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Cyclodextrins and Their Derivatives: A Basis for New Drug Formulations

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 30698

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Prof. Dr. Thomas Mavromoustakos

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Department of Chemistry, National & Kapodistrian University of Athens, Athens, Greece
Interests: hypertension; structure elucidation; nuclear magnetic resonance; spectroscopy; NMR spectroscopy; medicinal and pharmaceutical chemistry; molecular modeling; Raman spectroscopy; DSC; NMR structure elucidation
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Dr. Andreas Tzakos

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Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece
Interests: drug development; theranostics; diagnostics; therapeutics; plant extracts
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Prof. Dr. Georgia N. Valsami

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Department of Pharmacy, National & Kapodistrian University of Athens, Athens, Greece
Interests: drug–protein binding; drug-cyclodextrins interaction, characterization and effect on drug solubility/dissolution/absorption; development and in vitro–in vivo evaluation of novel dosage forms with optimized absorption (GI/nasal/pulmonary); PK/PD studies and dosage individualization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As Guest Editors, we would like to announce a Special Issue entitled “Cyclodextrins and their Derivatives. A Basis for New Drug Formulations”. This Special Issue will collect communications, research articles, and high-quality review papers in the research fields relating to cyclodextrins, cyclodextrin derivatives, and drug–cyclodextrin interactions, for application in drug formulation developments. We kindly encourage research groups working in various areas of pharmaceutical technology, biopharmaceutics, medicinal and pharmaceutical chemistry, and chemical biology to make contributions to this Special Issue involving, but not restricted to: trends in novel cyclodextrin/cyclodextrin derivatives development, drug–cyclodextrin interactions, applications for novel drug formulations, repurposing of known drug entities through the development of new dosage forms for different routes of administration, pulmonary, nasal, transdermal, etc., and evaluation in vitro/ex vivo/in vivo. In addition, researchers are encouraged to submit articles or reviews that include existing and new methodologies suitable for studying drug–cyclodextrin interactions. The molecular nature of these interactions is critical for rational drug design. Reviews outlining the advantages and disadvantages of existing formulations are also welcome. Furthermore, research articles and review papers on cyclodextrin design, development, and characterization for application in drug design are also suitable for this Special Issue.

Prof. Dr. Thomas Mavromoustakos
Prof. Dr. Andreas G. Tzakos
Prof. Dr. Georgia N. Valsami
Guest Editors

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

cyclodextrin design/development/characterization
drug–cyclodextrin interactions/formulations
analytical methodologies for drug–cyclodextrin interactions/structure elucidation
in vitro/ex vivo/in vivo evaluation
other routes of drug administration (nasal, pulmonary, transdermal, etc.)

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Related Special Issue

Unlocking the Formulation Potential of Cyclodextrins and Their Derivatives—2nd Edition in Molecules (2 articles)

Published Papers (9 papers)

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26 pages, 9495 KiB

Open AccessArticle

Polysorbates versus Hydroxypropyl Beta-Cyclodextrin (HPβCD): Comparative Study on Excipient Stability and Stabilization Benefits on Monoclonal Antibodies

by Hailong Zhang, Shiqi Hong, Sarah Si Kai Tan, Tao Peng, Lucas Yuan Hao Goh, Kwan Hang Lam, Keat Theng Chow and Rajeev Gokhale

Molecules 2022, 27(19), 6497; https://doi.org/10.3390/molecules27196497 - 1 Oct 2022

Cited by 10 | Viewed by 3927

Abstract

Polysorbates (PS 20 and PS 80) are the most widely used surfactants in biopharmaceutical formulations to protect proteins from denaturation, aggregation, and surface adsorption. To date, around 70% of marketed therapeutic antibodies contain either PS 20 or PS 80 in their formulations. However, polysorbates are chemically diverse mixtures, which are prone to degradation by oxidation and hydrolysis to produce peroxides and fatty acids, which, in turn, induce protein oxidation, aggregation, and insoluble particle formation. These will negatively impact protein quality and stability. Thus, polysorbate degradation has emerged as one of the major challenges in the development and commercialization of therapeutic protein products. KLEPTOSE^® HPβCD (hydroxypropyl beta-cyclodextrin), a new multifunctional excipient, has been shown to provide protein stabilization functions in biopharmaceutical downstream processes and in their final formulations. This study aims to evaluate HPβCD, a new molecule of its class, against polysorbates as a stabilizer in biologics formulations. In this study, the chemical stability of KLEPTOSE^® HPβCDs is compared with polysorbates (20 and 80) under various stress conditions. When subjected to heat stress, HPβCDs show little change in product recovery (90.7–100.7% recovery for different HPβCDs), while polysorbates 20 and 80 show significant degradation, with only 11.5% and 7.3% undegraded product remaining, respectively. When subjected to other chemical stressors, namely, autoclave, light, and oxidative stresses, HPβCD remains almost stable, while polysorbates show more severe degradation, with 95.5% to 98.8% remaining for polysorbate 20 and 85.5% to 97.4% remaining for polysorbate 80. Further, profiling characterization and degradation analysis reveal that chemical structures of HPβCDs remain intact, while polysorbates undergo significant hydrolytic degradation and oxidation. Lastly, the physicochemical stability of monoclonal antibodies in formulations is investigated. When subjected to light stress, adalimumab, as a model mAb, formulated in the presence of HPβCD, shows a significant decrease in protein aggregation, and superior monomer and total protein recovery compared to PS 80-containing formulations. HPβCD also reduces both agitation and thermal stress-induced protein aggregation and prevents subvisible particle formation compared to PS 80. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Derivatives: A Basis for New Drug Formulations)

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23 pages, 5090 KiB

Open AccessArticle

Comparative Interaction Studies of Quercetin with 2-Hydroxyl-propyl-β-cyclodextrin and 2,6-Methylated-β-cyclodextrin

by Vasiliki Vakali, Michail Papadourakis, Nikitas Georgiou, Nikoletta Zoupanou, Dimitrios A. Diamantis, Uroš Javornik, Paraskevi Papakyriakopoulou, Janez Plavec, Georgia Valsami, Andreas G. Tzakos, Demeter Tzeli, Zoe Cournia and Thomas Mauromoustakos

Molecules 2022, 27(17), 5490; https://doi.org/10.3390/molecules27175490 - 26 Aug 2022

Cited by 9 | Viewed by 3074

Abstract

Quercetin (QUE) is a well-known natural product that can exert beneficial properties on human health. However, due to its low solubility its bioavailability is limited. In the present study, we examine whether its formulation with two cyclodextrins (CDs) may enhance its pharmacological profile. Comparative interaction studies of quercetin with 2-hydroxyl-propyl-β-cyclodextrin (2HP-β-CD) and 2,6-methylated cyclodextrin (2,6Me-β-CD) were performed using NMR spectroscopy, DFT calculations, and in silico molecular dynamics (MD) simulations. Using T1 relaxation experiments and 2D DOSY it was illustrated that both cyclodextrin vehicles can host quercetin. Quantum mechanical calculations showed the formation of hydrogen bonds between QUE with 2HP-β-CD and 2,6Μe-β-CD. Six hydrogen bonds are formed ranging between 2 to 2.8 Å with 2HP-β-CD and four hydrogen bonds within 2.8 Å with 2,6Μe-β-CD. Calculations of absolute binding free energies show that quercetin binds favorably to both 2,6Me-β-CD and 2HP-β-CD. MM/GBSA results show equally favorable binding of quercetin in the two CDs. Fluorescence spectroscopy shows moderate binding of quercetin in 2HP-β-CD (520 M⁻¹) and 2,6Me-β-CD (770 M⁻¹). Thus, we propose that both formulations (2HP-β-CD:quercetin, 2,6Me-β-CD:quercetin) could be further explored and exploited as small molecule carriers in biological studies. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Derivatives: A Basis for New Drug Formulations)

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25 pages, 3269 KiB

Open AccessArticle

Hydroxylpropyl-β-cyclodextrin as Potential Excipient to Prevent Stress-Induced Aggregation in Liquid Protein Formulations

by Tanja Stolzke, Franziska Krieg, Tao Peng, Hailong Zhang, Olaf Häusler and Christoph Brandenbusch

Molecules 2022, 27(16), 5094; https://doi.org/10.3390/molecules27165094 - 10 Aug 2022

Cited by 8 | Viewed by 3245

Abstract

Due to the growing demand for patient-friendly subcutaneous dosage forms, the ability to increasing protein solubility and stability in formulations to deliver on the required high protein concentrations is crucial. A common approach to ensure protein solubility and stability in high concentration protein formulations is the addition of excipients such as sugars, amino acids, surfactants, approved by the Food and Drug Administration. In a best-case scenario, these excipients fulfil multiple demands simultaneously, such as increasing long-term stability of the formulation, reducing protein adsorption on surfaces/interfaces, and stabilizing the protein against thermal or mechanical stress. 2-Hydroxylpropyl-β-cyclodextrin (derivative of β-cyclodextrin) holds this potential, but has not yet been sufficiently investigated for use in protein formulations. Within this work, we have systematically investigated the relevant molecular interactions to identify the potential of Kleptose^®HPB (2-hydroxylpropyl-β-cyclodextrin from Roquette Freres, Lestrem, France) as “multirole” excipient within liquid protein formulations. Based on our results three factors determine the influence of Kleptose^®HPB on protein formulation stability: (1) concentration of Kleptose^®HPB, (2) protein type and protein concentration, and (3) quality of the protein formulation. Our results not only contribute to the understanding of the relevant interactions but also enable the target-oriented use of Kleptose^®HPB within formulation design. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Derivatives: A Basis for New Drug Formulations)

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18 pages, 2361 KiB

Open AccessArticle

Stability, Antioxidant Activity and Intestinal Permeation of Oleuropein Inclusion Complexes with Beta-Cyclodextrin and Hydroxypropyl-Beta-Cyclodextrin

by Hui Liu, Jinhua Luo, Ping Yang, Xiulan Yang, Jun Yan and Qian Yao

Molecules 2022, 27(16), 5077; https://doi.org/10.3390/molecules27165077 - 10 Aug 2022

Cited by 2 | Viewed by 2175

Abstract

Compared to beta-cyclodextrins (beta-CD), hydroxypropyl-beta-cyclodextrins (HP-beta-CD) are a more popular material used to prepare inclusion complexes due to their superior solubility and intestinal absorption. In this study, oleuropein (OL) inclusion complexes with beta-CD (beta-CD:OL) and HP-beta-CD (HP-beta-CD:OL) were prepared and the formation of inclusion complexes was validated by IR, PXRD, and DSC. A phase solubility test showed that the lgK (25 °C) and binding energy of beta-CD:OL and HP-beta-CD:OL was 2.32 versus 1.98, and −6.1 versus −24.66 KJ/mol, respectively. Beta-CD:OL exhibited a more powerful effect than HP-beta-CD:OL in protecting OL from degradation upon exposure to light, high temperature and high humidity. Molecular docking, peak intensity of carbonyls in IR, and ferric reducing power revealed that beta-CD:OL formed more hydrogen bonds with the unstable groups of OL. Both inclusion complexes significantly enhanced the solubility, intestinal permeation and antioxidant activity of OL (p < 0.05). Though HP-beta-CD:OL had higher solubility and intestinal absorption over beta-CD:OL, the difference was not significant (p > 0.05). The study implies that lower binding energy is not always associated with the higher stability of a complex. Beta-CD can protect a multiple-hydroxyl compound more efficiently than HP-beta-CD with the intestinal permeation comparable to HP-beta-CD complex. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Derivatives: A Basis for New Drug Formulations)

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25 pages, 7831 KiB

Open AccessArticle

Galangin/β-Cyclodextrin Inclusion Complex as a Drug-Delivery System for Improved Solubility and Biocompatibility in Breast Cancer Treatment

by Zainab S. Abbas, Ghassan M. Sulaiman, Majid S. Jabir, Salman A. A. Mohammed, Riaz A. Khan, Hamdoon A. Mohammed and Amal Al-Subaiyel

Molecules 2022, 27(14), 4521; https://doi.org/10.3390/molecules27144521 - 15 Jul 2022

Cited by 56 | Viewed by 3369

Abstract

The purpose of this study was to evaluate the potential of a newly modified cyclodextrin derivative, water-soluble β-cyclodextrin–epichlorohydrin (β-CD), as an effective drug carrier to enhance the poor solubility and bioavailability of galangin (GAL), a poorly water-soluble model drug. In this regard, inclusion complexes of GAL/β-CDP were prepared. UV-VIS spectrophotometry, Fourier-transform infrared spectroscopy (FTIR), X-ray crystallography (XRD), zeta potential analysis, particle size analysis, field emission scanning electron microscopy (FESEM), and transmission electron microscopy (TEM) were applied to characterize the synthesized GAL/β-CD. Michigan Cancer Foundation-7 (MCF-7; human breast cancer cells) and rat embryo fibroblast (REF; normal cells) were employed to examine the in vitro cytotoxic effects of GAL/β-CD using various parameters. The dye-based tests of MTT and crystal violet clearly exhibited that GAL/β-CD-treated cells had a reduced proliferation rate, an influence that was not found in the normal cell line. The cells’ death was found to follow apoptotic mechanisms, as revealed by the dye-based test of acridine orange/ethidium bromide (AO/EtBr), with the involvement of the mitochondria via caspase-3-mediated events, as manifested by the Rh 123 test. We also included a mouse model to examine possible in vivo toxic effects of GAL/β-CD. It appears that the inclusion complex does not have a significant influence on normal cells, as indicated by serum levels of kidney and liver enzymatic markers, as well as thymic and splenic mass indices. A similar conclusion was reached on the histological level, as manifested by the absence of pathological alterations in the liver, kidney, thymus, spleen, heart, and lung. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Derivatives: A Basis for New Drug Formulations)

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17 pages, 2536 KiB

Open AccessArticle

Losartan Interactions with 2-Hydroxypropyl-β-CD

by Vasiliki Palli, Georgios Leonis, Nikoletta Zoupanou, Nikitas Georgiou, Maria Chountoulesi, Nikolaos Naziris, Demeter Tzeli, Costas Demetzos, Georgia Valsami, Konstantinos D. Marousis, Georgios A. Spyroulias and Thomas Mavromoustakos

Molecules 2022, 27(8), 2421; https://doi.org/10.3390/molecules27082421 - 8 Apr 2022

Cited by 7 | Viewed by 2774

Abstract

Losartan potassium salt (LSR) is a well-known antihypertensive drug with proven beneficial effects on human health. Its formulation with the non-toxic 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) could improve its pharmacological profile. Thus, its molecular interactions are studied using a combination of Differential Scanning Calorimetry (DSC), Nuclear Magnetic Resonance (NMR) and Molecular Dynamics (MD). First, its complexation is shown through Differential Scanning Calorimetry as lyophilization provided distinct thermal properties in comparison to the mixture. The complexation is further proved by utilizing the chemical shift changes in the complexation and T1 values. Furthermore, the reversible favorable complexation was shown by MD calculations. Such physical chemical properties provide evidence that this formulation must be further explored through biological experiments. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Derivatives: A Basis for New Drug Formulations)

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18 pages, 3820 KiB

Open AccessArticle

Molecular Dynamic Simulation Analysis on the Inclusion Complexation of Plumbagin with β-Cyclodextrin Derivatives in Aqueous Solution

by Kulpavee Jitapunkul, Pisanu Toochinda and Luckhana Lawtrakul

Molecules 2021, 26(22), 6784; https://doi.org/10.3390/molecules26226784 - 10 Nov 2021

Cited by 6 | Viewed by 2648

Abstract

Stable encapsulation of medically active compounds can lead to longer storage life and facilitate the slow-release mechanism. In this work, the dynamic and molecular interactions between plumbagin molecule with β-cyclodextrin (BCD) and its two derivatives, which are dimethyl-β-cyclodextrin (MBCD), and 2-O-monohydroxypropyl-β-cyclodextrin (HPBCD) were investigated. Molecular dynamics simulations (MD) with GLYCAM-06 and AMBER force fields were used to simulate the inclusion complex systems under storage temperature (4 °C) in an aqueous solution. The simulation results suggested that HPBCD is the best encapsulation agent to produce stable host–guest binding with plumbagin. Moreover, the observation of the plumbagin dynamic inside the binding cavity revealed that it tends to orient the methyl group toward the wider rim of HPBCD. Therefore, HPBCD is a decent candidate for the preservation of plumbagin with a promising longer storage life and presents the opportunity to facilitate the slow-release mechanism. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Derivatives: A Basis for New Drug Formulations)

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20 pages, 5514 KiB

Open AccessArticle

On the Interactions of Melatonin/β-Cyclodextrin Inclusion Complex: A Novel Approach Combining Efficient Semiempirical Extended Tight-Binding (xTB) Results with Ab Initio Methods

by Riccardo Ferrero, Stefano Pantaleone, Massimo Delle Piane, Fabrizio Caldera, Marta Corno, Francesco Trotta and Valentina Brunella

Molecules 2021, 26(19), 5881; https://doi.org/10.3390/molecules26195881 - 28 Sep 2021

Cited by 22 | Viewed by 3957

Abstract

Melatonin (MT) is a molecule of paramount importance in all living organisms, due to its presence in many biological activities, such as circadian (sleep–wake cycle) and seasonal rhythms (reproduction, fattening, molting, etc.). Unfortunately, it suffers from poor solubility and, to be used as a drug, an appropriate transport vehicle has to be developed, in order to optimize its release in the human tissues. As a possible drug-delivery system, β-cyclodextrin (βCD) represents a promising scaffold which can encapsulate the melatonin, releasing when needed. In this work, we present a computational study supported by experimental IR spectra on inclusion MT/βCD complexes. The aim is to provide a robust, accurate and, at the same time, low-cost methodology to investigate these inclusion complexes both with static and dynamic simulations, in order to study the main actors that drive the interactions of melatonin with β-cyclodextrin and, therefore, to understand its release mechanism. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Derivatives: A Basis for New Drug Formulations)

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15 pages, 1196 KiB

Open AccessReview

Melatonin/Cyclodextrin Inclusion Complexes: A Review

by Aikaterini Sakellaropoulou, Angeliki Siamidi and Marilena Vlachou

Molecules 2022, 27(2), 445; https://doi.org/10.3390/molecules27020445 - 10 Jan 2022

Cited by 17 | Viewed by 3244

Abstract

Melatonin (MLT) is involved in many functions of the human body, mainly in sleeping-related disorders. It also has anti-oxidant potential and has been proven very effective in the treatment of seasonal affective disorders (SAD), which afflict some people during short winter days. Melatonin has been implicated in a range of other conditions, including Parkinson’s disease, Alzheimer’s and other neurological conditions, and in certain cancers. Its poor solubility in water leads to an insufficient absorption that led scientists to investigate MLT inclusion in cyclodextrins (CDs), as inclusion of drugs in CDs is a way of increasing the solubility of many lipophilic moieties with poor water solubility. The aim of this review is to gather all the key findings on MLT/CD complexes. The literature appraisal concluded that MLT inclusion leads to a 1:1 complex with the majority of CDs and increases the solubility of the hormone. The interactions of MLT with CDs can be studied by a variety of techniques, such as NMR, FT-IR, XRD and DCS. More importantly, the in vivo experiments showed an increase in the uptake of MLT when included in a CD. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Derivatives: A Basis for New Drug Formulations)

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