| Objective To study the release kinetics feature of both sold and lab-made different kind of Xiaohuoluo Pills(water pill,water-honeyed pill,small honeyed pill,large honeyed pill,starched pill),and Evaluate their quality and releasing mechanism.Based on the release kinetics feature of Xiaohuoluo Pills,study the preparation process of Xiaohuoluo sustained release drop pill,and to provide demonstration for the research of toxic Chinese medicine oral sustained and controlled release preparationsMethods 1.Prepare 5 different kinds of Xiaohuoluo Pills,and check the quality according to the Chinese Pharmacopoeia(2010 edition).UV spectrophotometry is applied to determine the material group release in Xiaohuoluo Pill.In materiomic release degree as the evaluation index,the drug release mechanism of sold Xiaohuoluo Pills will be discussed by investigating the release in various dissolution medium of different pH.2.HPLC is applied to determine the release of benzoylmesaconine in Xiaohuoluo Pills.Use both UV and HPLC are used to investigate the release correlation between benzoylmesaconine and material group,and to inspect the quality of prepared Xiaohuoluo Pills.3.HPLC is applied to determine benzoylmesaconine,benzoylaconine,benzoylhypa-coitine and hypaconitine in compound Xiaohuoluo drug powder.In content of total alkaloids as the evaluation index,use single factor study and orthogonal design to optimize the extraction process of compound Xiaohuoluo drug4.The extracting solution of optimized extraction process is used to prepare Xiaohuoluo concentrated pill.Check its quality and evaluate its material group release feature.The prescription of Xiaohuoluo sustained-release dropping pill was selected by single factor study according to roundness,tailing degree,adhesion degree,hardness and materiomic release kinetics.Orthogonal design is used to optimizing moulding techniques of dropping pill.Use both UV and HPLC are used to investigate the release kinetics and mechanism of Xiaohuoluo sustained-release dropping pillResults 1.The UV analytical method of material group release in various dissolution medium of different pH of Xiaohuoluo Pills has been established;respectively,a series of good linear relationship has been found in the range of 0.114-1.137mg·mL-1(r=0.9996,0.9990,0.9994,0.9990);RSD of precision,stability were all less than 3%.Sold Xiaohuoluo Pills of 3 different manufactures all revealed a sustained-release characteristics.Their accumulated dissolution of materiomic release kinetics in water,pH1 hydrochloric acid solution,pH4.5 ammonium acetate buffer,pH6.8 phosphate Buffer solution were:The first manufacturer:92.38%,84.34%,81.74%,85.39%;The second manufacturer:94.12%,83.93%,85.14%,92.63%;The third manufacturer:82.98%,86.66%,87.27%,79.66%,respectively.The sold Xiaohuoluo Pills hadn't completely released.And the release rate had significant difference between different manufacturer,the release rate also had significant difference between Pills from the same manufacturer(significance of T50,Td all less than 0.05).Prepared 5 different kinds of Xiaohuoluo Pills were all revealed too fast.The accumulated dissolution of materiomic release kinetics of water pill,water-honeyed pill,small honeyed pill,large honeyed pill,starched pill in 12h were:in water:93.13%,96.39%,93.03%,93.99%,95.33%;in pH1 hydrochloric acid solution:93.79%,93.09%,91.13%,96.77%,90.64%;in pH4.5 ammonium acetate buffer:93.32%,90.85%,91.26%,95.74%,88.57%;in pH6.8 phosphate Buffer solution:82.46%,92.73%,90.85%,94.17%,92.02%,respectively.5 kinds of prepared Xiaohuoluo Pills can almost completely released in 12h.The disadvantage is they released too fast.The materiomic release kinetics of same kind of Xiaohuoluo Pills in different dissolution medium had significant difference,as well.2.The HPLC analytical method of benzoylmesaconine release in various dissolution medium of different pH of Xiaohuoluo Pills has been established;respectively,a good linear relationship has been found in the range of 0.0033-0.1320mg·mL-1(r=0.9999),RSD of precision,stability were all less than 3%,average recovery rate were:101.41%,it's RSD was 1.10%.The release rate of benzoylmesaconine had significant difference between different kinds of prepared Xiaohuoluo Pills.Water pill,water-honeyed pill,small honeyed pill.large honeyed pill,starched pill in 12h were:in water:93.22%,91.30%,96.49%,94.89%,91.19%;in pHI hydrochloric acid solution:94.74%,96.57%,92.18%,96.77%,91.16%;in pH4.5 ammonium acetate buffer:94.74%,93.56%,94.75%,83.31%,85.94%;in pH6.8 phosphate Buffer solution:87.51%,91.05%,92.25%,89.77%,85.34%,respectively.5 kinds of Xiaohuoluo Pills's drug release model were Weibull model.The release rate of benzoylmesaconine and materiomic release kinetics were highly correlated.3.The HPLC analytical method of benzoylmesaconine,benzoylaconine,benzoylhypacoitine and hypaconitine in compound Xiaohuoluo drug powder has been established.A series of good linear relationship has been found in the range of 0.065-0.910?g,0.052-0.728?g,0.050-0.700?g,0.021-0.294?g(r=0.9999,0.9999,0.9999,0.9997),respectively.RSD of precision and stability were all less than 3%,average recovery rate were:98.26%,96.36%,101.88%,95.84%;RSD were:1.23%,0.75%,2.11%,0.63%,respectively.Optimized extraction process of Xiaohuoluo compound drugs were:refluxed the drugs with 60%ethanol in a water bath,add 10 times of extraction solvent,decocting 2 times and 2 hours every time.In verification test,the extraction rate of total alkaloids was 91%,extraction rate was 13%,the content of total alkaloids in dry extract was 0.4036%,which indicated that the optimized extraction process was stable and reliable4.The HPLC analytical method of benzoylmesaconine,benzoylaconine,benzoylhypacoitine and hypaconitine in Xiaohuoluo sustained-release dropping pill has been established.A series of good linear relationship has been found in the range of 0.065-0.910?g,0.052-0.728?g,0.050-0.700?g,0.021-0.294?g(r=0.9999,0.9999,0.9999,0.9997),respectively.Xiaohuoluo concentrated pill prepared by the optimized extraction process had higher content of total alkaloids(0.0506%)relative to the traditional pills.Concentrated pill's release rate was too quick,the risk of burst release still existed.Prescription of Xiaohuoluo sustained-release dropping pill were as follows:the ratio of drug(Xiaohuoluo dry extract powder)to matrix was 1:4;the matrix was composed by PEG6000:stearic acid as 1:1.5;condensed fluid was liquid paraffin;condensing temperature was 6-8?.The technological parameter of Xiaohuoluo sustained-release dropping pill were as follows:preparation temperature was 75?;dropping distance was 3cm;dropping rate was 40 drop/min.Xiaohuoluo sustained-release dropping pill had remarkable good sustained release effect.It's release characteristics conformed with first order and Weibull model.The content of total alkaloids before dosage refactoring pills were as follows:0.0266%in large-honeyed pill;0.0447%in water pill;0.0509%in concentrated pill,and 0.0669%in Xiaohuoluo sustained-release dropping pillConclusion The UV and HPLC detection method established is accurate,quick and simple,could meet the requirements of all analytical test.Xiaohuoluo sustained-release dropping pill has a good sustained release effect,it's release characteristics conformed with first order and Weibull model.The release rate of benzoylmesaconine and materiomic release kinetics were highly correlated.One day dose of Xiaohuoluo sustained-release dropping pill is once a day,and 2.4g for once.It has reduced part dose compared to large-honeyed pill(3g for once and twice a day).It could improve patient compliance,and be more safe and effective at the same time. |
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