Vitamin E TPGS vs. Amorphous Solid Dispersion as Oral Delivery Systems for Etoposide

Vitamin E TPGS (TPGS) has both surfactant and P-glycoprotein(P-gp) inhibitory effects. While surfactants were previously found to cause solubility-permeability tradeoff, TPGS P-gp inhibitory effects may change this unfavorable interplay. The purpose of thisresearch was to investigate the solubility-permeability interplay when using TPGS vs. amorphous solid dispersions (ASD) as oral drug delivery systems for the anticancer, P-gp substrate, lipophilicdrug etoposide. The concentration-dependent effects of TPGS (0-100 mg/mL) vs. ASD on the solubility of etoposide, as well as the in-vitro(PAMPA) vs. in-vivo (intestinal rat perfusion) permeability of the drug were studied, and the resulting solubility-permeabilityinterplay was analyzed. TPGS above CMC (0.3 mg/mL) increased etoposide solubility linearly, and ASD allowed significant supersaturation. Etoposide in-vitro PAMPA permeability decreased markedly with increasing TPGS levels, similarly to the solubility-permeabilitytradeoff previously defined for surfactants. In contrast, the presence of TPGS significantly increased etoposide in-vivo rat permeability, attributable to P-gp inhibition, similarly to the effect of the potent P-gp inhibitor GF120918(10 µg/mL). High supersaturation achieved via ASD increased the drug’s in-vivo permeability to the level obtained by TPGS or GF120918, supporting P-gp saturation. In conclusion, unique patternof solubility-permeability interplay was found, involving concomitant increase of both the solubility and the permeability, as opposed to the previously reported tradeoff for solubilization methodsand the unchanged permeability for supersaturation; P-gp inhibition/saturation by TPGS or by supersaturation allows simultaneous increase of both solubility and permeability, representing asignificant advantage of such drug delivery approaches when suitable.

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