Nobuaki Hirai

Photostable Solid Dispersion of Nifedipine by Porous Calcium Silicate.

Nifedipine (NIF) is a typical light-sensitive drug requiring protection from light during manufacture, storage, and handling of its dosage forms. The purpose of this study was to evaluate the utility of porous calcium silicate (PCS) for maintaining the photostability of NIF in a solid dispersion formulation. Adsorption solid dispersion (ASD) prepared using NIF and PCS as an amorphous formulation was more stable to light irradiation than a physical mixture of NIF and microcrystalline cellulose (a control physical mixture) as a crystalline formulation. In addition, PCS in physical mixtures with NIF adequately protected NIF from photodegradation, suggesting that this protective effect could be because of some screening effect by the porous structure of PCS blocking the passage of light reaching NIF in pores of PCS. These findings suggest that PCS is useful for improving the solubility and photostability of NIF in solid dispersion formulation.

Improvement of the agitation granulation method to prepare granules containing a high content of a very hygroscopic drug.

This study describes a new approach to the preparation of a granulate with a high content of a very hygroscopic powder or drug, using the agitation granulation method, and the development of a tablet formulation using these granulates. A Chinese medicine extract, Hatimi‐zio‐gan, was used as the model of a very hygroscopic drug. Among the several excipients tested, only porous calcium silicate could be used to prepare granules, with a mixing ratio (extract to porous calcium silicate) from 2:1 to 20:1. With other excipients, very large lumps were formed during the granulation process. The best mixing ratio of extract to porous calcium silicate was 6:1. For preparation of the granules, water could be added to the mixed powder within a range of 1‐ to 4‐times the amount of porous calcium silicate. From these results, it was concluded that the ability of porous calcium silicate to hold large amounts of water in its numerous pores may allow for the preparation of granulates with a high content of very hygroscopic drugs. Starch with partial α‐links, carboxymethyl starch sodium salt and crospovidone were used for selection of the disintegration agent. When crospovidone was used as a disintegration agent, tablets containing about 70% of the Chinese medicine extract disintegrated in less than 7 min, with good dissolution rates. The same process was applied to extracts of Hotyu‐ekki‐to, Syo‐seiryu‐to, Boi‐ogi‐to and Bohu‐tusyo‐san. The absorption of paeoniflorin, a characteristic monoterpene glucoside contained in Hatimi‐zio‐gan extract, was evaluated in beagle dogs after oral administration of the Hatimi‐zio‐gan tablets prepared in this study. The values of Cmax and AUC obtained after administration of the tablets prepared in this study were significantly greater than those obtained for commercial tablets.

Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate

The aim of this study was to prepare and evaluate solid dispersion tablets containing a poorly water-soluble drug using porous calcium silicate (PCS) by a wet granulation method. Nifedipine (NIF) was used as the model poorly water-soluble drug. Solid dispersion tablets were prepared with the wet granulation method using ethanol and water by a high-speed mixer granulator. The binder and disintegrant were selected from 7 and 4 candidates, respectively. The dissolution test was conducted using the JP 16 paddle method. The oral absorption of NIF was studied in fasted rats. Xylitol and crospovidone were selected as the binder and disintegrant, respectively. The dissolution rates of NIF from solid dispersion formulations were markedly enhanced compared with NIF powder and physical mixtures. Powder X-ray diffraction (PXRD) confirmed the reduced crystallinity of NIF in the solid dispersion formulations. Fourier transform infrared (FT-IR) showed the physical interaction between NIF and PCS in the solid dispersion formulations. NIF is present in an amorphous state in granules prepared by the wet granulation method using water. The area under the plasma concentration-time curve (AUC) and peak concentration (C(max)) values of NIF after dosing rats with the solid dispersion granules were significantly greater than those after dosing with NIF powder. The solid dispersion formulations of NIF prepared with PCS using the wet granulation method exhibited accelerated dissolution rates and superior oral bioavailability. This method is very simple, and may be applicable to the development of other poorly water-soluble drugs.