The pharmacokinetics of water-in-oil-in-water-type multiple emulsion of a new tacrolimus formulation

We developed a water-in-oil-in-water (W/O/W)-type multiple emulsion of a new tacrolimus formulation. A potential approach to avoid the complications of systemic immunosuppression and simultaneously enhance immunosuppressive efficacy is to deliver immunosuppressive agents locally to the site of the target organs. The W/O/W emulsion is dispersed oil drops containing smaller water droplets that allow the delivery of drugs preferentially to the reticuloendothelial system (RES). Since the liver and the spleen are primary components of the RES, and the brain and the kidney have a poor RES, we hypothesized that a W/O/W emulsion of tacrolimus would prossess the pharmacokinetic benefits of local immunosuppression. We evaluated this hypothesis in a rat model. The tacrolimus levels of whole blood, the liver, spleen, brain, and kidney in rats given intravenous emulsions of tacrolimus (W/O/W group) were compared with a group administered tacrolimus alone (T group). There were no significant differences between the pharmacokinetic parameters of W/O/W group and T group based on whole blood data. However, the W/O/W group had significantly decreased tacrolimus levels in the brain and kidney, and significantly increased levels in the liver and spleen compared with the T group. These data suggest that the W/O/W emulsion is applicable as an intravenous drug carrier for local immunosuppression.     

Permanganate oxidation of oleic acid using emulsion technology

Free oleic acid is emulsified in water and oxidized using potassium permanganate, to azelaic and pelargonic acids together with dihydroxy-, ketohydroxy-and diketo-stearic acids at neutral pH. The yield and the products distribution are controlled by: the type of emulsifier and its concentration; the oleic acid concentration in the emulsion; and the oleic acid-oxidant ratio.     

Pharmacokinetic advantages of a newly developed tacrolimus oil-in-water-type emulsion via the enteral route

We developed an oleic acid oil-in-water (o/w)-type emulsion of a new tacrolimus formulation that presented an improvement in the delivery of the drug for oral absorption. This investigation was undertaken to assess a sustained release drug delivery system and selective drug transfer into the lymphatic system. The whole blood concentration profiles after oral administration at a dose of 2mg/kg and bone marrow, spleen, liver, lung, small intestine, kidney, brain, and whole blood distribution after oral administration at a dose of 1 mg/kg of o/w emulsion formulation of tacrolimus (O/W group) were compared with those of commercially available formulation (T group) in the rat. The mean diameter of the o/w emulsion droplets was 0.47 μm immediately after preparation. The tacrolimus entrapping efficiency of o/w emulsion was 71.3+5.0% in 12 h and did not change for 2 d. The area under the whole blood concentration-time curve (AUC) in the O/W group was significantly higher (P<0.01) than that in the I group. In contrast, the values of constant elimination rate and total clearance in the O/W group were significantly lower (P<0.01) than those in the T group, with a comparative bioavailability of 115.9%. The tissue concentration of tacrolimus in the O/W group was significantly higher levels in the bone marrow, spleen, liver, lung, and small intestine, and significantly lower in the brain and kidney, relative to the T group. The o/w emulsion of tacrolimus may be an improved dosage form via the enteral route.     

Soybean oil microemulsions with oleic acid/glycols as cosurfactants

The preparation of biocompatible microemulsions of soybean oil in systems made of anionic surfactant, oleic acid, water, and several glycols was considered. The selected glycols were ether derivatives (methyl, ethyl, dimethyl, and diethyl ether) of ethylene glycol and diethylene glycol. The study was performed using pseudoternary phase diagrams in which the three apexes were occupied by soybean oil, a combination of surfactant/oleic acid, and a combination of water/glycol, respectively. The widest regions of microemulsions were obtained for systems containing methyl ether and especially ethyl ether of both ethylene glycol and diethylene glycol. The two latter compounds allowed the preparation of oil-in-water, bicontinuous, and water-in-oil microemulsions with final surfactant contents of 3–4%.     

Phosphorylated ordered mesoporous carbon as a novel solid acid catalyst for the esterification of oleic acid

A novel phosphorylated ordered mesoporous carbon (POMC) solid acid catalyst has been prepared by modifying mesoporous carbon with phosphoric acid, and was employed to catalyze the esterification oleic acid with methanol. The effects of the carbonization temperature on the type of phosphorus species formed, the phosphorus content and the amount of acid in the POMC were investigated. A mechanism for the phosphorylation of the ordered mesoporous carbon is proposed. The POMCs have good catalytic activity for the esterification of oleic acid and showed good reusability.     

Catalyzed esterification of oleic acid

Conclusions It has been shown that the effectiveness of certain divalent metal salts as esterification catalysts can be quantitatively compared and that for the Group II B series their effectiveness is inversely proportional to their ionic volume. The rates of esterification using these metal salts are not as great as for strong acids, but it is probable that the mechanism is similar and that the metal salts act as acids in the general sense. The rates of esterification differ appreciably for different primary polyols. It is also probable that these differences are related to the comparative acidity or basicity of the alcohols. It would be particularly desirable to investigate the activity of the catalysts in different alcohols. It is possible that infrared studies might show formation of a complex between the catalyst and either the alcohol or the acid or both. A number of possibilities may be formulated; at present we lack critical evidence to distinguish between them and this area provides a fruitful field for further research. Presented at the spring meeting, American Oil Chemists' Society, New Orleans, La., April 20–22, 1959.     

油酸催化氧化制壬二酸

对利用油酸氧化制取壬二酸进行了较为系统的探索。在 50℃ ,pH =2 .5,适宜催化剂条件下 ,壬二酸的收率提高到 60 %,且反应条件温和 ,具备工业生产的价值。     

Evaluation of chlorogenic acid and its metabolites as potential antioxidants for fish oils

The antioxidant effects on cod liver oil (CLO) of chlorogenic acid (CGA) and its metabolites, caffeic acid (CA) and quinic acid (QA), were investigated. All three chemicals were separately added to CLO at a concentration range of 0.001–0.080 wt‐% and tested by Rancimat. CA was the best antioxidant; its antioxidant effect was directly proportional to the dose added, but only within the concentration range of 0.005–0.050 wt‐%. QA did not show any effect on CLO oxidation, while CGA revealed itself as a weak antioxidant. Cytotoxicity was also evaluated by using murine 3T6 fibroblasts treated for 24 h with CGA, CA and QA at a concentration range of 0.1–5.0 mM. QA did not have an influence on cell proliferation, while CGA and CA showed a significant anti‐proliferative activity already at a concentration of 0.1 mM. Finally, compounds similar to the standard 8‐iso prostaglandin F_2α, called CLO‐“isoprostanes”‐like compounds, were isolated. At high temperature (100 and 110 °C) CLO‐“isoprostanes‐like” compounds did not show a relevant pro‐oxidant action on the refined olive oil to which they were added in variable amounts. On the contrary, the CLO‐“isoprostanes”‐like compounds significantly decreased the antioxidant effectiveness of CA. Indeed, at a CLO‐“isoprostanes‐like” compound dose of 300 µg, the antioxidant effectiveness of CA was halved.     

Cis-Trans isomerization of oleic acid by nitrous acid

Oleic acid wascis-trans isomerized by HNO₂ generatedin situ by reacting NaNO₂ with a mineral acid. The influence on the reaction of time, temp, agitation, solvent, amt of catalyst and type of mineral acid was investigated. Optimum reaction conditions were defined for achieving equilibrium isomerization in 30 min with minimum by-product formation. After isomerization, nitrogenous by-products were efficiently removed using silicic acid. The active species causingcis-trans isomerization was tentatively identified as free radical nitrogen dioxide. Presented at the AOCS Meeting in New Orleans, 1964.     

Characterization of dihydroxystearic acid from palm oleic acid

Dihydroxystearic acid (DHSA) was prepared from palm oleic acid and characterized by chromatographic and spectroscopic methods (gas chromatography, thin-layer chromatography, Fourier transform infrared and nuclear magnetic resonance spectroscopy) as well as wet chemistry. The crude product has a melting point of 62°C, acid value of 179, saponification value of 178, and hydroxyl value of 196. The yield was about 90% based on unsaturation. The product obtained was found to contain DHSA, saturated fatty acids, and unknown products. DHSA is soluble in alcohol, and its solubility decreased by increasing the alcohol chain length. An irritancy test of DHSA indicated that purified DHSA is nonirritating.     

油酸、聚甲基丙烯酸甲酯修饰可磁化颗粒的磁流变液的流变行为

主要研究了拥有相同极性基团不同长度的非极性基团的表面活性剂对磁流变液流变行为的影响。分别以油酸、聚甲基丙烯酸甲酯修饰后的羰基铁粉为可磁化颗粒,硅油为载液,经过超声分散制备磁流变液。黏度测试表明,低速剪切时,颗粒表面表面活性剂层的空间位阻作用（熵斥力）起主导作用,黏度降低;高速剪切时,表面活性剂层又会增大颗粒的内摩擦,使黏度增加。通过流变模型的定量分析也印证了上述结论。磁流变测试表明,油酸为表面活性剂的磁流变液对磁场有更强烈的响应,形成更强的链束结构,屈服应力增大,而聚甲基丙烯酸甲酯的作用相反。两种表面活性剂都明显改善磁流变液的沉降稳定性能,降低了沉降速率与最终沉降量。本研究为磁流变液表面活性剂的选用提供了参考。     

Consecutive reactions in an oleic acid and acetic anhydride reaction medium

When mixing acetic anhydride and oleic acid, two consecutive reactions take place. The first one yields acetic‐oleic anhydride (AOA) and acetic acid. In the second one, oleic acid reacts with AOA to form oleic anhydride at 5% in a mixture when the initial molar ratio is 1:1. Therefore, at equilibrium, the global reaction yields a mixture of AOA, acetic anhydride, oleic acid, acetic acid and oleic anhydride. Based on a new HPLC protocol, all the species of the reaction medium could be separated and quantified. This permitted for the first time to study the kinetics and thermodynamics of the reaction. In the 30–70 °C range, reactions were of order 2 with partial orders of 1 for each reactant. Equilibrium constants were determined for both reactions. Enthalpy, entropy and activation energies were calculated for the main reaction. The influence of molar ratio on the composition at equilibrium was also investigated. The synthesis of AOA could thus be understood and new data were obtained for this singular molecule scarcely cited in the CAS database.     

Application of the prins reaction on oleic acid

The probable structure of the various components of oleic acid-formaldehyde adducts is discussed. The adducts are reduced to alcohols by high pressure hydrogenation with copper chromite as a catalyst. The new alcohols are distilled, analyzed and used for the preparation of various esters with carboxylic acids. The esters were evaluated as low temperature lubricant base stocks and low temperature plasticizers.     

Efficient carbon-based solid acid catalysts for the esterification of oleic acid

A series of carbon-based solid acid catalysts was prepared by the sulfonation of mesoporous carbon substrates with thin pore walls, and catalytic activity for the esterification of oleic acid with methanol was tested. The highest turnover frequency (TOF) observed was 78 h^− 1, five times that of Amberlyst-15. The high catalytic activity may be attributed to the good dispersion of the catalysts in methanol. Catalysts with improved dispersion were obtained by a modified preparation, after which the highest TOF observed was 109 h^− 1, seven times that of Amberlyst-15.     

氟表面活性剂FN6810与油酸钠复配体系相行为及药物增溶研究

制备并考察了油/FN6810-油酸钠/丁醇/水微乳液体系的相行为及载药性能。采用最大增溶量法绘制了该体系的拟三元相图,筛选出具有较大微乳区面积的最佳处方,进而考察其载药性能及稳定性。结果表明,FN6810与油酸钠的质量比为1∶20,Km=1∶1时微乳体系具有较大的微乳区面积,对油或药物的增溶量较大,载药后粒径变化不大,长时间放置稳定。说明碳氟和碳氢表面活性剂可形成有效的微乳液复配体系,有望在药物制剂中取得应用。     

Highly unsaturated fatty acid might act as an antioxidant in emulsion system oxidized by azo compound

Now it is recognized that DHA is oxidatively stable fatty acid compared with linoleic acid (LA) in emulsified system, although DHA is oxidatively unstable in a bulk system. In fact, an emulsified mixture of DHA and LA behaves as in a bulk system, namely the oxidative stability of DHA becomes lower than that of LA. Therefore, in this study, tridocosahexaenoate (DDD) and glycerol trilinoleate (LLL) were separately emulsified using TritonX-100 as an emulsifier and DDD emulsion was mixed with the oxidizing LLL emulsion using a water-soluble radical initiator, 2,2'-azobis(2-aminopropane) dihydrochloride. As a result, DHA suppressed the oxidation of LA, while DHA was not significantly oxidized. This suppression ability was examined using glycerol trieicosapentaenoate, glycerol trilinolenate, or glycerol trioleate instead of DDD and it was found that this activity was increased with the increasing number of double bonds in the structure. Furthermore, the same type of experiment was carried out using a lipid-soluble radical initiator, 2,2'-azobisisobutyronitrile and the similar result was obtained. These results indicated that a highly polyunsaturated fatty acid might act as an antioxidant in an emulsion system oxidized by an azo compound.     

A comparison of the absorption of oleic acid in vitro as measured isotopically and by titration

Uptake of oleic acid by the everted sac of rat intestine has been shown to be net absorption and not merely exchange. Sodium fluoride, 10 mM, has been shown to inhibit absorption of oleic acid.     

羧甲基壳聚糖-油酸胶束的制备

通过接枝反应合成了具有两亲性的羧甲基壳聚糖-油酸聚合物,并测定了临界胶束浓度(CMC),评价其形成胶束的能力。首先对壳聚糖进行羧甲基化修饰,酸碱滴定法测定取代度,并以取代度为指标,正交实验法确定合成羧甲基壳聚糖过程中不同条件对取代度的影响,根据正交实验结果制备了3种不同取代度的羧甲基壳聚糖,分别与油酸进行接枝反应,合成了3批羧甲基壳聚糖-油酸聚合物,荧光光度法分别测定CMC值为0.013 8、0.039 0和0.039 0 mg/mL,结果表明羧甲基壳聚糖-油酸具有形成胶束结构的能力。