Dokument: Customizable Drug-Loaded Implants Produced via Fused Deposition Modeling
| Titel: | Customizable Drug-Loaded Implants Produced via Fused Deposition Modeling | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=62301 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20230327-092310-8 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Ponsar, Hanna [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Breitkreutz, Jörg [Gutachter] Prof. Dr. Kleinebudde, Peter [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | The aim of this work has been the development of customizable drug-loaded implants by using the 3D-printing technology fused deposition modeling. Triamcinolone acetonide (TA) was selected as model drug in need for improved individualized intraarticular (i.art.) therapy.
First, a two-compartment implant was conceptualized, consisting of a drug-free shell for shape adaption to anatomical structures and a drug-loaded network inlay to customize dose and drug release behaviour independently. As for printing via fused deposition modeling a polymeric filament is required as starting material, the initial studies of the thesis focused on the systematic formulation development of printable filaments via hot-melt extrusion (HME). The mechanical properties of filaments to ensure printability and the targeted drug release over several months were taken as key selection criteria. Different formulations and their properties were thoroughly investigated. Finally, drug-free and TA-loaded printable filaments based on ethyl cellulose for the two-compartment implant were successfully developed. The second aim was the HME process optimization towards a continuous, reproducible pharma-grade filament manufacturing. Thereby a high quality of filaments and printed drug dosage forms according to the requirements of the European Pharmacopoeia (Ph.Eur.) should be ensured. The diameter homogeneity was identified as key critical quality attribute, affecting the mechanical properties and filaments and mass uniformity of 3D-printed dosage forms. After implementing a winder into the HME-line for continuous filament conveyance and winding on spools, the specific feed load, as surrogate for the HME barrel filling degree, was identified as key parameter for homogenous melt transport and consequently consistent filament diameter in a systematic analysis. A threshold of diameter variations was successfully identified to ensure the quality maintenance of filaments (mechanical properties) and 3D-printed dosage forms (mass uniformity, Ph. Eur. 2.9.5). The optimized extrusion settings were successfully transferred to the developed filament formulations for 3D-printing of implants. A stability analysis according to the ICH-Guideline Q1A (R2) revealed an impact of water absorption and plasticizer evaporation during storage on filament quality. Primary packaging in sealed aluminium sachets was found to keep the initial quality over at least six months. To assess the TA release from novel parenteral dosage forms, analytical development of a dissolution set-up for long-term studies over several months was aimed at. TA degrades rapidly in the commonly used phosphate-buffered saline at pH 7.4. After degradation studies in different media, a suitable dissolution medium (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer) to reduce the decomposition rate was found. A dissolution method protocol with frequent medium change and simplified drug release quantification next to simultaneously proceeding TA degradation based on the extinction coefficient was established. A so-called “sample and separate set-up” was developed to enable an investigation of multiple implants at reduced volume. The evaluation of the modification of drug release via network variation using computer-aided design and FDMTM-printing and subsequent modelling of the dissolution behaviour for prediction purposes was the last main objective. The two-compartment implants were printed successfully and subjected to long-term drug-release studies. By changing the strand width and pore size of the drug-loaded network inlay of implants, the TA release was successfully varied in a wide range. Compared to current i.art. TA therapy options the release was drastically extended. Novel 3D-printed implants are therefore considered promising to improve therapy efficiency. A prediction of the drug release behaviour based on the Higuchi model was partially feasible. Limitations are caused by kinetic changes due to inhomogeneous medium perfusion, impact of hypromellose and the unidirectional drug release. The development of customizable implants was performed successfully. The generated knowledge in the present work is an important step towards continuous filament production and simplified drug product and process development while establishing 3D-printing as novel technology for individualized parenteral therapy. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische Technologie und Biopharmazie | |||||||
| Dokument erstellt am: | 27.03.2023 | |||||||
| Dateien geändert am: | 27.03.2023 | |||||||
| Promotionsantrag am: | 25.05.2022 | |||||||
| Datum der Promotion: | 04.08.2022 | |||||||
| Verweise: | Dieses Dokument ist neue Version von Dokument 61731 |
