A Biopredictive In Vitro Approach for Assessing Compatibility of a Novel Pediatric Hydrocortisone Drug Product within Common Pediatric Dosing Vehicles

Abstract

Purpose The objective of the present work was to screen whether a novel pediatric hydrocortisone granule formulation can be co-administered with common food matrices and liquids. Methods Pediatric hydrocortisone granules were studied using a biopredictive in vitro approach. Experiments included an in situ chemical compatibility study of active ingredient and drug product with liquid dosing vehicles and soft foods commonly ingested by infants, pre-school- and school children. Drug solubility and stability experiments in the different vehicle types and, drug release/dissolution experiments mimicking age-related pediatric gastric conditions after administering the hydrocortisone granules together with the dosing vehicles and after different exposure/mixing times were performed. Results In the simulated dosing scenarios applied in dissolution experiments, in vitro dissolution in gastric conditions was rapid and complete. Results of the chemical compatibility/stability studies indicated that mixing with the different dosing vehicles studied should not be an issue regarding drug degradation products. Conclusions A novel in vitro approach ensuring a proper risk assessment of the use of dosing vehicles in the administration of pediatric dosage forms was established and applied to a novel pediatric hydrocortisone drug product. The studied dosing vehicles were shown to not alter performance of the drug product and are thus considered suitable for administration with hydrocortisone granules.

Stability of Hydrocortisone in Oral Powder Form Compounded for Pediatric Patients in Japan

“…The impurity assay showed that impurity B (cortisone) and G (hydrocortisone-21-aldehyde) were found after 120 days of storage. This observation was similar to the findings reported by Wollmer et al [ 17 ]. They have also found small concentrations of impurity B and G, all of which were lower than the USP and EP limits.…”

“…Although several stakeholders have already expressed their support in developing pediatric formulations [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ], an urgent need exists to improve the standardization in compounded enteral formulations to increase the safety and compliance of preparations made in Japan. To date, most tested hydrocortisone formulations for pediatric patients are liquids [ 17 , 32 ]; however, the stability and safety of solid oral compounded products have not been reported, except for hydrocortisone mini-tablet forms [ 12 ].…”

“…Hydrocortisone (target substance, purity > 99.0%) was purchased from Tokyo Chemical Industry (Tokyo, Japan). Impurities of hydrocortisone were procured from Sigma-Aldrich (Tokyo, Japan) as follows: prednisolone (impurity A), cortisone (impurity B), hydrocortisone acetate (impurity C), 6β-hydroxy-hydrocortisone (impurity D), 6-dehydrocortisol (impurity E), Reichstein substance S (impurity F), hydrocortisone-21-aldehyde (impurity G), 7α-hydroxy-hydrocortisone (impurity H), 14α-hydroxy-hydrocortisone (impurity I), and hydrocortisone dimer (impurity N) [ 16 , 17 , 18 , 19 ] ( Figure 1 ). Lactose monohydrate (extra-fine crystal lactose hydrate “Hoei”, Pfizer, Tokyo, Japan) was used as a diluting agent.…”

“…Previously described hydrocortisone impurities (A, B, C, D, E, F, G, H, I, N) were identified with UV detection at 254 nm [ 17 ]. Their retention times were collected for potential identification and quantification during stability studies.…”

Hydrocortisone granules in capsules for opening (Alkindi) as replacement therapy in pediatric patients with adrenal insufficiency

“…Sprinkling medication onto food can alter its pharmacokinetic characteristics. To demonstrate hydrocortisone granules in capsules for opening compatibility with child appropriate fluids and soft foods; in vitro and in vivo studies were conducted [52][53][54]. In vitro data and modeling confirmed that pediatric patient exposure to hydrocortisone from the granules is unlikely to be impacted by co-administration with water, breast, cow or formula milk, orange, apple or tomato juice, or soft foods such as apple sauce or yogurt.…”