Research On Preparation Technology And Quality Standard Of Jianpi Tongfu Granules

Objective:This study is aiming to develop a new TCM preparation for curing constipation-predominant irritable bowel syndrome and then pathing a way for future medicine registration.Major parts of research focus on investigating the preparation technique,quality standard,stability and other preclinical pharmaceutical factors of a currently used formulation,Jianpi Tongfu Granules,on the basis of two official documents,Rules of medical formulation registration and management and Principles of TCM and Natural Medicine Research Technique.Methods:(1)Study on Jianpi Tongfu Granules preparation technologyStudy on extract preparation flow: based on previous studies,murine intestinal propulsive rate of extract was utilized as a parameter in selecting the best preparation flow.Study on extraction process: applying single factor comparison method,we chose the yield of volatile oil as an indicator in classifying extraction techniques.Three parameters,immersion time,decoction time and solute-to-solvent ratio,were considered in this process.Then combining single factor comparison method and orthogonal test,we used paeoniflorin and astragaloside contents as well as solid yields as indicators to figure out the most efficacious combination of extraction frequency,decocting time and solute-to-solvent ratio.Study on concentrating and drying technique: selecting the retention rate of paeoniflorin and astragaloside as indicators,we compared concentrating methods under normal and low pressure,and compared vacuum drying effects of concentrates under different material thickness,then determining the most suitable decocting and drying conditions.Study on dose-effect relation: to testify the minimum daily dosage needed to induce effect,with murine intestinal propulsive rate as an indicator.Study on forming process: firstly we testified the hygroscopic rate of powdered extract,then utilizing granular formability,hygroscopicity and dissolubility as indicators to select auxiliary material types and dosages,using granulation yield as an indicator to optimize wet granulating process,using granular critical relative humidity as an indicator to determine environmental moisture requirement for forming process,and using hygroscopic weight gain percentage as an indicator to select packages which will directly contact medicine and list on market.Pilot test: we carried out three groups of pilot tests to examine the efficiency of techniques selected from previous small experiments.(2)Study on quality standard and stabilityReferring to Chinese Medicine,2015 version,and related documents,we conducted researches on building various quality classification criteria for our formulation.Firstly,with thin layer chromatography(TLC),we created a TLC based technique in differentiating raw medicines involved in our formulation.After that we introduced a mensuration method in measuring paeoniflorin content within paeoniae radix,naringin and neohesperidin content within fructus aurantii,etc.In addition,complying with general requirements of medical preparation,we built a series of standard qualitative and quantitative examination methods to testify particle size,moisture,dissolubility,container capacity,etc.With all the above criteria we then carried out accelerated stability test and standard temperature stability test on our preparation inside marketing packages.Results:(1)Study on Jianpi Tongfu Granules preparation technologySelected extract preparation flow: weighing decoction pieces listed on diagnosis,extracting volatile oil from citrus aurtantium,atractylodes,tangerine peel and bupleurum extract,then decocting with the remaining seven types of materials.Selected Volatile Oil Extraction Process: adding 10 times amount of water and distilling for 6 hours.Extract yield was measured to be 0.33%.Selected decocting process: adding 8 times amount of water and decocting for 2 hours,then adding 6 times amount of water and decocting for 2 hours,finally adding another 6 times amount of water and decocting for 2 hours,filtering decoction liquid and mixing with the liquid from which volatile oil has been extracted.Testing experiments showed a 94.36% extraction rate of paeoniflorin,a 96.22% extraction rate of astragaloside and a 35.85% yield of solid products.Selected Concentration Method: low pressure concentration in 60℃,when extract has relative density 1.11.The average retention rate of paeoniflorin is 88.94%,and that of astragaloside is 92.83%.Selected Drying Method: Vacuum drying at-0.085 MPa,60～80℃,with extract spreading material thickness between 0.4 to 0.5 cm.Average retention rate of paeoniflorin under this condition is 86.91%,and that of astragaloside is85.38%.Dose-effect relation result: minimum dosage 65.5g per day to induce medical effect.Selected formation process: with medical dextrin filler and 0.96:1 ratio of powdered extract to auxiliary materials,the comprehensive score is 98.83 out of 100,with 83.23% formability,10.84% hygroscopicity and 95.7%dissolubility.Wet process granulation is preferred,with 75-80% ethanol as wetting agent and 3-5% particle moisture.Selected Packaging Material: medicinal polyester/aluminum/polyethylene compound film,proved by three groups of pilot tests,which showed 0.3%volatile oil yield,97.52% dry extract yield and 94.92% rate of finished products.In addition,the transfer rate of paeoniflorin and astragaloside is 32.23% and 33.12%,respectively.(2)Study on quality standard and stability.As indicated in previous part,we created TLC based differentiation method for distinguishing white peony root,bupleurum,astragalus and citrus aurtantium.Moreover,we set examination method and maximum contents of paeoniflorin,tangerine peel and neohesperidin in medical preparation.In addition,we built qualitative and quantitative testing process to examine shape,particle size,moisture,dissolubility and capacity difference of finished products.Last but also important,accelerated stability test and standard temperature stability test illustrated that our Jianpi Tongfu Granules are stable in real-life marketing packages,and we temporarily set its period of validity to be two years.Conclusion:The study reaches our expectation in designing a stable,practicable and high quality preparation technology of producing Jianpi Tongfu Granules.It also provides an experimental base for further clinical investigation and industrial production.