A pH-responsive citric-acid/α-cyclodextrin-functionalized Fe3O4 nanoparticles as a nanocarrier for quercetin: An experimental and DFT study.

Developing new nanocarriers and understanding the interactions between the drug and host molecules in the nanocarrier at the molecular level is of importance for future of nanomedicine. In this work, we synthesized and characterized a series of iron oxide nanoparticles (IONPs) functionalized with different organic molecules (citric acid, α-cyclodextrin, and citric acid/α-cyclodextrin composite). It was found that incorporation of citric acid into the α-cyclodextrin had negligible effect on the adsorption efficiency (<5%) of citric acid/α-cyclodextrin functionalized IONPs, while the isotherm adsorption data were well described by the Langmuir isotherm model (qmax = 2.92 mg/g at T = 25 °C and pH = 7). In addition, the developed nanocarrier showed pH-responsive behavior for releasing the quercetin molecules as drug model, where the Korsmeyer-Peppas model could describe the release profile with Fickian diffusion (n < 0.45 for at all pH and temperatures). Then, Density functional theory was applied to calculate the absolute binding energies (ΔEb) of the complexation of quercetin with different host molecules in the developed nanocarriers. The calculated energies are as follow: 1) quercetin and citric acid: ΔEb = -16.58 kcal/mol, 2) quercetin and α-cyclodextrin: ΔEb = -46.98 kcal/mol, and 3) quercetin and citric acid/α-cyclodextrin composite: ΔEb = -40.15 kcal/mol. It was found that quercetin tends to interact with all hosts via formation of hydrogen bonds and van der Waals interactions. Finally, the cytotoxicity of the as-developed nanocarriers was evaluated using MTT assay and both normal NIH-3T3 and cancereous HeLa cells. The cell viability results showed that the quercetin could be delivered effectively to the HeLa cells due to the acidic environment inside the cells with minimum effect on the viability of NIH-3T3 cells. These results might open a new window to design of stimuli-responsive nanocarriers for drug delivery applications.

AIE Supramolecular Assembly with FRET Effect for Visualizing Drug Delivery.

Here, we constructed a nanostructured pH/redox dual-responsive supramolecular drug carrier with both aggregation-induced emission (AIE) and Forster resonance energy transfer (FRET) effects, which enabled selective drug release and monitoring drug delivery and release processes. Taking the hyperbranched polyamide amine (H-PAMAM) with intrinsic AIE effects as the core, poly(ethylene glycol) (PEG) was bridged on its periphery by dithiodipropionic acid. Then, through the host-guest interaction of PEG and α-cyclodextrin, the supramolecular nanoparticles with AIE effects were constructed to load the anticancer drug doxorubicin (DOX). The supramolecular assembly has sufficiently large DOX loading due to the abundant cavities formed by branched structures. The hyperbranched core H-PAMAM has strong fluorescence, and the dynamic track of drug carriers and the dynamic drug release process can be monitored by the AIE and FRET effects between H-PAMAM and DOX, respectively. Furthermore, the introduction of disulfide bonds and the pH sensitivity of H-PAMAM enable the achievement of rapid selective release of loaded DOX at the tumor while remaining stable under normal physiological conditions. In vitro cytotoxicity indicates that the drug-loaded supramolecular assembly has a good therapeutic effect on cancer. In addition, the H-PAMAM core is different from the traditional AIE functional group, which has no conjugated structure, such as a benzene ring, thereby providing better biocompatibility. This technology will have broad applications as a new drug delivery system.

A Combined Approach of NMR and Mass Spectrometry Techniques Applied to the α-Cyclodextrin/Moringin Complex for a Novel Bioactive Formulation †.

Moringin, obtained via enzymatic conversion of the glucosinolate precursor glucomoringin, is an uncommon member of the isothiocyanate class, and has been proven to possess a broad range of biological activities such as antitumor activity, protection against neurodegenerative disorders and bactericidal effects. Since moringin is weakly soluble in water and unstable in aqueous medium, cyclodextrins (CDs) were considered for the development of a new moringin formulation, with a view to improving its solubility and stability in aqueous solution for use as an anti-inflammatory. A combined structural study using proton nuclear magnetic resonance (¹H-NMR), diffusion-ordered spectroscopy (DOSY) and ion mobility mass spectrometry (IM-MS) is reported, highlighting the formation of a 1:1 α-CD/moringin inclusion complex. The association constant K was determined (1300 M-1 at 300 K). Completion of the structural characterization was performed by T-ROESY and MS/MS experiments, which evidenced the mode of penetration of moringin into α-CD. Finally, the "chaperone-like" properties of α-CD with respect to the stability of moringin have been highlighted.

In Vitro and In Vivo Tumor-Targeting siRNA Delivery Using Folate-PEG-appended Dendrimer (G4)/α-Cyclodextrin Conjugates.

We previously reported that folate-polyethylene glycol (PEG)-appended dendrimer (generation 3)/α-cyclodextrin conjugate (Fol-PαC (G3)) shows folate receptor-α (FR-α)-overexpressing tumor cell-selective in vitro siRNA transfer activity. However, Fol-PαC (G3)/siRNA complex did not induce a significant in vivo RNAi effect after intravenous administration to tumor-bearing mice, possibly resulting from immediate dissociation of the complex in blood. Herein, to develop the novel siRNA carrier having high blood circulating ability, high in vivo siRNA transfer activity, and high safety profile, we newly prepared Fol-PαCs with higher generation (G4) and evaluated their potential as tumor-targeting siRNA carriers in vitro and in vivo. Fol-PαC (G4, average degree of substitution of α-cyclodextrin (DSC) 2.9, average degree of substitution of folate-PEG (DSF) 2)/siRNA complex had the prominent RNAi effect through adequate physicochemical properties, FR-α-mediated endocytosis, efficient endosomal escape, and siRNA delivery to cytoplasm with negligible cytotoxicity. Importantly, Fol-PαC (G4, DSC2.9, DSF2) improved the serum stability, blood circulating ability, and in vivo RNAi effects of siRNA, compared to Fol-PαC (G3). Furthermore, Fol-PαC (G4, DSC2.9, DSF2) complex with siRNA against Polo-like kinase 1 (siPLK1) suppressed the tumor growth compared to control siRNA complex. These results suggest that Fol-PαC (G4, DSC2.9, DSF2) has the potential as a novel tumor-targeting siRNA carrier in vitro and in vivo.

A review of the pharmacology and clinical application of alfaxalone in cats.

Alfaxalone-2-hydroxpropyl-ß-cyclodextrin (alfaxalone-HPCD) was first marketed for veterinary use in Australia in 2001 and has since progressively became available throughout the world, including the USA, where in 2012 Food and Drug Administration (FDA) registration was granted. Despite the growing body of published works and increasing global availability of alfaxalone-HPCD, the accumulating evidence for its use in cats has not been thoroughly reviewed. The purpose of this review is: (1) to detail the pharmacokinetic properties of alfaxalone-HPCD in cats; (2) to assess the pharmacodynamic properties of alfaxalone-HPCD, including its cardiovascular, respiratory, central nervous system, neuromuscular, hepatic, renal, haematological, blood-biochemical, analgesic and endocrine effects; and (3) to consider the clinical application of alfaxalone-HPCD for sedation, induction and maintenance of anaesthesia in cats. Based on the published literature, alfaxalone-HPCD provides a good alternative to the existing intravenous anaesthetic options for healthy cats.

Design and evaluation of polyamidoamine dendrimer conjugate with PEG, α-cyclodextrin and lactose as a novel hepatocyte-selective gene carrier in vitro and in vivo.

To develop a novel hepatocyte-selective gene carrier, we prepared polyamidoamine starburst dendrimer (generation 3, G3) conjugates with three functional molecules, i.e. α-cyclodextrin, polyethylene glycol (PEG, molecular weight = 2170) and lactose (PEG-LαCs), and evaluated gene delivery efficiency of these conjugates in vitro and in vivo. PEG-LαC (G3, degrees of substitution of the PEG moiety (DSP) 2.1) showed higher gene transfer activity than other PEG-LαCs (G3, DSP4.0, 6.2) in HepG2 cells, expressing asialoglycoprotein receptor, and the activity decreased in HeLa cells, non-expressing the receptor and in the presence of asialofetuin. High gene transfer activity of PEG-LαC (G3, DSP2.1) was retained even in the presence of 50% serum, although the activity of α-cyclodextrin/lactosylated dendrimer (G3) conjugate (Lac-α-CDE (G3)), which is lacking a PEG moiety, was severely decreased in the presence of 20% serum. PEG-LαC (G3, DSP2.1) provided negligible cytotoxicity up to a charge ratio of 50 (carrier/pDNA) in HepG2 cells and less acute organ toxicity. PEG-LαC (G3, DSP2.1) showed selective gene transfer activity to hepatic parenchymal cells rather than hepatic non-parenchymal cells. These results suggest that PEG-LαC (G3, DSP2.1) is useful as a hepatocyte-selective gene carrier in vitro and in vivo.

α-Cyclodextrin dimer complexes of dopamine and levodopa derivatives to assess drug delivery to the central nervous system: ADME and molecular docking studies.

This paper attempts to predict and emphasize molecular interactions of dopamine, levodopa, and their derivatives (Dopimid compounds) containing 2-phenyl-imidazopyridine moiety with the α-cyclodextrin dimer in order to assess and improve drug delivery to the central nervous system. The molecular docking method is used to determine the energetic profiles, hydrogen bond formation, and hydrophobic effect of 14 host-guest complexes. The results show that the "chemical branching" represented by additional ethyl-acetate residue is energetically unfavorable and promotes a conformational shift due to the high root mean square deviation levels. This phenomenon is characterized by a low number of H-bonds and a significant decrease of the host-guest hydrophobic potential surface. Finally, the overall docking procedure presents a powerful rationale for screening and analyzing various sets of promising drug-like chemical compounds in the fields of supramolecular chemistry, molecular sensing, synthetic receptors, and nanobiotechnology.

Formulations based on alpha cyclodextrin and soybean oil: an approach to modulate the oral release of lipophilic drugs.

The purpose of this work was to investigate the potential of α-cyclodextrin combined to soybean oil-based formulations to modulate the release of a model drug, indomethacin. Dry emulsion, naked and coated beads were prepared from the same initial formulation using the same manufacturing process. Dry emulsion was selected to accelerate drug release while beads coated with α-cyclodextrin were designed to sustain it. Indomethacin-loaded systems were prepared, characterised and evaluated in vitro. Pharmacokinetic studies were performed in fasted and fed rats. The presence of the α-cyclodextrin coat was confirmed by confocal microscopy, and an increase of the mass and diameter of the beads. The layer of α-cyclodextrin improved their resistance in simulated gastro-intestinal fluids. In vitro, the dissolution of indomethacin was slower with coated beads than with emulsion and naked beads. Lipid-based formulations showed an increase of relative bioavailability of IND versus Indocid®. Whatever the formulation, greater and faster release of indomethacin was noticed in sodium taurocholate-rich medium and in fed rats. Compared to naked beads, an increased Cp(max) with a shorter T(max) was observed with the emulsion while T(max) and MRT were increased and Cp(max) reduced with the coated beads. Interestingly, formulations based on alpha cyclodextrin and soybean oil can modify the release of a lipophilic drug depending on the system formed.

[Research progress of self-assembled beads drug delivery system prepared from cyclodextrins and oils].

Recently, increasing attention has been paid to beads, an innovative self-assembled drug delivery system prepared from cyclodextrins and oils. Beads are new core-shell minispheres containing poorly water-soluble drugs or lipophilic drugs dissolved in the lipid core without the use of organic solvents and surfactants. Therefore, beads with high drug loading and improved oral bioavailability have great potential for oral delivery of poorly water-soluble drugs and lipophilic drugs. The preparation mechanisms, formulations and methods, the in vitro and in vivo properties of beads were reviewed in order to provide the theoretical basis for further application of beads.

Prednisolone-α-cyclodextrin-star poly(ethylene glycol) polypseudorotaxane with delayed pH-sensitivity as a targeted drug delivery system.

The acylation of prednisolone 20-hydrazone with star poly(ethylene glycol) tetracarboxylic acid (M = 20,000) has been used to prepare the corresponding pH-sensitive conjugate. With α-cyclodextrin, this conjugate forms a polypseudorotaxane, which was characterised by means of (1)H NMR spectra, powder X-ray diffraction patterns and STM microscopy. The rate of acid-catalysed hydrolysis of the conjugate was studied under in vitro conditions in model media of hydrochloric acid solutions, phosphate and acetate buffers (pH 2-5.8). The acid-catalysed hydrolysis (at pH 2) of the polypseudorotaxane was ca 3.5 times slower than that of the original conjugate. After 1h in this medium, 86% of the covalently attached prednisolone remained unchanged. The prepared polypseudorotaxane represents a promising peroral transport system of prednisolone with a pH-sensitive linker with delayed acid-catalysed hydrolysis thanks to protection at the molecular level using α-cyclodextrin.

Permeation and distribution of ferulic acid and its α-cyclodextrin complex from different formulations in hairless rat skin.

Ferulic acid (FA) is a natural product that occurs in seeds of many plants where it is generally located in the bran. This compound is a multifunctional ingredient endowed with antioxidative, radical scavenging, sunscreening and antibacterial actions. The aim of this study was to analyse the ferulic acid cutaneous permeation and distribution, through and into the skin layers, from different cosmetic vehicles, an O/W emulsion (pH 6.0) and two gel-type formulations at different pH levels (6.0 and 7.4), containing FA alone or an inclusion complex with α-cyclodextrin (CD-FA). In vitro permeation studies were performed in vertical diffusion cells using hairless rat excised skin. At appropriate intervals of time, the amount of permeated sunscreen/radical scavenger was evaluated by high-performance liquid chromatography (HPLC). At the end of experiments, treated skin samples were sectioned with a cryomicrotome and the FA content of the individual slices was analysed by HPLC. FA-containing formulations, O/W emulsion, gels A and B, originated FA fluxes of 8.48 ± 2.31, 8.38 ± 0.89 and 5.72 ± 0.50 µg/cm(2) h, respectively, thus suggesting the pH influence on FA percutaneous permeation. The use of the inclusion complex, CD-FA, determined in all cases a decrease of FA transdermal permeation while no influence of pH was observed. Gel-type formulations containing FA ensured higher sunscreen storage in the superficial layers if compared with O/W emulsion. When FA was included in α-cyclodextrin, FA amount retained into skin layers decreased markedly.

Pharmacokinetic characteristics of a vasodilatory and antiplatelet agent, limaprost alfadex, in the healthy Korean volunteers.

Limaprost, a prostaglandin E1 analogue, with a strong vasodilatory and antiplatelet activity has been used to release from the symptoms of thromboangiitis obliterans (TAO), which is more prevalent in Korea and Japan, and lumbar spinal canal stenosis (LSCS). In spite of many uses of limaprost, the pharmacokinetics (PK) of it has not been studied in the Korean population. Therefore, a preliminary PK study was designed at a clinical oral dosage of 30-microg limaprost in 5 healthy Korean volunteers. Blood samples were obtained at 14 consecutive time points for 12 hours after dosing and analyzed by liquid chromatography-tandem mass spectrometry with electrospray ionization (LC-ESI/MS/ MS) at a very low detection limit of 0.5 pg/mL of limaprost in human plasma with considerably short run time (18 minutes). Pharmacokinetic characteristics resulted in ''time for maximal concentrations (T(max) 0.5 hour),'' ''elimination half-life (T(1/2) 1.64 hours),'' ''maximal concentration (C(max) 13.37 pg/mL),'' ''area under the curve (AUC(12 hours) 18.60 pg . h/mL),'' ''AUC extrapolated to infinity (AUC(infinity) 22.98 pg . h/mL),'' ''extrapolation (AUC(infinity - 12 hours)/AUC(infinity) 0.15%),'' ''elimination rate constant (k(e) 0.68 h(-1)),'' ''systemic clearance (CL 1.77 L/h),'' and ''mean residence time (MRT 1.74 hours).'' These results showed that orally administered 30-microg limaprost was rapidly and highly absorbed, and it was considerably eliminated fast from the blood stream in the healthy Korean volunteers.

Bioequivalence study of two limaprost alfadex 5 microg tablets in healthy subjects: moisture-resistant tablet (dextran formulation) versus standard tablet (lactose formulation).

OBJECTIVE: A study was conducted to assess the bioequivalence of two limaprost alfadex 5 microg tablets, a moisture-resistant tablet (dextran formulation) and a standard tablet (lactose formulation). MATERIALS AND METHODS: The clinical investigation was designed as a randomized, open-labeled, two-part, two-treatment, two-period crossover study, in 120 healthy male volunteers. One tablet of either formulation was administered with 200 ml of water after 10-hour overnight fast. After dosing, serial blood samples were collected for a period of 6 hours. Plasma harvested from blood was analyzed for limaprost by a validated LC/MS/MS method. The peak plasma concentration (Cmax) values and time associated with the maximal concentration (tmax) were obtained from the observed data. The elimination rate constant (lambda z) was obtained as the slope of the linear regression of the log-transformed concentration values vs. time data in the terminal phase, and the elimination half-life (t1/2) was calculated as 0.693/lambda z. The area under the curve to the last measurable point (AUC0-t) was estimated by the linear trapezoidal rule. The analysis of variance (ANOVA) was carried out using log-transformed AUC0-t, AUC0-A yen and Cmax and untransformed tmax, and 90% confidence intervals for AUC0-t and Cmax were calculated. If the 90% confidence intervals (CI) for both AUC0-t and Cmax fell fully within the interval 80 - 125%, the bioequivalence of the two formulations was established. RESULTS: The means of AUC0-t were 0.779 vs. 0.754 pg x h/ml (test vs. reference), and the means of the Cmax were 1.26 vs. 1.12 pg/ml (test vs. reference). The geometric mean ratios of the test formulation to reference formulation for AUC0-t and Cmax were 104.0 and 112.4%, respectively, and the 90% CI for AUC0-t and Cmax were 100.7 - 107.4% and 105.6 - 119.6%, respectively. Both 90% CI for AUC0-t and Cmax fell within the Ministry of Health, Labour and Welfare of Japan accepted bioequivalence range of 80 - 125%. CONCLUSIONS: Based on the results, the moisture-resistant tablet was determined to be bioequivalent to the standard tablet.

Improved stability of Opalmon tablets under humid conditions IV: effect of polysaccharides and disintegrants on the stability and dissolution property of Opalmon tablets.

We studied the effects of dextran, dextrin, and disintegrants on the chemical stability of Opalmon tablets containing Limaprost-alfadex (Limaprost/alpha-cyclodextrin complex) and found that the addition of dextran or dextrin significantly improved the chemical stability of Opalmon tablets under high humidity, compared to lactose. We also examined how dextran stabilizes Limaprost in Opalmon tablets and studied the formulation of Opalmon tablets in order to achieve higher chemical stability, rapid dissolution and reduced stickiness. The results suggested that dextran increases stabilization after moisture adsorption by decreasing the dissociation of Limaprost-alfadex to the free drug and alpha-cyclodextrin in the dextran matrix, when compared with the lactose matrix. The stickiness of Opalmon tablets containing dextran and dextrin was negligible when dextran and dextrin amounted to less than 20% of the formulation. By selecting a proper disintegrant, we obtained Opalmon tablets with higher chemical stability and rapid dissolution properties.

Alpha-cyclodextrin/oil beads as a new carrier for improving the oral bioavailability of lipophilic drugs.

The purpose of the present work was to investigate the potential of novel lipid-carrier "beads" consisting of minispheres made of alpha-cyclodextrin and soybean oil for the encapsulation and the oral delivery of drugs. Isotretinoin was chosen as a model of poorly-stable and lipophilic molecule. Isotretinoin-loaded beads were prepared, characterised and administrated orally in rats. Isotretinoin previously dissolved in soybean oil had no significant effect upon bead preparation and characteristics. Drug encapsulation efficiency was found to be particularly high (93+/-7%) and no isotretinoin degradation occurred during the preparation process. Freeze-drying advantageously concentrated isotretinoin in beads (3.4+/-0.2 mg/g) and facilitating ease of handling and use for oral administration. Isotretinoin exhibited good stability for at least 4 months when beads were stored protected from light. Finally, pharmacokinetics of isotretinoin in rats demonstrated that the drug was successfully released from beads in the digestive tract and that isotretinoin absolute bioavailability was doubled compared to isotretinoin lipid solution (32% and 15% respectively). In conclusion, these beads constitute a novel and efficient system for encapsulation and oral delivery of lipophilic and fragile drugs.

After-rinsing hair growth promotion of minoxidil-containing amino alpha-cyclodextrins.

Triamino alpha-cyclodextrin (CD) was synthesized and the inclusion complex with Minoxidil (MXD) was prepared. alpha-CD was azidated by modifying the 6-hydroxylmethyl CD rim with sodium azide. Then, mono-, di-, tri-, and tetra-azidocyclodextrins were separated by a flash column chromatography and reduced to the corresponding amines by hydrogenation with Pd/C. The substantivities of MXD included in either 2-hydroxypropyl alpha-CD (HP alpha-CD) or triamino alpha-CD were evaluated in vitro using hairless mice skins. After applying the preparations onto the skin and rinsing it, the amount of the drug left on the skin was determined using high-performance liquid chromatography (HPLC). It was the highest when the drug was included in triamino alpha-CD. The electrostatic interaction between the protonated amino CD and the negatively charged skin would be responsible for the relatively high substantivity. The in vivo hair growth promotion effect of each preparation was investigated, where the sample application onto the clipped backs of female mice (C57BL6) and the subsequent rinsing of the backs were done once a day for 30 days. Only MXD in triamino alpha-CD had hair growth promotion effect, possibly due to the significant substantivity.

Delivery of all trans-retinoic acid (RA) to hepatocyte cell line from RA/galactosyl alpha-cyclodextrin inclusion complex.

All trans-retinoic acid (RA) plays a role in regulation of P450RAI gene expression. In this study, hepatocyte cell line (HepG2) was used to study an effect of RA released from RA/galactosyl alpha-cyclodextrin (GCD) inclusion complex on regulation of P450RAI gene expression. A delivery system composed of RA/GCD inclusion complex was applied because RA is poorly water soluble, and organic solvents used to dissolve it often interfere with cytotoxicity. Solubility of RA in water was increased by forming complex with GCD. Inclusion complex between GCD and RA was checked by (1)H-nuclear magnetic resonance, Fourier transformation infrared (FT-IR) spectroscopy and X-ray diffraction (XRD). The chemical shifts of the interior and exterior GCD protons in the presence of RA indicated that the RA was included within the GCD macrocycle cavity. The carbonyl band of RA and crystalline peak of RA in RA/GCD inclusion complex disappeared from FT-IR and XRD measurements, respectively, indication of inclusion complex between RA and GCD. From the observation of fluorescence micrograph of hepatocytes and flow cytometry measurement of HepG2, the internalization of fluorescein isothiocyanate-GCD by the hepatocyte occurred. Gene expression of P450RAI in HepG2 by delivery of RA from RA/GCD complex was observed.