Vervaeck A, Monteyne T, Saerens L, De Beer T, Remon J P, Vervaet C
Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, Ghent, Belgium.
Eur J Pharm Biopharm. 2014 Oct;88(2):472-82. doi: 10.1016/j.ejpb.2014.06.018. Epub 2014 Jul 7.
This study focused on the evaluation of prilling as a technique for the manufacturing of multiparticulate dosage forms. Prills, providing controlled and immediate drug release, were processed and finally combined in capsules yielding a fixed-dose combination. Metoprolol tartrate (MPT) and hydrochlorothiazide (HCT) were used as controlled and immediate release model drugs, respectively. These drugs were embedded in matrices composed of fatty acids and polyethylene glycol (PEG). In order to tailor drug release from the prills, the type of fatty acid, the PEG molecular weight and the fatty acid/PEG ratio were varied. To provide controlled drug release, MPT was embedded in matrices containing PEG and behenic acid. Using different PEG molecular weights (PEG 4000, 6000 and 10,000), MPT release could be tailored over a wide range. To obtain immediate release, HCT was incorporated in matrices composed of PEG and stearic acid. Since high amounts (at least 60%) of PEG were needed for acceptable immediate release, HCT release was independent on PEG molecular weight. Solid state characterization revealed that MPT crystallinity was decreased, while HCT was molecularly dispersed throughout the matrix. Drug release of both MPT and HCT prills was stable during storage. Compared to a fixed-dose reference, oral co-administration of the MPT and HCT prills to dogs yielded a similar bioavailability for the HCT prills, while the MPT prills resulted in a significant higher bioavailability.
本研究聚焦于对造粒作为一种制备多颗粒剂型技术的评估。制备出具有控释和速释特性的颗粒，将其加工后最终装入胶囊中制成固定剂量复方制剂。分别使用酒石酸美托洛尔（MPT）和氢氯噻嗪（HCT）作为控释和速释模型药物。这些药物被包埋于由脂肪酸和聚乙二醇（PEG）组成的基质中。为了调整颗粒中的药物释放，改变了脂肪酸类型、PEG分子量以及脂肪酸/PEG比例。为实现控释，将MPT包埋于含有PEG和山嵛酸的基质中。使用不同的PEG分子量（PEG 4000、6000和10000），MPT的释放可在较宽范围内进行调整。为实现速释，将HCT掺入由PEG和硬脂酸组成的基质中。由于需要高含量（至少60%）的PEG才能实现可接受的速释，HCT的释放与PEG分子量无关。固态表征显示MPT的结晶度降低，而HCT以分子形式分散于整个基质中。MPT和HCT颗粒在储存期间的药物释放均稳定。与固定剂量参比制剂相比，给犬口服MPT和HCT颗粒的复方制剂，HCT颗粒的生物利用度相似，而MPT颗粒的生物利用度显著更高。
