臺灣博碩士論文加值系統

Lansoprazole是有效的氫離子幫浦抑制劑，但對水的溶解度不佳。為了改善lansoprazole的水溶性，將lansoprazole與HPβCD製備形成複合物，並評估溶液態和固態的複合物性質。由相溶解度圖可知在pH 8和pH 10的媒液中，lansoprazole呈現AL型式相溶解度圖，顯示lansoprazole與HPβCD以1: 1的比例形成複合物；pH 12的媒液中，lansoprazole呈現BS 型式相溶解度圖，顯示lansoprazole與HPβCD形成緊密結合的複合物，使lansoprazole的溶解度降低。冷凍乾燥法製備之lansoprazole和HPβCD複合物以DSC和FT- IR進行評估，結果顯示兩者形成複合物。
將lansoprazole製備口服投予腸溶圓粒劑型以避免受胃酸破壞。以伍斯特式流動床機器製備腸溶圓粒。將糖蕊依序包覆上藥層、底衣層和腸衣層。經耐酸性試驗發現腸衣層厚度須佔圓粒的總重量30 % 以上，才能抵抗胃酸的破壞。由溶離結果發現，藥層處方中添加HPβCD可以增加lansoprazole的溶離釋出率。安定性試驗結果顯示處方中的賦形劑，例如HPβCD、PVP K30、talc可與lansoprazole配伍而不會產生交互作用。

Lansoprazole is an effective proton pump inhibitor, but it is a poor-
solubility drug. Inclusion complexes between lansoprazole and hydroxyl- propyl- β- cyclodextrin ( HPβCD ) were prepared to improve the solubility of lansoprazole and evaluated in aqueous environment and in solid state. From the phase solubility study results, lansoprazole showed AL type phase solubility in pH 8 and pH 10 medium, demonstrating the formation of 1: 1 stoichiometric inclusion complexes. Lansoprazole showed BS type phase solubility in pH 12 medium, and the decreasing of solubility was caused by the tightly combination between lansoprazole and HPβCD. The inclusion complexes made by lyophilization were evaluated by DSC and FT- IR spectroscopy, and the results indicated that lansoprazole and HPβCD could form inclusion complexes.
Lansoprazole enteric- coated pellets for the oral administration were developed in order to avoid gastric degradation. The coating processes were accomplished by Wurster type fluidized bed coating machine. The nonpareils were coated with drug, subcoating and enteric coating solution subsequently. Gastric resistance test showed that the enteric coating amount of pellets should be great than 30 % of total weight, and lansoprazole would not be degraded by acid. The dissolution profiles showed that the addition of HPβCD in drug- coating solution improved apparently the dissolution rate of lansoprazole. Stability test results indicated that HPβCD, PVP K30 and talc were compatible with lansoprazole, and they did not interact with lansoprazole.

目錄
表次目錄----------------------------------------------------------------------I
圖次目錄--------------------------------------------------------------------III
中文摘要---------------------------------------------------------------------VI
英文摘要--------------------------------------------------------------------VII
本文
壹、緒論----------------------------------------------------------------------1
貳、實驗目的-----------------------------------------------------------------32
參、材料與儀器設備-----------------------------------------------------------33
肆、實驗方法
ㄧ、高效能液相層析儀（HPLC）分析方法
(一) HPLC之層析條件---------------------------------------------36
(二) 檢量線之製作-------------------------------------------------36
(三) 定量方法之確效
1. 同日內精密度----------------------------------------------37
2. 異日間精密度----------------------------------------------37
二、Lansoprazole- HPβCD包嵌複合物之製備及其溶解度之探討
(一) Lansoprazole- HPβCD包嵌複合物之製備
1. 相溶解度試驗 ( Phase solubility studies )-------------38
2. 以冷凍乾燥方法製備lansoprazole – HPβCD固態包嵌複合物---------41
(二) Lansoprazole- HPβCD包嵌複合物物理性質之檢測
1. 示差掃描熱分析（DSC）-----------------------------------42
2. 傅立葉轉換紅外光譜儀分析（FT- IR）------------------42
三、Lansoprazole腸溶圓粒之製備
(一) 藥層、底衣層、腸衣層包覆液製備方法
1. 藥層（Drug layer）包覆液之製備-------------------------43
2. 底衣層（Subcoating）包覆液之製備----------------------43
3. 腸衣層（Enteric- coating）包覆液之製備----------------43
(二) Lansoprazole 腸溶圓粒之包衣（coating）流程-----------49
(三) 自製腸溶圓粒之評估
1. 自製腸溶圓粒之藥物含量分析--------------------------52
2. 自製腸溶圓粒之腸衣層厚度試驗 (耐酸性試驗)-----52
3. 體外溶離試驗-----------------------------------------------52
4. 掃描式電子顯微鏡-----------------------------------------53
(四) 市售品與自製腸溶圓粒之安定性試驗-------------------54
(五) 市售品及自製腸溶圓粒( lansoprazole 延遲釋放膠囊)之藥物釋放( Drug release )
分析
1. 酸階段之藥物釋放分析----------------------------------54
2. pH 6.8緩衝液之藥物釋放分析--------------------------55
伍、結果與討論
ㄧ、藥品之定量分析
(一) HPLC 分析方法
1. 檢量線製作-------------------------------------------------56
2. 同日內與異日間精密度----------------------------------56
二、Lansoprazole- HPβCD包嵌複合物之溶解度研究
(一) 相溶解度試驗-------------------------------------------------59
(二) 示差掃描熱分析----------------------------------------------63
(三) 傅立葉轉換紅外光譜儀分析-------------------------------65
三、自製腸溶圓粒之評估
(一) 不同處方之腸溶圓粒耐酸試驗之探討-------------------69
(二) 體外溶離試驗-------------------------------------------------71
(三) 掃描式電子顯微鏡 ( SEM )分析--------------------------76
四、安定性試驗------------------------------------------------------------82
五、Lansoprazole 延遲釋放膠囊(delayed- release capsules) 之
藥物釋出分析--------------------------------------------------------89
陸、結論---------------------------------------------------------------------91
柒、參考文獻-----------------------------------------------------------------93

表次目錄
表1 Lansoprazole在n- octanol和水之間的分配係數-------------------3
表2 環糊精及其衍生物之物理化學性質----------------------------------9
表3 甲基丙烯酸共聚合物的分類------------------------------------------20
表4 流動床機器優缺點之比較---------------------------------------------28
表5 不同酸鹼值緩衝液與不同莫耳濃度的HPβCD之組合配方----40
表6 處方1藥層、底衣層、腸衣層包覆液之配方組成-----------------44
表7 處方2藥層、底衣層、腸衣層包覆液之配方組成-----------------45
表8 處方3藥層、底衣層、腸衣層包覆液之配方組成-----------------46
表9 處方4藥層、底衣層、腸衣層包覆液之配方組成-----------------47
表10 處方5藥層、底衣層、腸衣層包覆液之配方組成---------------48
表11 處方1至處方5藥層、底衣層及腸衣層之流動床操作條件----51
表12 同日內精密度分析------------------------------------------------------58
表13 異日間精密度分析------------------------------------------------------58
表14 Lansoprazole於不同酸鹼值的緩衝液與不同莫耳濃度的HPβCD媒液中之溶解度----62
表15 Lansoprazole 在相溶解度圖中，其截距、斜率、安定常數及相關係數----------62
表16 市售品與處方4中不同腸溶性膜衣重量百分比的圓粒，於0.1 N HCl媒液中，2小時
後，藥物之剩餘含量、剩餘百分比與釋出百分比------------------------------70
表17 Lansoprazole 市售品及自製處方之腸溶圓粒的溶離累積百分率( % )-----------73
表18 市售品圓粒，在40 ℃, 75 % RH下，經3個月安定性試驗後的藥物含量( mg )-----83
表19 含有39 %腸溶性膜衣之處方1的圓粒，在40 ℃, 75 % RH下，經3個月安定性試驗後的
藥物含量( mg )--------------------83
表20 含有19 %腸溶性膜衣之處方4的圓粒，在40 ℃, 75 % RH下，經3個月安定性試驗後的
藥物含量( mg )--------------------83
表21 含有34 %腸溶性膜衣之處方4的圓粒，在40 ℃, 75 % RH下，經3個月安定性試驗後的
藥物含量( mg )--------------------84
表22 含有38 %腸溶性膜衣之處方5的圓粒，在40 ℃, 75 % RH下，經3個月安定性試驗後的
藥物含量( mg )--------------------84
表23 安定性試驗90天，lansoprazole 市售品及自製處方之腸溶圓粒的溶離累積百分比
( % )---------------------------------------86
表24 Lansoprazole 延遲釋放膠囊在酸階段試驗的藥物釋出百分比------------------90
表25 Lansoprazole 延遲釋放膠囊在pH 6.8溶離媒液試驗的藥物釋出百分比----------90

圖次目錄
圖1 Lansoprazole結構---------------------------------------------------------1
圖2 溶液的pH值和lansoprazole分解速率常數之關係-----------------4
圖3 溶液的pH值和lansoprazole溶解度之關係---------------------------4
圖4 Lansoprazole作用機轉---------------------------------------------------6
圖5 β-環糊精之化學結構式(a)與中空圓筒狀之環形結構(b)----------8
圖6 環糊精-阿斯匹靈之包嵌複合物--------------------------------------11
圖7 流動床之基本設備------------------------------------------------------23
圖8 傳統式流動床機器構造------------------------------------------------24
圖9 伍斯特式流動床機器構造---------------------------------------------26
圖10 離心式流動床機器構造------------------------------------------------27
圖11 膜衣形成過程與形成機制---------------------------------------------29
圖12 腸溶圓粒藥層、底衣層及腸衣層包覆液之包覆流程------------50
圖13 Lansoprazole各濃度與面積比值之校正曲線---------------------57
圖14 Lansoprazole ( 70 μg / mL ) 與內部標準品n-propyl benzene
( 500 μg / mL) 之HPLC層析圖---------------------------------------57
圖15 溶解度典型等溫線圖---------------------------------------------------61
圖16 Lansoprazole在不同酸鹼值緩衝液與不同莫耳濃度HPβCD
媒液中之溶解度圖-----------------------------------------------------61
圖17 示差掃描熱分析圖譜 ( a ) lansoprazole；( b ) HPβCD；( c )
物理混合；( d ) lansoprazole- HPβCD包嵌複合物---------------64
圖18 Lansoprazole之傅立葉轉換紅外線圖譜---------------------------67
圖19 HPβCD 之傅立葉轉換紅外線圖譜--------------------------------67
圖20 Lansoprazole與HPβCD物理混合粉末之傅立葉轉換紅外線圖譜------------------68
圖21 由冷凍乾燥法製備lansoprazole- HPβCD包嵌複合物之傅立葉轉換紅外線圖譜-----68
圖22 處方4中不同腸溶性膜衣重量百分比 ( 25、29、34 %) 圓粒之溶離曲線圖--------70
圖23 Lansoprazole 市售品及自製處方之腸溶圓粒的溶離累積百分比( % )-----------74
圖24 處方5腸溶圓粒在pH 7.2與pH 6.8溶離媒液中的溶離曲線圖---------------------75
圖25 處方5腸溶圓粒進行溶離試驗，檢品於溶離後立即分析與溶離2小時後分析的溶離
曲線圖--------------------------------------75
圖26 糖蕊表面之SEM照片-------------------------------------------------77
圖27 包覆藥層圓粒表面之SEM照片-------------------------------------78
圖28 包覆底衣層膜衣圓粒表面之SEM照片-----------------------------78
圖29 包覆腸溶性膜衣圓粒表面之SEM照片----------------------------79
圖30 市售品腸溶圓粒表面之SEM照片-----------------------------------79
圖31 市售品腸溶圓粒橫切面之SEM照片( 100倍)---------------------80
圖32 市售品腸溶圓粒橫切面之SEM照片( 500倍)--------------------80
圖33 自製腸溶圓粒橫切面之SEM照片( 100倍)-----------------------81
圖34 自製腸溶圓粒橫切面之SEM照片( 500倍)-----------------------81
圖35 不同處方之腸溶圓粒在40 ℃, 75 % RH下，經3個月安定性試驗後的藥物含量( mg )- --------------------------------------------85
圖36 市售品腸溶圓粒與貯存90天後之溶離曲線圖--------------------87
圖37 處方1腸溶圓粒與貯存90天後之溶離曲線圖-------------------87
圖38 處方4腸溶圓粒與貯存90天後之溶離曲線圖-------------------88
圖39 處方5腸溶圓粒與貯存90天後之溶離曲線圖-------------------88

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