Nanosuspension-loaded dissolving bilayer microneedles for hydrophobic drug delivery to the posterior segment of the eye.

Abstract

Intravitreal injections (IVT) are regarded as the gold standard for effective delivery of hydrophobic drugs to the back of the eye. However, as a highly invasive procedure, the injection itself may lead to poor patient compliance and severe complications. In this research work, a hybrid system of nanosuspensions (NS) and dissolving microneedles (MNs) was developed as an alternative to conventional hypodermic needles used in IVT for minimally invasive transscleral delivery of hydrophobic drugs. NS of a hydrophobic drug, triamcinolone acetonide (TA), were fabricated using a wet milling technique. TA NS optimised by central composite factorial design had a proven diameter of 246.65±8.55nm. After optimisation, TA NS were incorporated into MN arrays to form a bilayer structure by high-speed centrifugation. TA NS-loaded MNs were robust enough to pierce excised porcine sclera with insertion depth higher than 80% of the needle height and showed rapid dissolution (<3min). In contrast, the plain TA-loaded MNs exhibited poor mechanical and insertion performances and took more than 8min to be fully dissolved in the scleral tissue. Importantly, transscleral deposition studies showed that 56.46±7.76μg/mm2 of TA was deposited into the sclera after 5min of NS-loaded MN application, which was 4.5-fold higher than plain drug-loaded MNs (12.56±2.59μg/mm2). An ex vivo distribution study revealed that MN arrays could promote the transscleral penetration of hydrophobic molecules with higher drug concentrations observed in the deep layer of the sclera. Moreover, the developed TA NS-loaded MN array was biocompatible with ocular tissues, as demonstrated using the hens egg-chorioallantoic membrane assay and cytotoxicity test. The results presented here demonstrate that the hybrid system of NS and dissolving MNs can provide a novel and promising technology to alleviate retinal diseases in a therapeutically effective and minimally invasive manner.