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18 pages, 2429 KiB

Open AccessArticle

Thymus vulgaris Essential Oil in Beta-Cyclodextrin for Solid-State Pharmaceutical Applications

by Aldo Arrais, Elisa Bona, Valeria Todeschini, Alice Caramaschi, Nadia Massa, Maddalena Roncoli, Alessia Minervi, Elena Perin and Valentina Gianotti

Pharmaceutics 2023, 15(3), 914; https://doi.org/10.3390/pharmaceutics15030914 - 11 Mar 2023

Cited by 6 | Viewed by 1567

Abstract

Antimicrobial resistance related to the misuse of antibiotics is a well-known current topic. Their excessive use in several fields has led to enormous selective pressure on pathogenic and commensal bacteria, driving the evolution of antimicrobial resistance genes with severe impacts on human health. [...] Read more.

Antimicrobial resistance related to the misuse of antibiotics is a well-known current topic. Their excessive use in several fields has led to enormous selective pressure on pathogenic and commensal bacteria, driving the evolution of antimicrobial resistance genes with severe impacts on human health. Among all the possible strategies, a viable one could be the development of medical features that employ essential oils (EOs), complex natural mixtures extracted from different plant organs, rich in organic compounds showing, among others, antiseptic properties. In this work, green extracted essential oil of Thymus vulgaris was included in cyclic oligosaccharides cyclodextrins (CD) and prepared in the form of tablets. This essential oil has been shown to have a strong transversal efficacy both as an antifungal and as an antibacterial agent. Its inclusion allows its effective use because an extension of the exposure time to the active compounds is obtained and, therefore, a more marked efficacy, especially against biofilm-producing microorganisms such as P. aeruginosa and S. aureus, was registered. The efficacy of the tablet against candidiasis opens their possible use as a chewable tablet against oral candidiasis and as a vaginal tablet against vaginal candidiasis. Moreover, the registered wide efficacy is even more positive since the proposed approach can be defined as effective, safe, and green. In fact, the natural mixture of the essential oil is produced by the steam current method; therefore, the manufacturer employs substances that are not harmful, with very low production and management costs. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses)

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20 pages, 4734 KiB

Open AccessArticle

Hyper-Branched Cationic Cyclodextrin Polymers for Improving Plasmid Transfection in 2D and 3D Spheroid Cells

by Yousef Khazaei Monfared, Mohammad Mahmoudian, Claudio Cecone, Fabrizio Caldera, Sanya Haiaty, Hamid Reza Heidari, Reza Rahbarghazi, Adrián Matencio, Parvin Zakeri-Milani and Francesco Trotta

Pharmaceutics 2022, 14(12), 2690; https://doi.org/10.3390/pharmaceutics14122690 - 01 Dec 2022

Cited by 6 | Viewed by 1733

Abstract

In this article, we used monolayer two dimensional (2D) and 3D multicellular spheroid models to improve our understanding of the gene delivery process of a new modified cationic hyper-branched cyclodextrin-based polymer (Ppoly)-loaded plasmid encoding Enhanced Green Fluorescent Protein (EGFP). A comparison between the [...] Read more.

In this article, we used monolayer two dimensional (2D) and 3D multicellular spheroid models to improve our understanding of the gene delivery process of a new modified cationic hyper-branched cyclodextrin-based polymer (Ppoly)-loaded plasmid encoding Enhanced Green Fluorescent Protein (EGFP). A comparison between the cytotoxicity effect and transfection efficiency of the plasmid DNA (pDNA)-loaded Ppoly system in 2D and 3D spheroid cells determined that the transfection efficiency and cytotoxicity of Ppoly–pDNA nanocomplexes were lower in 3D spheroids than in 2D monolayer cells. Furthermore, histopathology visualization of Ppoly–pDNA complex cellular uptake in 3D spheroids demonstrated that Ppoly penetrated into the inner layers. This study indicated that the Ppoly, as a non-viral gene delivery system in complex with pDNA, is hemocompatible, non-toxic, high in encapsulation efficiency, and has good transfection efficiency in both 2D and 3D cell cultures compared to free pDNA and lipofectamine (as the control). Full article

(This article belongs to the Special Issue Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses)

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22 pages, 5477 KiB

Open AccessArticle

Cyclodextrin Derivatives as Promising Solubilizers to Enhance the Biological Activity of Rosmarinic Acid

by Anna Stasiłowicz-Krzemień, Natalia Rosiak, Anita Płazińska, Wojciech Płaziński, Andrzej Miklaszewski, Ewa Tykarska and Judyta Cielecka-Piontek

Pharmaceutics 2022, 14(10), 2098; https://doi.org/10.3390/pharmaceutics14102098 - 30 Sep 2022

Cited by 8 | Viewed by 2094

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 P_app 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)

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21 pages, 4645 KiB

Open AccessArticle

Alternative Methotrexate Oral Formulation: Enhanced Aqueous Solubility, Bioavailability, Photostability, and Permeability

by Bhupendra Raj Giri, Hyun Seok Yang, Im-Sook Song, Han-Gon Choi, Jung Hyun Cho and Dong Wuk Kim

Pharmaceutics 2022, 14(10), 2073; https://doi.org/10.3390/pharmaceutics14102073 - 28 Sep 2022

Cited by 4 | Viewed by 3407

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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15 pages, 2679 KiB

Open AccessArticle

Preparation and Characterisation of a Cyclodextrin-Complexed Mānuka Honey Microemulsion for Eyelid Application

by Ilva D. Rupenthal, Priyanka Agarwal, Benedict Uy, Jaeun Kim, Angela A. Cunningham, Ali Seyfoddin, Simon Swift and Jennifer P. Craig

Pharmaceutics 2022, 14(7), 1493; https://doi.org/10.3390/pharmaceutics14071493 - 19 Jul 2022

Cited by 2 | Viewed by 1697

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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22 pages, 4913 KiB

Open AccessArticle

Another Move towards Bicalutamide Dissolution and Permeability Improvement with Acetylated β-Cyclodextrin Solid Dispersion

by Tatyana V. Volkova, Olga R. Simonova and German L. Perlovich

Pharmaceutics 2022, 14(7), 1472; https://doi.org/10.3390/pharmaceutics14071472 - 15 Jul 2022

Cited by 3 | Viewed by 1380

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, M_n = 58,000) and hydroxypropylmethylcellulose (HPMC, M_n ~ 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

A U C_{C (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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21 pages, 7595 KiB

Open AccessArticle

Cyclodextrin Complexation of Fenofibrate by Co-Grinding Method and Monitoring the Process Using Complementary Analytical Tools

by Balázs Attila Kondoros, Ottó Berkesi, Zsolt Tóth, Zoltán Aigner, Rita Ambrus and Ildikó Csóka

Pharmaceutics 2022, 14(7), 1329; https://doi.org/10.3390/pharmaceutics14071329 - 23 Jun 2022

Cited by 3 | Viewed by 1408

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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21 pages, 1502 KiB

Open AccessArticle

Chiral Recognition R- and RS- of New Antifungal: Complexation/Solubilization/Dissolution Thermodynamics and Permeability Assay

by Tatyana V. Volkova, Olga R. Simonova, Igor B. Levshin and German L. Perlovich

Pharmaceutics 2022, 14(4), 864; https://doi.org/10.3390/pharmaceutics14040864 - 15 Apr 2022

Cited by 2 | Viewed by 1463

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.

A_{L}

- and

A_{L}^{-}

-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

Jump to: Research

36 pages, 2334 KiB

Open AccessReview

Cyclodextrins: Only Pharmaceutical Excipients or Full-Fledged Drug Candidates?

by Tamas Kovacs, Peter Nagy, Gyorgy Panyi, Lajos Szente, Zoltan Varga and Florina Zakany

Pharmaceutics 2022, 14(12), 2559; https://doi.org/10.3390/pharmaceutics14122559 - 22 Nov 2022

Cited by 11 | Viewed by 2350

Abstract

Cyclodextrins, representing a versatile family of cyclic oligosaccharides, have extensive pharmaceutical applications due to their unique truncated cone-shaped structure with a hydrophilic outer surface and a hydrophobic cavity, which enables them to form non-covalent host–guest inclusion complexes in pharmaceutical formulations to enhance the [...] Read more.

Cyclodextrins, representing a versatile family of cyclic oligosaccharides, have extensive pharmaceutical applications due to their unique truncated cone-shaped structure with a hydrophilic outer surface and a hydrophobic cavity, which enables them to form non-covalent host–guest inclusion complexes in pharmaceutical formulations to enhance the solubility, stability and bioavailability of numerous drug molecules. As a result, cyclodextrins are mostly considered as inert carriers during their medical application, while their ability to interact not only with small molecules but also with lipids and proteins is largely neglected. By forming inclusion complexes with cholesterol, cyclodextrins deplete cholesterol from cellular membranes and thereby influence protein function indirectly through alterations in biophysical properties and lateral heterogeneity of bilayers. In this review, we summarize the general chemical principles of direct cyclodextrin–protein interactions and highlight, through relevant examples, how these interactions can modify protein functions in vivo, which, despite their huge potential, have been completely unexploited in therapy so far. Finally, we give a brief overview of disorders such as Niemann–Pick type C disease, atherosclerosis, Alzheimer’s and Parkinson’s disease, in which cyclodextrins already have or could have the potential to be active therapeutic agents due to their cholesterol-complexing or direct protein-targeting properties. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses)

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71 pages, 885 KiB

Open AccessReview

Cyclodextrin Inclusion Complexes with Antibiotics and Antibacterial Agents as Drug-Delivery Systems—A Pharmaceutical Perspective

by Dariusz Boczar and Katarzyna Michalska

Pharmaceutics 2022, 14(7), 1389; https://doi.org/10.3390/pharmaceutics14071389 - 30 Jun 2022

Cited by 30 | Viewed by 6114

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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