Cyclodextrin solubilization of celecoxib: solid and solution state characterization

The low aqueous solubility of celecoxib (CCB) hampers its oral bioavailability and permeation from aqueous environment through biological membranes. The aim of this study was to enhance the aqueous solubility of CCB by complexation with cyclodextrin (CD) in the presence of water-soluble polymer. The effects of different CDs (αCD, βCD, γCD, 2-hydroxypropyl-β-cyclodextrin and randomly methylated β-cyclodextrin (RMβCD)) and mucoadhesive, water-soluble polymers (hydroxypropyl methylcellulose (HPMC), chitosan and hyaluronic acid) were investigated. The phase solubility profiles and CCB/CD complex characteristics were determined. RMβCD exhibited the greatest solubilizing effect of the two CDs tested. However, γCD was also selected for further investigations due to its safety profile. Addition of polymer to the aqueous CD solutions enhanced the CD solubilization. Formation of CCB/RMβCD/HPMC and CCB/γCD/HPMC ternary complexes resulted in 11 and 19-fold enhancement in the apparent complexation efficiency in comparison to their CCB/CD binary complex, respectively. The size of ternary complex aggregates in solution were determined to be from about 250 to about 350 nm. The data obtained from Fourier transform infra-red, differential scanning calorimetry and powder X-ray diffraction indicated presence of CCB/CD inclusion complexes in the solid state. Proton nuclear magnetic resonance data demonstrated that CCB was partially and totally inserted into the hydrophobic central cavities of RMβCD and γCD.     

Effect of self-aggregation of γ-cyclodextrin on drug solubilization

The purpose of this study was to investigate the physicochemical properties of drug-saturated aqueous cyclodextrin (CD) solutions. Phase solubility profiles of different drugs were determined in aqueous solutions containing γ-cyclodextrin (γCD) and/or hydroxypropyl-γ-cyclodextrin (HPγCD) in absence or presence of water-soluble polymers. ¹H-NMR and turbidity analysis were performed as well as permeation studies. Phase solubility diagrams showed that the observed γCD content (1–20% w/v) was only slightly different from the theoretical values for aqueous solutions that had been saturated with indomethacin, diclofenac sodium or amphotericin B, all displayed A-type profiles, while it was less than the theoretical value in solutions that had been saturated with corticosteroids (hydrocortisone and dexamethasone) that displayed B_S-type profiles. In the latter case self-assemble of drug/CD complexes decreased the overall CD solubility. Water-soluble polymers enhanced aqueous solubility of the drugs tested by stabilizing the drug/CD complexes, i.e. enhancing their stability constants, without affecting the observed aqueous γCD solubility. When the drug solubility leveled off (the B_S-type profiles) the amount of dissolved γCD increased and approached the theoretical values. Hydrocortisone formed partial inclusion complex with γCD and HPγCD and no non-inclusion or aggregates could be detected in diluted solutions by ¹H-NMR. Both permeation and turbidity studies showed that formation of dexamethasone/γCD complex promoted CD aggregation. All these observations indicate that CD aggregate formations play a role in CD solubilization of lipophilic and poorly water-soluble drugs and that the water-soluble polymers enhance the complexation efficiency of γCD and HPγCD by stabilizing the self-assembled drug/CD nanoparticles and promote non-inclusion complex formation.     

Formation of CoQ10 reduced form by mixing CoQ10 oxidized form γCD complex and vitamin C in powder

We have already reported the enhancement of the stability and bioavailability of coenzyme Q10 (CoQ10) oxidized form by γ-cyclodextrin (γCD) complexation. In a series of the studies, we investigated an easy and economical conversion of CoQ10 oxidized form to its reduced form in complex powder, using inexpensive vitamin C (VC) as the reductant. CoQ10 oxidized form or its γCD complex and VC were physically mixed at the molar ratio of 1:0 to 1:50. The mixtures were stored at 60 °C and 75% RH. The sampling was made at certain interval, and both CoQ10 oxidized and reduced form contents were measured by high performance liquid chromatography (HPLC). The result shows that the conversion ratio to CoQ10 reduced form in γCD complex was significantly higher than that of non-inclusion compound (ca. 80% versus ca. 30% at the maximum). It was also confirmed that CoQ10 reduced form in γCD complex remains as stable as its oxidized form in γCD complex. Free radical scavenging potential of partially reduced CoQ10–γCD complex was assayed with 1,1-diphenyl-2-picrylhydrazyl (DPPH).     

Characterization of the complexation of tauro- and glyco-conjugated bile salts with γ-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin using affinity capillary electrophoresis

The complexation of seven bile salts, present in the small intestine of rat, dog and man, (taurocholate, tauro-β-muricholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, glycodeoxycholate and glycochenodeoxycholate) with γ-cyclodextrin and the chemically modified 2-hydroxypropyl-γ-cyclodextrin, was studied using affinity capillary electrophoresis (ACE). The cyclodextrins (CDs) were investigated due to their use in drug formulation as excipients for solubilisation of poorly soluble drugs and drug candidates. Using mobility shift ACE, the bile salt cyclodextrin interactions were characterized demonstrating 1:1 binding stoichiometry with stability constants ranging from 2 × 10³ to 8 × 10⁴ M^?1. The binding constants showed a systematic dependence on the number and position of hydroxyl groups on the steroid skeleton and the stability constants were in general higher for complexation with the native cyclodextrin than with the modified cyclodextrin. Based upon the size of the complexation constants, it was suggested that the interaction between the CDs and the bile salts takes place at the C and D ring of the steroid skeleton. The complexation of bile salts with the γ-cyclodextrins may compete with drug-γ-cyclodextrin complex formation and, thus, potentially affect drug absorption and efficacy.     

2,4-Dichlorophenol sorption on cyclodextrin polymers

The sorption of β-cyclodextrin polymer (β-CDP) and γ-cyclodextrin polymer (γ-CDP) toward 2,4-dichlorophenol (2,4-DCP) in aqueous solutions was investigated. The influence of sorption conditions including initial 2,4-DCP concentration, contact time and pH on sorption capability were discussed. Their sorption behaviors for 2,4-DCP were conducted and it was found the sorption kinetics followed the Ho and McKay equation and the film diffusion was the rate-determined step. The sorption isotherm can be correlated to Freundlich model and the sorption capacity on β-CDP was much larger than that on γ-CDP. The maximum sorption capacity of 2,4-DCP for β-CDP was measured to be 0.16 mmol/g with the initial concentration at 0.67 mmol/L at 288 K. The CDPs were easily recovered by ethanol as washing solvent and they could be used as a kind of recyclable sorbents.     

Determination of the structure of quinolone-γ-cyclodextrin complexes and their binding constants by means of UV–Vis and <Superscript>1</Superscript>H NMR

The host–guest inclusion complex structure and binding ability of two different quinolones with γ-cyclodextrin (γ-CD) were investigated in solution by means of UV–Vis and ¹H NMR spectroscopy. Competition of oxolinic and nalidixic acid molecules for the γ-CD cavity was evaluated by determination of association constants. Both quinolones form 1:1 inclusion complexes, their binding constants at room temperature (25 °C) under acidic and basic conditions were calculated using Benesi–Hildebrand equation. The stability of the complexes was dependent on the structure of the quinolone. In general, the weaker binding constants were observed for oxolinic acid-γ-CD complexes (1616 and 1765 M^?1) and the larger binding constants were obtained for nalidixic acid-γ-CD complexes (3760 and 3840 M^?1). ¹H NMR studies in D₂O were performed to elucidate the structure of each inclusion complex, nalidixic acid molecule penetrates more deeply into the γ-CD cavity and an intermolecular hydrogen bond is formed. Knowledge about structure and relative stability of quinolone-γ-CD complexes will be useful for future applications of these antimicrobial agents in medicinal chemistry.     

γ-环糊精诱导的2-萘甲酸酯光二聚反应

本文研究了水溶液中γ-环糊精诱导2-萘甲酸酯的光二聚反应.γ-环糊精的限制性疏水空腔能够容纳两个2-萘甲酸甲酯(或乙酯)分子形成稳定的2:1包结复合物NA@γ-CD,光照NA@γ-CD包结物水溶液能高效、快速、高选择地生成2-萘甲酸酯的类立方烷光二聚体,并且该反应有一定程度的对映体选择性.     

Effect of β-cyclodextrin complexation on physicochemical properties of zaleplon

The physicochemical properties and dissolution profile of zaleplon (ZPN) β-cyclodextrin (βCD) inclusion complex were investigated. The phase solubility profile of ZPN with β-cyclodextrin was classified as A_L-type. Stability constant with 1:1 molar ratio was calculated from the phase solubility diagram and the aqueous solubility of ZPN was found to be enhanced by 714% (p < 0.001) for β-cyclodextrin. Binary systems of ZPN with βCD were prepared by kneading method. The solid-state properties of complex were characterized by differential scanning calorimetry, Fourier transformation-infrared spectroscopy and powder X-ray diffractometry. It could be concluded that ZPN could form inclusion complex with β-cyclodextrin. The dissolution profile of inclusion complex was determined and compared with those of ZPN alone and its physical mixture. The dissolution rate of ZPN was significantly increased by complexation with βCD, as compared with pure drug and physical mixture.     

Supramolecular Adduct of γ-Cyclodextrin and [{Re<Subscript>6</Subscript>Q<Subscript>8</Subscript>}(H<Subscript>2</Subscript>O)<Subscript>6</Subscript>]<Superscript>2+</Superscript> (Q=S,Se)

Slow evaporation of water solution of [{Re₆S₈}(H₂O)₆]²⁺ generated in situ from [{Re₆S₈}(OH)₆]^4– in presence of γ-cyclodextrin (CD) leads to crystallization of {[{Re₆S₈}(H₂O)₆] ? [γ-CD]}(NO₃)₂·12H₂O (1·12H₂O) supramolecular complex, which was characterized by single-crystal X-ray diffraction crystallography, IR-spectroscopy, thermogravimetric and elemental analyses. X-ray analysis confirms the formation of 1:1 {[{Re₆S₈}(H₂O)₆] ? [γ-CD]}²⁺ inclusion compound in the solid state. However, no adduct formation was detected between [{Re₆S₈}(H₂O)₆]²⁺ and γ-cyclodextrin in solution, according to ¹H NMR spectroscopy. In the case of in situ generated [{Re₆Se₈}(H₂O)₆]²⁺ the reaction solution with γ-cyclodextrin is unstable and during the crystallization only amorphous precipitate has been obtained.     

Inclusion complexes of γ-cyclodextrin and carboxyl-modified γ-cyclodextrin with C60: synthesis, characterization and controlled release application via microgels

Carboxyl modified γ-cyclodextrin (CDSA) with a substitution degree of about 9.5 was prepared by the esterification of γ-cyclodextrin (CD) with succinic anhydride in pyridine at 90 °C. The chemical composition and the structure of CDSA were characterized by FT-IR, MALDI-TOF, X-ray diffraction pattern, potentiometric titration and TGA. Modified and native γ-cyclodextrin associate with fullerene (C₆₀) in DMF-toluene mixture resulting 1:1 CDSA:C₆₀ and CD:C₆₀ inclusion complexes. Aqueous solutions of native cyclodextrin, carboxyl-modified cyclodextrin and their inclusion complexes with C₆₀ were used as microgel solvent (or swelling agent) for controlled release application. The release of solutions was induced by shear stress and demonstrated using rheo-optical set-up.     

Host–guest complexation of a nitroheterocyclic compound with cyclodextrins: a spectrofluorimetric and molecular modeling study

Nitroheterocyclic compounds (NC) were candidate drugs proposed for Chagas disease chemotherapy. In this study, we investigated the complexation of hydroxymethylnitrofurazone (NFOH), a potential antichagasic compound, with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), Hydroxypropyl-β-cyclodextrin (HP-β-CD), Dimethyl-β-cyclodextrin (DM-β-CD) and γ-cyclodextrin (γ-CD) by fluorescence spectroscopy and molecular modeling studies. Hildebrand–Benesi equation was used to calculate the formation constants of NFOH with cyclodextrins based on the fluorescence differences in the CDs solution. The complexing capacity of NFOH with different CDs was compared through the results of association constant according to the following order: DM-β-CD > β-CD > α-CD > HP-β-CD > γ-CD. Molecular modeling studies give support for the experimental assignments, in favor of the formation of an inclusion complex between cyclodextrins with NFOH. This is an important study to investigate the effects of different kinds of cyclodextrins on the inclusion complex formation with NFOH and to better characterize a potential formulations to be used as therapeutic options for the oral treatment of Chagas disease.     

Spectroscopic study and antioxidant activity of the inclusion complexes of cyclodextrins and amlodipine besylate drug

The aim of the study was to synthesize and characterization the inclusion complexes of amlodipine besylate (AML) drug with β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD) which has antioxidating activity property. The guest/host interaction of AML with β-CD and γ-CD in order to complexation drug in β-CD and γ-CD were investigated. The interaction inclusion complexes was characterized by fourier transform infrared and ultraviolet–visible spectroscopies. The formation constant was calculated by using a modified Benesi–Hildebrand equation at 25 °C. The stoichiometry of inclusion complexes was found to be 1:1 for β-CD and γ-CD with AML drug. The antioxidant activity of AML drug and its inclusion complexes were determined by the scavenging of stable radical 2,2′-diphenyl-1-picrylhydrazyl (DPPH^·). Kinetic studies of DPPH^· with AML and CDs complexes were done. The experimental results confirmed the forming of AML complexes with CDs also these indicated that the AML/β-CD and AML/γ-CD inclusion complexes was the most reactive than its free form into antioxidant activity.     

Synthesis and Characterization of Linear Water-soluble γ-Cyclodextrin based Polymers as Drug Carrier Systems

A series of new linear water-soluble homo and copolymers of γ-cyclodextrin are reported. These water-soluble polymers were synthesized from γ-cyclodextrin (γ-CD) and triazine through a single pot condensation polymerization procedure and the synthetic parameters optimized. Lactose and maltose based γ-cyclodextrin copolymers were also prepared. The physicochemical properties of these synthesized polymers were characterized by FT-IR spectroscopy, XRD analysis, thermogravimetry analysis (TGA) and aqueous solubility determination. The formation of a 1:1 efavirenz (an anti HIV drug)/γ-CD polymer inclusion complex was confirmed from FT-IR and UV–VIS spectroscopy and phase solubility studies. The release performance of efavirenz was investigated through phase solubility and dissolution studies. It was found that these copolymers showed improved drug dissolution abilities.     

Self-assembly of zinc chlorophyll derivatives possessing a pyrenyl group at the 17-propionate residue and effects of additional γ-cyclodextrins on their optical properties

Two kinds of zinc 3¹-hydroxy-13¹-oxo-chlorins 1 and 2 possessing a pyrenyl group at the 17-propionate residue, of which the linker length between the chlorin and the pyrene moieties was varied, were synthesised from naturally occurring chlorophyll a, and were self-assembled in an aqueous solution. Both zinc chlorins 1 and 2 exhibited Q_y absorption bands around 720 nm accompanying circular dichroism signals in the Q_y region, indicating that these zinc chlorins could form self-aggregates like chlorosomes of green photosynthetic bacteria. Addition of γ-cyclodextrin into an aqueous solution containing the self-aggregates of zinc chlorin 1 esterified with 1-pyrenylmethanol induced the appearance of excimer emission of the pyrene moieties around 480 nm as well as increased the fluorescence intensities of the pyrene monomers at 378 and 396 nm, while only an increase in fluorescence from the monomeric pyrene moiety was observed in the case of 2 esterified with 4-(1-pyrenyl)butanol. Exogenous γ-cyclodextrin unchanged the spectral features derived from the chlorin moieties of 1 and 2 in the aqueous phase. These suggest that the encapsulation of the pyrenyl groups in the zinc chlorins unchanged their assembling states under the present conditions.     

Multiplex localization of sequential peptide epitopes by use of a planar microbead chip

Epitope mapping is crucial for the characterization of protein-specific antibodies. Commonly, small overlapping peptides are chemically synthesized and immobilized to determine the specific peptide sequence. In this study, we report the use of a fast and inexpensive planar microbead chip for epitope mapping. We developed a generic strategy for expressing recombinant peptide libraries instead of using expensive synthetic peptide libraries. A biotin moiety was introduced in vivo at a defined peptide position using biotin ligase. Peptides in crude Escherichia coli lysate were coupled onto streptavidin-coated microbeads by incubation, thereby avoiding tedious purification procedures. For read-out we used a multiplex planar microbead chip with size- and fluorescence-encoded microbead populations. For epitope mapping, up to 18 populations of peptide-loaded microbeads (at least 20 microbeads per peptide) displaying the primary sequence of a protein were analyzed simultaneously. If an epitope was recognized by an antibody, a secondary fluorescence-labeled antibody generated a signal that was quantified, and the mean value of all microbeads in the population was calculated. We mapped the epitopes for rabbit anti-PA28γ (proteasome activator 28γ) polyclonal serum, for a murine monoclonal antibody against PA28γ, and for a murine monoclonal antibody against the hamster polyoma virus major capsid protein VP1 as models. In each case, the identification of one distinct peptide sequence out of up to 18 sequences was possible. Using this approach, an epitope can be mapped multiparametrically within three weeks.     

Preparation,Mass Diffusion,and Biocompatibility Analysis of Porous-Channel Controlled Calcium-Alginate-Gelatin Hybrid Microbeads for In Vitro Culture of NSCs

The Ca-alginate/gelatin (CAG) microbeads were prepared and evaluated through assays for their mechanical strength, permeability, and the feasibility as a cell carrier for in vitro culture of neural stem cells. The effects of different concentrations of sodium alginate, gelatin, and calcium chloride on the mechanical strength of CAG microbeads were determined using a self-made puncture force tester. Following this, the microbeads were immersed in DMEM media for a specified period to test its decay resistance. A diffusion model including a calculation formula of diffusion coefficient was built to investigate the diffusion of glucose and bovine serum albumin (BSA) through the wall of the microbeads. Furthermore, the feasibility of the microbeads for in vitro culture was identified using neural stem cells from Kunming mouse. Through a systematic approach and comprehensive analysis, the optimal gelatin conditions for microbead preparation were determined; the final combination of parameters of 1.5 % (wt%) sodium alginate (SA), 0.5 % (wt%) gelatin, and 4 % (wt%) CaCl₂ were the best conditions for NSC cultures. This experiment demonstrated that CAG microbeads had good cytocompatibility that made it suitable for the culture and successfully maintained stemness of neural stem cells.     

Dexamethasone delivery to posterior segment of the eye

Due to anatomic barriers and lacrimal drainage it is difficult to obtain therapeutic drug concentrations in the posterior part of the eye after topical drug administrations. Lipophilic cyclodextrins, such as randomly methylated β-cyclodextrin (RMβCD), are known to act both as solubilizers of water-insoluble drugs in aqueous solutions and as penetration enhancers that reduce the barrier function of lipophilic membranes. The purpose of this study was to investigate the effects of RMβCD on dexamethasone delivery from aqueous eye drop solution into rabbit eyes. Dexamethasone (0.5 and 1.5% w/v) drops (50 μl) were administered to the left eye of rabbits (n = 6) and the drug levels measured in different eye tissues 2 h after administration. In aqueous humor dexamethasone levels were 1,190 ± 110 and 1,670 ± 630 ng/g (mean ± SD) after administration of the 0.5 and 1.5% dexamethasone eye drops, respectively. In the retina the levels were 33 ± 7 and 66 ± 49 ng/g, and in optic nerve 41 ± 12 and 130 ± 50 ng/g, respectively. In a previous study the dexamethasone concentration in aqueous humor after topical administration of 1.3% (w/v) dexamethasone eye drops in aqueous 2-hydroxypropyl-β-cyclodextrin (HPβCD) solution was determined to be 320 ± 230 ng/g and 66 ± 20 ng/g after administration of Maxidex^® eye drops. Both the hydrophilic HPβCD and the lipophilic RMβCD enhance topical dexamethasone delivery into the eye, but of the two, the lipophilic RMβCD results in higher dexamethasone concentrations.     

Production of Ultra-high Molecular Weight Poly-γ-Glutamic Acid with Bacillus licheniformis P-104 and Characterization of its Flocculation Properties

A novel strain of Bacillus licheniformis P-104 was isolated from Chinese soybean paste to produce a bioflocculant. The bioflocculant was confirmed as ultra-high molecular weight poly-γ-glutamic acid (γ-PGA) using Fourier transform infrared spectrum, high-performance liquid chromatography, and gel permeation chromatography with multi-angle laser light scattering. The production technology and flocculation properties of γ-PGA were investigated. By fed-batch fermentation in a 7-L bioreactor, the maximum γ-PGA yield reached 41.6 g L^?1 with a productivity rate of 1.07 g L^?1 h^?1. The flocculating activity of γ-PGA for kaolin suspension was 33.5?±?1.6 1/OD under the optimized flocculation conditions (6 mM Ca²⁺, 1.5 mg L^?1 γ-PGA, and pH 6.0). The optimized dosage of γ-PGA for flocculation was just about 30 % of that of reported γ-PGA produced by other strains. Moreover, the flocculation activity of γ-PGA produced by strain P-104 was much higher than commercial γ-PGA with the molecular weight ranging 200–500 kDa and 1,500–2,500 kDa. This study provided a promising strain and an efficient method for production of ultra-high molecular weight γ-PGA which could be used as a potential green bioflocculant.     

Inclusional association as studied by the drying dissipative structure. Part 1. Drying patterns of α-, β- and γ-cyclodextrin

Macroscopic and microscopic drying patterns were observed on a cover glass, a watch glass, and a Petri glass dish during the course of dryness of aqueous solutions of α-cyclodextrin (αCD), β-cyclodextrin (βCD), and γ-cyclodextrin (γCD), i.e., cone shape oligomers of polysaccharide. For all CD molecules, two kinds of macroscopic patterns, outside and inner broad rings and spoke lines formed. Multi-broad rings were formed for βCD in the inner region of the main broad ring at the outside edge especially at the high concentrations. Cooperative drying processes of the convection, sedimentation, and solidification were clarified. Microscopic drying patterns showing the formation of rod-like and/or sward-like crystals were observed mainly in the direction along the spoke lines. The microscopic patterns of βCD were similar to those of some of polysaccharides and polynucleotides the authors studied previously. α- and γ-cyclodextrins were slightly hygroscopic, and clear-cut drying patterns were not observed.     

Sustained release applications of a fluoroalkyl ester-functionalized amphiphilic cyclodextrin by inclusion complex formation with water-soluble drugs in supercritical carbon dioxide

An amphiphilic γ-cyclodextrin, selectively functionalized with perfluorobutanoyl group, octakis(6-O-perfluorobutanoyl)-γ-cyclodextrin (γ-CyD-F), was investigated as a potential sustained release carrier for hydrophilic drugs, taking molsidomine (MOL) as a model drug. Supercritical carbon dioxide, an environmentally benign solvent, was used for the preparation of MOL/γ-CyD-F inclusion complexes. The molecular encapsulation of MOL by the amphiphilic cyclodextrin was confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD) studies. Additionally, ¹H NMR spectroscopy was used to investigate the inclusion mode of drug with the γ-CyD-F. The in-vitro release of MOL from the peanut oil suspensions into aqueous phase was found to be significantly retarded by the complexation with γ-CyD-F, mainly due to the hydrophobic properties associated with the γ-CyD-F.