Pharmaceutical and Biomedical Applications of Cyclodextrins and Derivatives

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 22996

Special Issue Editors

Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, H-4032 Debrecen, Hungary
Interests: cyclodextrins; host-guest complexation; drug delivery; biological barriers; cellular effects of cyclodextrins; pharmacokinetics and tissue distribution of cyclodextrins
Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, H-4032 Debrecen, Hungary
Interests: drug delivery; biological barriers; pharmaceutics; inflammation; phytochemicals; natural products; polyphenols; antioxidants

Special Issue Information

Dear Colleagues,

Cyclodextrin research has had almost continuous progress for more than a hundred years, and in recent decades new ideas concerning pharmaceutical and biomedical applications have spread. The widely known pharmaceutical application of cyclodextrins is based on their efficient complexing ability to improve the solubility and bioavailability of poorly soluble small drug molecules. Indeed, to this day, complexation is one of the most important uses of cyclodextrins. On the other hand, recently, cyclodextrins have also been used for the formulation of large molecules, such as peptides and nucleic acids. Applying cyclodextrin derivatives including polymers, new cyclodextrin-based systems were developed for improved drug delivery. Despite the extensive research, complexation, and formulation with cyclodextrins has untapped potential.

Host–guest interaction is also the basis of their effects in biological systems, as they can interact with biomolecules. From this point of view, they are not inactive molecules and this ability can be used in biomedical applications. Great progress can be seen in the research of infectious diseases, cardiovascular diseases, and cholesterol-related neurodegenerative diseases. A milestone of the history of cyclodextrins is the approval of 2-hydroxypropyl-β-cyclodextrin as an orphan drug in the treatment of Niemann–Pick disease type C. Nevertheless, there are still many unresolved questions in the field of biological activities and the behavior of cyclodextrins at different levels of biological systems. Effects on cellular organelles, cells, barriers, tissues, and organs must be studied to reveal and understand their full spectrum of actions.

This Special Issue will collect the latest innovative researches in the field of pharmaceutical and biomedical applications of cyclodextrins. The highlighted topics are closely related to each other and to understand the effects of cyclodextrins and reveal their potentials these questions must be examined in a complex manner. Reviews, original research articles, and short communications will be considered.

Dr. Ferenc Fenyvesi
Dr. Judit Váradi
Guest Editor

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Keywords

  • Complexation with cyclodextrins
  • Host–guest interaction
  • Drug delivery
  • Biological effects of cyclodextrins
  • Cyclodextrin-based therapeutics

Published Papers (8 papers)

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Research

14 pages, 5528 KiB  
Article
Physico-Chemical, In Vitro and Ex Vivo Characterization of Meloxicam Potassium-Cyclodextrin Nanospheres
by Patrícia Varga, Rita Ambrus, Piroska Szabó-Révész, Dávid Kókai, Katalin Burián, Zsolt Bella, Ferenc Fenyvesi and Csilla Bartos
Pharmaceutics 2021, 13(11), 1883; https://doi.org/10.3390/pharmaceutics13111883 - 06 Nov 2021
Cited by 3 | Viewed by 2013
Abstract
Nasal drug delivery has many beneficial properties, such as avoiding the first pass metabolism and rapid onset of action. However, the limited residence time on the mucosa and limited absorption of certain molecules make the use of various excipients necessary to achieve high [...] Read more.
Nasal drug delivery has many beneficial properties, such as avoiding the first pass metabolism and rapid onset of action. However, the limited residence time on the mucosa and limited absorption of certain molecules make the use of various excipients necessary to achieve high bioavailability. The application of mucoadhesive polymers can increase the contact time with the nasal mucosa, and permeation enhancers can enhance the absorption of the drug. We aimed to produce nanoparticles containing meloxicam potassium (MEL-P) by spray drying intended for nasal application. Various cyclodextrins (hydroxypropyl-β-cyclodextrin, α-cyclodextrin) and biocompatible polymers (hyaluronic acid, poly(vinylalcohol)) were used as excipients to increase the permeation of the drug and to prepare mucoadhesive products. Physico-chemical, in vitro and ex vivo biopharmaceutical characterization of the formulations were performed. As a result of spray drying, mucoadhesive nanospheres (average particle size <1 µm) were prepared which contained amorphous MEL-P. Cyclodextrin-MEL-P complexes were formed and the applied excipients increased the in vitro and ex vivo permeability of MEL-P. The highest amount of MEL-P permeated from the α-cyclodextrin-based poly(vinylalcohol)-containing samples in vitro (209 μg/cm2) and ex vivo (1.47 μg/mm2) as well. After further optimization, the resulting formulations may be promising for eliciting a rapid analgesic effect through the nasal route. Full article
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17 pages, 5047 KiB  
Article
Preformulation Studies and Bioavailability Enhancement of Curcumin with a ‘Two in One’ PEG-β-Cyclodextrin Polymer
by Ádám Haimhoffer, Eleftheria Dossi, Monika Béresová, Ildikó Bácskay, Judit Váradi, Ashfaq Afsar, Ágnes Rusznyák, Gábor Vasvári and Ferenc Fenyvesi
Pharmaceutics 2021, 13(10), 1710; https://doi.org/10.3390/pharmaceutics13101710 - 16 Oct 2021
Cited by 4 | Viewed by 2741
Abstract
Drug delivery systems are used to improve the biopharmaceutical properties of curcumin. Our aim was to investigate the effect of a water-soluble ‘two in one’ polymer containing covalently bonded PEG and βCD moieties (βCPCD) on the solubility and bioavailability of curcumin and compare [...] Read more.
Drug delivery systems are used to improve the biopharmaceutical properties of curcumin. Our aim was to investigate the effect of a water-soluble ‘two in one’ polymer containing covalently bonded PEG and βCD moieties (βCPCD) on the solubility and bioavailability of curcumin and compare it to a polymeric β-cyclodextrin (βCDP) cross-linked with epichlorohydrin. Phase-solubility and dynamic light scattering (DLS) experiments showed that the solubility of curcumin increased significantly in 10 m/m % βCPCD and βCDP solutions, but βCPCD–curcumin particles had higher hydrodynamic volume. The formation of the βCPCD–curcumin complex in solution and sedimented phase was confirmed by NMR spectroscopy. Biocompatibility and permeability experiments were performed on Caco-2 cells. Polymers did not show cytotoxicity up to 10 m/m % and βCPCD significantly increased the permeability of curcumin. DLS measurements revealed that among the interaction of polymers with mucin, βCPCD formed bigger aggregates compared to βCDP. Curcumin complexes were lyophilized into capsules and structurally characterized by micro-CT spectroscopy. Drug release was tested in a pH 1.2 medium. Lyophilized complexes had a solid porous matrix and both βCPCD and βCDP showed rapid drug release. βCPCD provides an opportunity to create a swellable, mucoadhesive matrix system for oral drug delivery. Full article
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13 pages, 2372 KiB  
Article
Proving Nanoscale Chiral Interactions of Cyclodextrins and Propranolol Enantiomers by Means of SERS Measurements Performed on a Solid Plasmonic Substrate
by Gabriela Fabiola Știufiuc, Valentin Toma, Anca Onaciu, Vasile Chiș, Constantin Mihai Lucaciu and Rareș Ionuț Știufiuc
Pharmaceutics 2021, 13(10), 1594; https://doi.org/10.3390/pharmaceutics13101594 - 01 Oct 2021
Cited by 8 | Viewed by 1751
Abstract
Chiral separation is an important issue for the pharmaceutical industry. Over the years, several separation methods have been developed, mainly based on chromatography. Their working principle is based on the formation of transient diastereoisomers, but the very subtle nanoscale interactions responsible for separation [...] Read more.
Chiral separation is an important issue for the pharmaceutical industry. Over the years, several separation methods have been developed, mainly based on chromatography. Their working principle is based on the formation of transient diastereoisomers, but the very subtle nanoscale interactions responsible for separation are not always understood. Recently, Raman and surface-enhanced Raman (SERS) spectroscopy have provided promising results in this field. Here we present Raman/SERS experimental data that provide useful information concerning the nanoscale interactions between propranolol enantiomers and α, β, and γ cyclodextrins. Raman spectroscopy was used to prove the formation of host–guest intermolecular complexes having different geometries of interaction. The occurrence of new vibrational bands and a change in the intensities of others are direct proofs of complexes’ formation. These observations were confirmed by DFT calculations. By performing SERS measurements on a new type of plasmonic substrate, we were able to prove the intermolecular interactions responsible for PRNL discrimination. It turned out that the interaction strength between the substrate and the intermolecular complexes is of paramount importance for SERS-based chiral discrimination. This approach could represent a very good starting point for the evaluation of molecular interactions manifesting between other pharmaceutical compounds and different classes of chiral selectors. Full article
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23 pages, 17846 KiB  
Article
When Cyclodextrins Met Data Science: Unveiling Their Pharmaceutical Applications through Network Science and Text-Mining
by Juliana Rincón-López, Yara C. Almanza-Arjona, Alejandro P. Riascos and Yareli Rojas-Aguirre
Pharmaceutics 2021, 13(8), 1297; https://doi.org/10.3390/pharmaceutics13081297 - 19 Aug 2021
Cited by 12 | Viewed by 3149
Abstract
We present a data-driven approach to unveil the pharmaceutical technologies of cyclodextrins (CDs) by analyzing a dataset of CD pharmaceutical patents. First, we implemented network science techniques to represent CD patents as a single structure and provide a framework for unsupervised detection of [...] Read more.
We present a data-driven approach to unveil the pharmaceutical technologies of cyclodextrins (CDs) by analyzing a dataset of CD pharmaceutical patents. First, we implemented network science techniques to represent CD patents as a single structure and provide a framework for unsupervised detection of keywords in the patent dataset. Guided by those keywords, we further mined the dataset to examine the patenting trends according to CD-based dosage forms. CD patents formed complex networks, evidencing the supremacy of CDs for solubility enhancement and how this has triggered cutting-edge applications based on or beyond the solubility improvement. The networks exposed the significance of CDs to formulate aqueous solutions, tablets, and powders. Additionally, they highlighted the role of CDs in formulations of anti-inflammatory drugs, cancer therapies, and antiviral strategies. Text-mining showed that the trends in CDs for aqueous solutions, tablets, and powders are going upward. Gels seem to be promising, while patches and fibers are emerging. Cyclodextrins’ potential in suspensions and emulsions is yet to be recognized and can become an opportunity area. This is the first unsupervised/supervised data-mining approach aimed at depicting a landscape of CDs to identify trending and emerging technologies and uncover opportunity areas in CD pharmaceutical research. Full article
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18 pages, 2477 KiB  
Article
Nanofibrous Formulation of Cyclodextrin Stabilized Lipases for Efficient Pancreatin Replacement Therapies
by Gergő Dániel Tóth, Adrienn Kazsoki, Benjámin Gyarmati, András Szilágyi, Gábor Vasvári, Gábor Katona, Lajos Szente, Romána Zelkó, László Poppe, Diána Balogh-Weiser and György T. Balogh
Pharmaceutics 2021, 13(7), 972; https://doi.org/10.3390/pharmaceutics13070972 - 27 Jun 2021
Cited by 3 | Viewed by 2632
Abstract
Enzyme replacement therapies (ERT) have been of great help over the past 30 years in the treatment of various lysosomal storage disorders, including chronic pancreatitis and its common complication, exocrine pancreatic insufficiency. Research shows that difficulties in designing such drugs can be overcome [...] Read more.
Enzyme replacement therapies (ERT) have been of great help over the past 30 years in the treatment of various lysosomal storage disorders, including chronic pancreatitis and its common complication, exocrine pancreatic insufficiency. Research shows that difficulties in designing such drugs can be overcome by using appropriate additives and various enzyme immobilization techniques. Cyclodextrins (CDs) can be considered as a promising additive for enzyme replacement therapies, as they are known to enhance the activity of enzymes in a complex process due to their specific binding. In this study, we investigated the formulation of lipases (from Aspergillus oryzae and Burkholderia cepacia) paired with different cyclodextrins in poly(vinyl alcohol) (PVA) nanofibers by electrospinning technique. We examined the effect of the presence of cyclodextrins and nanoformulation on the lipase activity. The rheological and morphological characterizations of precursors and nanofibers were also performed using a viscometer as well as electron and Raman microscope. We found that by selecting the appropriate CD:lipase ratio, the activity of the investigated enzyme could be multiplied, and cyclodextrins can support the homogeneous dispersion of lipases inside the solid formula. In addition, the entrapment of lipases in PVA nanofibers led to a significant increase in activity compared to the preformulated precursor. In this way, the nanofibrous formulation of lipases combining CDs as additives can provide an efficient and sustainable possibility for designing novel solid medicines in ERT. Full article
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11 pages, 1574 KiB  
Article
Development of an Improved Method for the Determination of Iodine/β-Cyclodextrin by Means of HPLC-UV: Validation and the Thyroid-Stimulating Activity Revealed by In Vivo Studies
by Avez Sharipov, Zufar Boboev, Sunnatullo Fazliev, Shokhid Gulyamov, Akhmatkhodja Yunuskhodjayev and Jamoliddin Razzokov
Pharmaceutics 2021, 13(7), 955; https://doi.org/10.3390/pharmaceutics13070955 - 25 Jun 2021
Viewed by 2795
Abstract
Iodine, being an intrinsic part of thyroid hormones, is a vital microelement required for normal growth and development, particularly in children. Inadequate daily intake of iodine causes iodine deficiency, which is responsible for several health disorders, such as cretinism and goiters. Therefore, the [...] Read more.
Iodine, being an intrinsic part of thyroid hormones, is a vital microelement required for normal growth and development, particularly in children. Inadequate daily intake of iodine causes iodine deficiency, which is responsible for several health disorders, such as cretinism and goiters. Therefore, the development of new drugs and/or food supplements for iodine deficiency is crucial. We synthesized an iodine/β-cyclodextrin complex based on a host–guest model, and in this paper, we outline the development of a new quantitative analysis method. We suggest a robust and reliable high-performance liquid chromatography method to determine the total amount of iodine species in the complex. Moreover, we performed validation of our method. The results of validation presented here show the reliability, accuracy and high precision of the method. Furthermore, for the first time, we show results of in vivo studies for the thyroid-stimulating activity of the iodine/β-cyclodextrin complex. Our findings indicate that the thyroid-stimulating activity of iodine/β-cyclodextrin is comparable to that of potassium iodide, which is the main active pharmaceutical substance of conventional drugs for iodine deficiency. Full article
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19 pages, 4083 KiB  
Article
Formulation of Chewable Tablets Containing Carbamazepine-β-cyclodextrin Inclusion Complex and F-Melt Disintegration Excipient. The Mathematical Modeling of the Release Kinetics of Carbamazepine
by Adina Magdalena Musuc, Valentina Anuta, Irina Atkinson, Iulian Sarbu, Vlad Tudor Popa, Cornel Munteanu, Constantin Mircioiu, Emma Adriana Ozon, George Mihai Nitulescu and Mirela Adriana Mitu
Pharmaceutics 2021, 13(6), 915; https://doi.org/10.3390/pharmaceutics13060915 - 21 Jun 2021
Cited by 14 | Viewed by 3339
Abstract
Due to its low solubility, carbamazepine (CBZ) exhibits slow and incomplete release in the gastrointestinal tract and, hence, variable pharmacokinetics and pharmacodynamic effect. Lots of methods have been devised to improve its solubility, the large number of proposed solutions being a sign that [...] Read more.
Due to its low solubility, carbamazepine (CBZ) exhibits slow and incomplete release in the gastrointestinal tract and, hence, variable pharmacokinetics and pharmacodynamic effect. Lots of methods have been devised to improve its solubility, the large number of proposed solutions being a sign that the problem is not yet satisfactorily solved. The persistent problem is that predictable release kinetics, an increased rate but within defined limits, are required to avoid high absorption variability. This paper presents a synthesis of a carbamazepine-β-cyclodextrin inclusion complex (CBZ-β-CD), the characterization of the physical mixture, CBZ, β-CD and the CBZ-β-CD inclusion complex using Fourier transform infrared spectroscopy, scanning electron microscopy, simultaneous thermal analysis and X-ray diffraction, formulation of chewable tablets, determination of the dissolution of carbamazepine in medium containing 1% sodium lauryl sulfate (LSS), and in simulated saliva (SS), mathematical modeling of release kinetics. The kinetics of total CBZ release from tablets containing CBZ-β-CD and super-disintegrant F-Melt in both SS and LSS followed two steps: a burst release in the first minutes and a slower release in intervals up to 60 min. The release in the second phase has been well described by the Higuchi and Peppas models, which advocate a controlled release by combined diffusion and with some phenomena of swelling and relaxation of the matrix generated by the crospovidone component of the F-Melt excipient. Full article
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14 pages, 15667 KiB  
Article
Investigation of the Cellular Effects of Beta- Cyclodextrin Derivatives on Caco-2 Intestinal Epithelial Cells
by Ágnes Rusznyák, Milo Malanga, Éva Fenyvesi, Lajos Szente, Judit Váradi, Ildikó Bácskay, Miklós Vecsernyés, Gábor Vasvári, Ádám Haimhoffer, Pálma Fehér, Zoltán Ujhelyi, Béla Nagy Jr., Zsolt Fejes and Ferenc Fenyvesi
Pharmaceutics 2021, 13(2), 157; https://doi.org/10.3390/pharmaceutics13020157 - 25 Jan 2021
Cited by 10 | Viewed by 3273
Abstract
Cyclodextrins are widely used excipients for increasing water-solubility, delivery and bioavailability of lipophilic drugs. By using fluorescent cyclodextrin derivatives, we showed previously that cyclodextrins are able to enter Caco-2 intestinal cells by endocytosis, but the influence of different fluorescent labeling on the same [...] Read more.
Cyclodextrins are widely used excipients for increasing water-solubility, delivery and bioavailability of lipophilic drugs. By using fluorescent cyclodextrin derivatives, we showed previously that cyclodextrins are able to enter Caco-2 intestinal cells by endocytosis, but the influence of different fluorescent labeling on the same cyclodextrin derivative has not been studied. The consequences of the cellular internalization of cyclodextrins have not been revealed yet either. The aims of this study were to compare the cellular internalization of fluorescein- and rhodamine-labeled (2-hydroxypropyl)-, (HPBCD) and randommethyl-β-cyclodextrins (RAMEB) and to investigate the intracellular effects of these derivatives on Caco-2 cells. Stimulation of the NF-kappa B pathway and autophagy and localization of these derivatives in lysosomes were tested. The endocytosis of these derivatives was examined by fluorescence microscopy and flow cytometry. Both fluorescein- and rhodamine-labeled derivatives entered the cells, therefore the type of the fluorescent labeling did not influence their internalization. Cyclodextrin pretreatment did not activate the translocation of the p65 subunit of the NF-kappa B heterodimer into the cell nuclei from the cytoplasm. After HPBCD or RAMEB treatment, formation of the autophagosomes did not increase compared to the control sample and at the same time these derivatives could be detected in lysosomes after internalization. Full article
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