D1 Drug delivery systems for the controlled release
For proteins as active pharmaceutical ingredients, the parenteral route is the most important way of administration. Efficient Drug Delivery Systems (DDS) allow a controlled and locally defined release of therapeutic proteins. Furthermore, the DDS can positively affect protein stability during storage and during the release period after administration. For the therapeutical application of proteins, hydrogels prepared from suitable polymers are promising matrices for DDS due to their controlled release kinetics, their hydrophilic environment and biocompatibility.
The aim of the subproject D1 is the development of hydrogel-based DDS with controlled local release. Entrapment of antibodies in cooperation with subproject A6 (Dübel/Hust) is the main research focus. The hydrogels under investigation are mainly based on hydroxyethyl starch (HES), a well known and biocompatible substance, modified with a crosslinkable side group (e.g., hydroxyethyl methacrylate (HEMA)). The resulting polymers can be chemically crosslinked in aqueous solution in the presence of proteins.
The network density can be adjusted by the amount of crosslinkable side chains, which in turn leads to controllable release kinetics. As an approach to control the phase separation process during gelation, as well as to accelerate the hydrolytic degradation hydrophilic spacers are going to be introduced between the polymer backbone and the crosslinkable side group. Moreover, a specific degradation by enzymes can be achieved by using peptides as linker.
Hydrogel-based Drug Delivery Systems are mainly prepared from modified hydroxyethyl starch (HES).
On the basis of the crosslinkable polysaccharides hydrogels can be prepared as larger (e.g. cylindrical) bodies but also in the form of microparticles when a special w/w emulsion process is used. Microparticulate DDS are of special interest for pharmaceutical purposes because they can easily be administered by injection.
Mikroparticulate hydrogel-based DDS (Microgels). Left: Scanning electron micrograph of the microparticles; Center: Confocal laser scanning micrograph of a microparticle loaded with fluorescence-labelled dextran; Right: Particle size distribution of a microgel system.
Release studies reveal a significant dependence of the release on the molecular weight of the drug, which is an ideal precondition for the incorporation of antibodies and antibody fragments as well as bifunctional antibodies in cooperation with subproject A6 (Dübel/Hust). Realistic release models which mimic the physiological situation as closely as possible are going to be developed in order to monitor the release characteristics of the hydrogels. For their validation, first in vivo studies are planned (animal model).
Release of fluorescence-labelled dextran in dependence on the degree of substitution of the crosslinkable hydroxyethyl starch (HESHEMA).
Another important aspect is the stability of the antibodies in the hydrogel under the conditions of storage and administration, particularly with regard to a risk of aggregation due to the entrapment of high amount of the antibodies as required for therapeutic purposes. Therefore, studies are planned to monitor the influence of the chemical and physical hydrogel constitution, its different states (dried/swollen; bulk/microparticles), as well as the production process on the antibody stability.
Where appropriate, the preparation procedures for the microparticles as well as drying processes are going to be further developed. The required range of analytical techniques will be covered by close collaboration with the subprojects A6 (Dübel/Hust) and C6 (Schilling/ Ludwig) in addition to the use of standard physicochemical methods. Together with the subproject D2 (Büttgenbach/Dübel) the development of a microfluidic device for an advanced production of microparticles is pursued. Beyond the development of DDS, the experiences with hydrogel production and polymer modification of surfaces are going to be transferred to studies regarding the production of valves for microfluidic devices in the subproject D2 (Büttgenbach/Dübel).