Preparation Of Felodipine Tablets Based On Nanosuspendion Technique

Felodipine, a widely used clinical selective dihydropyridine calcium channel blockers whose oral bioavailability is only about 15%, is a typical BCSⅡdrug with high permeability and low solubility. The key point to improve the bioavailability is increasing its dissolution rate. In this paper, we improved the dissolution rate by preparing felodipine nanosuspensions, and resolved the poor stability of the liquid system by succedent lyophilization and tabletting.UV spectrophotometric was used to determine the content and dissolution of relevant felodipine formulations in this paper, HPLC was used to detect the related substance of felodipine tablets, UPLC-MS-MS method was established and used to assay the felodipine concentration in dog plasma. These methods were proved to be accurate, reliable and can meet the research requirements.After formulation and technology study, the scheme for producing felodipine nanosuspension, with which DMSO as the organic solvent, Pluronic F68 as stabilizer for the oil phase, HPMC E5 and Tween-80 as the aqueous phase stabilizer, and ultrasonic controlling precipitating was worked out. Determination showed that the average Particle size of produced nanosuspension stabilized at 140±10 nm; TEM scan revealed the nanosuspension was consist of regular ultrafine homogeneous club-shaped particles; Zeta potential was-29.11 mV. The dissolution result showed that the dissolution amount in 2 min of nanosuspension (170 nm) in pure water and 0.1%Tween-80 was 10 time and 2 times higher than that of the microsuspension (6μm) respectively.Through prescription screening,20%(W/V) mixture of mannitol:glycine (1:1) was selected as lyoprotectant. Mean diameter before and after reconstitution was 114 nm and 375 nm; DSC and X-ray diffraction analysis showed that drug crystal form changeed and a new phase was formed after lyophillization.Felodipine tablets was made from the freeze-dried powder. Dissolution of the self-made felodipine tablets in 0.1% Tween-80 reached 85% in 15 min; The preliminary study of stability of the tablets showed that the related substances increased obviously at high temperature and light (for 10 days), and no significant changes were discovered in other conditions. Pharmacokinetic experiments on 6 dogs were performed by two-agent two cross-cycle to study the differents between the self-made and commercial felodipine tablets. The results calculated by non-compartmental model revealed that tmax of self-made and referrence ones were 1.38±0.77 and 1.29±1.12 h; Those Cmax were 32.15 ng.mL-1 comparing with 21.34 ng.mL-1; The relative bioavailability of AUC(0-t) and AUC(0-∞) was 186.3% and 162.5%, respectively. So the conclusion was drawn that tmax of them were approximate, but Cmax of self-made tablets was 1.98 times larger than that of the referrence ones, and bioavailability improved greatly.