Sponges carrying self-microemulsifying drug delivery systems

Self-microemulsifying drug delivery systems (SMEDDS) increase the solubility of lipophilic drugs. One barrier to their wide application is their liquid nature. We report on a new method to solidify SMEDDS—their incorporation in sponges made from a hydrophilic natural polymer. Using different freeze-drying schemes, sponges were prepared from alginate gels containing microemulsions. The sponges’ structures were studied with scanning electron microscopy and small angle X-ray scattering. The oil droplets survived the drying process, and SMEDDS were present as 9 nm-sized objects in the dried sponges. The sponges were rehydrated in water, and evidence of the presence of SMEDDS in the rehydrated sponges was found. A model hydrophobic molecule, Nile red, was soluble in all dry and rehydrated sponges. SMEDDS containing Nile red were gradually released from the sponges, at a rate that depended on the drying method. The equilibrium water uptake of the sponges was also found to be influenced by the drying scheme. The combination of SMEDDS and sponges may be a way to overcome the disadvantages of each component separately, provide a solid dosage form for SMEDDS that can sustain the release of drugs and also enable utilization of hydrophilic sponges for the delivery of hydrophobic drugs.     

Box-Behnken响应面法优化吲哚美辛口服自微乳剂的处方

目的 采用Box-Behnken响应面分析法优化吲哚美辛口服自微乳剂的处方.方法 考察吲哚美辛在各种油相、乳化剂、助乳化剂中的溶解度,根据结果绘制伪三元相图,寻找自微乳区域;以油相、乳化剂、助乳化剂为自变量,透光率为因变量,通过对自变量中各种溶媒筛选的多元线性回归及多项式拟合,采用Box-Behnken响应面法优化处方,并进行预测分析.结果 处方中吲哚美辛、桉叶油、吐温20、二乙二醇单乙醚占自微乳处方的含量分别为3.1％、15.6％、56.3％、25％;透光率为98.8％±0.17％,平均粒径为14.57±0.77 nm;处方的实际值与预测值偏差为0.20％.结论 应用Box-Behnken响应面法能快速、方便地得到吲哚美辛自微乳剂的处方,所建模型预测性良好.     

水飞蓟素自微乳的研制

目的筛选水飞蓟素自微乳的处方并对其体外溶出及稳定性进行考察。方法通过溶解度实验、正交设计及伪三元相图的建立,筛选水飞蓟素自微乳的组成。采用HPLC法测定处方中的药物含量,并对照市售制剂考察其溶出度及稳定性。结果水飞蓟素自微乳化系统的组成为水飞蓟素、油酸乙酯、聚氧乙烯氢化蓖麻油(Cremophor EL)和乙二醇单乙基醚(transcutol)的质量比为0.07∶0.45∶0.45∶0.1;自微乳的平均粒径为72.1 nm;于4种溶出介质中均完全溶出,且溶出曲线明显高于市售制剂;强光照射(4 500 lx)、高温(60℃)及高低温循环实验(40℃和4℃)结果表明,该自微乳性状、含量均无明显变化。结论水飞蓟素自微乳粒径小,溶出度及稳定性良好。     

多替拉韦自微乳化释药系统的制备与大鼠药动学评价

目的 制备多替拉韦自微乳化释药系统（DTG-SMEDDSs）,并对其在大鼠体内的药动学行为进行评价。方法 2021年6月至2023年3月通过测定多替拉韦（DTG）在不同种类油、乳化剂和助乳化剂中的平衡溶解度、辅料配伍相容性实验来确定DTG-SMEDDSs的处方组成,根据伪三元相图初步确定各辅料的用量范围,评价DTG-SMEDDSs的热力学稳定性以及在不同稀释倍速中的稳定性,通过透射电镜观察到DTG-SMEDDSs形成乳液的微观形态,考察DTG-SMEDDSs的体外药物溶出速率,通过大鼠口服给药比较DTG混悬剂与DTG-SMEDDSs的大鼠体内药动学特征。结果 平衡溶解度和辅料配伍相容性实验确定选择单亚油酸甘油酯（Maisine）作为油相,吐温80作为乳化剂,二乙二醇单乙基醚（Transcutol HP）作为助乳化剂,其配比为30∶35∶35,制备的DTG-SMEDDSs具有良好的热力学稳定性及稀释稳定性,其自乳化形成的微乳呈类球形;DTG-SMEDDSs中的药物在10 min内基本完全溶出,其溶出速率显著快于DTG原料药;大鼠体内药动学结果显示,大鼠口服DTG-SMEDDSs后的达峰浓...     

替尼泊苷自微乳的处方筛选及体外评价

目的筛选替尼泊苷自微乳的最优处方,并对其进行体外评价。方法通过溶解度实验、伪三元相图的绘制、粒径考察筛选出最优处方;以替尼泊苷混悬液为对比,测定替尼泊苷自微乳在不同溶出介质中的溶出度;考察替尼泊苷自微乳的稳定性。结果实验筛选得到的最优处方为油酸乙酯∶Cremopher ELP∶异丙醇=20∶60∶20,载药量1.5%。在不同溶出介质中,替尼泊苷释药2h后的累积释药量均可达90%以上,且3h后的累积释药量接近100%。稳定性实验结果表明替尼泊苷自微乳在40℃、25℃和冷热循环条件下是稳定的。结论实验制得替尼泊苷自微乳具有较好的溶解度,在不同溶出介质中有较高溶出度,稳定性良好。     

自乳化复乳给药系统的制备

目的 筛选自乳化复乳处方并考察其制备工艺.方法 以伪三元相图、自复乳的显微结构和粒径为指标,考察内水相质量分数、亲水乳化剂的种类和用量以及高速分散强度对自乳化复乳处方的影响,并研究其稳定性.结果 内水相-油相-Span80-Cremophor EL比例为12.5:75:25:10,高速分散强度为12×103 r·min-1时所得自复乳的显微形态及抗稀释能力较好.结论 制备了由油包水及亲水乳化剂构成的自乳化复乳给药系统.     

自微乳释药系统及其制剂的研究进展

根据近期报道的自微乳释药系统最新研究进展,详细阐述自微乳释药系统的特点、性质、机制、处方工艺和质量评价,并介绍了有代表性的自微乳制剂。自微乳释药系统能显著增加某些药物的吸收和生物利用度,在药学领域将有很好的应用前景。     

阿托伐他汀自微乳释药系统的制备和评价

目的制备阿托伐他汀自微乳，为自微乳释药系统的处方设计和体内外评价提供参考。方法采用伪三元相图法研究不同乳化剂、助乳化剂和油相形成微乳的能力和区域，绘制不同处方组成的相图，在此基础上制备阿托伐他汀自微乳，比较温度、介质、稀释等因素对自微乳效率的影响，进行自微乳时间、所成微乳的形态、粒径分布、zeta电位、含量和稳定性等体外评价Beagle犬体内药代动力学研究。结果理想的处方经分散后可得到平均粒径在100 nm以下、呈高斯分布的微乳，稳定性好，自微乳效率高，在Beagle犬体内的吸收明显高于市售片剂。结论本文首次研制阿托伐他汀自微乳，稳定性好，在Beagle犬体内的生物利用度高。     

银杏酮酯口服自微乳化给药系统的药物代谢动力学分析

目的：探讨自微乳化给药系统（SMEDDS）促进银杏酮酯（GBE50）口服吸收的效果。方法采用高效液相色谱法,以其市售颗粒剂做对照,桑色素为内标,柚皮素、黄芩素、槲皮素为对照品,进行大鼠体内生物利用度研究,并利用DAS药动学软件处理血药浓度数据。结果血药浓度数据表明,市售的对照品颗粒剂与银杏酮酯口服自微乳化给药系统（GBE50-SMEDDS）对比,发现对照品颗粒剂消除半衰期（t1/2β）、药峰浓度（Cmax）和0-25 h药时曲线下面积（AUC0-25）分别为（4.327±0.768）h,（199.49±24.59） ng/ml,（240.29±24.22）mg/（h·ml） GBE50-SMEDDS则分别为（10.975±1.887）h,（221.53±46.88）ng/ml,（378.83±20.65）mg/（h·ml）,两组t1/2β、Cmax和AUC0-25比较,差异有统计学意义（P〈0.05）。结论与市售颗粒剂相比, GBE50-SMEDDS明显提高了生物利用度,在临床上值得推广应用。     

Development and characterization of a lovastatin-loaded self-microemulsifying drug delivery system

The objective of the work was to develop, optimize and evaluate a self-microemulsifying drug delivery system of the poorly water soluble drug, lovastatin. Solubility of lovastatin was determined in various vehicles. Ternary phase diagrams were constructed to identify the efficient self-emulsification region using oils, surfactants, and co-surfactants in aqueous environment. Optimized formulations were assessed for drug content, spectroscopic clarity, emulsification time, contact angle, zeta potential, particle size and dissolution studies. Zeta potential was measured in absence and presence of oleylamine, a positive charge inducer. On the basis of similarity and dissimilarity of particle size distribution, formulations were characterized using principal component analysis and agglomerative hierarchy cluster analysis, the multivariate statistical analysis. Transmission electron microscopy of selected formulations (F5–F7) confirmed the spherical shape of globules with no signs of coalescence of globules and precipitation of drug, even after 24?h post dilution in distilled water. The relevance of differences in t_50% and percentage dissolution efficiency was evaluated statistically by two-way ANOVA. Infrared spectroscopy, differential scanning calorimetric and x-ray diffraction studies indicated no incompatibility between drug, oil and surfactants. The results of this study indicate that the self-microemulsifying drug delivery system of lovastatin, owing to nanosize, has potential to enhance its absorption and without interaction or incompatibility between the ingredients.     

头孢泊肟酯自乳化制剂的研究

目的 优化制备头孢泊肟酯自乳化最佳处方条件使其达到目标浓度50mg·g-1.方法 通过溶解度实验、相图绘制、以及形成乳剂的乳化程度、乳滴粒径大小,对头孢泊肟酯自乳化体系中的油相、表面活性荆、助表面活性剂进行筛选,寻找最佳处方条件.结果 优选的头孢泊肟酯自乳化制剂处方中油相为Lauroglycol FCC,表面活性剂为Labrasol,助表面活性荆为Labrafil M1944 CS.结论 初步成功地制备了头孢泊肟酯自乳化传递体系.     

Oral bioavailability enhancement of vinpocetine using self-microemulsifying drug delivery system containing long chain triglycerides: Preparation and in vitro/in vivo evaluation

Vinpocetine, a widely used neurotropic agent, has low oral bioavailability due to its poor solubility and extensive hepatic first-pass metabolism. In the present work, self-microemulsifying drug delivery systems (SMEDDS) employing long chain triglycerides (LCT) were successfully developed to increase vinpocetine’s solubility and reduce its hepatic first pass metabolism, thus enhancing its overall oral bioavailability. Maisine^?35-1 was chosen as the lipid component in the formulated SMEDDS as it showed the maximal vinpocetine solubility within different LCT tested. Feasibility of obtaining SMEDDS, containing Maisine^?35-1, together with Transcutol^®HP and either Cremophor^®EL or Tween 80, was evaluated using ternary phase diagrams. In vitro release studies performed in phosphate buffer of pH 7.4 illustrated that extent of vinpocetine release from SMEDDS was drastically higher than that obtained from commercial Cavinton^® tablets. The industrial usefulness of the developed SMEDDS was evaluated regarding their moisture sorption isotherms when filled into gelatin capsules and stored at different relative humidity. Vinpocetine’s optimal SMEDDS did not induce gross changes in the gastrointestinal mucosa of rats at the investigated dose. Moreover, it significantly improved the relative oral bioavailability of vinpocetine compared to Cavinton^® tablets. Accordingly, this study suggests that SMEDDS containing LCT under proper optimization and safety assessment can be effectively utilized for oral bioavailability enhancement of vinpocetine.     

黄芩素自微乳的制备及大鼠体内生物利用度研究

目的:制备黄芩素自微乳化制剂(SMEDDS),考察其大鼠体内生物利用度。方法:采用伪三元相图法筛选自微乳的油相、表面活性剂及助表面活性剂;采用HPLC法测定大鼠血浆中药物浓度,与原料比较,对黄芩素自微乳进行大鼠体内生物利用度评价。结果:通过使用混合油相、混合表面活性剂及助表面活性剂,可获得较为理想的黄芩素自微乳。大鼠体内血药浓度-时间曲线结果表明,黄芩素自微乳的AUC是原料的3.77倍,且药时曲线的形状发生一定的改变。结论:自微乳系统可显著增加黄芩素的溶解度,有利于提高口服生物利用度,且自微乳可能改变其胃肠道吸收行为。     

银杏酮酯口服自微乳化给药系统的制备

研究制备银杏酮酯口服自微乳化给药系统。采用平衡溶解度方法筛选乳化剂与助乳化剂; 采用伪三元相图法制备微乳; 采用正交法优化处方组成; 并考察自微乳化制剂的乳化效率、溶出度、稳定性与药动学研究等。结果表明, 由肉豆蔻酸异丙酯IPM、聚氧乙烯蓖麻油Cremophor EL、丙二醇与银杏酮酯组成的自微乳化给药系统遇水可自发形成粒径为20～50 nm的稳定微乳。自微乳化给药系统的乳化效率与溶出快, 且制剂稳定性高, 能提高生物利用度。制备的银杏酮酯口服自微乳化给药系统稳定有效。     

藤黄酸自微乳化释药系统的制备与质量评价

目的构建藤黄酸自微乳化释药系统(GA-SMEDDSs),并对其质量进行评价。方法通过溶解度实验确定GA-SMEDDSs使用的油相、乳化剂和助乳化剂种类,根据伪三元相图法绘制出影响其微乳液形成的辅料用量范围,采用中心复合设计-效应面法优化并确定GA-SMEDDSs的最佳处方组成,在透射电镜下观察GA-SMEDDSs形成微乳的微观结构,用马尔文激光粒度仪测定粒径分布,考察GA-SMEDDSs经模拟人体生理体液稀释后的稳定性,比较GA-SMEDDSs与原料药的体外药物溶出速率。结果通过实验优化得到GA-SMEDDSs的最优处方组成:肉豆蔻酸异丙酯(IPM)质量分数为20.0%,辛酸癸酸聚乙二醇甘油酯(labrasol)质量分数为35.0%,二乙二醇单乙基醚(transcutol P)质量分数为45.0%,GA-SMEDDSs经水分散可形成黄色透明状微乳液,透射电镜下可观察到微乳呈类球状,大小均匀,平均粒径为168.4±5.9 nm;经模拟人体生理体液稀释后微乳物理稳定性良好;GA-SMEDDSs在人工胃液和人工肠液中药物溶出速率均显著提高。结论藤黄酸制备成自微乳化释药系统可提高药物溶出速度,...     

吡罗昔康自微乳化药物传递系统的处方筛选与体外评价

筛选吡罗昔康自微乳化药物传递系统(SMEDDS)的处方并进行体外评价。考察了吡罗昔康在不同油相和表面活性剂中的溶解度；对不同油相和表面活性剂进行初步配伍研究；通过绘制三元相图研究处方中不同油相、表面活性剂和辅助表面活性剂形成微乳的能力和区域；对制剂粒径及溶出度进行考察。处方选用肉桂醇作为吡罗昔康的溶剂，以Labrafil M 1944CS为油相，Cremophor EL为表面活性剂，Transcotol P为辅助表面活性剂。所得3个处方乳化后的粒径及分布分别为(32.2±5.0)、(40.1±6.4)、(81.9±12.2)nm。制剂溶出速度快。通过处方研究确定了最优处方，研制了吡罗昔康SMEDDS。     

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。     

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.     

Application of freeze-drying in the development of oral drug delivery systems

ABSTRACT

Introduction: With continual focus on oral drug delivery systems (ODDS), the role of freeze-drying becomes increasingly valuable. While freeze-drying is fundamentally a desiccation process, the advantageous material properties attributed to freeze-drying extend far beyond the preparation of stable pharmaceutical products. The formulation and process variables are important considerations as they affect the final freeze-dried product characteristics. It is of interest to expound on the principles and effects of freeze-drying in the hope of introducing novel products for applications in the development of ODDS.

Areas covered: In this review, basic principles, general formulation and process variables associated with freeze-drying will be covered. The application of freeze-drying in 3 areas: modification of active ingredients, development of novel freeze-dried excipients and development of freeze-dried final dosage forms will be discussed.

Expert opinion: As a pharmaceutical unit operation, freeze-drying has created new dimensions in the area of oral drug delivery, where the properties of the drugs, excipients and characteristics of the final solid dosage form can be modified by the freeze-drying process. With the emergence of new applications, the role of freeze-drying technology in ODDS is indeed a relevant and promising one.