Study On Application Of Delavirdine Mesylate Crude Drug And Its Dispersible Tablets

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.