Interpreting permeability as a function of free drug fraction: The case studies of cyclodextrins and liposomes

Martina M Tzanova, Lisa Nguyen, Federica Moretti, Mario Grassi, Greta Camilla Magnano, Dario Voinovich, Paul C Stein, Marianne Hiorth, Massimiliano Pio di Cagno

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Abstract

In order to solubilize poorly soluble active pharmaceutical ingredients, various strategies have been implemented over the years, including the use of nanocarriers, such as cyclodextrins and liposomes. However, improving a drug's apparent solubility does not always translate to enhanced bioavailability. This work aimed to investigate to which extent complexation with cyclodextrins and incorporation into liposomes influence drug in vitro permeability and to find a mechanistic description of the permeation process. For this purpose, we investigated hydroxypropyl-β-cyclodextrin (HP-β-CD) and phosphatidylcholine liposomes formulations of three chemically diverse compounds (atenolol, ketoprofen and hydrocortisone). We studied drug diffusion of the formulations by UV-localized spectroscopy and advanced data fitting to extract parameters such as diffusivity and bound-/free drug fractions. We then correlated this information with in vitro drug permeability obtained with the novel PermeaPad Ⓡ barrier. The results showed that increased concentration of HP-β-CD leads to increased solubilization of the poorly soluble unionized ketoprofen, as well as hydrocortisone. However, this net increment of apparent solubility was not proportional to the increased flux measured. On the other hand, normalising the flux over the empirical free drug concentration, i.e., the free fraction, gave a meaningful absolute permeability coefficient. The results achieved for the liposomal formulation were consistent with the finding on cyclodextrins. In conclusion, we proved the adequacy and usefulness of our method for calculating free drug fractions in the examined enabling formulations, supporting the validity of the established drug diffusion/permeation theory that the unbounded drug fraction is the main driver for drug permeation across a membrane.

Original languageEnglish
Article number106559
JournalEuropean Journal of Pharmaceutical Sciences
Volume189
Number of pages9
ISSN0928-0987
DOIs
Publication statusPublished - 1. Oct 2023

Keywords

  • Absolute permeability coefficient
  • Drug diffusivity
  • Free drug fraction
  • Inclusion complex
  • PermeaPad
  • Solubilization

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