Impact on intestinal permeability of pediatric hyperosmolar formulations after dilution: Studies with rat perfusion method

Abstract

Introduction: There is no consensus on administering hyperosmolar formulations by mouth to neonates. In 1976, the Committee on Nutrition of the American Academy of Pediatrics published a recommendation of not administer formulations with an osmolarity higher than 400 mOsm/L due to the possible damage to intestine and relationship with necrotizing enterocolitis. Since this recommendation, exists a general trend of reducing osmolality of oral formulations without considering the pharmacokinetics of absorption of the drugs. The objective of this study was to characterize the permeability values of drugs formulated at different osmolalities by using a well-established rat intestinal perfusion model and to measure the osmolality of the most used formulations in our neonatology unit.

Methods: For the osmolality measurement study, most common used oral drugs were selected (compounded formulations and drug products). Osmolality of three dilutions (1:1, 1:4 and 1:8) were measured using a cryoscopic descent osmometer. Atenolol, caffeine, furosemide, hydrocortisone and paracetamol were selected for the permeability study. Three suspensions were elaborated of each drug (150 mOsm/kg, 300 mOsm/kg and 1500 mOsm/kg). Permeability values and absorption rate coefficients were determined in complete small intestine using in situ "closed loop" perfusion method.

Results: The formulations that resulted to be hyperosmolar (>400 mOsm/kg) were 86% (70% of these proved to be above 1500 mOsm/kg). The permeability study shown that the osmolality is inversely proportional to the apparent permeability of the drug in the studied drugs. The permeability values obtained with hyperosmolar samples were lower compared to 150 mOsm/kg or 300 mOsm/kg.

Conclusions: Osmolality parameter is of particular relevance in oral drug administration in neonate because the risk of damaging the gastrointestinal tract and because of the risk that modifying osmolality also modifies its permeability, resulting in a potential change in bioavailability.

Keywords: Bioavailability; Intestinal perfusion; Intestinal permeability; Necrotizing enterocolitis; Oral administration; Osmolarity; Pediatrics; Security.