Arslan Aslıhan, Yet Barbaros, Nemutlu Emirhan, Akdağ Çaylı Yağmur, Eroğlu Hakan, Öner Levent
Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey.
Department of Cognitive Science, Graduate School of Informatics, Middle East Technical University, 06800 Ankara, Turkey.
Pharmaceutics. 2023 Jan 20;15(2):363. doi: 10.3390/pharmaceutics15020363.
Celecoxib (CXB) is a Biopharmaceutical Classification System (BCS) Class II molecule with high permeability that is practically insoluble in water. Because of the poor water solubility, there is a wide range of absorption and limited bioavailability following oral administration. These unfavorable properties can be improved using dry co-milling technology, which is an industrial applicable technology. The purpose of this study was to develop and optimize CXB nanoformulations prepared by dry co-milling technology, with a quality by design approach to maintain enhanced solubility, dissolution rate, and oral bioavailability. The resulting co-milled CXB composition using povidone (PVP), mannitol (MAN) and sodium lauryl sulfate (SLS) showed the maximum solubility and dissolution rate in physiologically relevant media. Potential risk factors were determined with an Ishikawa diagram, important risk factors were selected with Plackett-Burman experimental design, and CXB compositions were optimized with Central Composite design (CCD) and Bayesian optimization (BO). Physical characterization, intrinsic dissolution rate, solubility, and stability experiments were used to evaluate the optimized co-milled CXB compositions. Dissolution and permeability studies were carried out for the resulting CXB nanoformulation. Oral pharmacokinetic studies of the CXB nanoformulation and reference product were performed in rats. The results of in vitro and in vivo studies show that the CXB nanoformulations have enhanced solubility (over 4.8-fold (8.6 ± 1.06 µg/mL vs. 1.8 ± 0.33 µg/mL) in water when compared with celecoxib pure powder), and dissolution rate (at least 85% of celecoxib is dissolved in 20 min), and improved oral pharmacokinetic profile (the relative bioavailability was 145.2%, compared to that of Celebrex, and faster t 3.80 ± 2.28 h vs. 6.00 ± 3.67 h, indicating a more rapid absorption rate).
塞来昔布（CXB）是生物药剂学分类系统（BCS）中的II类分子，具有高渗透性，但几乎不溶于水。由于水溶性差，口服给药后吸收范围广且生物利用度有限。使用干式共研磨技术可以改善这些不利特性，这是一种可应用于工业的技术。本研究的目的是通过干式共研磨技术开发并优化CXB纳米制剂，并采用质量源于设计的方法来维持其增强的溶解度、溶出速率和口服生物利用度。使用聚维酮（PVP）、甘露醇（MAN）和十二烷基硫酸钠（SLS）得到的共研磨CXB组合物在生理相关介质中显示出最大的溶解度和溶出速率。用石川图确定潜在风险因素，用Plackett-Burman实验设计选择重要风险因素，并用中心复合设计（CCD）和贝叶斯优化（BO）对CXB组合物进行优化。通过物理表征、固有溶出速率、溶解度和稳定性实验来评估优化后的共研磨CXB组合物。对所得的CXB纳米制剂进行溶出和渗透性研究。在大鼠中进行了CXB纳米制剂和参比产品的口服药代动力学研究。体外和体内研究结果表明，CXB纳米制剂具有增强的溶解度（与塞来昔布纯粉相比，在水中溶解度提高了4.8倍以上（8.6±1.06μg/mL对vs.l.8±0.33μg/mL））、溶出速率（至少85%的塞来昔布在20分钟内溶解），并改善了口服药代动力学特征（与西乐葆相比，相对生物利用度为145.2%，t更快（3.80±2.28小时对vs.6.00±3.67小时），表明吸收速率更快）。
