HPLC法测定非诺贝特缓释片中非诺贝特

目的采用HPLC法测定非诺贝特缓释片中非诺贝特。方法采用Dikma C18色谱柱(200 mm×4.6 mm,5μm);流动相:甲醇–水(90∶10);检测波长:288 nm;柱温:25℃;体积流量:1.0 mL/min;进样量10μL。结果非诺贝特在2.0~12.0μg/mL与其峰面积呈良好的线性关系(r=0.999 9);检测限和定量限分别为10、30 ng/mL;平均回收率为99.86%,RSD值为0.72%(n=9)。结论该方法准确、简便,可用于非诺贝特缓释片中非诺贝特的质量控制。     

生产过程清洁验证残留物阿哌沙班的HPLC法测定

目的：建立清洁验证中残留物阿哌沙班含量测定的高效液相色谱法。方法：色谱柱为Waters Nova-Pak C18（3.9 mm×150 mm,5μm）,流动相为乙腈-水（30∶70）,检测波长280 nm,流速1.0 ml/min,柱温30℃,进样量10μl。结果：阿哌沙班在0.01～20μg/ml范围内线性关系良好,r2=0.9992;回收率为75.90%,RSD=2.33%（n=18）。结论：该方法操作简便、结果准确,可以用于清洁验证残留物阿哌沙班的定量分析。     

HPLC法测定非诺贝特软胶囊中维生素E的含量

目的：建立非诺贝特软胶囊中维生素E含量测定方法。方法：采用HPLC法,色谱柱为Thermo BDS Hypersil C184.6mm×150 mm,5μm）,流动相为甲醇-水（98∶2）,流量1.0mL· min^-1,检测波长为284nm,柱温40℃。结果：维生素E在0.5～102μg· mL^-1浓度范围内线性关系良好,平均回收率为99.3％（RSD＝0.36％）。结论：所建方法专属性好,准确,重复性好,可为非诺贝特软胶囊中有效检测抗氧剂维生素E的含量提供参考。     

非诺贝特PEG2000-DSPE胶束的制备及在大鼠体内的口服药动学研究

目的:为提高非诺贝特溶解度,将非诺贝特包载于PEG₂₀₀₀-DSPE胶束中,研究其在SD大鼠体内的口服药动学情况。方法:对非诺贝特PEG₂₀₀₀-DSPE胶束进行表征,大鼠单剂量灌胃给予非诺贝特PEG₂₀₀₀-DSPE胶束和非诺贝特混悬液,眼底静脉丛取血,HPLC法测定血浆中非诺贝特酸含量,并用药物与统计（Drug and Statistics,DAS）软件分析处理药动学数据。结果:成功制备了非诺贝特PEG₂₀₀₀-DSPE胶束,平均粒径为（23.40±3.62）nm,包封率和载药量分别为（97.65±3.32）%和（1.33±0.32）%。大鼠体内口服药动学结果表明非诺贝特PEG₂₀₀₀-DSPE胶束和非诺贝特混悬液的药动学行为均符合二室模型,非诺贝特PEG20 00-DSPE胶束和非诺贝特混悬液的AUC_（0-24）分别为（61.41±5.71）μg·h·ml^-1和（8.49±0.66）μg·h·ml^-1,C_max分别为（9.67±1.65）μg·ml^-1和（0.71±0.09）μg·ml^-1。非诺贝特PEG₂₀₀₀-DSPE胶束的AUC_（0-24）和C_max相比于非诺贝特混悬液组分别提高了7倍和14倍。非诺贝特PEG₂₀₀₀-DSPE胶束相对于原料药生物利用度为723.3%。结论:非诺贝特PEG₂₀₀₀-DSPE胶束显著提高了非诺贝特在大鼠体内的口服吸收速度和生物利用度。PEG₂₀₀₀-DSPE胶束作为口服药物载体具有优良的应用前景。     

HPLC法测定苯扎贝特片的含量

目的：建立HPLC法测定苯扎贝特片的含量。方法：色谱柱C18柱（4.0 mm×250 mm,5μm）,流动相为0.01 mol/L磷酸二氢钾溶液（用磷酸调节pH值至3.8）-甲醇（35∶65）,检测波长为228 nm,流速为1.0 ml/min,柱温为室温,进样量为20μl。结果：苯扎贝特在16～160μg/ml浓度范围内线性关系良好（r=0.999 9）,平均回收率为99.5%,RSD为1.15%。结论：本法简便快速,准确可靠。     

高效液相色谱法同时测定大鼠在体肠循环液中非诺贝特和非诺贝酸的含量

目的:建立同时测定大鼠在体肠循环液中非诺贝特和非诺贝酸的方法。方法:采用高效液相色谱法,色谱柱为Kro-masil C18柱(150 mm×4.6 mm5μm),流动相为甲醇-水(80∶20),pH3.0,柱温为室温,流速1.0mL.min-1,检测波长286 nm。结果:非诺贝特、非诺贝酸分别在0.25～124.68 mg.L-1、0.01～5.05 mg.L-1范围内与峰面积呈良好线性关系,r分别为0.999和0.999 9。其平均回收率分别为98.83%、101.13%,RSD均小于4%。结论:该法操作简便、结果准确、灵敏度高,可同时测定大鼠在体肠循环液中非诺贝特和非诺贝酸的含量。     

HPLC法测定非诺贝特胶囊中非诺贝特的含量

摘 要 目的：建立非诺贝特胶囊中非诺贝特的含量测定方法。方法: 采用HPLC法,色谱柱：Dikma Diamonsil C₁₈柱（150 mm×4.6 mm,5 μm）,流动相：乙腈-水（70∶30,用磷酸调节pH值至2.5）,检测波长：286 nm,流速：1.0 ml·min^-1,柱温：30℃,进样量：20 μl。 结果: 非诺贝特浓度在10.07～60.42 μg·mL^-1范围内线性关系良好（r=0.999 6）,平均回收率为99.26%,RSD为0.5%（n=6）。结论:本法简便、准确、专属性强,可用于该制剂的含量测定。     

非诺贝特对大鼠勃起功能和睾酮水平的影响

目的：观察非诺贝特对大鼠勃起功能和睾酮水平的影响,探讨非诺贝特致勃起功能障碍（ED）的原因。方法：30只雌性SD大鼠去势2周后分别在交配实验前48h和4h皮下注射苯甲酸雌二醇20μg和黄体酮500μg。将30只雄性大鼠随机分为2组：非诺贝特组和对照组,每组15只。非诺贝特组大鼠用非诺贝特31.5mg/kg溶于蒸馏水中（总体积4mL）灌胃,1次/d,连续14d;对照组大鼠用同等容积蒸馏水灌胃,1次/d,连续14d。在停药后第1天行交配实验,观察记录30min内2组大鼠的骑跨次数（MF）、插入次数（IF）、骑跨潜伏期（ML）和射精潜伏期（EL）,并用放射免疫法检测血清和阴茎组织中睾酮水平。结果：非诺贝特组大鼠的MF和IF分别为（9.45±1.65）和（4.15±1.38）次/min、ML和EL分别为（14.1±7.0）和（5.3±5.9）min,对照组大鼠上述指标分别为（31.23±3.85）和（12.80±3.02）次/min、（6.2±4.3）和（16.2±6.0）min,差异有统计学意义（均P〈0.05）;大鼠血清和阴茎组织的睾酮水平非诺贝特组分别为（51.26±34.15）和（62.57±46.37）nmol/L,对照组分别为（153.72±83.93）和（164.89±94.02）nmol/L,差异有统计学意义（均P〈0.05）。结论：非诺贝特能降低大鼠的性功能和睾酮水平。非诺贝特引致睾酮水平降低可能是勃起功能障碍的主要原因之一。     

HPLC测定利胆消石颗粒中槲皮素和山奈素含量

目的：建立利胆消石颗粒中槲皮素和山奈素含量测定方法。方法：色谱柱：DIKMA-C18柱（4.6 mm ×250 mm;5μm）,流动相为甲醇-0.4%磷酸（45∶55）,流速为1.0 mL/min,检测波长为360 nm,柱温为30℃。结果：利胆消石颗粒中槲皮素和山奈素的线性范围分别为0.988～98.8μg/mL（r=0.9998）,0.979～97.9μg/mL（r=0.9997）,平均回收率为98.21%,98.18%,RSD值为0.71%,0.56%。结论：该方法简便,结果准确,可作为利胆消石颗粒的质量控制方法。     

HPLC法测定血浆中非诺贝特活性代谢物非诺贝酸的浓度

目的:建立高效液相色谱法测定血浆中非诺贝特活性代谢产物非诺贝特酸浓度。方法:以甲醇直接沉淀血浆蛋白,色谱柱为Waters sunfire C_(18)柱(150mm×4.6mm,5μm),流动相为0.05 mol·L~(-1)磷酸二氢钾溶液-甲醇(70:30),用磷酸调pH 2.5,检测波长286nm。结果:非诺贝酸的保留时间约为6.7 min,线性范围为0.2～20.0μg·ml~(-1)(r=0.999 9),最低定量限为0.2μg·ml~(-1),方法回收率99.28%～101.38%,提取回收率97.18%～107.28%,日内和日间RSD均小于10%。结论:本法简便、快捷、灵敏,适用于非诺贝特药物动力学研究。     

Fenofibrate

Fenofibrate is a fibric acid derivative with lipid-modifying effects that are mediated by the activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has a number of nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein, and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes. The beneficial effects of fenofibrate on the lipid profile have been shown in a number of randomized controlled trials. In primary dyslipidemia, fenofibrate monotherapy consistently decreased triglyceride (TG) levels to a significantly greater extent than placebo; significantly greater increases in high-density lipoprotein cholesterol (HDL-C) levels and significantly greater reductions in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were also seen in some trials. Monotherapy with fenofibrate or gemfibrozil had generally similar effects on TG and HDL-C levels, although in one trial, TC and LDL-C levels were reduced to a significantly greater extent with fenofibrate than with gemfibrozil. Fenofibrate monotherapy tended to improve TG and HDL-C levels to a significantly greater extent than statin monotherapy in primary dyslipidemia, whereas statin monotherapy decreased LDL-C and TC levels to a significantly greater extent than fenofibrate monotherapy. Fenofibrate also had a beneficial effect on atherogenic dyslipidemia in patients with the metabolic syndrome or type 2 diabetes mellitus, reducing TG levels, tending to increase HDL-C levels, and promoting a shift to larger low-density lipoprotein particles. In terms of cardiovascular outcomes, fenofibrate did not reduce the risk of coronary heart disease (CHD) events to a greater extent than placebo in patients with type 2 diabetes in the FIELD trial. However, the risk of some nonfatal macrovascular events (e.g. nonfatal myocardial infarction, revascularization) and certain microvascular outcomes (e.g. amputation, first laser therapy for diabetic retinopathy, progression of albuminuria) was reduced to a significantly greater extent with fenofibrate than with placebo. Subgroup analysis revealed a significant reduction in the cardiovascular disease (CVD) event rate among fenofibrate recipients in the subgroup of patients with marked hypertriglyceridemia or marked dyslipidemia at baseline. In the ACCORD Lipid trial, there were no significant differences between patients with type 2 diabetes and a high risk of CVD events who received fenofibrate plus simvastatin and those who received placebo plus simvastatin for any of the primary or secondary cardiovascular outcomes. However, fenofibrate plus simvastatin was of benefit in patients who had markedly high TG levels and markedly low HDL-C levels at baseline. In addition, fenofibrate plus simvastatin slowed the progression of diabetic retinopathy. Fenofibrate is generally well tolerated. Common adverse events included increases in transaminase levels that were usually transient, minor, and asymptomatic, and gastrointestinal signs and symptoms. In conclusion, monotherapy with fenofibrate remains a useful option in patients with dyslipidemia, particularly in atherogenic dyslipidemia characterized by high TG and low HDL-C levels.     

国产非诺贝特片与进口非诺贝特胶囊人体生物等效性研究

目的:评价国产非诺贝特片与进口非诺贝特胶囊人体生物等效性。方法:采用双周期双交叉试验设计,将24名健康受试者随机平均分为2组,在每个给药周期,单次口服受试制剂或参比制剂非诺贝特200 mg,以高效液相色谱法测定血浆中非诺贝酸的浓度,药-时数据经DAS2.1统计软件处理,计算主要药动学参数,并评价二者的生物等效性。结果:非诺贝特片和非诺贝特胶囊的主要药动学参数分别为:t_1/2（18.5±4.3）、（19.3±4.4）h,C_max（9.0±3.3）、（8.7±2.8）μg·ml^-1、t_max（5.3±0.9）、（5.0±0.8）h、AUC_0-72h（128.1±37.7）、（134.2±42.1）μg·h·ml^-1,AUC_0-∞（140.1±41.6）、（146.8±97.4）μg·h·ml^-1。非诺贝特片的相对生物利用度F_0-72h为（91.6±3.4）%,F_0-∞为（92.6±2.5）%,受试制剂AUC_0-72h和C_max的90%可信限分别落在参比制剂的90.4%～102.0%和87.2%～116.8%范围内。结论:2种制剂具有生物等效性。     

国家食品药品监督管理局国家药品标准修订——非诺贝特分散片

本品含非诺贝特(C₂₀H₂₁ClO₄)应为标示量的93.0%~107.0%。     

Micronized Fenofibrate in Dyslipidemia

▲ The prodrug fenofibrate, a synthetic phenoxy-isobutyric acid derivative, is rapidly hydrolyzed in vivo to form fenofibric acid, which alters plasma lipid levels by activating the peroxisome proliferator-activated receptor α. ▲ The micronized fenofibrate 200mg capsule formulation, and the recently developed micronized fenofibrate 160mg tablet formulation, are bioequivalent. ▲ Micronized fenofibrate 200 mg/day (capsules) increased high density lipoprotein cholesterol (HDL-C) levels significantly from baseline in up to 7098 patients with various dyslipidemias in noncomparative studies. ▲ Micronized fenofibrate 200 mg/day (capsules) produced significantly greater elevations in HDL-C levels than a variety of HMG-CoA reductase inhibitors in small, randomized, double-blind and nonblind studies in patients with dyslipidemia (n = 91 to 227). This formulation of fenofibrate and gemfibrozil produced similar increases in HDL-C levels in a randomized, double-blind study (n = 234). ▲ Micronized fenofibrate 160mg once daily (tablet) increased HDL-C levels significantly from baseline by 10.6 to 14.5% in patients with type IIa or IIb dyslipidemia (n = 353) in two noncomparative studies. Additionally, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and LDL-C to HDL-C and TC to HDL-C ratios were lowered significantly from baseline. ▲ The tablet and capsule formulations of fenofibrate were both generally well tolerated in two noncomparative studies in 375 or 9884 patients. In double-blind, placebo-controlled trials in a total of 804 patients, the pooled incidences of individual adverse events were generally similar with fenofibrate and placebo.     

Fenofibrate and human liver

In rodents fenofibrate shares with other triglyceride-lowering agents the potential to increase the liver peroxisome population. It was therefore of interest to look for this effect in hyperlipoproteinemic patients receiving this drug. Light and electron microscopy of liver biopsies from a group of 10 patients treated with fenofibrate and from another group of 15 receiving diet only, show no morphological difference between both groups. In contrast with the rodent data the morphometric study reveals no significant changes in the number (fenofibrate group: 7.96 10(10) cm-3; group receiving diet alone: 8.41 10(10) peroxisomes/cm3 of liver tissue) or in the size (fenofibrate group: Diameter = 0.53 +/- 0.07 micrometer--group receiving diet alone: 0.50 +/- 0.06) of peroxisomes. The difference between our results and those obtained consistently in rodents may be due to the relatively low dose in man and/or a species-dependent difference in enzyme content of liver peroxisomes, itself related to an apparent difference in the way in which lipids are handled.     

非诺贝特制剂的研究进展

非诺贝特属于贝特类降血酯药,是降低甘油三酯的首选药物之一,临床使用率高。由于非诺贝特难溶于水,不易于被吸收,导致生物利用度较低,影响药物疗效。为解决这一问题,不同类型的药物传递系统被应用与研究。本文综述非诺贝特制剂的研究进展,以期为其制剂的进一步开发提供思路。     

非诺贝特固体分散片的试制

以PEG4000和十二烷基硫酸钠为载体，采用溶剂—熔融法制备了非诺贝特固体分散体，再与适当辅料混合压片制得非诺贝特固体分散片。用正交设计表L9(3^4)筛选处方。溶出度实验表明自制片较市售两种制剂溶出快。