臺灣博碩士論文加值系統

近年來已有很多研究者嘗試以聚合物為材料取代明膠(Gelatin)，作為製備膠囊的材料。這種非明膠膠囊具有提供素食人口使用及安定之優點。本研究係利用熱熔法，將Polyethylene oxide (PEO) 或 Hydroxypropyl cellulose (HPC)等材料置於加熱過的模具底模凹洞內；用模杵擠壓成形。成品可符合膠囊品質均一的要求。為測試非明膠膠囊充填藥物後的效果，體外試驗利用藥典模擬胃及腸的緩衝液及添加不同鹽類下，評估不同材質膠囊殼的吸水情形。並利用Propranolol hydrochloride或Theophylline anhydrous為模式藥，添加lactose 或microcrystalline cellulose為賦形劑之配方測試藥物的溶離率。結果顯示 Propranolol hydrochloride因溶解度比theophylline anhydrous高，因此從膠囊裡釋出後的藥物溶離釋放速率也較快。此外，藥物的釋放也較不受賦形劑的影響。藥物釋放的速率也隨著所使用的HPC的平均分子量增加而減緩。添加無機鹽類的人工胃液或人工腸液緩衝溶離液，會明顯的減緩所有HPC膠囊殼之吸水速率及藥物的釋放；但對Gelatin或PEO所製成的膠囊之影響較不顯著。進一步的體內評估，選擇紐西蘭兔進行藥物動力學探討，以theophylline anhydrous為模式藥的非明膠膠囊配方在口服之後，所獲的藥物動力學參數，顯示所有膠囊的血中濃度曲線下面積(AUC0-∞)與半衰期(T1/2)在統計上並沒有明顯的差距。體外溶離50 %所需時間及體內藥動學參數的體內/體外相關性。此外，Hydroxypropyl methylcellulose (HPMC)以沾膠法，所作成的膠囊，也明顯的受溶離緩衝液鹽類的影響。其他於體內外藥物釋放評估的結果顯示，與明膠膠囊並沒有明顯的差異。

Recent years, many scientists attempt to use polymers as materials for instead of gelatin to prepare capsules. The non-gelatin capsules showed more stable were than gelatin capsules and accept for vegetarians. In this study, hard capsule shells were made by a heat-melting method, which involved heating Polyethylene oxide (PEO) or Hydroxypropyl cellulose (HPC) powder into a mold, followed by inserting a suitable size of pestle in a mold to coat the melted shell materials (HPC or PEO) onto the pestle, and formed the capsule shells. The water uptake and dissolution test of various non-gelatin capsule shells were evaluated in either simulated gastric fluid or intestinal fluid buffer media that added one of inorganic salts including lithium chloride, sodium chloride, potassium chloride, calcium chloride or aluminum chloride. Propranolol hydrochloride and theophylline were selected as the model drugs for drug release studies. It was found Propranolol hydrochloride released from various capsules was faster than that of theophylline due to the higher solubility of the former. There were no significantly different in the release rate from the formulation containing either microcrystalline cellulose or lactose as diluents. Moreover, release rate was decreased with increasing molecular weight grades of HPC used as shell materials. Inorganic salt showed having marked influence on the dissolution rate, and that decreased with increasing concentration of salt in dissolution medium. The drug release from HPC capsules was greater affected by electrolytes than that from gelatin and PEO capsules. In vivo studies were conducted in rabbits with novel capsules and compared with gelatin capsules. It was found that the pharmacokinetic parameters included AUC0-∞ and T1/2 has showed no significantly difference among various capsules, all containing theophylline formulation. The correlation between TD50 in vitro and several parameters in vivo were established. HPMC capsule were also prepared, and its in vivo-in vitro test shows no significantly difference from the gelatin capsule.

目 錄
正文目錄………………………………………………………… Ⅱ
附表目錄………………………………………………………… Ⅳ
附圖目錄………………………………………………………… Ⅸ
中文摘要………………………………………………………… ⅩⅥ
英文摘要………………………………………………………… ⅩⅦ
正 文 目 錄
第一章 緒論 ．．．．．．．．．．．．．．．．．．．．． 1
一、膠囊劑的發展歷史．．．．．．．．．．．．．．．．． 1
二、明膠膠囊的組成與添加物．．．．．．．．．．．．．． 2
三、膠囊劑型之製造方法．．．．．．．．．．．．．．．． 4
四、非明膠膠囊及膠囊相關製程的發展．．．．．．．．．．12
五、製備膠囊所選用材料之介紹．．．．．．．．．．．．．19
六、模式藥的介紹．．．．．．．．．．．．．．．．．．．23
七、研究動機與目的．．．．．．．．．．．．．．．．．．28

第二章 PEO、HPC及HPMC膠囊製作的研究．．．．．．．．．．30
一、緒言．．．．．．．．．．．．．．．．．．．．．．． 30
二、實驗材料與設備．．．．．．．．．．．．．．．．．． 31
三、實驗方法與步驟．．．．．．．．．．．．．．．．．． 32
四、結果與討論．．．．．．．．．．．．．．．．．．．． 37
五、結論．．．．．．．．．．．．．．．．．．．．．．． 63

第三章PEO、HPC與HPMC膠囊溶離之探討
一、緒言．．．．．．．．．．．．．．．．．．．．．．． 64
二、實驗材料與方法．．．．．．．．．．．．．．．．．． 65
三、結果與討論．．．．．．．．．．．．．．．．．．．．．．．．．． 69
四、結論．．．．．．．．．．．．．．．．．．．．．．． 102

第四章 藥物在PEO、HPC與HPMC膠囊的藥物動力學研究．．．．103
一、緒言．．．．．．．．．．．．．．．．．．．．．． ．103
二、實驗材料、方法與分析確效．．．．．．．．．．．．． 105
三、結果與討論．．．．．．．．．．．．．．．．．．． 115
四、結論．．．．．．．．．．．．．．．．．．．．．．． 152

總結論．．．．．．．．．．．．．．．．．．．．．．．． 153
參考文獻．．．．．．．．．．．．．．．．．．．．．．． 154
研究成果．．．．．．．．．．．．．．．．．．．．．．． 161
附 表 目 錄
第一章 緒論
表1-1 一般軟膠囊的體積、形狀及應用．．．．．．．．．．．．．．． 10

第二章 PEO、HPC及HPMC膠囊製作的研究
表2-1 HPMC膠囊殼配方．．．．．．．．．．．．．．．．． 35
表2-2 以不同溫度製作PEO 200K膠囊殼之硬度(N) ．．．．． 38
表2-3 以不同溫度製作HPC 80K膠囊殼之硬度(N) ．．．．．．40
表2-4 以不同溫度製作HPC 100K膠囊殼之硬度(N) ．．．．． 41
表2-5 以不同溫度製作HPC 370K膠囊殼之硬度(N) ．．．．． 43
表2-6 於80 ℃下以不同壓力製作PEO 200K膠囊殼的頂端
厚(mm) ．．．．．．．．．．．．．．．．．．．．．46
表2-7 於135 ℃下以不同壓力製作HPC 80K膠囊殼的頂端
厚度(mm) ．．．．．．．．．．．．．．．．．．． 47
表2-8 於140 ℃下以不同壓力製作HPC 100K膠囊殼的頂端
厚度(mm) ．．．．．．．．．．．．．．．．．．．．47
表2-9 於180 ℃下以不同壓力製作HPC 370K膠囊殼的頂端
厚度(mm) ．．．．．．．．．．．．．．．．．．．．48
表2-10 Gelatin、PEO及HPC膠囊的帽長及厚度．．．．．．． 51
表2-11 Gelatin、PEO及HPC膠囊的身長及厚度．．．．．．． 52
表2-12 不同HPMC配方膠囊帽的長度及厚度．．．．．．．．．53
表2-13 不同HPMC配方膠囊帽的長度．．．．．．．．．．．．54
表2-14 Gelatin、PEO及HPC膠囊膠囊之重量均一度．．．．． 56
表2-15 不同HPMC配方膠囊之重量均一度．．．．．．．．．．56
表2-16 Gelatin、PEO及HPC膠囊之硬度．．．．．．．．．． 58
表2-17 不同HPMC配方膠囊之硬度．．．．．．．．．．．．．58
表2-18 Gelatin、PEO及HPC膠囊之透光度．．．．．．．．． 60
表2-19 不同HPMC配方膠囊之透光度 (%)．．．．．．．．．．60
表2-20 Gelatin、PEO及HPC膠囊之含水量．．．．．．．．． 62
表2-21 不同HPMC配方之膠囊的含水量．．．．．．．．．．．62

第三章 HPC、PEO與HPMC膠囊溶離之探討
表3-1 Gelatin、PEO與HPC膠囊殼在人工胃液(pH=1.2)或分別
添加不同鹽類之吸水飽和所需的時間．．．．．．．． 70
表3-2 Gelatin、PEO與HPC膠囊殼在人工腸液(pH=6.8)或分別
添加不同鹽類之吸水飽和所需的時間．．．．．．．． 71
表3-3 Propranolol HCl分別以Lactose、Avicel和Magnesium
stearate 組成配方充填於HPC 80K膠囊於人工胃液或腸液下
的溶離圖．．．．．．．．．．．．．．．．．．．． 74
表3-4 Theophylline添加Lactose、Avicel和Magnesium stearate
組成配方充填於Gelatin、PEO或HPC膠囊劑於人工胃液(pH
1.2)或人工腸液(pH6.8)的溶離數．．．．．．．．．．75
表3-5 Theophylline添加Lactose和Magnesium stearate組成配方充
填在HPMC 配方A或B膠囊於人工胃液(pH 1.2)或人工腸液
(pH6.8)的溶離參數．．．．．．．．．．．．．．．．82
表3-6 一般人體腸胃道的離子濃度．．．．．．．．．．．． 85
表3-7 Theophylline添加Lactose和Magnesium stearate組成配方
充填於Gelatin、PEO 200K、HPC 80K、HPC 100K及HPC
370K膠囊膠囊於添加不同鹽類的人工胃液(pH 1.2)之溶
離參數(n=6)．．．．．．．．．．．．．．．．．．．86
表3-8 Theophylline添加Lactose和Magnesium stearate組成配方
充填於Gelatin、PEO 200K、HPC 80K、HPC 100K及
HPC 370K膠囊膠囊於添加不同鹽類的人工腸液(pH 6.8)之溶
離參數．．．．．．．．．．．．．．．．．．．．． 87

第四章 藥物在HPC、PEO、HPMC膠囊的藥物動力學研究
表4-1文獻中於家兔體內Theophylline之藥動學參數．．．．．103
表4-2 文獻中以HPLC定量Theophylline之系統條件及檢品前處理．．．．．．．．．．．．．．．．．．．．．．．．．． 104
表4-3 實驗兔子重量表．．．．．．．．．．．．．．．．． 109
表4-4 對照標準血漿檢品之製備表．．．．．．．．．．．． 111
表4-5 Theophylline之定量極限．．．．．．．． ．．．．．101
表4-6 Theophylline之回收率．．．．．．．．．． ．．．．102
表4-7 同日確效．．．．．．．．．．．．．．．．．．．． 103
表4-8 異日確效．．．．．．．．．．．．．．．．．．．． 104
表4-9 於25 ℃度下之安定性．．．．．．．．．．．．．．．105
表4-10 -20 ℃度下的安定性．．．．．．．．．．．．．．．106
表4-11 儲存液的安定性．．．．．．．．．．．．．．．．．107
表4-12 連續解凍之安定性．．．．．．．．．．．．．．．．108
表4-13 含Theophylline之Gelatin膠囊劑，餵食家兔後，血漿中
Theophylline的濃度．．．．．．．．．．．．．．．129
表4-14 含Theophylline之PEO 200K膠囊劑，餵食家兔後，血
漿中Theophylline的濃度 ．．．．．．．． ．．．．130
表4-15 含Theophylline之HPC 80K膠囊劑，餵食家兔後，血漿中
Theophylline的濃度．．．．．．．．．．．．．．．131
表4-16 含Theophylline之HPC 100K膠囊劑，餵食家兔後，血漿中
Theophylline的濃度．．．．．．．．．．．．．．．132
表4-17 含Theophylline之HPC 370K膠囊劑，餵食家兔後，血漿中Theophylline的濃度．．．．．．．．．．．．．．．．．． 133
表4-18 含Theophylline之HPMC A配方膠囊劑，餵食家兔後，血漿中Theophylline的濃度．．．．．．．．．．．．．．．．．．．134
表4-19 含Theophylline之Gelatin膠囊劑，餵食家兔後，Theophylline．．．．．．．．．．．．．．．．．．．．．．135
表4-20含Theophylline之PEO 200K膠囊劑，餵食家兔後，Theophylline的藥動學參數．．．．．．．．．．．．．．．．136
表4-21 含Theophylline之HPC 80K膠囊劑，餵食家兔後，Theophylline的藥動學參數．．．．．．．．．．．．．．．．137
表4-22 含Theophylline之HPC 100K膠囊劑，餵食家兔後，Theophylline的藥動學參．．．．．．．．．．．．．．．．．138
表4-23 含Theophylline之HPC 370K膠囊劑，餵食家兔後，Theophylline的藥動學參數．．．．．．．．．．．．．．．．139
表4-24 含Theophylline之HPMC A配方膠囊劑，餵食家兔後，Theophylline的藥動學參數．．．．．．．．．．．．．．．．140
表4-25 含Theophylline之膠囊劑，個別餵食家兔後，Theophylline的藥動學參數之平均值．．．．．．．．
141
附 圖 目 錄
第一章 緒論
圖1-1 1999年Suzuki 等以泡泡法製作無縫膠囊的設備．．．．14
圖1-2 Vilivalam V. D.等之射出成型機器之裝置圖．．．．．15
圖1-3 Mehuys E.等之熱熔擠壓法的裝置圖．．．．．．．．．16
圖1-4 接枝聚合物結構圖．．．．．．．．．．．．．．．． 18
圖1-5 Hydroxypropyl cellulose的結構圖．．．．．．．．．19
圖1-6 Hydroxypropyl methylcellulose結構圖．．．．．．．20
圖1-7 鹿角菜膠結構圖．．．．．．．．．．．．．．．．．．．．．．．．．． 21
圖1-8 結冷膠結構圖．．．．．．．．．．．．．．．．．．．．．．．．．． 22
圖1-9 Propranolol HCl結構圖．．．．．．．．．．．．．．．．．．．．．．．．．． 23
圖1-10 Theophylline anhydrous結構圖．．．．．．．．．．25

第二章 PEO、HPC及HPMC膠囊製作的研究
圖2-1 熱熔法模具實物圖．．．．．．．．．．．．．．．． 32
圖2-2 硬膠囊製作步驟圖．．．．．．．．．．．．．．．． 33
圖2-3 膠囊實物圖．．．．．．．．．．．．．．．．．．． 37
圖2-4 以不同溫度製作PEO 200K膠囊殼之硬度與溫度關係圖． 39
圖2-5 以不同溫度製作HPC 80K膠囊殼之硬度與溫度關係圖．．40
圖2-6 以不同溫度製作HPC 100K膠囊殼之硬度與溫度關係圖． 42
圖2-7 以不同溫度製作HPC 370K膠囊殼之硬度與溫度關係圖． 44
圖2-8 以不同製作膠囊溫度與膠囊殼硬度的關係圖．．．．． 45
圖2-9 施以不同壓力所製作膠囊殼頂端之厚度關係圖．．．． 49

第三章 HPC、PEO與HPMC膠囊溶離之探討
圖3-1 Propranolol HCl分別以Lactose、Avicel和Magnesium stearate組成配方充填於Gelatin膠囊於人工胃液或腸液下的溶離圖．．．．．．．．．．．．．．．．．．．．．．．．．． 76
圖3-2 Propranolol HCl分別以Lactose、Avicel和Magnesium
stearate組成配方充填於PEO 200K膠囊於人工胃液或
腸液下的溶離圖．．．．．．．．．．．．．．．．．．．． 76
圖3-3 Propranolol HCl分別以Lactose、Avicel和Magnesium
stearate組成配方充填於HPC 80K膠囊於人工胃液或腸液下的溶離圖．．．．．．．．．．．．．．．．．．．．．．．．．．77
圖3-4 Propranolol HCl分別以Lactose、Avicel和Magnesium
stearate組成配方充填於HPC 100K膠囊於人工胃液或腸液下的溶離圖．．．．．．．．．．．．．．．．．．．．．．．．．．77
圖3-5 Propranolol HCl分別以Lactose、Avicel和Magnesium
stearate組成配方充填於HPC 370K膠囊於人工胃液或腸液下的溶離圖．．．．．．．．．．．．．．．．．．．．．．．．．．78
圖3-6 Theophylline分別以Lactose、Avicel和Magnesium stearate
組成配方充填於Gelatin膠囊於人工胃液或腸液下的溶
離圖．．．．．．．．．．．．．．．．．．．．．．．．．78
圖3-7 Theophylline分別以Lactose、Avicel和Magnesium stearate
組成配方充填於PEO 200K膠囊於人工胃液或腸液下
的溶離圖．．．．．．．．．．．．．．．．．．．．．．．79
圖3-8 Theophylline分別以Lactose、Avicel和Magnesium stearate
組成配方充填於HPC 80K膠囊於人工胃液或腸液下的溶離圖．．．．．．．．．．．．．．．．．．．．．．．．．．79
圖3-9 Theophylline分別以Lactose、Avicel和Magnesium stearate
組成配方充填於HPC 100K膠囊於人工胃液或腸液下
的溶離圖．．．．．．．．．．．．．．．．．．．．．．．80
圖3-10 Theophylline分別以Lactose、Avicel和Magnesium stearate
組成配方充填於HPC 370K膠囊於人工胃液或腸液下
的溶離圖．．．．．．．．．．．．．．．．．．．．．．．80
圖3-11 Theophylline分別以Lactose和Magnesium stearate組成
配方充填於HPMC 配方A膠囊於人工胃液與人工腸液下的溶離圖．．．．．．．．．．．．．．．．．．．．．．．．． 83
圖3-12 Theophylline分別以Lactose和Magnesium stearate組成
配方充填於HPMC 配方B膠囊於人工胃液或人工腸液下的溶離圖．．．．．．．．．．．．．．．．．．．．．．．．．．83
圖3-13 Theophylline添加Lactose和Magnesium stearate組成配
方充填Gelatin膠囊於添加不同鹽類的人工胃液下之溶離圖．．．．．．．．．．．．．．．．．．．．．．．．．．88
圖3-14 Theophylline添加Lactose和Magnesium stearate組成配
方充填Gelatin膠囊於添加不同鹽類的人工腸液下之溶
離圖．．．．．．．．．．．．．．．．．．．．．．．．．89
圖3-15 Theophylline添加Lactose和Magnesium stearate組成配
方充PEO 200K膠囊於添加不同鹽類的人工胃液下之
溶離圖．．．．．．．．．．．．．．．．．．．．．．．．90
圖3-16 Theophylline添加Lactose和Magnesium stearate組成配
方充填PEO 200K膠囊於添加不同鹽類的人工腸液下
之溶離圖．．．．．．．．．．．．．．．．．．．．．．． 91
圖3-17 Theophylline添加Lactose和Magnesium stearate組成配
方充填HPC 80K膠囊於添加不同鹽類的人工胃液下之
溶離圖．．．．．．．．．．．．．．．．．．．．．．．． 92
圖3-18 Theophylline添加Lactose和Magnesium stearate組成配
方充填HPC 80K膠囊於添加不同鹽類的人工腸液下之
溶離圖．．．．．．．．．．．．．．．．．．．．．．．．93
圖3-19 Theophylline添加Lactose和Magnesium stearate組成配
方充填HPC 100K膠囊於添加不同鹽類的人工胃液下
之溶離圖．．．．．．．．．．．．．．．．．．．．．．．94
圖3-20 Theophylline添加Lactose和Magnesium stearate組成配
方充填HPC 100K膠囊於添加不同鹽類的人工腸液下
之溶離圖．．．．．．．．．．．．．．．．．．．．．．．95
圖3-21 Theophylline添加Lactose和Magnesium stearate組成配
方充填HPC 370K膠囊於添加不同鹽類的人工胃液下之溶離圖．．．．．．．．．．．．．．．．．．．．．．．．．．96
圖3-22 Theophylline添加Lactose和Magnesium stearate組成配
方充填HPC 370K膠囊於添加不同鹽類的人工腸液下
之溶離圖．．．．．．．．．．．．．．．．．．．．．．．97
圖3-23 於不同的離子強度下之人工胃液中，Gelatin、PEO 200K、HPC 80K、HPC 100K及HPC 370K膠囊劑的溶離50 %所需時間關係圖．．．．．．．．．．．．．．．．．．．．．．．．．．98
圖3-24 於不同的離子強度下之人工腸液中，Gelatin、PEO 200K、HPC 80K、HPC 100K及HPC 370K膠囊劑的溶離50 %所需時間關係圖．．．．．．．．．．．．．．．．．．．．．．．．．．99
圖3-25 Theophylline以lactose當賦形劑充填於A配方膠囊於添加0.1 M KCl 的人工胃液或腸液下的溶離圖．．．．．．．．．101

第四章 非明膠膠囊的生體可用研究
圖4-1 Theophylline、β- Hydroxyethyltheophylline在家兔血漿中之高效液相層析圖(HPLC)圖．．．．．．．．．．．．．． 117
圖4-2 在血漿中Theophylline的檢量線．．．．．．．．． 118
圖4-3 含Theophylline之Gelatin膠囊劑，餵食家兔後，個別血漿中
theophylline之濃度半對數曲線圖．．．．．．．． 142
圖4-4 含Theophylline之PEO 200K膠囊劑，餵食家兔後，個別血漿
中theophylline之濃度半對數曲線圖．．．．．．． 143
圖 4-5 含Theophylline之HPC 80K膠囊劑，餵食家兔後，個別血漿
中theophylline之濃度半對數曲線圖．．．．．．．144
圖4-6 含Theophylline之HPC 100K膠囊劑，餵食家兔後，個別血漿
中theophylline之濃度半對數曲線圖．．．．．． ．145
圖 4-7 含Theophylline之HPC 370K膠囊劑，餵食家兔後，個別血漿
中theophylline之濃度半對數曲線圖．．．．．．．146
圖4-8 含Theophylline之HPMC A配方膠囊劑，餵食家兔後，個別血
漿中theophylline之濃度半對數曲線圖．．．．． 147
圖4-9 含Theophylline之不同膠囊劑，分別餵食家兔後，血漿中
theophylline之濃度曲線圖．．．．．．．．．．． 148
圖4-10 含Theophylline之不同膠囊劑，分別餵食家兔後，血漿中
theophylline之濃度半對數曲線圖．．．．．． ．．149
圖4-11 Theophylline充填於各種膠囊中體外溶離50%與體內吸收50%
所需平均時間的相關圖．．．．．．．．．．．．．151

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