Antimicrobial Activity of Parabens in Submicron Emulsions Stabilized with Lecithin

Antimicrobial efficacy of methyl and propylparaben combination as potential preservatives for submicron emulsions, and the effect of oil and lecithin concentration on the microbial growth were investigated. Parabens were ineffective in standard or doubled concentrations as per pharmacopoeial criteria. Poor growth inhibition and multiplication of reference strains point to protective and growth properties of submicron emulsions. No correlation was observed between oil/lecithin ratio and efficacy of parabens; partitioning of the latter into the oily phase and lipophilic domains could be the reason for such effect. Further studies are necessary to establish a stable and safe composition of such formulations.     

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.     

Development of industrially feasible concentrated 30% and 40% nanoemulsions for intravenous drug delivery

Emulsions for parenteral nutrition loaded with drugs are used for optimized drug delivery, but in case of poorly oil soluble drugs, the injection volume can be too large when using commercial 10–20% oil emulsions. To reduce the injection volume, the feasibility of producing injectable, physically stable concentrated emulsions up to 40% oil content was investigated. Emulsions were made from fish oil, stabilized with egg lecithin, using high-pressure homogenization. Emulsions with oil contents of 10%–40% were investigated to assess basic correlations between increasing oil content, applied production pressures, homogenization cycles and resulting bulk droplet size, content of larger particles, zeta potential, viscosity and short-term stability. The observed correlations showed that in high-pressure homogenization, the contribution of the dispersive effect dominated the coalescence effect at low and Optimum production conditions for 30% and 40% nanoemulsions, i.e. 800 bar and 2 -3 homogenization cycles, were established on lab scale. These production conditions are industrially feasible. The obtained droplet sizes (about 200?nm) and the content of larger droplets were comparable to 10% commercial emulsions of parenteral nutrition, being important for in vivo tolerability and organ distribution. Despite the high oil concentration, the viscosity of the nanoemulsions was sufficiently low for injection. The short-term storage study showed physical stability for 1 month. A concentrated nanoemulsion base formulation from regulatory accepted excipients is now available, ready for loading with drugs.     

Development of industrially feasible concentrated 30% and 40% nanoemulsions for intravenous drug delivery

Emulsions for parenteral nutrition loaded with drugs are used for optimized drug delivery, but in case of poorly oil soluble drugs, the injection volume can be too large when using commercial 10-20% oil emulsions. To reduce the injection volume, the feasibility of producing injectable, physically stable concentrated emulsions up to 40% oil content was investigated. Emulsions were made from fish oil, stabilized with egg lecithin, using high-pressure homogenization. Emulsions with oil contents of 10%-40% were investigated to assess basic correlations between increasing oil content, applied production pressures, homogenization cycles and resulting bulk droplet size, content of larger particles, zeta potential, viscosity and short-term stability. The observed correlations showed that in high-pressure homogenization, the contribution of the dispersive effect dominated the coalescence effect at low and Optimum production conditions for 30% and 40% nanoemulsions, i.e. 800 bar and 2 -3 homogenization cycles, were established on lab scale. These production conditions are industrially feasible. The obtained droplet sizes (about 200?nm) and the content of larger droplets were comparable to 10% commercial emulsions of parenteral nutrition, being important for in vivo tolerability and organ distribution. Despite the high oil concentration, the viscosity of the nanoemulsions was sufficiently low for injection. The short-term storage study showed physical stability for 1 month. A concentrated nanoemulsion base formulation from regulatory accepted excipients is now available, ready for loading with drugs.     

Preparation and Evaluation of 2-(Allylthio)Pyrazine-Loaded Lipid Emulsion with Enhanced Stability and Liver Targeting

To develop 2-(allylthio)pyrazine (2-AP)-loaded lipid emulsion for parenteral administration, various lipid emulsions were prepared with soybean oil, lecithin, and other carriers using homogenization method, and their physical stabilities were investigated by measuring their droplet sizes. The pharmacokinetics and tissue distribution of 2-AP in lipid emulsion after intravenous administration to rats were evaluated compared with 2-AP in solution. 2-AP was lipophilic, sparingly water-soluble, and unstable in aqueous medium. The 2-AP-loaded lipid emulsion composed of 1% of 2-AP, 4% of soybean oil, 4% of lecithin, and 91% of water was physically and chemically stable for at least 8 weeks. It gave significantly faster clearance of 2-AP and higher affinity to the organs, especially the liver, compared with the 2-AP in solution, suggesting that it could selectively deliver 2-AP to the liver. Thus, the lipid emulsion with soybean oil and lecithin could be used as a potential dosage form with the liver-targeting property and enhanced stability of sparingly water-soluble 2-AP.     

“Vitamin E” fortified parenteral lipid emulsions: Plackett–Burman screening of primary process and composition parameters

The objective of this study was to screen the effect of eight formulations and process parameters on the physical attributes and stability of “Vitamin E”-rich parenteral lipid emulsions. Screening was performed using a 12-run, 8-factor, 2-level Plackett–Burman design. This design was employed to construct polynomial equations that identified the magnitude and direction of the linear effect of homogenization pressure, number of homogenization cycles, primary and secondary emulsifiers, pre-homogenization temperature, oil loading, and ratio of vitamin E to medium-chain triglycerides (MCT) in the oil phase on particle size, polydispersity index, short-term stability, and outlet temperature of manufactured emulsions. The viscosity of vitamin E was reduced from 3700 (100%) to 64 mPa.s (30%) by MCT addition. As viscosity is critical for efficient emulsification, vitamin/MCT ratio was the most significant contributor for the stability of emulsions. Particle size increased from 236 to 388 nm, and percentage vitamin remaining emulsified after 48 h dropped from 100 to 73% with increase in vitamin/MCT ratio from 30/70 to 70/30. Significant decrease in particle size and PI, and an increase in outlet temperature were also observed with increase in homogenization pressure and number of homogenization cycles. Emulsifiers and oil loading, however, had insignificant effect on the responses. Overall, stable submicron emulsions at vitamin/MCT ratio of 30/70 could be prepared at 25,000 psi and 25 cycles in ambient conditions. The identification of these parameters by a well-constructed design demonstrated the utility of screening studies in the “Quality by Design” approach to pharmaceutical product development.     

Effect of the addition of oxybenzone or octyl-methoxycinnamate on particle size of submicron emulsions

The formulation of sunscreen products requires understanding of the solubilization of these products in different vehicles to obtain aesthetic preparations and to evaluate long-term stability. For this study, two different ultraviolet (UV) filters were selected: oxybenzone (powder) and octyl-methoxycinnamate (liquid). First, the solubility of these UV filters was tested using a three-component simplex-centroid design strategy. The mixtures were prepared with three oily phases used in this field of cosmetics: liquid paraffin, isopropyl myristate, and coconut oil. A phase diagram method was used to carry out a systematic study of submicron oil-in-water emulsions. Phase diagrams were produced by diluting fixed binary mixtures with water. The surfactant consisted of polyoxyethylene-20-sorbitan monostearate/sorbitan monostearate (50/50, w/w). The oily phase contained equal quantities of each oil studied. From this water/surfactant/oil ternary system, we selected two reference emulsions with receptively 75/5/20 and 68/7/25 proportions. Photon correlation spectroscopy (PCS) was used to investigate the influence of these two UV filters at several concentrations on droplet size and distribution of the oil droplets in the material. All emulsions were stored and checked every month for 6 months.     

Effect of the Addition of Oxybenzone or Octyl-Methoxycinnamate on Particle Size of Submicron Emulsions

The formulation of sunscreen products requires understanding of the solubilization of these products in different vehicles to obtain aesthetic preparations and to evaluate long-term stability. For this study, two different ultraviolet (UV) filters were selected: oxybenzone (powder) and octyl-methoxycinnamate (liquid). First, the solubility of these UV filters was tested using a three-component simplex-centroid design strategy. The mixtures were prepared with three oily phases used in this field of cosmetics: liquid paraffin, isopropyl myristate, and coconut oil. A phase diagram method was used to carry out a systematic study of submicron oil-in-water emulsions. Phase diagrams were produced by diluting fixed binary mixtures with water. The surfactant consisted of polyoxyethylene-20-sorbitan monostearate/sorbitan monostearate (50/50, w/w). The oily phase contained equal quantities of each oil studied. From this water/surfactant/oil ternary system, we selected two reference emulsions with receptively 75/5/20 and 68/7/25 proportions. Photon correlation spectroscopy (PCS) was used to investigate the influence of these two UV filters at several concentrations on droplet size and distribution of the oil droplets in the material. All emulsions were stored and checked every month for 6 months.     

Consideration on the Formulation of Benzoyl Peroxide at Ambient Temperature: Choice of Non-Polar Solvent and Preparation of Submicron Emulsion Gels

ABSTRACT

The aim of this study performed at ambient temperature was first to determine the solubility of benzoyl peroxide in various solvents with a large range of polarity. All these solvents can be used in the dermatological field. Then, using the most suitable solvent, a new drug vehicle submicron oil-in-water emulsion was formulated. Correlation between dielectric constant (ε) and drug solubility in various solvents and different binary mixtures was verified. An original ternary diagram with surfactant–co-surfactant/oil/water was performed at low temperature to determine the regions of submicron emulsions. A dramatic change in the magnitude of benzoyl peroxide solubility occurred above a dielectric constant value of about 20. The solubility of this drug can be enhanced by the replacement of polar solvent by a vehicle of lower dielectric constant. A stable submicron emulsion gel was made with cremophor EL, glycerol, caprilic–capric triglycerides, and water in the proportion of 20–20/35/25, respectively; 1.5% benzoyl peroxide was also added. This submicron emulsion vehicle consisted of oil droplets, with a mean diameter of approximately 100–150 nm, dispersed in a continuous water phase. These studies confirm the potential of benzoyl peroxide incorporation into submicron emulsion gel and the stability of this formulation.     

Consideration on the formulation of benzoyl peroxide at ambient temperature: choice of non-polar solvent and preparation of submicron emulsion gels

The aim of this study performed at ambient temperature was first to determine the solubility of benzoyl peroxide in various solvents with a large range of polarity. All these solvents can be used in the dermatological field. Then, using the most suitable solvent, a new drug vehicle submicron oil-in-water emulsion was formulated. Correlation between dielectric constant (ε) and drug solubility in various solvents and different binary mixtures was verified. An original ternary diagram with surfactant-co-surfactant/oil/water was performed at low temperature to determine the regions of submicron emulsions. A dramatic change in the magnitude of benzoyl peroxide solubility occurred above a dielectric constant value of about 20. The solubility of this drug can be enhanced by the replacement of polar solvent by a vehicle of lower dielectric constant. A stable submicron emulsion gel was made with cremophor EL, glycerol, caprilic-capric triglycerides, and water in the proportion of 20-20/35/25, respectively; 1.5% benzoyl peroxide was also added. This submicron emulsion vehicle consisted of oil droplets, with a mean diameter of approximately 100-150 nm, dispersed in a continuous water phase. These studies confirm the potential of benzoyl peroxide incorporation into submicron emulsion gel and the stability of this formulation.     

Freeze drying of double emulsions to prepare topotecan-entrapping liposomes featuring controlled release

Topotecan-entrapping liposomes were prepared by freeze drying double emulsions with hydrogenated soy phosphatidylcholine, N-(carbonyl-methoxypolyethyleneglycol2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and cholesterol. Different inner aqueous phases of different pH values containing topotecan together with different chemicals, such as citrate and sulfate, were used to modify the physicochemical state of the drug to prepare W1/O/W2 double emulsions that were then freeze dried to obtain dry products. Upon rehydration, the dry products, which were stable for at least 6 months, formed into unilamellar liposomes with a high encapsulation efficiency of up to 80% and a mean diameter below 200 nm. The in vitro release experiments demonstrated that different formulations displayed different drug release properties. Thus, stable submicron unilamellar topotecan-entrapping liposomes can be prepared by freeze drying double emulsions, and the drug release can be successfully controlled by altering the physicochemical state of the incorporated drug.     

不同油相对负载茶多酚的多重乳液稳定性的影响

采用高压均质和高速剪切的方法,观察其制备的初乳对多重乳液稳定性的影响,并研究了大豆油、芥花油、油茶籽油和葵花籽油四种不同的植物油作为油相对多重乳液稳定性的影响,实验结果表明,用高压均质方法制备的初乳能够获得稳定的、外观细腻的多重乳液。四种不同的油相制备的多重乳液在4000r/min,15min的离心条件下不分层;大豆油作为油相制备的多重乳液在室温下放置两个月分层,芥花油、油茶籽油和葵花籽油,在室温下放置三个月不分层。对四种不同油相制备的多重乳液的粒径进行测量,实验结果表明,油茶籽油的D0.1,D0.5和D0.9三个数据的粒径的稳定性比较好。     

Remediation of groundwater contaminated with DNAPLs by biodegradable oil emulsion

Emulsion-based remediation with biodegradable vegetable oils was investigated as an alternative technology for the treatment of subsurface DNAPLs (dense non-aqueous phase liquids) such as TCE (trichloroethylene) and PCE (perchloroethylene). Corn and olive oil emulsions obtained by homogenization at 8000rpm for 15min were used. The emulsion droplets prepared with corn and olive oil gave a similar size distribution (1-10microm) and almost all of initially injected oil, >90%, remained in a dispersed state. In batch experiments, 2% (v/v) oil emulsion could adsorb up to 11,000ppm of TCE or 18,000ppm of PCE without creating a free phase. Results of one-dimensional column flushing studies indicated that contaminants with high aqueous solubility could be efficiently removed by flushing with vegetable oil emulsions. Removal efficiencies exceeded 98% for TCE and PCE with both corn and olive oil emulsions. The results of this study show that flushing with biodegradable oil emulsion can be used for the remediation of groundwater contaminated by DNAPLs.     

A lyophilized etoposide submicron emulsion with a high drug loading for intravenous injection: preparation,evaluation, and pharmacokinetics in rats

Objective: To develop a submicron emulsion for etoposide with a high drug loading capacity using a drug–phospholipid complex combined with drug freeze-drying techniques. Methods: An etoposide–phospholipid complex (EPC) was prepared and its structure was confirmed by X-ray diffraction and differential scanning calorimetry analysis. A freeze-drying technique was used to produce lyophilized etoposide emulsions (LEPE), and LEPE was investigated with regard to their appearance, particle size, and zeta potential. The pharmacokinetic study in vivo was determined by the UPLC/MS/MS system. Results: It showed that EPC significantly improved the liposolubility of etoposide, indicating a high drug loading intravenous emulsion could be easily prepared by EPC. Moreover, the obtained loading of etoposide in the submicron emulsion was 3.0 mg/mL, which was three times higher than that of the previous liquid emulsions. The optimum cryoprotectant was trehalose (15%) in freeze-drying test. The median diameter, polydispersity index, and zeta potential of the optimum formulation of LEPE were 226.1 ± 5.1 nm, 0.107 ± 0.011, and ?36.20 ± 1.13 mV, respectively. In addition, these parameters had no significant change during 6 months storage at 4 ± 2°C. The main pharmacokinetic parameters exhibited no significant differences between LEPE and etoposide commercial solution except for area under the concentration–time curve and clearance. Conclusions: The stable etoposide emulsion with a high drug loading was successfully prepared, indicating the amount of excipients such as the oil phase and emulsifiers significantly decreased following administration of the same dose of drug, effectively reducing the metabolism by patients while increasing their compliance. Therefore, LEPE has a great potential for clinical applications.     

The effect of additives on the treatment of oil-in-water emulsions by vacuum evaporation

A simple batch vacuum evaporation process for the treatment of several oil-in-water (O/W) emulsions is reported. The experiments were carried out with waste emulsions from an industrial copper rolling process and with model emulsions prepared in the laboratory. No detailed information on the formulation of the industrial waste O/W emulsions was available. Several model emulsions were formulated using the same base oil (an 85–15% (w/w) mixture of a synthetic poly-α-olefin and a trimethylol propane trioleate ester, respectively) and one of the three following surfactants: Brij-76 (polyethylene glycol octadecyl ether, non-ionic), CTAB (hexadecyltrimethyl ammonium bromide, cationic), and Oleth-10 (glycolic acid ethoxylate oleyl ether, anionic). Experimental results show a strong influence of operating conditions, such as pressure or bath temperature, on the evaporation performance. As a general trend, the higher the values of these parameters, the higher the pollutant content in the obtained aqueous effluent. The presence of surfactants increase the evaporation rate, especially at low operating vacuum pressures, the solubility of oil molecules in water and the evaporation temperature of model O/W emulsions. Furthermore, COD reductions higher than 99.5% for the treated waste O/W emulsions were achieved.     

Improved oral delivery of paclitaxel following administration in nanoemulsion formulations

Nanoemulsion formulations were designed for enhancing the oral bioavailability of hydrophobic drugs. Paclitaxel was selected as a model hydrophobic drug, which is also a substrate for the P-glycoprotein efflux system. The oil-in-water (o/w) nanoemulsions were formulated with pine nut oil as the internal oil phase, egg lecithin as the primary emulsifier, and water as the external phase. Stearylamine and deoxycholic acid were used to impart positive and negative charge to the emulsions, respectively. Nanoemulsions were prepared by sonication method and characterized for particle size and surface charge. The control and nanoemulsion formulations with tritiated [3H]-paclitaxel were administered orally to female C57BL/6 mice and the distribution of the drug was examined. The formulated nanoemulsions had a particle size range of approximately 90-120 nm (laser diffraction method) and zeta potential values ranging from -56 mV to +34 mV. Following oral administration, a significantly higher concentration of paclitaxel was observed in the systemic circulation when administered in the nanoemulsion relative to control aqueous solution. The absorbed drug was found to be distributed in the liver, kidneys, and lungs. The results of this study suggest that nanoemulsions are promising novel formulations that can enhance the oral bioavailability of hydrophobic drugs, like paclitaxel.     

Formulation, characterization and treatment of metalworking oil-in-water emulsions

The performance of colloidal dispersion systems such as emulsions and suspensions depends greatly on their formulation. A proper characterization of the system oil–water–surfactant for emulsions used in metalworking operations may extend emulsion life and lower process costs. The behavior of an oil-in-water (O/W) emulsion formulated in our laboratory is described in this study. The base oil was selected from a list of mineral, synthetic, animal and vegetable oils according to their tribological properties. Three different surfactants (anionic, cationic and non-ionic) were used to stabilize the emulsion for subsequent O/W emulsion formulation. The effect of concentration of the three emulsifiers on the interfacial properties and emulsion stability is reported. It has been found that the type and concentration of emulsifier are key parameters with respect to O/W emulsion performance. Elastohydrodynamic film thickness measurements and extreme pressure tests were also conducted in order to determine how the O/W emulsion formulation affects its lubricating properties. The disposal of waste O/W emulsions has increasingly become an expensive challenge to industry and their treatment is described in this work using several techniques, such as coagulation, centrifugation, ultrafiltration and vacuum evaporation.     

亚微米石墨在润滑油中的分散行为研究

将石墨稳定地分散到润滑油中，可以有效改善润滑油的润滑性能。本文以天然石墨为原料、研磨获得亚微米级，考察了影响石墨粒子大小对其分散稳定性的影响；采用甲酸、硝酸以及硝化纤维素对石墨表面氧化处理，对比了表面改性后的石墨在润滑油中的分散情况，石墨在润滑油中较稳定分散的条件，经5％硝化纤维素在200℃-400℃范围内氧化的亚微米石墨的表面含有较多的羰基、碳氧键和醚基官能团，它们的存在改善了石墨粒子与润滑油的表面张力和表面化学作用，使其在润滑油中的分散稳定性最佳。     

The inducing effect of lecithin liposome organic template on the nucleation and crystal growth of calcium carbonate

Lecithin liposome was employed as an organic template to control the nucleation and growth of calcium carbonate. The specific interaction of lecithin liposome and calcium ions was investigated by measuring the Zeta potential of the lecithin liposome compound with Ca²⁺. The morphology and polymorphs of the CaCO₃ synthesized in lecithin liposome suspensions of different concentrations were studied. SEM and TEM images showed that spherical particles of CaCO₃, which were synthesized under the effect of lecithin liposome, composed of nano-particles in a hierarchical structure. The polymorph of the calcium carbonate was also modified by lecithin liposome. XRD results indicated lecithin liposome can induce the polymorph of vaterite of calcium carbonate as well.