Purpose
The aim of this research was to study the interplay of solid and solution state phase transformations during the dissolution of ritonavir (RTV) amorphous solid dispersions (ASDs).
Methods
RTV ...ASDs with polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) were prepared at 10–50% drug loading by solvent evaporation. The miscibility of RTV ASDs was studied before and after exposure to 97% relative humidity (RH). Non-sink dissolution studies were performed on fresh and moisture-exposed ASDs. RTV and polymer release were monitored using ultraviolet-visible spectroscopy. Techniques including fluorescence spectroscopy, confocal imaging, scanning electron microscopy (SEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC) and nanoparticle tracking analysis (NTA) were utilized to monitor solid and the solution state phase transformations.
Results
All RTV-PVP and RTV-PVPVA ASDs underwent moisture-induced amorphous-amorphous phase separation (AAPS) on high RH storage whereas RTV-HPMCAS ASDs remained miscible. Non-sink dissolution of PVP- and PVPVA-based ASDs at low drug loadings led to rapid RTV and polymer release resulting in concentrations in excess of amorphous solubility, liquid-liquid phase separation (LLPS) and amorphous nanodroplet formation. High drug loading PVP- and PVPVA-based ASDs did not exhibit LLPS upon dissolution as a consequence of extensive AAPS in the hydrated ASD matrix. All RTV-HPMCAS ASDs led to LLPS upon dissolution.
Conclusions
RTV ASD dissolution is governed by a competition between the dissolution rate and the rate of phase separation in the hydrated ASD matrix. LLPS was observed for ASDs where the drug release was polymer controlled and only ASDs that remained miscible during the initial phase of dissolution led to LLPS. Techniques such as fluorescence spectroscopy, confocal imaging and SEM were useful in understanding the phase behavior of ASDs upon hydration and dissolution and were helpful in elucidating the mechanism of generation of amorphous nanodroplets.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We study the second order nonlinear optical properties of GaAs quantum dot embedded in Ga
1-y
Al
y
As matrix. The effective mass approximation with the finite confinement potential is used to obtain ...intraband energy levels and the wavefunctions. Within the framework of density matrix formulation, including the dipole and quadrupole effects the second harmonic generation, the sum frequency generation and the difference frequency generation nonlinear optical processes are investigated in THz region for different dot radii of GaAs quantum dot.
Graphic abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Ritlecitinib is an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family inhibitor undergoing parallel clinical development for alopecia areata, vitiligo, ...ulcerative colitis, Crohn’s disease, and rheumatoid arthritis.
Objective
As studies read out simultaneously, strategic planning of population pharmacokinetic model development and evaluation is required to ensure timely decisions.
Methods
Data from healthy participants and patients from 12 clinical trials between December 2014 and July 2021 were included: seven phase I studies in healthy participants and organ impairment, five phase II/III studies in patients with rheumatoid arthritis, ulcerative colitis, alopecia areata, and vitiligo. Population pharmacokinetic models consisted of stepwise procedures to accommodate data availability and the model’s application to answering clinical development questions. At each iteration of the model update, parameters of the next model were re-estimated by leveraging previous information and new data.
Results
Three model development lifecycle iterations of the ritlecitinib population pharmacokinetic model were conducted to support alopecia areata, vitiligo, and ulcerative colitis study readouts. Initial structural modeling based on healthy participant data (and some rheumatoid arthritis and alopecia areata data) in iteration 1 provided a platform for comprehensive covariate testing during iteration 2, and model evaluation and implementation of the frequentist prior approach in iteration 3. The final model was a two-compartment model with first-order absorption and direct-response non-stationary clearance and bioavailability driven by concentrations in the peripheral compartment.
Conclusions
The present approach demonstrated the evolution of three population pharmacokinetic models with accumulating data, addressed clinical drug development questions related to systemic exposures of ritlecitinib, and informed the approved product label.
Clinical Trial Registration
NCT02309827, NCT02684760, NCT02958865, NCT02969044, NCT03232905, NCT03732807, NCT04016077, NCT03715829, NCT04037865, NCT04004663, NCT04634565, NCT02974868.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In this article, we develop a mathematical model considering susceptible, exposed, infected, asymptotic, quarantine/isolation and recovered classes as in case of COVID-19 disease. The facility of ...quarantine/isolation have been provided to both exposed and infected classes. Asymptotic individuals either recovered without undergo treatment or moved to infected class after some duration. We have formulated the reproduction number for the proposed model. Elasticity and sensitivity analysis indicates that model is more sensitive towards the transmission rate from exposed to infected classes rather than transmission rate from susceptible to exposed class. Analysis of global stability for the proposed model is studied through Lyapunov’s function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The purpose of this study was to develop a novel fluorescence technique employing environment-sensitive fluorescent probes to study phase separation kinetics in hydrated matrices of amorphous solid ...dispersions (ASDs) following storage at high humidity and during dissolution. The initial miscibility of the ASDs was confirmed using infrared (IR) spectroscopy and differential scanning calorimetry (DSC). Fluorescence spectroscopy, as an independent primary technique, was used together with conventional confirmatory techniques including DSC, X-ray diffraction (XRD), fluorescence microscopy, and IR spectroscopy to study phase separation phenomena. By monitoring the emission characteristics of the environment-sensitive fluorescent probes, it was possible to successfully monitor amorphous–amorphous phase separation (AAPS) as a function of time in probucol–poly(vinylpyrrolidone) (PVP) and ritonavir–PVP ASDs after exposure to water. In contrast, a ritonavir–hydroxypropylmethylcellulose acetate succinate (HPMCAS) ASD, did not show AAPS and was used as a control to demonstrate the capability of the newly developed fluorescence method to differentiate systems that showed no phase separation following exposure to water versus those that did. The results from the fluorescence studies were in good agreement with results obtained using various other complementary techniques. Thus, fluorescence spectroscopy can be utilized as a fast and efficient tool to detect and monitor the kinetics of phase transformations in amorphous solid dispersions during hydration and will help provide mechanistic insight into the stability and dissolution behavior of amorphous solid dispersions.
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IJS, KILJ, NUK, PNG, UL, UM
Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on ...lesional measures of disease severity are not yet well defined.
This phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n = 40) with mild-to-moderate AD.
Two target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Patients then applied crisaborole (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15.
Crisaborole treatment resulted in early improvement in lesional signs/symptoms versus vehicle, with improvement in pruritus (pruritus numeric rating scale) observed as early as 24 hours after the first application. Crisaborole-treated lesions showed significant percentage improvement from baseline in lesional transcriptomic profile compared with vehicle at day 8 (91.15% vs 36.02%, P < 10−15) that was sustained until day 15 (92.90% vs 49.59%, P < 10−15). Crisaborole significantly modulated key AD biomarkers versus vehicle, including TH2 and TH17/TH22 pathways and epidermal hyperplasia/proliferation. Molecular profiles and epidermal pathology normalized toward nonlesional skin and correlated with clinical changes in lesion severity and barrier function.
Crisaborole reversed biomarker profiles of skin inflammation and barrier function, with associated improvements in clinical efficacy measures, highlighting the therapeutic utility of targeting phosphodiesterase 4 in patients with AD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
The Tokamak plasma start-up is the first process to have a successful Tokamak plasma discharge. Considering the start-up condition, high electric field and neutral density with the absence ...of flux surfaces an enhanced electron transport to the Plasma-Facing Components (PFC) or the inner vessel wall is expected. Such electron excursion under an applied electric field induces electromagnetic emission, especially in the x-ray region. Such emission is important as it gives vital information about the initial condition of the plasma start-up and the potential for energy loss to the PFC/vessel walls. A Silicon Drift Detector (SDD) based soft x-ray (SX) spectrometer is installed at the ADITYA-U tokamak, operating within the range of 1–30 keV generating a 4 K channel spectrum. The energy calibration, spectra transformation from channel space to the energy space, is a pre-requisite for any spectroscopic measurement. The calibration is performed by natural radioactive sources
241
Am,
109
Cd,
133
Ba, and
55
Fe having micro-curie strength. Two-point and multipoint calibrations are applied to the SDD spectra. The results from the two processes establish that the multipoint calibration works well for the identification of the photon energy due to the realization of the detector linearity for a wider band.
In this study, we present and examine a fractional integral operator with an
I$$ I $$‐function in its kernel. This operator is used to solve several fractional differential equations (FDEs). FDE has ...a set of particular cases whose solutions represent different physical phenomena. Much mathematical physics, biology, engineering, and chemistry problems are identified and solved using FDE. We first solve the FDE and the integral operator for the incomplete
I$$ I $$‐function (I
I$$ I $$F) for the generalized composite fractional derivative (GCFD). This is followed by the discovery and investigation of several important exceptional cases. The significant finding of this study is a first‐order integer‐differential equation of the Volterra type that clearly describes the unsaturated nature of free‐electron lasers.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In this paper, we discuss the phenomenon of miscible flow with longitudinal dispersion in porous media. This process simultaneously occur because of molecular diffusion and convection. Here, we ...analyze the governing differential equation involving Caputo-Fabrizio fractional derivative operator having non singular kernel. Fixed point theorem has been used to prove the uniqueness and existence of the solution of governing differential equation. We apply Laplace transform and use technique of iterative method to obtain the solution. Few applications of the main result are discussed by taking different initial conditions to observe the effect on derivatives of different fractional order on the concentration of miscible fluids.
The iron and steelmaking industry is actively seeking to reduce its overall carbon footprint with major research and investment directed towards fossil fuel-free steelmaking. In this paper, we ...present a novel iron ore agglomeration process that produces a Lime Magnetite Pellet (LMP) feed using concentrated solar flux as the energy source that significantly reduces the CO2 emissions compared to existing pellet making processes. The process has been tested under laboratory experiments inside a solar simulator-electric furnace hybrid reactor setup. A detailed mass and energy balance analysis of the process was conducted for estimation of the emission reduction as well as for estimating the solar flux requirement at various percentages of fuel to solar flux substitution. The preliminary economics of the solar-based LMP process was also investigated. The estimated capital cost of a 2 Mtpa (million tonnes per annum) plant was between AU$165 M and AU$142 M assuming a solar reactor thermal efficiency of 50% and 80%, respectively. The payback period was likely to be 15–20 years (50% efficiency) and 7–9 years (80%). At current achievable reactor efficiencies, a solar-based LMP process is not economically attractive. However, with further development in reactor design, heliostat cost reductions and improvements in thermal storage performance, a solar-based LMP process could potentially be commercialised.
•Iron and steel making industry is one of the highest producers of CO2.•A novel lower carbon-footprint solar-iron ore agglomeration process is proposed.•Experimental results from solar simulator-hybrid reactor setup is presented.•Potential reduction in CO2 emission with solar integration is estimated.•Techno-economics of the solar-agglomeration process is presented.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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