(T1030-06-35) A Systematic In Vitro Study to Evaluate Age-Appropriate Oral Administration Routes for Clinical Pediatric Delivery of an Oral Granules Formulation

Purpose: Oral granules are considered as the future of pediatric oral formulations. With diameters of less than 2.5 millimeter, they offer a more appropriate oral formulation platform for pediatric population due to improved swallowability, and  offer rapid and flexible dose adjustments via simply varying the numbers of oral granules used, hence are suitable for age-appropriate dosing and rapid dose change in early development pediatric programs. When dosing the oral granules to pediatric population in a clinical setting, to fulfill the needs of those unique requirements and limitations of pediatric populations from newborn to adolescent, the feasibility of the dosing approaches need to be established. Factors such as dose manipulation to improve dosing feasibility, considerations for in use handling, analytical risks and restrictions of food vehicles and dosing devices, impact of food on the formulation performance need to be well understood. In this work, a systematic in vitro study was designed, coupled with analytical method development, to evaluate the appropriate administration approaches for clinical pediatric dosing of an oral granules formulation. This study can also serve as benchmark for future oral granules programs when a systematic in-vitro study is in need.

Methods: The preferred/appropriate administration approach varies with each age group. For pediatric patients younger than 6 months, oral granules will be reconstituted in liquid food vehicle to form a suspension and dosed with oral syringes. A study was designed to demonstrate that the formulation can disperse well in a small amount of liquid vehicle, remain stable and recoverable after being exposed to the liquid food. Liquid food such as milk, formula, and juices were studied to understand the impact of pH range, viscosity, fat/protein content. For pediatric patients older than 6 months, oral granules will be mixed with soft food for a direct consumption. A study was designed to demonstrate that the formulation was not fully dispersed in soft food containing varying water content, and to study the impact of soft food on the recovery and chemically stability of the formulation. Pudding and apple sauce were selected to bracket pH range, water content, fat/protein content. For all ages of pediatric patients who are unable to swallow, oral granules will be reconstituted in water and delivered with enteral feeding tubes such as Nasogastric (NG) tubes.  A study was performed to demonstrate that by selecting age-appropriate liquid volume and NG tube sizes for respective doses of each age group, the formulation can be fully dispersed in a small amount of water, can readily pass through NG tube without recovery loss and without any high back pressure or clogging caused by large aggregation or buildup.

Results: In this work, in-use risks of the clinical dosing of a pediatric oral granule formulation were well-studied, and three oral administration approaches have been well evaluated. For administration of reconstituted oral granules in liquid food vehicle, the reconstitution behavior in different liquid food of varying fat/protein content and viscosity was well studied, and formulation can fully disperse into a suspension within 9-25min. Additionally, a higher recovery loss was observed when preparing the suspension in a smaller volume of highly viscous liquid vehicles, hence one rinse step is recommended to achieve >95% recovery. The chemical stability of the suspension was established in even the most acidic cranberry juice during the 2 hrs period, allowing liquid food that ranges from neutral to acidic pH to be selected. Additionally, the feasibility of administration of oral granules mixed with soft food vehicle was established. The integrity and chemical stability of oral granules remained after being exposed to up to 4 teaspoons of either apple sauce or pudding tested for 2hrs. A high recovery of >95% was achievable for lowest applicable dose which poses highest loss risk, indicating that the rinsing is not needed. Lastly, NG tubes aided administration of the reconstituted oral granules was also deemed feasible. Varying sizes of NG tubes were selected for suspensions prepared in a dose-dependent volume of water for respective dose of each age group to mitigate clogging risk and to provide age-appropriate dosing, including selecting 5-8Fr NG tubes for preterm or neonates, 8-10Fr tubes for kids of 2 years or younger, and >10Fr NG tubes for older kids and adolescents. The chemical stability was demonstrated, and a high recovery of >98% was achievable by including one rinsing step with water.

Conclusion: In this work, through a systematic study design and method development, 3 age-appropriate oral administration routes for clinical pediatric delivery of an oral granules formulations were evaluated. Findings from the study will be used to guide the clinical study design, provide detailed preparation and use instructions, and provide guidance for other oral granules programs when a systematic study is needed to select clinical dosing routes.