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ISBN 9783843933209

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978-3-8439-3320-9, Reihe Pharmazeutische Technologie

Moritz Vollrath
Extruded lipid implants for intravitreal use - protein stability, release kinetics and process design

298 Seiten, Dissertation Ludwig-Maximilians-Universität München (2017), Softcover, A5

Zusammenfassung / Abstract

The present work was aimed to address the following objectives:

(i) further optimisation of the manufacturing process (extrusion parameters, formulation) with a focus on intraocular use. For this, a new extruder (ZE-5 mini extruder) was acquired allowing to manufacture small batches. In a first step, the established process was transferred from a MiniLab® Micro Rheology Compounder to a ZE-5 mini extruder. It was aimed to optimise the process to reach delivery time frames of at least 3 months. Second, as a potential intraocular use was considered, reducing implant dimensions and increasing the protein load while ensuring release patterns and storage stability was intended. To study the impact of the incorporated protein on release patterns, different protein formats were used including three commercially available products: Ranibizumab (Lucentis®), Bevacizumab (Avastin®) and Aflibercept (Eylea®). Additionally, another model mAb was used. To further tailor the release, triglycerides were pre-melted prior to extrusion to intentionally change their thermal and physicochemical properties.

(ii) A 3-month in-vivo study in rabbit eyes using Ranibizumab loaded SLIs was executed to evaluate the in-vitro-in-vivo release correlation and pharmacodynamic effects within a choroidal neovascularisation (CNV) model.

(iii) The bioactivity of fractions released from SLIs of the natural complement regulator Factor H (mini-FH) was studied to obtain information on its biological activity once released.

(iv) Further work included the systematic investigation on stability of released protein over the complete release duration covering colloidal, chemical and conformational stability. Comparison of stability profiles delivered from SLIs to PLGA- based implants was performed.

(v) Recent work pointed into the direction that not only the manufacturing settings influence release patterns but also the properties of the protein itself. Consequently, the influence of possible triglyceride-protein-interactions on protein stability was investigated.

(vi) Solid lipid extrusion (SLE) has been used previously within different works. However, the extrusion process itself and its impact on the lipid matrix and release patterns has not yet been described. It was therefore the aim to characterise the SLE process with regards to how changing process parameters affect the properties of the lipid matrix and the release patterns of the model mAb. Therefore, the impact of process parameters such as extrusion speed, temperature, and lipid composition on implant properties was investigated systematically.