臺灣博碩士論文加值系統

當前口服化療藥物生體可用率不佳為化學治療所困擾的問題，可能因為重複投予相同化療藥物而產生多重藥物抗藥性(Multidrug resistant，MDR)，在許多研究都已經證實P-gp與細胞色素(cytochrome P450 enzyme)與多重抗藥性有相關。P-gp與細胞色素(CYP450)分別影響受質藥物的吸收與活性，進而影響口服化療藥物生體可用率。另外，多數化療藥物受限於本身的疏水性特質，使其溶解度差造成溶離速度慢，進而限制藥物的吸收而無法經口服來達到臨床療效。有鑒於此，本研究使用中草藥萃取的雙效抑制劑來抑制P-gp與CYP450兩個因子，並利用自發性微乳化藥物傳輸系統(SMEDDS)或是胃滯留藥物傳遞系統(GRDDS)增加藥物的溶解度與吸收效率，以改善藥物疏水性特質的第三個因子。
本研究體外溶離結果顯示在結合SMEDDS與GRDDS後，幫助藥物達到快速溶離與胃滯留緩慢釋放的兩種效果。在藥物動力學試驗顯示將CPT11與四種雙效抑制劑或是胃滯留藥物系統結合後，對於CPT11與活性代謝物SN38的口服生體可用率都有不同程度的提升。在結合黃芩素(baicalein) 、水飛薊素(silymarin)、甘草酸(GLA)共口服的抑制劑組中， CPT11提升效果分別為13%、176.6%、86.3%；對於SN38分別提升36.8%、104%、58%。在胃滯留組別(GRDDS)則是以10%的PEO(7000K)組別效果最為顯著，其對於CPT11與SN38的生體可用率分別提升231%與149%。且在口服劑型中SN38具有較高的絕對生體可用率(AB)與轉換效率(conversion efficiency)。在DTX的藥物動力學試驗中，於無預處理組中結合水飛薊素或是甘草酸共口服組，對於DTX可提升90%與30%的生體可用率，另外，於預處理組中結合黃芩素或甘草酸組，對於DTX可提升38%與168%的生體可用率。
經由以上體外溶離與體內藥物動力學結果顯示，本研究成功開發一個強大且簡易製備乘載難溶性藥物的平台，期望此平台能應用在更多難溶性藥物，以解決當前口服化療藥物效果不彰之情況與提升病患順服度及生活品質。
 

Malignant tumor is on the top ranking of the leading cause of death for years. Although chemotherapeutic agent renews rapidly, patients with repeated treatment may suffered from drug resistance, which was shown to have highly-correlated to P-glycoprotein(P-gp) and Cytochrome P450 (CYP450). P-gp, encoded as multidrug resistance 1 (MDR1), is not only overexpression in tumor tissue, but also in the gastrointestinal tract (GIT) epithelial cells for active efflux of the therapeutic drugs across all the cell membranes. Thus, P-gp decreases drug accumulation in cancer cells. CYP450, mainly expressed in liver for catalyzing chemicals to higher water-soluble substance, inactivates oral drugs in intestinal epithelial cells and causes first-pass effect in liver tissue. Therefore, suppression of P-gp and CYP450 could effectively reduce drug resistance, decrease bioavailability and increase therapeutic outcome. In this study, Chinese herbal extracts with the dual-inhibitory effects of P-gp and CYP450 were selected and co-administrated with chemotherapeutic agents to improve the bioavailability of chemotherapeutic drugs.
Irinotecan (CPT11) and Chinese herbal extracts with dual-inhibitory effects of P-gp and CYP450 were encapsulated in self-microemulsifying drug delivery system (SMEDDS), spontaneously forming a clear, thermodynamically stable mixed liquid after contacting with an aqueous solution, in order to enhance their solubilities. Following by formulated as a gastroretentive drug delivery system (GRDDS) provided a great enhancement in oral bioavailability and absortion efficiency.
The oral bioavailability of CPT11 was significantly improved when co-administered with baicalein (13%)、silymarin (176.6%) and glycyrrhetinic acid (GLA) (86.3%) compared to control group. Moreover, the oral bioavailability of SN38 was also increased by 36.8%, 104%, 58%, respectively. In terms of GRDDS, the oral bioavailability for CPT11 and SN38 were increased 231% and 149% respectively when containing 10% PEO in the formula. Overall, the results showed that either co-administration of Chinese herb extracts with dual-inhibitory effects of P-gp and CYP450 or GRDDS can effectively improve the oral bioavailability of the model drug, CPT11/SN38, which is expected to have a better therapeutic outcome in cancer therapy than the control group.
Similar trend was found in the pharmacokinetic study of oral administraiton of Docetaxel (DTX). The oral bioavailability of DTX without pretreatment revealed an improvement of 90% and 30% when co-administered with silymarin and GLA, respectively. While the oral bioavailability of DTX with pretreatment co-administered with baicalein and GLA group showed 38% and 168% of improvement, we successfully developed a delivery platform which can control the release of CPT11 in an acidic environment and improved its bioavailability via co-administration of the P-gp and CYP450 inhibitors. We believe GRDDS will be an efficient delivery platform for various anticancer agents, specifically for poor soluble and substrate to CYP450 or P-gp; thus, it can benefit cancer patients through better therapeutic efficacy.

目錄
目錄 I
中文摘要 1
Abstract 2
縮寫表 4
附表目錄 5
附圖目錄 6
第壹章 緒論 8
第一節 研究背景介紹 8
一、口服劑型簡介 8
二、P-glycoprotein(P-gp) 10
三、Cytochrome P450 (CYP450) 16
四、P-gp與CYP450雙效抑制劑 18
五、自發性微乳劑系統(SMEDDS) 22
六、胃滯留藥物傳遞系統(GRDDS) 26
七、模式藥物-Irinotecan(CPT11)與活性代謝物-SN38 28
第二節 研究動機 35
第貳章 研究材料與實驗方法 36
第一節 實驗材料及儀器設備 36
一、實驗材料 36
二、儀器設備 37
第二節 實驗方法 38
一、CPT11、SN38及SN38G之高效液相層析分析方法(溶液) 38
二、CPT11、SN38之高效液相層析分析方法(血漿) 40
三、P-gp & CYP450雙效抑制劑之紫外分光光度計之體外分析方法 43
第三節 配方開發及體外溶離與體內藥動學試驗 46
一、配方開發與製備 46
二、配方粒徑分析 48
三、體外溶離試驗(Dissolution test) 50
四、體內藥物動力學試驗(Pharmacokinetics test) 52
第參章 結果與討論 55
第一節 分析方法的確立 55
一、CPT11及SN38之高效液相層析之分析方法(溶液) 60
二、CPT11及SN38之高效液相層析之分析方法(血漿) 69
三、P-gp & CYP450雙效抑制劑之紫外分光光度計之體外分析方法 77
第二節 配方開發及體外溶離與體內藥動學試驗 82
一、配方開發與製備 82
二、配方粒徑分析 84
三、體外溶離試驗(Dissolution test) 85
四、體內藥物動力學試驗(Pharmacokinetics) 90
第肆章 結論 110
附錄一 動物試驗核准函 112
參考文獻 113

附表目錄
Table 1 Parameters for particle size measurement. 49
Table 2 Pharmacokinetics of Irinotecan (CPT11) (unit: mg/rabbit). 54
Table 3 Pharmacokinetics of Docetaxel (DTX) (unit: mg/kg). 54
Table 4 Recovery assay of CPT11 in rabbit plasma (n=3). 59
Table 5 Recovery assay of SN38 in rabbit plasma (n=3). 59
Table 6 Intraday accuracy and precision (n=6) of CPT11 in solution. 61
Table 7 Interday accuracy and precision (n=6) of CPT11 in solution. 62
Table 8 Calibration curve (n=2) of CPT11 in solution (dissolution test). 63
Table 9 Intraday accuracy and precision (n=6) of SN38 in solution. 65
Table 10 Interday accuracy and precision (n=6) of SN38 in solution. 66
Table 11 Calibration curve (n=1) of SN38G in solution. 68
Table 12 Intraday accuracy and precision (n=6) of CPT11 in rabbit plasma. 70
Table 13 Interday accuracy and precision (n=6) of CPT11 in rabbit plasma. 71
Table 14 Calibration curve (n=1) of CPT11 in rat plasma. 72
Table 15 Intraday accuracy and precision (n=6) of SN38 in rabbit plasma. 74
Table 16 Interday accuracy and precision (n=6) of SN38 in rabbit plasma. 75
Table 17 Calibration curve of SN38 in rat plasma. 76
Table 18 Calibration curve (n=1) of baicalein in solution. 78
Table 19 Calibration curve (n=1) of silymarin in solution. 79
Table 20 Calibration curve (n=1) of Glycyrrhizic acid in solution. 80
Table 21 Calibration curve (n=1) of Glycyrrhetinic acid in solution. 81
Table 22 SMEDDS formulation ingredients. 83
Table 23 Solubility of SMEDDS formulation (unit: mg/g). 83
Table 24 Particle size and distribution trend of PC90C10P0 formulation (SMEDDS) 84
Table 25 Pharmacokinetics parameters of CPT11 (SMEDDS with or without GRDDS). 92
Table 26 Pharmacokinetics parameters of CPT11 (SMEDDS with or without inhibitors / GRDDS). 95
Table 27 Pharmacokinetics parameters of SN38 (SMEDDS with or without GRDDS). 99
Table 28 Pharmacokinetics parameters of SN38 ( SMEDDS with or without dual inhibitors / GRDDS). 102
Table 29 Pharmacokinetics parameters of DTX. (with or without dual inhibitors). 106
Table 30 Pharmacokinetics parameters of DTX. (with or without pretreatment half dose of dual inhibitors). 108

 
附圖目錄
Figure 1 Structure of P-glycoprotein [14] 11
Figure 2 P-gp restricts the distribution of its substrates into organs. 12
Figure 3 P-gp eliminates its substrates from excretory organs. 12
Figure 4 Structure of cytochrome P450 enzyme 17
Figure 5 Structure of Baicalein. 18
Figure 6 Structure of Silymarin. 19
Figure 7 Structure of Glycyrrhizic acid, GLA. 20
Figure 8 Structure of Glycyrrhetinic acid, GLA. 20
Figure 9 Preparation and formation of SMEDDS formulation. 23
Figure 10 Introduction of Gastroretentive drug delivery system (GRDDS). 27
Figure 11 Chemical structure of irinotecan hydrochloride trihydrate. 29
Figure 12 Conversion of lactone form and carboxylate form by changing pH environment. 30
Figure 13 Time-course of CPT-11 uptake by isolated intestinal cells. 31
Figure 14 Time-course of SN38 uptake by isolated intestinal cells.] 31
Figure 15 Chemical structure of irinotecan (CPT11) and its major metabolites. [94] 32
Figure 16 Affects absorption and metabolism and related side effects of oral administration of CPT11 34
Figure 17 UV wavelength scan of Baicalein (黃芩素，Conc=20µg/ml) 44
Figure 18 UV wavelength scan of Silymarin (水飛薊素，Conc=30µg/ml) 44
Figure 19 UV wavelength scan of Glycyrrhizic acid (甘草酸，Conc=40µg/ml). 45
Figure 20 UV wavelength scan of Glycyrrhetic acid (甘草次酸，Conc=40µg/ml). 45
Figure 21 Chromatograph of blank in solution. (Excitation380,Emission440/550). 56
Figure 22 Chromatograph of blank in solution. (Excitation370,Emission470/534). 56
Figure 23 Chromatograph of blank in plasma. 58
Figure 24 Chromatograph of blank in plasma. 58
Figure 25 Chromatograph of CPT11 in solution 60
Figure 26 Intraday calibration curve of CPT11 solution validation. 61
Figure 27 Interday calibration curve of CPT11 solution validation. 62
Figure 28 Calibration curve of CPT11 in solution 63
Figure 29 chromatograph of SN38 in solution. 64
Figure 30 Intraday calibration curve validation of CPT11 in solution. 65
Figure 31 Interday calibration curve validation of SN38 in solution. 66
Figure 32 Chromatograph of SN38G in solution. 67
Figure 33 Calibration curve of SN38G (in solution). 68
Figure 34 Chromatograph of CPT11 in plasma. 69
Figure 35 Intraday calibration curve validation of CPT11 in plasma. 70
Figure 36 Interday calibration curve validation of CPT11 in plasma. 71
Figure 37 Calibration curve of CPT11 in rat plasma. 72
Figure 38 Chromatograph of SN38 in plasma. 73
Figure 39 Intraday calibration curve validation of SN38 in rabbit plasma. 74
Figure 40 Intraday calibration curve validation of SN38 in rabbit plasma. 75
Figure 41 Calibration curve of SN38 in rat plasma. 76
Figure 42 Calibration curve of baicalein in solution. (黃芩素) 78
Figure 43 Calibration curve of silymarin in solution. (水飛薊素) 79
Figure 44 Calibration curve of Glycyrrhizic acid in solution. (甘草酸) 80
Figure 45 Calibration curve of Glycyrrhetinic acid in solution. (甘草次酸) 81
Figure 47 Dissolution profile of CPT11 without GRDDS (in vitro) 86
Figure 48 Dissolution profile of CPT11 combined with GRDDS (in vitro) 87
Figure 49 Dissolution profile of P-gp and CYP450 dual inhibitors. 89
Figure 50 Pharmacokinetics profiles of CPT11 in NZ rabbit. (SMEDDS with or without GRDDS) 93
Figure 51 Pharmacokinetics profiles of CPT11 in NZ rabbit. (SMEDDS with or without inhibitors/GRDDS) 96
Figure 52 Pharmacokinetics profiles of SN38 in NZ rabbit. (SMEDDS with or without GRDDS) 100
Figure 53 Pharmacokinetics profiles of SN38 in NZ rabbit. (SMEDDS with or without dual inhibitors/GRDDS) 103
Figure 54 Pharmacokinetics profiles of DTX in rat. (without pretreatment) 107
Figure 55 Pharmacokinetics profiles of DTX in rat (pretreatment) 109

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