SMEDDS在中药制剂中的应用研究进展

综述了近年SMEDDS在中药制剂中的应用研究进展情况,认为SMEDDS在中药制剂研究中已经得到了普遍的关注和应用,已经取得了一定的研究成果。但目前进行的大部分研究还是以中药中的单一成分或某一有效部位作为研究对象,真正意义上的中药复方SMEDDS研究开展的还很少,SMEDDS在中药制剂中的应用有待进一步深入研究。

Effect of ionization of drug on drug solubilization in SMEDDS prepared using Capmul MCM and caprylic acid

The purpose of this study was to investigate the effect of ionization of drug on drug solubilization in SMEDDS(self-microemulsifying drug delivery system) prepared using Capmul MCM and caprylic acid. Solubilization capacity of blank SMEDDS dispersions for danazol,indomethacin and haloperidol as model drugs was determined. Based on the outcomes of solubilization capacity study, drug-loaded SMEDDS formulations were prepared and subjected to dispersion/precipitation study and droplet size analysis. Blank SMEDDS dispersions exhibited the highest solubilization capacity for haloperidol followed by indomethacin and danazol. Furthermore, the solubilization of the three drugs in blank SMEDDS dispersions was explained by a modified mathematical model. Dispersion/precipitation studies indicate that drug-loaded SMEDDS formulations exhibited superiority in solubilizing the drugs in comparison to their respective drug powder. In addition, indomethacin and haloperidol were found to reduce the droplet size of the microemulsions while danazol did not affect droplet size formation for drug-loaded SMEDDS formulations. These findings suggest that ionization of drug affects drug solubilization, droplet size formation, drug loading and drug dispersion/precipitation profiles for the SMEDDS formulations.

Preparation and characterization of solidified SMEDDS containing flurbiprofen by spray drying method

Flurbiprofen, a non-steroidal anti-inflammatory agent, is used to treat rheumatoid arthritis and sore throat (1)However, it gave poor water solubility, and various solubilization technique such as self-microemulsifying drug delivery system(SMEDDS) has been used to improve the solubility, dissolution and oral bioavailability [2].The objective of this work was to develop redispersible solidified SMEDDS containing water-insoluble flurbiprofen with enhanced solubility.

Enhancement of solubility and therapeutic potential of poorly soluble lovastatin by SMEDDS formulation adsorbed on directly compressed spray dried magnesium aluminometasilicate liquid loadable tablets: A study in diet induced hyperlipidemic rabbits

The aim of present study was to formulate and evaluate a self-microemulsifying drug delivery systems(SMEDDS)containing lovastatin and to further explore the ability of porous Neusilin■ US2 tablet as a solid carrier for SMEDDS.SMEDDS formulations of varying proportions of peceol,cremophor RH 40 and transcutol-P were selected and subjected to invitro evaluation,including dispersibility studies,droplet size,zeta potential measurement and release studies.The results indicated that the drug release profile of lovastatin from SMEDDS formulations was statistically significantly higher(p-value<0.05)than the plain lovastatin powder.Thermodynamic stability studies also confirmed the stability of the prepared SMEDDS formulations.The optimized formulation,which consists of 12% of peceol,44% of cremophor RH 40,and 44% of transcutol-P was loaded into directly compressed liquid loadable tablet of Neusilin■ US2 by simple adsorption method.In order to determine the ability of Neusilin®US2 as a suitable carrier pharmacodynamics study were also carried out in healthy diet induced hyperlipidemic rabbits.Animals were administered with both liquid SMEDDS and solid SMEDDS as well.From the results obtained,Neusilin■ was found to be a suitable carrier for SMEDDS and was equally effective in reducing the elevated lipid profile.In conclusion,liquid loadable tablet(LLT)is predicted to be a promising technique to deliver a liquid formulation in solid state.

Gastrointestinal lipolysis and trans-epithelial transport of SMEDDS via oral route

Self-microemulsifying drug delivery systems(SMEDDSs)have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules.However,information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare.Aggregation-caused quenching(ACQ)fuorescent probes are utilized to visualize the in vivo behaviors of SMEDDSs,because the released probes during lipolysis are quenched upon contacting water.Two SMEDDSs composed of medium chain triglyceride and different ratios of Tween-80 and PEG-400 are set as models,meanwhile Neoral?was used as a control.The SMEDDS droplets reside in the digestive tract for as long as 24 h and obey frst order kinetic law of lipolysis.The increased chain length of the triglyceride decreases the lipolysis of the SMEDDSs.Ex vivo imaging of main tissues and histological examination confrm the trans-epithelial transportation of the SMEDDS droplets.Approximately 2%-4%of the given SMEDDSs are transported via the lymph route following epithelial uptake,while liver is the main termination.Caco-2 cell lines confrm the cellular uptake and trans-epithelial transport.In conclusion,a fraction of SMEDDSs can survive the lipolysis in the gastrointestinal tract,permeate across the epithelia,translocate via the lymph,and accumulate mainly in the liver.

牡丹籽油自微乳化软胶囊内容物的制备工艺研究

研究牡丹籽油自微乳化软胶囊内容物(SMEDDS系统)的制备工艺。通过溶解度实验和体外自乳化实验对乳化剂和助乳化剂的种类及用量范围进行了筛选,并绘制了三元相图;以自乳化平衡时间和平均粒径为指标,筛选出牡丹籽油、乳化剂和助乳化剂的最佳配比;同时,对SMEDDS系统自乳化后的外观、自微乳化能力、粒度分布和稳定性进行了考察。结果表明,牡丹籽油SMEDDS系统中φ(牡丹籽油)=5%~10%、φ(聚山梨酯-80)=66%~78%、φ(PEG-400)=15%~27%;三者最佳配比为V(牡丹籽油)∶V(聚山梨酯-80)∶V(PEG-400)=2.12∶0.53∶0.3;牡丹籽油SMEDDS系统自微乳化平衡时间<1min,体外自乳化后呈蓝色乳光,粒度分布在1 000nm以下,平均粒径约为100nm,离心后未见分层,稳定性好。牡丹籽油SMEDDS系统自微乳化速度快,自微乳化能力强,自乳化后粒度达到了纳米级别,稳定性好。

自微乳化给药系统促进银杏酮酯口服吸收效果实验研究

目的：观察自微乳化给药系统（SMEDDS）对提高银杏酮酯（GBE50）口服吸收效果的影响。方法：将12只SD大鼠随机分为2组各6只,观察组将经自微乳化给药系统处理得到的银杏酮酯口服自微乳灌入大鼠胃中,对照组应用市售杏灵颗粒剂进行灌胃,比较2组药物代谢动力学参数,以此评价2组的口服吸收效果。另以槲皮素、异鼠李素、山奈素对照品3种样品的回收率以检验高效液相色谱仪的精密度。结果：3种对照品进行5次试验,所得回收率比较无统计学意义（P〉0.05）。观察组消除半衰期（T1/2）、血药达峰时间（Tmax）均显著低于对照组,血药峰浓度（Cmax）、0~25 h药时曲线下面积（AUC0-25）、0~∞h药时曲线下面积（AUC0-∞）等参数则显著高于对照组（P〈0.05）。结论：与市售杏灵颗粒剂比较,SMEDDS可显著提高GBE50的生物利用度,强化口服吸收效果,值得推广应用。

PUBLISHER’S NOTE

February 2017Elsevier would like to bring to your attention a pagination gap in Volume/Issue 12/1.Unfortunately,there is a pagination gap between article'Effect of ionization of drug on drug solubilization in SMEDDS prepared using Capmul MCM and caprylic acid'(Authors:Suhua Li1,Parshotam Madan,Senshang Lin)and article'Preparation and characterisation of solid dispersions of tanshinone IIA,cryptotanshinone and total tanshinones”(Xifeng Zhai,Chunguang Li,George Binh Lenon,Charlie C.L.Xue,Weize Li).

长春西汀自微乳化给药系统的制备与体外评价

目的:制备长春西汀自微乳化给药系统,并对其体外释药及初步稳定性进行了评价。方法:通过溶解度实验、相分离实验以及三元相图的研究筛选了长春西汀自微乳化处方;并对制剂进行了粒径分布、溶出度及初步稳定性的考察。结果:长春西汀自微乳处方组成:Solutol HS 15(A)为表面活性剂;Transcutol P(B)为辅助表面活性剂;Ethyl Oleate(C)为油相。所得处方的自微乳化时间<1 min,粒径<100 nm。体外释放实验表明自微乳化制剂受溶出介质pH值影响小,在不同pH值非依赖型介质中均能快速完全释放药物。结论:所制备的长春西汀自微乳化制剂能够显著提高难溶性药物的溶解度,为体内研究提供实验依据。

HPLC同时检测姜黄素-胡椒碱复方自微乳中姜黄素和胡椒碱的含量

目的：建立在同一色谱条件下同时检测姜黄素-胡椒碱复方自微乳中姜黄素和胡椒碱含量的HPLC含量测定方法。方法：采用Purospher STAR LP C18色谱柱（4.6 mm×250 mm,5μm）,以乙腈-4%醋酸水溶液（55∶45）为流动相,流速1 mL·min^-1,检测波长342 nm,柱温30℃,进样量5μL。结果：姜黄素和胡椒碱浓度分别在20.2～80.8μg·mL^-1和0.408～1.632μg·mL^-1范围内线性关系良好;低、中、高3种浓度的平均加样回收率（n=9）分别为98.68%、98.99%、99.38%和98.40%、98.79%、99.48%,RSD分别为1.2%、0.66%、0.79%和0.69%、0.25%、0.95%;以标示量计算的平均含量分别为（43.40±0.55）mg·g^-1和（0.767±0.004）mg·g^-1。结论：经方法学验证,该方法是控制姜黄素-胡椒碱复方制剂内在质量的理想方法,适合复方自微乳中姜黄素和胡椒碱的含量测定。

Preparation of sorafenib self-microemulsifying drug delivery system and its relative bioavailability in rats

Sorafenib is a novel antitumor drug,which is poorly absorbed in the gastrointestinal tract due to its low solubility in water.To improve the bioavailability of sorafenib,a self-microemulsifying drug delivery system(SMEDDS) formulation of sorafenib was prepared and its relative bioavailability in rats was evaluated.The blank SMEDDS was prepared from a mixture of ethyl oleate(oil phase,20%,w/w),Cremophol EL(surfactant,48%,w/w),PEG-400(co-surfactant,16%,w/w) and ethanol (co-surfactant,16%,w/w).Sorafenib was subsequently dissolved in the blank SMEDDS to obtain a sorafenib SMEDDS formulation with a final sorafenib concentration at 20 mg/mL.The particle size of the emulsified sorafenib SMEDDS was about 20-25 nm. Compared with sorafenib suspension,the prepared SMEDDS formulation exhibited no effect on the T_(max),but significantly increased the AUC,C_(max) and MRT and decreased the drug clearance.Most importantly,the oral bioavailability based on AUC_(0-72h) increased about 25 times after formulating sorafenib in SMEDDS.We concluded that SMEDDS could be a promising vesicle for the oral delivery of the poorly soluble antitumor drug sorafenib.

Self-microemulsifying drug delivery system for improving the bioavailability of huperzine A by lymphatic uptake

Huperzine A(Hup-A) is a poorly water-soluble drug with low oral bioavailability. A selfmicroemulsifying drug delivery system(SMEDDS) was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion(SPIP) technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration–time curve(AUC) of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension(P <0.01).The absorption rate constant(K_a) and the apparent permeability coefficient(P_(app)) for Hup-A in different parts of the intestine suggested a passive transport mechanism, and the values of K_a and P_(app) of Hup-A SMEDDS in the ileum were much higher than those in other intestinal segments. The determination of Hup-A concentration in mesenteric lymph nodes can be used to explain the intestinal lymphatic absorption of Hup-A SMEDDS. For Hup-A SMEDDS, the values of AUC and maximum plasma concentration(C_(max)) of the blocking model were significantly lower than those of the control model(P<0.05). The proportion of lymphatic transport of Hup-A SMEDDS and Hup-A suspension were about 40% and 5%,respectively, suggesting that SMEDDS can significantly improve the intestinal lymphatic uptake and transport of Hup-A.

Combined use of phospholipid complexes and self-emulsifying microemulsions for improving the oral absorption of a BCS class IV compound, baicalin

The aim of this study was to develop a formulation to improve the oral absorption of baicalin(BA)by combining a phospholipid complex(PC)and self-emulsifying microemulsion drug delivery system(SMEDDS),termed BA–PC–SMEDDS.BA–PC was prepared by a solvent evaporation method and evaluated by complexation percentage(CP).The physicochemical properties of BA–PC were determined.The synergistic effect of PC and SMEDDS on permeation of BA was studied in vitro with Caco-2 cells and in situ with a single pass intestinal perfusion model.The improved bioavailability of BA in BA–PC–SMEDDS was confirmed in an in vivo rat model.The CP of BA–PC reached 100%when the molar ratio of drug to phospholipid(PP)was Z1:1.The solubility of BA–PC increased in both water and octanol,and the log P o/w of BA–PC was increased significantly.BA–PC–SMEDDS could be dispersed more evenly in water,compared to BA and BA–PC.Both the Caco-2 cell uptake and single-pass intestinal perfusion models illustrated that transport of BA in BA–PC was lower than that of free BA,while improved significantly in BA–PC–SMEDDS.The relative bioavailability of BA–PC(1:2)–SMEDDS was 220.37%.The combination system of PC and SMEDDS had a synergistic effect on improving the oral absorption of BA.

Preparation of sorafenib self-microemulsifying drug delivery system and its relative bioavailability in rats

Sorafenib is a novel antitumor drug, which is poorly absorbed in the gastrointestinal tract due to its low solubility in water. To improve the bioavailability of sorafenib, a self-microemulsifying drug delivery system （SMEDDS） formulation of sorafenib was prepared and its relative bioavailability in rats was evaluated. The blank SMEDDS was prepared from a mixture of ethyl oleate （oil phase, 20%, w/w）, Cremophol EL （surfactant, 48%, w/w）, PEG-400 （co-surfactant, 16%, w/w） and ethanol （co-surfactant, 16%, w/w）. Sorafenib was subsequently dissolved in the blank SMEDDS to obtain a somfenib SMEDDS formulation with a final sorafenib concentration at 20 mg/mL. The particle size of the emulsified sorafenib SMEDDS was about 20-25 nm. Compared with sorafenib suspension, the prepared SMEDDS formulation exhibited no effect on the Tmax, but significantly increased the AUC, Cmax and MRT and decreased the drug clearance. Most importantly, the oral bioavailability based on AUC0-72h increased about 25 times after formulating sorafenib in SMEDDS. We concluded that SMEDDS could be a promising vesicle for the oral delivery of the poorly soluble antitumor drug sorafenib.