Extensive improvement of oral bioavailability of mebendazole, a brick dust, by polymer-containing SNEDDS preparation: Disruption of high crystallinity by utilizing its counter ion.

Poorly water-soluble and poorly lipid-soluble drugs are called as "brick dust" and it is very hard for them to be formulated as some dosage form which can provide an effective bioavailability after oral administration. Mebendazole (MBZ), an anti-helminthic drug having anti-cancer properties, is one of the brick dusts and its poor bioavailability has been well known. The strategy of the current study was to improve the oral absorption of MBZ by SNEDDS formulation prepared by utilizing an MBZ-counter ion complex, of which the formation would disrupt the high crystallinity of MBZ. Among five different counter ions examined, (+)-10-camphorsulfonic acid (CSA), 2-naphthalene-sulfonic acid (NSA) and p-toluenesulfonic acid (TSA) largely improved MBZ solubility in the SNEDDS vehicle by forming the complex with MBZ. The solid state of these complexes, MBZ-CSA, MBZ-NSA and MBZ-TSA, was suggested to be amorphous by XRPD and DSC. SNEDDS formulations of the three complexes extensively improved MBZ dissolution under gastric and intestinal luminal conditions, compared with MBZ crystalline powder. However, since the dissolved concentrations of MBZ were time-dependently decreased so much by precipitation, we tried to maintain the high dissolution property by applying some polymer for SNEDDS preparation of MBZ-CSA which provided the highest solubility in the SNEDDS vehicle. Among ten different polymers examined, HPMCP-50 successfully maintained the high dissolution property of MBZ-CSA SNEDDS under both gastric and intestinal luminal conditions. In the in vivo oral administration study, SNEDDS preparations for the three MBZ complexes significantly improved MBZ absorption compared with MBZ crystalline powder, but 2% HPMCP-50-containing SNEDDS of MBZ-CSA provided further improvement of MBZ absorption, resulting in around 10-fold of crystalline powder in AUC.

Simultaneous measurements of K+ and calcein release from liposomes and the determination of pore size formed in a membrane.

The changes induced by biologically active substances in the permeability to K+ and calcein of liposomes composed of egg phosphatidylcholine and cholesterol were measured simultaneously in order to rapidly screen the sizes of pores formed in a membrane, using different sized markers. The substances examined in the present study were classified into three types based on differences in the rates at which K+ and calcein were released. The first type released only K+, and included gramicidin A. The second type predominantly released K+, preceding the release of calcein, and included amphotericin B and nystatin. The third type, including antimicrobial peptides, such as gramicidin S, alamethicin, and melittin, and several membrane-active drugs, like celecoxib (non-steroidal anti-inflammatory drug), 1-dodecylazacycloheptan-2-one (named azone; skin permeation enhancer), and chlorpromazine (tranquilizer), caused the release of K+ and calcein simultaneously. Thus, the sizes of pores formed in a liposomal membrane increased in the following order: types one, two, and three. We determined the size more precisely by conducting an osmotic protection experiment, measuring the release of calcein in the presence of osmotic protectants of different sizes. The radii of pores formed by the second type, amphotericin B and nystatin, were 0.36 - 0.46 nm, while the radii of pores formed by the third type were much larger, 0.63 - 0.67 nm or more. The permeability changes induced by substances of the third type are discussed in connection with a transient pore formed in a lipid packing mismatch taking place during the phase transition of dipalmitoylphosphatidylcholine liposomes.

Precise size determination of amphotericin B and nystatin channels formed in erythrocyte and liposomal membranes based on osmotic protection experiments.

The colloid osmotic nature of the cell lysis can be prevented by adding osmotic protectants of appropriate sizes to the outer medium. We introduced inorganic and organic electrolytes as protectants to determine the precise channel sizes of the polyene antibiotics, amphotericin B and nystatin, in addition to the sugars so far widely used for this purpose. Because colloid osmotic cell lysis is evidenced by the loss of membrane permeability barriers for small sizes of ions, such as K(+), preceding hemolysis, we firstly simultaneously monitored the time response of the K(+) efflux and hemolysis induced by amphotericin B by combining a fiber-optic spectrometer with a K(+)-selective electrode. Based on this experiment, we evaluated the sizes of channels of the polyene antibiotics formed in the erythrocyte membrane using the radii of hydrated ions calculated from a modified Stokes' law, as well as the radii of sugars. The radii of channels formed by amphotericin B and nystatin were found to be in a very narrow range of 0.36 - 0.37 nm. Similar experiments were performed using calcein-loaded liposomes containing cholesterol or ergosterol, and the radii of channels formed in these liposomal membranes were also found to be the same as when formed in an erythrocyte membrane. The present results demonstrated that introducing the sizes of hydrated ions can afford a more precise channel size than the use of sugars alone.

S,S,S-Tris(2-ethylhexyl) phosphorotrithioate as an effective solvent mediator for a mexiletine-sensitive membrane electrode.

S,S,S-tris(2-ethylhexyl) phosphorotrithioate proved to be an effective solvent mediator for constructing a mexiletine-sensitive membrane electrode in combination with an ion-exchanger, sodium tetrakis[3,5-bis(2-methoxyhexafluoro-2-propyl)phenyl]borate. Among a series of phosphorus compounds containing phosphoryl (P=O) groups, this solvent mediator showed the highest sensitivity to mexiletine in phosphate-buffered physiological saline containing 0.15 mol L-1 NaCl and 0.01 mol L-1 NaH2PO4/Na2HPO4 (pH 7.4), giving a detection limit of 2x10(-6) mol L-1 with a slope of 58.8 mV decade-1. This is the best reported detection limit of any mexiletine-sensitive electrode developed to date. Owing to its high selectivity toward inorganic cations, the electrode was used to determine the level of mexiletine in saliva, the monitoring of which is quite effective for controlling the dose of this drug noninvasively. The mexiletine concentrations determined with the mexiletine-sensitive electrode compared favorably with those determined by high-performance liquid chromatography.