EFFECT OF PARTICLES SIZE ON EPINEPHRINE SUBLINGUAL DIFFUSION FOR THE POTENTIAL FIRST-AID TREATMENT OF ANAPHYLAXIS: IN VITRO AND EX VIVO STUDY

Objective. To evaluate the in vitro and ex vivo diffusion of epinephrine microcrystals (Epi-MC) from our rapidly disintegrating sublingual tablets (RDSTs). Background. Epi 0.3 mg IM injection in the thigh is the drug of choice and the only available dosage form for the treatment of anaphylaxis in community settings. Previously, we showed that Epi 40 mg from RDST is bioequivalent to 0.3 mg IM Injection in our validated rabbit model. We hypothesized that substantial reduction in Epi particles size would significantly enhances its sublingual diffusion. Methods. Epi-MC were prepared by top-down technique using LV-1 Microfluidizer. RDSTs were manufactured by direct compression using our previously developed and published formulation. The in vitro and ex vivo diffusion of Epi 10, 20, and 40 mg RDSTs, and Epi-MC 10, 20 mg RDSTs (n=4) through dialysis and excised sublingual porcine mucosal membranes respectively, were evaluated using Franz cells. Epi 10 mg solution was used as a control. Results. Mean (SD) JAUC0- 90 of diffused Epi, Jmax, and Epi influx (J) from Epi 40 mg RDSTs (484,185±29,656μg/cm2/min, 7,508±569μg/cm2, 234±100μg/cm2/min, respectively) and Epi-MC 20 mg RDSTs (402,852±55,299μg/cm2/min, 6,727±736μg/cm2, 172±50μg/cm2/min, respectively) were not significantly different in vitro (p \u3e 0.05). Mean (SD) JAUC0-90 of diffused Epi, Jmax, and Epi influx (J) from Epi 40 mg RDSTs (264,556±182,820μg/cm2/min, 4,796±2,988μg/cm2, 106±82μg/cm2/min, respectively) and Epi-MC 20 mg RDSTs (211,369±116,025μg/cm2/min, 3,527±1,755μg/cm2, 91±55μg/cm2/min, respectively) were not significantly different ex vivo (p \u3e 0.05). Conclusion. The Epi-MC RDSTs improved Epi diffusion two-fold and have the potential to reduce the bioequivalent dose of sublingually administered Epi by 50%. Grants. This study was funded by the Health Professions Division Grant and the President\u27s Faculty Research & Development Grant, Nova Southeastern University