Formulation And Studies Of Azithromycin Slow-release Dry Suspension Agent

Objective:Azithromycin is a macrolide antibiotic,The listing of the dosage form had dry suspension agent, dispersing Tablet, capsule, granule.But they were bitter and had gastrointestinal reaction usually,such as nausea, vomiting, stomach acid et al. In order to control the drug release and minimized the adverse effects,This study would like to make Azithromycin sustained release solid dispersion and then made it to be dry suspension agent. The technology of solid dispersion could cover the bitter and improved patient compliance.Methods:1 The preparation of Azithromycin sustained release solid dispersion:Azithromycin sustained release solid dispersion was prepared by solvent-melting method with EC and eighteen alcohol;Firstly,weighted a formula volume of ethyl cellulose and dissolved in ethanol at 65 ℃ magnetic stirring, then added amount of Azithromycin in formula. Secondly,melt eighteen alcohol and polyethylene glycol 6000 and add them to EC at 65 ℃ magnetic stirring until the ethanol was evaporated. Thirdly,put the melt in the flat on the stainless steel plate and made it be solid rightly with cool air,when it become hard,grind and sieve it over 40 mesh. Select the best formula and preparation technology by single factor and orthogonal experiment design.2 The identification of solid dispersion and the study on stability: Identify the solid dispersion by the methods of release rate in vitro,differential scanning calorimetry,power X-ray diffraction; Study the stability of solid dispersion with the indexs of appearance,content,release rate.3 The preparation of Azithromycin dry suspension: Firstly, prepare granular by wet granulation; sieve it over 40 mesh; dry. Secondly,mix with solid dispersion,and select the best formula with the index of sedimentation rate and dispersion and insure the amount of flavoring agent by the study on bitter.4 Study on stability of Azithromycin dry suspension: established the method of Ultraviolet and visible spectrophotometry for the determination of Azithromycin dry suspension dissolution and HPLC for the determination of content. Prepare Azithromycin dry suspension with the proper formula and study the stability of dry suspension with the indexs of appearance, content, release rate by stress testing and accelerated testing.5 Established an LC-MS/MS method for the determination of Azithromycin in plasma. Commercial Azithromycin dry suspension as reference, the single-dose,two- treatment,two sequence and randomiaed crossover study was carried out to study its pharmacokinetics, bioailability and bioequivalence.Results:1 Drug release rate as the index,the optimum formula of solid dispersion were selected through the single factor and orthogonal experiment design. The optimum formula: Azithromycin 100 mg,EC15mg,eighteen alcohol 34.6mg,AZX-3100 mg, sieving over 40 mesh.2 The methods of differential scanning calorimetry and power X-ray diffraction were selected to identity the solid dispersion, the results of DSC and PXRD indicated that Azithromycin exited in solid dispersion as amorphous form.The study on stressing test indicated that the appearance,content,release rate of solid dispersion were not significantly changed under high temperature（ 40℃）, light and RH75% test conditions. But the hygroscopic weight limit in RH 92.5% and the solid dispersion were melt under high temperature（60℃）. This laid the foundation for the study on stability of dry suspension agent.3 Select the best formula of dry suspension agent with the index of sedimentation rate and dispersion: solid dispersion 0.8g,Sodium alginate 0.25 mg,Sucrose 1g,Lemon yellow 2mg, Strawberry flavor 2.5mg,silica gel2.5mg.4 Established the method of Ultraviolet and visible spectrophotometry for the determination of Azithromycin dry suspension dissolution with the detection wavelength of 482 nm, the study on methodology showed that Azithromycin concentration and Absorbance had a good linear relationship in the concentration range of 6.88μg·m L^-166.01μg·m L^-1, study on stability, precision and recovery all met the requirements,the method could be used to determinate the drug release rate.5 Established the method of HPLC for the determination of Azithromycin dry suspension concentration. The result showed that Azithromycin concentration and peak area had a good linear relationship in the concentration range of 0.025mg·m L^-14mg·m L^-1; Study on stability, precision and recovery all met the requirements.6 The study on Azithromycin dry suspension was similar with solid dispersion in stressing conditions which was effected by the characteristic of solid dispersion. The result showed that self-made Azithromycin dry suspension should be protected against high temperature and moisture.7 The results of Beagle pharmacokinetics showed that the AUC_0→∞ of self-made preparation and reference preparations had no significant difference, Tmax prolonged,and Cmax decreased.Conclusions:The formula and preparation process of Azithromycin dry suspension were simple and feasible and had good reproducibility. The self-made preparation could slow the drug release rate,cover the bitter and reduced the side effects and improved the compliance of patients. Established methods of dissolution,concentration and plasma sample which ensured the quality control. Self-made Azithromycin dry suspension should be protected against high temperature and moisture.The experiment in vivo indicated that reference preparation and self-preparation were not bioequivalent,the self-made preparation had sustained release effect.