| Secnidazole has outstanding therapeutic effect on diseases caused by the infection of amoeba, giardia lamblia and trichomoniasis etc. Oral secnidazole have common adverse gastrointestinal reactions such as nausea, vomiting, glossitis, anorexia, upper abdominal pain and metal-like odor ,etc. In order to reduce gastrointestinal adverse reactions caused by oral secnidazole, we can use prodrug modification to resolve this problem. Secnidazole benzoate is a former drug of secnidazole, this paper mainly study on the pharmacological activity of secnidazole benzoate. Secnidazole benzoate is almost insoluble in water (about 40mg·L-1), which affects the clinical application. So this paper mainly study on the complexation characteristics of secnidazole benzoate with hydroxylpropyl-β-cyclodextrin which has good water solution, to improve the bioavailability and water solution of secnidazole benzoate , and provide a theoretical reference on developing the secnidazole benzoate formulations of cyclodextrin inclusion complexes in aqueous solution. In addition , this paper also research the preparation of secnidazole benzoate-β-cyclodextrin inclusion complexes, which has been characterized. The main research content are summarized as following:(1) Pharmacodynamic studies on secnidazole benzoate in vitro and in vivoObjective To study the pharmacological activity of secnidazole benzoate on Trichomonas vaginalis in vitro and in vivo, study the effective concentration scope and the half effective dose of secnidazole benzoate on trichomonas vaginalis in vitro and in vivo, which are compared with secnidazole. Methods Cultivate trichomonas vaginalis in liver extracts medium, use the MTT colorimetric micro-enzyme reaction and the counting method to observe the inhibitory effects of secnidazole benzoate on proliferation of trichomonas vaginalis, establish trichomonas vaginitis in a mice model caused by trichomonas vaginalis to determine the the inhibitory effects of secnidazole benzoate on trichomonas vaginalis in vivo. Result (1) at the concentrations ranged from 0.15μg/mL to 20.0μg/mL and in the period ranged from 6h to 24h incubation, secnidazole benzoate inhibited the proliferation of trichomonas vaginalis in a concentration- dependent and time-dependent manner, respectively, the minimum sterilizing concentration of secnidazole benzoate,secnidazole and metronidazole were both 20μg/mL , the minimum inhibitory concentration of which were 0.15,0.63 and 0.63μg/mL respectively, the half effective concentration of secnidazole benzoate,secnidazole and metronidazole which calculated by the software DAS2.0 were 0.85, 1.31 and 1.42μg/mL, respectively (2) The therapeutic effect of high, medium-dose group of secnidazole benzoate have no significant difference with the model group of secnidazole( P>0.01) .Conclusion The inhibitory effects of secnidazole benzoate on proliferation of trichomonas vaginalis is basically similar to secnidazole and metronidazole; the high,medium-dose group of sbz have outstanding anti-trichomonas effect.(2) Acute toxicity testObjective research the mice toxicity of secnidazole benzoate,and compared with secnidazole. Methods use gavage method to determine the half lethal dose of secnidazole benzoate and secnidazole in mice, use the greatest volume of gavage that mice can withstand to determine the MTD of secnidazole benzoate.Result The LD50 of secnidazole benzoate can not be measured, the maximum tolerance of secnidazole benzoate on Kunming mice is 40g/kg, the LD50 of secnidazole is 2.238g/kg.Conclusion secnidazole benzoate is safer than secnidazole, and maybe have poor bioavailability.(3) Inclusion studyObjective To investigate the complexation of secnidazole benzoate with hydroxylpropyl-β-cyclodextrin (HP-β-CD) in aqueous solutions, inclusion molar radio of the host and guest molecules and change of thermodynamic parameters during the complexation process. Methods The measurements of the complexation mechanism, inclusion molar ratio of the host and guest molesules and change of thermodynamic parameters were carried out by the following methods separately: pHase solubility method, UV absorption spectroscopy , and equimolar series method, etc. Results (1) The pHase solubility diagrams showed a typical AL-type which defined by Higuchi etc in pH2.8,4.9 and 7.7 buffered solutions , the solubility of sbz is linearly increasing when the concentration of HP-β-CD increases; through the pHase solubility curve equation obtained, we calculate the apparent stability constants of inclusion complex are 1012.97 , 372.67 and 309.68L·mol-1,respectively.(2) In various temperature, the solubility of sbz is linearly increasing when the concentration of HP-β-CD increases ,and the pHase solubility diagrams showed a typical AL-type .However, with temperature increasing,the solubilization of HP-β-CD decline, the apparent stability constants of inclusion complex decreases, the heat,entropy and Gibbs free energy in complex process are negative. Thermodynamic parameter shows that the complexation could proceed spontaneously along with the decrease of entropy and the promoting of heat.(3) The result of equimolar series method and pHase solubility method show that an 1:1 molar ratio inclusion complex of secnidazole benzoate with HP-β-CD could be formed in aqueous solutions. Conclusion An 1:1 molar ratio inclusion complex of secnidazole benzoate with HP-β-CD could be formed spontaneously and, hence, the solubility of secnidazole benzoate in aqueous solution increased. Appropriate temperature and suitable media pH probably favor the progress of complexation procedure.(4) The preparation of secnidazole benzoate–β-cyclodextrin inclusion complexesObjective Prepare the inclusion complex of secnidazole benzoate withβ-cyclodextrin to improve the bioavailability of sbz. Methods Use the saturated aqueous solution method and grinding method to prepare the inclusion complex, use the rate of inclusion and yield to assess the advantages and disadvantages of technology, and identify the inclusion complex by ultraviolet spectroscopy,infrared spectroscopy and X-ray diffraction method. Results The result indicating that the inclusion complex had been formed, the rate of inclusion by the saturated aqueous solution method and grinding method are 0.97 % and1.04% ,respectively.Conclusion The inclusion complex produced by the saturated aqueous solution method had been formed,but the rate of inclusion and yield are both low, the technology should be improved.
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