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

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          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.

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          Melt extrusion: from process to drug delivery technology.

          Starting from the plastic industry, today melt extrusion has found its place in the array of pharmaceutical manufacturing operations. This article reviews the process technology with regard to the set up and specific elements of the extruder as well as its application. Melt extrusion processes are currently applied in the pharmaceutical field for the manufacture of a variety of dosage forms and formulations such as granules, pellets, tablets, suppositories, implants, stents, transdermal systems and ophthalmic inserts. As a specific area the manufacture of solid dispersions, in particular, solid molecular dispersions using the melt extrusion process is reviewed. Melt extrusion is considered to be an efficient technology in this field with particular advantages over solvent processes like co-precipitation. Potential drawbacks like the influence of heat stress and shear forces on the drug active have been overcome in a number of examples with drugs of different chemical structure. Examples of suitable excipients and recent findings like self-emulsifying preparations are presented. The article concludes with a number of published examples of melt extrudates applying the principle of solid molecular dispersions. Improved bioavailability was achieved again demonstrating the value of the technology as a drug delivery tool.
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            Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation.

            Hot-melt extrusion (HME) is a promising technology for the production of new chemical entities in the developmental pipeline and for improving products already on the market. In drug discovery and development, industry estimates that more than 50% of active pharmaceutical ingredients currently used belong to the biopharmaceutical classification system II (BCS class II), which are characterized as poorly water-soluble compounds and result in formulations with low bioavailability. Therefore, there is a critical need for the pharmaceutical industry to develop formulations that will enhance the solubility and ultimately the bioavailability of these compounds. HME technology also offers an opportunity to earn intellectual property, which is evident from an increasing number of patents and publications that have included it as a novel pharmaceutical formulation technology over the past decades. This review had a threefold objective. First, it sought to provide an overview of HME principles and present detailed engineered extrusion equipment designs. Second, it included a number of published reports on the application of HME techniques that covered the fields of solid dispersions, microencapsulation, taste masking, targeted drug delivery systems, sustained release, films, nanotechnology, floating drug delivery systems, implants, and continuous manufacturing using the wet granulation process. Lastly, this review discussed the importance of using the quality by design approach in drug development, evaluated the process analytical technology used in pharmaceutical HME monitoring and control, discussed techniques used in HME, and emphasized the potential for monitoring and controlling hot-melt technology.
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              Software tools for quantification of X-ray microtomography at the UGCT

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                Author and article information

                Contributors
                Journal
                Mater Today Bio
                Mater Today Bio
                Materials Today Bio
                Elsevier
                2590-0064
                12 September 2022
                December 2022
                12 September 2022
                : 16
                : 100414
                Affiliations
                [a ]Laboratory of Pharmaceutical Technology, Ghent University, Ottergemsesteenweg, 460 9000, Ghent, Belgium
                [b ]Supramolecular Chemistry Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Krijgslaan 281-S4 9000 Ghent University, Ghent, Belgium
                [c ]Avroxa BV., Technologiepark-Zwijnaarde, Ghent, Belgium
                [d ]Radiation Physics Research Group, Department of Physics and Astronomy, Ghent University, Belgium
                [e ]Center for X-ray Tomography (UGCT), Ghent University, Ghent, Belgium
                Author notes
                []Corresponding author. Chris.Vervaet@ 123456Ugent.be
                [∗∗ ]Corresponding author. richard.hoogenboom@ 123456Ugent.be
                Article
                S2590-0064(22)00212-5 100414
                10.1016/j.mtbio.2022.100414
                9483731
                0a81b8a3-f98f-4c8a-bdaa-a40414e40276
                © 2022 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 18 April 2022
                : 24 August 2022
                : 28 August 2022
                Categories
                Full Length Article

                poly(2-alkyl-2-oxazoline)s,alkyl side chain,sustained-release,hot-melt extrusion,injection molding,direct compression,in vivo

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