Synthesis of bifunctional peptide derivatives based on a β-cyclodextrin core with drug delivery potential

A selective, versatile, robust methodology for bifunctionalization of β-cyclodextrin is achieved allowing the attachment of peptides in varying C- and/or N-terminal combinations on resin using Fmoc SPPS. Two linkers are attached to cyclodextrin enabling selective binding to the resin (or a peptide attached to the resin). Continuation of peptide growth and/or cleavage from the resin follows, thus various combinations of peptide-cyclodextrin species are achieved. A model peptide (Gly-Ala) is used in this study to illustrate the potential of this system for attaching one or more bioactive peptides for drug transport and release purposes.     

Study of a water-soluble supramolecular complex of curcumin and β-cyclodextrin polymer with electrochemical property and potential anti-cancer activity

As a member of the curcuminoid compound family, curcumin (Cur) has many interesting therapeutic properties. However, its low aqueous solubility and stability have resulted in poor bioavailability and restricted clinical efficacy. Based on size matching, β-cyclodextrin polymer (β-CDP), with its hydrophilic polymer chains and hydrophobic cavities, can form an inclusion complex with Cur. To improve the water solubility and stability of Cur, a simple and eco-friendly grinding method was designed to form β-CDP inclusion complexes. According to the Boltzmann–Hamel's method and Job's method, the molar ratio of the β-CD unit in β-CDP to Cur was determined to be 1:1. The diffusion coefficient and diffusion activation energy of Cur-β-CDP were calculated in an electrochemical study. This supramolecular complex worked well in vitro to inhibit the proliferation of hepatoma carcinoma cells HepG2. Remarkably, this method visibly reduced the undesirable side effects on normal cells, without weakening the anti-cancer activity of the drugs. We expect that the obtained host–guest complex will provide a new approach for delivering natural drug molecules, having low water solubility.     

Study on inclusion behaviour of forsythiaside A with β-cyclodextrin

Inclusion behaviour of forsythiaside A with β-cyclodextrin (β-CD) was investigated by fluorescence spectrum, nuclear magnetic resonance (NMR) and molecular modelling. A ratio of 1:1 stoichiometry has been proposed for the inclusion complex of forsythiaside A with β-CD in aqueous media according to the continuous variation Job’s method based on the fluorescence spectroscopy data. The stability constant (K) of the inclusion complex was 669 M^?1. The pH, ionic strength and temperature of solution showed great effect on the formation of inclusion complex. The spatial configuration of complex demonstrated that the B ring of forsythiaside A might be embedded inside the lipophilic cavity of β-CD and the A ring of the forsythiaside A might be exposed outside the cavity of β-CD according to NMR spectra and molecular modelling.     

Novel nanoparticles composed of chitosan and β-cyclodextrin derivatives as potential insoluble drug carrier

This research was aim to develop novel cyclodextrin/chitosan(CD/CS) nanocarriers for insoluble drug delivery through the mild ionic gelation method previously developed by our lab. A series of different bcyclodextrin(β-CD) derivatives were incorporated into CS nanoparticles including hydroxypropyl-bcyclodextrin(HP-β-CD), sulphobutylether-β-cyclodextrin(SB-β-CD), and 2,6-di-O-methy-β-cyclodextrin(DM-β-CD). Various process parameters for nanoparticle preparation and their effects on physicochemical properties of CD/CS nanoparticles were investigated, such as the type of CD derivatives,CD and CS concentrations, the mass ratio of CS to TPP(CS/TPP), and p H values. In the optimal condition,CD/CS nanoparticles were obtained in the size range of 215–276 nm and with the zeta potential from30.22 m V to 35.79 m V. Moreover, the stability study showed that the incorporation of CD rendered the CD/CS nanocarriers more stable than CS nanoparticles in PBS buffer at p H 6.8. For their easy preparation and adjustable parameters in nanoparticle formation as well as the diversified hydrophobic core of CD derivatives, the novel CD/CS nanoparticles developed herein might represent an interesting and versatile drug delivery platform for a variety of poorly water-soluble drugs with different physicochemical properties.     

Physicochemical characterization of sanguinarine-hydroxypropyl-β-cyclodextrin binary and ternary systems

Complexation of sanguinarine with hydroxy-propyl-β-cyclodextrin (HPβCD) in the presence and absence of hydrophilic polymer—polyvinylpyrrolidone K30 was studied. Respective binary and ternary systems were prepared using two techniques, physical mixture and lyophilization, and characterized by FT-infrared spectrometry, differential scanning calorimetry and X-ray diffractometry. The Fourier Transform Infrared spectra of the lyophilized binary and ternary systems showed significant shifts in the regions of 1240–1300 cm^?1, 1450–1525 cm^?1 and 1600–1650 cm^?1, where absorptions of –C–O–C– asymmetrical stretching of sanguinarine rings A and F and ν_C=C ring vibrations of sanguinarine benzo[c]phenanthridine system can be observed respectively. Moreover, in the case of ternary products ν_C=O amide band absorption of polyvinylpyrrolidone (1600–1750 cm^?1) shifted to the lower wavenumbers in both the physical mixture and the lyophilized product. These changes in the spectra of the studied systems proved the involvement of the respective molecular groups in complexation process. Differential scanning calorimetry and X-ray diffractometry indicated different states of drug amorphization and entrapment in HPβCD in the presence and without polyvinylpyrrolidone. The obtained results let us conclude that obtained binary and ternary systems represent sanguinarine-HPβCD molecular complexes, with different rate of inclusion in the presence and without polyvinylpyrrolidone.     

Interaction of p-cymene with β-cyclodextrin

In this investigation, the study of inclusion complexes formation between p-cymene and ??-cyclodextrin using the methods of physical mixture, paste (PC) and slurry (SC), was evaluated. The results of DSC and TG/DTG showed that the products prepared by PC and SC methods were able to incorporate greater amounts of p-cymene, as evidenced by the weight loss of 7.15 and 3.97%, respectively, which occurred between 120 and 270?°C. SEM images showed decreased size of the household, especially in the SC product. The absorption bands in the IR spectrum, characteristic of p-cymene, were also identified in the preparations, indicating the presence of the compound in the complex.     

Synthesis and characterization of inclusion complex of the vasodilator drug minoxidil with β-cyclodextrin

The inclusion complex of β-cyclodextrin and minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) was synthesized using two methods—kneading and freeze-drying—and characterized by UV-Vis spectroscopy, infrared spectroscopy, powder X-ray diffractometry, differential scanning calorimetry, thermal gravimetric analysis, and nuclear magnetic resonance spectroscopy. These techniques have demonstrated the existence of inclusion compound formation between the host and guest with a molar ratio of 1:1. The studies of solubility and the data obtained by nuclear magnetic resonance spectroscopy showed a weak interaction between the guest and the cyclodextrin molecules in solution.     

Study of complexation of gliclazide with β-cyclodextrin in solution by nmr techniques

The study of complexation between GL and -CD in liquid medium has been carried out by phase-solubility,¹H and¹³C NMR studies. A formation complex is observed from the phase solubility diagram, being the average association constant of 1094 M^–1, The NMR studies revealed the preferent complexation of the aliphatic moiety of GL. The aromatic moiety is also entrapped, but in minor extent, by the CD molecules.     

Complexation of ebastine with β-cyclodextrin derivatives

Complexation of ebastine (EB) with hydroxypropyl and methyl-β-cyclodextrin (HP-β-CD and Me-β-CD) was studied in aqueous solutions and in the solid state. The formation of inclusion complexes in aqueous solutions was analysed by the solubility method. The assays were designed using low CD concentrations compared with the solubility of these derivatives in order to avoid non-inclusion phenomena and to obtain a linear increase in EB solubility as a function of CD concentration. The values of complexation efficiency for HP-β-CD and Me-β-CD were 1.9 × 10^?2 and 2.1 × 10^?2, respectively. It seems that the non polar character of the methyl moiety slightly favoured complexation. In relation to solid state complexation, 1:1 EB:CD systems were prepared by kneading, and by heating a drug-CD mixture at 90 ºC. They were analysed using X ray diffraction analysis by comparison with their respective physical mixtures. A complex with a characteristic diffraction pattern similar to that of the channel structure of β-CD was formed with Me-β-CD in 1:1 melted and 1:2 EB:CD kneaded systems. Complexation with HP-β-CD was not clearly evidenced because only a slight reduction of drug crystallinity was detected. Finally, the loading of EB in two β-CD polymers cross-linked with epichlorohydrin yielded 7.3 and 7.7 mg of EB/g polymer respectively.     

Dissolution enhancement of artemisinin with β-cyclodextrin

The main objective of this research is to improve the dissolution rate of artemisinin (ART) by fabrication with β-cyclodextrin (β-CD) as a hydrophilic carrier. Artemisinin nanoparticles and ART/β-CD complexes were successfully fabricated by means of evaporative precipitation of nanosuspension. Characterization of the samples was done by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and dissolution tester. Percent dissolution efficiency, mean dissolution time, relative dissolution and similarity factor were calculated for the statistical analysis of dissolution data. FT-IR showed some interaction between ART and β-CD, which can be due to the formation of some ART/β-CD complexes. XRD study indicated the presence of two polymorphs of ART, i.e. orthorhombic and triclinic form. Original ART particles and ART nanoparticles fabricated were orthorhombic whereas the free ART in the ART/β-CD complexes (not forming complex with β-CD) was of triclinic form. The crystallinity of ART reduced and more and more ART/β-CD complexes were formed with increasing concentration of β-CD as indicated by the DSC, XRD and FT-IR studies. Artemisinin nanoparticles and ART/β-CD complexes showed significantly faster dissolution than the pure drug due to smaller size (larger surface area), formation of the inclusion complex with β-CD, formation of the triclinic form for remaining free ART (not forming complex with β-CD), and amorphous state formation. Evaporative precipitation of nanosuspension was able to successfully fabricate artemisinin in the nanoparticles and complex forms with significantly faster dissolution rates than that of the original artemisinin. The two polymorphic forms of ART were also fabricated and studied.     

Preparation and evaluation of inclusion complexes of diacerein with β-cyclodextrin and hydroxypropyl β-cyclodextrin

The objective of this research was to improve the aqueous solubility, dissolution rate and, consequently, bioavailability of diacerein, along with avoiding its side effect of diarrhea, by complexation with β-cyclodextrin (β-CD) and HP-β-cyclodextrin (HP-β-CD). Phase solubility curve was classified as an A_N type for both the CDs, which indicated formation of complex of diacerein with β-CD and HP-β-CD in 1:1 stoichiometry and demonstrating that both CDs are proportionally less effective at higher concentrations. The complexes were prepared by kneading method and were evaluated to study the effect of complexation on aqueous solubility and rate of dissolution in phosphate buffer (pH 6.8). Based on the dissolution profile HP-β-CD was selected for preparing fast disintegrating tablet of diacerein which was compared with marketed formulation (MF-J). The HP-β-CD complex was probed for Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction studies which evidenced stable complex formation and increase in amorphousness of diacerein in complex. In brief, the characterization studies confirmed the inclusion of diacerein within the non-polar cavity of HP-β-CD. HP-β-CD complex showed improved in vitro drug release profile compared to pure drug and similar to that of marketed formulation respectively.     

Structure of guest-host complexes of β-cyclodextrin with arenes: a quantum-chemical study

The structure of β-cyclodextrin (β-CD), as well as the structure and energetics of β-CD-naphthalene, β-CD-fluorene, β-CD-phenanthrene, β-CD-cyclohexane (1:1), and β-CD-naphthalene (2:2) inclusion complexes was studied by the semiempirical MNDO/PM3 method. Calculations of a β-CD-naphthalene-cyclohexane (1:1:1) complex were also performed. The minimum heat of formation was found for the symmetric β-CD conformation withC ₇ symmetry axis. The structure is stabilized by the ring of interunit H-bonds formed by the protons of the 2-OH groups and the O atoms of the 3′-OH groups of the glucose units. Preferableness of this orientation of interunit H-bonds was confirmed byab initio calculations of the molecule of α-(1–4)-glucobiose (maltose) in the MP2/6-31G(d,p)//6-31G(d,p) approximation. The formation of any inclusion compounds of β-CD with arenes is energetically favorable: the complexation energy varies in the range −9 to −12 kcal mol⁻¹. Among complexes with naphthalene, that of composition 2:2 is the most energetically favorable, which is in agreement with experimental data. In this complex, β-CD exists as a dimer of the “head-to-head” type, in which both partners are linked by a system of H-bonds. The structure of the “head-to-head” dimer of β-CD was simulated byab initio calculations of the H-bonded dimer of α-d-glucose in the RHF/6-31G(d,p) approximation. In the dimer, both components are linked by a pair of H-bonds formed by the protons of the 3-OH groups and the O atoms of the, 2-OH groups. The dimerization energies obtained fromab initio and semiempirical MNDO/PM3 and AM1 calculations differ by about 2.5 times (8.6vs 3.2 and 3.8 kcal mol⁻¹, respectively).     

pH-dependent complex formation of amino acids with β-cyclodextrin and quaternary ammonium β-cyclodextrin

Stability constants for the complexes of anionic, neutral (zwitterionic) and protonated forms of l- and d-enantiomers of eight amino acids with β-cyclodextrin and the positively charged quaternary ammonium β-cyclodextrin (QA-β-CD, DS?=?3.6?±?0.3) have been determined by spectrophotometric and pH-potentiometric methods. The highest stability constants have been obtained for the aromatic amino acids phenylalanine, tyrosine and tryptophan. Except the dianion of tyrosine and QA-β-CD, values for the anions in the range of 80–120 have been found, the stability constants for the zwitterionic forms are much smaller and complex formation is negligible with the protonated species. In the case of the other amino acids the differences are less pronounced. The results are interpreted in terms of hydrogen bonding, steric effects and electrostatic interactions between the amino acid moiety and the rims of the cyclodextrins, in addition to the inclusion of the side chain, and are supported by ¹H and ¹³C NMR investigations on the systems containing l-phenylalanine and l-tyrosine. The differences between the complex formation constants of the l- and d-enantiomers do not exceed the limits of experimental error in most cases.     

Study on the complexation of isoquercitrin with β-cyclodextrin and its derivatives by spectroscopy

The inclusion complexes of isoquercitrin (IQ) with cyclodextrins (CDs) including β-cyclodextrin (β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD) and dimethyl-β-cyclodextrin (DM-β-CD) have been investigated using the methods of steady-state fluorescence, UV-vis absorption and induced circular dichroism. The stoichiometric ratio of the three complexes was found to be 1:1 and the stability constants (K) were estimated from spectrofluorometric titrations, as well as the thermodynamic parameters. Maximum inclusion ability was measured in the case of DM-β-CD due to the increased hydrophobicity of the host cavity, followed by HP-β-CD and β-CD. The effect of pH on the complexation process was also quantitatively assessed. IQ exists in different molecular forms depending on pH and β-CDs were most suitable for inclusion of the neutral form of IQ. The phase-solubility diagrams obtained with β-CD, HP-β-CD and DM-β-CD were all classical A_L type. And DM-β-CD provided the best solubility enhancement, 12.3-fold increase compared to 2.8- and 7.5-fold increase for β-CD and HP-β-CD. The apparent stability constants obtained from the solubility data at 25 °C were comparable with those obtained from the fluorescence assays. Moreover, ¹H NMR was carried out, which revealed that the IQ favorably inserted into the inner cavity from the chromone part instead of the phenyl part, which was in agreement with molecular modeling studies.     

Modeling of the inclusive complexation of natural drug trans 3,5,3′,4′-tetrahydroxystilbene with β-cyclodextrin

In this study, the complexation of trans 3,5,3′,4′-tetrahydroxystilbene, also known as piceatannol (PIC), with β-cyclodextrin (β-CD) was investigated using the semi-empirical PM3 method in vacuum. Two orientations were assessed for the encapsulation of piceatannol in the cavity of β-cyclodextrin. The orientation in which the A aromatic ring of PIC was directed toward the inner cavity of β-CD was named ‘A’ and that in which the B aromatic ring is located inside the β-CD cavity was named ‘B’. The results indicated that both orientations were favorable for the complexation of PIC/β-CD. Indeed, the energy difference between the two orientations was less than 1 kcal/mol. Additionally, the negative interaction energies obtained for a 1:1 stoichiometry suggest that the complexation process is exothermic and indicate that the PIC/β-CD complex was highly stable and enthalpically driven. HOMO and LUMO investigations confirmed these results.     

Inclusion complexes of β-cyclodextrin with dihydroxyphenols of various nature

The ways for the practical preparation of stable inclusion complexes of β-cyclodextrin with dihydroxyphenols of various nature are developed. Mutual orientation of hydroxy groups and the nature of the bridge in the bisphenols are shown to affect considerably their ability to the complex formation.     

Inclusion complexes of sulfanilamide with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin

Sulfanilamide belongs to the group of drugs that have a bacteriostatic effect on different pathogenic microorganisms. This activity originates from the competitive antagonism with p-aminobenzoic acid, which is an integral part of folic acid. The safe use of sulfanilamide is limited due to poor solubility in the aqueous medium. Therefore, the aim of this paper is the synthesis of sulfanilamide, as well as preparing and structural characterization of its inclusion complexes with cyclodextrins. The crude sulfanilamide was obtained in the synthesis between acetanilide and chlorosulfonic acid according to the standard procedure. The synthesized sulfanilamide was recrystallized from water in order to obtain the satisfactory purity of the substance. Sufanilamide was complexed with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin by the co-precipitation method. A molecular encapsulation of sulfanilamide was confirmed by using FTIR, ¹H-NMR, XRD and DSC methods. Phase-solubility techniques were used to assess the formation of the inclusion complex between sulfanilamide and cyclodextrins. The photostability of sulfanilamide and its inclusion complexes was estimated by UVB irradiation in a photochemical reactor by applying the UV–Vis method. Based on the UV–Vis analysis, sulfanilamide:2-hydroxypropyl-β-cyclodextrin complex was presented as more photostable than sulfanilamide:β-cyclodextrin complex and sulfanilamide. The obtained results enable the potential use of these inclusion complexes for the preparation of oral formulations due to the enhanced solubility of sulfanilamide.