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Abstract

The controlled release of therapeutic agents offers certain benefits in pharmacology, patient compliance and tolerability compared to conventional dosage forms. Nowadays, long acting injectables for peptide and protein therapeutics gain in importance as increasing numbers of biotherapeutics receive approval and subcutaneous self-administration attracts attention due to cost reductions and improved patient acceptance. The innovative polymer platform SynBiosys® claims to overcome weaknesses of conventional polymers for microparticle-based controlled release. As objective of this work, the suitability of these polymers for controlled release of biotherapeutics was evaluated based on various integrity analyses of representative models after in vitro and in vivo release from SynBiosys®-based microparticles. Microparticle formulations of the anti-diabetic peptide drug exenatide were examined in vitro and in vivo in comparison with the marketed benchmark formulation Bydureon®. Exenatide was released in vitro with high linearity over two to four weeks and integrity of liberated peptide was preliminarily confirmed with a cell-based functional assay. Likewise, SynBiosys® formulations exhibited a more continuous release behavior in vivo compared to the benchmark Bydureon®. Single subcutaneous injection of SynBiosys®-based microparticles significantly reduced non-fasting blood glucose between 25-50% over approximately four weeks and decreased glycated hemoglobin significantly by 3.4 - 4.6% in a rat model of type II diabetes (high fat diet/streptozotocin induced). Formulation of the monoclonal antibody mAbB in differently composed SynBiosys® polymer matrices allowed the choice of a suitable polymer composition for the controlled release of proteins with high molecular weight. The structural integrity of in vitro released mAbB was confirmed by circular dichroism and fluorescence spectroscopy. Based on these results, mAbX as oncological model drug was encapsulated and its integrity after linear in vitro release over 10-14 days was confirmed by a powerful combination of SE-HPLC, circular dichroism and fluorescence spectroscopy, ELISA as well as a cell-based functional assay. The in vivo liberation of mAbX resulted in highly dose-dependent antibody plasma levels as well as reproducible values for the absolute bioavailability of 25.7-30.6% in xenograft mouse models. Pharmacodynamic efficacy of mAbX released from SynBiosys® microparticles was demonstrated by significant growth reduction of A-431 epidermoid carcinoma cell tumors between 50 and 100%. In conclusion, the compatibility of SynBiosys® polymers with sensitive peptides and large protein therapeutics was demonstrated herein by in vitro and in vivo release of model biotherapeutics in highly functional condition as confirmed by a comprehensive analytical method composition. In the case of exenatide, the accelerated onset of therapeutic effect, the lower number of treatments and the significantly reduced total dose required were remarkable. The SynBiosys® platform is a promising tool for the improved controlled release of biologicals.