親水凝膠局部給藥製劑之藥物釋放研究
中文摘要
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 lidoc aine 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) lidocain e 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 c hitosan 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 c arbopol 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 ? 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。
Study of drug release from topical hydrogel formulation
英文摘要
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 del ivering locally anesthetic drugs. Lidocaine was selected as a model drug with local anesthetic activity. The swelling characteri stics 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 demonstrat e 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 b oth chitosan and carbopol showed to follow Fickian diffusion mechanism.
In the part of this study, polyethyelenimine- polyvinylpyrrolidone (PEI-PVP) crosslinked with various concentration of glutar aldehyde was evaluated as hydrogel filler for locally delivering lidocaine after tooth extraction. The experimental results prov ed that using PEI-PVP complex hydrogels added with various glutaraldehyde concentrations influenced the swelling of resulti ng 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 [7 6.05 (%)± 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 polyelectrol yte 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.
