Opioid overdose was responsible for less than 10,000 deaths in 1999 but increased to nearly 50,000 by 2019. Data reported by the Center for Diseases Control and Prevention's National Center for Health Statistics showed that the 12-month period leading up to April 2021 had more than 100,000 drug overdose deaths and over 74,000 opioid overdose deaths. Naloxone, derived from oxymorphone, decreases the effectiveness of opioids by competitively binding to µ-opioid receptors in the central nervous system. Even though naloxone has greatly helped to reduce the number of opioid overdose deaths, individuals with opioid use disorder often experience re-narcotization when treated with naloxone because of its relatively short half-life. Moreover, high or repeated doses of naloxone are needed to counteract its rapid metabolism with higher circulating naloxone levels, which can initiate precipitated opioid withdrawal symptoms in individuals with opioid addiction. This Phase I SBIR project will develop a cationic pH/temperature-sensitive hydrogel embedded with naloxone-encapsulated anionic solid lipid nanoparticles (SLNs) as an in situ gelling subcutaneous formulation for the long-lasting release of naloxone. The proposed hydrogel technology comprises a aqueous solution of a tri-block copolymer conjugated with poly(ethylene glycol) that once injected into the patient transitions to a gel under physiological conditions. Our approach will provide a double-encapsulation strategy for naloxone that would give an additional level of control over the spatial and temporal release while improving its stability. The nanoparticle-hydrogel composite will exploit the cationic nature of a stimuli-sensitive tri-block copolymer hydrogel system to achieve strong electrostatic interactions with naloxone loaded anionic SLNs, which would prolong the degradation and circulation of SLNs and therefore the activity of the loaded cargo. The first aim is the formulation and characterization of anionic naloxone-loaded SLNs dispersed in a cationic pH/temperature sensitive tri-block copolymer hydrogel system. This includes analyzing the properties of the hydrogel system such as the sol-gel phase diagram, viscosity, mechanical properties, swelling capacity, in vitro release kinetics, in vitro enzymatic degradation, and stability. The second aim evaluates the in vivo efficacy of the hydrogel system in a fentanyl- induced rat model of opioid overdose. A successful outcome will be a therapeutic candidate with sustained naloxone release which also can prevent fentanyl-induced respiratory depression and antinociception for up to 48 h following a single subcutaneous dose.
Public Health Relevance Statement: PROJECT NARRATIVE In the United States from 1999 to 2018, over 750,000 persons have died from a drug overdose; most of which involved an opioid. We propose to develop a cationic pH/temperature-sensitive hydrogel embedded with anionic solid lipid nanoparticles as an in situ gelling injectable formulation for the long-lasting release of naloxone, an opioid antagonist that is used to reverse the effects of an opioid overdose. The prolonged release of naloxone would be beneficial in preventing re-narcotization during emergency care and in relieving peripheral nervous system symptoms of opioid use without interfering with the pain management effects.
Project Terms: blood pressure elevation; elevated blood pressure; increase in blood pressure; increased blood pressure; Circulation; antinociception; antinociceptive; fabrication; Pain Control; Pain Therapy; pain treatment; Pain management; Competitive Binding; competitively bound; Cell Survival; Cell Viability; Centers for Disease Control and Prevention (U.S.); Centers for Disease Control; Centers for Disease Control and Prevention; United States Centers for Disease Control; United States Centers for Disease Control and Prevention; Charge; Contact Lenses; Data Reporting; data representation; data representations; Cessation of life; Death; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Emergency treatment; Emergency Therapy; Esters; ethylene glycol; 1,2-Ethanediol; 2-Hydroxyethanol; Dihydroxyethanes; Ethanediols; Ethylene Glycols; Monoethylene Glycol; Exhibits; Eye diseases; eye disorder; ocular disease; ocular disorder; ophthalmopathy; Fentanyl; Actiq; Duragesic; Fentanest; Fentyl; Phentanyl; Gel; Half-Life; Heart; In Vitro; Subcutaneous Injections; subdermal injection; Kinetics; Lipids; Marketing; Metabolism; Intermediary Metabolism; Metabolic Processes; Morphine; Infumorph; Kadian; MS Contin; MSir; Morphia; Oramorph; Oramorph SR; Roxanol; Statex SR; Musculoskeletal Pain; Naloxone; Narcan; Narcanti; Persons; United States National Center for Health Statistics; NCHS; National Center for Health Statistics; Nausea; Nose; Nasal; Nasal Passages Nose; Respiratory System, Nose, Nasal Passages; opioid withdrawal; opiate withdrawal; opioid detox; opioid detoxification; Overdose; Oxygen; O element; O2 element; Oxymorphone; Methylnaloxone; N-Methylnaloxone; Legal patent; Patents; Patients; Polymers; polymer; polymeric; Pulmonary Edema; lung edema; Rattus; Common Rat Strains; Rat; Rats Mammals; Opioid Receptor; Opiate Receptors; Risk; Seizures; Sweating; Swelling; Technology; Temperature; United States; Viscosity; Drug Delivery; Drug Delivery Systems; Psychomotor Agitation; Psychomotor Excitement; Psychomotor Hyperactivity; Psychomotor Restlessness; Restlessness; Agitation; Injectable; Withdrawal Symptom; dosage; improved; Surface; Solid; Encapsulated; Phase; Physiologic; Physiological; Peripheral Nervous System; Stimulus; Respiratory Depression; depressed breathing; depression of breathing; Ventilatory Depression; Individual; Opiates; Opioid; Therapeutic; Nature; Electrostatics; Mechanics; mechanic; mechanical; subcutaneous; subdermal; In Situ; System; Opiate Addiction; Opiate Dependence; opioid addiction; opioid dependence; opioid dependent; American; copolymer; cytotoxicity; Lytotoxicity; experience; hydrophilicity; Animal Model; Animal Models and Related Studies; model of animal; aqueous; Hydrogels; Toxic effect; Toxicities; novel; Modeling; craving; Property; response; Central Nervous System; CNS Nervous System; Neuraxis; Phase Transition; Effectiveness; preventing; prevent; Dose; Symptoms; Bolus Infusion; Bolus; in vivo; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Emergency Care; ED care; ER care; Emergency Department care; Emergency Room care; Emergency health care; Emergency healthcare; Emergency medical care; Behavioral; cost; local drug delivery; nano particle; nano-sized particle; nanosized particle; nanoparticle; Outcome; protective effect; Implant; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; overdose fatalities; overdose death; crystallinity; opiate use disorder; opioid use disorder; Formulation; improved outcome; opiate consumption; opiate drug use; opiate intake; opiate use; opioid consumption; opioid drug use; opioid intake; opioid use; mechanical properties; therapeutic candidate; Opiate Antagonist; Opiate receptor antagonist; Opioid receptor antagonist; Opioid Antagonist; opiate crisis; opioid crisis; opioid epidemic; opiate overdose; opiate related overdose; opioid drug overdose; opioid induced overdose; opioid intoxication; opioid medication overdose; opioid poisoning; opioid related overdose; opioid toxicity; opioid overdose; opiate deaths; opiate mortality; opioid deaths; opioid overdose death; opioid related death; opioid mortality; lipid based nanoparticle; lipid nanoparticle; synthetic opiate; synthetic opioid; side effect
