Currently there is no specific compendial assay for dissolution for topical ophthalmic emulsion formulations. Precorneal drainage, dilution of the formulations with tears and the effect of blinking on rheological properties of the formulation affect the efficacy of the topical Therapeutic efficacy of the ophthalmic emulsions. The drug in the emulsion system may exist in different phases (solubilized form, micelle form and emulsion form). Generic products prepared with the same ingredients &their concentration as that of the brand product may have different physicochemical properties and thereby altered therapeutic efficacy because of the differences in manufacturing process. It is therefore critical to develop appropriate dissolution test that can discriminate the product and formulation variables and also predict the bioequivalency of the generic products in in vivo conditions. Such quality control tests would not only help the product development process, but also facilitates the product approval. To date there are only three FDA approved ophthalmic emulsions are in the market (Restasis?; Durezol? and Refresh Endura?). The FDA requires the generics to have the same active ingredient at the same concentration, manufactured according to FDA standards, but inactive ingredients are allowed to differ. However bioequivalency in the eye tissue (cornea or aqueous humor) or efficacy to the brand are not required for ophthalmic generics. Hence clinical studies are rarely conducted and therefore safety and efficacy information on the generics is lacking. Durezol? (topical emulsion of Difluprednate) is used for the treatment of postoperative inflammation &pain and its patent rights expire in 2018. Difluprednate (DFBA) is insoluble in water and its systemic absorption was shown to be very limited. Hence it will be difficult establishing in vivo bioequivalence of the future generic formulations of DFBA. It is therefore critical to develop in vitro testing methods of bioequivalence for DFBA, and the in vitro tests should be able to discriminate the drug products and be able predict the clinical efficacy of the product. In the present study, DFBA emulsions with same ingredients (Q1) and the emulsions with same concentration of the ingredients (Q2) will be prepared under different process conditions. Physicochemical properties of the Q1 and Q2 formulations will be tested and the Critical Quality Attributes (CQA) that may affect the bioavailability of the product will be identified. Initially different dissolution tests will be employed to determine the dissolution rate from the emulsions. Formulations with large differences in physicochemical properties (that are expected to affect bioavailability) will be chosen for dissolution studies. Advantages and limitations of these methods and the capability of these methods in detecting the process differences and predicting the in vivo performance, and robustness will be assessed. Permeability of the above selected formulation will be tested using human corneal epithelial cell culture (HEC-2) model. Physicochemical properties and in vitro release data will be fit into Ocular Module of the Gastro Plus software and its use in predicting bioequivalence will be validated. Test formulations selected from physicochemical and release rate characteristics (those with largest differences in these properties) will be tested for in vivo efficacy in New Zealand white rabbits. The drug release data from dissolution studies will be correlated with in vivo bioavailability data (in vitro-in vivo correlation). A comprehensive analysis of the dissolution methods in terms of their advantages and disadvantages and the capability of detecting manufacturing differences and predicting in vivo performance will be performed.
Specific aims for the proposal are: 1. To formulate Q1/Q2 topical ophthalmic emulsions under different manufacturing conditions 2. To conduct dissolution studies with the prepared formulations using various in vitro release methods 3. To identify a dissolution method that can discriminate different ophthalmic emulsion formulations The expected outcome of the project is an in vitro dissolution assay for topical ophthalmic emulsions. We envision that the results from the study will help FDA in developing recommendations to determine bioequivalence of generic topical ophthalmic emulsion dosage forms.

Public Health Relevance

Currently there is no official dissolution method for topical ophthalmic emulsions. The proposal aims to develop microemulsions of Difluprednate (used for postoperative inflammation and pain) with diverse physicochemical properties and determine the drug release from the formulations using currently available dissolution tests and prepare a comprehensive report on the advantages and limitations of the dissolution tests. It is anticipated that the results from this study will help FDA in making recommendations for testing bioequivalence of generic parenteral sustained release products.

National Institute of Health (NIH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1)
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Texas A&M University
College Station
United States
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