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研究生:李欣潔
研究生(外文):Hsin-Chieh Lee
論文名稱:探討Water-in-oil-in-water乳化微粒於口服蛋白質類藥物傳遞系統上之應用
論文名稱(外文):To investigate the application of water-in-oil-in-water emulsion for the protein drugs in oral delivery system
指導教授:林佳靜林佳靜引用關係
指導教授(外文):Chai-Ching Lin
學位類別:碩士
校院名稱:國立宜蘭大學
系所名稱:生物技術研究所碩士班
學門:農業科學學門
學類:畜牧學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:99
中文關鍵詞:顆粒球生長刺激素油包水-水包油型複合乳化液蛋白質藥物口服藥物傳遞系統
外文關鍵詞:granulocyte colony-stimulating factor (G-CSF)w/o/w emulsionprotein drugsoral delivery system
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目前臨床上對於蛋白質和多肽類藥物之給藥方式仍以注射為主,在長期治療下,往往會對病患的身心和經濟上造成重大痛苦和負擔。因此,本研究目的為建立一有效口服傳遞系統以提高蛋白質藥物的吸收。利用乳化液 (emulsion) 的形式做為藥物傳遞系統,是目前廣為研究的方式之一。其中,油包水-水包油型 (water-in-oil-in-water, W/O/W) 的複合乳化液已被證實可將蛋白質藥物包裏於內部的水相,可避免被腸胃道的酵素所降解,並且可增進親水性藥物在體內的吸收性。因此本論文欲探討蛋白質藥物顆粒球細胞生長刺激素 (Granulocyte colony-stimulating factor, G-CSF) 經W/O/W 複合乳化法包裏後,對小鼠口服吸收性的影響。
試驗結果顯示,使用兩階段式的乳化方式所建構出的 W/O/W 乳化液,不論是在顆粒大小 (直徑 2 μm)、包覆率 (40±5%)、穩定性 (耐酸性 pH 1.2,2hr 及耐高溫 60°C,5天)、穿透率 (30分鐘內滲透入 Caco-2 cell monolayer) 及體外毒性試驗上,皆顯示此乳化液的配方有傾向去幫助小鼠體內吸收的效果。進一步藉由大腸桿菌表現系統 (E. coli expression system) 產製具有活性之重組人類 G-CSF (rhG-CSF) 蛋白,並包裏入上述乳化液中,測試其對小鼠的口服生物利用率。經實驗結果顯示,連續七天餵予不同劑量的乳化液或水溶液劑型之 rhG-CSF,在第七天的六小時後觀察,相較於餵食空白乳化液的對照組,高劑量 rhG-CSF (2,500 μg/kg/day) 包埋處理組的白血球數有顯著的增加 (p < 0.01);但乳化劑包埋與不包埋的兩組相互比較,兩者則無差異性。口服十二個小時後,所有餵食 rhG-CSF 的小鼠,其白血球數皆有顯著的提升 (p < 0.01)。此外,對餵食乳化劑的小鼠進行腸道組織切片的染色觀察與穿透腸黏膜細胞 Caco-2 cell 的測試,W/O/W 乳化劑對小鼠腸道組織並不會造成損害且可促進其穿透率。由本次試驗證實,W/O/W 乳化液可促進 rhG-CSF 於腸道黏膜細胞的穿透率、耐酸性、耐高溫及包覆率的效果,並且對小鼠的腸道組織不會造成損害。因此,在未來或許可運用此劑型做為蛋白質的口服傳遞系統。
Since the injection administration as the peptides and proteins delivery system, it imposes discomfort and inconvenience on patients, particularly for a long-term treatment. Therefore, the goal of this thesis is to find out an oral delivery system for improving the absorption of therapeutic protein drugs.
Emulsion is one of strategies known delivery vehicles for those oral medicines. Water-in-oil -in-water (W/O/W) multiple emulsion has been known to be possible to protect protein drugs from enzyme degradation and enhance the absorption of hydrophilic drugs to systemic circulation. Therefore, we tried to use granulocyte colony-stimulating factor (G-CSF) as the indicator to test the emulsion formulation for the oral delivery system in the study.
In this two-step emulsification procedure, the data of the droplet size (2 μm of diameter), encapsulation efficiency (40±5%), stability (at pH 1.2 for 2 hrs and 60°C for 5 days), permeability (into Caco-2 cell monolayer with 30 min) and in vitro cytotoxicity studies all showed that the emulsion formulation was indicated to promote the absorption of proteins drugs by oral administration. Thus, we used the E. coli expression system to express and purify the recombinant human G-CSF (rhG-CSF). And then, rhG-CSF was incorporated into the inner aqueous phase of the emulsion for the test of oral bioavailability. After 6 hrs of oral administration of various dosages of rhG-CSF in solution or in emulsion for 7 days, the proliferations of leukocytes in the two treatments with the highest dose of rhG-CSF (2,500 μg/kg/day) were significantly higher than the blank emulsion (p < 0.01). However, two of them, rhG-CSF in emulsion and not in emulsion, were not different. After 12 hrs of oral administration, mice, administrated by 50, 500, and 2500 μg/kg/day rhG-CSF emulsion, all presented a significant elevation in leukocyte numbers when compared to the blank emulsion (p < 0.01). Finally, it was indicated about the advantages of the W/O/W multiple emulsions with encapsulation efficiency, penetrating ability, and stability to resist acid pH (1.2) and high temperature (60°C). In the future, it could be potential for protein drugs delivery by oral administration.
誌謝 1
中文摘要 5
Abstract 7
Introduction 9
Chapter 1 Literature review 12
1.1 The development and delivery systems of protein drugs 12
1.1.1 The development of protein drugs 12
1.1.2 The approaches for non-invasive delivery of protein drugs 13
1.1.3 The obstacles of developing oral formulations for protein drugs 15
1.2 Strategies of the oral delivery for protein drugs 17
1.2.1 Chemical modifications 17
1.2.2 Protease inhibitors 18
1.2.3 Absorption enhancers 19
1.2.4 Colloidal carrier systems 20
1.3 Water-in-oil-in- water (W/O/W) multiple emulsions 30
1.3.1 The property of W/O/W multiple emulsions 30
1.3.2 The emulsifiers 30
1.4 Experimental framework 36
Chapter 2 Materials and methods 37
2.1 Objective 37
2.2 Preparation of the water-in-oil-in-water (W/O/W) multiple emulsion 38
2.2.1 Morphology observation 40
2.2.2 Droplet size analysis 40
2.3 Stability evaluation of the W/O/W emulsion 41
2.3.1 The pH-dependent stability of emulsions in simulated fluids 41
2.3.2 Accelerated stability studies 41
2.4 Penetrating pathway of EGFP into the Caco-2 cell monolayer 42
2.5 Gene construction of the recombinant human granulocyte colony stimulating factor (rhG-CSF) 43
2.5.1 Cell lines and isolation of RNA 43
2.5.2 Complimentary DNA (cDNA) cloning 43
2.5.3 Construction of the rhG-CSF expression vector 43
2.6 Expression and purification of rhG-CSF 45
2.6.1 Expression of rhG-CSF in E. coli 45
2.6.2 Isolation of inclusion bodies 46
2.6.3 Purification and refolding of rhG-CSF 47
2.6.4 Analysis of the expressed rhG-CSF 47
2.7 Measurement of rhG-CSF bioactivity 48
2.7.1 In vitro assay of cell proliferation 48
2.7.2 In vivo assay of leukocyte proliferation 49
2.8 Protein encapsulating efficiency 50
2.9 In vitro study to evaluate the cytotoxicity of emulsion 51
2.10 In vivo study to evaluate the bioactivity 52
2.11 Histological evaluation of intestinal tissue 52
2.12 Statistical analysis 53
Chapter 3 Result 54
3.1 Morphology, droplet size and encapsulating efficiency of the W/O/W multiple emulsions 54
3.2 The pH-dependent and accelerated stability of the W/O/W emulsion 54
3.3 Penetrated pathway of EGFP into the Caco-2 cell monolayer 55
3.4 Construction of expression vector of rhG-CSF 56
3.5 Expression and purification of rhG-CSF in E. coli 56
3.6 Bioactivity of rhG-CSF 57
3.7 In vitro study to evaluate the cytotoxicity of emulsion 58
3.8 In vivo study to evaluate the bioactivity 58
3.9 Histological observation of intestinal tissue 59
Chapter 4 Discussion 77
Chapter 5 Conclusion 82
Reference 83
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