臺灣博碩士論文加值系統

中文摘要
水難溶性藥物一般有生體可用率不佳的特性。此實驗的研究目的，是設計含有奈米粒子的膠體包埋系統來包埋Indomethacin，以增進其水溶性。親水膠體奈米微粒懸浮劑包埋Indomethacin的製作，藉由將藥物溶於固化凝膠以機械粉碎法，研磨成奈米微粒，再利用凍晶乾燥將懸浮劑凍乾。凍晶乾燥製程中，親水膠體因水的含量及溫度的變化，最後可能產生水難溶性的聚集，藉由pH值的調整及抗凍劑加入來防止聚集，在凍晶乾燥後儲存。藉由凍晶乾燥後的乾粉及加水復原的懸浮劑，進行物理性質的檢測。粒子大小是經由表面電位及粒徑大小分佈分析儀進行測定；除外，藥物－聚合膠體的交互作用則使用卡式熱分析儀(DSC)分析，藥物溶解度的測定是用濁度計來檢測。結果顯示，固化凝膠機械粉碎法可得到粒徑在 40 nm到 400 nm的Indomethacin－親水膠體奈米粒子。在凍晶乾燥前將奈米粒子鹼化及加入抗凍劑，也顯示對包埋的奈米粒子產生更好的安定性。由DSC的結果也顯示在凍晶乾燥的製造過程中，並無明顯的化學交互作用。由凍晶乾粉製程的奈米粒子，能迅速的在水中分散，形成清澈且穩定的狀態。此結果將有助於發展其他水難溶性藥物助溶系統。

Abstract
The bioavailability of water-insoluble drug is poor. The aim of the present study was to design a suspension composed of numberless nanoparticles to improve the solubility of indomethacin. Hydrogel based nanoparticles encapsulating indomethacin were prepared by using the solid jelly pulverization technique, and then freeze-dry to lyophilized powder. In the freeze-drying process, hydrogel based nanoparticles undergo change of temperature and water content, eventually forming water-insoluble aggregates. The pH value adjusted as well as the cryoprotectants was added to stable the dispersion system during formulation, lyophilization, and storage. The physical studies of hydrogel based nanoparticles were performed in a freeze-drying or resuspended form. The size of the indomethacin- hydrogel nanoparticles was assessed using a LS particle size analyzer. In addition, any drug-polymer interactions were assessed using a differential scanning calorimeter (DSC). The dissolution was determined by the apparatus of Franz diffusion and analyzed by turbidimeter. The results show that solid jelly pulverization technique yielded indomethacin hydrogel nanoparticles with a mean diameter of 40 nm to 400 nm. Alkalization of suspension containing nanoparticles or blending of cryoprotectants in suspension before the freeze-drying process showed better stabilization of encapsulated drug. The DSC measurements indicated that the chemical interaction does not occur among the components during manufacturing processes and lyophilized powder. The lyophilized powder of nanoparticles reconstitutes rapidly, the resulting product has remarkable clarity, and stability. The above results will be helpful to possible development of the other water-insoluble drug delivery systems.

目錄（Contents）
中文摘要......................................................I
Abstract......................................................II
誌謝..........................................................IV
目錄..........................................................V
表目錄........................................................IX
圖目錄........................................................X
縮寫表........................................................XV
第一章 緒論...................................................1
第二章 材料與方法.............................................9
§2-1 儀器設備及藥品...........................................9
2-1-1 儀器設備................................................9
2-1-2 藥品....................................................11
§2-2 製作方法.................................................12
2-2-1 含IMC的溶媒的製作.......................................12
2-2-2 Gel的製作...............................................12
2-2-3 Gel粒子的研磨...........................................14
2-2-4 檢量線的製作............................................14
§2-3 實驗測試.................................................15
2-3-1 Gel硬度測試.............................................15
2-3-2 IMC在不同物質下的溶解度試驗.............................16
2-3-2-1 IMC在水-醇中的溶解度試驗..............................16
2-3-2-2 酸鹼影響下對IMC在溶液中的溶解度影響試驗...............17
2-3-2-3 水-醇溶媒系統加入NH4OH時IMC最大溶解度試驗.............17
2-3-2-4 Agar Gel對IMC的助溶效果試驗...........................17
2-3-2-5 加入酸或鹼對IMC-Agar Gel的助溶效果....................18
2-3-3 加入酸或鹼後對Gel及溶媒的pH值變化測定...................19
2-3-3-1 酸或鹼對含Gel粒子分散懸液的pH值影響...................19
2-3-3-2 酸或鹼對溶媒的pH值影響................................19
2-3-4 光線、濕度及溫度變化對IMC-Agar Gel的助溶影響............20
2-3-5 Agar Gel微粒之測定......................................20
2-3-5-1 Agar Gel微粒之粒徑測定................................20
2-3-5-2 Agar Gel在光學顯微鏡下的外觀觀察......................21
2-3-6 奈米微粒懸液的流變學特性................................21
2-3-7 IMC在不同組成的溶媒及Agar Gel中的DSC實驗................21
2-3-7-1 溶媒對IMC的影響.......................................22
2-3-7-2 Gel粒子和藥物的交互情形...............................23
2-3-8 以抗凍劑防止奈米微粒在結凍過程凝集之濁度實..............23
2-3-9 IMC及Gel粒子在電子顯微鏡下型態..........................25
2-3-10 成品在DSC下的熱流量變化................................26
2-3-11 成品之包埋率...........................................26
2-3-12 成品加水還原的情況.....................................27
第三章 結果...................................................28
§3-1 Gel硬度測定..............................................28
3-1-1 Agar gel的硬度變化測定..................................28
3-1-2 含酸或鹼的Agar gel外觀變化及硬度測定....................29
§3-2 IMC在不同物質下的溶解度試驗..............................29
3-2-1 IMC在溶液中的溶解度實驗.................................29
3-2-2 酸鹼影響下對IMC在溶液中的溶解度影響試驗.................31
3-2-3 水-醇溶媒系統加入NH4OH時IMC最大溶解度試驗...............31
3-2-4 Agar gel對IMC的助溶效果試驗.............................32
3-2-5 加入酸或鹼對IMC-Agar Gel的助溶效果......................35
§3-3 加入酸或鹼後對Gel及溶媒的pH值變化測定....................36
3-3-1 酸或鹼對含Gel粒子分散懸液的pH值影響.....................36
3-3-2 酸或鹼對溶媒的pH值影響..................................36
§3-4 光線、濕度及溫度變化對IMC-Agar Gel的助溶影響.............37
§3-5 Agar Gel微粒的測定.......................................38
§3-6 流變學特性之測定.........................................39
§3-7 IMC在不同組成的溶媒及Agar Gel中的DSC實驗.................39
3-7-1 IMC在不同組成的溶媒中的DSC變化測試......................39
3-7-2 Gel粒子和藥物的交互情形.................................40
§3-8 以抗凍劑防止奈米微粒在結凍過程凝集之濁度實驗.............40
§3-9 IMC及Gel粒子在電子顯微鏡下型態...........................41
§3-10 成品在DSC下的熱流量變化.................................41
§3-11 成品之包埋率............................................41
§3-12 成品加水還原的情況......................................43
第四章 討論...................................................44
第五章 結論...................................................47
參考文獻......................................................48


表目錄
表 2-1：IMC與於溶媒的配置比例.................................55
表 2-2：Agar Gel的製作比例....................................56
表 2-3：Agar Gel對IMC的助溶效果製作比例.......................57
表 2-4：酸鹼對Agar Gel影響的製作比例..........................58
表 2-5：含酸鹼下的Agar gel對IMC助溶效果的製作比例.............59
表 2-6：鹼性助溶下，Agar gel的製作比例........................60
表 2-7：檢量線的配置比例......................................60
表 2-8：不同狀態下製成的IMC進行DSC時的配置比例與方式..........60
表 2-9：抗凍劑與Agar Gel粒子的混合比例........................61
表 3-1：四項成品的包埋率與包埋量的計算表......................62


圖目錄
圖 1-1 奈米微粒的包埋方式。...................................63
圖 1-2 顯微鏡下乳劑的型態。...................................63
圖 1-3 多重乳化相的製作方式。.................................63
圖 1-4 乳劑多重相與二重相圖示。...............................64
圖 1-5 依官能基不同所分類的界面化性劑種類.....................64
圖 1-6界面活性劑產生產生微胞的進程。..........................65
圖 1-7 微胞產生的類型及清潔劑的產生清潔效果之圖示。...........65
圖 1-8本實驗的實驗流程簡圖。..................................66
圖 1-9 Agarose的結構式。......................................67
圖 1-10 Agar 凝膠化的機轉。...................................67
圖 1-11 Indomethacin結構式。..................................68
圖 1-12 Indomethacin結晶結構式。..............................68
圖 1-13 非類固醇藥類的抑制途徑。..............................69
圖 2-1 水醇比9：1時IMC在267nm的檢量線。.......................69
圖 2-2 含IMC溶液過濾抽取方式。................................70
圖 2-3 成品之包埋率的實驗圖示。...............................70
圖 3-1-1 不含乙醇的下，不同的降溫速的對Agar Gel 硬度的影響。..71
圖 3-1-2 含10 %乙醇時，不同的降溫速度對Agar Gel 硬度的影響。..71
圖 3-1-3 含20 %乙醇時，不同的降溫速度對Agar Gel 硬度的影響。..71
圖 3-1-4 30 ℃下不同乙醇濃度對Agar Gel 硬度的影響。...........72
圖 3-1-5 0 ℃下不同乙醇濃度對Agar Gel 硬度的影響。............72
圖 3-1-7 不同醋酸量對Agar gel 外觀的影響。....................73
圖 3-1-8 不同氨水量對Agar gel 外觀的影響。....................74
圖 3-1-9 加入醋酸及氨水的Agar gel 硬度實驗結果。..............75
圖 3-2-1 IMC-水-醇製備後，時間對IMC溶解度的影響，吸光值部分。.76
圖 3-2-2 將檢量線方程式代入3-2-1的吸光值後，換算得的IMC濃度與時間的關係圖。..........................................................76
圖 3-2-3 醋酸加入IMC-水-醇中所產生的現象。....................77
圖 3-2-4 醋酸對IMC-水-醇的NTU變化。...........................78
圖 3-2-5 氨水加入IMC-水-醇中所產生的現象。....................79
圖 3-2-6 氨水對IMC-水-醇的NTU變化。...........................79
圖 3-2-7 室溫下冷卻的Agar Gel (水醇比4:1)，冷卻後的外觀。.....80
圖 3-2-8 30℃下水醇比9:1對IMC溶解度的影響。...................81
圖 3-2-9 20℃下水醇比9:1對IMC溶解度的影響。...................81
圖 3-2-10 0℃下水醇比9:1對IMC溶解度的影響。...................81
圖 3-2-11 30℃下水醇比4:1對IMC溶解度的影響。..................82
圖 3-2-12 20℃下水醇比4:1對IMC溶解度的影響。..................82
圖 3-2-13 0℃下水醇比4:1對IMC溶解度的影響。...................82
圖 3-2-14 酸或鹼對IMC-Agar Gel的影響。........................83
圖 3-2-15 圖3-2-14中(A)部分的A2~A7及(B)部分的B2~B7俯視圖。....84
圖 3-2-16 圖3-2-14中(C)部分的C2~C7及(D)部分的D2~D7俯視圖。....85
圖 3-2-17 圖3-2-14中(E)部分的E2~E7及(F)部分的F2~F7俯視圖。....86
圖 3-2-18 由濁度計測定酸或鹼對IMC-Agar Gel的影響的結果。......87
圖 3-3-1 Agar Gel 製作中未加入或加入醋酸及氨水後，凝固Agar Gel的pH值。..........................................................88
圖 3-3-2 水：乙醇 = 9：1時，逐次加入等量的醋酸後，所測得的pH值。..........................................................89
圖 3-3-3 水：乙醇 = 4：1時，逐次加入等量的醋酸後，所測得的pH值。..........................................................89
圖 3-3-4 水：乙醇 = 9：1時，加入氨水前後，所測得的pH值。......90
圖 3-3-5 水：乙醇 = 4：1時，加入氨水前後，所測得的pH值。......90
圖 3-4-1 Agar gel在室外保存的情況下。.........................91
圖 3-4-2 Agar gel室內保存的情況下。...........................91
圖 3-4-3 Agar gel陰涼處保存的情況下。.........................92
圖 3-4-4 Agar gel低溫下保存產生的變化。.......................92
圖3-4-5 儲存第一天的濁度值。..................................93
圖 3-4-6 圖3-4-5的群組直線圖。................................93
圖 3-4-7 第三天的濁度值。.....................................94
圖 3-4-8 圖3-4-7的群組直線圖。................................94
圖 3-4-9 第三天的濁度值。.....................................95
圖 3-4-10 圖3-4-9的群組直線圖。...............................95
圖 3-5-1 1% Agar Gel分別研磨不同的時間，所得 的奈米粒子大小分佈
圖。..................................................96
圖 3-5-2 含1.25% Agar Gel分別研磨不同的時間，所得的奈米粒子大小分
佈圖。.................................................96
圖 3-5-3 含1.5% Agar Gel分別研磨不同的時間，所得的奈米粒子大小分佈
圖。...................................................96
圖 3-5-4 Gel粒子在光學顯微鏡下的型態。........................97
圖 3-6 不同組成比例奈米粒子，隨時間變化攪拌下的黏度變化。.....98
圖 3-7-1 IMC 在受到高溫或低溫、壓力、不同溶媒時所產生的物理化學變
化。.................................................99
圖 3-7-2 膠體奈米粒子與藥物的交互關係。.......................100
圖 3-8-1 以水為溶劑時，冷凍前後的濁度變化。...................101
圖 3-8-2 不同的乳糖(LAC)濃度下防止奈米粒子聚集的效果。........102
圖 3-8-3 不同的甘露醇(MAN)濃度下防止奈米粒子聚集的效果。......103
圖 3-8-4 不同的山梨醇(SOR)濃度下防止奈米粒子聚集的效果。......104
圖 3-9-1 乳醣(LAC)與不同情況製成的IMC粉末的電顯圖。...........105
圖 3-9-2 以-20℃冷凍後凍晶乾燥所得之Gel粒子電顯圖。...........106
圖 3-9-3 以-80℃冷凍後凍晶乾燥所得之Gel粒子電顯圖。...........107
圖 3-10 LAC與四種成品在DSC下的熱流量表現。...................108
圖 3-12-1 Gel粒子凍乾前後加水還原時的濁度變化。...............109
圖 3-12-2 成品(1)~(4)俯視觀察的凍晶乾燥粉體。.................109
圖 3-12-3 圖3-12-2中(1)~(4)加入200ml水後的還原情況。..........110

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