Transnasal Microneedle Delivery of Naloxone and Atipamezole for Rapid and Sustained Reversal of Xylazine-Opioid Overdose
Abstract
Xylazine, a non-opioid veterinary sedative, is increasingly detected in fentanyl-related overdose cases, contributing to severe respiratory depression, hypotension, and bradycardia. Naloxone (NAL), the standard opioid overdose reversal agent, is ineffective against xylazine toxicity, necessitating the development of alternative therapeutic approaches. Atipamezole (ATI), an alpha-2 adrenergic antagonist, has shown potential in reversing xylazine-induced effects in preclinical models. However, both NAL and ATI have short half-lives, requiring repeated administrations to maintain therapeutic efficacy. To address this limitation, we propose a transnasal drug delivery system utilizing dissolvable microneedles (MNs) for the rapid and sustained delivery of NAL and ATI. MN patches containing NAL (~21 mg) and ATI (10 mg), individually were fabricated using polyvinyl pyrrolidone and Soluplus® polymers, respectively. Mold-casting and vacuum compression molding techniques were employed for the fabrication. The patches were evaluated for ex vivo transnasal permeation across porcine nasal mucosa using Franz Diffusion Cells. The permeation of NAL from the MN patches across the mucosa was significantly higher as compared to the transdermal route over the entire 24 h test period; drug permeation was 40-, 94-, and 71-fold higher across the nasal mucosa than skin after 5, 15, and 60 minutes, respectively (p<0.05). ATI-loaded MNs successfully porated nasal mucosa and sustained drug release over 24 h. Additionally, pharmacokinetic (PK) evaluation in rats shows that transnasal MNs provide prolonged NAL retention compared to standard nasal spray formulations. The preliminary data presented here shows proof-of-concept that ATI and NAL MNs will successfully porate the nasal mucosa and are capable of both rapid and sustained delivery. However, future studies will focus on further optimizing the transnasal MN-based NAL/ATI delivery to offer a minimally invasive, field-deployable alternative for the treatment of xylazine-opioid overdose.
Start Time
16-4-2025 9:00 AM
End Time
16-4-2025 11:30 AM
Presentation Type
Poster
Presentation Category
Health
Student Type
Clinical Doctoral Student (e.g., medical student, pharmacy student)
Faculty Mentor
Ashana Puri
Faculty Department
Pharmaceutical Sciences
Transnasal Microneedle Delivery of Naloxone and Atipamezole for Rapid and Sustained Reversal of Xylazine-Opioid Overdose
Xylazine, a non-opioid veterinary sedative, is increasingly detected in fentanyl-related overdose cases, contributing to severe respiratory depression, hypotension, and bradycardia. Naloxone (NAL), the standard opioid overdose reversal agent, is ineffective against xylazine toxicity, necessitating the development of alternative therapeutic approaches. Atipamezole (ATI), an alpha-2 adrenergic antagonist, has shown potential in reversing xylazine-induced effects in preclinical models. However, both NAL and ATI have short half-lives, requiring repeated administrations to maintain therapeutic efficacy. To address this limitation, we propose a transnasal drug delivery system utilizing dissolvable microneedles (MNs) for the rapid and sustained delivery of NAL and ATI. MN patches containing NAL (~21 mg) and ATI (10 mg), individually were fabricated using polyvinyl pyrrolidone and Soluplus® polymers, respectively. Mold-casting and vacuum compression molding techniques were employed for the fabrication. The patches were evaluated for ex vivo transnasal permeation across porcine nasal mucosa using Franz Diffusion Cells. The permeation of NAL from the MN patches across the mucosa was significantly higher as compared to the transdermal route over the entire 24 h test period; drug permeation was 40-, 94-, and 71-fold higher across the nasal mucosa than skin after 5, 15, and 60 minutes, respectively (p<0.05). ATI-loaded MNs successfully porated nasal mucosa and sustained drug release over 24 h. Additionally, pharmacokinetic (PK) evaluation in rats shows that transnasal MNs provide prolonged NAL retention compared to standard nasal spray formulations. The preliminary data presented here shows proof-of-concept that ATI and NAL MNs will successfully porate the nasal mucosa and are capable of both rapid and sustained delivery. However, future studies will focus on further optimizing the transnasal MN-based NAL/ATI delivery to offer a minimally invasive, field-deployable alternative for the treatment of xylazine-opioid overdose.