簡易檢索 / 詳目顯示

研究生: 謝秉軒
Hsieh, Ping-Hsuan
論文名稱: 以玻璃毛細管微流體裝置製備單一尺寸之包藥微球
Production of uniform-sized drug encapsulated microspheres using a simple capillary microfluidic device
指導教授: 胡晉嘉
Hu, Jin-Jia
學位類別: 碩士
Master
系所名稱: 工學院 - 生物醫學工程學系
Department of BioMedical Engineering
論文出版年: 2013
畢業學年度: 101
語文別: 中文
論文頁數: 40
中文關鍵詞: 微球微流體海藻酸鈉藥物釋放
外文關鍵詞: microsphere, microfluidic, alginate, drug delivery
相關次數: 點閱:161下載:2
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
  • 藥物制放系統相較傳統給藥途徑有許多具潛力的優點。目前有各種裝置用於控制藥物釋放,可降解的微球還是最常見的,本研究之重點即是微球的製備。微球目前可用很多種方法製造,例如溶液蒸發法、奈米薄膜擠壓法或是超音波震盪法,但是這些方法做出來的微球,尺寸較不一致且耗時。過去文獻中提到微球粒徑的大小與形態在藥物制放系統之中,扮演非常關鍵的角色。本研究中我們利用同軸玻璃毛細管微流體技術製備單一尺寸大小的海藻酸鈉微球;當中內管中通入海藻酸鈉溶液,而外管通入氮氣以剪應力產出微球。探討裝置的設計、氣體及液體的流率對於微球型態、微球粒徑及粒徑分布的影響,此外,並以acetaminophen作為藥物模型,研究微球在去離子水中的藥物釋放率及微球在與不同分子量之幾丁聚醣反應後藥物的釋放率。我們發現在玻璃毛細管尖端之間的距離需在250、500μm,才能產生完整圓形微球,其海伍德圓因子為1.019。微球粒徑大小會因氣體流速增加隨之減小,溶液流速則不影響粒徑大小。與幾丁聚醣反應後之微球可大幅降低藥物釋放與膨潤率,防止藥物快速大量釋放。低分子量幾丁聚醣-海藻酸鈉微球較中分子量幾丁聚醣-海藻酸鈉微球易於釋放藥物,在海藻酸鈉濃度2%下,粒徑50μm微球較粒徑150μm微球易釋放藥物,海藻酸鈉濃度1.5%下,則相反。

    Controlled release drug delivery systems provide several potential advantages over traditional methods. Biodegradable microspheres represent one of the most common carriers for controlled release drug delivery. These microspheres can be fabricated by various methods, such as the solvent evaporation, nanopore membrane extrusion, and sonication; however, these methods are generally time consuming and the resulting microspheres are generally polydispersed. Previous studies have suggested that particle size and its distribution play critical roles in drug delivery. In this study, we used a micro-capillary-based device to fabricate monodispersed microspheres and the influence of microfluidic parameters on the particle size, shape and size distributions were investigated. In addition, we further fabricated acetaminophen loaded chitosan-alginate composite microsphere and examined the cumulative release of acetaminophen in distilled water. We found that a device with tip-to-tip distance equals to 250 or 500 μm consistently produced microspheres with the Heywood circularity factor of 1.019, indicating that the microspheres were nearly spherical. The sizes of microspheres decreased with increasing gas flow rate while the flow rate of solution seemed to have little effects. Chitosan-alginate composite microspheres have significantly lower drug release rate as well as swelling ratio, indicating that controlled drug release was achieved. Also, chitosan-alginate microspheres fabricated using low molecular weight chitosan were better in drug release compared to those fabricated using medium molecular weight chitosan. Moreover, the microspheres of 50 μm diameter were better in drug release compared to microspheres of 150 μm diameter if 2% alginate was used while opposite results were observed if 1.5% alginate was used.

    摘要 i Abstract ii 誌謝 iii 圖目錄 vi 表目錄 viii 第一章 緒論 1 1.1藥物制放系統 1 1.2微球之簡介 1 1.3微球製備方式 2 1.3.1噴霧乾燥法(spray drying) 2 1.3.2溶液蒸發法(solvent evaporation) 2 1.3.3同軸氣流技術(coaxial air-flow) 3 1.3.4靜電場技術(electrostatic technique) 3 1.3.5振動技術(Vibration technique) 4 1.3.6旋轉切割法(JetCutter technique) 4 1.4海藻酸鈉 5 1.4.1海藻酸鈉微球於藥物制放上的應用 6 1.5微流體技術之簡介 7 1.5.1玻璃毛細管微流體裝置 7 1.6 實驗動機與目的 9 第二章 材料與方法 10 2.1實驗架構 10 2.2 實驗藥品、相關器材與設備 10 2.2.1實驗藥品 10 2.2.2 實驗器材與設備 10 2.3 玻璃毛細管微流體裝置之製作 11 2.4 海藻酸鈉微球之製備 11 2.5 粒徑與型態分析 12 2.6 黏滯度測定 13 2.7 含藥物微球製備 13 2.8 微球之膨潤率測定 14 2.9 含藥微球之載藥率(Drug loading capacity)測定 14 2.10 含藥物微球之藥物釋放測定 14 第三章 結果 15 3.1各種變因對微球型態的影響 15 3.1.1各種tip-to-tip距離對微球型態的影響 15 3.1.2氣體流率與溶液流率對微球型態的影響 18 3.2氣體流率與溶液流率對微球粒徑及粒徑分布的影響 18 3.2.1氣體流率與溶液流率對微球粒徑大小的影響 18 3.3氣體流率與溶液流率對產出微球形狀分析 25 3.4黏滯度測定 25 3.5膨潤率與載藥量測定 26 3.6藥物釋放 28 3.6.1海藻酸鈉微球釋放曲線 28 3.6.2不同海藻酸鈉濃度對釋放曲線影響 29 3.6.3與不同分子量幾丁聚醣反應對釋放曲線影響 30 3.6.4不同粒徑大小對釋放曲線影響 30 第四章 討論 32 第五章 結論 37 參考文獻 38

    [1] M. Ferrari and A. P. L. Lee, James (Eds.). (2006). BioMEMS and Biomedical Nanotechnology Volume I: Biological and Biomedical Nanotechnology.
    [2] V. T. Tran, J. P. Benoit, and M. C. Venier-Julienne, "Why and how to prepare biodegradable, monodispersed, polymeric microparticles in the field of pharmacy?," Int J Pharm, vol. 407, pp. 1-11, Apr 4 2011.
    [3] K. Laeschke, "Biocompatibility of microparticles into soft tissue fillers," Semin Cutan Med Surg, vol. 23, pp. 214-7, Dec 2004.
    [4] M. A. Kataria Sahil, Sandhu Premjeet, Ajay Bilandi and Bhawana Kapoor, "MICROSPHERE: A REVIEW," INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY, vol. 1, pp. 1184-1198, 2011.
    [5] S. B. Harshad Parmar, Nayan Gujarathi, Bhushan Rane, Sunil Pawar, "DIFFERENT METHODS OF FORMULATION AND EVALUATION OF MUCOADHESIVE MICROSPHERE.," International Journal of Applied Biology and Pharmaceutical Technology, vol. I, pp. 1157-1167, 2010.
    [6] J. L. Cleland, "Solvent Evaporation Processes for the Production of Controlled Release Biodegradable Microsphere Formulations for Therapeutics and Vaccines," Biotechnology Progress vol. 14 pp. 102-107, 1998.
    [7] U. Prüsse, L. Bilancetti, M. Bučko, B. Bugarski, J. Bukowski, P. Gemeiner, D. Lewińska, V. Manojlovic, B. Massart, C. Nastruzzi, V. Nedovic, D. Poncelet, S. Siebenhaar, L. Tobler, A. Tosi, A. Vikartovská, and K.-D. Vorlop, "Comparison of different technologies for alginate beads production," Chemical Papers, vol. 62, pp. 364-374, 2008.
    [8] K. Y. Lee and S. H. Yuk, "Polymeric protein delivery systems," Prog Polym Sci, vol. 32, pp. 669-697, 2007.
    [9] E. A. Kamal H. Bouhadir, David J. Mooney, "Hydrogels for combination delivery of antineoplastic agents.," Biomaterials vol. 22, pp. 2625-2633, 2001.
    [10] I. Colinet, V. Dulong, G. Mocanu, L. Picton, and D. Le Cerf, "New amphiphilic and pH-sensitive hydrogel for controlled release of a model poorly water-soluble drug," Eur J Pharm Biopharm, vol. 73, pp. 345-50, Nov 2009.
    [11] K. Y. Lee and D. J. Mooney, "Alginate: properties and biomedical applications," Prog Polym Sci, vol. 37, pp. 106-126, Jan 2012.
    [12] E. A. Silva and D. J. Mooney, "Effects of VEGF temporal and spatial presentation on angiogenesis," Biomaterials, vol. 31, pp. 1235-41, Feb 2010.
    [13] M. George and T. E. Abraham, "Polyionic hydrocolloids for the intestinal delivery of protein drugs: alginate and chitosan--a review," J Control Release, vol. 114, pp. 1-14, Aug 10 2006.
    [14] A. S. Utada, E. Lorenceau, D. R. Link, P. D. Kaplan, H. A. Stone, and D. A. Weitz, "Monodisperse double emulsions generated from a microcapillary device," Science, vol. 308, pp. 537-41, Apr 22 2005.
    [15] G. T. Vladisavljević, I. Kobayashi, and M. Nakajima, "Production of uniform droplets using membrane, microchannel and microfluidic emulsification devices," Microfluidics and Nanofluidics, vol. 13, pp. 151-178, 2012.
    [16] B. J.-N. Denis D.G. MATER, NAVA SAUCED0 Jose Edmundo, TRUFFAUT Nicole and THOMAS Daniel., "Effect of gelation temperature and gel-dissolving solution on cell viability and recovery of two pseuddomonas putida strains co-immobilized within calcium alginate or K-carrageenan gel beads," Biotechnology Techniques, vol. 9, pp. P747-752, 1995.
    [17] C. Ye, A. Chen, P. Colombo, and C. Martinez, "Ceramic microparticles and capsules via microfluidic processing of a preceramic polymer," J R Soc Interface, vol. 7 Suppl 4, pp. S461-73, Aug 6 2010.
    [18] G. T. Vladisavljevic, W. J. Duncanson, H. C. Shum, and D. A. Weitz, "Emulsion templating of poly(lactic acid) particles: droplet formation behavior," Langmuir, vol. 28, pp. 12948-54, Sep 11 2012.
    [19] B. Calija, J. Milic, N. Cekic, D. Krajisnik, R. Daniels, and S. Savic, "Chitosan oligosaccharide as prospective cross-linking agent for naproxen-loaded Ca-alginate microparticles with improved pH sensitivity," Drug Dev Ind Pharm, vol. 39, pp. 77-88, Jan 2013.
    [20] O. E. Selina, A. A. Chinarev, P. S. Obukhova, A. Bartkowiak, N. V. Bovin, and E. A. Markvicheva, "Alginate-chitosan microspheres for the specific sorption of antibodies," Russian Journal of Bioorganic Chemistry, vol. 34, pp. 468-474, 2008.
    [21] N. D. Cekic, J. R. Milic, S. D. Savic, M. M. Savic, Z. Jovic, and R. Daniels, "Influence of the preparation procedure and chitosan type on physicochemical properties and release behavior of alginate-chitosan microparticles," Drug Dev Ind Pharm, vol. 35, pp. 1092-102, Sep 2009.
    [22] Y. Zhang, W. Wei, P. Lv, L. Wang, and G. Ma, "Preparation and evaluation of alginate-chitosan microspheres for oral delivery of insulin," Eur J Pharm Biopharm, vol. 77, pp. 11-9, Jan 2011.
    [23] K. S. Piyasi Mukhopadhyay, Shweta Soam, P. P. Kundu, "Formulation of pH-Responsive Carboxymethyl Chitosan and Alginate Beads for the Oral Delivery of Insulin," J. APPL. POLYM. SCI., 2012.
    [24] H. Wu, C. Liao, Q. Jiao, Z. Wang, W. Cheng, and Y. Wan, "Fabrication of core–shell microspheres using alginate and chitosan–polycaprolactone for controlled release of vascular endothelial growth factor," Reactive and Functional Polymers, vol. 72, pp. 427-437, 2012.
    [25] S.-Q. L. Lin-Shu Liu , Steven Y. Ng , Michael Froix , Tadao Ohno , and J. Heller, "Controlled release of interleukin-2 for tumour immunotherapy using alginate / chitosan porous microspheres," Journal of Controlled Release, vol. 43, pp. 65 –74, 1997.
    [26] M. K. Akihiko Kikuchi, Masayasu Sugihara, Yasuhisa Sakurai, Teruo Okano, "Pulsed dextran release from calcium-alginate gel beads," Journal of Controlled Release, vol. 47, pp. 21-29, 1997.
    [27] M. M. a. M. K. Soheila Honary, "The effect of chitosan molecular weight on the properties of alginate/chitosan microparticles containing prednisolone," Tropical Journal of Pharmaceutical Research, vol. 8, pp. 53-61, 2008.
    [28] E. S. Chan, B. B. Lee, P. Ravindra, and D. Poncelet, "Prediction models for shape and size of ca-alginate macrobeads produced through extrusion-dripping method," J Colloid Interface Sci, vol. 338, pp. 63-72, Oct 1 2009.

    下載圖示 校內:2016-09-04公開
    校外:2016-09-04公開
    QR CODE