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.

Improvement of lipid solubility and oral bioavailability of a poorly water- and poorly lipid-soluble drug, rebamipide, by utilizing its counter ion and SNEDDS preparation.

Among drugs in development and/or in market, there are poorly water-soluble and poorly lipid-soluble compounds. Rebamipide, classified into BCS class IV, is one of those drugs which provide very low bioavailability and/or the difficulty of formulation for oral administration. Because of its low solubility in available lipoidal excipients, it was impossible to prepare an adequate SNEDDS formulation of rebamipide. Then, we tried to increase the solubility of rebamipide in lipoidal excipients for preparing a more practical SNEDDS formulation by making the complex with its counter ion, tetrabutylphosphonium hydroxide (TBPOH) or NaOH. Rebamipide concentration in ethanol was proportionally increased with the increment of TBPOH or NaOH added, indicating that the formation of complex with a counter ion should contribute to the solubilization of rebamipide in ethanol. Both Rebamipide-TBPOH complex (Reb-TBPOH) and Rebamipide-NaOH complex (Reb-NaOH) obtained by lyophilization showed no endothermic peak in DSC and no diffraction peak in XRPD, suggesting that the solid state of both complexes should be amorphous. Reb-TBPOH maintained the dissolution of rebamipide in SNEDDS vehicle (Capryol 90:Cremophor EL:Transcutol P = 4:3:3) at 20 mg/g at least for 28 days, while Reb-NaOH did it at 10 mg/g. In vitro dissolution study showed that Reb-TBPOH SNEDDS and Reb-NaOH SNEDDS containing rebamipide at 10 mg/g maintained the complete dissolution of rebamipide in FaSSIF (intestinal luminal condition). In the gastric luminal condition (pH3.9 acetate buffer), the high concentration, close to the complete dissolution, was transiently observed and quickly decreased to one-sixth of the maximum, but it was still around 70 times higher than that of the crystalline powder. The additional utilization of Eudragit EPO for SNEDDS preparations of both complexes successfully maintained the high concentrations of rebamipide in the gastric luminal condition. In vivo oral absorption studies clearly indicated that SNEDDS preparations utilizing Reb-counter ion complex successfully improved rebamipide absorption.