Nicorandil Pulsatile Delayed-release Tablets Preparation And In Vivo And In Vitro Release Study

Objective: The study aims to develop Nicorandil delayed release tablets by methods of modern science and technology.Preparing delayed release tablets of nicorandil and optimizing it’s prescription through the central composite design,to make it sure that the prepared tablets will be blast at the preset time,and can rapid release drug effectively.Rabbits as experiment object to study that the pharmacokinetics and bioavailability in vivo of the autonomous.Establish a method for determination of serum concentration of nicorandil.This topic founds new forms of research and development for Nicorandil.It provides a safe、efficient、stable and controllable quality of the new formulation on Nicorandil delayed release tablets for cardiovascular and cerebrovascular diseases.Methods:1.Study on the intestinal absorption of nicorandil in ratsThe physiological status of the small intestine in rats is similar to that of human.The model of rat intestinal absorption in vivo was established.The intestinal absorption kinetics of nicorandil was studied with this model for the first time.The content of nicorandil in the intestine perfusate was measured by HPLC.The content of phenol red in the intestine perfusate was measured by UV.Study on the absorptive kinetics of nicorandil in rats intestines.2.Study on Preparation prescription of Nicorandil delayed-release tabletsEstablish the method for determination of nicorandil delayed release tablets release degree in vitro.Determine the sampling point of the release curve and the release standard.An evaluation method of drug release behavior in vitro was established.Using nicorandil as the model drug,a system based on time-controlled principles was prepared by employing the techniques of compression coating.Targeting for the cumulative release percentage of Nicorandil establishes the method and standard to determine release in vitro and studies pharmaceutical formulations.On the basis of HPMC amount and viscosity,the amount of EC、MCC and lactose in the univariate study.Uses Design-Response surface methodology to optimize the test results,and formulates the best preparation prescription finally.And the release uniformity and process reproducibility of the self-made pulse delayed release tablets were investigated.3.Establish the methods of HPLC to determine the contents of Nicorandil delayed release tablets.4.Study on Pharmacokinetics and in Vivo-in Vitro CorrelationEstablish a method for determination of serum concentration of nicorandil.The reference preparation is nicorandil tablets.Using Nicorandil delayed release as test preparation.The plasma drug levels were determined by HPLC and fitting Pharmacokinetics Parameters.The relative bioavailability was calculated.Results:1.There was no significant difference between the nicorandil intestinal absorption rate constant under different drug concentrations or different pH conditions.In various parts of the intestine,the rate of absorption by the jejunum,duodenum,ileum,colon followed by decline.The absorption of nicorandil is a first-order process with the passive diffusion mechanism.2.Establish the method for determination of nicorandil delayed release tablets release degree in vitro.Provide reliable and accurate method for the optimization of the prescription of the delayed release tablets.Through single factor and design-response surface method,preparation prescription and processing were finally determined.Core prescription:Nicorandil 10mg、CMS-Na 3.2mg、CC-Na 1.6mg、lactose 65.2mg、0.5% magnesium stearate.Coating prescription: the dosage of HPMC was 89.0mg,EC was 46.2mg,MCC was 57.4mg,and lactose was 107.4mg,0.5% magnesium stearate.Production process was: core is prepared by direct compression methods.Delayed release table is prepared by press-coated.3.Established the determination of Nicorandil delayed-release tablets,and the method was accurate,simple and reliable.It provides an accurate and precise method for the quality control of the Nicorandil delayed-release tablets.4.The Pharmacokinetic studies showed Nicorandil sustained release tablets were fitted to one compartment model in rabbits.The drug elimination half-life is 0.326 h.The mean residence time was 3.04 h,which was significantly higher than that of common tablets(MRT(0-t)= 0.876h).With nicorandil tablets as reference preparation,delayed release tablets relative bioavailability was 94.53%.The lag time is 2.381 h.In vivo-vitro correlation studies,delayed release tablets have well in vivo-vitro correlation.Conclusions:Nicorandil are well absorbed across the intestine.Nicorandil can be designed as a controlled release formulation.The subject adopted design-response surface method to optimize pharmaceutical formulations,and identified the formulation and preparation of formulations.The subject established HPLC method for determination of Nicorandil content in delayed release tablets.The prepared sample of delayed release tablets were in line with quality standards.The subject studied Pharmacokinetics of Nicorandil sustained release tablets in rabbits.The dynamic changes and release properties of drug in animals were evaluated and studied.This study provides the experimental basis and foundation for the new formulation of nicorandil.