Effect of powder processing on performance of fenofibrate formulations

In this study, the effect of the order in which powder blending and jet-milling were performed for the production of the bulk powders on the performance of 200-mg dose orally disintegrating tablets (ODTs) of fenofibrate was evaluated. Bulk powders composed of fenofibrate, mannitol, copovidone S630, and docusate sodium in a 10:10:2:1.2 ratio were prepared by the following three processes: process A: fenofibrate+excipients-->blending; process B: fenofibrate-->jet-milling-->blending with excipients; process C: fenofibrate+excipients-->blending-->jet-milling. The bulk powders were granulated followed by blending and tableting. The materials were tested for Differential Scanning Calorimetry (DSC), drug particle sizing post-reconstitution, dissolution, optical micrography, Scanning Electron Microscopy (SEM), Energy Dispersive X-ray Spectroscopy (EDS) and disintegration of the ODTs. It was found that the crystallinity of fenofibrate was not impacted by the blending and jet-milling processes. Process A produced materials having poorer fenofibrate reconstitution as compared to processes involving jet-milling. It was discovered that milling a blend of fenofibrate/excipient (process C) was advantageous over milling the raw drug alone (process B). Process C yielded bulk powder that showed rapid dissolution and ODTs which exhibited rapid disintegration.     

辛伐他汀联合非诺贝特治疗混合性高脂血症的疗效观察

目的探讨辛伐他汀联合非诺贝特治疗混合性高脂血症的疗效及安全性。方法将146例混合性高脂血症患者随机分为两组,对照组73例给予辛伐他汀治疗,观察组73例在对照组的基础上加用非诺贝特,4周为1个疗程,观察两组患者降脂的疗效及不良反应发生情况。结果观察组临床效果总有效率为95.89%,对照组为78.08%(P<0.05);治疗后两组的TC、TG、LDL-C及HDL-C水平的变化均有显著性改善(P<0.05或P<0.01),但观察组的TG、LDL-C的改善情况优于对照组(P<0.05);观察组TC、TG、LDL-C的达标率分别为58.90%、45.21%、50.68%,3项达标率为36.99%,明显高于对照组的13.70%(P<0.05);两组总不良反应发生率比较差异无统计学意义(P>0.05)。结论辛伐他汀联合非诺贝特治疗混合性高脂血症可充分发挥药物互补、协同作用,有利于全面调节血脂异常,提高血脂水平的达标率,减少不良反应。     

非诺贝特对内皮细胞分泌E-选择素和细胞间黏附分子1的影响

目的 研究非诺贝特对内皮细胞产生E-选择素和细胞间黏附分子1(ICAM-1)的影响.方法 培养人内皮细胞株(ECV304),用肿瘤坏死因子α(TNF-α,浓度5、10、25、50、100ng/ml)刺激;用100μM非诺贝特刺激不同时间(1、6、8、12、18、24h)后用10ng/ml TNF-α刺激24h;用不同浓度非诺贝特(0、1、10、100μM)刺激后用10ng/ml TNF-α刺激24h;用ELISA的方法检测培养上清液中的可溶性E-选择素和ICAM-1浓度.结果 各浓度的TNF-α刺激24h后E-选择素和ICAM-1浓度明显增加(P＜0.05);100μM非诺贝特刺激12、18、24h刺激后抑制E-选择素和ICAM-1分泌增多(P＜0.05);用10、100μM非诺贝特刺激后抑制E-选择素和ICAM-1分泌增多(P＜0.05).结论 非诺贝特可以抑制E-选择素和ICAM-1分泌.     

A novel nanomatrix system consisted of colloidal silica and pH-sensitive polymethylacrylate improves the oral bioavailability of fenofibrate

A novel solid particle system with a nanomatrix structure and without surfactant for the oral delivery of insoluble drugs was prepared. This used a combination of pH-sensitive polymethylacrylate and nano-porous silica, in order to improve the drug absorption using only pharmaceutical excipients and a relative simple process. The in vitro drug dissolution and in vivo oral bioavailability of this formulation, using fenofibrate as the model drug, were compared with other reference formulations such as a suspension, micronized formulation or self microemulsion drug delivery system (SMEDDS). The supersaturation stabilizing effect of different polymers was evaluated and the physicochemical characterization of the optimal formulation was conducted by SEM, TEM, surface area analysis, DSC, and XRD. The optimized formulation prepared with polymethylacrylate (Eudragit®L100-55) and silica (Sylysia®350) markedly improved the drug dissolution compared with other reference preparations and displayed a comparative oral bioavailability to the SMEDDS. Fenofibrate existed in a molecular or amorphous state in the nanomatrix, and this state was maintained for up to 1 year, without obvious changes in drug release and absorption. In conclusion, the nanomatrix formulation described here is a promising system to enhance the oral bioavailability of water-insoluble drugs.     

Long-term safety and efficacy of fenofibrate/pravastatin combination therapy in high risk patients with mixed hyperlipidemia not controlled by pravastatin monotherapy

Abstract

Objective:

To assess the long-term safety and efficacy of a fenofibrate/pravastatin 160/40?mg fixed-dose combination in high-risk patients with mixed hyperlipidemia not controlled by pravastatin 40?mg monotherapy.     

高脂饲料诱发非酒精性脂肪肝实验研究

目的探讨正常饮食和高脂肪饮食对小鼠体重、血糖、葡萄糖耐受、血脂、脂肪肝的影响。方法雄性C57BL/6小鼠随机分为MD10%和MD45%脂肪含量饲料组,喂养3个月,检测动物体重、血糖、葡萄糖耐受、血脂,以及主要脏器重量及肝脏脂质含量。结果与正常组（MD10%脂肪含量）相比,高脂组（MD45%脂肪含量）动物体重显著增加,出现明显的糖耐量异常和血脂水平升高,同时伴有肝脏脂质含量增加。结论高脂饮食对非酒精性脂肪肝有较强的诱导作用。     

A high-throughput approach towards a novel formulation of fenofibrate in omega-3 oil

A novel lipid formulation containing fenofibrate in omega-3 oil was developed using a novel high-throughput screening platform. The optimized formulation combines the cardiovascular health benefits from omega-3 oil with the potent lipid-regulating effect of fenofibrate. When tested against the current marketed product Tricor^® in healthy human volunteers, the new formulation was shown to be equivalent to Tricor^®.     

保利尔胶囊联合非诺贝特治疗高脂血症的临床研究

目的 探讨保利尔胶囊联合非诺贝特治疗高脂血症的临床疗效。方法 选取2021年5月—2023年5月中国中医科学院广安门医院收治的98例高血脂症患者,按照随机数字法将患者分为对照组（49例）和治疗组（49例）。对照组随餐口服非诺贝特胶囊,0.2 g/次,1次/d。在对照组的基础上,治疗组口服保利尔胶囊,5粒/次,3次/d。两组患者治疗15 d。观察两组患者临床疗效,比较治疗前后两组患者症状改善时间,血清总胆固醇、瘦素、血沉、脂联素、白细胞介素-6（IL-6）、IL-1β、细胞间黏附分子-1（ICAM-1）和超氧化物歧化酶（SOD）水平,及不良反应情况。结果 治疗后,治疗组临床总有效率（97.96%）明显高于对照组（81.63%,P＜0.05）。治疗后,治疗组症状改善时间均明显早于对照组（P＜0.05）。治疗后,两组脂联素和SOD明显高于治疗前,而总胆固醇、瘦素、血沉、IL-6、IL-1β、ICAM-1水平均明显低于治疗前（P＜0.05）,且治疗组这些血清因子水平明显好于对照组（P＜0.05）。治疗后,治疗组不良反应发生率（6.22%）明显低于对照组发生率（16.33%,P＜0.05）。结论 非诺贝特与保利尔胶囊协同治疗效果确切,对临床症状可以有效改善,能使高血脂有效调节,并减弱机体炎性反应状态。     

Influence of polyvinylpyrrolidone quantity on the solubility,crystallinity and oral bioavailability of fenofibrate in solvent-evaporated microspheres

The objective of this study is to explore the influence of polyvinylpyrrolidone (PVP) quantity on the solubility, crystallinity and oral bioavailability of poorly water-soluble fenofibrate in solvent-evaporated microspheres. Numerous microspheres were prepared with fenofibrate, sodium lauryl sulphate (SLS) and PVP using the spray-drying technique. Their aqueous solubility, dissolution, physicochemical properties and pharmacokinetics in rats were assessed. The drug in the solvent-evaporated microspheres composed of fenofibrate, PVP and SLS at the weight ratio of 1:0.5:0.25 was not entirely changed to the amorphous form and partially in the microcrystalline state. However, the microspheres at the weight ratio of 1:4:0.25 provided the entire conversion to the amorphous form. The latter microspheres, with an improvement of about 115 000-fold in aqueous solubility and 5.6-fold improvement in oral bioavailability compared with the drug powder, gave higher aqueous solubility and oral bioavailability compared with the former. Thus, PVP quantity played an important role in these properties of fenofibrate in the solvent-evaporated microspheres.     

卡托普利联合非诺贝特对糖尿病大鼠视网膜病变保护作用的研究

目的研究卡托普利联合非诺贝特对糖尿病大鼠视网膜细胞凋亡作用、外周血血管内皮生长因子(Vascular endothelial growth factor,VEGF)及其氧化相关物质的影响,以明确其保护糖尿病视网膜病变(Diabetic retinopathy,DR)的作用机制。方法选取清洁级性成熟SD大鼠100只,随机分为5组(每组20只):A组(假造模组,普通饲料喂养并灌胃相同体积的生理盐水)、B组[模型组,高脂饲料喂养4周后给予腹腔注射链脲佐菌素(Streptozotocin,STZ),给予相同体积生理盐水8周]、C组(卡托普利干预组,高脂饲料喂养4周后给予腹腔注射链脲佐菌素,给予卡托普利干预8周)、D组(非诺贝特干预组,高脂饲料喂养4周后给予腹腔注射链脲佐菌素,给予非诺贝特干预8周)、E组(卡托普利+非诺贝特联合干预组,高脂饲料喂养4周后给予腹腔注射链脲佐菌素,给予卡托普利+非诺贝特干预8周),抽取外周血检测外周血清甘肽过氧化物酶(Glutathione peroxidase,GSHPX)、超氧化物歧化酶(Superioxide dismutase,SOD)、活性氧类物质(Reactive oxygen species,ROS)、丙二醛(M alondialdehyde,M DA)、VEGF浓度,处死大鼠,取出眼球,用Tunel染色法检测视网膜细胞凋亡情况。结果 A组大鼠外周血清GSH-PX、SOD活性值均高于其他4组(P<0.05),而ROS、MDA、VEGF和Tunel指数均低于其他4组(P<0.05);B组大鼠外周血清GSH-PX、SOD活性值均低于其他4组(P<0.05),而ROS、M DA、VEGF与Tunel指数均高于其他4组(P<0.05);E组大鼠外周血清GSH-PX、SOD活性值均高于C组、D组(P<0.05),而ROS、M DA、VEGF与Tunel指数均低于C组、D组(P<0.05);D组大鼠外周血清GSH-PX、SOD活性均高于C组(P<0.05),而ROS、MDA与Tunel指数均低于C组(P<0.05);D组大鼠外周血清VEGF浓度值低于C组(P<0.05)。结论卡托普利及非诺贝特均能改善DR,通过抑制凋亡与抗氧化对视网膜起到很好的保护作用,但两药联合应用效果更佳。     

非诺贝特与辛伐他丁治疗高脂血症的临床疗效对比研究

目的探讨非诺贝特及辛伐他丁对混合型高脂血症的疗效作用差异,为临床用药提供指导。方法将在我院接受治疗的54例混合型高脂血症患者随机分为联合治疗组、非诺贝特组和辛伐他丁组各18例,联合治疗组组患者使用非诺贝特联合辛伐他丁进行治疗,非诺贝特组使用非诺贝特进行治疗,辛伐他丁组使用辛伐他丁进行治疗,检测血清总胆固醇（TC）、三酰甘油（TG）、高、低密度脂蛋白（HDL-C、LDL-C来评价药物疗效差异。结果非诺贝特组LDL-C的含量与联合治疗组比较具有显著性差异（＊＊P〈0.01）,辛伐他丁组与联合治疗组比较TG、HDL-C含量具有显著性差异（＊P〈0.05或＊＊P〈0.01）;与非诺贝特组比较,辛伐他丁组TG、HDL-C、LDL-C含量具有显著性差异（#P〈0.05）。结论非诺贝特较辛伐他丁其降低TG、升高HDL-C作用较强,对TC也具有一定的降低作用,辛伐他丁较非诺贝特其降低TC、降低LDL-C作用较强。     

Comparison of in vitro tests at various levels of complexity for the prediction of in vivo performance of lipid-based formulations: Case studies with fenofibrate

The objectives of this study were to characterise three prototype fenofibrate lipid-based formulations using a range of in vitro tests with differing levels of complexity and to assess the extent to which these methods provide additional insight into in vivo findings. Three self-emulsifying drug delivery systems (SEDDS) were prepared: a long chain (LC) Type IIIA SEDDS, a medium chain (MC) Type IIIA SEDDS, and a Type IIIB/IV SEDDS containing surfactants only (SO). Dilution, dispersion and digestion tests were performed to assess solubilisation and precipitation behaviour in vitro. Focussed beam reflectance measurements and solid state characterisation of the precipitate was conducted. Oral bioavailability was evaluated in landrace pigs. Dilution and dispersion testing revealed that all three formulations were similar in terms of maintaining fenofibrate in a solubilised state on dispersion in biorelevant media. During in vitro digestion, the Type IIIA formulations displayed limited drug precipitation (<5%), whereas the Type IIIB/IV formulation displayed extensive drug precipitation (∼70% dose). Solid state analysis confirmed that precipitated fenofibrate was crystalline. The oral bioavailability was similar for the three lipid formulations (65–72%). In summary, the use of LC versus MC triglycerides in Type IIIA SEDDS had no impact on the bioavailability of fenofibrate. The extensive precipitation observed with the Type IIIB/IV formulation during in vitro digestion did not adversely impact fenofibrate bioavailability in vivo, relative to the Type IIIA formulations. These results were predicted suitably using in vitro dilution and dispersion testing, whereas the in vitro digestion method failed to predict the outcome of the in vivo study.     

Novel role of NPC1L1 in the regulation of hepatic metabolism: potential contribution of ezetimibe in NAFLD/NASH treatment

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and also in other parts of the world. NAFLD encompasses a histological spectrum ranging from simple steatosis to steatohepatitis, advanced fibrosis and inflammatory changes. It frequently occurs with features of the metabolic syndrome including obesity, type 2 diabetes mellitus, dyslipidemia and hypertension. In fact, the metabolic syndrome is a strong predictor of NAFLD. Recently, Niemann-Pick C1-like 1 (NPC1L1) has been shown to play a pivotal role in cholesterol absorption. Unlike mouse NPC1L1 protein, predominantly expressed in the intestines, human and rat NPC1L1 is also abundantly expressed in the liver. Though the exact functions of hepatic NPC1L1 remain unknown, NPC1L1 may facilitate the hepatic accumulation of cholesterol. This raises a potential possibility that ezetimibe may improve fatty liver formation. In this review, potential role of lipid metabolism in NAFLD and its possible modulation through NPC1L1 blockade is discussed.     

Effect of fenofibrate on the level of asymmetric dimethylarginine in individuals with hypertriglyceridemia

Objective To test whether treatment with fenofibrate decreases asymmetric dimethylarginine (ADMA) level in hypertriglyceridemic individuals. Methods In the present study, 45 subjects with hypertriglyceridemia were recruited to receive treatment with fenofibrate (200 mg/d). Serum concentrations of ADMA, malondialdehyde (MDA), nitric oxide (NO) and tumor necrosis factor-α (TNF-α) were measured. Endothelial function assessed by flow-mediated dilation (FMD) of the brachial artery was performed. Results Compared with control, serum levels of ADMA (0.47±0.05 μmol/L in control and 0.62±0.28 μmol/L in hypertriglyceridemic patients, P<0.01), MDA and TNF-α were markedly elevated, and the level of NO was significantly reduced, concomitantly with impaired endothelium-dependent vasodilation in individuals with hypertriglyceridemia. 8-week treatment with fenofibrate significantly reduced the elevated levels of ADMA (0.53±0.12 μmol/L, P<0.01), MDA and TNF-α, attenuated the decreased level of NO and improved endothelial function. Conclusions These results suggest that the beneficial effect of fenofibrate on the endothelium in hypertriglyceridemic individuals may be related to reduction of ADMA level.     

Impact of fillers on dissolution kinetic of fenofibrate dry foams

Abstract

Dry foam technology reveals the opportunity to improve the dissolution behavior of poorly soluble drugs tending to agglomeration due to micronization. In this study, the impact of fillers on the manufacturability, the properties of dry foams and granules as well as the dissolution kinetics of dry foam tablets was investigated using fenofibrate as a model compound. Different maltodextrins and dried glucose syrups, a maltodextrin–phosphatidylcholine complex, isomalt and a 1:1 mixture of mannitol/glucose syrup were used as filler. Within the group of maltodextrins and glucose syrups, the influences of dextrose equivalent (DE), particle morphology and botanical source of starch were investigated. Comparable macroscopic foam structures were obtained with maltodextrins and glucose syrups whereas different foam morphologies were obtained for the other fillers tested. Regarding the maltodextrins and glucose syrups, different physicochemical and particle properties had a minor impact on granule characteristics and tablet dissolution. Using the maltodextrin–phosphatidylcholine complex resulted in a low specific surface area of the granules and a slow tablet dissolution caused by a slow disintegration. In contrast, a high specific surface area and a fast release were obtained with isomalt and glucose syrup/mannitol mixture indicating that high soluble low molecular weight fillers enable the development of fast dissolving dry foam tablets.     

Effect of orlistat,micronised fenofibrate and their combination on metabolic parameters in overweight and obese patients with the metabolic syndrome: the FenOrli study

ABSTRACT

Background: Obesity is becoming increasingly common worldwide and is strongly associated with the metabolic syndrome (MetS). MetS is considered to be a cluster of risk factors that increase the risk of vascular events.

Objective: In an open-label randomised study (the FenOrli study) we assessed the effect of orlistat and fenofibrate treatment, alone or in combination on reversing the diagnosis of the MetS (primary end-point) as well as on anthropometric and metabolic parameters (secondary end-points) in overweight and obese patients with MetS but no diabetes.

Methods: Overweight and obese patients (N = 89, body mass index (BMI) > 28?kg/m²) with MetS [as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria] participated in the study. Patients were prescribed a low-calorie low-fat diet and were randomly allocated to receive orlistat 120?mg three times a day (tid) (O group), micronised fenofibrate 200?mg/day (F group), or orlistat 120?mg tid plus micronised fenofibrate 200?mg/day (OF group). Body weight, BMI, waist circumference, blood pressure, serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL‐C), high-density lipoprotein cholesterol (HDL‐C), non-HDL‐C, triglyceride, creatinine (SCr) and uric acid (SUA) levels, as well as homeostasis model assessment (HOMA) index and liver enzyme activities were measured at baseline and after 3 months of treatment.

Results: Of the 89 patients enrolled, three (one in each group) dropped out during the study due to side effects. After the 3‐month treatment period, 43.5% of patients in the O group, 47.6% in the F group and 50% in the OF group no longer met the MetS diagnostic criteria (primary end-point, p < 0.0001 vs. baseline in all treatment groups). No significant difference in the primary end-point was observed between the three treatment groups. Significant reductions in body weight, BMI, waist circumference, blood pressure, TC, LDL‐C, non-HDL‐C, triglyceride and SUA levels, as well as gamma-glutamyl transpeptidase activity and HOMA index were observed in all treatment groups. In the OF group a greater decrease in TC (–26%) and LDL‐C (–30%) was observed compared with that in the O and F groups (?p < 0.01) and a more pronounced reduction of triglycerides (–37%) compared with that in the O group (?p < 0.05). SUA levels and alkaline phosphatase activity decreased more in the F and OF groups compared with the O group (?p < 0.05). Moreover, SCr significantly increased and estimated creatinine clearance decreased in the F and OF groups but they were not significantly altered in the O group (?p < 0.01 for the comparison between O and either F or OF groups). Glucose (in groups O and OF), as well as insulin levels and HOMA index (in all groups), were significantly reduced after treatment (?p < 0.05 vs. baseline).

Conclusion: The combination of orlistat and micronised fenofibrate appears to be safe and may further improve metabolic parameters in overweight and obese patients with MetS compared with each monotherapy.     

Effect of fenofibrate on LDL-induced endothelial dysfunction in rats

Previous investigations have demonstrated that asymmetric dimethylarginine (ADMA) is an important factor contributing to endothelial dysfunction, and that fenofibrate has a protective effect on the endothelium in hyperlipidaemic patients. In the present study in rats treated with native low-density lipoprotein (nLDL), we addressed the question of whether the beneficial effect of fenofibrate on endothelial cells is related to reduction of the ADMA concentration. A single injection of nLDL (4 mg/kg, 48 h) markedly reduced endothelium-dependent relaxation in response to acetylcholine and the plasma level of nitrite/nitrate and increased the plasma concentrations of ADMA, malonyldialdehyde (MDA) and tumour necrosis factor- (TNF-). Treatment with fenofibrate (30 or 100 mg/kg) significantly reduced the inhibition of vasodilator responses to acetylcholine, decreased the elevated levels of ADMA, MDA and TNF-, and enhanced the decreased level of nitrite/nitrate in the rats treated with LDL. These results suggest that the protective effect of fenofibrate on endothelial cells in rats treated with LDL may be related to the reduction of ADMA concentration.     

从痰湿体质角度探析非酒精性脂肪肝的预防治疗

非酒精性脂肪肝是临床上常见疾病，其发病率呈逐年上升并且年龄有越来越小的趋势。非酒精性脂肪肝的病理体质类型与临床证型密不可分，在非酒精性脂肪肝中痰湿质和湿热质占大多数。按照“治未病”的原则，结合“体质可调”“从体论治”，采用中医中药调治非酒精性脂肪肝的病理体质向“平和质”发展转变，对治疗非酒精性脂肪肝有重要的意义。     

A New Formulation of Fenofibrate: Suprabioavailable Tablets

Summary

The rationale for, and development of, a new suprabioavailable fenofibrate tablet formulation is described. The new suprabioavailable tablet formulation combines wellestablished micronisation technology with a new micro-coating process. The new formulation provides more predictable and reliable drug absorption. Owing to the strong relationship between the fenofibrate dissolution performance and its oral bioavailability, equivalent plasma levels of active principal are achieved at a lower dose, with less inter-subject variability and a reduced food effect. The new suprabioavailable tablet may, therefore, be a more efficient and better tolerated formulation.