A Dynamic Artificial Gastrointestinal System for Studying the Behavior of Orally Administered Drug Dosage Forms Under Various Physiological Conditions

AbstractPurpose. 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.

[1]  J. Luten,et al.  "In vitro" availability of calcium, magnesium, iron, copper and zinc from white or brown bread separately or in combination with other foods , 1992 .

[2]  D R Abernethy,et al.  Absolute and relative bioavailability of oral acetaminophen preparations. , 1983, Journal of pharmaceutical sciences.

[3]  R. Havenaar,et al.  A computer-controlled system to simulate conditions of the large intestine with peristaltic mixing, water absorption and absorption of fermentation products , 1999, Applied Microbiology and Biotechnology.

[4]  J. Elashoff,et al.  Analysis of gastric emptying data. , 1982, Gastroenterology.

[5]  Vesa,et al.  Pharmacokinetics of Lactobacillus plantarum NCIMB 8826, Lactobacillus fermentum KLD, and Lactococcus lactis MG 1363 in the human gastrointestinal tract , 2000, Alimentary pharmacology & therapeutics.

[6]  G. Schaafsma,et al.  Folic acid and 5-methyltetrahydrofolate in fortified milk are bioaccessible as determined in a dynamic in vitro gastrointestinal model. , 2003, The Journal of nutrition.

[7]  M. Minekus,et al.  Recombinant Saccharomyces cerevisiae Expressing P450 in Artificial Digestive Systems: a Model for Biodetoxication in the Human Digestive Environment , 2003, Applied and Environmental Microbiology.

[8]  M. Raghoebar,et al.  Kinetics of acetaminophen after single‐ and multiple‐dose oral administration as a gradient matrix system to healthy male subjects , 1991, Biopharmaceutics & drug disposition.

[9]  B. Goldin,et al.  Survival of Lactobacillus species (strain GG) in human gastrointestinal tract. , 1992, Digestive diseases and sciences.

[10]  B. Goldin,et al.  Survival of lactic acid bacteria in the human stomach and adhesion to intestinal cells. , 1987, Journal of dairy science.

[11]  R. Havenaar,et al.  Estimation of the bioavailability of iron and phosphorus in cereals using a dynamic in vitro gastrointestinal model. , 1997 .

[12]  H. Englyst,et al.  Measurement of resistant starch in vitro and in vivo , 1996, British Journal of Nutrition.

[13]  P. Pochart,et al.  [Survival of Lactobacillus acidophilus and Bifidobacterium sp. in the small intestine following ingestion in fermented milk. A rational basis for the use of probiotics in man]. , 1992, Gastroenterologie clinique et biologique.

[14]  V. Feron,et al.  Application of a dynamic in vitro gastrointestinal tract model to study the availability of food mutagens, using heterocyclic aromatic amines as model compounds. , 2000, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[15]  J. Pélissier,et al.  In vitro simulation of gastric digestion of milk proteins: comparison between in vitro and in vivo data. , 1992 .

[16]  Philippe Marteau,et al.  A Multicompartmental Dynamic Computer-controlled Model Simulating the Stomach and Small Intestine , 1995 .

[17]  R. Havenaar,et al.  Survival of lactic acid bacteria in a dynamic model of the stomach and small intestine: validation and the effects of bile. , 1997, Journal of dairy science.

[18]  W. Verstraete,et al.  Development of a 5-step multi-chamber reactor as a simulation of the human intestinal microbial ecosystem , 1993, Applied Microbiology and Biotechnology.

[19]  L. Hartog,et al.  An in‐vitro method for prediction of the digestible crude protein content in pig feeds , 1990 .

[20]  R. Farinotti,et al.  Interactions of cimetidine and ranitidine with aluminum-containing antacids and a clay-containing gastric-protective drug in an "artificial stomach-duodenum" model. , 1994, Journal of pharmaceutical sciences.

[21]  D. Greenblatt,et al.  Effect of Food on Acetaminophen Absorption in Young and Elderly Subjects , 1982, Journal of clinical pharmacology.

[22]  F. Samdal,et al.  Absorption of effervescent paracetamol tablets relative to ordinary paracetamol tablets in healthy volunteers , 2000, European Journal of Clinical Pharmacology.

[23]  M. Verstegen,et al.  Description of a Dynamic In Vitro Model of the Dog Gastrointestinal Tract and an Evaluation of Various Transit Times for Protein and Calcium , 1999, Alternatives to laboratory animals : ATLA.

[24]  M. Alric,et al.  The 'biodrug' concept: an innovative approach to therapy. , 2001, Trends in biotechnology.

[25]  K. Venema,et al.  TNO's in vitro large intestinal model: an excellent screening tool for functional food and pharmaceutical research. , 2000 .

[26]  J. Jaffe,et al.  Effects of dietary components on GI absorption of acetaminophen tablets in man. , 1971, Journal of pharmaceutical sciences.

[27]  G. Tucker,et al.  A New Rapidly Absorbed Paracetamol Tablet Containing Sodium Bicarbonate. I. A Four-Way Crossover Study to Compare the Concentration–Time Profile of Paracetamol from the New Paracetamol/Sodium Bicarbonate Tablet and a Conventional Paracetamol Tablet in Fed and Fasted Volunteers , 2002, Drug development and industrial pharmacy.