Study of the influence of coating methods on lipid spheres manufactured on rotor fluidized bed process.

Different previous works have shown that various kinds of spheres can be manufactured by rotor granulation in a 'single-pot process' using a lipid base: hydrogenated castor oil. This single-pot technology is based on wet granulation where all components are placed in the powder form in the rotor bowl; then, they are continuously suspended in a fluidized air, with a tangentially sprayed liquid solution. This process allows the granulation and manufacturing of sphere during the same time. Previous experiments have studied the influence of the formulation and the manufacturing process parameters on spheres in terms of feasibility and dissolution properties. Both the spraying time and the weight of liquid sprayed were found to be the most relevant parameters that govern the final quality of the sphere. Now, in a second part of the work, a first comparison is made with two different fluid bed methods: the tangential rotor spray and the Wurster bottom spray for coating the lipid spheres previously manufactured with the rotor tangential spray. The external aspect of the coated spheres manufactured has been evaluated with an electronic microscopy analysis and a study of dissolution properties of the active ingredient has been done by USP in vitro dissolution tests.

Single process for manufacturing spheres with a lipid base (HCO).

Pellets and spheres are manufactured in the pharmaceutical industry by various processes which are not always easily automated. In this paper, a 'single pot process' is described using rotary fluid bed granulation with lipid fillers. This technology is based on wet granulation of powder components, continuously suspended in a fluidized air with a tangentially sprayed liquid solution. After a previous work devoted to selection of matrix filler, this work focuses on lipid component: hydrogenated castor oil, used as matrix filler associated with theophylline as tracer. Spheres manufactured can be introduced either directly into a hard gelatine capsule or compressed as tablets. The influence of the formulation and process parameters on the sphere manufacture in terms of feasibility is studied with in vitro tests. Spraying time and weight of liquid sprayed are found to be the most relevant parameters that governed the final quality of the sphere.

Gastrointestinal absorption and urinary excretion of trans-cinnamic and p-coumaric acids in rats.

trans-Cinnamic acid (CIN) and p-coumaric acid (COU) are ingested by humans in their diet. While the metabolism and health benefits of CIN have been widely documented, little is known about its absorption sites, and there have been few studies dedicated to COU. The gastrointestinal sac technique demonstrated that CIN and COU are absorbed by all digestive organs in rats and partially transported via MCT-mediated carrier. Absorption was lowest in the stomach. Regardless of the organs that were studied, CIN was more efficiently absorbed than COU. After their individual oral administration to rats, CIN and COU were excreted in 0-24 h urine (0.3% and 23% of ingested CIN and COU, respectively). This suggests that COU was less metabolized than CIN. CIN and COU are absorbed across the digestive epithelium and subsequently interact with target tissues. Despite its lower gastrointestinal absorption, COU may have greater health benefits because it seems to be less metabolized than CIN.

Effects of cryoprotectants on the viability and activity of freeze dried recombinant yeasts as novel oral drug delivery systems assessed by an artificial digestive system.

The aim of this study was to investigate, in a gastric-small intestinal system TIM-1, the effect of cryoprotectants on the survival of freeze-dried Saccharomyces cerevisiae expressing the heterologous P450 73A1 and their ability to convert trans-cinnamic acid into p-coumaric acid. Yeasts were lyophilized in suspensions of trehalose, maltose, lactose, or a milk proteins/trehalose mix. Freeze-dried or native yeasts and trans-cinnamic acid were introduced simultaneously into TIM-1 at the beginning of digestion. Yeast survival rate was evaluated by cell counting in the ileal effluents. P450 73A1 activity was followed by HPLC assay of p-coumaric acid. Freeze-dried yeasts showed high tolerance to digestive conditions. Nevertheless, their survival rate was lower than that of non-dried cells (around 80% whatever the protective agent vs. 96%). The ability of recombinant freeze-dried S. cerevisiae to perform a bioconversion reaction in the digestive tract was shown with all the protectants. The highest trans-cinnamic acid conversion rate (24 vs. 41% for native yeasts) was obtained with the milk proteins/trehalose mix. These results show that freeze-drying might be considered for the pharmaceutical formulation of new drug delivery systems based on orally administered recombinant yeasts and that TIM-1 could be a helpful tool for the pre-screening of oral dosage forms.

Iron availability from whey protein hydrogels: an in vitro study.

The influence of whey protein hydrogel microstructure, filamentous versus particulate, on iron delivery was studied under different conditions, including simulated gastrointestinal conditions. Experiments were initially conducted to determine the impact of pH and enzymes on iron release. The results show that different iron release profiles can be obtained from filamentous and particulate gels. Particulate gels released more iron than filamentous gels at acidic pH, but the opposite was observed at alkaline pH. In the presence of pepsin at pH 1.2 or pancreatin at pH 7.5, both gel types showed increased protein hydrolysis, but only filamentous gels showed increased iron release, suggesting that matrix structure plays an important role in iron delivery. A dissolution test was carried out under gastrointestinal conditions to mimic the in vivo dissolution process. Filamentous gel released most of its iron during the intestinal phase of a simulated digestion, hence protecting iron during its transit in the gastric zone. Absorption of iron by the Caco-2 system, used to estimate intestinal absorption, revealed that filamentous gels favored intracellular iron absorption. These results suggest that filamentous gels show promise as matrices for transporting iron and promoting its absorption and therefore should be of major interest in the development of innovative functional foods.

A dynamic artificial gastrointestinal system for studying the behavior of orally administered drug dosage forms under various physiological conditions.

PURPOSE: The purpose of this study was to demonstrate the potential of a dynamic, multicompartmental in vitro system simulating the human stomach and small intestine (TIM-1) for studying the behavior of oral drug dosage forms under various physiological gastrointestinal conditions. METHODS: Two model drug compounds were studied in TIM-1: a lyophilized Lactobacillus strain and paracetamol (acetaminophen). The Lactobacillus survival rate was determined by bacterial counting in the gastric and ileal effluents while simulating the conditions of the gastrointestinal tract of infants or adults. The availability for absorption of paracetamol from two oral dosage forms was investigated by measuring the drug concentration in jejunal dialysis fluid. The effect of gastrointestinal passage time and food intake on paracetamol absorption was also studied. RESULTS: The Lactobacillus survival rate in both gastric and ileal effluents was higher during simulation of the infant compared to adult conditions. We also showed that (i) paracetamol absorption was faster when it was administered as a free powder than in sustained-release tablet form, (ii) a slow passage time resulted in a delay in the absorption of paracetamol, and (iii) there was a lower rate of absorption when paracetamol was ingested with a standard breakfast as opposed to water. The in vitro results were consistent with in vivo data, showing the predictive value of TIM-1. CONCLUSIONS: TIM-1 is a powerful tool for supplying valuable information about the effects of various gastrointestinal conditions on biopharmaceutical behavior and efficacy of drug delivery systems in the development of oral formulations.