【摘要】：氯胺酮（Ketamine）是苯環(huán)己哌啶（Phencyclidine，，PCP）類衍生物，作為臨床唯一具有鎮(zhèn)痛性的靜脈全麻藥，是國家基本藥物目錄（2012版）品種。氯胺酮1962年合成成功，1965年首次應(yīng)用于臨床，國內(nèi)于1973年開始生產(chǎn)。由于氯胺酮的特殊藥理作用，其濫用問題愈演愈烈，特別是在歌廳舞廳等娛樂場所濫用氯胺酮的現(xiàn)象較為嚴重和普遍，因此氯胺酮被列入毒品范疇。目前氯胺酮及其鹽酸鹽和制劑按國家第一類精神藥品管理。 本文對鹽酸氯胺酮的雜質(zhì)進行系統(tǒng)研究，同時建立鹽酸氯胺酮及其制劑有關(guān)物質(zhì)檢查新方法，為該品種的質(zhì)量標準提高提供實驗依據(jù)。本課題主要包括以下三個部分：一、通過對我國現(xiàn)有鹽酸氯胺酮制備工藝的調(diào)研，總結(jié)出我國現(xiàn)存工藝條件下可能帶入的過程雜質(zhì)（羥亞胺），并針對該雜質(zhì)，建立專屬性強、靈敏度高的HPLC方法，用于該品種的有關(guān)物質(zhì)檢查和含量測定，并使用新建立的方法對9批不同批號的鹽酸氯胺酮注射液進行測定。希望通過實驗獲得的數(shù)據(jù)，為今后鹽酸氯胺酮原料及其制劑的質(zhì)量提高提供依據(jù)，進而提高該品種制劑的質(zhì)量。二、經(jīng)過檢索國內(nèi)外主要文獻庫，并未發(fā)現(xiàn)關(guān)于鹽酸氯胺酮及其已知過程雜質(zhì)羥亞胺毒性的相關(guān)報道。為了對雜質(zhì)羥亞胺進行科學(xué)合理的控制，從以下兩方面對鹽酸氯胺酮和羥亞胺毒性進行研究：①從細胞水平對鹽酸氯胺酮和羥亞胺進行增殖抑制試驗，比對二者對細胞增殖過程的抑制性；②選用國際認可度較高的斑馬魚為載體，對鹽酸氯胺酮和羥亞胺胚胎發(fā)育毒性和神經(jīng)毒性進行研究，從而彌補細胞增殖抑制試驗的不足。通過上述兩方面的研究使得該品種新質(zhì)量標準的擬定工作更加具備科學(xué)性、合理性和準確性。三、對鹽酸氯胺酮的有關(guān)物質(zhì)進行進一步分析研究。依據(jù)《化學(xué)藥物雜質(zhì)研究的技術(shù)指導(dǎo)原則》，將鹽酸氯胺酮于強酸、強堿、熱、光照以及氧化等條件下進行強制破壞，并利用HPLC、NMR、MS、UV等技術(shù)對未知雜質(zhì)進行初步定性。鹽酸氯胺酮作為公安機關(guān)重點打擊的毒品之一，對其有關(guān)物質(zhì)的進一步分析，有助于公安機關(guān)的毒品稽查以及毒品來源的追蹤。 通過一整套實驗，我們對鹽酸氯胺酮原料及制劑有關(guān)物質(zhì)進行了系統(tǒng)研究，同時建立了更為專屬、靈敏的HPLC檢測方法，為該品種的質(zhì)量標準提高工作做了充分準備。
[Abstract]:Ketamine (Ketamine) is a derivative of benzocyclohexidime (Phencyclidine,PCP), which is the only intravenous general anesthetic with analgesic effect in clinic and is a national essential drug catalogue (version 2012). Ketamine was successfully synthesized in 1962, first used in clinical practice in 1965 and started production in China in 1973. Because of the special pharmacological action of ketamine, the abuse of ketamine becomes more and more serious, especially the phenomenon of ketamine abuse in entertainment places such as ballroom and dance hall is serious and widespread, so ketamine is included in the category of drugs. Ketamine and its hydrochloride and preparations are currently administered according to the first class of state psychotropic drugs. In this paper, the impurity of ketamine hydrochloride is systematically studied, and a new method for the examination of ketamine hydrochloride and its related substances is established, which provides experimental basis for improving the quality standard of ketamine hydrochloride. This paper mainly includes the following three parts: first, through the investigation of the existing preparation process of ketamine hydrochloride in China, the process impurity (hydroxyimide) that may be brought in under the existing technological conditions in our country is summarized, and the specificity of this impurity is established. The HPLC method with high sensitivity was used for the determination of related substances in this variety and nine batches of ketamine hydrochloride injection with different batches were determined by the newly established method. It is hoped that the data obtained from the experiment will provide the basis for improving the quality of ketamine hydrochloride feedstock and its preparation in the future, and then improve the quality of this variety of preparation. Secondly, there were no reports on the toxicity of ketamine hydrochloride and its process impurity, hydroxyimide, after searching the main library at home and abroad. In order to control the impurity hydroxyimide scientifically and reasonably, the toxicity of ketamine hydrochloride and imine hydrochloride was studied from the following two aspects: 1. The proliferation inhibition test of ketamine hydrochloride and imine was carried out at the cell level. In order to make up for the deficiency of cell proliferation inhibition test, the inhibitory effect of the two methods on cell proliferation was studied by using zebrafish with high international recognition as carrier to study the developmental toxicity and neurotoxicity of ketamine hydrochloride and hydroxyimide. The new quality standard is more scientific, reasonable and accurate. Third, the related substances of ketamine hydrochloride were further analyzed and studied. According to the Technical guidelines for the study of Chemical Drug impurities, ketamine hydrochloride was forced to destroy under the conditions of strong acid, strong base, heat, light and oxidation, and the unknown impurity was preliminarily determined by HPLC,NMR,MS,UV technique. Ketamine hydrochloride is one of the most important drugs in public security organs. The further analysis of its related substances will be helpful to the investigation of drugs and the tracing of drug sources in public security organs. Through a whole set of experiments, we made a systematic study on the related substances of ketamine hydrochloride raw materials and preparations, and established a more specific and sensitive HPLC detection method, which made a good preparation for improving the quality standard of the product.
【學(xué)位授予單位】：中國食品藥品檢定研究院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R943

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