Development of Novel Excipient Screening Platform for Paediatric Oral Formulations

Abstract

The paediatric regulation came into effect in 2007 and aimed to improve the health of children aged 0-17 in Europe by facilitating the development and availability of medicines. However, despite the regulatory incentives and recent advances regarding paediatric formulation development over the last two decades, the lack of integrated and suitable paediatric formulations still remains. The struggle in developing paediatric medicines is owing to many reasons including incomplete paediatric clinical datasets, and the lack of translatable dosage form development technologies and standardised formulation development guidance available. There is also a limitation of paediatric medicine development in that knowledge and principles from adult studies are directly applied to paediatric patients and treatment preferences and acceptability are often ignored. The current formulation development programme for children is based on an empirical, iterative process of trial and error, which results in significant delays in medicines reaching the market. The overarching hypothesis of the proposal is that the development of an evidence based decision making tool will facilitate accelerated product development, meeting both patient group and regulatory requirements.

Model drug compounds were selected from the inventory of the needs for paediatric medicines (EMA), with the selection criteria taking account of properties such as low aqueous solubility, stability challenges and absence of paediatric friendly dosage forms. Carvedilol is a weakly basic biopharmaceutical class II model drug. Orodispersible mini-tablets (ODMTs) were successfully developed, characterised and evaluated in paediatric specific biorelevant media, followed by long term stability studies. Furosemide exhibits extremely low aqueous solubility and sensitivities to light, air and acidic conditions. Two variations (preservative free and preservative) of an ethanol free oral solution of furosemide were prepared and evaluated for preservative efficacy and stability. Famotidine is a BCS class III drug, exhibiting high solubility-low permeability. Two strengths (2 mg and 10 mg) of famotidine ODMTs were developed, followed by evaluation in biorelevant media and stability studies. Regarding nifedipine formulation development as an age-appropriate formulation, for the first time, an attempt to integrate PBPK modelling to a paediatric specific formulation development approach to clinically inform an appropriate dosage form design and strategy was made. A 5 mg sustained release mini-tablet was successfully developed, with duration of release extending over 24 h and an informed optimised dosing strategy of 450 μg/kg twice daily.

Formulation developments within this research resulted in the development and validation of a novel decision making tool that informs appropriate paediatric dosage form designs and formulation optimisation opportunities by integrating fundamental pharmaceutics with analytical methods and a paediatric specific, bottom up formulation development approach. Additionally, the screening platform considers product scale up and manufacturing feasibility and embeds principles of Quality by design (QbD) and quality target product profile (QTPP). Application of this novel decision making tool accelerates and de-risks the development of paediatric oral formulations and directs the formulation scientist to develop a product which is clinically efficacious and patient centric.

Date of Award	Sept 2022
Original language	English
Awarding Institution	Aston University
Supervisor	Afzal-Ur-Rahman Mohammed (Supervisor) & Daniel Kirby (Supervisor)