Preparation and characterization of nimesulide containing nanocrystal formulations

The aim of this study was to develop and characterize nanocrystal formulation containing nimesulide. Physical mixture of drug and excipient (nimesulide:pluronic F127, 1:0.5) was also prepared to compare the efficiency of formulations. The physicochemical characteristics of the formulations were determined by means of Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and X-ray diffractometry. Particle size, saturation solubilities as a function of pH, and permeability across Caco-2 monolayers were determined for nimesulide in powder, physical mixture, and nanocrystal formulations. In FT-IR analysis, the characteristic peaks that belong to nimesulide were seen in all formulations. X-ray diffractograms displayed that crystalline structure of nimesulide was conserved in the nanocrystal formulation. The interaction between nimesulide and pluronic F127 was demonstrated by DSC analysis. In all conditions, the average particle size of the nanocrystal formulations decreased significantly (p?<?0.05) as compared with nimesulide and physical mixture. The solubility of nimesulide in nanocrystal formulation was higher than those of nimesulide in powder and physical mixture. Permeability studies revealed that nimesulide is a highly permeable compound whether in powder form or in physical mixture and nanocrystal formulation. All these results clearly demonstrate that aqueous solubility of poorly water-soluble compounds can be improved by preparing nanocrystal formulations.     

Thermal Behavior of the Nimesulide-Salicylic Acid Eutectic Mixtures Prepared by Mechanosynthesis and Recrystallization

Nimesulide, salicylic acid and their binary mixtures were studied by differential scanning calorimetry (DSC) and Fourier Transform Infrared spectroscopy (FTIR). The study of such systems is a promising and viable approach for solving the problem of poor solubility of materials in general and drug systems in particular. All areas of human activity are inextricably linked to materials, and thus, the study presented in the paper and not reported in the literature is very important and provides useful data for those working in various fields. The eutectic mixtures were obtained by mechanosynthesis and by recrystallization from ethanol over the entire 0–1 range of molar fractions. For both situations at the molar fraction of nimesulide 0.5, the mixture has a eutectic that suggests an increase in solubility at this composition. The interactions that take place between the components were determined with the help of the excess thermodynamic functions (G^E, S^E, µ^E), which highlight the deviation from the ideality of the considered binary systems.     

热熔挤出法制备尼美舒利固体分散体

 目的 采用热熔挤出技术制备难溶性药物尼美舒利固体分散体,提高其溶出速率。方法 以共聚维酮（PVP-VA64,Kollidon VA64)、聚维酮（PVPK30）或聚乙烯醇-聚乙二醇（3∶1）接枝共聚物（Kollicoat IR）为亲水性载体材料,使用双螺杆热熔挤出机制备尼美舒利固体分散体,通过差示扫描量热法（DSC）、X射线衍射法（XRD）、傅立叶红外光谱（FTIR）和体外溶出度测定来表征和评价所制备的固体分散体。结果 以共聚维酮为载体制备的尼美舒利固体分散体药物溶出最快,在pH 7.4的磷酸盐缓冲液中10 min溶出达到81%,远快于物理混合物（1 h时只有37%）。X射线衍射图谱显示药物晶体衍射峰消失,差示扫描量热图谱显示药物晶体吸热峰消失,提示药物是以无定形态分散在载体材料中。结论 热熔挤出加工技术适用于制备尼美舒利-共聚维酮固体分散体,药物是以无定形态分散在载体中,溶出度得到显著提高。     

HPLC法测定尼美舒利片和胶囊的含量及溶出度

目的建立HPLC法测定尼美舒利片剂和胶囊剂的含量及溶出度。方法采用C18柱,以甲醇-0.004 mol/L K2HPO4(磷酸调pH为4.0±0.1)(体积比50∶50)为流动相,流速为1.2 mL/m in,检测波长298 nm。结果尼美舒利在20~150μg/mL范围内线性关系良好,片剂及胶囊剂的平均回收率分别为99.91%,99.83%。结论本法精密度高,重现性好,可用于尼美舒利片剂和胶囊剂的含量及溶出度测定。     

In vivo antidiabetic activity of nimesulide due to inhibition of amino acid transport

Inhibiting the intestinal and renal neutral amino acid transporter B0AT1 by genetic means has improved insulin sensitivity in mice, but there are no antagonists available for preclinical or clinical use. Since the anti-inflammatory agent nimesulide selectively inhibited B0AT1 in vitro, we hypothesized that nimesulide exhibits in vivo potential to restrict neutral amino acid absorption and, therefore, may improve insulin sensitivity. The dose-related effect of nimesulide (10 to 100 mg/kg, PO) on intestinal absorption of neutral amino acids was estimated in C57 mice. The effect of nimesulide (50 mg/kg, PO) on renal resorption of amino acids was also assessed. The effect of chronic nimesulide (50 mg/kg, PO, BID for 14 days) was assessed in high protein diet-fed C57 mice, diet-induced obese mice and obese and diabetic db/db mice. Acute and chronic nimesulide treatment decreased absorption of neutral amino acids and increased their urinary excretion. Nimesulide treatment improved insulin sensitivity and glycemic control, increased GLP-1, decreased liver lipids and improved FGF-21 in serum. Nimesulide improved insulin sensitivity and glucose tolerance by inhibiting neutral amino acid transport in the intestine and kidneys. Thus, it can serve as a tool compound for in vivo B0AT1 inhibition.     

COMPARATIVE ANTI-NOCICEPTIVE, ANTI-INFLAMMATORY AND TOXICITY PROFILE OF NIMESULIDE vs NIMESULIDE AND PIPERINE COMBINATION

Piperine is an inhibitor of various hepatic and other enzymes involved in the biotransformation of drugs. Preliminary pharmacokinetic studies conducted by us suggested the increased bioavailability of nimesulide co-administered with piperine. The present study was, thus, conducted to evaluate the antinociceptive, anti-inflammatory and toxicity profile of a new nimesulide-piperine combination administered orally as compared with nimesulide alone. Antinociceptive efficacy was tested using an acetic acid writhing test and tail flick latency test (TFL). The ED50 value of a nimesulide-piperine combination in writhing test was calculated to be significantly lower (1.5 mg kg(-1)) as compared to (11.2 mg kg(-1)) of nimesulide alone. The antinociceptive effect was lesser in the tail flick latency test as compared to what was observed in the writhing test indicating the peripheral action of the Non-Steriodal Anti-Inflammatory Drug (NSAID). In carrageenan-induced inflammatory tests, the nimesulide-piperine combination was found to be dose-to-dose superior than nimesulide alone. Acute toxicity studies on mice revealed a reduction in lethal dose (LD50) of the combination (980 mg kg(-1)) as compared to nimesulide (1500 mg kg(-1)) alone. Results from the present study suggest a better therapeutic index for the nimesulide-piperine combination indicating that this combination would further reduce the frequency of adverse effects associated with nimesulide alone.     

尼美舒利分散片临床药代动力学和相对生物利用度研究

目的　进行尼美舒利分散片的药代动力学研究，并与国产尼美舒利片进行生物等效性比较。方法　20名健康男性志愿者采用自身交叉给药方案，分别单剂量口服100　mg供试品或对照品后，用高效液相色谱紫外检测法测定血浆药物浓度。结果　单剂量口服尼美舒利分散片后体内过程符合开放式血管外一室模型，其cmax为（3.91±0.74）　μg     

In Vivo Selectivity of Nonsteroidal Antiinflammatory Drugs and Gastrointestinal Ulcers in Rats

The aim of the present work was to study in vivo COX-2–COX-1 selectivity of 16 nonsteroidal anti-inflammatory drugs (NSAIDs) in equipotent ulcerogenic doses in two in vivo experimental models. Indomethacin, ibuprofen, nimesulide, aceclofenac, aspirin, sodium diclofenac, meloxicam, naproxene, paracetamol, piroxicam, tenoxicam, nabumetone, ketoprofen, mefenamic acid, etodolac, and ketorolac were administered to female Wistar rats (N = 10 each group). In experiment I, solid food plus subcutaneous NSAIDs were given. In experiment II, NSAIDs were given by oral gavage and in bolus. Macroscopic gastric antral ulcer area (30%) and intestinal erosiva area (295 mm2) in experiment I and necrotic gastric fundus area (65%) and erosive intestinal area (182 mm2), in vivo the NSAIDs COX-1 was showed. Neutrofilia assessed in gastric intestinal mucosa where also ibuprofen and paracetamol not given neotrophilic infiltration. In conclusion, COX-2–COX-1 selectivity was demonstrated in vivo with the drugs aceclofenac, nabumetone, meloxicam, nimesulide, and paracetamol.     

当归拈痛丸联合尼美舒利治疗幼年反应性关节炎临床研究

目的:观察当归拈痛丸联合尼美舒利治疗幼年反应性关节炎的临床疗效。方法:将100例幼年反应性关节炎患者随机分为治疗组和对照组。对照组予以口服尼美舒利治疗,治疗组予以当归拈痛丸联合尼美舒利治疗。比较两组患者治疗2个月后的临床症状评分、血沉和C反应蛋白(C-reactionprotein,CRP)水平、日常生活能力(activity of daily living scale,ADL)、疼痛视觉模拟评分(visual analogue scale,VAS)及心理测评评分。结果:两组患者治疗后的疼痛、肿胀及功能活动评分均显著低于治疗前,差异有统计学意义(P0.05);治疗组治疗后的疼痛、肿胀及功能活动评分均显著低于对照组,差异有统计学意义(P0.05)。两组患者治疗后的血沉、CRP水平均显著低于治疗前,差异有统计学意义(P0.05);治疗组治疗后的血沉、CRP水平均显著低于对照组,差异有统计学意义(P0.05)。两组患者治疗后的ADL、VAS及心理测评评分均显著低于治疗前,差异有统计学意义(P0.05);治疗组治疗后的ADL、VAS及心理测评评分均显著低于对照组,差异有统计学意义(P0.05)。结论:当归拈痛丸联合尼美舒利治疗幼年反应性关节炎可有效降低其炎症反应,改善临床症状和生活质量。     

选择性和非选择性环氧合酶抑制剂对慢性压力小鼠模型具有保护作用(英文)

目的环氧合酶是广泛表达于大脑各区域的一类同功酶,主要用于治疗疼痛与炎症。最近研究还发现环氧合酶在大脑相关疾病的病理生理过程中扮演关键角色。本文运用慢性压力动物模型,对环氧合酶抑制剂的保护作用做一探讨。方法每只小鼠每天被迫游泳 6 min,共持续 15 天。结束后进行行为学(包括活动能力、焦虑以及记忆能力)和生化指标(包括脂质过氧化、亚硝酸盐水平、还原性型谷胱甘肽和过氧化氢酶水平)的检测。结果持续15天的强迫性游泳会损伤小鼠活动能力,引起焦虑样行为的产生,并削弱记忆力。在生化指标方面,脂质过氧化和亚硝酸盐水平均显著提高,还原型谷胱甘肽和过氧化氢酶活力则显著降低。此外,环氧合酶抑制剂,包括甲氧萘丙酸、罗非考昔、美洛昔康、尼美舒利和伐地考昔,都能显著减缓这些损伤。结论环氧合酶抑制剂可被用来治疗慢性疲劳综合症。