Cyclodextrins and their uses: a review

Cyclodextrins are a family of cyclic oligosaccharides composed of α-(1,4) linked glucopyranose subunits. Cyclodextrins are useful molecular chelating agents. They possess a cage-like supramolecular structure, which is the same as the structures formed from cryptands, calixarenes, cyclophanes, spherands and crown ethers. These compounds having supramolecular structures carry out chemical reactions that involve intramolecular interactions where covalent bonds are not formed between interacting molecules, ions or radicals. The majority of all these reactions are of ‘host–guest’ type. Compared to all the supramolecular hosts mentioned above, cyclodextrins are most important. Because of their inclusion complex forming capability, the properties of the materials with which they complex can be modified significantly. As a result of molecular complexation phenomena CDs are widely used in many industrial products, technologies and analytical methods. The negligible cytotoxic effects of CDs are an important attribute in applications such as rug carrier, food and flavours, cosmetics, packing, textiles, separation processes, environment protection, fermentation and catalysis.     

Effect of Cyclodextrin Complexation on the Aqueous Solubility and Solubility/Dose Ratio of Praziquantel

Praziquantel (PZQ), the primary drug of choice in the treatment of schistosomiasis, is a highly lipophilic drug that possesses high permeability and low aqueous solubility and is, therefore, classified as a Class II drug according to the Biopharmaceutics Classification System (BCS). In this work, β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) were used in order to determine whether increasing the aqueous solubility of a drug by complexation with CDs, a BCS-Class II compound like PZQ could behave as BCS-Class I (highly soluble/highly permeable) drug. Phase solubility and the kneading and lyophilization techniques were used for inclusion complex preparation; solubility was determined by UV spectroscopy. The ability of the water soluble polymer polyvinylpyrolidone (PVP) to increase the complexation and solubilization efficiency of β-CD and HP-β-CD for PZQ was examined. Results showed significant improvement of PZQ solubility in the presence of both cyclodextrins but no additional effect in the presence of PVP. The solubility/dose ratios values of PZQ-cyclodextrin complexes calculated considering the low (150 mg) and the high dose (600 mg) of PZQ, used in practice, indicate that PZQ complexation with CDs may result in drug dosage forms that would behave as a BCS-Class I depending on the administered dose.     

Modeling the influence of cyclodextrins on oral absorption of low‐solubility drugs: I. Model development

The ability to quantitatively predict the influence of a solubilization technology on oral absorption would be highly beneficial in rational selection of drug delivery technology and formulation design. Cyclodextrins (CDs) are cyclic oligosaccharides which form inclusion complexes with a large variety of compounds including drugs. There are many studies in the literature showing that complexation between CD and drug enhances oral bioavailability and some demonstrating failure of CD in bioavailability enhancement, but relatively little guidance regarding when CD can be used to enhance bioavailability. A model was developed based upon mass transport expressions for drug dissolution and absorption and a pseudo‐equilibrium assumption for the complexation reaction with CD. The model considers neutral compound delivered as a physical mixture with CD in both immediate release (IR) and controlled release (CR) formulations. Simulation results demonstrated that cyclodextrins can enhance, have no effect, or hurt drug absorption when delivered as a physical mixture with drug. The predicted influence depends on interacting parameter values, including solubility, drug absorption constant, binding constant, CD:drug molar ratio, dose, and assumed volume of the intestinal lumen. In general, the predicted positive influence of dosing as a physical mixture with CD was minimal, alluding to the significance of dosing as a preformed complex. The model developed enabled examination of which physical and chemical properties result in oral absorption enhancement for neutral drug administered as a physical mixture with CD, demonstrating the utility of modeling the influence of a drug delivery agent (e.g., CD) on absorption for rational dosage form design. Biotechnol. Bioeng. 2010; 105: 409–420. © 2009 Wiley Periodicals, Inc.     

Aggregation of cyclodextrins as an important factor to determine their complexation behavior

Here, we report a study on the complexation behavior of carotenoids with cyclodextrins (CDs) using solubility experiments and molecular-modelling methods. Carotenoids are an important group of naturally occurring dyes found in vegetables and fruits. Their antioxidant property has initiated investigations on their possible use as drugs. However, carotenoids are lipophilic molecules with very little inherent aqueous solubility. Cyclodextrin complexation has been widely used in order to increase the potential applications of hydrophobic compounds. Thus, the aim of our investigation was to design carotenoids with enhanced water solubility by cyclodextrin complexation. Molecular modelling of carotenoid-cyclodextrin complexes with a 1 : 1 stoichiometry successfully explained the experimentally observed capability of beta-cyclodextrins (beta-CDs) to form complexes with carotenoids as opposed to alpha-cyclodextrins (alpha-CDs) and gamma-cyclodextrins (gamma-CDs). Furthermore, molecular-dynamics calculations revealed that the aggregation properties of CD derivatives significantly influence their complexation behavior. Our docking calculations showed that RAMEB (random methylated beta-CD) is the beta-CD derivative that possesses the lowest tendency to aggregate. Solubility experiments yielded the same results, namely, RAMEB complexes possess the best water solubility. Our results showed that complexation of a ligand not buried inside of the CD cavity is dependent on two factors: i) the geometry of the inclusion part of the complex; ii) the self-aggregation property of the CD itself. The lower affinity the CDs possess for self-aggregation, the more likely are they involved in interactions with carotenoids. These results suggest that self-aggregation of CDs should be considered as an important parameter determining complexation in general.     

Development of a reversed phase high performance liquid chromatography method based on the use of cyclodextrins as mobile phase additives to determine pterostilbene in blueberries

In this work, a reversed phase high performance liquid chromatography (RP-HPLC) method was developed for the determination of pterostilbene in food samples. The novel method is based on the addition of cyclodextrins (CDs) to the mobile phase where the complexation of pterostilbene by CDs is carried out. In order to select the most suitable conditions for the RP-HPLC method, the effect of several physico-chemical parameters on the complexation of pterostilbene by CDs was studied. Our results show that the addition of 12 mM HP-β-CD to a 50:50 (v/v) methanol:water mobile phase at 25°C and pH 7.0 significantly improves the main analytical parameters. In addition, it was seen that pterostilbene forms a 1:1 complex with HP-β-CD, showing an apparent complexation constant of 251±13 M(-1). Finally, in order to study the validity of the proposed method, blueberries were analyzed and the concentration of pterostilbene has been determined.     

Encapsulation of citral isomers in extracted lemongrass oil with cyclodextrins: molecular modeling and physicochemical characterizations

The complexation between two isomers of citral in lemongrass oil and varying types of cyclodextrins (CDs), α-CD, β-CD, and HP-β-CD, were studied by molecular modeling and physicochemical characterization. The results obtained revealed that the most favorable complex formation governing between citrals in lemongrass oil and CDs were found at a 1:2 mole ratio for all CDs. Complex formation between E-citral and CD was more favorable than between Z-citral and CD. The thermal stability of the inclusion complex was observed compared to the citral in the lemongrass oil. The release time course of citral from the inclusion complex was the diffusion control, and it correlated well with Avrami's equation. The release rate constants of the E- and Z-citral inclusion complexes at 50 °C, 50% RH were observed at 1.32×10(-2) h(-1) and 1.43×10(-2) h(-1) respectively.     

Enhanced Solubilisation of Six PAHs by Three Synthetic Cyclodextrins for Remediation Applications: Molecular Modelling of the Inclusion Complexes

Solubilisation of six polycyclic aromatic hydrocarbons (PAHs) (acenaphthene, anthracene, fluoranthene, fluorene, phenanthrene and pyrene) by three synthetic cyclodextrins (CDs) (2-hydroxypropyl-β-CD, hydroxypropyl-γ-CD and ramdomly methylated-β-CD) was investigated in order to select the CD which presents the greatest increase in solubility and better complexation parameters for its use in contaminated scenarios. The presence of the three cyclodextrins greatly enhanced the apparent water solubility of all the PAHs through the formation of inclusion complexes of 1∶1 stoichiometry. Anthracene, fluoranthene, fluorene and phenanthrene clearly presented a higher solubility when β-CD derivatives were used, and especially the complexes with the ramdomly methylated-β-CD were favoured. On the contrary, pyrene presented its best solubility results when using 2-hydroxypropyl-γ-CD, but for acenaphthene the use of any of the three CDs gave the same results. Complementary to experimental phase-solubility studies, a more in-depth estimation of the inclusion process for the different complexes was carried out using molecular modelling in order to find a correlation between the degree of solubilisation and the fit of PAH molecules within the cavity of the different CDs and to know the predominant driving forces of the complexation.     

Molecular Modeling and Physicochemical Properties of Supramolecular Complexes of Limonene with α- and β-Cyclodextrins

This study evaluated three different methods for the formation of an inclusion complex between alpha- and beta-cyclodextrin (α- and β-CD) and limonene (LIM) with the goal of improving the physicochemical properties of limonene. The study samples were prepared through physical mixing (PM), paste complexation (PC), and slurry complexation (SC) methods in the molar ratio of 1:1 (cyclodextrin:limonene). The complexes prepared were evaluated with thermogravimetry/derivate thermogravimetry, infrared spectroscopy, X-ray diffraction, complexation efficiency through gas chromatography/mass spectrometry analyses, molecular modeling, and nuclear magnetic resonance. The results showed that the physical mixing procedure did not produce complexation, but the paste and slurry methods produced inclusion complexes, which demonstrated interactions outside of the cavity of the CDs. However, the paste obtained with β-cyclodextrin did not demonstrate complexation in the gas chromatographic technique because, after extraction, most of the limonene was either surface-adsorbed by β-cyclodextrin or volatilized during the procedure. We conclude that paste complexation and slurry complexation are effective and economic methods to improve the physicochemical character of limonene and could have important applications in pharmacological activities in terms of an increase in solubility.     

Enantioselective host-guest complexation of Ru(II) trisdiimine complexes using neutral and anionic derivatized cyclodextrins

Enantioselective host-guest complexation between five racemic Ru(II) trisdiimine complexes and eight derivatized cyclodextrins (CDs) has been examined by NMR techniques. The appearance of non-equivalent complexation-induced shifts of between the Δ and Λ-enantionomers of the Ru(II) trisdiimine complexes and derivatized CDs is readily observed by NMR. In particular, sulfobutyl ether-β-cyclodextrin sodium salt (SBE-β-CD), R-naphtylethyl carbamate β-cyclodextrin (RN-β-CD), and S-naphtylethyl carbamate β-cyclodextrin (SN-β-CD) showed good enantiodiscrimination for all five Ru complexes examined, which indicates that aromatic and anionic derivatizing groups are beneficial for chiral recognition. The complexation stoichiometry between SBE-β-CD and [Ru(phen)₃]²⁺ was found to be 1:1 and binding constants reveal that Λ-[Ru(phen)₃]²⁺ binds more strongly to SBE-β-CD than the Δ-enantiomer. Correlations between this NMR method and separative techniques based on CDs as chiral discriminating agents (i.e., selectors) are discussed in detail.     

Dichloro-, dimethyl-, and chloromethylphenylcarbamate derivatives of cyclodextrins as chiral stationary phases for high-performance liquid chromatography

New dichloro-, dimethyl-, and chloromethylphenylcarbamate derivatives of cyclodextrins (CDs) were prepared and their enantiomeric recognition abilities were evaluated as chiral stationary phases (CSPs) in normal phase high-performance liquid chromatography (HPLC). The effects of the type of cyclodextrins, the nature and position of the substituents on the phenyl ring, binding mode and spacer on the chiral recognition were studied in detail. No marked change of chiral recognition abilities was established by reversing the binding side of CDs (i.e., by the narrower [primary] opening of the cone-shaped CD to silica gel with the wider [secondary] opening sides). This result indirectly proves the previously drawn conclusion about the minor role of inclusion phenomena in chiral recognition in this case. Nevertheless, chiral recognition of these CSPs toward some compounds critically depends on the type of CDs used. All CD derivatives described in this study show rather low enantiomeric resolving abilities compared with corresponding polysaccharide (cellulose and amylose) derivatives, although very high enantioselectivity of separation was observed for a few compounds, such as racemic flavanone and cyclopropanedicarboxilic acid dianilide. © 1996 Wiley-Liss, Inc.     

SN-38-Cyclodextrin Complexation and Its Influence on the Solubility,Stability, and In Vitro Anticancer Activity Against Ovarian Cancer

SN-38, an active metabolite of irinotecan, is up to 1,000-fold more potent than irinotecan. But the clinical use of SN-38 is limited by its extreme hydrophobicity and instability at physiological pH. To enhance solubility and stability, SN-38 was complexed with different cyclodextrins (CDs), namely, sodium sulfobutylether β-cyclodextrin (SBEβCD), hydroxypropyl β-cyclodextrin, randomly methylated β-cyclodextrin, and methyl β-cyclodextrin, and their influence on SN-38 solubility, stability, and in vitro cytotoxicity was studied against ovarian cancer cell lines (A2780 and 2008). Phase solubility studies were conducted to understand the pattern of SN-38 solubilization. SN-38-βCD complexes were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction analysis (XRPD), and Fourier transform infrared (FTIR). Stability of SN-38-SBEβCD complex in pH 7.4 phosphate-buffered saline was evaluated and compared against free SN-38. Phase solubility studies revealed that SN-38 solubility increased linearly as a function of CD concentration and the linearity was characteristic of an A_P-type system. Aqueous solubility of SN-38 was enhanced by about 30–1,400 times by CD complexation. DSC, XRPD, and FTIR studies confirmed the formation of inclusion complexes, and stability studies revealed that cyclodextrin complexation significantly increased the hydrolytic stability of SN-38 at physiological pH 7.4. Cytotoxicity of SN-38-SBEβCD complex was significantly higher than SN-38 and irinotecan in both A2780 and 2008 cell lines. Results suggest that SBEβCD encapsulated SN-38 deep into the cavity forming stable inclusion complex and as a result increased the solubility, stability, and cytotoxicity of SN-38. It may be concluded that preparation of inclusion complexes with SBEβCD is a suitable approach to overcome the solubility and stability problems of SN-38 for future clinical applications.     

Cyclodextrins in drug delivery: An updated review

The purpose of this review is to discuss and summarize some of the interesting findings and applications of cyclodextrins (CDs) and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important CD applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules, and nanoparticles. In addition to their well-known effects on drug solubility and dissolution, bioavailability, safety, and stability, their use as excipients in drug formulation are also discussed in this article. The article also focuses on various factors influencing inclusion complex formation because an understanding of the same is necessary for proper handling of these versatile materials. Some important considerations in selecting CDs in drug formulation such as their commercial availability, regulatory status, and patent status are also summarized. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes. Published: October 14, 2005     

Encapsulation of Citral Isomers in Extracted Lemongrass Oil with Cyclodextrins: Molecular Modeling and Physicochemical Characterizations

The complexation between two isomers of citral in lemongrass oil and varying types of cyclodextrins (CDs), α-CD, β-CD, and HP-β-CD, were studied by molecular modeling and physicochemical characterization. The results obtained revealed that the most favorable complex formation governing between citrals in lemongrass oil and CDs were found at a 1:2 mole ratio for all CDs. Complex formation between E-citral and CD was more favorable than between Z-citral and CD. The thermal stability of the inclusion complex was observed compared to the citral in the lemongrass oil. The release time course of citral from the inclusion complex was the diffusion control, and it correlated well with Avrami’s equation. The release rate constants of the E- and Z-citral inclusion complexes at 50 °C, 50% RH were observed at 1.32×10^?2 h^?1 and 1.43×10^?2 h^?1 respectively.     

Hydroperoxidase activity of lipoxygenase in the presence of cyclodextrins.

The oxidation of xenobiotics by the hydroperoxidase activity of lipoxygenase in the presence of cyclodextrins was studied. These produced an inhibitory effect on xenobiotics oxidation, based on their degree of hydrophobicity and the charge (isoproterenol < 4-methyl-catechol (4MC) < 4-tert-butylcatechol (TBC) < 4-tert-octylcatechol (TOC)). This inhibitory effect was due to the complexation of xenobiotics in the hydrophobic cavity of cyclodextrins. The complexation constant Kc was calculated by nonlinear regression of the inhibition curves obtained in the presence of cyclodextrins, and the values obtained were 400, 16,250, and 35,127 M-1 for 4MC, TBC, and TOC, respectively. The validity of these values was checked at different points of the Michaelis-Menten saturation curve, and a sigmoidal inhibition curve was obtained at the saturating concentration of the o-diphenol, TBC, with no change in the Kc value. This demonstrates the validity of the equations used to calculate Kc for the complete range of the Michaelis-Menten equation.     

Comparative Evaluation of α-Amylase Refolding Through Two Different Artificial Chaperone Systems

Two different artificial chaperone systems were evaluated in this work using either detergents or CDs as the stripping agents. Upon dilution of urea-denatured α-amylase to a non-denaturing urea concentration in the presence of the capturing agent, complexes of the detergent and non-native protein molecules are formed and thereby the formation of protein aggregates is prevented. The so-called captured protein is unable to refold from the detergent-protein complex states unless a stripping agent is used to remove the detergent molecules. Our results by fluorescence, UV, turbidity measurement, circular dichroism, surface tension and activity assay indicated that the extent of refolding assistance was different due to different inter- and intra- molecular interactions in the two different systems. However, the high activity recovery in the presence of detergents, as the stripping agent, suggests that they can constitute suitable replacement for the more expensive and common stripping agent of cyclodextrins.     

Kinetic characterization of diphenolase activity from Streptomyces antibioticus tyrosinase in the presence and absence of cyclodextrins

Streptomyces antibioticus tyrosinase was kinetically characterized after purification by PEG-8000/phosphate phase partitioning and ammonium sulfate fractionation using tert-butylcathechol (TBC) and dopamine. The enzyme showed an optimal pH at 6.5 and a K_M of 1.2 mM and 8.4 mM, respectively. The effect of several modulators was studied on this Gram-positive bacterium tyrosinase. In addition, previously undescribed characterization of apparent inhibition and activation of a bacterial tyrosinase using different kinds of cyclodextrins was carried out. When a hydrophobic substrate of S. antibioticus tyrosinase, in this case, tert-butylcatechol was used, a marked substrate sequestrant effect was observed in the presence of hydroxypropyl-β-cyclodextrins (OH-β-CDs) and gamma cyclodextrins (γ-CDs). This sequestrant effect was due to the complexation of TBC into the CD cavity. Moreover, the effect of some hydrophobic inhibitors in the presence of OH-β-CDs and γ-CDs was studied using dopamine, a hydrophilic substrate of S. antibioticus tyrosinase. Increasing concentrations of CDs in the presence of inhibitors like hexestrol or hinokitiol, were able to reactivate the inhibited enzyme to reach the non-inhibited level, as a result of the complexation of these inhibitory compounds in the hydrophobic core of the CDs. This dual effect of CDs as apparent inhibitor and activator has never before described being observed in bacteria.     

Cyclodextrin-based hydrogels toward improved wound dressings

Abstract

Optimal wound dressings should be capable of mechanical wound protection and also facilitate the healing process via maintenance of suitable environmental conditions and the controlled delivery of bioactive molecules. Hydrogels present suitable properties for wound-dressing applications such as good biocompatibility, together with a high water content, the latter of which is important for the maintenance of a moist environment and ready removal from the wound with a minimal level of associated pain. However, their properties as drug delivery systems can be improved by the use of cyclodextrins as cross-linking agents. Cyclodextrins have been extensively used as “carriers” on food, textile, cosmetic and, most especially, in the pharmaceutical industry in view of their powerful complexation abilities and biocompatibilities, together with further desirable characteristics. The conjugation of cyclodextrins with hydrogels may allow the achievement of an optimal wound-dressing material, because the hydrogel component will maintain the moist environment required for the healing process, and the cyclodextrin moiety has the ability to protect and modulate the release of bioactive molecules. Therefore, this review aims to gather information regarding cyclodextrin-based hydrogels for possible wound-dressing applications.     

Physico-Chemical Characterization and In Vitro Dissolution Assessment of Clonazepam—Cyclodextrins Inclusion Compounds

The objectives of this research were to prepare and characterize inclusion complexes of clonazepam with β-cyclodextrin and hydroxypropyl-β-cyclodextrin and to study the effect of complexation on the dissolution rate of clonazepam, a water-insoluble lipid-lowering drug. The phase-solubility profiles with both cyclodextrins were classified as A_P-type, indicating the formation of 2:1 stoichiometric inclusion complexes. Gibbs free energy ( DG_tr^o ) \left( {\Delta {G_{tr}}^o} \right) values were all negative, indicating the spontaneous nature of clonazepam solubilization, and they decreased with increase in the cyclodextrins concentration, demonstrating that the reaction conditions became more favorable as the concentration of cyclodextrins increased. Complexes of clonazepam were prepared with cyclodextrins by various methods such as kneading, coevaporation, and physical mixing. The complexes were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry studies. These studies indicated that complex prepared kneading and coevaporation methods showed successful inclusion of the clonazepam molecule into the cyclodextrins cavity. The complexation resulted in a marked improvement in the solubility and wettability of clonazepam. Among all the samples, complex prepared with hydroxypropyl-β-cyclodextrin by kneading method showed highest improvement in in vitro dissolution rate of clonazepam. Mean dissolution time of clonazepam decreased significantly after preparation of complexes and physical mixture of clonazepam with cyclodextrins. Similarity factor indicated significant difference between the release profiles of clonazepam from complexes and physical mixture and from plain clonazepam. Tablets containing complexes prepared with cyclodextrins showed significant improvement in the release profile of clonazepam as compared to tablet containing clonazepam without cyclodextrins.     

Solubilization of cyclosporin A

This study investigated the solubilization of cyclosporin A (CsA), a neutral undecapeptide, by cosolvency, micellization, and complexation. Cosolvents (ethanol, propylene glycol, polyethylene glycol, tetrahydrofurfuryl alcohol polyethyleneglycol ether, and glycerin), surfactants (polyoxyethylene sorbitan monooleate [(Tween 80)], polyoxyethylene sorbitan monolaurate [(Tween 20)], and Cremophor EL), and cyclodextrins (α-cyclodextrin [(αCD)] and hydroxypropyl-β-cyclodextrin[(HP\CD)] were used as solubilizing agents in this study. Surfactants had a noticeable effect in increasing CsA solubility. Twenty percent solutions of Tween 20, Tween 80, and Cremophor EL increased the solubility by 60 to 160 fold. Cyclodextrins can increase the CsA solubility, but αCD was more effective than HP\CD. Cosolvents on the other hand did not increase the solubility of CsA as much as expected from the LOGP (logrithm of wateroctanol partition coefficent) value of CsA.     

Capillary electrophoresis of glutamate and aspartate in rat brain dialysate Improvements in detection and analysis time using cyclodextrins

Addition of cyclodextrins (CDs) to the electrolyte buffer in the capillary zone electrophoresis (CZE) separation of derivatized amino acids was evaluated in terms of fluorescence signal enhancement, resolution, and migration time effects. Maximum fluorescence signal enhancement was observed with separation buffers containing 4M β-cyclodextrin or 10 mM hydroxypropyl β-cyclodextrin. Resolution values decreased as the CD concentrations increased. Migration times were dependent on CD concentration. Inclusion complex formation constants calculated using changes in migration time showed slight agreement with those calculated by the steady-state fluorescence enhancement technique. Analysis of 20 μl of rat brain microdialysate by CZE using 4 mM β-cyclodextrin in borate buffer resulted in baseline resolution of glutamate and aspartate in 3.6 min. The results of this work indicate that, when used as separation buffer additives, cyclodextrins are capable of increasing the fluorescence signal and decreasing the migration times of NDA-derivatized acidic amino acids.