Cyclodextrin Inclusion Complexes Research Articles

超高圧処理によるシクロデキストリン包接化合物の解離抑制

超高圧処理によるシクロデキストリン包接化合物の解離抑制

Physicochemical characterisation and cyclodextrin complexation of erlotinib

Erlotinib (ERL), the anticancer drug of poor bioavailability, was quantified in terms of bio-relevant physicochemical parameters, such as acid–base properties, lipophilicity and solubility, and a comprehensive study on its inclusion complexation was carried out. The protonation constant of ERL (log K = 5.32) indicates that it exists mainly in deprotonated form at the pH of blood plasma. The high lipophilicity (log p = 2.75) explains its good permeability, while the very low solubility (S0 = 12.46 μM) causes its low bioavailability and renders injection formulation a difficult job. This problem could be alleviated by enhancing ERL solubility through cyclodextrin (CD) inclusion complexation. Therefore, ERL–CD interactions were studied by a number of analytical techniques. The apparent stability constants of ERL with seven different CDs were determined using affinity capillary electrophoresis. Results indicated that the seven-membered β-CD and its derivatives were the most suitable hosts. Using UV Job plot titration 1:1 stoichiometry was determined, confirmed by electrospray ionisation-mass spectrometry experiments. The geometry of the inclusion complex was investigated by 2D ROESY NMR techniques, revealing that the ethynylphenyl ring enters the β-CD cavity. Phase-solubility analysis shows greatly enhanced solution concentration by CD complexation. The determined equilibrium and structural information offer molecular basis to elaborate improved drug formulation with enhanced bioavailability.

Melatonin/HPβCD complex: Microwave synthesis, integration with chitosan scaffolds and inhibitory effects on MG-63CELLS

In this study, melatonin/2-hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complex was prepared by using microwave irradiation in a very short time. Phase-solubility studies indicated a linear increase in the solubility of melatonin with HPβCD demonstrating Higuchi’s AL-type phase solubility profiles and the formation of 1:1 stoichiometric inclusion complexes. Also, the ability of inclusion complex formation was promoted at microwave conditions compared to room conditions. The structure of inclusion complex was determined by FTIR, DSC, XRD, 1H NMR and 13C NMR studies. Both of pure melatonin and melatonin/HPβCD inclusion complex were loaded into the chitosan scaffolds that were prepared by freeze-drying method and the effect of released melatonin on human osteosarcoma cells (MG-63) was investigated in vitro. Approximately 9mM melatonin concentration caused time dependent cell death by reducing the proportion of the cells in the G2/M phase rather than S phase. In conclusion, melatonin/HPβCD inclusion complex loaded chitosan scaffolds could be considered as an alternative system for the human osteosarcoma therapy.

Designing and evaluation of extended release matrix tablet containing altretamine–HP-β-CD inclusion complex

The aim of present study was to prepare sustained release tablets of a poorly soluble anticancer drug using cyclodextrin complexation as a potential approach. Altretamine is an alkylating agent practically insoluble in water and posses poor oral bioavailability. For this, the most suitable binary system of ALT-HP-β-CD was selected to improve the aqueous solubility and then embedding the complexed drug into a matrix tablet with fusion method. Tablets were prepared using glycerol monostearate (GMS) and polyethylene glycol 4000 (PEG4000). Complexes were prepared at different ratios and mixed with other excipients to achieve tablets with efficient dissolution profile complying with the requirements for sustained delivery of solid dosage forms. Results of Fourier Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) proved that kneading was most efficient technique for preparation of amorphous cyclodextrin inclusion complex with ALT and entrapping this complex into tablet. Dissolution profile of ALT was enhanced significantly in pH 6.8 from the binary system and significant within the limits (t test Student p < 0.05). The release kinetics of the tablets showed that diffusion was responsible for controlling the release from the tablets.

Advances in novel carrier systems of chemical constituents from spice volatile oils

Recent years, chemical constituents from spice volatile oils have gained worldwide concern owing to its multiple pharmacological effects and safety for using as the natural antibacterial agents. However, their poor dissolution, strong volatility, serious irritation, weak stability, easy oxidation and low bioavailability characteristics are the major obstacle in the preparation of effective oral formulation and practical application. Therefore, there is an urgent need to select a novel carrier system that can delivery the chemical constituents from spice volatile oils more efficiently with improving their stability as well as alleviating the irritation, and develop the functional food, health products and even medicine for exerting their pharmacological effects, which also is the focus and nodus of the research on their application. This review presents recent systematic studies on their novel carrier systems, including cyclodextrin inclusion complex, liposomes, nanoemulsions, nanoparticles, solid dispersion and so on, and summarizes the characteristics, application range and problems of each novel carrier systems, in order to provide some beneficial thoughts in further developing new products of chemical constituents from spice volatile oils.

Parameterization of an effective potential for protein-ligand binding from host-guest affinity data.

Force field accuracy is still one of the "stalemates" in biomolecular modeling. Model systems with high quality experimental data are valuable instruments for the validation and improvement of effective potentials. With respect to protein-ligand binding, organic host-guest complexes have long served as models for both experimental and computational studies because of the abundance of binding affinity data available for such systems. Binding affinity data collected for cyclodextrin (CD) inclusion complexes, a popular model for molecular recognition, is potentially a more reliable resource for tuning energy parameters than hydration free energy measurements. Convergence of binding free energy calculations on CD host-guest systems can also be obtained rapidly, thus offering the opportunity to assess the robustness of these parameters. In this work, we demonstrate how implicit solvent parameters can be developed using binding affinity experimental data and the binding energy distribution analysis method (BEDAM) and validated using the Grid Inhomogeneous Solvation Theory analysis. These new solvation parameters were used to study protein-ligand binding in two drug targets against the HIV-1 virus and improved the agreement between the calculated and the experimental binding affinities. This work illustrates how benchmark sets of high quality experimental binding affinity data and physics-based binding free energy models can be used to evaluate and optimize force fields for protein-ligand systems. Copyright © 2015 John Wiley & Sons, Ltd.

Experimental and Theoretical Investigations on the Supermolecular Structure of Isoliquiritigenin and 6-O-α-D-Maltosyl-β-cyclodextrin Inclusion Complex.

Isoliquiritigenin (ILTG) possesses many pharmacological properties. However, its poor solubility and stability in water hinders its wide applications. The solubility of bioactive compounds can often be enhanced through preparation and delivery of various cyclodextrin (CD) inclusion complexes. The 6-O-α-d-maltosyl-β-CD (G2-β-CD), as one of the newest developments of CDs, has high aqueous solubility and low toxicity, especially stable inclusion characteristics with bioactive compounds. In this work, we for the first time construct and characterize the supermolecular structure of ILTG/G2-β-CD by scanning electron microscopy (SEM), ultraviolet-visible spectroscopy (UV), Fourier transform infrared spectroscopy (FT-IR), and X-ray diffractometry (XRD). The solubility of ILTG in water at 25 °C rises from 0.003 to 0.717 mg/mL by the encapsulation with G2-β-CD. Our experimental observations on the presence of the ILTG/G2-β-CD inclusion complex are further supported by the ONIOM(our Own N-layer Integrated Orbital molecular Mechanics)-based QM/MM (Quantum Mechanics/Molecular Mechanics) calculations, typically substantiating these supermolecular characteristics, such as detailed structural assignments, preferred binding orientations, selectivity, solvent effects, interaction energies and forces of the ILTG/G2-β-CD inclusion complex. Our results have elucidated how ILTG interacts with G2-β-CD, demonstrating the primary host-guest interactions between ILTG and G2-β-CD, characterized by hydrogen bonds, hydrophobic interactions, electrostatic forces, and conformational effects, are favored for the formation of the ILTG/G2-β-CD inclusion.

Effect of β-cyclodextrin inclusion complex on transport of major components of Xiangfu Siwu decoction essential oil in Caco-2 cell monolayer model

Although the essential oil of Xiangfu Siwu decoction (XFSWD) has strong pharmacological activity, its special physical and chemical properties restrict the clinical application and curative effect. In this paper, Xiangfu Siwu decoction essential oil (XFS-WO) was prepared by forming inclusion complex with β-cyclodextrin (β-CD). The present study is to investigate the effect of β-CD inclusion complex on the transport of major components of XFSWO using Caco-2 cell monolayer model, thus to research the effect of this formation on the absorption of drugs with low solubility and high permeability, which belong to class 2 in biopharmaceutics classification system. A sensitive and rapid UPLC-MS/MS method was developed for simultaneous quantification of senkyunolide A, 3-n-butylphthalide, Z-ligustilide, dehydrocostus lactone and α-cyperone, which are active compounds in XFSWO. The transport parameters were analyzed and compared in free oil and its β-CD inclusion complex. The result revealed that the formation of XFSWO/β-CD inclusion complex has significantly increased the transportation and absorption of major active ingredients than free oil. Accordingly, it can be speculated that cyclodextrin inclusion complex can improve bioavailability of poorly water-soluble drugs. Above all these mentioned researches, it provided foundation and basis for physiological disposition and pharmaceutical study of XFSWD.

Preparation and characterization of β-cyclodextrin inclusion complexes as a tool of a controlled antimicrobial release in whey protein edible films

Control release of eugenol and carvacrol is difficult to obtain even when WPI is used as a carrier. Active compounds cyclodextrin inclusion complexes may encourage molecular interaction intervening in their release. α-, β-, and γ-cyclodextrin (α-, β-, and γ-CD) complexes were prepared and added to WPI edible films. Inclusion/spray-drying process yield was low (<50%, weigh basis). β-CD was selected because it showed a higher retention for eugenol (50.4%, molar basis) and carvacrol (79.6%, molar basis). Protons that lie inside the β-CD cavity and aromatic rings protons from active compounds are involved in host–guest interaction. The initial molar ratio using during complex preparation was not maintained. The final stoichiometric ratio of β-CD:eugenol and β-CD:carvacrol was 1:0.5 and 1:0.7, respectively, showing a β-CD cavity preference for carvacrol. The study suggests that adding β-CD to the WPI matrix resulted in a decreased release rate in a food simulant medium (ethanol: water, 1:1, v/v) when there is an effective interaction between β-CD and active compound. This fact shows significance for delivery of antimicrobial compounds that must release gradually in time.

Nanosuspensions Containing Oridonin/HP-β-Cyclodextrin Inclusion Complexes for Oral Bioavailability Enhancement via Improved Dissolution and Permeability.

Chemotherapy via oral route of anticancer drugs offers much convenience and compliance to patients. However, oral chemotherapy has been challenged by limited absorption due to poor drug solubility and intestinal efflux. In this study, we aimed to develop a nanosuspension formulation of oridonin (Odn) using its cyclodextrin inclusion complexes to enhance oral bioavailability. Nanosuspensions containing Odn/2 hydroxypropyl-β-cyclodextrin inclusion complexes (Odn-CICs) were prepared by a solvent evaporation followed by wet media milling technique. The nanosuspensions were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and dissolution. The resulting nanosuspensions were approximately 313.8 nm in particle size and presented a microcrystal morphology. Nanosuspensions loading Odn-CICs dramatically enhanced the dissolution of Odn. Further, the intestinal effective permeability of Odn was markedly enhanced in the presence of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and poloxamer. Bioavailability studies showed that nanosuspensions with Odn-CICs can significantly promote the oral absorption of Odn with a relative bioavailability of 213.99% (Odn suspensions as reference). Odn itself possesses a moderate permeability and marginal intestinal metabolism. Thus, the enhanced bioavailability for Odn-CIC nanosuspensions can be attributed to improved dissolution and permeability by interaction with absorptive epithelia and anti-drug efflux. Nanosuspensions prepared from inclusion complexes may be a promising approach for the oral delivery of anticancer agents.

Complexation of Surfactant/β‐Cyclodextrin to Inhibit Surfactant Adsorption onto Sand, Kaolin, and Shale for Applications in Enhanced Oil Recovery Processes. Part III: Oil Displacement Evaluation

AbstractThis proof of concept research evaluates the performance of a surfactant/β‐cyclodextrin (β‐CD) inclusion complex during chemical flooding for enhanced oil recovery. It was hypothesized that the encapsulated surfactant propagates well through the porous media. Sodium dodecyl sulfate (SDS) was used to study the surfactant/β‐CD complexations. Phase behavior analysis was carried out to prepare the most favorable chemical slug formulation. A series of core flooding tests were conducted to determine the efficiency of the SDS/β‐CD inclusion complex in displacing residual oil. Surfactant flooding was conducted as tertiary oil recovery mode (after mature water flooding) by injecting 0.3 pore volume (PV) of the optimum surfactant slug that was chased by 0.3 PV of a polymer slug; followed by continuous water flooding until oil production stopped. The experimental results indicate that the encapsulated surfactant propagates well through the sandpack system and consistently produces higher incremental oil recoveries that range from 40 to 82 % over the incremental oil recovery achieved by conventional surfactant flooding.

Enhanced enzymatic activity of phenylalanine dehydrogenase caused by cyclodextrins

The influence of cyclodextrins (CDs) on the biotransformations of l-phenylalanine (Phe) and phenylpyruvate (PP) catalysed by phenylalanine dehydrogenase (PheDH) was evaluated. It was found that the reaction rate of both transformations was increased more than twice by CDs. The observed increase of the enzymatic activity is connected with the beneficial influence of CDs on the active conformation of PheDH due to formation of inclusion complexes on the surface of the enzyme protein. Moreover, the formation of the Phe–CD and PP–CD complexes was also postulated and studied theoretically by semiempirical calculations. The specificity of PheDH for Phe–CD increased over 6-fold in comparison with that for free Phe molecules. On the other hand, the specificity of PheDH for PP–CD decreased three times as compared with that for uncomplexed PP molecules. These reversed specificities of PheDH for complexed and free substrate molecules seem to be related to different properties of the Phe–CD and PP–CD inclusion complexes. Nevertheless, those CD complexes could not be considered as straight substrates for PheDH, the CDs rather play a role of transporting molecules with different abilities for donating free Phe or PP to the active site of the enzyme.

Determining the Binding Sites of β-Cyclodextrin and Peptides by Electron-Capture Dissociation High Resolution Tandem Mass Spectrometry.

Cyclodextrins (CDs) are a group of cyclic oligosaccharides, which readily form inclusion complexes with hydrophobic compounds to increase bioavailability, thus making CDs ideal drug excipients. Recent studies have also shown that CDs exhibit a wide range of protective effects, preventing proteins from aggregation, degradation, and folding. These effects strongly depend on the binding sites on the protein surface. CDs only exhibit weak interactions with amino acids, however; conventional analytical techniques therefore usually fail to reveal the exact location of the binding sites. Moreover, some studies even suggest that CD inclusion complexes are merely electrostatic adducts. Here, electron capture dissociation (ECD) was applied in this proof-of-concept study to examine the exact nature of the CD/peptide complexes, and CD binding sites were unambiguously located for the first time via Fourier-transform ion cyclotron resonance (FTICR) tandem mass spectrometry.

Antipyrine–gamma cyclodextrin inclusion complex: Molecular modeling, preparation, characterization and cytotoxicity studies

Molecular docking, semi-empirical and molecular dynamics studies were conducted for α, β and γ-cyclodextrin-associated inclusion complexes of antipyrine. The results of molecular modeling were systematically analyzed to determine the stability of inclusion complexes. In preliminary computational screening, β and γ-cyclodextrin inclusion complexes of antipyrine were found to be more stable as compared to α-cyclodextrin based on docking score and binding free energies. Further, inclusion complex of antipyrine with γ-cyclodextrin was prepared by freeze drying method. Formation of the inclusion complex was investigated by solid state characterization techniques such as thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction, Fourier transform infrared spectroscopy and scanning electron microscopy. The changes observed in decomposition temperature, diffractogram, vibrational frequencies and morphological appearance confirmed the formation of inclusion complex. In addition, results from 1H NMR and 2D NOESY studies supported the inclusion phenomenon. The results obtained from computational studies were found to be in consistent with experimental data to ascertain the encapsulation of antipyrine into γ-cyclodextrin. The inclusion complex was found to be non-toxic toward MDCK-1 cell lines. Thus, this approach may be helpful in the formulation of drug molecules using cyclodextrins.

Improvement of In vitro release of Glibenclamide using Cyclodextrin inclusion complexation

The present study aimed to improve the aqueous solubility of the oral hypoglycemic agent, glibenclamide (GLI), so as to improve its oral absorption, and hence bioavailability after oral administration. This was accomplished by complex formation between GLI and ?-cyclodextrin (?-CD). The study involves the preparation of the inclusion complexes using different techniques. Differential Scanning Calorimetry (DSC) and XRay Diffractometry (XRD) results confirmed the complex formation between GLI and ?-CD. The solubility increase of GLI was due to 1:1 complex formation. The dissolution rate of GLI from the complex prepared by neutralization method was more rapid as compared to other methods used. DOI: http://dx.doi.org/10.3329/dujps.v13i1.21855 Dhaka Univ. J. Pharm. Sci. 13(1): 15-21, 2014 (June)

The unexpected increase of clotrimazole apparent solubility using randomly methylated β-cyclodextrin.

Clotrimazole (CTZ) and cyclodextrin (CD) inclusion complexes having improved apparent water solubility were obtained from phase solubility diagrams. β-CD (1.5% w/w) and hydroxypropyl-β-CD (40% w/w) offered poor CTZ solubility enhancements (12 and 384 times, respectively). Unexpectedly, the apparent solubility of CTZ was 9980 times increased from 0.4 µg.mL(-1) (1.42 μM) without CD to 4.89 mg.mL(-1) (14.9 mM) using randomly-methylated β-CD (Me-β-CD) (40% w/w). This is the highest apparent CTZ solubility improvement ever reported in the literature using conventional CDs. Quantitative nuclear magnetic resonance ((1) H-NMR) coupled with two-dimensional nuclear Overhauser effect (NOESY) experiments and molecular docking calculations showed that the highest interactions with Me-β-CD were reported for CTZ two phenyl groups. A lower interaction was reported for chlorophenyl, while imidazole had the weakest interaction with Me-β-CD.

Influence of the preparation method on the physicochemical properties of indomethacin and methyl-β-cyclodextrin complexes

The main objective of this study was to investigate different manufacturing processes claimed to promote inclusion complexation between indomethacin and cyclodextrins in order to enhance the apparent solubility and dissolution properties of indomethacin. Especially, the effectiveness of supercritical carbon dioxide processing for preparing solid drug–cyclodextrin inclusion complexes was investigated and compared to other preparation methods. The complexes were prepared by physical mixing, co-evaporation, freeze drying from aqueous solution, spray drying and supercritical carbon dioxide processing methods. The prepared complexes were then evaluated by scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, solubility and dissolution studies. The method of preparation of the inclusion complexes was shown to influence the physicochemical properties of the formed complexes. Indomethacin exists in a highly crystalline solid form. Physical mixing of indomethacin and methyl-β-cyclodextrin appeared not to reduce the degree of crystallinity of the drug. The co-evaporated and freeze dried complexes had a lower degree of crystallinity than the physical mix; however the lowest degree of crystallinity was achieved in complexes prepared by spray drying and supercritical carbon dioxide processing methods. All systems based on methyl-β-cyclodextrin exhibited better dissolution properties than the drug alone. The greatest improvement in drug dissolution properties was obtained from complexes prepared using supercritical carbon dioxide processing, thereafter by spray drying, freeze drying, co-evaporation and finally by physical mixing.Supercritical carbon dioxide processing is well known as an energy efficient alternative to other pharmaceutical processes and may have application for the preparation of solid-state drug–cyclodextrin inclusion complexes. It is an effective and economic method that allows the formation of solid complexes with a high yield, without the use of organic solvents and problems associated with their residues.

Manipulation of multiple-responsive fluorescent supramolecular materials based on the inclusion complexation of cyclodextrins with Tyloxapol

Response of a 100 mg mL−1 α-CD/15 mg mL−1 Tyloxapol hydrogel towards additives, pH, temperature and solvent.

Physicochemical Characterization and In-Vitro Dissolution Enhancement of Bicalutamide-Hp-Β-Cd Complex

Abstract: Inclusion complex has been used as effective metllhod to improve the dissolution properties and bioavailability of poorly water soluble drugs. The aim of present study was to improve the dissolution rate of poorly soluble drug, bicalutamide (BIC), by cyclodextrin inclusion complexation. The phase solubility profile of bicalutamide with hydroxypropyl-β-Cyclodextrin (HP- β-CD) was classified as An-type. Stability constant with 1:2 molar ratio was calculated from the phase solubility diagram. Gibbs free energy (ΔGtr) values were negative, indicating the spontaneous nature of BIC solubilization. Solid inclusion complexes were prepared at 1:1.5, 1:2 drug/carrier ratio by physical mixing, kneading method and solvent evaporation techniques. Optimized complex was characterized by using FTIR and differential scanning calorimetry. It could conclude that stability of BIC and the absence of well define drugpolymer interaction. Inclusion complex prepared by kneading method showed the most improvement in wettability and dissolution rate as compare with pure BIC and physical mixture. Tablets prepared using optimized ratio with HP-β-CD showed significant improvement in the release profile of BIC as compared with marketed tablets (CALUT).

Influence of Ethanol as a Co-Solvent in Cyclodextrin Inclusion Complexation: A Molecular Dynamics Study.

Molecular dynamics (MD) simulations were used to investigate the dynamics and host-guest interactions of the inclusion complexes between a potent anti-HIV agent, UC781, and three different types of cyclodextrins (CDs) including βCD, 2,6-dimethyl-βCD (MβCD), and 2-hydroxypropyl-βCD (HPβCD) in aqueous solution with ethanol (EtOH) as a co-solvent. The MD simulation results revealed that EtOH as the co-solvent and the type of cyclodextrin affected the inclusion complex formation. From this study, UC781/MβCD provided the most stable inclusion complex. The competition for the cavity of βCD between UC781 and EtOH and the ensuing occupation of βCD cavities by EtOH resulted in a weaker interaction between βCD and UC781. In HPβCD, a supramolecular complex of UC781−HPβCD−EtOH was formed. The EtOH could easily fill the residual void space of the interior of unoccupied HPβCD due to the movement of UC781. In MβCD, the strong hydrogen bond interactions between the UC781 amide group and the secondary hydroxyl groups of MβCD significantly stabilized the inclusion complex in the presence of EtOH.