Ocular suspensions are used to deliver poorly soluble compounds as eye drops. About 20% of the topical ocular products are suspensions, but there are no established in vitro tests for bioequivalence studies. Therefore, generic products must undergo human testing with clinical end-points. Predictive, discriminative and robust in vitro dissolution test methods are needed to establish correlation between in vitro dissolution rates and ocular bioavailability. This one-year project aims to build in vitro - in vivo correlation (IVIVC) and toolbox to support bioequivalence guidance for ocular suspensions. The toolbox is based on in vitro release data and new dissolution test method, pharmacokinetic simulation models, and in vivo rabbit test data with ocular suspensions. The dissolution method mimics the conditions in the lacrimal fluid in vivo. Briefly, we will assess the effects of suspension properties (particle size, polymorphism, viscosity, pH, and buffer capacity) on the dissolution of dexamethasone, fluorometholone and indomethacin. The test formulations will be compared with commercial formulations in vitro and in vivo. The in vivo tests in rabbits include non-invasive capillary sampling of tear fluid and normal drug distribution studies to the ocular tissues. These analyses inform about the value of the dissolution test method and tear fluid sampling as alternatives to in vivo distribution studies. Finally, the in vitro dissolution data will be integrated to in vivo pharmacokinetic simulation model. The model allows sensitivity analyses and exploration of the in vitro to in vivo extrapolation (IVIVE). The project brings together the expertise and facilities in the laboratories at the Universities of Helsinki and University of Eastern Finland. This project will produce a method platform that combines in silico, in vitro and in vivo approaches to produce predictive, discriminative and robust tools for bioequivalence testing of ocular suspensions.

Public Health Relevance

Project?Narrative? ? This goal of this project is to develop new dissolution methods to support development and regulatory guidance of ocular suspension development. Such method would reduce the number of expensive clinical tests that are currently done during generic suspension development. The project will help FDA in the assessment of ocular suspensions. Therefore, this project will reduce the risks in the development of generic ocular suspensions. Successful completion of this project will facilitate ophthalmic science, industrial drug development, and practices of regulatory organizations at many levels.?

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1-SRC (99))
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University of Eastern Finland
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Deng, Feng; Ranta, Veli-Pekka; Kidron, Heidi et al. (2016) General Pharmacokinetic Model for Topically Administered Ocular Drug Dosage Forms. Pharm Res 33:2680-90