- 學位論文
生物可降解溫感性高分子水膠在抗生素藥物輸送系統之應用
A study on the delivery system for antibiotics based on biodegradable, thermosensitive polymeric hydrogels
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摘要
本研究分為兩部分，第一部分利用聚乙二醇(mPEG)聚酯類共聚物(mPEG-PLGA/mPEG-PCL)形成混合微胞，此混合微胞在一定溫度及15%濃度條件下，會形成水膠。此水膠兼具mPEG-PLGA良好溫度敏感性與mPEG-PCL降解緩慢的優點，在包覆抗生素下，可以穩定釋放所包覆的抗生素。但是成膠時間較長，限制了此水膠施打於體內的應用性。 第二部分利用聚乙二醇(mPEG)、聚乳酸(PLA)與芳香族聚酸酐(CPP、CPH)共聚而成兩性高分子。此兩性高分子也具有溫度敏感性，高分子溶液在低濃度下，能自我組裝形成微胞，在高濃度下，會因為微胞聚集而形成水膠，此特性被認為具有做為藥物載體的潛力。 此一部分之兩性高分子藉由1H-NMR、FT-IR及GPC確立高分子的結構，由臨界微胞濃度(CMC)和表面化學結構鑑定，確定高分子能在極低的濃度下形成微胞，並且形成穩定的疏水核心。溫度升高，微胞會聚集而形成粒徑較大的微胞。當微胞溶液添加抗生素時，亦不會明顯影響微胞溶液的性質。 在溫感性水膠性質方面，成膠溫度較人體體溫略低，適合用於體內注射。水膠的降解緩慢，在30天的體外降解後，僅降解約30%。在降解過程中，pH值變化不大且具有一定的機械強度。包覆萬古黴素與頭孢唑啉兩種抗生素後，水膠沒有出現突釋的現象且能穩定的釋放藥物，釋放曲線皆呈現零級反應。 體外生物相容性經由MTT 測試、live and dead染色測試與流式細胞儀的結果可證實水膠具有良好的生物相容性，僅25 wt%的水膠有較明顯的細胞毒殺性。由體內動物實驗發現，水膠具有良好的細胞通透性，在水膠注入大鼠體內數周後，細胞能長入水膠內部。利用抑菌圈測試，藉由抑菌圈的直徑大小可知，抗生素經由水膠包覆後，並未失去對大腸桿菌的抑制效果。 目前的實驗結果可知聚乙二醇-聚乳酸與芳香族聚酸酐所形成的共聚物為很好的親水性藥物載體，對於藥物治療的應用上有相當的潛力。
並列摘要
The first part of this thesis focuses on mixed hydrogels. The mixed micelles were formed by mPEG-PLGA and mPEG-PCL, the mixed micelles aggregated to form hydrogels under certain temperature and concentration above 15 wt%. The mixed hydrogels can successfully encapsulate a typical hydrophilic drug (vancomycin). Experimental results show that the mixed hydrogels have the features of stable durg release properties and slow degradation. The second part of this thesis focuses on polyanhydride hydrogels. The thermosensitive micelles mPEG-PLCPPA and mPEG-PLCPHA copolymers compose of methoxy polyethylene glycol (mPEG), polylactic acid (PLA) and 1,3-bis(p-carboxyphenoxy)propane (CPP) or 1,6-bis (p-carboxyphenoxy) hexane (CPH) are fabricated for application as a novel hydrophilic drug carrier. The copolymer can self-assemble into micelles in phosphate buffered saline (PBS) by hydrophobic interaction. The sol-gel transition profiles were investigated by the tube flipped upside method and a rheometer. The drug release profiles were investigated in PBS at 37°C with different concentrations of mPEG- PLCPPA and mPEG-PLCPHA solution. The in vitro and in vivo biocompatibility were also evaluated. Bacterial inhibition zone assay was performed by encapsulation of vancomycin and cefazolin. The diameters of these micelles increased as the temperature increased. The micelles increased in viscosity because of the aggregation of hydrophobic segments while temperature increased from the room temperature to the body temperature. The micelle properties of hydrogel containing vancomycin or cefazolin compared with hydrogel without drug loading were not significant difference. During the in vitro degradation process, hydrogels demonstrated a lower degradation rate and a light decrease in pH value. The in vitro and in vivo cytotoxicity results showed that the copolymer micelles had excellent biocompatibility. In vitro drug release profiles revealed a stable vancomycin release for 10 days and a stable cefazolin release for 30 days. The hydrogel encapsulating vancomycin and cefazolin had good antibacterial effects. Based on the results, mPEG-PLCPPA and mPEG-PLCPHA are promising as injectable depot gels for drug delivery.
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