Development of a Once-Daily Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772 using DiffCORE Technology

Purpose GSK2982772 is a selective inhibitor of receptor-interacting protein kinase-1 (RIPK1) with a short 2- to 3-h half-life. In a previous modified-release (MR) study, a matrix monolithic formulation (80% GSK2982772 released over 12 h) provided a once-daily (QD) pharmacokinetic (PK) profile in the fasted state; however, it was susceptible to food effects. The current study evaluated the safety and PK of MR formulations using GSK proprietary DiffCORE™ technology. Methods Part A evaluated PK following single-dose (240 mg) fasted and fed (high-fat meal) administration of three DiffCORE MR formulations within pre-defined in vitro extremes of 80% GSK2982772 released over 12 h (MR-12 h) to 80% GSK2982772 released over 18 h (MR-18 h) versus an immediate-release formulation. Part B evaluated MR-16 h (120–960 mg) in different prandial states. Results Pharmacokinetic profiles for all MR formulations and doses tested in the fasted and fed states were consistent with QD dosing. Conclusions The DiffCORE technology overcame the food effect vulnerability observed with the matrix monolithic formulation. The MR-16 h formulation was selected for further clinical development as a QD dosing regimen (NCT03649412 September 26, 2018).

AC loss simulation in a HTS 3-Phase 1 MVA transformer using H formulation

One of critical issues for HTS transformers is achieving sufficiently low AC loss in the windings. Therefore, accurate prediction of AC loss is critical for the HTS transformer applications. In this work, we present AC loss simulation results employing the H-formulation for a 1 MVA 3-Phase HTS transformer. The high voltage (HV) windings are composed of 24 double pancakes per phase wound with 4 mm – wide YBCO wire. Each double pancake coil has 38 ¼ turns. The low voltage (LV) windings are 20 turn single-layer solenoid windings wound with 15/5 (15 strands of 5 mm width) Roebel cable per phase. The numerical method was first verified by comparing the numerical and experimental AC loss results for two coil assemblies composed of two and six double pancake coils (DPCs). The numerical AC loss calculated for the transformer was compared with the measured AC loss as well as the numerical result obtained using the minimum magnetic energy variation (MMEV) method. The numerical AC loss result in this work and experimental result as well as the numerical result using MMEV at the rated current agree to within 20%. Further simulations were carried out to explore the dependence of the AC loss on the gap between the turns of the LV winding. The minimum AC loss at rated current in the 1 MVA HTS transformer appears when the gap between turns is approximately 2.1 mm turn gap in the LV winding. This is due to the change of relative heights between the HV and LV windings which results in optimal radial magnetic field cancellation. The same numerical method can be applied to calculate AC loss in larger rating HTS transformers. © This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/

AC loss simulation in a HTS 3-Phase 1 MVA transformer using H formulation

One of critical issues for HTS transformers is achieving sufficiently low AC loss in the windings. Therefore, accurate prediction of AC loss is critical for the HTS transformer applications. In this work, we present AC loss simulation results employing the H-formulation for a 1 MVA 3-Phase HTS transformer. The high voltage (HV) windings are composed of 24 double pancakes per phase wound with 4 mm – wide YBCO wire. Each double pancake coil has 38 ¼ turns. The low voltage (LV) windings are 20 turn single-layer solenoid windings wound with 15/5 (15 strands of 5 mm width) Roebel cable per phase. The numerical method was first verified by comparing the numerical and experimental AC loss results for two coil assemblies composed of two and six double pancake coils (DPCs). The numerical AC loss calculated for the transformer was compared with the measured AC loss as well as the numerical result obtained using the minimum magnetic energy variation (MMEV) method. The numerical AC loss result in this work and experimental result as well as the numerical result using MMEV at the rated current agree to within 20%. Further simulations were carried out to explore the dependence of the AC loss on the gap between the turns of the LV winding. The minimum AC loss at rated current in the 1 MVA HTS transformer appears when the gap between turns is approximately 2.1 mm turn gap in the LV winding. This is due to the change of relative heights between the HV and LV windings which results in optimal radial magnetic field cancellation. The same numerical method can be applied to calculate AC loss in larger rating HTS transformers. © This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/

Angle-dependence of the levitation force from a frustum-shaped magnet and recessed superconducting bulk

IEEE The widespread application of superconducting magnetic levitation bearings is limited by their relatively low stiffness. Recently we investigated a novel thrust bearing geometry comprised of a conical frustum (or truncated cone) shaped permanent magnet levitating inside a matching tapered hole machined into a high-temperature superconductor bulk. This configuration was found to produce superior restoring forces and stiffness compared to the conventional cylindrical magnet and superconductor arrangement. Here, using H-formulation finite-element simulations, we evaluate the angle-dependence of the frustum on the levitation force. We find that the optimal angle is not universal, but depends on the mode of displacement as well as the frustum dimensions. Correlations with the incident magnetic flux are identified for estimating the angle best suited to the operating regime of the bearing.

Angle-dependence of the levitation force from a frustum-shaped magnet and recessed superconducting bulk

IEEE The widespread application of superconducting magnetic levitation bearings is limited by their relatively low stiffness. Recently we investigated a novel thrust bearing geometry comprised of a conical frustum (or truncated cone) shaped permanent magnet levitating inside a matching tapered hole machined into a high-temperature superconductor bulk. This configuration was found to produce superior restoring forces and stiffness compared to the conventional cylindrical magnet and superconductor arrangement. Here, using H-formulation finite-element simulations, we evaluate the angle-dependence of the frustum on the levitation force. We find that the optimal angle is not universal, but depends on the mode of displacement as well as the frustum dimensions. Correlations with the incident magnetic flux are identified for estimating the angle best suited to the operating regime of the bearing.

Trapped field characteristics of an HTS magnet with two holes using four magnetization methods

High temperature superconducting (HTS) magnets have widespread applications in a strong and steady magnetic field at low temperature. However, they can not be operated in persistent current mode (PCM) due to their immature joint technique without resistance. In order to realize the PCM, an HTS magnet stacked by double-hole rectangular HTS plates was proposed and fabricated. The trapped field of the HTS magnet was measured and simulated under four kinds of magnetization methods, field cooling (FC), zero field cooling (ZFC) and inner magnetization (a solenoid is placed at right/left hole of double-hole rectangular HTS magnet to magnetize HTS magnet) as well as combination of both methods. Meanwhile, the H-formulation is applied to the 3D model to analyze the electromagnetic behaviour. It was found that the trapped field of double-hole rectangular HTS magnet magnetized by FC with inner magnetization or ZFC with inner magnetization is higher than pure FC or ZFC magnetization. In inner magnetization, the trapped field of one hole in HTS magnet has no effect on the other one. In addition, the experiment results are in good agreement with numerical analysis, which can provide significant references for the magnetization method.