Keiko Minami

This study provides insights into the in vivo performance of amorphous solid dispersion (ASD) formulations of a poorly water-soluble drug through deconvolution analysis using a surrogate marker for drug release. Carbamazepine (CAR) and fenofibrate (FEN) were used as surrogate markers of drug release from formulations and as a model of a poorly water-soluble drug, respectively. Three ASDs containing CAR (3 wt %) and FEN (30 wt %) were prepared using hydroxypropyl methylcellulose (HPMC) with immediate-release characteristics (ASD-HPMC) and two HPMC derivatives (HPMC acetate succinate, HPMCAS) exhibiting different pH-dependent drug release profiles (ASD-HPMCAS-LF and ASD-HPMCAS-HF). The in vitro drug release profiles of FEN for each ASD were comparable to those of CAR, with both compounds demonstrating polymer-dependent release behavior (release rate: ASD-HPMC > ASD-HPMCAS-LF > ASD-HPMCAS-HF). Slower FEN release prolonged the time to reach the maximum concentration; however, the maximum concentration itself was not affected. The improved oral FEN absorption in rats ranked as follows: ASD-HPMC > ASD-HPMCAS-HF > ASD-HPMCAS-LF, while CAR was completely absorbed regardless of the polymer used. Plasma CAR profile deconvolution analysis revealed that the in vivo drug release profiles corresponded to the in vitro release results. In the FEN absorption rate time-profiles, a hybrid parameter combining the drug concentration and absorption clearance, derived from deconvolution analysis, showed that ASD-HPMC maintained a relatively high and stable absorption rate until complete absorption. Conversely, ASD-HPMCAS-LF exhibited a half absorption rate compared to ASD-HPMC over 1.5 h, which then declined rapidly, resulting in limited FEN absorption improvement. For ASD-HPMCAS-HF, the absorption rate gradually increased and remained at half the rate compared to ASD-HPMC over 6 h, leading to an intermediate improvement in FEN absorption in three ASDs. These differences in absorption rate profiles indicate that drug release profiles significantly affect the amount of dissolved FEN, its retention time in the gastrointestinal tract, and the effective surface area available for absorption. This study demonstrates that the proposed method enables reliable evaluation of the in vivo performance of ASD formulations.

To assess the probability of bioequivalence (BE) between orally disintegrating tablets (ODTs) taken without water and conventional tablets (CTs) taken with water, an in vitro biorelevant methodology was developed using the BE Checker, which reproduces fluid shifts in the gastrointestinal tract and drug permeation. In addition to the fluid shift from the stomach to the small intestine, the process of ODT disintegration in a small amount of fluid in the oral cavity and the difference in gastric emptying caused by differences in water intake were incorporated into the evaluation protocol. Assuming a longer time to maximum plasma concentration after oral administration of ODTs taken without water than for CTs taken with water due to a delay in gastric emptying, the fluid shift in the donor chamber of the BE Checker without water was set longer than that taken with water. In the case of naftopidil ODTs and CTs, the values of the f₂ function, representing the similarity of the permeation profiles, were 50 or higher when the fluid shift in ODTs taken without water was set at 1.5 or 2 times longer than that of the CTs taken with water. The values of the f2 function in permeation profiles of pitavastatin and memantine ODTs were both 62 when the optimized experimental settings for naftopidil formulations were applied. This methodology can be useful in formulation studies for estimating the BE probability between ODTs and CTs.

This study demonstrates in vitro and in vivo controlof cocrystaldissolution with drug supersaturation/precipitation based on the solubilityproduct of a cocrystal. As a cocrystal model, KTZ-4ABA (ketoconazole,KTZ, a poorly water-soluble drug cocrystal, with 4-aminobenzoic acid,4ABA, a coformer) was used. The presence of 4ABA in the dissolutionmedia dramatically reduced the dissolution rate of KTZ-4ABAand regulated the supersaturation/precipitation of KTZ, supportedby the solubility product of KTZ-4ABA. In the in vitro dissolutionstudy, the combined solid form of KTZ-4ABA and a ten-fold amountof 4ABA significantly lowered the degree of KTZ supersaturation withoutprecipitation and further cocrystal dissolution. To confirm cocrystaldissolution control in the gastrointestinal tract with the same compositionas the in vitro study, an in vivo oral administration study with ratswas conducted. When KTZ was coadministered to rats in the cocrystalform, an excess of 4ABA coadministered with KTZ-4ABA in thesolid form reduced the maximum plasma KTZ concentration (C (max)), prolonged the time to reach the C (max), but did not influence the area under the plasma concentration-timecurve. These results demonstrate that both in vitro and in vivo cocrystaldissolution can be regulated by adding an appropriate amount of coformerbased on the solubility product, which can be one of the promisingstrategies for the oral use of cocrystal formulations.