In the past decades there is growing interest in the application of therapeutic proteins for the treatment of various diseases. Polymer based injectable depot preparations that release proteins over a prolonged period of time may form an attractive alternative to the conventional injections of these drugs that usually require frequent administrations. Hot melt extrusion (HME) is a generally applied technology for the preparation of polymer based implants for the controlled release of drugs. However, HME has not been extensively explored for the controlled release of proteins yet. The technique may be harmful to the proteins due to their sensitive nature. The aim of the present study was to investigate the stabilization of proteins prior to, during and after encapsulation into polymer matrices by HME as well as during the release of the proteins from the matrices.
Sugar glass technology was applied to stabilize proteins and the mechanism of stabilization was studied. Various sugar glass stabilized proteins were encapsulated into novel biodegradable multiblock copolymers using HME, which could be accomplished at relatively low temperatures (thus favourable in view of protein stability). As a result of pre-stabilization using sugar glasses and the low process temperature, the proteins remained fully stable during the HME process. It was shown that the protein release from polymer depots can be tailored by co-incorporation of sugars as pore forming excipients but also by varying protein size and polymer composition. Polymer degradation rate appeared to be an important factor in the design of depot formulations. However, too fast degradation did lead to unwanted polymer-protein interactions, hampering protein release.
In conclusion, in this thesis the interplay between different polymer and protein related factors relevant for the development of a platform technology for successful stabilization, encapsulation and controlled release of proteins is described.
Ms M. (Milica) Stankovic
December 08, 2014
prof. dr. H.W. (Erik) Frijlink
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