According to FDA guidelines as listed in 21CFR 314.94 (a)(9)(iv), generic drug products mustdemonstrate pharmaceutical equivalence and bioequivalence to the reference listed drug (RLD) togain FDA approval. For generic ophthalmic solutions that are qualitatively (Q1) and quantitatively(Q2) the same as the RLD, bioequivalence is considered to be self-evident and a waiver for in vivostudies can be requested. Unlike solutions, ophthalmic suspensions/emulsions require an additionalstep of 'dissolution or 'release' before the drug is absorbed from the dosage form. Pharmaceuticallyequivalent suspensions or emulsions can have varying physicochemical properties either because ofthe differences introduced during manufacturing or formulation, which in turn may affect precornealresidence time, drug release, and ocular bioavailability. Therefore, FDA guidelines recommend thatophthalmic dosage forms such as suspensions and emulsions that are Q1 and Q2 the same as theRLD, bioequivalence must be demonstrated. However, there is sparse literature explaining how thedifferences in physicochemical properties of ophthalmic suspensions/emulsions result in differencesin ocular bioavailability. Moreover, suitable bioequivalence methods are lacking for studying genericophthalmic suspensions and emulsions. An investigation of the relationship between physicochemicalproperties and their effect on ocular bioavailability is crucial to formulate suspensions/emulsions thatare both pharmaceutically equivalent and bioequivalent. We hypothesize that key physicochemicalproperties such as particle/globule size, size distribution, viscosity, pH, and zeta potential caninfluence drug release, residence time, and stability of the suspensions or emulsions, and hence,bioavailability. To address this hypothesis, we will manufacture corticosteroid suspension andemulsion formulations with different physicochemical properties and assess their drug release,stability, and ex vivo delivery. Based on these studies, we will identify stable formulations and keyphysicochemical properties that result in significant differences in release and/or ex vivo topical oculardelivery. A physicochemical property that shows maximum differences in drug release and/or ex vivodelivery for each the suspension/emulsion formulations will be identified and assessed for in vivoprecorneal residence and ocular bioavailability in rabbits. We will employ a statistical model forpopulation pharmacokinetic analyses to calculate the bioequivalence of suspensions and emulsions.Through collaborative consultations with FDA counterparts that allow optimal design of studies, thisproject will identify key physicochemical properties of Q1 and Q2 suspension/emulsion dosage formsthat alter ocular drug bioavailability. The findings of this project would lay a foundation for developingguidelines for conducting bioequivalence studies for generic ophthalmic suspensions and emulsions.

Public Health Relevance

Generic ophthalmic suspensions and emulsions with qualitatively and quantitatively similar active and inactive ingredients (pharmaceutical equivalents) may not be equivalent with innovator product in terms of rate and/or extent of drug delivered to the eye (bioavailability), that is, not bioequivalent on the basis of differences in physicochemical properties. However, literature is sparse in establishing the relationship between physicochemical properties of ophthalmic suspensions/emulsions and drug bioavailability. Therefore, this project will investigate the influence of physicochemical properties of ophthalmic suspensions/emulsions on drug bioavailability. The findings will help the FDA in the long run in establishing guidelines for the development of generic ophthalmic suspensions/emulsions that are bioequivalent to reference or innovator product.

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 Colorado Denver
Schools of Pharmacy
United States
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