Search

The potential application of gedunin, a pharmacologically active limonoid, is limited in medicine because it has poor aqueous solubility. This study was aimed at preparation and characterization of an inclusion complex of gedunin and 2-hydroxypropyl-β-cyclodextrin (HBD) to increase the solubility in aqueous solvents and thus enhance the possibility of pharmaceutical formulation and oral administration of gedunin. Inclusion complex of gedunin isolated from Entandrophragma angolense heartwood with 2-hydroxypropyl-β-cyclodextrin (HBD) was prepared using freeze-drying and kneading methods. The gedunin-2-hydroxypropyl-β-cyclodextrin complex (GCD) was characterized using elemental analysis, Fourier-transform infrared spectroscopy (FT-IR), 1H nuclear magnetic resonance (1H-NMR) and X-ray diffraction analysis (XRD). Elemental analysis indicated that gedunin and HBD formed 1:1 stoichiometric inclusion complex. Results of FT-IR indicated that gedunin was stabilized in HBD cavity by intra-molecular hydrogen bonds and van der Waals forces. 1H-NMR revealed that the entire gedunin molecule was not trapped into the core of the HBD. Nevertheless, the fraction trapped may be sufficient to enhance the apparent solubility of gedunin. XRD results showed the formation of new solid crystalline phase. The results obtained by different characterization techniques clearly indicated that both kneading and freeze-drying methods led to inclusion complex formation which may enhance oral administration of gedunin.

An inclusion complex of Primaquine (PQ) with 2-(Hydroxypropyl)-β-Cyclodextrin (2-HP-β-CD) in liquid state have been investigated by using absorption and fluorescence spectral techniques. From the s...

The widespread occurrence of sulfonamides (SAs) in the environment water has rasied great concerns about their potential to antibiotics resistance. In this study, the fluorescence behaviors of sulfamethoxazole (SMZ) representing certain properties of the SAs mixed with three different kinds of cyclodextrins (CDs) in water solutions were investigated, respectively. The result reported that the shapes of the fluorescence peak and its position for the SMZ that were mixed with the CDs were almost the same as those of the standard SMZ, respectively. In addition, compared with the identical control sample the fluorescence of SMZ mixed with each of the CD was greatly enhanced. Therefore, a new simple, and sensitive spectrofluorimetric method for the determination of SMZ was established in water solutions. and the dynamic linear ranges varied from 0.01 to 0.7 mg/L with the detection limit of 7.1 ng/L. And the correlation coefficient was more than 99.9%. Significantly, this new method was successfully applied to direct determination of SMZ in pharmaceutical compounds. Moreover, the results showed that the SMZ could separately form the 1:1 supramolecular compound with each of the CD.

Irbesartan (IRB) exerts beneficial effects either alone or in combination with other drugs on numerous diseases, such as cancer, diabetes, and hypertension. However, due to its high lipophilicity, IRB does not possess the optimum pharmacological efficiency. To circumvent this problem, a drug delivery system with 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) was explored. The 1:1 complex between IRB and 2-HP-β-CD was identified through ESI QTF HRMS. Dissolution studies showed a higher dissolution rate of the lyophilized IRB-2-HP-β-CD complex than the tablet containing IRB at pH = 1.2. DSC results revealed the differences of the thermal properties between the complex and various mixtures consisting of the two components, namely IRB and 2-HP-β-CD. Interestingly, depending on the way the mixture preparation was conducted, different association between the two components was observed. Molecular dynamics (MD) simulations predicted the favorable formation of the above complex and identified the dominant interactions between IRB and 2-HP-β-CD. In vitro pharmacological results verified that the inclusion complex not only preserves the binding affinity of IRB for AT1R receptor, but also it slightly increases it. As the complex formulation lacks the problems of the tablet, our approach is a promising new way to improve the efficiency of IRB.

Preexposure prophylaxis (PrEP) with antiretrovirals (ARV) can prevent human immunodeficiency virus (HIV) transmission, but its efficacy is highly dependent on strict patient adherence to daily dosing regimen. Long-acting (LA) ARV formulations or delivery systems that reduce dosing frequency may increase adherence and thus PrEP efficacy. While cabotegravir (CAB) long-acting injectable (CAB LA), an integrase strand transfer inhibitor (INSTI), reduces dosing frequency to bimonthly injections, variable pharmacokinetics (PK) between patients and various adverse reactions necessitate improvement in delivery methods. Here we developed a subcutaneously implantable nanofluidic device for the sustained delivery of CAB formulated with 2-hydroxypropyl-beta-cyclodextrin (beta CAB) and examined the pharmacokinetics (PK) in Sprague-Dawley rats for 3 months in comparison to CAB. Our study demonstrated beta CAB treatment group maintained clinically-relevant plasma CAB concentrations 2 times above the protein-adjusted concentration that inhibits viral replication by 90% (2xPA-IC90) and drug penetration into tissues relevant to HIV-1 transmission. Further, we successfully fitted plasma CAB concentrations into a PK model (R-2 = 0.9999) and determined CAB apparent elimination half-life of 47 days. Overall, our data shows the potential of sustained release of beta CAB via a nanofluidic implant for long-term PrEP delivery, warranting further investigation for efficacy against HIV infections.

The interaction between (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) and water-soluble betulin derivatives, betulin 3,28-disulfate (DSB) and betulin 3-acetate-28-sulfate (ASB), belonging to the class of pentacyclic lupane triterpenoids, was studied using affinity capillary electrophoresis. It was found that 1:1 and 1:2 complexes were formed. The stability constants of the complexes in the temperature range of 293.15–318.15 K were determined. The values obtained are sufficiently large; log K (1:1) and log K (1:2) are 4.25–5.02 and 6.08–7.59, respectively. This phenomenon can be explained by the presence of broad hydrophobic regions in the molecules of the compound studied. The stability constants decrease with increasing temperature. The stability constants for ASB complexes are slightly higher as compared to the constants for DSB complexes. The thermodynamic parameters for the complexation were calculated from the van't Hoff plots. The complexation was found to be controlled by the enthalpy change. The obtained values of stability constants at 298 K were compared with values for the β-CD complexes of the compounds under study and for the HP-β-CD and β-CD complexes of water-insoluble betulin derivatives. It was found that water-soluble betulin derivatives form more stable complexes with CDs as compared to water-insoluble derivatives (betulonic and betulinic acids), and the HP-β-CD complexes are more stable than the β-CD complexes.

The inclusion complexes of oxyresveratrol (Oxy) with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) were prepared and characterized by UV–vis spectroscopy, FT-IR spectroscopy, XRD, TG-DTG and SEM. Based on the optimal formulation, 222.23 ± 1.52 μg and 232.65 ± 2.64 μg of Oxy was included in 1.00 mg of the Oxy-β-CD and Oxy-HP-β-CD dried powder with the water solubility up to 14.44 ± 0.83 mg/mL and 47.33 ± 0.78 mg/mL, yielding about 30 and 100-fold increase in Oxy solubility (about 0.47 mg/mL), respectively. The physical stability and dissolution rate study showed that the formation of inclusion complexes significant enhanced the storage stability of Oxy and its dissolution rate. These results indicated that β-CD and HP-β-CD may be suitable delivery systems of Oxy. Furthermore, as illustrated in this study, inclusion complexes exhibited strong antibrowning effects on fresh grape juice in 24 h, showing its great potential application in the food industry.

In this study, a complex consisting of 2-hydroxypropyl-β-cyclodextrin and 5,10,15,20-tetrakis (4-hydroxyphenyl) porphyrin, (named dual chiral-achiral selector complex) was used for the determination of two novel potential anticancer agents of (I) and (II) aminoalkanol derivatives. This work aimed at developing an effective method that can be utilized for the determination of I (S), I (R), and II (S) and II (R) enantiomers of (I) and (II) compounds through the use of a dual chiral-achiral selector complex consisting of hydroxypropyl-β-cyclodextrin and 5,10,15,20-tetrakis (4-hydroxyphenyl) porphyrin system by applying capillary electrophoresis. This combination proved to be beneficial in achieving high separation selectivity due to the combined effects of different modes of chiral discrimination. The enantiomers of (I) and (II) compounds were separated within a very short time of 3.6–7.2 min, in pH 2.5 phosphate buffer containing 2-hydroxypropyl-β-cyclodextrin and 5,10,15,20-tetrakis (4-hydroxyphenyl) porphyrin system at a concentration of 5 and 10 mM, respectively, at 25 °C and +10 kV. The detection wavelength of the detector was set at 200 nm. The LOD for I (S), I (R), II (S), and II (R) was 65.2, 65.6, 65.1, and 65.7 ng/mL, respectively. LOQ for I (S), I (R), II (S), and II (R) was 216.5, 217.8, 217.1, and 218.1 ng/mL, respectively. Recovery was 94.9–99.9%. The repeatability and reproducibility of the method based on the values of the migration time, and the area under the peak was 0.3–2.9% RSD. The stability of the method was determined at 0.1–4.9% RSD. The developed method was used in the pilot studies for determining the enantiomers I (S), I (R), II (S), and II (R) in the blood serum.

Differential scanning calorimetry (DSC) is a widely utilized method for the interactions of drug molecules with drug delivery systems (DDSs). Herein is described a protocol for studying the interactions and entrapment efficiency of the prototype sartan losartan and the polydynamic, structurally similar irbesartan inside the nontoxic 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD). The thermal scan properties of both sartan molecules have been studied when physically mixed or complexed with the cyclodextrin. The thermograms indeed showed significant differences between the mixtures and complexes, establishing DSC as a valuable method to characterize the state of the drugs in these pharmaceutical formulations.

Cyclodextrins (CDs) are widely used in the pharmaceutical industry as transporters of lipophilic drugs due to their amphiphilic nature. The detailed study of the molecular interactions of drug complexes with CDs is very important in designing the best formulation for the transportation of lipophilic drugs. The drug: CD binding should be strong enough so that the complex is stable in the aquatic environment of the extracellular fluids, but also not very strong in order for the drug to be capable for being released in the proximity of the target receptor. In a recent study, we investigated the ΔG of binding between the commercially available, nontoxic 2-hydroxypropyl-β-cyclodextrin (2-HP-B-CD) and the antihypertensive drug candesartan cilexetil (CC), with the use of steered (or biased) molecular dynamics (sMD) and umbrella sampling method. This chapter describes comprehensively how to perform sMD and umbrella sampling in order to calculate the ΔGbinding of CC to the 2-HP-B-CD.

This study explores the molecular association between 4-(thiophen-2-yl)-1-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)butan-1-one (RTC1), an antidiabetic compound recently reported by our research group with challenging aqueous solubility, and 2-hydroxypropyl-β-cyclodextrin (HPBCD). The formation of a RTC1/HPBCD complex resulted in improved solubility. A phase-solubility diagram was used to determine the complex stability constant and stoichiometric ratio. 2D 1H NMR spectroscopy was utilized to study the molecular interaction between RTC1 and HPBCD in the complex. Differential scanning calorimetry and scanning electron microscopy was also employed to confirm complex formation. In vitro biological evaluation, using a glucose uptake assay, showed that the homogeneous RTC1/HPBCD complex solution showed the same activity to that of RTC1 alone, with no reduction in activity due to the presence of HPBCD.

The aim of the paper was to develop the simple procedures for preparation of inclusion complexes of ellagic acid (EA) with cyclodextrins (CDs) and to investigate their antioxidant and antimicrobial activity.The structural characterization was carried out using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and nuclear magnetic resonance (NMR) methods. The phase solubility technique was used to investigate the interactions between 'host' and 'guest' molecules and to estimate the molar ratio between them. The antioxidant and antimicrobial activity of EA and inclusion complexes were determined.The apparent stability constants were found to be 117 dmThe stability constants indicated the rapid release of EA from the inclusion complexes in the aqueous medium at 25 °C. The antioxidant activity of EA was increased, while the antimicrobial activity was preserved after complexation with CDs.

Zicao is a traditional Chinese herbal medicine that has been used for the topical treatment of wounds in the form of oil-based ointment for several hundred years. To overcome the disadvantages of oil-based ointment such as irritation, discomfort, and difficulty in cleaning, this study developed a water-based topical formulation of Zicao. An ethanol extract of Zicao was included in 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) to form a water-soluble Zicao-HP-β-CD complex. The formation of the Zicao-HP-β-CD complex was determined using LC-MS, 1H NMR, ROSEY, and solubility analysis. The bioactivity of Zicao-HP-β-CD complex in aqueous solution was evaluated using cellular uptake in vitro and experimental excision wounds in vivo. The LC-MS, 1H NMR, ROESY, and solubility analyses results show that Zicao extract was successfully included by the HP-β-CD. The results of the cellular uptake in vitro and wound healing in vivo suggest that the effect of Zicao was enhanced following the formation of the Zicao-HP-β-CD complex. Therefore, we concluded that complexation with HP-β-CD might provide a potential method for developing an effective water-based topical solution of Zicao.

It has been found that a cyclodextrin derivative, 2-hydroxypropyl-β-cyclodextrin (HPβCD), has reasonable therapeutic effect on Niemann-Pick disease type C, which is caused by abnormal accumulation of unesterified cholesterol and glycolipids in the lysosomes and shortage of esterified cholesterol in other cellular compartments. We study the binding affinity and mode of HPβCD with cholesterol to elucidate the possible mechanism of HPβCD for removing cholesterol from the lysosomes. The dominant binding mode of HPβCD with cholesterol is found based on the molecular dynamics simulation and a statistical mechanics theory of liquids, or the three-dimensional reference interaction site model theory with Kovalenko-Hirata closure relation. We examine the two types of complexes between HPβCD and cholesterol, namely, one-to-one (1:1) and two-to-one (2:1). It is predicted that the 1:1 complex makes two or three types of stable binding mode in solution, in which the βCD ring tends to be located at the edge of the steroid skeleton. For the 2:1 complex, there are four different types of the complex conceivable, depending on the orientation between the two HPβCDs: head-to-head (HH), head-to-tail (HT), tail-to-head (TH), and tail-to-tail (TT). The HT and HH cyclodextrin dimers show higher affinity to cholesterol compared to the other dimers and to all the binding modes of 1:1 complexes. The physical reason why the HT and HH dimers have higher affinity compared to the other complexes is discussed based on the consistency with the 1:1 complex. On the one hand, in case of the HT and HH dimers, the position of each CD in the dimer along the cholesterol chain comes right on or close to one of the positions where a single CD makes a stable complex. On the other hand, one of the CD molecules is located on unstable region along the cholesterol chain, for the case of TH and TT dimers.

In this study, the inclusion complex (IC) of thymol with 2-hydroxypropyl-β-cyclodextrin (HPβCD) was fast synthetized by ultrasonic technology and its antifungal activities were evaluated. The thymol/HPβCD-IC was characterized by UV-vis absorption spectroscopy, fluorescence emission spectroscopy, powder X-ray diffraction, FT-IR, 1H-NMR, TGA and DSC. The phase solubility studies proved that the aqueous solubility of thymol was significantly improved by forming the inclusion complex with HPβCD, and the thermal stability analysis showed that thymol/HPβCD-IC had a better thermal stability than pure thymol. The in vitro antifungal activities of thymol/HPβCD-IC against Botrytis cinerea, Penicillium digitatum and Alternaria alternata were significantly improved compared with pure thymol. Furthermore, the gray mold rot of tomatoes was evidently inhibited by thymol/HPβCD-IC treatment in vivo study. Therefore, the complexation with HPβCD assisted by ultrasound is a promising approach to solubilize and stabilize thymol for application as an antifungal agent in fruit preservation.

The formation of host-guest inclusion complex of Quercetin (QRC) with β-Cyclodextrin (β-CD) and (2-Hydroxypropyl)-β-Cyclodextrin (HP-β-CD) is prepared by various methods such as physical method (PM), kneading method (KM) and co-precipitation method (CP). The solid inclusion complex is characterized by UV, Fluorescence, FT-IR, SEM, powder XRD and TG/DTA analysis. The cytotoxic activity of the solid complex is performed against breast cancer cell line and it is noticed that there is better activity than the QRC alone. Hence, the solid complex showed an improvement in the anticancer activity against MDA MB 231 cell line.

An inclusion complex of praziquantel with 2-hydroxypropyl-β-cyclodextrin was designed and prepared by an optimized method and the inclusion complex was characterized by infrared absorption spectral, proton NMR spectral and scanning electron image studies. It was shown that the aqueous solubility of praziquantel has increased (~104 fold) in comparison with praziquantel alone, which is the best result so far for praziquantel solubility study. The in vivo pharmacokinetic properties of praziquantel in dogs such as Cmax, Tmax, AUC0-∞, and t1/2 have been improved significantly after complexation. The increased water solubility of the praziquantel in the complex resulted in the improved values of Cmax (4.82 μg/mL vs 0.51 μg/mL, 9.45 fold higher) and AUC0-∞ (98.06 μg h/mL vs 20.63 μg h/mL, 4.75 fold higher) in dog pharmacokinetic studies, which is useful to find a new praziquantel formulation as an anti-schistosomal agent.

Dimethyl disulfide (DMDS), a soil fumigant, is an effective, broad-spectrum compound that often replaces bromomethane (MB) in the prevention and treatment of soil-borne diseases. However, the disadvantages of DMDS include toxicity, volatility, pungent odor, risk of human exposure, and environmental pollution. Cyclodextrin (CD) has been widely used as a carrier of chemicals in many industries due to its functional advantages and safety. In this study, a DMDS-controlled release formulation was developed by encapsulating DMDS in the cavity of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). This formulation reduced DMDS usage and production costs. Orthogonal experimental design, Fourier transform infrared (FT-IR), Scanning electron microscopy (SEM), Thermal gravity analysis (TGA) characterization, efficacy comparison, safety, and other aspects of the evaluation showed that under the best preparation conditions, the encapsulation rate was 81.49%. The efficacy of DMDS@HP-β-CD was similar to unformulated DMDS. The efficacy duration of the formulation was about two times longer than DMDS, and it was safer to use. This study reveals a cyclodextrin-DMDS formulation with reduced toxicity, longer duration, environmental safety and sustainability.

The effect of the reaction conditions or the nature of the silylating agents on the silylation of hydroxypropyl-β-cyclodextrin with tert-butyldimethylchloro- and diphenyl-methylchlorosilanes is investigated.

ITH12674 is a multitarget drug, designed to exert a dual "drug-prodrug" mechanism of action, able to induce the phase II antioxidant and anti-inflammatory response for the treatment of brain ischemia. However, its physicochemical properties limit its potential preclinical development due to its low water solubility and instability towards heat and pH variations. In order to improve its properties, we prepared the inclusion complex of ITH12674 with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) by the freeze-drying method. The formation of the inclusion complex was confirmed by FT-IR spectroscopy, PXRD, DSC, 1H NMR and SEM techniques. Experimental results showed that the inclusion complex enhanced its water solubility and stability against heat, acidic and basic conditions. Furthermore, the inclusion complex, prepared in water solution, exerted the same potency to induce the phase II antioxidant response as the pure ITH12674. Thus the formation of the inclusion complex with HP-β-CD is a very effective method to stabilize and solubilize the active compound for its future preclinical development.

2-Hydroxypropyl-β-cyclodextrin (HPβCD) has unique properties to enhance the stability and the solubility of low water-soluble compounds by inclusion complexation. Understanding of the structural properties of HPβCD and its derivatives based on the number of 2-hydroxypropyl (HP) substituents at the a-D-glucopyranose subunits is rather important. In this work, replica exchange molecular dynamics simulations were performed to investigate the conformational changes of single- and double-sided HP-substitution called as 6-HPβCDs and 2,6-HPβCDs, respectively. The results show that glucose subunits in both 6-HPβCDs and 2,6-HPβCDs have lower chance to flip than in βCD. Also, HP groups are occasionally blocking the hydrophobic cavity of HPβCDs, thus hindering the drug inclusion. We found that HPβCDs with high number of HP-substitutions are more likely to be blocked, while HPβCDs with double-sided HP-substitution are even more probable to be blocked. Overall, 6-HPβCDs with three and four HP-substitutions are highlighted as the most suitable structures for guest encapsulation based on our conformational analyses such as structural distortion, radius of gyration, circularity and cavity self-closure of the HPβCDs.

Ferulic acid (FA) belongs to the family of phenolic acids and exhibits a wide variety of biological activities. However, the bioavailability of FA is not optimal, owing to its limited aqueous solubility. Several methods have been developed to increase FA bioavailability and enhance its cytoprotective effects. Complexing FA with cyclodextrins (CDs) may provide an alternative method to approach these goals. In this study, we prepared an FA-2-hydroxypropyl-β-CD (FA-HP-β-CD) complex, at a 1:1 M ratio of FA to HP-β-CD, which was characterized by 1H NMR, two-dimensional rotating frame spectroscopy and differential scanning calorimetry. Aqueous solubility of FA was improved after complexing with HP-β-CD. Furthermore, in vitro and in vivo experimental results indicated that the FA-HP-β-CD complex had greater bioactivity than FA alone. Therefore, we can conclude that the limitations of FA usage due to low aqueous solubility and bioavailability can be overcome by creating an HP-β-CD inclusion complex with the hydrophobic FA.

2-Hydroxypropyl-&beta, cyclodextrin (HP&beta, CD) has unique properties to enhance the stability and the solubility of low water-soluble compounds by inclusion complexation. An understanding of the structural properties of HP&beta, CD and its derivatives, based on the number of 2-hydroxypropyl (HP) substituents at the &alpha, d-glucopyranose subunits is rather important. In this work, replica exchange molecular dynamics simulations were performed to investigate the conformational changes of single- and double-sided HP-substitution, called 6-HP&beta, CDs and 2,6-HP&beta, CDs, respectively. The results show that the glucose subunits in both 6-HP&beta, CDs have a lower chance of flipping than in &beta, CD. Also, HP groups occasionally block the hydrophobic cavity of HP&beta, CDs, thus hindering drug inclusion. We found that HP&beta, CDs with a high number of HP-substitutions are more likely to be blocked, while HP&beta, CDs with double-sided HP-substitutions have an even higher probability of being blocked. Overall, 6-HP&beta, CDs with three and four HP-substitutions are highlighted as the most suitable structures for guest encapsulation, based on our conformational analyses, such as structural distortion, the radius of gyration, circularity, and cavity self-closure of the HP&beta, CDs.

It is extremely important for pharmaceutical formulators to have analytical methodology that provides efficient detection and quantification of HP&beta, CD aggregates. Five different methods were then evaluated for their potential to detect these aggregates and to determine critical aggregation concentration (cac): osmometry, viscometry, tensiometry, dynamic light scattering (DLS), and permeability studies. Overall, tensiometry was an inadequate method with which to study HP&beta, CD aggregation, since the addition of HP&beta, CD to water resulted in only minor changes in surface tension. Osmolality and viscosity studies have shown that for HP&beta, CD, solute&ndash, solvent interactions are the main contributors for the observed deviation from ideality. These deviations might be related to the presence of aggregates. The DLS method proved to be an effective method with which to detect HP&beta, CD aggregates and estimate their hydrodynamic diameter, although it presented some limitations concerning their quantification. In terms of the assessed methods, permeation studies were shown to be the best to study HP&beta, CD aggregation phenomena, since they were the only method where the detection of aggregates and the determination of apparent cac values was possible. Also, it was the least invasive for the HP&beta, CD samples and the method that provided more conclusive data. Results suggested that HP&beta, CD, as expected, has less tendency to form aggregates than &beta, CD.

Carvedilol is one of the most effective antihypertensive drugs used in the treatment of congestive heart failure. A major disadvantage of this pharmaceutical active substance is its limited solubility in water, gastric and intestinal fluids. One way to overcome this problem is the preparation of inclusion complexes. The aim of this study was to prepare the inclusion complexes of carvedilol with β-cyclodextrin (β-CD) and (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) and to investigate their physical properties. The formation of inclusion complexes with β-CD and HP-β-CD was confirmed using FTIR, 1H-NMR and XRD methods. Phase solubility studies indicate the formation of inclusion complexes in 1:2 molar ratio and the increase of carvedilol solubility. The stability constant (β 2) was found to be 3.4 × 104 and 5.1 × 104 M−2 for inclusion complexes of carvedilol:β-CD and carvedilol:HP-β-CD, respectively. Photostability of carvedilol was increased after preparation of inclusion complexes with β-CD and HP-β-CD. Based on the results of this study, it can be concluded that the prepared complexes of carvedilol improve the solubility and stability of carvedilol and give it an advantage to be applied for the design of new pharmaceutical formulations.

Ternary mutual diffusion coefficients (D11, D22, D12 and D21) measured by the Taylor dispersion method are reported for aqueous solutions of levodopa (L-dopa) (1) in the presence of 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) (2) at 25 °C and 37 °C and concentrations up to 0.005 mol · dm−3. The effects of HP-β-CD (HP-β-CD) on the transport of L-dopa are assessed by comparing the binary diffusion coefficient of aqueous L-dopa solutions with the main diffusion coefficient (D11) measured for ternary {L-dopa (1) + HP-β-CD (2)} solutions. 1H NMR spectroscopy suggests no significant complexation between HP-β-CD and L-dopa. However, coupled diffusion of L-dopa and HP-β-CD occurs, as indicated by non-zero values of the cross-diffusion coefficients, D12 and D21. HP-β-CD concentration gradients produce significant co-current coupled flows of L-dopa.

Pseudohybrid nanoparticles of 800 nm in diameter based on self-assembled high-substituted 2-hydroxypropyl-β-cyclodextrin fabricated in the presence of iron(II) salts were found to be thermally responsive within narrow range of temperature. As-prepared metal-free nanoparticles are stable in aqueous solution at room temperature. However, the increase in temperature results in break-like collapse of nanoparticles to yield species of 400 nm in diameter. On the example of phenolphthalein, it was shown that nanoparticles loaded with model drug decompose to release superficial guest-host inclusion complexes. Local hyperthermia provokes nanoparticles decomposing and drug releasing that allows recognizing focuses of pathology in human body. It might be used for diagnostic medicinal aims and be also considered as basis for the construction of intravascular drug delivery/release systems.

The aim of this study was to investigate the effects of resveratrol on its free form and complexed with 2-hydroxypropyl-β-cyclodextrin (HPβCD) when associated with sulfamethoxazole-trimethoprim (ST) on cytokines levels of mice (n = 60) experimentally infected by Toxoplasma gondii. Groups A and E were used as controls (untreated): negative and positive, respectively. The onset of treatment started 20 days post-infection (PI), and it lasted for 10 consecutive days. ST was administered orally in doses of 0.5 mg kg(-1) for groups B and F, while 100 mg kg(-1) was the dose for resveratrol in its free form (groups C - G), inclusion complex (groups D and H), and on free and inclusion complex together (groups I - J). On day 31 PI, blood samples were collected in order to evaluate the cytokine profile. The mice that received drug combination (I and J) showed a significant (P < 0.05) reduction in the number of cysts in the brain compared to other infected groups (E - H). The results showed that mice from the Group E had increased (P < 0.001) levels of pro-inflammatory cytokines, while IL-10 levels were reduced when compared to the Group A. Additionally, there were increased levels of IL-4 and IFN-γ in animals of groups C and D, respectively (P < 0.05). Animals of the Group B showed reduced levels of IL-1, IL-4, IL-6, TNF-α, and IFN-γ (P < 0.05). Mice infected and treated (groups F - J) showed increased levels of pro-inflammatory cytokines along with a reduction of IL-10. Treatment with the combination of drugs (the Group J) led to a protective effect, i.e. reduction in pro-inflammatory cytokines. Therefore, resveratrol associated with ST was able to modulate seric cytokine profile and moderate the tissue inflammatory process caused by T. gondii infection, as well as to reduce parasite multiplication.

Ortho-naphthoquinone β-lapachone, a compound originally isolated from the Tabebuia sp tree, has showed pronounced activity against different parasites and cancer cells. However, its use presents limitations mostly related to its low bioavailability, solubility, thermal instability and photodecomposition. In order to overcome such disadvantages, this work aimed to evaluate different methodologies to promote the formation of inclusion complexes between β-lapachone and 2-hydroxypropyl-β-cyclodextrin. For this purpose, manual and automated mechanochemical processes as well as liquid phase methods were employed. The complexes were evaluated for entrapment efficiency (EE) and stability, that is, the maintenance of the entrapment over time. The samples which showed the best results were submitted to a thorough physicochemical and spectroscopic characterization, including 2D NMR techniques, and such analyses revealed that the mechanochemical process furnished the most stable inclusion complex.

The thermodynamic and spectroscopic parameters of the betulin/2-hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complex and its hepatoprotective activity were investigated in rats with nonalcoholic steatohepatitis (NASH). The pentacyclic triterpene betulin was isolated from birch bark and complexed with HPβCD. The parameters of inclusion complex formation were evaluated by infrared spectroscopy and differential scanning and isothermal titration calorimetries. The aqueous solubility and stability of betulin were significantly increased due to the formation of a stable inclusion complex with a stoichiometry of 1:1. The determined changes in molar enthalpy (ΔH 0) and free energy (ΔG

In a previously performed small-scale clinical study, healthy volunteers were asked to ingest an oral solution of itraconazole (Sporanox®) containing 40% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) (i) with or (ii) without a standardized volume of water (240 mL) after which gastrointestinal and blood samples were collected. Although omitting water during the administration of Sporanox® resulted in noticeably higher duodenal concentrations of itraconazole, systemic exposure was almost unaffected. It is assumed that this discrepancy can be explained by differences in the extent of entrapment of itraconazole in the duodenum caused by differential complexation depending on the concentration of cyclodextrins. To further substantiate this hypothesis, the quantification of HP-β-CD concentrations in the aspirated intestinal fluids was performed by LC-MS/MS. When comparing the intestinal concentrations of itraconazole and HP-β-CD for one single healthy volunteer (HV02) in both test conditions, an excellent correlation was observed (Spearman's rank coefficient of 0.96). Moreover, the data suggest that, similar to aqueous buffer media, also in human intestinal fluids a non-linear relationship exists between itraconazole solubility and HP-β-CD concentration (Ap-type profile; Spearman's rank coefficient of 0.78), indicating that higher order complexes are formed at higher concentrations of HP-β-CD. This difference in extent of entrapment in the inclusion complexes helps to understand the observed impact of water intake on precipitation and permeation behavior of itraconazole in man. Without water intake, higher HP-β-CD concentrations resulted in less precipitation and increased duodenal concentrations of itraconazole. On the other hand, the stronger interaction at higher HP-β-CD concentrations reduced the free fraction of the drug explaining that increased intraluminal concentrations of itraconazole were not translated into an enhanced uptake. In conclusion, quantifying the concentrations of the solubilizing agent HP-β-CD in human intestinal fluids appeared to be of crucial importance to interpret the intraluminal behavior of an orally administered cyclodextrin-based solution. ispartof: EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS vol:13 pages:231-236 ispartof: location:Netherlands status: published

Background: The difficulty of eliminating bacteria infecting bone tissue during bone healing treatments or surgery makes it desirably to develop solid scaffolds capable of sustained release of antibiotics to achieve the regeneration of the damaged tissue. Methods: With this function in view, in this work we prepared HA scaffolds functionalized with1,2- Hydroxypropyl-β-Cyclodextrin to increase the loading and sustained release for ciprofloxacin. Results: The lowest amount of CD was sufficient to fabricate HA functionalized microparticles and allowing for the CPX loading to be increased more than 40 times with respect to the non-functionalized HA particles. Spray-drying process rendered spherical particles with irregular surface that improved the release and the solubility of low soluble CPX in pH 7.4 medium in form of free drug and cyclodextrin complexes although free cyclodextrins were also released to the medium. Conclusion: It is concluded that the synthesized microparticles based on HA functionalized with Hydroxypropyl -β-Cyclodextrin merit further investigation to be used as platform for delivering antibiotics in bone regeneration.

Amodiaquine has been used widely as an antimalarial drug. Amodiaquine is a mannich base 4-amino quinolone with a mode of action similar to that of chloroquine. The inclusion complex of amodiaquine with 2-(hydroxypropyl)-beta-cyclodextrin in solution phase is studied from the ground and excited state with absorption and fluorescence spectroscopic techniques, respectively. A binding constant and stoichiometric ratio between amodiaquine and 2-(hydroxypropyl)-beta-cyclodextrin are calculated by the use of Benesi–Hildebrand equation. The solid complexes are prepared by physical, kneading and coprecipitation methods. The solid complexes are characterized by Fourier-transform infrared spectral analysis, Differential scanning calorimetric curves and powder X-ray diffraction patterns. The anticancer activity was tested for pure amodiaquine and their complex with 2-(hydroxypropyl)-beta-cyclodextrin against MDA MB 231 cell line. It clearly showed that a significant improvement of anticancer activity of amodiaquine when forming a complex with 2-(hydroxypropyl)-beta-cyclodextrin.

A multivalent magnetic resonance imaging agent based on a 2-hydroxypropyl-β-cyclodextrin (HPCD):Pluronic F127 polyrotaxane carrier has been synthesized, and its blood pool contrast properties have been characterized. This Gd3+-DO3A-HPCD/Pluronic polyrotaxane construct is shown to circulate for more than 30 min and provide100-fold vascular enhancement relative to the monomeric Gd3+-DO3A-HPCD control that is rapidly cleared via the kidney. The high r1 relaxivity at 37 °C (23.83 mM(-1) s(-1) at 1.5 T; 34.08 mM(-1) s(-1) at 0.5 T), extended blood circulation, well-known pharmacology of the polyrotaxane precursors, and absence of acute toxicity make it a highly attractive blood pool contrast agent candidate.

A family of cationic Pluronic-based polyrotaxanes (PR(+)), threaded with 2-hydroxypropyl-β-cyclodextrin (HPCD), was synthesized for pDNA delivery into multiple cell lines. All PR(+) formed highly stable, positively charged pDNA complexes that were < 250 nm in diameter. The cellular uptake and pDNA transfection efficiencies of the PR(+):pDNA complexes was enhanced relative to the commercial transfection standards L2K and bPEI, while displaying similar or lower toxicity profiles. Charge density and threading efficiency of the PR(+) agent significantly influenced the colloidal stability and physical properties of the complexes, which impacted their intracellular transfection efficiencies. Taken together, our results suggest that HPCD: Pluronic PR(+) can be used as potent vectors for pDNA-based therapeutics.

The possibility of a intermolecular complex rifabutin (RB)-2-hydroxypropyl-β-cyclodextrin (HP-β-CD) formed as a result of the interaction of the piperidine fragment of the RB molecule and the hydrophobic cavity of the HP-β-CD molecule was found. The stability constant of the intermolecular complex was determined.

This paper reports on an experimental research of a 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) enveloped 10-methylphenothiazine (MPT) catalyst (MPT-HP-β-CD) with high sensitivity and wonderful electrical conductivity for the electrochemical detection of reduced glutathione (GSH) in a neutral environment. We obtained a linear response range from 10−6 mol L−1 to 5.8 × 10−4 mol L−1 for GSH with a low detection limit of 2.87 × 10−7 mol L−1, providing a potentially usefulness in the development of sensors for non-enzyme detection of GSH.

Angelica sinensis (AS) is a traditional Chinese medicinal herb. Its ethanolic extract contains active ingredients, such as ferulic acid, ligustilide, and butylidenephthalide, which are hydrophobic and have inhibitory effects on hepatoma cells. To increase the aqueous solubility/dispersibility of AS extract and study the consequent inhibitory effect on hepatoma cells, the ethanolic extract of AS was complexed with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), a cyclic oligosaccharide that has a hydrophilic outer surface and a hydrophobic central cavity. The AS-HP-β-CD complex (weight ratio of AS extract: HP-β-CD=1:5) was prepared and characterized. The effect of complexing the AS extract with HP-β-CD on Hep3B cell growth was investigated by analyzing cytotoxicity. Our results showed that cytotoxicity inhibition of AS-HP-β-CD complex was up to 94% and higher than that of AS extract (about 68%). These observations suggested that the use of HP-β-CD to stabilize AS extract in aqueous solution was possible for herbal medicine application.

A photochromic system based on dracoflavylium, a natural pigment extracted from Dragon's blood, a resin appearing in the injury parts of the tree Dracaena draco, is studied in water. The photochromism arises from the irradiation of the trans-chalcone, giving a mixture of flavylium cation/quinoidal base as a photoproduct via cis-chalcone and hemiketal. The performance of the photochromic system can be improved in the presence of (2-hydroxypropyl)-β-cyclodextrin. A mathematical model to account for the details of the kinetics and thermodynamics of the system was deduced. The model is general for all the host-guest systems involving the flavylium network of chemical reactions with 1 : 1 stoichiometric association.