Preparation and characterization of a submicron lipid emulsion of docetaxel: submicron lipid emulsion of docetaxel

Docetaxel, a widely used anticancer agent, has sparingly low aqueous solubility, thus Tween 80 and ethanol need to be added into its formulation, probably resulting in the toxic effects. In this study, we aimed to utilize submicron lipid emulsions as a carrier of docetaxel to avoid these potential toxic vehicles. Preformulation study was performed for rational emulsions formulation design, including drug solubility, distribution between oil and water, and degradation kinetics. Supersaturated submicron lipid emulsion of docetaxel was prepared by temperature elevation method. Soya oil and Miglyol 812 can incorporate docetaxel up to 1.0% (drug to lipid ratio) and were used as the oil phase of emulsions. The optimal formulation of docetaxel is composed of 10% oil phase, 1.2% soybean lecithin, 0.3% Pluoronic F68, and 0.4 or 0.8 mg/mL docetaxel, with particle size in the nanometer range, entrapment efficiency more than 90%, and is physicochemically stable at 4 and 25 degrees C for 6 months. Animal studies showed that docetaxel emulsion has significantly higher area under the curve (AUC) and C(max) in rats compared to its micellar solution. The results suggested that the submicron lipid emulsion is a promising intravenous carrier for docetaxel in place of its present commercially available docetaxel micellar solution with potential toxic effects.     

Preparation and Characterization of a Submicron Lipid Emulsion of Docetaxel: Submicron Lipid Emulsion of Docetaxel

Docetaxel, a widely used anticancer agent, has sparingly low aqueous solubility, thus Tween 80 and ethanol need to be added into its formulation, probably resulting in the toxic effects. In this study, we aimed to utilize submicron lipid emulsions as a carrier of docetaxel to avoid these potential toxic vehicles. Preformulation study was performed for rational emulsions formulation design, including drug solubility, distribution between oil and water, and degradation kinetics. Supersaturated submicron lipid emulsion of docetaxel was prepared by temperature elevation method. Soya oil and Miglyol 812 can incorporate docetaxel up to 1.0% (drug to lipid ratio) and were used as the oil phase of emulsions. The optimal formulation of docetaxel is composed of 10% oil phase, 1.2% soybean lecithin, 0.3% Pluoronic F68, and 0.4 or 0.8 mg/mL docetaxel, with particle size in the nanometer range, entrapment efficiency more than 90%, and is physicochemically stable at 4 and 25°C for 6 months. Animal studies showed that docetaxel emulsion has significantly higher area under the curve (AUC) and C_max in rats compared to its micellar solution. The results suggested that the submicron lipid emulsion is a promising intravenous carrier for docetaxel in place of its present commercially available docetaxel micellar solution with potential toxic effects.     

Encapsulation Study of 6-Methylprednisolone in Lipid Microspheres

The search for new pharmaceutical forms that provide greater security and efficiency is one of the main research activities of pharmaceutical technology. This paper concerns a detailed study of the encapsulation of a glucoconicoid with anti-inflammatory action (6-methylprednisolone) in lipid microspheres, one of the systems used for the transport and delivery of lipid-soluble-type drugs. The method used, in common with previous experiments, was that of the solubilization of the constituents of the oil phase (refined soybean oil, soybean lecithin, cholesterol, and the active agent) and, separately, of the aqueous phase of the emulsion (Tween 80, glycerol, and distilled water). The two phases were then mixed by mechanical shaking, and the micelles were homogenized and filtered through membranes of 1.20-μm pore diameter. To determine the percentage encapsulated of the active agent, the first step was the separation of the encapsulated fraction from the free fraction in the medium by molecular exclusion chromatography or filtration in gel. A dextrose (Sephadex G-50 fine) gel was used for the absorbent or stationary phase, and distilled water was used for the eland, or mobile phase. me determination of the free glucocorticoid in the hydroethanol solution by ultraviolet spectrophotometry at 243 nm permits us to calculate the percentage taken by the microspheres. The formula composed of soybean oil and lecithin in the ratio 1:1.1 (w/w), cholesterol (0.50 g/100 ml), Tween 80 (0.25 g/100 ml), and glycerol (0.63 g/100 ml) produced the greatest quantity of encapsulated active agent: 84.91 ± 4.45%.     

Characterization and body distribution of beta-elemene solid lipid nanoparticles (SLN)

Solid lipid nanoparticles (SLN) containing β-elemene, a volatile oil used for the treatment of cancer, were prepared by the method combining probe sonication and membrane extrusion. Effects of the formulations and procedures on the characteristics of SLN were investigated. Body distribution of β-elemene SLN in rats after intravenous administration was compared with that of the commercial emulsion. The results showed that dispersing the surfactant in the melted lipid matrix could obtain smaller particles than that dispersing in the water phase. Increasing the ratio of monostearin in the lipid matrix or the concentration of surfactant reduced the mean volume size of the SLN. Optimized formulation was composed of monostearin and precirol ATO 5 at a mass ratio of 3:7, which was quite stable for 8 months at room temperature. In vitro release of β-elemene from the SLN was slow and stable without obvious burst release and was found to follow the Higuich equation. After intravenous administration, the β-elemene levels after 5 min injection of SLN formulation were 1.5, 2.9, and 1.4 times higher than those of β-elemene emulsion in liver, spleen, and kidney, respectively, while the concentrations of β-elemene were decreased 30% in heart and lung. Therefore, the SLN containing β-elemene might be an attractive candidate for the treatment of liver cancer.     

Preparation,characterization, cellular uptake and evaluation in vivo of solid lipid nanoparticles loaded with cucurbitacin B

In this work, solid lipid nanoparticles loaded with cucurbitacin B (Cu B-SLNs) were prepared. It was found that the concentration of poloxamer 188 and soybean lecithin had effects on the mean particle size and size distribution. The zeta potentials were around ?33 mV. In vitro release studies showed a sustained release after a burst release. Internalization of Cu B into HepG2 cells could be enhanced by the encapsulation of SLN matrix. The IC50 values of Cu B-SLNs were lower than that of Cu B solution. Both free Cu B and Cu B-SLNs had effectively inhibited the tumor growth and displayed a dose-dependent anti-tumor efficacy. Cu B-SLNs at a dose of 0.11?mg/kg produced the greatest anti-tumor effects (53.3%), which was significant higher than Cu B solution (31.5%, p < 0.05). Cu B-SLNs showed a longer MRT in vivo. The AUC of Cu B-SLNs for tumor increased 3.5 –fold when compared to Cu B solution. The targeting efficiency of Cu B-SLNs was 1.94 times higher in liver as compared to that of Cu B solution. These results indicated that Cu-B SLNs could passively target the tumor with EPR effect, improve the therapeutic efficacy of Cu B, and reduce the doses.     

Chemical stability of teniposide in aqueous and parenteral lipid emulsions

The purpose of this study was to investigate the degradation kinetics of teniposide in lipid emulsion and aqueous solution. The chemical stability of teniposide in lipid emulsion and aqueous solution at various pH values and temperatures was monitored by high-performance liquid chromatography. In addition, the viscosities of emulsion at different temperatures were investigated. The degradation of teniposide both in emulsion and in aqueous solution was shown to follow pseudo-first-order degradation kinetics. The t (1/2) values of teniposide lipid emulsion (TLE) and the aqueous solution were 80 and 2.6 days at 10 degrees C, respectively. Under the most stable pH range of 6.0-6.5, stability of teniposide in the emulsion increased more than 30-fold compared with that in aqueous solution. Furthermore, there was a difference between the shelf life of TLE actually measured (29 days) at 10 degrees C and the one deduced (15 days) from the degradation data of high temperatures by Arrhenius equation. It could be hypothesized that the difference was due to a slower diffusion of teniposide from oil phase to aqueous phase at the lower temperatures, which would be a speed-limited process in the degradation of TLE. The results of viscosity test confirmed the presumption.     

Chemical Stability of Teniposide in Aqueous and Parenteral Lipid Emulsions

The purpose of this study was to investigate the degradation kinetics of teniposide in lipid emulsion and aqueous solution. The chemical stability of teniposide in lipid emulsion and aqueous solution at various pH values and temperatures was monitored by high-performance liquid chromatography. In addition, the viscosities of emulsion at different temperatures were investigated. The degradation of teniposide both in emulsion and in aqueous solution was shown to follow pseudo-first-order degradation kinetics. The t_1/2 values of teniposide lipid emulsion (TLE) and the aqueous solution were 80 and 2.6 days at 10°C, respectively. Under the most stable pH range of 6.0–6.5, stability of teniposide in the emulsion increased more than 30-fold compared with that in aqueous solution. Furthermore, there was a difference between the shelf life of TLE actually measured (29 days) at 10°C and the one deduced (15 days) from the degradation data of high temperatures by Arrhenius equation. It could be hypothesized that the difference was due to a slower diffusion of teniposide from oil phase to aqueous phase at the lower temperatures, which would be a speed-limited process in the degradation of TLE. The results of viscosity test confirmed the presumption.     

Characterization and Body Distribution of β-Elemene Solid Lipid Nanoparticles (SLN)

ABSTRACT

Solid lipid nanoparticles (SLN) containing β-elemene, a volatile oil used for the treatment of cancer, were prepared by the method combining probe sonication and membrane extrusion. Effects of the formulations and procedures on the characteristics of SLN were investigated. Body distribution of β-elemene SLN in rats after intravenous administration was compared with that of the commercial emulsion. The results showed that dispersing the surfactant in the melted lipid matrix could obtain smaller particles than that dispersing in the water phase. Increasing the ratio of monostearin in the lipid matrix or the concentration of surfactant reduced the mean volume size of the SLN. Optimized formulation was composed of monostearin and precirol ATO 5 at a mass ratio of 3:7, which was quite stable for 8 months at room temperature. In vitro release of β-elemene from the SLN was slow and stable without obvious burst release and was found to follow the Higuich equation. After intravenous administration, the β-elemene levels after 5 min injection of SLN formulation were 1.5, 2.9, and 1.4 times higher than those of β-elemene emulsion in liver, spleen, and kidney, respectively, while the concentrations of β-elemene were decreased 30% in heart and lung. Therefore, the SLN containing β-elemene might be an attractive candidate for the treatment of liver cancer.     

An inexpensive route to prepare mesoporous hollow silica microspheres using W/O ethanol/edible soybean oil macroemulsion as the template

Mesoporous hollow silica microspheres were prepared by using W/O emulsion consisting of ethanol droplets as a template in edible soybean oil. Ethanol droplets containing ammonia solution were generated by employing ultrasonication in pure soybean oil. The droplets were colloidally stabilized by means of a cationic surfactant, cetyltrimethylammonium bromide (CTAB). Later on, another proportion of soybean oil dissolving tetraethyl orthosilicate (TEOS) was added to the W/O emulsion. The sol-gel reaction of TEOS was achieved only at the interface of the emulsion droplets, resulting in hollow silica microspheres. After washing the resultant with acetone, mesoporous hollow silica microspheres were simply obtained. Throughout this liquid template-based process, mesoporous hollow silica microspheres can be inexpensively synthesized without employing solid templates.     

Studies on the encapsulation of oxymatrine into liposomes by ethanol injection and pH gradient method

Oxymatrine is the major active alkaloid constituent extracted from traditional Chinese herb medicine Sophora flavescens Ait (Kushen) and Sophora alopecuroides (Kudouzi). In recent years, oxymatrine had been found to posses remarkable anti-hepatic activity and has been used for treating hepatitis B in clinical therapy in China. In this study, we attempted to entrap oxymatrine into liposomes to facilitate the delivery of oxymatrine to the liver and enhance the therapeutic efficiency for hepatitis. Preformulation investigation was performed to obtain the drug physicochemical properties such as solubility, pKa, and logP for rational liposomes preparation design. Liposomes were prepared with soybean lecithin by ethanol injection and pH gradient loading methods. At the same time the factors affecting the entrapment efficiencies were investigated and compared. Ethanol injection method yielded liposomes with entrapment efficiency less than 20%. The lipid composition and aqueous medium had some effects on entrapment efficiency. However, liposomes could be produced with entrapment efficiency above 50% by pH gradient method. The internal pH buffer capacity, the lipid composition, and drug-to-lipid ratio greatly influenced the entrapment efficiency, while the incubation temperature had almost no effect on entrapment efficiency in the active loading procedure.     

改善水性光油防水性的研究

目的为了改善水性光油的防水性。方法通过乳液混拼技术将软硬乳液混合,并以机械共混的方法将蜡乳液、水溶性树脂溶液加入到混拼乳液中。结果软硬乳液的质量比为8∶2时,涂膜的表面吸水量最小,当混拼乳液中加入蜡乳液和水溶性树脂溶液时,涂膜的表面吸水量都会降低。结论软硬乳液混拼可以有效提高水性光油的防水性,加入蜡乳液和水溶性树脂溶液也可以提高水性光油的防水性。     

Studies on the Encapsulation of Oxymatrine into Liposomes by Ethanol Injection and pH Gradient Method

ABSTRACT

Oxymatrine is the major active alkaloid constituent extracted from traditional Chinese herb medicine Sophora flavescens Ait (Kushen) and Sophora alopecuroides (Kudouzi). In recent years, oxymatrine had been found to posses remarkable anti-hepatic activity and has been used for treating hepatitis B in clinical therapy in China. In this study, we attempted to entrap oxymatrine into liposomes to facilitate the delivery of oxymatrine to the liver and enhance the therapeutic efficiency for hepatitis. Preformulation investigation was performed to obtain the drug physicochemical properties such as solubility, pKa, and logP for rational liposomes preparation design. Liposomes were prepared with soybean lecithin by ethanol injection and pH gradient loading methods. At the same time the factors affecting the entrapment efficiencies were investigated and compared. Ethanol injection method yielded liposomes with entrapment efficiency less than 20%. The lipid composition and aqueous medium had some effects on entrapment efficiency. However, liposomes could be produced with entrapment efficiency above 50% by pH gradient method. The internal pH buffer capacity, the lipid composition, and drug-to-lipid ratio greatly influenced the entrapment efficiency, while the incubation temperature had almost no effect on entrapment efficiency in the active loading procedure.     

Lipid emulsions as a potential delivery system for ocular use of azithromycin

Objective: To obtain stable positively charged Azithromycin (AZI) emulsions with a mean droplet size of 120 nm for the treatment of eye diseases. Methods: The emulsions were obtained by using a suitable homogenization process. The physical stability was monitored by measuring the particle size, zeta potential, and visible appearance. The drug entrapment efficiency was measured by both ultracentrifugation and ultrafiltration methods. Compared with a phosphate solution of AZI, the stability profiles of AZI in lipid emulsions at various pH values were monitored by high-performance liquid chromatography. A pharmacokinetic study was performed to determine the drug levels in rabbit tear fluid using Ultra-performance liquid Chromatography–mass spectrometry. Results: Almost all the AZI in the lipid emulsion was distributed in the oil phase and small unilamellar liposomes without contact with water, thereby avoiding hydrolysis. The elimination of the AZI lipid emulsions in tear fluid was consistent with the basic linear pharmacokinetic characteristics. The AUC_0-t of the AZI lipid emulsion (1%, w/v) and aqueous solution drops (1%, w/v) was 1873.58 ± 156.87 and 1082.46 ± 179.06 μgh/ml respectively. Conclusions: This study clearly describes a new formulation of AZI lipid emulsion for ocular administration, and lipid emulsions are promising vehicles for ophthalmic drug delivery.     

Semisolid matrix filled capsules: an approach to improve dissolution stability of phenytoin sodium formulation

Seven semisolid fill bases were selected for the formulation of 24 capsule formulations, each containing 100 mg of phenytoin sodium. The fill materials were selected based on the water absorption capacity of their mixtures with phenytoin sodium. The fill matrices included lipophilic bases (castor oil, soya oil, and Gelucire (G) 33/01), amphiphilic bases (G 44/14 and Suppocire BP), and water-soluble bases (PEG 4000 and PEG 6000). The drug:base ratio was 1:2. Excipients such as lecithin, docusate sodium, and poloxamer 188 were added to some formulations. The dissolution rate study indicated that formulations containing lipophilic and amphiphilic bases showed the best release profiles. These are F4 (castor oil-1% docusate sodium); F10 (castor oil-3% poloxamer 188); F14 (G33/01-10% lecithin); F17 (G33/01-1% docusate sodium), and F20 (Suppocire BP). Further, the dissolution stability of the five formulations above was assessed by an accelerated stability study at 30°C and 75% RH using standard Epanutin capsules for comparison. The study included the test and standard capsules either packed in the container of marketed Epanutin capsules (packed) or removed from their outer pack (unpacked). Release data indicated superior release rates of castor oil based formulations (F4 and F10) relative to standard capsules in both the unpacked and packed forms. For instance, the extent of drug release at 30 min after 1 month was 91% for F4 and F10 and 20% for standard capsules. Drug release from packed capsules after 6 months storage was 88% for both formulations F4 and F10 and 35% for standard capsules. In conclusion, the pharmaceutical quality of phenytoin sodium capsules can be improved by using a semisolid lipophilic matrix filled in hard gelatin capsules.     

Triptolide loaded solid lipid nanoparticle hydrogel for topical application

Triptolide (TP) has been shown to have anti-inflammatory, antifertility, antineoplastic, and immunosuppressive activity. However, its clinical usage is limited to some extent due to its poor water solubility and toxicity. In order to use innovative ways to administer TP and to overcome or alleviate its disadvantages, controlled-release delivery systems such as solid lipid nanoparticle(SLN(s)) have been developed. In the present paper we describe the preparation and some characterization of specialized delivery systems for TP. The transdermal delivery and anti-inflammatory activity were also evaluated. The results indicated that SLN could serve as an efficient promoter of TP penetrating into skin. Furthermore, different formulations were optimized in this study. The best formulation of SLN, consisted of tristearin glyceride, soybean lecithin, and PEG400MS, with a particle size of 123 ± 0.9 nm, polydispersity index (PI) of 0.19, and zeta potential of - 45 mV. When this SLN dispersion was incorporated into hydrogel, the nanoparticulate structure was maintained, and aggregation and gel phenomena of the particle could be avoided. The cumulative transdermal absorption rate in 12 h was 73.5%, whereas the conventional TP hydrogel was 45.3%. The anti-inflammatory effect is over two-fold higher than that of conventional TP hydrogel. Moreover, this SLN hydrogel consists of pharmaceutically acceptable ingredients, such as soybean lecithin and lipid, and the nanoparticle can improve safety and minimize the toxicity induced by TP.     

Silicone emulsion-enhanced recovery of chlorinated solvents: batch and column studies

Batch and column experiments were conducted to investigate the feasibility of flushing with silicone oil emulsion for the removal of chlorinated solvents, including trichloroethylene (TCE), perchloroethylene (PCE) and 1,2-dichlorobenzene (DCB). In the batch experiments, solubilization potentials of emulsion and effects of surfactants as additives were examined. The emulsion prepared with 2% (v/v) silicone oil could solubilize 90.7% of 10,000 ppm TCE, 97.3% of 4000 ppm PCE and 99.7% of 7,800 ppm DCB. Results of one-dimensional column studies indicated that aqueous solubility and sorption of contaminants determined the flushing efficiency. The addition of surfactants below their critical micelle concentration (CMC) did not affect the removal of chlorinated solvents in batch and column experiments. The results of this study show that flushing with oil-based emulsion can be applied to treat the chlorinated solvents.     

Silica hollow spheres with nano-macroholes like diatomaceous earth

Artificial synthesis of hollow cell walls of diatoms is an ultimate target of nanomaterial science. The addition of some water-soluble polymers such as sodium polymethacrylate to a solution of water/oil/water emulsion system, which is an essential step of the simple synthetic procedure of silica hollow spheres (microcapsules), led to the formation of silica hollow spheres with nano-macroholes (>100 nm) in their shell walls, the morphologies of which are analogous to those of diatom earth.     

Selection of design parameters and optimization of operating parameters of soybean oil-based bulk liquid membrane for Cu(II) removal and recovery from aqueous solutions

The objectives of this work were to select suitable design parameters and optimize the operating parameters of a soybean oil-based bulk liquid membrane (BLM) for Cu(II) removal and recovery from aqueous solutions. The soybean oil-based BLM consists of an aqueous feed phase (Cu(II) source), an organic membrane phase (soybean oil (diluent), di-2-ethylhexylphosphoric acid (D2EHPA) (carrier) and tributylphosphate (phase modifier)) and an aqueous stripping phase (sulfuric acid solution (H(2)SO(4))). Effects of design parameters (stirring condition and stripping/membrane to feed/membrane interface area ratio) of soybean oil-based BLM on the Cu(II) removal and recovery from aqueous solutions were investigated and the suitable parameters were selected for further studies. Optimization of the operating parameters (D2EHPA concentration, H(2)SO(4) concentration, stirring speed, temperature and operating time) of soybean oil-based BLM for maximum percentage (%) recovery of Cu(II) was then conducted using Response Surface Methodology and the optimum parameters were determined. A regression model for % recovery was developed and its adequacy was evaluated. The experimental % recovery obtained under the optimum operating conditions was compared with the predicted one and they were found to agree satisfactorily with each other.     

Self-assembled core-shell vascular-targeted nanocapsules for temporal antivasculature and anticancer activities

A biocompatible core-shell nanocapsule is fabricated to target tumor vascular endothelial cells where it releases anti-angiogenesis and anticancer drugs sequentially. The fabrication of the core-shell nanocapsule is accomplished through a robust double self-assembly procedure: the hydrophobic polymeric core is first precipitated to encapsulate a poorly water-soluble anticancer drug paclitaxel (PTX) with the assistance of lecithin and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)2000] (DSPE-PEG) self-assembled in aqueous phase. Another lipid layer self-assembled around the above hydrophobic core is formed to load a second drug combretastatin A4 (CA4) as a vascular disrupting agent in the lipid layer. The lipid layer serves both as a depot for CA4, as well as a molecular fence to sustain the release of PTX from the polymeric core. The size of the resultant nanocapsule can be fine-turned by slightly adjusting the preparation conditions from several tens of nanometer to one hundred nanometers. The uptake of this nanocapsule by human umbilical vein endothelial cells (HUVEC) is efficient, and the two loaded drugs maintain their respective therapeutic potency. The time-dependent sequential release of these two drugs over a time difference of 36 h results in temporal ablation of endothelial cells and cancer cells. This self-assembled delivery system could serve as a universal prototype that can be applied for other combinatorial temporal drug delivery.     

紫杉醇静脉注射脂肪乳配方及制备工艺的考察

考察三种紫杉醇脂肪乳配方的时间及温度稳定性、制备工艺对其粒径的影响以及测定脂肪乳中紫杉醇的浓度,光子相关光谱法(PCS)测试结果表明,以单一F-68作为乳化剂的脂肪乳粒径为235±15nm,PDI为0.2±0.1,Zeta电位为-35±10mV,在室温(25℃)下放置60d粒径变化不明显,较含有92%、98%蛋黄卵磷脂的脂肪乳稳定;随着高压均质压力升高,脂肪乳的粒径减小,高压均质循环次数对粒径几乎无影响;4000r/min条件下离心15min不分层,说明脂肪乳具有良好的离心稳定性。高效液相色谱(HPLC)结果表明,脂肪乳中紫杉醇的浓度为0.291mg/mL,提高初始加入量后浓度可达0.673mg/mL。