臺灣博碩士論文加值系統

經皮吸收的預測模式是將皮膚滲透性與化合物結構作為探討，由化合物物化性質與其結構對比皮膚滲透性試驗數據，再以統計方法建立結構-皮膚穿透之相關性 (structure-permeation relationship, SPR)。到目前為止皮膚吸收的預測模式已被廣泛運用，並且已經發表數種主動擴散之經皮吸收和被動擴散之經皮吸收的回歸方程式，表明化合物分子量的大小、疏水性與對溶媒之溶解度是皮膚吸收能力主要的影響因子。黃酮類化合物存在於植物中屬於一種多酚類化合物與 benzoxazinone 原先是用來保護植物抵抗環境逆境，作為保護作用的化合物，這些化合物被發現具有抗氧化與抗發炎之藥理活性。在先前實驗室對一系列 aglycone flavonoids 與 glycoside flavonoids 進行化合物結構-皮膚之相關性，並且發現 naringenin 在投予不同濃度下與不同穿透屏障下皆顯示最高的經皮穿透能力以及皮內累積含量，因此我們進一步研究主結構相似於 naringenin 的 flavanone 類化合物，並建立更完整的 SPR，並使用Franz擴散裝置評估化合物滲透到豬皮和裸鼠皮之能力。在排除溶解度的影響後，隨著親脂性的增加皮膚蓄積量增加，6-Bromo-2-phenyl-(4H)-4-benzopyranone (BPB) 表現出最高的皮膚含量。在測試的滲透物中，flavanone 表現最佳的皮膚滲透且在毛囊路徑具有優勢穿透。然而 flavanone 在 250 μM 的濃度時，會造成 HaCaT 細胞大量凋亡。所有化合物先投予表皮細胞後皆會可以抑制由 imiquimod (IMQ) 所誘導的發炎因子和趨化因子，其中又以 naringenin 與 BPB 的抑制活性最佳，然而研究發現單獨投予 BPB 可能會誘導細胞發炎產生發炎因子，所以在高濃度的 BPB 與 IMQ 組別中所測量的數值不但沒有抑制效果反而會增加發炎的情形，因此我們認為 naringenin 比 BPB 更安全、更適合用於開發成為抑制發炎之藥物。

The predictive model of percutaneous absorption is broadly used to explore between the skin permeability and the structure of compounds, which follows by comparing the structural and physicochemical properties of the compound with the skin permeability test data to establish the correlation of structure of compounds and skin penetration by statistical methods (Structure-Permeation Relationship, SPR). Several regression equations of the percutaneous absorption of active diffusion and passive diffusion have been published, suggtsting that the molecular weight, hydrophobicity and solubility to the solvent of the compound are the major impact factors of skin absorption capacity. Flavonoids and benzoxazinone is a natural insecticide, both of them exist in plants as a protective function and against environmental stress. These compounds recently have been found to have anti-oxidant and anti-inflammatory activities. Previously, a series of aglycone flavonoids and glycoside flavonoids were studied in the laboratory for both of the relationship of skin permeability and structure of compound, and naringenin showed the highest percutaneous penetration and intradermal accumulation at different concentrations and different penetration barriers. Therefore, we further studied the correlation of percutaneous absorption and flavanones compounds, a major structure similar to naringenin, to establish a more complete SPR model, and used the Franz diffusion device to evaluate the ability of flavanones compounds in the penetration of pig skin and nude mice skin model. After excluding the effect of solubility, the flavanones compounds increased in skin deposition with increasing lipophilicity, and 6-Bromo-2-phenyl-(4H)-4-benzopyranone (BPB) showed the highest skin deposition. Flavanone had optimal skin penetration and had an advantage in the hair follicle pathway, however flavanone caused a large number cell death in HaCaT cells at a concentration of 250 μM. All compounds were pre-treated to HaCaT cells, which inhibited the expression of inflammatory factors and chemokines by imiqumod (IMQ) stimulating. Among of them, naringenin and BPB have the best inhibitory ability. Our study also found that BPB treatment alone could induce cells to produce inflammatory factors. The values of the inflammatory factors were measured in the high concentration BPB plus IMQ groups not only had no inhibitory effect but increased the inflammation. Therefore, our results suggested that naringenin is more safe and suitable for development as a drug that inhibits inflammation than BPB.

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致謝 iii
中文摘要 iv
Abstract v
目錄 vii
圖目錄 xii
表目錄 xiv
第一章、前言 1
第二章、緒論 2
第一節、皮膚 2
1-1. 表皮層 (epidermis) 3
1-2. 真皮層 (dermis) 4
1-3. 皮下組織 (hypodermis) 5
第二節、局部投予 (topical delivery) 及經皮傳輸藥物系統 (transdermal drug delivery system, TDDS) 5
1-1. 藥物滲透皮膚之路徑 5
1-1-1. 直接穿透角質層蛋白質-脂質基質 (transcellular pathway) 6
1-1-3. 透過附屬器官滲透 (transappendageal pathway) 6
1-2. 影響藥物穿透皮膚之吸收因素 7
1-2-1. 藥物之物理與化學性質 7
1-2-2. 載體選擇 8
1-2-3. 施藥的方式 8
1-2-4. 不同的生理之皮膚 8
1-3. 增進藥物滲透皮膚之吸收方法 8
第三節、結構-皮膚穿透之相關性 (structure-permeation relationship, SPR) 9
第四節、乾癬 (psoriasis) 10
1-1. Imiquimod (IMQ) 12
第五節、研究之化合物模式 14
1-1. 黃烷酮化合物 (flavanones) 14
1-2. Naringenin 之作用機轉 14
1-3. Hesperetin 之作用機轉 15
1-4. 6-Hydroxyflavanone之作用機轉 16
1-5. Flavanone 之作用機轉 17
1-6. 6-Bromo-2-phenyl-(4H)-4-benzopyranone (BPB) 之作用機轉 17
2-1. Benzoxazinone 衍生物 20
第三章、研究動機與實驗設計 22
實驗設計與流程： 23
第四章、材料及方法 24
第一節、實驗藥品溶劑與儀器設備 24
1-1. 藥物、溶劑 24
1-2. 儀器設備 26
第一節、 實驗方法 28
1-1. 合成 benzoxazinone 衍生物並評估皮膚吸收相關性 28
1-2. Benzoxazinone 衍生物及其原料之化學名稱及光譜資訊 28
第三節、黃烷酮化合物與 benzoxazinone 衍生物之 HPLC 分析條件建立 29
1-1. 六個化合物之 HPLC 分析條件建立 29
第四節、黃烷酮化合物之分子特性模擬與基本物化性質測試 30
1-1. 化合物之分子特性模擬 30
1-2. HPLC 之容積因子 30
1-3. 油水分配係數 30
1-4. 飽和化合物溶液之配置 31
1-5. 5 mM 化合物溶液之配置 31
第五節、化合物體外經皮吸收實驗皮膚 32
1-1. 化合物體外經皮吸收之累積穿透量分析 32
1-2. 化合物體外經皮吸收之皮內含量分析 33
1-3. 化合物體外經皮吸收之毛囊化合物含量分析 33
第六節、細胞試驗 34
1-1. 人類角質細胞培養 (HaCaT cell) 34
1-1-1. 化合物安全性試驗 34
1-1-2. 化合物活性試驗 34
第七節、動物皮膚以及其製備 35
1-1. 未處理之裸鼠皮 (intact nude mouse skin) 35
1-2. 未處理之豬皮 (intact porcine skin) 35
1-3. 去角質層之皮膚 (stratum corneum (SC)-stripping skin) 35
1-4. 去脂質之皮膚 (de-lipid skin) 35
1-5. 去皮脂之皮膚 (de-sebum skin) 36
1-6. 去蛋白之皮膚 (de-protein skin) 36
第八節、生物體內試驗 36
皮內化合物含量試驗 36
1-1-1. 化合物之抗發炎活性試驗 37
1-1-2. 皮膚生理檢測 37
1-2-1. 皮膚表皮之水分散失 (transepidermal water loss, TEWL) 37
1-2-2. 皮膚色差測定 37
1-2-3. 表皮酸鹼度測定 38
1-2-4. 組織病理學 38
第九節、數據分析及統計方法 38
第五章、實驗結果與討論 40
第一節、合成之化合物結構確認 40
1-1. 以核磁共振儀測量 H 原子數來確定其 benzoxazinone 衍生物之結構 40
第二節、化合物之物化性質測試 41
第三節、體外經皮吸收試驗 43
1-1. 化合物在裸鼠皮與豬皮之體外經皮吸收試驗 43
1-2. 化合物在 5 mM 濃度下之體外經皮吸收試驗 44
1-2-1. 以裸鼠皮為屏障 44
1-2-2. 以豬皮為屏障 45
1-3. 化合物在飽和濃度下之體外經皮吸收試驗 49
1-3-1. 以裸鼠皮為體外經皮系統 49
1-3-2. 以豬皮為體外經皮系統 50
第四節、化合物分子模擬 52
第五節、化合物穿透皮膚路徑探討 59
1-1. 5 mM 懸浮化合物於人工膜之累積穿透量與穿透速率 59
1-2. 5 mM 化合物於不同方式處理裸鼠皮之經皮吸收試驗 61
1-3. 5 mM 化合物於不同方式處理豬皮之經皮吸收試驗 62
1-4. 毛囊內含量 63
第六節、相似化合物之結構比較 65
1-1. Naringenin & hesperetin 65
1-2. 6-Hydroxyflavanone & flavanone 65
1-3. BPB & CFB 66
第七節、Flavanones化合物對細胞毒性與化合物活性 66
1-1. Flavanones 化合物對 HaCaT 細胞之毒性 66
1-2. Flavanones 化合物對 HaCaT 細胞之生物活性 69
第六章、結論 73
第七章、參考文獻 74

圖目錄
圖一、皮膚組織立體結構圖 2
圖二、表皮層示意圖 4
圖三、藥物利用直接穿透和非直接穿透的路徑圖 6
圖四、藥物透過附屬器官滲透路徑圖 7
圖五、增進藥物滲透皮膚之吸收方法 9
圖六、皮膚吸收能力主要的影響因子 10
圖七、乾癬誘導機制圖 12
圖八、IMQ 誘導皮膚發炎機制 13
圖九、Naringenin 透過轉錄作用抑制細胞因子的釋放機制圖 15
圖十、Hesperetin 在抗氧化、抗發炎、抗凋亡、抗腫瘤的機制圖 16
圖十一、γ-aminobutyric acid (GABA) 訊號傳遞系統示意圖 18
圖十二、各種黃酮類之分類 19
圖十三、將 6-Amino-4-chlorobenzoic acid 與 2-fluorobenzoyl chloride 進行脫氫反應合成 CFB 28
圖十四、Franz diffusion cell 裝置示意圖 32
圖十五、CFB 1H NMR光譜 (400 MHz, CDCl3) 40
圖十六、化合物經正常皮吸收之實驗結果圖 49
圖十七、化合物與神經醯胺二 (ceramide II) 之交互作用模擬 54
圖十八、化合物與神經醯胺三 (ceramide III) 之交互作用模擬 55
圖十九、化合物與神經醯胺六 (ceramide VI) 之交互作用模擬 56
圖二十、化合物與棕櫚酸 (palmitic acid) 之交互作用模擬 57
圖二十一、化合物與膽固醇硫酸鹽 (cholesteryl sulfate) 之交互作用模擬 58
圖二十二、5 mM 化合物在人工膜之累積穿透量與穿透速率 60
圖二十三、六個化合物存在於毛囊之含量 64
圖二十四、不同濃度之化合物對 HaCaT 細胞存活率的影響 68
圖二十五、不同濃度之化合物對經由 IMQ 所刺激 HaCaT 細胞產生的發炎因子與趨化因子抑制的結果圖 71

表目錄
表一、化合物結構與分子量 21
表一、黃烷酮類化合物與 benzoxazinone 衍生物之 HPLC 分析條件 29
表三、化合物之物化性質 42
表四、飽和化合物於 24 小時後裸鼠皮之皮內化合物含量、滲透速率及 S value 51
表五、飽和化合物於 24 小時之後裸鼠皮校正皮內含量、滲透係數及 S value 51
表六、飽和化合物於 24 小時後豬皮之皮內化合物含量、滲透速率及 S value 52
表七、飽和化合物於 24 小時之後豬皮校正皮內含量、滲透係數及 S value 52
表八、六種化合物之氫鍵與總極性表面積 53
表九、化合物與角質層富含成分交互作用之 negative CDOCKER energy 53
表十、5 mM 化合物至不同處理裸鼠皮之皮內含量 61
表十一、5 mM 化合物至不同處理裸鼠之穿透速率 62
表十二、5 mM 化合物至不同處理豬皮之皮內含量 63
表十三、5 mM 化合物至不同處理豬皮之穿透速率 63

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