Upper digestion fate of citrus pectin-stabilized emulsion: An interfacial behavior perspective.

Citrus pectin can serve as a naturally digestion-resistant emulsifier, although how it achieves this effect is still unknown. In this study, the upper digestion fate of an emulsion stabilized by different concentrations of citrus pectin, and changes in its interfacial properties during digestion, were investigated. Emulsions stabilized by high-concentration citrus pectin (3 %) were relatively stable during digestion and had a lower free fatty acid (FFA) release rate than emulsions stabilized by low-concentration citrus pectin (1 %). At the low concentration, the citrus pectin interface had a thin absorbing layer and was largely replaced by bile salts, while at high concentration the citrus pectin interface possessed a uniform and thick adsorbing layer that resisted the replacement of bile salts and enabled lipase adsorption. This study has improved our understanding of the digestion of emulsion from the interface and will be useful for designing emulsion-based functional foods that can achieve targeted release.

Evaluation of two dynamic in vitro models simulating fasted and fed state conditions in the upper gastrointestinal tract (TIM-1 and tiny-TIM) for investigating the bioaccessibility of pharmaceutical compounds from oral dosage forms.

Pharmaceutical research needs predictive in vitro tools for API bioavailability in humans. We evaluated two dynamic in vitro gastrointestinal models: TIM-1 and tiny-TIM. Four low-soluble APIs in various formulations were investigated in the TIM systems under fasted and fed conditions. API small-intestinal bioaccessibility profiles were evaluated between the two systems and in comparison with human data. Both TIM systems showed a higher bioaccessibility of ciprofloxacin and nifedipine during 3-4h after dosing immediate release (IR) compared to modified release (MR) formulations. Higher bioaccessibility levels from IR formulations were observed under fasted state in the first 30-90 min in tiny-TIM as compared to TIM-1, resulting in a tmax similar to clinical data. Absence (ciprofloxacin) or presence (posaconazole) of a food effect on bioaccessibility was observed in both TIM systems in line with human data. A higher bioaccessibility of fenofibrate from nano- vs micro-particle formulation was found in both TIM systems. This dataset shows the predictive quality of the TIM systems for clinical data on API small-intestinal bioaccessibility from IR and MR formulations and food effects. Tiny-TIM provides higher throughput and better prediction for IR formulations. TIM-1 provides detailed information on site-specific release of APIs, relevant for MR formulations and food effects.

Feasibility of capsule endoscopy for direct imaging of drug delivery systems in the fasted upper-gastrointestinal tract.

PURPOSE: To develop a minimally-invasive method for direct visualization of drug delivery systems in the human stomach and to compare the obtained results with an established in vitro model. The method should provide the capsule rupture, dispersion characteristics, and knowledge regarding the surrounding physiological environment in the stomach. METHODS: A capsule endoscopic method was developed. The disintegration time, dispersion characteristics and the impact of the physiological environment on different lipid based delivery systems in different gelatin capsules in the fasted stomach of nine healthy volunteers were visualized. Biorelevant dissolution studies using a USP II apparatus and a droplet size analysis of the released SNEDDS were performed. RESULTS: Visualization of the behavior of both hard and soft gelatin capsules formulations was possible. The disintegration and dispersion of EP oil in a soft capsule and SNEDDS in a hard shell capsule were visualized. The in vitro release rates were different from the in vivo release rates of the soft capsule due to volume, fluid composition and motility differences but not for the hard capsule containing SNEDDS. CONCLUSIONS: A minimally-invasive capsule endoscopic method was developed for direct visualizing of drug delivery systems in the human stomach and maybe later, in the duodenum.

The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a Beagle dog model predicts improved bioavailability and diminished food effect on absorption in human.

MK-0869 (aprepitant), a potent substance P antagonist, is the active ingredient of EMEND which has recently been approved by the FDA for the prevention of chemotherapy-induced nausea and vomiting. Early clinical tablet formulations of MK-0869 showed significant food effects on absorption, suggesting that formulation could have a significant role in improving bioavailability. A Beagle dog model was developed in an effort to guide novel formulation development. Using the suspension of the micronized bulk drug used for the tablet formulations, the food effect on absorption was confirmed in the dog at a similar magnitude to that observed in humans. Further dog studies demonstrated a clear correlation between particle size and in vivo exposures, with the nanoparticle (NanoCrystal) colloidal dispersion formulation providing the highest exposure, suggesting dissolution-limited absorption. The NanoCrystal dispersion also eliminated the food effect on oral absorption in the dog at a dose of 2mg/kg. Regional absorption studies using triport dogs indicated that the absorption of MK-0869 was limited to the upper gastrointestinal tract. These results provided strong evidence that the large increase in surface areas of the drug nanoparticles could overcome the narrow absorption window and lead to rapid in vivo dissolution, fast absorption, and increased bioavailability. In addition, the dog model was used for optimizing formulation processes in which the nanoparticles were incorporated into solid dosage forms, and for selecting excipients to effectively re-disperse the nanoparticles from the dosage units. The human pharmacokinetic data using the nanoparticle formulation showed excellent correlations with those generated in the dog.