臺灣博碩士論文加值系統

芍藥包括白芍Paeonia lactiflora Pallas與赤芍P. ovata Maxim.為常用中藥材之一，在中國、韓國及日本被廣泛的使用已有數年的歷史。芍藥常在傳統中藥處方中用於養血、平肝與鎮痛。Paeoniflorin (芍藥苷)是一種單萜配糖體，為芍藥中主要的活性成分，有很多文獻指出paeoniflorin具有多項的藥理活性，例如抗發炎、降血糖、抗血栓及促智作用等。而paeonol (丹皮酚)是芍藥中另一酚性成分，已知具有抑制血小板凝集、抗氧化及抗發炎等活性。Paeoniflorin及paeonol被當成是評估芍藥及牡丹皮品質的指標成分，廣泛用於含芍藥及牡丹皮之中藥製劑高效液相層析的分析定量。而指標成分品質的良劣會影響中藥定量的結果，因此需要建立高純度的指標成分以確保定量之準確性。本研究以各種管柱層析分離，於芍藥中分離出5種純化合物分別為sodium paeoniflorin sulfonate (1)， albiflorin (2)，paeoniflorin (3)，1,2,3,6-tetra-O-galloyl-β-D-glucopyranose (4)，1,2,3,4,6-penta-O-galloyl- β-D-glucopyranose (5)，並且建立paeoniflorin指標成分之分離純化標準操作程序及探討萃取的方法、溶媒、萃取倍數及萃取時間以制定paeoniflorin及paeonol分析標準操作程序，並利用高效液相層析去分析定量市售芍藥及牡丹皮中paeoniflorin及paeonol含量。然而由於純化後的標準品性質通常較不安定，因此以paeoniflorin及paeonol二種指標成分為目標，進行安定性及儲存試驗之評估，包括儲存時間、相對濕度、pH值、溫度、紫外線、日光燈及太陽光等之研究。
由安定性研究結果顯示，paeoniflorin較paeonol易受溫度、濕度之影響且在鹼性條件下並不安定，而經由一級反應圖可推算paeonol甲醇溶液儲存在-20℃下至少可存放91星期。在相對濕度75%及85%，溫度35, 45, 60℃的加速安定性實驗下，可藉由Arrhenius方程式推算paeoniflorin於相對濕度75%及85%在室溫25℃儲存時，成分殘存90%的架儲期(t 0.9)分別為31.23及31.22天，而溫度對paeoniflorin降解速度之影響，由Arrhenius方程式可推知在25℃的架儲期(t 0.9)為152天，且paeoniflorin會受溫度影響而降解成苯甲酸。綜合上述實驗結果可提供中藥保存條件之參考依據，並發現中藥裡的活性成分之安定性需做更詳細之研究探討，以提升中藥用藥之安全性，使中草藥邁向國際化。

目錄..........................................................................................................I
圖目錄....................................................................................................IV
表目錄..................................................................................................VIII
縮寫表.................................................................................................... X
中文摘要................................................................................................XI
英文摘要..............................................................................................XIII
總論...........................................................................................................1
第一章 芍藥成分之分離與鑑定……………………....……...…........16
I-1 前言………………………..……….…………..………..…......16
I-2 實驗材料……………….…………………………………........17
　 I-2-1 植物藥材……………………………………………….…17
　 I-2-2 溶媒及化學試劑……………………………………...…..17
I-2-3分離管柱及管柱填充劑………………………….…….....18
　 I-2-4儀器設備………………………….…………………….....18
　I-3 實驗方法……………………….…………………………….…20
　 I-3-1 赤芍成分分離與純化………………….……...……...…..20
I-3-2 芍藥苷之製備…………………....…………………….....22
　I-4 結果……………………………….………………………….....25
I-5 討論………………………………….……………………….…33
I-5-1、水解型單寧類結構解析…….………………….…….…33
I-5-2、單萜配糖體結構解析…….…………………….…….…34
第二章 市售品指標成分分析與芍藥之指紋圖譜……………….…..38
II-1前言……………………………………………………………..38
II-2 實驗材料……………………………………………………….39
II-2-1植物藥材………………………………………………….39
II-2-2 溶媒及化學試劑…………………………………………41
II-2-3分離管柱及管柱填充劑………………………….……....41
II-2-4儀器設備…………………………………………….…....41
II-3 實驗方法………………………..…………………….………..42
II-3-1、Paeoniflorin指標成分之分析標準操作程序制定…….42
II-3-2、Paeonol指標成分之分析標準操作程序制定….……...44
II-4 結果………………………...………………………….……....47
II-4-1芍藥與指標成分paeoniflorin之高效液相層析分析.......47
II-4-2 Paeoniflorin指標成分之分析標準操作程序制定……....51
II-4-3牡丹皮與指標成分paeonol之高效液相層析分析……..67
II-4-4 Paeonol指標成分之分析標準操作程序制定…………...70
II-4-5藥材之指紋圖譜…………………………………….........78
II-5 討論………………………………………………………....…83
第三章 芍藥成分之安定性…………...………………………….....…85
　III-1 前言……………………………………………………… .......85
　III-2 實驗材料……………………………………………….……...90
III-2-1植物藥材………………………………………....…........90
III-2-2溶媒及化學試劑……………………………………........90
III-2-3分離管柱及管柱填充劑……………………………........90
III-2-4儀器設備……………………………………………........90
　III-3 實驗方法……………………….………………………...........92
III-4 結果…………………………………....…………………...….96
III-4-1標準品甲醇溶液之安定性……………………………….96
III-4-2標準品粉末安定性試驗………………………....…...…116
III-4-3赤芍粉末之安定性及儲存試驗………………………...120
III-5 討論……………………...……………………………….…..126
III-5-1標準品安定性之研究……………………………….…..126
結論…………………………………………………………...…….….129
參考文獻……………………………………………………...……..…130
附圖…………………………………………………………..……..….140

















圖目錄
圖一 赤芍成分分離流程….…………..….…………………………..21
圖二 Paeoniflorin指標成分之分離純化標準操作程序流圖……….24
圖三 Paeoniflorin的化學結構……...………………………….….....27
圖四 Paeoniflorin的紫外線光譜圖………………………………….27
圖五 Sodium paeoniflorin sulfonate的化學結構............................…29
圖六 Sodium paeoniflorin sulfonate的紫外線光譜圖..……………..29
圖七 Albiflorin的化學結構................………………………….........30
圖八 1, 2, 3, 6-tetra-O-galloyl-β-D-glucopyranose的化學結構….….31
圖九 1, 2, 3, 4, 6-penta-O-galloyl-β-D-glucopyranose的化學結構…32
圖十 赤芍之層析圖……………………............................…...……...47
圖十一 芍藥苷之化學結構…………........................…………...….....48
圖十二 Paeoniflorin之HPLC層析圖：HPLC級MeOH(空白組)(A), Paeoniflorin (Nacalai) (B)及由芍藥中自行純化之Paeoniflorin (C)………………………………………………………........49
圖十三 Paeoniflorin標準檢量線……...................................….….....50
圖十四 芍藥最佳萃取方法分析……………………………………..51
圖十五 芍藥最佳萃取溶劑分析……………………………………..52
圖十六 芍藥最佳萃取溶劑比例分析…...….………………………..53
圖十七 芍藥最佳萃取時間分析…………………………..……...….54
圖十八 市售白芍paeoniflorin含量分析………………………….....56
圖十九 市售炒白芍paeoniflorin含量分析………………………….56
圖二十 市售赤芍paeoniflorin含量分析……………………..…...….57
圖二十一 市售炒赤芍paeoniflorin含量分析………………………..57
圖二十二 市售牡丹皮paeoniflorin含量分析…………………….…58
圖二十三 市售炒牡丹皮paeoniflorin含量分析……...………….....58
圖二十四 丹皮酚之化學結構…………………………………..…....67
圖二十五 丹皮酚之紫外線光譜圖……………………………..……68
圖二十六 Paeonol之標準檢量線………………….………………...68
圖二十七 牡丹皮指標成分 paeonol (A)及牡丹皮甲醇萃取液(B)之高效液相層析圖……………………………………...……...69
圖二十八 牡丹皮最佳萃取方法分析……………………...………...70
圖二十九 牡丹皮最佳萃取溶劑分析……...………………………...71
圖三十 牡丹皮最佳萃取溶劑比例分析…………...……………...71
圖三十一 牡丹皮最佳萃取時間分析……………………...………...72
圖三十二 市售白芍paeonol含量分析...............................................73
圖三十三 市售炒白芍paeonol含量分析…………...........................74
圖三十四 市售赤芍paeonol含量分析…………………………..….74
圖三十五 市售炒赤芍paeonol含量分析…………………………...75
圖三十六 市售牡丹皮paeonol含量分析...........................................75
圖三十七 市售炒牡丹皮paeonol含量分析……………………...…76
圖三十八 赤芍之HPLC指紋圖譜….................................................79
圖三十九 白芍之HPLC指紋圖譜……...…………………….......…80
圖四十 牡丹皮之HPLC指紋圖譜…………………………….….81
圖四十一 白芍(A)、赤芍(B)及牡丹皮(C)之雷達圖………………..82
圖四十二 一級反應圖……………………………………………......88
圖四十三 預測室溫穩定性的Arrhenius圖……………….………...89
圖四十四 Paeoniflorin及paeonol於4oC儲存成份之變化……...…96
圖四十五 Paeoniflorin 於4oC儲存之一級反應圖…………………97
圖四十六 Paeonol 於4oC儲存之一級反應圖……………..……….97
圖四十七 Paeoniflorin及paeonol於-20oC儲存成份之變化…………98
圖四十八 Paeoniflorin於-20oC儲存之一級反應圖…..…………….98
圖四十九 Paeonol於 -20oC儲存之一級反應圖……………………99
圖五十 Paeonol儲存在相對濕度75%溫度35，45，60 oC.………100
圖五十一 Paeonol儲存在相對濕度85%溫度35，45，60 oC……..101
圖五十二 Paeoniflorin儲存於相對濕度75%溫度35，45，60 oC…..101
圖五十三 預測Paeoniflorin於相對濕度75%室溫穩定性的Arrhenius圖………………………………………………………....102
圖五十四 Paeoniflorin儲存於相對濕度85%溫度35，45，60 oC.102
圖五十五 預測paeoniflorin於相對濕度85%室溫穩定性的Arrhenius圖………………………………………………….……....103
圖五十六 酸鹼值對paeoniflorin降解的影響…………………..….105
圖五十七 酸鹼值對paeonol降解的影響……………………..……106
圖五十八 溫度對paeoniflorin降解的影響…………..…………….107
圖五十九 Paeoniflorin分解成苯甲酸……………………………....108
圖六十 溫度對paeonol降解的影響……………………………..108
圖六十一 Paeoniflorin之層析圖…………………………………....109
圖六十二 Paeoniflorin於100oC儲存10天之指紋圖譜……………110
圖六十三 預測Paeoniflorin室溫穩定性的Arrhenius圖………..…111
圖六十四 紫外線對paeoniflorin降解的影響………………….…...112
圖六十五 紫外線對paeonol降解的影響………………………..….113
圖六十六 Paeoniflorin及paeonol於日光燈照射下反應………..…114
圖六十七 Paeoniflorin及paeonol於太陽光照射下反應…..…...…115
圖六十八 Paeoniflorin及paeonol標準品粉末於4oC儲存成份之變化……………………………………………………….…116
圖六十九 Paeoniflorin及paeonol標準品粉末於-20oC儲存成份之
變化………………………………………………..…….117
圖七十 溫、濕度對標準品粉末paeonol降解的影響……....…118
圖七十一 溫、濕度對標準品粉末paeoniflorin降解的影響….…118
圖七十二 溫度對赤芍中paeoniflorin含量之影響…………….…120
圖七十三 溫度對赤芍中paeonol含量之影響………………...….121
圖七十四 預測赤芍中paeoniflorin室溫穩定性的Arrhenius圖...121
圖七十五 預測赤芍中paeonol室溫穩定性的Arrhenius圖..……122
圖七十六 溫、濕度對赤芍中paeoniflorin降解的影響………….124
圖七十七 溫、濕度對赤芍中paeonol降解的影響…………....…124
圖七十八 Paeoniflorin可能代謝途徑……………..………………127




















表目錄
表一 芍藥之化學成分………………………………………………....2
表二 牡丹皮之化學成分……………………………………………....4
表三　藥材行樣品編號…………………………………………....…..40
表四 中藥材paeoniflorin於藥典中之含量規定……………………53
表五 Paeoniflorin日內差分析差異…………………………….……59
表六 Paeoniflorin日間差分析差異…………………………….…....59
表七 Paeoniflorin之不同比例添加回收率……………………….....60
表八 市售白芍色差及主成分含量比較…...……………….………..61
表九 市售炒白芍色差及主成分含量比較…………………………..62
表十 市售赤芍色差及主成分含量比較…………………………......63
表十一 市售炒赤芍色差及主成分含量比較………………………..64
表十二 市售牡丹皮色差及主成分含量比較…...........................…...65
表十三 市售炒牡丹皮色差及主成分含量比較.............................….66
表十四 Paeonol最佳萃取方式日內差分析…...........................…….76
表十五 Paeonol最佳萃取方式日間差分析…...................................77
表十六 Paeonol之不同比例添加回收率..................................…..…77
表十七 Paeoniflorin及paeonol殘存50%及90%的架儲期…....…..99
表十八 Paeoniflorin於相對濕度75%成份殘存50%及90%的架儲期.......................................................................................….103
表十九 Paeoniflorin於相對濕度85%成份殘存50%及90%的架儲期…………………………………………………………....104
表二十 Paeoniflorin在不同pH值降解殘存50%及90%的架儲期
……………………………………………………………....106
表二十一 Paeoniflorin在不同溫度降解殘存50%及90%的架儲期………............................................................................111
表二十二 Paeoniflorin及paeonol於不同波長殘存50%及90%的架儲期…………………………………………………......…..113
表二十三 Paeoniflorin及paeonol殘存50%及90%的架儲期........................................................................................115
表二十四 Paeoniflorin及paeonol在不同溫、濕度降解殘存50%及90%的架儲期…………………………………….…...….119
表二十五 赤芍中paeoniflorin在不同溫度降解殘存50%及90%的架儲期…………………………………………………...….122
表二十六 赤芍中paeonol在不同溫度降解殘存50%及90%的架儲期…..………………………………………………….….123
表二十七 赤芍中paeoniflorin及paeonol在不同溫濕度降解殘存50%及90%的架儲期…………………………………………125

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