In Vitro Model Simulating Gastro-Intestinal Digestion in the Pediatric Population (Neonates and Young Infants)

Abstract

The focus on drug delivery for the pediatric population has been steadily increasing in the last decades. In terms of developing in vitro models simulating characteristics of the targeted pediatric population, with the purpose of predicting drug product performance after oral administration, it is important to simulate the gastro-intestinal conditions and processes the drug will encounter upon oral administration. When a drug is administered in the fed state, which is commonly the case for neonates, as they are typically fed every 3 h, the digestion of the milk will affect the composition of the fluid available for drug dissolution/solubilization. Therefore, in order to predict the solubilized amount of drug available for absorption, an in vitro model simulating digestion in the gastro-intestinal tract should be utilized. In order to simulate the digestion process and the drug solubilization taking place in vivo, the following aspects should be considered; physiologically relevant media, media volume, use of physiological enzymes in proper amounts, as well as correct pH and addition of relevant co-factors, e.g., bile salts and co-enzymes. Furthermore, physiological transit times and appropriate mixing should be considered and mimicked as close as possible. This paper presents a literature review on physiological factors relevant for digestion and drug solubilization in neonates. Based on the available literature data, a novel in vitro digestion model simulating digestion and drug solubilization in the neonate and young infant pediatric population (2 months old and younger) was designed.

Design, characterization and in vivo evaluation of nanostructured lipid carriers (NLC) as a new drug delivery system for hydrochlorothiazide oral administration in pediatric therapy

“…Kamstrup et al. ( 2017 ) suggested an in vitro model to simulate the digestion process in the pediatric gastrointestinal tract, starting from the original model developed by Zangenberg et al ( 2001 ), providing general indications about the most important physiological factors to be considered as relevant such as media volume, pH and osmolality. However, also these authors highlighted the difficulty and the complexity of reproducing in vitro, the in vivo conditions, due to both the lack of commercial availability of HGL and PLRP2 and the difficulties of estimating the levels of digestive enzymes.…”

Biopharmaceutical considerations in paediatrics with a view to the evaluation of orally administered drug products – a PEARRL review

“…The proportions of casein to whey‐proteins, lipid composition, fat‐globule structure and size, and milk origin, (e.g. soy or cow's milk) are variable among different formulae and not equivalent when compared to human breastmilk . The presence of bile salts in human breastmilk, but not in formula milk, should be considered as an additional potential factor that might affect oral drug absorption .…”

Invited review: Dairy proteins and bioactive peptides: Modeling digestion and the intestinal barrier

“…Most of the established in vitro models have been designed to simulate the specific processes taking place within an adult human. The digestion process differs in children, seniors, and pathological patients (e.g., inflammatory bowel disease); therefore, the in vitro models developed to simulate the digestion in adults will not accurately reflect processes occurring in those individuals (Kamstrup et al, 2017). Customized models may represent new tools to accurately evaluate the bioaccessibility of tailored and personalized foods for a specific stratum of the human population, such as infants, the elderly, and patients with gastrointestinal disorders.…”