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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 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: 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: 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: 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: 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: 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: 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]