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. 2013 Jul 16;8(7):e68237.
doi: 10.1371/journal.pone.0068237. Print 2013.

Oral delivery of lipophilic drugs: the tradeoff between solubility increase and permeability decrease when using cyclodextrin-based formulations

Avital Beig  1 , Riad Agbaria, Arik Dahan
Affiliations

Oral delivery of lipophilic drugs: the tradeoff between solubility increase and permeability decrease when using cyclodextrin-based formulations

Avital Beig et al. PLoS One. .

Erratum in

  • PLoS One. 2013;8(10). doi:8(10): 10.1371/annotation/10ae05dc-90cb-46f1-aa2b-e63eb4a132e2

Abstract

The purpose of this study was to investigate the impact of oral cyclodextrin-based formulation on both the apparent solubility and intestinal permeability of lipophilic drugs. The apparent solubility of the lipophilic drug dexamethasone was measured in the presence of various HPβCD levels. The drug's permeability was measured in the absence vs. presence of HPβCD in the rat intestinal perfusion model, and across Caco-2 cell monolayers. The role of the unstirred water layer (UWL) in dexamethasone's absorption was studied, and a simplified mass-transport analysis was developed to describe the solubility-permeability interplay. The PAMPA permeability of dexamethasone was measured in the presence of various HPβCD levels, and the correlation with the theoretical predictions was evaluated. While the solubility of dexamethasone was greatly enhanced by the presence of HPβCD (K1:1 = 2311 M(-1)), all experimental models showed that the drug's permeability was significantly reduced following the cyclodextrin complexation. The UWL was found to have no impact on the absorption of dexamethasone. A mass transport analysis was employed to describe the solubility-permeability interplay. The model enabled excellent quantitative prediction of dexamethasone's permeability as a function of the HPβCD level. This work demonstrates that when using cyclodextrins in solubility-enabling formulations, a tradeoff exists between solubility increase and permeability decrease that must not be overlooked. This tradeoff was found to be independent of the unstirred water layer. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.

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Conflict of interest statement

Competing Interests: The work was supported by a research grant from AbbVie Incorporation. JMM is affiliated with AbbVie Incorporation. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. The molecular structures of dexamethasone (a) and 2-hydroxypropyl-β-cyclodextrin (b). R = -H or –CH2CHOHCH3.
Figure 2
Figure 2. Aqueous solubility of dexamethasone as a function of increasing HPβCD concentration at 25°C.
Data are presented as mean ± SD (error bars smaller than symbols); n = 3 in each experimental group.
Figure 3
Figure 3. Dexamethasone flux across Caco-2 monolayers as the free drug (•) vs the drug-HPβCD complex (○), and the corresponding Papp values in centimeters per second (right panel).
Data are presented as mean ± SD; n = 4 in each experimental group.
Figure 4
Figure 4. Papp values of dexamethasone across Caco-2 monolayers at different rotation speeds (0, 50, and 100 rpm).
Data are presented as mean ± SD; n = 4 in each experimental group.
Figure 5
Figure 5. Effective permeability values (Peff, cm/sec; right panel) and outlet/inlet concentration ratio (C′out/C′in; left panel) of dexamethasone as the free drug (○) vs the drug-HPβCD complex (•), determined using the in situ single-pass rat jejunal perfusion model.
Data are presented as mean ± SD; n = 4 in each experimental group.
Figure 6
Figure 6. Theoretical vs. experimental apparent permeability (Papp; cm/sec) of dexamethasone in the PAMPA model as a function of increasing HPβCD levels.
Experimental data presented as mean ± SD (error bars smaller than symbols); n = 4.
Figure 7
Figure 7. The overall effects of increasing HPβCD levels on dexamethasone apparent solubility and permeability, based on the mass transport model employed in this work.
See this image and copyright information in PMC

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