Perspective on Improving Passive Human Intestinal Absorption

Yalkowsky, Samuel H.

doi:10.1002/jps.23093

Cited by 17 publications

(13 citation statements)

References 11 publications

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“…Indeed, a critical review of the literature reveals that the use of cyclodextrins may lead to improved, unchanged, or even reduced overall absorption [14], [15]. This unpredicted effect may be attributable to the phenomenon that we have named the solubility-permeability interplay; several reports have emerged that while increasing the apparent solubility of the drug, cyclodextrins may on the same time reduce the apparent permeability of the co-administered drug [12], [16], [17], [18], [19], [20], [21], [22], [23].…”

Section: Introductionmentioning

confidence: 99%

Oral Delivery of Lipophilic Drugs: The Tradeoff between Solubility Increase and Permeability Decrease When Using Cyclodextrin-Based Formulations

2013

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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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Section: Introductionmentioning

confidence: 99%

Oral Delivery of Lipophilic Drugs: The Tradeoff between Solubility Increase and Permeability Decrease When Using Cyclodextrin-Based Formulations

2013

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“…Hence membrane transport can be increased by formulations that generate supersaturated solutions, since the number of molecules in solution is higher than for a saturated solution. However, not all formulation approaches that increase the number of molecules in solution are effective since speciation (i.e., the amount of drug available for membrane partitioning) needs to be considered (43). For example, incorporation of the solute into surfactant micelle increases the equilibrium solubility (solubilization rather than supersaturation) and hence the achievable solution concentration, but does not increase the amount of Bfree drug^available to partition into the membrane.…”

Section: Discussion Supersaturation and Thermodynamic Activity: Implimentioning

confidence: 98%

Impact of Solubilizing Additives on Supersaturation and Membrane Transport of Drugs

et al. 2015

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These findings clearly point out the flaws in using solute concentration in estimating solute activity or supersaturation, and reaffirm the use of flux measurements to understand supersaturated systems. Clear differentiation between solubilization and supersaturation, as well as thorough understanding of their respective impacts on membrane transport kinetics is important for the rational design of enabling formulations for poorly soluble compounds.

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“…In contrast, cyclodextrins, surfactants, and so forth increase the equilibrium solubility of the crystalline material and therefore do not increase the chemical potential of the solute in solution. Because of this, the latter solubilization techniques, while enhancing concentration, may not enhance passive absorption as the membrane transport rate is not increased . On account of their increased solute chemical potential, supersaturated solutions, such as those generated from amorphous formulations, can lead to enhanced membrane transport .…”

Section: Discussionmentioning

confidence: 99%

“…Because of this, the latter solubilization techniques, while enhancing concentration, may not enhance passive absorption as the membrane transport rate is not increased. 32,59,60 On account of their increased solute chemical potential, supersaturated solutions, such as those generated from amorphous formulations, can lead to enhanced membrane transport. 35 To understand the maximum potential enhancements in passive absorption that can be achieved through the use of supersaturating dosage forms, it is essential to develop a better understanding of the relationship between solution concentration, phase behavior, and membrane transport.…”

Section: Discussionmentioning

confidence: 99%

Enhancements and Limits in Drug Membrane Transport Using Supersaturated Solutions of Poorly Water Soluble Drugs

Raina

Zhang

Alonzo

et al. 2014

Journal of Pharmaceutical Sciences

170

215

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Perspective on Improving Passive Human Intestinal Absorption

Cited by 17 publications

References 11 publications

Oral Delivery of Lipophilic Drugs: The Tradeoff between Solubility Increase and Permeability Decrease When Using Cyclodextrin-Based Formulations

Oral Delivery of Lipophilic Drugs: The Tradeoff between Solubility Increase and Permeability Decrease When Using Cyclodextrin-Based Formulations

Impact of Solubilizing Additives on Supersaturation and Membrane Transport of Drugs

Enhancements and Limits in Drug Membrane Transport Using Supersaturated Solutions of Poorly Water Soluble Drugs

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