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We have developed a series of pH- and temperature-stimuli-sensitive vinyl hydrogels, bearing α-amino acid residues ( l -phenylalanine, l -valine) and incorporating magnetic nanoparticles of different chemical compositions (CoFe 2 O 4 and Fe 3 O 4 ). The goal was to study the potential applications of these nanocomposites in the controlled release of doxorubicin (DOXO), a potent anticancer drug. The strength of the electrostatic interaction between the protonated nitrogen of the DOXO molecule and the ionized carboxylic groups of the hydrogel allowed effective control of the drug release rate in saline solutions. The embedded magnetic nanoparticles were an additional remote control of the drug release under the stimulus of an appropriate external alternating magnetic field (AMF). Data showed that the controlled release of DOXO proceeded for months and followed a diffusion-controlled release mechanism, while maintaining the amount of released drug within acceptable therapeutic windows. The amount of the released DOXO was found in all cases substantially higher than the “control” because the application of the AMF augments in stimulating the nanoparticles within the DOXO-loaded hydrogel. In vitro experiments have shown that the released DOXO is able to induce cell death to cervix adenocarcinoma cells (HeLa cells). [ABSTRACT FROM AUTHOR]

Chitosan (CS)-based thermosensitive solutions that turn into semi-solid hydrogels upon injection at body temperature have increasingly drawn attention over the last decades as an attractive new type of in situ forming depot (ISFD) drug delivery system. Despite the great potential of the standard CS/β-glycerophosphate (β-GP) thermogelling solutions, their lack of stability over time at room temperature as well as at refrigerated conditions renders them unsuitable as ready-to-use drug product. In the present study, we investigated Glucose-1-Phosphate (G1-P) as an alternative gelling agent for improving the stability of CS-based ISFD solutions. The in vitro release performance of CS/G1-P formulations was assessed using several model compounds. Furthermore, the local tolerance of subcutaneously implanted CS/G1-P hydrogels was investigated by histological examination over three weeks. The thermogelling potential of CS/G1-P solutions, determined by rheology, is dependent on the polymer molecular weight (Mw) and concentration as well as on the G1-P concentration. Differential scanning calorimetry (DSC) measurements confirmed that sol/gel transition takes place at around body temperature and is not fully thermo-reversible. The long term storage stability was evaluated through the appearance, pH, viscosity and gelation time at 37 °C of the solution. The results emphasized an enhanced stability of the CS/G1-P system compared to the standard CS/β-GP. CS solution with 0.40 mmol/g G1-P is stable for at least 9 months at 2–8 °C, versus less than 1 month when using β-GP as gelling agent. Furthermore, the solution is easy to inject, as evidenced from injectability evaluation using 23–30 G needles. In vitro release experiments showed a sustained release over days to weeks for hydrophilic model compounds, demonstrating thereby that CS/G1-P may be suitable for the prolonged delivery of drugs. The inflammatory reaction observed in the tissue surrounding the hydrogel in rats was a typical foreign body reaction, similar to the one observed for CS/β-GP hydrogels. These features confirm the potential of CS/G1-P solutions as an injectable ready-to-use in situ forming hydrogel. [ABSTRACT FROM AUTHOR]

Biodegradable poly(ethyleneglycol)–poly(valerolactone)–poly(ethyleneglycol) [PEG–PVL–PEG] copolymers were synthesized through ring opening polymerization of δ-valerolactone (VL) followed by the coupling of monomethoxy poly(ethyleneglycol–poly(valerolactone) (mPEG–PVL) with hexamethylene diisocyanate (HDI). The copolymers were characterized by 1 H NMR, FT-IR, and GPC. Block copolymers of PEG and PVL with different VL/PEG molar ratios were successfully synthesized. One of the copolymers (Copolymer 2, PEG 550 – PVL 6768 – PEG 550 ) displayed a sol–gel transition at a physiological temperature based on the test tube inverting method and rheological studies. The thermogelling copolymer demonstrated a characteristic crystalline peak for PVL block as determined by DSC and XRD analysis. In vitro release from the copolymer hydrogel matrix indicated that dexamethasone (DEX), a hydrophobic model drug, released comparatively slower than 5-fluoruracil (5-FU), a hydrophilic model drug, due to the potential partitioning of DEX into the PVL core. 5-FU in vitro release from copolymer 2 was 86% in 22 h, whereas only 14% of DEX was released in 24 h. Cell viability studies confirmed that hydrogels composed of block copolymers are biocompatible. Copolymer 2 showed more than 80% relative cell viability at all concentrations, including concentrations greater than 200 fold CMC. In vivo gel formation studies indicate that gel integrity was maintained for 7 days upon subcutaneous injection into mice. These results indicate that PEG–PVL–PEG copolymers are suitable for drug delivery applications. [ABSTRACT FROM AUTHOR]

In vitro drug release testing is an appropriate approach to identify critical parameters helping to predict drug release from drug-eluting stents (DES) prior to studying drug release behavior under in vivo conditions. Drug release and distribution from DES coated with a fluorescent model substance were studied in vitro using the vessel-simulating flow-through cell equipped with different long-term stable hydrogel compartments composed of agarose, polyacrylamide or poly(vinyl alcohol). The obtained experimental results were compared with the results of finite-element modeling obtained using experimentally determined diffusion coefficients and partition coefficients. In spite of differences regarding these parameters, experimental and mathematical data yielded only minor differences between the different gels regarding the release and distribution behavior and reasonable agreement between the modeling and the experiment was obtained. In an attempt to further elucidate the dosage form behavior, the diffusion coefficients in the gel as well as in the stent coating were systematically varied in the finite-element model. Changes in the diffusivity in the stent coating mainly impacted on the initial concentrations. Slower diffusion inside the hydrogel yielded a retarded elution from the stent coating and a higher model substance accumulation in the gel compartment at late time points. [ABSTRACT FROM AUTHOR]

In the present work, an innovative approach based on the delivery of levofloxacin (LVF) from polysaccharide nanohydrogels for the treatment of bacterial intracellular infections is described. The nanohydrogels (NHs) were obtained by self-assembling of the hyaluronic acid-cholesterol amphiphilic chains in aqueous environment. LVF, a fluoroquinolone antibiotic scarcely efficient in intracellular infections, was entrapped within such NHs by nanoprecipitation, thus forming a drug delivery system (LVF-NHs) that was tested for its activity on different bacteria strains. The MIC values of levofloxacin-loaded nanohydrogels were determined for Staphylococcus aureus and Pseudomonas aeruginosa strains and compared to those obtained using free LVF. The intracellular antimicrobial activity of LVF-NHs and free LVF was compared on HeLa epithelial cell line infected by the above mentioned bacteria, and the increase in antibacterial efficacy of LVF-NHs with respect to that of free LVF was evidenced. The obtained results allow to conclude that this new approach can be considered as really promising method for intracellular infection treatments. [ABSTRACT FROM AUTHOR]

Abstract: The present study is concerned with the development and characterization of a novel nanaoparticulate system; cubosomes, loaded with silver sulfadiazine (SSD), which is the metallic salt of a sulfonamide derivative, and is considered as the drug of choice for topical treatment of infected burns. Cubosome dispersions were formulated by an emulsification technique using different concentrations of a lipid phase monoolein and the nonionic surfactant, Poloxamer 407, with or without polyvinyl alcohol. The prepared cubosomal dispersions were characterized regarding physical morphology, dimensional distribution, particle size, and in vitro drug release. The optimum formulae were incorporated in a chitosan, carbopol 940 or chitosan/carbopol mixture based hydrogels, to form cubosomal hydrogels (cubogels). The cubogels were characterized regarding in vitro release of SSD, rheological properties, pH, and mucoadhesion. For the optimal cubogel formulae, an in vivo histopathological study was conducted on rats to predict the effectiveness of the newly prepared cubogels in comparison with the commercially available cream (Dermazin®). In vivo histopathological study results showed that prepared cubogels were successful in the treatment of deep second degree burn which may result in better patient compliance and excellent healing results with least side effects in comparison with the commercially available product. [Copyright &y& Elsevier]

Abstract: This work investigated the use of in situ gelling hydrogels based on polypseudorotaxanes of Pluronic F-127 and partially methylated β-cyclodextrin as aqueous nail lacquers. N-acetylcysteine and urea were incorporated as penetration enhancers. The formulations were tested for their ability to deliver ciclopirox and triamcinolone across human nail plate and bovine hoof. Simple aqueous solutions of the drugs with N-acetylcysteine provided measurable fluxes across hoof membranes but became quickly depleted of drug. Further, these solutions would have a short residence time upon nail application. Addition of Pluronic F-127 facilitated drug solubilization and provided the formulations with in situ gelling properties but drug entrapment into the micelles slowed down the delivery process. This was solved by addition of methylated β-cyclodextrin; the formulations retained the thermogelling properties, drug solubilization was further increased, and drug delivery was accelerated. The polymer chains compete with the drugs for the cyclodextrin cavity forming polypseudorotaxanes, which facilitated drug release. The permeability of both drugs was higher across bovine hoof than human nail. The new polypseudorotaxanes formulation delivered more ciclopirox across human nail than a marketed organic lacquer which supports the growing hypothesis that aqueous-based nail lacquers represent a superior formulation strategy in nail topical delivery. [Copyright &y& Elsevier]

Abstract: In our previous work, a new kind of pH-sensitive hydrogel based on poly (lactic acid) (PLA), methoxyl poly (ethylene glycol) (MPEG) and itaconic acid (IA) was prepared by heat-initiated free radical polymerization without any organic solvent. For further application, the safety of prepared copolymers and hydrogels was evaluated in vitro and in vivo in this paper. In vitro toxicity evaluation of MPEG–PLA–AC (PLE–AC) copolymers included hemolytic test and cytotoxicity which were evaluated by cell viability assay using HEK293 cells. In vivo acute toxicity tests and histopathological study of PLE–AC copolymers were carried out on BALB/c mice which were administrated copolymers (1g/kgb.w.) intravenously. In acute toxicity test, the mice were observed continuously for 7 days, their body weight obtained everyday, at last the mice were sacrificed for the following study: the blood of the mice was assigned for blood chemistry and routine analysis, the heart, liver, spleen, lung, and kidneys were used for histopathological study. In acute oral toxicity test, mice were orally administered with a total 15g/kgbody weight (b.w.) of P(LE-IA-MEG) hydrogels, and were observed continuously for 14 days. For histopathologic study, samples including heart, liver, lung, kidneys, spleen, stomach, and intestine, were histochemically prepared and stained with hematoxylin–eosin for histopathologic examination. All results indicated that the PLE–AC copolymers and pH-sensitive hydrogels were non-toxic. Therefore it might be used as a safe candidate for drug delivery system. [Copyright &y& Elsevier]

Abstract: Strategies for further advancements in pulmonary drug delivery include the application of colloidal carriers. Freeze-drying in the presence of lyoprotectants is a valuable approach to improve long-term stability of biodegradable nanoparticles, but possibly constrains aerosol generation after powder rehydration, when employing traditional nebulizers. Here, we investigated the impact of lyoprotectants on both output and aerodynamic performance of air-jet, ultrasonic, and vibrating-mesh nebulization. Additionally, changes in formulation temperature and concentration were monitored, to estimate physicochemical alterations of formulations during nebulization. The stability of poly(d,l-lactide-co-glycolide) nanoparticles was maintained for lyoprotectant/nanoparticle ratios above 5/1. All nebulized formulations displayed suitable output and aerodynamic characteristics for peripheral lung deposition. Air-jet- and ultrasonic nebulization was associated with considerable temperature (∼10°C) and concentration changes (up to 156%) of the reservoir fluid, which consequently, caused significant shifting of surface tension and viscosity. By contrast, vibrating-mesh nebulization caused marginal temperature increase (∼5°C) with no apparent signs of concentration. Thus, the changing surface tension and viscosity were fitted employing Eötvös’ rule and the Andrade equation (R 2 >0.98), allowing to predict the physicochemical properties of each formulation for prolonged nebulization periods. In particular, vibrating-mesh nebulization seems to be promising for aerosol application of rehydrated freeze-dried biodegradable nanoparticles to the respiratory tract. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to develop and characterize a successful colloidal soft nano-carrier viz. microemulsion system, for the transdermal delivery of an angiotensin II receptor blocker: olmesartan medoxomil. Different microemulsion formulations were prepared. The microemulsions were characterized visually, with the polarizing microscope, and by photon correlation spectroscopy. In addition, the pH and conductivity (σ) of the formulations were measured. The type and structure of microemulsions formed were determined using conductivity measurements analysis, Freezing Differential Scanning Calorimetry (FDSC) and Diffusion-Ordered Spectroscopy (DOSY). Alterations in the molecular conformations of porcine skin were determined using Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) biophysical assessment. Olmesartan medoxomil delivery from the investigated formulations was assessed across porcine skin ex-vivo using Franz diffusion cells; the drug was analyzed by liquid chromatography mass spectroscopy (LC/MS/MS). A comparative pharmacokinetic study was done on healthy human subjects between the selected microemulsion and the commercial oral tablets. The physico-chemical and spectroscopic methods revealed the presence of water-in-oil and bicontinuous structures. Biophysical assessment demonstrated various stratum corneum (SC) changes. Olmesartan medoxomil was delivered successfully across the skin with flux achieving 3.65μgcm−2 h−1. Higher bioavailability compared to commercial oral tablets with a more sustainment behavior was achieved. [Copyright &y& Elsevier]

Abstract: Charge groups in polyelectrolyte gels can affect the entrapment and release of ionic drugs as well as influencing the stability of colloidal and nanoparticulate drug delivery systems. An accurate knowledge of gel charge properties is therefore important to the understanding and design of such drug delivery systems. Existing rotating disk method for quantifying the surface potential of flat surfaces is based on the classical electrokinetic model that neglects the effect of surface conductivity and is therefore only applicable to ion-impenetrable hard surfaces. This classical electrokinetic model would be inaccurate for polyelectrolyte gel systems involving ion-penetrable charged layers or “soft” surfaces. In this study, we developed a new rotating disk model for characterizing charge properties of ion penetrable soft surfaces and tested it on polyvinyl alcohol (PVA)/polyacrylic acid (PAA), gelatin, and gelatin/PAA polyelectrolyte gels. In addition to classical electrokinetic parameters, the contribution of surface conductivity known to be very significant for soft and ion-penetrable gel surfaces has been taken into account in this new rotating disk model. Based on this new approach, two rotating gel disks of different radius but with identical gel composition and preparation procedures were employed for determining the gel surface potential and density of fixed charge groups. A comparison of the resulting data with that obtained from existing rotating disk model ignoring the surface conductivity reveals a significant underestimation of the gel surface potential and the density of fixed charge groups by the ion-impenetrable hard surface approach. Our results thus confirm that the contribution of surface conductivity is significant in the electrokinetic characterization of polyelectrolyte gels that can be evaluated with our new rotating disk model. [Copyright &y& Elsevier]

Abstract: The competitive interactions between the poly-[propylene oxide] (POO)–poly-[ethylene oxide] (PEO) block copolymer poloxamer 407 (Pluronic F127) and two drugs, triamcinolone acetonide and ciclopirox olamine, by the formation of inclusion complexes with two cyclodextrin hydrophilic derivatives, hydroxypropyl-β-cyclodextrin (HPβCD; molar substitution (MS) 0.65) and partially methylated-β-cyclodextrin (MβCD; MS 0.57), were studied by means of one-dimensional 1H NMR, 2D ROESY experiments, solubility studies and drug release studies. 1D and 2D NMR and solubility studies indicate that both triamcinolone acetonide and ciclopirox olamine form stable inclusion complexes with the cyclodextrin derivatives. In the case of ciclopirox olamine the complex was more stable at pH 1. Effective complexation of poloxamer with the two cyclodextrins (CDs) was also evidenced by NMR analysis, and competitive displacement of the drugs from the CD cavity by the polymer was observed. Drug solubility in CD solutions was not modified by the addition of polymers, indicating that a decrease in solubility due to the competitive displacement is probably compensated by the solubilizing effect of polymer micellization. Finally, polypseudorotaxanes formation has a significant influence on the release of the drugs studied. Changes in the release rate depend on the stability of drug–CD inclusion complex and on cyclodextrin concentration in the bulk solution; so polypseudorotaxane formation can be employed to modulate drug controlled release from thermosensitive hydrogels. [Copyright &y& Elsevier]

Abstract: A series of vinyl hydrogels containing α-aminoacid (l-histidine, l-valine) residues was synthesized and their swelling properties evaluated at different pHs and temperatures. Unlike the zwitterionic compound containing only the l-histidine, a dual-stimuli responsiveness was improved in the carboxyl acid hydrogels carrying the l-valine residues (HVa). Besides the COOH functionality, the presence of either isopropyl and amido groups in the monomer structure renders the hydrogel also temperature-responsive, in a similar manner as the well-known poly(N-isopropylacrylamide) (pNIPAAm). The three HVa hydrogels (cross-linked with 1, 2, and 5mol% of N,N′-ethylene-bisacrylamide, EBA) show a phase separation at the same critical pH4, although a different swelling was improved by the amount of EBA. In buffered solutions, the effect of increasing temperature led to decrease the swelling and, as the pH is close to the critical one, a further and sharper collapse of the hydrogel may be tuned. The release study of pilocarpine in physiological conditions showed a burst effect within the first few hours, followed by a sustained release for a week. The initial burst effect was strongly dependent on the kind of hydrogel investigated. As the pilocarpine is a basic molecule (pK a 7.2), it may interact more strongly with the free carboxyl groups in the ionized state of the HVa hydrogels than the zwitterionic species of the histidine compounds. The releasing profile shows a three time greater release of the pilocarpine loaded in the HVa hydrogels. The hydrogels were found to be non-toxic against the mouse fibroblast NIH3T3 cells. The presence of pilocarpine strongly increased the cell proliferation even after 2days. [Copyright &y& Elsevier]

Abstract: The interactions of a number of commercially available dextran preparations with the lectin Concanavalin A (ConA) have been investigated. Dextrans over the molecular mass range 6×103–2×106 gmol−1 were initially characterised in terms of their branching and hence terminal ligand density, using NMR. This showed a range of branching ratios between 3% and 5%, but no clear correlation with molecular mass. The bio-specific interaction of these materials with ConA was investigated using microcalorimetry. The data obtained were interpreted using a number of possible binding models reflecting the known structure of both dextran and the lectin. The results of this analysis suggest that the interaction is most appropriately described in terms of a two-site model. This offers the best compromise for the observed relationship between data and model predictions and the number of parameters used based on the chi-squared values obtained from a nonlinear least-squares fitting procedure. A two-site model is also supported by analysis of the respective sizes of the dextrans and the ConA tetramer. Using this model, the relationship between association constants, binding energy and molecular mass was determined. [Copyright &y& Elsevier]

Abstract: Hexanediol diacrylate cross-linked oligoethylenimine (OEI-HD) is a non-viral polymeric vector designed to deliver siRNA. To achieve safe and effective in vivo siRNA delivery using this vector, the polyplex must have sufficient colloidal stability if administered intravenously or nebulized for delivery by the pulmonary route. In this study, polyplexes from OEI-HD and siRNA were formulated for aerosol-based lung delivery, regarding their colloidal stability, optimal particle size, and in vitro biological activity. Herein, we describe how these properties are dependent upon the polymer-to siRNA weight ratios, buffer composition they were complexed in, PEG-grafting, and the addition of commercial lung surfactants and/or non-ionic surfactants to the formulation. Lastly, the effects of nebulization of the formulation into aerosol droplets, on the polyplex particle size and transfection efficiency, were evaluated. Polyplex size was monitored for up to 2h after polyplex formation to determine the extent of aggregation and final particle sizes when stability was achieved. Our results suggest that PEG-grafting and polyethylenimine-PEG mixing were effective in achieving colloidal stability in isotonic saline buffers. In addition, colloidal stability was achieved in isotonic glucose buffers using commercially available non-ionic surfactant Pluronic™ P68 or the lung-derived surfactant Alveofact™. The smallest particle size, 140nm, was obtained with Pluronic™ F68. For transfection efficiency, both Alveofact™ and Pluronic™ F68 achieved equal or better transfection when added to the OEI-HD/siRNA polyplexes. For long term storage of OEI-HD/siRNA formulations, we propose a lyophilization method that created in situ polyplexes upon addition of water. Preparation of OEI-HD/siRNA polyplexes by this method allowed dry storage at room temperature for up to the 3months. In conclusion, we have identified approaches to achieve formulation and colloidal stability of OEI-HD/siRNA complexes, a step toward successful application of polyplexes for in vivo siRNA delivery. [Copyright &y& Elsevier]

Abstract: In this paper, a novel class of microspheric hydrogels was synthesized by grafting of N-isopropyacrylamide (NIPAAm) with gelatin. The possibility of inserting commercial gelatin in a crosslinked structure bearing thermo-sensitive moieties, by radical process, represents an interesting innovation that significantly improves the device performance, opening new applications in biomedical and pharmaceutical fields. This synthetic approach allows a modification of the polymeric network composition, producing hydrogels with suitable physico-chemical properties and a transition temperature higher than NIPAAm homopolymers. The incorporation of monomers into the network was confirmed by infrared spectroscopy, and the composition of the polymerization feed was found to strictly influence the network density and the shape of hydrogels. Thermal analyses showed negative thermo-responsive behaviour with shrinking/swelling transition values in the temperature range 34.6–34.8°C, according to the amount of the hydrophilic portions in the network. In order to test the preformed materials as drug carriers, diclofenac sodium salt was loaded into the spherical microparticles. After the determination of the drug entrapment percent, drug release profiles in media at different temperature were analysed. By using semi-empirical equations, the release mechanism was extensively studied and the diffusional contribution was evaluated. [ABSTRACT FROM AUTHOR]

Abstract: In the basic therapy of chronic skin diseases characterized by xerosis, the local treatment is an essential strategy to reach ideal therapeutic effects. Suitable active ingredients for this aim are fatty acids, in particular linoleic acid, which is an essential component for the organization and perpetuation of the skin barrier. In the present work, the development of a well-tolerated colloidal carrier system (microemulsion) containing linoleic acid as active ingredient is described. A comprehensive physiochemical characterization of the novel microemulsion system was performed using different techniques. The potential of the developed microemulsion system compared to a cream as suitable carrier for the dermal delivery of linoleic acid was determined. Penetration studies showed higher linoleic acids concentrations after administration of the colloidal carrier system in all skin layers independent of the time of incubation. Up to 23% of applied dose reached the skin from the colloidal carrier system whereas at most 8% of the active ingredient could be detected after applying the cream. Particularly, the percentage of the linoleic acids penetrated through the microemulsion in the stratum corneum and the viable epidermis differed significantly (p <0.01) when compared to that through a standard cream. Furthermore, linoleic acids accumulated in the epidermis at longer incubation times. Using the microemulsion, the penetration of linoleic acids was enhanced significantly (p <0.01). Hence, the microemulsion might be an innovative vehicle for the delivery of linoleic acids to the epidermis improving its use as their barrier regeneration and providing possible anti-inflammatory effects. [Copyright &y& Elsevier]

Abstract: The aim of this study was to establish and evaluate a screening method for the physical characterization of protein–protein interactions of therapeutic proteins based on the determination of the osmotic second virial coefficient (B22). B22 of an IgG1 was measured by self-interaction chromatography (SIC) and was compared to data obtained from static light scattering (SLS). As assessed by Fourier transform infrared spectroscopy (FTIR), the protein coupling to chromatography particles had no relevant influence on the three-dimensional native structure of the IgG1. B22 variations could be measured for physiological relevant excipient concentrations. Significant positive B22 values were observed for the following solution conditions of the investigated antibody: (i) acidic pH conditions, (ii) low buffer concentrations, (iii) low salt concentrations and (iv) high amino acid concentrations. B22 was compared to IgG1 stability data derived from a study conducted for 12weeks at 40°C. A concentration of 5mM histidine, which was the most promising buffer candidate according to B22, showed a slightly better physical stability (as assessed by turbidity and size exclusion chromatography) compared to the other tested formulations. This is confirmed in a stress study investigating the colloidal stability. Thus, measuring protein–protein interactions with SIC appeared as a promising screening tool for physical characterization of protein formulations for cases in which the protein stability is governed by interparticle interactions. [Copyright &y& Elsevier]

Abstract: The aim of the present work was the development of a thermally sensitive mucoadhesive gel based on chitosan derivatives for the treatment of oral mucositis. Trimethyl chitosan (TMC) and methylpyrrolidinone chitosan (MPC) were considered. They were mixed with glycerophosphate (GP) according to different polymer/GP molar ratios and characterized for gelation properties by means of rheological analysis in comparison with chitosan. The influence of molecular weight and substitution degree (SD) of TMC on gelation temperature and time was investigated. The mucoadhesive properties of the mixtures were also assessed using porcine buccal mucosa. The best properties were shown by TMC with high MW and low SD mixed with GP according to 1:2molar ratio. Such mixture was loaded with benzydamine hydrochloride, an anti-inflammatory drug with antimicrobial properties and subjected to in vitro drug release and wash away test. The formulation based on TMC/GP mixture was able to prolong drug release and to withstand the removal physiological mechanisms. The antimicrobial properties of both vehicle and formulation were investigated. Also in absence of drug, TMC/GP mixture was characterized by antimicrobial properties. [Copyright &y& Elsevier]

Abstract: Supramolecular organogels were formed by the self-assembly of gelator 1,3:2,4-di-O-benzylidene-d-sorbitol (DBS) in 1,2-propylene glycol. 5-Fluorouracil (5-Fu) was entrapped in the organogels as guest molecules. Field-emission scanning electron microscopic measurements of the organogels indicate that the diameters of the fibrillar aggregates formed by DBS self-assembly were in the range of 20–70nm. The host–guest interactions between 5-Fu and supramolecular gel matrix were investigated by using temperature-dependent differential UV spectroscopy and differential scanning calorimetry. The red shifts of the absorption band of 5-Fu in the organogels are indicative of the interaction between 5-Fu and DBS. The red shifts were enhanced upon decreasing the temperature. Calculation of optimized geometries revealed the formation of hydrogen bonds between 5-Fu and DBS aggregates. The analysis of differential scanning calorimetric data for the organogels with and without 5-Fu further showed that the self-assembly of DBS was interfered by the 5-Fu in the organogels, resulting in a decrease in the dissociating temperature of DBS aggregates. [Copyright &y& Elsevier]

Abstract: Hydrogel microparticles were produced by a radical polymerization of hydroxyethyl methacrylate–hydroxyethyl starch (HES–HEMA) in an all aqueous two-phase system (ATPS). The microspheres show a monomodal size distribution and have the ability to entrap high amounts of water. The release of proteins or other testing substances from the HES–HEMA hydrogels can be controlled by the choice of the network density of the hydrogel by varying the degree of substitution (DS), the size of the entrapped substance, and by conditions enhancing the degradation of the hydrogel network. [Copyright &y& Elsevier]

Abstract: This paper presents the development of new pH-sensitive, amphiphilic and biocompatible hydrogels based on alginate-g-PCL, cross-linked with calcium ions to form beads, prepared for controlled delivery of poorly water-soluble drug. We have focused our study on the effect of the length of PCL chains (530 and 1250gmol−1). Swelling profiles obtained clearly indicated that these hydrogels swell slightly (10–14%) in a simulated gastric fluid (pH 1.2), and strongly (700–1300% before disintegration) in a simulated intestinal fluid (pH 6.8). In both media, rates of swelling were lower for beads based on amphiphilic derivatives than for alginate/Ca2+ ones due to the hydrophobic PCL grafts, and decreased when hydrophobic character increased. A model drug, theophylline, was entrapped into these hydrogels and release studies were carried out. The drug was protected in acidic fluid (only 14–20% of release for alginate-g-PCL hydrogel against 35% of release for alginate hydrogel during 350min). The drug is released completely in neutral fluid due to ion exchanges and disintegration of the hydrogel. PCL leads to decrease in the release kinetics in SIF (2h for alginate-g-PCL/Ca2+ beads against 1h for alginate/Ca2+ beads). It was demonstrated that the establishment of clusters inside beads by intramolecular interactions between PCL grafts of 530gmol−1 in salt media allowed to retain the drug and to slow down its release considerably. [Copyright &y& Elsevier]

Abstract: The aims of this study were to determine the effect of ethyl docosahexaenoate (DHA-EE) on cyclosporine A (CsA) bioavailability, while also examining the effect of DHA-EE on CsA when DHA-EE was incorporated into a microemulsion formulation as an oil ingredient. The oral co-administration of DHA-EE and CsA increased the blood CsA concentration in a dose-dependent manner, and the AUC and C max both increased by about 2-fold with 100mg/kg DHA-EE. The microemulsion formulation of CsA consisted of Tween-20, ethanol, water, and DHA-EE (53.3/6.5/35.9/3.3w/w%) (namely DHA-ME) was transparent and stable with an average particle size of 50nm, which was similar to that of the control formulation incorporating vitamin E instead of DHA-EE (namely VE-ME). The permeabilities of CsA from DHA-ME, VE-ME and Neoral® formulations across an artificial membrane were not significantly different. The C max and AUC0–∞ of CsA in rats administered DHA-ME significantly increased by approximately 2-fold in comparison to that of VE-ME. The relative oral bioavailability (Fr ) of DHA-ME in comparison to Neoral® was determined to be 114%, while the Fr of VE-ME was only 60%. It was, therefore, suggested that the use of DHA-EE as an oil excipient may be promising for the development of a microemulsion formulation of CsA with an improved oral bioavailability. [Copyright &y& Elsevier]

Abstract: Doxorubicin was chemically conjugated to acrylated chitosan in order to obtain sustained-release profiles of doxorubicin from thermo-responsive and photo-crosslinkable hydrogels. Chitooligosaccharide was acrylated with glycidyl methacrylate and subsequently conjugated to doxorubicin via an amide linkage. A mixture of doxorubicin–chitosan conjugates, acrylated Pluronic, and doxorubicin formed physical gels at 37°C. Photo-irradiation was subsequently performed to chemically crosslink the physical hydrogel at 37°C. Chitooligosaccharide–doxorubicin conjugates in the doxorubicin hydrogels significantly reduced burst release of free doxorubicin from doxorubicin hydrogels compared hydrogels without the conjugates. Upon incubating doxorubicin hydrogels at 37°C, chitosan–doxorubicin conjugates were confirmed to be degraded into more hydrophilic oligomers by reversed-phase chromatography. In vitro cytotoxicity assay using released media from doxorubicin hydrogels showed that degraded chitosan–doxorubicin had cytotoxicity comparable to free doxorubicin. Athymic nude mice bearing human lung adenocarcinoma were subjected to intra-tumoral injections of physical hydrogels. After photo-crosslinking injected hydrogels using surgical catheters, tumor sizes, body weights, and survivals were measured for 1month. Released media from doxorubicin hydrogels exerted similar cytotoxicities to free doxorubicin, and the tumor volume was significantly reduced for 1month compared to other samples. Thus, doxorubicin hydrogels containing doxorubicin conjugates can be employed as a novel injectable anti-cancer drug aiming to achieve sustained release of doxorubicin for several weeks against solid tumors. [Copyright &y& Elsevier]

Abstract: Long-term exposure of the skin to UV light causes degenerative effects, which can be minimized by using antioxidant formulations. The major challenge in this regard is that a significant amount of antioxidant should reach at the site for effective photoprotection. However, barrier properties of the skin limit their use. In the present study, vitamin E (α-tocopherol) was loaded into a dextran hydrogel containing ferulic moieties, covalently linked, to improve its topical delivery, and also to increase its relative poor stability, which is due to direct exposure to UV light. Methacrylic groups were first introduced onto the dextran polymer backbones, then the obtained methacrylated dextran was copolymerized with aminoethyl methacrylate, and subsequently esterificated with trans-ferulic acid. The new biopolymer was characterized by Fourier transform infrared spectroscopy. The values of content of phenolic groups were determined. Its ability in inhibiting lipid peroxidation in rat liver microsomal membranes induced in vitro by a source of free radicals, that is tert-butyl hydroperoxide, was studied. Hydrogel was also characterized for swelling behaviour, vitamin E loading efficiency, release, and deposition on the rabbit skin. Additionally, vitamin E deposition was compared through hydrogels, respectively, containing and not containing trans-ferulic acid. The results showed that ferulate hydrogel was a more effective carrier in protecting vitamin E from photodegradation than hydrogel without antioxidant moieties. Then antioxidant hydrogel could be of potential use for cosmetic and pharmaceutical purposes as carrier of vitamin E that is an antioxidant that reduces erythema, photoaging, photocarcinogenesis, edema, and skin hypersensitivity associated with exposure to ultraviolet B (UVB) radiation, because of its protective effects. [Copyright &y& Elsevier]

Abstract: The goal of this critical review is to provide a critical analysis of the chain dynamics responsible for the action of micro- and nanoparticles of mucoadhesive biomaterials. The objective of using bioadhesive controlled drug delivery devices is to prolong their residence at a specific site of delivery, thus enhancing the drug absorption process. These mucoadhesive devices can protect the drug during the absorption process in addition to protecting it on its route to the delivery site. The major emphasis of recent research on mucoadhesive biomaterials has been on the use of adhesion promoters, which would enhance the adhesion between synthetic polymers and mucus. The use of adhesion promoters such as linear or tethered polymer chains is a natural result of the diffusional characteristics of adhesion. Mucoadhesion depends largely on the structure of the synthetic polymer gels used in controlled release applications. [Copyright &y& Elsevier]

Abstract: The overall goal of this study was to develop cremophor-free oral microemulsions of paclitaxel (PAC) to enhance its permeability and oral absorption. The mechanism of this enhancement, as well as characteristics of the microemulsions relevant to the increase in permeability and absorption of the low solubility, low permeability PAC was investigated. Phase diagrams were used to determine the macroscopic phase behavior of the microemulsions and to compare the efficiency of different surfactant-oil mixtures to incorporate water. The microemulsion region on the phase diagrams utilizing surfactant-myvacet oil combinations was in decreasing order: lecithin: butanol: myvacet oil (LBM, 48.5%)>centromix CPS: 1-butanol: myvacet oil (CPS, 45.15%)>capmul MCM: polysorbate 80: myvacet oil (CPM, 27.6%)>capryol 90: polysorbate 80: myvacet oil (CP-P80, 23.9%)>capmul: myvacet oil (CM, 20%). Oil-in-water (o/w) microemulsions had larger droplet sizes (687–1010nm) than the water-in-oil (w/o) microemulsions (272–363nm) when measured using a Zetasizer nano series particle size analyzer. Utilizing nuclear magnetic resonance spectroscopy (NMR), the self-diffusion coefficient (D) of PAC in CM, LBM and CPM containing 10% of deuterium oxide (D2O) was 2.24×10−11, 1.97×10−11 and 0.51×10−11 m2/s, respectively. These values indicate the faster molecular mobility of PAC in the two w/o microemulsions (CM and LBM) than the o/w microemulsion – CPM. The in situ permeability of PAC through male CD-IGS rat intestine was 3- and 11-fold higher from LBM and CM, respectively, than that from the control clinical formulation, Taxol® (CE, cremophor: ethanol) in a single pass perfusion study. PAC permeability was significantly increased in the presence of the pgp/CYP3A4 inhibitor cyclosporine A (CsA). This enhancement may be attributed to the pgp inhibitory effect of the surfactants, oil and/or the membrane perturbation effect of the surfactants. The oral disposition of PAC in CM, LBM and CPM compared to CE was studied in male CD-IGS rats after a single oral dose (20mg/kg). The area-under-the-curve of PAC in CM was significantly larger than LBM, CPM and CE. Oral microemulsions of PAC were developed that increased both the permeability and AUC of PAC as compared to CE. [Copyright &y& Elsevier]

Abstract: The present research work aimed at development and optimisation of mucoadhesive polyherbal gels (MPG) for vaginal drug delivery. As the rheological and mucoadhesive properties of the gels correlate well to each other the prepared MPGs were optimised for maximum mucoadhesion using a relationship between the storage modulus (G′) and Gel Index (GI), by employing a 3-factor, 3-level Box-Behnken statistical design. Independent variables studied were the polymer concentration (X 1), honey concentration (X 2) and aerosil concentration (X 3). Aerosil has been investigated for the first time to improve the consistency of gels. The dependent variables studied were the elastic modulus, G′(Y 1), gel index (Y 2), and maximum detachment force (Y 3) with applied constraints of 500⩽ Y 1 ⩽700 and 4⩽ Y 2 ⩽5. Response surface plots were drawn, statistical validity of the polynomials was established and optimised formulations was selected by feasibility and grid search. Three types of Carbopol studied were Carbopol 934P, Carbopol 974P and Polycarbophil. In vitro release studies were carried out for the optimised formulations and the data were fitted to release kinetics equations. Validation of the optimisation study with 8 confirmatory runs indicated high degree of prognostic ability of response surface methodology. Gels showed a gradual sustained release by a non-Fickian diffusion process. Incorporation of aerosil to gels was found to improve the rheological and mucoadhesion properties by about 50–54% and 7–11%, respectively. The Box-Behnken design facilitated the optimisation of polyherbal gel formulations for enhanced vaginal drug delivery by optimum mucoadhesion and longer retention. [Copyright &y& Elsevier]