盐酸维拉帕米择时缓释微丸的研制及犬体内药代动力学

Preparation of verapamil hydrochloride controlled-onset extended-release pellets and its pharmacokinetics in dogs

目的制备盐酸维拉帕米择时缓释微丸(VH-COERP);研究VH-COERP在犬体内的药代动力学,并与市售的盐酸维拉帕米缓释微丸(VH-DRP)进行比较。方法采用空白丸芯上药法制备含药丸芯,并用流化床对其包衣,其中羟丙基甲基纤维素为内层包衣溶胀层,乙基纤维素水分散体为外层包衣控释层,通过改变内外层衣膜的厚度达到择时缓释的效果。用RP-HPLC测定6只Beagle犬口服VH-COERP后不同时间血浆中盐酸维拉帕米的浓度,并与VH-DRP比较,通过3P97程序计算药代动力学参数。结果溶胀层和控释层的包衣厚度、溶胀层中添加剂的种类会影响药物释放的时滞、释药行为以及最终释药量,所制得的微丸释放不受介质pH及后处理的影响。体外溶出经5 h时滞后缓慢释药达24 h。与VH-DRP相比,VH-COERP体内释药具有明显的时滞(4 h),达峰时间明显延长(8 h),相对生物利用度为(94.56±7.64)%。结论VH-COERP在体内外经过明显的时滞后均能缓慢释放,达到了睡前服药,凌晨发挥疗效的目的。

Aim To prepare verapamil hydrochloride controlled-onset extended-release pellets （VH- COERP） and study its release behavior in vitro. To compare the pharmacokinetic characteristics and bioavailability in six Beagle dogs after oral administration of VH-COERP and verapamil hydrochloride delayed-release pellets （VH-DRP） as reference. Methods The core of VH-COERP were prepared in the fluidized bed （mini-glatt） by spraying water solution containing drugs onto sucrose-starch pellets with hydroroxy propyl methyl cellulose （HPMC） as the inner coating swelling layer and ethylcellulouse aqueous dispersion as the outer coating controlled layer. Through modifying the coating level of inner and outer layer, the VH-COERP with the optimized cumulative release profile was obtained. The concentration of VH in plasma of six dogs and its pharmacokinetic behaviors after oral administration of VH-COERP and VH-DRP at different times were studied by RP-HPLC. The pharmacokinetic parameters were computed by software program 3P97. Results The lag time, the release behavior and the amount of VH from VHCOERP within 24 hours were not influenced by the pH of dissolution medium and post-process, but obviously influenced by the different kinds of added material in swelling layer and the coating level of the inner swelling layer and the outer controlled layer. In vitro the lag time of release profile of VH from VH- COERP was 5 h and then VH was extended release from VH-COERP in the following time. Compared with the VH-DRP, VH-COERP in vivo has an obviously lag time （4 h） , Tmax was also delayed （8 h） and the relative bioavailability was （94.56 ± 7.64）%. Conclusion The release profile of VH from VH-COERP was shown to be extended-release after an conspicuous lag time in vitro and in vivo. So the drug can be taken by the patient before bed time and begin to work at the morning.