Study On A Three-Pulse Drug Release System Of Nimodipine

Nimodipine (NMP) is a dihydropyridine calcium channel blocker used for the treatment of ischemia cerebral vessels disease, migraine and high blood pressure. According to the chronopharmacology of these diseases, nimodipine immediate-release (IR) mini-tablets and pulsatile-release (PR) mini-tablets with different lag time were prepared. PR mini-tablets are used to cure ischemia cerebral vessels disease and migraine. A three-pulse drug release system of nimodipine was obtained by filling IR mini-tablets and PR mini-tablets with a lag time of 4 h and 8 h into capsule for curing high blood pressure. Decreasing the times of daily drug administration, improving patient compliance and reducing drug side effect could be expectable for this pusatile drug delivery system.Ultraviolet spectrophotometry (UV) was utilized to determine the content of NMP in tablets, and to assay the dissolution of IR tablets and the release of PR tablets. Physical and chemical properties of NMP such as stability of solution and apparent oil-water partition coefficient were investigated. The plasma concentration of self-made NMP three-pulse drug delivery system in beagle dog was determined by high-performance liquid chromatography (HPLC). Results showed the UV and HPLC method were precise and reliable.NMP IR tablets were prepared by solid dispersion technique. By single factor experiments, NMP solid dispersions were developed with different polymer carriers, different ratio of carrier to drug and various preparation methods. Differential scanning calorimetry (DSC) analysis was employed to determine drug status in solid dispersion. Results showed that the NMP dissolution rate increased as the carrier percentage rose within a certain range. Poloxamer 188 solid dispersions by melting method displayed the highest solution enhancing effect (accumulative dissolution of about 90%drug in 30 min) on nimodipine, compared with PEG6000 and PVP K30. DSC analysis suggested drug in solid dispersion existed in a stable amorphous state. Through formulation screening, the formulation (solid dispersion powder:microcrystalline cellulose:talc=120:15:5) was established to prepare IR tablets.Compression-coating technique was applied to prepare nimodipine pulsatile-release mini-tablets with lag-time of 4 h and 8 h. these pulsatile mini-tablets consists of core tablets coated with outer coating layer, and were subjected to in vitro release test. By single factor experiments, formulation of core tablets was screened; how HPMC type/amounts, bulking agent type/amounts in the outer coating layer and coating level affected drug release were investigated. Impacts of release medium’s pH value and rotation speed on drug release were also studied. The formulation (solid dispersion powder:microcrystalline cellulose:talc= 40:7.5:2.5) was established to prepare core tablets. Results suggested that, PR tablets with lag time of 2-14 h could be obtained by changing HPMC type/amounts, bulking agent type/amounts and varying coating level. PR tablets of all formulations completely release drug in 1-2 h after a certain time lag. The time lag was more prolonged with an increase in coating level and percentage/viscosity of HPMC. Release medium’s pH value almost didn’t affect drug release. But rotation speed lightly affected drug release. Increasing rotation speed tended to improve drug release rate and shorten lag time of PR tablets. The outer coating layer formulations of PR tablets with 4 h and 8 h lag time were (30 mg HPMC K100M+30 mg lactose) and (40 mg HPMC K100M+20 mg MCC), respectively.By two-period crossover design, pharmacokinetics in six healthy beagle dogs was studied after a single oral administration of commercial reference formulation and self-made NMP three-pulse drug delivery system. The pharmacokinetic parameters were analyzed by DAS 2.1.1 software and the one-compartment model theory. Results showed there were three peaks in plasma concentration-time profile of self-made NMP three-pulse drug delivery system, tmax were 1.50±0.32,5.17±0.41 and 11.00±0.63 h, respectively; cmax were 45.80±10.45,66.71±12.99 and 76.71±12.91 ng·mL-1, respectively. It’s thought these three peaks were formed by the release of immediate-release mini-tablets and two kind of pulsatile mini-tablets in the pulsatile system. The relative bioavailability of self-made pulsatile system was 122.45%,22.45%higher than the commercial reference formulation.In vivo and in vitro experiment results above indicated that prior experiment design objectives were basically met, and self-made NMP three-pulse drug delivery system is a potentially useful and promising drug delivery system for chronopharmacotherapy.