藥用輔料拉曼光譜庫構(gòu)建及其初步應(yīng)用
發(fā)布時間：2019-07-10 12:14
【摘要】：近年來發(fā)生的“齊二藥”事件、毒膠囊事件、以及大劑量采用吐溫80等助溶劑所造成的不良反應(yīng)等，深刻警示我們藥用輔料再也不是無活性、無危害的輔助性材料。有毒輔料不僅嚴(yán)重危害著人民群眾用藥安全與身體健康，而且不法分子利用不合格輔料攪亂醫(yī)藥市場的正常發(fā)展。目前，國際市場由于新材料、新劑型的開發(fā)應(yīng)用，輔料種類繁多，而國內(nèi)市場藥用輔料市場正處于初步上升期，生產(chǎn)水平不均衡導(dǎo)致藥用輔料質(zhì)量殘差不齊，假冒偽劣現(xiàn)象時有發(fā)生。如何解決藥用輔料在源頭、流通過程中、生產(chǎn)時的定性問題對分析檢測技術(shù)的能力提出了很大挑戰(zhàn)。分析檢測技術(shù)的推廣有賴于分析檢測技術(shù)的各項指標(biāo)包括快速性、簡便性、經(jīng)濟(jì)性以及準(zhǔn)確性等。用于藥用輔料大體分為三種分析方法：化學(xué)法、色譜法、光譜法等。其中，拉曼光譜技術(shù)具備簡單、快速、靈敏、無需樣品處理、特征豐富等獨特優(yōu)勢，已有較為廣泛的報道。 本論文首先概述了質(zhì)譜和光譜領(lǐng)域譜庫應(yīng)用核心算法，這些算法在建庫領(lǐng)域應(yīng)用較為成熟，借鑒意義很大。然后在準(zhǔn)備建庫的藥用輔料相關(guān)基本信息收集完整的基礎(chǔ)上，使用便攜式拉曼光譜儀采集藥用輔料拉曼光譜，經(jīng)過剪切平滑基線糾正預(yù)處理后構(gòu)建光譜庫，對各輔料的特征峰做解析并繪制特征峰樹狀圖，最后本文使用相似度算法和特征峰樹狀圖相結(jié)合的方法對未知藥用輔料樣品做定性鑒別，并在輔料建庫的基礎(chǔ)上，對仿冒藥及原研藥做定性判別。 第一部分概述�；瘜W(xué)計量學(xué)應(yīng)用數(shù)學(xué)和統(tǒng)計學(xué)、化學(xué)和計算機(jī)科學(xué)及其他學(xué)科的理論和方法，通過對化學(xué)數(shù)據(jù)的解析，最大限度地獲取有用的化學(xué)信息。目前，在質(zhì)譜和光譜建庫領(lǐng)域，合適的計量學(xué)方法得到廣泛應(yīng)用。質(zhì)譜譜庫檢索的應(yīng)用已經(jīng)成為蛋白質(zhì)組學(xué)、植物代謝組學(xué)研究的可靠手段。光譜建庫方法在如藝術(shù)品真假鑒別、司法鑒定、化學(xué)結(jié)構(gòu)式推斷方面有了廣泛應(yīng)用。這些領(lǐng)域的相關(guān)算法值得我們借鑒并用于藥用輔料拉曼光譜建庫和應(yīng)用。拉曼光譜技術(shù)提供了快速、簡單、靈敏且非破壞性的檢測分析，用于藥品分析中的研究報道日漸增多。本課題通過借鑒以上方法，建立了藥用輔料的拉曼光譜庫，目的是為藥用輔料的的現(xiàn)場快檢提供一種完整有效的解決方案。 第二部分藥用輔料拉曼光譜構(gòu)建。隨著國內(nèi)對藥用輔料市場監(jiān)管力度加強(qiáng)，建立可靠的拉曼光譜數(shù)據(jù)庫切實可行，目前，已有的拉曼光譜數(shù)據(jù)庫如Satler，Thermo數(shù)據(jù)庫，這些數(shù)據(jù)庫價格昂貴、未作出結(jié)構(gòu)解析、不適合國內(nèi)藥用輔料市場應(yīng)用。本論文收集整理了正規(guī)來源的145個藥用輔料，其中不同種類91個，收集名稱、廠家、用途等相關(guān)信息。在采集拉曼光譜圖后，經(jīng)過預(yù)處理，對藥用輔料的特征峰整理，并對拉曼光譜特征峰進(jìn)行光譜解析，最終將藥用輔料按結(jié)構(gòu)整理歸類為8類：多糖類、聚合物類、酯類及長鏈烴類、含羧基基團(tuán)類、單糖二糖及多元醇類、氨基酸及其鹽類、含硫無機(jī)鹽、含磷無機(jī)鹽類。根據(jù)特征峰所在拉曼光譜譜段及相對強(qiáng)度繪制這些種類特征峰樹狀圖。 第三部分藥用輔料光譜庫的初步應(yīng)用。針對國內(nèi)同種輔料廠家生產(chǎn)工藝不同、生產(chǎn)能力參次不齊、部分輔料命名不規(guī)范、輔料市場亟需加強(qiáng)管理等現(xiàn)狀，本文考察了三種預(yù)處理方法，不同閾值及其結(jié)合相似度算法鑒別未知藥用輔料，并考察哪種優(yōu)勢預(yù)處理方法與樹狀圖相結(jié)合后結(jié)果較理想。其中一階導(dǎo)數(shù)結(jié)合閾值0.9結(jié)果最佳，與樹狀圖定性未知藥用輔料。同時證明庫內(nèi)樣品增多后，結(jié)果與庫擴(kuò)增前一致。同時，本研究以市場上出現(xiàn)的采用藥典方法不能鑒別的仿冒藥，應(yīng)用相似度算法與特征峰樹狀圖及主成分分析相結(jié)合的方法，以苯磺酸氨氯地平片為工具藥，鑒別了其仿冒藥與原研藥。 本論文使用拉曼光譜法構(gòu)建藥用輔料光譜庫，用于藥用輔料的快速定性鑒別，具有廣闊的應(yīng)用前景。首先總結(jié)質(zhì)譜和光譜建庫方法的應(yīng)用領(lǐng)域與核心算法，在此基礎(chǔ)上，研究搜集的145個藥用輔料，其中包含了不同種類輔料91種，將藥用輔料類型按照結(jié)構(gòu)劃分為8個種類。在光譜解析的基礎(chǔ)上，根據(jù)特征峰繪制特征峰樹狀圖，這對于后續(xù)藥用輔料加入建庫分類有提示作用，并建立了一套較為完整的藥用輔料鑒別系統(tǒng)。同時本論文不僅僅是簡單的歸納總結(jié)藥用輔料，并且初步應(yīng)用藥用輔料庫，，解決了現(xiàn)實應(yīng)用中如何快速準(zhǔn)確鑒別片劑原研藥與仿冒藥，為監(jiān)管藥用輔料及片劑質(zhì)量貢獻(xiàn)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.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R927
本文編號：2512599
[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.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R927
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