A heuristic model to quantify the impact of excess cyclodextrin on oral drug absorption from aqueous solution

Niels Erik Olesen, Peter Westh, René Holm

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review


The intestinal drug solubilising capacity View the MathML source(DtotSC) of a drug formulated as an aqueous cyclodextrin solution is a recently proposed quantity to predict the cyclodextrin concentration needed to fully solubilise the drug in the intestinal lumen. According to this concept, the cyclodextrin concentration in the drug product must be higher than the amount needed to solubilise the compound, due to the displacement of the drug from the cyclodextrin cavity by bile salts in the intestinal lumen. On the other hand, dosing cyclodextrin at View the MathML source>DtotSC is expected to result in decreased free intestinal drug concentrations and thus potentially a lower fraction absorbed. In this study, data from three previous in vivo studies in rats with fixed concentrations of three compounds (danazol, cinnarizine and benzo[A]pyrene) and various cyclodextrin concentrations View the MathML source>DtotSC were analysed. The model was developed for danazol and applied to the two other compounds. Absorption, as quantified from the area under the plasma concentration–time profile, was predicted by the model to decrease at elevated concentrations of co-administered cyclodextrin in accordance with the in vivo data. In addition, at high cyclodextrin concentrations a delay in Tmax and a decrease in Cmax were predicted, again in accordance with the experimental observations. These observations were rationalised in terms of the free intestinal drug concentration by a chemical equilibrium model for View the MathML sourceDtotSC. This model depends on the quantity termed the dimensionless dose concentration, View the MathML sourceDtot∗=Do/Pn, given as the fraction of the permeation number (Pn) and dose number (Do). The model provides the formulation scientist with a critical quality attribute for assessing the implication of having excess cyclodextrin in an oral solution.
TidsskriftEuropean Journal of Pharmaceutics and Biopharmaceutics
Sider (fra-til)142-151
Antal sider10
StatusUdgivet - 2016

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