Microwave-Assisted Milligel Synthesis under Continuous Flow

Novel dosage forms of pharmaceutically active components are strongly demanded for abusefree application of drugs as well as by the demographic change, which has added high levels of importance to easy-to-use medication in order to leave older-aged individuals independent of nursery as long as possible. Polymer-based drug depots, which degrade in-vivo during a predefined time and constantly release the drugs required by the patients in the recommended dose, are a promising strategy to aid in this concern that will be investigated in the project "MIMIFLOW: Microwave-Assisted Milligel Synthesis under Continuous Flow", a collaboration of the University of Pau, the University of Bordeaux, and the Graz University of Technology. The aim of this project is the development of novel polymer carrier matrices based on crosslinked biopolyesters and poly(2-oxazoline)s. These polymer networks are assigned high potential to combine the advantages of both types of polymers involved and to overcome their respective limitations like too slow degradation kinetics, hydrophobicity, or bulk erosion. In order to correlate the networks` properties with their structures and to allow for tailor-made material fabrication from "desktop calculations", three-dimensional libraries of poly(ester-oxazoline)s will be synthesized. Drug inclusion will be performed in two alternative ways, either by in-situ inclusion during the polymerization or from post-synthetic swelling/diffusion/drying cycles of the polymers. In particular the latter approach will aim at the development of "carrier" materials that can be loaded with individual medication in order to yield personalized drug carriers. These drug carriers will be designed in a way that they degrade in-vivo and provide patients with constant drug levels, eliminating the risks of adroitness and mixed-up medications. The syntheses will be performed in state-of-the-art microwave reactors, with a dedicated focus on millifluidic continuous-flow systems in order to produce poly(ester-oxazoline) networks with defined shapes and geometries for their specific applications. Mechanical characterization of the polymer networks with and without drugs in the non-swollen and swollen state as well as the degradation and release kinetics will be determined. In particular the mechanical tests of the swollen specimens will be important for optimizing the materials` properties for in-vivo applications. Cytotoxicity tests of the polymer networks as well as the corresponding degradation products will be performed in order to validate the usage of this novel class of copolymers as drug depots in mammalians. At the end of the MIMIFLOW project, degradable poly(ester-oxazoline) networks will have been synthesized and characterized by wettability, swelling degrees, mechanical properties in the dry and swollen state and degradation / release kinetics. Representative candidates of this class of novel polymer matrices will have been in-vitro tested for applicability in mammalian bodies and their functionality as drug depots.

The demographic change and an increased awareness of drug misuse have revealed the necessity to develop novel dosage forms for drugs. These alternative dosage forms inherently bear the potential for elderly people to live independently for as long as possible: From implantable polymer-based drug depots, in which the polymer skeleton is slowly degraded, the occluded medicaments are released during a defined, several-week period. This approach was explored jointly by the University of Pau, the University of Bordeaux and the Polymer Competence Center Leoben in the project Microwave-Assisted Continuous-Flow Milligel Syntheses MimiFlow. The MimiFlow project was jointly funded by the Fund for Scientific Research FWF and the Agence Nationale de la Recherche ANR.The main objective of this project was the development of novel polymer-based carrier matrices based on crosslinked polyesters and poly(2-oxazoline)s. These polymeric networks combine the advantageous properties of both polymer classes and are fabricated in such a way that they no longer have the limitations of the individual polymer classes such as slow degradation, hydrophobicity or bulk erosion. In order to be able to correlate the properties of the polymer networks with the underlying structure and to tailor suitable polymer matrices at the desk, large material libraries of the poly(ester-oxazoline)s were synthesized and characterized. The loading of these polymer matrices with drugs can take place during or after the syntheses. These networks are slowly degraded under physiological conditions, releasing the stored active ingredients.The synthetic work was carried out in newly developed microwave reactors under continuous flow conditions, such that polymer networks with a defined shape could be produced. Cross-linking reactions, which were started upon irradiation with UV light, also offered the possibility of shaping the polymer matrices. These polymer frameworks were degraded in the alkaline range as well as by enzymes (esterases), and the incorporated active substances were released. The successful implementation of the project idea could thus be confirmed in the laboratory scale.