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  • Title: Controlled delivery of ganciclovir to the retina with drug-loaded Poly(d,L-lactide-co-glycolide) (PLGA) microspheres dispersed in PLGA-PEG-PLGA Gel: a novel intravitreal delivery system for the treatment of cytomegalovirus retinitis.
    Author: Duvvuri S, Janoria KG, Pal D, Mitra AK.
    Journal: J Ocul Pharmacol Ther; 2007 Jun; 23(3):264-74. PubMed ID: 17593010.
    Abstract:
    PURPOSE: The aim of this study was to develop a formulation for intravitreal delivery by dispersing ganciclovir (GCV)-loaded Poly(d,L-lactide-co-glycolide (PLGA) microspheres in thermogelling PLGA-PEG-PLGA gel and to study the mechanism of drug-release characteristics both in vitro and in vivo. METHODS: PLGA microspheres of GCV were prepared by the solvent evaporation method from Resomer RG 502H (D,L-lactide:glycolide::50:50; Mw, 8000 Da) and a 1:3 polymer blend of Resomer RG 502H and PLGA 6535 (D,L-lactide:glycolide::65:35; Mw, 45,000-75,000 Da). The prepared microspheres were dispersed uniformly and as a mixture (1:1) in 23% w/w of PLGA-PEG-PLGA aqueous gel solutions. GCV release in the aqueous medium was studied in vitro. A conscious rabbit microdialysis model with permanently implanted probes was selected as the method for investigating the vitreous GCV levels following an intravitreal administration of the formulation. RESULTS: The formulation prepared, by a physical mixture of microspheres, was prepared from Resomer RG 502H, and the polymer blend exhibited fairly constant in vitro GCV release profiles. The amounts of GCV entrapped in the microspheres were sufficient to administer therapeutically relevant doses in 60 microL of the formulation. The vitreal elimination half-life of GCV in the conscious rabbit microdialysis model was 6.45 +/- 0.83 h, with an apparent volume of distribution (V(z)) of 1.18 +/- 0.61 mL. A direct vitreous injection of GCV resulted in the maintenance of concentrations in the vitreous for only 54 h, whereas the gel formulation produced steady-state GCV levels in the vitreous for at least 14 days. CONCLUSIONS: PLGA microspheres containing GCV were prepared by two kinds of PLGA polymers and their blend (1:3). A formulation suitable for in vivo administration was prepared by dispersing GCV-loaded microspheres in a thermogelling PLGA-PEG-PLGA solution. An ideal in vitro release of encapsulated GCV was obtained by physically mixing microspheres prepared from different polymer blends prior to its dispersion in the thermogelling polymer. The formulation maintained mean vitreal concentrations of GCV at approximately 0.8 microg/mL for 14 days, whereas direct injections could maintain drug levels above 0.8 microg/mL for 54 h only.
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