Floating gastroretentive drug delivery systems based on functionalized calcium carbonate

Abstract

Orally-administered controlled-release drug delivery systems are associated with the short- comings of relatively short residence times in the human stomach as well as highly variable gastrointestinal (GI) transit times. Thus, considerable intra-individual and inter-individual differences in the bioavailability of drugs are observable. There are numerous drug substances which may benefit from prolonged and controlled GI passage times. As a solution to the problem, gastroretentive drug delivery systems (GRDDS), which feature an enhanced gastric residence time (GRT), were developed. Several gastric retention approaches, such as flotation, have been proposed and analyzed. Despite the extensive research performed in the field of GRDDS, the development, the production, and the evaluation of floating devices are still challenging. The aim of the thesis was to come up with a formulation strategy which facilitates the design of innovative floating drug delivery systems (FDDS). Hydrophilic and lipophilic floating formulations were prepared by wet granulation and melt granulation, respectively. Tablets with an inherent density of less than unity were compacted using porous functionalized calcium carbonate (FCC) as matrix-forming component. For the concurrent assessment of drug release by UV/Vis spectroscopy and floating behavior by visual observation, a custom-built stomach model method was set up. Our in vitro evaluation method was combined with in silico dissolution simulations to analyze the floating force as a function of drug release. To determine the in vivo gastric retention potential of FCC-based FDDS, a study protocol has been proposed for the assessment of the stomach residence time of floating tablets and non-floating references in humans. The production of tablets and mini-tablets, which met the requirements for immediately floating tablets (i.e. inherently low density accompanied by sufficient hardness), was possible due to the characteristic lamellar structures of the FCC particles. The tablets showed no floating lag time and remained afloat until complete release of the model drug substance caffeine. For the hydrophilic formulation, the drug release was erosion-controlled and the flotation mechanism was a reaction-based erosion mechanism with gelation-layer-forming polymers as imbibition-inhibiting and gas-entrapping components. In the case of the lipophilic formulations, flotation was achieved by slowing-down and/or inhibiting the reaction-based erosion of FCC due to hydrophobization of the particle’s stratum layer; the release of the drug was diffusion-controlled and erosion-controlled. A FDDS formulation design tool box (including the novel pharmaceutical excipient FCC, an in vitro stomach model, an in silico tablet dissolution simulation approach, and an in vivo clinical study concept) was proposed to assist the future formulation development, the production, and the analysis of innovative FDDS. We introduced and applied a classification system, including an “ideal” floating performance (i.e. no floating lag time, maintaining of the floating force until complete drug release, followed by a decrease of the floating capability) to categorize experimentally observed flotation behavior. It was shown that FCC is an enabling excipient for the manufacture of FDDS and the preparation of formulations with an “ideal” floating behavior was possible. The results of the in vivo experiment provided a first evidence for the gastric retention potential of FCC-based floating tablets in humans.