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系統識別號 U0026-3108201904534100
論文名稱(中文) 以具核-殼結構之PLGA-PVP/PVA微針經皮緩釋NO donor應用於原發性骨質疏鬆症之治療
論文名稱(英文) Sustained transdermal delivery of NO donor using PLGA PVP/PVA core-shell microneedles 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 107
學期 2
出版年 108
研究生(中文) 張家振
研究生(英文) Chia-Chen Chang
學號 n36064165
學位類別 碩士
語文別 中文
論文頁數 75頁
口試委員 指導教授-陳美瑾
口試委員-陳毓宏
口試委員-劉英麟
口試委員-吳彥緯
中文關鍵字 雌激素缺乏  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 estrogen deficiency  primary osteoporosis  nitric oxide  BMD  TNF-α 
學科別分類
中文摘要 停經後的婦女因缺乏雌激素,導致蝕骨細胞過度活化,易引發原發性骨質疏鬆症。低濃度的一氧化氮(NO)具有調整免疫系統之能力,能促使胸腺細胞凋亡以及減少T細胞增殖,進而減緩腫瘤壞死因子-α(Tumour necrosis factor-α, TNF-α)刺激蝕骨細胞分化,以抑制骨吸收,達到治療骨鬆的效果。本研究以molsidomine作為NO donor,並利用核-殼(core-shell)微針系統包覆藥物,讓微針鑲嵌至皮膚中緩釋molsidomine,提高生物可利用率與降低每日服藥之不便性。本微針乃以聚乳酸聚乙醇酸共聚物[poly(lactic-co-glycolic acid), PLGA]作為包覆藥物之主材料(core),探討不同PLGA共聚物比例及黏度對藥物釋放之影響;於微針外層塗覆聚乙烯吡咯烷酮與聚乙烯醇之混和物[poly(vinyl alcohol) and poly(vinyl pyrrolidone) blends, PVP/PVA]形成殼狀結構(shell),賦予微針更高的機械強度以加深穿刺深度。經體外藥物釋放評估,LA:GA = 85:15之PLGA能於兩週內以接近零次釋放的方式釋放藥物(R2 = 0.97, n = 5),且無初期突釋與二次釋放發生。PVP/PVA的外層殼狀結構,可明顯提高PLGA微針之穿刺深度,由665 ± 142 μm加深至948 ± 35 μm (n = 6),顯示殼狀結構不僅可加深穿刺深度,亦更加提高穿刺之穩定性。以去卵巢化誘發原發性骨鬆之S.D.大鼠進行有效性測試,每兩週分別給予2片(低劑量)、3片(高劑量)微針,同時以每日注射雌激素作為正控制組。治療8週後微針高劑量組之骨密度及其他骨參數皆明顯高於未治療組,並與正控制組於統計上無明顯差異,且亦能明顯抑制血中TNF-α濃度,證實長期釋放NO能調節因缺乏雌激素而導致的骨質流失、協助骨骼修復,具有治療原發性骨質疏鬆症之潛力。
英文摘要 In postmenopausal women, estrogen deficiency causes osteoclasts over activation, which easily suffers from primary osteoporosis. Low concentration of nitric oxide can regulate the immune system, which causes thymocytes apoptosis, reduces T cell proliferation, and slows down tumor necrosis factor-alpha (TNF-α) to stimulate osteoclasts differentiation, thus suppressing bone resorption. In this study, we developed a core-shell microneedle (MN) system for sustained transdermal delivery of molsidomine, a NO donor and evaluated its feasibility for treatment of osteoporosis. In the MN system, [poly(lactic-co-glycolic acid), PLGA] was used as a core material to encapsulate molsidomine; [poly(vinyl alcohol) and poly(vinyl pyrrolidone) blends, PVP/PVA] was selected as a shell material to provide mechanical strength for improving MN insertion capability. The in vitro drug release study showed that MN made by PLGA with LA:GA = 85:15 provided an approximate zero-order release profile (R2 = 0.97, n = 5) for two weeks and no initial burst release or second release occurred. Compared to the MN without the shell, the PVP/PVA shell can improve the insertion depth from 665 ± 142 μm to 948 ± 35 μm (n = 6), demonstrating the shell enhance the MN puncture stability. Ovariectomized (OVX) Sprague Dawley rat was used as a model of postmenopausal osteoporosis to evaluate the MN efficacy. The animals were divided into four groups: untreated (OVX), low-dose (two patches per two weeks) MN, high-dose MN (three patches per two weeks), and estradiol (E2, daily injection) treated groups. After 8 weeks of treatment, the bone mineral density and other bone parameters of the high-dose MN group were significantly higher than those of the untreated group, and there was no statistical difference compared to the E2 group. Additionally, the TNF-α levels were significantly reduced in both MN groups. These results demonstrated that using the PLGA-PVP/PVA core-shell microneedle 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
誌謝 X
Abstract XI
目錄 XIII
表目錄 XVI
圖目錄 XVII
第一章 緒論 1
1.1. 骨頭基本介紹與結構 1
1.2. 骨骼細胞之生理機轉 1
1.2.1骨細胞(Osteocyte) 2
1.2.2造骨細胞(Osteoblast) 2
1.2.3蝕骨細胞(Osteoclast) 3
1.3. 骨質疏鬆症之介紹 4
1.4. 骨質疏鬆症之臨床用藥 5
1.5. 雌激素缺乏致骨代謝失衡之機制 6
1.6. 一氧化氮之生理調節作用 7
1.7. 一氧化氮釋放劑於骨質疏鬆症治療之潛力 8
1.8. 藥物傳輸系統 9
1.8.1. 聚乳酸聚乙醇酸共聚物(PLGA)藥物載體 10
1.8.2 經皮藥物傳輸微針系統 12
1.9. 研究目的 13
1.10. 研究架構 15
第二章 實驗材料及方法 16
2.1. 實驗藥品 16
2.2. 實驗耗材及動物 18
2.3. 儀器設備 19
2.4. 含嗎多明之PLGA微針製備 21
2.5. PLGA 分子量分析 24
2.6. PLGA/molsidomine 結晶性分析 25
2.7. 定量微針中之 molsidomine (Loading content) 25
2.8. 體外藥物釋放 26
2.9. 微針機械強度測試 26
2.10. 微針穿刺測試 27
2.11. 罹患骨質疏鬆症大鼠之療效測試 28
2.11.1 實驗設計 28
2.11.2 血液中molsidomine濃度追蹤[45] 29
2.11.3 微電腦斷層影像分析(micro-CT) 31
2.11.4 脛骨組織切片分析 31
2.11.5 血中腫瘤壞死因子(TNF-α)濃度檢測 32
2.11.6 統計方法 33
第三章 結果與討論 34
3.1. 不同黏度之PLGA 分子量分析 34
3.2. Molsidomine/PLGA XRD結晶性分析 35
3.3. PLGA微針外觀 37
3.4. 包覆molsidomine之PLGA 微針 38
3.5. PLGA-PCL core-shell 微針 42
3.6. 體外藥物釋放 44
3.7. PLGA-PVP/PVA core-shell微針 49
3.7.1 PLGA-PVP/PVA core-shell微針外觀 50
3.8. PLGA-PVP/PVA core-shell機械強度 51
3.9. 穿刺能力測試 53
3.10. PLGA-PVP/PVA core-shell含藥微針應用於骨質疏鬆症治療 56
3.10.1 微電腦斷層影像分析(micro-CT) 57
3.10.2 脛骨組織切片 64
3.10.3 血中藥物濃度追蹤 66
3.10.4 血中腫瘤壞死因子(TNF-α)濃度 67
第四章 結論 68
第五章 參考文獻 70

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