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研究生:孫小玲
研究生(外文):Sun,Sheau - Ling
論文名稱:藥物之生物藥劑學研究I.Indapamide水溶液安定性之探討II.Benzonatate生體可用率之探討
論文名稱(外文):Biopharmaceutical Study on 1.Stability of Indapamide in aqueous;2.Bioequivalence Study of Benzonatate
指導教授:陳瑞龍陳瑞龍引用關係
指導教授(外文):Russel Rhei - Long Chen
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:1995
畢業學年度:83
語文別:中文
論文頁數:180
中文關鍵詞:藥品安定性衰減曲線一階次反應溫度效應生體相等性試驗軟膠囊
外文關鍵詞:Indapamidedrug stabilityArrhenius equationBenzonatatebioequivalencepseudocholinesterase
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一.Indapamide,化學名為 1-(4-Chloro-3-sulfamoyl-benzamido)-2-關 indapamide安定性的資料並不多,indapamide 具光敏感性,暴露在短波長的光線或高溫下會不安定而分解;但是若固體狀態保存於室溫則相當安定。本次的研究即探討 indapamide 在水溶液的分解動力學,以及其他外力對分解過程的影響 (pH 值、離子強度、溫度、緩衝溶液的濃度和種類)。
本研究利用高壓液相層析法來分析 indapamide 分解檢品,並以光偶列矩陣檢測器來驗證。安定性實驗結果顯示 indapamide 在各種反應條件下的分解情形是遵守擬一級反應動力學,在較高的溫度和 pH 值下indapamide 分解較快。由 Arrhenius 方程式計算而得之活化能為 12-16
kcal/mole,與一般水解反應相近。經由 ANOVA 比較,離子強度、緩衝溶
液的濃度以及種類對反應速率常數並無明顯之影響。同時其 pH-rate(log) profile 是呈現 s 形狀.
Indapamide 水溶液經酸鹼催化可產生二個產物:4-chloro-3-
sulfmoylbenzoic acid and N-amino-2-methyl-indoline,可經由 HPLC和 TLC 方法來確認。
二、Benzonatate 為一個具為局部麻醉性質,非鴉片類口服止咳藥劑.臨床上可用以減緩咳嗽的症狀。治療效果出現於口服後15-20分鐘,止咳
效果可持續3-8小時。
文獻上對於定量 benzonatate 血漿檢品的分析方法相當的少,且靈敏度不高,同時有關 benzonatate 藥物動態學的資料也付之闕如。因此在
本實驗中發展出一種可靈敏定量血中 benzonatate 的高壓液相層析法,並以此方法進行兩種 benzonatate 軟膠囊劑型的生體相等性之預試驗。
但由於其具有酯類結構,會快速被血漿中的 pseudocholinesterase 所代謝,因此改以 其代謝物 4- (butylamino) benzoic acid 做為將來評估benzonatate 生體相等性的指標。

1. Indapamide is a mild diuretic and antihypertensive agent.
It can be used for the treatment of hypertension or edema from
congestive heart failure. Data concerning the chemical stability
of indapamide are limited. Indapamide is unstable when expose to short wavelength light or high temperature. The present study
was undertaken for the indapamide degradation in the aqueous
solution and the influence of external factors (pH, buffer
concentration,ionic strength, species, temperature) on the
degradation processes.
The degradation of indapamide followed apparent first-order
reaction model at various conditions. The results indicate that
the higher pH and temperature the faster the degradation. The
Arrhenius plots indicated that the apparent activation energies
were in the range of 12-16 Kcal/mole. The ionic strength, buffer concentration and buffering species were found to not have significant effects on degradation rate constant.
Indapamide in aqueous solution was hydrolysis into two major
products: 4-chloro-3-sulfmoylbenzoic acid and N-amino-2-methyl-
indoline which can be identified by HPLC and TLC.
2. Benzonatate is a nonnarcotic oral antitussive agent with
local anesthetic properties. Its clinical application is for the
symptomatic relief of cough. The analysis of benzonatate in
plasma sample are very limited. In our study, an HPLC procedure
was established for the quantitatification of benzonatate in
plasma samples, for a subsequent bioequivalence study. In this
analysis method, benzonatate can be separated from its
metabolite and the detection limit of benzonatate in plasma
sample is 0.1 mg/l.
Due to the ester structure it is rapidly metabolized by plasma pseudocholinesterase, benzonatate was not detectable in our human blood sample. 4-(butylamino) benzoic acid, a metabolite of benzonatate , was then used as an indicator for future bioequivalence study.

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