Study on the Effect of Moslae Herba Oil on the Percutaneous Absorption of Active Ingredient of Evodia Rutaecarpa in vitro
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摘要:
目的 考察香薷挥发油对吴茱萸药效成分的促渗作用以及其促透皮吸收的能力。 方法 采用扩散池和大鼠离体皮肤进行体外透皮实验, 以吴茱萸中多种成分作为指标, HPLC测定计算各成分累积透过量。HE染色、免疫组化染色、ATR-FTIR观察皮肤及角质层的变化, GC-MS测定挥发油给药后皮内贮存挥发油成分。 结果 香薷挥发油对吴茱萸中多种药效成分均具有促渗作用, 与阳性药氮酮相比, 香薷挥发油对金丝桃苷、吴茱萸碱、吴茱萸次碱的累积透过量更大。且香薷挥发油中倍半萜成分及含量占比最大的麝香草酚更易在皮肤中贮存, 可以扰乱角质层脂质结构, 促进药物的渗透。 结论 为透皮吸收促进剂的选择提供参考。 Abstract:OBJECTIVE To investigate whether Moslae herba oil has penetration enhancing effect on the active components of Evodia rutaecarpa and its ability to promote transdermal absorption. METHODS In vitro transdermal experiments were performed using the diffusion pool and the isolated skin of rats. Using various components of Evodia rutaecarpa as indicators, HPLC was determined to calculate the umulative penetration amount of each component. Changes in the skin and cuticle layers were observed by HE staining, immunohistochemical staining, and ATR-FTIR. GC-MS was used to measure Moslae herba oil components after administration. RESULTS Moslae herba oil showed the penetration-enhancing effect on various components in Evodia rutaecarpa. Compared with the postive drug nitrogenone, the cumulative penetration amounts of hyperoside, evodiamine and rutaecarpine were greater. In addition, the sesquiterpene composition and thymol in the Moslae herba oil were more likely to be stored in the skin, which could disturb the lipid structure of the cuticle layer and promote the penetration of drugs. CONCLUSION The results provide reference for the selection of transdermal absorption agent. -
Key words:
- Moslae herba oil /
- Evodia rutaecarpa /
- penetration enhancers
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图 2 吴茱萸有效成分及透皮接收液HPLC图
注: 1.新绿原酸; 2.绿原酸; 3.隐绿原酸; 4.咖啡酸; 5.金丝桃苷; 6.去氢吴茱萸碱; 7.槲皮素; 8.吴茱萸碱; 9.吴茱萸次碱；A.混合对照品; B.吴茱萸提取物; C.空白透皮接收液; D.香薷挥发油组透皮接收液
Figure 2. HPLC diagram of active ingredient and transdermal receiving fluid of Evodia rutaecarpa
图 3 不同组别吴茱萸各成分的经皮渗透曲线(x±s, n=3)
注：A.新绿原酸; B.绿原酸; C.隐绿原酸; D.金丝桃苷; E.去氢吴茱萸碱; F.吴茱萸碱; G.空白组; H.香薷挥发油组; I.氮酮组
Figure 3. Percutaneous osmotic curves of each component of Evodia rutaecarpa in different groups (x±s, n=3)
图 4 各组大鼠皮肤HE染色
注: a.空白组; b.香薷挥发油组; c.氮酮组; 箭头指示外侧角质层变化。
Figure 4. HE staining of rat skin in different groups
图 5 各组大鼠皮肤免疫组化染色
注: a.空白组; b.香薷挥发油组; c.氮酮组; 箭头指示上皮细胞层。
Figure 5. Immunohistochemical staining of rat skin in different groups
图 7 挥发油给药后皮内成分分析
Figure 7. Analysis of intradermal composition after administration of volatile oil
表 1 香薷挥发油主要化学成分
Table 1. The main chemical composition of Moslae herba oil
t/min 化合物信息 峰面积百分比/% 结构 名称 分子量 化学式 CAS 10.327 β-蒎烯(β-Pinene) 136.234 C10H16 127-91-3 0.26 
11.360 萜品油烯(Terpinolene) 136.234 C10H16 586-62-9 0.71 
11.708 对伞花烃(p-Cymene) 134.22 C10H14 99-87-6 6.02 
13.280 γ-萜烯(γ-Terpinene) 136.236 C10H16 99-85-4 3.17 
13.619 α-水芹烯(α-Phellandrene) 136.234 C10H16 99-83-2 0.02 
18.543 4-乙酸松油烯(4-Terpinenyl acetate) 196.286 C12H20O2 4821-04-9 0.43 
20.923 长叶薄荷酮(Pulegone) 152.23 C10H16O 89-82-7 0.21 
22.787 麝香草酚(Thymol) 150.218 C10H14O 89-83-8 76.62 
23.018 香荆芥酚(Carvacrol) 150.218 C10H14O 499-75-2 6.90 
24.559 乙酸百里酚酯(Thymol acetate) 192.25 C12H16O2 528-79-0 3.25 
25.112 香芹酚乙酸酯(Carvacryl acetate) 192.25 C12H16O2 6380-28-5 0.13 
26.476 石竹烯(Caryophyllene) 204.351 C15H24 13877-93-5 0.15 
26.913 α-香柠檬烯(α-Bergamotene) 204.351 C15H24 17699-05-7 0.14 
27.395 蛇麻烯(Humulene) 204.351 C15H24 6753-98-6 1.82 
30.860 氧化石竹烯(Caryophyllene oxide) 220.351 C15H24O 1139-30-6 0.14 
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表 2 线性关系回归方程
Table 2. The linear relation regression equation
成分 回归方程 r 线性范围/(μg·mL-1) 新绿原酸 A=13 253C-20 617 0.999 2 6.67~133.40 绿原酸 A=13 429C-7 576.6 0.998 9 11.90~119.00 隐绿原酸 A=12 989C-3 735.2 0.999 0 4.40~88.00 咖啡酸 A=24 509C-26 381 0.998 8 4.91~98.20 金丝桃苷 A=25 974C-14 739 0.998 7 4.42~88.40 去氢吴茱萸碱 A=33 446C-29 158 0.998 7 8.10~162.00 槲皮素 A=36 660C-26 841 0.998 8 3.50~70.0 吴茱萸碱 A=11 835C-6 715.9 0.999 0 4.85~97.00 吴茱萸次碱 A=18 604C-9 718.5 0.999 0 4.75~95.00
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表 3 方法学考察结果(%)
Table 3. Methodological investigation results(%)
成分 日内精密度RSD (n=6) 日间精密度RSD (n=3) 稳定性RSD (n=3) 加样回收率RSD (n=5) 新绿原酸 1.67 2.38 1.43 4.43 绿原酸 1.54 2.46 1.30 4.34 隐绿原酸 1.55 2.39 1.35 5.64 咖啡酸 1.68 2.73 1.47 3.93 金丝桃苷 1.77 2.44 1.43 5.05 去氢吴茱萸碱 1.63 2.21 1.30 3.44 槲皮素 1.66 2.46 1.42 3.52 吴茱萸碱 1.03 2.85 1.19 4.43 吴茱萸次碱 0.93 2.76 1.17 6.64
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表 4 空白组累积透过量Q与时间T关系表(x±s, μg·cm-2，n=3)
Table 4. The cumulative passage volume Q and time T of the blank group (x±s, μg·cm-2, n=3)
时间/h 新绿原酸 绿原酸 隐绿原酸 金丝桃苷 去氢吴茱萸碱 吴茱萸碱 0 0 0 0 0 0 0 2 1.712 4±0.376 9 1.259 5±0.188 9 0.879 0±0.054 7 0.742 5±0.281 1 0.750 0±0.645 1 0.108 6±0.188 0 4 1.906 7±0.436 2 1.526 5±0.419 8 1.024 9±0.089 8 0.988 5±0.570 1 2.029 6±0.580 9 1.459 7±0.516 1 6 4.763 3±0.319 0 4.615 9±0.975 8 2.900 1±0.462 8 1.090 8±0.587 7 5.337 8±2.620 9 3.363 3±2.314 6 8 5.466 4±0.670 9 5.120 6±1.188 2 3.291 2±0.548 5 1.237 9±0.684 9 11.462 9±7.556 1 8.596 5±6.230 5 10 5.931 7±0.974 3 5.723 3±1.367 0 3.823 3±0.796 6 1.472 3±0.693 4 19.325 2±13.724 0 10.538 6±7.660 7 12 6.893 3±1.795 8 7.250 5±2.526 9 4.327 9±1.156 1 1.684 8±0.713 9 26.296 4±19.168 0 17.789 5±14.115 8
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表 5 香薷挥发油组累积透过量Q与时间T关系表(x±s, μg·cm-2，n=3)
Table 5. The cumulative passage volume Q and time T of the Moslae herba oil group (x±s, μg·cm-2, n=3)
时间/h 新绿原酸 绿原酸 隐绿原酸 金丝桃苷 去氢吴茱萸碱 吴茱萸碱 吴茱萸次碱 0 0 0 0 0 0 0 0 2 3.231 0±0.266 8 3.035 1±0.559 8 2.232 4±0.374 3 0.844 3±0.275 5 1.184 5±0.410 6 0.536 5±0.082 8 1.719 4±0.464 6 4 10.017 5±2.643 4 19.029 5±6.171 9 5.165 5±1.464 6 2.046 8±0.658 3 16.838 3±3.630 1 5.380 7±2.400 0 20.823 6±6.761 6 6 29.204 0±5.684 9 45.609 1±10.269 2 14.945 7±2.859 1 5.184 2±1.295 3 27.833 4±6.910 5 6.494 5±1.788 7 32.264 5±7.590 3 8 33.814 0±8.664 6 55.905 2±16.195 8 18.048 1±3.977 5 6.349 3±1.817 9 36.665 7±11.987 5 8.285 0±2.333 9 37.856 7±4.795 0 10 40.178 0±2.187 8 70.809 4±7.314 6 23.080 8±1.420 1 7.521 0±1.399 9 45.669 1±10.259 8 9.683 1±2.241 4 40.779 7±6.124 2 12 50.184 4±7.321 6 74.568 6±7.686 3 27.161 7±2.542 8 8.217 3±1.401 8 48.623 0±12.582 9 13.533 9±2.530 6 46.831 8±5.464 8
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表 6 氮酮组累积透过量Q与时间T关系表(x±s, μg·cm-2，n=3)
Table 6. The cumulative passage volume Q and time T of the azone group (x±s, μg·cm-2, n=3)
时间/h 新绿原酸 绿原酸 隐绿原酸 金丝桃苷 去氢吴茱萸碱 吴茱萸碱 0 0 0 0 0 0 0 2 3.062 8±0.788 6 3.181 5±1.530 3 1.784 3±0.349 9 0.678 2±0.092 3 2.176 7±2.037 6 0.501 6±0.469 8 4 21.613 4±9.826 3 33.610 1±14.934 9 10.937 9±4.966 3 2.134 2±0.598 9 32.076 1±11.320 6 3.323 3±0.985 1 6 43.849 7±5.812 5 70.504 3±9.908 8 21.038 2±2.924 6 3.453 9±0.651 8 53.920 9±3.628 9 4.485 5±1.091 6 8 56.951 1±6.147 8 95.584 9±5.217 6 27.281 7±3.269 7 4.653 3±0.200 9 70.643 5±4.048 1 5.190 1±0.968 5 10 65.774 9±4.072 7 108.889 8±8.760 0 32.055 3±3.220 8 5.146 3±0.189 5 77.431 7±3.191 0 5.502 0±1.028 7 12 69.635 5±4.163 0 117.285 8±8.182 7 35.473 0±3.433 2 6.435 6±1.244 8 80.857 5±3.168 1 5.967 1±1.045 3
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表 7 不同组别下吴茱萸中各成分渗透动力学参数(x±s, n=3)
Table 7. Osmotic kinetic parameters of each component of Evodia rutaecarpa in different groups (x±s, n=3)
成分 组别 透皮速率Js/(μg·cm-2·h-1) ER 新绿原酸 空白组 0.662 9±0.168 9C - 香薷挥发油组 3.569 0±1.302 2B 5.383 9 氮酮组 5.623 7±2.228 7A 8.483 5 绿原酸 空白组 0.599 6±0.171 8C - 香薷挥发油组 5.693 3±2.405 2B 9.495 2 氮酮组 9.059 2±3.946 7A 15.108 7 隐绿原酸 空白组 0.388 9±0.092 8C - 香薷挥发油组 1.954 4±0.625 0B 5.025 5 氮酮组 2.784 1±1.041 3A 7.158 9 金丝桃苷 空白组 0.207 1±0.121 4C - 香薷挥发油组 0.671 4±0.216 1A 3.241 9 氮酮组 0.513 5±0.112 7B 2.479 5 去氢吴茱萸碱 空白组 1.221 5±1.078 4C - 香薷挥发油组 3.773 8±1.722 6B 3.089 5 氮酮组 6.901 0±2.982 5A 5.649 6 吴茱萸碱 空白组 0.765 1±0.755 6A - 香薷挥发油组 0.971 3±0.439 7A 1.269 5 氮酮组 0.587 6±0.242 3B 0.627 5 吴茱萸次碱 空白组 - - 香薷挥发油组 4.026 0±1.752 1 - 氮酮组 - - 注: 相同字母为无显著性差异，不同字母间P < 0.01。
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表 8 大鼠皮肤脂质、酰胺振动峰位移
Table 8. Vibration peak shift of lipid and amide in rat skin
组别 脂质特征吸收峰 角蛋白特征吸收峰 C—H非对称 C—H对称 酰胺Ⅰ带 酰胺Ⅱ带 空白组 2 924.01 2 852.86 1 631.97 1 549.07 香薷挥发油组 2 926.26 2 854.38 1 630.69 1 548.34 氮酮组 2 924.20 2 853.09 1 631.20 1 550.67
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表 9 皮内挥发油主要成分
Table 9. The main components of the intradermal volatile oil
编号 t/min CAS 化合物 峰面积百分比/% 1 11.149 586-62-9 萜品油烯(Terpinolene) 1.83 2 11.500 99-87-6 对伞花烃(p-Cymene) 16.38 3 13.062 99-85-4 γ-萜烯(γ-Terpinene) 9.78 4 22.682 89-83-8 麝香草酚(Thymol) 59.60 5 24.419 528-79-0 乙酸百里酚酯(Thymol acetate) 5.61 6 26.278 13877-93-5 石竹烯(Caryophyllene) 0.67 7 26.729 17699-05-7 α-香柠檬烯(α-Bergamotene) 0.83 8 27.204 6753-98-6 蛇麻烯(Humulene) 5.30
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