Poly(2-alkyl-2-oxazoline)s: A polymer platform to sustain the release from tablets with a high drug loading

Aseel Samaro; Maarten Vergaelen; Martin Purino; Ali Tigrine; Victor R de la Rosa; Niloofar Moazami Goudarzi; Matthieu N Boone; Valérie Vanhoorne; Richard Hoogenboom; Chris Vervaet

doi:10.1016/j.mtbio.2022.100414

Poly(2-alkyl-2-oxazoline)s: A polymer platform to sustain the release from tablets with a high drug loading

Mater Today Bio. 2022 Sep 12:16:100414. doi: 10.1016/j.mtbio.2022.100414. eCollection 2022 Dec.

Authors

Affiliations

¹ Laboratory of Pharmaceutical Technology, Ghent University, Ottergemsesteenweg, 460 9000, Ghent, Belgium.
² Supramolecular Chemistry Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Krijgslaan 281-S4 9000 Ghent University, Ghent, Belgium.
³ Avroxa BV., Technologiepark-Zwijnaarde, Ghent, Belgium.
⁴ Radiation Physics Research Group, Department of Physics and Astronomy, Ghent University, Belgium.
⁵ Center for X-ray Tomography (UGCT), Ghent University, Ghent, Belgium.

Abstract

Sustaining the release of highly dosed APIs from a matrix tablet is challenging. To address this challenge, this study evaluated the performance of thermoplastic poly (2-alkyl-2-oxazoline)s (PAOx) as matrix excipient to produce sustained-release tablets via three processing routes: (a) hot-melt extrusion (HME) combined with injection molding (IM), (b) HME combined with milling and compression and (c) direct compression (DC). Different PAOx (co-)polymers and polymer mixtures were processed with several active pharmaceutical ingredients having different aqueous solubilities and melting temperatures (metoprolol tartrate (MPT), metformin hydrochloride (MTF) and theophylline anhydrous (THA)). Different PAOx grades were synthesized and purified by the Supramolecular Chemistry Group, and the effect of PAOx grade and processing technique on the in vitro release kinetics was evaluated. Using the hydrophobic poly (2-n-propyl-2-oxazoline) (P ⁿ PrOx) as a matrix excipient allowed to sustain the release of different APIs, even at a 70% (w/w) drug load. Whereas complete THA release was not achieved from the P ⁿ PrOx matrix over 24 h regardless of the processing technique, adding 7.5% w/w of the hydrophilic poly (2-ethyl-2-oxazoline) to the hydrophobic P ⁿ PrOx matrix significantly increased THA release, highlighting the relevance of mixing different PAOx grades. In addition, it was demonstrated that the release of THA was similar from co-polymer and polymer mixtures with the same polymer ratios. On the other hand, as the release of MTF from a P ⁿ PrOx matrix was fast, the more hydrophobic poly (2-sec-butyl-2-oxazoline) (P ^sec BuOx) was used to retard MTF release. In addition, a mixture between the hydrophilic PEtOx and the hydrophobic P ^sec BuOx allowed accurate tuning of the release of MTF formulations. Finally, it was demonstrated that PAOx also showed a high ability to tune the in vivo release. IM tablets containing 70% MTF and 30% P ^sec BuOx showed a lower in vivo bioavailability compared to IM tablets containing a low PEtOx concentration (7.5%, w/w) in combination with P ^sec BuOx (22.5%, w/w). Importantly, the in vivo MTF blood level from the sustained release tablets correlated well with the in vitro release profiles. In general, this work demonstrates that PAOx polymers offer a versatile formulation platform to adjust the release rate of different APIs, enabling sustained release from tablets with up to 70% w/w drug loading.

Keywords: Alkyl side chain; Direct compression; Hot-melt extrusion; In vivo; Injection molding; Poly(2-alkyl-2-oxazoline)s; Sustained-release.