Dokument: Pharmaceutical development of losartan mini-tablets for Epidermolysis Bullosa and investigations on the technological transfer into industrial scale

Titel:	Pharmaceutical development of losartan mini-tablets for Epidermolysis Bullosa and investigations on the technological transfer into industrial scale
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=70062
URN (NBN):	urn:nbn:de:hbz:061-20250708-134932-8
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Lura, Valentinë [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 460,8 KB in einer Datei [ZIP-Datei erzeugen] Dateien vom 01.07.2025 / geändert 01.07.2025
Beitragende:	Prof. Dr. Breitkreutz, Jörg [Betreuer/Doktorvater] Jun.-Prof. Dr. Hacker, Michael [Gutachter]
Dewey Dezimal-Klassifikation:	600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit
Beschreibung:	Mini-tablets are increasingly growing in importance which is reflected in the rise of publication counts, as illuminated by the systematic review paper. Also, the clinical evidence of mini-tablet acceptability among the paediatric population was being gradually consolidated by numerous clinical studies. The enhanced attention to this dosage form is emphasized by the recent market launches of Slenyto® and Aqumeldi®, representing the first available single-unit mini-tablets. The review paper sums up relevant advancements in the technological and clinical area, but also points out significant challenges. The review paper proposes a definition of mini-tablets, classifications and some suitable characterization methods. Mini-tablets present a valuable option to target paediatric patients, which is why this child-appropriate dosage form was chosen to make losartan potassium available for the treatment of Epidermolysis Bullosa. Highly drug-loaded mini-tablets were successfully developed on the compaction simulator and then on a rotary tablet press, while several challenges were encountered. Given the high drug load, the active pharmaceutical ingredient (API) properties dominated the formulation resulting in challenging flowability and sticking to the punches. These issues could be mitigated by the formulation and selection of the excipients, but the transfer to the rotary tablet press showed the additional problem of compaction in the hopper when increasing the batch size, so that an intermediate dry granulation was successfully introduced to address this concern. Taste masking via fluid bed coating was carried out successfully and dissolution studies exhibited the delay of release in the first minutes, preventing the high initial burst. Stability studies showed promising results, but also highlighted the relevance of appropriate packaging. Further insights were gained in the field of transfer and scale-up. The studies underlined certain effects that may show correlation with the tableting process directly but might not be noticeable on lab scale. Temperature rise is one of these factors that became apparent with greater batch size and hence longer production time in case of the study with placebo orodispersible mini-tablets (ODMTs). The disintegration time as a critical quality attribute (CQA), increased over time, which might be attributed to sintering effects due to the temperature elevation. The studies conducted with the losartan potassium formulation, however, showed that with magnesium stearate, over-lubrication took place, with the result that the transfer from the compaction simulator to the rotary tablet press did not show a good agreement of compactibility and tabletability. Residence time and shear stresses in the feed frame have a major influence depending on the formulation; lubricant sensitivity must be taken into account. Scale-up investigations reflected that the steady state was required to be reached for the transition to the plateau phase of the CQAs. Acceptance values below 15.0 were obtained at different settings. In total, adequate process understanding of the critical process parameters (CPPs) and the critical material attributes (CMAs) has to be established during development and scale-up of mini-tableting processes to ensure meeting required ranges of CQAs. As over-lubrication issues were encountered, feasibility studies were conducted to investigate external lubrication (EL) for the first time with mini-tablets on the rotary tablet press focusing on tensile strength (TS). EL proved to be feasible, as appropriate ejection forces were measured enabling mini-tableting. The systematic studies (Central Composite Design (CCD) and D-optimal study) were performed with silicified microcrystalline cellulose grades SMCC 90 and 50, respectively. Concluding, a temporal factor was recognized, mean TS were declining non-linearly over time, the degree was dependent on the dosing rate, while also a dependency of the dust extraction power is assumed, so that more magnesium stearate would be available in the tablet press contaminating powder and impacting TS. In total, the parameters tableting speed and dosing rate did not seem to have an effect on the response TS in the CCD study, while tableting pressure represented the highest positive coefficient, and the air spray pressure a slightly positive coefficient. Further studies are necessary to investigate this phenomenon that occurred at a specific machine and experimental setup, e.g. with further tablet presses and a setup with the possibility to control the air flow rate of the dust collector. Studies should also be also extended to further formulations in the future.
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:	08.07.2025
Dateien geändert am:	08.07.2025
Promotionsantrag am:	08.10.2024
Datum der Promotion:	12.12.2024