Study On The Preparation And Quality Of Shenfu Orally Disintegrating Tablets

1 PurposeShenfu soup is a classic decoction,clinical commonly used for the completed repair yangqi, and benefit the qi-solid off agent,its modern forms mainly Shenfu injection.With Shenfu injection in a large number of clinical use, its adverse reactions gradually increased. In retain the original curative effect significantly under the premise of safety usage,to reform of new dosage form of Shenfu soup,is designed to prepare a suitable hardness, taste good, shorter disintegration time, stable quality, a significant effect of the Shenfu orally disintegrating tablet, providing a new drug application for the expansion of clinical Shenfu soup.2 Methods and Results2.1 The investigation of Shenfu soup’s extraction processRe ginsenosides yield, aconitine yield and dry extract yield are taken as indexes for Shenfu soup three major extraction process-SBE, reflux extraction and boiling method to inspect. The results show that SBE above three indicators were 0.0880%,0.0065% and 35.13%; boiling method were 0.0790%,0.0044%,35.30%; reflux extraction were 0.1200%, 0.0091%,36.75%. Thus, reflux extraction extract these three indicators are highest, so the selection of reflux extraction method to extract herbs. Specific extraction parameters are as follows:each party ginseng 20g, aconite 15g, adding 10 times the amount of water and extracted three times, each time 0.5h,when used short, simple operation.2.2 Preparation of the Shenfu orally disintegrating tabletsFirst of all,the in vitro disintegration time as index,to the single factor investigation of the types of disintegrating agent, and in vitro disintegration time and angle of repose of indicators,to the single factor investigation of glidants, lubricants species.The results showed that on average the shortest disintegrator disintegration time aspect, CMS-Na was 87.2 seconds, PVPP is 16.7 seconds, L-HPC was 80.3 seconds, CCMC-Na was 19.8 seconds; glidants silica and talc powder in vitro disintegration times are 42 seconds, the angle of repose was 34.6° and 41.8°; lubricant magnesium stearate and PEG6000 in vitro disintegration time was 96.0 seconds and 29.8 seconds, the angle of repose was 37.2° and 36.7°. Therefore, the choice PVPP and CCMC-Na as co-disintegrating agents, silica powder as a flow aid, PEG6000 as a lubricant.Then, orally disintegrating tablets in vitro disintegration time, the powder angle of repose as an evaluation index, using orthogonal test method, the senate orally disintegrating tablet formulation were optimized.At the last, taste and oral disintegration time as the index, flavoring agents to inspect the amount of aspartame, found that when aspartame was 4%, that can significantly improve the taste.Final, optimal formulation was as follows:MCC mass fraction of 36%, PVPP mass fraction of 4%, CCMC-Na mass fraction of 5% silica powder mass fraction of 1.5%, PEG6000 mass fraction of 0.5%, aspartame the mass fraction of 4%, the main drug mass fraction of 40%.2.3 Choice of penetration enhancersIn order to facilitate oral absorption of drugs, better play quick action, the subject of the mucous membrane penetration enhancers were studied.The experiment has azone, menthol,1,2-propylene glycol, beta cricoid dextrin, hydroxypropyl-beta cricoid dextrin, oleic acid carried on the preliminary screening.Through the preliminary experiments found that at room temperature, the liquid penetration enhancers will seriously affect the tablet molding, direct compression of powder has a high requirement to the powder flow ability. Such as Azone, oleic acid, and so on will make the material humidity and viscosity increases, the mobility is greatly reduced, taking into account the More rigorous requirements of the dosage form, with the final choice for powder or solid form of β-cyclodextrin, hydroxypropyl cyclodextrin, and menthol-β-as research subjects.Bullfrog skin to replace the oral mucosa of large animals, frog skin mucous membrane permeability in vitro absorption experiment model is established.Through this model to study different kinds and proportion of promoting the permeability agent to join with Shenfu orally disintegrating tablets of the oral mucosa absorption,indicators for effective ingredient ginsenoside Re. Each time point the Qn of ginsenosides Re is calculated under different circumstances and Qn for t (h) according to zero-order kinetics equation setting up linear regression, the slope of the straight line J ss (μg/cm2/h) is the steady-state permeation rate constant, the results showed that most groups with the control group there was a significant difference (P<0.05), described β-CD, HP-β-CD and menthol penetration enhancers all having effect on promoting permeability of ginsenosides Re, especially the 3% menthol group, ER (enhancing rate) is 2.81, the most obvious effect of increasing penetration. Finally, the choice of 3 percent of menthol as this tablet penetration enhancers.2.4 Quality study of Shenfu orally disintegrating tabletsAccording to the quality inspection of "Chinese Pharmacopoeia" the relevant provisions of tablets items, the subject of the appearance of the final product, piece weight variation, hardness, friability, disintegration were examined, and reference Shenfu detoxification capsules and senate cardiac balls preparations, the aconitine limit was checked.This product is a light brown film, sheet-shaped beads no head, no defects, uniform thickness, uniform color, no stain, one-sided bright and clean, no wrinkles; odor specific, slightly bitter taste. Taking Shenfu orally disintegrating tablet 20, accurately weighed a total weight of 6909.06mg, determined the average tablet weight 345.45mg, each piece is heavy compared with the average piece in the specified limits of ± 5.0% range.Hardness to be appropriate, both to meet packaging and transportation, without affecting the rapid disintegration of the tablet, the hardness of the preparation is controlled within the range of 2.5～3Kg; because of smaller tablet hardness, friability will be changed, it will be 1% the limits increased to 4%. In determination of in vitro is used in the disintegration time limit disruption instrument improvement method, Measured average disintegration time of 38.4 seconds. This method is simple, reliable, and has great relevance with volunteers orally disintegrating test results, the remaining items conform to the requirements.Aconitine limited examination results obtained for the Shenfu extract contains aconitine amount of 0.026%, according to the measurement results of ginsenosides Re content of this preparation provisional,each tablet contains ginseng ginsenoside Re, shall not be less than 0.3500mg.2.5 Pharmacodynamic StudyThis experiment from the perspective of the treatment of heart failure, rats as experimental animals, injection of propafenone, establish animal model of acute heart failure in rats.With heart rate,+dp/d tmax (maximum rate of rise of left ventricular pressure), dp/dtmax (maximum rate of left ventricular pressure drop) within lh after administration as an indicator validated the efficacy of the drug.The four groups were established for the control group (N= 5), model control group (N= 5), Shenfu injection group (N= 5), the Shenfu orally disintegrating tablets group (N= 5). The results showed that the control group of rats during the experiment gentle breathing, limb warmer, long time no deaths; model rats after a successful modeling, heart rate was significantly slowed down,2min average dropped to 39.3 before administration%,+dp/d tmax in 2min average dropped to pre-dose 41.7%,-dp/d tmax increased significantly, the average percentage dropped to 43.1% before the administration, there is a significant difference compared with the control group; Shenfu group compared with the model group, heart rate,+dp/d tmax and-dp/d tmax are 5min when that is significantly improved; the senate orally disintegrating tablet group compared with model group, heart rate have improved significantly in 30min, the+dp/d tmax and-dp/d tmax, respectively, there is significant improvement in 10min and 20min time.This shows Shenfu injection group showed markedly rapid.Shenfu oral disintegrating tablets group was more slowly, but eventually achieve the purpose of treatment, to verify the efficacy of this formulation.3 ConclusionThe research institute made a kind of quality reliable, a clear effect Shenfu orally disintegrating tablets. Its prescription and preparation process is reasonable and feasible for large-scale production. Shenfu orally disintegrating tablets not only ensure drug safety but also have a quick effect.It plays a role available for the treatment of various types of heart failure and other acute illness, providing a new formulation of choice.