Ainousah Bayan E, Khadra Ibrahim, Halbert Gavin W
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
Pharmaceutics. 2023 Oct 17;15(10):2484. doi: 10.3390/pharmaceutics15102484.
Solubility is a critical parameter controlling drug absorption after oral administration. For poorly soluble drugs, solubility is influenced by the complex composition of intestinal media and the influence of dosage form excipients, which can cause bioavailability and bioequivalence issues. This study has applied a small scale design of experiment (DoE) equilibrium solubility approach in order to investigate the impact of excipients on fenofibrate solubility in simulated fasted and fed intestinal media. Seven media parameters (bile salt (BS), phospholipid (PL), fatty acid, monoglyceride, cholesterol, pH and BS/PL ratio) were assessed in the DoE and in excipient-free media, and only pH and sodium oleate in the fasted state had a significant impact on fenofibrate solubility. The impact of excipients were studied at two concentrations, and for polyvinylpyrrolidone (PVP, K12 and K29/32) and hydroxypropylmethylcellulose (HPMC, E3 and E50), two grades were studied. Mannitol had no solubility impact in any of the DoE media. PVP significantly increased solubility in a media-, grade- and concentration-dependent manner, with the biggest change in fasted media. HPMC and chitosan significantly reduced solubility in both fasted and fed states in a media-, grade- and concentration-dependent manner. The results indicate that the impact of excipients on fenofibrate solubility is a complex interplay of media composition in combination with their physicochemical properties and concentration. The results indicate that in vitro solubility studies combining the drug of interest, proposed excipients along with suitable simulated intestinal media recipes will provide interesting information with the potential to guide formulation development.
溶解度是控制口服给药后药物吸收的关键参数。对于难溶性药物，溶解度受肠道介质复杂成分和剂型辅料的影响，这可能会导致生物利用度和生物等效性问题。本研究应用了小规模实验设计（DoE）平衡溶解度方法，以研究辅料对非诺贝特在模拟禁食和进食肠道介质中溶解度的影响。在DoE和无辅料介质中评估了七个介质参数（胆盐（BS）、磷脂（PL）、脂肪酸、甘油单酯、胆固醇、pH值和BS/PL比值），仅禁食状态下的pH值和油酸钠对非诺贝特溶解度有显著影响。研究了两种浓度下辅料的影响，并对聚乙烯吡咯烷酮（PVP，K12和K29/32）以及羟丙基甲基纤维素（HPMC，E3和E50）研究了两个等级。甘露醇在任何DoE介质中均无溶解度影响。PVP以介质、等级和浓度依赖性方式显著增加溶解度，在禁食介质中变化最大。HPMC和壳聚糖在禁食和进食状态下均以介质、等级和浓度依赖性方式显著降低溶解度。结果表明，辅料对非诺贝特溶解度的影响是介质组成与其物理化学性质和浓度之间复杂的相互作用。结果表明，结合感兴趣的药物、拟用辅料以及合适的模拟肠道介质配方进行体外溶解度研究，将提供有价值的信息，有可能指导制剂开发。
