Dokument: Development of a dosing system for individualized therapy with oral films
| Titel: | Development of a dosing system for individualized therapy with oral films | |||||||
| Weiterer Titel: | Entwicklung eines Dosiersystems für die individualisierte Therapie mit oralen Filmen | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=49596 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20190515-083247-5 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Niese, Svenja [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Breitkreutz, Jörg [Gutachter] Prof. Dr. Dr. h.c. Kleinebudde, Peter [Gutachter] | |||||||
| Stichwörter: | individualized therapy, oral films, warfarin, personalized medicine, dosing system, dosing device | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | This work focused on the development of a novel dosing system for the individualized therapy with oral films. A long oral film containing warfarin as model API for individualized therapy was developed as well as a dosing device to flexibly dispense the oral film. The long oral film together with the dosing device represents the dosing system.
First, small-scale solvent casting was elaborated to conduct a systematical formulation development approach for oral films. The small-scale coating bench allowed for the formulation screening in small batches of 50 -100 g to reduce material consumption and manufacturing time. Different formulations were prepared and characterized regarding the viscosity of the polymer solution as a key parameter for the solvent casting manufacturing process, the mechanical properties and the disintegration time of the dried film as essential parameters for the correct application of the oral film. The interactions of the process liners and the polymer solutions were investigated for this manufacturing method. It can be concluded that the selection of a suitable process liner for casting an oral film can be assisted by contact angle measurements and the determination of the SFE of the liner and the SFT of the solution. For the most promising formulations from the small-scale trials, the film formulation development was pursued for the manufacturing process on the continuously working pilot-scale coating bench. This coating bench was used to obtain a long oral film of several meters applicable in the dosing device. First, drug-free formulations were tested for their suitability as films for the dosing device to reduce toxic waste with the API warfarin. Especially the mechanical properties of the prepared films were investigated since they represent important markers for the handling of the film in the device by a patient. The tensile test was preferred instead of the puncture test since it better represents the stresses the film is exposed to in the device and by the patient. A critical investigation of the tensile test for oral films showed that a rectangular test specimen was preferred over the often-used dumbbell-shaped specimen since no advantages of the dumbbell could be identified and the rectangle presented easier preparation and handling. The cutting of the specimens was performed with a cutting plotter instead of a knife to receive more accurate test specimens and to reduce preparation time and effort. The most promising formulations for long oral drug-free films were identified and used for the incorporation of the model drug warfarin. Two different warfarin ODFs based on HPMC and a mixture of PVA and HPMC as polymer matrix were successfully produced on the pilot-scale coating bench in a continuous manufacturing mode. These films were characterized with special regard on the content uniformity of the warfarin throughout the long film and the stability over three months. The mechanical properties as well as the warfarin content did not reveal problems during storage of the samples. The content uniformity was successfully achieved for the long oral films (AV of HPMC film = 5.97 and PVA/HPMC film = 2.75) due to the new in-line tool implemented in the continuous solvent casting process. The new in-line tool is a chromatic confocal optical measurement system that was applied for the first time into the film casting process to measure the wet film thickness during the solvent casting process before the film has been dried. The wet film thickness mainly determines the uniformity of dose in an oral film revealing the importance of controlling this parameter during the production process. The manufacturing process of long oral films was therefore significantly improved by this measuring tool since the thickness of the produced film was measured in real-time and monitoring as well as manual interventions became possible to reduce shortfall batches and inconsistent film products. Deviations from the targeted wet film thickness of up to 60 % were avoided and trial-and-error-based approaches can be reduced by implementation of the in-line tool. The long oral film was developed for the usage in a dosing device for individualized therapy with oral films. Therefore, a dosing device was developed using a 3D-CAD software. The virtually designed 3D-models were then produced with a fused filament fabrication 3D-printer to obtain a prototype. The 3D-printed prototype was stepwise tested regarding its functionality and further refined. The final prototype of the dosing device was fully functional without electricity. It was tested with a ribbon as model film and both long warfarin ODFs packed in aluminum packages regarding the tests of the European Pharmacopoeia for correct doses. Three different lengths of the films (1, 2 and 5 cm corresponding to 1, 2 and 5 mg warfarin) were dispensed to mimic the flexible dosing. The model film successfully passed the test for uniformity of mass of delivered doses from multidose containers (Ph.Eur. 2.9.27) and demonstrated correct working of the dosing device. The warfarin films were tested for Ph.Eur. 2.9.27 as well and furthermore for the more challenging tests for uniformity of content of single-dose preparations (Ph.Eur. 2.9.6) and uniformity of dosage units (Ph.Eur. 2.9.40). The HPMC film successfully passed all tests for all three dispensed film lengths. The acceptance values of ten delivered film samples were all lower than the accepted limit of 15 (1 cm: AV = 11.30, 2 cm: AV = 12.04, 5 cm: AV = 10.19). The PVA and HPMC film passed all tests for the longer dispensed pieces but revealed high scattering for the shortest dispensed film piece due to brittle film properties (1 cm: AV = 26.54, 2 cm: AV = 11.87, 5 cm: AV = 12.69). In conclusion, a dosing system that enables individualized therapy with oral films was successfully developed and tested according to the specifications given by the European Pharmacopoeia. The system passed the test for dose delivery of multidose containers as well as further tests with more challenging claims. The dosing system allows individual dosing of oral films, a dosage form suitable for all age groups, and therefore provides a promising option for personalized medicine. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische Technologie und Biopharmazie | |||||||
| Dokument erstellt am: | 15.05.2019 | |||||||
| Dateien geändert am: | 15.05.2019 | |||||||
| Promotionsantrag am: | 23.01.2019 | |||||||
| Datum der Promotion: | 04.04.2019 |
