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。     

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.     

Preparation and pharmacokinetics evaluation of oral self-emulsifying system for poorly water-soluble drug Lornoxicam

Abstract

The present work was performed aiming to develop a new solid self-emulsifying system (SMEDDS) for poorly water-soluble drug Lornoxicam and evaluate the bioavailability in Wister rats by oral gavage. Liquid SMEDDS of Lornoxicam was formulated with Labrafil M 1944 CS as oil phase, Kolliphor HS 15 as a surfactant and Transcutol HP as a cosurfactant after screening various vehicles. The microemulsion system selected from the phase diagram and optimized by central composite design (CCD) response surface method was transformed into solid-SMEDDS (S-SMEDDS) by lyophilization using sucrose as cryoprotectant. The formulations were further characterized by the particle size, poly dispersity index (PDI), self-emulsifying time, zeta potential, transmission electron microscope (TEM), differential scanning calorimeter (DSC), in vitro drug release and in vivo pharmacokinetics. Results of DSC studies confirmed that the drug was incorporated in the S-SMEDDS. The in vitro drug release from Lornoxicam SMEDDS was found to be greatly higher in comparison with that from the commercial tablets. It was indicated that SMEDDS might be effective in reducing the effect of pH variability of Lornoxicam and improving the release performance of Lornoxicam. HPLC system was applied to study the concentration of Lornoxicam in the plasma of the Wister rats after oral administration of Lornoxicam SMEDDS and Lornoxicam commercial tablets. The pharmacokinetics parameters of the rats were C_max 1065.91?±?224.90 and 1855.22?±?748.25?ngmL^?1, T_max were 2.5?±?0.4?h and 1.8?±?0.5?h, and AUC_0～t were 5316.35?±?323.62 and 7758.07?±?241.57?ngmL^?1?h, respectively. Calculated by AUC_0～∞, the relative bioavailability of Lornoxicam S-SMEDDS was 151.69?±?15.32%. It suggested that this S-SMEDDS could be used as a successful oral solid dosage form to improve the solubility and bioavailability of poorly water-soluble drug Lornoxicam as well.     

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。     

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 self-microemulsifying 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.     

Systematic development of design of experiments (DoE) optimised self-microemulsifying drug delivery system of Zotepine

The aim of present investigation is to improve dissolution rate of poor soluble drug Zotepine by a self-microemulsifying drug delivery system (SMEDDS). Ternary phase diagram with oil (Oleic acid), surfactant (Tween 80) and co-surfactant (PEG 400) at apex were used to identify the efficient self-microemulsifying region. Box–Behnken design was implemented to study the influence of independent variables. Principal Component Analysis was used for scrutinising critical variables. The liquid SMEDDS were characterised for macroscopic evaluation, % Transmission, emulsification time and in vitro drug release studies. Optimised formulation OL1 was converted in to S-SMEDDS by using Aerosil^® 200 as an adsorbent in the ratio of 3:1. The S-SMEDDS was characterised by SEM, DSC, globule size (152.1?nm), zeta-potential (?28.1?mV), % transmission study (98.75%), in vitro release (86.57%) at 30?min. The optimised solid SMEDDS formulation showed faster drug release properties as compared to conventional tablet of Zotepine.     

Self-microemulsifying drug delivery system (SMEDDS) – challenges and road ahead

Abstract

Self-microemulsifying drug delivery system (SMEDDS) has emerged as a vital strategy to formulate poor water soluble compounds for bioavailability enhancement. However, certain limitations are associated with SMEDDS formulations which include in vivo drug precipitation, formulation handling issues, limited lymphatic uptake, lack of predictive in vitro tests and oxidation of unsaturated fatty acids. These limitations restrict their potential usage. Inclusion of polymers or precipitation inhibitors within lipid based formulations helps to maintain drug supersaturation after dispersion. This, thereby, improves the bioavailability and reduces the variability on exposure. Also, formulating solid SMEDDS helps to overcome liquid handling and stability problems. Usage of medium chain triglycerides (MCT) and suitable antioxidants to minimize oxidation of unsaturated fatty acids are few of the steps to overcome the limitations associated with SMEDDS. The review discussed here, in detail, the limitations of SMEDDS and suitable measures that can be taken to overcome them.     

Self-microemulsifying drug delivery system (SMEDDS) of vinpocetine: formulation development and in vivo assessment

A new self-microemulsifying drug delivery system (SMEDDS) has been developed to increase the solubility, dissolution rate and oral bioavailability of vinpocetine (VIP), a poor water-soluble drug. The formulations of VIP-SMEDDS were optimized by solubility assay, compatibility tests, and pseudo-ternary phase diagrams analysis. The optimal ratio in the formulation of SMEDDS was found to be Labrafac : oleic acid : Cremophor EL : Transcutol P=40 : 10 : 40 : 10 (w/w). The average particle diameter of VIP was less than 50 nm. In vitro dissolution study indicated that the dialysis method in reverse was better than the ultrafiltration method and the dialysis method in simulating the drug in vivo environment. Comparing with VIP crude drug power and commercial tablets, (-)VIP-SMEDDS caused a 3.4- and 2.9-fold increase in the percent of accumulated dissolution at 3 h. Further study on the absorption property of VIP-SMEDDS employing in situ intestine of rats demonstrated that VIP in SMEDDS could be well-absorbed in general intestinal tract without specific absorption sites. In addition, the developed SMEDDS formulations significantly improved the oral bioavailability of VIP in rats. Relative bioavailability of (-)VIP-SMEDDS and (+)VIP-SMEDDS increased by 1.85- and 1.91-fold, respectively, in relative of VIP crude powder suspension. The mechanisms of enhanced bioavailability of VIP might contribute to the improved release, enhanced lymphatic transport, and increased intestinal permeability of the drug.     

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。     

Optimized self-microemulsifying drug delivery systems (SMEDDS) for enhanced oral bioavailability of astilbin

The main purpose of this research work was to design an optimized self micro-emulsifying drug delivery system (SMEDDS) to enhance the bioavailability of the poor water soluble drug, astilbin. The solubility of astilbin was evaluated in various vehicles. Pseudoternary phase diagrams were used to select the components and their ranges by evaluating the micro-emulsification area. Central composite design was applied to optimize the properties of the formulation, including particle size, polydispersity index, drug loading capacity and effective intestinal permeability. The optimized SMEDDS characteristics were investigated including the study of factors influencing particle size and showed the stability of microemulsion when varying the pH and volume of diluents. In vitro drug release profile study was performed using the reverse dialysis method where 95% of the drug was released after 4 h. The developed astilbin SMEDDS was subjected to bioavailability studies in beagle dogs by LC-MS and showed a significant enhancement of bioavailability, indicating the possibility of using SMEDDS as possible drug carrier for astilbin.     

In vitro evaluation of drug release from self micro-emulsifying drug delivery systems using a biodegradable homolipid from Capra hircus

Self micro-emulsifying drug delivery systems (SMEDDS) are specialized form of delivery systems in which drugs are encapsulated in a lipid base with or without a pharmaceutically acceptable surfactant. In this work, SMEDDS were formulated with a biodegradable homolipid from Capra hircus and Tween 65, and contained lipophilic drug-piroxicam, hydrophilic drug-chlorpheniramine maleate and hydrolipophilic drug-metronidazole. The SMEDDS formulated were evaluated for their drug release and drug content. The drug release studies were conducted in simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and distilled water, representing different pH values. Particle size of the SMEDDS was determined by light microscopy. The results of this study indicated that drug release was affected by the particle size of the SMEDDS. It was found that piroxicam release from the SMEDDS formulated with homolipids from Capra hircus was highest in SIF compared to the other drugs. This method of drug delivery could prove to be a versatile and reliable alternative to conventional drug delivery approaches.     

Comparison of different in vitro tests to assess oral lipid-based formulations using a poorly soluble acidic drug

The aim of the current work was to compare different modern in vitro tests using lipid-based formulations of a weakly acidic BCS II drug. Pure indomethacin and the drug-containing SMEDDS were tested using buffers and biorelevant media in a paddle apparatus, a physiologically motivated flow-through cell and a lipolysis test. The results of these dispersion/precipitation tests showed a generally increased solubility of indomethacin in the SMEDDS compared with the solubility of the pure drug. Only the flow-through test and the dispersion in 0.1 N HCl revealed a superior capacity of one SMEDDS in keeping the drug in solution, whereas the lipolysis test did not show similar formulation discrimination. We conclude that a suitable characterization of SMEDDS comprising an acidic drug should involve a physiologically based flow-through test or a dispersion/precipitation test in acidic environment together with a lipolysis test.     

Early identification of availability issues for poorly water-soluble microbicide candidates in biorelevant media: a case study with saquinavir

In the search for a successful HIV microbicide, many poorly water-soluble antiviral agents are currently being investigated. Unfortunately, solubility and precipitation issues may limit intravaginal concentrations and thus availability of these agents upon application of an aqueous gel formulation. In the present study, we evaluated the in vitro precipitation behavior of the HIV protease inhibitor saquinavir in vaginal and seminal fluid simulants (VFS and SFS). Despite its limited solubility, the mesylate salt of saquinavir enables formulation of sufficiently high concentrations (2.5 mM, i.e. ca. 10⁵-fold in vitro IC₅₀ values) in a standard aqueous vehicle. While saquinavir stays in solution upon dilution with VFS, SFS induces precipitation of saquinavir, resulting in a 5-fold reduced availability and antiviral potency. Inclusion of the solubilizing excipients polyethylene glycol 1000 (12%) and hydroxypropyl-β-cyclodextrin (2.5%) was required to avoid saquinavir precipitation in SFS and to restore the antiviral potency of the formulation. This study illustrates the importance of identifying solubility and precipitation issues of microbicide candidates in biorelevant media and provides a simple in vitro procedure to implement this evaluation in early microbicide development.     

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。     

芒果苷自微乳给药系统的制备及其大鼠体内药动学研究

目的制备芒果苷（mangiferin,MGF）自微乳给药系统（SMEDDS）,并对其进行药动学研究。方法评价系统自微乳化速度,激光散射仪测定乳化后形成微乳粒径的大小及分布情况;以PBS6.8缓冲液为释放介质,考察MGF-SMEDDS的体外释放行为;采用HPLC法测定大鼠血浆药物浓度,考察MGF-SMEDDS的体内吸收情况。结果体系在1min内可乳化完全,乳化后粒径在20nm左右;MGF-SMEDDS在120min的累积释放率可达80%以上;大鼠体内药动学研究结果表明,MGF-SMEDDS达峰时间为0.43h,是MGF的1/7;最大血药浓度为0.93mg/L,是MGF的2.16倍。结论自微乳给药系统可以显著提高MGF的体外释放,改善其药动学性质。     

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.     

An Examination of the Effect of Intestinal First Pass Extraction on Intestinal Lymphatic Transport of Saquinavir in the Rat

Purpose To assess the impact of intestinally based efflux/elimination processes on the extent of intestinal lymphatic transport of saquinavir. To compare the relative effects of co-administration of P-gp/CYP modulators on intestinal lymphatic transport versus systemic bioavailability of saquinavir. Methods A cremophor mixed micelle formulation of saquinavir alone, or co-administered with P-gp/CYP modulators, verapamil, ketoconazole or cyclosporine, was dosed intraduodenally in the mesenteric lymph duct cannulated anaesthetized rat model. Results Co-administration of P-gp/CYP modulators resulted in significant increases in the extent of intestinal lymphatic transport of saquinavir. A comparison of the relative enhancement of lymphatic transport and plasma bioavailability compared to control (i.e. saquinavir alone) reveals a greater effect of verapamil and ketoconazole on the amount of drug transported by the lymphatic route, an observation consistent with a preferential targeting of saquinavir via the intestinal lymphatics. In contrast co-administration of cyclosporine increased both the extent of lymphatic transport (5.5-fold), and systemic bioavailability (4.1-fold). Conclusions Intestinal P-gp/CYP efflux/elimination restricts saquinavir transport via the intestinal lymphatics in the rat. Targeted increases in intestinal lymphatic levels of saquinavir may be achieved by selective inhibition of intestinal P-gp and/or CYP.     

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。     

Development and characterisation of a self-microemulsifying drug delivery systems (SMEDDSs) for the vaginal administration of the antiretroviral UC-781

UC-781 is highly selective and potent against HIV-1. However, its hydrophobic nature (log P 5.1) and lack of aqueous solubility have limited its development as a HIV microbicide. Self-microemulsifying drug delivery systems (SMEDDSs) have been developed to enhance the water solubility and bioavailability of hydrophobic drugs, such as UC781. In this study, we show the development of UC781-loaded SMEDDS and their enhanced release of UC781 from hard gelatine capsules, when compared to UC781 powder only. The majority of antiretrovirals being evaluated as potential HIV microbicides are hydrophobic. Therefore, a SMEDDS formulation offers an alternative approach to enhancing the vaginal absorption of these microbicidal candidates.     

Disposition of lipid-based formulation in the intestinal tract affects the absorption of poorly water-soluble drugs

Solvent Green 3 (SG), a model poorly water-soluble compound, was orally administered to rats with soybean oil emulsion or the Self-microemulsifying drug delivery system (SMEDDS) composed of Gelucire44/14. The bioavailability of SG after oral administration with SMEDDS was 1.7-fold higher than that with soybean oil emulsion. The intestinal absorption of lipid-based formulations themselves was evaluated by the in situ closed loop method. The effect of lipase and bile salt on their absorption was also evaluated. SMEDDS itself was rapidly absorbed in the intestine even in the absence of lipase and bile salt, and the absorption was increased by the addition of lipase and bile salt. On the other hand, no soybean oil emulsion was absorbed in the absence of lipase and bile salt. However, mixed micelle prepared from emulsion by incubating soybean oil emulsion with lipase and bile salt was rapidly absorbed through the intestine. Without lipase and bile salt, SG was not absorbed after administration with soybean oil emulsion. Therefore, we concluded that the degradation of soybean oil emulsion was needed for SG to be absorbed through the intestine. Furthermore, we investigated the intestinal absorption of SG after oral administration to rats whose chylomicron synthesis were inhibited by pretreatment with colchicine. Colchicine completely inhibited the intestinal absorption of SG after administration with each lipid-based formulation, suggesting that SG was absorbed from the intestine via a lymphatic route. Absorption of the dosage formulation should be paid attention when poorly water-soluble drugs are orally administered with lipid-based formulation.