In vivo studies have demonstrated a positive food effect on the oral bioavailability of cinnarizine. Consequently, dosing instructions for tablets containing cinnarizine recommend taking the medication after consuming a meal. The influence of food on drug bioavailability may result from various mechanisms, including direct physical and chemical interactions between food components and the drug, as well as altered physiological conditions in the gastrointestinal tract. Some changes in physiological conditions can be simulated during in vitro dissolution tests.
The aim of this master's thesis is to examine the mechanisms of the positive food effect on cinnarizine bioavailability using an in vitro model that simulates certain properties of postprandial gasrtic content. The experimental procedures carried out involved dissolution testing of 25 mg and 75 mg cinnarizine tablets using paddle apparatus. Media were prepared to mimic viscosity, lipid content, and pH levels of gastric content in different time periods after meal ingestion. Gastric viscosity was replicated using various concentrations of HPMC, while emulsion for parenteral nutrition with 20 % lipid content was diluted to match early and late fed state gastric lipid content. Various media pH levels were achieved using fourfold diluted Mcllvaine buffers. The concentration of the released cinnarizine was calculated using the calibration curves and HPLC response. Samples containing lipids or HPMC underwent preparation for HPLC analysis which included addition of ice-cold acetonitrile followed by centrifugation. Alongside dissolution studies, we investigated the distribution of cinnarizine between aqueous and lipid phases. Phase separation was achieved by centrifugation of the sample. As the aqueous medium’s pH increased, cinnarizine release from the tablets slowed down, in line with its pH-dependent solubility. The addition of lipids enhanced drug release at pH values where the release was incomplete before lipid addition with greatest lipid concentrations having a more pronounced effect. Cinnarizine predominantly partitioned into the lipid phase with rising medium pH. The impact of lipid concentration on cinnarizine distribution was observed solely in pH 3 media. Elevated medium viscosity hindered drug release, while increasing HPMC concentrations disproportionally affected drug distribution between aqueous and lipid phases. By incorporating lipids into the media, we successfully replicated the positive food effect on cinnarizine’s in vivo bioavailability.
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