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系統識別號 U0026-2208201810321300
論文名稱(中文) 經皮緩釋molsidomine之PLGA微粒應用於治療原發性骨質疏鬆症
論文名稱(英文) Sustained transdermal delivery of molsidomine using PLGA microparticles for primary osteoporosis treatment
校院名稱 成功大學
系所名稱(中) 化學工程學系
系所名稱(英) Department of Chemical Engineering
學年度 106
學期 2
出版年 107
研究生(中文) 何國淵
研究生(英文) Guo-Yuan He
學號 N36054039
學位類別 碩士
語文別 中文
論文頁數 102頁
口試委員 指導教授-陳美瑾
口試委員-鍾宜璋
口試委員-吳彥緯
口試委員-江伯敏
口試委員-陳毓宏
中文關鍵字 嗎多明  原發性骨質疏鬆症  一氧化氮  骨密度  腫瘤壞死因子 
英文關鍵字 molsidomine  primary osteoporosis  nitric oxide  BMD  TNF-α 
學科別分類
中文摘要 停經後的婦女由於雌激素缺乏,導致免疫失調及蝕骨細胞(osteoclasts)的過度活化,引發原發性骨質疏鬆症(primary osteoporosis)。文獻指出,低濃度的一氧化氮(NO)具有調整免疫系統的能力,可促進造骨細胞的成長與分化,同時抑制骨吸收,達到治療骨鬆的效果。本研究探討以心血管用藥molsidomine(嗎多明)作為NO donor,找出其治療骨鬆的NO最佳給藥劑量,再以此劑量為目標,開發可長效經皮緩釋NO donor之藥物微粒,評估其應用在治療骨鬆之可行性。透過口服低(2 μg/day)、中(60 μg/day)及高(200 μg/day)劑量的molsidomine,治療去卵巢化誘發原發性骨鬆小鼠三個月,發現口服低劑量molsidomine可明顯降低腫瘤壞死因子(TNF-α)的濃度與脛骨組織中脂肪之比例,證明低劑量之組別具有最佳之骨質修復能力。為了提高給藥的方便性及降低給藥頻率,以長期緩釋低劑量molsidomine為目標,開發含藥聚乳酸聚乙醇酸共聚物[poly(lactic-co- glycolic acid), PLGA]微粒。利用乳化法製備PLGA含藥微粒,透過磷酸鹽調整PVA溶液至pH 5.2,製備之PLGA微粒(稱LOW-P)之體外釋放曲線最為接近零級釋放,且可緩慢持續釋出藥物長達70天。將微粒皮下注射於小鼠體內,由血中藥物濃度分析結果可知,第14天時血中藥物濃度趨於恆定,且能維持至少56天,顯示微粒可長期維持體內藥物濃度於特定區間。以去卵巢化誘發原發性骨鬆之小鼠進行有效性測試,分別於每隻小鼠皮下注射5、15、30 mg含藥微粒(OVX-low, medium, high dose)或15 mg不含藥之微粒(OVX-empty)。8週後注射含藥微粒治療之組別,其骨密度(bone mineral density, BMD)及骨體積比率(BV/TV)皆遠高於未治療組(OVX-control)。值得一提的是,OVX-medium dose於注射微粒8週後仍可持續抑制血中TNF-α的濃度,有助於長期防止骨質流失並協助骨質修復。
英文摘要 In postmenopausal women, estrogen deficiency causes rebound of thymus, over-activation of T cell and osteoclasts, thus inducing osteoporosis. Appropriate concentrations of nitric oxide (NO) have been shown to promote the growth and differentiation of osteoblasts and suppress bone resorption through regulating thymocytes and T cells for the treatment of osteoporosis. In this study, we use cardiovascular drug, molsidomine, as a NO donor, and find its optimal oral dosage for osteoporosis. Based on this dosage, we develop microparticles (MPs) for sustained transdermal delivery of the NO donor and evaluate its feasibility in ovariectomized (OVX) mice, a model of postmenopausal osteoporosis. Oral administration of low-, medium-, or high-dose molsidomine started on the fifth month after OVX for a period of 3 months. We observed that the administration of low-dose (2 μg/day) molsidomine significantly reduced TNF-α levels and bone marrow adiposity in the tibia compared to the untreated OVX group. These results demonstrated that long-term low-dose molsidomine therapy has the therapeutic potential to improve bone mass. To improve convenience of administration and reduce dosing frequency, poly(lactic-co-glycolic acid) (PLGA) MPs were developed for sustained delivery of low-dose molsidomine. In vitro drug release study showed that the PLGA particles fabricated at pH 5.2 (LOW-P) have an approximate zero-order release up to 70 days. After subcutaneous injection of MPs to the mice, serum concentration of molsidomine reached a steady-state value at day 14 and can be sustained for at least 56 days. The fact indicates the PLGA MPs can control drug release and maintain the blood drug concentration within a specific interval. The OVX mice were randomly assigned to the following groups: OVX-control, OVX-empty (drug-free MPs), OVX-low dose (5 mg MPs), OVX-medium dose (15 mg MPs), or OVX-high dose (30 mg MPs). Compared to the OVX-control group, all drug-loaded MP groups increased bone volume (BV/TV) and bone mineral density (BMD). Notably, the OVX-medium dose group showed the strongest effects on BV/TV, BMD, and TNF-α levels. This study demonstrates that using the PLGA MPs for sustained release of molsidomine could be a potential therapeutic strategy for the treatment and prevention of postmenopausal bone loss.
論文目次 摘要 I
Abstract XI
誌謝 XIII
目錄 XIV
表目錄 XVIII
圖目錄 XIX
第一章 緒論 1
1.1. 骨質疏鬆症之介紹與治療 1
1.1.1. 原發性骨質疏鬆症之成因 1
1.1.2. 骨質疏鬆症之臨床用藥 2
1.2. 雌激素缺乏致骨代謝失衡之機制 4
1.2.1. 雌激素及雌激素受體(ER)之作用機制 5
1.2.2. 涉及胸腺功能復甦及T cell異常增殖之作用機制 5
1.3. 一氧化氮之生理調節作用 8
1.3.1. 血管擴張及缺氧再灌注(ischaemia–reperfusion)之組織保護 10
1.3.2. 免疫系統調節 11
1.4. 心血管疾病用藥於骨質疏鬆症治療應用之潛力 13
1.4.1. NO donors之心血管疾病用藥 14
1.4.2. NO donors應用於骨質疏鬆症之治療 17
1.4.3. 雌激素缺乏後調節胸腺及T cell因子之假說 19
1.5. 藥物傳輸系統 21
1.5.1. 聚乳酸聚乙醇酸共聚物(PLGA)藥物載體 21
1.5.2. 經皮藥物傳輸微針系統 24
1.6. 研究目的 26
1.7. 研究架構 28
第二章 實驗材料及方法 29
2.1. 實驗藥品 29
2.2. 實驗耗材及動物 31
2.3. 儀器設備 32
2.4. 卵巢切除致使血液NO level之差異 34
2.5. 口服嗎多明應用於骨鬆小鼠之治療 34
2.6. 包覆嗎多明之PLGA微粒 35
2.6.1. 包覆嗎多明之PLGA微粒製作 35
2.6.2. 含藥微粒之體外藥物釋放[60] 37
2.6.3. 血中藥物濃度追蹤 38
2.7. 皮下注射包覆嗎多明PLGA微粒應用於骨鬆小鼠之治療 40
2.8. 包覆含藥微粒之玻尿酸微針貼片 41
2.8.1. 包覆含藥微粒之玻尿酸微針貼片製作 42
2.8.2. 微針穿刺能力測試 44
2.9. 血液NO level檢測 44
2.10. 微電腦斷層影像分析(micro-CT) 46
2.11. 脛骨組織切片分析 47
2.12. 血中腫瘤壞死因子(TNF-α)濃度檢測 49
2.13. 抗酒石酸酸性磷酸酶陽性分析(TRAP-positive) 50
2.14. 血中膠原蛋白碳末端肽鏈(CTX-I)濃度檢測 51
2.15. 肝臟毒性測試 53
第三章 結果與討論 54
3.1. 血液NO level追蹤 54
3.2. 口服molsidomine應用於骨鬆小鼠之治療 56
3.3. 包覆molsidomine之PLGA微粒 62
3.3.1. 含藥微粒之體外藥物釋放 66
3.3.2. 血中藥物濃度追蹤 70
3.4. 皮下注射包覆嗎多明PLGA微粒應用於骨鬆小鼠之治療 72
3.4.1. 血中腫瘤壞死因子(TNF-α)濃度 72
3.4.2. 微電腦斷層影像分析(micro-CT) 74
3.4.3. 脛骨組織切片 78
3.4.4. 血中膠原蛋白碳末端肽鏈(CTX-I)濃度 79
3.4.5. 血中NO level追蹤 81
3.4.6. 毒性測試 83
3.5. 包覆含藥微粒之玻尿酸微針貼片 85
3.5.1. 微針穿刺能力測試 86
第四章 結論 87
第五章 參考文獻 89
補充資料 101
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