Pulsatile Chronotherapeutic Drug Delivery for Controlling Early Morning Surge in Blood Pressure; Effect of Coating on Eplerenone In-vitro, In-vivo Release and Urinary Na/K Ratio

Abstract The objective of the present study was to develop time delayed chronotherapeutic formulation of Eplerenone (Ep) to provide rapid drug release after a pre-determined lag time for the treatment of early morning hypertension. Cyclodextrin complexation was used to prepare fast release Ep core tablets. The developed core tablets were then coated with different rate-controlling polymers using compression coating technique. The developed tablets were evaluated for hardness, friability, drug content and swelling index. The in-vitro drug release was carried out to study the effect of different coating materials on drug release and lag time. Tablets selected for stability study were those showing lag time of 5-7 hours followed by complete drug release; F2, F3, F7, F8, and F12. The in-vivo study was carried out on tablets with the highest t90 as compared to commercial tablets after being administered to healthy human volunteers where plasma Ep and urinary Na/K ratio were determined. Results suggested that this approach was able to provide delayed release Ep formulations that will be useful for patients with morning surge in blood pressure.

摘要 本研究旨在开发依普利酮（Eplerenone，Ep）的时滞型时辰给药制剂，使其在预设滞后时间后实现快速药物释放，用于治疗清晨高血压。采用环糊精包合技术制备速释型依普利酮片芯，随后通过压片包衣工艺，以多种控释聚合物对所得片芯进行包衣。对制备得到的包衣片开展硬度、脆碎度、药物含量及膨胀指数的质量评价。通过体外药物释放实验，考察不同包衣材料对药物释放行为及滞后时间的影响。选取滞后时间为5~7小时且可实现药物完全释放的制剂F2、F3、F7、F8及F12进行稳定性考察。选取体外释药t90值最高的制剂与市售制剂对照，对健康人体受试者给药后开展体内研究，测定血浆依普利酮浓度及尿钠钾比值。结果表明，该方法可制备得到延时释药的依普利酮制剂，适用于存在血压晨峰的高血压患者。