Meropenem
(MER) is an effective broad-spectrum antibiotic currently
only available in the parenteral form requiring frequent drug preparation
and administration due to its extremely poor stability. The unavailability
of oral Meropenem is primarily due to its ultrapoor handling and processing
stability, hydrophilic nature that inhibits the passive diffusion
across the gastrointestinal (GI) epithelium, degradation in the harsh
gastric environment, and GI expulsion through enterocyte efflux glycoproteins.
In this regard, we have developed an oral drug delivery system that
confines MER into mesoporous silica nanoparticles (MSNs i.e, MCM-41
∼141 nm) using a novel liquid carbon dioxide (CO2) method. MER was efficiently encapsulated within pristine, phosphonate
(negatively charged MSN), and amine (positively charged MSN) modified
MSNs with loading capacity ranging between 25 wt %
and 31 wt %. Next, the MER-MCM-NH2 particles
were electrostatically coated with Eudragit S100 enteric polymer that
protected MER against gastric pH (pH 1.9) and enabled site-specific
delivery in the small intestine (pH 6.8). Cellular uptake results
in RAW 264.7 macrophage, Caco-2, and LS174T cells confirming the efficient
cellular uptake of nanoparticles in all three cell lines. More importantly,
the bidirectional transport (absorptive and secretory) of MER across
Caco-2 monolayer was significantly improved for both MSN-based formulations,
particularly MSNs coated with a polymer (Eud-MER-MCM-NH2) where permeability was significantly enhanced (∼2.4-fold)
for absorptive transport and significantly reduced (∼1.8-fold)
for secretory transport. Finally, in vitro antibacterial
activity [minimum inhibitory concentration (MIC)] and time-kill assay
against S. aureus and P. aeruginosa showed that drug-loaded nanoparticles were able to retain antibacterial
activity comparable to that of free MER in a solution at equivalent
dose. Thus, Eudragit-coated silica nanoparticles could offer a promising
and novel solution for oral delivery of Meropenem and other such drugs.