Development of a mucoadhesive and multiparticulate colon drug delivery system

The physiology of the gastrointestinal tract presents serious barriers and challenges to oral drug delivery. The wide intra- and intersubject variability of gastrointestinal transit time is an important factor that can have a significant influence on drug bioavailability. Mucoadhesive formulations can increase and harmonize the passage time through the gastrointestinal tract, with the potential benefit of more reproducible drug bioavailability. This effect can be enhanced by using multiparticulate drug delivery system instead of single-unit dosage forms as the gastrointestinal transit of the formers is more reproducible and predictable. Delivery of such mucoadhesive multiparticulates to the colon can be of great benefit for local treatment of colonic diseases, such as Clostridium difficile infections, inflammatory bowel diseases (IBD) and colon cancer. However, so far no in vivo data on the usefulness of oral mucoadhesive formulations in the human proximal colon are available. Therefore, the aim of the work presented in this thesis was to develop a novel formulation platform for delivery of mucoadhesive multiparticulates to the colon for the treatment of Clostridium difficile infections. In the scope of the overall project a a proof-of-concept Phase 1 study was aimed. Therefore, a formulation and manufacturing method based on standardized pharmaceutical processes was envisaged.
Functionalized calcium carbonate (FCC, Omyapharm) porous microcarriers were selected as an alternative size range to nanoparticles and pellets. Drug loading of various substances into FCC was carried out on the principle of solvent evaporation and crystallization. The rotary-evaporation and fluidized-bed processes were feasible to achieve high drug loads up to 40% (w/w). Loaded metronidazole benzoate (MBZ) and nifedipine as model drugs for poor aqueous solubility showed increased dissolution rates compared to drug crystals due to enlarged surface area of the loaded drug onto the FCC particles.
Mucoadhesive coating of drug-loaded FCC microparticles was achieved with the cationic polymer chitosan using either a pH-dependent precipitation method, or a spray-coating method in the fluidized-bed process. To test the chitosan-coated microparticles for mucoadhesivity, an in vitro method to measure particle retention on porcine colonic mucosa (as model of the human colonic mucosa) was developed. This included the design of a flow-channel device and the validation of marker-ion analysis for quantification of detached microparticles.
Optimized formulations containing MBZ as model drug for local treatment of colonic diseases (Clostridium difficile infections) prepared using the fluidized-bed process resulted in good in vitro particle retention. To serve as control, non-mucoadhesive microparticles containing ethylcellulose were developed. These mucoadhesive and non-mucoadhesive microparticles filled into colonic-targeted hard-shell capsules (Tillotts Pharma innovation, outside the scope of the thesis) will be used in a gamma scintigraphy study for a proof-of-concept of mucoadhesion in the human colon as a strategy to increase residence time.