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

Abstract

Issues: 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.

Approach: (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'.

Key findings: 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 (10-40 mg mL^-1 ) had been developed and tested. Sublingual bioavailability was very low (1%; relative to intravenous). Non-concentrated intranasal spray (1 mg mL^-1 ; 1 mL per nostril) had low bioavailability (11%). Concentrated intranasal formulations (≥10 mg mL^-1 ) had bioavailability of 21-42% (relative to intravenous) and 26-57% (relative to intramuscular), with peak concentrations (dose-adjusted C_max = 0.8-1.7 ng mL^-1 ) reached in 19-30 min (t_max ).

Implications: Exploratory analysis identified intranasal bioavailability as associated positively with dose and negatively with volume.

Conclusion: 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 0.1 mL 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].

Keywords: drug overdose; intranasal; naloxone; opioid; pharmacokinetics.