本論文的研究方向是欲解決市面無法量產微針載體及無法控制釋放效率問題。就製備方法而言，目前全世界99％專利皆採用以MEMS微機電設備的光蝕刻製造技術，並透過PDMS無毒高分子材料翻脫膜；而本論文的製造技術為一種微針載體之製備方法，具備擁有量產技術且多樣化設計的dMNs整合技術，有別於以往PDMS翻模技術，本技術利用高解析度3D列印機工藝技術及光固化設備製備微針模具；任何不同形狀、大小、曲度、皮膚貼注處模具，皆可透過3D設計客製化設計及生產，簡單、快速且精準。透過大氣電漿法技術改變模具表面之親疏水性，再將有機高分子和無機高分子、多糖體等混合成的配方形成於模具之多個孔洞內，增加塗佈效益，進而乾燥脫膜後得到高良率微針半成品，可大量生產混合型、囊孔型微針貼片且製造成本低；最後再利用大氣電漿蝕刻技術進行等向性蝕刻，調整針高及孔洞深度，產生囊孔型及不同需求針型以製備每根不超過1000微米長度的微針，可有效量產製造混合型及囊孔型微針做為醫美、醫藥及疫苗之載體。

The research direction of this thesis is to solve the problem that the microneedle carrier cannot be mass-produced in the market and the release efficiency cannot be controlled. As far as the preparation method is concerned, 99% of the patents in the world currently use the photo-etching manufacturing technology of MEMS micro-electromechanical equipment, and the film is removed through PDMS non-toxic polymer material; and the manufacturing technology of this paper is a preparation method of a microneedle carrier. , has the dMNs integration technology with mass production technology and diversified design, which is different from the previous PDMS mold turning technology. This technology uses high-resolution 3D printer technology and light curing equipment to prepare microneedle molds; any shape, size , curvature, and skin sticking molds can be customized and produced through 3D design, which is simple, fast and accurate. The hydrophilicity and hydrophobicity of the surface of the mold is changed by the atmospheric plasma method, and then the formula formed by mixing organic polymers, inorganic polymers, polysaccharides, etc. is formed in multiple holes of the mold to increase the coating efficiency. High-yield semi-finished microneedles can be mass-produced with hybrid and capsular microneedle patches with low manufacturing cost; finally, atmospheric plasma etching technology is used for isotropic etching to adjust needle height and hole depth to produce capsular and Different types of needles are required to prepare microneedles with a length of no more than 1000 microns, which can effectively mass-produce hybrid and cystic microneedles as carriers for medical aesthetics, medicine and vaccines.

目錄
	頁次
謝誌	I
總目錄	V
圖目錄	VII
表目錄	VIII
第一章、序論	
　　1-1前言	1
　　1-2一般藥物傳輸系統	3
　　1-3口服劑型	4
　　1-4注射劑型	6
　　1-5經皮輸送劑型	9
　　1-6疫苗起源	15
第二章、微針製造原理以及方法	
　　2-1微針貼片	20
　　2-2固體微針(Solid microneedle)	21
　　2-3塗層型微針(Coated microneedle)	23
　　2-4中空型微針(Hollow microneedle)	26
　　2-5高分子聚合物微針(Polymer microneedle) 	30
　　2-6微針製程	31
　　2-7鼓風拉伸風乾(Droplet-born air blowing, DAB)	31
　　2-8製模∕脫模反覆成形的技術(Polydimethylsiloxane, PDMS)	32
第三章、微針產業發展及3D列印發展趨勢	
　　3-1微針產業發展趨勢	34
　　3-2專利檢索及分析(WIPS)	37
　　3-3列印工藝技術設計流程	40
    3-4分子理論計算與原理	59
　　3-5研究動機與目的	61
第四章、研究設備與工具	
　　4-1儀器設備	62
　　4-2實驗材料	69
第五章、微針載體製備與量產方法	
　　5-1簡介	76
　　5-2微針模具製備方法	80
　　5-3微針模具改質實驗方法	84
　　5-4溶解型微針貼片製備方法	86
　　5-5囊孔型微針貼片製備方法	89
　　5-6微針貼片之豬皮穿刺實驗	105
第六章、結論	106
參考資料	108
	
	
	
	


 
圖目錄
圖1-1	藥物傳輸系統	3
圖1-2	皮膚構造示意圖	11
圖1-3	微針長度對於疼痛感的影響	12
圖1-4	微針厚度與寬度對疼痛感的影響	12
圖1-5		微針尖角對疼痛感的影響	13
圖1-6	定製化的微針疫苗貼片	16
圖1-7	無需電池的電穿孔注射器	18
圖1-8	ePatch疫苗注射器的設計原理圖	19
圖2-1	由(a-d)矽、(e-h)金屬和(i-l)聚合物製成的實心微針	22
圖2-2	塗層微針示意圖	25
圖2-3 	塗層型微針上的分子和微粒的寬度	25
圖2-4	中空型微針示意圖	27
圖2-5 	中空型微針模擬繪圖	28
圖2-6	中空型微針SEM圖像	28
圖2-7	中空型微針的光學顯微照片	29
圖2-8	高分子聚合物微針	30
圖2-9	DAB微針製作技術	31
圖2-10 	製模∕脫模反覆成形的技術	32
圖3-1	全球經皮給藥系統市場預測及技術分析	34
圖3-2	溶解型微針使用方式	35
圖3-3	微針製備方法專利技術分析	37
圖3-4	技術服務業應具備之技術能量	39
圖3-5	比較STO-1G、STO-2G、STO-3G不同基底函數與1s軌域的Slater函數近似程度	54
圖3-6	對於極性分子系統的軌域型態，用加入額外軌域型態函數來加以修正	57
圖4-1	Nobel Superfine3D列印機	64
圖4-2	MultiCure180光固化機	66
圖4-3	DesignSpark Mechanical	68
圖4-4	聚乙烯醇化學結構圖	69
圖4-5	完全醇解PVA及部分醇解PVA	70
圖4-6	PVA 3D Model image	71
圖4-7	PVA Van der Waals Spheres	71
圖4-8	PVA Measurement Distance	71
圖4-9	PVA Measurement Angle	71
圖4-10	PVA Molecular Electrostatic    Potential (MEP)
71
圖4-11	PVA Calculations Charge	71
圖4-12	PVA Bond dipoles and overall dipole	72
圖4-13	聚乙烯吡咯烷酮化學結構圖	73
圖4-14	PVP 3D Model image	74
圖4-15	PVP Van der Waals Spheres	74
圖4-16	PVP Measurement Distance	75
圖4-17	PVP Measurement Angle	75
圖4-18	PVP Molecular Electrostatic    Potential (MEP)
75
圖4-19	PVP Calculations Charge	75
圖4-20	PVP Bond dipoles and overall dipole	75
圖5-1	微針載體製備與量產流程圖	77
圖5-2	混合型微針陣列製備方法	78
圖5-3	囊孔型微針陣列製備方法	79
圖5-4	微針模具製備方法	80
圖5-5	微針眼膜電子設計圖	81
圖5-6	XYZware Nobel軟體等比例大小調整	81
圖5-7	列印樹脂材料選擇	82
圖5-8	3D列印模板厚度以及解析度選擇	83
圖5-9	大氣電漿技術改變微針模具極性示意圖	85
圖5-10	大氣電漿技術改變微針孔洞示意圖	90
圖5-11	使用9.8牛頓力量垂直下壓示意圖	90
圖5-12	眼膜形狀微針模具基底設計圖	91
圖5-13	不同需求針型微針針型設計圖(A)羽毛球針型(B)子彈型針型	91
圖5-14	不同孔洞大小、不同密度及不同形狀微針模具設計圖	93
圖5-15	微針模具實拍圖	95
圖5-16	微針模具於顯微鏡下影像圖	95
圖5-17	大氣電漿後模具親疏水性比前後比較	96
圖5-18	聚乙烯醇可溶式微針於不同倍率之顯微鏡影像
微針模板尺寸：200 µm、200 µm、200 µm	97
圖5-19	聚乙烯醇可溶式微針於不同倍率之顯微鏡影像
微針模板尺寸：300 µm、300 µm、300 µm	98
圖5-20	聚乙烯醇可溶式微針於顯微鏡之影像
300 µm、300 µm、600 µm	99
圖5-21	聚乙烯醇可溶式微針於顯微鏡之影像
微針模板尺寸：600 µm、600 µm、600 µm	100
圖5-22	聚乙烯醇可溶式微針於顯微鏡之影像
微針模板尺寸：600 µm、600 µm、1000 µm	101
圖5-23	聚乙烯醇可溶式微針於顯微鏡之影像/囊孔型微針貼片影像
微針模板尺寸：600 µm、600 µm、1000 µm	102
圖5-24	不同參數設定下的大氣電漿蝕刻處理後的微針貼片	103
圖5-25	囊孔型微針貼片(A)大氣電漿蝕刻處理過後的囊孔型微針貼片背面顯微鏡圖像。(B)染色囊孔型微針貼片顯微鏡圖像。	105
圖5-26	螺旋型微針	105
圖5-27	蝦殼素集中於針尖微針	105
圖5-28	豬皮穿刺圖	106

 
表目錄
表4-1	C2H4O之分子模擬結果	70
表4-2	C2H4O分子組成百分比	70
表4-3	C6H9NO之分子模擬結果	74
表4-4	C6H9NO分子組成百分比	74

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