Formulation-Dependent Modulation of Ibuprofen Absorption Kinetics in Fixed-Dose Combinations: An Exploratory Analysis of the Dissolution-Absorption Relationship.

We conducted a pharmacokinetic study to compare two fixed-dose combinations of ibuprofen/acetaminophen (IP-TA and IP-TB) with different formulation designs and excipient compositions, and explored how formulation differences influence ibuprofen pharmacokinetics by comparing in vitro dissolution and in vivo absorption profiles. In an open-label, randomized, 2-treatment, 2-period, 2-sequence crossover study, 24 healthy Japanese participants received a single oral dose of IP-TA (ibuprofen 195 mg and acetaminophen 195 mg) or IP-TB (ibuprofen 160 mg and acetaminophen 160 mg) under fasting conditions. Pharmacokinetic data were analyzed using a linear mixed-effects model. Fraction absorbed (Fa) was estimated using the Loo-Riegelman method, and ibuprofen dissolution was evaluated at pH 1.2, 4.0, and 6.8. The relationship between weighted mean dissolution rates (D) and Fa was examined. Ibuprofen absorption from IP-TA was faster than from IP-TB, as reflected by higher Cmax and greater early exposure, and these differences remained after dose normalization. Dissolution profiles showed temporal similarity with absorption profiles, particularly for IP-TA. Analysis of Fa also suggested a relatively high degree of synchronization between ibuprofen and acetaminophen absorption in IP-TA. These findings indicate that formulation-dependent differences in dissolution behavior may influence early ibuprofen absorption, although further studies are needed to clarify the underlying mechanisms.