Formulation and In Vivo Evaluation of Pediatric Epinephrine Sublingual Tablets

Grant Winners

Dean

Abstract

A fast-disintegrating sublingual tablet (FDST) of epinephrine (Epi) for the treatment of anaphylaxis in adults has been successfully evaluated in vitro and in vivo. The sublingual Epi dose was then successfully reduced by half using nanotechnology. This Epi FDST was recently licensed for clinical testing. For the purpose of developing a pediatric FDST (PFDST), the effect of the absorption medium's pH and penetration enhancers on Epi permeability were assessed to further optimize Epi sublingual permeability. Incorporating an alkalizing excipient and a penetration enhancer into FDSTs were able to significantly enhance Epi permeability through excised porcine sublingual membranes.

We hypothesized in this proposal that the incorporation of an alkalizing agent and a penetration enhancer along with flavoring agents to smaller FSDT suitable for pediatric administration is feasible and would result in bioequivalent pharmacokinetic parameters similar to the ones obtained following the intramuscular administration of pediatric Epi using auto-injectors.

The objectives of this proposal are to 1) formulate PFDSTs with a wide range of Epi (microcrystals) doses suitable for administration to children; 2) perform in vitro characterization of formulated and manufactured PFDST; and 3) evaluate the sublingual absorption of Epi from the developed PFDSTs.

Epi PFDST will be formulated, manufactured, and characterized according to our previously developed and published techniques and USP quality control tests. An alkalizing excipient and a penetration enhancer will be incorporated into the PFDST formulation based on results from our previous permeability studies. Dose-response animal studies will be performed, following IACUC approval, in a validated rabbit animal model for sublingual drug administration. PFDSTs containing various Epi doses will be administered to rabbits using our previously established and published technique using a controlled and randomized crossover study design. Placebo PFDSTs and Epi auto-injectors for children will be used as negative and positive controls, respectively. Blood samples will be collected at preselected time intervals, extracted, and analyzed using High Performance Liquid Chromatography (HPLC) system equipped with electrochemical detection according to our previously established and published methods. Pharmacokinetic parameters will be calculated using WinNonlin software and compared statistically using NCSS statistical analysis software at a significance level of p<0.05.

Upon completion of this project, the bioequivalent sublingual Epi doses using PFDSTs to the pediatric Epi auto-injectors will be determined. This novel Epi PFDST will provide a patient-friendly, non-invasive, convenient, and more accessible alternative dosage form for treatment of anaphylaxis in children.