The work described in this proposal introduces novel methods for assessing the bioequivalence of ocular semi- solid formulations. These include dissolution test optimization, the use of an artificial cornea to measure corneal transport of Active Pharmaceutical Ingredients (APIs) in ocular ointments, and the correlation of these measurements to in vitro dissolution/drug release measurements. This will be accomplished using methods designed to determine differences between reference listed drugs (RLDs) and generic formulations manufactured in our labs that contains the same active and inactive ingredients ( Q1 ) and in the same concentrations ( Q2 ) as the RLDs. The RLDs chosen for this study include ocular ointments containing a single API (Tobrex - tobramycin ophthalmic ointment) as well as a related ocular ointment containing two distinct APIs (Tobradex - tobramycin and dexamethasone ophthalmic ointment). The only currently recommended bioequivalence studies for these RLDs are a pharmacokinetic study and an in vitro microbial kill rate study. Regarding dissolution test method development and sampling times, the recommendation in the FDA database is please develop an in vitro drug release testing method for this drug product for stability and quality controls. Specifications will be determined upon review of the data submitted in the application. Because conventional dissolution methods exhibit limited biorelevance in predicting bioequivalence of ocular semi-solid products, the aims of the proposed studies are (1) to prepare Q1/Q2 generic products of the RLDs using different manufacturing processes and to fully characterize their physicochemical properties, (2) to compare the in vitro release of the APIs from different Q1/Q2 generic preparations using a modified USP Dissolution Apparatus 4, a vertical diffusion cell apparatus, and an immersion cell in an adapted USP Dissolution Apparatus 2, and (3) to measure transport of the APIs from the two RLDs across artificial corneas and identify a dissolution method that can discriminate between different Q1/Q2 generic ocular semi-solid formulations. An analysis of the dissolution methods used in these studies will be conducted in order to identify the advantages and disadvantages of each method as well as an assessment of their capability to detect differences in manufacturing methods, to predict in vivo performance, and to assess method robustness. The results of these studies are expected to assist the FDA in developing Guidelines for Industry that can be used by manufacturers of generic ocular semi-solid drug products containing one or more APIs for establishing bioequivalence to innovator products. It is anticipated that these results will improve the health outcomes of patients who have been prescribed semi-solid products for ocular administration by helping to identify products that could lead to delivery of super- or sub-therapeutic doses of API, the consequences of which could be significant.
The work described in this proposal introduces novel methods for assessing the bioequivalence of ocular semi- solid formulations. These include the use of an artificial cornea to measure corneal transport of Active Pharmaceutical Ingredients (APIs) in ocular ointments, and the correlation of these measurements to in vitro dissolution/drug release measurements. The results of these studies are expected to assist the FDA in developing Guidelines for Industry that can be used by manufacturers of generic ocular semi-solid drug products containing one or more APIs for establishing bioequivalence to innovator products.
