Self-Emulsifying Drug Delivery Systems for Improving Oral Absorption of Ginkgo Biloba Extracts

Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils, surfactants, and cosurfactants, which are emulsified in aqueous media under conditions of gentle stirring and digestive motility that would be encountered in the gastrointestinal tract. We found that SEDDS could efficiently improve oral absorption of the sparingly soluble drugs by rapid self-emulsification and subsequently dispersion in the absorption sites. Ginkgo biloba extract (GBE) has become a widely used herbal remedy for increasing cognitive function in elderly people. The main purpose of our work is to prepare SEDDS for improving oral absorption of GBE. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsification region, and particle size distributions of resultant emulsions were determined. The optimized formulation for bioavailability assessment consisted of 45% Tween 80-Cremophor EL35 (1:1, w/w), 10% 1, 2-propanediol, and 45% ethyl oleate. The mean droplet size distribution of the optimized SEDDS was ～100 nm when diluted with 500-fold volume of the distilled water. The in vitro dissolution rates of the active components of GBE SEDDS form were significantly faster than those of the GBE tablets. After single oral administration of 800 mg GBE as SEDDS or tablets to fasted dogs, the relative bioavailability of SEDDS for bilabolide and ginkgolide A and B was 162.1, 154.6, and 155.8% compared with the reference tablets, respectively. Our results suggested the potential and promising use of SEDDS for the efficient delivery of the sparingly soluble drugs or traditional Chinese medicines, such as GBE by oral administration.     

Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment

The goals of our investigations are to develop and characterize self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10 (CoQ10), using polyglycolyzed glycerides (PGG) as emulsifiers and to evaluate their bioavailability in dogs. Solubility of CoQ10 was determined in various oils and surfactants. SEDDS consisted of oil, a surfactant and a cosurfactant. Four types of self-emulsifying formulations were prepared using two oils (Myvacet 9-45 and Captex-200), two emulsifiers (Labrafac CM-10 and Labrasol) and a cosurfactant (lauroglycol). In all the formulations, the level of CoQ10 was fixed at 5.66% w/w of the vehicle. The in vitro self-emulsification properties and droplet size analysis of these formulations upon their addition to water under mild agitation conditions were studied. Pseudo-ternary phase diagrams were constructed identifying the efficient self-emulsification region. From these studies, an optimized formulation was selected and its bioavailability was compared with a powder formulation in dogs. Medium chain oils and Myvacet 9-45 provided higher solubility than long chain oils. Efficient and better self-emulsification processes were observed for the systems containing Labrafac CM-10 than formulations containing Labrasol. Addition of a cosurfactant improved the spontaneity of self-emulsification. From these studies, an optimized formulation consisting of Myvacet 9-45 (40%), Labrasol (50%) and lauroglycol (10%) was selected for its bioavailability assessment. A two-fold increase in the bioavailability was observed for the self-emulsifying system compared to a powder formulation. SEDDS have improved the bioavailability of CoQ10 significantly. The data suggest the potential use of SEDDS to provide an efficient way of improving oral absorption of lipophilic drugs.     

Self-emulsifying drug delivery system and the applications in herbal drugs

Abstract

Herbal drugs have been used for thousands of years in the east and have had a recent resurgence in popularity among consumers in the west. However, most of herbal drug are poorly soluble and have hydrophobic properties and poor distribution, leading to reduced bioavailability and hence decreased treatment efficacy, requiring repeated administration or increased dose. In the past few decades, considerable attention has been focused on the development of self-emulsifying drug delivery system (SEDDS) for herbal drugs. SEDDS is isotropic and thermodynamically stable solutions consisting of oil, surfactant, co-surfactant and drug that can spontaneously form oil-in-water micro/nanoemulsion when mixed with water under gentle stirring. The formulation can be a viable alternative to classical formulations to take advantage of their lipophilic nature and to solve their problems of poor solubility, poor bioavailability, low oral absorption and instability. The mechanism of self-emulsification, solubility studies, construction of phase diagram, optimization and characterization of herbal drugs-loaded SEDDS formulation and in situ absorption evaluation of herbal drugs in rat intestine are presented in our article.     

自乳化药物传递系统的研究进展

本文对近几年国内外有关自乳化药物传递系统的特点、吸收机制、组成、影响因素及其在药剂学方面的应用进行了归纳和分析。自乳化药物传递系统可显著地提高难溶性或亲脂性药物口服生物利用度，具有广阔的发展前景。     

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.     

Formulation development and pharmacokinetics of puerarin self-emulsifying drug delivery systems

The main purpose of this work was to prepare a self-emulsifying drug delivery system (SEDDS) for a poorly water-soluble drug, puerarin. The solubility of puerarin was determined in various oils and surfactants. Oleic acid and Tween 80 provided relatively higher solubility. The addition of propylene glycol as a cosurfactant improved the solubility of puerarin and the spontaneity of self-emulsification. A series of mixtures composed of oleic acid, propylene glycol, and Tween 80 were prepared and their self-emulsifying properties were studied. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification region, and the particle sizes of the resultant emulsions were determined using a laser diffraction sizer. The pharmacokinetic behaviors of three different SEDDS formulations were investigated in beagle dogs. The bioavailability of puerarin was compared using the pharmacokinetic parameters, peak plasma concentration (C(max)), time to reach peak plasma concentration (T(max)), and total area under the plasma concentration-time curve (AUC(0-infinity)). The analysis of the data showed a statistically significant difference between F2 and F4 (P < 0.01) as well as F3 and F4 (P < 0.01) with regard to the values of AUC(0-infinity) and C(max) but not between those of F2 and F3 (P > 0.05). In the case of parameter T(max), ke, no statistically significant difference (P > 0.05) among the values were observed. From these studies, a SEDDS containing oleic acid (17.5%), Tween 80 (34.5%), and propylene glycol (34.5%) (w/w) was selected as an optimized SEDDS formulation for puerarin. The data suggest the potential use of SEDDS to improve the oral absorption of puerarin.     

Enhanced oral bioavailability of etodolac by self‐emulsifying systems: in‐vitro and in‐vivo evaluation

Objectives The objective of this study was to prepare a self‐emulsifying drug delivery system (SEDDS) for oral bioavailability enhancement of a poorly water‐soluble drug, etodolac. The SEDDS formulations were optimized by evaluating their ability to self‐emulsify when introduced to an aqueous medium under gentle agitation, and by determination of the particle size of the resulting emulsion. Methods An optimized formulation of SEDDS (composed of 20% etodolac, 30% oil Labrafac WL1349, 10% Lauroglycol 90 and 40% Labrasol) was selected for bioavailability assessment in rabbits. The anti‐inflammatory effect was also determined in rats, and compared with powder drug and etodolac suspension in water (50 mg/kg). Key findings The peak plasma concentration of 16.4 ± 1.1 μg/ml appeared after 1.3 ± 0.2 h, whereas with powder drug and etodolac suspension the values were 7.5 ± 0.5 and 10.6 ± 0.7 μg/ml at 4.2 ± 0.4 and 2.4 ± 0.2 h, respectively. The AUC_0–8 of the etodolac SEDDS formulation was 2.3 times that of the pure drug and 1.4 times that of the suspension form. SEDDS formulation exhibits a 21% increase in paw thickness compared with a 39% increase on oral administration of etodolac suspension after 4 h at the same dose of the drug (20 mg/kg). Conclusions The result indicates the utility of SEDDS for the oral delivery of etodolac and potentially other lipophilic drugs.     

Systematic Development of Self-Emulsifying Drug Delivery Systems of Atorvastatin with Improved Bioavailability Potential

The aim of this study was to prepare and characterize a self-emulsifying drug delivery system (SEDDS) with a high drug load of poorly water-soluble atorvastatin for the enhancement of dissolution and oral bioavailability. Solubility of atorvastatin in oil, surfactant, and cosurfactant was determined. Pseudo-ternary phase diagrams were constructed by the aqueous titration method, and formulations were developed based on the optimum excipient combinations. A high drug load (10% w/w) was achieved with a combination of oleic acid, Tween 80, and polyethylene glycol 400, ensuring the maximum dissolution property (in the case of SES6). Effects of lipids and surfactants on physical properties of SEDDS such as in vitro emulsification efficiency in terms of self-emulsification time, emulsion droplet size, and percent transmittance were measured. Multiple regression analysis revealed that a higher amount of surfactants significantly increased dissolution of ATV while decreasing emulsion droplet size and emulsification time. About a four-fold increase in dissolution was achieved by SEDDS compared to pure ATV powder. Overall, this study suggests that dissolution and oral bioavailability of ATV could be improved by SEDDS technology.     

Preparation and evaluation of Vinpocetine self-emulsifying pH gradient release pellets

The main objective of this study was to develop a pH gradient release pellet with self-emulsifying drug delivery system (SEDDS), which could not only improve the oral bioavailability of Vinpocetine (VIN), a poor soluble drug, but reduce the fluctuation of plasma concentration. First, the liquid VIN SEDDS formulation was prepared. Then the self-emulsifying pH gradient release pellets were prepared by extrusion spheronization technique, and formulation consisted by the liquid SEDDS, absorbent (colloidal silicon dioxide), penetration enhancer (sodium chloride), microcrystalline cellulose, ethyl alcohol, and three coating materials (HPMC, Eudragit L30D55, Eudragit FS30D) were eventually selected. Three kinds of coated pellets were mixed in capsules with the mass ratio of 1:1:1. The release curves of capsules were investigated in vitro under the simulated gastrointestinal conditions. In addition, the oral bioavailability and pharmacokinetics of VIN self-emulsifying pH gradient release pellets, commercial tablets and liquid VIN SEDDS were evaluated in Beagle dogs. The oral bioavailability of self-emulsifying pH gradient release pellets was about 149.8% of commercial VIN tablets, and it was about 86% of liquid VIN SEDDS, but there were no significant difference between liquid SEDDS and self-emulsifying pH gradient release pellets. In conclusion, the self-emulsifying pH gradient release pellets could significantly enhance the absorption of VIN and effectively achieve a pH gradient release. And the self-emulsifying pH gradient release pellet was a promising method to improve bioavailability of insoluble drugs.     

The novel formulation design of self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion I: enhancing effects on oral bioavailability of poorly water soluble compounds in rats and beagle dogs

We examined the design of the versatile novel self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion formulation which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds. Namely, seven kinds of poorly water soluble compounds such as disopyramide, ibuprofen, ketoprofen, tolbutamide, and other new compounds, as the model compounds were used to compare the plasma concentration profile of the compound following single oral administration of each compound to rats and beagle dogs as a solution, an oily solution, a suspension (or a powder), an O/W microemulsion, and a SEDDS type O/W microemulsion. And the enhancing effect of the SEDDS type O/W microemulsion on the gastrointestinal absorption of these compounds was evaluated. In the components of the SEDDS type O/W microemulsion, medium chain fatty acid triglyceride (MCT), diglyceryl monooleate (DGMO-C), polyoxyethylene hydrogenated castor oil 40 (HCO-40), and ethanol were used as an oil, a lipophilic surfactant, a hydrophilic surfactant, and a solubilizer, at the mixture ratio of 25/5/45/25 (w/w%), respectively. Thereby, to six kinds of the model compounds except disopyramide, the solubility was from 340 to 98,000 times that in water, and the AUCs in plasma concentration of the compound were equivalent to that of solution or O/W microemulsion administration, or was increased by 1.5 to 78 times that of suspension administration. Accordingly, this novel SEDDS type O/W microemulsion is the versatile, useful formulation which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds.     

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。     

Solid self-emulsifying nitrendipine pellets: Preparation and in vitro/in vivo evaluation

Objective of this study is to develop and evaluate the new solid self-emulsifying (SE) pellets of poorly soluble nitrendipine (NTD). These pellets were prepared via extrusion/spheronization technique, using liquid SEDDS (NTD, Miglyol^® 812, Cremophor^® RH 40, Tween 80, and Transcutol^® P), adsorbents (silicon dioxide and crospovidone), microcrystalline cellulose and lactose. The resulting SE pellets with 30% liquid SEDDS exhibited uniform size (800–1000 μm) and round shape, droplet size distribution following self-emulsification was nearly same to the liquid SEDDS (72 ± 16 nm and 64 ± 12 nm). The in vitro release was similar for the two SE formulations (over 80% within 30 min), both significantly higher than the conventional tablets (only 35% within 30 min). The oral bioavailability was evaluated for the SE pellets, liquid SEDDS and conventional tablets in fasted beagle dogs. AUC of NTD from the SE pellets showed 1.6-fold greater than the conventional tablets and no significant difference compared with the liquid SEDDS. In conclusion, our studies illustrated that extrusion/spheronization technique could be a useful large-scale producing method to prepare the solid SE pellets from liquid SEDDS, which can improve oral absorption of NTD, nearly equivalent to the liquid SEDDS, but better in the formulation stability, drugs leakage and precipitation, etc.     

Self-emulsifying drug delivery systems: a novel approach to deliver drugs

Self-emulsifying drug delivery systems (SEDDS) are a proven method for poorly soluble substances works by increasing the solubility and bioavailability. SEDDS and isotropic mixtures, are composed of oils, surfactants, and occasionally cosolvents. The ability of these formulations and methods to produce microemulsions or fine oil-in-water (o/w) emulsions after moderate stirring and dilution by water phase along the GI tract might be a promising technique for lipophilic agents with dissolution rate-limited absorption. This review provides an outline of SEDDS''s numerous advances and biopharmaceutical elements, types, manufacturing, characterization, limitations, and future prospects. The evaluation of SEDDS and its applications are also discussed, focusing on the advances of SEDDS''s solid self-emulsifying delivery mechanism and dosage form. By integrating suitable polymer into the formulation, SEDDS may be studied for the creation of a formulation with sustained drug release. This technology''s improvement might lead to a new application in the field of medicine delivery. SEDDS has been demonstrated to be quite efficient in increasing oral bioavailability of lipophilic products. SEDDS is one of the promising methods for controlling the characteristics of medications that are not great choices for oral delivery. It is also worth mentioning that SEDDS may be made in variety of solid dosage forms that are acceptable for both oral and parenteral administration.     

通过体外自乳化性能及体内药代动力学评价优化葛根素自乳化制剂

本文将水不溶性药物葛根素制备成自乳化制剂。测定了葛根素在不同油相及表面活性剂的溶解度，结果表明葛根素在油酸、Tween 80中的溶解度较好，1，2-丙二醇不但能增加药物的溶解度，而且能够提高自乳化能力。以油酸为油相，Tween 80为表面活性剂，1，2-丙二醇为助表面活性剂，配制一系列混合物，通过绘制三元相图得到自乳化区，考察不同自乳化处方的自乳化性质，采用激光粒度散射仪测定乳化后粒子大小，在体外评价基础上选择较好的3个处方进行比格犬体内药动学研究，比较不同处方自乳化制剂在比格犬体内的生物利用度包括药代动力学参数Cmax， Tmax， AUC0-t。结果表明处方2和处方3的AUC0-t值［(5.201±0.511) ng·mL^-1·h， (5.174±0.498) ng·mL^-1·h］和Cmax值［(1.524±0.125) ng·mL^-1， (1.513±0.157) ng·mL^-1］显著高于处方4［(3.013±0.623) ng·mL^-1·h， (0.939±0.089) ng·mL^-1］，通过体内研究结果获得较优处方为油酸(17.5%)、Tween 80(34.5%)、1，2-丙二醇(34.5%)。自乳化释药系统提供了水不溶性药物口服给药的新途径。     

Self‐emulsifying system for improving drug dissolution and bioavailability: in vitro/in vivo evaluation

The present study focuses on enhancement of the dissolution and oral absorption of poorly water‐soluble etodolac. A self‐emulsifying drug delivery system (SEDDS) composed of oil, surfactant, and co‐surfactant for oral administration was formulated. The SEDDS formulations were optimized by evaluating their ability to self‐emulsifying when introduced to an aqueous medium under gentle agitation, and by determination of particle size of the resulting emulsion. Optimized formulation of SEDDS was selected for bioavailability assessment in rabbits. Also, the anti‐inflammatory effect of SEDDS formulation was determined in rats, compared with powder drug and etodolac suspension in water (50 mg kg^?1). The peak plasma concentration of 16.4±1.07 µg ml^?1 appeared after 1.3±0.2 h, whereas with powder drug and etodolac suspension the values were 7.5±0.5 and 10.6±0.7 µg ml^?1 appearing at 4.2±0.4 and 2.4±0.2 h, respectively. The AUC_0‐8 of the etodolac SEDDS formulation was approximately 2.3 times as that of the pure drug and 1.5 times as much as that of the suspension form. There was no significant change in the elimination rate constant and the elimination half‐life. Thus, oral absorption is improved significantly using the SEDDS formulation. The anti‐inflammatory activity of SEDDS formulation was compared with etodolac suspended in water at a dose of 20 mg kg^?1, using a carrageenan‐induced rat paw edema model. At 4 h, the SEDDS formulation reduced edema by 69% as compared a similar dose of etodolac suspension, which reduced edema by 45%. The results support the utility of SEDDS formulation for the oral delivery of etodolac, and potentially other lipophilic drugs. Drug Dev Res 2009. © 2009 Wiley‐Liss, Inc.     

Self-Emulsifying Drug Delivery Systems: Formulation and Biopharmaceutic Evaluation of an Investigational Lipophilic Compound

Self-emulsifying drug delivery systems (SEDDSs) represent a possible alternative to traditional oral formulations of lipophilic compounds. In the present study, a lipophilic compound, WIN 54954, was formulated in a medium chain triglyceride oil/nonionic surfactant mixture which exhibited self-emulsification under conditions of gentle agitation in an aqueous medium. The efficiency of emulsifi-cation was studied using a laser diffraction sizer to determine particle size distributions of the resultant emulsions. An optimized formulation which consisted of 25% (w/w) surfactant, 40% (w/w) oil, and 35% (w/w) WIN 54954 emulsified rapidly with gentle agitation in 0.1 N HCl (37°C), producing dispersions with mean droplet diameters of less than 3 µm. The self-emulsifying preparation was compared to a polyethylene glycol 600 (PEG 600) solution formulation by administering each as prefilled soft gelatin capsules to fasted beagle dogs in a parallel crossover study. Pharmacokinetic parameters were determined and the absolute bioavailability of the drug was calculated by comparison to an i.v. injection. The SEDDS improved the reproducibility of the plasma profile in terms of the maximum plasma concentration (C _max) and the time to reach the maximum concentration (t _max). There was no significant difference in the absolute bioavailability of WIN 54954 from either the SEDDS or the PEG formulations.     

Enhanced oral bioavailability of piperine by self-emulsifying drug delivery systems: in vitro,in vivo and in situ intestinal permeability studies

Abstract

The main purpose of this work was to develop and evaluate a self-emulsifying drug delivery system (SEDDS) of piperine to enhance its solubility and bioavailability. The formulation was optimized by solubility test and ternary phase diagrams. Then physiochemical properties and in vitro release of SEDDS were characterized. In vivo pharmacokinetics study and in situ single-pass intestinal perfusion were performed to investigate the effects of SEDDS on the bioavailability and intestinal absorption of piperine. The optimized formulation was composed of ethyl oleate, Tween 80 and Transcutol P (3:5.5:1.5, w/w), with the level of the piperine reached 2.5% (w/w). The in vitro dissolution rates of piperine SEDDS were significantly higher than the self-prepared capsules. In vivo pharmacokinetic study showed C_max1, C_max2 and area under the curve of piperine after oral administration of SEDDS in rats were 3.8-, 7.2- and 5.2-fold higher than the self-prepared capsules, respectively, and the relative bioavailability of SEDDS was 625.74%. The in situ intestinal absorption study revealed that the effective permeability and the effective absorption rate values of piperine for SEDDS were significantly improved comparing to solutions (p?<?0.01). So SEDDS formulation could improve the oral bioavailability and intestinal absorption of piperine effectively.     

Role of lipid-based excipients and their composition on the bioavailability of antiretroviral self-emulsifying formulations

Abstract

The objective of this study was to develop self-emulsifying drug delivery system (SEDDS) to improve solubility and enhance the oral absorption of the poorly water-soluble drug, nevirapine. This lipid-based formulation may help to target the drug to lymphoid organs where HIV-1 virus resides mainly. The influence of the oil, surfactant and co-surfactant types on the drug solubility and their ratios on forming efficient and stable SEDDS were investigated in detail. Two SEDDS (F1 and F2) were prepared and characterized by morphological observation, droplet size and zeta potential determination, cloud point measurement and in vitro diffusion study. The influence of droplet size on the absorption from formulations with varying concentration of oil and surfactant was also evaluated from two self-emulsifying formulations. Oral bioavailability of nevirapine SEDDS was checked by using rat model. Results of diffusion rate and oral bioavailability of nevirapine SEDDS were compared with marketed suspension. The absorption of nevirapine from F1 and F2 showed 1.92 and 1.98-fold increase (p?<?0.05) in relative bioavailability, respectively, compared with that of the suspension. There was no statistical significant difference (p?<?0.05) between F1 and F2 in their AUC and C_max. This indicated that there was apparent poor correlation between the droplet size and in vivo absorption. However, nevirapine in SEDDS showed higher ex vivo stomach and intestinal permeability and in vivo absorption than the marketed suspension, suggesting that the SEDDS may be a useful delivery system for targeting nevirapine to lymphoid organs.     

靛玉红及其磷脂复合物和自乳化释药系统在犬体内的药动学

目的:考察靛玉红及其磷脂复合物和自乳化释药系统在犬体内的药动学过程。方法:采用三周期交叉试验设计法,取6条健康beagle犬随机分成3组,分别服用剂量为100mg的靛玉红片、靛玉红磷脂复合物和靛玉红自乳化释药系统,用高效液相色谱(HPLC)法测定靛玉红的血药浓度,利用3P97软件包和统计矩方法计算主要药动学参数和相对生物利用度。结果:以靛玉红片为对照,靛玉红磷脂复合物和自乳化释药系统的相对生物利用度分别为(157±s 10)%和(162±16)%。结论:磷脂复合物和自乳化释药系统有利于改善靛玉红口服生物利用度。     

Nonlinear Absorption Kinetics of Self-Emulsifying Drug Delivery Systems (SEDDS) Containing Tocotrienols as Lipophilic Molecules: In Vivo and In Vitro Studies

Self-emulsifying drug delivery systems (SEDDS) have been broadly used to promote the oral absorption of poorly water-soluble drugs. The purpose of the current study was to evaluate the in vivo oral bioavailability of vitamin E isoforms, δ-tocotrienol (δ-T3) and γ-tocotrienol (γ-T3) administered as SEDDS, as compared to commercially available UNIQUE E® Tocotrienols capsules. Results from studies in rats showed that low dose treatment with δ-T3 (90%) and γ-T3 (10%) formulated SEDDS showed bioavailability of 31.5% and 332%, respectively. However, bioavailability showed a progressive decrease with increased treatment dose that displayed nonlinear absorption kinetics. Additional in vitro studies examining cellular uptake studies in Caco 2 cells revealed that the SEDDS formulation increased passive permeability of δ-T3 and γ-T3 by threefold as compared to the commercial capsule formulation. These studies also showed that free surfactants decreased δ-T3 and γ-T3 absorption. Specifically, combined treatment cremophor EL or labrasol with tocotrienols caused a 60–85% reduction in the cellular uptake of δ-T3 and γ-T3 and these effects appear to result from surfactant-induced inhibition of the δ-T3 and γ-T3 transport protein Niemann–Pick C1-like 1 (NPC1L1). In summary, results showed that SEDDS formulation significantly increases the absorption and bioavailability δ-T3 and γ-T3. However, this effect is self-limiting because treatment with increasing doses of SEDDS appears to be associated with a corresponding increase in free surfactants levels that directly and negatively impact tocotrienol transport protein function and results in nonlinear absorption kinetics and a progressive decrease in δ-T3 and γ-T3 absorption and bioavailability.