In vitro and in vivo evaluation of organic solvent-free injectable melatonin nanoformulations

Alicja Molska, Axel Karl Gottfrid Nyman, Alexandros Marios Sofias, Kåre Andre Kristiansen, Sjoerd Hak, Marius Widerøe

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Melatonin is a neurohormone with potenial therapeutic effects in many diseases including neonatal hypoxic-ischemic (HI) brain injury. Due to limited solubility in water there is currently no clinically available melatonin formulation for parenteral use. Clinical use of melatonin has thus relied on oral administration, which in many cases is hampered by low and variable bioavailability. In animal treatment studies of neonatal HI, this issue have been circumvented by using parenteral administration of melatonin dissolved in ethanol (EtOH) or dimethyl sulfoxide (DMSO), solvents that are potentially neurotoxic, especially to the newborn brain. Thus, there is an urgent need for a non-toxic injectable melatonin formulation. The aim of this study was to develop such a formulation comprised of melatonin and biocompatible lipid-based nanoparticles with improved melatonin bioavailability. We herein report the development and characterization of an injectable system composed of melatonin and liposomes (LP) or oil-in-water nanoemulsions (NE). Nanoparticle characterization confirmed physicochemical stability over a week and an improvement with respect to melatonin solubilization in water (2.6 mg/mL in our injectable system). Determination of the in vitro release kinetics showed a prolonged release when melatonin is solubilized in nanoparticles (T1/2: 81 min vs 50 min vs 26 min for melatonin-LP, melatonin-NE, and melatonin-EtOH respectively). The pharmacokinetic (PK) parameters were confirmed in vivo in adult rats as similar melatonin levels detected in blood and indicated higher bioavailability in brain after intravenous administration of melatonin nanoformulations (10 mg/kg) in comparison to the free-melatonin administration. In conclusion, we have developed an organic solvent-free injectable formulation for melatonin by utilizing FDA-approved components, as a safe alternative for facilitating the potential of melatonin against variety of pathological conditions.

Original languageEnglish
Pages (from-to)248-256
Number of pages9
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume152
DOIs
StatePublished - Jul 2020
Externally publishedYes

Keywords

  • Brain microdialysis
  • Hypoxic-ischemic brain injury
  • Liposome
  • Melatonin
  • Nanoemulsion
  • Nanomedicine

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