Recent Aspect of Cyclodextrin-Based Drug Delivery System

The pharmaceutically useful cyclodextrins (CyDs) are classified into hydrophilic, hydrophobic, and ionic derivatives. These CyDs can serve as multi-functional drug carriers, through the formation of inclusion complex or the form of CyD/drug conjugate. In addition, the combined use of different CyDs and/or pharmaceutical excipients is capable of alleviating the undesirable properties of drug molecules, improving efficacy and reducing side effects. This contribution outlines the potential use of CyDs in the design and evaluation of CyD-based drug formulation, focusing on their ability to enhance the drug absorption across biological barriers, the ability to control the rate and time profiles of drug release, and the ability to deliver a drug to targeted site.     

Model Analysis for Oral Absorption of a Drug/Cyclodextrin Complex Involving Competitive Inclusion Complexes

The bioavailability parameters of a drug after oral administration of a preparation containing drug/CyD complexes may be modified by formation of competitive inclusion complexes. In this study, we examined the effects of competitors on drug permeation from its CyD complex through in-vitro artificial membranes and in-situ recirculation conditions, for comparison with the results under in-vivo conditions in the bile duct of cannulated rats. Phenacetin, an antipyretic, was used as a model drug, natural CyDs and maltosyl--CyD as host molecules, and benzoic acid derivatives, sodium taurocholate and acetaminophen as competitors. The in-vitro cellophane membrane permeation rate and the in-situ absorption rate of phenacetin were quantitatively predicted by theoretical calculation using the stability constants of drug/CyD and competitor/CyD complexes when CyD weakly interacts with membrane components in lower CyD concentrations (generally below 10 mM). The in-vivo absorption behavior was only qualitatively reproducible by the theoretical calculation, probably because of various physicochemical and physiological factors affecting the absorption. The present results may be useful not only for prediction of intestinal absorption of drugs from CyD preparations, but also for formulation design of CyD preparations containing multi-components.     

Modification of the physicochemical properties of minocycline hydrochloride ointment with cyclodextrines for optimum treatment of bedsore

Modification to find the best physicochemical properties of minocycline hydrochloride ointment for optimum treatment of bedsore was investigated by coformulating various types of cyclodextrins (CyD) in the ointment base. It was found that the drug release rate from the ointment base was modified according to the preparation method of ointment base and the type of CyD admixed. The physicochemical properties, such as viscosity, elution volume, water absorption of ointment base were also modified by those factors. The mechanism of physicochemical modification with CyD was explained by the structural change of ointment base and the change of surface tension of emulsifying agent solution with the CyD. The stability of ointment was investigated by confirming the reproducibility of drug release rate after storage at ambient and cooled temperature conditions. In conclusion, a fused mixed ointment with beta-CyD was found to be preferable for treatment of bedsore, because of the improved drug release rate, lowered viscosity and increased elution volume of the resultant ointment.     

Circular dichroic investigation of factors that affect inclusion complexes of cyclodextrins as a drug carrier

Drug/cyclodextrin (CyD) inclusion complexes have become one of the most widely used approaches to increase aqueous solubility of poorly soluble drugs, to increase their bioavailability and stability, to reduce undesirable side effects and prevent drug–drug and drug–excipient interactions. Although drug molecules as well as CyDs exhibit detectable changes in their physicochemical properties upon complexation, to date, the interaction of CyDs with drugs is not well understood. So far, only few methods can be applied to obtain structural information on drug/CyD complexes. Circular dichroism spectroscopy (CD) has often been used to study molecular binding, nevertheless, rarely do these studies exploit the full potential of optical techniques. The objective of this article is to highlight important factors that affect drug/CyD binding interaction in particular β-CyD. On the basis of chirality, (S)-(+)-ibuprofen, meta-chlorobenzoic acid and aspirin were used to study binding interaction with β-CyD using CD. Based on CD equations for a simple 1:1 binding complex, the Levenberg–Marquadt non-linear equation was used for binding analysis and the production of simulated graphical presentations to explain the effect of various factors that influence the binding reaction and the binding curve. The results show reliability indicated by the binding constant which is in agreement with literature values. In addition, the effect of guest/host concentrations and the extent of binding on the inclusion complexes are elucidated with accuracy. This work provides useful information that can prove valuable in drug binding studies.     

Design and evaluation of cyclodextrin-based drug formulation

The pharmaceutically useful cyclodextrins (CyDs) are classified into hydrophilic, hydrophobic, and ionic derivatives. Because of the multi-functional characteristics and bioadaptability, these CyDs are capable of alleviating the undesirable properties of drug molecules through the formation of inclusion complexes or the form of CyD/drug conjugates. This review outlines the current application of CyDs in design and evaluation of CyD-based drug formulation, focusing on their ability to enhance the drug absorption across biological barriers, the ability to control the rate and time profiles of drug release, and the ability to deliver a drug to a targeted site.     

Preparation of inclusion complex between polyaniline and β‐cyclodextrin in aqueous solution

Two routes have been developed inorder to prepare an inclusion complex of polyaniline (PANI) and β‐cyclodextrin (βCyD). The first route was to in situ polymerize N‐phenyl‐1,4‐phenylenediamine (PPD) which was encapsulated in βCyD in advance. The formation of an inclusion complex was confirmed by UV‐vis, circular dichroism (CD), and NMR spectra. It was found that the synthesized complex was readily dissolved in a range of solvents due to the solubility of βCyD. In these solvents, PANI was well encapsulated by βCyD with some conformation change in the chain of PANI, which was proved by the CD spectra of PANI. The second route involved preparing the inclusion complex by post‐encapsulation of PANI emeraldine base (EB) into βCyD in aqueous solution at room temperature. The encapsulation of EB into βCyD was confirmed by FT‐IR and UV‐vis spectra. The band shift in UV‐vis spectra indicated that the inclusion complexation was a gradual process, and the change in the chain conformation of PANI was also observed after it was encapsulated into βCyD. Copyright © 2003 John Wiley & Sons, Ltd.     

Cyclodextrin Polymers as Delivery Systems for Targeted Anti-Cancer Chemotherapy

In the few last years, nanosystems have emerged as a potential therapeutic approach to improve the efficacy and selectivity of many drugs. Cyclodextrins (CyDs) and their nanoparticles have been widely investigated as drug delivery systems. The covalent functionalization of CyD polymer nanoparticles with targeting molecules can improve the therapeutic potential of this family of nanosystems. In this study, we investigated cross-linked γ- and β-cyclodextrin polymers as carriers for doxorubicin (ox) and oxaliplatin (Oxa). We also functionalized γ-CyD polymer bearing COOH functionalities with arginine-glycine-aspartic or arginine moieties for targeting the integrin receptors of cancer cells. We tested the Dox and Oxa anti-proliferative activity in the presence of the precursor polymer with COOH functionalities and its derivatives in A549 (lung, carcinoma) and HepG2 (liver, carcinoma) cell lines. We found that CyD polymers can significantly improve the antiproliferative activity of Dox in HepG2 cell lines only, whereas the cytotoxic activity of Oxa resulted as enhanced in both cell lines. The peptide or amino acid functionalized CyD polymers, loaded with Dox, did not show any additional effect compared to the precursor polymer. Finally, studies of Dox uptake showed that the higher antiproliferative activity of complexes correlates with the higher accumulation of Dox inside the cells. The results show that CyD polymers could be used as carriers for repositioning classical anticancer drugs such as Dox or Oxa to increase their antitumor activity.     

Statistical design analysis of isophorone electrocatalytic hydrogenation: the use of cyclodextrins as inverse phase transfer catalysts

Fundamentals and applications of a 2³ factorial design were performed for assessing the influence of the cyclodextrin (CyD) type, concentration and encapsulation time on the electrocatalytic hydrogenation (ECH) of isophorone. Electrolysis were carried out using nickel as electrocatalyst and sacrificial anode. A discussion of model validation is presented. The analysis of the results showed that the most significant factors to the conversion rate were the CyD type and concentration, with 3 mmol dm^?3 of βCyD giving the best results. The isophorone C=C hydrogenation yield, in the presence of βCyD, was 28 % higher than in its absence, and it is comparable to those obtained by other well-established ECH procedures in terms of hydrogenation yield, selectivity and current efficiency.     

NMR spectroscopic investigation of inclusion complexes between cyclodextrins and the neurotoxin tetramethylenedisulfotetramine

The binding stoichiometry, strength and structure of inclusion complexes formed between the neurotoxin tetramethylenedisulfotetramine (TETS) and both native and modified cyclodextrins (CyDs) were investigated using nuclear magnetic resonance (NMR) spectroscopy. Of all six examined cases, native β‐cyclodextrin (β‐CyD) and its chemically modified counterpart heptakis‐(2,3,6‐tris‐(2‐hydroxypropyl))‐β‐cyclodextrin (2HP‐β‐CyD) were found to associate most strongly with TETS as reflected in the magnitude of their binding constants (K = 537 ± 26 M^?1 for β‐CyD and K = 514 ± 49 M^?1 for 2HP‐β‐CyD). Two‐dimensional rotating‐frame Overhauser effect spectroscopy NMR experiments confirm close proximity of the TETS molecule to both β‐CyD and 2HP‐β‐CyD as intermolecular, through‐space interactions between the H3 and H5 protons located in the interior of the CyD cavity and the methylene protons of TETS were identified. Copyright © 2012 John Wiley & Sons, Ltd.     

Absorption enhancement of polypeptide drugs by cyclodextrins. I. Enhanced rectal absorption of insulin from hollow-type suppositories containing insulin and cyclodextrins in rabbits.

The absorption of insulin (from porcine pancreas) from the rectum of rabbits after the administration of hollow-type suppositories containing insulin and five kinds of cyclodextrins (CyDs) was investigated. Three types of suppositories were employed: suppository I containing insulin (approximately 26 IU/mg) and various amounts of each CyD in citric buffer solution at pH 3.0 or powder in its cavity, suppository II containing CyD without insulin, and suppository III containing insulin without CyD. Without CyD, the insulin and glucose levels in plasma were unchanged, whereas a significant increase in the plasma insulin concentration and a marked decrease in the glucose levels were found following simultaneous administration of insulin and CyDs by suppository I. The enhancing effect of CyD on rectal insulin absorption (absorption-enhancing effect) by chemically modified CyDs (heptakis(2,6-di-O-methyl)-beta-CyD (DM-beta-CyD) and 2-hydroxypropyl-beta-CyD (HP-beta-CyD)) was higher than those by natural CyDs (alpha-, beta-, and gamma-CyD). The area under the plasma concentration-time curve (AUC) and Cmax of insulin significantly decreased with the preadministration (administration of CyD 6, 24 and 48 h before rectal insulin administration) of DM-beta-CyD. The absorption-enhancing effect disappeared 24 h after preadministration. These results suggest that CyDs enhance insulin absorption from the rectum, and that attenuation of the membrane transport barrier function in the rectum recovers at a maximum of 24 h after administration of CyDs.     

Rational Design for Cooperative Recognition of Specific Nucleobases Using β‐Cyclodextrin‐Modified DNAs and Fluorescent Ligands on DNA and RNA Scaffolds

We propose a binary fluorimetric method for DNA and RNA analysis by the combined use of two probes rationally designed to work cooperatively. One probe is an oligonucleotide (ODN) conjugate bearing a β‐cyclodextrin (β‐CyD). The other probe is a small reporter ligand, which comprises linked molecules of a nucleobase‐specific heterocycle and an environment‐sensitive fluorophore. The heterocycle of the reporter ligand recognizes a single nucleobase displayed in a gap on the target labeled with the conjugate and, at the same time, the fluorophore moiety forms a luminous inclusion complex with nearby β‐CyD. Three reporter ligands, MNDS (naphthyridine–dansyl linked ligand), MNDB (naphthyridine–DBD), and DPDB (pyridine–DBD), were used for DNA and RNA probing with 3′‐end or 5′‐end modified β‐CyD – ODN conjugates. For the DNA target, the β‐CyD tethered to the 3′‐end of the ODN facing into the gap interacted with the fluorophore sticking out into the major groove of the gap site ( MNDS and DPDB ). Meanwhile the β‐CyD on the 5′‐end of the ODN interacted with the fluorophore in the minor groove ( MNDB and DPDB ). The results obtained by this study could be a guideline for the design of binary DNA/RNA probe systems based on controlling the proximity of functional molecules.     

Analysis of the phase solubility diagram of a phenacetin/competitor/beta-cyclodextrin ternary system, involving competitive inclusion complexation

The competitive inclusion complexations in the ternary phenacetin/competitors/beta-cyclodextrin (beta-CyD) systems were investigated by the solubility method, where m-bromobenzoic acid (m-BBA) and o-toluic acid (o-TA) were used as competitors. The solubility changes of the drug and competitors as a function of beta-CyD concentration in the ternary systems were formulated using their stability constants and intrinsic solubilities. The decrease in solubility of phenacetin by the addition of competitors could be quantitatively simulated by the formulation, when both drug and competitor give A(L) type solubility diagrams. On the other hand, when one of the guests gives a B(S) type solubility diagram, its solubility change was clearly reflected in that of the another guest, i.e., phenacetin gave an A(L) type solubility diagram in the binary phenacetin/beta-CyD system and o-TA gave a B(S) type diagram in the binary o-TA/beta-CyD system, but in the ternary phenacetin/o-TA/beta-CyD system, a new plateau region appeared in the original A(L) type diagram of phenacetin. This was explained by the solubilization theory of Higuchi and Connors. The solubility analysis of the ternary drug/competitor/CyD systems may be particularly useful for determination of the stability constant of a drug whose physicochemical and spectroscopic analyses are difficult, because they can be calculated by monitoring the solubility change of a competitor, without monitoring that of a drug. Furthermore, the present results suggest that attention should be paid to the type of the phase solubility diagram, as well as the magnitude of the stability constant and the solubility of the complex, for a rational formulation design of CyD complexes.     

Interactions of cyclodextrins with aromatic amino acids: a basis for protein interactions

Cyclodextrins (CyD) have proven effects on the stability of proteins and can be used in the formulation of aggregation prone therapeutic proteins. This effect stems from specific interactions between the CyD (preferably β-CyD) and solvent exposed amino acid residues. Here the interaction with hydrophobic aromatic amino acid residues stands out and the interaction between CyDs and these amino acid residues holds the key to understanding the observed effects, which CyDs exerts on proteins and peptides. Here we present a comparative study of the interactions between free and peptide bound aromatic amino acids and their derivatives with α, β and γ-CyDs using NMR spectroscopy. We propose a novel, quantitative means of assessing the penetration depth of guest molecules in CyD cavities, the penetration gauge Π, and apply it to the observed interaction patterns from ROESY NMR spectra. We demonstrate that the penetration depths of the aromatic rings within the CyDs rely highly on the nature of the remainder of the guest molecule. Thus the presence of charges, neighboring amino acids and the specific positioning on the surface of a protein highly influences the penetration depth and geometry of guest–CyD interactions.     

A polyrotaxane gel using boronic acid-appended γ-cyclodextrin as a hybrid cross-linker

A boronic acid-appended γ-cyclodextrin (BA-CyD) was synthesized as a hybrid cross-linker of polyvinyl alcohol (PVA) to form a new type of hydrogel. The CyD moiety of BA-CyD forms an inclusion complex with the PVA chain to produce a mechanically interlocking structure. At the same time, the BA moiety of BA-CyD forms covalent bonds with the 1,3-diol moieties of PVA. On the basis of these two modes of interaction, the hybrid cross-linker connects two PVA chains, thus resulting in the formation of a hydrogel. To investigate the possibility of this hydrogel becoming the basis for an intelligent material for drug delivery, sugar-responsive drug release from the hydrogel was demonstrated.     

Behavior of rifampicin in association with<Emphasis Type="Italic"> β</Emphasis>-cyclodextrin in aqueous media: a spectroscopic and conductometric study

The behavior of rifampicin (D) with -cyclodextrin (-CyD) in aqueous media (W) has been examined by means of UV-vis spectroscopy and conductivity measurements over the temperature range 15–30 °C. The UV-vis study has been used to characterize the systems. The estimated molar absorption coefficient for D/CyD/W system was 10757±280 M^–1 cm^–1 in comparison to the value of 6133±99 M^–1 cm^–1 for D/W system. The conductivity was measured (i) as a function of [D] for binary D/W systems, (ii) as a function of [CyD], keeping the concentration of drug constant, for D/CyD/W system, and (iii) as a function of [D] in the presence of a constant cyclodextrin concentration. Two transition points were observed for D/CyD/W system at constant [CyD], which were assigned as cac-1 and cac-2. The stoichiometry of the association was estimated from the conductivity data. This was obtained from [drug] value at which the change in slope of occurs. The standard free energy change, of aggregation was also calculated from the critical concentration data. An attempt has also been made to estimate the stoichiometry of -cyclodextrin:rifampicin association.     

Structure and energy of formation of β- and γ-cyclodextrin complexes with amino acid enantiomers

The interaction between cyclodextrins (CyD), β-CyD, and γ-CyD, and the L- and D-optical isomers of several amino acids (Ala, Leu, His, Phe) are calculated using DFT. It is found that the L-forms of the investigated amino acids bond more strongly to CyD, due to the different numbers of hydrogen bonds that form. The structures of the resulting complexes are analyzed.     

Enhancement of Enantioselectivity in the Optical Resolution of Primary Alcohols with Modified Cyclodextrin Colyophilized Lipase

Colyophilization of lipase was carried out with immobilized β‐cyclodextrins (β‐CyD) bearing methyl, acetyl, benzoyl, and nicotinoyl substituents. The colyophilizates enhanced stereoselectivity in the acylation of several alcohols. The enantioselectivity in the acylation of ethyl‐1‐hydroxymethyl‐phenylphosphine oxide using colyophilized lipase with nicotinoyl‐β‐CyD increased approximately threefold (from E=34 to E=113). The amphiphilic character of modified CyDs has been found to influence the enhancement of enantioselectivity.     

POSS end‐linked peptide‐functionalized poly(ɛ‐caprolactone)s and their inclusion complexes with α‐cyclodextrin

In this report, we have synthesized organic/inorganic hybrid peptide–poly(?‐caprolactone) (PCL) conjugates via ring opening polymerization (ROP) of ?‐caprolactone (CL) in the presence of two sequence defined peptide initiators, namely POSS‐Leu‐Aib‐Leu‐NH₂ (POSS: polyhedral oligomeric silsesquioxane; Leu: Leucine; Aib: α‐aminoisobutyric acid) and OMe‐Leu‐Aib‐Leu‐NH₂. Covalent attachment of peptide segments with the PCLs were examined by ¹H and ²⁹Si NMR spectroscopy, matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF‐MS) and FTIR spectroscopy. Supramolecular inclusion complexations of synthesized peptide‐PCL conjugates with α‐cyclodextrin (α‐CyD) were studied to understand the effect of POSS/OMe‐peptide moieties at the PCL chain ends. Inclusion complexation of peptide‐PCL conjugates with α‐CyD produced linear polypseudorotaxane, confirmed by ¹H NMR, FTIR, powder X‐ray diffraction (PXRD), polarized optical microscopy (POM) and differential scanning calorimetry (DSC). Extent of α‐CyD threading onto the hybrid peptide‐PCL conjugated polymers is less than that of α‐CyD threaded onto the linear PCL. Thus, PCL chains were not fully covered by the host α‐CyD molecules due to the bulky POSS/OMe‐peptide moieties connected with the one edge of the PCL chains. PXRD experiment reveals channel like structures by the synthesized inclusion complexes (ICs). Spherulitic morphologies of POSS/OMe‐peptide‐PCL conjugates were fully destroyed after inclusion complexation with α‐CyD and tiny nanoobjects were produced. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3643–3651.     

Inter- and innermolecular reactions of chloro(phenyl)carbene

Supramolecular photolyses of 3-chloro-3-phenyl-3H-diazirine (8) were performed within cyclodextrin (CyD) hosts to determine whether these toroidal inclusion compounds could alter the reactivity of the ensuing carbene reaction intermediate, chloro(phenyl)carbene (9). Remarkably, no intramolecular products stemming from carbene 9 could be detected. Instead, modified CyDs were formed via so-called innermolecular reactions. Hence, diazirine 8 was photolyzed in various conventional solvents to gauge the intermolecular reactivity of carbene 9. Relevant results were used to rationalize the CyD innermolecular reaction products.     

Enhancing effect of cyclodextrins on nasal absorption of insulin and its duration in rabbits.

The absorption of insulin (from porcine pancreas) in rabbits after the nasal administration of aqueous preparations containing insulin and five kinds of cyclodextrins (CyDs) in phosphate buffer solution at pH 7.0 was investigated. Without CyD, the insulin and glucose levels in plasma were unchanged, whereas a marked increase in the plasma levels of insulin and a decrease in glucose concentrations were observed following the simultaneous administration of insulin and CyD such as alpha- and heptakis (2,6-di-O-methyl)-beta-CyD (DM-beta-CyD). The largest enhancing effect on the nasal absorption of insulin was obtained by DM-beta-CyD. To evaluate the duration of the absorption-enhancing effect of CyDs, preadministration (administration of CyD 0.5, 6, 12 and 24 h before insulin administration) was performed. The area under plasma concentration-time curve (AUC) and Cmax of insulin significantly decreased with the preadministration of DM-beta-CyD 6, 12 and 24 h before nasal administration. The absorption-enhancing effect disappeared 24h after the preadministration. These findings demonstrate that CyDs enhance the nasal absorption of insulin, and the recovery of the membrane transport barrier function in nasal mucosa is achieved, at the latest, 24 h after the administration of CyDs.