(M1530-01-05) Rapidly Dissolving Polymeric Microneedle Skin Patch of Naloxone for Opioid Overdose Treatment

Purpose: Worldwide opioid abuse affects over 16 million people. A major cause of death in abusers is overdosing. Typically, this results mainly from the depression of the respiratory system by the action of opioids on the mu receptor. Naloxone (NAL) is an opioid inhibitor that reverses its respiratory depressing effect. The use of this drug is limited mostly to invasive delivery: intravenous (IV), intramuscular (IM) and subcutaneous (SC) due to its significant hepatic clearance and poor oral bioavailability (2%) [1,2]. These routes are painful and worse still is the need for frequent injections for patient stabilization due to the short half-life of NAL. Non-invasive intranasal forms exist but this is fraught with a couple of limitations such as nasal damage and epistaxis [1]. The need for alternatives without these limitations is thus evident. The feasibility of the use of metal microneedles (MNs) for the transdermal delivery of NAL was demonstrated in-vitro and through in-vitro in-vivo correlation modeling in our lab [1]. The goal of the current study was to design a rapidly dissolving polymeric MN patch with delivery and pharmacokinetic (PK) properties comparable to that seen with the commercially available NAL products, eliminating their highlighted limitations.

Methods: NAL loaded rapidly dissolving polyvinyl pyrrolidone-based MN arrays (500 µm, 100 needles) were fabricated by the mold casting technique. The permeation profile of fabricated MNs over a predetermined time was assessed via an in-vitro permeation set up using porcine ear skin. Samples were analyzed via HPLC. To improve on drug flux and amount permeated, the effect of increasing MN length and density (no. of needles/unit area) were assessed by fabricating MNs 300 µm longer and those with density double that of the initial array. More detailed description of the different dimensions of MNs fabricated are shown in Table 1. 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.

Results: Factors such as drug load and polymer strength influenced needle fabrication. Drug crystallization was observed with drug concentrations over 50mg/ml, indicating the saturation limit of Naloxone in the polymer strength used. Compared to passive permeation, a reduced lag time of about 15 min was observed with a significant drug flux of 15.09 ± 7.68 < ![if !msEquation] >< ![if !vml] >< ![endif] >< ![endif] >g/cm²/h seen in the first 1 h (p < 0.05) (Figure 1). Increasing MN length and density made a significant difference in the amount permeated and flux (p < 0.05) (Figure 2). Pharmacokinetic modeling simulations and analyses revealed the significance of needle base diameter and needle count in improving systemic pharmacokinetics of NAL, with this approach, an optimized design of the patch that can reproduce the clinical PK of NAL was obtained with commercial devices was predicted.

Conclusion: Overall, drug flux seen over 1 h depicts the applicability of fabricated needles in opioid overdose emergencies with delivery properties comparable to that of IM and IN delivery. Increasing needle density and/or patch area was found to be of greater significance.

References: 1. Puri A, Frempong D, Mishra D, Dogra P. Microneedle-mediated transdermal delivery of naloxone hydrochloride for treatment of opioid overdose. International Journal of Pharmaceutics. 2021;604:120739. doi:10.1016/j.ijpharm.2021.120739
2. Gao X, Brogden NK. Development of Hydrogels for Microneedle-Assisted Transdermal Delivery of Naloxone for Opioid-Induced Pruritus. J Pharm Sci. 2019;108(11):3695-3703. doi:10.1016/J.XPHS.2019.08.025

Acknowledgements: Prashant Dogra and Maria J. Peláez thank Dr. Javier Ruiz Ramírez for helpful scientific discussions with mathematical model development. Ashana Puri would like to thank Dr. Hiep Nguyen for useful discussions pertaining to microneedle fabrication protocol.


Table 1. Dimensions of fabricated NAL MN patches


Figure 1 (a) 24 h permeation profile of passive delivery and all fabricated MNs (b) Average cumulative amount permeated per sq.cm over 1 h of NAL, comparing passive delivery and P1 (c) P1 and P2 (d) P1 and P3 (p < 0.05, *= significant difference at individual time points)


Figure 2. In vitro over 1 h permeation flux of NAL with passive delivery, P1, P2, and P3 (p < 0.05 ***=significantly higher than passive, **=significantly higher than passive and P1, “n.d.” no significant difference