Injectable peptide-based hydrogel formulations for the extended in vivo release of opioids

To overcome drawbacks related to repeated opioid administration during the treatment of chronic pain, several controlled-drug delivery systems of opioids have been designed. In order to address some of the limitations of the existing systems, injectable peptide-based hydrogels represent a promising alternative. This work reports on the design and synthesis of short amphipathic peptide-based hydrogels as controlled-drug delivery systems for opioids. Based on the lead sequence H-FEFQFK-NH2, a new set of peptide hydrogelators was designed including beta-homo and D-amino acids, mainly aiming at enhancing proteolytic resistance of the peptides, and which hypothetically allows an extension of the drug release period. After self-assembly in aqueous media, the resulting hydrogels were characterized by dynamic rheometry, cryogenic transmission electronic microscopy and their cytotoxicity was assessed. The cry-oTEM images of drug loaded hydrogels show the association of microcrystals of the loaded drug along the axes of the fibres, suggesting that the peptide fibres play a key-role as nucleating site for the drug crystals. Hydrogelators devoid of cytotoxicity were considered for further in vivo evaluation. Upon encapsulation of morphine and 14-methoxymetopon, two opioid analgesics, the applicability of the peptide hydrogels as controlled-drug delivery platforms was validated in vivo using the mouse tail-flick test. A sustained antinociceptive effect was observed after subcutaneous injection of the drug loaded gels and, in comparison with the lead sequence H-FEFQFK-NH2, novel sequences revealed extension of the in vivo antinociception up to 72-96 h post injection. (C) 2017 Elsevier Ltd. All rights reserved.