title: Toward the establishment of standardized in vitro tests for lipid-based formulations, part 6: effects of varying pancreatin and calcium levels.
abstract: The impact of pancreatin and calcium addition on a wide array of lipid-based formulations (LBFs) during in vitro lipolysis, with regard to digestion rates and distribution of the model drug danazol, was investigated. Pancreatin primarily affected the extent of digestion, leaving drug distribution somewhat unaffected. Calcium only affected the extent of digestion slightly but had a major influence on drug distribution, with more drug precipitating at higher calcium levels. This is likely to be caused by a combination of removal of lipolysis products from solution by the formation of calcium soaps and calcium precipitating with bile acids, events known to reduce the solubilizing capacity of LBFs dispersed in biorelevant media. Further, during the digestion of hydrophilic LBFs, like IIIA-LC, the un-ionized-ionized ratio of free fatty acids (FFA) remained unchanged at physiological calcium levels. This makes the titration curves at pH 6.5 representable for digestion. However, caution should be taken when interpreting lipolysis curves of lipophilic LBFs, like I-LC, at pH 6.5, at physiological levels of calcium (1.4 mM); un-ionized-ionized ratio of FFA might change during digestion, rendering the lipolysis curve at pH 6.5 non-representable for the total digestion. The ratio of un-ionized-ionized FFAs can be maintained during digestion by applying non-physiological levels of calcium, resulting in a modified drug distribution with increased drug precipitation. However, as the main objective of the in vitro digestion model is to evaluate drug distribution, which is believed to have an impact on bioavailability in vivo, a physiological level (1.4 mM) of calcium is preferred.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Philip
authors.initials: P
authors.lastname: Sassene
authors.forename: Karen
authors.initials: K
authors.lastname: Kleberg
authors.forename: Hywel D
authors.initials: HD
authors.lastname: Williams
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Bakala-N'Goma
authors.forename: Frédéric
authors.initials: F
authors.lastname: Carrière
authors.forename: Marilyn
authors.initials: M
authors.lastname: Calderone
authors.forename: Vincent
authors.initials: V
authors.lastname: Jannin
authors.forename: Annabel
authors.initials: A
authors.lastname: Igonin
authors.forename: Anette
authors.initials: A
authors.lastname: Partheil
authors.forename: Delphine
authors.initials: D
authors.lastname: Marchaud
authors.forename: Eduardo
authors.initials: E
authors.lastname: Jule
authors.forename: Jan
authors.initials: J
authors.lastname: Vertommen
authors.forename: Mario
authors.initials: M
authors.lastname: Maio
authors.forename: Ross
authors.initials: R
authors.lastname: Blundell
authors.forename: Hassan
authors.initials: H
authors.lastname: Benameur
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
authors.forename: Colin W
authors.initials: CW
authors.lastname: Pouton
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
mesh_terms: D002118:Calcium / Q000737:chemistry* / Q000502:physiology; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D003613:Danazol / Q000737:chemistry / Q000493:pharmacokinetics*; D004063:Digestion / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000032:analysis; D066298:In Vitro Techniques; D008055:Lipids / Q000737:chemistry*; D008066:Lipolysis; D008954:Models, Biological; D010194:Pancreatin / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility
chemical_list: D005227:Fatty Acids; D008055:Lipids; D010194:Pancreatin; D003613:Danazol; D002118:Calcium