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課程 : 功能性高分子 授課老師 : 謝慶東 學生 : 魏伯翰 學號 :49940004

課程 : 功能性高分子 授課老師 : 謝慶東 學生 : 魏伯翰 學號 :49940004. Outline. Introduction Material Methods Experiments Results Conclusions. Introduction.

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課程 : 功能性高分子 授課老師 : 謝慶東 學生 : 魏伯翰 學號 :49940004

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  1. 課程:功能性高分子 授課老師:謝慶東 學生: 魏伯翰 學號:49940004

  2. Outline • Introduction • Material • Methods • Experiments • Results • Conclusions

  3. Introduction 在藥物輸送的領域，一直致力於發展半固態的水凝膠，而目前較有前途的研究方向是以溫度應答型水膠，可在治療部位形成凝膠以延長藥物釋放時間且方便管理與使用，並且以具有良好生物黏附力的玻尿酸來加強其結構組織。而此研究則使用Pluronic F127 及 F68 混合玻尿酸，設計出新型的熱敏性水膠以改良其機械性質與黏膜黏附力，且搭載藥物Acyclovir在模擬淚液(STF)中進行物要釋放測試。

  4. 本實驗所使用的溫度應答型材料為Pluronic，Pluronic為可逆之熱感應膠體，其成膠原理起因於共聚物中Poly(ethylene oxide)(PEO)與Poly(propylene oxide)(PPO)之間的交互作用。PEO在高、低溫皆為親水性，而PPO在低溫為親水；但在高溫則變成疏水性。因此，當外界溫度上升時Pluronic之間的共聚物會自發性的凝集成球型Micelles，此球型核心是由疏水的PPO聚合而成，而包覆在表面則是親水的PEO鏈。成膠現象乃是因Micelles之間相互糾結纏繞所形成。

  5. 玻尿酸（Hyaluronic Acid，簡稱HA）又稱玻醣醛酸或透明質酸，是一種天然的酸性多醣體，單體結構為N-乙醯葡糖胺（N-acetyl-D-glucosamine）及D-葡萄糖醛酸（D-glucuronic acid）結合的雙醣體，藉由β-1-3鍵結所鏈結而成的直鏈高分子多醣。透明質酸平均分子量介於100萬到1000萬之間，分子式為(C14H20NNaO11)n，外觀為透明且具黏性的膠狀物質。玻尿酸的分子能攜帶500倍以上的水分，為膠原蛋白（collagen）的16倍。保水值可達1000cc/g，是當今文獻中公認之最佳保濕因子。玻尿酸填充於人體的細胞與膠原纖維的空間中，且覆蓋在某些結締組織上，具有保持皮膚彈性、鎖住大量水分子等功能，對組織具有保濕潤滑作用，也是作爲眼球水晶體、關節潤滑液等物質的構成成分，因此經常被用來製造美容化妝品以及治療關節炎和白內障等疾病的藥物。

  6. Material • Pluronic F127 • Pluronic F68 • Hyaluronic acid (HA) • Acyclovir

  7. Methods Add Hyaluronic acid to poloxamers at room temperature Pluronic F127 and F68 mixing in water are stirred at 4℃

  8. formulations

  9. Experiments • Rheological characterization • Photon correlation spectroscopy • Mucoadhesion analysis • In vitro release study

  10. Results

  11. Rheological characterization-1 Fig. 3. Elastic and viscous moduli as a function of temperature of Pol-2 and Pol-2/H1 at a frequency value of 0.01 Hz. Results are the means of three measurements. SD was always lower than 10%. Error bars are mitted for clarity purpose. Fig. 2. Elastic and viscous moduli as a function of temperature of Pol-1,Pol-1/H1 and Pol-1/H2 at a frequency value of 0.01 Hz. Results are the means of three measurements. SD was always lower than 10%. Error bars are omitted for clarity purpose.

  12. 由彈性模數G ′及黏性模數G 〞曲線的交叉點可得知此種配方的膠體溶液的成膠溫度，而由fig.2及fig.3可得知Pol-1、Pol-1/H1、Pol-1/H2、Pol-2 、Pol-2/H1的成膠溫度分別為 37、36、34、35、27 ℃。

  13. Rheological characterization-2 Fig. 4. Mechanical spectra of Pol-1 at 25 °C (A) and 43 °C (B). Results are the means of three measurements. SD was always lower than 10%

  14. Fig.4是經由彈性模數G ′及黏性模數G 〞在25℃及43℃剪切頻率0.1~1的範圍下， Pol-1會產生什麼樣的變化，由fig.2得知Pol-1的成膠溫度為37 ℃，由fig.4(A)可看出在25 ℃、剪切頻率0.1~1的條件下， G 〞 ＞ G ′，由此篇文章定義來說這是未成膠的狀態，而在43 ℃、剪切頻率0.1~1的條件下，G 〞 ＜ G ′，文章定義此為成膠狀態，此結果呼應了前面fig.2所得要的數據結果Pol-1在過了37 ℃後會是成膠的狀態。

  15. Rheological characterization-3 Fig. 5. Elastic modulus as a function of frequency of Pol-1 containing different amount of HA at 43 ℃. Results are the mean of three measurements. SD was always lower than 10%. Error bars are omitted for clarity purpose.

  16. Photon correlation spectroscopy Table 2 Hydrodynamic diameters, elastic and viscous moduli values (at 0.5 Hz and 43 ℃) of Pol-1 containing 0.5%, 0.8%, 1% and 2% w/w of HA Results are the means of three measurements. SD was always lower than 10%.

  17. Fig.5及table.2可得知依彈性模數G ′、黏性模數G 〞和流體動力學直徑(HD)的大小，由大而小分別是Pol-1/H2、Pol-1/H1、 Pol-1/H08、 Pol-1/H05、 Pol-1，由此數據來決定Pol-1/H2具有較佳的生物黏附性。

  18. Mucoadhesion analysis-1 Fig. 6. Flow curves of mucin dispersion at 15% w/w (M), Pol-1/H2 and their mixture (M + Pol-1/H2) at pH 1 (A) and 5.5 (B); measurement were performed at 37 ℃. Results are the mean of three measurements. SD was always lower than 15%. Error bars are omitted for clarity purpose.

  19. Mucoadhesion analysis-2 Table 3 Viscosity (ηp ηm ηt ηb) and F values calculated at a shear rate value equal to 10 s-1 Results are the means of three measurements. SD was always lower than 15%.

  20. 由fig.6及table.3，觀察出該混合物的黏度值對剪切速率的相對比較。制定黏蛋白分散的生物黏合劑通過提高溫度和pH值變得更強。特別是，在剪切速率等於10 s≤1，F值從6.93增大到57.80Pa是經由25~37 ℃、pH值1，以及F值從30.50到104.36Pa在pH 5.5。

  21. Platforms feasibility for ocular drug delivery Fig. 7. Acyclovir release from Pol-1, Pol-1/H1 and Pol-1/H2 in simulated tear fluid at 37 ℃. Results are the means of three measurements ± SD.

  22. Fig.7為眼藥的藥物釋放測試，可由圖中曲線的斜率得知其載體釋放藥物的快慢，是否具有緩釋的效果存在，在圖中Pol-1斜率最大釋放藥物最快6hr時，藥物濃度達50%以上，而斜率最小的Pol-1/H2最具緩釋藥物的效果，且藥物濃度穩定，6hr時達約15%。Fig.7為眼藥的藥物釋放測試，可由圖中曲線的斜率得知其載體釋放藥物的快慢，是否具有緩釋的效果存在，在圖中Pol-1斜率最大釋放藥物最快6hr時，藥物濃度達50%以上，而斜率最小的Pol-1/H2最具緩釋藥物的效果，且藥物濃度穩定，6hr時達約15%。

  23. Conclusions • 低分子量的玻尿酸在此研究中為黏性溶液，可將溶液分子視為個別流動單體且具有降低空間位阻的效果，因此玻尿酸分子可進行凝膠作用產生填充孔洞與鍵結，進而補強物理凝膠的機械性質，更能有效的控制藥物釋放。先前研究指出添加高分子量的玻尿酸與Pluronic混合後會使凝膠後的強度下降，導致藥物釋放加速。 • Pol-1/H2的生物黏附力，若持續增加pH值使玻尿酸離子化程度提高，則可改善Pol-1/H2的生物黏附力。 • 藥物釋放上Pol-1/H2可延長6小時以上，但若只有Pol-1則會使藥物釋放過快。

  24. References • A. Hatefi, B. Amsden, Biodegradable injectable in situ forming drugdelivery systems, J. Control. Release 80 (2002) 9–28. • S.D. Desai, J. Blanchard, Evaluation of pluronic F127-basedsustained-release ocular delivery systems for pilocarpine using thealbino rabbit eye model, J. Pharm. Sci. 10(1998) 1190–1195. • K. Lindell, S. Engstrom, In vitro release of timolol maleate from anin situ gellingpolymer system, Int. J. Pharm. 95 (1993) 219–228. • R. Gurny, T. Boye, H. Ibrahim, Ocular therapy with nanoparticulatesystems forcontrolled drug delivery, J. Control. Release 2 (1985) 353–361. • B. Srividya, R.M. Cardoza, P.-D. Amin, Sustained ophthalmicdelivery of ofloxacin from a pH triggered in situ gelling system, J.Control. Release 2–3 (2001) 205–211. • K. Mortensen, W. Brown, B. Norden, Inverse melting transition andevidence ofthreedimensional cubatic structure in a block–copolymermicellar system, Phys. Rev. Lett. 15 (1992) 2340–2343. • D. Dodou, P. Breedveld, P.A. Wieringa, Mucoadhesives in thegastrointestinal tract: revisiting the literature for novel applications,Eur. J. Pharm. Biopharm. 1 (2005) 1–16.

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