Mechanisms of burst release from pH-responsive polymeric microparticles.

Microencapsulation of drugs into preformed polymers is commonly achieved through solvent evaporation techniques or spray drying. We compared these encapsulation methods in terms of controlled drug release properties of the prepared microparticles and investigated the underlying mechanisms responsible for the “burst release” effect. Using two different pH-responsive polymers with a dissolution threshold of pH 6 (Eudragit L100 and AQOAT AS-MG), hydrocortisone, a model hydrophobic drug, was incorporated into microparticles below and above its solubility within the polymer matrix. Although, spray drying is an attractive approach due to rapid particle production and relatively low solvent waste, the oil-in-oil microencapsulation method is superior in terms of controlled drug release properties from the microparticles. Slow solvent evaporation during the oil-in-oil emulsification process allows adequate time for drug and polymer redistribution in the microparticles and reduces uncontrolled drug burst release. Electron microscopy showed that this slower manufacturing procedure generated non-porous particles whereas thermal analysis and X-ray diffractometry showed that drug loading above the solubility limit of the drug in the polymer generated excess crystalline drug on the surface of the particles. Raman spectral mapping illustrated that drug was homogeneously distributed as a solid solution in the particles when loaded below saturation in the polymer with consequently minimal burst release

Hydrogen-bonded complexes and blends of poly(acrylic acid) and methylcellulose: nanoparticles and mucoadhesive films for Ocular Delivery of Riboflavin

Poly(acrylic acid) (PAA) and methylcellulose (MC) are able to form hydrogen-bonded interpolymer complexes (IPCs) in aqueous solutions. In this study, the complexation between PAA andMC is explored in dilute aqueous solutions under acidic conditions. The formation of stable nanoparticles is established,whose size and colloidal stability are greatly dependent on solution pH and polymers ratio in the mixture. Poly(acrylic acid) and methylcellulose are also used to prepare polymeric films by casting from aqueous solutions. It is established that uniform films can be prepared by casting from polymer mixture solutions at pH 3.4–4.5. At lower pHs (pH<3.0) the films have inhomogeneous morphology resulting from strong interpolymer complexation and precipitation of polycomplexes, whereas at higher pHs (pH 8.3) the polymers form fully immiscible blends because of the lack of interpolymer hydrogen-bonding. The PAA/MC films cast at pH 4 are shown to be non-irritant to mucosal surfaces. These films provide a platform for ocular formulation of riboflavin, a drug used for corneal crosslinking in the treatment of keratoconus. An in vitro release of riboflavin as well as an in vivo retention of the films on corneal surfaces can be controlled by adjusting PAA/MC ratio in the formulations

Novel polyvinylpyrrolidones to improve delivery of poorly-water soluble drugs; from design to synthesis and evaluation

Polyvinylpyrrolidone is a widely used in tablet formulations with the linear form acting as a wetting agent and disintegrant whereas the cross-linked form is a super-disintegrant. We have previously reported that simply mixing the commercial cross-linked polymer with ibuprofen disrupted drug crystallinity with consequent improvements in drug dissolution behavior. In this study, we have designed and synthesized novel cross-linking agents containing a range of oligoether moieties which have then be polymerized with vinylpyrrolidone to generate a suite of novel excipients with enhanced hydrogen-bonding capabilities. The polymers have a porous surface and swell in most common solvents and in water; properties which suggest their value as disintegrants. The polymers were evaluated in simple physical mixtures with ibuprofen as a model poorly-water soluble drug. The results show that the novel PVPs induce the drug to become “X-ray amorphous”, which increased dissolution to a greater extent than that seen with commercial cross-linked PVP. The polymers stabilize the amorphous drug with no evidence for recrystallization seen after 20 weeks storage

Delivery of riboflavin-5’-monophosphate into the cornea: can liposomes provide any enhancement effects?

Keratoconus is a progressive condition caused by the thinning of the cornea, which eventually deforms the front surface of the eye into a cone shape leading to ghosting, multiple images, glare and several other vision problems. Currently keratoconus is treated with UV-induced ribofiavin-mediated collagen cross-linking, which requires a physical removal of the corneal epithelium under topical anesthesia. This study reports the penetration of riboflavin (Rb) and its more water-soluble form, riboflavin-5’- monophosphate (RbP), into the bovine cornea ex vivo. Using ex vivo bovine corneal tissues and 0.8 mg/mL drug solutions in phosphate buffer, it was established that RbP penetration into the cornea within 3 hours of diffusion experiment was greater (17.3 ± 0.8 μg) compared to Rb (10.4 ± 4.2 μg). In the cornea RbP was found to convert to Rb, which is mediated with enzymes present in this tissue. Several formulations including the conventional and propylene glycol-containing liposomes with encapsulated RbP have been developed and their effect on the drug penetration into the bovine cornea was evaluated. Encapsulation of RbP into the liposomes did not provide any statistically significant improvement in the penetration of RbP into the cornea

Hydrogels based on copolymers of 2‐hydroxyethylmethacrylate and 2‐hydroxyethylacrylate as a delivery system for proteins: Interactions with lysozyme

Hydrogels have attracted considerable attention due to numerous applications, in particular as contact lenses and carriers for sustained drug delivery. The aim of the present work is to characterize the interactions of copolymer hydrogels consisted of 2-hydroxyethylmethacrylate (HEMA) and 2-hydroxyethylacrylate (HEA) with a small protein (lysozyme) and to assess the potential applications of these hydrogels as a drug delivery system for sustained release of protein-based therapeutics. Physicochemical properties of protein-loaded hydrogels, as well as lysozyme in vitro loading and release and the conformation of the protein released from hydrogels were studied. The effect of copolymer composition on the protein deposition on hydrogels and protein aggregation in the presence of hydrogels was also assessed. The results show that introduction of HEA into the copolymeric hydrogels enhances their suitability as a delivery system for proteins. Copolymerisation of HEMA and HEA allows controlling the physicochemical properties of hydrogels and the protein release rate

Antimicrobial hydrogels based on autoclaved poly(vinyl alcohol) and poly(methyl vinyl ether-alt-maleic anhydride) mixtures for wound care applications

Novel antimicrobial hydrogels with good mechanical and physical properties were synthesized by autoclaving aqueous mixtures of poly(vinyl alcohol) and poly(methyl vinyl ether-alt-maleic anhydride). The structure of these materials was studied by infrared spectroscopy, scanning electron microscopy and solid state nuclear magnetic resonance. The swelling behavior, mechanical properties and adhesion of the hydrogels to porcine skin were evaluated. It was established that these hydrogels exhibited antimicrobial properties and inhibited bacteria growth against Staphylococcus aureus. The biocompatibility of the hydrogels was confirmed using an MTT assay (indirect cytotoxicity) and by monitoring cell proliferation in contact with the gels (direct cytotoxicity)

Novel poly(L-lactic acid)/hyaluronic acid macroporous hybrid scaffolds : characterization and assessment of cytotoxicity

Poly(L-lactic acid), PLLA, a synthetic biodegradable polyester, is widely accepted in tissue engineering. Hyaluronic acid (HA), a natural polymer, exhibits an excellent biocompatibility, influences cell signaling, proliferation, and differentiation. In this study, HA crosslinking was performed by immersion of the polysaccharide in water-acetone mixtures containing glutaraldehyde (GA). The objective of this work is to produce PLLA scaffolds with the pores coated with HA, that could be beneficial for bone tissue engineering applications. PLLA tridimensional scaffolds were prepared by compression molding followed by salt leaching. After the scaffolds impregnation with soluble HA solutions of distinct concentration, a GA-crosslinking reaction followed by inactivation of the unreacted GA with glycine was carried out. An increase on surface roughness is shown by scanning electron microscopy (SEM) with the addition of HA. Toluidine blue staining indicates the present of stable crosslinked HA. An estimation of the HA original weight in the hybrid scaffolds was performed using thermal gravimetric analyses. FTIR-ATR and XPS confirmed the crosslinking reaction. Preliminary in vitro cell culture studies were carried out using a mouse lung fibroblast cell line (L929). SEM micrographs of L929 showed that cells adhered well, spread actively throughout all scaffolds, and grew favorably. A MTS test indicated that cells were viable when cultured onto the surface of all scaffolds, suggesting that the introduction of crosslinked HA did not increase the cytotoxicity of the hybrid scaffolds.Contract grant sponsor: Portuguese Foundation for Science and Technology (FCT) through POCTIContract grant sponsor: FEDER programs including project ProteoLight; contract grant number: PTDC/FIS/68517/2006Contract grant sponsor: European Union funded STREP Project HIPPOCRATES; contract grant number: NMP3-CT-2003-505758Contract grant sponsor: European NoE EXPERTISSUES; contract grant number: NMP3-CT-2004-500283Contract grant sponsor: Spanish Ministry of Science (The FEDER financial support); contract grant number: MAT2007-66759-C03-01The authors acknowledge the funding for research in the field of Regenerative Medicine through the collaboration agreement from the Conselleria de Sanidad (Generalitat Valenciana) and the Instituto de Salud Carlos III (Ministry of Science and Innovation). The European Union Financing, as part of the SOCRA-TES/Erasmus program is also gratefully acknowledged

Доказательная база отсутствия связи между профилактическими прививками и расстройствами аутистического спектра (обзор литературы)

The etiology of autism spectrum disorders still remains unclear. Recently a number of research have emerged linking the increment of vaccination in population and the increased frequency of autism spectrum disorders. In this review we analyzed the most representational studies on this issue. The main hypotheses linking autism spectrum disorders and vaccination were identified: association of vaccination against measles and enteropathy caused by the components of the measles virus vaccine strain which indirectly affects the brain; the onset of autism symptoms as a result of postvaccine encephalitis due to the use of various vaccines: the Measles, Mumps, Rubella vaccine, Diphtheria, Pertussis, Tetanus vaccine; the effect of multivaccine on the development of autism spectrum disorders; the effect of individual components of vaccines, particularly thimerosal, on the development of childhood autism and similar conditions. The data of epidemiological studies that refute these hypotheses were presented. Large samples in these studies provide a level of statistical significance sufficient enough to reveal even rare statistical associations. These results actually disproved the notion that vaccines cause autism.Расстройства аутистического спектра — это группа патологических состояний, с неясной этиологией. В последнее время появился ряд работ, связывающих рост вакцинирования с увеличением аутистических расстройств. В обзоре проанализированы наиболее репрезентативные работы, посвященные данной проблеме. Выделены основные гипотезы, связывающие аутизм и вакцинацию: связь противокоревой вакцинации с энтеропатией, вызванной компонентами вакцинального вируса кори, опосредованно влияющей на головной мозг; возникновение симптомов аутизма в связи с поствакцинальным энцефалитом вследствие применения различных вакцин «Корь-краснуха-паротит», «Коклюшдифтерия-столбняк»; влияние поливакцинации на развитие расстройств аутистического спектра; влияние отдельных компонентов профилактических прививок, в частности тимеросала, на развитие детского аутизма и сходных состояний. Представлены данные эпидемиологических исследований, которые опровергают данные гипотезы. Большая выборка популяций обеспечивает уровень статистической достоверности, достаточный для выявления даже редких взаимосвязей. Данные результаты фактически опровергли мнение о том, что вакцины вызывают аутизм