Photochemical stability of the inclusion complexes formed by modified 1,4-dihydropyridine derivatives with β-cyclodextrin

The results of studies of photochemical stability of the derivatives of 1,4-dihydropyridine (NR) are reported. The NR with various substituents (-NO₂, -Cl, -F, CF₃) at different positions in the phenyl ring were identified by UV spectrophotometry. Photodegradation of NR in the inclusion complexes with β-cyclodextrin (β-CD) was studied in the liquid phase. The rate of photodegradation of NR derivatives was dependent on the position of -NO₂ group in the phenyl ring; for the ortho isomer it is ten times higher than for the meta one. The rate of photodegradation of 2-NO₂-NR (ortho isomer) in inclusion complex with β-CD was 200 times slower than that for this compound in the crystal phase. In the case of halogeno- and cyanoderivatives, the presence of β-CD caused a 4-fold increase in the photodegradation rate.     

Study of the dissolution characteristics of oxazepam via complexation with β-cyclodextrin

Complex formation of oxazepam and β-cyclodextrin in solution was studied by phase solubility and spectral shift methods. The value of the apparent stability constant, K_c, calculated using these techniques, was 205 and 498 M⁻¹, respectively. Solid complexes of oxazepam and β-CD were prepared using the kneading and spray-drying methods. These complexes led to an improvement in the dissolution rate over free oxazepam, spray-drying being the most efficient technique. These complexes were characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray diffraction.     

Enhancement of norfloxacin solubility via inclusion complexation with β-cyclodextrin and its derivative hydroxypropyl-β-cyclodextrin

The objectives of the study were to investigate the effects of β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD) on the solubility and dissolution rate of norfloxacin prepared using three different methods, at drug to cyclodextrin weight ratios of 1:1, 1:2, 1:4 and 1:8. All the methods increased the solubility and dissolution rate of norfloxacin via inclusion complexation with βCD and HPβCD. Norfloxacin was converted from crystalline to amorphous form through inclusion complexation. Solvent evaporation method was the most effective method in terms of norfloxacin solubilisation, while inclusion complex of HPβCD has higher solubility than βCD complex when prepared using the same procedure.     

Analysis of triclosan inclusion complexes with β-cyclodextrin and its water-soluble polymeric derivative

Interaction in solution and in the solid state of triclosan (TR), a practically water-insoluble antimicrobial agent, with parent β-cyclodextrin (βCD) and its water-soluble epichlorohydrin polymer (EPI-βCD) was investigated by several analytical techniques, to evaluate the role of the carrier features on the physicochemical properties of the drug-cyclodextrin complex. Phase-solubility studies showed the higher solubilizing and complexing ability of EPI-βCD (K(s) =1 1,733 M(-1)) than parent βCD (K(s) = 2526 M(-1)). Actual inclusion complex formation between TR and both cyclodextrins tested was confirmed by 2D (1)H NMR studies (ROESY), which also gave insight into some different drug/cyclodextrin binding modes between polymeric and parent βCD. Addition of hydrophilic polymers (hydroxypropylcellulose, hypromellose or amidated pectin) to TR/βCD systems increased βCD solubilizing efficacy, but, unexpectedly, decreased its complexing ability towards the drug. Solid binary and ternary samples prepared by co-grinding of components in high energy mills were carefully characterised by Differential Scanning Calorimetry, X-ray powder diffractometry and Fourier transform infrared spectroscopy. The results pointed out the higher affinity of EPI-βCD than βCD for the interaction with TR even in the solid state, resulting in the formation of completely amorphous products with superior dissolution properties. Addition of hydrophilic polymers failed to effectively promote solid-state interactions between TR and βCD, while their positive influence on drug solubility, observed in phase-solubility studies, was absent in solid TR/βCD/polymer products. Finally, the time-kill analysis, used to evaluate the TR antimicrobial activity against Streptococcus mutans, demonstrated the significantly (p < 0.001) superior performance of both cyclodextrin complexes than drug alone, and confirmed the higher effectiveness (p < 0.05) of TR/EPI-βCD than TR/βCD complex.     

Solid-state characterization and dissolution characteristics of gliclazide-β-cyclodextrin inclusion complexes

Solid complexes between gliclazide and β-cyclodextrin (β-CD) were prepared by kneading, coprecipitation, neutralization, co-grinding and spray-drying. Characterization of gliclazide-β-CD inclusion complexes was performed using X-ray diffractometry and cross polarizing/magic angle spinning ¹³C-nuclear magnetic resonance spectroscopy. These techniques have clearly demonstrated the existence of solid-state inclusion compound formation. The complexes, obtained by neutralization and spray-drying methods, showed enhanced dissolution rates of gliclazide.     

Evaluation of antibacterial activity of caffeic acid encapsulated by β-cyclodextrins

Abstract

Context: Caffeic acid is described as antibacterial, but this bioactive molecule has some issues regarding solubility and stability to environmental stress. Thus, encapsulation devices are required. Objective: The aim of this work was to study the effect of the caffeic acid encapsulation by cyclodextrins on its antibacterial activity. Materials and methods: The interactions between the caffeic acid and three cyclodextrins (β-cyclodextrin (βCD), 2-hydroxypropyl-β-cyclodextrin (HPβCD) and methyl-β-cyclodextrin were study. Results and discussion: The formation of an aqueous soluble inclusion complex was confirmed for βCD and HPβCD with a 1:1 stoichiometry. The βCD/caffeic acid complex showed higher stability than HPβCD/caffeic acid. Caffeic acid antibacterial activity was similar at pH 3 and pH 5 against the three bacteria (K. pneumoniae, S. epidermidis and S. aureus). Conclusions: The antibacterial activity of the inclusion complexes was described here for the first time and it was shown that the caffeic acid activity was remarkably enhanced by the cyclodextrins encapsulation.     

Optimisation of β-cyclodextrin inclusion complexes with natural antimicrobial agents: thymol,carvacrol and linalool

Beta-cyclodextrin (β-CD) inclusion complexes with naturally derived antimicrobial (AM) agents: thymol, carvacrol and linalool were prepared using a co-precipitation technique. Conditions including solvent composition, temperature, reaction time and total solvent volume were investigated to optimise the inclusion efficiency (IE) and yield. Electrospray ionisation mass spectrometry was used to confirm the formation of the thymol/β-CD complex and gas chromatography was used to quantify the amount AM agent that was encapsulated, absorbed onto the surface, or remaining in the filtered solvent. The systematic optimisation of the conditions improved both the yield of the complex and the IE of the AM agents compared to previously reported methods that have been applied to other agents. Using a 1:1?mole ratio of the AM agent to β-CD, the optimised parameters resulted in maximum yields of 87, 84 and 86% (w/w) for thymol, carvacrol and linalool, respectively, with IE’s close to 100% (w/w) for each agent.     

Mechanical complex formation of tolbutamide with β-cyclodextrin by solid phase roll mixing

The mechanical complexing behavior of tolbutamide (TB) and β-cyclodextrin (βCD) was closely examined from measurements of the time-course curve of the complex yield, the complexing ratio of βCD to TB and the phase solubility diagrams of roll mixing systems in the solid phase. The crystalline equimolar mixture of TB and βCD was readily transformed to an amorphous form by roll mixing. The roll mixture exhibited above 90% conversion in the complex yield for 10 min roll mixing periods. The complex yield increased with increasing shear rates between two rotating rollers. The roll mixing products were estimated stoichiometrically to be an equimolar ratio complex of βCD and TB. It was obtained from the phase solubility diagram that an apparent stability constant of the TBβCD complex in the roll mixture system was enhanced about four times over TB roll mixed without βCD. The equimolar ratio complex changed to an inclusion compound with complex ratio 2.5, when it was kept on 97% relative humidity for 48 h. The equimolar ratio complex was proposed to be a metastable amorphous solid form.     

Improvement of water solubility and in vitro dissolution rate of aceclofenac by complexation with β-cyclodextrin and hydroxypropyl-β-cyclodextrin

The present study deals with the inclusion complexation of aceclofenac with β-cyclodextrin by grinding, microwave and spray-drying techniques. A derivative of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, was also subjected to the complexation process with aceclofenac by spray-drying technique. The samples were subjected to in-vitro dissolution studies, fourier transform infra-red spectroscopy, differential scanning calorimetry, nuclear magnetic resonance spectroscopy and x-ray diffraction studies. The in-vitro dissolution of aceclofenac-hydroxypropyl-β-cyclodextrin complex was faster as compared to the aceclofenac- β-cyclodextrin complex and aceclofenac alone. Spray-dried aceclofenac-β-cyclodextrin complex were subjected to anti-inflammatory and analgesic activity and showed significant anti-inflammatory and analgesic activity.     

Formulation and evaluation of pH sensitive hydrogel of camptothecin with enhanced solubility by using β-cyclodextrin

The use of a novel injectable biocompatible and biodegradable camptothecin (CPT) formulation for controlled intra-tumoral release of CPT is described. The drug delivery vehicle is an autogelling pH sensitive formulation, which is based on the natural biopolymer chitosan. The formulation was prepared by Crosslinking methods. The formulations were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, gelation time and viscosities were investigated for controlled release hydrogel formulation. The formulation, containing homogeneously dispersed CPT, was studied by MTT assay on tumor cell MCF-7. The effectiveness of treatment was measured in terms of percentage control tumor growth inhibition (TGI). The hydrogel formulation of CPT showed good release profile with polymer [chitosan (C)/glyceryl monooleate (GMO)/β-cyclodextrin (β-CD)] compare to without polymer. The gelation pH of the formulation PF, PF4, PF6, PF10 and PF12 were found to be 6.58, 7.42, 7.20, 6.98 and 7.30 respectively and calculated values of viscosity in centipoises of the formulation PF, PF4, PF6, PF10 and PF12 were 3,413.3, 5,843.1, 6,948.8, 5,212.6 and 6,972.6 respectively at 25 °C. It was found that cumulative percentage drug release for formulations prepared PF, PF4, PF6, PF10 and PF12 were released 48.48, 76.92, 83.72, 78.97 and 59.23 % respectively. The formulation PF6 showed maximum cumulative percentage drug release which has 3 % w/v chitosan, 3 % w/v GMO and 1.5 % w/v β-CD. The TGI was found that for formulations CPT, PF, PF4, PF6, PF10 and PF12 were 10.2 ± 1.22, 10.4 ± 0.85, 14.92 ± 1.06, 16.42 ± 1.11, 13.58 ± 1.21 and 11.71 ± 1.14 % respectively. The formulation PF6 showed maximum TGI in comparison to other formulation. The system formulated with CPT was found to be stable and the release profiles of a formulation with chitosan, GMO and β-CD showed all most effective release kinetics. These findings show chitosan/GMO/β-CD hydrogel to be a safe, effective, homogeneous, injectable and stable formulation for delivery of CPT and this approach represents an attractive technology platform for the delivery of other clinically important hydrophobic drugs.     

Enhanced oral bioavailability of acyclovir by inclusion complex using hydroxypropyl-β-cyclodextrin

Abstract

The therapeutic potential of acyclovir is limited by the low oral bioavailability owing to its limited aqueous solubility and low permeability. The present study was a systematic investigation on the development and evaluation of inclusion complex using hydroxypropyl-β-cyclodextrin for the enhancement of oral bioavailability of acyclovir. The inclusion complex of acyclovir was prepared by kneading method using drug: hydroxypropyl-β-cyclodextrin (1:1 mole). The prepared inclusion complex was characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, NMR spectroscopy and evaluated in vitro by dissolution studies. In vivo bioavailability of acyclovir was compared for inclusion complex and physical mixture in rat model. Phase solubility studies indicate the formation of acyclovir–hydroxypropyl-β-cyclodextrin complex with higher stability constant and linear enhancement in drug solubility with increase in hydroxypropyl-β-cyclodextrin concentration. Characterization of the prepared formulation confirms the formation of acyclovir–hydroxypropyl-β-cyclodextrin inclusion complex. Dissolution profile of inclusion complex demonstrated rapid and complete release of acyclovir in 30?min with greater dissolution efficiency (90.05?±?2.94%). In vivo pharmacokinetic data signify increased rate and extent of acyclovir absorption (relative bioavailability ～160%; p?<?0.0001) from inclusion complex, compared to physical mixture. Given the promising results in the in vivo studies, it can be concluded that the inclusion complex of acyclovir could be an effective and promising approach for successful oral therapy of acyclovir in the treatment of herpes viruses.     

Release behaviour of diclofenac sodium dispersed in Gelucire® and encapsulated with alginate beads

Sustained release polymeric particles containing diclofenac sodium dispersed in Gelucire® matrix and encapsulated in calcium alginate shell were prepared with different drug-to-polymer ratios and also with different concentrations of sodium alginate for a fixed drug-to-polymer ratio in an aqueous environment. Spherical particles were formed by dropping an emulsion of diclofenac sodium in Gelucire® matrix, emulsified with sodium alginate, into calcium chloride solution. The gelled beads formed by ionotropic gelation of alginate with calcium ions showed sustained release of the water soluble drug in in-vitro release study. Drug release was a function of square-root of time, suggesting a matrix diffusion release pattern. The rate of release was significantly suppressed with increasing proportions of Gelucire® in the mixture. Sustained and complete release was achieved with Gelucire® of low melting point and low HLB value. No significant drug release occurred in a dissolution medium of pH 1.5, whereas complete release was observed at pH 6.8, consistent with considerable swelling of the alginate gel at this pH.     

Solubilization of naphthoquinones by complexation with hydroxypropyl-β-cyclodextrin

The effects of the hydroxypropyl-β-cyclodextrin (HPCD) on the solubility of 2-hydroxy-N-(5-methyl-3-isoxazolyl)-1,4-naphthoquinone-4-imine (I) were investigated. I is an experimental drug for the treatment of cancer which exhibits low water solubility and it is therefore difficult to prepare the solutions for biological tests. The presence of an ionizable hydroxyl moiety (pK_a=5.80) increases the solubility via pH adjustment, but only a solubility of 0.124 mg/ml was obtained at pH 8.00. I was found to form inclusion complexes in either its neutral or its anionic form with HPCD. Although the stability constant of the I complex is larger in the neutral form, a greater overall solubility is obtained when I is in its ionized form. A 270-fold solubility enhancement is possible by using a combined approach of pH adjustment and complexation with HPCD.     

Halogenation effects of pheniramines on the complexation with β-cyclodextrin

This study investigated the inclusion complexes of β-cyclodextrin with pheniramine and its halogenated derivatives chlorpheniramine and brompheniramine both experimentally and theoretically to characterize the effects of a halogenated phenyl ring on the intermolecular interactions. Fourier transform infrared and nuclear magnetic resonance (NMR) experiments provided evidence of the formation of inclusion complexes and NMR were conducted to evaluate the apparent binding constants. The two-layered hybrid ONIOM method, ONIOM(B3LYP/6-31G(d):PM3), was adopted to optimize the geometry. The linear relationships between the calculated and experimental values for frequencies (with a scaling factor of 0.96) and for magnetic properties (with a scaling factor of 1.05) demonstrate that the quantum chemical calculations were consistent with the experimental spectra. Additionally, the calculated binding energies were consistent with the experimental results: the stability order of the complexes and the trend of the binding energy is: brompheniramine > chlorpheniramine > pheniramine; S-enantiomer > R-enantiomer. Natural Bond Orbital analysis further demonstrated three major electronic delocalizations—from the substituent on the phenyl moiety of pheniramine to β-CD and from β-CD to the phenyl and amine moieties in pheniramine—which were the dominant intermolecular forces that were responsible for the substantially different binding strengths. Geometrical data and the partial charge distribution obtained by NBO analysis are provided as supplementary data.     

Novel non-acidic formulations of haloperidol complexed with β-cyclodextrin derivatives

Haloperidol (Hal), a highly hydrophobic drug, was complexed with two β-cyclodextrin (β-CD) derivatives. Hal solubility was increased 20-fold in the presence of a 10-fold excess of methyl β-CD (Meβ-CD) and 12-fold in the presence of a 10-fold excess of 2-hydroxypropyl β-CD (HPβ-CD). The stoichiometries and stability constants of Hal–Meβ-CD (1:1 and 2345 M⁻¹ at 27°C) and Hal–HPβ-CD (1:1 and 2112 M⁻¹ at 27°C) complexes were calculated by the continuous variation and phase solubility methods respectively. Differential scanning calorimetry and ¹H-NMR were used to confirm the formation of inclusion complexes. Moreover, the enthalpy and entropy of the complexation process were calculated for both complexes in order to obtain such information as the main `driving force' and whether or not complex formation is thermodynamically favoured. This was achieved by monitoring the isothermic solubility lines at various temperatures.     

Preparation,release and physicochemical characterisation of ethyl butyrate and hexanal inclusion complexes with β- and γ-cyclodextrin

Abstract

Complexes of ethyl butyrate and hexanal encapsulated by β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD) were prepared by coprecipitation, and gas chromatography was used to quantity the flavour compounds in the complexes. The ethyl butyrate–γ-CD complex had the highest inclusion ratio (12.20%) followed by the ethyl butyrate-β-CD, hexanal-β-CD and hexanal-γ-CD complexes (11.29, 4.41 and 3.33%, respectively). Release experiments were performed under different relative humidities (RH 93, 75 and 52%) and temperatures (4 and 25?°C). The flavour release behaviours of the complexes were described by the Avrami equation. The rate of flavour release was enhanced with both increasing temperature and RH, although the effect of RH was stronger. Physicochemical characterisation using FT-IR, XRD, DSC and SEM analyses demonstrated that crystalline complexes were formed. Both β-CD and γ-CD were able to encapsulate ethyl butyrate and hexanal, and lower RH and temperature were more suitable for the storage of these complexes.     

Study on the inclusion complex of OGP-49 with hydroxypropyl -β-cyclodextrin

目的 制备OGP - 49羟丙基-β-环糊精包合物,为OGP - 49的注射给药提供基础.方法 采用超声法制备.经差示扫描量热法、红外光谱法验证包合物的形成.结果 羟丙基-β-环糊精和OGP - 49以20∶1的比例形成包合物,40％的羟丙基-β-环糊精可使OGP - 49的水中溶解度提高330倍.结论 OGP - 49羟丙基-β-环糊精包合物能显著提高OGP -49的水中溶解度.     

The encapsulation of β-lapachone in 2-hydroxypropyl-β-cyclodextrin inclusion complex into liposomes: a physicochemical evaluation and molecular modeling approach

The aim of this study was to encapsulate lapachone (β-lap) or inclusion complex (β-lap:HPβ-CD) in liposomes and to evaluate their physicochemical characteristics. In addition, the investigation of the main aspects of the interaction between β-lap and 2-hydroxypropyl-β-cyclodextrin (HPβ-CD), using both experimental and molecular modeling approaches was discussed. Furthermore, the in vitro drug release kinetics was evaluated. First, a phase solubility study of β-lap in HPβ-CD was performed and the β-lap:HPβ-CD was prepared by the freeze-drying technique. A 302-fold increase of solubility was achieved for β-lap in HPβ-CD solution with a constant of association K(1:1) of 961 M(-1) and a complexation efficiency of β-lap of 0.1538. (1)H NMR, TG, DSC, IR, Raman and SEM indicated a change in the molecular environment of β-lap in the inclusion complex. Molecular modeling confirms these results suggesting that β-lap was included in the cavity of HPβ-CD, with an intermolecular interaction energy of -23.67 kJ mol(-1). β-lap:HPβ-CD and β-lap-loaded liposomes presented encapsulation efficiencies of 93% and 97%, respectively. The kinetic rate constants of 183.95±1.82 μg/h and 216.25±2.34 μg/h were calculated for β-lap and β-lap:HPβ-CD-loaded liposomes, respectively. In conclusion, molecular modeling elucidates the formation of the inclusion complex, stabilized through hydrogen bonds, and the encapsulation of β-lap and β-lap:HPβ-CD into liposomes could provide an alternative means leading eventually to its use in cancer research.     

Oral bioavailability of naproxen-β-cyclodextrin inclusion compound

An inclusion complex between naproxen and β-cyclodextrin was prepared by the freeze-drying method. Dissolution profiles in a pH 1.2 medium (gastric juice) of naproxen, freeze-dried naproxen, a physical mixture and 1:1 and 1:3 inclusion complexes demonstrated a faster dissolution rate of the inclusion complex. After 5 min the amount of drug dissolved was around 5% for the drug, 12% for freeze-dried naproxen, 11% for the physical mixture and 61 and 99% for the 1:1 and 1:3 inclusion complexes, respectively. The bioavailability of naproxen administered as its 1:1 inclusion complex with β-cyclodextrin has been evaluated using a new HPLC method for determining the drug and its glucuronide conjugate in urine. Renal excretion levels after oral administrations of naproxen, freeze-dried naproxen and the 1:1 inclusion complex with β-cyclodextrin, measured by this method, show no statistical differences, indicating that the three formulations assayed are bioequivalent.