply warned that the medicinal auxiliary materials are no longer active and have no harmful auxiliary materials. The toxic and auxiliary materials not only seriously endanger the people's safety and health, but also use the unqualified auxiliary materials to stir up the normal development of the medical market. At present, due to the development and application of new materials and new dosage forms in the international market, the types of auxiliary materials are various, and the market of pharmaceutical auxiliary materials in the domestic market is in the initial rising period, the production level is not balanced, the quality residual of the medical auxiliary materials is not uniform, and the fake and shoddy phenomenon occurs frequently. It is a great challenge to the ability of the analysis and detection technology to solve the qualitative problems in the process of source and circulation. The extension of the analysis and detection technology depends on the speed, simplicity, economy and accuracy of the analysis and detection technology. The medicinal auxiliary materials are generally divided into three analytical methods: chemical method, chromatography, spectroscopy, etc. In which, the Raman spectrum technology has the unique advantages of simple, rapid and sensitive, no need of sample processing, rich characteristics and the like, and has a wide range of reports. In this paper, the core algorithms of the spectral library in the mass spectrum and the spectral domain are summarized, and the application of these algorithms in the library is more mature and the reference is very important. And collecting a complete basis information on the basic information related to the medicinal auxiliary materials of the building library, collecting the medicinal auxiliary material Raman spectrum by using the portable Raman spectrometer, correcting the pre-treatment by the shearing and smoothing baseline, building a spectrum library, and analyzing the characteristic peaks of each auxiliary material and drawing the characteristic peak tree. In the end, the method of similarity algorithm and characteristic peak tree is used for the qualitative identification of unknown medicinal auxiliary materials, and on the basis of the material building of the auxiliary materials, the counterfeit medicine and the original medicine are judged qualitatively. Don't. The first one The theory and method of the application of mathematical and statistical, chemical and computer science and other subjects in chemometrics. In that field of mass spectrometry and spectral building, suitable metrology methods have been widely used in the field of mass spectrometry and spectral building. The application of the mass spectrum library search has become the proteomics and the research of the plant metabolomics. By means of the method, the method of spectral building is widely used in the identification of the true and false of the art, the authentication of the forensic and the chemical structure. The relevant algorithms in these fields are useful for reference and use in the Raman spectroscopy of pharmaceutical excipients. And the application of the Raman spectrum technology provides a rapid, simple, sensitive and non-destructive detection analysis, which is used for researching and reporting the drug analysis. The purpose of this study is to provide a complete and effective solution for the on-site rapid detection of pharmaceutical excipients by using the above method. the second part of the medicinal auxiliary material In the light of the strengthening of the market supervision of the pharmaceutical excipients in China, it is feasible to establish a reliable Raman spectrum database. At present, the existing Raman spectrum database, such as the Satler and the Thermo database, is expensive, and the structure analysis is not made. It is not suitable for medical and auxiliary in the country. This paper has collected 145 pharmaceutical excipients from the regular source, among which 91 of the different kinds, the collection name, the manufacturer and the application and carrying out spectrum analysis on the characteristic peak of the Raman spectrum, and finally, the medicinal auxiliary materials are classified into 8 groups according to the structure, and the polysaccharide, the polymer type, the ester and the long-chain hydrocarbon group a base group, a monosaccharide disaccharide and a polyhydric alcohol, an amino acid and a salt thereof, a sulfur-containing inorganic salt, according to the Raman spectrum of the characteristic peak and the relative intensity, peak-to-peak tree; third part of the pharmaceutical adjuvant light The preliminary application of the spectrum library is as follows: the production process of the domestic and auxiliary materials factory is different, the production capacity is different, the naming of some auxiliary materials is not standardized, the auxiliary material market is in urgent need of strengthening the management, and the like, the three pre-processing methods, the different threshold values and the combination similarity algorithm are discussed in this paper. don't know the pharmaceutical excipients, and look at which of the dominant pre-treatment methods are in phase with the tree The results of the combination of the first derivative and the threshold of 0.9 are the best, and the result is similar to that of the tree. The medical auxiliary materials with unknown sex are also shown. The results are as follows: after the internal sample is increased, the results It is consistent with the pre-amplification of the library. At the same time, the present study uses the method of combining the similarity algorithm with the characteristic peak tree diagram and the main component analysis to identify the amlodipine besylate tablet as a tool and the method of combining the similarity algorithm with the characteristic peak tree diagram and the main component analysis, The invention uses the Raman spectroscopy to construct a medicinal auxiliary material spectrum library, and is used for rapid and qualitative identification of medicinal auxiliary materials, In this paper, the application field and the core algorithm of mass spectrum and spectral building method are summarized, and 145 medical auxiliary materials are collected, including 91 kinds of auxiliary materials, and the types of medicinal auxiliary materials are as follows: The structure is divided into 8 types. On the basis of the analysis of the spectrum, the characteristic peak tree is drawn according to the characteristic peak, which is helpful for the following medicinal auxiliary materials to be added into the building library classification, and a complete set of characteristic peaks is established The medical auxiliary material identification system is not only a simple induction and a summary medicinal auxiliary material, but also a medicinal auxiliary material library is applied to a preliminary application, so that the traditional medicine and the counterfeit medicine of the tablet can be quickly and accurately identified in the real application, and the pharmaceutical auxiliary material and the tablet are used for the supervision of the medicinal auxiliary materials and the tablets.
【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R927

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