title: Solid lipid nanoparticles as promising tool for intraocular tobramycin delivery: Pharmacokinetic studies on rabbits.
abstract: Eye drops are widely accepted as formulations for targeting the anterior segment notwithstanding their limitations in terms of bioavailability. The unique structure of the eye requires specially-designed formulations able to favor the pharmacokinetic profile of administered drugs, mainly minimizing the influence of ocular barriers. Nanotechnology-based delivery systems lead to significant technological and therapeutical advantages in ophthalmic therapy. The aim of the present study was to determine whether tobramycin as ion-pair incorporated in mucoadhesive Solid Lipid Nanoparticles (SLN) reaches the inner parts of the eye favoring drug activity. After technological characterization of the tobramycin entrapped SLN formulation (Tobra-SLN), a pharmacokinetic study in rabbits after topical instillation and intravenous administration of the formulation has been carried out. In addition, the intracellular activity of Tobra-SLN formulation against phagocytosed Pseudomonas aeruginosa was investigated. The SLN were spherical in shape, and showed a hydrodynamic diameter of about 80nm, a negative zeta potential (-25.7mV) with a polydispersity index of 0.15, representative of a colloidal dispersion with high quality, characterized by an unimodal relatively narrow size distribution. As demonstrated by FTIR and DSC, tobramycin ion-pair could be concentrated into lipid inner core of SLN, without interaction with the stearic acid, thus promoting a slow and constant drug release profile in the dissolution medium. Surprisingly, the drug concentration was significantly higher in all ocular tissues after ocular and intravenous administration of Tobra-SLN formulation with respect to reference formulations and only Tobra-SLN allowed the penetration of drug into retina. Furthermore, the use of Tobra-SLN resulted in both higher intraphagocytic antibiotic concentrations in polymorphonuclear granulocytes and greater bactericidal activity against intracellular Pseudomonas aeruginosa, probably due to the ability of Tobra-SLN to penetrate either into phagocytic cells, or alternatively to cross bacterial barrier. The present study broadens the knowledge on the use of SLN as carriers for ocular drug delivery to the posterior chamber and might open new avenues for treatment of ocular infections, representing a strategy to overcome the microbial resistance.
authors: Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors: Patrizia
authors: P
authors: Chetoni
authors: Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors: Susi
authors: S
authors: Burgalassi
authors: Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors: Daniela
authors: D
authors: Monti
authors: Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors: Silvia
authors: S
authors: Tampucci
authors: Department of Public Health and Paediatrics, Microbiology Division, University of Turin, Via Santena 9, 10126 Turin, Italy.
authors: Vivian
authors: V
authors: Tullio
authors: Department of Public Health and Paediatrics, Microbiology Division, University of Turin, Via Santena 9, 10126 Turin, Italy.
authors: Anna Maria
authors: AM
authors: Cuffini
authors: Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125 Turin, Italy.
authors: Elisabetta
authors: E
authors: Muntoni
authors: Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125 Turin, Italy.
authors: Rita
authors: R
authors: Spagnolo
authors: Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125 Turin, Italy.
authors: Gian Paolo
authors: GP
authors: Zara
authors: Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125 Turin, Italy. Electronic address: roberta.cavalli@unito.it.
authors: Roberta
authors: R
authors: Cavalli
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D065546:Drug Liberation; D004352:Drug Resistance, Microbial; D005128:Eye Diseases / Q000188:drug therapy*; D006098:Granulocytes / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D008297:Male; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry*; D009504:Neutrophils / Q000187:drug effects; D010316:Particle Size; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011817:Rabbits; D012160:Retina / Q000187:drug effects; D013696:Temperature; D014031:Tobramycin / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000900:Anti-Bacterial Agents; D004337:Drug Carriers; D008055:Lipids; D014031:Tobramycin
keywords: Antimicrobial; DSC; Ocular pharmacokinetic; Rabbits; Solid lipid nanoparticles; Tobramycin