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

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.

2. Materials and methods

2.1. Chemicals

Fenofibrate, cinnarizine, sodium phosphate monobasic dihydrate, sodium phosphate dibasic dihydrate, and trifluoroacetic acid were purchased from Sigma Aldrich (Brøndby, Denmark). Hydroxypropyl methylcellulose TC-5 E (HPMC) of pH. Eur. quality was donated as a gift from JRS Pharma GmbH & Co. KG (Rosenberg, Germany). Sodium dodecyl sulfate (SDS) was purchased from Caesar & Loretz GmbH (Hilden, Germany). 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was bought from Abcr GmbH (Karlsruhe, Germany). Acetonitrile of HPLC quality was purchased from VWR international A/S (Søborg, Denmark). The water used in experiments was highly purified, prepared by a Milli-Q reference A+ water purification system from Merck KGaA (Darmstadt, Germany). If not otherwise stated, the chemicals were of analytical grade.

Download the full study as PDF here: Insight into the mechanism behind oral bioavailability-enhancement by nanosuspensions through combined dissolution/permeation studies

or read it here

Jakob Tobias Lynnerup, Jonas Borregaard Eriksen, Annette Bauer-Brandl, Ann Mari Holsæter, Martin Brandl, Insight into the mechanism behind oral bioavailability-enhancement by nanosuspensions through combined dissolution/permeation studies, European Journal of Pharmaceutical Sciences, Volume 184, 2023, 106417, ISSN 0928-0987,
https://doi.org/10.1016/j.ejps.2023.106417.