Ramipril是一種具降血壓效能的「血管緊縮素轉化脢抑制劑」。它用於治療高血壓、心衰竭，並改善心衰竭病人之心肌梗塞。本實驗利用複因子試驗設計法來找出最適合ramipril快速釋放膠囊的處方。
本實驗將探討自製處方與原廠處方在ramipril膠囊製備、含量均一度、安定性及溶離曲線圖的差異。二因子的三階試驗設計法將以ramipril膠囊釋出的百分比為依據，並以ANOVA來分析檢定變因。體外溶離試驗是依據USP 23的第一法來進行。膠囊的溶離及含量均一度是利用HPLC來分析的。膠囊貯存在不同的溫度及溼度下，以便檢測安定性。
試驗設計法證明prejel與溶媒pH值，對ramipril膠囊釋出有顯著的影響。在高溫貯存膠囊時，會使ramipril膠囊的含量明顯減少。自製處方與原廠處方皆有符合藥典對含量均一度的要求。自製處方與原廠處方的溶離曲線圖，將以相似因子法來評估二者的差異。
本實驗的結果指出，當處方含有高劑量的prejel，且在溶媒pH值為7.4時，會與原廠的處方有相似的溶離曲線圖。

Ramipril is an active inhibitor of angiotensin converting enzyme with antihypertensive activity. It is used in the treatment of all forms of hypertension, heart failure, and following myocardial infarction to improve survival in patients with clinical evidence of heart failure. A statistical factorial experimental design was used to optimize the formulation of immediate-release ramipril capsules.
The ramipril capsules properties, uniformity content, storage effects, and dissolution profile, were studied and then compared to those of the innovator’s product. A three-level factorial design was employed to evaluate the effects of the two factors on the percentage release of ramipril; the subsequent data was compared using analysis of variance (ANOVA). In-vitro drug release test of the ramipril capsules was performed according to the USP 23 apparatus 1. The concentration of the dissolution solution and uniformity content of the capsules were assayed using a HPLC method. Storage effects at various temperatures and relative humidity on the stability of the formulations were also studied.
The experimental design study illustrated that prejel and pH value of the media had significant effect on the release percentage of ramipril capsules determined. A higher storage temperature showed a significant degradation effect on the ramipril capsules. It was found that the qualities of the innovator’s product met the pharmacopoeia requirements. The similarity factor (f2) between innovator’s product and the formulated samples was employed to compare their similarity, and satisfactory results were obtained.
These preliminary results indicate that to mimic the release profile of the innovator’s product by incorporating a higher percentage of prejel in pH 7.4 is possible.

目錄

中文摘要...................................................................VIII
英文摘要.....................................................................IX
壹、緒論......................................................................1
一、Ramipril的基本概述........................................................1
二、預膠化澱粉(prejel)的概述..................................................4
三、Sodium stearyl fumarate的概述.............................................4
四、可壓性澱粉(starch 1500)的概述.............................................5
五、試驗設計法(experimental design)...........................................5
貳、實驗目的.................................................................12
參、材料與儀器設備...........................................................13
一、材料.....................................................................13
二、儀器設備.................................................................14
肆、實驗方法.................................................................15
一、Ramipril膠囊之鏡檢.......................................................15
二、複因子實驗設計法探討Ramipril膠囊之組成...................................16
三、高壓液相層析儀分析Ramipril成分...........................................18
四、探討Ramipril與賦形劑之交互作用...........................................19
五、Ramipril膠囊之體外溶離試驗與相似因子ƒ 2 (similarity factor)評估..........20
六、Ramipril膠囊之含量均一度試驗.............................................22
七、Ramipril膠囊之安定性試驗.................................................23
伍、結果與討論...............................................................24
一、Ramipril膠囊之鏡檢.......................................................24
二、23複因子實驗設計法(Full Factorials)實驗數據之統計結果分析................32
三、高壓液相層析儀分析Ramipril成分...........................................49
四、Ramipril與賦形劑之交互作用...............................................50
五、Ramipril膠囊之體外溶離試驗與相似因子ƒ 2 (similarity factor)評估..........60
六、Ramipril膠囊之含量均一度試驗.............................................67
七、Ramipril膠囊之安定性試驗.................................................70
陸、結論.....................................................................73
柒、參考文獻.................................................................74

表目錄

表1：23複因子實驗設計之設計之矩陣(Design Matrix)..............................9
表2：23複因子直交係數表.......................................................9
表3：23複因子試驗設計之變方分析表............................................10
表4：23 複因子試驗設計之試驗因子及處理組合表.................................16
表5：23複因子實驗設計之設計之處理組合表......................................17
表6：23複因子實驗設計八種處理組合之實際重量..................................17
表7：複因子實驗設計之設計之矩陣(Design Matrix)...............................33
表8：複因子實驗設計之各Effect之評估值(Estimate)..............................34
表9：相似因子ƒ 2 (similarity factor)結果：各Effects之評估值(Estimate)........34
表10：溶離試驗之變方分析表表.................................................35
表11：溶離試驗:各處方之Residuals值...........................................46
表12：處方之相似因子ƒ 2 (similarity factor)結果..............................61
表13：處方VI (2% Ramipril, 0.5% SSF, 65.4% Starch 1500, 32.1% Pre-jel)人工胃液(SGF, pH=1.2)中之體外溶離結果................................................62
表14：處方VIII (2% Ramipril, 0.5% SSF, 60.4% Starch 1500, 37.1% Pre-jel)人工胃液(SGF, pH=1.2)中之體外溶離結果..............................................62
表15：處方IV (2% Ramipril, 1% SSF, 59.9% Starch 1500, 37.1% Pre-jel)人工胃液(SGF, pH=1.2)中之體外溶離結果................................................63
表16：處方II (2% Ramipril, 1% SSF, 64.9% Starch 1500, 32.1% Pre-jel)人工胃液(SGF, pH=1.2)中之體外溶離結果................................................63
表17：處方V (2% Ramipril, 0.5% SSF, 65.4% Starch 1500, 32.1% Pre-jel)人工腸液(SIF, pH=7.4)中之體外溶離結果................................................64
表18：處方VII (2% Ramipril, 0.5% SSF, 60.4% Starch 1500, 37.1% Pre-jel)人工腸液(SIF, pH=7.4)中之體外溶離結果................................................65
表19：處方I (2% Ramipril, 1% SSF, 64.9% Starch 1500, 32.1% Pre-jel)人工腸液(SIF, pH=7.4)中之體外溶離結果................................................65
表20：處方III (2% Ramipril, 1% SSF, 59.9% Starch 1500, 37.1% Pre Jel)人工腸液(SIF, pH=7.4)中之體外溶離結果................................................66
表21：Ramipril定量方法之同日間精密度與異日間精密度分析結果...................68
表22：自製處方VII膠囊之含量均一度試驗結果....................................69
表23：原廠膠囊之含量均一度試驗結果...........................................69
表24：貯存於25 °C / 75% R.H. 之條件中，原廠膠囊與自製處方VII膠囊含量%對照表..71
表25：貯存於55 °C / 75% R.H. 之條件中，原廠膠囊與自製處方VII膠囊含量%對照表..72

圖目錄

圖1：23複因子實驗設計法示意圖................................................10
圖2(A)：23複因子實驗設計主效應(main effects)之幾何圖示.......................11
圖2(B)：23複因子實驗設計兩試驗因子交感效應(Two-factor interactions)之幾何圖示...........................................................................11
圖2(C)：23複因子實驗設計三試驗因子交感效應(Three-factor interactions)之幾何圖示...........................................................................11
圖3：23複因子實驗設計法(Full Factorials)條件之示意圖.........................18
圖4：Ramipril膠囊內容物之鏡檢(400 X).........................................25
圖5：Ramipril原料藥品之鏡檢(400 X)...........................................26
圖6：Ramipril原料藥品經超音波震盪後之鏡檢(400 X).............................26
圖7：Pre-Jel之鏡檢(400 X)....................................................27
圖8：Sodium stearyl fumarate (SSF)之鏡檢(400 X)..............................27
圖9：Ramipril原料藥品之掃描式電子顯微鏡圖像..................................28
圖10：Sodium stearyl fumarate (SSF)之掃描式電子顯微鏡圖像....................29
圖11：Starch 1500之掃描式電子顯微鏡圖像......................................30
圖12：Pre-Jel之掃描式電子顯微鏡圖像..........................................31
圖13：23複因子實驗設計法(Full Factorials)條件及結果之示意圖..................35
圖14：不同處方之相似因子f2 (similarity factor)比較...........................36
圖15：主效應和各交互作用效應因子之Pareto Plot................................36
圖16：藥品相似因子之Pareto Plot..............................................37
圖17：各Effect之Normal probability分佈圖.....................................37
圖18(A)：Main effect A plots.................................................38
圖18(B)：Main effect B plots.................................................39
圖18(C)：Main effect C plots.................................................39
圖19：Interaction plot of A and C [A: pH (A1為ph 1.2, A2為ph 7.4), C: sodium stearyl fumarate]............................................................40
圖20：Interaction plot of A and B [A: pH (A1為ph 1.2, A2為ph 7.4), B: amount of prejel]...................................................................41
圖21：Interaction plot of B and C [A: A1 (ph 1.2), B: amount of prejel, C: sodium stearyl fumarate].....................................................42
圖22：Interaction plot of B and C [A: A2 (ph 7.4), B: amount of prejel, C: sodium stearyl fumarate].....................................................43
圖23：當A因子為A1 (ph 1.2)時，B因子與C因子之交互作用圖之等高線圖(contour)....43
圖24：當A因子為A1 (ph 1.2)時，B因子與C因子之交互作用圖之3D立體圖.............44
圖25：當A因子為A2 (ph 7.4)時，B因子與C因子之交互作用圖之等高線圖(contour)....44
圖26：當A因子為A2 (ph 7.4)時，B因子與C因子之交互作用圖之3D立體圖.............45
圖27：預測值與實際值之相似因子ƒ 2 (similarity factor)檢查....................47
圖28：殘差值與預測值之相似因子ƒ 2 (similarity factor)檢查....................47
圖29：殘差值與Normal probaility之相似因子ƒ 2 (similarity factor)檢查.........48
圖30：殘差值與實驗順序之相似因子ƒ 2 (similarity factor)檢查..................48
圖31：Ramipril高壓液相層析圖譜，Lorazepam為內部標準品........................49
圖32：Ramipril 粉體之DSC圖...................................................51
圖33：Starch 1500粉體之DSC圖.................................................52
圖34：Prejel粉體之DSC圖......................................................52
圖35：Sodium Stearyl Fumarate粉體之DSC圖.....................................53
圖36：原廠膠囊粉體之DSC圖....................................................53
圖37：自製處方VII膠囊粉體之DSC圖.............................................54
圖38：Ramipril粉體、自製處方VII膠囊粉體、原廠膠囊粉體與賦型劑之DSC圖.........54
圖39：Ramipril粉體之傅立葉轉換紅外光譜圖譜...................................57
圖40：Starch 1500粉體之傅立葉轉換紅外光譜圖譜................................57
圖41：Prejel粉體之傅立葉轉換紅外光譜圖譜.....................................58
圖42：Sodium Stearyl Fumarate粉體之傅立葉轉換紅外光譜圖譜....................58
圖43：原廠處方粉體之傅立葉轉換紅外光譜圖譜...................................59
圖44：自製處方VII粉體之傅立葉轉換紅外光譜圖譜................................59
圖45：原廠藥品在人工胃液(SGF, pH=1.2)及人工腸液(SIF, pH=7.4)中之體外溶離結果.61
圖46：處方VI、VIII、IV、II在pH 1.2溶離條件下之藥品釋出溶離圖.................64
圖47：處方V、VII、I、III在pH 7.4溶離條件下之藥品釋出溶離圖...................66
圖48：Ramipril在pH 1.2的酸緩衝液下的檢量線(n=3)..............................67
圖49：原廠膠囊與自製處方VII膠囊之含量均一度(%)...............................70
圖50：貯存於25oC / 75% R.H. 之條件中原廠膠囊與自製處方VII膠囊衰變圖..........71
圖51：貯存於55oC / 75% R.H. 之條件中原廠膠囊與自製處方VII膠囊衰變圖..........72

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沈明來，實驗設計學，九州圖書文物有限公司，86年，p.175-266