摘要
本研究利用先进的纳米技术,对传统中药紫苏子油进行改造,制备紫苏子油纳米乳。通过空白纳米乳的基础研究筛选处方,利用伪三元相图优选处方,采用滴定法制备紫苏子油纳米乳,并对其稳定性、安全性、药效学和药动学等进行较为系统的研究。研究摘要如下:
1.空白纳米乳的基础研究
筛选出空白纳米乳处方,制备空白纳米乳,并对其影响因素进行考察,为后续试验奠定基础。利用亲水亲油平衡值法和纳米乳的评价标准筛选出可形成纳米乳的处方;利用滴定法制备空白纳米乳;通过透射电子显微镜和激光粒度分布仪考察其形态和粒径;利用伪三元相图对纳米乳形成的影响因素进行考察。纳米乳处方筛选结果显示:可形成纳米乳的表面活性剂为吐温类(80和60)、司盘类(80和60)、蓖麻油聚氧乙烯醚-40和氢化蓖麻油聚氧乙烯醚-40,助表面活性剂为无水乙醇、甘油、1,2-丙二醇和正丁醇,油相为肉豆蔻酸异丙酯、液体石蜡、橄榄油和小麦胚芽油;制备的空白纳米乳为澄清、透明、淡黄色或略带淡蓝色乳光的液体,电镜下呈圆球形,粒径为20.7 nm,亚甲基蓝染料在其中的扩散速度明显大于苏丹红III的扩散速度;纳米乳形成的影响因素考察结果显示:表面活性剂与油相的种类及比例是纳米乳形成最主要的和关键的影响因素。在能形成纳米乳范围内,表面活性剂亲水亲油平衡值越大、助表面活性剂的链越短、油相与混合表面活性剂的亲水亲油平衡值越匹配,纳米乳区越大;在一定范围内,药物加入量增加,纳米乳区增大。表明制备的空白纳米乳质量稳定,为水包油型。
2.紫苏子油纳米乳的研制及质量评价
制备紫苏子油纳米乳,对其质量进行评价。建立紫苏子油纳米乳含量检测的气相色谱分析方法,并考察其载药量和包封率;利用透射电子显微镜、激光粒度分布仪、旋转黏度计、折光仪和电导仪等对其形态、粒径及理化性质进行考察;通过稳定性参数测定、加速试验、光加速试验、经典恒温加速试验及纳米乳中紫苏子油的过氧化值测定考察其稳定性。气相色谱分析结果显示:制剂的标准曲线在50 ng/mL~1 600 ng/mL范围内线性关系良好,平均回收率为99.3%,回收率的RSD为0.69%,平均保留时间为33.398 min,进样重复性的RSD为0.52%和0.34%;血浆的标准曲线在10 ng/mL~1 600 ng/mL范围内线性关系良好,平均回收率为95.8%,回收率的RSD为2.95%,平均保留时间为33.545 min,进样重复性的RSD为0.58%和0.83%;质量评价结果显示:制备的氢化蓖麻油聚氧乙烯醚-40/乙醇/小麦胚芽油/紫苏子油纳米乳为澄清、透明、略带淡蓝色乳光的液体,电镜下呈球形,平均粒径为26.0 nm,包封率大于80%,粘度为5.64±0.09 mm2.s-1,折光率为1.178±0.0023 nD20,电导率为366±1.36 mS-1,Zeta电位为-2.18±0.04 mV,紫苏子油纳米乳的稳定性参数为4.60±0.16。表明本研究建立的分析方法回收率和精密度高、重复性好,可用于其质量控制和动力学研究。制备的紫苏子油纳米乳质量很稳定,符合用药要求。
3.紫苏子油纳米乳的安全性评价
通过家兔股四头肌注射试验、溶血性试验、血管刺激性试验、热原检测试验、小鼠急性毒性试验和细胞毒性试验对紫苏子油纳米乳的安全性进行评价。股四头肌注射试验显示:注射部位轻度充血,直径均在0.5 cm以下,属于1级;溶血性试验结果显示:试管中未见澄明红色,且红细胞全部下沉,上层液体无色澄明,经振摇后红细胞能均匀分散;血管刺激性试验结果显示:皮肤组织结构正常,表皮无增厚,皮下组织未见充血、水肿等形态学改变,耳缘静脉未见扩张,血管壁无增厚;热原检查结果显示:每只家兔的体温升高均低于0.6℃,三只家兔体温升高的总和低于1.4℃;小鼠急性毒性试验结果显示:紫苏子油纳米乳对小鼠的最大耐受量为140 g/kg,折合成人的剂量为35 000 g/kg,是临床用量的7 777倍,累积的LD50为602.0 g/kg;细胞毒性试验结果显示:紫苏子油纳米乳组细胞比正常细胞生长速度稍减慢,但形态并无明显差异,紫苏子油纳米乳的细胞毒性属于1级。表明紫苏子油纳米乳无注射刺激性,无溶血现象,热原检查符合规定,对小鼠成纤维细胞无明显的毒性作用,安全性高。
4.紫苏子油纳米乳的药效学研究
通过紫苏子油纳米乳对抗小鼠急性高血脂症试验、紫苏子油纳米乳对高血压大鼠血压及心率的影响试验和紫苏子油纳米乳诱导小鼠乳腺癌细胞EMT-6凋亡试验对其药效进行研究。对抗高血脂试验结果显示:腹腔注射0.25 mL/10 g 75%的蛋黄乳可成功复制小鼠急性高血脂症模型。紫苏子油纳米乳降低小鼠总甘油三酯、总胆固醇及动脉硬化指数的相对值,分别是紫苏子油软胶囊的4.48倍、2.06倍和2.61倍,是非诺贝特的4.62倍、1.28倍和1.45倍;对高血压大鼠血压及心率的影响试验结果显示:紫苏子油纳米乳与模型组比较,血压降低28%(P<0.01),心率增快14% (P<0.01),心指数降低19% (P<0.01);紫苏子油纳米乳诱导EMT-6细胞凋亡试验结果显示:浓度为100μg/mL~800μg/mL时的紫苏子油纳米乳较紫苏子油软胶囊对EMT-6细胞的诱导凋亡作用强,差异显著(P<0.05),透射电镜下,EMT-6细胞染色质边集,胞质内出现空泡,形成凋亡小体。800μg/mL剂量紫苏子油纳米乳处理EMT-6细胞48 h后,凝胶电泳可见明显的“阶梯状”DNA条带,约为180~200 bp整数倍递增分布。800μg/mL剂量紫苏子油纳米乳处理EMT-6细胞24 h后,可见凋亡峰出现,且峰值随处理时间的延长而增高。表明紫苏子油纳米乳能显著降低小鼠血浆总甘油三酯,总胆固醇和低密度脂蛋白,并提高高密度脂蛋白;紫苏子油纳米乳能显著降低高血压大鼠血压;紫苏子油纳米乳具有明显的诱导EMT-6细胞凋亡的作用。制备的紫苏子油纳米乳药效比紫苏子油软胶囊显著提高。
5.紫苏子油纳米乳的药物代谢动力学研究
对紫苏子油纳米乳在家兔体内的药动学进行研究。给家兔灌胃25 mL/kg紫苏子油纳米乳,于给药后0.5h、1h、1.5h、2h、2.5h、3h、3.5h、4h、8h、10h、12h、14h、18h、24 h经心脏采血1 mL,用气相色谱法测定家兔血浆中的α-亚麻酸含量,用残数法对药-时曲线进行拟合,计算出药动学参数。药动学结果显示:在家兔体内,紫苏子油纳米乳符合有吸收的一室模型。紫苏子油纳米乳的平均达峰时间为4.929 h,比紫苏子油软胶囊的3.279 h延长了1.650 h;理论平均最高血药浓度Cmax(136.058μg/L)是紫苏子油软胶囊(110.237μg/L)的1.2倍;相对生物利用度是紫苏子油软胶囊的283.1%。表明紫苏子油纳米乳较紫苏子油软胶囊的相对生物利用度明显提高,且具有一定的缓释作用。本研究制备的紫苏子油纳米乳质量稳定、安全性高,与传统剂型比较药效显著提高。已申请国家发明专利,申请号为200610104621.X。
In this research,we used the advanced nanotechnology to transform the traditional Chinese herb fructus perillae oil,prepared fructus perillae oil nanoemulsion.Screening the prescription through basic researching of the blank nanoemulsion,used pseudo-triangular phase diagram to optimal prescription and used titrimetric method to prepare fructus perillae oil nanoemulsion,the quality stability,security,pharmacodynamics and pharmacokinetics of fructus perillae oil nanoemulsion were systematic studied.The abstracts are as follows:
1.Basic research of blank nanoemulsion
To screen blank nanoemulsion prescription and prepare it,carried on the inspection to its influencing factor.Used the hydrophilic-lipophilic balance and nanoemulsion evaluation criteria to screen prescription;used titrimetric method to prepare blank nanoemulsion;inspected the shape and particle diameter through transmission electron microscope and laser particle size distribution meter;inspected influential factor of nanoemulsion formation though pseudo-triangular phase diagram.The result indicated that nanoemulsion prescription is, the surfactant is the Tween (80 and 60),Span (80 and 60),EL40 and RH40;the cosurfactant is dehydrated alcohol,glycerine,1,2-butylene-glycol and n-butanol;the oil phase is IPM,whiteruss,olive oil and wheat embryo oil;the blank nanoemulsion is clarify,diaphanous,stramineous or light blue opaline liquid,assumed globular below electron microscope,particle diameter is 20.7 nm,the spreading rate of methylene blue is obviously greater than magdala red III;the influencing factor inspection result showed that surfactant and oil phase type and proportion are most main factor;in nanoemulsion form scope,the cosurfactant HLB value is bigger,the chain of cosurfactant is shorter and the HLB value of oil and cosurfactant are better matcher,nanoemulsion area is bigger;in a range,the medicine joins increased nanoemulsion area.The quality of blank nanoemulsion is stable,the type is oil in wate.
2. Development and quality evaluate of fructus perillae oil nanoemulsion
To prepare fructus perillae oil nanoemulsion and overall assess it’s quality.To establish the analytical method for content determining of fructus perillae oil nanoemulsion drug delivery system,to inspect it’s carry dosage and entrapment efficiency;used of transmission electron microscopy,laser particle size distribution device,rotary viscometer and refractometers conductivity,etc.to evaluate the quality;to inspect the stability through determin stability parameter,accelerated test,light accelerated test,classical homeothermia accelerated test and peroxide value determination.Gas chromatography detection results showed that the good linear range of the preparation was 50 ng/mL ~1 600 ng/mL,the mean recovery is 99.3 percent, RSD of the recovery is 0.69 percent,the mean retention time is 33.398 min,the type duplication is 0.52 percent and 0.34 percent;the good linear range of the blood plasma was 10 ng/mL~1 600 ng/mL,the mean recovery is 95.8 percent,RSD of the recovery is 2.95 percent,the mean retention time is 33.545 min,the type duplication is 0.58 percent and 0.83 percent;quality evaluate results show that the nanoemulsion drug delivery system of fructus perillae oil contains RH40/ethyl alcohol/wheat embryo oil is transparent spherical bubble,its average diameter is 26.0 nm,encapsulation efficiency is over 80 percent,consistency is 5.64±0.09 mm2.s-1,refractive index is 1.178±0.0023 nD20,conductivity is 366±1.36 mS-1,Zeta electric potential is -2.18±0.04 mV.The stability parameter of fructus perillae oil nanoemulsion is 4.60±0.16.The analysis method we established in this study have high recovery,accuracy and repeatable,it can be used in quality control and dynamics research. Fructus perillae oil nanoemulsion drug delivery system is stable, correspond to medication requirement.
3. The safety evaluation on fructus perillae oil nanoemulsion
Through quadriceps injection testing, hemolytic test, vascular stimulation test, pyrogen testing, mouse acute toxicity and cytotoxicity test to estimate the safety of fructus perillae oil nanoemulsion. Quadriceps injection testing showed that the injection site has lightly congestion,it’s diameter is below 0.5 cm,belongs to 1 class;hemolytic test showed no clarity red in tube,and RBC are all sink,the upper liquid clarity,the red blood cells can dispersed after rock and fructus perillae oil nanoemulsion without hemolysis;vascular stimulation test results showed that the organizational structure of normal skin,skin thickening no congestive,subcutaneous tissue has no edema and other morphological changes,ear vein has no expansion,artery wall has no thicker,pyrogen test results showed that body temperature increase of every rabbit is lower than 0.6℃,the sum of three rabbits temperature increase is lower than 1.4℃;acute toxicity results showed that the maximal tolerance dose test on mice of the fructus perillae oil nanoemulsion is 140 g/kg,converted into adult's dosage (50 kg) is 3 5000 g/kg,7 777 times of clinical amount used,calculated its accumulation LD50 is 602.0 g/kg; cytotoxicity test showed that compared with normal cell,fructus perillae oil nanoemulsion group cell growth velocity is slightly step down,the shape has no significant difference,belongs to 1 level.Fructus perillae oil nanoemulsion has no vascular irritation,has no hemolytic crisis, pyrogen inspection conforms to the regulation,has no evident toxic effect to L cell,and has high security.
4. Study of pharmacodynamics on fructus perillae oil nanoemulsion
Through against acute hyperlipemia,the impact of hypertension rats blood pressure and heart rate and induction EMT-6 cell apoptosis test to study the pharmacodynamics.Acute hyperlipemia test showed injection of 0.25 mL/10 g 75 percent of the yolk milk can be successfully reproduced in mice with acute high blood lipid model,the relative magnitude of reduce mouse plasma total cholesterol,triglyeride and atherogenic index is 4.48 times,2.06 times and 2.61 times than fructus perillae oil capsulae,and 4.62 times,1.28 times and 1.45 times than fenofibrate;hypertension test showsed it can significantly reduce blood pressure,compared with the model group,the blood pressure decreased 28 percent (P<0.01),heart rate increase 14 percent(P<0.01),and cardiac index reduced 19 percent (P<0.01);apoptosis test result showed that fructus perillae oil nanoemulsion has significantly inhibited proliferation when drug concentration is 100μg/mL~800μg/mL,apoptosis of fructus perillae oil nanoemulsion is better than fructus perillae oil capsule,significant differences on statistically (P<0.05).Fructus perillae oil nanoemulsion of 800μg/mL dose induced EMT-6 cells,under TEM showed cytoplasmic margination,apoptotic bodies formed within the cytoplasmic vacuoles,and after 48 h,we can see the length of a DNA degradation of 180~200 bp integer multiple oligonucleotide fragments of the ladder.After 24 h,apoptosis peak apparence and peak extension with the processing time increased by flow cytometer detection. Fructus perillae oil nanoemulsion can significantly cut down mouse triglyeride,total cholesterol and low-density lipoprotein,and raise high-density lipoprotein,fructus perillae oil nanoemulsion can significantly cut down hypertension rat blood pressure,fructus perillae oil nanoemulsion has evident apoptosis to EMT-6 cell.In short,the pharmacodynamic of fructus perillae oil nanoemulsion is much better than fructus perillae oil capsule.
5. The pharmacokinetics study on fructus perillae oil nanoemulsion
To study the fructus perillae oil nanoemulsion on pharmacokinetics.The fructus perillae oil nanoemulsion was administered to the rabbit by lavage with 25 mL/kg,in the time of 0.5h、1h、1.5h、2h、2.5h、3h、3.5h、4h、8h、10h、12h、14h、18h、24 h,α-LNA was determined through gas chromatographyin,the medicine kinematics parameter was calculated.The result showed that fructus perillae oil nanoemulsion is fit for the one room open model in rabbit.The average peak time values of fructus perillae oil nanoemulsion was 4.929 h,extend 1.650 h than capsule (3.279 h);the average highest plasma concentration Cmax(136.058μg/L) is 1.2 times of capsule (110.237μg/L),the relative bioavailability is 283.1% to capsule pharmacokinetics.The relative bioavailability of fructus perillae oil nanoemulsion increased significantly than fructus perillae oil capsulae,and has a certain degree of sustained-release effect.
Fructus perillae oil nanoemulsion has stable quality,high safety,pharmacodynamic action has significant raised than tradition dosage form of fructus perillae oil.The research outcome has applied for national invention patent,apply order is 200610104621.X.
引文
[1]KeahlerT.Nanotechnology: basic concepts and definitions[J].ClinChem,1994,40(9):1797.
[2]王汝兴,刘翠哲,刘喜纲,等.纳米技术及其在药学研究中的应用[J].承德医学院学报,2005,22(3):248- 249.
[3]顾憋瑜,李虹影,吴秀英,等.纳米技术在药学研究领域中的应用[J].药品评价,2005,3(2):170-172.
[4]Warisnoicharoen W, Lansley AB, and Lawrence MJ.Nonionicoil-in-water microemulsions: the effect of oil type on phase behaviour [J].Int J Pharm, 2000, 198:7-27.
[5]Attwood D.Colloidal drug delivery systems [M].New York: Marcel Dekker, 1994.
[6]张文萍,张志耘.我国纳米技术在药学领域中应用现状[J].天津药学,2002,14 (5):17.
[7]胡志洁,张志耘.纳米技术在医药学领域中研究应用进展[J].天津药学,2001,13(5):10-15.
[8]吴顺芹,李三鸣,赵国斌.微乳及其在药剂学中的应用[J].沈阳药科大学学报,2003,20 (5):381-384.
[9]屠梅芳,施顺清.试论中药剂型改进的思路[J].中草药,2001,32(10):956.
[10] 徐碧辉 , 杨祥良 , 谢长生 , 杨亚江 . 纳米技术在中药 研究中的应用 [J]. 中国药科大 学学报,2001,32(3):162.
[11]张颖,陈世玲,盖国胜,张兰英,等.中草药与难溶药物超细粉碎技术的应用[J].世界科学技术.2001,3(2):9-12.
[12]Constantinides PP, Yiv SH.Pharmaceutical selfemulsifying m icroemulsion comp rising surfactants [P].WO9408610, 1994-04-28.
[13]Actis G C,Lagget M,Rizzetto M,et al. Long-term efficacy of oral microemulsion cyclosporine for refractory ulcerative colitis[J].Mienrva Med.2004,Feb,95(1):65-70.
[14]Kraeling M E and Ristschel W A. Development of a colonic release capsule dosage form and absorption of insulin [J].Methods Find Exp Clin Pharm acol, 1992, 14(3):199-209.
[15]Hsu C H,Cui Z,Mulllper R J.et al.Preparation and characterization of novel coenzyme Q10 nanoparticles engineered from micoremulsion percrusors[J].AAP SPhamr SciTech.2003,4(3):E32.
[16]Agatonovic-Kustrin S,Glass B D,Wisch M H,et al.Prediction of a stable micoremulsion formulation for the oral delivery of a combination of antitubercular drugs using ANN methodology[J].Pharm Res.2003, Nov,20(11):1760-1765.
[17]L.Moberger, K.Larsson, W.Buchheim, et al.J.Disp.Sci.Techn, 1987, 8:207.
[18]Park KM, Kim CK. Preparat ion and evalua tion of flurbiprofen-loaded microemulsion for parenteral delivery [J].Int J Pharm, 1999 Apr30, 181(2):173-179.
[19]Ktistis G.Niopas I.A study on the in-vitro percutaneous absoption of propr anolol from disperse syestms [J].J Pharm Pharmacol.1998, 50(4):413-418.
[20]Mei Z,Chen H,WengT.et.al Solid lipid nanoparticle and microemulsion for topical delivery of triptolide[J].Eur J Pharm Biopharm.2003Sep,56(2):189-196.
[21]Alvarez-Figueroa MJ, Blanco-Mendez J, Transdermal delivery of methotrexate: iontophoertic delivery from hydorgels and passive delivery from micoremulsions [J].Int J Pharm.2001 Mar l4, 215(1-2):57-65.
[22]Can Pat.Appl.CA.2112231.
[23]Lee J M,Park K M,Lim S J,et al. Microemulsion formu1ation of clonixic acid:solubility enhancement and pain redcution[J].J Pharm Phamacol.2002 Jan,54 (1):43-49.
[24]Li L, Nandi I, and Kim KH.Development of an ethyl laurate-based microemulsion for rapid-onset intranasal delivery of diazepam [J] .Int J Pharm, 2002, 237(1-2):77-85.
[25]D’Cruz O J,Yiv S H,Waurzyniak B,et al.Contraceptive efficacy and safety studies of a novel micoremulsion-based lipophilic vaginal spemricide[J].Fertil Steril,2001,Jan,75(1):115-124.
[26]叶国庆,严宝霞,张强.环孢素A微乳浓缩液的制备及稳定性研究[J].中国医药工业杂志,1999,30(7): 299-302.
[27]阎家麒,王惠杰,童岩,等.紫杉醇微乳的研究[J].中国药学杂志,2000,(35)3:173-176.
[28]张建春,李培勋,等.环磷酰胺微乳制剂的研制[J].中国医院药学杂志,2003,23(1):9-10.
[29]吴永良,卢海燕.O/W型中药按摩微乳的制备研究[J].海峡药学,200,12(1):20-21.
[30]张宁,范青,吕慧怡,等.丹参酮微乳的制备及其质量评价[J].中国中药杂志,2003,28(11):1081-1082.
[31]王新春,侯世祥,阳长明,等.大黄复方液体喷雾剂中挥发油微乳与相图的应用[J].中成药,2004, 26(3):25.
[32]刘家强,王洪光.中药现代化与中药基因组学的建立[J].中医药学刊,2004,22(10):102-103.
[33]Uchegbu I.F. non-ionic surfactant based vesicles (niosomes) in drug delivrery [J].Int JPharm, 1998,172(1):33.
[34]赵建,张钧寿,张瑛,等.胰岛素微乳大鼠结肠给药的药效学研究[J].中国药科大学学报,2004, 35(6):491.
[35]叶海英,张忠义,等.法莫替丁微乳的研制及其质量评价[J].第一军医大学学报,2003,23(1):68-70.
[36]国家药典委员会编.中华人民共和国药典[S].北京:化学工业出版社,2005 版,一部.
[37]郭英,蔡秀成,李华娟,等.紫苏油和松籽油对大鼠机体脂类和脂质过氧化的影响[J].营养学报,1996,18(3):268.
[38]T.Shimokawa,A .Moriuchi,T.Hori,et al.Effect of dietarv a-linolenate/linoleate balance on mean survival time,incidence of stroke and blood pressure of spontaneously bypertensive rats[J].Life Sciences.1998,43(25):2067-2075.
[39]J.Hirano, Y.Isoda, Y. Nishizawa. Utilization of n-3 plant oils.perilla and flaxseed oils [J].Ynkagaku, 1991, 40(10):942.
[40]T.Hori, A .Moriuchi, H.Okuyama, et al. Effect of dietary essential fatty acid on pulmonary metastasis of ascites rumor cells in rats[J].Chem.Pharm Bull,1987,35(9):3925.
[41]张阳德.纳米药物学[M].北京:化学工业出版社,2006.
[42]高中.现代药物新剂型新技术[M].北京:人民军医出版社,2002,229-252.
[43]T.P.Hoar and J.H. Schulman, Nature, 152:102.
[44]S.Friberg,et al. In Encyclopedia of Emulsion Technology[M].Vol.1, Basic Theory,Edited by P.Becher,Chapter4,Marcel Dekker,New York and Basel,1984.
[45]K.Shinoda and S.Friberg, Adv Colloid Interface Sci [M].1975, 4:281.
[46]Schmalfu U,Neubert R,Wohlrab W.Modification of drug penetration into human skin using microemulsions[J].J Control Release,1997,46(1):279-285.
[47]吴绍情.乳化燃料油[J].化学通报,1989,(3):17-20.
[48]蔺恩惠,李兴福.掺水汽油微乳状液的生成和应用[J].石油炼制,1991:26-30.
[49]李兴福,蔺恩惠,肖泰,等.掺水汽油微乳状液的生成和应用[J].西北师范大学学报(自然科学版),1994,30(1):51-57.
[50]李兴福,康敬万,傅正生,等.微乳汽油的生成原理和配制技术[J].西北师范大学学报(自然科学版),1999,35(4):94-99.
[51]周雅文,张高勇,王红霞.汽油微乳化技术研究[J].日用化学工业,2002,32(2):1-4.
[52]钱宇,胡智华,江燕斌等.燃油清洁添加剂的研究[R].第十一届全国化学工程科技报告会,湘潭大学,中国化工学会化学工程专业委员会,2002,901-904.
[53]梁文平.乳状液科学与技术基础[M].北京:科学出版社,2001,211-235.
[54]朱埗瑶,赵振国.界面化学基础[M].北京:化学工业出版社,1996,159-163.
[55]杜永锋,吕方.微乳状液体系应用研究进展[J].化学世界,1999,10:511-513.
[56]王雪松.微乳法制纳米无机颜料的研究[D].天津:天津大学,1999.
[57]郭荣,王秀文,李干佐.微乳乳液的微观结构与稳定理论[J].日用化学工业,1989,299:125.
[58]hhtp://www.patent.com.cn
[59]hhtp://www.uspto.gov
[60]hhtp://www.sipo.gov.cn
[61]hhtp://www.cnipr.com
[62]李干佐,郭荣编著.微乳液理论及其应用[M].北京:石油化工出版社,1995.
[63]崔正刚,段福珊编著.微乳化技术及应用[M].北京:中国轻工业出版社,1999.
[64]HaA, Keipert S.Development and characterization of microemulsions for ocular application [J].Eur J Pharm Biopharm, 1997, 43(2):179-183.
[65]LUY,JI XX,GAO S,et a1.Studies of lidocaine-lecithin micrcemulsion[J].J Pharm practice,2004,22(3): 141-143.
[66]张柯萍,蔺胜照,陈国广,李学明.鸦胆子油微乳的制备及稳定性研究[J].华西药学杂志,2005,(20)3: l99-20l.
[67]马玉坤,冯杨,孔蓓蓓,等.微乳对槲皮素增溶作用的试验研究[J].齐鲁药事,2004,23(3):46.
[68]袁泉,李馨儒,王会娟,等.水飞蓟素微乳大鼠在体小肠吸收的动力学[J].药学学报,2004,38(8): 631-634.
[69]汪龙,邓瑾,金玉燕,等.低分子肝素微乳及其纳米脂质体作大鼠口服抗凝效果的比较[J].江苏药学与临床研究,2005,13(2):4-6.
[70]Kim CK,Cho YJ,Gao ZG.Preparation and evaluation of biphenyl dimethyl dicarboxylate microemulsions for oral delivery[J].Controlled Release,2001,70(1-2):149-155.
[71]仝新勇,黄春玉,姚静,等.尼莫地平微乳在小鼠体内的分布及靶向性评价[J].中国药科大学学报,2002,33(4):293-296.
[72]张莉,向东,洪诤,等.肝靶向去甲斑蝥素微乳的研究[J].药学学报,2004,39(8):650-655.
[73]Junping W,Takayama K,Nagai T,et al.Pharmacokinetics and antitumor effects of vincristine carried by microemulsions composed of PEG lipid,oleic acid,vitamin E and cholesterol[J].Int J Pharm,2003,251(12):13-16.
[74]Lawrence M J, Gareth D R.Microemulsion based media as novel drug delivery systems [J].Adv Drug Delivery Rev, 2000, 45:89-121.
[75]陈华兵,翁婷,常雪曼,等.布洛芬微乳的制备及其透皮吸收研究[J].中国药学杂志,2004,39(1):43-45.
[76]Baroli B,Lopez-Quintela MA,Delgado-Charro MB,etal.Microemulsions for topical delivery of 8-methoxsalen[J].J Control Release,2000,69(1):209-218.
[77]苏德森,王思玲,主编.物理药剂学[M].化学工业出版社.
[78]孙红武.黄连素纳米乳给药系统的研究[D].西北农林科技大学博士论文,2007.
[79]Shah D O and Hamlin R M. Structure of water in Microemulsion: Electrical, Birefringence and Nuclear Magnetic Resonance Studies[J].Science, 1971,171(2):483-485.
[80]Dvolaitzky M and Lagues M A.Structural Description of Microemulsion.Small-Angle Neutron Scattering and Electrical Conductivity Study[J].JPhys Chem,1980, 84:1532-1535.
[81]郭荣,李干佐.阴离子型微乳液的电导行为及其溶液结构[J].化学学报,1987,45:55-58.
[82]郝京城,汪汉卿,鲁润华,等.微乳液相行为和微观结构的研究[J].中国科学(B 辑),1997,27(2):131-139.
[83]Friberg S E, Lapczynska I and Gillberg G. Microemulsions Containing Nonionic Surfactants the Importance of the PIT Value[J].J.Colloid.Inter.Sci,1976,56:19-32.
[84]ScriwenL E. Equilibrium Bicontinuous structure[J].Nature, 1976, 263:123-125.
[85]陈宗淇,郭荣.微乳的微观结构[J].化学通报,1994,2:22-24.
[86]Yuri Feldman and Nick koziovich, Mechanism of Transport of Charge Carriers in the Sodium Bis(2-ethylhexyl) Sulfosuccinate-Water-Decane Microemulsion near the PercolationTemperature Threshold[J].J Phys Chem,1996,100:3745-3748.
[87]Lagues M and Sauterey C. Percolation Transition in Water in oil Microemulsion Electrical Conductivity[J].J Phys Chem, 1980, 84:3503-3508.
[88]Amarnath Maitra and Charlly Mathew.Closed and open structure aggregates in microemulsions and mechanism of percolative conduction[J].Phys Chem, 1990, 94:5290-5292.
[89]Lagourette B and Peyrelasse J.Percolative Conduction in Microemulsion Type Systems[J].Nature, 1979, 281(9):60-62.
[90]张丽,张冬柏,马季铭.非水反相微乳的加溶与电导性质研究[J].物理化学学报,2003,19(2):120-124.
[91]严乐美,王雪松,杨桂琴,等.以Span80和Tween60为混合表面活性剂的微乳液研究[J].化学工业与工程,2000,17(5):249-253.
[92]夏剑忠,庞振,鲍景旦,等.水/十一烷基硫酸钠/正丁醇/正辛烷体系的微乳液相行为和结构[J].华东华工学院学报,1991,17(5):600-604.
[93]曾红霞,李子平,王汉卿.水/TX-100/正己醇/正辛烷反相微乳液中水的微乳环境研究[J].化学研究与应用,1999,11(2):142-145.
[94] 莫 春 生 . 半 微 分 电 分 析 研 究 CTAB/n-C7H16/n-C7H16/H2O 微 乳 结 构 [J]. 化 学 学报,2002,60(2):1179-1185.
[95]Gracidac,Melchor J L,Miranda M E, et al. Evaluation of tolerability, safety, and efficiency of cyclosporine microemulsion in renal transplant recipients[J].Transplant proc, 1996, 28(4):2171.
[96]黄仁杰.低毒药用微乳的研制[J].海峡药学,2003,15(6):19-21.
[97]Schechter R S and Bourrel M.Microemulsions and Related Systems [M].New York: Marcel Dekker, 1998.
[98]Suchat Watnasirichaikul,Nigel M Davies,Thomas Rades,et al.Preparation of biodegradable insulin nanocapsules from biocompatible microemulsions[J].Pharm Res,2000,6:684-689.
[99]Jayne LM, Gareth D R.Microemulsion-based media as novel drug delivery systems[J].Advanced Drug Delibery Reviews, 2005, 45:89-121.
[100]L.M.Prince, Microemulsion, Theory and Practice [M].Academic Press, New York, 1977.
[101]寇贺红.丁香酚纳米乳的研制[D].西北农林科技大学硕士论文,2006.
[102]Paschalis Alexandridis, Dali Zhao and Ali Khan.Lyotropic Liquid Crystallinity in Amphiphilic Block Copolymers: Temperature Effect on Phase Behavior and Structure for Poly (ethylene oxide)-b-poly (propylene oxide)-b-poly (ethelene oxide) Coplymers of Different Composition Langmui[J].1996, 12:2690-2700.
[103]US Patent4, 946,901.
[104]颜肖慈,罗明道编著.界面化学[M].北京:化学工业出版社,2005.
[105]Schmalfub U,Neubert R,Wohlrab W.Modification of drug penetration into human skin using microemulsions[J].J Control Rel,1997,46:279-285.
[106]L.M.Prince.Academic Microemulsion [M].New York: ChapterPress, 1997.
[107]滕弘霓,滕大为,陈宗淇.醇的链长对微乳状液形成的影响[J].化学研究与应用,1997,9(4):420-424.
[108]Robbins M L.Microemulsion Solubilization and Microemulsion[M].Plenum Press,New York, 1997,713.
[109]Michell D J and Ninham B W[J].Chem Soc,Faraday Trans,1981,2(77):601.
[110]徐岩,陈祖基,宋洁贞,等.毛果芸香碱微乳滴眼剂及滴眼液在兔眼房水中的药代动力学研究[J].中华眼科杂志,1999,35(6):446.
[111]Noguchi N,Horiuchi T,Hatautori R,et al.Manufacture of arbutin with β-glucosdase from glucose and hydroquinone[P].日本公开专利:93,176, 785, 1993.
[112]L. J. Magid and C. A. Martin,in “Reverse Micelles”(P. L. Luisi and B.E.Straub, eds.).P.181,Plenum Press,New York,1984.
[113]D.J.Michell and B.W.Ninham, J.Chem.Soc.Faraday Trans, 277:601(1981).
[114]Shinoda K,Araki M,Sadaghiani A,et al.Lecithinbased microemulsions:phase behavior and microstructure[J].JPhys Chem,1991,95:989-993.
[115]Milan Johann Schwuger, Katrin Stiekdom.Microemulsion in technical processes[J].American Chemical Society,1995,95:849-864.
[116]E. Ruckenstein and R. Krishnan, J. Colloid Interface Sci.75:476, 76:188,201(1980).
[117]M. Burrel and C.Chambu, Soc. Pet.Eng.J.23:327.
[118]M.Bourrel and R.S.Schechter,in“Microemution and Related Systems:Formation,Solvency,and Physical Properties”,Chapter 1,Surfactant Science Series Vol. 30,Marcel Dekker,Inc.New York and Basel(1988).
[119]Eli Ruckenstein.Concentrated emulsion polymerization [M].Springer Berlin, 1997.
[120]Cao ZS, Lu FQ.Microemulsion and their application for the drugs [J].World Pharmacy,1993, 14(6):289-293.
[121]Tooka Hidemi,Ogawa,Etsuko,et al.Formulation of W/O type microemulsion in biocompatible surfactant systems[J].Nihon yukagakkaishi,1997,46(12):1475-1479.
[122]鲁莹,刘英,蒋雪涛.新型药物载体:微乳[J].国外医药-合成药、生化药制剂分册,1999,20(4):253-258.
[123]Panyiotisp,Constantinides,Jean-pauls.Formulation and physical characterization of water-in-oil microemulsions containing long-cersusmedium-chain glycerides[J].Int J Pharm,1997,158(1):57-68.
[124]Corswant CV,Thoren P,Engstrom S.Triglyceride-Based microcinulsion for intravenous administration of sparingly soluble substances[J].J Pharm sci,1998,87(2):200-208.
[125]Warisnoicharoen W,Lansley AB,Lawrence MJ.Nonionic oil-in-water microemulsions:the effect of oil type on phase behaviour[J].Int J Pharm,2000,198:7-27.
[126]Kawakami,Takayoshiyoshikawa,Yasushimoroto.Microcinulsion formulation for enhanced absorption of poorly soluble drug prescription design [J].JControl Rel, 2002, 81:65-74.
[127]Malcolmson C,Satra C,Kantaria S.Effect of oil on the level of solubilization of testosterone propionate into nonionic oil-in-vater microemulsions [J].Pharm Sci,1998,87(4):109-116.
[128]张文娟.利福平微乳的研制[D].西北农林科技大学硕士论文,2006.
[129]董红宾.熊果苷微乳的研制[D].西北农林科技大学硕士论文,2007.
[130]于力,张钧寿,周建平.纳米乳的研究及其在制剂学领域的应用[J].药学进展.2006,30(11):491-498.
[131]赵国玺,朱埗瑶.表面活性剂作用原理[M].北京:中国轻工业出版社,2003,1:589-634.
[132]Zhang Q Z,Jiang X G,Jiang W M,et al.Preparation of nimodipine-loaded microem- ulsion for intranasal delivery and evaluation on the targeting efficiency to the brain[J].Int J Pharm,2004,275: 85-96.
[133]奉建芳.我国纳米给药系统的研究与应用[J].中南药学,2004,2(1):29-33.
[134]安红丽.原花青素纳米乳的研制[D].西北农林科技大学硕士论文,2007.
[135]D Attwood,L R Currie,P H Elworthy. J.Colloid Interface Sci, 1974, 46:249-256.
[136]王晓黎,蒋雪涛.微乳在药剂学上的应用[J].解放军药学学报,2000,16(2):88-91.
[137]姚静,周建平,杨宇欣,等.微乳对难溶性药物增溶机理的研究[J].中国药科大学学报,2004,35(6):495.
[138]陆彬主编.药物新剂型与新技术[M].北京:人民卫生出版社,1998.
[139]许琼明,莫凤奎.反胶束体系在药学领域中的应用[J].沈阳药科大学学报,2001,18(5):386-389.
[140]Lawrence MJ.Surfactant system: Microemulsion and vesicles for drug delivery[J].Eur J Drug Metab Pharmacokinet, 1994, 19:257.
[141]Kemken J, Ziegler A, Muller B W.Influence of superstaturation on the pharnacodynamic effect of bupranolol after dermal adiministration using microemulsions as vehicle[J].Pharm Res, 1992, 9(4):554.
[142]张立超,胡晋红.微乳透皮给药系统的研究进展[J].国外医学-药学分册,2004,31(1):44-48.
[143]Kreilgaard M, Kemme MJ, Burggraaf J,et al. Influence of a microemulsion vehicle on cutaneous bioequivalence of a lipophilic model drug assessed by microdialysis and pharmacodynamics[J].Pharm Res,2001,18(5):593-599.
[144]Peira E,Scolari P,Gasco MR.Transdermal permeation of apomorphine through hairless mouse skin from microemulsions[J].Int J Pharm,2001,226(1-2):47-51.
[145]Peltola S, Saarinen Savolainen P, Kiesvaara J, et al.Microemulsionsfor top ical delivery of estradiol [J].Int J Pharm, 2003, 254:99-107.
[146]Trotta M, Morel S, Gasco MR. Effect of oil phase composition on the skin permeation of felodipine from o/w microemulsions[J].Pharmazie, 1997, 52(1):50.
[147]Rhee YS,Choi JG,Park ES,et al.Transdermal delivery of ketoprofen using microemulsions[J].Int J Pharm,2001,228(1-2):161-170.
[148]Pao1ino D,Ventura CA,Nistico S,et al.Lecithin microemulsions for the topical administration of ketoprofen:percutaneous absorption through human skin and in vivo human skin to1erability[J].Int J Pharm,2002,244(1-2):21-31.
[149]Gloor M, Haus G, Keipert S.Keratolytic activity of microenrdsions[J].Skin Pharmacol Appl, 2003, 16(3):151.
[150]Kemken J, Ziegler A, Muller BW.Pharmacodynamic efects of transdermal bupranolol and timololin-vivo:comparison of microemulsions and matrix patches as vehide[J].Methods Find Exp Clin Pharmacol,1991,13(5):361.
[151]Wu H,Ramachandran C,Weiner ND,et a1.Topical transport of hydrophilic compounds using water-in-oil nanoemulsions[J].Int J Phann.2001,220(1-2):63.
[152]Gloor M and Gehring W. Effects of emulsions on the stratum corneum barrier and hydration [J].Der Hautarzt, Zeitschriftfur Dermatologie, Venerologie, and verwandte Gebiete. Hautarzt, 2003, 54(4):324.
[153]Sintov AC,Shapiro L.New microemulsion vehicle facilitates percutaneous penetrationin vitro and cutaneous drug bioavailability in vivo[J].J ControlRelease,2004,95:173.
[154]Huailiang W U,Chandrasekharan Ramachandran and Norman D Weiner.Topical transport of hydrophilic compounds using water-in-oil nanoemulsion[J].Int J Pharm,2001,220:63-75.
[155]Cortesi R,Esposito E,Maietti A,etal. Formulion study for the antitumor drug camptothecin: liposomes, micellarsolitions and a microemulsion[J].Int J Pharm, 1997, 159:95.
[156]沈熊,吴伟.自乳化和自微乳化释药系统[J].复旦学报(医学版),2003,30(2):180-183.
[157]Cottens S,Haeberlin B,Sedrani R,etal. Pharmaceaticecl microemulsion preconcent rates containing cyclosporings and macrecides[J].Swifz, WO 96132739 May 1996.
[158]叶国庆,张强,严宝霞.环孢素 A 微乳浓缩液的药代动力学和生物等效性评价[J].中国抗生素杂志,1999,30(7):299-301.
[159]梁月兰,黄春新,张音音.Bayesian 反馈法估算肾移植患者环孢素 A 的血药浓度[J].中国药房,2007,18(29):2272-2273.
[160]Mueller EA,Kovarik JM,van Bree JB,et al. Influence of afat-rich meal on the pharmacokinetics of a new oral formulationof cyclosporine in a crossover comparison with the marketformulation[J].Pharm Res,1994,11(1):151-155.
[161] 沈海蓉 , 李中东 , 钟明康 . 自微乳释药系统及其制剂的研究进展 [J]. 中国新药与临床杂志,2005,24(5):409-412.
[162]Yang J,Wang HD,Lu DX,et al. Effects of neutral sulfate berberine on LPS-induced cardiomyocyte TNF-αsecretion,abnormal calcium cycling, and cardiac dysfunction in rats[J].Acta Pharmacol Sin,2006,27(2):173-178.
[163]SHUI MK,ANDREW JH,CHRISTOPHER JHP.Formulation design and bioavailability assessment of lipidic self-emulsifying form ulations of halofantrine[J].Int J Pharm,1998,167(2):155-164.
[164]Khoo SM, Shackleford DM, Porter CJ.Intestinal lymphatic transport of halofantrine OOClllXS after oral administration of a trait-dose lipidbased formulation to fasted dogs[J].Res, 2003, 20(9):1460.
[165]黄春玉,周建平,姚 静,等.尼莫地平微乳及自微乳的家兔口服生物利用度研究[J].中国药科大学学报,2004,35(5):409-4l2.
[166]Lu Y,Jiang X T,Zen R J,et al.Pharm acokinetics of diclofenac sodium microemulsion in human[J].Acad J Sec Mil Med Univ,2001,22(4):364-366.
[167]Ritschel WA.Microemulsions for improved peptide absorption from the gastrointestinal tract[J].Methods Find Exp Clin Pharmacol,1993,13(3):205-220.
[168]Myers RA, Stella VJ.Factors affecting the lymphatic transport of penclomedine (NSC-338720), liposome cytotoxic drug: comparison to DDT and hexachlorobenzene[J].Int J Pharm,1992, 80(1):51-62.
[169]王召,杨金奎,陆丽芳,等.胰岛素口服微乳经狗十二指肠给药的体内吸收途径研究[J].中国药科大学学报,1997,28(6):323-325.
[170]崔晶,翟光喜,邹满.微乳给药系统的研究与应用[J].食品与药品,2005,7(1):23-25.
[171]王倩,丁红梅,周海源.微乳相图及工艺研究[J].西北药学杂志,1997,12(2):72.
[172]Lee MJ,Lee MH,Shim CK.Inverse targeting of drugs to reticuloendothelial system-rich organs by lipid microemulsion emulsified with poloxamer 338[J].Int J Pharm,1995,113(2):175-187.
[173]张学农,唐丽华,阎雪莹,等.紫杉醇自乳化微乳的制备及其在大鼠体内的药动学[J].中国新药与临床杂志,2005,24(4):294-298.
[174]Gasco MR,Pattarino F,Lattanzi F.Long-acting delivery systems for peptides: reduced plasma testosterone levels in male rat s after a singleinjection[J].Int J Pharm,1990,62:119.
[175]He L,Wang GL,Zhang Q.An alternative paclitaxel microemulsion formulation: hypersensitivity evaluation and pharma cokinetic profile[J].Int J Pharm,2003,250(1):45-50.
[176]Beilin M, Bar-Ilan A, Amselem S.Ocular retention time of submicron emulsion (SME) and the miotic response to pilocarpine delivered in SME[J].Invest Ophathalmol Vis Sci,1995,36(4):S166.
[177]Keipert S.Development and characterization of microemulsions for ocular application[J].Eur J Pharm Biopharm,1997,43(2):179-183.
[178]Muchtar S,Abdulrazik M,Frucht-Pery J,et al.Ex-vivo permeation study of indomethacin from a submicron emulsion through albino rabbit cornea[J].J Controlled Release,1997,44(1):55-64.
[179]Elbaz E,Zeevi A,Klang S,et a.Positively charged submicronemulsions,a new type of colloidal drug carrier[J].Int J Pharm,1993,96(1-3):R1-R6.
[180]Klang SH,Frucht-Pery J,Hoffman A,et al.Physicochemical characterization and acute toxicity evaluation of a positively charged submicron emulsion vehicle[J].J Pharm Pharmacol,1994,46(12): 986-993.
[181]Xu HB,Huang KX,Zhu YS,et al.Hypoglycaemic effect of anovel insulin buccal formulation on rabbits [J].Pharmacol Res,2002,46(5):459-467.
[182]Ceschel GC,Maffei P,Moretti MD,et al.In vitro permeationthrough porcine buccal mucosa of Salvia desoleana Atzei&Picciessential oil from topical formulations[J].Int J Pharm,2000,195(1-2):171-177.
[183]殷朝洲,李保存,朱来汀,等.紫苏的开发和利用[J].植物杂志,1990 (4):18-22.
[184]彭小玉,邓焕彩,涂剑平等.紫苏脂肪油理化性质分析[J].江西化工,2003,3:32-34.
[185]张太平.黔南山区苏子种质资源研究[J].中国油料,1997,19(1):67-68.
[186]张卫民,刘月秀,王红.紫苏子的化学成分研究[J].中国野生植物资源,1998,17(1):42-44.
[187]张贵君主编.常用中药鉴定大全[M].哈尔滨:黑龙江科学技术出版社,1993.
[188]王永奇,李滦宁,杨英华.紫苏子的化学成分[J].中草药,1995,26(5):236-238.
[189]殷朝洲.紫苏的种籽、茎叶营养[J].上海农业学报,1993,9(1):13-15.
[190]黄启飞,丁德蓉.紫苏的研究进展[J].中国野生植物资源,1999,18(2):12-15.
[191]李素芬.苏子饼的饲用价值[J].饲养研究,1994 (1):26-28.
[192]王静珍.紫苏与白苏药理作用的研究[J].中国中药杂志,1997,22(1):48-51.
[193]陈文麟.紫苏油的特点及其利用[J].中国油料,1992 (3):26-28.
[194]Kazunori I,Tsuyoshi Y,Soyao M,et al. Isolation and purification of α-linolenic acid[P].Jap.Kokai Tok Koho JP,1988,63,295,698,02.
[195]J.Hirano, Y.Isoda, Y.Nishizawa.Utilizationof n-3 plant oils.perilla and flaxseed oils[J].YuKagakn, 1991,40(10):942.
[196]Watababe S, Suzuki E, Kojima N, et al.Effect of dietary alphalinolenate/linoleate balance on collagen-inducted platelet aggregation and serotonin release in rats[J].Chem Pharm Bull,1989, 37(6):1572.
[197]Boudreau MD,Chanmugam PS,Hart SB,et al.Lack of dose reponse by dietary n-3 fatty acids at a contant ratio of n-3 to n-6 fatty acids in suppressing eicosanid biosynthesis from arachidonic acid[J].AmJ Clin Nutr,1991,54(1):111.
[198]Garg ML, Thomson ABR, Chandinin MT.Interactions of saturated n-6 and n-3 polyunsaturated fatty acids to mo late arachidonic acidmetabolism[J].J Lipid Res,1990,31:271.
[199]徐章华,邵玉芬.苏子油对大鼠血脂及血液流变性的影响[J].营养学报,1997,19(1):11-15.
[200]郭英.紫苏油和松子油对大鼠机体脂类和脂质过氧化的影响[J].营养学报,1996,18 (3):78-79.
[201]严少敏,李玲玲,高南南等.白苏子脂肪油的调血脂作用研究[J].中草药.1993,24 (4):193-194.
[202]Shimokawa T,Moriuchi A,Hori T,et al. Effect of dietary-linolenate/linoleate balance on mean survival time, incidence of stroke and blood pressure of spontaneously hypertensive rates[J].Life Sci,1988,43(25):2067.
[203]Berry EM, Hirsch J.Dose dietary linolenic acid influene blood pressure[J].Am J Clin Nutr, 1986, 44:336.
[204]刘冬,石山,杨玉梅.植物来源的 ω-3 脂肪酸一 α-亚麻酸[J].中草药,1992,23(9):495-496.
[205]刘继华,王威,黄莺,等.紫苏磷脂侧链脂肪酸组成的分析及含量的测定[J].中草药,1998,29 (11):743-744.
[206]周丹.紫苏油对小鼠学习记忆力的影响[J].中草药,1994,25(5):36-38.
[207]Michio W,Shiro A,Nobukazu T,et al.Pharmaceuticals containing xanthine oxidase inhibitor for treatment of gout[P].Eur.Pat.Appl.EP 429,038,29.
[208]周立新,黄风洪,严兴初.α-亚麻酸与 γ-亚麻酸[J].西部粮油科技,2000,25(6):46-48.
[209]BjerveKS, FischerS, S1mrK. Alpha-linolenic acid deficiency in man: efect of ethyllinolenate on plasma and erythrocyte fatty acid composition and biosynthesis of prostanoids[J].Am J Clin Nutr, 1987, 46(4):570-576.
[210]SinclairH M, There latioe importance of essential fatty acids of the Linoleicand/linolenic families Studies with aneskimodiet[J].Prog LipRos, 1981, 20:897.
[211]张欣欣,钱凯先.ω-3 多烯脂肪酸在鸡蛋蛋黄中的积累研究[J].营养学报,1998,21(1):51-53.
[212]傅渝滨.高温加热对食用油中 α-亚麻酸等含量的影响[J].重庆医科大学学报,1998,23 (2):123-125.
[213]万家余,高宏伟.微藻作为动物产品多不饱和脂肪酸来源[J].饲料博览,2002(1):9-11.
[214]Tinoco.J.Prog Lipid Res,1982,21:1.
[215]卢灵军,陈晓理.ω-3 多不饱和脂肪酸与炎症反应[J].国外医学外科学分册,2002,29 (6):340-343.
[216] 修 宇 .18 家 单 位 联 袂 推 出 阿 法 林 分 子 化 提 取 技 术 一 我 国 α- 亚 麻 酸 研 究 获 突破.http://www.sohu.net,1999-03-29.
[217]Hu FB et al .A m J Clin Nutr,1999,69:890-897.
[218]Simopoulpos A P. AmJ Clin Nutr,1991,54:438-493.
[219]Linder MC.Nutirtional Biochemistry and Metabolism with Clinical Applications.2nded,1991:51-83.
[220]Steven D et al.Ann Rev Nutr,1994,14:83-89.
[221]Grundy SM,Denke M A.J Lipid Res,1990,31:1149-1172.
[222]Mensink RP,Katun MB.Arterioscler Thromb,1992,12:911-919.
[223]Bang HO et al.Acta Med scand,1976,200:69-73.
[224]De Lorgeril M et al.Lancet,1994,343:1454-1459.
[225]Nair SSD et al.J Nutr,1997,127:383-393.
[226]Simon JA et al.Stroke.1995,26:778-782.
[227]DyerbergJ, Bang H O.Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis [J].Lanet,1978,2:117.
[228]Kromhout D.Dietary fats long term implications for hearty[J].Nutr.Rev.1992, 50(4):49-53.
[229]Chun SY et al.Nippon Eiyo, Shokuryo Gakkai Shi, 1988, 41(4):279.
[230]Garg ML et al.Lipids,1988,23:847.
[231]Bruce JK et al.A m.J.Clin.Nutr.1991,53:1230-1234.
[232]Cunnane SC et al.Am.J.Clin.Nutr.1994,61:62-68.
[233]Bierenbaum ML et al.J.Am.Coll.Nutr.1993,12:501-504.
[234]Rand MD et al.Atherosclerosis,1986,62:267.
[235]汪鲲,高占峰,齐广海,等.富含 n-3PUFA 蛋黄保健作用的研究[J].饲料工业,2000,21(6):1-4.
[236]何万红.多聚不饱和脂肪酸及其在蛋鸡生产上的应用[J].畜禽业,2000(9):31-32..
[237]Field FJ et al,J L ipids Res,1987,28:50.
[238]Bolton-Smith VC et al.Atherosclerosis, 1988, 72:29.
[239]Sanders TAB et al.Proc Nutr Soc, 1985:44:391.
[240]熊正英,张崇旭,郑毅.多不饱和脂肪酸与运动[J].青海师范大学学报(自然科学版),2002(3):67-70.
[241]齐广海.家禽多不饱和脂肪酸营养作用的研究进展(上)[J].国外畜牧科技,1994,21(4):11-27.
[242]穆照梅.营养学报,1990,12:134.
[243]张康健,王蓝.药用植物资源开发利用学[M].北京:中国林业出版社,1997,136-140.
[244]ShimokawaT, MoriuchA, HoriT,et al.Effect of dietaryal-pha-linolenate/linolenate/linoleata balance on mean survival time,incidence Of stroke and blood pressure of spontaneously Hypertensive rats[J].Life Sci,1988,43(25):2067.
[245]Parks JI et al.Atherosclerosis,1990, 84:93.
[246]Boulanger C et al.Br.J Phannacol,1990,99(1):176.
[247]Knapp HR,FitzGerald GA.N Engl J Med,1989,320:1037-1043.
[248]Rupp H et al.Mol Cell Biochem,1996,162(1):59-64.
[249]Kestin M et al.Am J Clin Nutr,1990,51(6):1028-1034.
[250]Singer et al.J Hum Hypertens,1990,4(3):227-233.
[251]Sanders TAB et al.Nutrition 1985:101.
[252]OwrenP Ae ta l.Lancet,1964,975.
[253]Levine PH et al.Arch Intenr Med, 1989, 149:1113.
[254]Hunter JE.Life Sci.1989, 171:45-55.
[255]Conor L et al.Am.J.Clin.Nutr, 1997, 66:51020-51030.
[256]钟兹声主编,一氧化氮的生物医学[M].上海:上海医科大学出版社,1997:4-7.
[257]Jing X et al.Lipids,1996,31:541-544.
[258]于占洋.紫苏属植物的研究及其新进展[J].国外医学药学分册,1986,(3):173-176.
[259]野田泰久.油脂,1990,43(5):44.
[260]Hashionoto TH et al.N Eng J Med,1985,312:1217.
[261]Horii T et al.J Immunol,1991,147(5):1607.
[262]Prescot SM, J Biol Chem,1984,259:7615.
[263]Careaa-Houck M et al.J.Lipid Res,1989,30:1277.
[264]Ziboh VA et al.Arch dennatol,1986,122:1277.
[265]Dwingt R et al.Lipids,1996,31:523-532.
[266]吉田好弘.油脂,1991,44(6):49.
[267] 曹忠春 , 张力 , 周晓刚 , 等 .γ- 亚麻酸膳食干预对免疫系统疾病的调节作用 [J]. 中国油脂,2000,25(6):189-191.
[268]孙铁路.日粮脂肪酸与动物免疫机能[J].畜禽业,2000,119(3):46-48.
[269]Jeffery N M.1997.Effects of variations in the proportions of saturated, monosaturated and polyunsaturated fatty acids in the rat diet on spleen lymphocyte function [J].British Journal of Nutrition, 77:805-823.
[270]Fritsche K L,Cassity N.A.Dietary ω-3 fatty acids reduce antibody-dependent cell cytotoxicity and alter eicosanoid release by Chicken immune cells[J].Poult Sci,1992.16:46-57.
[271]Lokesh B .R.Interleukin-1 and tumor necorsis factor synthesis by mouse peritoneal macrophage is enhanced by dietaryω-3 polyunsaturated fatty acids[J].Immunol.letts.1990:281-286.
[272]De wille J.W Effect of dietary fatty acids on delayed-type hypersensitivity in mice J[J].Nutr,1981, 20:39-43.
[273]MurphyM.G.Dietaryfattyacids andmembrane protein Function[J].Nuti, Biochem, 1990, (1):68-77.
[274]Bourre JM et al.Nutrition,1989,5(4):266.
[275]Bourre JM et al.J.Nutr,1989,119:1880.
[276]Bourre JM et al.Lipids,1987,22:535.
[277]曲永洵.谈谈油脂的保健功能[J].中国油脂,2000,25(5):39-40.
[278]吴葆杰.人体的必须脂肪酸 ω-3 型多烯脂肪酸癌细胞转移抑制剂[J].国外医讯,1997 (12):25-26.
[279]Devi MA et al .Experientia,1994,50:489-492.
[280]Fritsche K L.JohnstonP.Effect of dietary omega-3 fatty acid profile and prostag landing production of two murine mam-many adenocarcinomas [J].J Nutr, 1990,120 (12):1601-1609.
[281]王淑丽,陈济民.苏子油与 α-亚麻酸[J].沈阳药科大学学报,1995,12(3):228-233.
[282]谢丽涛,黄济群.不饱和脂肪酸及其硒化物对 BEL-7402 人肝癌细胞的杀伤作用及 DNA 合成的影响[J].中国肿瘤临床,1998,25(7):501.
[283]谢丽涛,黄济群,陈家坤.三种脂肪酸对人肝癌细胞 DNA 合成和甲胎蛋白分泌的影响[J].癌变畸变突变,1998(5):298.
[284]邱磊,姜远英.多不饱和脂肪酸的药理研究进展[J].药学实践杂志,1996,14(2):77-80.
[285]Horri T et al.Chem Pharm Bull,1987,35(9):3925.
[286]Sauer LA et al.Br J Cancer,1992,66:297-303.
[287]Ramesh G et al.Cancer Leters 1998,123:207-214.
[288]Alison C et al.Biochem Mol Bio Inter,1998,45(2):331-336.
[289]刘程.表面活性剂大全[M].北京:北京工业大学出版社,1994.
[290]王新伟.高效氯氰菊酯微乳液形成规律研究和形成机理初探[D].中国优秀博硕士学位论文, 2004.
[291]吴顺芹,李三鸣,郎轶咏,等.水包油型微乳形成因素的考察[J].沈阳药科大学学报,2005,2:96-99.
[292]Aboofazeli R, Lawrence C B, Wicks S R, et al. Investigations into the formation and characterization of phospholipid microemulsions.Ⅲ. Pseudo-ternary phase diagrams of systems containing water-lecithin-isoropyl myristate and either an alkanoic acid, amine, alkanediol, polyethylene glycol alkyl ether or alcohol as cosurfactant [J].Int J Pharm,1994,111(1):63-72.
[293]Rosen M.J.Surfactant Science and Technology.2nd Edition[M].NewYork: John Wiley &Sons,1989, 325-333.
[294]Myers D.Surfactant Science and Technology[M].New York: VCH Publisher,Inc,1988,235-245.
[295]Macek TJ.Preparation of parenteral dispersions[J].J Pharm Sci 1963,52:694-699.
[296]Fletcher P D,Binks B P,Taylor D J F,Taylor P.Rodham D K.Winn P D.Pesticide Sci,1999,55:638.
[297]Oh K H,Baran J R J.Wade W H.Weerasooriya V.Journal of dispersion Science and Technology[J]. 1995,16(2):165.
[298]陈福良,王仪,郑斐能,等.微乳剂低温稳定性的研究[J].物理化学学报,2002,18(7):661-664.
[299]李慧韫,张天胜.混合脂肪酸甲酯的气相色谱一质谱联用分析[J].皮革化工.2003, 20(6):18-27.
[300]何海冰,唐星.莪术油纳米乳剂的制备及制备工艺影响因素考察[J].沈阳药科大学学报,2005, 5,22,(3):164-167.
[301]杨惊宇.隐丹参酮微乳的制备工艺及相对生物利用度的测定[D].湖南中医学院硕士学位论文,2005.
[302]吴冀华,裘爱永.气相色谱法分析共扼亚油酸异构体[J].中国油脂,2002,27(1):75-79.
[303]张学杰,王程田,程传格等.益母草种子油中脂肪酸组成的气相色谱一质谱联用分析[J].中国油脂,2003,28(5):29-34.
[304]陈奇.中药药理研究方法学(第一版)[M].北京:人民卫生出版社,1996.
[305]周力国主编.药物毒理学[M].北京:中国医药科技出版社,2001.
[306]中华人民共和国卫生部药政管理局.中药新药研究指南[M].北京:人民卫生出版社,1986.
[307]徐钢梅,张彩霞,宁丽.MTT 法评价镓合金的细胞毒性[J].中华口腔医学杂志,2001,36(3):189-192.
[308]徐爱凤,方玉,侯本祥.天然生物膜的细胞毒性的试验研究[J].北京口腔医学,2004,12(1):30-31.
[309]Richardson R R,Miller J A,Reichert WM.Polyimides as biomaterials: preliminary biocompatibility testing[J].Biomaterials,1993,14(8):627-635.
[310]凌树森,张菊,孔维林.小鼠高胆固醇血症快速造型法的研究[J].药学通报,1985,70(1):152-161.
[311]丁向东,周文泉,崔玲,等.络活胶囊对高血压大鼠血浆肾上腺髓质和组织因子途径抑制物的影响[J].山东中医药大学学报,2004,28(1):56-58.
[312]鱼达.抗癌药物敏感性试验进展[J].肿瘤防治研究,1991,18(1):57-59.
[313]Hyo-JinAn,Hwan-SuckChung,Na-HyungKim,et al.Park Regulatory Effect Sense Line Dieton Cholesteroland Body Weightin Mice Fed High-fat[J].Annals of Nutrition & Metabolism 2004, 48(6):398-400.
[314]Sinzinger H,Wolfram R,Peskar BA.Muscular side effects of statins[J].J Cardiovasc Pharmacol, 2002,40:163-171.
[315]Mastroianni CM,Ettorre G,Forcina G,et al.Rhabdomyolysis after cerivastatin-gemfibrozil therapy in an HIV-infected patient with protease inhibitor-related hyperlipidemia[J].AIDS,2001,15:820-821.
[316]Ihara M,Umekawa H,Takahashi T,et al.Comparative effects of short and long-term feeding of safflower oil and perilla oil on lipid metabolism in rats[J].Comp Biochem Physiol B Biochem Mol Biol,1998,121:223-231.
[317]Sakai K,Shimokawa T,Kobayashi T,et al.Lipid lowering effects of high linoleate and high alpha-linolenate diets in rats and mice.Consequence of long-term feedings[J].Chem Pharm Bull(Tokyo),1992,40:2129-2132.
[318]Morise A,Serougne C,Gripois D,et al.Effects of dietary alpha linolenic acid on cholesterol metabolism in male and female hamsters of the LPN strain[J].J Nutr Biochem,2004,15:51-61.
[319]王淑丽,陈济民.紫苏子油乳剂中alpha-亚麻酸的药物动力学与生物利用度研究[J].沈阳药科大学学报.1998,7,15(3):157-166.
[320]魏树礼主编.生物药剂学与药物动力学(第二版)[M].北京:北京医科大学和中国协和医科大学联合出版社,1990.