PURPOSE: To develop lipid semisolid formulations of EMD 50733, a poorly soluble, neutral drug candidate and to develop an in vitro-in vivo correlation for these formulations using the dog as the in vivo model. METHODS: The model drug, EMD 50733, (with BCS Class II properties) was dissolved in molten lipid/surfactant mixtures and the melt was filled into hard capsules and allowed to re-solidify at room temperature. The dissolution profiles in bio-relevant dissolution media and the bioavailability in dogs were measured and compared to that of a standard formulation consisting of a lactose/drug mixture. RESULTS: The best results with respect to dissolution, stability upon storage and bioavailability were obtained with a formulation that contained a commercially available lipid mixture (Gélucire 44/14) and a solubilizing agent (2-vinylpyrrolidone). With this formulation it was possible to dissolve a typical drug dose in a fill volume suitable for a #0 capsule. Additionally, surface tension measurements showed that the formulation formed micelles during dissolution in aqueous media: the molecular dispersion of the drug in this self-micelle forming system is postulated to protect the drug from precipitation in vivo as well as in vitro. For other formulations tested, neither the in vitro nor the in vivo performance indicated sufficient drug solubilizing properties. CONCLUSION: To achieve adequate and reliable dissolution of poorly soluble drugs in vivo, lipid excipients should not only have appropriate solubilizing properties for the drug in the formulation, but should also assist in maintaining drug in solution during release in the GI tract.
PURPOSE: To develop lipid semisolid formulations of EMD 50733, a poorly soluble, neutral drug candidate and to develop an in vitro-in vivo correlation for these formulations using the dog as the in vivo model. METHODS: The model drug, EMD 50733, (with BCS Class II properties) was dissolved in molten lipid/surfactant mixtures and the melt was filled into hard capsules and allowed to re-solidify at room temperature. The dissolution profiles in bio-relevant dissolution media and the bioavailability in dogs were measured and compared to that of a standard formulation consisting of a lactose/drug mixture. RESULTS: The best results with respect to dissolution, stability upon storage and bioavailability were obtained with a formulation that contained a commercially available lipid mixture (Gélucire 44/14) and a solubilizing agent (2-vinylpyrrolidone). With this formulation it was possible to dissolve a typical drug dose in a fill volume suitable for a #0 capsule. Additionally, surface tension measurements showed that the formulation formed micelles during dissolution in aqueous media: the molecular dispersion of the drug in this self-micelle forming system is postulated to protect the drug from precipitation in vivo as well as in vitro. For other formulations tested, neither the in vitro nor the in vivo performance indicated sufficient drug solubilizing properties. CONCLUSION: To achieve adequate and reliable dissolution of poorly soluble drugs in vivo, lipid excipients should not only have appropriate solubilizing properties for the drug in the formulation, but should also assist in maintaining drug in solution during release in the GI tract.