Concomitant solubility-permeability increase: Vitamin E TPGS vs. amorphous solid dispersion as oral delivery systems for etoposide

Eur J Pharm Biopharm. 2017 Dec:121:97-103. doi: 10.1016/j.ejpb.2017.09.012. Epub 2017 Sep 25.

Abstract

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 this research 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, lipophilic drug etoposide. The concentration-dependent effects of TPGS (0-100mg/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-permeability interplay was analyzed. TPGS above CMC (0.3mg/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-permeability tradeoff 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 (10µg/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 pattern of solubility-permeability interplay was found, involving concomitant increase of both the solubility and the permeability, as opposed to the previously reported tradeoff for solubilization methods and the unchanged permeability for supersaturation; P-gp inhibition/saturation by TPGS or by supersaturation allows simultaneous increase of both solubility and permeability, representing a significant advantage of such drug delivery approaches when suitable.

Keywords: Drug absorption; Intestinal permeability; Oral drug delivery; P-glycoprotein inhibition; Solubility; Supersaturation.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemistry
  • Drug Delivery Systems / methods
  • Etoposide / chemistry*
  • Male
  • Permeability
  • Rats
  • Rats, Wistar
  • Solubility
  • Surface-Active Agents / chemistry
  • Vitamin E / chemistry*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Surface-Active Agents
  • Vitamin E
  • Etoposide
  • tocophersolan