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Antiretroviral Solid Drug Nanoparticles with Enhanced Oral Bioavailability: Production, Characterization, and In Vitro–In Vivo Correlation
Author(s) -
McDonald Tom O.,
Giardiello Marco,
Martin Philip,
Siccardi Marco,
Liptrott Neill J.,
Smith Darren,
Roberts Phill,
Curley Paul,
Schipani Alessandro,
Khoo Saye H.,
Long James,
Foster Alison J.,
Rannard Steven P.,
Owen Andrew
Publication year - 2014
Publication title -
advanced healthcare materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.288
H-Index - 90
eISSN - 2192-2659
pISSN - 2192-2640
DOI - 10.1002/adhm.201300280
Subject(s) - bioavailability , in vivo , nanomedicine , drug , pharmacokinetics , efavirenz , pharmacology , nanoparticle , materials science , chemistry , nanotechnology , human immunodeficiency virus (hiv) , medicine , antiretroviral therapy , virology , microbiology and biotechnology , viral load , biology
Nanomedicine strategies have produced many commercial products. However, no orally dosed HIV nanomedicines are available clinically to patients. Although nanosuspensions of drug particles have demonstrated many benefits, experimentally achieving >25 wt% of drug relative to stabilizers is highly challenging. In this study, the emulsion‐templated freeze‐drying technique for nanoparticles formation is applied for the first time to optimize a nanodispersion of the leading non‐nucleoside reverse transcriptase inhibitor efavirenz, using clinically acceptable polymers and surfactants. Dry monoliths containing solid drug nanoparticles with extremely high drug loading (70 wt% relative to polymer and surfactant stabilizers) are stable for several months and reconstitute in aqueous media to provide nanodispersions with z ‐average diameters of 300 nm. The solid drug nanoparticles exhibit reduced cytoxicity and increased in vitro transport through model gut epithelium. In vivo studies confirm bioavailability benefits with an approximately four‐fold higher pharmacokinetic exposure after oral administration to rodents, and predictive modeling suggests dose reduction with the new formulation may be possible.