(T1330-11-76) Development of an Iontophoresis-Coupled Microneedle Skin Patch of Naloxone for Emergency Treatment of Opioid Overdose

Purpose: The use of naloxone (NAL) for opioid overdose treatment is limited mostly to the parenteral (intravenous, intramuscular, and subcutaneous) or intranasal route due to significant first-pass metabolism associated with oral delivery [1]. Injectables are painful and frequent administrations by the existing routes for patient stabilization due to the short half-life of NAL are needed. Alternative delivery systems would be beneficial if they provide a balance between sustained release properties and a comparable rapid release as is achievable with the available parenteral forms [2,3]. Thus, the goal of our study is to design a clinically viable polymeric microneedle (MN) patch for NAL

Methods: MNs of varying geometric dimensions were fabricated and characterized via dye-binding studies and imaging techniques (Table 1). In vitro skin permeation data for the best-performing patch was mathematically modeled and predictions on geometric parameters for a MN patch of comparable pharmacokinetic properties to parenteral and intranasal NAL as seen in the market were determined. From these evaluations, the need to devise ways to improve flux and amount of drug released from a patch per time was identified. We explored the influence of iontophoretically driving ionized drug content in MN patches on cumulative permeation of NAL from the best-performing MN patch. Through the MN patch, a current of 0.5 mA/cm² was applied on dermatomed porcine skin for a period of 4 h. To optimize the iontophoresis parameters, the influence of citro-phosphate buffer (pH 5) strength on the drug release profile was evaluated. Also, the impact of combining iontophoresis and higher drug loading was evaluated.

Results: MN characterization studies revealed that patches fabricated were of good mechanical integrity and skin penetration efficiency. A reduced lag time of about 5-15 min was observed with fabricated polymeric MN patches. From the polymeric MN patch P1 loaded with 50 mg/mL of NAL, a significant drug flux of 15.09 ± 7.68 𝜇g/cm²/h was observed in the first 1 h (p < 0.05) in comparison to passive delivery. Increasing MN length and density (P2 and P3) made a significant difference in the amount permeated and flux (p < 0.05) over 24 h (Figure 1). Mathematical modeling of in-vitro release from the best-performing patch (P3) revealed the significance of needle base diameter and needle count in improving systemic pharmacokinetics of NAL from the MN patches. With this approach, an optimized design of the patch that can reproduce the clinical pharmacokinetics of NAL obtained with commercial devices was predicted. Investigation on the influence of iontophoresis in improving flux from the P3 patch shows about a 2-fold (p < 0.05) increase in drug flux over 1 h. Variation of the buffer strength used in ionizing drug for iontophoresis-assisted delivery was found to impact drug release from patches (Figure 2). Iontophoretic patches loaded with 70 mg/mL drug produced greater (p < 0.05) cumulative drug release in 1h and 24 h over the 50 mg/ml patches given the same iontophoretic conditions.

Conclusion: Overall, drug flux seen over 1 h depicts the applicability of iontophoresis coupled polymeric MNs in delivering therapeutically significant amount of NAL for opioid overdose emergencies.

References: 1. Panchagnula R, Bokalial R, Sharma P, Khandavilli S. Transdermal delivery of naloxone: skin permeation, pharmacokinetic, irritancy and stability studies. Int J Pharm [Internet]. Int J Pharm; 2005 [cited 2021 Dec 21];293:213–23. Available from: https://pubmed.ncbi.nlm.nih.gov/15778059/
2. Puri A, Frempong D, Mishra D, Dogra P. Microneedle-mediated transdermal delivery of naloxone hydrochloride for treatment of opioid overdose. Int J Pharm. Elsevier B.V.; 2021;604:120739.
3. Tijani A, Dogra P, Peláez MJ, Wang Z, Cristini V, Puri A. Mechanistic modeling-guided optimization of microneedle-based skin patch for rapid transdermal delivery of naloxone for opioid overdose treatment. Drug Deliv Transl Res [Internet]. Drug Deliv Transl Res; 2022 [cited 2022 Dec 4]; Available from: https://pubmed.ncbi.nlm.nih.gov/35879533/

Table 1. Dimensions of fabricated NAL MN patches.

Figure 1. In vitro permeation profile of naloxone-loaded polymeric microneedle.

Figure 2: Permeation profile of Naloxone from iontophoresis coupled microneedle patches.