title: High-throughput in vitro drug release and pharmacokinetic simulation as a tool for drug delivery system development: application to intravitreal ocular administration.
abstract: In vitro estimation of release kinetics from drug delivery systems is needed in formulation development. Cost-effective methods of assessment for delivery systems are needed particularly in the case of biologicals and drug administration routes that are difficult to screen in vivo (e.g. intraocular drug delivery). As a proof-of-concept, we demonstrate here a practical high-throughput methodology to investigate in vitro drug release and predict resulting drug concentrations in the eye after intravitreal administration. 96-well plate based assay aided with robotic sampling was used to study release of eight model drugs of varying physicochemical properties (dexamethasone, vancomycin, alpha-lactalbumin, lysozyme, myoglobin, albumin, lactoferrin, human IgG) from twelve alginate microsphere formulations. The amount of drug released over a period of time was assessed by photometric and fluorescence methods. In vitro drug release rates obtained were used in pharmacokinetic simulations using one-compartment model of the vitreal cavity with anatomical volume of distribution and clearance estimates based on the literature precedence. An integrated approach of drug release screening and pharmacokinetic simulations can prove to be a useful methodology in guiding formulation development for ocular delivery in animal models. In general, the methodology has the potential to be a cost-effective tool for early stage drug delivery system discovery and development.
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, 00014, Finland. Electronic address: sanjay.sarkhel@helsinki.fi.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sarkhel
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, 00014, Finland.
authors.forename: Eva
authors.initials: E
authors.lastname: Ramsay
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, 00014, Finland.
authors.forename: Leena-Stiina
authors.initials: LS
authors.lastname: Kontturi
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, 00014, Finland.
authors.forename: Jonne
authors.initials: J
authors.lastname: Peltoniemi
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, 00014, Finland; School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Arto
authors.initials: A
authors.lastname: Urtti
mesh_terms: D000464:Alginates / Q000737:chemistry; D003198:Computer Simulation; D004337:Drug Carriers / Q000737:chemistry; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D057166:High-Throughput Screening Assays / Q000379:methods*; D058449:Intravitreal Injections; D008863:Microspheres; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry; D010599:Pharmacokinetics; D013499:Surface Properties
chemical_list: D000464:Alginates; D004337:Drug Carriers; D004364:Pharmaceutical Preparations
keywords: Alginate microspheres; Drug release; High-throughput; Ophthalmic drug delivery; Pharmacokinetics