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研究生:王新元
研究生(外文):Hsin-Yuan Wang
論文名稱:以物理性經皮吸收促進方法提升親水性大分子及小分子藥物之皮膚穿透能力
論文名稱(外文):Enhancement of transdermal delivery of hydrophilic macro- and micro-molecules by a series of physical methods
指導教授:方嘉佑
指導教授(外文):Jia-You Fang
學位類別:碩士
校院名稱:長庚大學
系所名稱:天然藥物研究所
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:104
中文關鍵詞:電破法 電離子透入法 鉺雅鉻雷射
外文關鍵詞:iontophoresis electroporation Solupor® size-exclusion
相關次數:
  • 被引用被引用:1
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本實驗設計可分為三大部分 :
(一) 以fluorescein isothiocyanate-Dextran (FD) 及 fluorescein
isothiocyanate-Insulin (FITC-insulin) 作為親水性大分子模式藥物 (M.W
389-77,000 Dalton),檢視不同分子量藥品以鉺雅鉻雷射作為經皮吸收促進方法後觀察其穿透量的變化。皮膚經過雷射處理後,隨著能量上升,藥品穿透量隨之增加。另外隨著藥品分子量上升,穿透量則呈遞減現象。由掃描式電子顯微鏡可發現隨著角質層的剝離越明顯,藥品的穿透呈現明顯上升趨勢。而在FITC 與 FD 分子量4,400 (FD 4.4) 兩藥品部分,透過螢光顯微鏡發現兩者的穿皮途徑並不相同,FITC 主要是透過皮膚附屬器官如毛囊等穿透,而 FD 4.4 則可直接穿透角質層而滲入表皮,也因為此兩者間的分子量差異相對較小,因此穿透途徑的不同使得其穿透量相近。
(二) 以sodium nonivamide acetate (SNA) 及sodium nonivamide propionate (SNP) 作為親水性小分子模式藥物,並加上 Solupor® 人工控制釋放薄膜以評估其經過 electroporation 和 iontophoresis 促進後 SNA 與 SNP 體外穿透量的變化。 0.5 mA/cm2之電流可大幅增加 SNA 和 SNP 穿透皮膚之穿透速率 (flux)。8P07A 膜幾乎無阻抗效果,而其餘四種膜則展現控制釋放的特性。另外於 10P05A 以及 16P05A 膜經過被動穿透實驗以及 iontophoresis 後,膜表面有粒子產生,且纖維構造有分解成平滑狀的趨勢。在 SNA 與 SNP 兩藥品對於 Solupor® 都有相似的控制釋放效果,代表 Solupor® 的速率限制步驟並非全於藥品的分子大小,與其本身的物化特性如孔徑,厚度,Gurley number等也有關係。
(三) 以 buprenorphine 作為親水性小分子藥品,將其溶於蠶絲蛋白、 PF-127與甲殼素三種水性凝膠中觀察其於不同濃度之凝膠之體外釋放結果。由黏滯度測量可發現隨著水膠濃度的提升,黏滯度皆呈現遞增趨勢。而當加入平均分子量1-2萬之蠶絲蛋白 (SP (M.W 10-20 kDa)) 時,黏滯度呈現下滑趨勢。於蠶絲蛋白內加入尿素後黏滯度呈現遞減趨勢。而當我們於 PF-127 內加入尿素,黏滯度有提升現象。而當甲殼素中加入低濃度尿素,黏滯度急遽下降。由 FT/IR實驗結果發現本次所用之蠶絲蛋白為部分 random coil 構型,部分 β-sheet 構型,當加入甲醇後可促進其形成 β-sheet。由體外穿透實驗可發現隨者平均分子量7-8萬之蠶絲蛋白 (SP (M.W 70-80 kDa)) (SP (M.W 7-8)) 濃度增加,藥品的穿透呈現遞減趨勢。當加入 SP (M.W 10-20 kDa) (SP M.W 1-2) 時穿透量呈現下滑趨勢。於 PF-127 內加入 SP (M.W 7-8) 時藥品的穿透呈現遞減趨勢。於甲殼素中加入 SP (M.W 7-8) 後穿透亦呈現遞減趨勢。給與 iontophoresis 刺激後可發現藥品於蠶絲蛋白凝膠之促進穿透效果比於 pH 3.8 溶液中來的好。接者將 nalbuphine 與 nalbuphine propionate 溶於蠶絲蛋白水性凝膠中可發現相似的控制釋放效果。當以 FITC 與 FD 4.4 為模式大分子藥物加入蠶絲蛋白水膠後會出現 size exclusion 現象,但蠶絲蛋白仍提供了控制釋放的效果。以上證實了蠶絲蛋白對於小分子及大分子藥品皆提供控制釋放的效果,因此除了可用於穿皮製劑外,對於皮下或肌肉注射等投藥路徑也可作為緩釋劑型的考量。
Abstract
This study can be separated into three parts. The first part, fluorescein isothiocyanate-dextran (FD) had been chosen for hydrophilic macromolecules to find out the relationship between different molecular weight molecules and erbium laser as an enhancer. When the energy of laser increased, the flux increased. When the molecular weight of FD increased, the flux decreased. By SEM, the flux of FD increased when the ablation of stratum corneum became serious. The flux between FITC and FD 4.4 did not have significant differences at lower laser energy, which might be due to the different transdermal pathways. FITC mainly acrossed skin by hair follicles, while FD 4.4 mainly passed through by stratum corneum. The second part, sodium nonivamide (SNA) and sodium nonivamide propionate (SNP) had been chosen for hydrophilic micromolecules. We also used Solupor® to evaluate the effect of iontophoresis (ITP) and electroporation (EP) to the flux of SNA and SNP. The results showed that ITP greatly enhanced the flux of SNA and SNP, compared to EP. 8P07A membrane that had little resistance and drugs could freely pass through. Other four membranes showed control release effect. For 10P05A and 16P05A membranes, the fiber structure seems dissolved and particles attached on the surface was observed after passive and ITP experiments. SNA and SNP had similar control release effects by Solupor®. The reason might be the rate-limiting step for Solupor® was not the molecular weight, but was the physicochemical properties of Solupor® (ex: pore size, width, gurley number…). The third part, we used narcotic analgesics-buprenorphine as a model drug and put it into three kinds of hydrogels to see its control release effects. From the measurement of viscosities, we found that when the concentration of hydrogels increased, the viscosities increased. When molecular weight 10-20 kDa silk protein was added in, the viscosity decreased. When urea was added into silk protein and chitosan hydrogels, the viscosities decreased. When urea added into PF-127, the viscosity increased. From FT/IR, we found the structure of silk protein was β-sheet mixed with random coil conformation. When methanol was added, the conformation changed into β-sheet alone. When the concentration of silk protein, chitosan and PF-127 increased, the flux decreased. ITP could greatly enhance the flux of buprenorphine in silk protein hydrogels compared to solution. Silk protein hydrogels also provided the same control release effect to nalbuphine and its prodrug. For macromolecules, silk protein hydrogels provided size-exclusion effect. In conclusion, silk protein provided control release effect for hydrophilic macro- and micro-molecules. Thus, the function of silk protein hydrogels was not only for transdermal patch, but also for other parenteral pathways.
目 錄
表目錄 iii 圖目錄 v
中文摘要 viii
英文摘要 x
壹、緒論 1
一、皮膚及皮膚用藥 1
1. 皮膚結構 1
2. 角質層 1
3. 藥物穿透皮膚的途徑 2
4. 影響藥物穿透因素 2
5. 藥物在皮膚穿透的原理 2
6. 皮膚製劑的改善方式 4
7. 水性凝膠 7
二、模式藥物 10
1. Fluorescein isothiocyanate (FITC) 10
2. Dextran 10
3. Insulin 12
4. Capsaicin 之衍生物 – sodium nonivamide acetate 12
(SNA) & sodium nonivamide propionate (SNP)
5. Buprenorphine 16 6. Nalbuphine & nalbuphine propionate 16
三、 研究目的 17
貳、材料與方法 20
一、試劑與醫材、儀器設備 20
二、溶媒備製 22
三、 含藥處方製備 25
四、 實驗方法 27
五、 統計方法 32
參、結果與討論 33
一、 Fluorescein isothiocyanate – Dextran 33
1. FITC, FD 體外穿透試驗 33
2. 螢光顯微鏡試驗 38
3. 掃描式電子顯微鏡 (SEM) 38
二、 Sodium nonivamide acetate, Sodium nonivamide propionate 41
1. 體外穿透試驗 41
2. 掃描式電子顯微鏡 (SEM) 47
3. 飽和溶解度測試 48
三、 Buprenorphine 49
1. 紅外線光譜分析 49
2. 黏滯度測定 52
3. Buprenorphine 體外穿透試驗 64
4. Buprenorphine 之 iontophoresis (ITP) 促進體外穿透試驗 64
5. 掃描式電子顯微鏡 68
四、 Nalbuphine, nalbuphine propionate於蠶絲蛋白水膠之體外穿透實驗 71
五、 FITC, FD 4.4於蠶絲蛋白水膠之體外釋放實驗 71
肆、結論 74
伍、參考文獻 76
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