Oral bioavailability of microdoses and therapeutic doses of midazolam as a 2-dimensionally printed orodispersible film in healthy volunteers

Abstract

Abstract Purpose Use of two-dimensional (2D) printing technologies of drugs on orodispersible films (ODF) can promote dose individualization and facilitate drug delivery in vulnerable patients including children. We investigated midazolam pharmacokinetics after administration of 2D-printed ODF (EudraCT 2020-003984-24). Methods Midazolam doses of 0.03 mg and 3 mg were printed on an ODF using a 2D drug printer. We investigated the bioavailability of the two midazolam doses with ODF swallowed immediately (ODF-IS) or delayed after 2 min (ODF-DS) by comparing their pharmacokinetics with intravenous and oral midazolam solution in 12 healthy volunteers. Results The relative bioavailability of ODF-IS 0.03 mg was 102% (90% confidence interval: 89.4–116) compared to oral solution and for 3 mg 101% (86.8–116). Cmax of ODF-IS 0.03 mg was 95.5% (83.2–110) compared to oral solution and 94.3% (78.2–114) after 3 mg. Absolute bioavailability of ODF-IS 0.03 mg was 24.9% (21.2–29.2) and for 3 mg 28.1% (23.4–33.8) (oral solution: 0.03 mg: 24.4% (22.0-27.1); 3 mg: 28.0%, (25.0-31.2)). Absolute bioavailability of ODF-DS was significantly larger than for ODF-IS (0.03 mg: 61.4%; 3 mg: 44.1%; both p < 0.0001). Conclusion This trial demonstrates the tolerability and unchanged bioavailability of midazolam printed on ODF over a 100-fold dose range, proving the suitability of ODF for dose individualization. Midazolam ODF-IS AUC0−∞ in both doses was bioequivalent to administration of an oral solution. However, Cmax of the therapeutic dose ODF-IS missed bioequivalence by a clinically not relevant extent. Prolonged mucosal exposure increased bioavailability.