Reflection on the Pharmaceutical Formulation Challenges Associated with a Paediatric Investigation Plan for an Off-Patent Drug

Abstract

In Europe, the development of pediatric medicines for new patent protected products is mandatory and applicants are required to submit a Paediatric Investigation Plan (PIP) to the regulatory authorities. The process is voluntary for off-patent medicines and despite the availability of incentives, there is still a huge unmet need for the development of off-patent pediatric medicines. The aim of the EU grant funded "Labeling of Enalapril from Neonates to Adolescents" (LENA) project is to develop a new pediatric dosage form of the off-patent drug enalapril, for the treatment of heart failure in patients aged from birth to 18 years. This article provides an overview of some of the key formulation challenges that were faced during the product development programme and PIP process, including selection of dosage form and excipients, methodology for administration of the product and evaluation of patient acceptability.

Drug Formulations: Standards and Novel Strategies for Drug Administration in Pediatrics

“…Other working groups have also investigated the suitability of mini‐tablets in the past few years . Thomson et al were the first group to publish the findings of administration of 1 placebo uncoated mini‐tablet (3‐mm diameter) to children aged 2 to 6 years.…”

“…They enable a precise dose adjustment and a specific dose titration of the API. Since 2015, the first orodispersible mini‐tablets containing 0.25 mg and 1.0 mg of enalapril maleate have been utilized within a multicenter clinical trial for the treatment of congenital heart failure in children of all age groups, from birth to adolescence …”

“…Other working groups have also investigated the suitability of mini-tablets in the past few years. [36][37][38][39] Thomson et al 40 were the first group to publish the findings of administration of 1 placebo uncoated minitablet (3-mm diameter) to children aged 2 to 6 years. The authors concluded that it was safe to use 3-mm mini-tablets in children aged 4 to 6 years because of their finding that only 46% of the 2-year-old children were able to swallow the mini-tablets, whereas up to 86% of the oldest children were capable of swallowing.…”

Relative Bioavailability of Enalapril Administered as Orodispersible Minitablets in Healthy Adults

“…[2][3][4][5] The pharmacopoeial form of enalapril is its maleate salt. 7 For this new galenic formulation, PK data in adults have to be provided in order to compare the bioavailability of enalapril in the new galenic formulation with that of the existing standard formulation, a conventional immediate-release tablet. 6 The aims of the LENA (Labeling of Enalapril from Neonates up to Adolescents) project are to address these shortcomings and to provide a basis for a future pediatric use marketing authorization of enalapril maleate by developing an age-appropriate orodispersible minitablet (ODMT) suitable for all pediatric subsets.…”

Pediatric Drug Development and Dosage Form Design

“…Subsequent articles in this theme issue address the pharmaceutical formulation challenges associated with a Pediatric Investigation Plan (Europe) or Pediatric Study Plan (United States). Various initiatives have been set up to promote and facilitate the preparation of better and safe medicines for children (3,4).…”