口服固体自微乳化给药系统的研究进展

目的对新近发展的固体自微乳化给药系统（S-SMEDDS）文献进行综述。方法查阅近年国内外相关文献并进行归纳和总结。结果对固体自微乳的载体、固化技术以及缓控释制剂进行了探讨,为研究水难溶性药物的生物利用度及适合药物释放特性的S-SMEDDS技术提供相关参考。结论固体自微乳化系统可以显著提高难溶性药物的口服生物利用度,且兼顾了液态自微乳和固体制剂二者的优势,是一个极具潜力的新型制剂。     

自微乳化释药系统研究进展

近年来,药剂学领域出现许多增加水难溶性药物溶解度和吸收的技术,其中自乳化释药系统(self-emulsifying drugdelivery systems,SEDDS)得到了广泛的发展。SEDDS 是由药物、油、乳化剂及助溶剂等组成的一种油状混合物,在体外轻微振荡或体内胃肠道的蠕动下自发的形成一种热力学稳定的乳状液,其粒径大约100～300 nm,粒径小于100 nm的乳剂称为自微乳化释药系统(self-microemulsifying drugdelivery systems,SMEDDS)。与 SEDDS 相比,SMEDDS 的最大优点是粒径小、溶液澄清透明、药物增溶量大、制剂更稳定。本文就 SMEDDS 的处方组成、结构与理化性质、质量评价以及应用等方面作一简要综述。1 处方组成SEDDS 的基本处方组成包括药物、油、乳化剂及助溶剂等。SMEDDS 的基本处方组成与 SEDDS 相同,其特殊性在     

卡维地洛自乳化释药系统的制备及细胞转运研究

摘要：目的:制备卡维地洛自乳化释药系统（CAR-SEDDS）,并通过Caco-2单层细胞转运实验评价其渗透性。方法:根据平衡溶解度实验和自乳化能力评估考察CAR-SEDDS的处方组成及用量;评价CAR-SEDDS的理化性质,并比较卡维地洛片和CAR-SEDDS的体外药物溶出速率;通过Caco-2单层细胞转运实验比较卡维地洛原料药与CAR-SEDDS形成微乳的渗透性。结果:CAR-SEDDS的处方组成为：丙二醇辛酸酯（Capmul PG8）为油相,聚氧乙烯蓖麻油（Cremophor EL）为表面活性剂,二乙二醇单乙基醚（Transcutol HP）为助表面活性剂,其质量比为4∶4∶3;CAR-SEDDS经pH 1.2盐酸溶液稀释后可快速形成微乳,在透射电镜下可观察到微乳呈类球形,在3种不同pH介质溶液中,CAR-SEDDS的药物溶出速率均比卡维地洛片快;Caco-2单层细胞渗透性研究结果显示,CAR-SEDDS形成微乳的渗透性显著高于CAR原料药。结论:本研究将卡维地洛制备成自乳化释药系统,可显著提高药物的溶出速率,有利于药物充分吸收。     

9-硝基喜树碱自微乳化给药系统研究

以Maisine 35-1为油相,Cremophor EL、Labrasol为表面活性剂,Transcutol P为助表面活性剂,制得9-硝基喜树碱(1)负电荷自微乳化制剂;在此基础上加入油胺作为正电荷剂可得1正电荷自微乳化制剂.用HPLC法测定大鼠体内1含量.结果表明含药的负、正电荷自微乳化制剂经水稀释10倍时,粒径分别为(24.7±7.9)和(25.0±8.3)nm,电位分别为-(4.8±0.5)和(2.4±0.9)mV.大鼠分别以6mg/kg的剂量灌胃给予1溶液和负、正电荷自微乳化制剂后,三者的Cmax分别为(93.8±72.8)、(176.4±93.4)和(128.9±49.1)ng/ml;AUC分别为(127.6±51.6)、(331.9±261.1)和(595.1±42.0)ng·ml-1·h;MRT分别为(1.6±0.9)、(1.2±0.6)和(4.3±2.4)h.正、负电荷自微乳化制剂的相对生物利用度分别是溶液的4.7和2.6倍,表明前者提高药物的口服吸收作用优于后者(P＜0.05).     

自乳化制剂的研究进展

本文综述了近年来自微乳化给药系统(SMEDDS)的研究进展,对自微乳化给药系统的处方优化、质量评价和新型表面活性剂的使用进行了探讨,并对自乳化制剂(SEDDS)在中药新制剂的形成与实际应用进行了展望。     

尼莫地平自微乳化释药系统的研制

目的:研制尼莫地平(nimodipine,NM)自微乳化释药系统(SMEDDS).方法:以溶解度,相容性试验、自乳化效率及伪三元相图法筛选最佳油相、表面活性剂及助表面活性剂;以星点设计-效应面法优化处方;对NM-SMEDDS分散后粒径、体外溶出度及初步稳定性进行考察.结果:经处方筛选和星点效应面法优化得出最佳处方为:Captex200P,Cremophor EL,Labrosol 分别为油相,乳化剂和助乳化剂,比例为30:47:23;NM-SMEDDS的粒径分别为33.8±3.42 nm,1h累积溶出百分率为98.83％,约为市售片剂的3.84倍;经高温(60℃)、低温(4℃)、强光(4 500±500) Lx考察10 d,除强光可引起NM含量降低外,其他各项指标均无明显变化.结论:该处方及工艺筛选、优化法简便可行,容易控制,制备得到的NM-SMEDDS体外溶出度显著增加,稳定性较好,为进一步研发尼莫地平新制剂提供了理论和试验基础.     

川芎油自微乳化软胶囊大鼠在体肠吸收研究

为了考察川芎油剂型选择的合理性,进行了原料、包合物和自微乳化软胶囊的比较吸收实验;并进一步明确自乳化软胶囊的小肠吸收特点,进行了不同浓度、不同肠段、有无胆汁分泌的在体肠吸收实验。通过药液在肠腔内循环,以藁本内酯为川芎油的指标性成分测定不同时间回流液中蒿本内酯浓度变化,得到药物的吸收情况。结果表明,自微乳化软胶囊显著提高藁本内酯的吸收 (P < 0.001), 效果最好。400 μg·mL^-1藁本内酯的吸收显著高于200和100 μg·mL^-1 (P < 0.001),而后两个浓度的吸收无差异。胆管结扎与否不影响药物吸收。自乳化软胶囊可被大鼠全肠段吸收,其中十二指肠吸收最好,各肠段K_a、P_app是十二指肠>空肠>回肠=结肠。

     

自微乳化给药系统增加索拉非尼的口服吸收生物利用度

目的:为了增加难溶性药物索拉非尼(Sorafenib)的口服吸收,本研究制备索拉非尼自微乳化给药系统并测定其口服相对生物利用度。方法:以油酸乙酯(20%,w/w)为油相,聚山梨酯-80(48%,w/w)为主要乳化剂,聚乙二醇400(16%,w/w)和乙醇(16%,w/w)为助乳化剂制备索拉非尼自微乳化给药系统,以大鼠为实验动物测定其口服相对生物利用度。结果:自微乳化给药系统中索拉非尼的终浓度为20 mg.mL-1。该制剂乳化后粒径为20～25 nm,并可在去离子水,生理盐水及5%葡萄糖溶液中稳定存在8 h。与索拉非尼混悬液相比,自微乳化给药系统可以显著增加索拉非尼的血药浓度-时间曲线下面积(AUC0～72 h),峰浓度(Cmax)和平均滞留时间(MRT),降低清除率(CL)。尤其是与口服混悬液相比,其相对生物利用度提高约25倍。结论:索拉非尼自微乳化给药系统可以显著提高索拉非尼的口服吸收相对生物利用度,有望开发成为增加其口服吸收的药物制剂。     

自微乳化释药系统（SMEDDS）的研究进展

对近年国内外的文献报道进行检索、分类和整理,综述了微乳的形成机制、结构类型和理论、处方组成,在药剂学领域的应用及其存在的问题.为利用微乳载药系统的优势,开发中药微乳新制剂,解决中药剂型存在的某些问题提供参考.     

Effect of self-microemulsifying drug delivery systems containing Labrasol on tight junctions in Caco-2 cells

The aim of this study was to investigate the effect of two novel self-microemulsifying drug delivery systems (SMEDDS) containing Labrasol with different dilutions on tight junctions. Changes in barrier properties of Caco-2 cell monolayers, including transepithelial electrical resistance (TEER) and permeability to the paracellular marker, i.e., mannitol, were assessed in response to dilutions and surfactants contents within formulations. The cytotoxicity of SMEDDS and the effect of surfactants on Caco-2 cells were evaluated by the MTT. Changes in subcellular localization of the tight junction proteins, ZO-1 and F-actin, were examined by confocal laser scanning microscopy. Results demonstrated that negatively charged SMEDDS with different dilutions had no effect on the TEER, but significantly increased the permeability of mannitol. In contrast, the positively charged formulation showed a dilution-dependent reduction in TEER. A corresponding increase in mannitol permeability of up to 29.4-fold to 64.7-fold greater than the control was also observed across the monolayer. Labrasol with the concentration of 0.1 and 1% was shown to increase the permeability of mannitol by 4.6-fold and 33.8-fold, respectively. The mechanism of opening of tight junctions was found to involve F-actin-related changes and redistribution of ZO-1.     

新型促吸收剂研究进展——以细胞间紧密连接为靶点

亲水性小分子药物、多肽和蛋白质主要通过胞旁通路吸收。这类药物膜通透性较差，口服生物利用度较低。紧密连接是构成胞旁通路的结构基础，传统的胞旁通路促吸收剂一般对黏膜损伤较大，限制了这些药物的临床应用。近年来，随着对紧密连接结构、功能认识日益加深，许多特异性的促吸收剂被发现，如NO供体、CPE和Zot等，实验表明，通过瞬间可逆的打开紧密连接，这些促吸收剂可显著增加胞旁转运标志物和亲水性药物的吸收，而其毒副作用较传统的促吸收剂大为降低。总之，新型促吸收剂提供了一个增加亲水性药物生物利用度的有益思路。     

Progress in absorption enhancers based on tight junction

Absorption enhancers have been investigated since the 1960s, in order to assist the transfer of drugs across the paracellular space in the intestinal epithelium. However, few absorption enhancers are presently used clinically, due to the difficulty of developing enhancers with high specificity and low toxicity. Using high-throughput genomic techniques, new drug candidates such as, non-Lipinski molecules, peptides, antibodies and nucleic acids, are being discovered, so the need for oral drug delivery strategies using absorption enhancers is gaining importance. The key to addressing this issue is to understand the molecular mechanism of the paracellular route in epithelial cell sheets. Towards this end, basic research in cell biology has revealed the components that regulate the paracellular route, and how the transport of substances is regulated. Based on these findings, novel strategies for enhancing drug absorption have been proposed. In this article, the authors first survey the development of absorption enhancers, then outline recent progress in the cell biology of tight junctions, and finally discuss novel approaches for absorption enhancers based on these advances.     

自微乳化技术与固体分散技术在改善长春西汀溶出度和生物利用度上的比较(英文)

探讨与比较自微乳化释药系统 (self-microemulsifying drug delivery systems, SMEDDS) 与固体分散体 (solid dispersion, SD) 在改善难溶性药物长春西汀 (vinpocetine, VIP) 溶出度和生物利用度方面的差异。本文选用中链甘油三酯 (Labrafac)、油酸、聚氧乙烯氢化蓖麻油 (Cremophor EL) 和二乙二醇单乙基醚 (Transcutol P) 为材料, 以微粉硅胶吸附制备长春西汀固体自微乳化释药系统 (VIP-SMEDDS); 采用泊洛沙姆188 (F68) 为载体制备长春西汀固体分散体 (VIP-SD)。溶解度实验结果表明, VIP在SMEDDS中的溶解度是SD载体中的17.3倍; 体外溶出度实验表明, VIP-SMEDDS的溶出效果和稳定性比VIP-SD更好; 大鼠体内生物利用度实验表明VIP-SMEDDS是VIP原料的1.89倍, 且不受食物影响, 而VIP-SD的生物利用度与VIP原料相比不具有显著性差异。给药2 h后组织分布结果表明, VIP-SMEDDS在Peyer’s节、肠道、肝脏的药物浓度分别是VIP-SD的3.7、2.2和1.5倍。Caco-2细胞转运实验表明VIP-SMEDDS的表观渗透系数 (P_app, cm·s⁻¹) 是VIP-SD的2.65倍。透射电镜下观察, VIP-SMEDDS组Caco-2细胞间隙是空白对照组的9.6倍, 而VIP-SD组与空白组比较无显著性差异。由此可见, 自微乳化技术在改善长春西汀溶解度、溶出度、肠黏膜透过率、淋巴吸收和生物利用度以及减少食物影响方面优于固体分散技术。     

大黄素对肠上皮细胞损伤的保护作用及机制研究

目的观察缺氧/复氧(hypoxia/reoxygenation,H/R)损伤条件下大黄素(Emodin)对肠上皮细胞表达紧密连接蛋白Occludin和ZO-1的影响,以研究大黄素对肠黏膜屏障的保护作用机制。方法体外培养肠上皮细胞株Caco-2建立H/R模型,将细胞随机分为正常细胞(N)组、缺氧复氧(H/R)组、缺氧复氧+Hank平衡盐溶液(H/R+HBSS)组、缺氧复氧+大黄素(H/R+EN)组。检测跨上皮细胞电阻(transepithelial electrical resistance,TEER)值;使用透射电子显微镜观察紧密连接的变化;用Western blot法测定Occludin和ZO-1蛋白的表达水平;半定量RT-PCR法测定Occludin和ZO-1的mRNA表达水平。结果与H/R组、H/R+HBSS组相比,H/R+EN组的紧密连接破坏明显减少;H/R+EN组的TEER值、Occludin和ZO-1的蛋白及mRNA表达水平明显高于H/R组、H/R+HBSS组(P<0.05)。结论大黄素可通过减少Occludin、ZO-1的破坏并增加其表达来保护肠黏膜屏障。     

Impact of ozone on claudins and tight junctions in the lungs

Claudins (CLDNs) are a major transmembrane protein component of tight junctions (TJs) in endothelia and epithelia. CLDNs are not only essential for sustaining the role of TJs in cell permeability but are also vital for cell signaling through protein‐protein interactions. Ozone induces oxidative stress and lung inflammation in humans and experimental models, but the impact of ozone on claudins remains poorly understood. This study was to determine the expression of TJ proteins, such as claudin 3, 4, 5, and 14 following ozone exposure. Mice were exposed to 0.1, 1, or 2 ppm of ozone or ambient air for 6 h for 3 days. The impact of ozone on CLDNs, Nrf2, Keap1, and reactive oxygen species (ROS) were estimated using immunoblotting, immunohistochemical staining, confocal imaging, and ELISA analysis in mice and bronchial epithelial cells. Mice exposed to ozone experienced increased airway inflammatory cell infiltration and bronchial hyper‐responsiveness compared to control mice. Additionally, CLDN3, CLDN4, ROS, Nrf2, and Keap1 protein expression increased, and lung CLDN14 protein expression decreased, in mice exposed to ozone compared with control mice. These results indicate that CLDNs are involved in airway inflammation following ozone exposure, suggesting that ozone affects TJ proteins through oxidative mechanisms.     

口服药物吸收的细胞模型研究进展

多种细胞模型如最常用的Caco-2和MDCK细胞,以及新近开发的MDCK-MDR1、M细胞、药物溶出/Caco-2细胞组合、HT-29和TC7细胞等均可用于口服药物吸收的评价,但也存在一定的局限性。本文综述各类细胞模型的特点及其应用等相关研究进展。     

汉防己甲素自微乳的研制

目的研究汉防己甲素白微乳的制备。方法通过考察汉防己甲素在不同介质中的溶解度,采用伪三元相图法制备汉防己甲素自微乳,利用自微乳化效率和载药量考察,筛选最佳处方。结果汉防己甲素自微乳化制剂的处方为：乳化剂OP-10：异丙醇：油酸：油酸乙酯=4：8：1．5：1．5。结论汉防己甲素自微乳载药量为33．31g·L^-1,处方切实可行,性质稳定。     

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。     

Improving the absorption of earthworm fibrinolytic enzymes with mucosal enhancers

Earthworm fibrinolytic enzymes (EFEs), an ideal drug for cardiovascular diseases, have a very low oral bioavailability. In order to improve the absorption of EFEs, six different enhancers were selected to increase the intestinal absorption of EFEs. In vitro (Caco-2 monolayers) and in vivo (mice) experiments were carried out to find the optimum concentration and action time of these enhancers for EFE absorption. We found that EFEs could be transported into blood across intestinal endothelial membrane after administration via intragastric administration with low bioavailability. These results obtained from in vitro experiments were similar to those in vivo. Moreover, menthol and glucose showed absorption enhancement properties with a relatively low cytotoxicity.