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Principal Investigator: Cesar Torres Luna
Organization: LYNTHERA CORPORATION
Fiscal Year: 2023
Award: $320,000
Funding agency: National Institute on Drug Abuse
PROJECT SUMMARY
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.
Terms: <1,2-Ethanediol><2-Hydroxyethanol><Actiq><Agitation><American><Animal Model><Animal Models and Related Studies><Behavioral><Bolus><Bolus Infusion><CNS Nervous System><Cell Survival><Cell Viability><Centers for Disease Control><Centers for Disease Control and Prevention><Centers for Disease Control and Prevention (U.S.)><Central Nervous System><Cessation of life><Charge><Circulation><Common Rat Strains><Competitive Binding><Contact Lenses><Data Reporting><Death><Dihydroxyethanes><Dose><Drug Delivery><Drug Delivery Systems><Drugs><Duragesic><ED care><ER care><Effectiveness><Electrostatics><Emergency Care><Emergency Department care><Emergency Room care><Emergency Therapy><Emergency health care><Emergency healthcare><Emergency medical care><Emergency treatment><Encapsulated><Esters><Ethanediols><Ethylene Glycols><Exhibits><Eye diseases><Fentanest><Fentanyl><Fentyl><Formulation><Gel><Half-Life><Heart><Hydrogels><Implant><In Situ><In Vitro><Individual><Infumorph><Injectable><Intermediary Metabolism><Kadian><Kinetics><Legal patent><Lipids><Lytotoxicity><MS Contin><MSir><Marketing><Mechanics><Medication><Metabolic Processes><Metabolism><Methylnaloxone><Modeling><Monoethylene Glycol><Morphia><Morphine><Musculoskeletal Pain><N-Methylnaloxone><NCHS><Naloxone><Narcan><Narcanti><Nasal><Nasal Passages Nose><National Center for Health Statistics><Nature><Nausea><Neuraxis><Nose><O element><O2 element><Opiate Addiction><Opiate Antagonist><Opiate Dependence><Opiate Receptors><Opiate receptor antagonist><Opiates><Opioid><Opioid Antagonist><Opioid Receptor><Opioid receptor antagonist><Oramorph><Oramorph SR><Outcome><Overdose><Oxygen><Oxymorphone><Pain Control><Pain Therapy><Pain management><Patents><Patients><Peripheral Nervous System><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Phase Transition><Phentanyl><Physiologic><Physiological><Polymers><Property><Psychomotor Agitation><Psychomotor Excitement><Psychomotor Hyperactivity><Psychomotor Restlessness><Pulmonary Edema><Rat><Rats Mammals><Rattus><Respiratory Depression><Respiratory System, Nose, Nasal Passages><Restlessness><Risk><Roxanol><SBIR><Seizures><Small Business Innovation Research><Small Business Innovation Research Grant><Solid><Statex SR><Stimulus><Subcutaneous Injections><Surface><Sweating><Swelling><Symptoms><System><Technology><Temperature><Therapeutic><Toxic effect><Toxicities><United States><United States Centers for Disease Control><United States Centers for Disease Control and Prevention><United States National Center for Health Statistics><Ventilatory Depression><Viscosity><Withdrawal Symptom><antinociception><antinociceptive><aqueous><blood pressure elevation><competitively bound><copolymer><cost><craving><crystallinity><cytotoxicity><data representation><data representations><depressed breathing><depression of breathing><dosage><drug/agent><elevated blood pressure><ethylene glycol><experience><eye disorder><fabrication><hydrophilicity><improved><improved outcome><in vivo><increase in blood pressure><increased blood pressure><lipid based nanoparticle><lipid nanoparticle><local drug delivery><lung edema><mechanic><mechanical><mechanical properties><model of animal><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ocular disease><ocular disorder><ophthalmopathy><opiate consumption><opiate crisis><opiate deaths><opiate drug use><opiate intake><opiate mortality><opiate overdose><opiate related overdose><opiate use><opiate use disorder><opiate withdrawal><opioid addiction><opioid consumption><opioid crisis><opioid deaths><opioid dependence><opioid dependent><opioid detox><opioid detoxification><opioid drug overdose><opioid drug use><opioid epidemic><opioid induced overdose><opioid intake><opioid intoxication><opioid medication overdose><opioid mortality><opioid overdose><opioid overdose death><opioid poisoning><opioid related death><opioid related overdose><opioid toxicity><opioid use><opioid use disorder><opioid withdrawal><overdose death><overdose fatalities><pain treatment><polymer><polymeric><prevent><preventing><protective effect><response><side effect><subcutaneous><subdermal><subdermal injection><synthetic opiate><synthetic opioid><therapeutic candidate>