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Our work aimed at evaluating the use of permeability glycoprotein (P-gp) inhibiting nanoparticles (NPs) as a part of a suitable oral solid dosage to improve bioavailability. Famotidine (Pepcid®), a stomach acid production inhibitor, was used as a drug model to test our hypothesis. Famotidine-loaded NPs were prepared by solvent emulsion evaporation using PEG grafted on a polylactide acid (PLA) polymer backbone (PLA-g-PEG), with a 5% molar ratio of PEG versus lactic acid monomer and PEG of either 750 or 2000 Da molecular weight. Tablet formulation was composed of 40% Famotidine-loaded NPs, 52.5% microcrystalline cellulose as filler, 7% pre-gelatinized starch as binder/disintegrant, and 0.5% magnesium stearate as lubricant. Tablets containing 1.6 mg of Famotidine were prepared at an average weight of 500 mg, thickness of 6.2-6.5 mm, hardness of 5-8 kp, and disintegration time of <1 min. Our results suggest that Famotidine-loaded NPs using grafted PEG-g-PLA polymers can be formulated as an oral solid dosage form while effectively inhibiting P-gp mediated Famotidine efflux, irrespective of PEG molecular weights. This could therefore represent an attractive formulation alternative to enhance oral permeability and bioavailability of drugs that are P-gp substrates. [ABSTRACT FROM AUTHOR]

cis-4,40-(Diazenediyl)bis(2,3,5,6-tetrafluorobenzoic acid), C14H2F8N2O4, and its ethanol disolvate, C14H2F8N2O4•2C2H5OH, represent new examples of selfstabilized cis-configured azobenzenes obtained by a common crystallization procedure at room temperature under normal laboratory lighting conditions. The target structure constitutes of two 2,3,5,6-tetrafluorobenzoic acid residues linked to each other by a cis-configured azo group and was confirmed for two isolated specimens extracted from the same sample, corresponding to a solventfree form and an ethanol disolvate. In the solvent-free form, the molecule is characterized by rotational symmetry around a twofold rotation axis bisecting its central N N bond while this symmetry is not present in the solvated form. The values of the inclination angles of the terminal carboxyl groups towards the corresponding benzene rings vary from 5.2 (4) to 45.7 (2)°, depending on the crystal composition. In the unsolvated form, the molecules are linked through identical hydrogen bonds with a classical R²2(8) graph-set ring motif of carboxylic acids, by generating supramolecular chains running approximately parallel to [101]. The presence of ethanol in the solvated form also leads to changes in the short-contact pattern to produce both the R4 4(12) ring and open-chain motifs with alternating alcohol and dicarboxylic acid molecules. [ABSTRACT FROM AUTHOR]

In the title compound, C17H15N3O3, the plane of the pyrrolidone ring is inclined at an angle of 59.791 (2)° to that of the azo­benzene segment, which adopts a configuration close to planar. In the crystal, mol­ecules are oriented pairwise by (2-oxopyrrolidin-3-yl)­oxy moieties at an angle of 76.257 (3)°, linked by hydrogen bonds and π-stacking inter­actions, forming zigzag supra­molecular chains parallel to [010] further linked via additional C—Hπ inter­actions [ABSTRACT FROM AUTHOR]

Bioavailability of oral drugs can be limited by an intestinal excretion process mediated by P-glycoprotein (P-gp). Polyethylene glycol (PEG) is a known P-gp inhibitor. Dispersion of Famotidine (a P-gp substrate) within PEGylated nanoparticles (NPs) was used to improve its oral bioavailability. In this work, we evaluated the potential impact of NPs prepared from a grafted copolymer of polylactic acid and PEG on P-gp function by studyingin vitropermeability of Famotidine across Caco-2 cells. Copolymers of PEG grafted on polylactic acid (PLA) backbone (PLA-g-PEG) were synthesised with 1 mol% and 5 mol% PEG vs. lactic acid monomer using PEG 750 and 2000 Da. The polymers were used to prepare Famotidine-loaded NPs and testedin vitroon Caco-2 cells. Significant decrease in basolateral-to-apical transport of Famotidine was observed when Famotidine was encapsulated in NPs prepared from PLA-g-PEG5%. NPs prepared from PLA-g-PEG5% are promising to improve oral bioavailability of P-gp substrates. [ABSTRACT FROM PUBLISHER]

New polyester- co-polyether dendritic macromolecules of first generation characterized by different flexibility of their central part (core) are synthesized and proposed as simplified models of new drug encapsulation agents for itraconazole (ITZ), an antifongic agent. Chemical structures of obtained products are characterized by FTIR, UV-vis, 1H and 13C NMR, and GPC techniques, as well as by elemental analysis and mass spectrometry. The absence of cytotoxicity limitation for further applications in drug delivery is evidenced by the results of MTT assay on the murine macrophage cell line RAW-262.7. To elucidate the role of hydrophobic core structure of dendrimers in the process of ITZ encapsulation, the in silico simulations with reduced model structures are performed. The results of studies in vitro and in silico are found consistent, suggesting that the drug encapsulation efficiency can be determined by the possibility of an effective bending of hydrophobic central core segments of dendrimer around ITZ molecule. [ABSTRACT FROM AUTHOR]

New symmetrically poly(ethylene glycol) (PEG)-decorated triglycerides of fatty acid are synthesized and proposed as drug-encapsulation systems. A method of effective grafting of PEG on secondary hydroxy groups located on long alkyl chains by the use of a short spacer represented by succinic acid is elaborated. Synthesis of new derivatives of triacylglycerols of fatty acids (TAG) based on the triolein standard and commercial olive oil, with PEG chains of different lengths (1000, 550, and 220 Da) is performed. MTT assay on the murine macrophage cell line RAW-262.7 shows the absence of cytotoxic effects caused by the obtained products. Encapsulation tests using itraconazole (ITZ) as a hydrophobic drug model are carried out. The influence of the PEG chain length, as well as of the presence of ITZ on the size of micelles, are studied by the dynamic light scattering (DLS) method. The reduced cytotoxicity observed on Candida albicans cells of ITZ formulated with the PEG-decorated TAG versus the free drug indicates that the systems may be promising to increase the duration of drug release and to reduce toxic side effects. [ABSTRACT FROM AUTHOR]

Synthesis of a novel multifunctional block based on asymmetrically substituted pentaerythritol, succinic acid, and tetraethylene glycol is reported. The proposed reaction conditions allow selective preparation of the product in high overall yield. The block can be used in the assembly of biocompatible polyester- co-polyether (PEPE) hyperbranched macromolecules, which allows the product to be considered as a promising intermediate for the development of new biomedical dendrimers. As an example, the use of the 'block by block' strategy is employed to obtain a second-generation dendron. It is shown that the approach is much more efficient than the pathway of step-by-step grafting of separate molecular fragments. [ABSTRACT FROM AUTHOR]

Elaborating novel triacylglyceride (TAG) based polyester hyperbranched unimolecular encapsulating agents represents an original and promising approach to the selective delivery of hydrophobic biologically active compounds. However, selective modification of double bonds in unsaturated TAG to obtain corresponding pure polyhydroxy derivatives with high yields is still a big challenge. Two novel approaches to synthesize the glyceryl tris[9,10-( threo)-dihydroxyoctadecanoate] were proposed and tested: (1) via the bromination and nucleophilic substitution of secondary halide functions by oxyacetyl groups followed by the hydrolysis of acetyls, and (2) direct transformation of the double bonds by the reaction with peroxoformic acid in an excess of formic acid, and the removal of formyl protective groups. Glycerol trioleate and natural olive oil were used as starting materials. The first synthetic route allowed for successful preparation of the corresponding polyhalide and polyoxyacetyl products; however, a more effective final deacetylation procedure is required. The second proposed approach showed a very good reproducibility in obtaining hydroxy-oxyformyl derivatives. The optimal conditions of the reaction involve the use of diethyl ether as a cosolvent and stirring at room temperature for 30 min. To remove the formyl groups, three original procedures using organic solvent medium at room temperature were proposed: in the presence of cesium carbonate in chloroform-methanol mixture, and two methods using hydrochloric acid in chloroform-methanol mixture or in acetone. All three methods were efficient to carry out the deformylation; nevertheless, TAG esters remained stable only with 15-17 % hydrochloric acid in acetone. Simple isolation procedures and high overall yields (95.6 and 94.9 % for both triolein and olive oil, respectively) allow considering the second approach as a promising method to obtain threo-polyhydroxy derivatives from unsaturated TAG. [ABSTRACT FROM AUTHOR]

Poly(ethylene glycol)/polylactic acid (PEG/PLA) nanoparticles (NPs) containing the hydrophobic antifungal itraconazole (ITZ) were developed to provide a controlled release pattern of ITZ as well as to improve its aqueous dispersibility and hence enhance its antifungal action. Two PEG/PLA copolymers (PEGylated PLA polymers) were used in this study; branched PEGylated polymer in which PEG was grafted on PLA backbone at 7% (mol/mol of lactic acid monomer), PEG7%-g-PLA, and multiblock copolymer of PLA and PEG, (PLA-PEG-PLA) n with nearly similar PEG insertion ratio and similar PEG chain length. ITZ-loaded PLA NPs were also prepared and included in this study as a control. ITZ-NPs were prepared from a 1 : 1 w/w blend of PLA and each PEGylated polymer either PEG7%-g-PLA or (PLA-PEG-PLA) n using an oil-in-water emulsion evaporation method. The NPs morphology, size and size distribution, zeta potential, loading efficiency, release profile and antifungal activity were characterized. All ITZ-NPs were nearly spherical with smooth surface and showed less aggregating tendency with a size range of 185-285 nm. All ITZ-NPs measured nearly neutral zeta potential values close to 0 mV. The % LE of ITZ was ∼94% for PEG7%-g-PLA NPs and ∼83% for (PLA-PEG-PLA) n at 15.3% w/w theoretical loading. PEG/PLA NPs were stable over time regarding size and size distribution and % ITZ loading efficiency (% LE). ITZ release showed an initial burst followed by a gradual release profile for ITZ-NPs over 5 days. (PLA-PEG-PLA) n NPs exhibited faster release rates than PEG7%-g-PLA NPs particularly at the last 2 days. Differential scanning calorimetry and powder X-ray diffractometry data confirmed that ITZ exists in an amorphous state or a solid solution state into the NPs matrix. Fourier transform infrared revealed the possibility of chemical interaction between ITZ and the NPs matrix polymer indicating the successful entrapment of ITZ inside the particles. In haemolysis test, ITZ-NPs caused mild haemolysis over the concentration range (5-20 µg/mL) compared to free ITZ, indicating better safety profile of ITZ-NPs. ITZ-loaded PEG/PLA NPs inhibited fungal growth more efficiently than either free ITZ or ITZ-loaded PLA NPs. Our results suggest that PEG/PLA-ITZ could be used efficiently as a nanocarrier to improve the aqueous dispersibility of ITZ, control its release over time and, thereby, enhance its antifungal efficacy. [ABSTRACT FROM AUTHOR]

Cell encapsulation in microcapsules allows the in situ delivery of secreted proteins to treat different pathological conditions. Spherical microcapsules offer optimal surface-to-volume ratio for protein and nutrient diffusion, and thus, cell viability. This technology permits cell survival along with protein secretion activity upon appropriate host stimuli without the deleterious effects of immunosuppressant drugs. Microcapsules can be classified in 3 categories: matrix-core/shell microcapsules, liquid-core/shell microcapsules, and cells-core/shell microcapsules (or conformal coating). Many preparation techniques using natural or synthetic polymers as well as inorganic compounds have been reported. Matrix-core/shell microcapsules in which cells are hydrogel-embedded, exemplified by alginates capsule, is by far the most studied method. Numerous refinement of the technique have been proposed over the years such as better material characterization and purification, improvements in microbead generation methods, and new microbeads coating techniques. Other approaches, based on liquid-core capsules showed improved protein production and increased cell survival. But aside those more traditional techniques, new techniques are emerging in response to shortcomings of existing methods. More recently, direct cell aggregate coating have been proposed to minimize membrane thickness and implants size. Microcapsule performances are largely dictated by the physicochemical properties of the materials and the preparation techniques employed. Despite numerous promising pre-clinical results, at the present time each methods proposed need further improvements before reaching the clinical phase. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009 [ABSTRACT FROM AUTHOR]

This work evaluates and interprets underlying mechanisms behind various aspects related to preparation and physical characteristics of polymeric nanoparticles (NP). These were prepared from different biodegradable polymers according to a water-in-oil-in-water emulsion solvent evaporation method. Polymers used were poly(lactic- co -glycolic) acid (PLGA), poly (lactic acid) (PLA), (PLA-PEG-PLA) triblock and (PLA-PEG-PLA) n multi-block co-polymers. A model DNA, as an example of a hydrophilic drug, was encapsulated in the internal aqueous phase. The primary emulsion was prepared using a high shear turbine mixer. The secondary emulsion was prepared by high-pressure homogenization. Surface morphology and internal structure were characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM). Influence of process variables on the physical properties of NP has been studied. Release of DNA was evaluated. In addition, changes occurring to NP porosity and surface area during degradation were followed. Nanoparticle size was ranging between 200–700&ThickSpace;nm, according to the preparation conditions. Homogenizing pressure, concentration of the emulsifying agent used, polymer concentration and type and the concentration of a cryoprotectant had variable effects on NP size, surface area and porosity. Batches of NP where no emulsifying agent was added were obtained successfully. The release rate of the DNA from NP was mainly dependent on porosity, which varied significantly among used polymers. The preparation technique was efficient in encapsulating the model DNA and will be used for plasmid encapsulation in a future work. [ABSTRACT FROM AUTHOR]

Artificial Neural Networks (ANNs) were used to predict nanoparticle size and micropore surface area of polylactic acid nanoparticles, prepared by a double emulsion method. Different batches were prepared while varying polymer and surfactant concentration, as well as homogenization pressure. Two commercial ANNs programs were evaluated: Neuroshell® Predictor, a black-box software adopting both neural and genetic strategies, and Neurosolutions®, allowing a step-by-step building of the network. Results were compared to those obtained by statistical method. Predictions from ANNs were more accurate than those calculated using non-linear regression. Neuroshell® Predictor allowed quantification of the relative importance of the inputs. Furthermore, by varying the network topology and parameters using Neurosolutions®, it was possible to obtain output values which were closer to experimental values. Therefore, ANNs represent a promising tool for the analysis of processes involving preparation of polymeric carriers and for prediction of their physical properties. [ABSTRACT FROM AUTHOR]

Purpose. To investigate the spinal disposition, the cerebrospinal fluid (CSF) bioavailability, and the ex vivo meningeal permeability of six homologous pipecoloxylidide local anesthetics and to search for correlations with lipophilicity. Methods. The ex vivo meningeal permeability was studied on fresh specimen of meninges (dura mater and arachnoid mater) removed from lumbar and cervical level of rabbit spine following laminectomy. Spinal disposition and CSF bioavailability were investigated using microdialysis sampling after simultaneous injection of an equimolar dose of the six homologs in the epidural or in the intrathecal spaces. In a first step, intrathecal and epidural microdialysis were performed after epidural administration. In a second step, intrathecal microdialysis was performed after intrathecal administration. Results. Permeability through cervical and lumbar meninges was linearly correlated, and the cervical permeability was around 60% of the lumbar permeability. Apparent permeability data showed a parabolic relationship with the lipophilicity of the derivatives with a marked decrease in permeability for log P above 3. In vivo experiments have shown that the absorption rate constant linearly decreased with lipophilicity of the derivatives (0.171 to 0.125 min-1) whereas the intrathecal bioavailability, which was low, increased with lipophilicity (7.2 to 15.9%). Conclusions. The unexpected increase in CSF bioavailability with a decrease in absorption rate through meninges emphasizes the role of specific competitive clearance and distribution processes in the epidural space. [ABSTRACT FROM AUTHOR]

Purpose. To characterize and evaluate in vitro and in vivo the release mechanisms involved in spray-dried biodegradable microspheres having differents Poly(D,L-lactide) blend formulations and containing an antihypertensive drug (L-158,809). Methods. Microspheres and blended polymers were characterized by DSC, SEM, confocal laser microspcopy and size analysis. In vitro release studies were evaluated by using microspheres made from various blends of high and low molecular weight polymer. In vivo studies were evaluated by L-158,809 antagonist ATI function versus the shift of the normal dose-response curve of blood pressure induced by Angio-tensine II. Results. The average yield of L-158,809 microspheres (10% (w/w)) was 95% of the theoritical loading. The average diameter of the microspheres was from 1 to 3 micrometers. In all release experiments, a significant burst effect (< 15%) was observed followed by a near zero-order release kinetics. In vivo studies with two different formulations show a strong shift of angiotensin II dose-response curve. Conclusions. The release kinetics and photomicrographs suggest that the system is best described as a multi-parameter controlled released system in which the drug is molecularly dispersed. In vivo results demonstrating the controlled release of L-158,809. [ABSTRACT FROM AUTHOR]

Improving nanoparticles (NPs) transport across biological barriers is a significant challenge that could be addressed through understanding NPs diffusion in dense and confined media. Here, we report the ability of soft NPs to shrink in confined environments, therefore boosting their diffusion compared to hard, non-deformable particles. We demonstrate this behavior by embedding microgel NPs in agarose gels. The origin of the shrinking appears to be related to the overlap of the electrostatic double layers (EDL) surrounding the NPs and the agarose fibres. Indeed, it is shown that screening the EDL interactions, by increasing the ionic strength of the medium, prevents the soft particle shrinkage. The shrunken NPs diffuse up to 2 orders of magnitude faster in agarose gel than their hard NP counterparts. These findings provide valuable insights on the role of long range interactions on soft NPs dynamics in crowded environments, and help rationalize the design of more efficient NP-based transport systems. Understanding the transport of nanomaterials, especially nanoparticles, through a porous medium has major implications in many different fields. Here the authors report the ability of soft nanoparticles to shrink in confined environments, therefore boosting their diffusion compared to hard, non-deformable particles. [ABSTRACT FROM AUTHOR]