The pediatric formulation
The Pediatric Praziquantel Consortium is working on a pediatric praziquantel formulation suitable for use in the target group of pre-school age children (3 months to 6 years). Compared to the praziquantel tablets commercially available today, this formulation will use small, orally dispersible tablets with an acceptable taste.
Getting started: a need for orally dispersible tablets
Soon after its formation, the Consortium collaborated with a panel of experts in schistosomiasis and pediatric formulations, at a meeting in Geneva in August 2012. The goal was to develop a target product profile (TPP) delineating both required and desirable formulation features.
The participants agreed on a need for orally dispersible tablets (ODTs) or fast dispersible tablets, administered as a single dose, to treat children aged 3 months to 6 years infected with S. mansoni and/or S. haematobium, the two most prevalent species of schistosomes. The tablets should be suitable both for individual case treatments and for mass treatment campaigns, and remain stable in a tropical climate, meeting WHO zone IVb stability requirements.
Astellas Pharma Inc. (Japan) took on the initial pediatric formulation development of Praziquantel for early clinical phases based on its pharmaceutical technologies. The pediatric tablets that Astellas Pharma developed are at about one-fourth the size of commercial 600 mg Praziquantel tablets and have orally dispersible property so that they can be taken with or even without water. Moreover, taste masking agents introduced to the pediatric formulation enabled children to swallow praziquantel more easily, which promises enhanced compliance and pharmacological effects. Apart from palatability, efficacy, safety and affordability of the new formulation, an appropriate shelf-life to withstand the challenging field temperature and logistics that prevail in Africa are the striven key characteristics.
After successful technology transfer from Astellas to Merck KGaA (Darmstadt, Germany) and Farmanguinhos (Brazil), both partners started manufacturing and supply of clinical trial material. Further formulation development and production process optimization activities were initiated simultaneously to support the later development phases.
Active pharmaceutical ingredient (API)
The existing PZQ formulation is a racemic mixture of levopraziquantel (L-PZQ) and dextropraziquantel (D-PZQ). Only one of these components is pharmacologically active: the L-PZQ enantiomer. The other component, D-PZQ has been shown to be inactive and contributes to the bitter taste that makes treating young children difficult.
Apart from using the current commercially available racemic praziquantel API to develop the pediatric formulation, one strategy employed by the Consortium is to use only the biologically active L-PZQ enantiomer. This is expected to decrease the amount of required dose and to decrease its severe bitter taste. To this end, a new manufacturing processes yielding only the L-PZQ enantiomer was successfully developed and scaled-up.