In Vivo Evaluation of Taste-Masked Fast-Disintegrating Sublingual Tablets of Epinephrine Microcrystals

Abstract

In community settings, IM injection of 0.3?mg epinephrine (Epi) using an auto-injector is the drug of choice for treatment of anaphylaxis. Previously, a taste-masking (TM) formulation of fast-disintegrating sublingual tablets (FDSTs) was developed in our lab. Also, Epi was micronized (Epi-MC) successfully and reduced the previously achieved bioequivalent sublingual Epi dose to 0.3?mg IM injection by half using non-taste-masked fast-disintegrating sublingual tablets (TM-FDSTs). Our objective for this study was to evaluate the sublingual absorption of Epi-MC using TM-FDST. These sublingual Epi tablets have potential for out-of-hospital treatment of anaphylaxis and are suitable for human studies. TM-FDSTs containing Epi-MC were manufactured by direct compression. The rate and extent of Epi absorption from our developed 20?mg Epi-MC-TM-FDSTs (n = 5) were evaluated in rabbits and compared to the previous result from 20?mg Epi-MC in non-TM-FDSTs and EpiPen? auto-injector. Blood samples were collected over 1?h, and Epi concentrations were measured using HPLC with electrochemical detection. Mean ? SEM AUC 0?1 h and C max from 20?mg Epi-MC-TM-FDSTs (733 ? 78?ng/ml/min and 30 ? 8?ng/ml) and 20?mg Epi-MC-non-TM-FDSTs (942 ? 109?ng/ml/min and 38 ? 4?ng/ml) were not significantly different (p > 0.05) from each other or from EpiPen? (592 ? 50?ng/ml/min and 28 ? 3?ng/ml) but were significantly higher (p < 0.05) than endogenous Epi after placebo FDSTs (220 ? 32?ng/ml/min and 8 ? 1?ng/ml). Mean ? SD T max was not significantly different (p > 0.05) among all formulations. Epi-MC-TM-FDSTs formulation improved Epi absorption twofold and reduced the required bioequivalent dose by 50%, similar to results obtained using non-TM-FDSTs. The incorporation of TM excipients did not interfere with the absorption of Epi-MC.