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研究生:楊智惠
研究生(外文):Chih-Hui Yang
論文名稱:基因重組人類表皮生長激素局部控釋輸藥系統之研究
論文名稱(外文):Study of Recombinant Human Epidermal Growth Factor with Topical Controlled Drug Delivery System
指導教授:蔡義弘蔡義弘引用關係
指導教授(外文):Yi-Hung Tsai
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:藥學研究所博士班
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:2004
畢業學年度:92
語文別:中文
論文頁數:157
中文關鍵詞:安定性人類表皮生長激素局部控釋輸藥系統傅利葉轉換紅外線顯微分光光譜法微脂粒膠原蛋白
外文關鍵詞:topical controlled drug delivery systemhuman epidermal growth factorFTIRliposomestabilitycollagen
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表皮生長激素(Epidermal Growth Factor,簡稱EGF)為由53個氨基酸組成的polypeptide,其分子量為6216 daltons,因具有眾多的藥理活性作用, EGF被認為是臨床上極有開發為加速傷口癒合的治療藥物之價值。過去的研究曾報導有關EGF在不同溶液及體液的安定性,以及一些劑型的設計,但至目前為止,尚缺乏有系統的安定性評估及較理想的處方製劑出現,主要歸因於EGF的安定性不佳,及未考量使用基劑之合適性。因此,在本研究中,將進行一系列基因重組人類表皮生長激素(recombinant human Epidermal Growth Factor,簡稱rhEGF)局部使用之控釋輸藥系統設計及評估,包括rhEGF在物理、化學及酵素中安定性的探討;微脂粒製劑的製備及膠原蛋白傷口敷料的設計,以期得到一最佳化之rhEGF局部使用具控釋輸藥特性之處方,使rhEGF在投與時,不僅能具有持續釋放作用,且能發揮其生物活性。
經過一系列rhEGF之安定性評估顯示,在物理安定性方面,成功地建立以新穎之FTIR microspectroscopy來分析rhEGF之安定性,進而推估並篩選製備rhGF製劑的條件,經評估製備溫度必須控制在40oC以下;將pH值調整為中性及加入2 M的氯化鈉,皆可增加rhEGF之安定性;反之,若在含有結構干擾劑及碘離子的溶液中,則會降低rhEGF之安定性。在化學安定性方面,建立rhEGF在不同pH值及溫度下之反應速率,而篩選出較佳製備rhEGF之pH值及溫度。在酵素安定性方面,發現aminopeptidase inhibitor類之蛋白酶抑制劑中的Bestatin,可有效地保護EGF避免受到酵素的破壞。
除此之外,確定大白豬是比較接近人類皮膚,且可作為模擬人類燙傷模式之可替代性的實驗動物。且皮膚一經燙傷後,會誘發體內酸性之蛋白酶(capthesin B)及內生性rhEGF的增加,並會使rhEGF因體內誘發酵素含量的增加而加速分解。
在rhEGF局部使用控釋輸藥系統之設計方面,rhEGF的微脂粒製劑,在低膽固醇含量及帶負電的磷脂質的包埋下,包埋率約為25-75%,且顆粒大小約介於0.11~0.21 �慆。而在經戊二醛交聯劑修飾後的含rhEGF膠原蛋白傷口敷料,可控制rhEGF的釋放速率,方便於選擇適合病患受傷傷口的大小,且具有網狀立體結構、良好的吸水性、機械強度及細胞相容性。此外,由體內動物傷口實驗結果,印證了當初設計的構想,成功地發展出rhEGF局部使用控釋輸藥系統,可有效地攜帶rhEGF,使其在臨床上使用時,能完全地發揮其生物活性,對於傷口的癒合,能有明顯的促進作用。
Epidermal growth factor (EGF) is a polypeptide of 53 amino acid residues with a molecular weight of 6216. Based on it has many bioactivities, it has developed to accelerate wound healing as clinical pharmaceutical formulations. Although several approaches were reported the related studies about the stability of EGF in different solutions and body fluids and in progress to develop pharmaceutical formulations that allow administration of EGF effectively. Until present, there still had no appropriately optimized pharmaceutical formulations due to the instability of EGF and the used materials inappropriately. Herein we enclosed the stability of EGF completely including the physical, chemical and enzymatic stability of EGF, and choose the best prepared condition to design the optimize formulations of EGF, including liposome and collagen sponge, with topical controlled drug release system for bringing the EGF into full play.
In these studies, we successfully developed the FTIR micro- spectroscopy to analyze the stability of EGF in physical stability and choose the conditions for preparation. For examples, the temperature of preparation controlled below 40oC, the pHs controlled to natural and 2M sodium chloride added to EGF solution could increase the stability of EGF. It would decrease the stability of EGF in the solutions containing structure perturbants and iodide ion. In chemical stability of EGF, we discussed the reactive kinetics of EGF in different pHs and temperatures. In enzymatic stability of EGF, we found the aminopeptidase inhibitor, Bestatin, could avoid EGF to be broken from enzyme.
In addition, pig skins were the most closed to human skin and could be used to modify the burned model as the replaced animal models. It could induce the acid proteases, capthesin B, and increase the endocrine EGF of body after the skin burned. Then, due to the enzyme increased, EGF would be rapidly depredated.
In the design of EGF into topical controlled release system, the encapsulation efficacy of EGF-liposome formulation was about 25-75% under the low content of cholesterol and the negative charge of phospholipids encapsulated. And the particles size could be controlled between 0.11~0.21 �慆. Besides, the EGF-collagen sponge modified with the cross-linkage reagent, glutaraldehyde, could be chosen by the patient’s requirement depended on the different size of wound and the released rate of EGF needed. And it contained 3D structure, nice water uptake, stronger mechanical strength, and cell stimulation ability. Therefore, we successfully developed the formulation of EGF with topical controlled release properties from the animal study. It could carry EGF sufficiently into full play and increase the wound healing.
中文摘要…………………………………………………………………… I
英文摘要……………………………………………………………….. III
目錄…………………………………………………………………...….... V
附圖目錄………………………………………………………………….. IX
附表目錄…………………………………………………………………... XIII

第壹章 諸論
1.1 表皮生長激素之簡介(Epidermal Growth Factor, EGF) …………... 1
1.1.1 表皮生長激素之起源…………...………... …………....... 1
1.1.2 表皮生長激素之結構…………...………... …………....... 1
1.1.3 表皮生長激素的作用機制…………... ………... ………… 2
1.1.4 表皮生長激素之研究背景…………... …………... ……… 3
1.2 皮膚的構造 ……………………………………………………...… 4
1.3 皮膚傷口癒合機制 ……………………………………...………… 6
1.4 燒燙傷傷口創面的病理變化 ………………………………...…… 6
1.5 人工敷料 ……………………………………………………...…… 7
1.6 微脂粒之簡介………………………………………………………. 8
1.6.1 微脂粒的種類……………………………………...………… 8
1.6.2 製備微脂粒之材料………………………………...………… 9
1.6.3 微脂粒的製備法…………………………………………...… 11
1.6.4 微脂粒之形成條件及影響因素…………………………...… 13
1.6.5 控制微脂粒粒徑大小與分佈之方法……………………...... 15
1.6.6 影響微脂粒安定性的因素…………………………………... 16
1.6.7 微脂粒之應用優缺點………………………………………... 17
1.7 膠原蛋白之簡介…………………………………... ………………. 18
1.7.1 膠原蛋白的來源與生合成…………………………………... 18
1.7.2 膠原蛋白的結構與特性……………………………………... 22
1.7.3 膠原蛋白的分類……………………………………………... 26
1.7.4 膠原蛋白在生醫材料之應用及其優缺點…………………... 30
1.8 研究動機與目的……………………………………………………. 36

第貳章 實驗藥品、設備與方法
2.1 實驗藥品與儀器設備………………………………………….... 37
2.1.1 實驗藥品……………………………………………........... 37
2.1.2 儀器設備……………………………………………........... 40
2.2 分析方法的建立……………………………………………….... 42
2.2.1 高效能液相層析儀之分析條件 ………………………….… 42
2.2.2 免疫酵素連結分析法 (ELISA) ………………………….…. 42
2.2.3 放射性活性含量測定法……………………………………... 43
2.3 rhEGF活性分析方法………………………………………........ 43
2.3.1 WST-細胞增殖性偵測法…………………………………….. 43
2.3.2 不同血清濃度之培養液對纖維母細胞生長之影響………... 44
2.3.3 EGF不同濃度對細胞生長之動力影響…………………….. 44
2.3.4 rhEGF處方之細胞活性試驗………………………………… 44
2.4 探討rhEGF的物理化學性質及其安定性研究……………....... 45
2.4.1 rhEGF物理安定性之探討…………………………………… 45
2.4.2 rhEGF化學安定性之探討…………………………………… 47
2.4.3 rhEGF酵素中安定性之探討………………………………… 48
2.5 動物皮膚燙傷實驗……………………………………………… 50
2.5.1 動物皮膚燙傷模式之建立…………………………………... 50
2.5.2 皮膚燙傷後內生性EGF之變化量………………………….. 51
2.6 rhEGF微脂粒之製劑……………………………………………. 52
2.6.1 磷脂質的定量分析…………………………………………... 52
2.6.2 rhEGF微脂粒的製備方法…………………………………… 53
2.6.3 rhEGF微脂粒的包埋率……………………………………… 54
2.6.4 微脂粒粒徑分佈之測定法…………………………………... 57
2.6.5 微脂粒帶電性之測定法……………………………………... 57
2.7 含EGF之膠原蛋白傷口敷料之製劑…………………………… 58
2.7.1 膠原蛋白濃度測定…………………………………………... 58
2.7.2 含EGF之膠原蛋白傷口敷料之製備……………………….. 59
2.7.3 rhEGF由膠原蛋白傷口敷料釋放模式的建立……………… 59
2.7.4 rhEGF由膠原蛋白傷口敷料體外釋放模式之資料分析......... 60
2.7.5 含EGF之膠原蛋白傷口敷料其體外性質的探討………….. 62
2.8 EGF局部使用控釋輸藥系統在動物傷口應用的評估... 64

第叁章 實驗結果與討論
3.1 分析方法的建立………………………………………………… 66
3.1.1 高效能液相層析儀之分析條件 ……………………..……... 66
3.1.2 免疫酵素連結分析法 (ELISA) ……………………..……… 68
3.2 rhEGF活性分析方法………………………………………........ 71
3.2.1 不同血清濃度之培養液對纖維母細胞生長之影響……...… 71
3.2.2 EGF不同濃度對細胞生長之動力學影響……………….….. 72
3.3 探討rhEGF的物理化學性質及其安定性研究………………… 73
3.3.1 sheaf物理安定性之探討…………………………………… 73
3.3.2 rhEGF化學安定性之探討…………………………………… 91
3.3.3 rhEGF酵素中安定性之探討………………………………… 94
3.4 動物皮膚燙傷實驗……………………………………………… 97
3.4.1 動物皮膚燙傷模式之建立……. ……………….…………… 97
3.4.2 皮膚燙傷後內生性EGF之變化量……………………..…… 101
3.5 rhEGF微脂粒之製劑………………………………………….… 102
3.6 含EGF之膠原蛋白傷口敷料之製劑…………………………… 104
3.6.1 含EGF之膠原蛋白傷口敷料之製劑方法……………..…… 104
3.6.2 rhEGF由膠原蛋白傷口敷料釋放模式的建立……………… 104
3.6.3 含EGF之膠原蛋白傷口敷料之製劑條件………………….. 106
3.6.4 rhEGF由膠原蛋白傷口敷料體外釋放模式之資料分析…... 112
3.6.5 含EGF之膠原蛋白傷口敷料其體外性質的探討………….. 113
3.6.6 EGF局部使用控釋輸藥系統在動物傷口應用的評估……... 127

第肆章 結論………………………………………………………………... 130
第伍章 參考文獻…………………...……………………………...………. 133
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