Dokument: 3D-Printed Drug-loaded Intravesical Inserts – Development, Manufacturing and Biopharmaceutical Performance
| Titel: | 3D-Printed Drug-loaded Intravesical Inserts – Development, Manufacturing and Biopharmaceutical Performance | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=61952 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20230222-103656-9 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Rahman-Yildir, Jhinuk [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Breitkreutz, Jörg [Gutachter] Prof. Dr. Seidlitz, Anne [Gutachter] | |||||||
| Stichwörter: | 3D-printing, intravesical drug delivery, biorelevant dissolution, bladder model | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Marketed drug products for the treatment of bladder conditions such as overactive bladder are currently still confined to their adverse effects that limit patient’s compliance and adherence to therapy. Therefore, recent research has focused on manufacturing new drug delivery systems to overcome these problems and allow effective and safe therapy while using the intravesical route. The aim of the present work was to develop flexible drug-loaded intravesical inserts that have the potential to overcome the existing limitations and allow local application of various APIs.
3D-printing by pressure-assisted micro syringe system was thereby selected as suitable manufacturing method due to its many favourable attributes such as easy incorporation of various (pharmaceutical) polymers into semi-solid feedstock material for the 3D-printer, processability at low temperatures and the possibility to generate flexible drug delivery devices (DDD) that could be applied via urinary catheter. After thorough investigations regarding process understanding, semi-solid printable inks containing EVA as non-degradable polymer and PCL as degradable polymer were developed and characterized regarding their critical quality attributes such as rheological properties and recovery after printing. Suitable post-printing drying conditions were defined based on obtained porosity, geometry and dissolution of the inserts. The question of printability was addressed by assessing different quality defining attributes of the formulation and the printed structures. The printability score as a new parameter for objective evaluation of the quality of a printed object was developed and its suitability investigated in a design of experiments. After development of trial formulations, it was feasible to successfully incorporate the freely soluble APIs lidocaine hydrochloride monohydrate (LC-HCl) and trospium chloride (TrCl) and the poorly soluble hydrochlorothiazide (HCT) into sustained release inserts that released the respective API over the course of at least two weeks. The release rate of the inserts could be flexibly tailored by adapting the geometry and the corresponding surface area to volume ratio or drug load. The effect of porosity on release behaviour and its influencing factors were extensively investigated via µCT imaging and image analysis that allowed quantification of the porosity and gave valuable insights into pore sizes and surface areas before and after dissolution. It revealed that generally within the same pressure condition applied during drying, the porosity increased with increasing temperature while the mean dissolution time decreased. Since the degradation of the PCL inserts was found to be minimal under the investigated experimental conditions and could potentially pose a challenge for its applicability in case of frequently repeated administrations, refinement of the degradable DDD revealed a PCL-PEG copolymer as suitable candidate. This matrix polymer was further suitable to prolong the release of TrCl to achieve clinically relevant release rates. Overall, clinically relevant dissolution could be achieved for LC-HCl and TrCl over the course of at least two weeks for non-degradable and degradable inserts. While compendial setups are commonly used during drug development for evaluation of the release behavior, they can rarely take physiological conditions into account and are not always a sensible choice for determining whether therapeutically relevant concentrations may be achieved at the target site. Therefore, in the scope of this work, a biorelevant dissolution model has been developed and manufactured in order to investigate drug release of the newly developed inserts within a more physiological environment. The new bladder model could be operated fully automated and allowed determination of the local API concentration within the bladder at a given time-point. Media flow rates, temperature, voiding and movement as well as angular positioning of the bladders could be freely modified for investigation of drug release under various experimental conditions. Compared to the compendial setup, the cumulative release profiles only differed slightly, while the corresponding concentration profiles displayed great differences and revealed periodic fluctuations in 24 h intervals that were not detectable within the USP apparatus. Its key advantage lies in the possibility of investigating various conditions and scenarios and their effect on drug release without the need for estimated release rates based on mathematical calculations. Nevertheless, further investigations regarding different (non-porous) matrix systems and operating conditions would be required in the future together with in-vivo experiments to further evaluate the relevance of the new model and validate the findings. In conclusion, the present work demonstrated the ability of using PAM 3D-printing as manufacturing tool for sustained release, flexible drug-loaded inserts and allowed incorporation of various polymers and APIs. Process understanding was thereby essential to obtain reliable and reproducible results. The release of the inserts could be determined in a newly developed biopharmaceutically relevant bladder model that may serve as platform for investigating various (patho-)physiological conditions and may reduce the need for mathematical estimations of drug release at the target site. | |||||||
| 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: | 22.02.2023 | |||||||
| Dateien geändert am: | 22.02.2023 | |||||||
| Promotionsantrag am: | 05.09.2022 | |||||||
| Datum der Promotion: | 09.11.2022 |
