International patent applications for non‐injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database

McDonald, Rebecca; Glende, Øyvind Danielsson; Dale, Ola; Strang, John

doi:10.1111/dar.12571

Cited by 14 publications

(19 citation statements)

References 25 publications

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“… was due probably to use of dilute (2 mg/5 ml) naloxone solution for injection which led to administration of high volumes—far in excess of what can be absorbed nasally without significant loss from the nasal cavity or post‐nasal drip. Low bioavailability of dilute nasal sprays is also seen in a recent conference report and data contained in patent registrations .…”

Section: Discussionmentioning

confidence: 79%

Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study

et al. 2017

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Background and AimsTake‐home naloxone can prevent death from heroin/opioid overdose, but pre‐provision is difficult because naloxone is usually given by injection. Non‐injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.n.) spray dose must be adequate but not excessive, and early absorption must be comparable to intramuscular (i.m.) injection. We report on the pharmacokinetics (PK) of a specially produced concentrated novel nasal spray. The specific aims were to: (1) estimate PK profiles of i.n. naloxone, (2) compare early systemic exposure with i.n. versus i.m. naloxone and (3) estimate i.n. bioavailability.DesignOpen‐label, randomized, five‐way cross‐over PK study.SettingClinical trials facility (Croydon, UK).ParticipantsThirty‐eight healthy volunteers (age 20–54 years; 11 female).Intervention and comparatorThree doses of i.n. (1 mg/0.1 ml, 2 mg/0.1 ml, 4 mg/0.2 ml) versus 0.4 mg i.m. (reference) and 0.4 mg intravenous (i.v.) naloxone.MeasurementsRegular blood samples were taken, with high‐frequency sampling during the first 15 minutes to capture early systemic exposure. PK parameters were determined from plasma naloxone concentrations. Exploratory analyses involved simulation of repeat administration.FindingsMean peak concentration (Cmax) values for 1 mg (1.51 ng/ml), 2 mg (2.87 ng/ml) and 4 mg (6.02 ng/ml) i.n. exceeded 0.4 mg i.m. (1.27 ng/ml) naloxone. All three i.n. doses rapidly achieved plasma levels > 50% of peak concentrations (T50%) by 10 minutes, peaking at 15–30 minutes (Tmax). For comparison, the i.m. reference reached Tmax at 10 minutes. Mean bioavailability was 47–51% for i.n. relative to i.m. naloxone. Simulation of repeat dosing (2 × 2 mg i.n. versus 5 × 0.4 mg i.m. doses) at 3‐minute intervals showed that comparable plasma naloxone concentrations would be anticipated.ConclusionsConcentrated 2 mg intranasal naloxone is well‐absorbed and provides early exposure comparable to 0.4 mg intramuscular naloxone, following the 0.4 mg intramuscular curve closely in the first 10 minutes post‐dosing and maintaining blood levels above twice the intramuscular reference for the next 2 hours.

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Section: Discussionmentioning

confidence: 79%

Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study

et al. 2017

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“…Subsequent examination of patent records located data confirming only poor bioavailability (approximately 10% of dose administered) [82] and recent direct pharmacokinetic comparison of the improvised kits vs. the new concentrated naloxone nasal spray formulations found bioavailability of only approximately 20% with the improvised kits vs. more than 40% with the new concentrated naloxone sprays [83]. Nevertheless, the evident successful reversals of opioid overdoses with these improvised kits [75–77] should raise questions about the dose necessary for layperson reversal which, in these instances, appears to have been achieved with much lower absorbed concentrations of naloxone.…”

Section: Pharmacokinetics and The Development Of New Non-injectable Nmentioning

confidence: 99%

“…Most importantly, these high-concentrate sprays deliver therapeutic doses (0.4–2.0 mg) in a single 0.1-mL spray, and a second spray gives a proportionate rise in serum concentrations. In contrast, dilute nasal spray (2 mg/2 mL) administered via the MAD only had 11–20% absolute bioavailability, implying that a sub-therapeutic dose of approximately 0.2–0.4 mg was delivered [74, 82, 83]. A recent study confirmed that, even after two administrations, dilute nasal spray (2 mg/2 mL, administered via a MAD) failed to achieve naloxone plasma concentrations comparable to concentrate nasal sprays (2 mg/0.1 mL, 4 mg/0.1 mL) at any time [83].…”

Section: Pharmacokinetics and The Development Of New Non-injectable Nmentioning

confidence: 99%

“…Despite somewhat different follow-up procedures in these studies, low rates for re-dosing (9%) were reported. This indicates that nasal systemic doses equivalent to 0.2–0.4 mg IV/IM [74, 82], which may be below the lowest World Health Organization-recommended starting dose of 0.4 mg [9], seem both safe and effective in most circumstances when given in medical settings (in contrast to layperson administration).…”

Section: Pharmacodynamics and Efficacy And Safety Of Naloxone For Thmentioning

confidence: 99%

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Take-Home Naloxone for the Emergency Interim Management of Opioid Overdose: The Public Health Application of an Emergency Medicine

Strang

McDonald

Campbell

et al. 2019

Drugs

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Naloxone is a well-established essential medicine for the treatment of life-threatening heroin/opioid overdose in emergency medicine. Over two decades, the concept of ‘take-home naloxone’ has evolved, comprising pre-provision of an emergency supply to laypersons likely to witness an opioid overdose (e.g. peers and family members of people who use opioids as well as non-medical personnel), with the recommendation to administer the naloxone to the overdose victim as interim care while awaiting an ambulance. There is an urgent need for more widespread naloxone access considering the growing problem of opioid overdose deaths, accounting for more than 100,000 deaths worldwide annually. Rises in mortality are particularly sharp in North America, where the ongoing prescription opioid problem is now overlaid with a rapid growth in overdose deaths from heroin and illicit fentanyl. Using opioids alone is dangerous, and the mortality risk is clustered at certain times and contexts, including on prison release and discharge from hospital and residential care. The provision of take-home naloxone has required the introduction of new legislation and new naloxone products. These include pre-filled syringes and auto-injectors and, crucially, new concentrated nasal sprays (four formulations recently approved in different countries) with speed of onset comparable to intramuscular naloxone and relative bioavailability of approximately 40–50%. Choosing the right naloxone dose in the fentanyl era is a matter of ongoing debate, but the safety margin of the approved nasal sprays is superior to improvised nasal kits. New legislation in different countries permits over-the-counter sales or other prescription-free methods of provision. However, access remains uneven with take-home naloxone still not provided in many countries and communities, and with ongoing barriers contributing to implementation inertia. Take-home naloxone is an important component of the response to the global overdose problem, but greater commitment to implementation will be essential, alongside improved affordable products, if a greater impact is to be achieved.

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“…2 The volumes administered were far above the recommended 0.1-0.2 mL level, ideal for systemic uptake of the drug through the nasal mucosa. 3 The bioavailability of injection solutions administered through the nose has been found to be as low as 11%, 4 implying that lowvolume solutions with higher concentrations Strengths and limitations of this study ► In this trial, an approved high-concentration/lowvolume formulation of naloxone designed for intranasal (IN) administration is investigated. ► Patients studied are treated for opioid overdose and primary endpoint, the return of spontaneous respiration is clinically relevant.…”

Section: Introductionmentioning

confidence: 99%

NTNU intranasal naloxone trial (NINA-1) study protocol for a double-blind, double-dummy, non-inferiority randomised controlled trial comparing intranasal 1.4 mg to intramuscular 0.8 mg naloxone for prehospital use

et al. 2020

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IntroductionIntranasal (IN) naloxone is widely used to treat opioid overdoses. The advantage of nasal administration compared with injection lies in its suitability for administration by lay people as it is needless. Approved formulations of nasal naloxone with bioavailability of approximately 50% have only undergone trials in healthy volunteers, while off-label nasal sprays with low bioavailability have been studied in patients. Randomised clinical trials are needed to investigate efficacy and safety of approved IN naloxone in patients suffering overdose. This study investigates whether the administration of 1.4 mg naloxone in 0.1 mL per dose is non-inferior to 0.8 mg intramuscular injection in patients treated for opioid overdose.Methods and analysisSponsor is the Norwegian University of Science and Technology. The study has been developed in collaboration with user representatives. The primary endpoint is the restoration of spontaneous respiration≥10 breaths/min based on a sample of 200 opioid overdose cases. Double-dummy design ensures blinding, which will be maintained until the database is locked.Ethics and disseminationThe study was approved by the Norwegian Medicines Agency and Regional Ethics Committees (REC: 2016/2000). It adheres to the Good Clinical Practice guidelines as set out by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.Informed consent will be sought through a differentiated model. This allows for deferred consent after inclusion for patients who have regained the ability to consent. Patients who are unable to consent prior to discharge by emergency services are given written information and can withdraw at a later date in line with user recommendations. Metadata will be published in the Norwegian University of Science and Technology Open repository. Deidentified individual participant data will be made available to recipients conditional of data processor agreement being entered.Trial registration numbersEudraCT Registry (2016-004072-22) and Clinicaltrials.gov Registry (NCT03518021).

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International patent applications for non‐injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database

Cited by 14 publications

References 25 publications

Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study

Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study

Take-Home Naloxone for the Emergency Interim Management of Opioid Overdose: The Public Health Application of an Emergency Medicine

NTNU intranasal naloxone trial (NINA-1) study protocol for a double-blind, double-dummy, non-inferiority randomised controlled trial comparing intranasal 1.4 mg to intramuscular 0.8 mg naloxone for prehospital use

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