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Meredith Lane opublikował 5 miesięcy, 1 tydzień temu
Astrogliosis has a unique reaction during spinal cord damage, with helpful or adverse impacts on recovery. There is consequently a pressing need for treatment to target activated astrocytes and their unsafe response after injury to ensure some preservative effect during the progressive damage. We specifically developed and characterized a functionalized nanogel-based nanovector in vitro and in vivo, demonstrating its selectivity towards astrocytes, and limited uptake by macrophages when functionalized with both NH2 and Cy5 groups. In vitro experiments showed that the internalization was mediated by a clathrin-dependent endocytic pathway. After internalization into the cytoplasm of astrocytes, nanogels undergo lysosomal degradation and release compounds with potential therapeutic efficacy.New drugs are frequently found with poor water-solubility in recent pharmaceutical projects, which brings difficulties of bioavailability for the clinical development of new drugs. When these drug compounds in a crystalline state are absorbed by gastrointestinal tract, their dissolution rates and absorption rates are very limited. Nowadays, various methods have been developed to improve the solubility, dissolution and bioavailability of drugs. According to the characteristics of drugs, this work suggests the use of spray drying technology to amorphize APIs (active pharmaceutical ingredients) to improve their bioavailability. This work reviews the properties of the spray-dried amorphous drugs, the progress made in drug synthesis and application, and the existing problems.The purpose of this study was to optimize the melt granulation process of fenofibrate using twin-screw granulator. Initial screening was performed to select the excipients required for melt granulation process. A 3 × 3 factorial design was used to optimize the processing conditions using the % drug loading (X1) and screw speed (X2) as the independent parameters and granule friability (Y1) % yield (Y2) as the dependent parameters. The effect of the independent parameters on the dependent parameters was determined using response surface plots and contour plots. A linear relationship was observed between % drug loading (X1) and % friability (Y1) and a quadratic relationship was observed between the independent parameters (X1 and X2) and % yield (Y2). The processing conditions for optimum granules were determined using numerical and graphical optimization and it was found that 15% drug loading at 50 rpm results in maximum % yield of 82.38% and minimum friability of 7.88%. The solid-state characterization of the optimized granules showed that the drug turned from crystalline state to amorphous state during melt granulation process. The optimized granules were compressed into tablets using Purolite® as the super disintegrating agent. The optimized formulation showed >85% drug release in 0.75% SLS solution within 60 min.Therapeutic monoclonal antibodies and related products have steadily grown to become the dominant product class within the biopharmaceutical market. Production of antibodies requires special precautions to ensure safety and efficacy of the product. In particular, minimizing antibody product heterogeneity is crucial as drug substance variants may impair the activity, efficacy, safety, and pharmacokinetic properties of an antibody, consequently resulting in the failure of a product in pre-clinical and clinical development. This review will cover the manufacturing and formulation challenges and advances of therapeutic monoclonal antibodies, focusing on improved processes to minimize variants and ensure batch-to-batch consistency. Processes put in place by regulatory agencies, such as Quality-by-Design (QbD) and current Good Manufacturing Practices (cGMP), and how their implementation has aided drug development in pharmaceutical companies will be reviewed. Advances in formulation and considerations on the intended use of a therapeutic antibody, including the route of administration and patient compliance, will be discussed.Acetaminophen, a central antipyretic and analgesic drug, is one of the most commonly used drugs among individuals of all ages throughout the world. This study pharmacokinetically and pharmacodynamically investigated the transport of acetaminophen to the central nervous system and systemic circulation after intranasal (i.n.) administration, and evaluated the potential of a transnasal acetaminophen formulation in comparison to other routes of administration. Direct transport to the brain and the pharmacological effect after the i.n. administration of acetaminophen with polyvinylpyrrolidone (PVP; a mucoadhesive agent) and poly-l-arginine (PLA; an absorption enhancer) were investigated to improve retention of the dosage solution in the olfactory epithelium region and enhance the transfer of acetaminophen to the brain. The transport of acetaminophen to the brain was rapid, and the concentration in the brain, especially the olfactory bulb, was higher after i.n. administration, resulting in a greater antipyretic effect in comparison to other routes of administration. The delivery system using PVP and PLA produced a high and prolonged antipyretic effect by enhancing the transfer of acetaminophen to the brain through suppression of the transfer to systemic circulation. Thus, this transnasal drug delivery system using PVP and PLA may be a promising method for transporting acetaminophen to the brain.In an attempt to optimize the anti- hyperlipidemic effect and reduce statins induced hepatotoxicity, Atorvastatin Calcium (ATC) transdermal proniosomal gel (PNG) was developed. Different non-ionic surfactants (NISs) (Spans, Tweens, Cremophor RH 40 and Brij 52) were incorporated in the vesicle’s lipid bilayer, in combination with lecithin. PNG formulae were characterized for encapsulation efficiency percent (% EE), vesicle size, polydispersity index (PDI) and zeta potential (ZP). Ex-vivo permeation study was performed using full thickness rat skin measuring drug flux and skin permeability coefficients. The pharmacodynamic performance of optimized transdermal ATC- PNG on both lipid profile and liver biomarkers was assessed and compared to oral ATC administration in poloxamer 407-induced hyperlipidemic rats. The liver tissues were subjected to histological examination as well. The results revealed nano-size range vesicles with relatively high ATC entrapment efficiency. Ex-vivo results demonstrated the permeation superiority of ATC proniosomes over free drug. Pharmacodynamic study revealed that transdermal administration of ATC- PNG succeeded in retaining the anti-hyperlipidemic efficacy of orally administered ATC without elevating liver biomarkers. The histological examination signified the role of optimized ATC-PNG in hindering statin- induced hepatocellular damage. The obtained results suggested a promising, easy-to-manufacture and effective ATC proniosomal gel for safe treatment of hyperlipidemia.Current treatment for pelvic organ prolapse (POP) and stress urinary incontinence (SUI) involves transvaginal implantation of surgical mesh, conventionally made of polypropylene (PP). However, it has recently become apparent that the mechanical properties of PP are unsuitable, resulting in serious complications such as tissue erosion. In this study, thermoplastic polyurethane (TPU) was chosen as an alternative material, and hormone-loaded meshes were produced by fused deposition modelling (FDM). Filaments containing various concentrations (0%, 0.25%, 1%) of 17-β-estradiol (E2) were prepared by hot-melt extrusion (HME) and were 3D printed into meshes with various geometries. The resulting meshes were characterised through a variety of instruments such as attenuated total reflection-Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), thermal analysis, fracture force and in vitro release studies. The results showed that E2 was homogeneously distributed throughout the TPU matrix. Moreover, the thermogravimetric analysis (TGA) showed degradation temperatures above those used during the FDM process, showing that the meshes can be produced below the degradation temperatures of the materials. The fracture force testing showed that material and mesh geometry influence mechanical properties, with TPU meshes appearing more elastic and therefore more suitable for pelvic floor repair than PP mesh. However, interestingly the mechanical properties of the TPU70 filament was not affected by the inclusion of E2. In addition, the 3D printed meshes showed a linear E2 release profile over a two weeks period, which can be modified according to the percentage of E2 added to the 3D printed construct. This proof of concept study demonstrates the potential of using FDM to create a new generation of safer mesh implants.Determination of an equilibrium pH value in complex aqueous solution and deconvolution of this equilibrium to evaluate phenomena related to mixing, dilution, or progress of reaction is increasingly important in areas ranging from water quality to pharmaceutical formulations and manufacturing. Linearization of pH problems by simple algebraic substitution enables equilibria within complex buffered aqueous solutions to be modeled as an eigenvalue problem. This formulation approach makes rigorous determination of equilibrium pH values and reactor dynamics more accessible than with previous calculation methods, even when activity coefficients and non-ideality are considered. This work demonstrates how such calculations can enable detailed modeling of enthalpic changes in an isothermal titration calorimeter. In support of this work, the acid dissociation constants for three furancarboxylic acids (2-furancarboxylic acid, FA; 5-formyl-2-furancarboxylic acid, FFA; and 2,5-furandicarboxylic acid, FDCA), two of them novel, were determined and compared with multi-wavelength ultraviolet-visible spectrophotometry. The thermodynamic pKa values were determined to be 3.1 for FA, 2.2 for FFA, and 2.1 and 3.4 for the first and second ionization steps of FDCA, respectively.The potential application of human embryonic stem cells in regenerative medicine using cell, tissue or organ transplantation has aroused great interest. However, HLA incompatibility between donor cells or tissues and the recipient is a primary obstacle to the use of unmatched human embryonic stem cells and their derivatives as donor 'grafts’ for patient treatment without some form of immunosuppressive therapy. This is because, for most tissues, which express HLA Class I antigens, the recipient patient’s immune system will recognize the difference between their and the donor’s HLA types, leading to graft rejection in the absence of immunosuppressive therapy. One approach to overcoming this obstacle and enabling the use of a single or limited range of suitably selected human embryonic stem cells and their derivatives without needing extensive HLA matching is to use gene-editing technology to establish a universally or widely HLA compatible human embryonic stem cell line, thereby providing a potentially unlimited source of cells for future cell, tissue or organ transplantation. This article reviews current strategies and methods for establishing such universal or near universally HLA compatible human embryonic stem cell lines.