title: Thermosensitive hydrogel based on chitosan and its derivatives containing medicated nanoparticles for transcorneal administration of 5-fluorouracil.
abstract: A thermosensitive ophthalmic hydrogel (TSOH) - fluid at 4°C (instillation temperature), semisolid at 35°C (eye temperature), which coupled the dosing accuracy and administration ease of eyedrops with the increased ocular bioavailability of a hydrogel - was prepared by gelling a chitosan hydrochloride (ChHCl) solution (27.8 mg/mL) medicated with 1.25 mg/mL 5-fluorouracil (5-FU) with β-glycerophosphate 0.8 mg/mL. Polymer mixtures, where Ch was partially (10%, 15%, or 20%) replaced by quaternary ammonium-chitosan conjugates (QA-Ch) or thiolated derivatives thereof, were also used to modulate 5-FU-release properties of TSOH. Also, Ch-based nanoparticles (NPs; size after lyophilization and redispersion 341.5±15.2 nm, polydispersity 0.315±0.45, ζ-potential 10.21 mV) medicated with 1.25 mg/mL 5-FU prepared by ionotropic cross-linking of Ch with hyaluronan were introduced into TSOH. The 5-FU binding by TSOH polymers in the sol state was maximum with plain Ch (31.4%) and tended to decrease with increasing QA presence in polymer mixture. 5-FU release from TSOH with or without NPs was diffusion-controlled and linear in √t. The different TSOH polymers were compared on a diffusivity basis by comparing the slopes of √t plots. These showed a general decrease with NP-containing TSOH, which was the most marked with the TSOH, where Ch was 20% replaced by the derivative QA-Ch50. This formulation and that not containing NP were instilled in rabbits and the 5-FU transcorneal penetration was measured by analyzing the aqueous humor. Both TSOH solutions increased the area under the curve (0-8 hours) 3.5 times compared with the plain eyedrops, but maximum concentration for the NP-free TSOH was about 0.65 µg/mL, followed by a slow decline, while the NP-containing one showed a plateau (0.25-0.3 µg/mL) in a time interval of 0.5-7 hours. This is ascribed to the ability of this TSOH to control drug release to a zero order and that of NPs to be internalized by corneal cells.
authors.affiliation: Department of Pharmacy, University of Pisa.
authors.forename: Angela
authors.initials: A
authors.lastname: Fabiano
authors.affiliation: NEST, Istituto Nanoscienze CNR (CNR-NANO) and Scuola Normale Superiore, Pisa, Italy.
authors.forename: Ranieri
authors.initials: R
authors.lastname: Bizzarri
authors.affiliation: Department of Pharmacy, University of Pisa.
authors.forename: Ylenia
authors.initials: Y
authors.lastname: Zambito
mesh_terms: D000818:Animals; D001682:Biological Availability; D048271:Chitosan / Q000737:chemistry*; D003315:Cornea / Q000187:drug effects*; D003956:Dialysis; D065546:Drug Liberation; D005472:Fluorouracil / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005612:Freeze Drying; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D007091:Image Processing, Computer-Assisted; D007700:Kinetics; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D013696:Temperature
chemical_list: D009883:Ophthalmic Solutions; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D048271:Chitosan; D005472:Fluorouracil
keywords: 5-fluorouracil; chitosan multifunctional derivatives; chitosan nanoparticles; ocular delivery; thermosensitive hydrogels