Food and Drug Administration

Description

The development of generic liposomal drug products is challenged by a lack of compendial or bio-relevant in vitro release methods. The traditional in vitro release method relies on dialyzing the liposomal formulation against a large volume of buffer. This method suffers from poor in vivo predictive power due to its inability to mimic the complex in vivo release conditions such as the large membrane pool present in systemic circulation or drug release conditions at the tumor sites or in the macrophages. Modifications to the traditional method include dialyzing against serum, serum protein solution, or surfactant solution and performing multiple stage dialyses. In addition, advances in separation techniques, such as filtration, centrifugation, and solid phase extraction, makes possible novel in vitro release assays in the presence of excess acceptor multilamellar or unilamellar vesicles. The robustness and predictive power of these methods have not been systemically evaluated or compared for specific type of liposomal drug products. The optimization and establishment of a standard in vitro release assay will advance the regulatory review of generic liposomal product applications.Objectives: The purpose of this study is to evaluate different in vitro release methods for liposomal drug products and analyze their robustness, capability of detecting formulation differences, and predictive power for in vivo performance. This study is intended to advance the regulatory review process of generic liposomal drug products, which in turn will help provide the US public with access to high quality generic liposomal drug products.Detailed description: Using amphotericin B, daunorubicin citrate, or vincristine sulfate liposomal injection as a model drug product, the project will involve the following:a. Review available in vitro release methods for the selected model liposomal drug product(s).b. Prepare a series of liposome formulations with similar formulation composition to the marketed model product but with different process conditions. Characterize physicochemical properties including mean particle size and distribution, surface charge, pH, shape, lamellarity and others.c. Conduct dissolution studies of prepared liposome formulations (including the marketed model product) with various in vitro release methods. Both conventional methods and innovative in vitro release study design can be explored. d. Vary in vitro release conditions and identify critical factors that affect the performance of each type of in vitro release method evaluated.e. Identify in vitro release methods which can distinguish liposome formulations with different in vitro characteristics. Use the in vitro release data together with animal data or human data to establish an in silico platform and explore in vitro in vivo correlation of selected liposomal drug product(s).

Who can apply

• State governments
• County governments
• City or township governments
• Special district governments
• Independent school districts
• Public and State controlled institutions of higher education
• Native American tribal governments (Federally recognized)
• Public housing authorities / Indian housing authorities
• Native American tribal organizations (other than Federally recognized)
• Nonprofits with 501(c)(3) status (other than higher education)
• Nonprofits without 501(c)(3) status (other than higher education)
• Private institutions of higher education
• For-profit organizations other than small businesses
• Small businesses
• Others

Contact

Gladys Melendez-Bohler <br/>Grants Management Specialist <br/>Phone 240-402-7565
gladys.bohler@fda.hhs.gov