紫苏子油纳米乳的研究
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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.
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
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