A proposal is submitted for RFA-FD-14-080: Predictive in vitro Methods for Characterizing Product Performance, Case Study: Furosemide. The goal of the proposed work is to investigate the effects of milk and related products (baby formula, Ensure) on in vitro dissolution, and establish a basis to relate such data with in vivo absorption. This is of particular relevance to groups such as pediatric patients. This problem is challenging because some previous studies indicate that milk increases in vitro dissolution, which would likely predict faster and more complete absorption in vivo. There is little data directly relating milk with in vivo absorption, but numerous studies show that food reduces/slows furosemide absorption in vivo, while the presence of milk increases in vitro dissolution rates and might be expected to increase absorption rates. Thus, in vivo effects of milk on bioavailability are not well understood. A number of methods have been employed to study in vitro dissolutions, including sampling methodologies and setups that mimic the GI tract. However, we postulate that two other factors are critically important to understand the effects of milk on dissolution and absorption identifying how the milk components interact with furosemide, and using a better sampling methodology during in vitro dissolutions that isolates the dissolved, free furosemide concentration (as opposed to furosemide that is bound to casein or taken up in fats or emulsions). One of the goals of this proposal is to identify and characterize interactions between furosemide and components of milk and related products, including the protein casein as well as fats contained in milk. This will include studying possible protein binding, and effects of adding surfactants such as bile salts. Another goal is to use PMD to study interactions of furosemide with these components and subsequent effects on the drug distribution. A third goal is to perform dissolution experiments using PMD for sampling, and relate the dissolution data to the physical and chemical behaviors characterized in this study. The ultimate objective is to use in vitro dissolution data to predict in vivo results, and incorporate the effects of milk and related products into these predictions. Thus, modeling will also be done to relate the furosemide and milk effects and resulting dissolution data, especially as related to the free drug, which corresponds to the absorbable form in vivo. In-house software will be TM developed as needed to supplement commercially available software such as GastroPlus , and in vivo simulations will be performed as appropriate. 1/1

Public Health Relevance

Furosemide is a poorly soluble drug that is given to adults and pediatric patients. When given with food, the oral absorption is reduced. However, it is also known that milk increases in vitro dissolution of furosemide, which would likely predict higher absorption. In this project, methods for improving the evaluation of furosemide dissolutions will be developed and used to evaluate possible interactions of furosemide with components of milk such as casein and fats. The insights gained from this project will allow improved understanding of in vivo absorption of furosemide when taken with milk. This may be of considerable importance when dosing pediatric patients, for whom milk and baby formula are major dietary components. 1/1

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZFD1-SRC (99))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Physical Pharmaceutica, LLC
United States
Zip Code