非诺贝特制剂研究进展

非诺贝特是降低甘油三酯的首选药物之一,但其普通制剂顺应性差、个体差异大且生物利用度低.本文综述非诺贝特的理化性质、药理作用、药动学、不良反应及制剂研发进展,以期能为非诺贝特制剂的进一步开发提供新思路.     

非诺贝特体外溶出度考察及其微粉化制剂的研究

目的考察不同厂家非诺贝特固体制剂体外溶出度以及微粉化对非诺贝特溶出度的影响。方法分别以 40 % (φ)乙醇溶液、5 0 % (φ)乙醇溶液、5g/L十二烷基硫酸钠溶液、1 0g/L十二烷基硫酸钠溶液为溶出介质 ,对 4种市售非诺贝特固体制剂的体外溶出度进行考察。采用球磨机制备微粉化非诺贝特 ,对其溶出度进行测定。结果 1 0 g/L十二烷基硫酸钠溶液中微粉化制剂的溶出速率明显快于其余 3种非微粉化制剂 ,初步探讨了非诺贝特固体制剂体外溶出度标准。用相似因子法对自制微粉化胶囊和法国生产的微粉化胶囊的溶出实验数据进行统计分析 ,结果表明两者溶出行为相似 ,相似因子f2 =72 4(5 0≤f2 ≤ 1 0 0 )。结论不同厂家非诺贝特固体制剂的溶出度差异较大 ,微粉化工艺能显著提高非诺贝特的溶出度     

非诺贝特新制剂在美国上市

Skye Pharma制药公司的合作伙伴First Horizon制药公司上市fenofibrate（非诺贝特IDD-P，Triglide）新制剂，本品于5月7日上市，用于治疗高血脂症。上市规格有50mg和160mg。Triglide运用了Skye Pharma制药公司的IDD技术-P溶解技术，可使药物在进食和空腹时均能被吸收，而老的非诺贝特制剂需与食物同服。非诺贝特可有效增加高密度脂蛋白水平。Triglide于2004年许可转给First Horizon制药公司。     

非诺贝特片和胶囊的溶出度评价

目的利用光纤药物溶出度仪(FODT-601)实时测定非诺贝特片(胶囊)的溶出度,并通过比较溶出曲线评价其制剂工艺和内在质量的差异。方法采用FODT-601仪,以《中国药典》2010年版规定的溶出度测定条件实时监测非诺贝特制剂的溶出曲线;并采用直观分析、Weibull分布模型拟合以及f2相似因子法比较不同剂型、不同厂家、不同批号间的溶出曲线。结果《中国药典》2010年版规定非诺贝特片及胶囊溶出度标准是:60min时取样,其限度为标示量的60%,所选的所有药物均在20min时就满足其限度规定。非诺贝特片与胶囊原创厂家的溶出行为较为一致,但国产厂家的非诺贝特片与胶囊溶出行为不一致;非诺贝特片国产厂家的溶出行为与原创厂家溶出行为差异较大,但非诺贝特胶囊国产厂家的溶出行为与原创厂家溶出行为较为一致;Weibull分布模型拟合法和f2相似因子法评价结果基本一致。结论用FODT-601仪测定非诺贝特制剂,操作简单,得到的数据信息完整,其溶出曲线用Weibull分布模型或f2相似因子法评价均可。     

不同剂型非诺贝特对高血脂大鼠血脂水平的影响

目的　比较微粉化非诺贝特与标准化非诺贝特的降血脂作用。方法　用高脂饲料喂养Wistar大鼠 ,导致大鼠高脂血症 ,然后分别给予微粉化非诺贝特每天 2 0、30、40mg·kg- 1 及标准化非诺贝特每天 2 0、30、40、60、80mg·kg- 1 。于实验d 1 0取血清测定TC、TG。结果　①相同实验条件下 ,微粉化非诺贝特胶囊降低高血脂大鼠血清TC和TG的最低有效剂量为每天 30mg·kg- 1 ,而标准化非诺贝特胶囊为每天 80mg·kg- 1 ;②两种剂型非诺贝特在有效剂量下 ,可使高血脂大鼠的TG水平降至正常 ,使高血脂大鼠的TC水平下降 36 69%～ 51 56 %。结论　微粉化非诺贝特优于标准化非诺贝特制剂 ,非诺贝特对血脂的调节以降低血清TG为主 ,尚能降低血清TC水平     

非诺贝特对高血压调脂治疗的研究探讨

非诺贝特是一种前体药物 ,在体内吸收后被组织和血浆酯酶水解成其主要活性代谢产物非诺贝特酸。微粒化非诺贝特是苯氧芳酸衍生物非诺贝特的一种新的剂型 ,其药物颗粒比标准剂型更小 (直径 5 0 μｍ) ,使药物溶解的表面积增加 ,因此药物在胃肠道的溶解率增加。与标准剂型相比 ,微粒化非诺贝特生物利用度约提高 30 %。我们于 1998年 7月～ 2 0 0 0年 12月应用微粒化非诺贝特对 2 78例高血压病患者进行调脂治疗 ,探讨高血压病患者在控制血压的同时加用调脂治疗对颈动脉ＩＭＴ的干预作用。1 临床资料与方法1 1病例选择 :随机选取门诊及住院高血…     

Cost-effectiveness Analysis of Two Therapeutic Schemes by Fenofibrate for Hyperlipidemia

目的 评价口服非诺贝特片与非诺贝特缓释胶囊治疗高脂血症的成本-效果.方法 运用药物经济学成本分析的方法将高血脂门诊患者共100例,随机分为两组,分别给予非诺贝特片与非诺贝特缓释胶囊,30天为一疗程.根据药物经济学计算两种治疗方案的成本效果分析.结果 非诺贝特片组与非诺贝特缓释胶囊组成本分别为220.7与329.6元,有效率分别为88％与94％,成本-效果比分别为250.8与350.6;缓释胶囊组相对于普通片剂组的增量成本-效果比为1815.结论 普通片剂用药方案治疗高脂血症较佳.     

非诺贝特胶囊剂及家犬体内生物利用度

目的采用纳米分散技术制备非诺贝特胶囊剂,以提高其溶出度及生物利用度。方法用反溶剂沉淀法和高压匀质法制备非诺贝特纳米混悬剂,并通过喷雾干燥将其固化以制备胶囊剂,用差示扫描量热法(differential scanning calorimetry,DSC)和X-射线粉末衍射分析表征药物在胶囊剂中的存在状态,并测定药物的溶出度及家犬体内的生物利用度。结果非诺贝特以纳米晶体状态分散于胶囊剂中,自制胶囊溶出度为国产胶囊的3倍,相对生物利用度为国产胶囊的(274.5±15.6)%。结论自制非诺贝特胶囊剂可以通过增加非诺贝特的分散度来提高药物的溶出度与生物利用度。     

两种非诺贝特治疗高脂血症的成本一效果分析

目的评价口服非诺贝特片与非诺贝特缓释胶囊治疗高腊血症的成本．效果。方法运用药物经济学成本分析的方法将高血脂门诊患者共100例。随机分为两组。分别给予非诺贝特片与非诺贝特缓释胶囊,30天为一疗程。根据药物经济学计算两种治疗方案的成本效果分析,结果非诺贝特片组与非诺贝特缓释胶囊组成本分别为220．7与329．6元,有效率分别为88％与94％,成本．效果比分别为250．8与350．6;甥释胶囊组相对于普通片剂组的增量成本．效果比为1815。结论普通片剂用药方案治疗高脂血症较佳。     

降脂新药非诺贝特及其胶囊通过鉴定

降脂新药非诺贝特及其胶囊制剂的鉴定会由上海市卫生局和上海市医药管理局联合主持,于1984年4月27日在上海召开。参加会议的有各级主管部门、药厂、医院、药检、院校等26个单位的74名专家和代表。非诺贝特是一种高效速效的安妥明类降脂药物,1982年由上海大众制药厂试制成     

The conflict between in vitro release studies in human biorelevant media and the in vivo exposure in rats of the lipophilic compound fenofibrate

The performance of four different lipid-based (Tween 80-Captex 200P, Tween 80-Capmul MCM, Tween 80-Caprol 3GO and Tween 80-soybean oil) and one commercially available micronized formulation (Lipanthyl Micronized(?)) of the lipophilic compound fenofibrate was compared in vitro in various biorelevant media and in vivo in rats. In simulated gastric fluid without pepsin (SGF(sp)) and fasted state simulated intestinal fluid (FaSSIF), only Tween 80-Captex 200P system resulted in a stable fenofibrate concentration, but no supersaturation was obtained. The other three lipid based systems created fenofibrate supersaturation; however they did not maintain it. In fed state simulated intestinal fluid (FeSSIF), all lipid-based formulations resulted in complete dissolution of fenofibrate during the experiment, which represented a supersaturated state for Tween 80-Capmul MCM and Tween 80-Caprol 3GO systems. In both FaSSIF and FeSSIF, all lipid-based formulations yielded a higher fenofibrate concentration than the micronized formulation. Contrary to the in vitro results, no significant difference in the in vivo performance was observed among the four tested lipid-based formulations both in the fasted and the fed states. The in vivo performance of all lipid-based formulations was better than that of Lipanthyl Micronized(?), in the fasted as well as in the fed state. The fact that for the lipid based systems the in vitro differences in pharmaceutical performance were not translated into in vivo differences can be attributed to the continuous excretion of bile in the gastrointestinal tract of rats, causing enhanced solubilizing capacity for lipophilic drugs. This study clearly points to the conflicting situation that might arise during the preclinical phase of the development of lipid based formulations of lipophilic drugs as the performance of such systems is very often evaluated by both in vitro release studies in human biorelevant media as well as in vivo studies in rats. Care must be taken to select a relevant animal model.     

Pharmacokinetic evaluation of oral fenofibrate nanosuspensions and SLN in comparison to conventional suspensions of micronized drug

An increasing number of newly developed drugs show bioavailability problems due to poor water solubility. Formulating the drugs as nanosuspensions may help to overcome these problems by increasing saturation solubility and dissolution velocity. In the present study the bioavailability of the poorly soluble fenofibrate following oral administration was investigated in rats. Four formulations were tested: a nanosuspension type DissoCube(R), one solid lipid nanoparticle (SLN) preparation and two suspensions of micronized fenofibrate as reference formulations, one suspension in sirupus simplex and a second in a solution of hydroxyethy-cellulose in physiological saline. Both colloidal drug delivery systems showed approximately two-fold bioavailability enhancements in terms of rate and extent compared to the reference formulations. No significant differences were found in AUC(0-22 h) as well as in C(max) and t(max) between the two colloidal delivery systems. In conclusion, nanosuspensions may be a suitable delivery system to improve the bioavailability of drugs with low water solubility.     

Design of Lipid-Based Formulations for Oral Administration of Poorly Water-Soluble Drugs: Precipitation of Drug after Dispersion of Formulations in Aqueous Solution

This study was designed to investigate the precipitation of a lipophilic drug following dispersion of lipid formulations in water. The model drug fenofibrate was formulated in representative lipid delivery systems designed for oral administration, using medium chain glycerides, polysorbates, and propylene glycol as excipients. Aqueous dispersion of water-insoluble self-emulsifying lipid formulations resulted in turbid emulsions, followed subsequently by very slow precipitation of 3–7% of the dose of fenofibrate. Self-emulsifying formulations that included water-soluble surfactants, which dissolved a lower mass of drug in solution at equilibrium, nevertheless typically maintained drugs in a metastable state, following dilution with water, for several hours or even days. Formulations with higher contents of hydrophilic materials resulted in more rapid precipitation. Extensive precipitation of fenofibrate from oil-free formulations, comprising of only surfactants and cosolvents, took place within 30 min. The results indicated that most of the lipid systems were supersaturated with respect to the drug on dilution, but the extent of precipitation varied significantly between formulations and was influenced by the extent of supersaturation after dilution. The study suggests that the use of hydrophilic formulations for delivery of lipophilic drugs may result in a greater extent of drug precipitation in the stomach. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3582–3595, 2009     

Analysis of the enhanced oral bioavailability of fenofibrate lipid formulations in fasted humans using an in vitro–in silico–in vivo approach

Lipid-based formulations have established a significant role in the formulation of poorly soluble drugs for oral administration. In order to better understand their potential advantages over solid oral dosage forms, we studied the solubility and dissolution/precipitation characteristics of three self-microemulsifying drug delivery system (SMEDDS) formulations and one suspension of micronized fenofibrate in lipid excipients, for which pharmacokinetic studies had already been reported in the open literature. The in vitro dispersion/dissolution studies were carried out in biorelevant media using USP II apparatus. These were followed up by in silico simulations using STELLA® software, in which not only dispersion/dissolution, but also the precipitation and re-dissolution of fenofibrate was taken into account. While unformulated drug exhibited poor solubility (0.22 μg/mL in FaSSGF and 4.31 μg/mL in FaSSIF-V2(PO₄)) and dissolved less than 2% in dissolution tests, the solubility of fenofibrate in the presence of the lipid excipients increased dramatically (e.g., to 65.44 μg/mL in the presence of the Myritol 318/TPGS/Tween 80 SMEDDS) and there was an attendant increase in the dissolution (over 80% from capsules containing the Myritol 318/TPGS/Tween 80 SMEDDS and about 20% from the dispersion of fenofibrate in lipid excipients). For the four lipid-based fenofibrate formulations studied, combining in vitro data in biorelevant media with in silico simulation resulted in accurate prediction of the in vivo human plasma profiles. The point estimates of C_max and AUC ratio calculated from the in silico and in vivo plasma profiles fell within the 0.8–1.25 range for the SMEDDS solution and capsule formulations, suggesting an accurate simulation of the in vivo profiles. This similarity was confirmed by calculation of the respective f₂ factors. Sensitivity analysis of the simulation profiles revealed that the SMEDDS formulations had virtually removed any dependency of absorption on the dissolution rate in the small intestine, whereas for the dispersion in lipid excipients, this barrier remained. Such results pave the way to optimizing the performance of oral lipid-based formulations via an in vitro–in silico–in vivo approach.     

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.     

Manufacturing Nanosized Fenofibrate by Salt Assisted Milling

Purpose  The aim of this study is to develop a new process for manufacturing a nano-sized form of the popular cholesterol-reducing drug fenofibrate which can be implemented on industrial scale with minimal changes of currently used production schemes. Methods  Salt-assisted milling was used to reduce particle size of commercial fenofibrate from micron-sized particles to nanometer domains. Results  The optimal parameters for the salt milling are reported, allowing one to reduce the particle size from tens of micrometers to a hundred of nanometers. Dissolution of nano-sized fenofibrate was studied in various formulations and compared against the micron-sized commercially available fenofibrate. Conclusions  The nano-sized fenofibrate demonstrates faster dissolution kinetics in aqueous media, simulating stomach environment, within the first 60 min as compared to the micronized form. The highest dissolution rate is achieved with the nano-sized fenofibrate when surfactants, such as sodium dodecyl sulfate or inclusion complex forming agents such as alpha-cyclodextrin, are used.     

IVIVC for Fenofibrate Immediate Release Tablets Using Solubility and Permeability as In Vitro Predictors for Pharmacokinetics

The goal of this study was to investigate the in vitro-in vivo correlation (IVIVC) for fenofibrate immediate release (IR) tablet formulations based on MeltDose®-technique. The in vitro determined drug solubility and permeability data were related to the C_max values observed from two in vivo human studies. Solubility and permeation studies of fenofibrate were conducted in medium simulating the fasted state conditions in the upper jejunum, containing the surfactant compositions of the six formulations at different concentrations. The behavior of all surfactant compositions was characterized by surface tension, dynamic light scattering, and cryo-TEM. The obtained solubility and permeation data were combined and compared with the C_max values for the fenofibrate formulations, assuming a 50 mL in vivo dissolution volume. A good IVIVC was observed for five fenofibrate formulations (R² = 0.94). The in vitro studies revealed that the formulation compositions containing sodium lauryl sulfate (SLS) interfered with the vesicular drug solubilizing system of the biorelevant medium and antagonized its solubilization capacity. The opposing interaction of surfactants with the emulsifying physiological constituents in intestinal juice should be taken into consideration in order to prevent unsatisfactory in vivo performance of orally administered formulations with low soluble active pharmaceutical ingredients.     

Application of mixtures of polymeric carriers for dissolution enhancement of fenofibrate using hot-melt extrusion

Hot-melt extrusion was applied to improve dissolution behavior of poorly soluble model drug fenofibrate. Blends of polymers were used as carrier: copovidone (COP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (PVCL-PVAc-PEG) and hypromellose 2910/5 (HPMC). The ratio of fenofibrate to COP remained constantly 1+3 (weighted parts) with varying amounts of PVCL-PVAc-PEG and HPMC. Solid state of fenofibrate was characterized by X-ray diffractometry and differential scanning calorimetry. Dissolution performance was compared to marketed formulations Lipidil and Lipidil-Ter. Stability studies were conducted at 25°C/60%rH. The dissolution rate from extrudates was significantly increased when compared to pure fenofibrate powder or physical mixture of the components. A supersaturation of 7.6-12.1 was reached with the pelletized extrudates. All extrudates were superior to marketed formulations. No recrystallization was observed after 26 weeks of storage for fenofibrate-COP extrudates 1+3 (weighted parts) with or without polymeric additives. Even so, both degree and duration of supersaturation decreased with increasing storage periods with the exception of fenofibrate-HPMC extrudates. Of particular interest is the finding that by adding polymers with differing release characteristics to the drug-carrier mixture, the dissolution performance of hot-melt extruded solid dosage forms can be readily adapted to meet specific requirements.     

Preparation and in vivo evaluation of SMEDDS (self-microemulsifying drug delivery system) containing fenofibrate

The present work was aimed at formulating a SMEDDS (self-microemulsifying drug delivery system) of fenofibrate and evaluating its in vitro and in vivo potential. The solubility of fenofibrate was determined in various vehicles. Pseudoternary phase diagrams were used to evaluate the microemulsification existence area, and the release rate of fenofibrate was investigated using an in vitro dissolution test. SMEDDS formulations were tested for microemulsifying properties, and the resultant microemulsions were evaluated for clarity, precipitation, and particle size distribution. Formulation development and screening was done based on results obtained from phase diagrams and characteristics of resultant microemulsions. The optimized formulation for in vitro dissolution and pharmacodynamic studies was composed of Labrafac CM10 (31.5%), Tween 80 (47.3%), and polyethylene glycol 400 (12.7%). The SMEDDS formulation showed complete release in 15 minutes as compared with the plain drug, which showed a limited dissolution rate. Comparative pharmacodynamic evaluation was investigated in terms of lipid-lowering efficacy, using a Triton-induced hypercholesterolemia model in rats. The SMEDDS formulation significantly reduced serum lipid levels in phases I and II of the Triton test, as compared with plain fenofibrate. The optimized formulation was then subjected to stability studies as per International Conference on Harmonization (ICH) guidelines and was found to be stable over 12 months. Thus, the study confirmed that the SMEDDS formulation can be used as a possible alternative to traditional oral formulations of fenofibrate to improve its bioavailability.     

Randomised crossover studies of the bioequivalence of two fenofibrate formulations after administration of a single oral dose in healthy volunteers

Bioequivalence of a newly developed semi-solid formulation (Lidose) of fenofibrate (CAS 49562-28-9), and a reference, micronized formulation of fenofibrate was investigated in two randomised, open-label clinical studies with a crossover design. Both studies involved two distinct groups of 24 healthy volunteers. Doses of 67 mg and 200 mg, respectively, were used in study 1 and study 2. On day 1, a single oral dose was administered to all subjects, using one of the two formulations to be compared. Single oral dosing with the other formulation occurred after a washout period of at least 8 days. Blood samples were taken after each dosing for measurement of plasma fenofibric acid concentrations by high-performance liquid chromatography (HPLC) combined with fluorescence detection, and plasma pharmacokinetic parameters were determined. No statistically significant differences were noted for Cmax, Tmax, AUC0-t and AUC0-variation of between subjects treated with the new formulation and those receiving the reference formulation. Side effects were mild and not significantly different between the two fenofibrate preparations. These two studies based on validated methods demonstrate that the new and the reference fenofibrate formulations are bioequivalent when administered at the two doses studied.