Development of midazolam/γ-cyclodextrin orodispersible films using direct powder extrusion 3D printing: A novel approach to inclusion complex and drug delivery systems formulation.

Direct printing of pharmaceutical powders allows the creation of personalized paediatric dosage forms, such as orodispersible films (ODFs). In this study, we present an optimized protocol to prepare midazolam (MDZ)/γ-cyclodextrin (γ-CD) inclusion complex-loaded ODFs using the innovative direct powder extrusion 3D printing technique (DPE). ODFs were formulated with a polymer blend consisting of polyethylene oxide and hydroxypropyl methylcellulose, in the presence or without γ-CD. An in-depth analytical investigation using NMR and LC-MS spectrometry demonstrated that MDZ/γ-CD inclusion complex could form in situ during the printing process. ODFs with the preformed inclusion complex and MDZ alone were also prepared and characterized in terms of drug loading, morphology, disintegration, drug release, and mucoadhesion. ODFs containing either the in situ-formed or preformed inclusion complex were equivalent and exhibited superior performance compared to films without γ-CD. The use of γ-CD was particularly advantageous in enhancing the film disintegration and MDZ dissolution. MDZ-loaded ODFs were successfully developed using DPE to produce thin, fast-dissolving films that are particularly suitable for paediatric populations. This approach facilitated the production of personalized dosage forms suitable for emergency scenarios, including sedation, acute anxiety, and epilepsy and enabled the creation of beneficial molecular interactions that would typically require additional pharmaceutical processes.