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Folate receptor alpha (FRα) is overexpressed in >80% of epithelial ovarian cancer (EOC). Accordingly, folate is attracting attention as a targeting ligand for EOC. For EOC patients, paclitaxel (PTX) is generally used as a first-line chemotherapeutic agent in combination with platinum-based drugs. Cyclodextrin (CyD) is a potential new formulation vehicle for PTX that could replace Cremophor-EL, a traditional formulation vehicle that causes significant side effects, including neutropenia. Several years ago, folate-appended β-CyD (Fol-c 1 -β-CyD) was developed as an FRα-targeting drug carrier, but its efficacy as a treatment for EOC remains to be determined. In this study, we assessed the antitumor activity of PTX in Fol-c 1 -β-CyD (PTX/Fol-c 1 -β-CyD) in EOC-derived cell lines. We found that PTX/Fol-c 1 -β-CyD killed not only FRα-expressing cells but also FRα-negative cells. In the FRα-negative A2780 cells, knockdown of proton-coupled folate transporter (PCFT) significantly decreased the cytotoxicity of PTX/Fol-c 1 -β-CyD, whereas knockdown of FRα did not. By contrast, knockdown of either FRα or proton-coupled folate transporter (PCFT) decreased the cytotoxicity of PTX/Fol-c 1 -β-CyD in FRα-expressing SK-OV-3 cells. Furthermore, the cytotoxicity of PTX/Fol-c 1 -β-CyD in A2780 cells was increased at acidic pH, and this increase was suppressed by PCFT inhibitor. In mice intraperitoneally inoculated with FRα-expressing or PCFT-expressing EOC cells, intraperitoneal administration of PTX/Fol-c 1 -β-CyD significantly suppressed the growth of both types of EOC cells relative to PTX alone, without inducing a significant change in the neutrophil/white blood cell ratio. Our data suggest that Fol-c 1 -β-CyD targets not only FRα but also PCFT, and can efficiently deliver anticancer drugs to EOC cells in the peritoneal cavity., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Hydrogels formed through reversible supramolecular interactions may attain self-healing in the in situ environment. However, the low grafting degree of functional groups and steric hindrance effect of polymer backbones significantly reduced the self-healing efficacy and kinetics. To overcome these deficiencies, we designed a novel hydrogel via non-covalent host-guest interaction between β-cyclodextrin modified hyaluronic acid (HA-CD) and adamantane modified 4-arm-PEG (4-arm-PEG-Ad). The multi-armed monomer enabled to increase the number of functional groups and avoid steric hindrance effects, offering more efficient host-guest interaction. The insoluble dexamethasone could be loaded in the β-CDs' hydrophobic cavities. The designed hydrogels exhibited excellent self-healing properties. The mechanical strengths, swelling rate and release of dexamethasone could be adjusted by adding 4-arm-PEG-Ad. The novel hydrogels significantly improved the therapeutic effect of the dexamethasone in burn wound healing. Herein, these hydrogels had great potential for direct, convenient, and efficient delivery of hydrophobic drugs and improved their therapeutic effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

β-Cyclodextrin-based nanosponges (β-CDNSs) play an important role in new arrays of agriculture, floriculture, cosmetics, medicine, high molecular weight proteins, novel flame retardants, gas carriers and water filters. In recent years, the field of advance nanostructured systems witnesses a rapid development due to miniaturization, dose-reduction, sustained and controlled release of actives and long-term stability of material. β-CDNSs are colloidal and cross-linked nanocarrier comprising of solid mesh-like structure with nano-cavities for encapsulation of complex lipophilic and hydrophilic chemical substances. The release of enthalpy-rich water molecules from the polymeric structures accounts for high complexation efficiency with different molecular substrates. This review primarily focuses on the important characteristics of β-CDNS, methods of preparation, release kinetics of chemical entity, potential applications and commercial products. The advantages of β-CDNS involve sustained and controlled release of entrapped molecules with high efficiency and excellent stability. Thus, nanosponges are effective carrier for the delivery of actives and developed as a commercial drug delivery system in pharmaceutical industries after certified clinical studies. In the near future, β-CDNS-based product will capture the market due to its diverse applications in anti-cancer, antiviral, antiplatelet, antihypertensive therapy, etc., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a neurodegenerative disease with a complex pathogenesis. Controlled release, target ability, and multi-channel synergistic treatment are key factors associated with the success of AD drugs. Herein, we report a novel mesoporous nano-selenium (MSe) release delivery system (MSe-Res/Fc-β-CD/Bor) based on the borneol (Bor) target, β-cyclodextrin nanovalves (Fc-β-CD) with loaded resveratrol (Res). Previous experiments have shown that MSe-Res/Fc-β-CD/Bor first releases Bor by interacting with blood or intracellular esterases, allowing the nanosystem to pass through the blood-brain barrier (BBB). Subsequently, the Fc-β-CD is opened by the redox (H 2 O 2 ) response to the release of Res at the lesion site. We demonstrated that MSe-Res/Fc-β-CD/Bor inhibited aggregation of β-amyloid proteins (Aβ), mitigated oxidative stress, and suppressed tau hyperphosphorylation, while protecting nerve cells and successfully improving memory impairment in APP/PS1 mice. Interestingly, compared with rivastigmine (Riv) positive drugs alone, the MSe/Fc-β-CD/Bor loaded with Riv had a better pharmacokinetic index. These results indicate that MSe-Res/Fc-β-CD/Bor could be a prospective drug for treating AD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cyclodextrins (CDs) have beneficial characteristics for drug delivery, including hydrophobic interior surfaces. Nanocarriers with β -CD ligands have been prepared with simple surface modifications as drug delivery vehicles. In this study, we synthesized β -CD derivatives on an Ag-embedded silica nanoparticle (NP) (SiO₂@Ag NP) structure to load and release doxorubicin (DOX). Cysteinyl- β -CD and ethylenediamine- β -CD (EDA- β -CD) were immobilized on the surface of SiO₂@Ag NPs, as confirmed by transmission electron microscopy (TEM), ultraviolet-visible (UV-Vis) spectrophotometry, and Fourier transform infrared (FTIR) spectroscopy. DOX was introduced into the β -CD on the SiO₂@Ag NPs and then successfully released. Neither cysteinyl- β -CD and EDA- β -CD showed cytotoxicity, while DOX-loaded cysteinyl- β -CD and EDA- β -CD showed a significant decrease in cell viability in cancer cells. The SiO₂@Ag NPs with β -CD provide a strategy for designing a nanocarrier that can deliver a drug with controlled release from modified chemical types.

Aim: The β-CD-LPC molecule was synthesized based on the conjugation of LPC and β-CD molecules and it could self-assemble into liposome which was used to encapsulate the Dox to form nanomedicine for the cancer therapy., Materials & Methods: The anticancer and antitumor effect of β-CD-LPC-Dox nanomedicine was studied with the vitro and vivo experimental methods., Results: The result showed that β-CD-LPC liposome had high Dox drug-loading rate and a good sustained-release effect. Cell experiment showed that the β-CD-LPC-Dox nanomedicine could effectively induce cancer cell apoptosis and in vivo experiments showed that β-CD-LPC-Dox liposome could effectively inhibit tumor growth and had an effective anticancer activity with lower biotoxicity., Conclusion: The β-CD-LPC-Dox nanomedicine could be applied as a candidate drug to therapy the cancer.

In this study, a cell-penetrating peptide conjugate, R8-carboxymethyl-β-cyclodextrin (R8-CM-β-CD), was synthesized, and then we prepared the supramolecular complex (insulin/R8-CM-β-CD). The physicochemical properties of the complex were characterized. The supramolecular complex could facilitate the uptake of insulin, meanwhile, induce a significantly higher internalization of insulin. Interestingly, the transportation efficiency of insulin/R8-CM-β-CD across the Caco-2 cell monolayer was about 3 times greater than that of insulin/CM-β-CD. Further studies on the mechanism in increasing uptake efficiency showed that R8-CM-β-CD was internalized via different styles of endocytosis and could inhibit P-glycoprotein (P-gp) efflux pumps. Importantly, the formulation of insulin/R8-CM-β-CD showed the highest increase in the permeability of insulin and the best biological response in diabetic rats of all the treatments. In addition, no sign of toxicity was observed after administrations of R8-CM-β-CD. These results demonstrated that R8-CM-β-CD was a promising carrier for use in protein drug delivery., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The purpose of this study was to fabricate a triple-component nanocomposite system consisting of chitosan, polyethylene glycol (PEG), and drug for assessing the application of chitosan-PEG nanocomposites in drug delivery and also to assess the effect of different molecular weights of PEG on nanocomposite characteristics. The casting/solvent evaporation method was used to prepare chitosan-PEG nanocomposite films incorporating piroxicam-β-cyclodextrin. In order to characterize the morphology and structure of nanocomposites, X-ray diffraction technique, scanning electron microscopy, thermogravimetric analysis, and Fourier transmission infrared spectroscopy were used. Drug content uniformity test, swelling studies, water content, erosion studies, dissolution studies, and anti-inflammatory activity were also performed. The permeation studies across rat skin were also performed on nanocomposite films using Franz diffusion cell. The release behavior of films was found to be sensitive to pH and ionic strength of release medium. The maximum swelling ratio and water content was found in HCl buffer pH 1.2 as compared to acetate buffer of pH 4.5 and phosphate buffer pH 7.4. The release rate constants obtained from kinetic modeling and flux values of ex vivo permeation studies showed that release of piroxicam-β-cyclodextrin increased with an increase in concentration of PEG. The formulation F10 containing 75% concentration of PEG showed the highest swelling ratio (3.42±0.02) in HCl buffer pH 1.2, water content (47.89±1.53%) in HCl buffer pH 1.2, maximum cumulative drug permeation through rat skin (2405.15±10.97 μg/cm 2 ) in phosphate buffer pH 7.4, and in vitro drug release (35.51±0.26%) in sequential pH change mediums, and showed a significantly (p<0.0001) higher anti-inflammatory effect (0.4 cm). It can be concluded from the results that film composition had a particular impact on drug release properties. The different molecular weights of PEG have a strong influence on swelling, drug release, and permeation rate. The developed films can act as successful drug delivery approach for localized drug delivery through the skin., (Copyright © 2017. Published by Elsevier B.V.)

Background: Complexes of Genipin and different water-soluble adjuvant polysaccharides, such as arabinogalactane, hydroxyethyl starch, fibergum, and oligosaccharides β-CD and HP-β-CD, were synthesized as drug delivery system using mechanochemical technology., Method: We have investigated physicochemical properties, stability, and hepatotoxicity of the synthesized complexes in solid state and aqueous solution. The formation of the complexes was evidenced by different physical and spectroscopy assays, and the stability constants of our synthesized Genipin-based complexes were also calculated., Results: The HP-β-CD inclusion complex showed the highest characteristics. We have found that the molecule of Genipin was completely included in the cyclodextrin cavity of the HP-β-CD. This complex of Genipin has shown a 6.14-fold increase of solubility compared with the original Genipin, and more stable in solvent and solid states., Conclusion: The hepatotoxicity assays showed that our investigated complexes of Genipin are much safer than the original Genipin. These results suggest that new Genipin-based preparations can be synthesized with advantageous of higher stability and safety., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Retinal neovascularization (NV) is the leading cause of blindness in the majority of ocular diseases. Several treatment approaches have been developed for retinal NV; of these methods, instillation of nanoparticles into the conjunctival sac has shown potential for retinal NV treatment because it does not cause physical damage and is easy to operate., Methods: In this study, honokiol-loaded chitosan/sulfobutylether-β-cyclodextrin nanoparticles (HKCS- NPs) were prepared for ophthalmic drug delivery systems. An inclusion complex of honokiol and sulfobutylether-β-cyclodextrin was used to incorporated insoluble honokiol into chitosan nanoparticles, which were prepared through ionotropic gelation., Results: HK-CS-NPs featured a spherical surface with a narrow size distribution of polydispersity index less than 0.250, a mean size range of 373-523 nm, a positive surface charge of +19.9 to +24.2 mV, and an entrapment efficiency of 84.92%. In vitro release studies showed an initial burst release phase and a sustained release phase of nanoparticles. Moreover, in vivo study showed that HK-CS-NPs exhibited good ocular tolerability and could improve ophthalmic bioavailability of honokiol. In particular, the maximum concentration of honokiol after administration of HK-CS-NPs was enhanced by 1.65 times compared with that after instillation of the honokiol suspension alone., Conclusion: This study proposes HK-CS-NPs as a potential ophthalmic delivery system., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The objective of this study was the development of a mucoadhesive vaginal delivery system for acyclovir (Acv). Sodium-per-iodate (NaIO4) was used to introduce aldehyde substructures into beta-cyclodextrin (β-CD) by oxidative cleavage of vicinal diol bonds. Cysteamine was covalently attached to β-CD-CHO via reductive amination. Ellman's reagent was utilized for quantification of free thiol groups attached and resazurin assay was used for cytotoxicity studies. Mucoadhesive properties were evaluated on porcine vaginal mucosa in comparison to intestinal mucosa. Quantification of thiol groups revealed 851.84 ± 107, 1040.44 ± 132, and 1563.72 ± 171 μmol/g of free thiol groups attached to the β-CD-SH851, β-CD-SH1040, and β-CD-SH1563, respectively. β-CD-SH derivatives at concentrations of 0.5% (m/v) did not show significant reduction of viability of Caco-2 cells within 24 h. Furthermore, water solubility of β-CD-SH1563 was improved 7.6-fold in comparison to unmodified β-CD. β-CD-SH851, β-CD-SH1040, and β-CD-SH1563 showed 5.84-, 15.95-, and 17.14-fold improved mucoadhesive properties on porcine vaginal mucosa and 3-, 12.47-, and 32.13-fold on porcine intestinal mucosa, respectively. Inclusion complex of Acv with β-CD-SH1563 resulted in significantly improved drug dissolution. According to the results, β-CD-SH derivatives might be promising new tools for local vaginal delivery of Acv., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The aim of this in vivo study was to assess the ability of the prodrug conjugate diclofenac-β-cyclodextrin to release diclofenac in the colon following oral administration, using sulfapyridine (a metabolite of sulfasalazine) as a marker of colonic absorption. Two groups of rats were used; the test rats received a suspension containing the two prodrugs, diclofenac-β-cyclodextrin and sulfasalazine, while the control rats received a suspension containing the corresponding free drugs, sodium diclofenac and sulfapyridine. The rats were fasted overnight with free access to water before and throughout the first 12h of the study. Blood was collected from the tail vein at pre-determined time points and the plasma analyzed for the concentrations of diclofenac and sulfapyridine. Following the oral administration of the two prodrugs, a more extended absorption profile was observed and Cmax was achieved 10h post-dose, in contrast to rapid absorption of the free drugs (tmax of diclofenac being 1.3h, and that of sulfapyridine being 2.1h). In addition to a later tmax, conjugation of diclofenac to β-cyclodextrin also resulted in a reduced Cmax and a reduced AUC. The same tmax for diclofenac-β-cyclodextrin as for sulfasalazine confirms the colonic metabolism of diclofenac-β-cyclodextrin. This study shows the potential of this new cyclodextrin-based prodrug to target and release diclofenac specifically in the colon following oral administration., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Following the preparation of an inclusion complex of β-cyclodextrin and meropenem, methods based on FT-IR, Raman and DSC were used for its characterization. An analysis of changes in the stability of meropenem after complexation showed that the complex may serve as a valuable delivery system significantly contributing to enhanced meropenem stability in aqueous solutions and in the solid phase. Due to a sustained transfer of meropenem from the cavity of the cyclodextrin it was possible to maintain a constant desired meropenem concentration over a period of 20 h, as confirmed by a release study. An evaluation of microbial activity not only demonstrated that the bactericidal action of meropenem was not stopped as a result of complexation but even pointed to greater growth inhibition in certain clinically important strains. The fact that investigations of meropenem stability and microbial activity proposed the carbonyl groups as those domains of a meropenem molecule that are instrumental in the formation of a complex with β-cyclodextrin supports the findings of theoretical studies based on molecular modeling., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The present study describes the preparation and evaluation of a poloxamer 407 (P407)-based thermoreversible gel using Carbopol 934P (C934P) as a mucoadhesive polymer and hydroxypropyl-β-cyclodextrin (HP-β-CD) for enhancing the aqueous solubility and intranasal absorption of fexofenadine hydrochloride (FXD HCl). The prepared gels were characterized by gelation temperature, viscoelasticity, and drug release profile. Thermoreversibility of P407/C934P gel was demonstrated by rheological studies. The incorporation of carbopol into P407 gel also reduced the amounts of drug released from the gel formulations (p < 0.05). In vivo pharmacokinetic results of the prepared gel formulations in rabbits (at 0.5 mg/kg dose) showed that the relative bioavailability of drug from P407/C934P gel was 11.3 and 2.7-fold higher than those of drug solution and P407 gel group, respectively. These findings suggested that developed thermoreversible gels could be used as promising dosage forms to improve intranasal drug absorption.

Purpose: We attempted to develop anti-glaucoma eye drops using 0.5% disulfiram (DSF), 5% 2-hydroxypropyl-β-cyclodextrin, 0.1% hydroxypropylmethylcellulose, and 2% methylcellulose (MC) (DSF eye drops with MC), and tested the ability of a DSF eye drops with MC to reduce intraocular pressure (IOP) in rabbit models., Methods: Elevated IOP was induced by the rapid infusion of 5% glucose solution (15 ml/kg of body weight) through the marginal ear vein or by keeping rabbits in the dark for 5 h. IOP and the nitric oxide (NO) level in the aqueous humor were measured with an electronic tonometer and by a microdialysis method, respectively. ΔIOP and ΔNO values were analyzed as the differences in IOP and NO in rabbits instilled with saline or eye drops, respectively., Results: Increased IOP in rabbit models was reduced by the instillation of DSF eye drops with or without MC, and a close relationship was observed between IOP and NO levels in rabbit receiving a rapid infusion of isotonic glucose. We present kinetic parameters [secondary AUC (prolonged drug effect) and secondary MRT (prolonged effective time)] analyzed as the area under the curve (AUC) of ΔIOP or ΔNO versus time using rabbits instilled with eye drops 10, 50, or 90 min prior to the infusion of the isotonic glucose solution. The elevations in IOP and NO level were reduced by the instillation of DSF eye drops with or without MC; the addition of MC increased the secondary AUC and MRT of DSF eye drops., Conclusions: The present study demonstrates that 0.5% DSF eye drops suppress increased IOP in rabbit models, probably by inhibiting the elevation in NO levels. In addition, we propose a kinetic analysis method to predict drug effects and effective time. These findings suggest that a low-substituted MC-based drug delivery system promotes drug effectiveness and effective time.

Polymeric microparticles have been previously demonstrated to deliver various therapeutic agents efficiently to targeted regions by protecting the drug from harsh gastric milieu of the gastrointestinal tract. In this study, we investigated the hypoglycemic effect of β-cyclodextrin polymeric insulin microparticles in diabetic rats via the oral route of administration. β-cyclodextrin microparticles were prepared by a unique one-step spray-drying technique and stabilized by incorporating enteric retardant polymers in the formulation. The insulin-loaded microparticles had a mean size of 0.8 ± 0.25 μm with a zeta potential of 3.57 + 0.62 mV. As seen with the chromatographic analysis, the drug content in the microparticles was determined to be 94.9 ± 2.77%. RAW macrophage cells showed greater than 80% viability after 24 h of incubation with the insulin and blank microparticles. For the in vitro release study, the microparticles were able to protect the insulin in gastric fluid where no significant release was detected, followed by only 50% release in intestinal fluid for the first 8 h of the study. This was seen to correlate with the in vivo data where 50% glucose inhibition was seen after 8 h of oral administration in diabetic rats. This data suggest that the oral insulin microparticles were able to reduce glucose levels in disease conditions and would be a favorable route of administration to patients as an alternative to daily subcutaneous injections.

The objective of this investigation was to develop a novel cationic polymer, hydroxypropyl-β-cyclodextrin grafted polyethyleneimine (HP-β-CD-PEI1800), as a penetration enhancer, and evaluate its viability on improving transdermal delivery of diclofenac sodium. In this study, HP-β-CD-PEI1800 was characterized by (1)H NMR and DSC methods, respectively. The hydrophilic drug diclofenac sodium was chosen as model drug, and the transdermal permeation enhancement of HP-β-CD-PEI1800 was estimated in vitro by using Franz diffusion cells fitted with mouse dorsal skins, the in vivo kinetics of diclofenac sodium was analyzed by high-performance liquid chromatography (HPLC). The cumulative drug content deposited in epidermis and dermis was measured at the pre-determined time point of 3, 6, and 9h, and the permeation profile was significantly higher than that of the control groups. In addition, the cytotoxicity and skin irritation of enhancer was evaluated by MTT assay and histological examination, respectively, and the results indicated that the polymer we prepared were non-toxic and non-irritant after exposure to skins. All the results suggested that HP-β-CD-PEI1800 could be a safe and efficient penetration enhancer of diclofenac sodium., (Copyright © 2014. Published by Elsevier B.V.)

Currently, clinical operation treatments, chemotherapy and radiotherapy just could eliminate local tumor cells. However, chemotherapy and radiotherapy also injury normal cells and lead to serious side effects and toxicities. So, it is necessary to find an effective target cancer carrier that delivers the anticancer agents into tumor cells and reduces normal cells' injury. Folic acid (FA) is a classical targeting agent mediates internalization of chemical drugs into tumor cells which over-express folate receptor (FR) on their surface. We herein report that based on host-guest interaction, NPs decorated by novel folate enhance antitumor drug delivery. BSA-NPs were prepared by desolvation method and carboxymethyl-β-cyclodextrin (CM-β-CD) was conjugated to the surface of NPs by carbodiimide coupling to hold FA. From in vitro cytotoxicity assay, cell apoptosis study, intracellular ATP level assay and western blot, we can see that FA-CM-β-CD-BSA NPs as good monodispersity, negative charge, and homogenous particle size have a high encapsulation efficiency. The results showed that MTT and cell apoptosis demonstrated that FA-decorated NPs exhibit stronger inhibition rate and induce obvious apoptosis in FR positive Hela cells as compared to free drug and FA undecorated NPs. Moreover, 5-fluorouracil (5-Fu) loaded FA-CM-β-CD-BSA NPs down-regulate ATP levels and increase the expression of caspase-3. Taken together, FA-CM-β-CD-BSA NPs enhance FR receptor-mediated endocytosis and lead to more intracellular uptake of drug, inducing the higher apoptosis ratio of cells than free 5-Fu., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Gaucher disease (GD) is a rare monogenetic disorder leading to dysfunction of acid β-glucosidase (β-glucocerebrosidase; GCase) and accumulation of glucosylceramide in lysosomes, especially in macrophages (Gaucher cells). Many of the mutations at the origin of GD do not impair the catalytic activity of GCase, but cause misfolding and subsequent degradation by the quality control system at the endoplasmic reticulum. Pharmacological chaperones (PCs) capable of restoring the correct folding and trafficking of the endogenous mutant enzyme represent promising alternatives to the currently available enzyme replacement and substrate reduction therapies (ERT and SRT, respectively), but unfavorable biodistribution and potential side-effects remain important issues. We have now designed a strategy to enhance the controlled delivery of PCs to macrophages that exploit the formation of ternary complexes between the PC, a trivalent mannosylated β-cyclodextrin (βCD) conjugate and the macrophage mannose receptor (MMR). First, PC candidates with appropriate relative avidities towards the βCD cavity and the GCase active site were selected to ensure efficient transfer of the PC cargo from the host to the GCase active site. Control experiments confirmed that the βCD carrier was selectively recognized by mannose-specific lectins and that the corresponding PC:mannosylated βCD supramolecular complex retained both the chaperoning activity, as confirmed in human GD fibroblasts, and the MMR binding ability. Finally, fluorescence microscopy techniques proved targeting and cellular uptake of the PC-loaded system in macrophages. Altogether, the results support that combined cyclodextrin encapsulation and glycotargeting may improve the efficacy of PCs for GD.

Systemic administration of voriconazole, a novel anti-fungal agent, is associated with adverse effects including visual disturbances and hepatic abnormalities. The purpose of this study was to improve the aqueous solubility of voriconazole using 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and to study the effect of addition of viscosity modifiers to these solutions. Statistical analysis was done by one-way analysis of variance followed by Dunnett's test. The phase solubility studies indicated that voriconazole solubility increased with increase in HP-β-CD concentration. Using a combination of chitosan 0.2%, BAK 0.01% and EDTA 0.01% in voriconazole- HP-β-CD based aqueous drops (1.5%, pH 7.0), a 3.9 times and 5.4 times higher Papp was obtained than with formulation without chitosan and control formulation (without chitosan and preservative), respectively. Thus, it could be concluded voriconazole aqueous drops formulated using HP-β-CD can be used topically for the treatment of fungal keratitis and the addition of chitosan to the voriconazole aqueous drops can produce significantly higher permeation.

The aim of this research is to develop novel chitosan nanoparticles including cyclodextrins complexes for docetaxel (DTX), evaluate the performance of nanoparticles which could enhance the oral permeability and bioavailability of DTX in vitro and in vivo. DTX/sulfobutylether-β-cyclodextrin inclusion complexes were made and it was the main ingredient to prepare the DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles due to their promising physicochemical properties. DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles were prepared by the ionic gelation of chitosan with tripolyphosphate in the presence of cyclodextrins. Results indicated that DTX/sulfobutylether-β-cyclodextrin inclusion complexes and docetaxel/sulfobutylether-β-cyclodextrin/chitosan nanoparticles both had good performances in the studies of release and the rat small intestinal absorption in vitro. DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles showed preferable capability in improving the small intestinal absorption and inhibiting the efflux of DTX. In pharmacokinetics study, the DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles increased the AUC0→t and decreased the clearance significantly, and the oral relative bioavailability of the DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles was as high as 1447.53% compared to the pure DTX formulation. The DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles prepared in this study have a good prospect for oral administration as an alternative of current DTX formulations.

In the present study, we prepared an inclusion complex of methotrexate (MTX) with β-cyclodextrin (β-CD) in order to decrease its photosensitivity and enhance its aqueous solubility. Then we incorporated this inclusion complex in a self-microemulsifying drug delivery system (SMEDDS) overall to increase its oral bioavailability. The inclusion complex has been prepared by freeze drying method and characterized by differential scanning calorimetry (DSC), ultraviolet (UV), and infrared (IR) spectroscopy assays. The proper molecular ratio of MTX/β-CD was found to be of 1:7, and the water-solubility of MTX was increased in an average of 10-fold. The photostability studies showed that the MTX became stable on exposure to light. Construction of pseudoternary diagrams were investigated to prepare a MTX/β-CD inclusion complex loaded SMEDDS which was characterized by measuring the particle size and the zeta-potential. The optimum formulation of SMEDDS was a system consisting of ethyl oleate, tween 80, and propylene glycol with a mean droplet size of 39.42 nm. In vitro drug release in different pH media showed that the release profile of MTX from the MTX/β-CD loaded SMEDDS was influenced by the pH of the release medium and presented the characteristics of a sustained release profile. Finally, in-vivo studies showed an enhancement of the bioavailability of MTX from the MTX/β-CD loaded SMEDDS form of 1.57-fold. We concluded that the β-CD inclusion complex loaded SMEDDS improved the chemical and physiological properties of MTX and could be a promising means for the delivery of MTX and other unstable and lipophilic drugs by oral route.

The aim of this work was to synthesize an ester prodrug of diclofenac and β-cyclodextrin suitable for colonic delivery. The synthesis of an ester linkage between diclofenac and β-cyclodextrin was conducted by the nucleophilic substitution of mono-6-tosyl-β-cyclodextrin under microwaves irradiation. After purification, the conjugate was characterized by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry; infrared (IR) spectroscopy; proton nuclear magnetic resonance ((1)H NMR) spectroscopy; and two-dimensional rotating frame nuclear overhauser effect (ROESY) spectroscopy. The purity was qualified by high pressure liquid chromatography (HPLC). To assess its potential for colonic delivery, the conjugate was evaluated for stability in simulated gastric and small intestinal fluids, and in fecal material from humans processed within a slurry under anaerobic conditions. The conjugate was successfully synthesized with a yield of 20% following purification. The mass spectra showed the parent peak m/z 1434 corresponding to [conjugate+Na] adduct. IR and NMR results confirmed that the carboxyl group of diclofenac is covalently bound to one of the hydroxyl groups of cyclodextrin by an ester linkage. Moreover, ROESY data indicated that the formation of the conjugate is not accompanied by the inclusion of diclofenac within the cyclodextrin. The conjugate was otherwise stable in simulated gastric and small intestinal conditions, but was also readily hydrolyzed liberating diclofenac in less than 2h within the human fecal slurry. This confirmed the potential for this new prodrug as a carrier for colonic delivery., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Thienorphine hydrochloride (ThH) is a highly insoluble and readily metabolized partial-opioid agonist. It is used for the treatment of pain and heroin addiction. This study aimed to formulate and evaluate sublingual delivery systems containing ThH. Dimethyl-β-cyclodextrin (DM-β-CD) can enhance the solubility and permeability of hydrophobic drugs. In this paper, ThH cyclodextrin inclusion complexes were prepared and administrated sublingually with the objective of improving the drug's aqueous solubility, in vitro permeation rate, and in vivo absorption rate. The formulation was prepared with DM-β-CD using the freeze-dried method and characterized using phase solubility, differential scanning calorimetry (DSC), X-ray and NMR analyses. The results of each test indicated the formation of dynamic inclusion complexes between ThH and DM-β-CD. The inclusion complexes also showed significant increases in in vitro aqueous solubility and mucosal permeability. According to the pharmacokinetic study of the complex in rats, the AUC and C(max) values of the sublingual delivery group were 40 and 46 times higher than those of the gastrointestinal group, whereas t(max) was shorter, which proved that in vivo absorption and metabolism had been improved. It can therefore be concluded that the inclusion technology and sublingual delivery system were suitable for ThH development.

A novel approach in target specific molecular prototype drug delivery system concerns the attempt to employ radical affording substances (RAS) or radical quenching substances (RQS) as prodrugs able to produce irreversible damage on the desired target and therefore to stimulate cellular apoptosis. However, radical species generated can react quickly within the chemical environment prior to reaching its proper site of action. In this short communication, we report our investigations towards developing two alternative novel, simple, flexible and effective drug delivery systems that provide optimal dosage of drugs precisely where and when needed and therefore achieve and sustain a complex delivery profile. We have demonstrated the application of two effective molecular prototype delivery systems able to harness free radical reactivity within the laboratory where biological processes can be studied and controlled, leading to the prevention of disease and the development of new treatments for disease states mediated by free radicals.

Hydroxypropyl-sulfobutyl-β-cyclodextrin (HP-SBE-β-CD) inclusion complex was developed and used as a drug delivery system for DTX (DTX/HP-SBE-β-CD). The objective of the present study was to evaluate and compare the biological properties of DTX/HP-SBE-Β-CD with Taxotere®. The pharmacokinetics, biodistribution, antitumor efficacy in vivo and in vitro, and safety evaluation of DTX/HP-SBE-β-CD were studied. The most significant finding was that it was possible to prepare a Polysorbate-80-free inclusion complex for DTX. Studies based on pharmacokinetics, biodistribution, and antitumor efficacy indicated that DTX/HP-SBE-β-CD had similar pharmacokinetic properties and antitumor efficacy both in vitro and in vivo as Taxotere®. Fortunately, this new drug delivery system attenuated the side effects when used in vivo. As a consequence, DTX/HP-SBE-β-CD may be a promising alternative to Taxotere® for cancer chemotherapy treatment with reduced side effects. The therapeutic potential against a variety of human tumors and low toxicity demonstrated in a stringent study clearly warrant clinical investigation of DTX/HP-SBE-β-CD for possible use against human tumors.

Improvement of the oral bioavailability of flurbiprofen (Flu) after oral administration of flurbiprofen/beta-cyclodextrin inclusion complex (Flu/beta-CD) by the action of cinnarizine (CN) was investigated. Flu and Flu/beta-CD were administered orally to fasted rats at a dose of 20mg/kg as Flu. Thirty minutes after drug administration, CN dissolved in pH 4.0 buffer solution or pH 4.0 buffer solution alone was administered to the rats. The dose of CN was 0.17 mg/kg. Blood samples were taken from rats and Flu concentrations in plasma samples were determined by HPLC. It was found from the comparison of Flu and Flu with CN (Flu+CN) that CN had no effect on plasma concentrations of Flu after oral administration of Flu. The mean plasma levels after oral administration of Flu/beta-CD with CN (Flu/beta-CD+CN) were larger not only than those of Flu and Flu+CN but also than those of Flu/beta-CD. The value of C(max) in Flu/beta-CD+CN was significantly larger than that of Flu/beta-CD. This is considered to be caused by the action of CN as a competing agent. This mechanism was supported by the result of solubility study in which Flu solubility in beta-CD solution decreased with the addition of CN. It was found from these results that CN had strong ability as a competing agent in vivo.

Glimepiride is a third generation oral antidiabetic sulphonylurea drug frequently prescribed to patients of type 2 diabetes. However, its oral therapy is encountered with bioavailability problems due to its poor solubility leading to irreproducible clinical response, in addition to adverse effects like dizziness and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy, the rationale of this study was to develop a transdermal delivery system for glimepiride. Chitosan polymer was utilized in developing transdermal films for glimepiride. Chitosan has film forming ability, bioadhesive and absorption enhancing properties. Aiming at optimizing the drug delivery and circumventing the skin barrier function, inclusion complexation of glimepiride with beta-cyclodextrin (beta-CyD) as well as the use of several conventional penetration enhancers were monitored for augmenting the drug flux. The physical and mechanical properties of the prepared films were investigated using tensile testing, IR spectroscopy and X-ray diffractometry. Release studies revealed adequate release rates from chitosan films. Permeation studies through full thickness rat abdominal skin were conducted. High flux values were obtained from films comprising a combination of the drug with limonene and ethanol as well as from films containing glimepiride-beta-CyD complex. In vivo studies on diabetic rats for selected formulae revealed a marked therapeutic efficacy sustained for about 48 hours. The above-mentioned results shed light on feasibility of utilizing chitosan as an effective, safe transdermal delivery system for glimepiride characterized by increased patient compliance and better control of the disease.

Bupranolol is a promising candidate for transdermal drug delivery system (TDDS) development. The effect of permeation enhancers on the in vivo delivery and beta-blocking effect of reservoir type TDDS was studied in comparison with intravenous BPL in rabbits. The beta-blocking effect was quantified by measuring the inhibition of isoprenaline induced tachycardia in rabbits after BPL administration via transdermal and intravenous routes. The reservoir type TDDS containing a hydroxypropyl cellulose gel and polyethylene membrane was used as a control device. In comparison, the TDDS containing skin penetration enhancers, either 2-pyrrolidone or partially methylated beta cyclodextrin (PMbetaCD) were evaluated. The control device (no enhancer) produced about 52% inhibition of isoprenaline induced tachycardia at 2 h and the effect continued over 24 h application period, however, the devices with 2-pyrolidone or PMbetaCD produced about 85% inhibition of isoprenaline induced tachycardia at 3 h and the same effect continued over 24 h application period. Likewise, the AUC of these devices were significantly higher than that of control device. The intravenous bupranolol showed rapid decline in the pharmacodynamic effect with time indicating its rapid elimination. The in vivo delivery of bupranolol (as estimated by a mass balance study) from the devices made with pyrolidone or PMbetaCD was 3-fold higher than that of control. The results of this study strongly suggest that the penetration enhancers in the TDDS increased the in vivo delivery of BPL, thereby increased the beta-blocking activity of BPL by 50-60% higher than control, enabling the reduction of the TDDS patch size, accordingly.

Nanoparticle based delivery systems can offer opportunities for targeting, controlled release, and enhanced stability of their drug, protein, or gene therapy payload. This study investigated the use of chitosan in combination with the ionic additives sulfobutyl-ether-7-beta-cyclodextrin (SB-CD) or SB-CD/dextran sulfate (SB-CD/DS) mixture in comparison with chitosan: DS in the formulation of nanoparticles incorporating the hexapeptide dalargin. The physical characteristics (particle size, zeta potential), entrapment and loading efficiency, and release of dalargin were quantified. It was demonstrated that anionic cyclodextrin, SB-CD, can be used in complex coacervation with chitosan, with and without the presence of DS, to form nanoparticles. The presence of SB-CD or DS in the nanoparticle formulation and the weight ratio of chitosan to anionic additive(s) influenced the physical properties of the nanoparticles and their ability to carry dalargin. In addition, the particle size of nanoparticles was also affected by the molecular weight of chitosan and DS. The use of either DS or SB-CD/DS mixture produced chitosan nanoparticles with small particle size, high dalargin entrapment efficiency, enhanced peptide stability, and sustained release characteristics., ((c) 2008 Wiley Periodicals, Inc.)

The potential use of hydroxypropyl-beta-cyclodextrin (HP-betaCD) in the solubilization and stabilization of prostaglandin E(1) (PGE(1)) was investigated. The solubility and chemical stability of PGE(1) were significantly improved upon complexation with HP-betaCD. The nasal delivery of PGE(1) from the complex formulation was also studied in Wistar rats and compared with intravenous administration. PGE(1) complex after nasal administration caused a rapid decrease of blood pressure and exhibited an obvious dose-efficacy relationship, showing results nearly similar to those obtained for intravenous route. The time to reach the peak effect (T(max)) was approximately 3-4 min. Except T(max), other pharmacodynamic parameter values such as the maximal percent of blood pressure decrease (E(max), %), the lasting time of effect (T(d)), and the area under the curve (AUC, blood pressure decrease % min) were increased with increasing the administered doses. The E(max), T(d), and in particular AUC values between doses were significantly different (P < 0.01), but T(max) between doses were not significantly different (P < 0.05). The AUC values per unit dose of PGE(1) for nasal administration, however, were smaller than those for intravenous route, probably due to the incomplete absorption of nasally administered PGE(1). Besides, the in vitro effect of the PGE(1) complex on nasal mucociliary movement was also investigated with a toad palate model. The PGE(1) complex formulation exerted only minor effect on nasal mucociliary movement. These results indicate that the PGE(1)-HP-betaCD complex formulation for nasal delivery is a very promising preparation with advantages such as rapid and effective absorption, good chemical stability, ease of administration, and minor nasal ciliotoxicity.

The tumor targeting properties of a new drug carrier synthesized by bioconjugation of folic acid (FA) to beta-cyclodextrins through a poly(ethylene glycol) (PEG) spacer (CD-PEG-FA) were investigated. Surface plasmon resonance demonstrated that CD-PEG-FA specifically interacts with immobilized folate binding protein (FBP) while the naked beta-cyclodextrins do not display any specific interaction. In vitro studies demonstrated that CD-PEG-FA was devoid of cell toxicity. [(3)H]-folic acid/CD-PEG-FA competition binding investigations performed with folate receptor overexpressing human epidermal carcinoma KB cells showed that CD-PEG-FA had about 14 times lower tumor cell binding capacity than free folic acid. The carrier cell trafficking properties were investigated using rhodamine-B as fluorescent probe, which possesses 3000 and 4580 M(-)(1) inclusion constants for CD-PEG-FA and beta-cyclodextrins, respectively. Cell-associated fluorescence measurements showed that CD-PEG-FA does not promote the rhodamine-B uptake into non-folate receptor expressing human lung carcinoma MCF7 cells while 19% higher accumulation in KB cells was found with respect to rhodamine-B loaded beta-cyclodextrins. Confocal laser scanning microscopy indicated the presence of cytosolic red fluorescent spots after 2 h of incubation of KB cells with rhodamine-B included CD-PEG-FA. The fluorescent dye resided primarily in small spots, namely, endosomes and multivesicular bodies. At 1 h after pulsed incubation, wider red fluorescent cellular structures appeared as a fusion of previous structures.

Purpose: To test the effect of aqueous eye drops containing a high concentration of disulfiram (DSF) in a cyclodextrin- based drug delivery system. This system increases both the drug solubility in aqueous eye drops and the permeability of drug into the rabbit eye, by the formation of a drug-cyclodextrin inclusion complex, and so enhances the ocular bioavailability and anti-cataract effect of DSF., Methods: The DSF and hydroxypropyl-beta-cyclodextrin (HPbetaCD) inclusion (DSF/HPbetaCD) was studied using solubility methods, IR spectra and X-ray diffraction patterns. Suitable formulations for DSF eye drops were first identified by a trans-corneal penetration experiment in vitro. Finding a new p-bromophenacyl bromide (p-BPB) derivative reagent for diethyldithiocarbamic acid (DDC), which was a metabolite of DSF, allowed precise determination of the contents of DSF in aqueous humor. The ocular bioavailability was calculated by a transcorneal experiment of DSF in vivo. The lens opacity of a selenite-induced cataract in rat pups was monitored using a slit lamp with an anterior eye segment analysis system., Results: The formation of DSF/HPbetaCD inclusion and the addition of hydroxypropylmethylcellulose (HPMC), as a penetration enhancer, played very important roles in increasing the ocular bioavailability of DSF. DSF eye drops, with a formulation of 1.26% (w/v) DSF/HPbetaCD inclusion, 0.01% (w/v) HPMC, 0.005% (w/v) benzalkonium chloride and 0.9% (w/v) sodium chloride, inhibited the onset of selenite-induced cataracts effectively., Conclusions: The cyclodextrin-based drug delivery system enhances both the solubility of DSF in aqueous eye drops and permeability of the drug into the rabbit eye. DSF ocular bioavailability in rabbit aqueous humor exceeded those reported for the DSF ophthalmic preparation. DSF eye drops effectively prevent the development of selenite-induced cataracts.