Chemical Structural Effects of Amphipathic and Water-soluble Phospholipid Polymers on Formulation of Solid Dispersions.

For the polymeric carriers of solid dispersions, it is important that carriers themselves dissolve quickly and maintain the supersaturated state of amorphous drugs during their dissolution period to improve bioavailability. Amphipathic 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers can be dissolved in water, owing to the extremely high hydrophilicity of the MPC units, and are used as an ideal feeder for drug molecules to form aggregates in aqueous conditions. We synthesized amphipathic MPC copolymers with different hydrophobic side chains and molar ratios of MPC units, and evaluated the effect of the polymers on dissolution rate and supersaturation maintenance of solid dispersions of indomethacin. In most of the water-soluble amphipathic MPC copolymers, "spring-parachute"-like dissolution behavior was observed, where the drug initially became supersaturated followed by slow precipitation. In particular, MPC copolymers with aromatic rings in their side chains or polymers with a high percentage of hydrophobic units remained in a supersaturated state for a longer period. In contrast, urethane groups, which form hydrogen bonds with drug molecules, could also interact with water and were not conducive to maintaining supersaturation. In addition, water solubility of the polymer is important for rapid dissolution.

Quantitative analysis of an impact of P-glycoprotein on edoxaban's disposition using a human physiologically based pharmacokinetic (PBPK) model.

The purpose of this study was to evaluate the impact of P-glycoprotein (P-gp) efflux on edoxaban absorption in gastrointestinal tracts quantitatively by a physiologically based pharmacokinetic (PBPK) model constructed with clinical and non-clinical observations (using GastroPlus™ software). An absorption process was described by the advanced compartmental absorption and transit model with the P-gp function. A human PBPK model was constructed by integrating the clinical and non-clinical observations. The constructed model was demonstrated to reproduce the data observed in the mass-balance study. Thus, elimination pathways can be quantitatively incorporated into the model. A constructed model successfully described the difference in slopes of plasma concentration (Cp)-time curve at around 8 - 24 hr post-dose between intravenous infusion and oral administration. Furthermore, the model without P-gp efflux activity can reproduce the Cp-time profile in the absence of P-gp activity observed from the clinical DDI study results. Since the difference of slopes between intravenous infusion and oral administration also disappeared by the absence of P-gp efflux activity, P-gp must be a key molecule to govern edoxaban's PK behavior. The constructed PBPK model will help us to understand the significant contribution of P-gp in edoxaban's disposition in gastrointestinal tracts quantitatively.

Scale-Free Soft Sensor for Monitoring of Water Content in Fluid Bed Granulation Process.

In-line monitoring of granule water content during fluid bed granulation is important to control drug product qualities. In this study, a practical scale-free soft sensor to predict water content was proposed to cope with the manufacturing scale changes in drug product development. The proposed method exploits two key ideas to construct a scale-free soft sensor. First, to accommodate the changes in the manufacturing scale, the process parameters (PPs) that are critical to water content at different manufacturing scales were selected as input variables. Second, to construct an accurate statistical model, locally weighted partial least squares regression (LW-PLSR), which can cope with collinearity and nonlinearity, was utilized. The soft sensor was developed using both laboratory (approx. 4 kg) data and pilot (approx. 25 kg) scale data, and the prediction accuracy in the commercial (approx. 100 kg) scale was evaluated based on the assumption that the process was scaled-up from the pilot scale to the commercial scale. The developed soft sensor exhibited a high prediction accuracy, which was equivalent to the commonly used near-infrared (NIR) spectra-based method. The proposed method requires only standard instruments; therefore, it is expected to be a cost-effective alternative to the NIR spectra-based method.

Application of void forming index (VFI): Detection of the effect of physical properties of dry powder inhaler formulations on powder cohesion.

Dry powder inhaler (DPI) is an attractive alternative for non-invasive drug administration and can make the use of critical biopharmaceutical formulations more convenient for patients. Inhalation of biopharmaceutical formulations can provide targeted delivery to the lungs as well as systemic delivery. Generally, biopharmaceutical DPI formulations consist of highly cohesive powders that tend to agglomerate. For successful delivery to the lungs, the detection of powder cohesiveness and its effect on the performance of the formulations is mandatory. Herein, the effects of the physical properties of mannitol on the cohesiveness of DPI formulations were investigated. The powder cohesion was detected using the void forming index (VFI) measured by inverse gas chromatography (iGC) at 4 h (VFI4h), which was defined as the pressure drop ratio of 4 h purged sample to that of the initial sample. VFI4h was found to correlate well with the cohesiveness of DPI formulations. The amount of investigated samples required for VFI measurement was less than that required for conventional measurements. VFI showed a good relationship between the cohesiveness of DPI formulations and the physical properties of mannitol. Thus, VFI can be a reliable standard index to evaluate the cohesiveness of DPI formulations.

Effects of inner polarity and viscosity of amphiphilic phospholipid polymer aggregates on the solubility enhancement of poorly water-soluble drugs.

We quantitatively evaluated the properties of aggregates of amphiphilic polymers formed in an aqueous medium and clarified the effect of the inside polarity and viscosity of the polymer aggregate on the solubilization of poorly water-soluble drugs. Three water-soluble amphiphilic 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers with various hydrophobic monomer units, namely, n-butyl methacrylate (BMA), 2-methacryloyloxyethyl butylurethane (MEBU), and 2-methacryloyloxyethyl benzylurethane (MEBZU), were synthesized. The different molecular interactions between the hydrophobic monomer units, such as hydrophobic interactions, hydrogen bonding, and dispersion force between the aromatic rings, were considered. Fluorescence spectroscopic measurements revealed that every polymer aggregate had almost the same polarity as that of ethanol. Also, the polymers with urethane bonds, poly(MPC-co-MEBU) and poly(MPC-co-MEBZU) had slightly higher polarity and viscosity inside the polymer aggregate than that of poly(MPC-co-BMA). The water solubility of nifedipine and indomethacin was clearly enhanced in the MPC polymer aqueous solution depending on the polymer structure. As indomethacin is less soluble in polar solvents than is nifedipine, it needed to be transferred deeper into the polymer aggregates for stable solubilization. It is plausible that the high viscosity inside the polymer aggregate prevented the diffusion of drug molecules. We concluded that not only the polarity inside the polymer aggregates and the strength of the interaction force between the polymer and drug, but also the viscosity inside the polymer aggregates were responsible for enhancing the solubilization of poorly water-soluble drugs.

Establishment of a clinically relevant specification for dissolution testing using physiologically based pharmacokinetic (PBPK) modeling approaches.

This paper presented how to establish a clinically relevant specification (CRS) using in silico physiologically based pharmacokinetic (PBPK) modeling. Three different formulations of model drug products were used in the clinical studies in order to distinguish between bioequivalent (BE) batches from non-BE batches. A human PBPK model was constructed by integrating the clinical and non-clinical observations by using GastroPlusTM software. The developed model was verified by the comparison between human PK behavior observed in clinical studies and human PK behavior predicted from the software. The simulation results were obtained by using the dissolution profiles showing clinically relevant discriminatory power as input variables for the developed PBPK model. For three investigated formulations, the simulated PK behavior was comparable to the PK behavior observed in clinical studies. In addition, in silico BE simulation studies confirmed that the verified PBPK model can successfully reproduce the clinical study results. In conclusion, a CRS was established with the BE simulation by using the verified PBPK model, in order to detect and reject non-BE batches of drug products. The establishment of the CRS is useful for a quality control and finding optimal formulation to accomplish target PK behavior, safety, and efficacy.

Integration of In Silico Pharmacokinetic Modeling Approaches Into In Vitro Dissolution Profiles to Predict Bioavailability of a Poorly Soluble Compound.

The objective of present study is to develop pharmacokinetic (PK) prediction methods using in silico PK model for oral immediate release drug products (i.e. solution, suspension, and amorphous solid dispersion). A poorly water soluble compound with low bioavailability in rat was used (CS-758 as a model compound). A constructed in silico PK model contained an advance compartmental absorption and transit model. For solution, the in silico PK model reproduced an observed rat plasma concentration (Cp)-time profile. In addition, an in vitro dissolution method was developed to predict a rat Cp-time profile for suspension. As a result, the in silico PK model could predict the observed one by using dissolution profiles as the input. Furthermore, a dissolution profile of amorphous solid dispersion was applied to verify the in silico PK model. A result indicated the simulated rat Cp-time profile was significantly comparable to the observed one. This study demonstrated that the integration of an in silico PK model into dissolution profiles can predict rat Cp-time profiles for suspension and amorphous solid dispersion. These results suggest that the integration of in silico PK modeling approaches into dissolution profiles can contribute to the formulation screening for poorly soluble compounds by predicting PK behaviors.

Influence of particle size and blender size on blending performance of bi-component granular mixing: A DEM and experimental study.

The effect of particle size enlargement and blender geometry down-scaling on the blend uniformity (BU) was evaluated by Discrete Element Method (DEM) to predict the blending performance of a binary granular mixture. Three 10 kg blending experiments differentiated by the physical properties specifically particle size were performed as reference for DEM simulations. The segregation behavior observed during the diffusion blending was common for all blends, while the sample BU, i.e., standard deviation of active ingredient content % was different among the three blends reflecting segregation due to the particle size differences between the components. Quantitative prediction of the sample BU probability density distribution in reality based on the DEM simulation results was successfully demonstrated. The average root mean square error normalized by the mean of the mean sample BU in the blends was 0.228. Beside the ratio of blender container to particle size, total number of particles in the blender and the number of particles in a sample were confirmed critical for the blending performance. These in-silico experiments through DEM simulations would help in setting a design space with respect to the particle size and in a broader sense with respect to the physical properties in general.

Preparation and Characterization of Itraconazole- or Miconazole-Loaded PLGA Microspheres.

The purpose of this study was to prepare poly(lactide-co-glycolide) (PLGA) microspheres (MS) loaded with itraconazole (ITCZ) or miconazole (MCZ) under different evaporation temperatures (25 or 40°C) using an oil-in-water emulsion solvent evaporation method in order to evaluate the initial burst release of drug. Loading efficiencies were comparatively good and the diameters of prepared drug-loaded PLGA MS were around 20 µm in all formulations. The release rates of ITCZ-PLGA MS prepared at 40°C showed a significantly restricted release profile compared with the corresponding ITCZ-PLGA MS prepared at 25°C. This difference in release rate of ITCZ was thought to be caused by the self-healing effect of PLGA, as the glass transition temperature of PLGA is around 40°C. With respect to the MCZ-PLGA MS, the initial burst release was similar in formulations prepared at both 25 and 40°C. Scanning electron microscope results suggested that the initial burst release was due to the localization of MCZ on the surface of MCZ-PLGA MS at higher concentrations. Differential scanning calorimetry measurements suggested complete amorphization of MCZ in MCZ-PLGA MS, whereas crystalline ITCZ was detected in the ITCZ-PLGA MS. This complete amorphization of MCZ is considered to be one of the reasons for the initial burst release.

Selection of a round convex tablet shape that mitigates the risk of chipping and capping based on systematic evaluation by utilizing multivariate analysis.

Selecting a tablet shape that minimizes the risk of chipping and capping during manufacture is important in pharmaceutical industry. Here, the selection was performed based on systematic evaluation for the first time. Abrasion and stress relaxation time were utilized as indices of the occurrences of chipping and capping, respectively. Partial least square regression models that used tablet shape parameters to estimate the tablet's abrasion and stress relaxation time were utilized to develop response surface plots of the effect of the tablet shapes on the occurrence of chipping and capping systematically, and to identify an optimum tablet shape that is expected to have a low occurrence of chipping and capping. A verification study using commercial scale facilities proved that the optimum tablet shape had a lower occurrence of chipping and capping compared to suboptimum examples as speculated by their abrasion and stress relaxation time. The observed mathematical relationship between the tablet shapes and the occurrence of chipping and capping were consistent with the previous studies based on the comparison of limited number of tablet shapes using different formulations. Consequently, it is expected to be applicable to other formulations beyond the evaluated formulation in the present study.

Effect of preparation method on properties of orally disintegrating tablets made by phase transition.

In order to evaluate the effect of preparation method on the properties of orally disintegrating (OD) tablets, OD tablets were prepared by compressing a mixture of high melting point sugar alcohol (HMP-SA) and low melting point sugar alcohol (LMP-SA) and subsequent heating. In the direct compression method (DCM) where the LMP-SA was added as a powder, both hardness and disintegration time were increased by decreasing the particle size of the LMP-SA. In the wet granule compression method (WGCM), where the LMP-SA was added as an aqueous binder solution, the tablets became harder with less heating compared to tablets prepared by DCM. Using 1% xylitol as the LMP-SA provided tablets with sufficient hardness when prepared by WGCM, as opposed to DCM where 5% xylitol was necessary to prepare tablets with similar hardness. These results suggest that uniformly distributed LMP-SA on the surface of HMP-SA particles in WGCM might diffuse more easily during the heating process compared to mechanically mixed LMP-SA in DCM, resulting in an increase in tablet hardness even with a short heating time and low content of LMP-SA. In addition, disintegration and hardness stability of the tablets were affected by the LMP-SA content when prepared by WGCM, suggesting that the LMP-SA content should be regulated to assure the stability of OD tablet characteristics.

Evaluation of rapidly disintegrating tablets manufactured by phase transition of sugar alcohols.

The aim of the present study was to assess the properties of rapidly disintegrating (RD) tablets manufactured by the phase transition method. RD tablets were produced by compressing powder containing erythritol (melting point: 122 degrees C) and xylitol (melting point: 93 approximately 95 degrees C), and then heating at about 93 degrees C for 15 min. The hardness and oral disintegration time of the heated tablets increased with an increase of the xylitol content. These results suggested that the heating process and xylitol content might influence the properties of RD tablets. Then we evaluated the physicochemical properties of the RD tablets, including the median pore size, crystallinity, hardness, and oral disintegration time of tablets made with and without heating. After heating, the median pore size of the tablets was increased and tablet hardness was also increased. The increase of tablet hardness with heating and storage did not depend on the crystal state of the lower melting point sugar alcohol. It is concluded that a combination of low and high melting point sugar alcohols, as well as a phase transition in the manufacturing process, are important for making RD tablets without any special apparatus.