本研究以海藻酸鈉(sodium alginate)為材質之奈米膠囊，由於其具有生物相容性及生物降解性，因此在近幾年來已經被廣泛的研究，希望能成為有效之藥物載體系統。以相轉移法(PIT)製備之微乳劑系統，是屬於熱力學上的穩定分散系統，因此在適當的溫度及組成條件下，毋需外加能量的幫助即可自發性形成並穩定存在。
皮膚對大多數物質是一道難以滲透的屏障，使得許多療效型的有效成分達不到良好的效果。在某些程度上是由於此有效成分的滲透性不佳或配方組成對有效成分的釋放能力所致。熊果苷(Arbutin)是一種酪氨酸酶(Tyrosinase)抑制劑，普遍被應用於美白去斑產品，由於熊果苷為水溶性之有效成分，其滲透性一直都是有待解決課題。因此本研究以海藻膠奈米膠囊作為載體，以相轉移法製備出結構穩定之奈米膠囊，並針對各種會對奈米膠囊之粒子型態及表面電位所產生影響的製備條件做進一步的探討。其次探討以奈米膠囊作為載體對體外模擬釋放及藥物經皮穿透或滲入之影響。
研究結果顯示，海藻膠奈米微粒之平均粒徑範圍為10~200nm。且此奈米膠囊會隨著海藻酸鈉的分子量大小、濃度及交聯劑種類、濃度而呈現不同的粒子型態與粒徑範圍。在經皮吸收試驗方面，以Arbutin起始投藥量相同的情況下，以奈米膠囊為載體的經皮吸收最佳，24小時後接近平衡，釋放量約為投藥量的82%；Arbutin微乳劑組的藥物釋放量與時間的曲線與Arbutin水溶液組的經皮吸收情況類似，而釋放量分別為投藥量57%與35%。顯示以奈米膠囊作為經皮吸收之載體，確實可以提供小分子水溶性藥物一個有效的傳遞方式，但此藥物的傳輸機制仍有待進一步之研究與發展。

Alginate nanoparticles have gained extensive interest as drug carriers because of the biocompatibility and biodegradability of polymer .Microemulsions are thermodynamically stable system and can be formed spontaneously when properly formulated.
Arbutin is a glycosylated hydroquinone. Its properties are skin whitening by inhibiting melanin synthesis, sunscreen agent and antioxidant, but it’s a hydrophilic drugs . Researching for enhancement methods of drug percutaneous absorption is one of the important topics on medications. A major problem in transdermal drug delivery is the low penetration rate of substances through the barrier of skin, the stratum corneum, which consists of corneocytes embedded in a lipid matrix. One of the methods to increase the rate across the skin is encapsulation of drugs in alginate nanoparticles.
In our study, the drug was encapsulated in nanoparticles were applied on the results by various preparation formulations, in vitro drug release studies and transdermal drug delivery system.
The results demonstrated that the diameter of prepared nanoparticles was controlled in a range of 10~200nm. Factors included molecular weight, concentration of sodium alginate, and initial concentration of the cross-link agent, have been examined to investigate effect on particle size and zeta potential. The results of alginate NP on arbutin delivery, penetration across skin was 82% of initial doses. Free drug and arbutin nanoemulsion resulted in transport was 35% and 57% of initial doses. Based on the results, the amount of absorbed arbutin have additive effect with a nano-encapsulation technology
Accordingly, alginate nanoparticle could facilitate the transport of hydrophilic molecules through skin. But the mechanism of the transdermal drug delivery system is needed further research and development.

目錄
中文摘要…………………………………………………………….Ι
英文摘要…………………………………………………………….Ⅲ
目錄………………………………………………………………….Ⅴ
圖表目錄…………………………………………………………….Ⅹ

壹、 緒論……………………………………………………………..1
一、 奈米藥物載體………………………………………………...1
1-1微粒包覆技術…………………………………………….1
1-2 奈米藥物載體…………………………………………... 2
1-3 傳統奈米藥物載體的製造方法…………………………4
二、 生物高分子……………………………………………………7
2-1奈米藥物載體之材料……………………………………..7
2-2水膠………………………………………………………..8
2-3海藻酸鈉…………………………………………………...9
三、 微乳劑系統…………………………………………………....12
3-1微乳劑的特性……………………………………………..12
3-2微乳劑系統的應用……………………………………......14
四、 本研究所用微乳劑系統………………………………………16
4-1 HLB溫度………………………………………………….17
五、 藥物控制釋放動力學模式………………………………........20
5-1 一階溶出模式………………………………………….....20
5-2 Higuchi間質化溶出模式………………………………….22
5-3 零階溶出模式………………………………………….....23
六、 經皮系統………………………………………………………24
6-1皮膚…………………………………………………….......24
6-1-1表皮……………………………………………….....25
6-1-2真皮……………………………………………….....28
6-1-3皮下組織………………………………………….....28
6-1-4表皮的細胞……………………………………….....29
6-2美白活性成分及美白機制…………………………….......32
6-3經皮吸收…………………………………………………..36
6-3-1 被動式經皮輸藥系統之穿透路徑………………...36
6-3-2影響經皮給要之因素……………………………....41
6-3-3 促進經皮吸收之方法……………………………...42
七、 所用模式藥之簡介………………………………………........44
八、 所用物性測量方法之理論…………………………………....45
8-1粒徑測量…………………………………………………..45
8-2電子顯微鏡技術(Transmission Electron Microscope)……47
8-3表面電位測量(zeta(ζ)potential)…………………………...49
8-4高效能分子篩層析(HPSEC)……………………………...51
貳、 研究目的…………………………………………………………53
參、 實驗方法…………………………………………………………54
一、 實驗藥品及儀器………………………………………….....54
1-1實驗藥品…………………………………………………...54
1-2實驗器材…………………………………………………...56
二、 實驗步驟………………………………………………….....58
2-1製備程序………………………………………………......58
2-1-1擬似分配係數(Apparent partition coefficient)….....58
2-1-2測定微乳劑之相轉移溫度………………………...59
2-1-3海藻酸鈉之水解方法……………………………...59
2-1-4海藻酸鈉之分子量測定…………………………...60
2-1-5硬脂酸鈣的合成…………………………………...60
2-1-6以calcium chloride為交聯劑之奈米膠囊的製備...61
2-1-7以calcium carbonat為交聯劑之奈米膠囊的製備...61
2-1-8以calcium stearate為交聯劑之奈米膠囊的製備…62
2-1-9以calcium acetate為交聯劑之奈米膠囊的製備.....63
2-1-10分離程序………………………………………….68
2-2分析程序………………………………………………………69
2-2-1載藥包覆率測量…………………………………..69
2-2-2粒徑大小量測……………………………………..70
2-2-3奈米膠囊表面電位（zeta potential）之測定…….70
2-2-4以穿透式電子顯微鏡（TEM）觀測奈米膠囊的結構
……………………………………………………………71
2-2-5體外模擬釋放……………………………………...71
2-2-6經皮吸收…………………………………………...72
肆、 結果與討論………………………………………………………73
4-1針對微乳劑之組成做探討………………………………73
4-2海藻酸鈉分子量對奈米膠囊包覆上的影響……………80
4-3不同交聯劑對奈米膠囊之影響…………………………84
4-4不同海藻酸鈉濃度對奈米膠囊之影響…………………89
4-5不同起始藥物濃度對奈米膠囊之影響………………....92
4-6不同油水比例對奈米膠囊之影響………………………94
4-7不同界面活性劑比例對奈米膠囊之影響………………96
4-8不同交聯劑濃度下之製程對奈米膠囊的影響…………98
4-9影響奈米膠囊包覆效率的因素探討…………………..102
4-10針對體外模擬釋放做探討…………………………....106
4-11包覆藥物之奈米膠囊對小鼠腹部皮膚經皮吸收之研究
…………………………………………………………..…..109

伍、 結論………………………………………………………….….111
參考文獻………………………………………………………………113

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