【作者】 管清香；

【导师】 王恩思；

【作者基本信息】 吉林大学 ， 生物化学与分子生物学， 2008， 博士

【摘要】 本课题首先测定了抗艾滋病新药地拉韦啶的pKa值及分配系数,并采用X-射线粉末衍射等技术进行了多晶型的鉴别,研究了不同条件下晶型的转变,测定了高温等影响因素对多晶型的影响,为进一步研究奠定了基础。按照国家化药3类新药的报批要求,首先对已经合成出的地拉韦啶原料进行了系统的质量研究,建立了其质量标准(草案)。对其进行了新剂型的研究,通过正交设计法进行处方的优化,制备了地拉韦啶分散片,并通过一系列的质量研究,建立了地拉韦啶分散片的质量标准(草案)。对原料药及其制剂进行了初步稳定性考察,并按照化药3类新药要求形成了申报材料,已报国家食品药品监督管理局审批。将具有免疫调节等多种药理作用的白藜芦醇分子连接到抗HIV的地拉韦啶中间体上,期望合成抗HIV-1变异性更强、具有自主知识产权的抗艾滋病新药,并进行了体外活性的初步研究。体外活性测定结果表明,地拉韦啶衍生物可抑制HIV-1逆转录酶的转录,EC50为4.54μM,对感染细胞的抑制率达95%。原料药及其制剂的各项研究结果,为该药的临床前研究提供了可靠的理论依据。合成的新型抗HIV药物为艾滋病的治疗提供了新的研究思路,其研究结果为其进一步研究开发奠定了理论基础。更多还原

【Abstract】 AIDS is an acquired human immunedeficiency syndrome, which is caused by retrovirus HIV. Since the first AIDS sufferer was reported in 1981, 70 million pepole have been infected with HIV in the world and 20 million of them died fom AIDS. AIDS has become one of main menaces to human health. Generally speaking, AIDS is serious infection disease which can destroy human immunity system, cause human body to lose resistent ability against all kinds of pathogeny, then result in various infections or tumours and finally lead human to death. HIV bring out different degree resistance to drugs applied in HIV treatment beause of HIV uninterrupt mutation. Though death rate of AIDS have descended after applying potent anti-AIDS drugs, the sum of global AIDS patients still rise with tendency of index number. It will provide a novel idea for AIDS treatment if a new drug with the antivirus activity and the ability to proving human immunity be developed.At present, AIDS has been spreaded in China. The patients infected with HIV have been found in 31 provinces, autonomous region and municipality directly under the Central Government. Ministry of Public Health, the United Nations AIDS project office and World Health Organization together proclaimed that there were 700 thousand AIDS viral infection persons and AIDS patients of which 85 thousand AIDS patients inChina by the end of 2007. Relevant expert analyze that there will be one million AIDS viral infection person by the end of 2010 in China if no effective steps were taken. Though the price of imported anti-HIV drugs has been decreased recently, it’s impossible to afford for the AIDS patients who live in the region of poor economy and bad medical condition.It’s necessary that we should produce the anti-AIDS drugs with definite therapeutic effect and reasonable price. The expense of drugs will descreased from eighty thousand to 4～5 thousand after they buy the anti-AIDS drugs produced in China. We should accelerate to develope a anti-AIDS drugs possessing autonomic and intellectual property rights when we replicate the anti-AIDS drugs that won’t be about to be protected in order to cut down the drug expense.Delavirdine mesylate would have a potent antiviral effect when it coadministrated with nucleoside reverse transcriptase such as zidovudine or with ptotein inhibitors. So far, Delavirdine mesylate haven’t been reported and produced in China. So it will bring economic and social significance if delavirdine mesylate is manufactured.For all the above reasons, the experiment was arranged as the following: fistly, The dissociation constant and partition coefficient were determined and polymorphism was identified, which establish a base advanced study. Secondly, the quality control of dalavirdine mesylate and its preparation were investigated. The corresponding quality criteria was established according to the investigated results of quality control. Thirdly, the study of primary stability was carried out. All the data were summed up based on the request of SFDA and send to SFDA. Natural compound possessing immunomodulation effect was linked to anti-HIV drug in order to synthesize a novel anti-AIDS drug possessing potent anti-HIV-1 variability and the ability of aelevating the immunity.The dissociation constant was determined with acid-base titration method and the partition coefficient was determined with bottle-shaking method by HPIC. The pKa and P of mesylate delavirdine in n-octyl alcohol were 4.635 and 2.907 respectively. Polymorphism of Delavirdine mesylate was identified by the techniques such as X-ray power diffraction. Polymorphism transition and the factors affecting the polymorphism stability were investigated. All the above results provide certain foundation of advanced study.Delavirdine mesylate was identified indluding the methods such as physical and chemical property, infrared spectra and HPLC. The content and relative substance was determined by HPLC. The organic solvent from delvirdine mesylate was investigated by GC. Moreover, loss of drying, arsenicum and heavy metals were investigated. Quality criteria was formulated on the basis of the above results and it is suitable to control delavirdine mesylate.The stability to the three batches of delavirdine mesylate was carried out on the basis of its quality criteria. The results indicated that characters, discriminations, contents, relative substances and the hygiology index of delavirdine mesylate had no obvious variety and can meet various regulation of the standard drafted plan of quantity, which prove that the stability of raw drug meet the new medicine requirement under the condition of indoor temperature.The orthogonal design was applied to optimize formulation with disintegrated time and dissolution rates in vitro as consideration index. The dissolution rates in vitro, disintegration time and dispersion uniformity were determined. The content and relative substance was determined by HPLC. Quality criteria was formulated on the basis of the above results and it is suitable to control delavirdine mesylate dispersible tablets. Its quality reached the standard of Chp.2000 and the dissolution rate in vitro was faster than marketed tablet.The stability to the three batches of delavirdine mesylatediset dispersible tablets was carried on the basis of its quality criteria. The results indicated that characters, discriminations, water content, disintegrated time, dissolution rates, contents, relative substances and the hygiology index in delavirdine mesylate dispersible tablets had no obvious variety and can meet various regulation of the standard drafted plan of quantity, which prove that the stability of dispersible tablets meet the new medicine requirement. under the condition of indoor temperature.According to principle of hybridization, a natural immunocompetent compound resveratrol (trans -3, 4, 5’-trihydrolystilbene) and analogue delavirdine(1-[3-[(1-methylethyl)amino]-2-pyridinyl]-4[(5-amino-1H-indol-2-yl)-carbonyl]-piperazine) were linked wtih different cyclic anhydrides as conjugated agent. The structur of main intermediates and target compound were confirmed by means of 1H NMR, 13C NMR, IR, MS and elemental analysis. For the quantification of the inhibitory effect in vitro of reverse transcriptase inhibitors, all steps of the HIV-1 Reverse Transcriptase(RT) Assay including the RT reaction, can be performed directly in the MP modules by supplied with the kit. EC50 of Resdelasu (the concentration of an inhibitor that is required for 50% inhibition) was 4.54μm and its inhibitory activity was concentration dependent(r = 0.941). The inhibition activity of delavirdine derivate was 95% .The results of delavirdine mesylate and its disperble tablets can provide a reliable theory accordance for the advanced clinical investigation. Mesnwhile, a novel anti-HIV compound has been successfully synthesized according to principle of hybridization. It will provide a new direction to the research of new type of anti-HIV drugs.更多还原