title: The use of three different solid dispersion formulations--melt extrusion, film-coated beads, and a glass thermoplastic system--to improve the bioavailability of a novel microsomal triglyceride transfer protein inhibitor.
abstract: A bioavailable formulation for a water-insoluble microsomal triglyceride transfer protein inhibitor, R103757, was developed using solid dispersion technology. The need for an advanced formulation was tested in the dog by assessing the oral bioavailability of three generic concepts: a tablet (crystalline drug), a capsule (film-coated beads), and an oral solution. These screening studies steered further development in the direction of a solid dispersion. Three solid dispersion platforms were assessed: melt extrusion, film-coated beads, and a glass thermoplastic system. Thermal and spectrophotometric analysis revealed that no crystalline drug was present in any of the formulations. The dissolution profiles of the three dispersion systems showed that release was improved compared with the unmanipulated drug. In addition, stability studies confirmed the physical and chemical integrity of the formulation. A human clinical trial was performed to assess the pharmacokinetics of the three amorphous dispersions. Plasma levels were obtained after single oral administration in both the fasting and fed state. The study indicated that all three approaches improved the bioavailability of R103757 with the glass thermoplastic system providing the best performance. These studies point to the potential usefulness of solid dispersion approaches and expand the possible number of ways to implement these methodologies.
authors.affiliation: Department of Pharmaceutical Sciences, Drug Evaluation, Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium. gverreck@prdbe.jnj.com
authors.forename: Geert
authors.initials: G
authors.lastname: Verreck
authors.forename: Roger
authors.initials: R
authors.lastname: Vandecruys
authors.forename: Val
authors.initials: V
authors.lastname: De Conde
authors.forename: Lieven
authors.initials: L
authors.lastname: Baert
authors.forename: Jef
authors.initials: J
authors.lastname: Peeters
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Brewster
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D002214:Capsules; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D004285:Dogs; D005898:Glass / Q000737:chemistry*; D006801:Humans; D008297:Male; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism*; D010879:Piperazines / Q000737:chemistry* / Q000493:pharmacokinetics; D012995:Solubility; D014230:Triazoles / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D002214:Capsules; D002352:Carrier Proteins; D010879:Piperazines; D014230:Triazoles; C106092:microsomal triglyceride transfer protein; C493731:mitratapide