本文選題：鹽酸替羅非班 + 質(zhì)量研究�。� 參考：《成都中醫(yī)藥大學》2014年碩士論文

【摘要】：鹽酸替羅非班(Tirofiban Hydrochloride),化學名為N-正丁基磺�；�-0-[4-(4-哌啶基)丁基]-L-酪氨酸鹽酸鹽一水合物,是一種非肽類血小板表面糖蛋白GPⅡb/Ⅲa受體拮抗劑,臨床常用于治療急性冠狀脈綜合癥,包括不穩(wěn)定性心絞痛或非Q波心肌梗死患者,以及行徑皮腔內(nèi)冠狀動脈成形術或動脈粥樣斑塊切除術的患者。本課題的主要目的是研制與市售品質(zhì)量一致的鹽酸替羅非班注射液。質(zhì)量源于設計(Quality by Design, QbD),為了縮小自制鹽酸替羅非班注射液與原研產(chǎn)品之間的差距,該課題對原料藥的穩(wěn)定性、注射液處方設計、注射液工藝路線的確定、自制產(chǎn)品的質(zhì)量等進行了詳細的考察,具體內(nèi)容如下： 1、鹽酸替羅非班注射液相關的基礎研究 鹽酸替羅非班注射液相關的基礎研究主要包括用于制劑的原料藥與輔料的研究。原料藥的研究主要包括強制降解試驗以及影響因素試驗,用于初步考察原料藥的穩(wěn)定性,結果發(fā)現(xiàn)其耐受性好,對熱相對穩(wěn)定。同時根據(jù)其質(zhì)量屬性對制劑進行風險評估,為制劑工藝研究提供依據(jù)；輔料的研究主要包括氯化鈉、氫氧化鈉以及活性炭的研究。 2、鹽酸替羅非班注射液的工藝研究 影響仿制藥與原研產(chǎn)品質(zhì)量的關鍵因素為制劑因素,因此本實驗對鹽酸替羅非班注射液的工藝進行了詳細的研究,主要包括兩個方面：(1)劑型的選擇、規(guī)格、處方中主藥與輔料的組成與用量；(2)配制過程中的各種關鍵工藝參數(shù)的考察,包括藥液的PH范圍,最佳配液溫度,活性炭的用量,產(chǎn)品殘氧量,滅菌條件及包材的相容性的考察。 3、鹽酸替羅非班注射液的質(zhì)量標準研究 由于鹽酸替羅非班注射液未收載于藥典之中,因而只有查閱相關文獻及標準對其質(zhì)量進行評價。參考鹽酸替羅非班氯化鈉注射液注冊試行標準(YBH12132004)和鹽酸替羅非班注射液進口注冊標準(JX20080265),本課題著重對其專屬性檢查項(有關物質(zhì)、含量、異構體)的檢查方法進行了優(yōu)化與驗證,最終確定的了有關物質(zhì)的檢查方法為以乙腈為流動相A,0.025mol/L KH2P04溶液(三乙胺調(diào)pH至6.8)-乙腈(80：20)為流動相B,進行如下梯度洗脫：T (min)/B(V/V)0/100,10/95,20/94,20/94,30/81,50/81,55／100；含量HPLC檢測方法為以0.025mol/L KH2PO4溶液(三乙胺調(diào)pH至6.8)-乙腈(78：22)為流動相等度洗脫；異構體的檢測方法為正己烷-異丙醇-甲醇-7二胺-冰醋酸(300：400：300：3：3)。對于其他的如pH值、不溶性微粒等均采用2010年版藥典附錄規(guī)定方法進行檢測,未專門進行考察。 4、鹽酸替羅非班注射液與原研產(chǎn)品的質(zhì)量一致性研究 為了考察自制酸替羅非班注射液與原研品(艾卡特)的區(qū)別,本實驗做了以下幾個方面考察：(1)比較中試產(chǎn)品與原研品在有關物質(zhì),pH,含量,外觀性狀等方面的差異(2)考察自制產(chǎn)品與肝素鈉配伍試驗,觀察結果是否與市售品配伍試驗結果描述一致(3)將中試產(chǎn)品與原研產(chǎn)品同置于影響因素試驗、加速試驗、長期試驗條件下進行考察,比較二者有關物質(zhì),pH,含量,外觀性狀等方面的差異。
[Abstract]:Tirofiban (Tirofiban Hydrochloride), a chemical named N- n-butyl sulfonyl -0-[4- (4- piperidine) butyl]-L- tyrosine monohydrate, is a non peptide platelet surface glycoprotein GP II b/ III a receptor antagonist. It is commonly used in the treatment of acute coronary vein syndrome, including unstable angina or non Q wave myocardial infarction. Dead patients, and patients with percutaneous transluminal coronary angioplasty or atheromatectomy. The main purpose of this project is to develop Tirofiban Hydrochloride Injection that is in line with the quality of the market products. The quality is based on the design (Quality by Design, QbD), in order to narrow the gap between the homemade Tirofiban Hydrochloride Injection and the original product. In this subject, the stability of the API, the design of the injection prescription, the determination of the injection process route and the quality of the homemade products were investigated in detail. The specific contents are as follows:
1, the basic research related to Tirofiban Hydrochloride Injection
The basic research related to Tirofiban Hydrochloride Injection mainly includes the study of raw materials and excipients used for preparation. The research of the API mainly includes the forced degradation test and the influence factor test, which is used to investigate the stability of the API initially. The results show that the drug is well tolerated and the heat is relatively stable. Risk assessment is to provide basis for preparation process research; the study of excipients mainly includes sodium chloride, sodium hydroxide and activated carbon.
2, research on the process of Tirofiban Hydrochloride Injection
The key factors affecting the quality of generic drugs and original products are preparation factors. Therefore, this experiment has carried out a detailed study on the process of Tirofiban Hydrochloride Injection, including two aspects: (1) the selection of the dosage forms, the specifications, the composition and dosage of the main drugs and excipients in the prescription, and (2) the investigation of the key technological parameters in the preparation process, It includes the PH range of the liquid medicine, the optimum temperature of the solution, the amount of activated carbon, the oxygen content of the product, the sterilization condition and the compatibility of the package.
3, research on the quality standard of Tirofiban Hydrochloride Injection
Since Tirofiban Hydrochloride Injection has not been collected in the Pharmacopoeia, it has only consulted the relevant documents and standards to evaluate its quality. With reference to the Tirofiban hydrochloride Sodium Chloride Injection registration test standard (YBH12132004) and the Tirofiban Hydrochloride Injection import registration standard (JX20080265), this topic focuses on its specificity inspection items ( The inspection method of material, content and isomer was optimized and verified. The final determination method of the related substances was the liquid phase A with acetonitrile, 0.025mol/L KH2P04 solution (three ethylamine pH to 6.8) - acetonitrile (80:20) as the mobile phase B, and the following gradient elution was made: T (min) /B (V/V) 0/100,10/95,20/94,20/94,30/81,50/81,55 / 100 The content HPLC detection method is 0.025mol/L KH2PO4 solution (three ethylamine pH to 6.8) - acetonitrile (78:22) as the flow equality; isomer detection method is hexane - isopropanol - methanol, -7 two amine - glacial acetic acid (300:400:300:3:3). For other such as pH value, insoluble particles, and so on using the 2010 Edition of the Pharmacopoeia appendix The method was tested, and no special investigation was carried out.
4, quality consistency between Tirofiban Hydrochloride Injection and original research products
In order to investigate the difference between the self-made acid tirobiban injection and the original research product (Eckart), the experiment was studied in the following aspects: (1) to compare the differences between the pilot products and the original products in the related substances, pH, content, and appearance characters (2) to investigate the compatibility test of home-made products and hepatin sodium, and whether the observation results were compatible with the market products. The fruit description is consistent (3) the pilot products are placed in the influence factor test, the accelerated test and the long-term test conditions are carried out to compare the differences in the related substances, pH, content and appearance properties of the two parties.
【學位授予單位】：成都中醫(yī)藥大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R927.1

【參考文獻】

相關期刊論文 前1條

1 葉家林;李宏名;曹勝華;丁小東;;鹽酸替羅非班的合成[J];化學研究與應用;2012年05期

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本文編號：2107966