臺灣博碩士論文加值系統

目錄
指導教授推薦書
論文口試委員審定書
中文摘要 iii
Abstract v
目錄 vii
圖目錄 x
表目錄 xii
第一章 序論 1
1.1前言 1
1.2研究動機與目的 2
1.3現今胰島素的給藥方式 3
1.3.1胰島素口服制劑 3
1.3.2胰島素皮下注射 4
1.3.3胰島素眼藥劑 4
1.3.4胰島素滴鼻劑 5
1.3.5胰島素噴霧劑 5
1.3.6胰島素幫浦 5
1.3.7胰島素經皮滲透 6
1.4胰島素的種類與藥效 8
1.5微針種類的介紹 10
1.5.1固體型微針 12
1.5.2塗覆型微針 13
1.5.3中空型微針 14
1.5.4高分子微針 15
1.6可溶型微針之材料與應用 17
1.7實驗架構 19
第二章 材料與方法 21
2.1材料與藥品 21
2.2實驗儀器設備 25
2.3材料配製 27
2.3.1材料溶液的配製 27
2.3.2 FITC-胰島素的配製 29
2.4微針的製程 31
2.4.1負向模板的製備 31
2.4.2離心法製程 32
2.5微針的外觀與規格定義 33
2.6體外豬皮穿刺測試 34
2.6.1穿刺能力 34
2.6.2微針穿刺後的外觀與型態 36
2.6.3穿刺深度 37
2.7體外藥物釋放測試 38
2.7.1擴散深度 38
2.7.2體外藥物釋放速率 39
2.8活體的降血糖效果 40
第三章 結果與討論 42
3.1微針的製作與外觀 42
3.1.1微針外觀-解剖顯微鏡 44
3.1.2微針外觀-電子式掃描顯微鏡 48
3.1.3微針外觀-正立式螢光顯微鏡 50
3.1.4微針的規格與比較 52
3.2體外豬皮穿刺測試 55
3.2.1穿刺能力 55
3.2.2穿刺後的外觀與型態 57
3.2.3穿刺深度 -光學式同調斷層掃描 59
3.3體外藥物釋放測試 62
3.3.1擴散深度-共軛焦雷色掃描式顯微鏡 62
3.3.2體外藥物釋放速率 65
3.4活體的降血糖效果 67
3.4.1藥理利用度 67
3.4.2生物利用度 69
第四章 結論 71
參考文獻 73

圖目錄
圖一 微針應用於皮膚之示意圖 8
圖二 各種微針的藥物輸送的機制示意圖 11
圖三 固體型微針的應用 12
圖四 塗覆型微針的應用 13
圖五 中空型微針的應用 15
圖六 高分子微針的應用 16
圖七 實驗架構 20
圖八 自製推進器裝置圖 26
圖九 配製含藥物之10%(w/w)明膠溶液 28
圖十 配製無藥物之10%(w/w)CMC溶液 28
圖十一 配製FITC-胰島素步驟 30
圖十二 兩層式可溶性微針製程 33
圖十三 微針的規格定義 34
圖十四 微針貼片體外豬皮穿刺測試之示意圖 35
圖十五 微針穿刺後的外觀與型態實驗之流程圖 36
圖十六 體外穿刺深度實驗流程之示意圖 38
圖十七 擴散深度實驗流程之示意圖 39
圖十八 兩層式可溶性微針之解剖顯微鏡圖像(低倍率45度角) 47
圖十九 兩層式可溶性微針之解剖顯微鏡圖像(高倍率90度角) 47
圖二十 兩層式微針之SEM圖像(45度角) 49
圖二十一 兩層式微針之SEM圖像(90度角) 49
圖二十二 兩層式微針之螢光顯微鏡圖像(90度角) 51
圖二十三 3M正向主模板與兩層式可溶性微針的規格統計比較圖 54
圖二十四 兩層式可溶性微針穿刺豬皮後之解剖顯微鏡圖像 56
圖二十五 微針穿刺後的外觀之螢光顯微鏡圖像以及Rhodamine 6G在豬皮擴散之解剖顯微鏡圖像 58
圖二十六 微針穿刺前後的新生小豬耳朵皮之OCT即時掃描圖像 61
圖二十七 包覆Rhodamine 6G的兩層式可溶性微針貼片穿刺新生小豬的耳朵皮60分鐘後隨深度變化的CLSM圖像 63
圖二十八 包覆FITC-胰島素的兩層式可溶性微針貼片穿刺新生小豬的耳朵皮60分鐘後隨深度變化的CLSM圖像 64
圖二十九 兩層式可溶性微針的累積釋放胰島素曲線圖 66
圖三十 兩層式胰島素微針對糖尿病小鼠之血糖濃度之效果 68
圖三十一 兩層式胰島素微針對糖尿病小鼠之血漿中胰島素濃度 70

表目錄
表一 現今各種胰島素給藥方式的比較 8
表二 胰島素的來源與分類 9
表三 不同胰島素劑型之藥物動力學比較 10
表四 各種微針的優劣勢比較 17
表五 可溶性微針的材料與應用 19
表六 3M正向主模板與兩層式可溶性微針的結構規格統計 53
表七 胰島素微針與皮下注射之藥理利用度 68
表八 胰島素微針與皮下注射之生物利用度 70

[1] Melmed S, Polonsky KS, Larsen PR and Kronenberg HM. Williams Textbook of Endocrinology. 2012:1371–435.
[2] Shi Y, Hu FB. The global implications of diabetes and cancer. The Lancet. 2014;383:1947-8.
[3] Chiang JL, Kirkman MS, Laffel LM, Peters AL. Type 1 diabetes through the life span: a position statement of the American diabetes association. Diabetes Care. 2014;37:2034-54.
[4] Leonor G, Tim N, Jessica B, Ute L, Olivier J. IDF diabetes atlas. International Diabetes Federation. 2013;101:349-51.
[5] Liu S, Jin MN, Quan YS, Kamiyama F, Katsumi H, Sakane T. The development and characteristics of novel microneedle arrays fabricated from hyaluronic acid, and their application in the transdermal delivery of insulin. Journal of Controlled Release. 2012;161:933-41.
[6] Hultstrom M, Roxhed N, Nordquist L. Intradermal insulin delivery: a promising future for diabetes management. Journal of Diabetes Science and Technology. 2014;8:453-7.
[7] Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery. Diabetic Medicine. 2003;20:886–98.
[8] Palermo A, Napoli N, Manfrini S, Lauria A, Strollo R, Pozzilli P. Buccal spray insulin in subjects with impaired glucose tolerance: the prevoral study. Diabetes, Obesity &; Metabolism. 2011;13:42-6.
[9] Pozzilli P, Raskin P, Parkin CG. Review of clinical trials: update on oral insulin spray formulation. Diabetes, Obesity &; Metabolism. 2010;12:91-6.
[10] Hou T, Xin W, Dong Z. Functional and pathological study of intranasal absorption of insulin aided by azone. Chinese Journal of Otorhinolaryngology Head and Heck Surgery. 2002;37:271-3.
[11] Dondeti P, Zia H, Needham TE. In vivo evaluation of spray formulations of human insulin for nasal delivery. International Journal of Pharmaceutics. 1995;122:91-105.
[12] Pillion DJ, Amsden JA, Kensil CR, Recchia J. Structure-function relationship among quillaja saponins serving as excipients for nasal and ocular delivery of insulin. Journal of Pharmaceutical Sciences. 1996;85:518-24.
[13] Pillion DJ, Hosmer S, Meezan E. Dodecylmaltoside-mediated nasal and ocular absorption of lyspro insulin : independence of surfactant action from multimer dissociation. Journal of Pharmaceuical Research. 1998;15:1637-9.
[14] Xuan B, McClellan DA, Moore R, Chiou GC. Alternative delivery of insulin via eye drops. Diabetes Technology &; Therapeutics. 2005;7:695-8.
[15] 李素霞, 鄒立家, 張天民. 胰島素經眼給藥製劑的研究. 中國生化藥物志. 1998;19:10.
[16] Migalska K, Morrow DI, Garland MJ, Thakur R, Woolfson AD, Donnelly RF. Laser-engineered dissolving microneedle arrays for transdermal macromolecular drug delivery. Pharmaceutical Research. 2011;28:1919-30.
[17] Deng YL, Juang YJ. Polydimethyl siloxane wet etching for three dimensional fabrication of microneedle array and high-aspect-ratio micropillars. Biomicrofluidics. 2014;8:026502.
[18] Zhu Z, Luo H, Lu W, Luan H, Wu Y, Luo J. Rapidly dissolvable microneedle patches for transdermal delivery of exenatide. Pharmaceutical Research. 2014;31:3348-60.
[19] Moga KA, Bickford LR, Geil RD, Dunn SS, Pandya AA, Wang Y. Rapidly-dissolvable microneedle patches via a highly scalable and reproducible soft lithography approach. Advanced Materials. 2013;25:5060-6.
[20] Matsuo K, Yokota Y, Zhai Y, Quan YS, Kamiyama F, Mukai Y. A low-invasive and effective transcutaneous immunization system using a novel dissolving microneedle array for soluble and particulate antigens. Journal of Controlled Release. 2012;161:10-7.
[21] Kim JD, Kim M, Yang H, Lee K, Jung H. Droplet-born air blowing: novel dissolving microneedle fabrication. Journal of Controlled Release. 2013;170:430-6.
[22] Ito Y, Nakahigashi T, Yoshimoto N, Ueda Y, Hamasaki N, Takada K. Transdermal insulin application system with dissolving microneedles. Diabetes Technology &; Therapeutics. 2012;14:891-9.
[23] Hirobe S, Azukizawa H, Matsuo K, Zhai Y, Quan YS, Kamiyama F. Development and clinical study of a self-dissolving microneedle patch for transcutaneous immunization device. Pharmaceutical Research. 2013;30:2664-74.
[24] Pankowska E, Blazik M, Dziechciarz P, Szypowska A, Szajewska H. Continuous subcutaneous insulin infusion vs. multiple daily injections in children with type 1 diabetes: a systematic review and meta-analysis of randomized control trials. Pediatric Diabetes. 2009;10:52-8.
[25] Davidson A, Al-Qallaf B, Das DB. Transdermal drug delivery by coated microneedles: geometry effects on effective skin thickness and drug permeability. Chemical Engineering Research and Design. 2008;86:1196-206.
[26] Hong X, Wei L, Wu F, Wu Z, Chen L, Liu Z. Dissolving and biodegradable microneedle technologies for transdermal sustained delivery of drug and vaccine. Drug Design, Development and Therapy. 2013;7:945-52.
[27] Donnelly RF, Singh TR, Alkilani AZ, McCrudden MT, O'Neill S, O'Mahony C. Hydrogel-forming microneedle arrays exhibit antimicrobial properties: potential for enhanced patient safety. International Journal of Pharmaceutics. 2013;451:76-91.
[28] 行政院衛生署. 糖尿病用降血糖藥胰島素. 藥物食品安全週報. 2007;第116期.
[29] 佛教慈濟綜合醫院. 藥物Q&;A:胰島素分類與使用. 慈濟藥訊. 第56期:21.
[30] Hiraishi Y, Nakagawa T, Quan YS, Kamiyama F, Hirobe S, Okada N. Performance and characteristics evaluation of a sodium hyaluronate-based microneedle patch for a transcutaneous drug delivery system. International Journal of Pharmaceutics. 2013;441:570-9.
[31] Kim YC, Park JH, Prausnitz MR. Microneedles for drug and vaccine delivery. Advanced Drug Delivery Reviews. 2012;64:1547-68.
[32] McAllister DV, Wang PM, Davis SP, Park JH, Canatella PJ, Allen MG. Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:13755-60.
[33] Henry S, Devin V. Mcallister, Allen MG, Prausnitz MR. Microfabricated microneedles: anovel approach to transdermal drug delivery. Pharmaceutical Sciences. 1998;87:922-5.
[34] Gill HS, Prausnitz MR. Coated microneedles for transdermal delivery. Journal of Controlled Release. 2007;117:227–37.
[35] Martanto W, Davis SP, Holiday NR, J. Wang HSG, Prausnitz MR. Transdermal delivery of insulin using microneedles in vivo. Pharmaceutical Research. 2004;21:947–52.
[36] Matriano JA, Cormier M, Johnson J, Young WA, Buttery M, NyamK. Macroflux (R) microprojection array patch technology: a new and efficient approach for intracutaneous immunization. Pharmaceutical Research. 2002;19: 63–70.
[37] Omatsu T, Chujo K, Miyamoto K, Okida M, Nakamura K, Aoki N. Metal microneedle fabrication using twisted light with spin. Optical Express. 2010;18:17967–73.
[38] Jung PG, Lee TW, Oh DJ, Hwang SJ, Jung ID, Lee SM. Nickel microneedles fabricated by sequential copper and nickel electroless plating and copper chemical wet etching. Sensors and Materials. 2008;20:45-53.
[39] Bystrova S, Luttge R. Micromolding for ceramic microneedle arrays. Microelectronic Engineering. 2011;88:1681-4.
[40] Gittard SD, Ovsianikov A, Chichkov BN, Doraiswamy A, Narayan RJ. Two-photon polymerization of microneedles for transdermal drug delivery. Expert Opinion on Drug Delivery. 2010;7:513-33.
[41] Moon SJ, Lee SS, Lee HS, Kwon TH. Fabrication of microneedle array using LIGA and hot embossing process. Microsystem Technologies. 2005;11:311-8.
[42] McGrath MG, Vrdoljak A, O'Mahony C, Oliveira JC, Moore AC, Crean AM. Determination of parameters for successful spray coating of silicon microneedle arrays. International Journal of Pharmaceutics. 2011;415:140-9.
[43] Lee KJ, Park SH, Lee JY, Joo HC, Jang EH, Youn YN. Perivascular biodegradable microneedle cuff for reduction of neointima formation after vascular injury. Journal of Controlled Release. 2014;192:174-81.
[44] Gill HS, Prausnitz MR. Coating formulations for microneedles. Pharmaceutical Research. 2007;24:1369-80.
[45] Davis SP, Martanto W, Allen MG, Prausnitz MR. Hollow metal microneedles for insulin delivery to diabetic rats. IEEE Transactions on Biomedical Engineering. 2005;52:909–15.
[46] Roxhed N, Gasser TC, Griss P, Holzapfel GA, Stemme G. Penetration-enhanced ultrasharp microneedles and prediction on skin interaction for efficient transdermal drug delivery. Journal of Microelectromechanical Systems. 2007;16:1429–40.
[47] Luttge R, Berenschot EJW, Boer MJd, Altpeter DM, Vrouwe EX, Berg AVD. Integrated lithographic molding for microneedle-based devices. Journal of Microelectromechanical Systems. 2007;16:872–84.
[48] Ma B, Liu S, Gan Z, Liu G, Cai X, Zhang H. A PZT insulin pump integrated with a silicon microneedle array for transdermal drug delivery. Microfluidics and Nanofluidics. 2006;2:417-23.
[49] Park SY, Lee HU, Lee YC, Kim GH, Park EC, Han SH. Wound healing potential of antibacterial microneedles loaded with green tea extracts. Materials Science and Engineering C. 2014;42:757-62.
[50] Katsumi H, Liu S, Tanaka Y, Hitomi K, Hayashi R, Hirai Y. Development of a novel self-dissolving microneedle array of alendronate, a nitrogen-containing bisphosphonate: evaluation of transdermal absorption, safety, and pharmacological effects after application in rats. Journal of Pharmaceutical Sciences. 2012;101:3230-8.
[51] Lee JW, Park JH, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials. 2008;29:2113-24.
[52] Lee JW, Choi SO, Felner EI, Prausnitz MR. Dissolving microneedle patch for transdermal delivery of human growth hormone. Small. 2011;7:531-9.
[53] Fukushima K, Ise A, Morita H, Hasegawa R, Ito Y, Sugioka N. Two-layered dissolving microneedles for percutaneous delivery of peptide/protein drugs in rats. Pharmaceutical Research. 2011;28:7-21.
[54] Ling MH, Chen MC. Dissolving polymer microneedle patches for rapid and efficient transdermal delivery of insulin to diabetic rats. Acta Biomaterialia. 2013;9:8952-61.
[55] Chu LY, Prausnitz MR. Separable arrowhead microneedles. Journal of Controlled Release. 2011;149:242-9.
[56] Wendorf JR, Ghartey-Tagoe EB, Williams SC, Enioutina E, Singh P, Cleary GW. Transdermal delivery of macromolecules using solid-state biodegradable microstructures. Pharmaceutical Research. 2011;28:22-30.
[57] Choi CK, Lee KJ, Youn YN, Jang EH, Kim W, Min BK. Spatially discrete thermal drawing of biodegradable microneedles for vascular drug delivery. European Journal of Pharmaceutics and Biopharmaceutics. 2013;83:224-33.
[58] G¨ok E, Olgaz S. Binding of fluorescein isothiocyanate to insulin: afluorimetric labeling study. Journal of Fluorescence. 2004;14:203-6.
[59] Yan G, Warner KS, Zhang J, Sharma S, Gale BK. Evaluation needle length and density of microneedle arrays in the pretreatment of skin for transdermal drug delivery. International Journal of Pharmaceutics. 2010;391:7-12.
[60] Donnelly RF, Garland MJ, Morrow DI, Migalska K, Singh TR, Majithiya R. Optical coherence tomography is a valuable tool in the study of the effects of microneedle geometry on skin penetration characteristics and in-skin dissolution. Journal of Controlled Release. 2010;147:333-41.
[61] Garland MJ, Migalska K, Tuan-Mahmood TM, Raghu Raj Singh T, Majithija R, Caffarel-Salvador E. Influence of skin model on in vitro performance of drug-loaded soluble microneedle arrays. International Journal of Pharmaceutics. 2012;434:80-9.