title: The interaction of nifedipine with selected cyclodextrins and the subsequent solubility-permeability trade-off.
abstract: The purpose of this study was to investigate the interaction of 2-hydroxypropyl-β-cyclodextrin (HPβCD) and 2,6-dimethyl-β-cyclodextrin (DMβCD) with the lipophilic drug nifedipine and to investigate the subsequent solubility-permeability interplay. Solubility curves of nifedipine with HPβCD and DMβCD in MES buffer were evaluated using phase solubility methods. Then, the apparent permeability of nifedipine was investigated as a function of increasing HPβCD/DMβCD concentration in the hexadecane-based PAMPA model. The interaction with nifedipine was CD dependent; significantly higher stability constant was obtained for DMβCD in comparison with HPβCD. Moreover, nifedipine displays different type of interaction with these CDs; a 1:1 stoichiometric inclusion complex was apparent with HPβCD, while 1:2 stoichiometry was apparent for DMβCD. In all cases, decreased apparent intestinal permeability of nifedipine as a function of increasing CD level and nifedipine apparent solubility was obtained. A quasi-equilibrium mass transport analysis was developed to explain this solubility-permeability interplay; the model enabled excellent quantitative prediction of nifedipine's permeability as a function of CD concentrations. This work demonstrates that when using CDs in solubility-enabling formulations, a trade-off exists between solubility increase and permeability decrease that must not be overlooked. This trade-off was found to be independent of the type of CD-drug interaction. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Beig
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Miller
authors.forename: Arik
authors.initials: A
authors.lastname: Dahan
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000042:Absorption; D000473:Alkanes / Q000737:chemistry; D001692:Biological Transport; D002121:Calcium Channel Blockers / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004347:Drug Interactions; D006801:Humans; D007408:Intestinal Absorption; D007422:Intestines / Q000187:drug effects*; D009543:Nifedipine / Q000737:chemistry* / Q000493:pharmacokinetics; D010539:Permeability; D012995:Solubility; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000473:Alkanes; D002121:Calcium Channel Blockers; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C038119:heptakis(2,6-O-dimethyl)beta-cyclodextrin; C007932:n-hexadecane; D009543:Nifedipine
keywords: Cyclodextrins; Intestinal permeability; Low-solubility drugs; Oral absorption; Solubility-enabling formulations; Solubility–permeability interplay