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

Abstract

Non-injectable naloxone formulations are being developed for opioid overdose reversal, but only limited data have been published in the peer-reviewed domain. Through examination of a hitherto-unsearched database, we expand public knowledge of non-injectable formulations, tracing their development and novelty, with the aim to describe and compare their pharmacokinetic properties. (i) The PatentScope database of the World Intellectual Property Organization was searched for relevant English-language patent applications; (ii) Pharmacokinetic data were extracted, collated and analysed; (iii) PubMed was searched using Boolean search query '(nasal OR intranasal OR nose OR buccal OR sublingual) AND naloxone AND pharmacokinetics'. Five hundred and twenty-two PatentScope and 56 PubMed records were identified: three published international patent applications and five peer-reviewed papers were eligible. Pharmacokinetic data were available for intranasal, sublingual, and reference routes. Highly concentrated formulations (10-40mgmL-1 ) had been developed and tested. Sublingual bioavailability was very low (1%; relative to intravenous). Non-concentrated intranasal spray (1mgmL-1 ; 1mL per nostril) had low bioavailability (11%). Concentrated intranasal formulations (≥10mgmL-1 ) had bioavailability of 21-42% (relative to intravenous) and 26-57% (relative to intramuscular), with peak concentrations (dose-adjusted Cmax =0.8-1.7ngmL-1 ) reached in 19-30min (tmax ). Exploratory analysis identified intranasal bioavailability as associated positively with dose and negatively with volume. We find consistent direction of development of intranasal sprays to high-concentration, low-volume formulations with bioavailability in the 20-60% range. These have potential to deliver a therapeutic dose in 0.1mL volume. [McDonald R, Danielsson Glende Ø, Dale O, Strang J. International patent applications for non-injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database. Drug Alcohol Rev 2017;00:000-000].