Kohsaku Kawakami

Microemulsion formulation for enhanced absorption of poorly soluble drugs: I. Prescription design

Microemulsion formulations, which can be used to improve the bioavailability of poorly soluble drugs, were designed using only pharmaceutical excipients. Several types of oils and surfactants were tested and it was found that propyleneglycol monoalkyl ester and glycerol monoalkyl ester were solubilized easily in an aqueous medium by various types of surfactants. Although propyleneglycol dialkyl ester was difficult to be solubilized, the solubility was significantly enhanced by mixing it with glycerol monoalkyl ester at the ratio of 1:1. The most suitable surfactants for preparing microemulsion formulations were HCO-40, HCO-60, Tween 80, BL-9EX and Pluronic P84. The use of additional surfactants such as sodium dodecyl sulfate or sodium deoxycholate significantly improved the solubilization capacity of the oils, although formulations free of these surfactants were also available. These microemulsion formulations can be administered as a form of water-in-oil microemulsion or surfactant-oil mixture, and are expected to convert to oil-in-water microemulsion in the small intestine.

Microemulsion formulation for enhanced absorption of poorly soluble drugs: II. In vivo study

Oral administration study of microemulsion formulations, which are known to improve the bioavailability of poorly soluble drugs, was performed using rats. Nitrendipine was used as a poorly soluble model drug, and its absorption was enhanced significantly by employing the microemulsion formulations compared to a suspension or an oil solution. The effect of the fed state on the oral absorption of nitrendipine became insignificant with the microemulsion formulations, although it affected the absorption from the suspension formulation significantly. The absorption behavior also varied with the type of surfactant. The absorption from Tween 80-based formulation was very rapid, while HCO-60-based formulation showed prolonged plasma concentration profile. However, the absorption from BL-9EX (polyoxyethylene alkyl ether)-based formulation was hardly observed. Damage to the gastrointestinal mucosa, which seems to be a serious problem of surfactant-based formulations, also differed with the type of surfactant employed. HCO-60 and Tween 80-based formulations were mild to the organs, while BL-9EX-based formulation caused serious damage. The behavior and absorption mechanism of the microemulsion formulations are discussed.

Correlation between Glass-Forming Ability and Fragility of Pharmaceutical Compounds

Fragility is a measure of the departure from non-Arrhenius behavior for supercooled liquids and glasses, and various simple methods are available for its quantification. However, the obtained values usually do not agree with each other. One of the purposes of this study was to compare the fragility values obtained by different methodologies. Thermodynamic fragility (FT) is a simple concept that is evaluated from the heat capacity change at the glass transition temperature (Tg). Dynamic fragility is evaluated using three methodologies in this study: extrapolation of the configurational entropy (Sc) to the Kauzmann temperature (Tk) (FDC), ramp-rate dependence of Tg (FDTg), and that of the fictive temperature (Tf) (FDTf). FT and FDC of 19 pharmaceutical compounds were correlated, whereas FDTg and FDTf did not correlate with either of them. This result seems reasonable because both FT and FDC are calculated from thermodynamic parameters in the quasi-equilibrium state, but FDTg and FDTf are likely affected by kinetics as well. Another goal of this study was to find the correlation between the glass-forming ability (GFA) and fragility. FDTg was shown to correlate with GFA, presumably because both were determined on the balance of thermodynamic and kinetic factors. This correlation suggests that fragile glass has low GFA. Furthermore, the relevance of fragility to isothermal crystallization is discussed. Compounds with small FDTg and FDTf tended to exhibit pressure-controlled crystallization, for which better storage stability can be expected relative to temperature-controlled compounds. Fragility was shown to be a useful parameter practically as well as scientifically.

Dynamics of ribavirin glass in the sub-Tg temperature region.

Fragility and the effect of annealing in the sub-T(g) temperature region on the characteristics of ribavirin glass were investigated using thermal analysis. The onset T(g) of ribavirin glass was determined to be 55.5 °C from modulated differential scanning calorimetry measurements under a heating rate of 2 °C/min. The ribavirin glass was proved as fragile from dynamic analysis using three evaluation methods and as very fragile from thermodynamic analysis based on the heat capacity difference between glassy and crystalline states. Enthalpy recovery was found for even freshly prepared ribavirin glass and was initiated far below T(g) in the thermal analysis, which suggested low cooperativity of the molecular motion. The width of the glass transition region was significantly narrowed, and T(g) was increased by sub-T(g) annealing at 40-45 °C, suggesting that a temperature region exists for the effective enhancement of molecular cooperativity. Quantification of the recovery enthalpy was conducted by integrating the thermal curve through a wide temperature range that included a baseline to determine the relaxation constants because peak integration, which is a frequently used procedure to determine recovery enthalpy, was not adequate due to significant alteration in the shape of the heat flow curves by annealing. Relaxation times obtained by the baseline integration procedure were larger than those from the conventional peak integration approach and exhibited better agreement with the Vogel-Tammann-Fulcher equation, revealing that this method may be notably beneficial for the evaluation of glasses with low molecular cooperativity. The size of the cooperative rearranging region (CRR) was determined from the width of the glass transition region and indicated the existence of an optimum temperature range to increase the size of the CRR just below T(g).

Applications of capillary electrophoresis for analysis of liposome dispersions

Publisher Summary This chapter introduces the applications of capillary electrophoresis (CE) for the analysis of liposome dispersions. This method can be useful for investigating the bimodal size distributions, which have often been failed to be analyzed by the conventional light scattering method. Following this, the chapter reports the application of CE to detect the compositional homogeneity of liposome membranes. In the case of charged guest molecules distributed on monodispersed liposome membranes, the amount of charge on each particle (zeta-potential of each particle) is the only factor which controls the migration time in the analysis. Therefore, all particles would be detected as a single peak if the guest molecules are homogeneously dispersed on the membranes, i.e., the amount of charge per particle is equivalent. However, several distinguishable peaks are observed if they are heterogeneously dispersed. If the guest molecules are noncharged, taking the signal ratio obtained at two different wavelengths would enable the investigation of the homogeneity if they have UV or visible light absorption. If they are homogeneously dispersed, the signal ratio obtained at two different wavelengths (one of them should be that at which the maximal absorption of the guest molecules occurs) shows a constant value.