Twin-screw extruded lipid implants for controlled protein drug delivery

Triglyceride based lipid implants which were prepared by tsc-extrusion (tsc-extrudates) were investigated for their characteristics regarding protein release and biodegradation. Tsc- extrudates consist of a low melting and a high melting lipid, a dry protein powder formulation (drug) and a pore-forming/precipitating agent. The mixture of low melting and high melting lipids facilitates extrusion at moderate temperature without affecting protein integrity and the porogen/precipitant is used to control the rate of protein release. We were able to establish a linear and sustained release of a monoclonal IgG1 antibody (mabB) from tsc-extrudates by utilizing a precipitation and re-dissolution mechanism (chapter III). PEG was used as porogen/precipitating agent and allowed complete release of mabB from tsc-extrudates. We were able to achieve a sustained release of the antibody over a period of 150 days with very little burst. Furthermore we could proof the influence of the protein precipitation step on the antibody release rate by changing the pH of the incubation medium from 7.4 to 4.0 and thereby preventing in-situ precipitation of mabB. Indeed, release rates at pH 4.0 were much faster than at 7.4. Interestingly, mabB was released from tsc- extrudates mainly in its monomeric form, which was ascribed to the application of HP-β-CD which was used as cryo-/lyo-protectant and stabilizes the protein within the triglyceride material like it was already shown for IFNα [28]. In chapter IV we compared 4 different methods for the preparation of triglyceride based implants (RAM extrusion, tsc-extrusion, compression and compression of tsc-extruded material) and showed that tsc-extrusion led to a more sustained lysozyme release than compression or RAM extrusion. The production of ́compressed tsc-extrudates` by grinding and subsequent compression of tsc-extrudates resulted in a more sustained protein release profile than simple compression but exhibited a similar release rate than tsc-extrusion. We got a dear indication that partial melting of the triglyceride matrix materials during the manufacturing process plays a major role in controlling release kinetics from tsc-extrudates. Minor changes in triglyceride crystallinity and melting behavior were detected in tsc-extrudates by X-ray and DSC measurements. These changes derived from the melting process but were not negatively impacting implant stability.