Koji Shiraki

Rate-Limiting Steps of Oral Absorption for Poorly Water-Soluble Drugs in Dogs; Prediction from a Miniscale Dissolution Test and a Physiologically-Based Computer Simulation

ABSTRACTPurposeNonlinear oral absorption due to poor solubility often impedes drug development. The purpose of this study was to elucidate the rate-limiting process in oral absorption of Biopharmaceutical Classification System (BCS) class II (low solubility–high permeability) drugs in order to predict nonlinear absorption of dose caused by solubility-limited absorption.MethodsOral absorption of danazol, griseofulvin, and aprepitant was predicted from a miniscale dissolution test and a physiologically-based model. The effect of particle size reduction and dose increase on absorption was investigated in vitro and in vivo to clarify the rate-limiting steps of dissolution-rate-limited and solubility-limited absorption.ResultsThe rate-limiting steps of oral absorption were simulated and increase in the dissolution rate and administration dose showed a shift from dissolution rate-limited to solubility-limited absorption. In the study in dogs, particle size reduction improved the oral absorption of large particle drugs but had little effect on small particle drugs. Dose nonlinearity was observed with small particles at a high dose. Our model quantitatively predicted results observed in vivo, including but not exclusively, dissolution-rate-limited and solubility-limited absorption.ConclusionThe present study provides a powerful tool to predict dose nonlinearity and will aid in the success of BCS class II drug development.

Characterizing the dissolution profiles of supersaturable salts, cocrystals, and solvates to enhance in vivo oral absorption

The purposes of this study were to elucidate the type-specific characteristics of salt, cocrystal, and solvate formulations upon dissolution and precipitation, and to clarify their effect on enhancing oral absorption. Several types of solid formulations (dantrolene sodium salt [DAN-NA], pioglitazone hydrochloride salt [PIO-HCL], megestrol acetate saccharin cocrystal [MEG-SA], and an in-house compound ZR ethanolate [ZR-ETH]) that induce supersaturation of BCS class II drugs were compared to their crystalline free forms. An in vitro miniscale dissolution test in biorelevant media was used to characterize their dissolution profiles and residue forms. Both salts (DAN-NA and PIO-HCL) rapidly reached the maximum concentration within 5min, whereas the cocrystal (MEG-SA) did so slowly. After the maximum concentration had been reached, the dissolved concentrations of DAN-NA, PIO-HCL, and MEG-SA decreased, but that of ZR-ETH did not. Time-dependent XRPD analysis revealed that the initial solid state of each salt dissolved within 5min, whereas the cocrystal remained for more than 10min, and the solvate remained for 4h. It also revealed that PIO-HCL and MEG-SA precipitated to the stable free form, while DAN-NA precipitated to the metastable form, which maintains a higher concentration than the stable free form continuously. In vivo absorption in beagle dogs was also examined. The plasma AUC of DAN-NA, MEG-SA, and ZR-ETH was respectively 1.5-, 2.1-, and 11-fold more than each free form. On the other hand, the absorption of PIO-HCL was not enhanced compared with its free form. The results in the present study clarified that not only the precipitation rate and the form of precipitation but also the retention of the initial solid state in the absorption process contribute to enhancing the in vivo absorption of Class II drugs from solid formulations such as salts, solvates, and cocrystals.

Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning

Substituting a carbon atom with a nitrogen atom (nitrogen substitution) on an aromatic ring in our leads 11a and 13g by applying nitrogen scanning afforded a set of compounds that improved not only the solubility but also the metabolic stability. The impact after nitrogen substitution on interactions between a derivative and its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel) was also detected, most of them contributing to weaker interactions. After identifying the positions that kept inhibitory activity on HCT116 cell growth and Raf/MEK, compound 1 (CH5126766/RO5126766) was selected as a clinical compound. A phase I clinical trial is ongoing for solid cancers.

Miniaturized Screening Tools for Polymer and Process Evaluation

There has been an increasing interest in studying amorphous solid dispersion (ASD) approaches in response to the increasing number of poorly soluble compounds from pharmaceutical discovery in recent years. Although ASD has demonstrated drastic bioavailability enhancement, concerns over the physical instability remain as valid. By engineering amorphous solid dispersion with an appropriate polymer, the physical stability of ASD can be improved significantly. The identification of appropriate polymer and drug loading for ASD development, however, has been based on “trial and error” and is time consuming. High-throughput miniaturized screening systems offer attractive opportunities for the development of ASD by streamlining the polymer and drug loading selection processes with low demand on material, time, and resources. The main focus of this chapter is to describe and review the current miniaturized experimental ASD screening methods, including solvent casting, solvent shift, coprecipitation, melt fusion, freeze drying, and spin coating. The criticality of understanding basic physicochemical properties of active pharmaceutical ingredient (API) in developing a successful ASD is discussed. The drug–polymer interaction in the solid state and in solution upon dissolution is also briefly tackled. Finally, a rational approach for polymer and drug loading selection based on the balance of biopharmaceutical performance and ASD stability is provided.

Cocrystal structure design for CH5134731 based on isomorphism

We succeeded in forming a benzoic acid cocrystal of CH5134731 by focusing on the isomorphism shown by its solvates. As a result of evaluation, the benzoic acid cocrystal showed good solubility. This crystal engineering approach made it possible to reduce the amount of compound and study time in the early stage of research and development.