Urapidil Sustained-release Pellets

Urapidil, a postsynaptic al-adrenoceptor antagonist, is an anti-hypertension medicine. The elimination half-life of Urapidil is about 3 hours. The aim of this work is to develop Urapidil sustained release pellets to reduce dosing frequency and narrow the fluctuation of blood concentration.UV methods were used to determine both the content in pellets and the concentration in dissolution media. The solubility of Urapidil in different media (pH value from 1.2 to 7.4) and the apparent partition coefficient in n-octanol/H2O system were determined.Urapidil pellets were prepared in a centrifugal granulator with MCC as dilute agent and HPMC solution as adhesive agent by powder layer technology. The powdery probability of the pellets was determined.The pellets were coated with a blend of Eudragit SI00/ LI00. The two enteric materials were dissolved in 70% alcohol. The mixing proportions of SI 00/LI 00, the amount of HPMC and coating level were found to have significant influence on release rate. The formulation of which release rate in different media are similar to the release rate of Germany capsules was picked out through optimum test.The pellets were coated with a blend of Eudragit NE30D/L30D-55 as well. The most important factors that influence the release rate of Urapidil from pellets are the same as above. The most similar formulation (Tl) was picked out through optimum test.The pellets were also coated with Eudragit NE30D only. The formulation (T2) of which release rate is similar to that of Germany capsules in pH2.0 mediabut much slower in pH6.8 media was picked out through optimum test.HPLC method was used to detect the concentration of Urapidil in plasma. The plasma concentrations of Urapidil in three healthy volunteers after a single oral administration of Tl and T2 were studied with Germany capsules as a reference preparation. Cmax,Tmax,and MRT of Tl were 302ng/ml, 4.7hours and l0hours respectively. Compared with Germany capsules, the relative bioavailability was 110.9%. So we could reach the conclusion that Tl was bioequivalent to Germany capsules. Cmax,Tmax of T2 were 121ng/ml, 13.0 hours respectively and the relative bioavailability was 68.1% only.The absorption of Urapidil in rat's colon was studied. It was verified that the absorption rate is first-order and ka is equal to O.O33lh-1.Base on the above study, a further research was carried on. The pellets were coated with a blend of Eudragit NE30D/ L30D-55 to produce pellets that could maintain pharmacodynamics effect within a day. The dissolution tests suggested that the sustained pellets could release Urapidil with zero-order in different media and the release rates were similar. The bioavailability study was performed in three healthy volunteers. The pharmacokinetics parameters were listed below: Cmax=160ng/ml,Tmax=5.0h,MRT=15h. Compared with Germany capsules, bioavailability is similar (Fr=110.6%) while mean residence time is prolonged.