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Fennel essential oil (FEO) a natural spice that has versatile biological activities. However, the direct use of FEO is limited due to its water insolubility and poor stability. Chilled pork is prone to spoilage during storage. To solve these problems, this study aimed to prepare an inclusion complex (IC) of FEO with hydroxypropyl-β-cyclodextrin via co-precipitation and apply it to the preservation of chilled pork. Results indicated that the optimal parameters were encapsulating temperature 37 °C, wall-core ratio 14:1 g/mL, stirring speed 600 r/min, and encapsulating time 240 min, obtaining an encapsulation efficiency of 83.75%. The results of scanning electron microscopy, Fourier transform infra-red spectroscopy, and nuclear magnetic resonance demonstrated the successful preparation of IC. The release of FEO from IC was controllable through adjusting the different temperatures and relative humidities. Furthermore, IC effectively delayed the spoilage of chilled pork and extended its shelf life by 6 days at 4 °C., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A diallyl amine salt monomer bearing a β-CD substituent was cyclopolymerized for the first time. The reaction of 6-O-toluenesulfonyl-β-cyclodextrin [(C 6 H 10 O 5 ) 6 -(C 5 H 7 )]-CH 2 OTs with diallylamine followed by protonation afforded the diallylamine salt monomer [(C 6 H 10 O 5 ) 6 -(C 5 H 7 )]-CH 2 NH + (CH 2 CH=CH 2 ) 2 Cl - ] (I). The cyclopolymerization of monomer I and its copolymerization with monomer [Me 2 N + (CH 2 CH=CH 2 ) 2 Cl - ] (II), [ - O 2 CCH 2 NH + (CH 2 CH=CH 2 ) 2 ] (III), [H 2 O 3 PCH 2 NH + (CH 2 CH=CH 2 ) 2 Cl - ] (IV) or [HO 2 CCH 2 CH(CO 2 H)NH + (CH 2 CH=CH 2 ) 2 Cl - ] (V) yielded a series of copolymers having residues of β-CD and glycine or methyl phosphonate or aspartic acid. Terpolymerization in the presence of SO 2 afforded polymers with alternating placements of the SO 2 units. The solution properties of the pH-responsive polyzwitterions, including their viscosity, were examined. The water-insoluble terpolymer I/V/SO 2 with 20 mol% β-CD residues removed the organic micropollutant 2-naphthol from an aqueous system via host/guest complexation. This work paves the way for the possible synthesis of cross-linked polymers that can simultaneously remove organic micropollutants and toxic metal ions (by complexation with the chelating glycine, aspartic acid, and aminomethyl phosphonate ligands) from contaminated aqueous systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Many active pharmaceutical ingredients have a specific bitter taste. To enhance patient compliance and treatment efficacy, taste-masking agents are crucial in oral drug formulations. Confronting numerous bitter drug molecules with varied structures, the pharmaceutical field strives to explore and develop universal and effective masking approaches. Here, we reported sulfonated azocalix[4]arene (SAC4A), a universal supramolecular masking agent with deep cavity that provides stronger hydrophobic effect and larger interaction area during recognition, allowing high binding affinity to bitter drug molecules. Moreover, bitter drugs could deeply buried in the cavity, with the bitterness effectively masked. As a result, SAC4A can bind to 16 different bitter drugs with high affinities, encompassing alkaloids, flavonoids, terpenoids, and more, while maintaining high biocompatibility. As anticipated, SAC4A effectively masks the unpalatable bitter taste associated with these drugs. Consequently, SAC4A is a promising universal and effective supramolecular masking agent.

Genistein could interact with starch to slow starch digestion by forming starch-genistein complexes. However, genistein had low solubility in water, which hindered the interaction with starch and therefore the formation of the complexes. This study presented a pathway to promote the formation of starch-genistein complexes using an antisolvent method in two steps: (i) adding ethanol to the solution containing starch and genistein to increase genistein solubility, and (ii) evaporating ethanol from the solution to promote genistein interaction with starch. The complexes prepared using this antisolvent method had higher crystallinity (9.45 %), complex index (18.17 %), and higher content of resistant starch (RS) (19.04 %) compared to samples prepared in pure water or ethanol-containing aqueous solution without ethanol evaporation treatment (these samples showed crystallinity of 6.97 %-8.00 %, complex index of 9.09 %-11.4 2%, and RS of 4.45 %-14.38 %). Molecular dynamic simulation results confirmed that the changes in solution polarity significantly determined the formation of starch-genistein complexes. Findings offered a feasible pathway to efficiently promote starch interaction with genistein and in turn mitigate starch digestibility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Itraconazole (ITZ) is one of the broad-spectrum antifungal agents for treating fungal keratitis. In clinical use, ITZ has problems related to its poor solubility in water, which results in low bioavailability when administered orally. To resolve the issue, we formulated ITZ into the inclusion complex (ITZ-IC) system using β-cyclodextrin (β-CD), which can potentially increase the solubility and bioavailability of ITZ. The molecular docking study has confirmed that the binding energy of ITZ with the β-CD was -5.0 kcal/mol, indicating a stable conformation of the prepared inclusion complex. Moreover, this system demonstrated that the inclusion complex could significantly increase the solubility of ITZ up to 4-fold compared to the pure drug. Furthermore, an ocular drug delivery system was developed through dissolving microneedle (DMN) using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA) as polymeric substances. The evaluation results of DMN inclusion complexes (ITZ-IC-DMN) showed excellent mechanical strength and insertion ability. In addition, ITZ-IC-DMN can dissolve rapidly upon application. The ex vivo permeation study revealed that 75.71% (equivalent to 3.79 ± 0.21 mg) of ITZ was permeated through the porcine cornea after 24 h. Essentially, ITZ-IC-DMN exhibited no signs of irritation in the HET-CAM study, indicating its safety for application. In conclusion, this study has successfully developed an inclusion complex formulation containing ITZ using β-CD in the DMN system. This approach holds promise for enhancing the solubility and bioavailability of ITZ through ocular administration.

In this study, a double-layer active and intelligent packaging system was developed based on two main natural macromolecules i.e. protein and carbohydrate with green perspective. Firstly, the salep-based films containing different concentrations (0-8 % w/w) of the inclusion complex of β-cyclodextrin/black chickpea anthocyanins (βCD/BCPA) were produced. The salep film containing 8 % of βCD/BCPA complex was specified as the optimized film sample based on its performance as a color indicator. The electrospinning of black chickpea protein isolate nanofibers (BCPI NFs) containing citral nanoliposomes (NLPs) was done on the optimized salep film. The cross-sectional field emission scanning electron microscopy approved the creation of double-layer structure of the developed film. The study of chemical and crystalline structure, as well as the thermal properties of the film exhibited the physical attachment of BCPI electrospun NFs on salep film. The effectiveness of the developed system was studied in detection of spoilage and increasing the shelf life of seafood products, including shrimp and fish fillet. The performance of the intelligent layer in detection of freshness/spoilage was acceptable for both seafood products. In addition, the active layer of the film controlled the changes of pH, total volatile basic nitrogen, oxidation, and microbial load in samples during storage time., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The incorporation of active compounds into polymeric matrices using traditional methods has several drawbacks mainly due to the high volatility and thermal sensitivity of these substances. A solution to this problem could be the incorporation of bioactive compounds forming inclusion complexes as a strategy to improve the chemical stability, bioactivity and achieve controlled release. In this work, β-cyclodextrin/carvacrol inclusion complex was prepared by spray drying to be incorporated into poly(lactic acid) (PLA) and Mater-Bi® films by supercritical CO 2 impregnation. The impregnation process was carried out at pressures of 10, 15 and 20 MPa and at 40 °C. Both polymers showed the highest amount of incorporated inclusion complex at 15 MPa, where the percentage of impregnation varied from 0.6 % to 7.1 % in Mater-Bi® and PLA, respectively. Release tests for PLA films impregnated with inclusion complex showed a slow release of the active compound, which did not reach equilibrium after 350 h under the experimental conditions. This prolonged release was not observed in Mater-Bi® due to the lower incorporation of the inclusion complex. The release rate was described herein by a comprehensive phenomenological model considering the decomplexation kinetics combined with the equilibrium and mass transfer expressions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Cyclodextrins (CD) entrapped in nanofiber composite membranes are potential selective adsorbing materials to remove steroid hormone (SHs) micropollutants from water. This study aims to elucidate the role of CD macrocyclic host type on the SHs inclusion complexation and uptake in filtration. Three CD types (α, β, and γ) are cross-linked with epichlorohydrin to form polymers (αCDP, βCDP and γCDP) and entrapped into a nanofiber composite membrane by electrospinning. TGA analysis confirmed the CD entrapment into the nanofiber without loss of CD molecules during filtration. The CD type plays a dominant role in controlling the removal of different SHs. A similar removal (range 33 to 50 %) was observed with αCDP, irrespective of the SH type. In contrast, removal and uptake dependent on SH type were observed for β and γCDP, with the highest removal of 74 % for progesterone, followed by estradiol (46 %) and estrone (27 %) and the lowest removal of 3 % for testosterone. Molecular dynamic (MD) simulation revealed a stronger and more stable complex formed with βCDP, as demonstrated by: i) the closer spatial distribution of SH molecules from the βCDP cavity and, ii) the quantum chemistry calculations of the lower de-solvation energy (+6.0 kcal/mol), which facilitates the release of water molecules from interacting interface of CD molecule and hormone. Regarding γCDP, the highest de-solvation energy (+8.3 kcal/mol) poses an energetic barrier, which hinders the formation of the inclusion complex. In the case of αCDP, a higher interaction energy (-8.9 kcal/mol) compared to βCDP (-4.9 kcal/mol) was obtained, despite the broader spatial distribution observed from the MD simulation attributed to a dominant hydrogen bonding interaction with the OH primary groups on the external surface cavity. The findings highlight the relevance of the CD type in designing selective adsorbing membranes for steroid hormone micropollutant uptake. Experimental results and MD simulation suggest that βCD is the most suitable CD type for steroid hormone uptake, due to a more stable and stronger inclusion complexation than α and γCD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

A host-guest supra-molecular inclusion complex was obtained from the co-crystallization of A1/A2-bromo-but-oxy-hy-droxy difunctionalized pillar[5]arene ( PilButBrOH ) with adipo-nitrile ( ADN ), C 47 H 53.18 Br 0.82 O 10 ·C 6 H 8 N 2 . The adipo-nitrile guest is stabilized within the electron-rich cavity of the pillar[5]arene host via multiple C-H⋯O and C-H⋯π inter-actions. Both functional groups on the macrocyclic rim are engaged in supra-molecular inter-actions with an adjacent inclusion complex via hydrogen-bonding (O-H⋯N or C-H⋯Br) inter-actions, resulting in the formation of a supra-molecular dimer in the crystal structure., (© Vinodh and Al-Azemi 2024.)

Although niflumic acid (NA) is one of the most used non-steroidal anti-inflammatory drugs, it suffers from poor solubility, low bioavailability, and significant adverse effects. To address these limitations, the complexation of NA with cyclodextrins (CDs) is a promising strategy. However, complexing CDs with low molecular weight drugs like NA can lead to low CE. This study explores the development of inclusion complexes of NA with 2-hydroxypropyl-β-cyclodextrin (2HP-β-CD), including the effect of converting NA to its sodium salt (NAs) and adding hydroxypropyl methylcellulose (HPMC) on complex formation. Inclusion complexes were prepared using co-evaporation solvent and freeze-drying methods, and their CE and Ks were determined through a phase solubility study. The complexes were characterized using physicochemical analyses, including FT-IR, DSC, SEM, XRD, DLS, UV-Vis, 1 H-NMR, and 1 H-ROESY. The dissolution profiles of the complexes were also evaluated. The analyses confirmed complex formation for all systems, demonstrating drug-cyclodextrin interactions, amorphous drug states, morphological changes, and improved solubility and dissolution profiles. The NAs-2HP-β-CD-HPMC complex exhibited the highest CE and Ks values, a 1:1 host-guest molar ratio, and the best dissolution profile. The results indicate that the NAs-2HP-β-CD-HPMC complex has potential for delivering NA, which might enhance its therapeutic effectiveness and minimize side effects.

Neuropathic pain is a high-intensity pain that can be caused by compression, transection, injury, nerve infiltration and drug treatment of cancer. Furthermore, drug therapy has low clinical efficacy, many adverse effects and remission of painful symptoms. In this way, natural products derived from plants constitute a promising therapeutic alternative. Therefore, the aim of this study was to evaluate the antihyperalgesic effect of γ-terpinene (γ-TPN) e γ-terpinene in β-cyclodextrin inclusion complexes (TPN/CD) on neuropathic pain induced by tumor cells. Complexation extended the effect time for another 5 h and daily treatment for six days with γ-TPN (50 mg/kg, p.o.) and γ-TPN/β-CD (50 mg/kg, p.o.) significantly reduced (p < 0.001) the mechanical hyperalgesia induced by the administration of 2x10 6 sarcoma cells 180 in the around the sciatic nerve. In addition, the Grip and Rota-rod techniques demonstrated that there was no interference on the muscle strength and motor coordination of the animals, suggesting that the compound under study does not have central nervous system depressant effects at the doses used. Molecular docking studies demonstrate favorable binding energies between γ-TPN and β-CD, and alpha-2 adrenergic, glutamatergic, opioid and cholinergic receptors. Thus, this study demonstrates the potential of terpinene complexation in controlling neuropathic pain induced by tumor cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nanoencapsulation has gained considerable attention because of its unique features and advantages in anticancer drug delivery. Amygdalin (AMY) is an anticancer compound, showing limitations in its applications by low stability. Herein, the inclusion complexes (ICs) of AMY with β-cyclodextrin (βCD), and its derivatives such as 2-hydroxypropyl-βCD (HPβCD) and methyl-βCD (MβCD) were fabricated. The fabricated AMY/CD-ICs were thoroughly evaluated using Fourier-transform infrared spectroscopy, powder X-ray diffraction, thermogravimetric/differential thermal analysis, proton nuclear magnetic resonance, ultraviolet-visible diffuse reflectance spectroscopy, and photoluminescence techniques. Double reciprocal profile study of the absorption and fluorescence spectra revealed that the AMY formed the ICs with βCD derivatives at a guest/host stoichiometric ratio of 1/1. The thermal stability of AMY was enhanced as the IC formation aid observed by the shift of thermal degradation temperature of AMY from the range of ∼ 220-250 °C to > 295 °C. Theoretical analyses of the energetic, electronic, and global reactivity parameters of the AMY/CD-ICs were evaluated using the PM3 method. Further assessment of the dissolution diagrams of AMY/CD-ICs revealed a burst release profile. In addition, cell toxicity was evaluated using the MTT assay, and the results showed that AMY/CD-ICs had significantly more efficacious in inhibiting HeLa cancer cells than AMY. These results proved that the IC formations with CDs significantly enhanced the anticancer activity of AMY., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The essential oil and β-cyclodextrin inclusion complex was able to inhibit the growth of Penicillium digitatum, a damaging pathogen that causes green mold in citrus fruit. In this study, cinnamaldehyde-β-cyclodextrin inclusion complex (β-CDCA) for controlling citrus green mold was synthesized by the co-precipitation method. Characterization of β-CDCA revealed that the aromatic ring skeleton of cinnamaldehyde (CA) was successfully embedded into the cavity of β-CD to form the inclusion complex. β-CDCA inhibited P. digitatum at a minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of 4.0 g/L. FT-IR spectroscopy analysis, calcofluor white staining, extracellular alkaline phosphatase (AKP) activity and propidium iodide (PI) staining of hyphae morphology showed that β-CDCA may damage the cell ultrastructure and membrane permeability of P. digitatum. The study further demonstrated that hydrogen peroxide (H 2 O 2 ), malondialdehyde (MDA), and reactive oxygen species (ROS) markedly accumulated in 1/2 MIC β-CDCA treated hyphae. This implied that β-CDCA inhibited growth of P. digitatum by the triggering oxidative stress, which may have caused cell death by altering cell membrane permeability. In addition, in vivo results showed that β-CDCA alone or combined with L-phenylalanine (L-PHe) displayed a comparable level to that of prochloraz. Therefore, β-CDCA combined with L-PHe can thus be used as an eco-friendly preservative for the control green mold in postharvest citrus fruit., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Multi-stimuli-responsive chromic materials have immense potential for utilization. Herein, two supramolecular inclusion complexes were prepared by self-assembly of β-cyclodextrin (β-CD) with dialkylcarboxyl-substituted viologens, N,N '-di(3-carboxy-propyl)-4,4'-bipyridinium dichloride (CPV·Cl 2 ) and N,N '-di(6-carboxy-hexyl)-4,4'-bipyridinium dibromide (CHV·Br 2 ). The self-assembled inclusion complexes CPV 2+ @β-CD and CHV 2+ @β-CD 2 in the solid-state exhibited naked-eye photochromism, thermochromism, and electrochromism in response to multiple external stimuli including light, temperature, and electric field, respectively. Solid-state UV-vis diffuse reflectance and electron spin resonance (ESR) spectroscopy revealed that the observed photochromism, thermochromism and electrochromism are attributed to the formation of viologen free radicals induced by electron transfer under external stimuli. The excellent stimuli-response chromic properties of the title inclusion complexes support their practical utility in visual display, multiple anticounterfeiting, and multilevel information encryption.

Background: Papaya, a highly nutritious and economically significant fruit, is susceptible to infections caused by phytopathogenic fungi. Cinnamon essential oil, derived from Cinnamomum cassia (CC), shows promise in preserving papaya due to its antifungal properties. However, CC is volatile, sensitive to environmental factors, and carries a strong aroma. γ-Cyclodextrin (γ-CD) is known for encapsulating hydrophilic molecules, shielding them from environmental influences, reducing odor, and enabling controlled release due to its unique channel structure. This study aimed to tackle these challenges by preparing and characterizing an inclusion complex of CC with γ-CD (CC-γ-CD), and subsequently evaluating its efficacy in preserving papaya fruits., Results: Analyses, including Fourier-infrared, powder X-ray diffraction, thermal gravity analysis, differential scanning calorimeter, and scanning electron microscopy, revealed successful encapsulation of CC components within the γ-CD cavity. Evaluations of the CC-γ-CD complex's impact on papaya fruit shelf life and quality showed notable enhancements. Fruits treated with CC-γ-CD inclusion complex at a dose of 10 g kg -1 exhibited a 55% extension in shelf-life, evidenced by reduced disease severity index compared with untreated fruit in the same storage conditions. Detailed physicochemical and bromatological assessments highlighted significant improvements, particularly in fruit treated with CC-γ-CD inclusion complex at a dose of 10 g kg -1 ., Conclusion: The application of CC-γ-CD inclusion complex at 10 g kg -1 extended the shelf-life of papaya fruit, significantly and markedly improved the overall quality. These findings underscore the potential of the CC-γ-CD inclusion complex as an effective preservative for papaya, offering a promising solution for its postharvest management and marketability. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

As the main active compound of Glycyrrhiza glabra L., glabridin (GLD) has been shown to have multiple bioactivities, whereas the clinical application of GLD is restricted by its low water solubility. In this study, GLD was encapsulated into a sulfobutylether-β-cyclodextrin (SBE-β-CD)-based inclusion complex (SBE-β-CD/GLD) by the freeze-drying method. The materials characterization, antibacterial activity, stimulated cellular behavior and in vivo full-thickness diabetic wound healing ability of the hydrogels were assessed and analyzed. The successful encapsulation of the inclusion complex was confirmed by ultraviolet (UV) visible spectroscopy, Fourier transform infrared (FT-IR), X-ray diffractometer (XRD), scanning electron microscope (SEM), and nuclear magnetic resonance (NMR). SBE-β-CD as an excipient significantly enhances the water solubility of GLD, and SBE-β-CD/GLD showed excellent biocompatibility on human vascular endothelial cells (HUVECs) and erythrocytes. The SBE-β-CD/GLD inclusion complex exerted a pronounced antibacterial activity on Staphylococcus aureus and Escherichia coli in vitro. The SBE-β-CD/GLD inclusion complex markedly enhanced the antioxidant activity compared with free GLD. The SBE-β-CD/GLD inclusion complex potently accelerates the healing of full-thickness skin defects by inhibiting inflammation. The outcomes suggest that SBE-β-CD could be used as a promising drug delivery system for the clinical application of GLD., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

The octanol-water distribution coefficient (logP), used as a measure of lipophilicity, plays a major role in the drug design and discovery processes. While average logP values remain unchanged in approved oral drugs since 1983, current medicinal chemistry trends towards increasingly lipophilic compounds that require adapted analytical workflows and drug delivery systems. Solubility enhancers like cyclodextrins (CDs), especially 2-hydroxypropyl-β-CD (2-HP-β-CD), have been studied in vitro and in vivo investigating their ADMET (adsorption, distribution, metabolism, excretion and toxicity)-related properties. However, data is scarce regarding the applicability of CD inclusion complexes (ICs) in vitro compared to pure compounds. In this study, dopamine receptor (DR) ligands were used as a case study, utilizing a combined in silico/in vitro workflow. Media-dependent solubility and IC stoichiometry were investigated using HPLC. NMR was used to observe IC formation-caused chemical shift deviations while in silico approaches utilizing basin hopping global minimization were used to propose putative IC binding modes. A cell-based in vitro homogeneous time-resolved fluorescence (HTRF) assay was used to quantify ligand binding affinity at the DR subtype 2 (D 2 R). While all ligands showed increased solubility using 2-HP-β-CD, they differed regarding IC stoichiometry and receptor binding affinity. This case study shows that IC-formation was ligand-dependent and sometimes altering in vitro binding. Therefore, IC complex formation can't be recommended as a general means of improving compound solubility for in vitro studies as they may alter ligand binding., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Here, we investigated the complexation of short chain amylose (SCAs) and palmitic acid (PA), serving as polymeric building blocks that alter the selectivity and directionality of particle growth. This alteration affects the shape anisotropy of the particles, broadening their applications due to the increased surface area. By modifying the concentration of PA, we were able to make spherical, macaron, and disc-shaped particles, demonstrating that PA acts as a structure-directing agent. We further illustrated the lateral and longitudinal stacking kinetics between PA-SCA inclusion complexes during self-assembly, leading to anisotropy. Transmission electron microscope (TEM) and scanning electron microscope (SEM) revealed the structural difference between the initial and final morphologies of palmitic acid-short chain amylose particles (PA-SCAPs) compared to those of short-chain amylose particle (SCAPs). The presence of PA-SCA inclusion complex in the anisotropic particles was confirmed using nuclear magnetic resonance (NMR) and powder x-ray diffraction (XRD) analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The freeze-drying approach was used to create inclusion complexes utilizing alkyl gallates and β-cyclodextrin, namely dodecyl gallate, octyl gallate, butyl gallate, and ethyl gallate, which are exemplary examples of phenolic esters. The everted-rat-gut-sac model demonstrated that the inclusion complexes released alkyl gallates, which were subsequently hydrolyzed to generate free gallic acid, as evidenced by HPLC-UV analysis. Both gallic acid and short-chain alkyl gallates were capable of permeating the small intestinal membrane. The transport rate of gallic acid (or alkyl gallates) exhibited an initial rise followed by a drop when the carbon-chain lengths varied. The inclusion complex groups exhibited a superior sustained-release effect compared to the comparable alkyl gallates groups, thus possibly leading to higher bioavailability and stronger bioactivity. Moreover, altering the length of the carbon chain will allow for the effortless achievement of regulated release of phenolic compounds and short-chain phenolic esters from such β-cyclodextrin inclusion complexes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Neurodegenerative diseases such as Alzheimer's are very common today. Idebenone (IDE) is a potent antioxidant with good potential for restoring cerebral efficiency in cases of these and other medical conditions, but a serious drawback for the clinical use of IDE in neurological disorders lies in its scarce water solubility, which greatly inhibits its bioavailability. In this work, we prepared the inclusion complex of IDE with randomly methylated β-cyclodextrin (RAMEB), resulting in improved water solubility of the included drug; then its in vitro biological activity and ex vivo permeability was evalutated. The solid complex was characterized through FT-IR spectroscopy, Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC). A 78-fold improvement of the solubility of IDE in water resulted, together with a strong 1:1 host-guest interaction (association constant of 12630 M -1 ), and dissolution of the complex within 15 min, all evidenced during the in-solution studies. Biological in vitro studies were then performed on differentiated human neuroblastoma cells (SH-SY5Y) subjected to oxidative stress. Pretreatment with IDE/RAMEB positively affected cell viability, promoted the nuclear translocation of Nrf2, and increased the levels of GSH as well as those of the endogenous antioxidant enzymes Mn-SOD and HO-1. Lastly, the complexation significantly improved the permeation of IDE through isolated rat nasal mucosa., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The dynamic combination of aromas and cyclodextrins is an important means to achieve their stability and controllability, and accurately revealing their interaction rules is the key to designing and constructing high-quality aroma nanocarriers. In this study, the inclusion mechanism between alcohol aroma compounds with different structures and β-cyclodextrin (β-CD) was studied by combining molecular dynamics simulation and experimental methods. Results showed that the selected alcohol aroma compounds formed inclusion complexes (ICs) with β-CD in a 1:1 ratio, while alcohol aroma compounds containing cyclic structures were more tightly bound to β-CD. Van der Waals forces were the primary forces driving the formation and stabilization of the ICs. Cinnamyl alcohol/β-CD ICs showed the most significant antimicrobial effect and notably prolonged the shelf life of strawberries. This study aimed to provide theoretical support for precisely designing and preparing highly stable flavours and fragrances, as well as expanding their application range., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The inclusion complex (IC) was successfully obtained by encapsulating glycerol monolaurate (GML) into the cavity of hydroxypropyl-β-cyclodextrin (HP-β-CD). Compared with solubility of pure GML <80 μg/mL in water, and the water-solubility of encapsulated GML was significantly improved and reached to 270,000 μg/mL. IC can form nanoparticles by self-assembly, probably assigned to its strong capability to form micellar-type aggregates. A Higuchi's A L -type phase-solubility diagram indicated the strong interaction between host and guest molecules with the formation of 1:1 GML/HP-β-CD complex and the stability constant at 6248 L/mol. Compared with pure GML, encapsulated GML at the same concentration can also show good antibacterial capabilities against S. aureus and E. coli in sterile water, and the effective preservative capabilities towards beef meatballs. The boosted enhancement in water-solubility of GML and the effective antibacterial capabilities endowed IC with potential in the application of food decontamination., Competing Interests: Declaration of competing interest The authors declared that they have no conflicts of interest to this work., (Copyright © 2023. Published by Elsevier Ltd.)

A thermoresponsive highly branched polysaccharide derivative was revealed from commercially available highly branched cyclic dextrin (HBCD), originally synthesized from amylopectin. Eight samples of partially substituted ethyl carbamate derivatives of HBCD (HEC) were prepared with a degree of substitution DS ranging from 0.27 to 1.46. Three samples with DS = 0.88, 1.05, and 1.22 showed LCST type phase separation in water. The intrinsic viscosity and form factor in water were typical of the hyperbranched structure. The intermolecular interactions between HEC and iodine or 1-anilinonaphthalene-8-sulfonic acid (ANS) were appreciably different from those of the linear analog (AEC), suggesting that the locally bent helical conformation of highly branched HEC chains has a different interaction with small molecules. The phase diagram of HEC-water systems was accidentally similar to that of the linear chain with the same molar mass and DS, although the one phase region of the branched polymer chain-poor solvent system is usually wider than that of the corresponding linear chain. This is likely due to the lower hydration nature of the polymer segment of HEC chains than that of the corresponding linear chain., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ken Terao reports financial support was provided by Japan Society for the Promotion of Science. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Baicalein, a flavone derived from Scutellaria baicalensis Georgi, exhibits potent anti-inflammatory, antiviral, and anticancer properties. Its derivative, known as 8-bromobaicalein (BB), has been found to have strong cytotoxic effect on MCF-7 human breast cancer cells. However, its limited solubility in water has hindered its potential for wider applications. To address this issue, we investigated the use of cyclodextrins specifically βCD, 2,6-di-O-methyl-β-cyclodextrin (DMβCD), and hydroxypropyl-β-cyclodextrin (HPβCD) to improve the solubility of BB through inclusion complexation. During 250 ns molecular dynamics simulations, it was found that BB can form inclusion complexes with all βCDs. These complexes exhibit two distinct orientations: chromone group insertion (C-form) and phenyl group insertion (P-form). The formation of these complexes is primarily driven by van der Waals interactions. DMβCD has the highest number of atom contacts with BB and the lowest solvent accessibility in the hydrophobic cavity. These results coincide with the highest binding affinity from the MM/GBSA-based free energy calculation method. Experimental phase solubility diagrams revealed a 1:1 stoichiometric ratio (A L type) between BB and βCDs, in which BB/DMβCD showed the highest stability. The formation of inclusion complexes was confirmed by differential scanning calorimetry and scanning electron microscope methods. Additionally, the BB/DMβCD inclusion complex demonstrated significantly higher anticancer activity against MCF-7 human breast cancer cells compared to BB alone. These findings underscore the potential of DMβCD for formulating BB in pharmaceutical and medical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

4-Terpineol (4-TA), a typical monocyclic monoterpene essential oil compound with important biological activities, poor stability and solubility severely hamper its biological activities. To date, β-cyclodextrin (β-CD) encapsulating essential oil to form inclusion complexes (ICs) is considered as a satisfactory treatment. Nevertheless, the detailed inclusion mechanism of β-CD for 4-TA especially the behavior of 4-TA during inclusion formation have not available yet. Herein, 4-TA/β-CD ICs were successfully synthesized by the co-precipitation method, and hydrogen bonds and hydrophobic interactions played a key role in the formation of ICs, and the isopropyl of 4-TA entered the cavity through the wide rim of β-CD. Moreover, the release profile demonstrated that high RH (85 % and 99 %) triggered the release of TA from ICs. This study suggests the great potential of cyclodextrin inclusion strategy for improving the stability and sustained release of 4-TA in food preservation application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Neoponcirin causes anxiolytic-like effects in mice when administered intraperitoneally but not orally. Neoponcirin is non-water-soluble and insoluble in solvents, and in medium acid, it isomerizes, reducing its bioavailability. To improve the pharmacological properties of neoponcirin, we formed a neoponcirin complex with beta-cyclodextrin (NEO/βCD), which was characterized by FT-IR, UV-Vis, and NMR, and their solubility profile. We evaluated the antidepressant-like effects of NEO/βCD acutely administered to mice orally in the behavioral paradigms, the tail suspension (TST) and the forced swimming (FST) tests. We also analyzed the benefits of repeated oral doses of NEO/βCD on depression- and anxiety-like behaviors induced in mice by chronic unpredictable mild stress (CUMS), using the FST, hole board, and open field tests. We determined the stressed mice's expression of stress-related inflammatory cytokines (IL-1β, IL-6, and TNFα) and corticosterone. Results showed that a single or chronic oral administration of NEO/βCD caused a robust antidepressant-like effect without affecting the ambulatory activity. In mice under CUMS, NEO/βCD also produced anxiolytic-like effects and avoided increased corticosterone and IL-1β levels. The effects of the NEO/βCD complex were robust in both the acute and the stress chronic models, improving brain neurochemistry and recovering immune responses previously affected by prolonged stress.

In this paper the binding of noscapine (NOS) as an anticancer drug with poor bioavailability and low solubility with beta and methyl-beta cyclodextrins (β-CD and M-β-CD) as the biocompatible drug carriers were discussed using ultraviolet-visible, fluorescence and nuclear magnetic resonance spectroscopy, as well as molecular docking. The absorption of NOS changed when it was bound to both cyclodextrins, resulting in a hyperchromic shift. It formed a 1:1 stoichiometry inclusion complex with both cyclodextrins according to the Benesi-Hildebrand equation. The binding affinity was larger in NOS-M-β-CD (5.9 (± 0.66) × 10 3 M - 1 ) than NOS-β-CD (3.7 (± 0.22) × 10 3 M - 1 ) complex. The fluorescence emission band of NOS at 408 nm was quenched when NOS was complexed with β-CD, and enhanced in the presence of M-β-CD, while the shoulder at 350 nm was enhanced selectively when NOS was complexed with M-β-CD. The fluorescence quenching of NOS with β-CD showed a negative deviation from the Stern-Volmer. The thermodynamic parameters have been estimated with the help of the Van't Hoff equation in different temperatures, and a dynamic mechanism was proposed for quenching. Also, both ΔH and ΔS have positive values thus the main interactions result in hydrophobic forces. Moreover, the negative value of ΔG indicates that the bonding process is spontaneous. 1 H NMR chemical shift changes were observable for NOS and both CDs protons due to the chemical environment changes of some nuclei upon complexation. The molecular docking results revealed that the 1:1 inclusion complex possesses a good molecular shape complementarity score for their most probable structures, and indicated that the M-β-CD inclusion system gave the higher complexation efficiency. The binding energy values for β-CD and M-β-CD were determined to be -6.7 and - 9.5 kcal/mol, respectively. These findings suggest the same as the result of experimental tests that the NOS-M-β-CD complex is more stable than the NOS-β-CD complex., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

There is an urgent need to develop safer and more effective modalities for the treatment of numerous pathologies due to the increasing rates of drug resistance, undesired side effects, poor clinical outcomes, etc. Over the past decades, cyclodextrins (CDs) have gathered great attention as potential drug carriers due to their ability to enhance their bioactivities and properties. Likewise, selenium (Se) and tellurium (Te) have been extensively studied during the last decades due to their possible therapeutical applications. Although there is limited research on the relationship between Se and Te and CDs, herein, we highlight different representative examples of the advances related to this topic as well as give our view on the future directions of this emerging area of research. This review encompasses three different aspects of this relationship: (1) modification of the structure of the different CDs; (2) formation of host-guest interaction complexes of naïve CDs with Se and Te derivatives in order to overcome specific limitations of the latter; and (3) the use of CDs as catalysts to achieve novel Se and Te compounds.

The characteristic accumulation of circulating uremic toxins, such as indoxyl sulfate (IS), in chronic kidney disease (CKD) further exacerbates the disease progression. The gut microbiota, particularly gut bacterial-specific enzymes, represents a selective and attractive target for suppressing uremic toxin production and slowing the progression of renal failure. This study investigates the role of 4-phenylbutyrate (PB) and structurally related compounds, which are speculated to possess renoprotective properties in suppressing IS production and slowing or reversing renal failure in CKD. In vitro enzyme kinetic studies showed that 7-phenylheptanoic acid (PH), a PB homologue, suppresses the tryptophan indole lyase (TIL)-catalyzed decomposition of tryptophan to indole, the precursor of IS. A hydroxypropyl β-cyclodextrin (HPβCD) inclusion complex formulation of PH was prepared to enhance its biopharmaceutical properties and to facilitate in vivo evaluation. Prophylactic oral administration of the PH-HPβCD complex formulation reduced circulating IS and attenuated the deterioration of renal function and tubulointerstitial fibrosis in adenine-induced CKD mice. Additionally, treatment of moderately advanced adenine-induced CKD mice with the formulation ameliorated renal failure, although tissue fibrosis was not improved. These findings suggest that PH-HPβCD can slow the progression of renal failure and may have implications for preventing or managing CKD, particularly in early-stage disease.

Cyclodextrins are macrocyclic rings composed of glucose residues. Due to their remarkable structural properties, they can form host-guest inclusion complexes, which is why they are frequently used in the pharmaceutical, cosmetic, and food industries, as well as in environmental and analytical chemistry. This review presents the reports from 2011 to 2023 on the quantitative structure-activity/property relationship (QSAR/QSPR) approach, which is primarily employed to predict the thermodynamic stability of inclusion complexes. This article extensively discusses the significant developments related to the size of available experimental data, the available sets of descriptors, and the machine learning (ML) algorithms used, such as support vector machines, random forests, artificial neural networks, and gradient boosting. As QSAR/QPR analysis only requires molecular structures of guests and experimental values of stability constants, this approach may be particularly useful for predicting these values for complexes with randomly substituted cyclodextrins, as well as for estimating their dependence on pH. This work proposes solutions on how to effectively use this knowledge, which is especially important for researchers who will deal with this topic in the future. This review also presents other applications of ML in relation to CD complexes, including the prediction of physicochemical properties of CD complexes, the development of analytical methods based on complexation with CDs, and the optimisation of experimental conditions for the preparation of the complexes.

The β-cyclodextrin and short-chain alkyl gallates (A-GAs), which are representative of phenolipids, such as butyl, propyl, ethyl, and methyl gallates, were chosen to form inclusion complexes by the use of the freeze-drying process. In the everted rat gut sac model, HPLC-UV analysis demonstrated that the released A-GAs from inclusion complexes were degraded to yield free gallic acid (GA) (sustained-release function 1). The small intestine membrane may be crossed by both the GA and the A-GAs. A-GAs may also undergo hydrolysis to provide GA (sustained-release function 2) following transmembrane transfer. Clearly, a helpful technique for the dual sustained-release of phenolic compounds is to produce β-cyclodextrin inclusion complexes with short-chain phenolipids. This will increase the bioactivities of phenolic compounds and prolong their in vivo residence length. Moreover, changing the carbon-chain length of these β-cyclodextrin inclusion complexes would readily modify the dual sustained-release behavior of the phenolic compounds. Thus, our work effectively established a theoretical foundation for the use of β-cyclodextrin inclusion complexes containing short-chain phenolipids as new source of functional food components to provide the body with phenolic compounds more efficiently., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Eugenol-β-cyclodextrin complex has been widely used because of the enhanced stability and conservation of the properties of eugenol. Applications in food and health sciences have been shown previously, which makes this complex an excellent model to understand and develop methodologies for the analysis and prediction of physical properties. In this work, the dynamics of eugenol incorporated into β-cyclodextrin are presented, using NMR relaxation rates, and the predictive capabilities of molecular dynamics simulations are discussed. Results show a hindered rotation of eugenol around the principal inertial axes when located inside β-cyclodextrin. Moreover, a translational movement of the whole complex is demonstrated., (© 2024 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.)

The aim of the research was to investigate and compare the interaction between flavanones (flavanone, 4-chloro-flavanone) with potential anticancer activity and selected cyclodextrins. Measurements were made using calorimetric (ITC, DSC) and spectrophotometric (UV-Vis spectroscopy, FT-IR, 1 H NMR) methods. The increase in the solubility in aqueous medium caused by the complexation process was determined by the Higuchi-Connors method. As a result of the study, the stoichiometry and thermodynamics of the complexation reaction were determined. The formation of stable inclusion complexes at a 1:1 M ratio between flavanone and 4-chloroflavanone and the cyclodextrins selected for research was also confirmed.

Coumarins have great pharmacotherapeutic potential, presenting several biological and pharmaceutical applications, like antibiotic, fungicidal, anti-inflammatory, anticancer, anti-HIV, and healing activities, among others. These molecules are practically insoluble in water, and for biological applications, it became necessary to complex them with cyclodextrins (CDs), which influence their bioavailability in the target organism. In this work, we studied two coumarins, and it was possible to conclude that there were structural differences between 4,7-dimethyl-2 H -chromen-2-one (DMC) and 7-methoxy-4-methyl-2 H -chromen-2-one (MMC)/β-CD that were solubilized in ethanol, frozen, and lyophilized (FL) and the mechanical mixtures (MM). In addition, the inclusion complex formation improved the solubility of DMC and MMC in an aqueous medium. According to the data, the inclusion complexes were formed and are more stable at a molar ratio of 2:1 coumarin/β-CD, and hydrogen bonds along with π-π stacking interactions are responsible for the better stability, especially for (MMC) 2 @β-CD. In vivo wound healing studies in mice showed faster re-epithelialization and the best deposition of collagen with the (DMC) 2 @β-CD (FL) and (MMC) 2 @β-CD (FL) inclusion complexes, demonstrating clearly that they have potential in wound repair. Therefore, (DMC) 2 @β-CD (FL) deserves great attention because it presented excellent results, reducing the granulation tissue and mast cell density and improving collagen remodeling. Finally, the protein binding studies suggested that the anti-inflammatory activities might exert their biological function through the inhibition of MEK, providing the possibility of development of new MEK inhibitors.

Atenolol (ATE) and propranolol (PRO) inclusion complexes with β-cyclodextrin have been investigated in aqueous solution. The aqueous solution was examined and characterized using UV-vis, fluorescence spectroscopy, and 1 H NMR. The physical mixture was characterized using FTIR. The existence of inclusion complexes is confirmed by observing changes in spectroscopic properties. The ATE complex with β-CD exhibited an interaction as host and (β-CD) as a guest in a 1:1 ratio, with an inclusion constant K of 2.09 × 10 -3 µM -1 , as determined by the typical double-reciprocal graphs. Similarly, the PRO complex with β-CD exhibited an interaction as host and (β-CD) guest in 1:1 and 1:2 stoichiometry at the same time; the inclusion constants were K1 = 5.80 × 10 -5 µM -1 and K2 = 4.67 × 10 -8 µM -1 , as determined by typical double-reciprocal graphs. The variables influencing the formation of the inclusion complexes were investigated and optimized. Based on the enhancement in fluorescence intensity due to the formation of inclusion complexes, spectrofluorometric methods were developed and validated for determination of each drug's pharmaceutical formulation. The quantification of the fluorescence intensity for ATE and PRO was conducted at λ ex /λ em 226/302 nm and λ ex /λ em 231/338 nm, respectively. Under the optimal reaction circumstances, linear relationships with good correlation coefficients of 0.9918 and 0.99 were found in the concentration ranges of 0.3-1.7 μM, and 0.1-1.1 μM for ATE and PRO, respectively. The limits of detection (LODs) were found to be 0.13 and 0.01 μM for ATE and PRO, respectively. The suggested approach was effectively applied to the analysis of both drugs' pharmaceutical formulations.

Sugammadex, marketed as Bridion™, is an approved cyclodextrin (CD) based drug for the reversal of neuromuscular blockade in adults undergoing surgery. Sugammadex forms an inclusion complex with the neuromuscular blocking agent (NMBA) rocuronium, allowing rapid reversal of muscle paralysis. In silico methods have been developed for studying CD inclusion complexes, aimed at accurately predicting their structural, energetic, dynamic, and kinetic properties, as well as binding constants. Here, a computational study aimed at characterizing the sugammadex-rocuronium system from the perspective of docking calculations, free molecular dynamics (MD) simulations, and biased metadynamics simulations with potential of mean force (PMF) calculations is presented. The aim is to provide detailed information about this system, as well as to use it as a model system for validation of the methods. This method predicts results in line with experimental evidence for both the optimal structure and the quantitative value for the binding constant. Interestingly, there is a less profound preference for the orientation than might be assumed based on electrostatic interactions, suggesting that both orientations may exist in solution. These results show that this technology can efficiently analyze CD inclusion complexes and could be used to facilitate the development and optimization of novel applications for CDs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AMA, RGF, AP, and MSO report financial support was provided by Cyclarity Therapeutics Inc. AMA, RGF, AP, and MSO report a relationship with Cyclarity Therapeutics Inc. that includes: employment, consultation or advisory, equity or stocks, and travel reimbursement. RGF and AP report a relationship with the company MD.USE that includes: employment, and equity or stocks., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Raloxifene hydrochloride (RLX) is used extensively in the treatment of osteoporosis, only 2% of RLX's bioavailability remains after a significant first pass metabolism. Besides coming from BCS class II, RLX is not very soluble in water. Thus, the goal of the current study was to improve RLX solubility by creating an inclusion complex using β cyclodextrin (β-CD) as a carrier and solid dispersion with Poloxamer 407., Methods: Inclusion complex and solid dispersion were made using a variety of techniques, including kneading, co-precipitation, and physical mixing and solid dispersion using different drug to carrier ratios (1:1, 1:2 and 1:3)., Results: Inclusion complex made using the co-precipitation method had shown 9-fold improvements in water solubility when compared with plain RLX. In order to assess the optimized complex's compatibility, thermal analysis, and crystallinity, X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy were used. The XRD and DSC study's results indicated that RLX changed from a crystalline to an amorphous state. IC-6 exhibits effective water solubility based on the outcome. However, upon comparison of the two techniques, the β-CD complexation method shown an impressive rise in drug solubility when compared to solid dispersion.

In this study, we report a novel per-6-substituted β-cyclodextrin ( 4 ) featuring seven phosphoramidate moieties as an innovative host for inclusion. This structurally well-defined host has remarkable water solubility and was isolated in pure form. Analytical techniques such as NMR and ITC were used to probe the molecular interactions with different drug molecules. Our investigations revealed that host 4 can form 2:1 inclusion complexes with various drugs. Further studies showed that the inclusions of drugs by β-CD host ( 4 ) are mostly enthalpy driven, highlighting the potential roles played by the phosphoramidate functionalities of the host. Comparatively, a per-O2, O3-acetylated analog ( 6 ) of compound 4 was also obtained, which also shows unusual water solubility but diminished inclusion capability.

Listeria monocytogenes (L. monocytogenes) and Staphylococcus aureus (S. aureus) are widely acknowledged as two of the most dangerous foodborne pathogens. Nevertheless, reports on the development of non-toxic food preservatives that specifically target these two bacterial strains are scarce. Here, we present an inclusion complex (IC) of Hinoki essential oil with β-cyclodextrin, which exhibited dual anti-L. monocytogenes and anti-S. aureus activities. For the first time, an innovative ultrasound-aided co-precipitation technique was utilized for the preparation of IC. Compared with the traditional co-precipitation method, this new technique demonstrated superior encapsulation and time efficiencies, making it well-suited for large-scale production. X-ray diffraction and scanning electron microscopy analyses revealed a transition in the morphological and crystal structures after formation of the IC. Fourier transform infrared spectroscopy and Raman spectroscopy analyses indicated that Hinoki essential oil was effectively encapsulated by β-cyclodextrin. The differential scanning calorimetry and thermogravimetric thermograms indicated that the formed IC was more thermally stable than the free Hinoki essential oil. Importantly, 100 % antibacterial ratios for both L. monocytogenes and S. aureus were determined, indicating that the IC prepared in this study is a promising food preservative., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sustainable release of drug by utilizing β-cyclodextrin (β-CD) based inclusion complex (IC) is the prime objective of the present work. Herein, polyacrylamide/dextran containing carbon quantum dots (PAM/Dex/CQD) nanocomposite hydrogels are prepared by in situ polymerization of acrylamide. The incorporation of CQD triggers the change in orientation of the PAM/Dex polymeric chains to result the formation of stacked surface morphology of the hydrogel. The average particle size of CQD is found to be 4.13 nm from HRTEM analysis. As-synthesized nanocomposite hydrogel exhibits an optimum swelling ratio of 863 % in aqueous medium. The cytotoxicity study is conducted on HeLa cells by taking up to 2 μM concentration of the prepared nanocomposite hydrogel demonstrate 78 % cell viability. In present study, ciprofloxacin (Cipro) is taken as model drug that achieves release of 64.15 % in 32 h from β-Cipro@PAM/Dex/CQD hydrogels in acidic medium. From theoretical study, release rate constants, R 2 , Akaike information criterion (AIC) and model selection criterion (MSC) are computed to determine the best fitted kinetics model. Peppas-Sahlin model is the best fitted kinetics model for β-Cipro@PAM/Dex/CQD and concluded that the release of Cipro follows Fickian drug diffusion mechanism in acidic medium., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Natural preservatives such as cinnamaldehyde (CIN) are garnering increasing interest to replace their synthetic counterparts in maintaining fruit freshness and safety. However, their long-term effectiveness and widespread application have been greatly limited due to high volatility and potent aroma. To address these challenges, we developed a viable and simple strategy to prepare a multifunctional active coating for fruit preservation by incorporating host-guest inclusion complex of CIN and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) CIN@HP-β-CD into hyaluronic acid (HA), a natural polysaccharide with exceptional film-forming properties. The as-prepared HA/CIN@HP-β-CD coatings exhibited universal surface affinity, excellent antimicrobial performance, and satisfactory antioxidant properties with no potential toxicity. Release kinetic studies have demonstrated that CIN in the coating is continuously and slowly released. Furthermore, freshness preservation experiments on bananas and fresh-cut apples demonstrated that the developed coating is effective in preserving the color of fruit, decreasing the weight loss rate, preventing the microorganism's growth, and significantly extending the period of freshness, exhibiting the potential for application in fruit preservation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hydroxypropyl-gamma-cyclodextrin (HPγCD) inclusion complex nanofibers (Lut/HPγCD-IC-NF) containing Luteolin (Lut) were prepared by electrospinning technology. Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) spectra confirmed the formation of Lut/HPγCD-IC-NF. Scanning electron microscopy (SEM) images showed that the morphology of Lut/HPγCD-IC-NF was uniform and bead-free, suggesting that self-assembled aggregates, macromolecules with higher molecular weights, were formed by strong hydrogen bonding interactions between the cyclodextrin inclusion complexes. Confocal laser scanning microscopy (CLSM) images showed that Lut was distributed in Lut/HPγCD-IC-NF. Proton nuclear magnetic resonance ( 1 H NMR) spectroscopy revealed the change in chemical shift of the proton peak between Lut and HPγCD, confirming the formation of inclusion complex. Thermogravimetric analysis (TGA) proved that Lut/HPγCD-IC-NF had good thermal stability. The phase solubility test confirmed that HPγCD had a solubilizing effect on Lut. When the solubility of HPγCD reached 10 mM, the solubility of Lut increased by 15-fold. The drug loading test showed that the content of Lut in fibers reached 8.57 ± 0.02 %. The rapid dissolution experiment showed that Lut/HPγCD-IC-NF dissolved within 3 s. The molecular simulation provides three-dimensional evidence for the formation of inclusion complexes between Lut and HPγCD. Antibacterial experiments showed that Lut/HPγCD-IC-NF had enhanced antibacterial activity against S. aureus. Lut/HPγCD-IC-NF exhibited excellent antioxidant properties with a free radical scavenging ability of 89.5 ± 1.1 %. In vitro release experiments showed Lut/HPγCD-IC-NF had a higher release amount of Lut. In conclusion, Lut/HPγCD-IC-NF improved the physicochemical properties and bioavailability of Lut, providing potential applications of Lut in the pharmaceutical field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cyclodextrins (CDs) can enhance the stability and bioavailability of pharmaceutical compounds by encapsulating them within their cavities. This study utilized molecular dynamics simulations to investigate the interaction mechanisms between hydrocortisone (HC) and various methylated CD derivatives. The results reveal that the loading of HC into CD cavities follows different mechanisms depending on the degree and position of methylation. Loading into βCD and 6-MeβCD was more complete, with the hydroxyl groups of HC facing the primary hydroxyl rim (PHR) and the ketone side facing the secondary hydroxyl rim (SHR). In contrast, 2,3-D-MeβCD and 2,6-D-MeβCD showed a different loading mechanism, with the ketone side facing the PHR and the hydroxyl groups facing the SHR. The root mean square fluctuation (RMSF) analysis demonstrated that methylation increases the flexibility of CD heavy atoms, with 3-MeβCD and 2,3-D-MeβCD exhibiting the highest flexibility. However, upon inclusion of HC, 3-MeβCD, 2,3-D-MeβCD, 2-MeβCD, and 6-MeβCD showed a significant reduction in flexibility, suggesting a more rigid structure that effectively retains HC within their cavities. The radial distribution function revealed a significant reduction in the number of water molecules within the innermost layer of the methylated CD cavities, particularly in TMeβCD, indicating a decrease in polarity. The presence of HC led to the release of high-energy water molecules, creating more favorable conditions for HC loading. Conformational analysis showed that methylation caused a partial decrease in the area of the PHR, a significant decrease in the area of the middle rim, and a notable decrease in the area of the SHR. The loading of HC increased the area of the PHR in most derivatives, with the most pronounced increase observed in 2,6-D-MeβCD and 6-MeβCD. The analysis of interaction energies and binding free energies demonstrated that the binding of HC to methylated CD derivatives is thermodynamically more favorable than to βCD, with the strongest association observed for 6-MeβCD, 2-MeβCD, and 2,3-D-MeβCD., (© 2024. The Author(s).)

Fluconazole (FNL) is one of the first-line treatments for fungal keratitis as it is an effective broad-spectrum antimicrobial commonly administered orally or topically. However, FNL has a very low water solubility, limiting its drug formulation, therapeutic application, and bioavailability through tissues. To overcome these limitations, this study aimed to develop FNL inclusion complexes (FNL-IC) with cyclodextrin (α-cyclodextrin, sulfobutylether-β-cyclodextrin, and hydroxypropyl-γ cyclodextrin) and incorporate it into a dissolvable microneedle (DMN) system to improve solubility and drug penetration. FNL-IC was evaluated for saturation solubility, Fourier transform infrared spectroscopy, differential scanning calorimetry, in vitro release, minimum inhibitory concentration, minimum fungicidal concentration, and time-killing assay. DMN-FNL-IC was evaluated for mechanical and insertion properties, surface pH, moisture absorption ability, water vapor transmission, and drug content recovery. Moreover, ocular kinetic, ex vivo antimicrobial, in vivo antifungal, and chorioallantoic membrane (HET-CAM) assays were conducted to assess the overall performance of the formulation. Mechanical strength and insertion properties revealed that DMN-FNL-IC has great mechanical and insertion properties. The in vitro release of FNL-IC was significantly improved, exhibiting a 9-fold increase compared to pure FNL. The ex vivo antifungal activity showed significant inhibition of Candida albicans from 6.54 to 0.73 log cfu/mL or 100-0.94%. In vivo numbers of colonies of 0.87 ± 0.13 log cfu/mL (F2), 4.76 ± 0.26 log cfu/mL (FNL eye drops), 3.89 ± 0.24 log cfu/mL (FNL ointments), and 8.04 ± 0.58 log cfu/mL (control) showed the effectiveness of DMN preparations against other standard commercial preparations. The HET-CAM assay showed that DMN-FNL-IC (F2) did not show any vascular damage. Finally, a combination of FNL-IC and DMN was developed appropriately for ocular delivery of FNL, which was safe and increased the effectiveness of treatments for fungal keratitis.

As an orally effective benzimidazole anthelmintic agent, fenbendazole was not only widely used in agriculture and animal husbandry to prevent and treat parasites, but also shows anti-cancer effects against several types of cancer, exhibits anti-cancer effects in paclitaxel and doxorubicin-resistant cancer cells. However, fenbendazole's poor in water solubility (0.3 µg/mL), limits its clinical applications. Even great efforts were made toward increasing its water solubility, the results were not significant to reach anti-cancer drug delivery requirement (5-10 mg/mL). Through single factor and orthogonal strategy, many complex conditions were designed and used to prepare the complexes, the inclusion complex with methyl-β-cyclodextrin with 29.2 % of inclusion rate and 89.5% of inclusion yield can increase drug's water solubility to 20.21 mg/mL, which is the best result so far. Its structure was confirmed by differential scanning calorimetry, scanning electron microscopic image, 1D and 2D NMR spectra in D 2 O. In its in vitro pharmacokinetic study, fenbendazole was 75% released in 15 min., in its in vivo pharmacokinetic study, the bio-availabilities of fenbendazole, its major metabolic anthelmintic agent oxfendazole and its minor metabolic anthelmintic agent oxfendazole were increased to 138%, 149% and 169% respectively, which would allow for fewer drug doses to achieve the same therapeutic effect and suggest that the complex can be used as a potential anticancer agent., (© 2024. The Author(s).)

α-CD:N 2 O "host-guest" type complexes were formed by a simple solid-gas reaction (N 2 O sorption into α-CD) under different gas pressures and temperatures. The new N 2 O inclusion method applied in the present study was compared with the already known technique based on the crystallization of clathrates from a water solution of α-CD saturated with N 2 O. A maximum storage capacity of 4.5 wt.% N 2 O was achieved when charging the cyclodextrin from a gas phase. The amount of included gas decreases to 1.3 wt.% when the complex is stored in air at 1 atm and room temperature, analogous to that achieved by the crystallization of α-CD:N 2 O. Furthermore, it was shown that the external coordination of N 2 O to either the upper or lower rim of α-CD without hydration water displacement is the preferred mode of binding, due to hydrogen bonds with neighboring -OH groups from the host macrocycle and three of the hydration water molecules nearby. The capacity of α-CD to store N 2 O and the thermal stability of the α-CD:N 2 O complex demonstrated promising applications of these types of complexes in food and beverages.

We prepared a naturally occurring flavanoid namely quercetin from tea leaves and analyzed by Absorption, Emission, FT-IR, 1 H, 13 C nmr spectra and ESI-MS analysis. The inclusion behavior of quercetin in cyclodextrins like α-, β-, γ-, per-6-ABCD and mono-6-ABCD cavities were supported such as UV-vis., Emission, FT-IR and ICD spectra and energy minimization studies. From the absorption and emission results, the type of complexes formed were found to depend on stoichiometry of Host:Guest. FT-IR data of CD complexes of quercetin supported inclusion complex formation of the substrate with α-, β- and γ-CDs. The inclusion of host-guest complexation of quercetin with α-, β-, γ-CDs, per-6-ABCD and mono-6-ABCDs provides very valuable information about the CD:quercetin complexes, the study also shows that β-CD complexation improves water solubility, chemical stability and bioavailability of quercetin. Besides, phase solubility studies also supported the formation of 1:1 drug-CD soluble complexes. All these spectral results provide insight into the binding behavior of substrate into CD cavity in the order per-6-ABCD > Mono-6-ABCD > γ-CD > β-CD > α-CD. The proposed model also finds strong support from the fact with excess CD this exciton coupling disappears indicates the formation of only 1:1 complex., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Olmesartan medoxomil (OLM) is a selective angiotensin II receptor antagonist used in the treatment of hypertension. Its therapeutic potential is limited by its poor water solubility, leading to poor bioavailability. Encapsulation of the drug substance by two methylated cyclodextrins, namely randomly methylated β-cyclodextrin (RM-β-CD) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD), was carried out to overcome the limitation related to OLM solubility, which, in turn, is expected to result in an improved biopharmaceutical profile. Supramolecular entities were evaluated by means of thermoanalytical techniques (TG-thermogravimetry; DTG-derivative thermogravimetry), spectroscopic methods including powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier-transform infrared (UATR-FTIR) and UV spectroscopy, saturation solubility studies, and by a theoretical approach using molecular modeling. The phase solubility method reveals an A L -type diagram for both inclusion complexes, indicating a stoichiometry ratio of 1:1. The values of the apparent stability constant indicate the higher stability of the host-guest system OLM/RM-β-CD. The physicochemical properties of the binary systems are different from those of the parent compounds, emphasizing the formation of inclusion complexes between the drug and CDs when the kneading method was used. The molecular encapsulation of OLM in RM-β-CD led to an increase in drug solubility, thus the supramolecular adduct can be the subject of further research to design a new pharmaceutical formulation containing OLM, with improved bioavailability.

Ethanamizuril (EZL) is a new anticoccidial drug developed by our Shanghai Veterinary Research Institute. Since EZL is almost insoluble in water, we conducted a study to improve the solubility of EZL by forming inclusion complexes with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD). In this study, we performed molecular docking and then systematically compared the interactions of EZL with β-CD and HP-β-CD in both aqueous solution and the solid state, aiming to elucidate the solubilization effect and mechanism of cyclodextrins (CDs). The interactions were also examined in the solid state using DSC, PXRD, and FT-IR. The interactions of EZL with CDs in an aqueous solution were investigated using PSA, UV-vis spectroscopy, MS, 1 H NMR, and 2D ROESY. The results of phase solubility experiments revealed that both β-CD and HP-β-CD formed inclusion complexes with EZL in a 1:1 molar ratio. Among them, HP-β-CD exhibited higher K f (stability constant) and CE (complexation efficiency) values as well as a stronger solubilization effect. Furthermore, the two cyclodextrins were found to interact with EZL in a similar manner. The results of our FT-IR and 2D ROESY experiments are in agreement with the theoretical results derived from molecular simulations. These results indicated that intermolecular hydrogen bonds existing between the C=O group on the triazine ring of EZL and the O-H group of CDs, as well as the hydrophobic interactions between the hydrogen on the benzene ring of EZL and the hydrogen of CDs, played crucial roles in the formation of EZL/CD inclusion complexes. The results of this study can lay the foundation for the future development of high-concentration drinking water delivery formulations for EZL.

Sildenafil citrate (SIL) as a first-line treatment for erectile dysfunction is currently reported to have poor solubility and bioavailability. Moreover, SIL undergoes first-pass metabolism when taken orally and its injection can lead to discomfort. In this study, we introduce a novel transdermal delivery system that integrates hydrogel-forming microneedles with the inclusion complex tablet reservoir. The hydrogel-forming microneedle was prepared from a mixture of polymers and crosslinkers through a crosslinking process. Importantly, the formulations showed high swelling capacity (>400 %) and exhibited adequate mechanical and penetration properties (needle height reduction < 10 %), penetrating up to five layers of Parafilm® M (assessed to reach the dermis layer). Furthermore, to improve the solubility of SIL in the reservoir, the SIL was pre-complexed with β-cyclodextrin. Molecular docking analysis showed that SIL was successfully encapsulated into the β-cyclodextrin cavity and was the most suitable conformation compared to other CD derivatives. Moreover, to maximize SIL delivery, sodium starch glycolate was also added to the reservoir formulation. As a proof of concept, in vivo studies demonstrated the effectiveness of this concept, resulting in a significant increase in AUC (area under the curve) compared to that obtained after administration of pure SIL oral suspension, inclusion complex, and Viagra® with relative bioavailability > 100 %. Therefore, the approach developed in this study could potentially increase the efficacy of SIL in treating erectile dysfunction by being non-invasive, safe, avoiding first-pass metabolism, and increasing drug bioavailability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)