Self-nanoemulsifying drug delivery system (SNEDDS) of the poorly water-soluble grapefruit flavonoid Naringenin: design,characterization, in vitro and in vivo evaluation

Abstract

Naringenin (NRG), predominant flavanone in grapefruits, possesses anti-inflammatory, anti-carcinogenic, hepato-protective and anti-lipid peroxidation effects. Slow dissolution after oral ingestion due to its poor solubility in water, as well as low bioavailability following oral administration, restricts its therapeutic application. The study is an attempt to improve the solubility and bioavailability of NRG by employing self-nanoemulsifying drug delivery technique. Preliminary screening was carried out to select oil, surfactant and co-surfactant, based on solubilization and emulsification efficiency of the components. Pseudo ternary phase diagrams were constructed to identify the area of nanoemulsification. The developed self-nanoemulsifying drug delivery systems (SNEDDS) were evaluated in term of goluble size, globule size distribution, zeta potential, and surface morphology of nanoemulsions so obtained. The TEM analysis proves that nanoemulsion shows a droplet size less than 50?nm. Freeze thaw cycling and centrifugation studies were carried out to confirm the stability of the developed SNEDDS. In vitro drug release from SNEDDS was significantly higher (p?<?0.005) than pure drug. Furthermore, area under the drug concentration time-curve (AUC_0–24) of NRG from SNEDDS formulation revealed a significant increase (p?<?0.005) in NRG absorption compared to NRG alone. The increase in drug release and bioavailability as compared to drug suspension from SNEDDS formulation may be attributed to the nanosized droplets and enhanced solubility of NRG in the SNEDDS.     

辛伐他汀自乳化胶囊的体内外评价

目的研究辛伐他汀自乳化胶囊的自乳化能力及在Beagle犬体内的药动学.方法以总体液平衡反向透析法考察自乳化胶囊与市售片的体外释药过程;通过测定不同时间的粒子的散射光强度来评价自乳化速度,光学显微镜下考察乳化后形成的乳滴的大小和分布;采用HPLC法测定Beagle犬血浆药物浓度,并与市售片比较考察自乳化胶囊的体内药动学.结果溶出度结果显示辛伐他汀自乳化胶囊比市售片溶出快、浓度高.辛伐他汀自乳化胶囊在10 min内已基本乳化完全,光学显微镜下检视,乳化后乳滴粒子大多数在2μm以下.药动学测定结果表明与市售片比较,自乳化胶囊血药浓度达峰时间提前[Tmax(1.62±0.15)vs(2.65±0.42)h,P＜0.05],最高血药浓度增大[Cmax(44.28±6.29)vs(12.43±2.51)ng·mL-1,P＜0.05],相对生物利用度为市售片剂的216.8%.结论自乳化胶囊可以显著提高辛伐他汀的体外溶出和体内吸收.     

氯雷他定自乳化释药系统的制备和质量评价

目的制备氯雷他定自乳化制剂，并对其质量进行评价。方法通过测定药物在不同油相中的溶解度，研究油相与各种乳化剂、助乳化剂的配伍对自乳化效率的影响，并结合伪三元相图，筛选氯雷他定自乳化制剂的处方。考察该制剂经水稀释后形成的微乳的外观、粒径和Zeta电位，测定药物的油水分配系数及溶解度，并通过加速实验评价制剂的稳定性。结果自乳化介质处方为油酸乙酯-吐温80-正丁醇（10：54：36）；氯雷他定自乳化制剂稀释50倍后仍为澄清透明液体，粒径为（13．9±3．2）nm，（电位为（16．7±0．8）mv，药物的油水分配系数（10gP）和在自乳化介质中的溶解度分别为2．30和256．2mg·mL^-1；加速实验表明氯雷他定自乳化制剂的各项指标稳定。结论氯雷他定自乳化制剂制备简单，质量稳定，能显著提高药物的溶解度。     

盐酸小檗碱纳米乳口服给药系统的制备及体外评价

目的 制备盐酸小檗碱纳米乳,优选其处方组成和制备工艺,并对其外观、粒径及体外释放行为等进行评价.方法 采用水滴加法制备盐酸小檗碱纳米乳,绘制纳米乳伪三元相图.选择星点设计-效应面法对纳米乳处方进行优化,确定最优处方组成比例.对制备的盐酸小檗碱纳米乳的粒径、电位、外观形态、体外释药行为等进行表征.结果 确定了盐酸小檗碱纳...     

Application of hot-melt extrusion technology for designing an elementary osmotic pump system combined with solid dispersion for a novel poorly water-soluble antidepressant

TP1 is a novel antidepressant with poor solubility. To reduce fluctuations in blood concentration and increase oral bioavailability, a controlled-release system was developed by combining a solid dispersion (SD) and an elementary osmotic pump (EOP). The study compared different methods of preparing SDs. Hot-melt extrusion (HME) exhibited clear advantages over the traditional melting technique. An in vitro release study demonstrated that HME-EOP tablets released TP1 in a zero-order manner over 12?h and the drug release was in dependent of the release medium and agitation speed, whereas release from molten-EOP tablets lasted only 8?h. In contrast to immediate-release tablets, the HME-EOP tablets exhibited less fluctuation in blood concentration and higher bioavailability in vivo. In summary, the osmotic pump system combined with an HME-based SD of TP1 presented controlled release in vitro, high bioavailability in vivo and a good in vivo–in vitro correlation.     

Solid self-nanoemulsifying drug delivery system (SNEDDS) for enhanced oral bioavailability of poorly water-soluble tacrolimus: physicochemical characterisation and pharmacokinetics

Abstract

To develop a novel self-nanoemulsifying drug delivery system (solid SNEDDS) with better oral bioavailability of tacrolimus, the solid SNEDDS was obtained by spray-drying the solutions containing the liquid SNEDDS and colloidal silica. Its reconstitution properties were determined and correlated to solid state characterisation of the powder. Moreover, the dissolution and pharmacokinetics in rats was done in comparison to the commercial product. Among the liquid SNEDDS formulations tested, the liquid SNEDDS comprised of Capryol PGMC, Transcutol HP and Labrasol (10:15:75, v/v/v) presented the highest dissolution rate. In the solid SNEDDS, this liquid SNEDDS was absorbed in the pores and attached onto the surface of the colloidal silica. Drug was present in the amorphous state in it. The solid SNEDDS with 5% w/v tacrolimus produced the nanoemulsions and improved the oral bioavailability of tacrolimus in rats. Therefore, this solid SNEDDS would be a potential candidate for enhancing the oral bioavailability of tacrolimus.     

拉帕替尼自微乳给药系统的制备与体内外质量评价

目的 制备拉帕替尼自微乳给药系统,进行体外质量评价与大鼠体内药动学性质考察。方法 通过检测拉帕替尼在不同辅料中的溶解度,选择合适的辅料绘制伪三元相图,利用星点设计-效应面法优化处方组分,确定最终处方。对制备的拉帕替尼自微乳进行粒径、Zeta电位检测,采用透射电镜观察微观形态,并考察不同介质、不同稀释倍数、不同放置时间对粒径的影响,进行拉帕替尼自微乳与拉帕替尼混悬液体外释放实验与大鼠体内药动学研究。结果 最终确定拉帕替尼自微乳处方为玉米油∶油酸∶RH40∶TP=20∶20∶48∶12,平均粒径为（35.88±0.61） nm,Zeta电位为（-2.81±0.25） mV;在不同介质（pH 1.0、pH 4.5、pH 6.8）、不同稀释倍数（1∶50、1∶100、1∶200）下放置6 h,粒径稳定;体外释放48 h,药物累计释放量达70%;大鼠药动学实验结果显示,与拉帕替尼混悬液相比,拉帕替尼自微乳的C_max与AUC显著提高。结论 拉帕替尼自微乳给药系统性质稳定,改善了药物的溶解度,提高了拉帕替尼在大鼠体内的生物利用度,对拉帕替尼新剂型的研发有一定的参考价值。     

大蒜素自微乳的制备与质量评价

目的:制备大蒜素(DATS)自微乳制剂,并评价其质量.方法:采用伪三元相图法,以聚氧乙烯氢化蓖麻油RH-40为表面活性剂,无水乙醇为助表面活性剂,油酸为油相,绘制该系统的相图,在此基础上制备DATS自微乳;建立HPLC法测定DATS自微乳中DATS的含量;对自微乳的外观性状、相对密度、黏度、pH值、电导率、形态、粒径及粒度分布、Zeta电位、含量、配伍和稳定性等进行研究.结果:DATS自微乳为无色澄明液体,稳定性良好,相对密度为0.840 g·mL-1,黏度为5.447 mPa·s,遇水形成O/W型微乳,稀释250倍后电镜下观察成圆球形,平均粒径26.4 nm,Zeta电位0.398 mV,pH值5.62,电导率为8.37μs·cm-1,3批制剂的含量分别为31.77,31.45,32.15 mg·mL-1.DATS自微乳与葡萄糖注射液、氯化钠注射液等配伍稳定.结论:DATS自微乳制备工艺简单,性质稳定,质量易控.     

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.     

星点设计-效应面法优化黄肝微丸的制备工艺

目的:采用挤出滚圆法制备黄肝微丸,筛选最佳处方工艺.方法:用挤出滚圆造粒机制备黄肝微丸;以微丸的粉体学性质及得率为指标,在单因素试验基础上,通过星点设计-效应面法优化制备工艺.结果:制备黄肝微丸的最佳工艺为:挤出速度33 Hz,滚圆速度29 Hz,滚圆时间为12 min,所得微丸的圆整度好、大小均匀、收率高.验证实验证...     

星点设计-效应面法优化盐酸氨溴索漂浮渗透泵给药系统及犬体内药动学

本文设计了具有漂浮特性的盐酸氨溴索渗透泵胶囊。采用中国药典(2010版)附录XD释放度测定法第三法装置同时评价制剂的体外释放和漂浮性能。以葡萄糖用量、致孔剂用量和包衣增重为自变量,自制处方释放曲线与目标释放曲线相比而得的相似因子(f2)为应变量,采用星点设计-效应面法优化系统。优化处方:葡萄糖100.99 mg,致孔剂用量11.70%,包衣增重4.21%。f2为89.14,高于市售胶囊(69.02)和自制片(72.15)。优化后零级释药明显(r=0.994 4),释药完全(>90%)。Beagle犬体内实验证明,自制胶囊Cmax、tmax低于市售胶囊、自制片,体内外相关性好(r=0.985 1),且生物利用度高(110.77%),说明自制胶囊有明显的控释特征。     

Development of clinical dosage forms for a poorly water-soluble drug II: formulation and characterization of a novel solid microemulsion preconcentrate system for oral delivery of a poorly water-soluble drug

The solution of a poorly water-soluble drug in a liquid lipid-surfactant mixture, which served as a microemulsion preconcentrate, was converted into a solid form by incorporating it in a solid polyethylene glycol (PEG) matrix. The solid microemulsion preconcentrates thus formed consisted of Capmul PG8 (propylene glycol monocaprylate) as oil, Cremophor EL (polyoxyl 35 castor oil) as surfactant, and hydrophilic polymer PEG 3350 as solid matrix. The drug (aqueous solubility: 0.17 microg/mL at pH 1-8 and 25 degrees C) was dissolved in a melt of the mixture at 65-70 degrees C and then the hot solution was filled into hard gelatin capsules; the liquid gradually solidified upon cooling below 55 degrees C. The solid system was characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), confocal Raman microscopy (CRM), and the dispersion testing in water. It was confirmed that a solid microemulsion preconcentrate is a two-phase system, where clusters of crystalline PEG 3350 formed the solid structure (m.p. 55-60 degrees C) and the liquid microemulsion preconcentrate dispersed in between PEG 3350 crystals as a separate phase. The drug remained dissolved in the liquid phase. In vitro release testing showed that the preconcentrate dispersed readily in water forming a microemulsion with the drug dissolved in the oil particles (<150 nm) and the presence of PEG 3350 did not interfere with the process of self-microemulsification.     

星点设计-效应面法优化姜黄素牛血清白蛋白纳米粒的制备工艺

摘 要 目的：星点设计 效应面法优化姜黄素牛血清白蛋白纳米粒(CUR BSA NPs)的制备工艺,考察其外观粒径分布及体外释放特性。 方法: 以牛血清白蛋白为载体材料,姜黄素作为模型药物,采用去溶剂法制备CUR BSA NPs,通过星点设计 效应面法优化其制备工艺,并对CUR BSA NPs的外观形态、粒径分布、包封率、载药量及体外释放进行研究。 结果: CUR BSA NPs制备的最佳工艺条件为牛血清白蛋白浓度10 mg·ml-1,乙醇体积7.79 ml,搅拌速度915 r·min-1。根据优化处方工艺制备的CUR BSA NPs外观呈圆形或类圆形,平均粒径（203.93±83.10） nm,Zeta电位-40～-50 mV;包封率为86.53%,载药量为3.89%。 结论: 最优工艺条件下制备的CUR BSA NPs包封率和载药量高,粒径分布较为均匀,体外释放试验表明与姜黄素原料药相比制备的CUR BSA NPs有良好的缓释特性。     

多西他赛普朗尼克P123胶束的制备

摘 要 目的： 优化以普朗尼克P123为载体材料的多西他赛胶束处方工艺。方法: 采用薄膜水化法制备多西他赛普朗尼克P123胶束。采用星点设计 效应面法优化胶束处方工艺,以包封率作为评价指标,考察投药量、有机溶剂体积、水化体积、水化温度。采用透射电镜观察胶束形态,并测定胶束的粒径和Zeta电位,以透析法进行胶束体外释放特性考察。结果: 以多元线性回归和二次、三次多项式拟合指标与因素之间的数学关系,结果表明三次多项式拟合度较好,制备出的胶束形态圆整,平均粒径和Zeta电位分别为108.3 nm和 3.99 mV,多分散指数为0.265,平均包封率和载药率分别为（97.91%±0.28％）和（3.72%±0.12％）,多西他赛胶束120 h的累积释放率达95.03%,具有一定的缓释能力。结论:采用薄膜水化法制备的多西他赛胶束工艺简单可行,具有较高的包封率,在体外具有较好的缓释效果。     

茴拉西坦自乳化给药系统与片剂的药代动力学及体内外相关性的研究

目的：研究茴拉西坦自乳化制剂和普通片剂的体内外相关关系;评价其大鼠口服给药的体内药代动力学。方法：通过测定自乳化制剂和普通片剂的体外溶出度考察其释药特性,采用RP-HPLC法测定活性代谢产物对氨基甲氧基丁酸的浓度血浆中,通过Wagner-Nelson法计算体内吸收分数（f）,研究两制剂的吸收分数（f）与体外累积溶出度（Q%）的相关性。结果：自乳化微乳体外15min的溶出度为（80±4）%,比片剂的溶出度（50%）明显提高;体内代谢产物的回收率为90%,日内日间精密度分别小于4%和6%,该方法灵敏度高、准确可靠。自乳化微乳的AUC0-∞为（11168±2395）ng·mL^-1·h,是普通片剂的3倍。自乳化微乳和片剂的MRT0-∞分别为（2.7±0.6）h和（1.7±0.5）h,具有统计学差异（P〈0.05）。体内外相关性结果表明,片剂的体内吸收与体外溶出度呈线性相关,线性方程的斜率为0.7765,截距为-2.9527;自乳化微乳的体内外相关性符合二次模型,其拟合系数为0.972。结论：茴拉西坦自乳化给药系统可显著提高药物体内的生物利用度。自乳化制剂处方中含有促吸收的复合表面活性剂和油相,其体外药物呈快速释放的特性,而体内自发与胃肠液形成o/w型微乳后可通过淋巴转运的吸收途径。     

白矾星点设计-效应面法炮制工艺研究

摘 要 目的：利用烤箱炮制结合星点设计 效应面法优选白矾的最佳炮制工艺,为炮制白矾规范化生产提供依据。方法: 以白矾为原料,在单因素试验基础上,选取炮制温度、炮制时间、白矾质量3个因素为自变量,用滴定法对枯矾中硫酸铝钾进行含量测定,采用星点设计 效应面法优选白矾最佳炮制工艺。结果: 白矾的最佳炮制工艺为：炮制温度：250℃;炮制时间：40 min;白矾质量：8 g。结论: 星点设计 效应面法选白矾炮制工艺,方法简便,工艺稳定且预测性良好,可为炮制白矾规范化生产提供依据。     

紫杉醇超饱和自微乳化给药系统的制备及大鼠体内药动学研究

目的:制备紫杉醇超饱和自微乳化给药系统(supersaturatable self-microemulsifying drug delivery system,S-SMEDDS),并对其在大鼠体内的药动学进行研究。方法:采用伪三元相图的方法,优化紫杉醇自微乳化给药系统(SMEDDS)的处方。18只大鼠随机分为3组,分别灌胃给予10 mg/kg紫杉醇溶液、SMEDDS和S-SMEDDS,测定紫杉醇的血药浓度c、max、AUC和tmax,计算相对生物利用度。结果:确定紫杉醇SMEDDS最优处方为:油相∶表面活性剂∶助表面活性剂=50∶33∶17。油相为Lauroglycol FCC∶橄榄油(2∶1),表面活性剂为Cremophor EL∶吐温-80(1∶1),助表面活性剂为PEG-400。S-SMEDDS在此处方基础上添加5%羟丙基甲基纤维素。稀释对制剂的粒径无显著影响。SMEDDS和S-SMEDDS的粒径分别为(92.7±47.7)和(93.6±36.8)nm,粒径分布呈高斯分布。SMEDDS和S-SMEDDS的cmax和AUC显著高于溶液剂,tmax<溶液剂,生物利用度分别为333.9%和719.3%。结论:紫杉醇S-SMEDDS的口服吸收强于溶液剂和SMEDDS。     

漆黄素纳米混悬剂和冻干粉末的制备及体外评价

目的:制备漆黄素纳米混悬剂及其冻干粉末,提高药物溶解度及溶出度.方法:高压均质法制备漆黄素纳米混悬剂.以粒径为评价指标,单因素考察聚乙烯吡咯烷酮K30 (PVP K30)用量、有机相与水相体积比、均质压力和次数的影响.采用Box-Behnken响应面法优化漆黄素纳米混悬剂的处方工艺,并制备成冻干粉.扫描电镜观察纳米混悬...     

Design,optimization and evaluation of glipizide solid self-nanoemulsifying drug delivery for enhanced solubility and dissolution

A solid self-nanoemulsifying drug-delivery system (solid SNEDDS) has been explored to improve the solubility and dissolution profile of glipizide. SNEDDS preconcentrate was systematically optimized using a circumscribed central composite design by varying Captex 355 (Oil), Solutol HS15 (Surfactant) and Imwitor 988 (Co-surfactant). The optimized SNEDDS preconcentrate consisted of Captex 355 (30% w/w), Solutol HS15 (45% w/w) and Imwitor 988 (25% w/w). The saturation solubility (SS) of glipizide in optimized SNEDDS preconcentrate was found to be 45.12 ± 1.36 mg/ml, indicating an improvement (1367 times) of glipizide solubility as compared to its aqueous solubility (0.033 ± 0.0021 mg/ml). At 90% SS, glipizide was loaded to the optimized SNEDDS. In-vitro dilution of liquid SNEDDS resulted in a nanoemulsion with a mean droplet size of 29.4 nm. TEM studies of diluted liquid SNEDDS confirmed the uniform shape and size of the globules. The liquid SNEDDS was adsorbed onto calcium carbonate and talc to form solid SNEDDS. PXRD, DSC, and SEM results indicated that, the presence of glipizide as an amorphous and as a molecular dispersion state within solid SNEDDS. Glipizide dissolution improved significantly (p < 0.001) from the solid SNEDDS (∼100% in 15 min) as compared to the pure drug (18.37%) and commercial product (65.82) respectively.Abbreviations: solid SNEDDS, solid self-nanoemulsifying drug delivery system; SS, saturation solubility; DR_15min, percentage drug release in 15 minutes; LCT, long chain triglycerides; MCT, medium chain triglycerides     

星点设计-效应面法优化芸香苷纳米乳的制备工艺

摘 要 目的：优化芸香苷纳米乳的制备工艺。方法: 绘制芸香苷在不同表面活性剂与助表面活性剂质量比（Km）时的伪三元相图,以纳米乳处方中油相比例和Km为考察因素,粒径和载药量为考察指标,采用星点设计 效应面法优化其制备工艺。结果:芸香苷纳米乳的最佳处方为：油酸乙酯 聚氧乙烯氢化蓖麻油（RH 40） 1,2 丙二醇 水（质量之比为7∶〖KG-*2〗13∶〖KG-*2〗5∶〖KG-*2〗25）,制备的纳米乳粒径为26.51 nm,载药量为8.97 mg·m^-1 。结论:星点设计 效应面法可以优化芸香苷纳米乳的处方,其模型具有良好的预测功能。