Combined electrospun fibre-microneedle patches for enhanced transmucosal delivery of benzodiazepines and proteins

The oral mucosa is highly vascularised, which permits rapid drug uptake into the systemic circulation, avoiding first-pass metabolism for chemicals that penetrate the epithelial permeability barrier. Electrospun mucoadhesive patches have been developed for controlled drug delivery and although contact times and drug distribution are improved, transmucosal drug permeation is still limited to small lipophilic molecules. Incorporation of solid microneedles with an electrospun patch to physically disrupt the epithelial barrier whilst simultaneously delivering a payload, can overcome these issues whilst addressing the drug-loading limitations often experienced with microneedles. Here, we developed a mucoadhesive patch and microneedle composite for delivery of the benzodiazepine, midazolam hydrochloride, required for rapid, systemic delivery to treat status epilepticus and antigen-binding fragments (f(ab)), proteins too large to cross the epithelial permeability barrier. Solid polylactic acid microneedles were manufactured through reverse micromoulding, optimised for buccal permeation and imaged using optical coherence tomography. Electrospun mucoadhesive patches, loaded with midazolam hydrochloride or f(ab), were combined with the microneedles and permeation through tissue-engineered buccal mucosa quantified by high-performance liquid chromatography or immunoassay and imaged by fluorescence confocal microscopy. Microneedle-mediated patch delivery enhanced patch retention time, drug delivery rates and overall permeation when compared to patch-only controls, facilitating rapid delivery of time-sensitive midazolam within minutes, and a 15-fold increase in f(ab) permeation over 2 h, importantly delivering it through the epithelium into the underlying lamina propria. This study demonstrates that microneedle-mediated mucoadhesive patches can enhance transmucosal drug delivery for poorly-permeable drugs and holds significant potential when rapid, systemic drug delivery is required.