Special Issue "Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses"

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: 31 October 2022 | Viewed by 3607

Special Issue Editors

Prof. Dr. Frederico B. De Sousa
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Guest Editor
Laboratório de Sistemas POliméricos e Supramoleculares, Instituto de Física Química, Universidade Federal de Itajubá, Itajubá 37500-903, MG, Brazil
Interests: cyclodextrin; polymer; electrospinning; chromism; hybrid materials
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Juliana Fedoce Lopes
E-Mail Website
Guest Editor
Laboratório de Química Computacional (LaQC), Instituto de Física Química, Universidade Federal de Itajubá, Itajubá 37500-903, MG, Brazil
Interests: cyclodextrin; inclusion complexes; computational chemistry; thermodynamic

Special Issue Information

Dear Colleagues,

Cyclodextrins comprise a family of compounds structured by (α-1,4) glucopyranose units with a hydrophilic outer surface and hydrophobic cavity. Being one of the most versatile molecules in pharmaceutical technology, cyclodextrins are capable of forming inclusion complexes with a variety of guest molecules. Moreover, cyclodextrins are also a prominent subject in different research areas, especially chemistry, pharmaceutics, and pharmacology. Structured by non-covalent interaction, the host–guest supramolecular systems have been used in pharmaceutical formulations since 1970. Therefore, understanding supramolecular structures interactions, including physical and chemical parameters of the host–guest systems, are crucial when analyzing in vitro and in vivo data from the superstructures compared to the free drug molecules. Among many drug molecules properties that can be modified by cyclodextrins, the most common pharmaceutical applications are to enhance drug solubility, stability, and bioavailability. This Special Issue will collect researches covering physical and/or chemical characterization (by experimental and computational findings) of cyclodextrins inclusion complexes and their uses in the pharmaceutical and biomedical application topics.

Prof. Dr. Frederico De Sousa
Prof. Dr. Juliana Fedoce Lopes
Guest Editors

Manuscript Submission Information

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Keywords

  • cyclodextrin
  • cyclodextrin polymers
  • inclusion complexes
  • characterization
  • physical–chemical characterization
  • computational chemistry
  • supramolecular structure
  • host–guest interaction
  • drug release
  • in vitro and/or in vivo studies

Published Papers (7 papers)

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Research

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Article
Cyclodextrin Derivatives as Promising Solubilizers to Enhance the Biological Activity of Rosmarinic Acid
Pharmaceutics 2022, 14(10), 2098; https://doi.org/10.3390/pharmaceutics14102098 (registering DOI) - 30 Sep 2022
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Abstract
Rosmarinic acid (RA) is a natural antioxidant with neuroprotective properties; however, its preventive and therapeutic use is limited due to its slight solubility and poor permeability. This study aimed to improve RA physicochemical properties by systems formation with cyclodextrins (CDs): hydroxypropyl-α-CD (HP-α-CD), HP-β-CD, [...] Read more.
Rosmarinic acid (RA) is a natural antioxidant with neuroprotective properties; however, its preventive and therapeutic use is limited due to its slight solubility and poor permeability. This study aimed to improve RA physicochemical properties by systems formation with cyclodextrins (CDs): hydroxypropyl-α-CD (HP-α-CD), HP-β-CD, and HP-γ-CD, which were prepared by the solvent evaporation (s.e.) method. The interactions between components were determined by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Fourier Transform infrared spectroscopy (FTIR). The sites of interaction between RA and CDs were suggested as a result of in silico studies focused on assessing the interaction between molecules. The impact of amorphous systems formation on water solubility, dissolution rate, gastrointestinal (GIT) permeability, and biological activity was studied. RA solubility was increased from 5.869 mg/mL to 113.027 mg/mL, 179.840 mg/mL, and 194.354 mg/mL by systems formation with HP-α-CD, HP-β-CD, and HP-γ-CD, respectively. During apparent solubility studies, the systems provided an acceleration of RA dissolution. Poor RA GIT permeability at pH 4.5 and 5.8, determined by parallel artificial membrane permeability assay (PAMPA system), was increased; RA–HP-γ-CD s.e. indicated the greatest improvement (at pH 4.5 from Papp 6.901 × 10−7 cm/s to 1.085 × 10−6 cm/s and at pH 5.8 from 5.019 × 10−7 cm/s to 9.680 × 10−7 cm/s). Antioxidant activity, which was determined by DPPH, ABTS, CUPRAC, and FRAP methods, was ameliorated by systems; the greatest results were obtained for RA–HP-γ-CD s.e. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) was increased from 36.876% for AChE and 13.68% for BChE to a maximum inhibition of the enzyme (plateau), and enabled reaching IC50 values for both enzymes by all systems. CDs are efficient excipients for improving RA physicochemical and biological properties. HP-γ-CD was the greatest one with potential for future food or dietary supplement applications. Full article
(This article belongs to the Special Issue Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses)
Article
Alternative Methotrexate Oral Formulation: Enhanced Aqueous Solubility, Bioavailability, Photostability, and Permeability
Pharmaceutics 2022, 14(10), 2073; https://doi.org/10.3390/pharmaceutics14102073 - 28 Sep 2022
Viewed by 275
Abstract
The poor aqueous solubility and/or permeability and thereby limited bioavailability largely restricts the pharmaco-therapeutic implications of potent anticancer drugs such as methotrexate (MTX). Furthermore, MTX’s inherently unstable nature makes it difficult to develop a viable oral formulation. In this study we developed the [...] Read more.
The poor aqueous solubility and/or permeability and thereby limited bioavailability largely restricts the pharmaco-therapeutic implications of potent anticancer drugs such as methotrexate (MTX). Furthermore, MTX’s inherently unstable nature makes it difficult to develop a viable oral formulation. In this study we developed the spray-dried amorphous inclusion complexes of MTX with native β-cyclodextrin (β-CD) and its derivatives, namely HP-β-CD, M-β-CD, and DM-β-CD to enhance the aqueous solubility, photostability, permeability, and oral bioavailability of MTX in rats. Our findings show that the 1:1 stoichiometry ratio of MTX and CDs improves the aqueous solubility, stability, and pharmacokinetic profiles of the drug, the better results being obtained particularly with DM-β-CD as a host, which has a higher complexation ability with the drug compared to other β-CDs. Specifically, the pharmacokinetic analysis demonstrated 2.20- and 3.29-fold increments in AUC and Cmax, respectively, in comparison to free MTX. Even though the absorptive permeability of MTX and MTX/DM-β-CD inclusion complexes was similar, the efflux of the absorbed MTX from ICs was significantly lower compared to the free MTX (4.6- vs. 8.0-fold). Furthermore, the physicochemical characterization employing SEM, DSC, and PXRD confirmed the transformation of crystalline MTX to its amorphous state. In solution, 1H NMR studies revealed that MTX embedded into the DM-β-CD cavity resulting in both H-3 and H-5 chemical shifts implied the presence of intermolecular interaction between the drug and CD moiety. It was, therefore, evident that an MTX IC could be a successful oral formulation technique, preventing MTX degradation and enhancing its pharmacologically relevant properties. Full article
(This article belongs to the Special Issue Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses)
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Article
Preparation and Characterisation of a Cyclodextrin-Complexed Mānuka Honey Microemulsion for Eyelid Application
Pharmaceutics 2022, 14(7), 1493; https://doi.org/10.3390/pharmaceutics14071493 - 19 Jul 2022
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Abstract
Honey has been widely purported as a natural remedy due to its antimicrobial and anti-inflammatory effects. In recent years, several studies have suggested that the considerably high methylglyoxal (MGO) concentration in Mānuka honey (MH) makes it particularly effective to manage bacterial overload, such [...] Read more.
Honey has been widely purported as a natural remedy due to its antimicrobial and anti-inflammatory effects. In recent years, several studies have suggested that the considerably high methylglyoxal (MGO) concentration in Mānuka honey (MH) makes it particularly effective to manage bacterial overload, such as that observed in blepharitis. However, the poor solubility, high viscosity, and osmolarity of aqueous honey solutions, especially at the high MGO concentrations studied in the literature, render the formulation of an acceptable dosage form for topical application to the eyelids challenging. Here, the antibacterial properties of raw MH and alpha-cyclodextrin (α-CD)-complexed MH were evaluated at relatively low MGO concentrations, and a liquid crystalline-forming microemulsion containing α-CD-complexed MH was formulated. After determining pH and osmolarity, ocular tolerability was assessed using human primary corneal epithelial cells and chorioallantoic membranes, while the antibacterial efficacy was further evaluated in vitro. The α-CD–MH complex had significantly greater antibacterial activity against Staphylococcus aureus than either constituent alone, which was evident even when formulated as a microemulsion. Moreover, the final formulation had a physiologically acceptable pH and osmolarity for eyelid application and was well-tolerated when diluted 1:10 with artificial tear fluid, as expected to be the case after accidental exposure to the ocular surface in the clinical setting. Thus, a safe and efficient MH dosage form was developed for topical application to the eyelids, which can potentially be used to support optimal eyelid health in the management of blepharitis. Full article
(This article belongs to the Special Issue Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses)
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Article
Another Move towards Bicalutamide Dissolution and Permeability Improvement with Acetylated β-Cyclodextrin Solid Dispersion
Pharmaceutics 2022, 14(7), 1472; https://doi.org/10.3390/pharmaceutics14071472 - 15 Jul 2022
Viewed by 385
Abstract
The complex formation of antiandrogen bicalutamide (BCL) with methylated (Me-β-CD) and acetylated (Ac-β-CD) β-cyclodextrins was investigated in buffer solution pH 6.8. A two-fold strongly binding of BCL to Ac-β-CD as compared to Me-β-CD was revealed. The solid dispersion of BCL with Ac-β-CD was [...] Read more.
The complex formation of antiandrogen bicalutamide (BCL) with methylated (Me-β-CD) and acetylated (Ac-β-CD) β-cyclodextrins was investigated in buffer solution pH 6.8. A two-fold strongly binding of BCL to Ac-β-CD as compared to Me-β-CD was revealed. The solid dispersion of BCL with Ac-β-CD was prepared by the mechanical grinding procedure to obtain the complex in the solid state. The BCL/Ac-β-CD complex was characterized by DSC, XPRD, FTIR, and SEM techniques. The effect of Ac-β-CD in the BCL solid dispersions on the non-sink dissolution/permeation simultaneous processes was disclosed using the side-by-side diffusion cell with the help of the cellulose membrane. The elevated dissolution of the ground complex, as compared to the raw drug as well as the simple physical mixture, accompanied by the supersaturation was revealed. Two biopolymers—polyvinylpyrrolidone (PVP, Mn = 58,000) and hydroxypropylmethylcellulose (HPMC, Mn ~ 10,000)—were examined as the precipitation inhibitors and were shown to be useful in prolonging the supersaturation state. The BCL/Ac-β-CD complex has the fastest dissolution rate in the presence of HPMC. The maximal concentration of the complex was achieved at a time of 20, 30, and 90 min in the pure buffer, with PVP and with HPMC, respectively. The effectiveness of the BCL dissolution (release) processes (illustrated by the AUCC(t) parameter) was estimated to be 7.8-, 5.8-, 3.0-, and 1.8-fold higher for BCL/Ac-β-CD (HPMC), BCL/Ac-β-CD (PVP), BCL/Ac-β-CD (buffer), and the BCL/Ac-β-CD physical mixture, respectively, as compared to the BCL_raw sample. The excipient gain factor (EGF), calculated for the dissolution of the BCL complex, was shown to be 2.6 in the presence of HPMC, which is 1.3-fold greater as compared to PVP. From the experimental dissolution results, it can be concluded that the formation of BCL ground complex with Ac-β-CD enhances the dissolution rate of the compound. The permeation was also shown to be advantageous in the presence of the polymers, which was demonstrated by the elevated fluxes of BCL through the membrane. The comparison of the dissolution/permeation processes was illustrated and discussed. The conclusion was made that the presence of HPMC as a stabilizer of the supersaturation state is promising and seems to be a useful tool for the optimization of BCL pharmaceutical formulations manufacturing. Full article
(This article belongs to the Special Issue Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses)
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Article
Cyclodextrin Complexation of Fenofibrate by Co-Grinding Method and Monitoring the Process Using Complementary Analytical Tools
Pharmaceutics 2022, 14(7), 1329; https://doi.org/10.3390/pharmaceutics14071329 - 23 Jun 2022
Viewed by 444
Abstract
Solvent-free preparation types for cyclodextrin complexation, such as co-grinding, are technologies desired by the industry. However, in-depth analytical evaluation of the process and detailed characterization of intermediate states of the complexes are still lacking in areas. In our work, we aimed to apply [...] Read more.
Solvent-free preparation types for cyclodextrin complexation, such as co-grinding, are technologies desired by the industry. However, in-depth analytical evaluation of the process and detailed characterization of intermediate states of the complexes are still lacking in areas. In our work, we aimed to apply the co-grinding technology and characterize the process. Fenofibrate was used as a model drug and dimethyl-β-cyclodextrin as a complexation excipient. The physical mixture of the two substances was ground for 60 min; meanwhile, samples were taken. A solvent product of the same composition was also prepared. The intermediate samples and the final products were characterized with instrumental analytical tools. The XRPD measurements showed a decrease in the crystallinity of the drug and the DSC results showed the appearance of a new crystal form. Correlation analysis of FTIR spectra suggests a three-step complexation process. In vitro dissolution studies were performed to compare the dissolution properties of the pure drug to the products. Using a solvent-free production method, we succeeded in producing a two-component system with superior solubility properties compared to both the active ingredient and the product prepared by the solvent method. The intermolecular description of complexation was achieved with a detailed analysis of FTIR spectra. Full article
(This article belongs to the Special Issue Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses)
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Article
Chiral Recognition R- and RS- of New Antifungal: Complexation/Solubilization/Dissolution Thermodynamics and Permeability Assay
Pharmaceutics 2022, 14(4), 864; https://doi.org/10.3390/pharmaceutics14040864 - 15 Apr 2022
Cited by 1 | Viewed by 474
Abstract
Novel potential antifungal of 1,2,4-triazole class have been synthesized as pure enantiomer (R-98) and racemic (RS-186). The effect of 2-hydroxypropyl-β-cyclodextrin (CD) on the solubility and permeability of RS-186 and R-98 in terms of chiral recognition was investigated. Phase solubility studies were [...] Read more.
Novel potential antifungal of 1,2,4-triazole class have been synthesized as pure enantiomer (R-98) and racemic (RS-186). The effect of 2-hydroxypropyl-β-cyclodextrin (CD) on the solubility and permeability of RS-186 and R-98 in terms of chiral recognition was investigated. Phase solubility studies were carried out at 4 temperatures in 0–0.05 M CD concentration range for pH 2.0 and pH 7.4. AL- and AL-type phase-solubility profiles were obtained for both compounds in pH 2.0 and pH 7.4. The racemic formed more stable complexes with CD as compared to R-isomer. Disclosing of chiral discrimination was facilitated using the approach based on the complex consideration of the derived complexation/solubilization/inherent dissolution thermodynamic functions, including the differential parameters between the racemic compound and R-enantiomer. The differences in the thermodynamic parameters determined by the chirality were discussed in terms of the driving forces of the processes and the main interactions of the compounds with CD in solution. The membrane permeability of both samples in the presence of CD was accessed in order to evaluate the specificity of enantioselective transport through the lipophilic membrane. The solubility/permeability interrelation was disclosed. The investigated compounds were classified as medium permeable in pure buffers and low permeable in the presence of 0.01 M CD. The obtained results can be useful for the design of pharmaceutical products in the form of liquid formulations based on the investigated substances. Full article
(This article belongs to the Special Issue Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses)
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Review

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Review
Cyclodextrin Inclusion Complexes with Antibiotics and Antibacterial Agents as Drug-Delivery Systems—A Pharmaceutical Perspective
Pharmaceutics 2022, 14(7), 1389; https://doi.org/10.3390/pharmaceutics14071389 - 30 Jun 2022
Viewed by 751
Abstract
Cyclodextrins (CDs) are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits linked by α-1,4 glycosidic bonds. The shape of CD molecules is similar to a truncated cone with a hydrophobic inner cavity and a hydrophilic surface, which allows [...] Read more.
Cyclodextrins (CDs) are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits linked by α-1,4 glycosidic bonds. The shape of CD molecules is similar to a truncated cone with a hydrophobic inner cavity and a hydrophilic surface, which allows the formation of inclusion complexes with various molecules. This review article summarises over 200 reports published by the end of 2021 that discuss the complexation of CDs with antibiotics and antibacterial agents, including beta-lactams, tetracyclines, quinolones, macrolides, aminoglycosides, glycopeptides, polypeptides, nitroimidazoles, and oxazolidinones. The review focuses on drug-delivery applications such as improving solubility, modifying the drug-release profile, slowing down the degradation of the drug, improving biological membrane permeability, and enhancing antimicrobial activity. In addition to simple drug/CD combinations, ternary systems with additional auxiliary substances have been described, as well as more sophisticated drug-delivery systems including nanosponges, nanofibres, nanoparticles, microparticles, liposomes, hydrogels, and macromolecules. Depending on the desired properties of the drug product, an accelerated or prolonged dissolution profile can be achieved when combining CD with antibiotics or antimicrobial agents. Full article
(This article belongs to the Special Issue Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses)
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