title: Nanoparticle-based topical ophthalmic formulation for sustained release of stereoisomeric dipeptide prodrugs of ganciclovir.
abstract: Poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NP) of Val-Val dipeptide monoester prodrugs of ganciclovir (GCV) including L-Val-L-Val-GCV (LLGCV), L-Val-D-Val-GCV (LDGCV) and D-Val-L-Val-GCV (DLGCV) were formulated and dispersed in thermosensitive PLGA-PEG-PLGA polymer gel for the treatment of herpes simplex virus type 1 (HSV-1)-induced viral corneal keratitis. Nanoparticles containing prodrugs of GCV were prepared by a double-emulsion solvent evaporation technique using various PLGA polymers with different drug/polymer ratios. Nanoparticles were characterized with respect to particle size, entrapment efficiency, polydispersity, drug loading, surface morphology, zeta potential and crystallinity. Prodrugs-loaded NP were incorporated into in situ gelling system. These formulations were examined for in vitro release and cytotoxicity. The results of optimized entrapment efficiencies of LLGCV-, LDGCV- and DLGCV-loaded NP are of 38.7 ± 2.0%, 41.8 ± 1.9%, and 45.3 ± 2.2%; drug loadings 3.87 ± 0.20%, 2.79 ± 0.13% and 3.02 ± 0.15%; yield 85.2 ± 3.0%, 86.9 ± 4.6% and 76.9 ± 2.1%; particle sizes 116.6 ± 4.5, 143.0 ± 3.8 and 134.1 ± 5.2 nm; and zeta potential -15.0 ± 4.96, -13.8 ± 5.26 and -13.9 ± 5.14 mV, respectively. Cytotoxicity studies suggested that all the formulations are non-toxic. In vitro release of prodrugs from NP showed a biphasic release pattern with an initial burst phase followed by a sustained phase. Such burst effect was completely eliminated when NP were suspended in thermosensitive gels with near zero-order release kinetics. Prodrugs-loaded PLGA NP dispersed in thermosensitive gels can thus serve as a promising drug delivery system for the treatment of anterior eye diseases.
authors.affiliation: a Division of Pharmaceutical Sciences, School of Pharmacy , University of Missouri - Kansas City , Kansas City , MO , USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: a Division of Pharmaceutical Sciences, School of Pharmacy , University of Missouri - Kansas City , Kansas City , MO , USA.
authors.forename: Sujay J
authors.initials: SJ
authors.lastname: Shah
authors.affiliation: a Division of Pharmaceutical Sciences, School of Pharmacy , University of Missouri - Kansas City , Kansas City , MO , USA.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Wang
authors.affiliation: a Division of Pharmaceutical Sciences, School of Pharmacy , University of Missouri - Kansas City , Kansas City , MO , USA.
authors.forename: Vibhuti
authors.initials: V
authors.lastname: Agrahari
authors.affiliation: a Division of Pharmaceutical Sciences, School of Pharmacy , University of Missouri - Kansas City , Kansas City , MO , USA.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Pal
authors.affiliation: a Division of Pharmaceutical Sciences, School of Pharmacy , University of Missouri - Kansas City , Kansas City , MO , USA.
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D060433:Administration, Ophthalmic; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D004151:Dipeptides / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions; D005128:Eye Diseases / Q000188:drug therapy*; D015774:Ganciclovir / Q000008:administration & dosage* / Q000737:chemistry; D005782:Gels / Q000008:administration & dosage* / Q000737:chemistry; D019344:Lactic Acid / Q000008:administration & dosage / Q000737:chemistry*; D008863:Microspheres; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011091:Polyesters / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011355:Prodrugs / Q000737:chemistry*
chemical_list: D003692:Delayed-Action Preparations; D004151:Dipeptides; D004655:Emulsions; D005782:Gels; D011091:Polyesters; D011355:Prodrugs; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C034792:valylvaline; D011092:Polyethylene Glycols; D015774:Ganciclovir
keywords: Ganciclovir prodrugs; HSV-1 keratitis; PLGA nanoparticles; thermosensitive gel; topical administration