Ryusuke Takano

Oral Absorption of Poorly Water-Soluble Drugs: Computer Simulation of Fraction Absorbed in Humans from a Miniscale Dissolution Test

PurposeThe purpose of this study was to develop a new system for computer simulation to predict fraction absorbed (Fa) of Biopharmaceutical Classification System (BCS) class II (low solubility–high permeability) drugs after oral administration to humans, from a miniscale dissolution test.MethodsHuman oral absorption of 12 lipophilic drugs was simulated theoretically by using the dissolution and permeation parameters of the drugs. A miniscale dissolution test and a solubility study were carried out in a conventional buffer and a biorelevant medium (pH 6.5). A dissolution parameter, which can simulate in vivo dissolution, was obtained from the in vitro dissolution curve. Human intestinal permeability was estimated assuming that the permeation was limited by diffusion through the unstirred water layer. The Fa in humans was predicted and then compared with clinical data.ResultsThe dissolution and solubility of most model drugs were faster and higher in a biorelevant medium than in a conventional buffer. The simulated absorption was limited by the drug dissolution rate and/or solubility. Predicted Fa was significantly correlated with clinical data (correlation coefficient r2 = 0.82, p < 0.001) when the dissolution profiles in biorelevant medium were used for the simulation.ConclusionsThis new system quantitatively simulated human absorption and would be beneficial for the prediction of human Fa values for BCS class II drugs.

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.

Quantitative Analysis of the Effect of Supersaturation on in Vivo Drug Absorption

The purpose of this study is to clarify the effects of intestinal drug supersaturation on solubility-limited nonlinear absorption. Oral absorption of a novel farnesyltransferase inhibitor (FTI-2600) from its crystalline free base and its HCl salt was determined in dogs. To clarify the contribution of supersaturation on improving drug absorption, in vivo intraluminal concentration of FTI-2600 after oral administration was estimated from the pharmacokinetics data using a physiologically based model. Dissolution and precipitation characteristics of FTI-2600 in a biorelevant media were investigated in vitro using a miniscale dissolution test and powder X-ray diffraction analysis. In the in vitro study, the HCl salt immediately dissolved but precipitated rapidly. The metastable amorphous free base precipitant, which did not convert into the stable crystalline free base in the simulated intestinal fluids for several hours, generated a 5-fold increase in dissolved concentration compared to the equilibrium solubility of the crystalline free base. By computer simulation, the intraluminal drug concentration after administration of the free base was estimated to reach the saturated solubility, indicating solubility-limited absorption. On the other hand, administration of the HCl salt resulted in an increased intraluminal concentration and the plasma concentration was 400% greater than that after administration of the free base. This in vivo/in vitro correlation of the increased drug concentrations in the small intestine provide clear evidence that not only the increase in the dissolution rate, but also the supersaturation phenomenon, improved the solubility-limited absorption of FTI-2600. These results indicate that formulation technologies that can induce supersaturation may be of great assistance to the successful development of poorly water-soluble drugs.

Integrating drug permeability with dissolution profile to develop IVIVC

In this review article, three different approaches to predict in vivo oral absorption based on the in vitro data of drug permeability, solubility and dissolution were introduced. At the drug discovery stage, the absorption potential of each candidate is most important to select better compounds for further development. The concept of maximum absorbable dose is applied widely, not only to evaluate the absorption potential but also to elucidate the rate‐limiting process of oral absorption that helps us to understand the cause of poor absorption. To integrate the permeability of the drug with its dissolution profile, two different approaches, in vitro dissolution/permeation system (D/P system) and in silico model and simulation method, are proposed. In the D/P system, by mimicking the in vivo process of drug absorption, the permeated amount of drugs, that is the total output of dissolution and permeation processes, are correlated with the fraction absorbed in human (Fa). This system is powerful for evaluating the improved absorption by various formulations and the effect of food intake. On the other hand, in the model and simulation approach, an intrinsic dissolution parameter of drug particle, z, was extracted from the small scale in vitro test and the process of intestinal absorption was re‐constructed in silico by incorporating the physiological parameters in human. The effective use of these approaches for the development of oral drug products is discussed through various case studies. Copyright

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.

Effects of spray drying process parameters on the solubility behavior and physical stability of solid dispersions prepared using a laboratory-scale spray dryer

Purpose: The purpose of this study is to determine the process parameters of the laboratory-scale spray dryer affecting the solubility behavior and physical stability of solid dispersions. Methods: Solid dispersions of the model drug (nilvadipine or nifedipine) and hypromellose (HPMC) (w/w: 1/1) were prepared using the laboratory-scale spray dryer. As process parameters, nitrogen flow rate, sample concentration and pump speed were investigated. The samples were characterized by dissolution tests, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), scanning electron microscope (SEM), and nanoscale thermal analysis (Nano-TA). The physical stability was monitored after 7 months storage at 25°C. Results: Solubility behavior and physical stability were improved by setting the low nitrogen flow rate and high sample concentration. DSC showed that the physical state depends on the spray drying conditions, whereas, every sample showed the similar morphology from SEM results. The difference of solubility behavior and physical stability were found to come from the microstructural phase separation of the spray dried particles using a novel analytical technique (Nano-TA). Conclusions: This study demonstrated that nitrogen flow rate and sample concentration should be the critical parameters for the enhancements of the solubility and physical stability of solid dispersions.

Physiologically Based Absorption Modeling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Alectinib.

Alectinib, a lipophilic, basic, anaplastic lymphoma kinase (ALK) inhibitor with very low aqueous solubility, has received Food and Drug Administration-accelerated approval for the treatment of patients with ALK+ non-small-cell lung cancer. This paper describes the application of physiologically based absorption modeling during clinical development to predict and understand the impact of food and gastric pH changes on alectinib absorption. The GastroPlus™ software was used to develop an absorption model integrating in vitro and in silico data on drug substance properties. Oral pharmacokinetics was simulated by linking the absorption model to a disposition model fit to pharmacokinetic data obtained after an intravenous infusion. Simulations were compared to clinical data from a food effect study and a drug-drug interaction study with esomeprazole, a gastric acid-reducing agent. Prospective predictions of a positive food effect and negligible impact of gastric pH elevation were confirmed with clinical data, although the exact magnitude of the food effect could not be predicted with confidence. After optimization of the absorption model with clinical food effect data, a refined model was further applied to derive recommendations on the timing of dose administration with respect to a meal. The application of biopharmaceutical absorption modeling is an area with great potential to further streamline late stage drug development and with impact on regulatory questions.

High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation.

Purpose: To design a high drug loading formulation of self-microemulsifying/micelle system. Methods: A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400). Results: As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400 = 8:2 was selected, and achieved the target loading level (200 mg/mL). The formulation formed fine emulsion/micelle (49.1 nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation. Conclusions: The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.

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.