New openable softgel use in oral: need for suitable forms in pediatrics and proof of concept

The need for commercial specialties adapted to the pediatric population remains well-known problem. Moreover, some of the existing adapted specialties expose children to excipients with a known effect or endocrine disruptors. The best pharmaceutical form would be a single dose device containing a liquid dose, without exposure to problematic excipients. An openable softgel use as an oral delivery device could fulfil these conditions. The objectives are therefore to determine the lack of specialties and potential exposure to problematic excipients, to create a list of compounds to formulate in the new form, and to establish the proof-of-concept for the oral use of an openable softgel capsule.

A review was carried out using the PRISMA method. The active pharmaceutical ingredients (API) cited in the selected publications have been identified. The EMA and WHO lists of essential API were combined with the first results. This produced a list sorted by occurrence. Among the analyses carried out on this list was an analysis of the problematic excipient composition of adapted specialties available on the French market. A first API (vitamin K, dose of 2 mg) was used to carry out the proof of concept for the new Paediatrix^® form (supplied by Paediatis^® Pharma). A stability and dose accuracy study were carried out using existing specialties as comparators: 10 mg/mL ampoule with a 1 mL syringe for multidose modality and 2 mg/0.2 mL ampoule with the supplied administration device for single dose modality (Cheplapharm^®). To do so, a stability indicating HPLC-UV method has been fully developed and validated.

392 APIs are included in the list, with top 5 in decreasing order: acetaminophen, propranolol, spironolactone, prednisolone and omeprazole. Among this list of APIs, 58.7% have no child-friendly form on the French market at all. Furthermore, of those which had at least one form suitable for children, 57.0% had at least one excipient with known effect. The top 3 excipients with known effect of the 131 formulations suitable for children were: methyl Para hydroxybenzoate (35.9%), sorbitol (30.5%) and sucrose (29.8%). Of all the excipients identified in the formulations analyzed, 31.4% were preservatives. The stability-indicating HPLC-UV method has been fully validated. The capsule showed better accuracy than the other modalities (p value = 0.72 one-tailed comparison Wilcoxon test below the theoretical value). The pre-prepared doses of commercial specialties did not enable vitamin K to be preserved above 90% of the initial dose for more than 2 hours.

This new form seems promising, because it could satisfy an identified and well-known need, particularly in terms of administration safety (ready-to-administer form) and non-exposure to preservatives, which are mostly endocrine disruptor. Challenge remains for the formulation of more hydrophilic API which require a class III and IV lipid-based formulation.

Keywords: administration, oral ; capsule ; pediatrics ; health services needs and demand