Adequate formulation approach for oral chemotherapy: Etoposide solubility, permeability, and overall bioavailability from cosolvent- vs. vitamin E TPGS-based delivery systems

Noa Fine-Shamir, Avital Beig, Arik Dahan

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Injectable-to-oral conversions for anticancer drugs represent an important trend. The goal of this research was to investigate the suitability of formulation approaches for anticancer oral drug delivery, aiming to reveal mechanistic insights that may guide oral chemotherapy development. TPGS vs. PEG-400 were studied as oral formulations for the anticancer drug etoposide, accounting for drug solubility, biorelevant dissolution, permeability, solubility-permeability interplay, and overall bioavailability. Increased etoposide solubility was demonstrated with both excipients. Biorelevant dissolution revealed that TPGS or PEG-400, but not aqueous suspension, allowed complete dissolution of the entire drug dose. Both TPGS and PEG-400 resulted in decreased in-vitro etoposide permeability across artificial membrane, i.e. solubility-permeability tradeoff. While PEG-400 resulted in the same solubility-permeability tradeoff also in-vivo, TPGS showed the opposite trend: the in-vivo permeability of etoposide was markedly increased in the presence of TPGS. This increased permeability was similar to the drug permeability under P-gp inhibition. Rat PK study demonstrated significantly higher etoposide bioavailability from TPGS vs. PEG-400 or suspension (AUC of 72, 41, and 26 µg·min/mL, respectively). All in all, TPGS-based delivery system allows overcoming the solubility-permeability tradeoff, increasing systemic etoposide exposure. Since poor solubility and strong efflux are common to many anticancer agents, this work can aid in the development of better oral delivery approach for chemotherapeutic drugs.

Original languageEnglish
Article number120295
JournalInternational Journal of Pharmaceutics
Volume597
DOIs
StatePublished - 15 Mar 2021

Keywords

  • Chemotherapy
  • Drug solubility/permeability
  • Oral drug absorption/bioavailability
  • Solubility-enabling formulation
  • Solubility-permeability interplay

ASJC Scopus subject areas

  • Pharmaceutical Science

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