Molecular and Structural Stability of Infliximab: Spray-Dried Powder versus Freeze-Dried Cake.

he current study compared the stability of Infliximab powder following 2 drying procedures namely spray drying and freeze drying. Introduction: Infliximab as a chimeric anti-TNFα monoclonal antibody was approved for the treatment of inflammatory diseases namely Crohn's disease and rheumatoid arthritis. In prospect of preparing stable formulation of Infliximab, freeze drying and spray drying were compared as processing method. Methods and Results: Spray-dried formulation was prepared in the presence of Trehalose and Sucrose besides Cysteine. Powders were characterized via SEC-HPLC to quantify the level of induced aggregates/fragments after process along with upon 1 and 3 months of storage at 45̊C. Kinetic of aggregation and fragmentation was calculated for each sample. FTIR-spectroscopic assessments were employed to determine the secondary structure of antibody. Trehalose generated more stable particle within spray drying, with least aggregation and fragmentation rate constants of 0.22 and 0.27 (1/month). Combination of Cysteine and Trehalose significantly reduced aggregation upto 0.87, 1.07 and 2.26 % after process, up on 1 and 3 months of storage (rate constant of aggregation of 0.14,(1/month)). Fragmentation was 0.31, 0.38 and 0.98 % respectively with 0.17 (1/month) rate constant of fragmentation. The induced aggregates in Remicade were 0.11, 0.18 and 0.32% (aggregation rate constant:0.15 (1/month)) and fragments were 0.1, 0.14 and 0.29% after process, 1 month and 3 months at 45̊C (fragmentation rate constant of 0.15 (1/month)). The conformation of antibody was shown to be composed of 66.68% and 69.43% beta-sheet in spray-dried powder and freeze-dried cake (Remicade®) respectively. Conclusions: This study demonstrated that, both spray drying and freeze drying may be efficient for powder production of Infliximab with regards to molecular and structural stability after storage at high temperatures

Analysis of saturation effects on the operation of magnetic-controlled switcher type FCL

With the extensive application of electrical power system, suppression of fault current limiter is an important subject that guarantees system security. The superconducting fault current limiters (SFCL) have been expected as a possible type of power apparatus to reduce the fault current in the power system. The results shown that under normal state, the FCL has no obvious effect on the power system; under fault state, the current limiting inductance connected in the bias current will be inserted into the fault circuit to limit the fault current. By regulating the bias current, the FCL voltage loss under normal state and the fault current can be adjusted to prescribed level. This kind of SFCL used the nonlinear permeability of the magnetic core for create a sufficient impedance and The transient performance considering the magnetic saturation is analyzed by Preisach model. Preisach model that intrinsically satisfies nonlinear properties is used as the numerical method for analysis of saturation effects. It is able to identification isotropic and no isotropic behaviour. The main idea is to compute the magnetization vector in two steps independently, amplitude and phase. The described model yield results in qualitative agreement with the experimental results

A Review on Suggested Mechanisms in Thrombocytopenia and Thrombosis Following ChAdOx1 nCoV-19 Vaccination

Background: ChAdOx1 nCov-19 vaccine is a viral vector-based vaccine with desirable protection (about 70.4%, two weeks after the second dose). Few reports were released on thrombocytopenia associated with thrombotic events shortly after the ChAdOx1 nCov-19 vaccination. However, the exact pathophysiologic mechanism of this vaccineinduced thrombotic complication has not yet been elucidated. Vaccine-induced thrombotic thrombocytopenia syndrome (VITTS) is associated with detecting anti-platelet factor 4 (PF4) antibodies that are not yet linked to previous exposure to heparin. Materials and Methods: In the current review, based on relevantly reported cases, possible mechanisms are suggested on the relationship between the anti-platelet factor 4 (anti-PF4) antibody assays, previous exposure to heparin, and the involved mechanisms of post-vaccination thrombocytopenia and thrombotic events, which might help the experts for selecting the appropriate therapeutic measures. Results: Possibly involved mechanisms in VITTS after ChAdOx1 nCoV-19 vaccination include binding of anti-PF4 antibodies to heparin/PF4 complex or receptor-binding domain (RBD) protein-PF4 complex. Another mechanism could be the binding of anti-RBD antibodies to the RBD protein-PF4 complex. Finally, anti-RBD or anti-PF4 antibodies may bind to the heparin-RBD protein-PF4 complex. The binding of either of the mentioned antibodies to these complexes via the Fc/angiotensin-converting enzyme 2 receptors can cause activation/removal of platelets leading to thrombocytopenia and thrombosis. Conclusion: The suggested mechanisms in this article provide a relationship between the results of anti-PF4 antibody assays, previous exposure to heparin, and the involved mechanisms of post-vaccination thrombocytopenia and thrombotic events, which might help the experts in selecting the therapeutic measures

Salinomycin nanoparticles interfere with tumor cell growth and the tumor microenvironment in an orthotopic model of pancreatic cancer

<p><b>Aims:</b> Recently, salinomycin (SAL) has been reported to inhibit proliferation and induce apoptosis in various tumors. The aim of this study was to deliver SAL to orthotopic model of pancreatic cancer by the aid of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs).</p> <p><b>Methods:</b> The NPs were physico-chemically characterized and evaluated for cytotoxicity on luciferase-transduced AsPC-1 cells <i>in vitro</i> as well as implanted orthotopically into the pancreas of nude mice.</p> <p><b>Results:</b> SAL (3.5 mg/kg every other day) blocked tumor growth by 52% compared to the control group after 3 weeks of therapy. Western blotting of tumor protein extracts indicated that SAL treatment leads to up-regulation of E-cadherin, <i>β</i>-catenin, and transforming growth factor beta receptor (TGF<i>β</i>R) expressions in AsPC-1 orthotopic tumor. Noteworthy, immunofluorescence staining of adjacent tumor sections showed that treatment with SAL NPs cause significant apoptosis in the tumor cells rather than the stroma. Further investigations also revealed that TGF<i>β</i>R2 over-expression was induced in stroma cells after treatment with SAL NPs.</p> <p><b>Conclusion:</b> These results highlight SAL-loaded PLGA NPs as a promising system for pancreatic cancer treatment, while the mechanistic questions need to be subsequently tested.</p

A Comparative Study to Evaluate the Effect of Different Carbohydrates on the Stability of Immunoglobulin G during Lyophilization and Following Storage

Background: Although the stabilizing effects of cyclodextrins (CDs) on the liquid protein formulations have been proven, there is no comprehensive data on evaluation of their effects on the lyophilized antibody powders. In this study, the influence of two CD derivatives namely beta-cyclodextrin (βCD) and hydroxypropyl beta-cyclodextrin (HPβCD) was compared with trehalose and mannitol regarding the molecular and thermodynamic stability of lyophilized IgG formulations as well as its biological activity. Methods: Sugars were separately added to IgG solutions and lyophilization process was conducted. In each group of carbohydrates, the formulations with lowest amounts of aggregates were examined regarding the biological activity. The storage stability of selected formulations was subsequently determined following 1 and 3 month of storage at 45 °C. Results: Trehalose and HPβCD in the ratios of 80% showed the most stabilizing effects by control of aggregated forms in the orders of 1.02% and 0.83%, respectively. Also, it was shown that trehalose and HPβCD could incomparably preserve IgG activity in values of 100% and 96.5%. The results of DSC and SEM analysis confirmed the existence of crystalline parts in mannitol and βCD formulations of antibody. During the storage time, the lowest rate constant of aggregation was observed in formulations containing trehalose 80% (0.16/month). All prepared formulations were beta-dominant and no fragmentation was detected. Conclusion: Molecular, thermodynamic and biological stability of lyophilized IgG was more desirable in the presence of trehalose and HPβCD in comparison to mannitol and βCD