Thymoquinone (2-Isopropyl-5-methyl-1, 4-benzoquinone) as a chemopreventive/anticancer agent: Chemistry and biological effects

Cancer remains the topmost disorder of the mankind and number of cases is unceasingly growing at unprecedented rates. Although the synthetic anti-cancer compounds still hold the largest market in the modern treatment of cancer, natural agents have always been tried and tested for potential anti-cancer properties. Thymoquinone (TQ), a monoterpene and main ingredient in the essential oil of Nigella sativa L. has got very eminent rankings in the traditional systems of medicine for its anti-cancer pharmacological properties. In this review we summarized the diverse aspects of TQ including its chemistry, biosynthesis, sources and pharmacological properties with a major concern being attributed to its anti-cancer efficacies. The role of TQ in different aspects involved in the pathogenesis of cancer like inflammation, angiogenesis, apoptosis, cell cycle regulation, proliferation, invasion and migration have been described. The mechanism of action of TQ in different cancer types has been briefly accounted. Other safety and toxicological aspects and some combination therapies involving TQ have also been touched. A detailed literature search was carried out using various online search engines like google scholar and pubmed regarding the available research and review accounts on thymoquinone upto may 2019. All the articles reporting significant addition to the activities of thymoquinone were selected. Additional information was acquired from ethno botanical literature focusing on thymoquinone. The compound has been the centre of attention for a long time period and researched regularly in quite considerable numbers for its various physicochemical, medicinal, biological and pharmacological perspectives. Thymoquinone is studied for various chemical and pharmacological activities and demonstrated promising anti-cancer potential. The reviewed reports confirmed the strong anti-cancer efficacy of thymoquinone. Further in-vitro and in-vivo research is strongly warranted regarding the complete exploration of thymoquinone in ethnopharmacological context.     

Effect of Dosing Cup Size on the Aerosol Performance of High-Dose Carrier-Based Formulations in a Novel Dry Powder Inhaler

This study investigated how varying the dosing cup size of a novel reservoir dry powder inhaler (DPI) affects the detachment of a micronized active pharmaceutical ingredient from larger carrier particles, and the aerosol performance of a DPI carrier formulation. Three different-sized dosing cups were designed: 3D printed with cup volumes of 16.26 mm³, 55.99 mm³, and 133.04 mm³, and tested with five different carrier type formulations with beclomethasone dipropionate (BDP) concentrations between 1% and 30% (w/w). The morphology of the BDP attached to the carrier was investigated using scanning electron microscopy and the aerosol performance using the Next Generation Impactor. Increasing the volume of the dosing cup led to a reduction of BDP deposition in the Next Generation Impactor preseparator, and an increase in BDP detachment from the carrier was observed, leading to increased aerosol performance. The decreased amount of BDP attached to carrier after aerosolization was attributed to the increased dosing cup void volume. This may enable greater particle-particle and particle-wall collisions, with greater BDP detachment from the carrier and deagglomeration of smaller agglomerates. The dosing cup volume was observed to have significant influence on particle dispersion and the overall aerosol performance of a DPI.     

A Proposed Complete Methodology to Predict Gravity Flow Obstruction of Pharmaceutical Powders in Drug Product Manufacturing

We present herein a comprehensive methodology to evaluate the risks involved in gravity-driven flow of pharmaceutical powders, including mass flow/funnel flow pattern, arch formation under active stress state (initial discharging) and passive stress state (following initial discharging), and rathole formation. Built on original theories underpinning the hopper design procedure, the methodology was modified to accommodate practices of pharmaceutical powder handling. All data required are generated from conventional ring shear tester. We applied the methodology to evaluate the powder flow risks during drug product manufacturing campaigns, where two powder blends with distinct flow behavior were discharged from a 200-L bin. The predicted results are in agreement with experiments where visual observations were possible, including the flow pattern, arch formation under active stress state, and rathole formation. One notable discovery is that pharmaceutical powders exhibit high risk of arch formation under active stress state, because of the exceeding major principal stress than the passive state. This phenomenon has been so far overlooked and the existing flow function-based classification cannot capture this risk. We propose, through this methodology, that reliable powder flow assessment should consider factors preventing flow (i.e., flow function), as well as factors facilitating flow (i.e., external stress).     

Development of Solid Dispersion by Hot Melt Extrusion Using Mixtures of Polyoxylglycerides With Polymers as Carriers for Increasing Dissolution Rate of a Poorly Soluble Drug Model

Various polyoxylglycerides have been researched extensively in the development of solid dispersions (SDs) for bioavailability enhancement of poorly water-soluble drugs. However, because of their low melting points (40°C-60°C), SDs produced are usually soft and semisolid. The objective of present study was to prepare SDs of a Biopharmaceutical Classification System class II drug, carvedilol, in mixtures of stearoyl polyoxylglycerides (Acconon^® C-50; m.p. ～50°C) with polymers by hot melt extrusion to obtain free-flowing powder upon grinding. Miscibility of carvedilol with Kollidon^® VA64, hydroxypropyl methylcellulose acetate succinate, and Klucel^? EXF was first evaluated by film casting, and Kollidon^® VA64 was selected for further study. SDs containing 5%-20% carvedilol, 0%-20% Acconon^® C-50, and the remaining Kollidon^® VA64 were prepared for hot melt extrusion. SDs were characterized by differential scanning calorimetry and powder X-ray diffraction analysis, and dissolution tests were conducted in 250 mL of pH 6.8 phosphate buffer by filling powders in capsules. Carvedilol was miscible with all polymers tested up to 50% and remained amorphous in SDs. The drug release from formulations containing 20% carvedilol and 0, 5%, 10%, and 20% Acconon^® C-50 were 30%, 30%, 70%, and 90%, respectively, in 60 min. SDs containing carvedilol and Acconon^® C-50, up to 20% each, as well as Kollidon^® VA64, were physically stable after 3 months of storage at 25°C/60% relative humidity.     

Freeze-Drying From Organic Co-Solvent Systems,Part 2: Process Modifications to Reduce Residual Solvent Levels and Improve Product Quality Attributes

The use of co-solvent systems can benefit the freeze-drying process and product performance. In this study, cycle designs were applied based on existing recommendations for water-based formulations. Modifications thereof and the influence on the process (e.g., drying times) and product quality attributes (e.g., product appearance, residual solvent) were tested for various cosolvent systems. It was found that fast freezing was associated with the formation of large crystals for 50 mg/g polyvinylpyrrolidone in 40% 1,4-dioxane (w/w), resulting in a 7% reduction of primary drying. The application of high shelf temperatures during primary drying for 50 mg/g polyvinylpyrrolidone in 70% tert-butanol was feasible, resulting in shorter primary drying times but high residual solvent levels (7.7%). Most notable was that the inclusion of an evaporation step after freezing improved the product appearance for low-melting co-solvents (10% ethanol and 10% acetone). No ice or solvent nucleation occurred in the case of 50 mg/g mannitol in 50% N,N-dimethylacetamide during the normal freezing stage. Instead, the solution viscosity significantly increased after cooling to low shelf temperatures, followed by product evaporation (rather than sublimation) during the drying phase and failure to form a product cake after drying. The application of annealing enabled nucleation and sublimation.     

Enhancing the Pharmaceutical Behavior of Nateglinide by Cocrystallization: Physicochemical Assessment of Cocrystal Formation and Informed Use of Differential Scanning Calorimetry for Its Quantitative Characterization

The aim of this study was to synthetize cocrystals of nateglinide, an antidiabetic agent of biopharmaceutics classification system Class IIa, as a strategy to improve both the solubility and the dissolution rate of the drug. Benzamide was selected by a screening procedure as a suitable coformer, and binary mixtures with different compositions were prepared and analyzed by differential scanning calorimetry (DSC). An in-depth analysis of DSC data allowed obtaining both the eutectic mixture and cocrystal compositions. The rationale of such an analysis was highlighted and explained. Cocrystals were prepared by kneading and solvent evaporation. Their formation was proved by DSC and confirmed by X-ray powder diffraction, solid-state nuclear magnetic resonance, and Fourier-transform infrared spectroscopy. The functional groups involved in the interaction leading to cocrystals formation were investigated by spectroscopic techniques. The in vitro dissolution profiles show that cocrystals have definite better pharmaceutical performances than the pure drug.     

Crystallization of Cyclophosphamide Monohydrate During Lyophilization

The purpose of this study was to investigate the phase behavior of cyclophosphamide (CPA) during various stages of lyophilization, with special emphasis on obtaining crystalline CPA monohydrate (CPA-MH) in the lyophilized product. Subambient differential scanning calorimetry and low-temperature X-ray diffractometry (LTXRD) were used to study the phase behavior of CPA solution (3.7% w/v). In situ lyophilization in LTXRD chamber was used to monitor the phase transitions occurring during the drying stages. Finally, the implications of these findings were confirmed by freeze-drying the aqueous solution in a laboratory-scale freeze-dryer. The results suggested that CPA remains amorphous during freeze concentration, with a T_g' of ?50°C. However, its crystallization as CPA-MH can be induced by annealing the frozen solution between ?5°C and ?10°C. In situ lyophilization in LTXRD showed that the CPA-MH crystallized during annealing, rapidly dehydrated during primary drying, thereby causing structural collapse. The dehydration of CPA-MH can be prevented by lowering the escaping tendency of water molecules from the crystal lattice of CPA-MH by maintaining the chamber pressure to 300, 400, or 500 mTorr. This study highlights the relationship of process parameters used during lyophilization with the solid form of lyophilized CPA.     

红油膏和八宝生肌散联合西药对肛瘘术后的疗效观察

为观察红油膏和八宝生肌散联合西药对肛瘘术后的临床效果,将肛瘘患者80例随机分为观察组和对照组,每组40例,对照组40例患者采用常规西药治疗,观察组40例患者在常规西药治疗的基础上加用红油膏、八宝生肌散治疗,比较两组患者的临床疗效。结果显示,治疗后,观察组患者的总有效率为92．5％,对照组为80．0％,观察组明显高于对照组（P〈0．05）。用药3d、10d后,观察组患者的疼痛评分、创面渗液评分均明显优于对照组（P〈0．05）,观察组患者的创面愈合时间明显短于对照组,住院费用明显低于对照组。结果表明,红油膏和八宝生肌散联合西药对肛瘘术后患者具有显著的疗效,可加快手术创口的愈合,明显改善患者的临床症状,缓解局部疼痛等不适,提高患者的生活质量。     

Induction of protective immunity against H1N1 influenza A(H1N1)pdm09 with spray-dried and electron-beam sterilised vaccines in non-human primates

Currently, the need for cooled storage and the impossibility of terminal sterilisation are major drawbacks in vaccine manufacturing and distribution. To overcome current restrictions a preclinical safety and efficacy study was conducted to evaluate new influenza A vaccine formulations regarding thermal resistance, resistance against irradiation-mediated damage and storage stability. We evaluated the efficacy of novel antigen stabilizing and protecting solutions (SPS) to protect influenza A(H1N1)pdm09 split virus antigen under experimental conditions in vitro and in vivo.     

蛹虫草液体发酵产物冻干粉的抗氧化活性及保肝作用

目的研究蛹虫草液体发酵产物冻干粉的抗氧化活性及保肝作用。方法采用真空冷冻干燥的方法将蛹虫草液体发酵产物制成干粉并对冻干粉主要成分进行分析测定,通过DPPH自由基清除实验和衰老小鼠模型验证蛹虫草发酵产物冻干粉的抗氧化活性,通过小鼠急性肝损伤实验研究冻干粉的保肝作用,采用急性毒性试验验证冻干粉的安全性。结果蛹虫草发酵产物冻干粉含丰富的粗纤维、粗多糖、粗三萜及黄酮类物质。蛹虫草发酵产物冻干粉对DPPH自由基的半数有效浓度（EC50）为8．12mg／mL,在16mg／mL时对DPPH自由基的清除率为61．56％,与0．02mg／mL的维生素C（Vc）清除能力相当;蛹虫草发酵产物能显著提高衰老模型小鼠血清和肝脏中的总超氧化物歧化酶（T-SOD）、谷胱甘肽过氧化物酶（GSH-px）活力水平,降低丙二醛（MDA）含量,高剂量组的抗衰老效果与阳性药Vc组的抗氧化能力相当。小鼠急性肝损伤试验结果显示,冻干粉能有效降低模型组小鼠血液中门冬氨酸氨基转移酶（AST）与丙氨酸氨基转移酶（ALT）水平（P〈0．05）。冻干粉的半数致死量（LD50）远大于国家无毒标准15g／kg,属于无毒级别。结论蛹虫草发酵产物具有良好的抗氧化活性和保肝作用,且安全无毒。