| Objiective:Gout and hyperuricemia have been become a kind of common metabolic diseases, or even the risk factors of hypertension, coronary heart disease and of such insulin resistance metabolic disease,so the therapeutic drug research of which have been become the focus at home and abroad.However,there exists some problems can not be ignored on western drug therapy:①Drugs used in acute stage of gout can relieve the symptoms, but can not lower serum uric acid. Otherwise,drugs used in intermission stage of gout can lower the serum uric acid but can not be used in acute stage.②Drug’s side effect are heavy.③The choice of drugs are limitation in gout therapy as gout are always accompanied by a variety of complications.So to develop the safe, effective, and economical drugs used in gout treatment is urgent.Evodia as an traditional chinese medicine used commonly in clinical are always considered as an interior-warming drug combined with other drugs used into the prescription.Such as wuzhuyu Tang as for headache treatment,jiming San for "Jiaoqi".EVO as the main active alkaloid in Evodia,the effects of the serum uric acid reduction and feet tumefaction suppression on Hyperuricemia rat are firstly found out by screening compund prescription,decomposed recipes,general and single ingredients.The research indicates that EVO has the functions of anti-inflamatory,analgesic and can lower serum uric acid which means it can be used to treat both symptoms and causes of urarthritis.So far.no other agents possess all these functions.According to the pharmacodynamic research,drug properties and clinical requirement, dosage form of oral administration are choosed and EVO dispersible tablets are prepared.Methods:To provide the basis for EVO dispersible tablet formulation design, acu-te toxicity and main pharmacodynamic research were firstly researched. Maximum dos-e test was to research the EVO’s acute toxicity. Middle、 low and high three dose gr oups were set and according animal models were established to investigate the effect of antiinflammatory.analgesia, lowering serum uric acid,inhibiting acute tumefaction on the foot of rats of EVO. Method of xylene-induced tumefaction on the ear of mice a-nd the method of acetic acid-induced mouse writhing were separately taken to investig ate the effect of EVO’s analgesia and anti-inflammatory. Method of sodium injection given to form the model of acute tumefaction on the foot of rats and method of feedi-ng hypoxanthine firstly and then injecting oxygen hydrochloride acid potassium saltsu bcutaneously to establish the model of hyperuricemia mice were separately taken to in vestigate the effect of EVO inhibiting foot tumefaction and the effect of EVO lowerin-g serum uric acid.Secondly was the preparation technology and prescription research.C-onsidering EVO is a poorly water solube drug, physical and chemical properties of E VO were firstly investigated,including solubility,crystal and impact factors tests.Combin ed the properties of EVO and the characteristic of dispersible tablet preparation,particl e size reduction combined with dispersion increase methods were taken to design EV O dispersible tablet, as a result the ultrafine grinding combined with solid dispersion t echnology were applie. EVO ultrafine grinding time,solid dispersion materials and prep aration methods were screened by using the particle size, dissolution rate as evaluation indexs EVO solid dispersion quality were assessed through the methods of X-ray, Inf rared Spectroscopy and SEM. Solubility and stripping curve were tested and have fitte d the model of it.Lastly was about the molding process of EVO dispersible tablet. Sin gle factor test was used to screen fillers, disintegrating agents, lubricants and other typ es of accessories, orthogonal test was used to optimize the materials ratio.Thirdly was to research and formulate the quality standard of EVO dispersible tablets. Determinati on methods of content and dissolution were set by using the index of EVO. Its chara cter, identification, content uniformity, had also been systematically studied. Accelera ted stability tests on three batches of samples were investigated under the reference of2010version Chinese Pharmacopoeia as well as the setted quality standard draft of E VO dispersible tabletResults:Under the maximum dose2.68g/kg EVO intragastric administrated to rat,there was no significant toxicity response,EVO has no significant toxicity.EVO has significantly anti-gout effect, prescription specifications amount is10mg per tablet,150mg per tablet weight,3times a day,two tablets each time.EVO is poorly water-soluble drug, it was stable under the strong light, high temperature and high humidity conditions.20minutes micronization could achieve the10um particle size, dissolution rate was more than60%by using F68as a water-soluble carrier materials and molten technology was screened to prepare EVO solid dispersion.EVO existed as microcrystal in solid dispersion.Optimized preparation technology and prescription were as fllows:10g EVO ultrafine powder, coming from the pure EVO which are micronized for20minutes, mix well with40g F68,and to melt and stir at80℃for30minutes, then poure into a pre-cooled stainless steel pan immediately.Set it into the freezer frozen at-20℃four4hours.Remove it to a dryer to dry for1to2days until it has become brittle.Crash it until it can pass through the60mesh sieve.Add41g MCC,41g lactose.5.5g L-HPC,5.5g PVPP,2.5g magnesium stearate,2.5g superfine silica gel powder and2g aspartame,all of them are mixed well, compressed into1000tablets and finally package them.6months accelerated stability studies indicated that the quality of EVO dispersible tablet was stable.Conclusion:EVO has significant anti-gout effect.the preparation is feasible and quality is stable. The subject initially completed pharmacy research of the EVO dispersible tablets, which has laved the foundation for the development of a new drug simultaneously owning the effects of anti-inflammatory, analgesic and lowering uric acid on the treatment of gout... |
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