Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: Studies with halofantrine

• Published in: Journal of pharmaceutical sciences 2004-05, Vol.93 (5), p.1110-1121
• Main Authors: Porter, Christopher J.H., Kaukonen, Ann Marie, Taillardat-Bertschinger, Agnes, Boyd, Ben J., O'Connor, Jacquelyn M., Edwards, Glenn A., Charman, William N.
• Format: Article
• Language: English
• Subjects: absorption bioavailability; Administration, Oral; Animals; Biological and medical sciences; Chemistry, Pharmaceutical; Digestion - drug effects; Digestion - physiology; Dogs; General pharmacology; lipid digestion; lipid-based drug delivery; Male; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Phenanthrenes - administration & dosage; Phenanthrenes - chemistry; Phenanthrenes - metabolism; poorly water-soluble drugs; Solubility - drug effects; Triglycerides - administration & dosage; Triglycerides - metabolism; Water - metabolism
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.20039

The relative oral bioavailability (BA) of halofantrine base (Hf) was assessed in male beagle dogs after administration of a medium chain triglyceride (MCT), a long chain triglyceride (LCT), and a blended LCT/MCT lipid solution formulation of Hf (Study 1) and after administration of suspensions of Hf base and Hf · HCl in LCT (Study 2). A series of in vitro lipid digestion experiments were also performed in an attempt to clarify the data obtained. In vitro drug solubilization profiles were markedly dependent on the mass of lipid employed in lipid digestion experiments. At high lipid masses (∼25 mg triglyceride/mL), MCT formulations gave maximal benefit, whereas at low lipid concentrations (∼5 mg triglyceride/mL), LCT formulations provided improved solubilization capacity. The in vitro digestion and solubilization data at lower lipid masses were consistent with the in vivo data where the BA of Hf after oral administration of the LCT solution > LCT/MCT blend > MCT solution. The second BA study showed similar, albeit variable, exposure after oral administration of a suspension of Hf base or Hf · HCl in LCT and this trend was broadly consistent with in vitro results. This study demonstrates the potential utility of in vitro digestion models to assess and rank order the in vivo performance of lipid solution and suspension formulations of poorly water-soluble drugs such as Hf. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1110–1121, 2004