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Chandrasekar Durairaj, Rajendra S. Kadam, John W. Chandler, Stephen L. Hutcherson, Uday B. Kompella; Nanosized Dendritic Polyguanidilyated Translocators for Enhanced Solubility, Permeability, and Delivery of Gatifloxacin. Invest. Ophthalmol. Vis. Sci. 2010;51(11):5804-5816. doi: 10.1167/iovs.10-5388.
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Dendrimeric polyguanidilyated translocators (DPTs) are nanosized novel dendrimers that efficiently translocate molecules across biological barriers. The purpose of this study was to develop a DPT that could serve as an ophthalmic delivery vehicle for gatifloxacin and to evaluate its in vitro and in vivo delivery after topical application.
The gatifloxacin (GFX) solubility-enhancing property of a six-guanidine group–containing dendrimer (g6 DPT) was investigated as a function of pH and dendrimer concentration. Mechanisms of drug interaction with the dendrimer were investigated by using isothermal titration calorimetry (ITC), Fourier-transformed infrared spectroscopy (FTIR), and nuclear magnetic resonance spectroscopy (NMR). Permeability of the dendrimer was assessed in human corneal epithelial cells (HCECs) and across isolated bovine sclera-choroid-RPE (SCRPE). In vitro efficacy of the dendrimer formulation was evaluated with a time-to-kill assay for methicillin resistant Staphylococcus aureus (MRSA). In vivo delivery of GFX in a dendrimer eye drop formulation was studied in New Zealand White rabbits after a single dose or multiple doses over 3 weeks. Drug levels in various ocular tissues were analyzed by liquid chromatography–tandem mass spectrometry (LC-MS/MS).
An optimized DPT-GFX formulation (final pH 5.9, no preservative) increased GFX solubility by fourfold. The dendrimer formed isotonically stable, nanosized (346-nm) complexes with GFX via ionic bond, hydrogen bond, and hydrophobic interactions. The dendrimer gained rapid entry into the HCECs (within 5 minutes) and increased the transport of GFX by 40% across the SCRPE in 6 hours. DPT-GFX exhibited a three times faster killing rate for MRSA when compared with GFX alone. In vivo administration of DPT-GFX (1.2% wt/vol) resulted in ∼13-fold, and ∼2-fold higher areas under the curve (AUCs) for tissue concentrations in conjunctiva and cornea, respectively, when compared with GFX (0.3%) after a single dose. Further, a single dose of DPT-GFX sustained aqueous humor and vitreous humor drug levels during the 24-hour study, with a t 1/2 of 9 and 32 hours, respectively. After multiple doses, similar advantages were seen with DPT-GFX.
The DPT forms stable complexes with GFX and enhances its solubility, permeability, anti-MRSA activity, and in vivo delivery, potentially allowing a once-daily dose regimen.
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