Browsing by Author "Masania, Jinit"

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    Artemisinin Cocrystals for Bioavailability Enhancement. Part 1: Formulation Design and Role of the Polymeric Excipient
    (ACS, 2021-11-01) Kaur, Manreet; Yardley, Vanessa; Wang, Ke; Masania, Jinit; Botana, Adolfo; Arroo, R. R. J.; Li, M.
    Artemisinin (ART) is a most promising antimalarial agent, which is both effective and well-tolerated in patients, though it has therapeutic limitations due to its low solubility, bioavailability and short half-life. The objective of this work was to explore the possibility of formulating ART cocrystals, i.e., artemisinin-orcinol (ART-ORC) and artemisinin-resorcinol (ART2-RES) as oral dosage forms to deliver ART molecules for bioavailability enhancement. This is the first part of the study, aiming to develop a simple and effective formulation which can then be tested on an appropriate animal model (i.e. mouse selected for in vivo study) to evaluate their preclinical pharmacokinetics for further development. In the current work, the physicochemical properties (i.e., solubility and dissolution rate) of ART cocrystals were measured to collect information necessary for the formulation development strategy. It was found that the ART solubility can be increased significantly by its cocrystals, i.e., 26-fold by ART-ORC and 21-fold by ART2-RES respectively. Screening a set of polymers widely used in pharmaceutical products, including Polyvinylpyrrolidone, Hydroxypropyl Methylcellulose and Hydroxypropyl Methylcellulose Acetate Succinate, based on the powder dissolution performance parameter analysis, revealed that Polyvinylpyrrolidone/vinyl Acetate (PVP-VA) was the most effective crystallisation inhibitor. The optimal concentration of PVP-VA at 0.05 mg/mL for the formulation was then determined by a dissolution/permeability method which represented a simplified permeation model to simultaneously evaluate the effects of a crystallization inhibitor on the dissolution and permeation performance of ART cocrystals. Furthermore, experiments, including surface dissolution of single ART cocrystals monitored by Raman spectroscopy and SEM and diffusion properties of ART in solution measured by 1H and diffusion-ordered spectroscopy (DOSY) nuclear magnetic resonance (NMR) spectroscopy, provided insight into how the excipient affects the ART cocrystal dissolution performance and bioavailability.
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    Artemisinin Cocrystals for Bioavailability Enhancement: Part 2. In-vivo Bioavailability and PBPK Modelling
    (ACS, 2021-11-08) Kaur, Manreet; Yardley, Vanessa; Wang, Ke; Masania, Jinit; Arroo, R. R. J.; Turner, David B.; Li, M.
    We report the evaluation and prediction of the pharmacokinetic (PK) performance of artemisinin (ART) cocrystal formulations, i.e., 1:1 Artemisinin-Orcinol (ART-ORC) and 2:1 Artemisinin-Resorcinol (ART2-RES), using in vivo murine animal and PBPK (physiological based pharmacokinetic) models. The efficacy of the ART cocrystal formulations along with the parent drug ART were tested in mice infected with Plasmodium berghei. When given at the same dose, the ART-cocrystal formulation showed a significant reduction in parasitaemia at day 4 post infection compared to ART alone. The PK parameters including Cmax (maximum plasma concentration), Tmax (time to Cmax), AUC (area under the curve) were obtained by determining drug concentrations in the plasma using LC-HRMS (Liquid Chromatography-High Resolution Mass Spectrometry), showing enhanced ART levels after dosage with the cocrystal formulations. The dose-response tests revealed that a significantly lower dose of the ART cocrystals in the formulation was required to achieve a similar therapeutic effect as ART alone. A PBPK model was developed using a PBPK mouse simulator to accurately predict the in vivo behaviour of the cocrystal formulations by combining in vitro dissolution profiles with the properties of the parent drug ART. The study illustrated that information from classical in vitro and in vivo experimental investigations of the parent drug of ART formulation can be coupled with PBPK modelling to predict the PK parameters of an ART cocrystal formulation in an efficient manner. Therefore, the proposed modelling strategy could be used to establish in vitro and in vivo correlations for different cocrystals intended to improve dissolution properties and to support clinical candidate selection, contributing to assessment of cocrystal developability and formulation development.
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    Benchtop NMR Spectroscopy and Spectral Analysis of the cis- and trans-Stilbene Products of the Wittig Reaction
    (ACS, 2019-07-16) Edgar, Mark; Percival, Benita; Gibson, Miles; Masania, Jinit; Beresford, Ken; Wilson, Philippe B.; Grootveld, Martin
    Benchtop NMR spectrometers are now becoming more widely employed in university teaching laboratories. These low-field instruments are increasingly used in reaction monitoring and product purity applications. NMR spectra obtained using these spectrometers (40–80 MHz) tend to suffer from significant overlap of signals when compared to those obtained at 300–400 MHz or above, and therefore, some reactions may be less suited to analysis using such benchtop systems. While some reactions can be modified to make them more amenable to analysis on low-field benchtop spectrometers, the fact remains that many common undergraduate laboratory chemistry reactions remain as a stalwart of the university education system. Therefore, there is currently a major requirement for benchtop NMR analysis to improve in order to facilitate student understanding. Herein, it is demonstrated that a combination of spectral analysis and simulation at low-fields (40–80 MHz) allows the fine structure of second-order effects and overlapping spectra to be deduced, enabling an improved understanding of the low-field benchtop NMR technique within undergraduate student cohorts. The evolution of well-resolved and distinct multiplets at 400 MHz to complex, overlapping multiplets at 40–80 MHz also serves as a useful guide for laboratory demonstrators and academic staff when explaining the advantages of such benchtop systems. The Wittig reaction has been a standard reaction practical session in many university teaching laboratories since the 1980s, the products of which are a mixture of cis- and trans-stilbenes. This reaction serves as an ideal example of how benchtop NMR spectrometers and analysis can support chemistry teaching laboratories.
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    Effect of antidepressant drugs on the brain sphingolipid system
    (Sage, 2020-05-14) Zetterstrom, Tyra; Jaddoa, Estabraq; Masania, Jinit; Masiero, Eva; Sgamma, Tiziana; Arroo, R. R. J.; Sillence, Daniel J.
    Background: Major depression is a common mood disorder and the central sphingolipid system has been identified as a possible drug target of this condition. Here we investigated the action of antidepressant drugs on sphingolipid levels in rat brain regions, plasma and in cultured mouse macrophages. Methods: Two antidepressant drugs were tested; the serotonin reuptake inhibitor paroxetine and the noradrenaline reuptake inhibitor desipramine, either following acute or chronic treatments. Content of sphingosine and ceramide were analysed using LC-MS or HPLC-UV respectively. This from samples of brain, plasma and cultured mouse macrophages. Antidepressant induced effects on mRNA expression for two key genes of the sphingolipid pathway, SMPD1 and ASAH1 were also measured by using quantitative Real-Time PCR. Results: Chronic but not acute administration of paroxetine or desipramine reduced sphingosine levels in the prefrontal cortex and hippocampus (only paroxetine) but not in the striatum. Ceramide levels were also measured in the hippocampus following chronic paroxetine and likewise to sphingosine this treatment reduced its levels. The corresponding collected plasma samples from chronically treated animals did not show any decrease of sphingosine compared to the corresponding controls. Both drugs failed to reduce sphingosine levels from cultured mouse macrophages. The drug-induced decrease of sphingolipids coincided with reduced mRNA expression of two enzymes of the central sphingolipid pathway, i.e. acid sphingomyelinase (SMPD1) and acid ceramidase (ASAH1). Conclusions: This study supports the involvement of brain sphingolipids in the mechanism of action by antidepressant drugs and for the first time highlights their differential effects on brain versus plasma levels.
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    Microemulsification of essential oils for the development of antimicrobial and mosquito repellent functional coatings for textiles
    (Oxford University Press, 2021-05-22) Soroh, Anita; Owen, Lucy; Rahim, Noor; Masania, Jinit; Abioye, Amos; Qutachi, Omar; Goodyer, Larry; Shen, Jinsong; Laird, Katie
    Aims: To develop an essential oil (EO)-loaded textile coating using an environmentally-friendly microemulsion technique to achieve both antimicrobial and mosquito repellent functionalities. Methods and Results: Minimum inhibitory concentrations and fractional inhibitory concentrations of litsea, lemon and rosemary EOs were determined against Staphylococcus aureus, Escherichia coli, Staphylococcus epidermidis, Pseudomonas aeruginosa and Trichophyton rubrum. A 1:2 mixture of litsea and lemon EOs inhibited all the microorganisms tested and was incorporated into chitosan-sodium alginate assembly by a microemulsification process. The EO-loaded microemulsions were applied to cotton and polyester fabrics using a soak-pad-dry method. The textile challenge tests demonstrated 7-8 log10 reductions of S. epidermidis, S. aureus and E. coli after 24 h and T. rubrum after 48 h. Aedes aegypti mosquito repellency was also assessed which demonstrated 71.43% repellency compared to 52.94% by neat EO-impregnated cotton. Conclusions: Textiles treated with the litsea and lemon EO microemulsion showed strong antimicrobial activity against the skin associated microorganisms E. coli, S. aureus, S. epidermidis and T. rubrum and potential mosquito repellent properties. Significance of Study: EOs could be useful for the development of natural, environmentally-friendly functional textiles to protect textiles and users from microbial contamination in addition to possessing other beneficial properties such as mosquito repellency.