Dokument: Regorafenib Amorphous Solid Dispersions: Formulations, Properties and Biopharmaceutical Performance
| Titel: | Regorafenib Amorphous Solid Dispersions: Formulations, Properties and Biopharmaceutical Performance | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=56001 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20210422-132410-3 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Müller, Martin Günter [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Breitkreutz, Jörg [Betreuer/Doktorvater] Prof. Dr. Kleinebudde, Peter [Gutachter] | |||||||
| Stichwörter: | Amorphous Solid Dispersion; Poorly soluble drugs; Supersaturation; Precipitation; Regorafenib; in-vivo pharmacokincetics; in-situ analytics; | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Regorafenib monohydrate (RGF MH), marketed by the company Bayer as Stivarga, is a poorly water-soluble API formulated as an amorphous solid dispersion (ASD), which shows undesired bioavailability variability in-vivo. To gain a deeper understanding of the underlying mechanisms and to reduce this variability, the impact of different ASD formulation strategies was investigated. Besides binary compositions of the drug in a matrix of one polymer, ternary formulations comprising the drug, one polymer and one surfactant or a second polymer were investigated.
Biorelevant dissolution studies at simulated intestinal conditions revealed strongly different drug release and supersaturation behavior, dependent of the ASD composition. These findings were underlined by seeded dissolution studies, i.e. the co-administration of de-stabilizing compounds. From the results presented in this work, a new formulation concept was developed by coating of a stabilizing polymer with enteric functionality on a fast-release RGF ASD formulation, leading to superior in-vitro dissolution performance. The different drug release and supersaturation stabilization properties were attributed to molecular interactions of the ASD polymers with RGF in the dry and dissolved states. The physicochemical properties of arising precipitates of different formulations during biorelevant dissolutions were explored off-line and in-situ. Besides common technologies, more advanced analytical in-situ methods were applied, such as confocal Raman microscopy, wide-angle and small-angle X-ray scattering and isothermal titration calorimetry. Regorafenib was found to precipitate in different (pseudo-) polymorphic states depending on the precipitation environment, as such the ASD polymer(s) and the type of biorelevant media. The RGF permeation of the newly proposed formulation was compared to Stivarga. In-vitro permeation studies and an in-vivo study in rats indicated that stronger RGF supersaturation stabilization in dissolved state did not lead to decreased drug permeation. To date, the concept of a dual function of one excipient as supersaturation stabilizing agent and enteric coating material is not published and provides an elegant formulation approach by reducing the number of excipients. The general concept of co-administration of a stabilizing agent to a fast-release ASD seems to be highly promising. Here, further research will have to be conducted with structurally different APIs to evaluate its full potential for formulation scientists. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische Technologie und Biopharmazie | |||||||
| Dokument erstellt am: | 22.04.2021 | |||||||
| Dateien geändert am: | 22.04.2021 | |||||||
| Promotionsantrag am: | 27.10.2020 | |||||||
| Datum der Promotion: | 16.02.2021 |
