Development and in vivo validation of phospholipid-based depots for the sustained release of bupivacaine

By direct deposition of the drug at the local site of action, injectable depot formulations – intended for treatment of a local disease or for local intervention – are designed to limit the immediate exposure of the active principle at a systemic level and to reduce the frequency of administration. To overcome known drawbacks in the production of some marketed phospholipid-based depots, here we propose to manufacture drug-loaded negatively charged liposomes through conventional technologies and to control their aggregation mixing a solution of divalent cations prior to administration. We identified phosphatidylglycerol (PG) as the most suitable phospholipid for controlled aggregation of the liposomes and to modulate the release of the anesthetic bupivacaine (BUP) from liposomal depots. In vivo imaging of the fluorescently-labelled liposomes showed a significantly higher retention of the PG liposomes at the injection site with respect to neutral ones. In situ mixing of PG liposomes with calcium salts significantly extended the area under the curve of BUP in plasma compared to the non-depot system. Overall, controlling the aggregation of negatively charged liposomes with divalent cations not only modulated the particle clearance from the injection site but also the release in vivo of a small amphipathic drug such as BUP.

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1,2-dipalmitoyl-sn-glycero-3-phosphate (DPPA), 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA) 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC); 1,2-distearoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (DSPG) (Lipoid, Ludwigshafen, Germany); cholesterol (Chol), bromphenolblue and sodium chloride (NaCl) (Sigma Aldrich, Schnelldorf, Germany); Bupivacaine (BUP) hydrochloride monohydrate was obtained from Fagron (Glinde, Germany); Bupivacaine-d9 was obtained from Cayman Chemical Company, USA. LC/MS grade acetonitrile, water, and formic acid 98 % – 100 % were purchased from Merck (Darmstadt, Germany); 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate salt (DiD) (Invitrogen, Carlsbad, USA); calcium chloride hexahydrate (CaCl2), magnesium chloride (MgCl2) hexahydrate and ammonium sulfate (NH4)2SO4 (Carl Roth, Karlsruhe, Germany); isoflurane (Attane™, Piramal Pharma, India); pentobarbital (Esconarkon®; Streuli Tiergesundheit SA, Switzerland). Gibco™ water for injection (WFI) Fischer scientific (Switzerland). Acetonitrile (ACN), methanol (MeOH), chloroform, tetrahydrofuran (THF) and trifluoroacetic acid (TFA) were obtained from Carl Roth (Karlsruhe, Germany); Purified and deionized water (H2O) was prepared with Smart2Pure3 (Thermo Scientific, Niederelbert, Germany).

Simone Aleandri, Lisa Rahnfeld, Despo Chatzikleanthous, Alessandra Bergadano, Claudia Bühr, Carlotta Detotto, Sara Fuochi, Kevin Weber-Wilk, Stefan Schürch, Peter van Hoogevest, Paola Luciani,
Development and in vivo validation of phospholipid-based depots for the sustained release of bupivacaine,
European Journal of Pharmaceutics and Biopharmaceutics, Volume 181, 2022, Pages 300-309,
ISSN 0939-6411,

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