Design of Biorelevant Test Setups for the Prediction of Diclofenac In Vivo Features After Oral Administration

作者：Guhmann Marie; Thommes Markus; Gerber Frederic; Poellinger Norbert; Klein Sandra; Breitkreutz Joerg; Weitschies Werner^*

来源：Pharmaceutical Research, 2013, 30(6): 1483-1501.

DOI：10.1007/s11095-013-0974-y

• biorelevant test setups
• diclofenac
• mouth exposure
• multiple absorption peaks
• orodispersible tablets

Design of biorelevant test setups mimicking the physiological conditions experienced by drugs after oral administration along the passage through the mouth and the GI tract for the in vitro evaluation of diclofenac exhibiting multiple-peak phenomenon during absorption. %26lt;br%26gt;The biorelevant models simulated successively saliva (SSF, pH 6.2-6.75-7.4, 5 mL, 3 min), gastric (SGF-FaSSGF, pH 1.2-1.6, 50-250 mL, 30 min) and intestinal (FaSSIF, pH 6.8, 250 mL, 60 min) fluids. Applying these models, diclofenac free acid and its sodium/potassium salt were comparatively evaluated for dissolution and further characterized by HPLC, optical morphogranulometry, DSC and PXRD to elucidate peculiar behaviors. %26lt;br%26gt;Diclofenac salts almost completely dissolved in SSF and showed a transitional dissolution pattern before complete precipitation in SGF/FaSSGF. This peculiar pattern correlated with simultaneous chemical modification and formation of agglomerates. With low dissolution in SSF and almost immediately complete precipitation, these behaviors were not observed with diclofenac free acid. Distinct diclofenac features were strongly determined by pH-modifications after oral administration. %26lt;br%26gt;The multiple-peak phenomenon observed after administrating a solution, suspension or dispersible formulation of diclofenac salts are likely caused by drug precipitation and agglomeration in the stomach leading to irregular gastric-emptying. Diclofenac free acid may provide more reliable in vivo features.

• 出版日期2013-6