Yoshitaka Nishihara

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.

A novel and simple type of liposome carrier for recombinant interleukin-2.

The strong interaction between recombinant interleukin‐2 (IL‐2) and liposome was characterized and its possible application to drug‐delivery control considered. The liposomes were prepared with egg phosphatidylcholine, distearoyl‐phosphatidylglycerol (DSPG), dipalmitoyl‐phosphatidylcholine, dipalmitoyl‐phosphatidylglycerol or distearoyl‐phosphatidylcholine (DSPC). Small and hydrophobic liposomes were selected, which were composed of saturated and long‐fatty‐acid‐chain phospholipids. When the composition and the mixture ratio of IL‐2 and the liposome were optimized, more than 95% of the lyophilized IL‐2 (Imunace, 350000, JRU) was adsorbed consistently onto the DSPC‐DSPG liposome (molar ratio, 10:1; 25 μmol mL−1; 30 nm in size). Merely mixing IL‐2 lyophilized with liposome suspension is convenient pharmaceutically. After intravenous administration to mice, liposomal IL‐2 was eliminated half as slowly from the systemic circulation as free IL‐2, with more than 13 and 18 times more IL‐2 being delivered to the liver and spleen, respectively. After subcutaneous administration of liposomal IL‐2 to mice, the mean residence time of IL‐2 in the systemic circulation was 8 times that of free IL‐2. These results show that IL‐2 consistently adsorbs onto the surface of liposomes after optimization of its composition and mixing ratio. Intravenous and subcutaneous administration to mice demonstrates the gradual release of IL‐2. Further trials are warranted using these liposomes.

A significant enhancement of therapeutic effect against hepatic metastases of M5076 in mice by a liposomal interleukin-2 (mixture).

Recombinant interleukin-2 (IL-2) was strongly and almost completely adsorbed onto small hydrophobic liposomes under optimal conditions (liposome: DSPC-DSPG; molar ratio, 10:1; 30-50 nm in size, ratio of IL-2 to liposome: 4.0 JRU/nmol lipid). This liposomal IL-2 improved the distribution of IL-2 after intravenous administration as reported, previously. Liposomal IL-2 (300-10000 JRU/mouse per day) was significantly more effective than free IL-2 alone for inhibiting against the experimental metastases of M5076 in mice. The inhibitory effect of liposomal IL-2 was greatest in the liver. The ED(50) of liposomal IL-2 and that of free IL-2 in the liver were 1640 and 12500 JRU/mouse per day, respectively. This simple preparation (mixture) using IL-2 and liposome suspension is expected to have potential for increasing therapeutic efficacy against hepatic metastases.

Continuous release of interleukin-2 from liposomal IL-2 (mixture of interleukin-2 and liposomes) after subcutaneous administration to mice.

Abstract Recombinant interleukin-2 (IL-2) was strongly and almost completely adsorbed onto small and hydrophobic liposomes by simple mixing under optimal conditions (liposome: DSPC-DSPG; molar ratio, 10:1; 30–50 nm in size, ratio of IL-2 to liposome: 4.0 JRU/nmol lipid). This liposomal IL-2 displayed better distribution after intravenous administration in mice and improved therapeutic effect against experimental M5076 metastases, as reported previously. In this study, the elimination of IL-2 from the dosing area was investigated when the liposomal IL-2 was administered to mice subcutaneously. The results suggest that the release of IL-2 from this liposome was continuous and almost complete. The mean residence time (MRT) of IL-2 in the dosing area was 11.0 ± 1.65 hr. This resulted in the 8-fold times enhancement of MRT in the systemic circulation by the presence of liposomes, and IL-2 was detected in the serum for 2 days. Using this liposomal IL-2 is expected to have the potential to decrease the number of injections and enhance the efficacy of IL-2 in immunotherapies and therapies against tumor.

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.