In the past few decades, FDA has approved various ophthalmic products including: 16 ointments, four gels and one in situ forming gel. These products have features of increased viscosity as well as mucoadhesion and therefore increased pre-corneal residence time;imparting sustained release characteristics and improved availability at the site of action. Development of generic and innovator products is complicated by: 1) pre-corneal factors;2) pathophysiology;and 3) complex manufacturing processes, where small product variations can result in significant differences in product quality (e.g. viscosity) with consequent differences in pharmacodynamic behavior. Until now only seven ointment-based generic ophthalmic products have been approved in the US in spite of no patent and exclusivity protection barriers for the majority of these products. In vitro release testing is recommended by FDA as part of the demonstration of bioequivalence between test and reference products in the approval of most generic drugs. The USP 37 NF <1724>has recommended: the vertical diffusion cell (Franz diffusion cells);the Immersion cell with USP apparatus 2;and USP apparatus 4 with a special adapter cell for in vitro release testing of semisolid dosage forms. The FDA has recommended the use of Franz diffusion cells or any other appropriate method to determine the acceptability of minor process and/or formulation changes in approved semisolid dosage forms. With this variety of recommended in vitro release testing methods as well as other methods described in the literature, it is important to understand the advantages and disadvantages of each method to facilitate method selection. Over the past 16 years our laboratory has made considerable progress in the development and validation of in vitro release methods for complex dosage forms (i.e. microspheres, liposomes and implants). For example, a robust USP apparatus 4 method has been developed with demonstrated capability of distinguishing formulation differences, and predicting in vivo performance for microspheres. Following on this background, it is proposed to conduct a systematic evaluation of current in vitro release methods for ophthalmic drug products. Lotemax? (loteprednol etabonate) ointment has been selected as the model product. Q1/Q2 equivalent formulations of loteprednol etabonate with manufacturing differences will be prepared and compared to Lotemax?. Robust release method(s) capable of detecting manufacturing differences will be identified and/or developed. The identified and/or developed method(s) will be used in future studies to predict the in vivo performance of Q1/Q2 equivalent ophthalmic ointment formulations through use of pharmacokinetic data (not a part of the current proposal due to time and financial constraints). A comprehensive understanding of current in vitro release testing methods, as well as the effect of manufacturing differences on the critical physicochemical properties and in vitro performance of ophthalmic ointments will be obtained. This research will facilitate the development of bioequivalence recommendations for generic ophthalmic ointments, which will in turn help provide the public with safe and effective generic products at reduced cost and in a timely fashion.

Public Health Relevance

This proposal seeks to systematically evaluate current in vitro dissolution testing methods for semisolid ocular drug products and to identify and/or develop the most robust dissolution testing method(s) with the capability of detecting manufacturing differences and for future prediction of in vivo performance. This will facilitate the development of bioequivalence recommendations for generic semisolid ocular drug products and hence facilitate the development of generic products. Consequently, the regulatory burden will be reduced and human studies will be minimized without sacrificing product quality and safety.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1)
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University of Connecticut
Schools of Pharmacy
United States
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