复方降脂软胶囊的研制及作用机制研究
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摘要
目的：结合新疆葡萄和番茄的开发现状，以番茄红素和葡萄籽提取物为主要功效成分，研制纯天然保健食品—复方降脂软胶囊，并进行毒理学、功效学评价，制定产品质量标准，研究降脂作用机制。方法：通过单因素设计筛选影响葡萄籽中原花青素超临界CO2萃取的主要因素，通过正交实验设计研究萃取最佳工艺；以原花青素和番茄红素为主要功效成分，按照设计处方进行胶囊制备工艺研究、质量标准研究及毒理学研究；通过建立小鼠高脂血症模型对胶囊处方功效进行初步验证，建立混合型大鼠高脂血症模型进行胶囊降脂作用及机制研究。结果：1．复方降脂软胶囊的研制：（1）葡萄籽原花青素超临界CO2萃取工艺研究：1）单因素实验结果表明：萃取压力15MPa、温度50℃、时间30min、携带剂加入量400mL条件下，原花青素收率最高；2）正交实验研究结果表明：葡萄籽中原花青素超临界CO2萃取的最优工艺为：萃取压力18MPa、温度50℃、时间40min、携带剂加入量500mL。3）建立了高分离快速液相色谱测定超临界葡萄籽萃取液中原花青素含量的方法，在设定色谱条件下回归方程为：y=639.0818x-28.961，R2=0.9997，在0.60～3.60mg/mL范围内线性关系良好。（2）复方降脂软胶囊处方筛选及制备工艺研究：1）胶囊处方：葵花籽油63.5%，葡萄籽提取物8.0%，番茄红素油树脂28.5%，按处方配制胶囊内容物药液，其流动性、切断性、内容物悬浮稳定性均符合制剂要求；在胶囊壳常规配方基础上，确定TiO2、苋菜红、葡萄紫分别占囊壳总质量的0.50%、0.20%、0.06％时，囊壳遮蔽及感观效果最好，经小试和中试证明制备工艺科学可行；2）制定了复方降脂软胶囊的质量标准，建立了胶囊中原花青素和番茄红素的含量测定方法，经考察，上述测定方法专属性强，精密度、重复性好，准确度佳；通过加速实验考察软胶囊制剂的稳定性，装量差异、崩解时限检查均符合《中华人民共和国药典》（2010版）相关要求；胶囊内容物中功效成分的含量、过氧化值等均符合相关规范的要求，产品的保质期不少于2年。2．复方降脂软胶囊毒理学与功效学评价：（1）胶囊急性毒性研究：经测试，胶囊对实验各性别小鼠体重无明显影响（P＞0.05），动物各系统未出现明显中毒症状和体征，胶囊的经口急性毒性MTD大于10g/kg BW，属实际无毒物。（2）胶囊内容物处方、葡萄籽提取物和番茄红素对正常小鼠和高脂血症小鼠的影响：1）胶囊内容物处方、葡萄籽提取物和番茄红素无论单独给药还是联合给药，在实验剂量下均对正常小鼠的体重和血清TC、TG、HDL、LDL没有明显影响（P＞0.05），各组动物生长状态良好；2）胶囊处方中、高剂量组可降低高脂血症小鼠血清TC和LDL水平，升高HDL水平（P＜0.05）；但葡萄籽提取物和番茄红素单独给药对高脂血症小鼠血脂没有明显影响（P＞0.05）。（3）复方降脂软胶囊功效学研究：1）从第0周开始，各组动物与空白组比较体重均明显增加（P＜0.01）；第1周时，胶囊高剂量组与模型组比较，体重增长放缓（P＜0.05）；第6周时，各干预组体重均低于模型组（P＜0.05）；2）在给药第4周和第6周，与模型组比较，胶囊各剂量组和阳性对照组均可显著降低高脂血症模型大鼠血清TG和TC含量（P＜0.05）；3）胶囊在给药第4周和第6周，与模型组比较，胶囊高剂量组血清HDL水平升高（P＜0.05），胶囊各剂量组和阳性对照组大鼠血清LDL水平降低（P＜0.01）；4）与模型组比较，胶囊中、高剂量组和阳性对照组可降低高脂血症模型大鼠血清ApoB、LPa含量及ApoB/ApoAI比值（P＜0.01），适当提高血清ApoAI水平，但差异无统计学意义（P＞0.05）；5）与模型组相比，胶囊各剂量组和阳性对照组可使肝组织SOD活性、GSH-Px活力上升，MDA含量降低(P＜0.01)。6）各组之间动物脏器指数差异无统计学意义（P＞0.05）；7）病理组织学结果显示，胶囊可以明显改善由于高脂饮食造成的肝细胞病理损伤，随着剂量的增加病理损伤改善程度越明显。3．复方降脂软胶囊作用机制研究：（1）胶囊对脂代谢关键酶的影响：1）胶囊中、高剂量组和阳性对照组可升高高脂血症大鼠肝组织中HL含量，降低HMG-CoA含量，与模型组比较，差异有统计学意义（P＜0.05）；2）与模型组比较，胶囊高剂量组大鼠LCAT和LPL的含量升高（P＜0.01）。（2）胶囊降脂作用分子机制研究：1）与模型组比较，胶囊高剂量组动物肝脏LDL-RmRNA的相对表达量上升（P＜0.05）；2）胶囊中、高剂量组动物肝脏PPARγmRNA的相对表达量高于模型组（P＜0.01）；3）胶囊可以上调高脂血症模型大鼠肝脏LXRamRNA的相对表达量，但各组动物间差异无统计学意义（P＞0.05）；4）胶囊各剂量组动物肝脏SR-BImRNA的相对表达量上升，其中高剂量组与模型组比较，差异有统计学意义（P＜0.01）；5）与模型组比较，胶囊各剂量组肝脏ABCA1mRNA相对表达量上升，其中高剂量组与模型组差异有统计学意义（P＜0.01）。结论：1．葡萄籽中原花青素超临界CO2萃取的最优工艺为：萃取压力18MPa、温度50℃、时间40min、携带剂加入量500mL，放大实验证实其工艺方法可靠，可用于工业生产；用高分离快速液相色谱检测萃取液中原花青素含量，方法准确、可靠，重复性好，精密度佳，可以作为葡萄籽超临界CO2萃取液中原花青素含量测定的方法；胶囊处方设计合理，制备工艺科学可行，质量可控，相关指标符合国家药典（2010版）等规范要求，保质期不少于2年；胶囊中功效成分检测方法准确可靠，原花青素平均含量87.90mg/g，RSD为1.32%，番茄红素含量为15.24mg/g，RSD为1.27%；2．胶囊经口急性毒性MTD大于10g/kg·BW，属实际无毒物；按胶囊设计处方配制的内容物，可以有效降低高脂血症小鼠血清TC、LDL水平，升高血清HDL水平，降脂效果明显优于番茄红素和原花青素单独应用，提示二者在降脂功效方面具有协同作用；胶囊中试产品能显著降低高脂血症模型大鼠血清TG、TC、LDL、ApoB和LPa水平，降低ApoB/ApoA1比值，适当升高HDL和ApoA1水平；能提高机体抗氧化酶活性，降低MDA含量；能减轻高脂饮食导致的大鼠肝脏病理损害，随剂量增加，病理损伤逐渐缓解。3．胶囊主要通过提高体内HL、LPL、LCAT的活性，加速体内TG、TC的降解，抑制HMG-CoA的活性，使体内胆固醇合成减少；上调动物体内胆固醇逆转运和脂代谢关键基因LDL-R mRNA、PPARγ mRNA、SR-BI mRNA及ABCA1mRNA的表达，加速脂质代谢和胆固醇逆转运而发挥降脂作用。
Objective: To develop pure natural health food, compound lipid-lowering softcapsule with grape seed procyanidins and lycopene as main efficacy components; at thesame time, to study on its quality standard, acute oral toxicity, lipid-lowering effect andmechanisms. Methods: To research the optimum process conditions of procyanidinsextracting in grape seed by supercritical CO2extraction (SCF-CO2). By single factor andorthogonal experiment design, the optimum process conditions were studied. Theprescription of capsule consisted of grape seed procyanidins, lycopene and sunflowerseed oil. The quality standard of the capsule was established according to the relevantspecifications of governmental health food standards. The acute oral toxicity andlipid-lowering effect of the capsule were studied according to health food inspection andevaluation of technical specifications (2003), and its mechanisms of lipid-lowering effectwere studied. Results:1. The development of compound lipid-lowering soft capsule:(1)The technical study of extracting procyanidins from grape seed by supercritical CO2:1)The single factor experiment results showed when the extraction pressure was15MPa,the extraction temperature was50℃, the extraction time was30min, and the volume ofethylalcohol was400mL respectively, the extraction yield of procyanidins was thehighest.2) The orthogonal experiment results showed that the optimum processconditions: the extraction pressure was18MPa，the extraction temperature was50℃，the extraction time was40min, and the volume of ethylalcohol was500mL.3) Themethod for determination of procyanidins content in supercritical CO2extraction fluid ofgrape seed by rapid resolution liquid chromatogruphy (RRLC) was established. ZorbaxXDB-C18Column (4.6mm×50mm,1.8μm) was used, and1.5%acetic acidmethanol-1.5%acetic acid water (90:10, V/V) was used as mobile phase. The flow ratewas0.9mL·min-1, the detection wavelength was280nm and the column temperature was at 40℃. The line correlation of procyanidins content was observed from0.60~3.60mg/mL,y=639.0818x-28.961, R2=0.9997.(2) To study the prescription screening and preparingtechnology of capsule:1) Prescription of capsule: sunflower seed oil63.5%,grape seedprocyanidins8.0%, lycopene oleoresin28.5%, the flowability, cut off and suspensionstability corresponded with requirement of pharmaceutics. On the basis of the basicprescription of soft capsule shell,0.5%TiO2,0.2%amaranth,0.06%grape purple wereadded, the effect of shield and appearance were satisfying. The results of laboratory scaletest and pre-production showed that the preparation technology was scientific andfeasible.2) The quality standard for capsule was established, the content of lycopene incapsule was detected by high-performance liquid chromatography (HPLC) withKromasilC18Column (4.6mm×150mm,5μm), moving phase: acetonitrile:methanol(50:50, V/V), flow rate:1mL·min-1, wavelength:472nm and the column temperaturewas30℃. The line correlation of lycopene content was observed from0.2000～20.0000μg/mL, y=37743676x+893291.2, r=0.9996. The average recovery was101.20%,RSD was1.09%. The content of procyanidins in capsule was detected by catalyticcolorimetry with ferric ions. The line correlation of procyanidins content was observedfrom0.00~1.50mg/mL, y=0.33969x-0.00889, r=0.99909. The average recovery was102.507%, the RSD was5.565%. The uniformity, disintegration time limited of capsuleconformed to the requirements of pharmacopoeia of the People's Republic of China(2010); the content of functional components and peroxide value of capsule were up tothe standard, and the quality guarantee period was at least2years.2. Toxicology andfunction evaluation:(1) The acute toxicity test was carried out with mice, at the dose of10g/kg·BW, the capsule had no effect on body weight of normal mice (P＞0.05). Theacute oral toxicity test showed that the maximum tolerated dose (MTD) of the capsulewas higher than10g/kg·BW.(2) The influence of GSPE, lycopene and capsuleprescription on normal and hyperlipidemia mice:1) The GSPE, lycopene and capsuleprescription were dosed respectively, which had no effect on body weight, serum TC, TG,HDL and LDL of normal mice (P＞0.05).2) In middle and high dose groups of capsuleprescription, serum TC and LDL levels were decreased, serum HDL level was enhanced(P＜0.05); at the same dose,GSPE or lycopene had no same effect (P＞0.05).(3)Assessment of assisting blood lipids reduction function of capsule.1) From the0week,in comparison with control group, the body weight of other groups was markedlyincreased (P＜0.01); from the1st week, the increase of body weight in model group wasfaster than that of high dose capsule group (P＜0.01); in sixth week, the body weight of all other groups was lighter compared with model group (P＜0.05);2) Compared withmodel group, capsule and positive control Zhibituo groups could decrease the sreum TG,TC levels in the4th and the6th week (P＜0.05).3) In the4th and the6th week,compared with model group, the sreum HDL level was enhanced in high dose capsulegroup (P＜0.05), but the sreum LDL level was decreased in capsule and positive controlZhibituo groups (P＜0.01).4) Compared with model group, the sreum ApoB, LPa andApoB/ApoAI levels decreased in middle, high capsule groups and positive controlZhibituo group (P＜0.01), the sreum ApoAI level enhanced lightly (P＞0.05).5) The allcapsule groups and positive control Zhibituo group could decrease the liver MDA leveland enhance the liver SOD and GSH-Px activities (P＜0.01).6) The organ coefficientwas no difference among groups (P＞0.05).7）The capsule could alleviate the liverpathologic changes induced by high fat diet distinctly.3. Study on the mechanisms ofcompound lipid-lowering soft capsule:(1) Effect of capsule on lipid-metabolizedenzyme level in hyperlipidemia rats.1) The liver HMG-CoA level in middle, high dosegroup and positive control Zhibituo group was decreased，HL level was increased (P＜0.05);2) Compared with the model group, the serum LCAT and LPL levels of high dosegroup were increased significantly (P＜0.01);(2) Study on the molecular mechanisms oflipid-lowing effect in capsule.1) In high dose group treated with capsule, the relativeexpression of LDL-R mRNA in liver was higher than that of mode lgroup (P＜0.05);2)Compared with the model group, the middle, high capsule groups treated with capsuleupregulated the relative expressions of PPARγ mRNA in liver (P＜0.01);3) The relativeexpressions of liver LXRa mRNA in all capsule groups were higher than those of modelgroup, but the difference was no statistical significance (P＞0.05);4) In high dosecapsule group, the relative expression of liver SR-BI mRNA was increased significantly(P＜0.01).5）Compared with the model group, the relative expression of liver ABCA1mRNA was increased in high dose capsule group (P＜0.01). Conclusions:1.Theoptimum process conditions of procyanidins extracting in grape seed: the extractionpressure is18MPa; the extraction temperature is50℃; the extraction time is40min; theethylalcohol addition is500mL. The determination of grape seed proanthocyanidins inthe extract liquor with rapid resolution liquid chromatogruphy (RRLC) is accuracy andprecision, it can provide a new reference method for determination of procyanidinscontent. The prescription of capsule is reasonable, the preparation technology of capsuleis scientific and operable; quality control is simple, quick and accurate. All of relatedindexes conform to the requirements of pharmacopoeia of the People's Republic of China (2010) and the related standards. The quality guarantee period is2years at least. Thedetection methods of functional components in capsule are accurate and reliable. In softcapsule, the average content of procyanidins is87.9000mg/g, RSD is1.32%, the averagecontent of lycopene in soft capsule is15.2418mg/g, RSD is1.27%.2. The maximumtolerated dose (MTD) of capsule is higher than10g/kg·BW. The prescription of capsulecan decrease serum TC and LDL levels and enhance serum HDL level; lipid-loweringeffect of capsule is better than that of grape seed procyanidins or lycopene usedrespectively. So the lycopene and grape seed procyanidins may have synergistic effect inlipid-lowering. The capsule can reduce the serum TG, TC, LDL, ApoB, LPa levels andthe value of ApoB/ApoA1, increase liver SOD and GSH-Px activities, decrease MDAcontent. The capsule can alleviate the liver pathologic changes induced by high fat dietdistinctly.3. The lipid-lowering mechanisms of capsule: elevating the HL, LPL andLCAT levels, inhibitting the enzyme activity of HMG-CoA in hyperlipidemia rats,accelerating the degradation of TG and TC, and reducing cholesterol synthesis. Capsulecan enchance the relative expressions of LDL-R mRNA, PPARγ mRNA, SR-BI andABCA1mRNA, but the expression of LXRa mRNA does not change significantly. Thereverse cholesterol transport (RCT) is major lipid-lowering mechanism.
Objective: To develop pure natural health food, compound lipid-lowering softcapsule with grape seed procyanidins and lycopene as main efficacy components; at thesame time, to study on its quality standard, acute oral toxicity, lipid-lowering effect andmechanisms. Methods: To research the optimum process conditions of procyanidinsextracting in grape seed by supercritical CO2extraction (SCF-CO2). By single factor andorthogonal experiment design, the optimum process conditions were studied. Theprescription of capsule consisted of grape seed procyanidins, lycopene and sunflowerseed oil. The quality standard of the capsule was established according to the relevantspecifications of governmental health food standards. The acute oral toxicity andlipid-lowering effect of the capsule were studied according to health food inspection andevaluation of technical specifications (2003), and its mechanisms of lipid-lowering effectwere studied. Results:1. The development of compound lipid-lowering soft capsule:(1)The technical study of extracting procyanidins from grape seed by supercritical CO2:1)The single factor experiment results showed when the extraction pressure was15MPa,the extraction temperature was50℃, the extraction time was30min, and the volume ofethylalcohol was400mL respectively, the extraction yield of procyanidins was thehighest.2) The orthogonal experiment results showed that the optimum processconditions: the extraction pressure was18MPa，the extraction temperature was50℃，the extraction time was40min, and the volume of ethylalcohol was500mL.3) Themethod for determination of procyanidins content in supercritical CO2extraction fluid ofgrape seed by rapid resolution liquid chromatogruphy (RRLC) was established. ZorbaxXDB-C18Column (4.6mm×50mm,1.8μm) was used, and1.5%acetic acidmethanol-1.5%acetic acid water (90:10, V/V) was used as mobile phase. The flow ratewas0.9mL·min-1, the detection wavelength was280nm and the column temperature was at 40℃. The line correlation of procyanidins content was observed from0.60~3.60mg/mL,y=639.0818x-28.961, R2=0.9997.(2) To study the prescription screening and preparingtechnology of capsule:1) Prescription of capsule: sunflower seed oil63.5%,grape seedprocyanidins8.0%, lycopene oleoresin28.5%, the flowability, cut off and suspensionstability corresponded with requirement of pharmaceutics. On the basis of the basicprescription of soft capsule shell,0.5%TiO2,0.2%amaranth,0.06%grape purple wereadded, the effect of shield and appearance were satisfying. The results of laboratory scaletest and pre-production showed that the preparation technology was scientific andfeasible.2) The quality standard for capsule was established, the content of lycopene incapsule was detected by high-performance liquid chromatography (HPLC) withKromasilC18Column (4.6mm×150mm,5μm), moving phase: acetonitrile:methanol(50:50, V/V), flow rate:1mL·min-1, wavelength:472nm and the column temperaturewas30℃. The line correlation of lycopene content was observed from0.2000～20.0000μg/mL, y=37743676x+893291.2, r=0.9996. The average recovery was101.20%,RSD was1.09%. The content of procyanidins in capsule was detected by catalyticcolorimetry with ferric ions. The line correlation of procyanidins content was observedfrom0.00~1.50mg/mL, y=0.33969x-0.00889, r=0.99909. The average recovery was102.507%, the RSD was5.565%. The uniformity, disintegration time limited of capsuleconformed to the requirements of pharmacopoeia of the People's Republic of China(2010); the content of functional components and peroxide value of capsule were up tothe standard, and the quality guarantee period was at least2years.2. Toxicology andfunction evaluation:(1) The acute toxicity test was carried out with mice, at the dose of10g/kg·BW, the capsule had no effect on body weight of normal mice (P＞0.05). Theacute oral toxicity test showed that the maximum tolerated dose (MTD) of the capsulewas higher than10g/kg·BW.(2) The influence of GSPE, lycopene and capsuleprescription on normal and hyperlipidemia mice:1) The GSPE, lycopene and capsuleprescription were dosed respectively, which had no effect on body weight, serum TC, TG,HDL and LDL of normal mice (P＞0.05).2) In middle and high dose groups of capsuleprescription, serum TC and LDL levels were decreased, serum HDL level was enhanced(P＜0.05); at the same dose,GSPE or lycopene had no same effect (P＞0.05).(3)Assessment of assisting blood lipids reduction function of capsule.1) From the0week,in comparison with control group, the body weight of other groups was markedlyincreased (P＜0.01); from the1st week, the increase of body weight in model group wasfaster than that of high dose capsule group (P＜0.01); in sixth week, the body weight of all other groups was lighter compared with model group (P＜0.05);2) Compared withmodel group, capsule and positive control Zhibituo groups could decrease the sreum TG,TC levels in the4th and the6th week (P＜0.05).3) In the4th and the6th week,compared with model group, the sreum HDL level was enhanced in high dose capsulegroup (P＜0.05), but the sreum LDL level was decreased in capsule and positive controlZhibituo groups (P＜0.01).4) Compared with model group, the sreum ApoB, LPa andApoB/ApoAI levels decreased in middle, high capsule groups and positive controlZhibituo group (P＜0.01), the sreum ApoAI level enhanced lightly (P＞0.05).5) The allcapsule groups and positive control Zhibituo group could decrease the liver MDA leveland enhance the liver SOD and GSH-Px activities (P＜0.01).6) The organ coefficientwas no difference among groups (P＞0.05).7）The capsule could alleviate the liverpathologic changes induced by high fat diet distinctly.3. Study on the mechanisms ofcompound lipid-lowering soft capsule:(1) Effect of capsule on lipid-metabolizedenzyme level in hyperlipidemia rats.1) The liver HMG-CoA level in middle, high dosegroup and positive control Zhibituo group was decreased，HL level was increased (P＜0.05);2) Compared with the model group, the serum LCAT and LPL levels of high dosegroup were increased significantly (P＜0.01);(2) Study on the molecular mechanisms oflipid-lowing effect in capsule.1) In high dose group treated with capsule, the relativeexpression of LDL-R mRNA in liver was higher than that of mode lgroup (P＜0.05);2)Compared with the model group, the middle, high capsule groups treated with capsuleupregulated the relative expressions of PPARγ mRNA in liver (P＜0.01);3) The relativeexpressions of liver LXRa mRNA in all capsule groups were higher than those of modelgroup, but the difference was no statistical significance (P＞0.05);4) In high dosecapsule group, the relative expression of liver SR-BI mRNA was increased significantly(P＜0.01).5）Compared with the model group, the relative expression of liver ABCA1mRNA was increased in high dose capsule group (P＜0.01). Conclusions:1.Theoptimum process conditions of procyanidins extracting in grape seed: the extractionpressure is18MPa; the extraction temperature is50℃; the extraction time is40min; theethylalcohol addition is500mL. The determination of grape seed proanthocyanidins inthe extract liquor with rapid resolution liquid chromatogruphy (RRLC) is accuracy andprecision, it can provide a new reference method for determination of procyanidinscontent. The prescription of capsule is reasonable, the preparation technology of capsuleis scientific and operable; quality control is simple, quick and accurate. All of relatedindexes conform to the requirements of pharmacopoeia of the People's Republic of China (2010) and the related standards. The quality guarantee period is2years at least. Thedetection methods of functional components in capsule are accurate and reliable. In softcapsule, the average content of procyanidins is87.9000mg/g, RSD is1.32%, the averagecontent of lycopene in soft capsule is15.2418mg/g, RSD is1.27%.2. The maximumtolerated dose (MTD) of capsule is higher than10g/kg·BW. The prescription of capsulecan decrease serum TC and LDL levels and enhance serum HDL level; lipid-loweringeffect of capsule is better than that of grape seed procyanidins or lycopene usedrespectively. So the lycopene and grape seed procyanidins may have synergistic effect inlipid-lowering. The capsule can reduce the serum TG, TC, LDL, ApoB, LPa levels andthe value of ApoB/ApoA1, increase liver SOD and GSH-Px activities, decrease MDAcontent. The capsule can alleviate the liver pathologic changes induced by high fat dietdistinctly.3. The lipid-lowering mechanisms of capsule: elevating the HL, LPL andLCAT levels, inhibitting the enzyme activity of HMG-CoA in hyperlipidemia rats,accelerating the degradation of TG and TC, and reducing cholesterol synthesis. Capsulecan enchance the relative expressions of LDL-R mRNA, PPARγ mRNA, SR-BI andABCA1mRNA, but the expression of LXRa mRNA does not change significantly. Thereverse cholesterol transport (RCT) is major lipid-lowering mechanism.
引文
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