title: Head-To-Head Comparison of Different Solubility-Enabling Formulations of Etoposide and Their Consequent Solubility-Permeability Interplay.
abstract: The purpose of this study was to conduct a head-to-head comparison of different solubility-enabling formulations, and their consequent solubility-permeability interplay. The low-solubility anticancer drug etoposide was formulated in several strengths of four solubility-enabling formulations: hydroxypropyl-β-cyclodextrin, the cosolvent polyethylene glycol 400 (PEG-400), the surfactant sodium lauryl sulfate, and an amorphous solid dispersion formulation. The ability of these formulations to increase the solubility of etoposide was investigated, followed by permeability studies using the parallel artificial membrane permeability assay (PAMPA) and examination of the consequent solubility-permeability interplay. All formulations significantly increased etoposide's apparent solubility. The cyclodextrin-, surfactant-, and cosolvent-based formulations resulted in a concomitant decreased permeability that could be modeled directly from the proportional increase in the apparent solubility. On the contrary, etoposide permeability remained constant when using the ASD formulation, irrespective of the increased apparent solubility provided by the formulation. In conclusion, supersaturation resulting from the amorphous form overcomes the solubility-permeability tradeoff associated with other formulation techniques. Accounting for the solubility-permeability interplay may allow to develop better solubility-enabling formulations, thereby maximizing the overall absorption of lipophilic orally administered drugs.
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Beig
authors.affiliation: AbbVie Incorporation, North Chicago, Illinois, 60064.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Miller
authors.affiliation: AbbVie Incorporation, North Chicago, Illinois, 60064.
authors.forename: David
authors.initials: D
authors.lastname: Lindley
authors.affiliation: AbbVie Incorporation, North Chicago, Illinois, 60064.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Carr
authors.affiliation: AbbVie Incorporation, North Chicago, Illinois, 60064.
authors.forename: Philip
authors.initials: P
authors.lastname: Zocharski
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
authors.forename: Riad
authors.initials: R
authors.lastname: Agbaria
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
authors.forename: Arik
authors.initials: A
authors.lastname: Dahan
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D002463:Cell Membrane Permeability / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003505:Cyclodextrins / Q000737:chemistry; D005047:Etoposide / Q000737:chemistry*; D007408:Intestinal Absorption / Q000187:drug effects; D008567:Membranes, Artificial; D011092:Polyethylene Glycols / Q000737:chemistry; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D003505:Cyclodextrins; D008567:Membranes, Artificial; D013501:Surface-Active Agents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D012967:Sodium Dodecyl Sulfate; D011092:Polyethylene Glycols; D005047:Etoposide
keywords: BCS; intestinal permeability; oral drug absorption; solubility-enabling formulations; solubility-permeability interplay