Extended-release of opioids using fentanyl-based polymeric nanoparticles for enhanced pain management

Abstract

Opioid receptor agonists form the backbone of pharmacological pain management. The use of these drugs through the current delivery routes poses significant health risks, including abuse, addiction, respiratory depression, and death. Those risks can be alleviated through controlled release of opioids at therapeutic levels for prolonged periods. Biodegradable polymeric nanoparticles (NPs) have been utilized as controlled drug delivery vehicles due to their unique ability of presenting different molecules of interest at their surfaces. In this study, we focus on extended-release of the synthetic opioid fentanyl analogs for improved pain management. To this end, we report the formulation of fentanyl-bearing polylactide and polyglicolide NPs (Fen-PLA/PLGA NPs) with controlled size, surface features, and antinociceptive properties. Biocompatible Fen-PLA/PLGA NPs were formulated through opioid initiators Fen-OH and Fen-Ary-EtOH, to prepare opioid chain-end functional biodegradable polymers. The results demonstrate that a single subcutaneous dose of the prepared NPs delivers therapeutically relevant doses for up to six days in a mouse model of acute nociception without unwanted burst-release. To further our aim of precise administration of the novel opioid delivery systems into skin tissue, we envisioned and fabricated dissolvable microneedle arrays (MNAs) that integrate the formulated NPs at their tips. Our novel biohybrids, which can be delivered precisely and minimally-invasively using dissolvable MNAs, may be utilized to formulate opioids towards preventing overdose and abuse.