簡易檢索 / 詳目顯示

回結果列表
研究生： 蕭孟烜
Hsiao, Meng Hsuan
論文名稱： 聚乳酸微針貼片製作與其帶藥之可行性評估
Microneedle Patches Made by Poly-Lactic Acid and the Assessment of Drug Loading Feasibility
指導教授： 劉大佼
Liu, Ta Jo
口試委員: 吳平耀
Wu, Ping Yao
王潔
Wang, Jane
學位類別： 碩士
Master
系所名稱： 工學院 - 化學工程學系
Department of Chemical Engineering
論文出版年： 2016
畢業學年度： 105
語文別： 中文
論文頁數： 103
中文關鍵詞： 非水溶性微針貼片 、浸沾式塗佈 、外塗帶藥 、流場觀測
外文關鍵詞： hydrophobic MN patches, dip coating, drug coating, flow visualization
相關次數： 點閱：3  下載：0 
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報

    • 本研究目標為以聚乳酸 (poly(lactic acid), PLA)製作非水溶性高分子微針貼片，並搭配螢光染劑，分別以定量注藥及浸沾式塗佈方式探討藥物外塗於微針貼片之現象及定量藥物之可行性，以提供完整微針貼片之藥物傳輸平台。
    本研究一共分為兩階段進行，第一階段為疏水性微針貼片之製作，包含配方、製程、檢測三個部分，第二階段則為微針搭配螢光染劑之帶藥探討。第一階段微針載具製作部分，本研究選用PLA混合丙酮之疏水性高分子塗液，分別製作兩種形態之微針，其一為室溫乾燥型微針，經由塗佈、真空抽氣、乾燥三大步驟製成微針貼片；另一熔融型微針為利用塗液抽真空搭配高溫熔融製程，抑或直接以顆粒熔融方式製作微針貼片。經由顯微鏡觀察微針表面結構、微針機械強度分析以及豬皮穿刺，以確認第一階段微針貼片品質之後，方可進行第二階段之螢光染劑藥物結合。
    目前研究結果顯示，已可製作出品質良好之微貼片，至於外塗帶藥部分，首先在定體積注藥方面，我們發現在乾燥過程中，塗液將在微針間形成一半月形圖形，且其曲率半徑將在液體於微針表面形成一固定接觸點後，方開始有劇烈變化；而此過程中，雖然液體黏度越高，曲率半徑越小，且固定點所形成位置越高，然而表面張力會消弭掉黏度所造成之差異，為影響最終乾燥狀態之主要因子。而在浸沾式塗佈帶藥方面，我們建立一浸沾式塗佈系統，並搭配流場觀測攝影機，利用調控不同塗液特性及操作參數來了解帶藥過程。初步結果顯示其帶藥量與Ca值(=μV/σ)呈正相關，其中μ為液體黏度，V為塗佈拉升速度，σ為液體表面張力，而造成此結果之原因推測為拉升過程中，微針與液體間所形成之液體橋斷裂現象有關；另外我們也發現在乾燥時，塗液將會受重力影響而於微針表面形成一薄膜，然而因毛細現象影響，仍在努力解決如何精準控制每一根微針浸入高度，進而精準控制帶藥量。

    The objective of this research is to fabricate a poly(lactic acid) hydrophobic microneedle (MN) patch and also to assess the feasibility of drug loading process with dropping and dip coating techniques.
    This research is divided into two stages: fabrication of MN patches and the study of the drug loading process. The first stage includes three parts, i.e., formulation, experimental process and microneedle property test. We fabricated two different kinds of MN patches. The first one was based on PLA solution. The development included coating, vacuuming and drying under room temperature (RT). The other one is the melting type MN patches. We could either employ the high temperature melting process, or directly melt the PLA particles to obtain the patches. As soon as the fabrication process was completed, we then used digital camera to visualize the structure and configuration of the needles. Needle fracture force test and porcine skin penetration test were also applied to make sure the needle achieve the designated strength. When obtaining the acceptable MN patches, we then moved to the second stage - using the fluorescent drug test solution to study the drug loading process on the MNs.
    The results indicate that we can successfully fabricate a high quality MN patch. As for drug loading, when dropping a designated volume of drug solution, we found the solution could form a meniscus shape between the needles, and there also existed a “pin point”, where the curvature would start to change dramatically. In this drying process, although higher viscosities would lead to higher curvature and pin point positions, liquid surface tension would mitigate the effect of viscosity, which was actually the dominant factor on the curvature of the meniscus. As for the study of dip coating, we established a dip coating system with a flow visualization apparatus. The preliminary results show that the drug loading amount is proportional to the capillary number (=μV/σ) where μ,V and σ represent liquid viscosity, coating velocity and fluid surface tension, respectively. During the drying process, gravity would pull the liquid flow downward and thus formed a thin film on the needle surface. However, due to the capillary effect, the prediction of the dipping length could be difficult.

    目錄 摘要 I Abstract III 目錄 VI 圖目錄 VIII 表目錄 XII 第一章 緒論 1 1-1 微針簡介 1 1-2 研究動機與目標 3 1-3 研究架構 4 第二章 文獻回顧 8 2-1 微針貼片 8 2-2-1 微針型態分類 10 2-1-2 外塗微針塗佈技術 13 2-1-3 微針機械強度 16 2-2 浸沾式塗佈技術 (Dip Coating Technique) 18 2-3 PLA特性與應用 22 第三章 研究方法 23 3-1 實驗材料 23 3-2 實驗設備 27 3-3實驗方法 40 3-3-1 微針貼片載具製作 40 3-3-2 微針外塗螢光染劑之帶藥可行性觀察 47 第四章 實驗結果與討論 55 4-1 微針載具製作探討 55 4-1-1 室溫乾燥微針製作探討 56 4-1-2 熔融型微針製作探討 65 4-1-3 微針載具品質檢驗 66 4-2 微針外塗藥物之可行性分析 75 4-2-1 定量注藥 75 4-2-2 浸沾式塗佈帶藥觀察與測試 84 第五章 初步結論與未來方向 97 參考文獻 99 希臘子母 103 圖目錄 圖 1-1 微針示意圖 2 圖 1-2 微針穿刺皮膚示意圖 2 圖 1-3 微針研究團隊架構圖 6 圖 1-4 微針第一部分研究架構圖 6 圖 1-5 微針第二部分研究架構圖 7 圖 2-1 微針的主要基本結構…………………………………………...9 圖 2-2 四種微針貼片給藥方式 13 圖 2-3 微針不同幾何形狀角度設計 17 圖 2-4 柱狀型微針(左)與金字塔型微針(右)之斷裂強度測試圖 17 圖 2-5 自身計量式塗佈 20 圖 2-6 預先計量式塗佈 21 圖 2-7 浸沾式塗佈分區示意圖 21 圖 3-1黏度計…………………………………………………………..27 圖 3-2 表面張力計 28 圖 3-3 精密天秤 28 圖 3-4 金屬微針模仁-1 29 圖 3-5金屬微針模仁-2 30 圖 3-6 金屬微針模仁-3 31 圖 3-7 真空烘箱 32 圖 3-8 真空顯示器 33 圖 3-9 真空幫浦 33 圖 3-10 杜爾瓶 34 圖 3-11 數位式顯微鏡 34 圖 3-12 電磁加熱攪拌器 35 圖 3-13 刮刀塗佈器 35 圖 3-14 場發射掃描式電子顯微鏡配備元素微分析系統圖 36 圖 3-15 多功能微量盤分光光譜儀 37 圖 3-16 萬能拉力機台與製具外觀 38 圖 3-17 流場觀測系統與自製微調平台 39 圖 3-18 浸沾式塗佈機台 39 圖 3-19 金屬模仁及PDMS母模 41 圖 3-20 抽真空裝置 42 圖 3-21 PLA顆粒置於微針模仁之上 43 圖 3-22 數位式顯微鏡觀測系統 44 圖 3-23 位移對斷裂強度之關係圖 45 圖 3-24 萬能拉利機搭配自製平台 45 圖 3-25 豬皮穿刺切片染色圖 46 圖 3-26 2.5 cm×2.5 cm之微針貼片 48 圖 3-27 注入不同體積之液體 49 圖 3-28 滴入同體積之液體分布狀況 49 圖 3-29 完好塗液定體積注藥圖 49 圖 3-30 600 µm之微針裝置 53 圖 3-31 1200 µm之微針裝置 53 圖 3-32 尖錐碰觸液面定義零點位置圖 53 圖 3-33 以1200 µm之微針確認零點位置 54 圖 3-34 微針製具泡入水中圖 54 圖 4-1 於烘箱中乾燥後之有缺陷PLA薄膜………………………....57 圖 4-2 於室溫乾燥後之較完整PLA膜面 …………………………...57 圖 4-3 PLA薄膜於PDMS上順利脫膜 58 圖 4-4 特製抽真空觀察用之公模具與母模具 59 圖 4-5 抽真空後塗液膜面破損 62 圖 4-6 抽真空後塗液表層形成一膠態薄膜 62 圖 4-7 塗液表面氣泡滯留 63 圖 4-8 浸泡丙酮除泡前後比較 64 圖 4-9 脫膜後之完好微針貼片 64 圖 4-10 PLA顆粒熔融之微針 65 圖 4-11 PLA塗液抽真空搭配熔融製程之微針貼片 66 圖 4-12 整體微針結構SEM圖 69 圖 4-13 微針針尖圖 69 圖 4-14 微針間距及底部直徑SEM圖 69 圖 4-15 微針載具抗壓強度圖 71 圖 4-16 穿刺過後之染色豬皮 74 圖 4-17 豬皮組織切片圖 74 圖 4-18 理想進入人體藥量之示意圖 76 圖 4-19 塗液液滴於殘留有丙酮之PLA基材上情形 82 圖 4-20 塗液液滴於無丙酮之PLA基材上情形 83 圖 4-21 單一液體橋 91 圖 4-22 多根液體橋 92 圖 4-23 模擬預測體積與Ca值作圖結果 94 表目錄 表 2-1 開發中之微針輔助型疫苗和抗原之種類 9 表 3-1 定量注藥觀察之塗液物性表………………………………….48 表 3-2 塗液參數及操作參數調整表 51 表 4-1 真空度對填孔深度之影響…………………………………….60 表 4-2 真空停留時間對填孔洞之影響 61 表 4-3 有無以丙酮填孔洞之比較 63 表 4-4 微針型態觀察 68 表 4-5 微針斷裂強度測試後型態 72 表 4-6 相同黏度不同表面張力之乾燥過程與結果 77 表 4-7 高表面張力下，不同黏度相同表面張力 78 表 4-8 低表面張力下，不同黏度相同表面張力 80 表 4-9 不同表面性值之微針貼片於相同塗液條件下之乾燥狀態 82 表 4-10 無因次群於操作系統內之範圍 87 表 4-11 微針浸入不同黏度塗液之毛細現象 89 表 4-12 Flow 3D®軟體之Ca值對應帶藥量之預測 94 表 4-13 實驗拉升結果與模擬預測之比較 95 表 4-14 直接乾燥以及翻面乾燥之狀態 96

    1. Lee, S.S. and B.J. Sul, Flexible microneedle patch system and method for manufacturing the same. 2010: Korea.
    2. Pharma, Z. and Inc. http://www.zosanopharma.com.
    3. 廖郁庭, 以精密塗佈技術製作高分子微針. 清華大學化學工程學系學位論文, 2013: p. 1-103.
    4. Yuzhakov, V.V., Tissue conforming microneedle device for drug delivery or biological fluid collection. 2010, Google Patents.
    5. Tuan-Mahmood, T.-M., et al., Microneedles for intradermal and transdermal drug delivery. European Journal of Pharmaceutical Sciences, 2013. 50(5): p. 623-637.
    6. Henry, S., et al., Microfabricated microneedles: a novel approach to transdermal drug delivery. Journal of pharmaceutical sciences, 1998. 87(8): p. 922-925.
    7. Kim, Y.-C., J.-H. Park, and M.R. Prausnitz, Microneedles for drug and vaccine delivery. Advanced drug delivery reviews, 2012. 64(14): p. 1547-1568.
    8. Vrdoljak, A., Review of recent literature on microneedle vaccine delivery technologies. electronic form only:: DA, 2013.
    9. Gill, H.S. and M.R. Prausnitz, Coating formulations for microneedles. Pharmaceutical research, 2007. 24(7): p. 1369-1380.
    10. Chen, M.-C., et al., Fully embeddable chitosan microneedles as a sustained release depot for intradermal vaccination. Biomaterials, 2013. 34(12): p. 3077-3086.
    11. Donnelly, R.F., et al., Hydrogel‐Forming Microneedle Arrays for Enhanced Transdermal Drug Delivery. Advanced functional materials, 2012. 22(23): p. 4879-4890.
    12. Leroux-Roels, I. and F. Weber, Intanza® 9 µg intradermal seasonal influenza vaccine for adults 18 to 59 years of age. Human vaccines & immunotherapeutics, 2013. 9(1): p. 115-121.
    13. Indermun, S., et al., Current advances in the fabrication of microneedles for transdermal delivery. Journal of Controlled Release, 2014. 185: p. 130-138.
    14. Martanto, W., et al., Transdermal delivery of insulin using microneedles in vivo. Pharmaceutical research, 2004. 21(6): p. 947-952.
    15. Bystrova, S. and R. Luttge, Micromolding for ceramic microneedle arrays. Microelectronic Engineering, 2011. 88(8): p. 1681-1684.
    16. Chabri, F., et al., Microfabricated silicon microneedles for nonviral cutaneous gene delivery. British Journal of Dermatology, 2004. 150(5): p. 869-877.
    17. Ling, M.-H. and M.-C. Chen, Dissolving polymer microneedle patches for rapid and efficient transdermal delivery of insulin to diabetic rats. Acta biomaterialia, 2013. 9(11): p. 8952-8961.
    18. Park, J.-H., M.G. Allen, and M.R. Prausnitz, Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. Journal of Controlled Release, 2005. 104(1): p. 51-66.
    19. Park, J.-H., M.G. Allen, and M.R. Prausnitz, Polymer microneedles for controlled-release drug delivery. Pharmaceutical research, 2006. 23(5): p. 1008-1019.
    20. Ito, Y., et al., Feasibility of microneedles for percutaneous absorption of insulin. European Journal of pharmaceutical sciences, 2006. 29(1): p. 82-88.
    21. Sullivan, S.P., et al., Dissolving polymer microneedle patches for influenza vaccination. Nature medicine, 2010. 16(8): p. 915-920.
    22. Lee, J.W., J.-H. Park, and M.R. Prausnitz, Dissolving microneedles for transdermal drug delivery. Biomaterials, 2008. 29(13): p. 2113-2124.
    23. Yang, S., et al., A scalable fabrication process of polymer microneedles. International journal of nanomedicine, 2012. 7: p. 1415.
    24. Atmar, R.L., S.M. Patel, and W.A. Keitel, Intanza®: a new intradermal vaccine for seasonal influenza. 2010.
    25. Haj-Ahmad, R., et al., Microneedle coating techniques for transdermal drug delivery. Pharmaceutics, 2015. 7(4): p. 486-502.
    26. Ma, Y. and H.S. Gill, Coating Solid Dispersions on Microneedles via a Molten Dip‐Coating Method: Development and In Vitro Evaluation for Transdermal Delivery of a Water‐Insoluble Drug. Journal of pharmaceutical sciences, 2014. 103(11): p. 3621-3630.
    27. Ameri, M., et al., Human growth hormone delivery with a microneedle transdermal system: preclinical formulation, stability, delivery and PK of therapeutically relevant doses. Pharmaceutics, 2014. 6(2): p. 220-234.
    28. Gill, H.S. and M.R. Prausnitz, Coated microneedles for transdermal delivery. Journal of controlled release, 2007. 117(2): p. 227-237.
    29. Vrdoljak, A., et al., Coated microneedle arrays for transcutaneous delivery of live virus vaccines. Journal of controlled release, 2012. 159(1): p. 34-42.
    30. Boehm, R.D., et al., Inkjet printing for pharmaceutical applications. Materials Today, 2014. 17(5): p. 247-252.
    31. Boehm, R.D., et al., Polyglycolic acid microneedles modified with inkjet-deposited antifungal coatings. Biointerphases, 2015. 10(1): p. 011004.
    32. Davis, S.P., et al., Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force. Journal of biomechanics, 2004. 37(8): p. 1155-1163.
    33. Falo Jr, L.D., G. Erdos, and O.B. Ozdoganlar, Dissolvable microneedle arrays for transdermal delivery to human skin. 2014, Google Patents.
    34. 蔡志平, 高黏度流體鑄膜之分析. 清華大學化學工程學系學位論文, 2011: p. 1-78.
    35. 林岡誼, 基板性質對浸沾式塗佈之影響與分析. 2005.
    36. Kistler, S.F. and P.M. Schweizer, Liquid film coating. Chapman Hall, 1997.
    37. Landau, L., B., Levich,“. Dragging of a Liquid by a Moving Plate,” Acta Physicochim. URSS, 1942. 17: p. 42.
    38. White, D. and J. Tallmadge, Theory of drag out of liquids on flat plates. Chemical Engineering Science, 1965. 20(1): p. 33-37.
    39. Yusuf, O.B., Improved Non-Linear Solution of Dip Coating Flow. 2012, The University of Western Ontario.
    40. Tharmalingam, S. and W. Wilkinson, The coating of Newtonian liquids onto a rotating roll. Chemical Engineering Science, 1978. 33(11): p. 1481-1487.
    41. Engelberg, I. and J. Kohn, Physico-mechanical properties of degradable polymers used in medical applications: a comparative study. Biomaterials, 1991. 12(3): p. 292-304.
    42. Chen, M.-C., et al., Chitosan microneedle patches for sustained transdermal delivery of macromolecules. Biomacromolecules, 2012. 13(12): p. 4022-4031.
    43. Pasparakis, M., I. Haase, and F.O. Nestle, Mechanisms regulating skin immunity and inflammation. Nature Reviews Immunology, 2014. 14(5): p. 289-301.

    無法下載圖示 全文公開日期 本全文未授權公開 (校內網路)
    全文公開日期 本全文未授權公開 (校外網路)

    QR CODE