title: Toward the establishment of standardized in vitro tests for lipid-based formulations. 2. The effect of bile salt concentration and drug loading on the performance of type I, II, IIIA, IIIB, and IV formulations during in vitro digestion.
abstract: The LFCS Consortium was established to develop standardized in vitro tests for lipid-based formulations (LBFs) and to examine the utility of these tests to probe the fundamental mechanisms that underlie LBF performance. In this publication, the impact of bile salt (sodium taurodeoxycholate, NaTDC) concentration and drug loading on the ability of a range of representative LBFs to generate and sustain drug solubilization and supersaturation during in vitro digestion testing has been explored and a common driver of the potential for drug precipitation identified. Danazol was used as a model poorly water-soluble drug throughout. In general, increasing NaTDC concentrations increased the digestion of the most lipophilic LBFs and promoted lipid (and drug) trafficking from poorly dispersed oil phases to the aqueous colloidal phase (AP(DIGEST)). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 mM, NaTDC effects on either digestion or drug solubilization were modest. In contrast, increasing drug load had a marked impact on drug solubilization. For LBFs containing long-chain lipids, drug precipitation was limited even at drug loads approaching saturation in the formulation and concentrations of solubilized drug in AP(DIGEST) increased with increased drug load. For LBFs containing medium-chain lipids, however, significant precipitation was evident, especially at higher drug loads. Across all formulations a remarkably consistent trend emerged such that the likelihood of precipitation was almost entirely dependent on the maximum supersaturation ratio (SR(M)) attained on initiation of digestion. SR(M) defines the supersaturation "pressure" in the system and is calculated from the maximum attainable concentration in the AP(DIGEST) (assuming zero precipitation), divided by the solubility of the drug in the colloidal phases formed post digestion. For LBFs where phase separation of oil phases did not occur, a threshold value for SR(M) was evident, regardless of formulation composition and drug solubilization reduced markedly above SR(M) > 2.5. The threshold SR(M) may prove to be an effective tool in discriminating between LBFs based on performance.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, 3052, Australia.
authors.forename: Hywel D
authors.initials: HD
authors.lastname: Williams
authors.forename: Mette U
authors.initials: MU
authors.lastname: Anby
authors.forename: Philip
authors.initials: P
authors.lastname: Sassene
authors.forename: Karen
authors.initials: K
authors.lastname: Kleberg
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Bakala-N'Goma
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: Frédéric
authors.initials: F
authors.lastname: Carrière
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
authors.forename: Colin W
authors.initials: CW
authors.lastname: Pouton
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
mesh_terms: D001647:Bile Acids and Salts / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D003613:Danazol / Q000737:chemistry* / Q000378:metabolism; D004063:Digestion; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D012995:Solubility / Q000187:drug effects; D013678:Technology, Pharmaceutical / Q000379:methods / Q000592:standards*; D014867:Water / Q000737:chemistry*
chemical_list: D001647:Bile Acids and Salts; D008055:Lipids; D014867:Water; D003613:Danazol