连翘种子挥发油化学成分、生物学活性及其自乳化药物传递系统的研究
摘要
连翘Forsythia suspensa (Thunb.)Vahl为木犀科(Oleaceae)连翘属(Forsythia)植物,药用其果壳,而种子多废弃不用或仅被产地农民作为燃料使用。据文献报道,连翘种子占果实重35%-40%,种子中挥发油含量在4%以上。‘经过对连翘原植物的名称、药用部位、形态及产地的本草考证发现,除果壳外,其根茎叶花种子也可药用。为了综合开发与利用连翘资源,本文对其种子挥发油进行了提取分析,并对其挥发油的抗菌、抗氧化生物学活性及自乳化药物传递系统进行了研究,结果如下：
(1)利用水蒸气蒸馏法提取陕西商洛、河南洛阳、山东日照三个不同产地的连翘种子挥发油,经比较发现山东日照地区的种子平均出油率最高,达到3.18%。利用GC-MS联用技术对工业生产的连翘种子挥发油以及三个不同产地的挥发油成分进行分析对比,各成分的质谱图与标准谱对照,分别鉴定出56种、39种、37种、30种化合物,其中萜类化合物均占70%以上,主要为β-蒎烯。但各产地种子挥发油成分含量和种类有所不同,β-蒎烯含量最高的为山东产地,占49.97%,且独有香桧烯；陕西和河南产地松油醇含量较高,尤其是河南产地,4-松油醇和α-松油醇总含量高达17.72%；工业生产的种子挥发油中β-水芹烯的含量高达14.91%,而其它三个产地的种子中p-水芹烯含量较少甚至没有。
(2)分别考察了水蒸气蒸馏法提取连翘种子挥发油时,连翘种子粉碎程度、加水量和提取时间对出油率的影响程度,在此基础上采用三因素三水平正交实验,确定了连翘种子挥发油的提取工艺为药材粉碎30目,加水8倍量,提取时间6h。此条件下,连翘种子挥发油的得率为4.59%。
(3)建立了连翘种子挥发油中主要成分β-蒎烯的GC测定方法。色谱条件为：色谱柱：HP-5毛细管色谱柱(30m×0.32mm×0.25um)；柱温：采用程序升温,初始温度为40℃,以1℃·min-1升到50℃,保持1min,再以5℃·min-1升到70℃,保持1min,最后以20℃·min-1升到205℃,保持3min；进样口温度：250℃；检测器温度：280℃；FID检测器；载气为氮气；进样量1uL。测定了不同批次的连翘种子挥发油的β-蒎烯含量,平均为522.8mg/g。
(4)采用牛津杯法测定了连翘种子挥发油对11种指示细菌,3种常见真菌和3种葡萄致病真菌的抑制作用,结果表明连翘种子挥发油对藤黄八叠球菌等11种细菌具有不同程度的抑制作用,对黑曲霉等3种常见真菌和3种葡萄致病真菌同样具有一定的抑制作用。
(5)分别采用透射电镜和SDS-聚丙烯酰胺凝胶电泳的方法,观察了连翘种子挥发油的抑菌作用,推测连翘种子挥发油的抑菌作用机理：其一主要是通过破坏大肠杆菌、金黄色葡萄球菌和酿酒酵母3种指示菌的细胞壁和细胞膜结构,导致细胞内容物的外漏,从而引起细胞的凋亡；其二可能是连翘种子挥发油破坏了3种指示菌生长过程中某些蛋白质或蛋白质合成酶,从而导致细胞生长周期的终断,导致细胞的死亡。
(6)采用DPPH(1,1-diphenyl-2-picrylhydrazyl,二苯代苦味酰基)法和邻苯三酚自氧化法测定了连翘种子挥发油的抗氧化活性,结果发现连翘种子挥发油对有机自由基(DPPH)和超氧阴离子自由基(O2-)均有显著清除作用,清除率高达90%以上。具有作为天然抗氧化剂的潜质。
(7)以自乳化药物传递系统(self-emulsifying drug delivery systems, SEDDS)为载体,通过溶解度实验、正交实验和三元相图绘制,以体外乳化效果、乳化平衡速率、乳剂粒径大小及分布为指标,筛选了最佳处方并找出自乳化区域。通过考察其乳滴形态、粒径大小、分布、毛电位、自乳化平衡时间以及稳定性,对其进行体外评价。结果发现连翘种子挥发油SEDDS的最佳处方组成为连翘种子挥发油,Tween-80,乙醇三相,其最佳配比为45：41：14,乳化后乳滴呈规则的圆形,分布均匀,有效粒径90.9nm,自乳化速度快,5min之内达到平衡,强光,低温,冷热交替放置10天以及长时间室温放置3个月条件下稳定性良好。
(8)通过动物的急性毒性试验,评价了连翘种子挥发油及其SEDDS药物传递系统的毒性,其LD50分别为4.111mL/kg和6.619mL/kg。结果表明,SEDDS药物传递系统可以降低药物对胃肠的刺激作用,降低药物本身的毒性。同时采用MTT法测定了连翘种子挥发油及其SEDDS对CaCo-2细胞的抑制作用,同样可以看出其SEDDS的毒性低于原油本身。
(9)通过对连翘种子挥发油及其SEDDS制剂在大鼠体内的药代动力学实验,建立了β-蒎烯血浆样品的处理方法,绘制了口服给药后,连翘种子挥发油SEDDS及其混悬剂的药时曲线,拟合了其房室模型均为1室。测定了连翘种子挥发油的相对生物利用度,对其SEDDS进行了体内评价,结果表明,SEDDS药物传递系统可以提高连翘种子挥发油的相对生物利用度,是较理想的一种药物传递系统。
(10)测定了连翘种子挥发油SEDDS药物传递系统三批样品中β-蒎烯的含量,平均为236.7mg/g,为连翘种子挥发油SEDDS质量标准的制定提供了一定的依据。
以上研究结果,为连翘资源的综合开发与利用提供了一定的依据。
Fructus Forsythia is the dry fruit of the plant of Forsythia suspense (Thunb.)Vahl. It is bitter, non-toxic and charactered as slightly cold. Forsythia suspense (Thunb.) Vahl. can clear away heat and toxic, and commonly used in Chinese medicine. It can be usually classified into unripe Fructus Forsythia and ripe Fructus Forsythia due to its different harvest seasons. The shell part of Forsythia is usually used in traditional medicine use, and the seeds are abandoned or only used as a fuel by the local farmers. According to the literature, the seeds weight accounted from 35 percent to 40 percent of the Forsythia fruit, while the volatile is more than 4 percent. After the herbal plant research of the name, medicinal parts, and the original site of the forsythia, it was founded that The root, stem and seed can be medicinal.
The present research includes the following sections:
(1)The volatil oil was extracted from the seeds of Forsythia suspense (Thunb.) Vahl. with steam distillation method in three different areas of Chian, such as Shangluo in Shaanxi, Luoyang in Henan, and Rizhao in Shandong province. By comparison, the highest average oil yield is in Shandong Rizhao, arriving at 3.18 percent. The essential oil of Forsythia suspense (Thunb.) Vahl., which was extracted in industrial methods in the three different areas, was analyzed and compared by GC-MS technique. The result is that 57,39,37,30 components were respectively separated and identified by their mass spectrogram compared with the standard mass spectrogram, among which the terpenoid was account for more then 70 percent. However, the content and species of the chemical composition were different. For example, Shandong origin had the highest content ofβ-Pinene, accounting for 49.97 percent, and had the special material——Sabinene; Shaanxi and Henan origin had the highest content of Terpineol, especially the total content of 4-Terpineol and alpha.-Terpineol reaching 17.72 percent in Henan origin; the content ofβ-Phellandrene from industrial extraction accounting for 14.91% was more than other three areas, which had only a little even no content in Shandong origin.
(2)The crushed level of forsythia seeds, amount of water, and extraction time were investigated to know the impact on essential oil yield of Forsythia suspense (Thunb.).It was adpoted three factors and three level orthogonal experiments. And it was determined of the extraction process of essential oil from Forsythia seeds, which is the medicinal herbs crushed 30 mesh,8 times with water, extraction time 6 hours. In these conditions, essential oil yield of Forsythia seed was 4.59%.
(3)The GC method ofβ-pinene in volatile oil of Forsythia seeds was established. Chromatographic condition:Column:HP-5 FFAP(30m X 0.32mm X 0.25um); Column temperature:the temperature program involved in this study consisted of an initial temperature of 40℃,ramped up to 50℃at a rate of 1℃/min followed by a hold at 40℃for 1 min,and continuely ramped up to 70℃at a rate of 5℃/min followed by a hold at 70℃for 1 min,and finally ramped up to 205℃at a rate of 20℃/min followed by a hold at 205℃for 3 min; Injection temperature:250℃; Detector temperature:280℃; FID detector; Carrier gas:N2.Injection volume:luL. Different batches ofβ-pinene in Forsythia seeds'volatile oil was determined,and the mean was 522.8mg/g.
(4)A oxford cup assay was used to assess the antimicrobial activity of volatile oil from Forsythia seeds.Eleven bacterial indicator, three common fungi, and three grape pathogenic fungi were used.The results indicated that eleven bacterium were susceptible to volatile oil from Forsythia seeds.There was also antimicrobial activity on three fungi, Penicillium, Rhizopus,and Grey mould.
(5)Surveied the bacteriostasis of volatile oil of Forsythiae seeds by transmission electron microscope and SDS-PAGE, supposed the mechanism of bacteriostasis of the volatile oil from Forsythiae seeds that mainly destroied the cell membrane of three indicator bacteria i.e Escherichia coli, Staphylococcus aureus and Saccharomyces cerevisia, induce outleakage of cell content, and to cause apoptosis. Otherwise probably because that it breakdown the protein synthetase of process of growth of the three indicator bacteria, to lead to blocking of cell growth cycle and cell death.
(6)The antioxidant activities were assayed through scavenging effects to DPPH and superoxide anion free radical. The result found that essential oil from seeds of Forsythia suspense(Thunb.) Vahl. showed much high antioxidant activity and the clear rate was more than 90 percent, which Has the potential as a natural antioxidant.
(7)According to the nature of essential oil from seeds of Forsythia suspense(Thunb.) Vahl., the oil non-ionic surfactant and co-surfactant were screened for the best formula through solubility experiment, orthogonal screen and drawing phase diagram, taking the emulsifying degree, equilibrium time and effective diameter as index. In order to investigate self-emulsifying ability, the micro emulsion of morphology, particle size, dissolution, zeta potential, the rat of self-emulsifyinand the stability in vitro were determined. The result showed that the best formulation of self-emulsifying drug delivery system was made up of the Essential oil of Forsythia suspense (Thunb.) Vahl., Tween-80, ethanol (45:41:14). After being emulsified, the morphology of micro emulsion was homogeneous small spherical drops observed under the electro-microscopy. The particle size was 90.9nm and the selected formulation could completely emulsify in 5 min. The quality of essential oil of Forsythia suspense (Thunb.)Vahl. self-emulsified formulation was stable after strong light exposure, low temperature, thermal-cold cycling for 10 days and constant temperature for 3 months. The self-emulsifying drug delivery system of essential oil of Forsythia suspense (Thunb.) Vahl. is significantly increased in self-emulsified system and the formulation is stable and easy to prepare. The study could provide theoretical foundation for further studying and developing of the essential oil from seeds of Forsythia suspense(Thunb.) Vahl.
(8)Through animal acute toxicity test, it was assessed the toxicity of seed oil of Fructus Forsythiae and its SEDDS, their LD50 was 4.111mL/kg and 6.619mL/kg.Respectively. The results indicated that SEDDS can depress the stimulation of drug to stomach and intestine, reduce the toxicity of drug. Simultaneously, the MTT method was adopted, it assaied inhibitory action of seed oil of Fructus Forsythiae and its SEDDS to CaCo-2 cell, also it can be founded that the toxicity of its SEDDS was lower than that of the seed oil itself.
(9)It was established the treatment method ofβ-pinene blood plasma sample through the endosomatic pharmacokinetics experiment in rats.The essential oil of Forsythiae Suspensae seeds and it's SEDDS preparations were used. Based on Oral Drug Administration, the drug age curves of seeds essential oil and its suspension was drawn. Combining the compartment model as 1 room, the relative bioavailability of seeds essential oil was evaluated. The results indicated that SEDDS could improve the relative bioavailability of essential oil from Forsythia suspense seeds, so as to become an ideal drug transmission system.
(10)In the three samples SEDDS of essential oil from Forsythiae Suspensae seeds,the content ofβ-pinene were evaluated by GC method.they averaged to 236.7mg/g.It provided evidences for the institution of quality standard of Forsythiae Suspensae essential oil's SEDDS.
(1)利用水蒸气蒸馏法提取陕西商洛、河南洛阳、山东日照三个不同产地的连翘种子挥发油,经比较发现山东日照地区的种子平均出油率最高,达到3.18%。利用GC-MS联用技术对工业生产的连翘种子挥发油以及三个不同产地的挥发油成分进行分析对比,各成分的质谱图与标准谱对照,分别鉴定出56种、39种、37种、30种化合物,其中萜类化合物均占70%以上,主要为β-蒎烯。但各产地种子挥发油成分含量和种类有所不同,β-蒎烯含量最高的为山东产地,占49.97%,且独有香桧烯；陕西和河南产地松油醇含量较高,尤其是河南产地,4-松油醇和α-松油醇总含量高达17.72%；工业生产的种子挥发油中β-水芹烯的含量高达14.91%,而其它三个产地的种子中p-水芹烯含量较少甚至没有。
(2)分别考察了水蒸气蒸馏法提取连翘种子挥发油时,连翘种子粉碎程度、加水量和提取时间对出油率的影响程度,在此基础上采用三因素三水平正交实验,确定了连翘种子挥发油的提取工艺为药材粉碎30目,加水8倍量,提取时间6h。此条件下,连翘种子挥发油的得率为4.59%。
(3)建立了连翘种子挥发油中主要成分β-蒎烯的GC测定方法。色谱条件为：色谱柱：HP-5毛细管色谱柱(30m×0.32mm×0.25um)；柱温：采用程序升温,初始温度为40℃,以1℃·min-1升到50℃,保持1min,再以5℃·min-1升到70℃,保持1min,最后以20℃·min-1升到205℃,保持3min；进样口温度：250℃；检测器温度：280℃；FID检测器；载气为氮气；进样量1uL。测定了不同批次的连翘种子挥发油的β-蒎烯含量,平均为522.8mg/g。
(4)采用牛津杯法测定了连翘种子挥发油对11种指示细菌,3种常见真菌和3种葡萄致病真菌的抑制作用,结果表明连翘种子挥发油对藤黄八叠球菌等11种细菌具有不同程度的抑制作用,对黑曲霉等3种常见真菌和3种葡萄致病真菌同样具有一定的抑制作用。
(5)分别采用透射电镜和SDS-聚丙烯酰胺凝胶电泳的方法,观察了连翘种子挥发油的抑菌作用,推测连翘种子挥发油的抑菌作用机理：其一主要是通过破坏大肠杆菌、金黄色葡萄球菌和酿酒酵母3种指示菌的细胞壁和细胞膜结构,导致细胞内容物的外漏,从而引起细胞的凋亡；其二可能是连翘种子挥发油破坏了3种指示菌生长过程中某些蛋白质或蛋白质合成酶,从而导致细胞生长周期的终断,导致细胞的死亡。
(6)采用DPPH(1,1-diphenyl-2-picrylhydrazyl,二苯代苦味酰基)法和邻苯三酚自氧化法测定了连翘种子挥发油的抗氧化活性,结果发现连翘种子挥发油对有机自由基(DPPH)和超氧阴离子自由基(O2-)均有显著清除作用,清除率高达90%以上。具有作为天然抗氧化剂的潜质。
(7)以自乳化药物传递系统(self-emulsifying drug delivery systems, SEDDS)为载体,通过溶解度实验、正交实验和三元相图绘制,以体外乳化效果、乳化平衡速率、乳剂粒径大小及分布为指标,筛选了最佳处方并找出自乳化区域。通过考察其乳滴形态、粒径大小、分布、毛电位、自乳化平衡时间以及稳定性,对其进行体外评价。结果发现连翘种子挥发油SEDDS的最佳处方组成为连翘种子挥发油,Tween-80,乙醇三相,其最佳配比为45：41：14,乳化后乳滴呈规则的圆形,分布均匀,有效粒径90.9nm,自乳化速度快,5min之内达到平衡,强光,低温,冷热交替放置10天以及长时间室温放置3个月条件下稳定性良好。
(8)通过动物的急性毒性试验,评价了连翘种子挥发油及其SEDDS药物传递系统的毒性,其LD50分别为4.111mL/kg和6.619mL/kg。结果表明,SEDDS药物传递系统可以降低药物对胃肠的刺激作用,降低药物本身的毒性。同时采用MTT法测定了连翘种子挥发油及其SEDDS对CaCo-2细胞的抑制作用,同样可以看出其SEDDS的毒性低于原油本身。
(9)通过对连翘种子挥发油及其SEDDS制剂在大鼠体内的药代动力学实验,建立了β-蒎烯血浆样品的处理方法,绘制了口服给药后,连翘种子挥发油SEDDS及其混悬剂的药时曲线,拟合了其房室模型均为1室。测定了连翘种子挥发油的相对生物利用度,对其SEDDS进行了体内评价,结果表明,SEDDS药物传递系统可以提高连翘种子挥发油的相对生物利用度,是较理想的一种药物传递系统。
(10)测定了连翘种子挥发油SEDDS药物传递系统三批样品中β-蒎烯的含量,平均为236.7mg/g,为连翘种子挥发油SEDDS质量标准的制定提供了一定的依据。
以上研究结果,为连翘资源的综合开发与利用提供了一定的依据。
Fructus Forsythia is the dry fruit of the plant of Forsythia suspense (Thunb.)Vahl. It is bitter, non-toxic and charactered as slightly cold. Forsythia suspense (Thunb.) Vahl. can clear away heat and toxic, and commonly used in Chinese medicine. It can be usually classified into unripe Fructus Forsythia and ripe Fructus Forsythia due to its different harvest seasons. The shell part of Forsythia is usually used in traditional medicine use, and the seeds are abandoned or only used as a fuel by the local farmers. According to the literature, the seeds weight accounted from 35 percent to 40 percent of the Forsythia fruit, while the volatile is more than 4 percent. After the herbal plant research of the name, medicinal parts, and the original site of the forsythia, it was founded that The root, stem and seed can be medicinal.
The present research includes the following sections:
(1)The volatil oil was extracted from the seeds of Forsythia suspense (Thunb.) Vahl. with steam distillation method in three different areas of Chian, such as Shangluo in Shaanxi, Luoyang in Henan, and Rizhao in Shandong province. By comparison, the highest average oil yield is in Shandong Rizhao, arriving at 3.18 percent. The essential oil of Forsythia suspense (Thunb.) Vahl., which was extracted in industrial methods in the three different areas, was analyzed and compared by GC-MS technique. The result is that 57,39,37,30 components were respectively separated and identified by their mass spectrogram compared with the standard mass spectrogram, among which the terpenoid was account for more then 70 percent. However, the content and species of the chemical composition were different. For example, Shandong origin had the highest content ofβ-Pinene, accounting for 49.97 percent, and had the special material——Sabinene; Shaanxi and Henan origin had the highest content of Terpineol, especially the total content of 4-Terpineol and alpha.-Terpineol reaching 17.72 percent in Henan origin; the content ofβ-Phellandrene from industrial extraction accounting for 14.91% was more than other three areas, which had only a little even no content in Shandong origin.
(2)The crushed level of forsythia seeds, amount of water, and extraction time were investigated to know the impact on essential oil yield of Forsythia suspense (Thunb.).It was adpoted three factors and three level orthogonal experiments. And it was determined of the extraction process of essential oil from Forsythia seeds, which is the medicinal herbs crushed 30 mesh,8 times with water, extraction time 6 hours. In these conditions, essential oil yield of Forsythia seed was 4.59%.
(3)The GC method ofβ-pinene in volatile oil of Forsythia seeds was established. Chromatographic condition:Column:HP-5 FFAP(30m X 0.32mm X 0.25um); Column temperature:the temperature program involved in this study consisted of an initial temperature of 40℃,ramped up to 50℃at a rate of 1℃/min followed by a hold at 40℃for 1 min,and continuely ramped up to 70℃at a rate of 5℃/min followed by a hold at 70℃for 1 min,and finally ramped up to 205℃at a rate of 20℃/min followed by a hold at 205℃for 3 min; Injection temperature:250℃; Detector temperature:280℃; FID detector; Carrier gas:N2.Injection volume:luL. Different batches ofβ-pinene in Forsythia seeds'volatile oil was determined,and the mean was 522.8mg/g.
(4)A oxford cup assay was used to assess the antimicrobial activity of volatile oil from Forsythia seeds.Eleven bacterial indicator, three common fungi, and three grape pathogenic fungi were used.The results indicated that eleven bacterium were susceptible to volatile oil from Forsythia seeds.There was also antimicrobial activity on three fungi, Penicillium, Rhizopus,and Grey mould.
(5)Surveied the bacteriostasis of volatile oil of Forsythiae seeds by transmission electron microscope and SDS-PAGE, supposed the mechanism of bacteriostasis of the volatile oil from Forsythiae seeds that mainly destroied the cell membrane of three indicator bacteria i.e Escherichia coli, Staphylococcus aureus and Saccharomyces cerevisia, induce outleakage of cell content, and to cause apoptosis. Otherwise probably because that it breakdown the protein synthetase of process of growth of the three indicator bacteria, to lead to blocking of cell growth cycle and cell death.
(6)The antioxidant activities were assayed through scavenging effects to DPPH and superoxide anion free radical. The result found that essential oil from seeds of Forsythia suspense(Thunb.) Vahl. showed much high antioxidant activity and the clear rate was more than 90 percent, which Has the potential as a natural antioxidant.
(7)According to the nature of essential oil from seeds of Forsythia suspense(Thunb.) Vahl., the oil non-ionic surfactant and co-surfactant were screened for the best formula through solubility experiment, orthogonal screen and drawing phase diagram, taking the emulsifying degree, equilibrium time and effective diameter as index. In order to investigate self-emulsifying ability, the micro emulsion of morphology, particle size, dissolution, zeta potential, the rat of self-emulsifyinand the stability in vitro were determined. The result showed that the best formulation of self-emulsifying drug delivery system was made up of the Essential oil of Forsythia suspense (Thunb.) Vahl., Tween-80, ethanol (45:41:14). After being emulsified, the morphology of micro emulsion was homogeneous small spherical drops observed under the electro-microscopy. The particle size was 90.9nm and the selected formulation could completely emulsify in 5 min. The quality of essential oil of Forsythia suspense (Thunb.)Vahl. self-emulsified formulation was stable after strong light exposure, low temperature, thermal-cold cycling for 10 days and constant temperature for 3 months. The self-emulsifying drug delivery system of essential oil of Forsythia suspense (Thunb.) Vahl. is significantly increased in self-emulsified system and the formulation is stable and easy to prepare. The study could provide theoretical foundation for further studying and developing of the essential oil from seeds of Forsythia suspense(Thunb.) Vahl.
(8)Through animal acute toxicity test, it was assessed the toxicity of seed oil of Fructus Forsythiae and its SEDDS, their LD50 was 4.111mL/kg and 6.619mL/kg.Respectively. The results indicated that SEDDS can depress the stimulation of drug to stomach and intestine, reduce the toxicity of drug. Simultaneously, the MTT method was adopted, it assaied inhibitory action of seed oil of Fructus Forsythiae and its SEDDS to CaCo-2 cell, also it can be founded that the toxicity of its SEDDS was lower than that of the seed oil itself.
(9)It was established the treatment method ofβ-pinene blood plasma sample through the endosomatic pharmacokinetics experiment in rats.The essential oil of Forsythiae Suspensae seeds and it's SEDDS preparations were used. Based on Oral Drug Administration, the drug age curves of seeds essential oil and its suspension was drawn. Combining the compartment model as 1 room, the relative bioavailability of seeds essential oil was evaluated. The results indicated that SEDDS could improve the relative bioavailability of essential oil from Forsythia suspense seeds, so as to become an ideal drug transmission system.
(10)In the three samples SEDDS of essential oil from Forsythiae Suspensae seeds,the content ofβ-pinene were evaluated by GC method.they averaged to 236.7mg/g.It provided evidences for the institution of quality standard of Forsythiae Suspensae essential oil's SEDDS.
引文
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