College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea; Pharmaceutical Research Centre, Hanmi Pharm. Co., Paltan-myeon, 893-5 Hwaseong, Gyeonggi-Do 445-913, South Korea.
College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea.
Int J Pharm. 2015 Jul 25;490(1-2):273-80. doi: 10.1016/j.ijpharm.2015.05.059. Epub 2015 May 27.
The objective of this study was to develop a novel fenofibric acid-loaded controlled release pellet showing enhanced, or equivalent to, bioavailability compared with two commercially available products containing fenofibrate or choline fenofibrate. The effect of solubilizing agents on drug solubility and the impact of fillers on core properties were investigated. Among them, magnesium carbonate most improved drug solubility, and κ-carrageenan provided the best spherical cores. The fenofibric acid-loaded pellet was prepared with magnesium carbonate and κ-carrageenan employing the extrusion/spheronizing technique followed by coating with ethylcellulose. Furthermore, dissolution and pharmacokinetic study in beagle dogs were performed compared to the fenofibrate-loaded commercial tablet (FCT) and choline fenofibrate-loaded commercial mini-tablet (CFCM). This fenofibric acid-loaded pellet showed controlled release of the drug in phosphate buffer (pH 6.8) and 0.025 M sodium laurylsulfate within 4h. Furthermore, this pellet and CFCM exhibited similar dissolution profiles. Plasma concentrations greater than 1,000 ng/ml were maintained from 30 min to 8h, suggesting a sustained release pattern. Also, the fenofibric acid-loaded pellet gave significantly higher AUC and Cmax values than FCT, indicating that it improved the bioavailability of fenofibrate due to enhanced solubility and sustained release. In addition, this pellet and CFCM were not significantly different in terms of pharmacokinetic parameters including AUC, Cmax and Tmax. Thus, this pellet was bioequivalent to CFCM in beagle dogs. In conclusion, this fenofibric acid-loaded controlled release pellet would be a potential alternative to the choline fenofibrate-loaded commercial product.
本研究旨在开发一种新型的非诺贝特酸控释微丸，与含有非诺贝特或胆碱非诺贝特的两种市售产品相比，显示出增强或等效的生物利用度。考察了增溶剂对药物溶解度的影响以及赋形剂对核心性质的影响。其中，碳酸镁最能提高药物溶解度，κ-卡拉胶提供了最好的球形核心。采用挤出/滚圆技术，用碳酸镁和κ-卡拉胶将非诺贝特酸制成载药微丸，然后用乙基纤维素进行包衣。此外，与非诺贝特载药市售片剂（FCT）和胆碱非诺贝特载药市售迷你片剂（CFCM）进行了溶出度和药代动力学研究。该非诺贝特酸载药微丸在磷酸盐缓冲液（pH6.8）和 0.025 M 十二烷基硫酸钠中 4 小时内可控制药物释放。此外，该微丸和 CFCM 具有相似的溶出曲线。从 30 分钟到 8 小时，血浆浓度保持在 1000ng/ml 以上，表明呈持续释放模式。此外，非诺贝特酸载药微丸的 AUC 和 Cmax 值明显高于 FCT，表明由于溶解度提高和持续释放，其生物利用度得到改善。此外，该微丸和 CFCM 在 AUC、Cmax 和 Tmax 等药代动力学参数方面没有显著差异。因此，该微丸在比格犬中与 CFCM 生物等效。总之，该非诺贝特酸控释微丸可能是胆碱非诺贝特载药市售产品的一种替代选择。
