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Impact on intestinal permeability of pediatric hyperosmolar formulations after dilution: Studies with rat perfusion
J M delMoral-Sanchez1, A Ruiz-Picazo1, M Gonzalez-Alvarez2
1Institute of Molecular and Cellular Biology of Miguel Hernandez University, Avda de la Universidad s/n, 03202 Elche (Alicante), Spain; Department of Pharmacokinetics and Pharmaceutical Technology, Miguel Hernandez University, San Juan de Alicante, 03550 Alicante, Spain.
Insights
Hyperosmolar oral formulations in neonates may damage the gastrointestinal tract and reduce drug permeability. This study investigated drug absorption rates and osmolality of common neonatal medications.
Area of Science:
- Neonatal Pharmacology
- Gastrointestinal Physiology
- Drug Formulation
Background:
- Lack of consensus exists regarding the safety of hyperosmolar oral formulations for neonates.
- Previous recommendations advised against formulations exceeding 400 mOsm/L due to potential intestinal damage and necrotizing enterocolitis risk.
- Current trends reduce osmolality without fully considering drug pharmacokinetic implications.
Purpose of the Study:
- To assess the impact of formulation osmolality on drug permeability in a neonatal context.
- To measure the osmolality of frequently used oral medications in a neonatal intensive care unit.
Main Methods:
- Osmolality of common neonatal oral drugs and compounded formulations was measured at various dilutions.
- Drug permeability and absorption rates were determined using an in situ rat intestinal perfusion model.
- Specific drugs studied included atenolol, caffeine, furosemide, hydrocortisone, and paracetamol at different osmolalities (150, 300, and 1500 mOsm/kg).
Main Results:
- A significant majority (86%) of tested formulations were hyperosmolar (>400 mOsm/kg), with 70% exceeding 1500 mOsm/kg.
- Drug permeability was inversely proportional to osmolality; hyperosmolar samples exhibited lower permeability.
- Reduced permeability was observed with hyperosmolar formulations compared to those at 150 or 300 mOsm/kg.
Conclusions:
- Osmolality is a critical factor in neonatal oral drug administration.
- Hyperosmolar formulations pose a risk of gastrointestinal tract damage.
- Altering osmolality can significantly impact drug permeability and potentially alter bioavailability in neonates.
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.
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