TY - JOUR
T1 - In vitro and in vivo evaluation of organic solvent-free injectable melatonin nanoformulations
AU - Molska, Alicja
AU - Nyman, Axel Karl Gottfrid
AU - Sofias, Alexandros Marios
AU - Kristiansen, Kåre Andre
AU - Hak, Sjoerd
AU - Widerøe, Marius
N1 - Funding Information:
The authors gratefully thank Catharina de Lange Davies for allowing to use the facilities at the Department of Physics at the Norwegian University of Science and Technology, and Francis Combes from the Department of Nutrition, Genetics and Ethology at Ghent University, Merelbeke, Belgium for technical support during the animal study. We thank Margareta Hammarlund-Udenaes at the Department of Pharmaceutical Biosciences, Uppsala University, for help with establishing the microdialysis method. This work was financially supported by the Norwegian University of Science and Technology, Faculty of Medicine and Health Sciences (AM and AKGN: PhD stipend), the Central Norway Regional Health Authority (Helse Midt-Norge; AMS: PhD stipend; SH: researcher grant) and the Norwegian Research Council. MR and animal studies were performed at the MR Core Facility and Comparative Medicine Core Facility at the Norwegian University of Science and Technology. The authors declare no competing interests.
Funding Information:
The authors gratefully thank Catharina de Lange Davies for allowing to use the facilities at the Department of Physics at the Norwegian University of Science and Technology , and Francis Combes from the Department of Nutrition, Genetics and Ethology at Ghent University, Merelbeke, Belgium for technical support during the animal study. We thank Margareta Hammarlund-Udenaes at the Department of Pharmaceutical Biosciences, Uppsala University, for help with establishing the microdialysis method. This work was financially supported by the Norwegian University of Science and Technology , Faculty of Medicine and Health Sciences (AM and AKGN: PhD stipend), the Central Norway Regional Health Authority (Helse Midt-Norge; AMS: PhD stipend; SH: researcher grant) and the Norwegian Research Council . MR and animal studies were performed at the MR Core Facility and Comparative Medicine Core Facility at the Norwegian University of Science and Technology .
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
KW - Brain microdialysis
KW - Hypoxic-ischemic brain injury
KW - Liposome
KW - Melatonin
KW - Nanoemulsion
KW - Nanomedicine
UR - http://www.scopus.com/inward/record.url?scp=85085392086&partnerID=8YFLogxK
U2 - 10.1016/j.ejpb.2020.05.003
DO - 10.1016/j.ejpb.2020.05.003
M3 - Article
C2 - 32439308
AN - SCOPUS:85085392086
VL - 152
SP - 248
EP - 256
JO - European Journal of Pharmaceutics and Biopharmaceutics
JF - European Journal of Pharmaceutics and Biopharmaceutics
SN - 0939-6411
ER -