Epinephrine for the treatment of anaphylaxis: do all 40 mg sublingual epinephrine tablet formulations with similar in vitro characteristics have the same bioavailability?

Abstract

Epinephrine autoinjectors are underutilized in the first aid emergency treatment of anaphylaxis in the community; so non-invasive sublingual epinephrine administration is being proposed. In order to determine the effect of changing excipients on the bioavailability of sublingual epinephrine, four distinct fast-disintegrating epinephrine 40 mg tablet formulations, A, B, C and D, were manufactured using direct compression. All formulations were evaluated for tablet hardness (H), disintegration time (DT) and wetting time (WT). In a prospective 5-way crossover study, four sublingual formulations and epinephrine 0.3 mg i.m. as a control were tested sequentially in a validated rabbit model. Blood samples were collected before dosing and at intervals afterwards. Epinephrine plasma concentrations were measured using HPLC-EC. All tablet formulations met USP standards for weight variation and content uniformity, and resulted in similar mean H, DT and WT (n=6). The area under the curve (AUC), maximum concentration (C(max)) and time at which C(max) was achieved (T(max)) did not differ significantly after the sublingual administration of formulation A and epinephrine 0.3 mg i.m. The AUC after B, C and D were significantly lower (p<0.05) than after epinephrine 0.3 mg i.m. These results suggest that the selection of excipients used in these tablet formulations can affect the bioavailability of sublingually administered epinephrine.

An Electronic Tongue: Evaluation of the Masking Efficacy of Sweetening and/or Flavoring Agents on the Bitter Taste of Epinephrine

“…A fast disintegrating SL tablet formulation of E has been successfully formulated in our laboratory (6). The bioavailability profile of this E formulation is similar to that of an IM injection of E (7,8). The SL tablet formulation has not been approved for administration to humans.…”

Dissolution Testing of Sublingual Tablets: A Novel In Vitro Method

“…Data represent means of at least three replicates tablets which have similar in vitro DTs. In previous in vitro and in vivo studies, E SL tablet formulations with similar DTs had different bioavailabilities (18). Although the DT test ensures tablet breakdown into smaller particles, it does not evaluate the rate and extent of the API release, and in general, disintegration has been proved to be a poor indicator of bioavailability (36).…”

“…In addition, an in vitro dissolution method should be capable of detecting and discriminating among minor changes in SL tablet formulations (16). Due to the short residence time within the SL cavity, we propose that the minor changes in formulations might have major effects on the rate and the extent of SL absorption (17,18). It is therefore mandatory to develop a dissolution method that meets these requirements.…”

Sublingual Diffusion of Epinephrine Microcrystals from Rapidly Disintegrating Tablets for the Potential First-Aid Treatment of Anaphylaxis: In Vitro and Ex Vivo Study

“…Epi auto-injectors such as EpiPen ® (Mylan Inc, Basking Ridge, NJ) and Auvi-Q™ (Sanofi-Aventis, Bridgewater, NJ) are widely recommended for the treatment of anaphylaxis in community settings; however, they are not necessarily carried or used by patients at risk for anaphylaxis in the community (1)(2)(3)(4). An alternative Epi formulation, rapidly disintegrating sublingual tablets (RDSTs), is being developed for the potential use in community settings (5)(6)(7)(8) and might offer the advantages of a wider dose range of Epi beyond the 0.15-and the 0.3-mg fixed doses currently available in EpiPen ® and Auvi-Q™ auto-injectors, and enhanced stability of Epi in a solid dosage form that might reduce the need for annual replacement associated with the use of auto-injectors containing Epi in aqueous solution (9).…”

“…The sublingual route is a promising alternative route for Epi administration (5)(6)(7)(8). Drugs absorbed sublingually bypass metabolic conversion in the gastrointestinal tract and hepatic first-pass metabolism and reach the systemic circulation in a pharmacologically active form (5)(6)(7)(8)10).…”