New Formulation of a Methylseleno-Aspirin Analog with Anticancer Activity Towards Colon Cancer

Aspirin (ASA) has attracted wide interest of numerous scientists worldwide thanks to its chemopreventive and chemotherapeutic effects, particularly in colorectal cancer (CRC). Incorporation of selenium (Se) atom into ASA has greatly increased their anti-tumoral efficacy in CRC compared with the organic counterparts without the Se functionality, such as the promising antitumoral methylseleno-ASA analog (1a). Nevertheless, the efficacy of compound 1a in cancer cells is compromised due to its poor solubility and volatile nature. Thus, 1a has been formulated with native α-, β- and γ-cyclodextrin (CD), a modified β-CD (hydroxypropyl β-CD, HP-β-CD) and Pluronic F127, all of them non-toxic, biodegradable and FDA approved. Water solubility of 1a is enhanced with β- and HP- β-CDs and Pluronic F127. Compound 1a forms inclusion complexes with the CDs and was incorporated in the hydrophobic core of the F127 micelles. Herein, we evaluated the cytotoxic potential of 1a, alone or formulated with β- and HP- β-CDs or Pluronic F127, against CRC cells. Remarkably, 1a formulations demonstrated more sustained antitumoral activity toward CRC cells. Hence, β-CD, HP-β-CD and Pluronic F127 might be excellent vehicles to improve pharmacological properties of organoselenium compounds with solubility issues and volatile nature.     

Determination of Fexofenadine in Tablets by Capillary Electrophoresis in Free Solution and in Solution with Cyclodextrins as Analyte Carriers

ABSTRACT

Capillary electrophoresis (CE) methods for the determination of fexofenadine (FEX) in commercial pharmaceuticals were developed. It was demonstrated that FEX could be effectively analyzed in free solution cationic CE at low pH. Another analytical approach studied was based on cyclodextrin (CD) modified CE where highly charged CD derivatives served as analyte carriers. In this way, the separation range was spread to physiological pH region and a CE analysis of FEX, present actually in its zwitterionic form, could be accomplished. Several parameters affecting the separations were studied, including the type and concentration of carrier ion, counterion, analyte carrier, and pH of the buffer. The methods based on the free solution CE and CD-modified CE were compared each other, validated, and applied for the determination of FEX in tablets.     

Improvement of drug loading onto ion exchange resin by cyclodextrin inclusion complex

Context: Ion exchange resins have ability to exchange their counter ions for ionized drug in the surrounding medium, yielding “drug resin complex.” Cyclodextrin can be applied for enhancement of drug solubility and stability.

Objective: Cyclodextrin inclusion complex of poorly water-soluble NSAIDs, i.e. meloxicam and piroxicam, was characterized and its novel application for improving drug loading onto an anionic exchange resin, i.e. Dowex^® 1×2, was investigated.

Methods: β-cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrin (HP-β-CD) were used for the preparation of inclusion complex with drugs in solution state at various pH. The inclusion complex was characterized by phase solubility, continuous variation, spectroscopic and electrochemistry methods. Then, the drug with and without cyclodextrin were equilibrated with resin at 1:1 and 1:2 weight ratio of drug and resin.

Results and discussion: Solubility of the drugs was found to increase with increasing cyclodextrin concentration and pH. The increased solubility was explained predominantly due to the formation of inclusion complex at low pH and the increased ionization of drug at high pH. According to characterization studies, the inclusion complex was successfully formed with a 1:1 stoichiometry. The presence of cyclodextrin in the loading solution resulted in the improvement of drug loading onto resin.

Conclusions: Enhancing drug loading onto ion-exchange resin via the formation of cyclodextrin inclusion complex is usable in the development of ion-exchange based drug delivery systems, which will beneficially reduce the use of harmful acidic or basic and organic chemicals.     

分子模拟技术在环糊精包结过程中的应用

环糊精具有疏水的空腔,可以选择性结合各种客体分子,形成稳定的包结物,在实验和理论研究中受到广泛的关注。本文总结了近年来分子模拟技术在环糊精包结过程中的应用,重点介绍半经验PM3方法、双层ONIOM方法及自然键轨道（NBO）分析方法。最后展望了分子模拟技术在环糊精领域的发展方向。     

Preparation,characterization and pharmacokinetic evaluation of rosuvastatin calcium incorporated cyclodextrin-polyanhydride nanoparticles

Abstract

Objective: The aim of the study was to formulate, cyclodextrin (CD)-polyanhydride (PA) nanoparticles (CPNs) with rosuvastatin calcium (RCa) in order to enhance the poor oral bioavailability.

Methods: CPNs containing RCa/CD complexes were prepared by a modified solvent displacement method and morphological analyses, particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), DSC, FT-IR, XRD, ¹H-NMR analyses were performed. In vitro release properties, release kinetics, cytotoxicity, in vitro permeability and pharmacokinetic studies were also studied. The stability of the formulations were evaluated during the storage period of 3?months.

Results: The physicochemical studies showed that the RCa/CD complexes were well incorporated into CPNs resulted in nanosized particles (215.22 and 189.13?nm) with homogenous size distribution (PDI: 0.203 and 0.182) with relatively high incorporation capacity (76.11 and 68.18%) for the CPN1 and CPN2 formulations respectively. Sustained release of RCa from CPNs were achieved. The cytotoxicity values showed that the safety of the formulations. According to permeability studies, pure RCa had lowest permeability data (3.08?×?10^?7?cm?s^?1 P_app value) while CPNs gained higher permeability data (1.36?×?10^?5 and 1.12?×?10^?5?cm?s^?1 P_app values) for the CPN1 and CPN2 formulations respectively. CPN2 formulation was selected for pharmacokinetic studies and analyses results demonstrated that approximately 8-fold relative oral bioavailability enhancement compared to the pure RCa was achieved.

Conclusion: Considering the analyses results of the study, CPNs can be regarded as suitable, safe, functional oral delivery systems for RCa with enhanced oral bioavailability.     

Fluorescence studies on the interaction between pyrene‐labelled poly(acrylic acid) and cyclodextrins

The interactions, in aqueous media, between a pyrene‐labelled polyelectrolyte poly(acrylic acid) (PAAMePy) with two different degrees of labelling and β‐ and γ‐cyclodextrins (β‐ and γ‐CD) were studied using absorption and fluorescence (steady‐state and time‐resolved) techniques. In addition to qualitative and quantitative parameters obtained from absorption and steady‐state fluorescence spectra, time‐resolved fluorescence data are presented, allowing additional important observations regarding the nature of the interactions. From the overall data it was possible to conclude that in the case of interaction with γ‐CD the efficient encapsulation of two pyrene units into the cavity of the cyclodextrin molecule leads to a decrease in the number of available free monomers and an increase in the number of preformed ground‐state dimers (GSDs) of pyrene. It was also shown that contrary to the situation in water, where only intramolecular interactions are present, the addition of γ‐CD leads to new interpolymeric interactions. The absence of significant changes is noted when the interactions of PAAMePy polymers take place with β‐CD. The excimer‐to‐monomer fluorescence intensity ratio (I_E/I_M) was found to increase with the added amount of γ‐CD but not with β‐CD. This increase is justified on the basis of the increase of the GSD contribution. The photophysical behaviour was found to be dependent on the pH of the media, but with the absence of relevant interactions between CD and PAAMePy polymer at alkaline values. Copyright © 2007 Society of Chemical Industry     

Cobalt catalyzed hydroformylation of higher olefins in the presence of chemically modified cyclodextrins

The cobalt catalyzed hydroformylation of higher olefins in the presence of chemically modified cyclodextrins was investigated in an aqueous biphasic system. The effect of various parameters, such as the nature of the cyclodextrin and olefin, the temperature, the CO/H₂ pressure, the concentration of the cyclodextrin and TPPTS was studied. The results demonstrate that the partially methylated β-cyclodextrin gives good conversion (>92%) and selectivity (>92%) for the hydroformylation of higher olefins without impeding the recovery of the catalytic system.     

Super porous α-, β-, γ-cyclodextrin cryogels with high active agent loading and controllable release profiles

Cyclodextrins (CDs) are truncated cone-like structures that are natural cyclic oligosaccharides. Here, a simple preparation method for super porous poly(α-CD), poly(β-CD), and poly(γ-CD) cryogels crosslinking with divinyl sulfone at 150%, 100% and 125% mole ratios with respect to the α-CD, β-CD, and γ-CD molecules, respectively, under cryogenic conditions, is reported. The interconnected homogeneous pore distribution of CD-based cryogels with pore sizes in the range of 5–100 μm is confirmed by SEM analysis. The CD-based cryogels weighing 10 mg are determined as hemocompatible with <1% hemolysis ratios and >79% blood clotting indexes; whereas the same materials weighing 1 mg are biocompatible with >75% cell viability on L929 fibroblasts. Additionally, active agent adsorption/delivery efficiencies of CD-based cryogels utilizing two active agents, Bisphenol A (BPA, a carcinogenic compound) and Curcumin (CUR, a polyphenolic compound), are individually evaluated. It was revealed that p(γ-CD) cryogels exhibited the highest active agent loading capacity for BPA, 87 ± 13 mg/g, whereas p(α-CD) cryogels showed the highest loading capacity for CUR, 136 ± 4 mg/g. Moreover, the active agent release from p(α-CD), p(β-CD), and p(γ-CD) cryogel networks at pH 7.4 and 37°C were determined as 40.6 ± 2, 35.3 ± 2, and 34 ± 1 mg/g for BPA, and 1.07 ± 0.2, 1.27 ± 0.1, and 1.37 ± 0.1 mg/g for CUR, respectively, within 96 h.     

基于环糊精的食品级Pickering乳液构建

考察环糊精（cyclodextrins,CD）结构、CD质量浓度、油相类型、油水比等因素对O/W型Pickering乳液形成的影响,系统比较了α-、β-及γ-CD稳定的中链脂肪酸甘油三酯（medium-chain triglyceride,MCT）基Pickering乳液的微观结构、微流变性质及稳定性,结合分子对接方法,模拟CD/MCT包合物的形成,揭示造成CD乳化能力差异的原因。结果表明α-CD和β-CD有较好的乳化稳定性,其乳化稳定性随油水比和CD质量浓度的增加而增强,油相类型对乳化稳定性也有显著影响。α-CD和β-CD均能显著降低油/水界面张力,且效果接近。α-CD与MCT分子间结合作用强,易于形成两亲性超分子,因而其在低质量浓度（5 mg/mL）时乳化稳定性优于β-CD。β-CD在油水界面的驻留性虽略逊于α-CD,但在高质量浓度（15、25 mg/mL）时其不仅可在油/水界面发挥乳化作用,还可通过水相中的沉淀聚集,阻碍油滴间的碰撞和凝聚,表现出更好的乳化稳定性。本研究对于研发新型食品级Pickering乳液产品,推动CD在食品领域的应用具有一定的参考意义。