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研究生:楊右任
研究生(外文):Young yo zen
論文名稱:親水凝膠局部給藥製劑之藥物釋放研究
論文名稱(外文):Study of drug release from topical hydrogel formulation
指導教授:何秀娥
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:藥學系
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:中文
論文頁數:138
中文關鍵詞:利度卡因幾丁聚醣親水性凝膠卡波姆聚乙烯吡咯烷酮帶電膠體藥物釋放
外文關鍵詞:drug rleasecarbopolionic gelchitosanhydrogelPVPlidocaine
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疼痛是病患拔牙後相當常見的主訴,拔牙後疼痛造成的不適感使病患必須重回診間做進一步的治療,因此不管是對病患或者是醫師而言都造成相當大的困擾。而目前針對疼痛的治療方式主要是將紗布浸泡於局部麻醉劑後置入牙槽內來達到止痛的效果,但是紗布並不是可分解的材質,因此病患仍須回到診間將紗布取出。
本研究是希望設計出能做為局部麻醉藥的載體且能應用在拔牙後止血的海綿狀填充物。本次實驗中所選用局部麻醉藥的的模式藥物為lidcoaine,利用帶陰電性的carbopol以及帶正電性的chitosan兩種不同的親水凝膠,來觀察lidocaine膨脹以及藥物釋放的特性。
由於lidocaine為帶有正電性的特質,因此在聚電性親水凝膠中,藥物的輸送特性可分為兩種不同的方式:(1) lidocaine以鹽類型式存在於親水凝膠之水溶性液體中(2) lidocaine以自由態型式存在於親水凝膠的聚合物中。利用穿皮吸收裝置以0.9%生理食鹽水當溶媒模擬體內的環境來評估藥物釋放動力學。從實驗結果,得知lidocaine從carbopol和chitosan親水凝膠的釋放行為與時間、酸鹼值、藥物類型、藥物含量和膠體的濃度及種類有關。無論lidcocaine是從carbopol抑或是chitosan親水凝膠中釋放出來的圖形,都遵守費氏擴散機制。
本實驗的另一部分是以不同濃度的戊二醛來交聯聚乙烯亞胺和聚乙烯吡咯烷酮(PEI-PVP)做為拔牙後局部藥物傳遞的親水性凝膠敷料,從實驗結果得知添加不同濃度的戊二醛會影響膠體的膨脹但是在藥物的釋放速率是相當類似的。PEI-PVP hydrogel的藥物釋放機制也是遵循費氏擴散機制。為了評估PEI-PVP hydrogel的生物相容性,體外的細胞毒性試驗是利用牙齦纖維母細胞直接接觸材質後,計算細胞的存活率來進行。從本試驗中發現PEI-PVP hydrogel [76.05±12.31(%)]與市售品斯般佳®止血棉膠塊[90.38±6.04(%)]比較下兩者無顯著細胞毒性差異。在動物實驗中觀察到PEI-PVP hydrogel具有良好的固持性,在拔牙後兩天仍能固定在牙槽處而傷口的癒合情形與市售品斯般佳®止血棉膠塊比較下,在兩週後就無顯著的差異。
就carbopol和chitosan兩種不同膨脹特性的親水凝膠而言,只適用填充在乾性牙槽的病患上,然而可利用兩種不同的聚電性膠體來調整所需要的藥物釋放特性;在另一方面而言PEI-PVP hydrogel比較適合做為拔牙後牙槽敷料,但是藥物不容易調整成我們所需要的釋放情形。
Pain is the chief complains of patients after extraction and the main causes of the patient revisit. For a long time, gauze soaked with anesthetic drug, such as lidocaine, was used in packing the post-extraction socket, but it will need to be removed.
In this study, hydrogels were developed as sponge filler for stopping the bleeding after tooth extraction and as a carrier for delivering locally anesthetic drugs. Lidocaine was selected as a model drug with local anesthetic activity. The swelling characteristics and the release behavior of lidocaine from two types of hydrogels, anionic hydrogel of carbopol and cationic hydrogel of chitosans, were examined. Lidocaine with cationic characteristics was conveyed in polyelectrolytes hydrogel in two different ways: (1) in the form of salt in solution in the aqueous phase, and (2) in free form with the same polymer. The Franz diffusion cell with 0.9% NaCl medium was used to simulate in vivo environment and evaluate drug release kinetics. Results demonstrate that release behavior of lidocaine from chitosan and carbopol hydrogel was dependent on time, pH value, drug form, loading content of drug, and type and concentration of hydrogel. All release profiles of lidocaine from those hydrogels derived from both chitosan and carbopol showed to follow Fickian diffusion mechanism.

In the part of this study, polyethyelenimine- polyvinylpyrrolidone (PEI-PVP) crosslinked with various concentration of glutaraldehyde was evaluated as hydrogel filler for locally delivering lidocaine after tooth extraction. The experimental results proved that using PEI-PVP complex hydrogels added with various glutaraldehyde concentrations influenced the swelling of resulting hydrogel but the drug release rate remaining to be similar. The drug release from hydrogel prepared by PEI-PVP complex might also follow Fickian diffusion mechanism. The biocompatibility of PEI-PVP complex hydrogel was confirmed with the evaluation of in vitro cytotoxicity test using gingival fibroblast as a qualitative indicator based on cell viability when in direct contact with the materials. No significant changes were observed for these cells in contact with PEI-PVP complex hydrogel [76.05 (%)± 12.31] and Spongostan® [90.38 ± 6.04(%)]. In vivo study, PEI-PVP complex hydrogel had good retention in socket for two days and showed comparable wound healing rate within 2 weeks to a commercially available product of Spongostan®

In conclusion, the swelling characteristics of two types of hydrogel, chitosan and carbopol, were only well enough to be used as filling materials for dry socket. However, the release behavior of lidocaine was adjustable in these two types of polyelectrolyte hydrogels. On the other hand, PEI-PVP complex hydrogel was better to use as the socket dressing materials for extraction, but the drug release was not adjustable for manipulating the desired profiles.
目錄
目錄 1
附圖目錄 3
附表目錄 6
中文摘要 7
英文摘要 9
研究動機 11
壹、緒論 13
第一節 牙槽敷料 13
一、口腔概述 13
二、拔牙適應症 14
三、傷口處理及注意事項 14
四、拔牙併發症的預防及處理 15
五、現今敷料在拔牙傷口的應用 18
第二節 親水性凝膠 22
ㄧ、定義 22
二、形成方式 22
三、生物粘著性應用 24
四、幾丁質與幾丁聚醣 25
五、卡波姆(carbopol)簡介 37
六、聚乙烯吡咯烷酮(polyvinylpyrrrilidone, PVP) 43
第三節 Lidocaine 45
一、Lidocaine藥理作用 45
二、Lidocaine物化性質 47
三、Lidocaine藥物動力學 47
貳、實驗材料與方法 49
第一節 實驗材料 49
第二節 儀器設備 50
第三節 實驗方法 52
ㄧ、Lidocaine分析方法 52
二、親水性凝膠之製備 53
三、藥物釋放研究 58
四、吸水性試驗 (Water absorption experiment) 63
五、牙齦纖維母細胞的細胞毒性試驗 64
六、PEI-PVP complex hydrogel於拔牙傷口臨床癒合試驗 66
參、實驗理論 68
第一節 Higuchi equation 68
第二節 Power law 70
肆、結果與討論 72
第一節 Lidocaine分析確效 72
第二節 Lidocaine牙槽敷料體外釋放模式建立 76
第三節Lidocaine親水凝膠釋放機制 83
ㄧ、Spongostan®中藥物釋放情形 83
二、PEI-PVP complex hydrogel的藥物釋放機制 86
三、Carbopol親水凝膠的藥物釋放機制 90
四、chitosan親水凝膠的藥物釋放機制 102
第四節 吸水性試驗 109
一、溶媒影響 109
二、交聯劑影響 114
第五節 牙齦纖維母細胞的細胞毒性試驗 119
第六節PEI-PVP complex hydrogel於拔牙傷口臨床癒合試驗 121
一、拔牙後置入牙槽敷料臨床觀察 121
二、置入牙槽敷料第二天臨床癒合情形 122
三、置入牙槽敷料ㄧ周後臨床癒合情形 124
四、置入牙槽敷料二周後臨床癒合情形 126
伍、結論 129
陸、參考文獻 131
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