臺灣博碩士論文加值系統

近年來，隨著老化人口增加，前列腺癌罹患率與死亡率有逐年攀升的趨勢。其中，荷爾蒙治療與化學治療又為目前臨床常用於轉移性前列腺癌的治療方式。然而，病患在經由荷爾蒙治療一段時間後，可能會逐漸產生抗藥性，使得癌細胞轉變成去勢抗性前列腺癌 (Castration-resistant prostate cancer, CRPC) 而再度擴散及復發。因此，本研究目的希望透過開發自微乳化藥物傳遞系統 (Self-microemulsifying drug delivery system) 以及使用親水性載體葡聚醣 (Dexttan-40) 於噴霧乾燥技術 (Spray drying) 製備固態自微乳化藥物傳遞系統 (solid self-microemulsifying drug delivery system, s-SMEDDS) 藉此來提升液體自微乳化藥物傳遞系統 (liquid self-microemulsifying drug delivery system, l-SMEDDS) 的穩定性，有助於改善藥物於體內之溶解度與穿透率，解決Abiraterone acetate屬於 Class IV之藥物，存在溶解度低且口服生體可用率不佳的問題。
另外，同時利用實驗設計法 (Design of Experiment, DoE) 之Box-Behnken Design (BBD) 統計方法應用於優化噴霧乾燥之參數條件，藉以較少的實驗次數、實驗時間與成本，以最有效率的方法篩選出最佳化之s-SMEDDS處方。最終是由MCT、TPGS、Transcutol ®P以2 : 7 : 1 (w/w/w%) 的比例為組成l-SMEDDS的處方，平均粒徑大小約為25 nm 左右，且最終的藥物承載率 (Drug loading) 為48 mg/mL。經由Box-Behnken Design優化噴霧乾燥之最佳參數條件分別為噴霧氣體流速 (35 %)、樣品進樣速度 (20 %)、樣品溶液濃度 (10 %) 可得最低之粒徑大小。
X光粉末繞射與低溫示差掃描量熱研究結果顯示，在s-SMEDDS製劑中的藥物結晶皆形成無晶態形式。體外溶離試驗中顯示，l-SMEDDS和s-SMEDDS處方皆能在30分鐘釋放超過80 %的藥物。安定性試驗結果中也顯示，在三個月內藥物含量皆能達到90 %以上。於體內藥物動力學結果顯示，l-SMEDDS 與直接口服 Abiraterone acetate 相比，其相對生體可用率提升 1.1 倍，s-SMEDDS 則提升了 1.7 倍。
綜觀上述結果，本研究成功應用Box-Behnken Design實驗設計法開發出最佳化s-SMEDDS處方並於各項試驗中都有突出的表現，藉由SMEDDS之包載達到最佳安定性和藥物釋放，同時也能有效地提升相對生體可用率。

關鍵字：自微乳化藥物傳遞系統、Abiraterone acetate、噴霧乾燥、Box-Behnken Design、前列腺癌

In recent years, with the increase in the aging population, the incidence and mortality rates of prostate cancer have been increasing year by year. Among them, hormonal therapy and chemotherapy are currently commonly used clinical treatments for metastatic prostate cancer. However, after a period of hormonal treatment, patients may gradually develop drug resistance, causing the cancer cells to transform into castration-resistant prostate cancer (CRPC) and spread again and relapse. Therefore, the purpose of this research is to develop a self-microemulsifying drug delivery system and use hydrophilic carrier dextran (Dexttan-40) to prepare solid self-microemulsifying technology through spray drying. The drug delivery system (solid self-microemulsifying drug delivery system, s-SMEDDS) uses this to improve the stability of the liquid self-microemulsifying drug delivery system (l-SMEDDS), which helps to improve the drug's The solubility and penetration rate in the body solve the problem of low solubility and poor oral bioavailability of Abiraterone acetate, a Class IV drug.
In addition, the Box-Behnken Design (BBD) statistical method of Design of Experiment (DoE) is also used to optimize the parameter conditions of spray drying, so as to reduce the number of experiments, experimental time and cost, and achieve the most efficient Methods to screen out the optimal s-SMEDDS prescription. The final formulation of l-SMEDDS is composed of MCT, TPGS, and Transcutol ®P in a ratio of 2:7:1 (w/w/w%). The average particle size is about 25 nm, and the final drug loading rate is (Drug loading) is 48 mg/mL. The best parameter conditions for spray drying optimized through Box-Behnken Design are spray gas flow rate (35%), sample injection speed (20%), and sample solution concentration (10%) to obtain the lowest particle size.
The results of X-ray powder diffraction and low-temperature differential scanning calorimetry studies showed that the drug crystals in the s-SMEDDS formulation all formed an amorphous form. In vitro dissolution tests showed that both l-SMEDDS and s-SMEDDS formulations could release more than 80% of the drug in 30 minutes. The stability test results also show that the drug content can reach more than 90% within three months. In vivo pharmacokinetic results show that compared with direct oral administration of Abiraterone acetate, the relative bioavailability of l-SMEDDS is increased by 1.1 times, while that of s-SMEDDS is increased by 1.7 times.
To sum up the above results, this study successfully applied the Box-Behnken Design experimental design method to develop the optimal s-SMEDDS formula and performed outstandingly in various tests. The optimal stability and drug release were achieved through the inclusion of SMEDDS. , and can also effectively improve the relative bioavailability rate.


Keywords: Self-microemulsifying drug delivery system, Abiraterone acetate, spray drying, Box-Behnken Design, prostate cancer

目錄
致謝 I
縮寫對照表 I
目錄 IV
圖目錄 IX
表目錄 XII
中文摘要 XIV
Abstract XVI
第一章 緒論 1
1.1 前列腺癌 (Prostate cancer, Prostate Ca) 1
1.1.1 流行病學 (Epidemiology) 1
1.1.2. 前列腺癌介紹 2
1.1.3 前列腺癌分期 3
1.1.4 治療與用藥方式 5
1.2 模式藥物介紹 (Model drug) 6
1.2.1 阿比特龍乙酸酯 (Abiraterone acetate, AA) 6
1.2.2 物理化學性質 7
1.2.3 藥理機轉 8
1.3 自微乳化藥物傳遞系統 (Self-microemulsifying drug delivery system, SMEDDS) 9
1.3.1 SMEDDS組成份介紹 11
1.3.1.1 油相 (Oil) 11
1.3.1.2 界面活性劑 (Surfactant) 13
1.3.1.3 輔助界面活性劑 (Co-surfactant) 14
1.4 自微乳化藥物傳遞系統之作用機制 15
1.6 噴霧乾燥技術 (Spray drying technique) 19
1.7 藥物開發的品質源於設計 (Quality by Design, QbD) 20
1.8 實驗設計 (Design of Experiment, DoE) 21
1.9 反應曲面法 (Response surface methodology, RSM) 23
1.9.1 Box-Behnken 設計 (Box-Behnken Design, BBD) 25
1.9.2 中央合成設計 (Central Composite Design, CCD） 26
第二章 研究動機與目的 27
實驗設計與流程 28
第三章 實驗材料與儀器 29
3.1 實驗材料 (Materials) 29
3.2 實驗儀器 (Instruments) 30
第四章 實驗方法 31
4.1 自微乳化藥物傳遞系統 (Self-miceormulsifying drug delivery system, SMEDDS) 之處方與製程開發 31
4.1.1 製備未承載藥物之空白Liquid-SMEDDS (Blank l-SMEDDS) 31
4.1.2 藥物於SMEDDS之溶解度試驗 (Solubility test) 31
4.1.3 製備承載Abiraterone acetate 之 SMEDDS (Abiraterone acetate loaded-SMEDDS) 32
4.2 實驗設計法 (Design of Experiment, DoE) 32
4.2.1 Box-Behnken Design (BBD) 應用之模型擬合與資料分析 32
4.3 固態自微乳化藥物傳遞系統 (Solidified self-microemusifying drug delivery system, s-SMEDDS) 之處方與製程開發 34
4.4 噴霧乾燥技術 (Spray drying technique) 35
4.4.1 實驗參數及條件設定 35
4.5 Abiraterone acetate分析方法建立與確效 36
4.5.1 高效能液相層析儀 (High Performance Liquid Chromatography, HPLC) 分析方法 36
4.5.1.1 Abiraterone acetate之HPLC分析條件 36
4.5.1.2 Abiraterone acetate之HPLC儲備溶液 (Stock solution) 與檢量線標準品溶液配製 37
4.5.1.3 Abiraterone acetate之HPLC分析方法確效 37
4.5.2 串聯式四極桿質譜儀 (Triple Quadrupole Mass Spectrometry, TQ-MS) 分析方法 38
4.5.2.1 Abiraterone acetate之UPLC-MS/MS分析條件 38
4.5.2.2 Abiraterone acetate之UPLC-MS/MS儲備溶液與檢量線標準品溶液配製 40
4.5.2.3 Abiraterone acetate之 UPLC-MS/MS 血漿標準溶液配製 40
4.5.2.4 Abiraterone acetate之UPLC-MS/MS分析方法確效 41
4.5 固態自微乳化藥物傳遞系統之物化特性評估 42
4.5.1 物理化學特性評估 42
4.5.1.1 粒徑分析 (Particle size analysis) 42
4.5.1.2 掃描式電子顯微鏡分析 (Scanning electron microscope, SEM) 42
4.5.1.3 X光粉末繞射分析 (X-ray powder diffraction, XRPD analysis) 43
4.5.1.4 熱重分析 (Thermogravimetric analysis) 44
4.5.1.5 低溫示差掃描量熱分析 (Low-temperature differential scanning calorimetry, LT-DSC) 45
4.6 安定性試驗 (Stability study) 46
4.6.1 藥物含量測定 (Drug content) 46
4.6.2 粒徑大小測定 (Particle size measurement) 46
4.6.2 藥物加速性試驗 (Accelerated testing) 46
4.6 藥物體外釋放試驗 (In vitro drug release study) 47
4.6.1 Abiraterone acetate之藥物體外溶離試驗 (Dissolution test) 47
4.6.2 製備模擬胃液與模擬腸液 47
4.6.2.1 模擬胃液配製 (Stimulated intestinal fluid, SGF) 48
4.6.2.2 模擬腸液配製 (Simulated intestinal fluid, SIF) 48
4.6.3 藥物於溶媒液之溶解度試驗 (Solubility test) 48
4.8 藥物動力學試驗 (Pharmacokinetic study) 48
4.8.1 動物照護 48
4.8.2 動物實驗程序 49
4.8.3 藥物動力學之數據分析 50
第五章 結果與討論 51
5.1 自微乳化藥物傳遞系統之處方開發與物化特性評估 51
5.1.2 Liquid-SMEDDS (l-SMEDDS) 之處方與製程開發 51
5.1.3 製備承載Abiraterone acetate 之SMEDDS (Abiraterone acetate-loaded SMEDDS) 52
5.2 實驗設計 (Design of Experiment, DoE) 53
5.2.1 利用Box-Behnken Design (BBD) 之最佳化s-SMEDDS處方設計與製程條件 53
5.2.2 多項回歸方程式之模型擬合與反應曲面分析 (Response surface analysis) 54
5.3 分析方法建立與確效 61
5.3.1 Abiraterone acetate 之 HPLC 分析方法確效 61
5.3.2 Abiraterone acetate血漿樣品之UPLC-MS/MS分析方法確效 64
5.4 固態自微乳化藥物傳遞系統之物化特性評估 67
5.4.1 粒徑分析 (Particle size analysis) 67
5.4.2 熱重分析 (Thermogravimetric analysis) 68
5.4.3 掃描式電子顯微鏡分析 (Scanning electron microscope, SEM) 70
5.4.4 X光粉末繞射分析 (X-ray powder diffraction, XRPD analysis) 71
5.4.5 低溫示差掃描量熱分析 (Low-temperature differential scanning calorimetry, LT-DSC) 72
5.5 安定性試驗 (Stability study) 73
5.5.1 藥物含量測定 (Drug content) 73
5.5.2 粒徑大小測定 (Particle size measurement) 74
5.5.3 藥物加速性試驗 (Accelerated testing) 75
5.6 體外釋放試驗 (In vitro drug release study) 77
5.7 體內動物試驗 79
5.7.1 藥物動力學試驗 (Pharmacokinetic study) 79
第六章 結論與未來展望 82
第七章 參考文獻 83
附錄 92



















圖目錄

Figure 1. Age-standardized incidence rates (ASR) of prostate cancer throughout the word in 2020 [5]. 1
Figure 2. Position of prostate cancer [6]. 2
Figure 3. A schematic of the development of prostate cancer [12]. 4
Figure 4. The chemical structure of Abiraterone acetate. 7
Figure 5. Mechanism of action Abiraterone acetate [24]. 8
Figure 6. Illustration of microemulsions and nanoemulsions [30]. 9
Figure 7. Surfactants for nanoparticle as stabilization [39]. 13
Figure 8. The Biopharmaceutics Classification System (BCS) as defined by Amidon et al. at 1995 [47]. 15
Figure 9. Challenges in SMEDDS formulations [26]. 16
Figure 10. Mechanism of intestinal drug transport from lipid-based formulations for absorption enhancement [54]. 18
Figure 11. Schematic diagram of the spray dryer and process [62]. 20
Figure 12. The flow chart of Design of Experiments (DoE). 22
Figure 13. Application of response surface methodology [72]. 24
Figure 14. Box-Behnken Design (BBD) for (A) k=3 BBD (B) Matrix of 23 BBD [77]. 25
Figure 15. Central Composite Design (CCD) for k=3, 23 (A) Cube portion (B) Star portion (C) Matrix of 23 CCD [79]. 26
Figure 17. A schematic illustration showing used spray drying method to prepared 27
Figure 18. Images of blank l-SMEDDS, Abiraterone acetate loaded-SMEDDS and SMEDDS microemulsion. (A) l-SMEDDS stored at 25 ℃ (B) l-SMEDDS storage at 37 ℃ (C) SMEDDS microemulsion (dissolved in DDW). 52
Figure 19. Predicted versus actual plot obtained by the Box-Behnken Design based on the (A) spray gas flow (B) feed rate (C) solution concentration for spray drying. 59
Figure 20. The response surface plots showing the effect of (A) spray gas flow (B) feed rate (C) solution concentration on particle size (Y1). 60
Figure 21. HPLC chromatograms showed the retention time peaks of Abiraterone acetate. 61
Figure 22. Intraday calibration curve of Abiraterone acetate solution (n=3). 62
Figure 23. Interday accuracy and precision of Abiraterone acetate solution (n=3). 63
Figure 24. UPLC-MS/MS chromatograms of Abiraterone acetate, Abiraterone and Estradiol in blood. 64
Figure 25. The intraday calibration curve of UPLC-MS/MS method obtained from Abiraterone acetate spiked plasma standards (n=3). 65
Figure 26. The interday calibration curve of UPLC-MS/MS method obtained from Abiraterone acetate spiked plasma standards (n=3). 66
Figure 27. The thermogravimetric analysis (TGA) and derivative thermogravimetric (DTG) curves of Abiraterone acetate, Dextran 40, Physical mixture, (s)-SMEDDS_BK, AA-(s)-SMEDDS. 69
Figure 28. The scanning electron microscope (SEM) images of (A) Abiraterone acetate (B) Dextran 40 (C) s-SMEDDS_BK (D) AA-(s)-SMEDDS at different magnifications. 70
Figure 29. The X-ray powder diffraction (XRPD) patterns of Abiraterone acetate, physical mixture, Dextran 40, TPGS, (s)-SMEDDS_BK and AA-(s)-SMEDDS. 71
Figure 30. The low-temperature differential scanning calorimetry (LT-DSC) curves of Abiraterone acetate, Dextran 40, Physical mixture, AA-(s)-SMEDDS. 72
Figure 31. The drug content of Abiraterone acetate and Abiraterone acetate loaded-SMEDDS formulations in stability study of storage at 25 ℃. Each point shown as mean ± SD (n=3). 73
Figure 32. The particle size of Abiraterone acetate loaded-SMEDDS formulations in stability study of storage at temperature (A) 25 ℃ (B) 40 ℃. Each point shown as mean ± SD (n=3). 75
Figure 33. The drug content of Abiraterone acetate and Abiraterone acetate loaded-SMEDDS formulations in stability study of storage at 40 ℃. Each point shown as mean ± SD (n=3). 76
Figure 34. Drug release profiles of Abiraterone acetate powder, Abiraterone acetate loaded-(l)-SMEDDS and (s)-SMEDDS in (A) pH 1.2 simulated gastric fluid (SGF) (B) pH 6.8 simulated intestinal fluid (SIF). Each point shown as mean ± SD (n=3). 78
Figure 35. In vivo pharmacokinetic profiles of Abiraterone acetate after oral administration with Abiraterone acetate, (l)-SMEDDS and (s)-SMEDDS. Each point shown as mean ± SD (n=3). 80




表目錄
Table 1. Therapies for the treatment of metastatic castration-resistant prostate cancer [16, 18, 19]. 5
Table 2. Commercially marked product of SMEDDS drugs [31]. 10
Table 3. List of oil excipients used in formulation of SMEDDS [37]. 12
Table 4. Composition of SMEDDS. 31
Table 5. Variables and response used in the Box-Behnken Design. 33
Table 6. Design model build information. 33
Table 7. Parameters of the spray drying. 35
Table 8. Parameters of the chromatographic system of Abiraterone acetate. 36
Table 9. Parameters of mass spectrometry. 38
Table 10. Conditions of UPLC-MS/MS. 39
Table 11. Gradient condition of UPLC-MS/MS. 39
Table 12. Optimized MRM parameters of Abiraterone acetate and internal standard. 40
Table 13. Parameters of particle size analyzer. 42
Table 14. Parameters of scanning electron microscope. 43
Table 15. Parameters of X-ray powder diffraction. 44
Table 16. Parameters of thermogravimetric analysis. 45
Table 17. Parameters of low-temperature differential scanning calorimetry. 45
Table 18. Dose and formulation preparation methods for pharmacokinetic study. 49
Table 19. Box-Behnken Design for optimization of s-SMEDDS_BK formulations and the associated response data. 56
Table 20. Analysis of quadratic model of the measured response with ANOVA. 57
Table 21. The predicted and observed values of optimized AA-s-SMEDDS. 58
Table 22. Intraday accuracy and precision of Abiraterone acetate solution. 62
Table 23. Interday accuracy and precision of Abiraterone acetate solution. 63
Table 24. Intraday precision and accuracy of UPLC-MS/MS method for Abiraterone aetate spiked plasma standards (n=3). 65
Table 25. Interday precision and accuracy of UPLC-MS/MS method for Abiraterone aetate spiked plasma standards (n=3). 66
Table 26. The particle size of blank l-SMEDDS, s-SMEDDS and Abiraterone acetate loaded-SMEDDS formulations. 67
Table 27. Pharmacokinetic parameters of Abiraterone acetate after oral administration with Abiraterone acetate, l-SMEDDS and s-SMEDDS. 81

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