Study On The Preparation Technology And Quality Evaluation Of Xiaohuoluo Sustained Release Pellets

Objective The total alkaloid of aconitum and earthworm active ingredients were extracted from the prescription of Xiaohuoluo pill,the sustained-release pellets were prepared by adding frankincense and myrrh.Preformulation study,extraction process,preparation technology,quality evaluation and drug release mechanism,preliminary stability was accomplished.Methods Preformulation study:The active ingredients of aconitum alkaloids were established with the indicator of benzoylmesaconine,benzoylaconitine,and benzoylhypacoitine in alcohol extraction process;the active ingredients of earthworm and bile arisaema were established with the indicator of hypoxanthine in water extraction process.Extraction process:The optimum alcohol extraction and optimum water extraction were determined by single factor test and orthogonal test.Molding technology:The sustained-release pellets with ethyl cellulose and stearic acid as hydrophobic materials were prepared by extrusion-spheronization method.Single factor experiment and orthogonal test were performed to evaluate the quality of pellets,by appearance,roundness,bulk density,pellet yield and in vitro dissolution rate as the index.The mathematical model of sustained-release pellets fittedQuality evaluation:quality evaluation of Xiaohuoluo sustained-release pellets from traits,thin layer identification,examination,content determination,and in vitro dissolution rate and so on.Preliminary stability:The influence factors of three batches of Xiaohuoluo sustained-release pellets were investigated,and accelerated test was carried out.Results Preformulation study:The active ingredients of aconitum alkaloids and hypoxanthine methodology were established,the aconitum alkaloidswith the indicator of benzoylmesaconine,benzoylaconitine,and benzoylhypacoitine,the standard curve equations are:Y=137695x+30.594,R2=0.9999;Y=258165x-0.2472,R2=0.9999;Y=222650x-21.455,R2=0.9992.The linear range were 6.1～76.25μg/mL,0.94～1.75μg/mL、0.96～12.00μg/mL.The active ingredients of earthworm and bile arisaema were established with the indicator of hypoxanthine,the standard curve equations was Y=23038x-14.914,R2=0.9991.The linear range was 5.05～30.6μg/mL.The precision,stability and reproducibility of the two methods were satisfactory,and the recoveries were all in accordance with the requirements.The methods were practicable.Extraction process:The optimum alcohol extraction factorswere established as 65%ethanol 3 hour 20-fold 2 times;the optimal conditions of water decocting process was 12-fold,boiled ltimes,3h each time.The verification tests show that the process conditions are stable,reasonable and feasible.Molding technology:The best process of extrusion spheronization was:extrusion speed 50rpm/min,spheronization speed 1200rpm/min,spheronization time 5min.The optimal formulation of the sustained-release pellets was:drug loading 30%,MCC dosage was 20%,SA:EC=2:1.Sustained-release pellets were similar to Higuchi release,and the releasing mechanism was diffusion synergistic matrix dissolution.Quality evaluation:The three batches of samples were brown pellets;the appearance of uniformity,roundness was good;herbs thin layer identification hadvigoroso specificity;moisture check,microbiological limit check,loading difference,heavy metal,arsenic salt and aconitine limit were in line with pharmacopoeia regulations.Content Determination of aconitine total alkaloids of not less than 2.93mg/g,the transfer rate was 75.06%.The dissolution rate of 12h was above 80%in vitro.Preliminary stability:Results from influencing factors test showed instability under high temperature,high humidity and strong light,and hence the pellets should be stored in a cool dry place,and away from light.The preparation was placed in low temperature and low humidity conditions for three months,the detection index compared with "0 month",no significant change.Conclusions In this study,the extraction technology,molding technology,quality standard and preliminary stability of Xiaohuoluo sustained-release pellets were completed,not only providing a reliable quality control method for the preparation,but also for the future to further develop the pharmacokinetic study had laid a theoretical basis.