盐酸齐拉西酮自微乳的制备及其体内外活性

目的制备盐酸齐拉西酮自微乳,提高其体外溶出度及其空腹口服生物利用度。方法选择对盐酸齐拉西酮溶解能力较强的油相,乳化剂和助乳化剂,观察微乳的形成并绘制伪三元相图比较微乳区域大小,通过乳化时间的测定,粒径和Zeta电位测定来确定最佳处方,测定盐酸齐拉西酮自微乳的体外溶出度以及其在Beagle犬体内药物动力学研究。结果以油酸乙酯(油相)-吐温80(乳化剂)-聚乙二醇200(助乳化剂)(质量比为30∶47∶23)时制得的自微乳经水稀释后可形成稳定的微乳,平均粒径为58.4nm,Zeta电位为-31mV。自制盐酸齐拉西酮自微乳和市售胶囊相比,其体外溶出度显著提高,达到93%。Beagle犬体内实验表明,自制盐酸齐拉西酮自微乳的吸收不受食物影响。结论盐酸齐拉西酮自微乳制备简单,微乳粒径小,可显著提高盐酸齐拉西酮的体外溶出度,及其空腹口服生物利用度。     

苦杏仁苷自微乳的制备及理化性质的研究

目的 制备苦杏仁苷自微乳,并进行初步质量评价研究.方法 通过平衡溶解度的测定和伪三元相图的绘制筛选苦杏仁苷的最佳处方,并对苦杏仁苷自微乳的粒径、多分散系数、稳定性进行评价.结果 苦杏仁苷自微乳的最优处方为Peceol/MCT(1∶1)-乳化剂OP-1,2-丙二醇=45％∶40％∶15％,载药量为6mg·mL-1.所得苦...     

天然维生素E微乳给药系统的研制

研究天然维生素E微乳的制备并对其质量进行评价。考察天然维生素E在不同油相中的溶解情况,再采用逐滴加水法绘制伪三元相图,研究不同乳化剂、助乳化剂和Km值形成微乳的区域和能力,用origin 8.0软件绘制不同处方组成的相图,在此工作基础上制备天然维生素E水包油微乳。以Labrafac Lipophile WL 1349（MCT）/Cremophor EL-35/甘油/水形成了均匀稳定的微乳系统;用不同的介质稀释后,天然维生素E微乳粒径无明显变化;初步稳定性实验表明,室温储存3个月,药物含量和粒径均没有显著变化,稳定性良好。天然维生素E微乳易于制备,质量稳定,为开发新型天然维生素E制剂提供了依据。     

4-氨基-2-三氟甲基苯基维甲酸酯自微乳胶囊的研制

目的制备4-氨基-2-三氟甲基苯基维甲酸酯固体自乳化制剂,以解决该药水溶性差的问题,提高药物胃中溶出度和口服生物利用度。方法通过伪三元相图法考察不同乳化剂、助乳化剂和油相形成微乳的能力和区域,制备自微乳。然后采用mix-ture design方法进行处方优化,并对其乳化后粒径、制剂综合评分和载药量进行考察。结果制备出的最佳处方(含HS1570%,PEG400 10%,油酸乙酯20%)自乳化后粒径在30 nm左右,体外溶出10 min即可溶出80%以上。结论该处方制备出的ATPR固体自微乳可用于提高其溶出速度。     

紫杉醇自乳化微乳的制备及其在大鼠体内的药动学

目的:制备紫杉醇微乳,并对其急性过敏反应和大鼠体内的药动学进行考察。方法:三角相图法探讨了紫杉醇自乳化微乳(以下简称自微乳)的形成条件,采用均匀设计优化组成制备自微乳。以紫杉醇注射液对照,比较自微乳豚鼠的急性过敏反应和大鼠体内的药动学。结果: 以三辛酸甘油酯三丁酸甘油酯(1 ∶1)为油相,无水乙醇作助乳化剂制备的紫杉醇自微乳经生理盐水稀释后形成稳定的微乳,平均粒径为(16±s3)nm。以紫杉醇注射液作对照,自微乳豚鼠的急性过敏反应明显降低。统计矩分析,紫杉醇自微乳与紫杉醇注射液大鼠体内平均滞留时间分别为3. 89h和2. 52h,自微乳延长药物在大鼠体内的滞留时间。结论:通过优化处方制备的紫杉醇自微乳具有较好的稳定性,并可显著降低急性过敏反应。     

葛根素自微乳制剂的制备工艺研究

目的:研究制备葛根素自微乳制剂。方法:根据葛根素的饱和溶解度选取油相、乳化剂和助乳化剂,通过伪三元相图,以自乳化效率及成乳后粒径为指标,确定最佳处方。结果:最佳处方为油酸乙酯∶吐温80/蓖麻油聚氧乙烯醚40(1∶2)∶聚乙二醇400∶葛根素∶三七总皂苷=15∶35∶35∶6∶9;微乳的平均粒径为32.9nm。结论:加入三七总皂苷的葛根素自微乳粒径小,稳定性好,这为自微乳制剂的增效减毒提供了新的思路和途径。     

尼莫地平微乳的制备及质量评价

目的:研究尼莫地平微乳的制备和质量评价.方法:考察尼莫地平在不同油相、乳化剂和助乳化剂中的平衡溶解度,并通过滴定法绘制伪三元相图,确定最优的Km值和处方,分别考察载药微乳的外观、稳定性、形态和粒径大小.用高效液相色谱法测定微乳中尼莫地平的包封率和载药量.结果:尼莫地平微乳为澄清或略带乳光的淡黄色液体,稳定,透射电镜下呈圆球形,分布均匀.平均粒径18.2 nm,呈Gauss分布.微乳经0.9%氯化钠注射液和5%葡萄糖注射液稀释50倍后,外观、pH值、载药量、粒径均无明显变化,高效液相色谱法测定包封率为97.62%,载药量为0.402 g·L-1.结论:微乳能提高尼莫地平的溶解度,微乳制剂质量稳定,易于制备.     

葛根素自微乳的制备工艺研究

目的筛选葛根素自微乳的处方。方法通过药物溶解度实验和伪三元相图的绘制,以粒径大小和分布为指标,筛选油相、乳化剂、助乳化剂的处方配比。测定葛根素自微乳释药系统的溶出度。结果确定的葛根素自微乳处方比例为葛根素∶油酸聚乙醇甘油酯(labrafil M 1944CS)∶聚氧乙烯氢化蓖麻油(RH-40)∶聚乙二醇400(PEG 400)=9.1%∶36.4%∶36.4%∶18.1%。结论通过研究确定了最优化的葛根素自微乳处方,微乳粒径分布均匀。     

磷脂对自微乳口服吸收、淋巴转运和体外特征的影响

目的以黄芩素为模型药物制备自微乳(SMEDDS),考察磷脂作为联合乳化剂对SMEDDS乳化、体外释放、体内胃肠吸收以及淋巴转运的影响。方法本研究以油酸乙酯为油相,吐温-80/磷脂为联合乳化剂,Transcutol HP为助乳化剂,构建黄芩素自微乳(BA-PC-SMEDDS),对乳化效率、粒径、Zeta电位、长期储存稳定性、大鼠体内药代动力学和淋巴转运等特征进行考察,并与处方中不含磷脂的传统自微乳(CBA-SMEDDS)进行比较。结果当磷脂作为联合乳化剂时,自微乳的长期储存稳定性提高,药物析出现象得到抑制。BA-PC-SMEDDS口服吸收后的AUC_0～_t为CBA-SMEDDS的1.37倍,淋巴转运程度从56.2%提高到68.6%。结论综上所述,处方中使用磷脂作为联合乳化剂,有利于改善SMEDDS的稳定性,提高难溶性药物的口服吸收,且对淋巴转运有促进作用。     

含天然乳化剂的盐酸小檗碱自微乳的制备与体内外性能评价

目的:制备含阿拉伯胶的盐酸小檗碱自微乳,考察其体内外性能。方法:以天然乳化剂阿拉伯胶部分代替合成非离子型乳化剂聚山梨酯80制备盐酸小檗碱自微乳;评价两种自微乳的自乳化速率、微乳形态、粒径分布和释放度;采用大鼠在体单向肠灌流模型对两种自微乳的吸收动力学进行体内评价。结果:与合成乳化剂自微乳相比,天然乳化剂自微乳的自乳化速率基本相同,微乳乳滴粒径及粒径分布范围有所变大,体外释放速度略有降低,对盐酸小檗碱在大鼠在体肠吸收的促进效果更好。结论:用天然乳化剂阿拉伯胶部分代替合成乳化剂所制备的盐酸小檗碱自微乳可保持自微乳原有的体内外行为。     

Preparation and evaluation of self-microemulsifying drug delivery systems (SMEDDS) containing atorvastatin

Atorvastatin is insoluble in aqueous solution and the bioavailability after oral administration is low. Self-microemulsifying drug delivery systems (SMEDDS) containing atorvastatin have been successfully prepared to improve its bioavailability. SMEDDS is a mixture of lipid, surfactant, and cosurfactant, which are emulsified in aqueous medium under gentle digestive motility in the gastrointestinal tract. Pseudo-ternary phase diagrams composed of various excipients were plotted. Droplet size, zeta-potential and long-term physical stability of the formulations were investigated. The release of atorvastatin from SMEDDS capsules was studied using the dialysis bag method in 0.1 M HCl and phosphate buffer (pH 7.4), compared with the release of atorvastatin from a conventional tablet. A pharmacokinetic study was performed in 6 beagle dogs after oral administration of 6 mg kg-1 atorvastatin. The bioavailability of atorvastatin SMEDDS capsules was significantly increased compared with that of the conventional tablet. SMEDDS capsules consisting of Labrafil, propylene glycol and Cremophor RH40 provided the greatest bioavailability. Our studies indicate that the use of SMEDDS for the delivery of atorvastatin can improve its bioavailability.     

和厚朴酚口服自微乳制剂的制备及药代动力学研究

目的:制备和厚朴酚(HNK)口服自微乳制剂(SMEDDS),并考察自微乳制剂促进和厚朴酚口服吸收的效果。方法:采用伪三元相图法优化自微乳制剂处方组成,稀释法评价含HNK的SMEDDS制剂的乳化效果。并以和厚朴酚混悬液(含1%CMC-Na的溶液为分散介质)为对照,考察了自微乳制剂大鼠口服给药后体内生物利用度情况。结果:由MCT,cremaphor EL和labrasol(质量比为3∶5∶2)组成的和厚朴酚自微乳制剂经去离子水稀释后可自发形成平均粒径和表面电势分别为(35.48±4.21)nm和(-2.04±0.26)mV的微乳(HNK-ME),并且在10～100倍稀释范围内乳化效果良好且性质稳定。大鼠体内的药代动力学结果表明,和厚朴酚微乳(HNK-ME)的生物利用度(AUC)为混悬剂的1.33倍,Cmax为混悬剂的1.53倍。结论:自微乳制剂可显著提高和厚朴酚的口服生物利用度。     

Development of self-microemulsifying drug delivery systems for oral bioavailability enhancement of alpha-Asarone in beagle dogs

A self-microemulsifying drug delivery system (SMEDDS) for enhancement of oral absorption of a poor water-soluble drug, alpha-Asarone (ARE), is reported. Solubility of ARE was determined in various vehicles. SMEDDS consisted of a mixture of oils, surfactants, and cosurfactants that were emulsified in an aqueous medium under the gentle agitation and digestive motility. Pseudo-ternary phase diagrams were used to identify the efficient self-emulsification regions. The particle size distribution of the resulting microemulsions was determined using a laser scatter particle size analyzer (LSPSA). The optimized SMEDDS formulations containing Ethyl oleate (20%), Tween 80 (60%), and PEG 400 (20%) were tested for in vitro dissolution. The percentage of ARE released from the SMEDDS was significantly higher than that from the conventional tablets. Oral bioavailability of ARE in the SMEDDS via the hard capsules and the conventional tablets was evaluated in fasted beagle dogs. The bioavailability of ARE formulated in SMEDDS showed approximately 4.8-fold higher bioavailability than that in the conventional tablets. The results indicated that SMEDDS is potentially a good drug delivery system for oral delivery of the hydrophobic compound ARE.     

Characterization and evaluation of self-microemulsifying sustained-release pellet formulation of puerarin for oral delivery

The present study aims to develop self-microemulsifying drug delivery systems (SMEDDS) in sustained-release pellets of puerarin to enhance the oral bioavailability of puerarin. The performances of puerarin-SMEDDS including oils, emulsifiers, and co-emulsifiers were evaluated. Pseudo-ternary phase diagrams shows that the optimized formulation consisted of castor oil as the oil phase, Cremophor EL as the emulsifier, and 1,2-propanediol as the co-emulsifier. SMEDDS sustained-release pellets were prepared via extrusion-spheronization. The particle size distributions of the formulations were determined using transmission electron microscopy and scanning electronic microscopy. The mean particle size was 50 ± 8 nm. The pharmacokinetics and bioavailability of the puerarin-SMEDDS sustained-release pellets and puerarin tablets were evaluated and compared in beagle dogs. The absolute bioavailability of the puerarin-SMEDDS sustained-release pellets was enhanced by approximately 2.6-fold compared with that of the puerarin tablet. The relative bioavailability (F(rel)) of the SMEDDS pellets was 259.7% compared with the tablet group. The results demonstrated that the puerarin-SMEDDS sustained-release pellets had a sustained-release effect, and could remarkably improve the oral bioavailability of puerarin.     

Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors

PURPOSE: The objective of this study was to evaluate the pharmacokinetics of paclitaxel in a novel self-microemulsifying drug delivery system (SMEDDS) for improved oral administration with or without P-glycoprotein (P-gp) inhibitors. METHODS: Paclitaxel SMEDDS formulation was optimized, in terms of droplet size and lack of drug precipitation following aqueous dilution, using a ternary phase diagram. Physicochemical properties of paclitaxel SMEDDS and its resulting microemulsions were evaluated. The plasma concentrations of paclitaxel were determined using a HPLC method following paclitaxel microemulsion administrations at various doses in rats. RESULTS: Following 1:10 aqueous dilution of optimal paclitaxel SMEDDS, the droplet size of resulting microemulsions was 2.0 +/- 0.4 nm, and the zeta potential was -45.5 +/- 0.5 mV. Compared to Taxol, the oral bioavailability of paclitaxel SMEDDS increased by 28.6% to 52.7% at various doses. There was a significant improvement in area under the curve (AUC) and time above therapeutic level (0.1 microM) of paclitaxel SMEDDS as compared to those of Taxol following coadministration of both formulations with 40 mg cyclosporin A (CsA)/kg. The oral absorption of paclitaxel SMEDDS slightly enhanced following coadministration of tacrolimus and etoposide, but plasma drug concentrations did not reach the therapeutic level. The nonlinear pharmacokinetic trend was not modified after paclitaxel was formulated in SMEDDS. CONCLUSIONS: The results indicate that SMEDDS is a promising novel formulation to enhance the oral bioavailability of paclitaxel, especially when coadministered with a suitable P-gp inhibitor, such as CsA.     

Self-microemulsifying drug delivery system for improved oral bioavailability of dipyridamole: Preparation and evaluation

Dipyridamole shows poor and variable bioavailability after oral administration due to pHdependent solubility, low biomembrane permeability as well as being a substrate of P-glycoprotein. In order to improve the oral absorption of dipyridamole, a self-microemulsifying drug delivery system (SMEDDS) for dipyridamole was prepared and evaluated in vitro and in vivo. The optimum formulation was 18% oleic acid, 12% Labrafac lipophile WL 1349, 42% Solutol HS 15 and 28% isopropyl alcohol. It was found that the performance of self-microemulsification with the combination of oleic acid and Labrafac lipophile WL 1349 increased compared with just one oil. The results obtained from an in vitro dissolution assay indicated that dipyridamole in SMEDDS dissolved rapidly and completely in pH 6.8 aqueous media, while the commercial drug tablet was less soluble. An oral bioavailability study in rats showed that dipyridamole in the SMEDDS formulation had a 2.06-fold increased absorption compared with the simple drug suspension. It was evident that SMEDDS may be an effective approach to improve the oral absorption for drugs having pH-dependent solubility.     

葛根素自微乳化释药系统的处方筛选与体外评价

目的筛选葛根素自微乳化释药系统（Pur-SMEDDS）的处方并进行体外评价。方法通过溶解度、处方配伍实验和伪三元相图的绘制,以色泽、乳化时间和乳化后粒径大小为指标,筛选油相、表面活性剂、助表面活性剂的处方配比。测定葛根素自微乳化释药系统的溶出度。结果处方选用油酸为油相,聚山梨酯80为表面活性剂,Transcutol P为助表面活性剂。自微乳化后的粒径为（49.8±4.7）nm,ξ电位为（4.8±0.8）mV。pH 6.8磷酸盐缓冲液中30 min累积溶出百分率〉85%,而葛根素片60 min的累积溶出百分率〈10%。结论通过处方研究确定了最优处方,研制了葛根素SMEDDS。     

In vitro and in vivo evaluation of a self-microemulsifying drug delivery system for the poorly soluble drug fenofibrate

Fenofibrate is indicated in hypercholesterolemia and hypertriglyceridemia alone or combined (types IIa, IIb, III, IV, and V dyslipidemias). However, due to its low solubility in water, it has low bioavailability after oral administration. In order to improve the dissolution rate, fenofibrate was formulated into a self-microemulsifying drug delivery system (SMEDDS). We used pseudoternary phase diagrams to evaluate the area of microemulsification, and an in vitro dissolution test was used to investigate the dissolution rate of fenofibrate. The optimized formulation for in vitro dissolution and bioavailability assessment consisted of propylene glycol laurate (Lauroglycol FCC) (60 %), macrogol-15-hydroxystearate (Solutol HS 15) (27 %), and diethylene glycol monoethyl ether (Transcutol-P) (13 %). The mean droplet size of the oil phase in the microemulsion formed by the SMEDDS was 131.1 nm. The dissolution rate of fenofibrate from SMEDDS was significantly higher than that of the reference tablet. In vivo pharmacokinetics study of fenofibrate in beagles administered SMEDDS-A form resulted in a 3.7-fold increase in bioavailability as compared with the reference drug. Our studies suggested that the fenofibrate containing SMEDDS composition can effectively increase the solubility and oral bioavailability of poorly water-soluble drugs.     

Comparison of solid self-microemulsifying drug delivery system (solid SMEDDS) prepared with hydrophilic and hydrophobic solid carrier

In order to compare the effects of hydrophilic and hydrophobic solid carrier on the formation of solid self-microemulsifying drug delivery system (SMEDDS), two solid SMEDDS formulations were prepared by spray-drying the solutions containing liquid SMEDDS and solid carriers. Colloidal silica and dextran were used as a hydrophobic and a hydrophilic carrier, respectively. The liquid SMEDDS, composed of Labrafil M 1944 CS/Labrasol/Trasncutol HP (12.5/80/7.5%) with 2% w/v flurbiprofen, gave a z-average diameter of about 100 nm. Colloidal silica produced an excellent conventional solid SMEDDS in which the liquid SMEDDS was absorbed onto its surfaces. It gave a microemulsion droplet size similar to that of the liquid SMEDDS (about 100 nm) which was smaller than the other solid SMEDDS formulation. In the solid SMEDDS prepared with dextran, liquid SMEDDS was not absorbed onto the surfaces of carrier but formed a kind of nano-sized microcapsule with carrier. However, the drug was in an amorphous state in two solid SMEDDS formulations. Similarly, they greatly improved the dissolution rate and oral bioavailability of flurbiprofen in rats due to the fast spontaneous emulsion formation and the decreased droplet size. Thus, except appearance, hydrophilic carrier (dextran) and hydrophobic carrier (colloidal silica) hardly affected the formation of solid SMEDDS such as crystalline properties, dissolution and oral bioavailability.