Insight into the mechanism behind oral bioavailability-enhancement by nanosuspensions through combined dissolution/permeation studies

Jakob Tobias Lynnerup; Jonas Borregaard Eriksen; Annette Bauer-Brandl; Ann Mari Holsæter; Martin Brandl

doi:10.1016/j.ejps.2023.106417

Insight into the mechanism behind oral bioavailability-enhancement by nanosuspensions through combined dissolution/permeation studies

Eur J Pharm Sci. 2023 May 1:184:106417. doi: 10.1016/j.ejps.2023.106417. Epub 2023 Mar 2.

Authors

Jakob Tobias Lynnerup¹, Jonas Borregaard Eriksen², Annette Bauer-Brandl², Ann Mari Holsæter³, Martin Brandl⁴

Affiliations

¹ Department of Physics Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark; Drug Transport and Delivery Research Group, Department of Pharmacy, Faculty of Health Sciences, University of Tromsø The Arctic University of Norway, Tromsø 9037, Norway.
² Department of Physics Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
³ Drug Transport and Delivery Research Group, Department of Pharmacy, Faculty of Health Sciences, University of Tromsø The Arctic University of Norway, Tromsø 9037, Norway.
⁴ Department of Physics Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark. Electronic address: mmb@sdu.dk.

PMID: 36870578
DOI: 10.1016/j.ejps.2023.106417

Abstract

As numerous new drug candidates are poorly water soluble, enabling formulations are needed to increase their bioavailability for oral administration. Nanoparticles are a conceptually simple, yet resource consuming strategy for increasing drug dissolution rate, as predicting in vivo oral absorption using in vitro dissolution remains difficult. The objective of this study was to obtain insight into nanoparticle characteristics and performance utilizing an in vitro combined dissolution/permeation setup. Two examples of poorly soluble drugs were examined (cinnarizine and fenofibrate). Nanosuspensions were produced by top-down wet bead milling using dual asymmetric centrifugation, obtaining particle diameters of approx. 300 nm. DSC and XRPD studies indicated that nanocrystals of both drugs were present with retained crystallinity, however with some disturbances. Equilibrium solubility studies showed no significant increase in drug solubility over the nanoparticles, as compared to the raw APIs. Combined dissolution/permeation experiments revealed significantly increased dissolution rates for both compounds compared to the raw APIs. However, there were substantial differences between the dissolution curves of the nanoparticles as fenofibrate exhibited supersaturation followed by precipitation, whereas cinnarizine did not exhibit any supersaturation, but instead a shift towards faster dissolution rate. Permeation rates were found significantly increased for both nanosuspensions when compared to the raw APIs, indicating a direct implication that formulation strategies are needed, be it stabilization of supersaturation by precipitation inhibition and/or dissolution rate enhancement. This study indicates that in vitro dissolution/permeation studies can be employed to better understand the oral absorption enhancement of nanocrystal formulations.

Keywords: Dissolution/permeation; Dual asymmetric centrifugation; Nanomilling; Nanosuspension; Poorly soluble drugs; Supersaturation.

MeSH terms

Administration, Oral
Biological Availability
Cinnarizine* / administration & dosage
Cinnarizine* / chemistry
Fenofibrate* / administration & dosage
Fenofibrate* / chemistry
Nanoparticles* / administration & dosage
Nanoparticles* / chemistry
Particle Size
Pharmaceutical Preparations
Solubility

Substances

Cinnarizine
Fenofibrate
Pharmaceutical Preparations