The Biological Fate of Pharmaceutical Excipient β-Cyclodextrin: Pharmacokinetics,Tissue Distribution,Excretion, and Metabolism of β-Cyclodextrin in Rats

β-cyclodextrin has a unique annular hollow ultrastructure that allows encapsulation of various poorly water-soluble drugs in the resulting cavity, thereby increasing drug stability. As a bioactive molecule, the metabolism of β-cyclodextrin is mainly completed by the flora in the colon, which can interact with API. In this study, understanding the in vivo fate of β-cyclodextrin, a LC-MS/MS method was developed to facilitate simultaneous quantitative analysis of pharmaceutical excipient β-cyclodextrin and API dextromethorphan hydrobromide. The established method had been effectively used to study the pharmacokinetics, tissue distribution, excretion, and metabolism of β-cyclodextrin after oral administration in rats. Results showed that β-cyclodextrin was almost wholly removed from rat plasma within 36 h, and high concentrations of β-cyclodextrin distributed hastily to organs with increased blood flow velocities such as the spleen, liver, and kidney after administration. The excretion of intact β-cyclodextrin to urine and feces was lower than the administration dose. It can be speculated that β-cyclodextrin metabolized to maltodextrin, which was further metabolized, absorbed, and eventually discharged in the form of CO₂ and H₂O. Results proved that β-cyclodextrin, with relative low accumulation in the body, had good safety. The results will assist further study of the design and safety evaluation of adjuvant β-cyclodextrin and promote its clinical development.     

Diffusion Measurements vs. Chemical Shift Titration for Determination of Association Constants on the Example of Camphor–Cyclodextrin Complexes

Measurements on camphor–cyclodextrin complexes reveal that precise association constants are more easily determined by chemical shift titration. Diffusion measurements using HR-DOSY allow easy following of the complex composition at different concentration ratios and estimation of the binding energy. Linear dependence of the diffusion coefficients on the molecular mass of free and associated cyclodextrins has been observed in D₂O. The solution structures of α- and β-cyclodextrin complexes of camphor in D₂O were deduced from intermolecular cross-relaxation data. Different preferential orientation in the 2:1 α-CD and 1:1 β-CD species have been derived in contrast to the loose 1:1 complex with γ-CD. Proton NMR chemical shift values proved to be much more sensitive to diastereomeric complex formation than diffusion coefficients.     

The formation of homogeneous and heterogeneous 2:1 complexes between dialkyl- and diarylammonium ions and α-cyclodextrin and cucurbit[6]uril in aqueous formic acid

Dialkyl- and diarylammonium ions are able to form complexes with α-cyclodextrin and cucurbit[6]uril. These amines are able to complex two guest molecules simultaneously resulting in the formation of homogeneous or heterogeneous 1:2 (ratio of dialkylammonium to ligand) complexes. The stability constants and reaction enthalpies for the formation of 1:1 complexes have been measured using potentiometric and calorimetric titrations. Differences between the values obtained by these methods can be attributed to solvent composition. Only for the 1:2 complex formation with cucurbit[6]uril, the ligands influenced each other. The polar carbonyl groups at each portal of the cucurbit[6]urils interacted simultaneously with the protonated amino group resulting in an electrostatic repulsion between both molecules. No further interactions between two complexed molecules of α-cyclodextrin or cucurbit[6]uril and α-cyclodextrin were observed. The absence of polar groups in the case of α-cyclodextrin led to unaffected formation of homogeneous and even heterogeneous 1:2 complexes.     

Complexation of Monosulfonated Triphenylphosphine with Chemically Modified β-Cyclodextrins: Effect of Substituents on the Stability of Inclusion Complexes

Interactions between the meta-substituted monosulfonated triphenylphosphine and chemically modified β-cyclodextrins were investigated in aqueous solution by NMR and UV–vis spectroscopy. Titration and continuous variation plots obtained from ³¹P NMR data indicate that the monosulfonated triphenylphosphine forms 1:1 inclusion complexes with the 2-hydroxypropylated β-cyclodextrin, the methylated β-cyclodextrin and the (2-hydroxy-3-trimethylammoniopropyl)-β-cyclodextrin chloride. These inclusion complexes are more stable that those formed with native β-cyclodextrin, confirming that poisoning of the chemically modified β-cyclodextrins by the hydrosoluble phosphine occurs when modified cyclodextrins are used as mass transfer promoters in aqueous-phase organometallic catalysis.     

Preparation of a novel clay/metal complex hybrid film and its catalytic oxidation to chiral 1,1-binaphthol

An ITO electrode modified with a hybrid film of chiral metal complex (Λ-[Os(phen)₃]²⁺) and a clay (montmorillonite) has been prepared for the purpose of chiral sensing. As a first step, a floating monolayer of amphiphilic Os(II) complex, [Os(phen)₂(dC18bpy)](ClO₄)₂ (phen=1,10-phenanthroline, dC18bpy=4,4^′-dioctadecyl-2,2^′-bipyridyl), was formed on an aqueous dispersion of sodium montmorillonite. The monolayer acted as an organic part for the hybridization of clay particles in an aqueous phase. The hybrid film of clay and amphiphilic metal complex was transferred onto an indium tin oxide (ITO) substrate by the vertical dipping method. The next step was to immerse the electrode in chloroform, during which the amphiphilic Os(II) complex was removed from the clay surface. Thereafter the electrode was immersed in an aqueous solution of 0.5 mM Λ-[Os(phen)₃](ClO₄)₂ and rinsed with water. Cyclic voltammetric measurements were performed at each step of the above procedures. When the observed curves were simulated on the basis of a double-layered modified electrode, the electron transfer rate constant (k₁) for Λ-[Os(phen)₃]²⁺/Λ-[Os(phen)₃]³⁺ was determined to be 0.25 s⁻¹. This Os^II/Os^III redox couple was found to mediate the electrochemical oxidation of chiral 1,1^′-2-binaphthol in a stereoselective way: i.e., the S-isomer was oxidized at a 1.4 times higher rate than the R-isomer.     

TICT state formation in the 4′-dimethylaminoacetophenone–α-cyclodexdtrin inclusion complex

Fluorescence properties of excited 4′-dimethylaminoacetophenone (DMAAP) complexed with α-cyclodextrin (CD) were studied. The complex exhibited dual fluorescence in neutral aqueous solutions and no TICT fluorescence was observed in alkaline solutions. The dependence of TICT emission intensity on pH and α-CD concentration suggested that a 1:2 DMAAP–α-CD complex, which was formed by the association of the 1:1 complex and α-CD, was responsible for the TICT fluorescence.     

Complexation of Monosulfonated Triphenylphosphine with Chemically Modified β-Cyclodextrins: Effect of Substituents on the Stability of Inclusion Complexes

Interactions between the meta-substituted monosulfonated triphenylphosphine and chemically modified β-cyclodextrins were investigated in aqueous solution by NMR and UV–vis spectroscopy. Titration and continuous variation plots obtained from ³¹P NMR data indicate that the monosulfonated triphenylphosphine forms 1:1 inclusion complexes with the 2-hydroxypropylated β-cyclodextrin, the methylated β-cyclodextrin and the (2-hydroxy-3-trimethylammoniopropyl)-β-cyclodextrin chloride. These inclusion complexes are more stable that those formed with native β-cyclodextrin, confirming that poisoning of the chemically modified β-cyclodextrins by the hydrosoluble phosphine occurs when modified cyclodextrins are used as mass transfer promoters in aqueous-phase organometallic catalysis.This revised version was published online in July 2005 with a corrected issue number.     

壳层悬挂β-环糊精单元的两亲性超支化聚合物的分子包合与识别行为

采用紫外分光光度法研究了两种壳层悬挂β-环糊精单元的两亲性超支化聚合物在缓冲溶液(25 ℃, pH=11)中的分子包合与识别行为. 结果表明, 两种聚合物具有来自环糊精单元和两亲性超支化聚合物的双重包合能力, 可分别与水溶性染料分子酚酞(PP)、甲基橙(MO)、有机小分子对硝基苯酚(p-NP)等3种客体分子发生单客体包合效应, 而且其包合能力强于单一的环糊精或两亲性超支化聚合物; 通过客体分子PP和MO证实了这两种聚合物还具有双重识别能力, 可以与PP和MO发生双客体包合效应.     

Analysis of Bioactive Triterpenes from Rubus chingii by Cyclodextrin-Modified Capillary Electrophoresis

A capillary electrophoretic (CE) method with β-cyclodextrin (CD) as modifier has been developed to enable separation, for the first time, of bioactive pentacyclic triterpene acids from the fruits of Rubus chingii. The effects of conditions such as the concentration of the running buffer, amounts of added β-cyclodextrin and organic modifier, applied voltage, and column temperature were systematically investigated to optimize the separation conditions. Baseline separation was achieved for the seven triterpenes by use of background electrolyte consisting of 200 mmol L⁻¹ disodium tetraborate, 15 mmol L⁻¹ β-cyclodextrin, and 12.5% (v/v) methanol. Binding constants between β-cyclodextrin and the triterpenes in the capillary electrophoresis buffer were calculated from the order of migration to elucidate the separation mechanism. The amounts of the triterpenes in the fruits of R. chingii were also determined by use of the method after a relatively simple extraction procedure.Revised: 5 January and 22 April 2005     

Influence of the Solvation Upon the Reaction of α-Cyclodextrin with Carboxylic Acids,Their Methyl Esters,and Their Sodium Salts in Aqueous Solution Studied by Calorimetric Measurements

The complex formation of α-cyclodextrin with carboxylic acids, their methyl esters, and their sodium salts has been studied using calorimetric titrations. The stronger solvation of the carboxylic sodium salts compared with the free acid or their methyl esters lowers the values of the reaction enthalpy and entropy. Complex formation is influenced in the positive direction by the release of “high-energy water” from the cavity of α-cyclodextrin. The values of the reaction enthalpy and entropy increase for the complex formation of α-cyclodextrin with increasing chain length of the carboxylic acids and their derivatives, and reach an approximately constant upper limit in the case of five methylene groups.     

Thermal Degradation of Linalool-Chemotype Cinnamomum osmophloeum Leaf Essential Oil and Its Stabilization by Microencapsulation with β-Cyclodextrin

The thermal degradation of linalool-chemotype Cinnamomum osmophloeum leaf essential oil and the stability effect of microencapsulation of leaf essential oil with β-cyclodextrin were studied. After thermal degradation of linalool-chemotype leaf essential oil, degraded compounds including β-myrcene, cis-ocimene and trans-ocimene, were formed through the dehydroxylation of linalool; and ene cyclization also occurs to linalool and its dehydroxylated products to form the compounds such as limonene, terpinolene and α-terpinene. The optimal microencapsulation conditions of leaf essential oil microcapsules were at a leaf essential oil to the β-cyclodextrin ratio of 15:85 and with a solvent ratio (ethanol to water) of 1:5. The maximum yield of leaf essential oil microencapsulated with β-cyclodextrin was 96.5%. According to results from the accelerated dry-heat aging test, β-cyclodextrin was fairly stable at 105 °C, and microencapsulation with β-cyclodextrin can efficiently slow down the emission of linalool-chemotype C. osmophloeum leaf essential oil.     

Thermosensitive amphiphilic polyphosphazenes and their interaction with ionic surfactants

Temperature-responding physical hydrogels are promising materials as injectable drug delivery carriers which could hold useful bioactive materials inside the polymer networks for further controlled releases. Aimed at desired qualities at body temperature, those gel characteristics need to be adjusted carefully. In this point of view, surfactant is one of the useful molecules to be used by simple formulations without harmful chemical reactions. In this study, thermothickening of amphiphilic nonionic polyphosphazene solution is modified by anionic and cationic surfactants with different alkyl chains and counter-ions. Specified in the thermothickening system, a maximum viscosity (η_max) and a temperature at that point (T_max) are changed independently reflecting unique intermolecular interactions. At low concentration (1–9 mM) of the added surfactant, the η_max is maximized at 3 mM surfactant regardless of the surfactant type while the T_max is increased continuously along with the surfactant concentration. From a kinetic point of view, this 3 mM surfactant at the maximized η_max reflects a polymer-dominating interaction and highly favorable polymer–surfactant interaction with a low selectivity in the surfactant type. However, the magnitude of the maximum viscosity (η_max) is dependent on the surfactant tail, which reflects the lifetime and the strength of the hydrophobic domains of the polymer network affected by the surfactants. Meanwhile, the magnitude of the T_max depended on the surfactant head group, which means the interfacial tension of the polymer solutions changed by the surfactants. At high concentration (10 and 30 mM) of the cationic surfactants added to the polymer solutions with two different viscosities, the cationic surfactants are supposed to interact either with the hydrophobic parts of the aggregated polymer with high viscosity or on the backbone of the less- or non-aggregated polymer with low viscosity.Ionic surfactants change the thermothickening of the amphiphilic nonionic polyphosphazene solution in a unique tail- or head-dependent way. Moreover, the concentration of the added surfactants and the association pattern of the pure polymer solutions are also crucial for the thermothickening phase behaviors. Temperature-responsive polyphosphazenes in this work exhibit unique and controllable interactions with ionic surfactants.     

An efficient regio-specific synthetic route to multiply substituted acyl-sulphated β-cyclodextrins

The regio-specific synthesis of a series of novel amphiphilic β-cyclodextrins is described. We are able to check the degree of sulphatation at upper rim and the degree of acylation and over-acylation at lower rim by electrospray mass spectrometry. The 6-O-silyl-2,3-O-acyl-β-cyclodextrin is synthesised in large scale by one pot reaction from β-cyclodextrin. The products are generally mixtures with varying degrees of substitution. These amphiphilic cyclodextrin form micellar aggregates.     

Preparation and Properties of Cyclodextrin Inclusion Complexes of Hyperoside

In order to improve the aqueous solubility and enhance the bioavailability of Hyperoside (Hyp), three inclusion complexes (ICs) of Hyp with 2-hydroxypropyl-β-cyclodextrin (2H-β-CD), β-cyclodextrin (β-CD), and methyl-β-cyclodextrin (M-β-CD) were prepared using the ultrasonic method. The characterization of the inclusion complexes (ICs) was achieved using Fourier-transform infrared spectroscopy (FTIR), scanning electronic microscopy (SEM), X-ray powder diffraction (XRPD), thin-layer chromatography (TLC), and ¹H nuclear magnetic resonance (¹H NMR). The effects of the ICs on the solubility and antioxidant activity of Hyp were investigated. A Job’s plot revealed that the Hyp formed ICs with three kinds of cyclodextrin (CD), all at a 1:1 stoichiometric ratio. The FTIR, SEM, XRPD, TLC, and ¹H NMR results confirmed the formation of inclusion complexes. The water solubility of the IC of Hyp with 2-hydroxypropyl-β-cyclodextrin was enhanced 9-fold compared to the solubility of the original Hyp. The antioxidant activity tests showed that the inclusion complexes had higher antioxidant activities compared to free Hyp in vitro and the H₂O₂–RAW264.7 cell model. Therefore, encapsulation with CDs can not only improve Hyp’s water solubility but can also enhance its biological activity, which provides useful information for the potential application of complexation with Hyp in a clinical context.     

Dual Fluorescence and Photoprototropic Characteristics of 2-Aminodiphenylsulphone-β-Cyclodextrin Inclusion Complex

The absorption and fluorescence spectral characteristics of 2-aminodiphenylsulphone (2ADPS) have been investigated in the presence of β-cyclodextrin (β-CDx) in water. Dual emission is observed upon the complexation of 2ADPS in β-CDx. The stoichiometry of the host:guest inclusion complex is found to be 2:1. Steady state and time-resolved fluorescence spectral analysis support the formation of 2:1 complex between β-CDx and 2ADPS. The large enhancement in fluorescence intensity of twisted intramolecular charge transfer (TICT) band in aqueous β-CDx solution is due to the decrease in non-radiative processes. The ground and the excited state pK_a values for the monocation-neutral equilibrium of 2ADPS in β-CDx are found to be different from the pK_a values in aqueous solution. In the presence of β-CDx, 2ADPS is found to be less basic in the ground and the excited states.     

Driving force prediction for inclusion complexation of α-cyclodextrin with benzene derivatives by a wavelet neural network

A wavelet neural network (WNN) has been constructed and used to predict the binding constant for the inclusion of α-cyclodextrin with benzene derivatives from the substituent molar refraction (R_m) and hydrophobic constant (π). The ln K_a values predicted by WNN from R_m and π are close to the experimental data. The results indicate that the inclusion complexation of α-cyclodextrin with mono- and 1,4-disubstituted benzene is dominantly driven by the van der Waals force and hydrophobic interactions.     

A multi-technique study of compact and hydrous Au oxide growth in 0.1 M sulfuric acid solutions

The growth and reduction of compact (α-) and overlying hydrous (β-) oxide films on polycrystalline Au electrodes in aqueous 0.1 M H₂SO₄ solutions have been investigated using potentiostatic, cyclic voltammetry, ellipsometric and quartz crystal microbalance (QCMB) techniques. All α-oxide films, formed with time at constant potentials up to 2.6 V, or by multicycling of the potential, are non-hydrated in nature, even when covered by a thick β-oxide film. The α-oxide film composition is suggested to be AuO below 1.5 V, and a mixture of AuO+Au₂O₃ at potentials above this, becoming predominantly Au₂O₃ at very high potentials. Up to three monolayers of Au₂O₃ can be formed. When formed at constant potential, the β-oxide film becomes increasingly hydrated as it thickens with time of growth, with a mass to charge ratio and refractive index consistent with Au₂O₃·H₂O and later with Au₂O₃·2H₂O. In contrast, the β-oxide film formed by multicycling has a higher mass overall, and becomes less hydrated as it thickens with time, with a mass and refractive index consistent with Au₂O₃·10H₂O at short times, ranging to Au₂O₃·2H₂O as the film thickens.     

Polarographic behavior of cadmium and lead in -caprolactam

The stability constants of the complexes formed by cadmium and lead with -caprolactam have been determined polarographically. The reductions are reversible and diffusion-controlled. Lead forms two complexes having β₁ and β₂ values 1.75 and 19.55. Cadmium is found to form 1:1 and 1:2 complexes with the values of the constants β₁ = 4.95 and β₂ = 22.65. The percentage distribution of various complex species has been presented. Method is suitable for quantitative determination of these metals.     

Complexation Study and Spectrofluorimetric Determination of Pipemidic Acid with γ-Cyclodextrin

The fluorimetric characteristics of pipemidic acid (PIPE) have been investigated. It has been proven that the fluorescence emission band of pipemidic acid at 439 nm is significantly intensified in the presence of γ-cyclodextrin. The inclusional complexation between the antibacterial pipemidic acid and γ-cyclodextrin (γ-CD) has been studied. A 1:1 stoichiometry of the complex was established and its association constant was calculated by a nonlinear regression method, monitoring the changes in the fluorescence signal of pipemidic acid in the presence of γ-CD. According to the results obtained, a spectrofluorimetric method for the determination of PIPE has been proposed. The best limits of detection and quantification were obtained in presence of γ-CD, in acidic media. The dynamic range of the method was comprised between 0.18 and 1.40 μg/ml.     

Effect of the acyl group and the dodecylsulfonate chain on the inclusion of pyrene inside the cavity of β-cyclodextrin

The solubilization of pyrene in aqueous solution of β-cyclodextrin (β-CD) or its derivatives such as β-CD-hexanoyl, β-CD-benzoyl and β-CD-dodecylsulfonate was investigated by spectrophotometry. Linear and non-linear regression methods were used to estimate the association constants (K₁). A 1:1 stoichiometric ratio and different effects of the hexanoyl, benzoyl and dodecylsulfonate groups on the association constant were observed for the binary inclusion complex between pyrene and β-CD. The formation constant was shown to decrease when β-CD was modified by a dodecylsulfonate chain. The value of K₁ was 190 ± 10 L mol⁻¹ for the [pyrene/β-CD] complex and 145 L mol⁻¹ for the [pyrene/β-CD-dodecylsulfonate] complex. Partitioning of the pyrene molecules between the dodecylsulfonate chains and cyclodextrin cavities can explain the decrease in the association constant value. In the cases of β-CD-hexanoyl and β-CD-benzoyl derivatives, no association constants were detected. Results suggest that the high hydrophobicity of the hexanoyl and benzoyl groups prevents the inclusion of pyrene molecules inside the cyclodextrin cavity.