Formulation and physical characterization of water-in-oil microemulsions containing long- versus medium-chain glycerides

Stable self-emulsifying water-in-oil (w/o) microemulsions of extremely small particle size (5–30 nm) and consisting of an oil, a blend of a low and high HLB surfactants and an aqueous phase, have been developed using commercially available and pharmaceutically acceptable components. Their formation was monitored by the corresponding pseudo-ternary phase diagram. The oil phase contained long- or medium-chain triglycerides, and mono-/diglycerides or sorbitan esters (low HLB surfactants). Polysorbate 80 (Tween 80) was used as a high HLB surfactant. Microemulsions were readily prepared by admixing appropriate quantities of the various components with gentle hand-mixing or stirring to ensure thorough mixing. In the case of microemulsions incorporating long-chain glycerides and/or sorbitan esters, high temperature (40–60°C) was used to reduce viscosity and solubilize all components during the formation of microemulsions. Limited levels of aqueous phase (< 10%, w/w) can be solubilized within w/o microemulsions incorporating long-chain glycerides and/or sorbitan esters. Microemulsions containing medium-chain glycerides (mono-/di-/triglycerides) can be formulated at ambient temperature and can solubilize aqueous phase up to 40% (w/w). The conductance, viscosity, refractive index, density and mean particle diameter of a typical w/o microemulsion incorporating medium-chain glycerides (Captex 355/Capmul MCM/Tween 80/saline, 65/22/10/3, % w/w), were: 0.540 μmhos/cm, 56.7 cP, 1.449, 0.9677, and 15.2 ± 4.1 nm (polydispersity of 0.153), respectively. The corresponding values of a w/o microemulsion incorporating long-chain triglycerides and monoglycerides (Soybean oil/Arlacel 186/Tween 80/saline, 65/22/10/3, % w/w) were: 0.177 μmhos/cm, 125.1 cP, 1.471, 0.9010, and 10.3 ± 2.5 nm (polydispersity of 0.114), respectively. Several water-soluble molecules/peptides of different molecular size and charge have been formulated in these w/o microemulsions at pharmacological relevant levels. These systems are discussed in terms of their drug delivery potential.     

POSSIBLE ROLE OF GLUTATHIONE IN PREVENTION OF ACETAMINOPHEN-INDUCED HEPATOTOXICITY ENHANCED BY FISH OIL IN MALE WISTAR RATS

It has been reported that fish oil protects the rat liver against acetaminophen (APAP) induced toxicity; however, this finding is controversial. The present study was undertaken to investigate the effects of fish oil-enriched diet on APAP-induced liver injury in Wistar rats. Rats were fed a diet supplemented with either 8% fish oil or 8% corn oil, or standard rat feed for 6 wk. After an overnight fast, rats in each group were given either 2 g/kg APAP or saline orally. Our findings showed that APAP increased serum alanine aminotransferase (ALT) and that this rise was potentiated in the presence of dietary fat. Further fish oil ingestion increased the glutathione (GSH) content in rat liver; however, this was not effective in protecting liver from APAP-induced toxicity. Data suggest that GSH may be necessary to detoxify APAP metabolites, which are known to induce hepatotoxicity but are increased by dietary fat.     

Final report on the safety assessment of Peanut (Arachis hypogaea) Oil, Hydrogenated Peanut Oil, Peanut Acid, Peanut Glycerides, and Peanut (Arachis hypogaea) Flour

Peanut (Arachis Hypogaea) Oil is the refined fixed oil obtained from the seed kernels of Arachis hypogaea. Hydrogenated Peanut Oil, Peanut Acid, and Peanut Glycerides are all derived from Peanut Oil. Peanut Flour is a powder obtained by the grinding of peanuts. The oils and glycerides function in cosmetic formulations as skin-conditioning agents. The acid functions as a surfactant-cleansing agent, and the flour functions as an abrasive, bulking agent and/or viscosity-increasing agent. In 1998, only Peanut Oil and Hydrogenated Peanut Oil were reported in use. When applied to the skin, Peanut Oil can enhance the absorption of other compounds. Hepatic changes were noted at microscopic examination of rats fed diets containing 15% edible Peanut Oil for 28 days, although no control group was maintained and the findings were also noted in rats fed fresh corn oil. United States Pharmacopeia (USP)-grade Peanut Oil was considered relatively nonirritating when injected into guinea pigs and monkeys. Technical-grade Peanut Oil was moderately irritating to rabbits and guinea pigs and mildly irritating to rats following dermal exposure. This same oil produced reactions in < or = 10% of 50 human males. Peanut Oil was not an ocular irritant in rabbits. Peanut Oil, either "laboratory expressed" or extracted using a food-grade solvent, was not carcinogenic to mice. Peanut Oil exerted anticarcinogenic activity when tested against known carcinogens. Peanuts are the food most likely to produce allergic and anaphylactic reactions. The major allergen is a protein that does not partition into Peanut Oil, Hydrogenated Peanut Oil, Peanut Acid, and Peanut Glycerides. Aflatoxins can be produced in stored agricultural crops such as peanuts, but do not partition into the oils, acids, or glycerides. Manufacturers were cautioned to make certain that the oils, acids, and glycerides are free of aflatoxins and protein. Formulators were cautioned that the oils, acids, or glycerides may enhance penetration and can affect the use of other ingredients whose safety assessment was based on their lack of absorption. The available studies on Peanut Oil supported the conclusion that Peanut Oil, Hydrogenated Peanut Oil, Peanut Acid, and Peanut Glycerides are safe for use in cosmetic formulations. Peanut (Arachis Hypogaea) Flour, however, is sufficiently different from the above ingredients such that its safety can not be supported by studies using the oil. The additional data needed for Peanut (Arachis Hypogaea) Flour are (1) concentration of use; (2) chemical specifications (i.e., aflatoxin and protein levels); (3) method of preparation; and (4) contact urticaria and dermal sensitization at concentration of use. Although data on aflatoxin levels are sought, it is expected that concentrations of aflatoxin should comply with U.S. government stipulations. Absent the additional data, it was concluded that the available data are insufficient to support the safety of Peanut (Arachis Hypogaea) Flour for use in cosmetic products.     

姥鲨鱼肝油乳抗肿瘤作用的研究

使用30%姥鲨肝油乳剂在15-30ml/kg的剂量范围内,通过对S_(180)、HePA、Lewis等三种小鼠移植性实体型肿瘤实验,最高抑制率分别为58%、55%、49%。     

Inhalation versus oral administration of acetone: effect of the vehicle on the potentiation of CCl4-induced liver injury

Acetone potentiation of liver injury is greater when corn oil is given with acetone 18 h prior to a challenge with CCl4. This study aimed to further characterize the effects of the vehicle used to administer acetone on the severity of acetone-potentiated CCl4-induced liver injury. The more severe acetone-potentiated liver injury observed when corn oil was the vehicle does not seem to be due to greater liver acetone concentrations. When corn oil was used as the vehicle to administer acetone, liver and blood CCl4 concentrations were not significantly different from those where water was the vehicle. Therefore the relationship between blood or liver acetone concentration and plasma ALT activity for orally-administered acetone was modified by corn oil. Liver triglyceride concentration measured 18 h after a gavage of corn oil was significantly higher than that for the water-treated group. A direct effect of corn oil on liver, in particular a promotion of the propagation phase in the lipid peroxidation process induced by CCl4, is proposed to explain the increase in acetone-potentiated CCl4-induced liver injury.     

Effects of dietary lipids on whole-body retention and organ distribution of organic and inorganic mercury in mice.

The effect has been investigated of dietary lipids on the whole-body retention and organ distribution of organic and inorganic mercury in mice. A single oral dose of methylmercury chloride or mercuric chloride labelled with 203Hg was given to female NMRI mice fed semi-synthetic diets containing varying amounts (5, 10, 20 or 50%) of energy derived from lipid (coconut oil, soya oil, or cod liver oil). The whole-body retention and relative organ distribution of mercury depended on diet composition. Thus, a significant reduction of the whole-body retention of mercury was seen in mice fed a diet containing 50% cod liver oil compared with mice fed a diet containing 50% coconut oil. After oral administration of mercuric chloride the relative deposition of mercury in the kidneys increased while that in the liver decreased with increasing concentrations of soya oil or coconut oil in the diet. The whole-body retention of mercury after treatment with methylmercury chloride was significantly decreased in mice fed cod liver oil compared with mice fed coconut oil; there was no difference between mice fed cod liver oil and those fed soya oil. The relative disposition of mercury was significantly higher in all organs of mice fed a diet containing 20% energy from cod liver oil compared with mice fed a diet containing 20% energy from soya oil. The present study demonstrates that diet composition is of major importance to the toxicokinetics of methylmercury and mercuric mercury.     

Formulation of self-nanoemulsifying drug delivery systems containing monoacyl phosphatidylcholine and Kolliphor® RH40 using experimental design

 The development of self-nanoemulsifying drug delivery systems (SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil (Kolliphor? RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80 (LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components).The investigated SNEDDS comprised of long-chain or medium-chain glycerides (40% to 75%), Kolliphor? RH40 (5% to 55%), LPC (0 to 40%) and ethanol (0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200 nm. The use of mediumchain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor? RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor? RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor? RH40 as a reference for formulation developers.     

月见草油乳剂的生理药物动力学模型探讨

本文考察了大鼠按9ml/kg静注2号月见草油乳剂后,血浆、心、肝、脾、肺、肾、胃肠道、脑、肌肉中γ-亚麻酸浓度变化;大鼠静注一负荷剂量4.5ml/kg 1号月见草油乳剂后,再以4.5ml/kg·h静脉输注至稳态,测定γ-亚麻酸组织-血浆表观分配系数。在此基础上,进一步设计了一个血流限速生理药物动力学模型,在IBM微型计算机上用MAXSIM程序模拟γ-亚麻酸在大鼠体内的分布与清除,模型包括肝、肾、胃肠道、肌肉和血浆。离心过滤法测得γ-亚麻酸血浆中游离分数为0.459。     

鱼肝油中脂肪酸的气相色谱及气相色谱-质谱分析

目的 采用气相色谱法（GC）结合气相色谱-质谱（GC-MS）联用技术,对3种不同来源共26批鱼肝油样品中的脂肪酸成分进行测定。方法 通过氢氧化钾-甲醇碱催化法对鱼肝油样品进行甲基衍生化预处理,选用极性毛细管柱对样品中的衍生化产物脂肪酸甲酯进行分离,后经气相色谱仪-氢火焰离子化检测器（GC-FID）和气相色谱-质谱（GC-MS）联用仪进行分析检测。利用对照品定位法结合NIST谱库检索准确鉴定出棕榈酸、棕榈油酸、油酸、亚油酸、二十碳五烯酸（eicosapentaenoic acid,EPA）和二十二碳六烯酸（docosahexaenoic acid,DHA）等14种脂肪酸,并通过面积归一化法对这14种脂肪酸进行定量分析。结果 这14种脂肪酸在国内鱼肝油中的含量与模拟天然鱼肝油和进口鱼肝油样品中的含量存在较大差异。其中,EPA和DHA等脂肪酸在模拟天然鱼肝油和进口鱼肝油样品中的含量远高于其在国内鱼肝油样品中的含量,而亚油酸在国内鱼肝油样品中的含量却高达44%以上,10倍于其在另外2种鱼肝油样品中的含量。结论 不同来源的鱼肝油样品中的脂肪酸成分不尽相同,可根据脂肪酸的组成区别鱼肝油样品中是否添加天然鱼肝油成分。