Mechanistic modeling-guided optimization of microneedle-based skin patch for rapid transdermal delivery of naloxone for opioid overdose treatment

Abstract Naloxone, an FDA approved opioid inhibitor, used to reverse opioid overdose complications has up till date faced challenges associated with its delivery. Limitations include the use of invasive delivery forms and the need for frequent redosing due to its short half-life. Further, the use of the non-invasive commercially available intranasal form is faced with limitations such as nasal epistaxis and inability to use the intranasal channel due to nasal trauma common in addicts from frequent drug snorting. The goal of the current study was to design a rapidly dissolving polymeric microneedle (MN) patch with delivery and pharmacokinetic properties comparable to that seen with the commercially available NAL products, eliminating their highlighted limitations. Factors such as drug loading and polymer strength influenced the fabrication of the MNs. Compared to passive permeation, a reduced lag time of about 5-15 min was observed with a significant drug flux of 15.09 ± 7.68 g/cm 2 /h seen in the first 1 h (p<0.05) with an array of 100 needles (500 µm long). Increasing the MN length and density (no. of needles/unit area) made a significant difference in the amount permeated and flux (p<0.05), with latter being more influential. Further, through a mechanistic model of drug release from the patch, integrated with pharmacokinetic modeling, we optimized the design of the patch to reproduce in-silico the clinical pharmacokinetics of NAL obtained through commercial intramuscular and intranasal devices. Model simulations and analyses revealed the significance of needle base diameter and needle count in improving systemic pharmacokinetics of NAL.