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Article Dans Une Revue Molecular Pharmaceutics Année : 2019

Nanoscale Lipophilic Prodrugs of Dexamethasone with Enhanced Pharmacokinetics

Résumé

⊥ Lip(Sys) 2 EA7357 Lipides, Systemes analytiques et biologiques, Univ. Paris-Sud, Univ. Paris-Saclay, ABSTRACT: The encapsulation of glucocorticoids, such as dexamethasone, in nanoparticles (NPs) faces two main issues: a low drug loading and the destabilization of the nanoparticle suspension due to drug crystallization. Here, we successfully formulated a prodrug of dexamethasone, dexamethasone palmitate (DXP), into nanoparticles stabilized by the sole presence of distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (DSPE-PEG 2000). Two formulation processes, nanoprecipitation and emulsion-evaporation, allowed the formation of stable nanoparticles. By adjusting the drug/lipid ratio and the DXP concentration, nanoparticles of DXP (DXP-NPs) with a size between 130 and 300 nm can be obtained. Owing to the presence of DSPE-PEG 2000 , a high drug entrapment efficiency of 98% w/w was reached for both processes, corresponding to a very high equivalent dexamethasone drug loading of around 50% w/w in the absence of crystallization upon storage at 4°C. The anti-inflammatory activity of DXP-NPs was preserved when incubated with macrophages activated with lipopolysaccharide. Pharmacokinetics parameters were evaluated after intravenous (IV) injection of DXP-NPs to healthy mice. The release of DXM from DXP-NPs in plasma was clearly controlled up to 18 h compared with the free drug, which was rapidly eliminated from plasma after administration. In conclusion, a novel type of nanoparticle combining the advantages of prodrugs and nanoparticles was designed, easy to produce with a high loading efficiency and leading to modified pharmacokinetics and tissue distribution after IV administration.
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Dates et versions

hal-02323659 , version 1 (22-10-2019)

Identifiants

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Mathilde Lorscheider, Nicolas Tsapis, Rosana Simón-Vázquez, Nicolas Guiblin, Noureddine Ghermani, et al.. Nanoscale Lipophilic Prodrugs of Dexamethasone with Enhanced Pharmacokinetics. Molecular Pharmaceutics, 2019, 16 (7), pp.2999-3010. ⟨10.1021/acs.molpharmaceut.9b00237⟩. ⟨hal-02323659⟩
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