Preparation And Quality Evaluation Of Toad Skin Extract Hydrophilic Gel Matrix Sustained-release Tablet

Objective: Chanpi is the dry skin of Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider.It is widely used in clinic for its pharmacologic actions of cardiotonic , antitumor , local anesthesia , analgesia and antiinflammatory.Now commonly used dosage forms are tablet,oral liquid,capsule and injecta.The shortcomings of normal tablet is that patients have to take large doses everyday,the oral liquid is smelling and injecta may hurt the blood vessels and result in phlebitis.So to invention a new dosage form to improve the condition is urgent.Hydrophilic Matrix Tablet is a kind of tablet made of hydrophilic polymer or natural rubber.It is the simplest and cheapest form of oral sustained release system.When matrix materials meet water or digestive juice,they begin to inflate and form a gel barrier to control drug release.The dosage form has a adventage in low productive cost,simple product technology,high level of mechanization,perfect drug release ability,stabile and convenient to take.Now it is 60%⁷0% of matrix tablets in the market.We are trying to use HPMC as matrix material to produce Chanpi extract hydrophilic gel matrix sustaine release tablet,the purpose is to decrease drug dosage and side effect,so that patients will be pleasant to take it.Method:To study the technology of Chanpi extraction. HPLC was established to determine the content of Cinobufagin in Chanpi extract.Water absorption rate and soak time of Dry Chanpi was investigated. Traditional way of water extraction and alcohol precipitation and orthogonal test of three factors-three levels were taken to screen the optimization technology.The orthogonal test factors were volume of water added,decoction time and decoction times.The experiment was arranged according to L₉(3⁴) orthogonal Table .Synthetic weighted mark method was taken to value the result,The yield of extract and content of Cinobufagin were choosed as the value index.The optimization technology was validated.Quality control of Chanpi extract was established.The solubility of Cinobufagin in distilled water,pH6.8 phosphate buffer and methanol was determined in the way of thermostatic waterbath.The moisture absorption rate and critical relative humidity were determined to supply a guidance of production and storage condition.Qualitative identification was investigated by thin layer chromatography.Content of Cinobufagin in Chanpi extract were determined by HPLC.In vitro release rate of Cinobufagin was detemined by small cup method according to Chinese pharmacopoeia of 2005 editon .The evaluation index was the accumulative release rate of 2,6,10 h are 15%³5%,40%⁶0%,70%. Formula and technology factors such as viscosity of HPMC,filler,moistening agent,dosage of HPMC,pore former,dosage of pore former,granulation way and hardness of tablet and methodology factors such as release media,volume of release media and use sink basket or not were investigated.Method of direct analysis and similarity factor were combined to value the release rate.Moisture absorption rate and critical relative humidity of granulation were determined.Quality control standard of Chanpi extract hydrophilic gel matrix sustained-release tablet was established according to Chinese pharmacopoeia of 2005 editon. Appearance of tablet,thin layer chromatography identification and tablet weight variation were investigated.HPLC was established to determine the content of Cinobufagin.In vitro accumulative release rate was determined and fitted to Zero,First,Higuchi and Peppas equations.The in vitro release mechanism was studied.Result:HPLC to determine the content of cinobufagin was specificity and reliable.The water absorption rate of dry Chnapi was 150%,it means that 1.5 times more water should be added in first decoction and Chanpi should be soaked for 30min before decoction.The best technology of Chanpi extraction is decoct for three times.First time use 11.5 times of water,soak for 30min, then decoct for 45min.Then use 10 times of water decoct for 45min twice.Solubility of Chanpi extract in distilled water,pH6.8 phosphate buffer and methanol were3.2mg·ml-1,3.1 mg·ml-1,2.5mg·ml-1.The extract get to a balance in a circumstance that the relative humidity is 75% in 10 d,the moisture regain rate is 54.1%.CRH is 56.33%.Thin layer chromatograph show that there is a same pot in the sample layer and standard layer,it means that there is Cinobufagin in the sample.The extract yield is 4.04%,the content of Cinobufagin is 1.53mg/g.The formula and technology screening experiment showed that matrix material had a significant effect on drug release rate,the drug release rate decreased when the viscosity of HPMC increase.We found that the release rate followed the order of K4M>K15M>K100M.As filler of the tablet,lactose and MCC both can improve the release rate,while starch had little effect.The repose angle of granulations made by 4 different moistening agent were smaller than 30°.It is easy to granulate by 90% ethanol solution,not stick to the screen,but leave too much powder;it is a little difficult to granulate by 50% ethanol solution,easy to stick to the screen;it is a little difficult to granulate by 2%PVP ethanol solution,but easy to stick to the screen and leave too much powder;it is easy to granulate by 70% ethanol solution,not stick to the screen and little powder.There is a burst release when 10% HPMC K4M was used,the release curve were similar when dosage of HPMC K4M was 15%³0%.It showed that the release rate decreased when HPMC K4M increased,but there was no significant differences when the dosage reach to a certain range.Mannitol used as pore former could improve the release rate,the release rate order was mannitol>none>PVP>glucose.There was no significant differences when 5% and 10% mannitol were used,when mannitol increase to 15% , the release rate was significantly improved and nearly release completely at 6h.The release rate of modified granulation method was faster than traditional granulation method.The harder tablet were,the slower drug released,but there was no significant differences when the tablet hardness reached to a certain range.So the optimization prescription of tablet is total weight of tablet is 0.5g.Chanpi extract 40%,K4M 20%,mannitol 10%,the rest is MCC.The optimization technology is 70% ethanol as moistening agent,half of the extract mix with K4M,the other half mix with the rest accessories.Two parts are mix and tabletting after drying. The granulation get to a balance in a circumstance that the relative humidity is 75% in 96h,the moisture regain rate is 24.87%.CRH is 72.81%.RSD of tablet weight of Three groups are 0.51%,0.40%,0.44%.The result showed that it was qualified.The content of Cinobufagin in three groups are 0.18 mg,0.25 mg,0.22mg.RSD are 14.85%,1.02%,11.45%.The drug release equation fitted result showed that it is well fit to First order,the mechanism is non-Fick diffuse.The drug release is the result of diffuse and matrix erosion.Conclusions: We produce the Chanpi extract hydrophilic gel matrix sustained-release tablet.Drug can release in 12 h,the productive technology is sTable ,the quality standard is accurate and reliable.