Evaluation of Injectable Naloxone-Releasing Hydrogels

Abstract

The opioid epidemic in the United States is a serious public health crisis affecting over 1.7 million Americans. In the last two decades, almost 450 000 people have died from an opioid overdose, with nearly 20% of these deaths occurring in 2017 and 2018 alone. During an overdose, overstimulation of the μopioid receptor leads to severe and potentially fatal respiratory depression. Naloxone is a competitive μ-opioid-receptor antagonist that is widely used to displace opioids and rescue from an overdose. Here, we describe the development of a slow-release, subcutaneous naloxone formulation for potential management of opioid overdose, chronic pain, and opioid-induced constipation. Naloxone is loaded into self-assembling peptide hydrogels for controlled drug release. The mechanical, chemical, and structural properties of the nanofibrous hydrogel enable subcutaneous administration and slow, diffusion-based release kinetics of naloxone over 30 days in vitro. The naloxone hydrogel scaffold showed cytocompatibility and did not alter the β-sheet secondary structure or thixotropic properties characteristic of self-assembling peptide hydrogels. Our results show that this biocompatible and injectable self-assembling peptide hydrogel may be useful as a vehicle for tunable, sustained release of therapeutic naloxone. This therapy may be particularly suited for preventing renarcotization in patients who refuse additional medical assistance following an overdose.

Covalently Loaded Naloxone Nanoparticles as a Long-Acting Medical Countermeasure to Opioid Poisoning

“…24,25 More recent advances in this area have also focused on the development of novel, long-acting naloxone formulations with minimal withdrawal symptoms including a first-in-class oral nanoparticle preparation derived from a functional PLA-PEG-HCDA polyester copolymer 26 as well as a slow-release, subcutaneous naloxone dosage form based on self-assembling peptide hydrogels. 27 While these disclosures speak to the efficacy of their corresponding drug delivery systems toward epoxymorphinan-based opioid structures like morphine, none of the previously described methodologies had been evaluated against synthetic opioids. 28 In order to more fully explore the potential of novel antiopioid countermeasures, this study focused on assessing the in vivo efficacy of extended-release cNLX-NP technology against the more potent synthetic MOR agonist, fentanyl.…”

“…Given the widely recognized need for therapeutics that more effectively counteract synthetic opioid toxicity, several research groups have recently taken steps to address this critical issue in the context of extended-release MOR antagonist delivery systems. − Our laboratory has demonstrated the utility of covalently loaded naloxone nanoparticle ( c NLX-NP) technology as an effective, long-lasting MOR antagonist formulation against high dose morphine (10 mg/kg) . The subcutaneously administered covalent nanoparticles ( c NPs) were based on a biodegradable poly­(lactic acid) polymer scaffold and presented minimal indications of precipitated withdrawal in morphine-dependent mice relative to free naloxone. , More recent advances in this area have also focused on the development of novel, long-acting naloxone formulations with minimal withdrawal symptoms including a first-in-class oral nanoparticle preparation derived from a functional PLA-PEG-HCDA polyester copolymer as well as a slow-release, subcutaneous naloxone dosage form based on self-assembling peptide hydrogels . While these disclosures speak to the efficacy of their corresponding drug delivery systems toward epoxymorphinan-based opioid structures like morphine, none of the previously described methodologies had been evaluated against synthetic opioids …”

Nanotechnology-Enhanced Naloxone and Alternative Treatments for Opioid Addiction

“…However, these studies were restricted to in vitro testing, where the scaffolds exhibited a slow release for up to 30 days. 94 Similarly, microneedlemediated transdermal delivery systems, aiming to eliminate the need for frequent administrations were developed. 95 Developing innovative dosage forms is crucial, but it is equally important to consider pharmacokinetics, pharmacogenetics, and pharmacodynamics (3Ps) for the development of customized treatments.…”

“…In addition to nanoparticulate naloxone, other dosage forms, such as self-assembled injectable peptides, K2 and E2, were developed with properties similar to VEGF (vascular endothelial growth factor). However, these studies were restricted to in vitro testing, where the scaffolds exhibited a slow release for up to 30 days . Similarly, microneedle-mediated transdermal delivery systems, aiming to eliminate the need for frequent administrations were developed .…”

Materials and Cytokines in the Healing of Diabetic Foot Ulcers

“…MDP concentration, overall net charge, and stiffness are variables that can be tuned to modulate the release of these small molecule drugs, and may be exploited to optimize cargo delivery in vivo. [ 197 ] When loaded with drug, these hydrogels exhibit sustained localized release profiles at the initial injection site, a feature that can be exploited to reduce off‐target side effects, improve drug efficacy, and allow for lowered total dosages. [ 198 ] Crucial for all medical applications, the structure and function of proteins delivery by MDPs do not show significant or unwanted changes conferred by the hydrogel, indicating high biocompatibility of the material.…”