Study On Preparation Of Nimodipine Pulsed-release Pellets Capsule And The Pharmacokinetics In Beagle Dogs

Chronopharmacology studies have shown that the onset of certain diseases has obvious physical changes in rhythm,such as myocardial infarction,cerebral infarction, high blood pressure,arrhythmia,as well as the patient's death according with diseases above are all Showing the characteristics of circadian rhythm.Cerebral infarction most vulnerable to attack at 3:00,myocardial infarction at 8:00 am～1:00 pm,the highest death rate in 3 hours after wake up in early morning.If reaching to peak concentration at this time,the drug can significantly reduce the onset of disease and mortality.Pulsed releasing system is cutting-edge research and hot spots at home and abroad in recent years.Nimodipine,as the 1,4-dihydropyridine calcium channel blocker,having highly selective on brain receptors,easily permeation to the blood-brain barrier,can effective prevention and treatment isehemie brain injury by the cerebral angio spasm caused by subarachnoid hemorrhage,anti-thrombosis,expansion the cerebral vascular and improve to post-stroke cognitive function effectively.Nimodipine is used for the prevention and treatment of subarachnoid hemorrhage,hypertension,ischemic cerebrovascular disease and migraine in clinical.According to the principles of chronopharmacology,we select the Nimodipine as a model drug,use modem pharmaceutical technology of pellets-coated and puled-release, adopt the orthogonal experiment to optimize and screen the formula and craft.We prepared the pulsed-release capsules of Nimodipine coated-pellets.Using of pulsed coating to controlled the releasing time,can make the drugs reach the best efficacy and reduced side effects and low toxicity in preset time,improve patient medication compliance.Through release kinetics in vitro and pharmacokinetics in vivo to explore pulsed releasing mechanism of coated-pellets and the relevance in vitro and in vivo,providing a theoretical basis for research and development of new drug delivery systems,possessing high science technology value and prospects for clinical utility.Firstly,the ultraviolet spectrophotometry method was applied to determine the content of the Nimodipine and the releasing behavior of the pellets in vitro.The drug-loaded pellets were prepared using the extrusion-spheronization method.The behaviors of the pellets were evaluated by the characteristics of drug releasing,roundness degree of the pellets(aspect ratio),product yield and size distributions,etc.The effects of the sizes of the sieve,the extrusion speed,spheronization speed and spheronization time on the the pellets were invested;and the influences of the category and amount of the disintegrating agent,bulking agent,and adhesive material,the drug loading were discussed,the optimum formulation and technology of the Nimodipine pellets were achieved by orthogonal design and the stability of the formulation and the technique were validated by the reproducibility test.The results showed that the UV method is convenient,sensitive,and of high specificity.The ratio and amount of the MCC and lactose,SDS,Tween-80,content of adhesives,spheronization speed and spheronization time have important effects on the characteristics of drug release and the roundness degree of the pellets.The optimum technology parameters were as follows:the grit diameter(L/R=0.477) was 1.0 mm,the extrusion speed was 18 Hz,while the spheronization speed and time were 23Hz 0.5 minutes firstly and 20 Hz 2.5 minutes then. The optimum formulation was as follows:Nimodipine concentration in the pellets was 30%,MCC was 30%,and the lactose was 30%,with the appropriate amount of water as the moistening agent.The drug-loaded pellets showed a good powder-technology characteristic and the release behavior met the requirement as designed.The equation for pellets release catered to One-order release dynamics according to the prescription and technology:ln(100-Q)=-0.7926t+5.8707,r=0.942.The Peppas equation was used for the model fitting,n=0.5426,0.45＜n＜0.89,it indicated that the course of pellet's release included extension and bulk erosion at the same time. Pill core were coated by stomach dissolved clothing,pH6.8 and 7.4 dissolved enteric coating,and finally different coated sustained-release pellets were mixed in proportion, and filled in the hard capsules.UV used for drug determination in vitro,the Excipients do not interfere with the determination of the drugs。The method is simple,sensitive,rapid and accurate.The cumulative release studies in vitro showed that there was no difference in same batches or different batches.That manifested the stability in the preparation and reproducible.The stability of the initial studies have shown that Nimodipine pulsed-release pellets capsule is light-sensitive,Vulnerable to moisture absorption,Therefore,packaging and storage needs of shade,moisture.The result of accelerate testing and long-term testing shows that there was no obvious change for the parameter of appearance,content,drug release etc.The determination of the plasma concentration of NM was established by HPLC; Nimodipine pulsed-release pellets capsule and sustained-release tablets were administered to the Beagle dogs.Plasma were taked after oral administration the drugs. The results show that the method of determination of the concentration of NM in plasma, simple,sensitive and specific.Pharmacokinetics studies using double-cross design:6 Beagle dogs were randomly divided into two groups,a group of subjects of oral formulations T and another group of oral reference preparation R;A week after the cross-administration,the test results T test preparation and reference preparation(R) pharmacokinetics were as follows:The Tmax were 9.5±1.2h and 4.5±1.2h;Peak C_max were 41.4±6.0ng/mL and 39.0±3.6ng/mL,t_1/2 were 6.8±1.1h and 5.6±0.7h,AUC_0-t were 604.6±53.6ng·h/mL and 626.0±34.0ng·h/mL;The relative Bioavailability of Nimodipine pulsed-release pellets capsule is 97.0±11.6%.The two agents of C_max and AUC were carried out the analysis of variance after the logarithmic transformation conversion.Result showed:AUC_0-t and C_max were not equivalent to refuse the different effective assumption;The test of the 90%of preparation's AUC_0-t confidence interval fall on the reference between preparation of the corresponding parameters's 81.9 percent to 118.1 percent,90%of C_max confidence interval fall on the Senate Agents of the corresponding parameters of 84.1 percent to 115.9 percent;T_max were significantly different(p＜0.05).So that,Nimodipine pulsed-release pellets capsule were bioequivalently of the absorption degree with the sustained-release tablets of Nimodipine.The release pellets coated with a clear pulse of the Nimodipine capsules had clearly timing characteristics.In this paper,W-N method were used to calculated the corresponding score points after oral administration,according to the release of the least-squares regression method, we achieved a regression equation:Fa=1.1636Ft-1.4228,r=0.9857,helping showed that Nimodipine pulsed-release pellets capsule in vitro had a good correlation and it could be used in vitro to detect the dynamic parameters of drug's releasing law in the body;It had importantly significance in the industrial production enterprises of the sustained-release pellets to control the quality of preparation in the future.To sum up,Nimodipine pulsed-release pellets capsule may be administrated at 18:00,and reach peaking at 3:00～4:00 after 9～10 hours.Thus effectively prevent the occurrence of cerebral infarction,make choosing time drug-release come true,be in line with chronopharmacology theory.The preparation reducing the administration times,from ordinary tablets of 3～4 and sustained-releasing tablets of 2 to 1 one day,increasing patient's compliance and reaching the design purpose.