Abstract
PurposeTo identify conditions allowing the use of cell-based models for studies of drug absorption during in vitro lipolysis of lipid-based formulations (LBFs).MethodsCaco-2 was selected as the cell-based model system. Monolayer integrity was evaluated by measuring mannitol permeability after incubating Caco-2 cells in the presence of components available during lipolysis. Pure excipients and formulations representing the lipid formulation classification system (LFCS) were evaluated before and after digestion. Porcine mucin was evaluated for its capacity to protect the cell monolayer.ResultsMost undigested formulations were compatible with the cells (II-LC, IIIB-LC, and IV) although some needed mucin to protect against damaging effects (II-MC, IIIB-MC, I-LC, and IIIA-LC). The pancreatic extract commonly used in digestion studies was incompatible with the cells but the Caco-2 monolayers could withstand immobilized recombinant lipase. Upon digestion, long chain formulations caused more damage to Caco-2 cells than their undigested counterparts whereas medium chain formulations showed better tolerability after digestion.ConclusionsMost LBFs and components thereof (undigested and digested) are compatible with Caco-2 cells. Pancreatic enzyme is not tolerated by the cells but immobilized lipase can be used in combination with the cell monolayer. Mucin is beneficial for critical formulations and digestion products.
Highlights
Drug dissolution in gastrointestinal fluids is crucial for drug absorption
All culture media and supplements were purchased from Invitrogen AB (Sweden). [14C]-mannitol was purchased from PerkinElmer Sverige AB (Sweden); Novozym® 435 was obtained from Strem chemicals (France); and fasted state simulated intestinal fluid (FaSSIF) powder was obtained from biorelevant.com (UK)
Caco-2 cells were exposed to the single excipients used in the lipid-based formulations (LBFs) for 2 h (Fig. 1)
Summary
Drug dissolution in gastrointestinal fluids is crucial for drug absorption. Approximately 70% of new drug candidates show insufficient solubility to allow intestinal absorption [1]. Lipid-based formulations (LBFs) often provide a means to deliver highly lipophilic, poorly water-soluble compounds at concentrations high enough to support absorption. These formulations consist of various mixtures of oils, surfactants, and co-solvents and are classified according to their composition and physical characteristics in the lipid formulation classification system (LFCS) [2]. LBFs are employed to keep the compounds in solution during their transit in the gastrointestinal tract and expose the absorptive site to drugs in a solubilized and/or supersaturated state
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