Cyclodextrins and Drug Membrane Permeation: Thermodynamic Considerations

Sripetch, Suppakan; Prajapati, Manisha; Loftsson, Þorsteinn

doi:10.1016/j.xphs.2022.04.015

Cited by 12 publications

(15 citation statements)

References 41 publications

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“…Consequently, the release of a drug molecule from the CD cavity will generally not be a limiting factor, such as during drug permeation from an aqueous CD solution through a lipophilic biological membrane. One exception is the effect of CDs on the thermodynamic activity of drugs in aqueous solutions, which can result in reduced drug permeation [ 86 ]. In this respect, the effect of CDs on drug permeation from the aqueous exterior through biological membranes is similar to that of organic cosolvents.…”

Section: The Anomalous Properties Of Cyclodextrinsmentioning

confidence: 99%

“…Passive drug permeation follows Fick’s first law that states that the drug flux ( J ) is the product of the permeation coefficient ( P ) and drug concentration gradient over the barrier. A greater concentration gradient results in faster permeation of the drug molecules (i.e., a larger value of J ) [ 86 ]. A higher concentration of a dissolved lipophilic drug in the aqueous gastrointestinal fluid results in faster absorption of the drug through the mucosa into the systemic blood circulation and more complete absorption (i.e., higher drug bioavailability).…”

Section: The Anomalous Properties Of Cyclodextrinsmentioning

confidence: 99%

“…CDs are very hydrophilic and, thus, unable to partition from the aqueous exterior into the lipophilic membrane. Furthermore, maximum absorption is obtained when the aqueous exterior is saturated with the drug, i.e., when C A is equal to drug-saturated solubility ( Figure 5 ) [ 86 ]. Under such conditions, the dissolved drug molecules have the maximum ability to leave the aqueous exterior and partition into the lipophilic membrane.…”

Section: The Anomalous Properties Of Cyclodextrinsmentioning

confidence: 99%

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Anomalous Properties of Cyclodextrins and Their Complexes in Aqueous Solutions

2023

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Cyclodextrins (CDs) are cyclic oligosaccharides that emerged as industrial excipients in the early 1970s and are currently found in at least 130 marketed pharmaceutical products, in addition to numerous other consumer products. Although CDs have been the subject of close to 100,000 publications since their discovery, and although their structure and properties appear to be trivial, CDs are constantly surprising investigators by their unique physicochemical properties. In aqueous solutions, CDs are solubilizing complexing agents of poorly soluble drugs while they can also act as organic cosolvents like ethanol. CDs and their complexes self-assemble in aqueous solutions to form both nano- and microparticles. The nanoparticles have diameters that are well below the wavelength of visible light; thus, the solutions appear to be clear. However, the nanoparticles can result in erroneous conclusions and misinterpretations of experimental results. CDs can act as penetration enhancers, increasing drug permeation through lipophilic membranes, but they do so without affecting the membrane barrier. This review is an account of some of the unexpected results the authors have encountered during their studies of CDs as pharmaceutical excipients.

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Section: The Anomalous Properties Of Cyclodextrinsmentioning

confidence: 99%

Section: The Anomalous Properties Of Cyclodextrinsmentioning

confidence: 99%

Section: The Anomalous Properties Of Cyclodextrinsmentioning

confidence: 99%

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Anomalous Properties of Cyclodextrins and Their Complexes in Aqueous Solutions

2023

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“…Similarly to PAMPA, Permeapad has been used to study the permeability of drugs in the presence of solubilizing excipients such as cyclodextrins [ 82 , 83 , 84 , 85 ] and poloxamers [ 86 , 87 ]. Due to its extremely high mechanical and chemical stability, PermeaPad has also found applicability in enabling formulation testing, including the testing of lipid-based formulations such as self-nanoemulsifying drug delivery systems (SNEDDSs) [ 88 ], which can contain very high amounts of surfactants, and phospholipid-based dispersions [ 67 , 89 ].…”

Section: Commercially Available Biomimetic Cell-free In Vitro Permeab...mentioning

confidence: 99%

Commercially Available Cell-Free Permeability Tests for Industrial Drug Development: Increased Sustainability through Reduction of In Vivo Studies

et al. 2023

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Replacing in vivo with in vitro studies can increase sustainability in the development of medicines. This principle has already been applied in the biowaiver approach based on the biopharmaceutical classification system, BCS. A biowaiver is a regulatory process in which a drug is approved based on evidence of in vitro equivalence, i.e., a dissolution test, rather than on in vivo bioequivalence. Currently biowaivers can only be granted for highly water-soluble drugs, i.e., BCS class I/III drugs. When evaluating poorly soluble drugs, i.e., BCS class II/IV drugs, in vitro dissolution testing has proved to be inadequate for predicting in vivo drug performance due to the lack of permeability interpretation. The aim of this review was to provide solid proofs that at least two commercially available cell-free in vitro assays, namely, the parallel artificial membrane permeability assay, PAMPA, and the PermeaPad® assay, PermeaPad, in different formats and set-ups, have the potential to reduce and replace in vivo testing to some extent, thus increasing sustainability in drug development. Based on the literature review presented here, we suggest that these assays should be implemented as alternatives to (1) more energy-intense in vitro methods, e.g., refining/replacing cell-based permeability assays, and (2) in vivo studies, e.g., reducing the number of pharmacokinetic studies conducted on animals and humans. For this to happen, a new and modern legislative framework for drug approval is required.

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“…Cyclodextrins (CDs) are ring-shaped oligosaccharides that are used in numerous drug delivery systems. They are utilized to complex, solubilize, and protect drugs in an aqueous biological environment. , One of the key advantages of CDs is their small size with a height and external diameter of up to 7.9 and 16.9 Å, respectively, making them likely the smallest drug carrier systems. , One limitation of CDs as drug delivery systems is that they do not interact with the mucus layer, resulting in a short mucosal residence time . Mucoadhesion is provided by ionic interactions and hydrogen bonding in combination with the interpenetration of polymeric chains into the mucus gel layer, followed by chain entanglements. − Since CDs are nonionic and too small for chain entanglements, they are not mucoadhesive at all.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Mucoadhesion of Thiolated β-Cyclodextrin by S-Protection with 2-Mercaptoethanesulfonic Acid

Kali,

Taha,

Campanella

et al. 2024

ACS Omega

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This study aimed at designing an S-protected thiolated β-cyclodextrin (β-CD) exhibiting enhanced mucoadhesive properties. The native β-CD was thiolated with phosphorus pentasulfide resulting in a thiolated β-CD (β-CD-SH) and subsequently Sprotected with 2-mercaptoethanesulfonate (MESNA) to form β-CD-SS-MESNA. The structure of the novel excipient was confirmed by 1 H NMR and Fourier-transform infrared spectroscopy. The sulfhydryl content of β-CD-SH, determined by Ellman's test, was 2281.00 ± 147 μmol/g, and it was decreased to 45.93 ± 19.40 μmol/g by Sprotection. Due to thiolation and S-protection, the viscosity of the mixture of mucus with β-CD-SH and β-CD-SS-MESNA increased 1.8 and 4.1-fold, compared to native β-CD, respectively. The unprotected β-CD-SH diffused to a lesser extent into the mucus than native β-CD, while S-protected β-CD-SS-MESNA showed the highest mucodiffusion among the applied CDs. A 1.5-and 3.0-fold higher cellular uptake of β-CD-SH and β-CD-SS-MESNA, compared to the native one, was established on Caco-2 cell line by flow cytometry, respectively, causing slightly decreased cell viability. On account of the enhanced mucoadhesion, this higher cellular uptake does not affect the application potential of β-CD-SS-MESNA as an oral drug delivery system since the carrier remains in the mucus and does not reach the underlying epithelial layer. According to these results, the S-protection of β-CD-SH with MESNA promotes improved mucodiffusion, strong mucoadhesion, and prolonged mucosal residence time.

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Cyclodextrins and Drug Membrane Permeation: Thermodynamic Considerations

Cited by 12 publications

References 41 publications

Anomalous Properties of Cyclodextrins and Their Complexes in Aqueous Solutions

Anomalous Properties of Cyclodextrins and Their Complexes in Aqueous Solutions

Commercially Available Cell-Free Permeability Tests for Industrial Drug Development: Increased Sustainability through Reduction of In Vivo Studies

Enhanced Mucoadhesion of Thiolated β-Cyclodextrin by S-Protection with 2-Mercaptoethanesulfonic Acid

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