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研究生:劉宛昀
研究生(外文):WanYun Liu
論文名稱:Captopril小兒使用臨場調製方法最適性之探討
論文名稱(外文):Study on optimal extemporaneous compounding method for pediatric use of captopril
指導教授:高純琇高純琇引用關係
指導教授(外文):ChurnShiouh Gau
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:臨床藥學研究所
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:2002
畢業學年度:90
語文別:中文
論文頁數:104
中文關鍵詞:臨場調製小兒使用
外文關鍵詞:captoprilextemporaneouscompoundingpediatric
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Captopril為一血管收縮素轉化抑制劑,亦為小兒高血壓及心臟衰竭等疾病治療用主要藥物之一。因缺乏適合小兒使用的劑型,國內醫療院所一般以磨粉分包方式,提供小兒病人使用。本研究擬藉由captopril的簡易水溶液劑型的安定性試驗結果,評估以臨場製備成水溶液劑型的方式提供captopril小兒使用的可行性,並且建立一個正確的使用方法以及使用期限,以提供病人有效且安全的給藥途徑。
本實驗為探討溶劑、儲存溫度、及光照條件對captopril水溶液安定性的影響,因此,依Factorical設計將實驗分成8種組合進行captopril水溶液安定性之試驗。實驗所用之溶劑為冷開水或滅菌注射用水;儲存溫度為攝氏4度或攝氏25度;以及儲存環境避光與否。取用captopril錠劑(25 mg/tab)將之配製成濃度1 mg/mL或0.5 mg/mL的水溶液,依實驗分組儲存於各條件下,並在實驗的第0、1、3、5、7、10、14、21及28天時,以HPLC方法測定水溶液中captopril及captopril disulfide的含量,以評估其化學性安定性。在實驗過程,同時對水溶液之物理學及微生物學之安定性作記錄與評估。
在進行的三個批次安定性實驗結果,在化學安定性的實驗結果顯示,置於冷藏儲存之captopril水溶液其captopril含量於儲存14∼28天,仍可維持起始含量的90 %以上;captopril disulfide的相對含量也大多低於3 %。另外,藉由評估儲存期間水溶液之外觀及氣味,也顯示在冷藏儲存有相當良好的物理學安定性。至於在微生物安定性方面,室溫儲存的組別在10天內並無肉眼可見的微生物生長,然而冷藏儲存則可維持至少28天的安定性。綜合而論,若是經由緊密加蓋且置於冷藏儲存,captopril水溶液經由10天儲存時,其各方面的安定性皆相當良好。不過,在臨床使用時,則建議採較保守的估計,而將captopril水溶液之使用期限定為7天。
  另外,為模擬病人或其家屬居家自行配製captopril水溶液的情境,進行了配製captopril水溶液過程中,量測配製水溶液體積或是取藥量時誤差大小的探討。在量測配製水溶液體積方面,由11位受試者使用塑膠瓶量測50 mL水,藉稱重來評估量測誤差大小。結果顯示,在同一人或是不同人之間以量測塑膠瓶配製水溶液體積之誤差皆低於2 %。而在給藥時取量誤差大小的探討,則是由15位受試者使用量杯倒取5 mL水,由稱重結果作評估取量誤差大小。其結果顯示,在同一人的取量變異係數約為1.86∼10.03 %,不同人之間取量的變異係數則為4.77 %。而且15位受試者中,有4位取量之變異係數大於6 %。其他11位則低於6 %,綜合所有可能誤差,大致仍可控制在15 %以內。此結果和文獻中提到小兒劑量磨粉分包之重量差異或含量變異係數可高致30 %以上相比較,臨場調配captopril水溶液的方式應能提供較一致的劑量準確性。
  由以上結果,可知captopril水溶液,配製或是儲存上皆相當方便,使用前若經明確的病患教育,告知病人或其家屬正確的配製方式及服用藥量,並強調冷藏儲存以確保安定性,應是有其臨床使用之可行性,可提供藥事服務的參考。而且,本研究應也可提供一個檢討藥事服務品質保證的模式。

Captopril, an angiotensin converting enzyme inhibitor, is often used to treat hypertension and congestive heart failure in pediatric patients. Because there is no suitable dosage form of captopril for pediatric use, providing compounding service for divided powders for pediatric patients has been considered as a required service in most of the health care institutions in Taiwan.
Through this study, stability studies of captopril solution would be used to evaluate the plausibility of clinical use of extemporaneously prepared oral captopril solution. The aim is to establish an accurate procedure and beyond-use date of captopril solution to provide an effective and safe extemporaneous preparation for pediatric patients.
This study was designed to investigate factors that may affect the stability of captopril solution, such as solvent, storage temperature and light. Therefore, there were eight combinations of different captopril solution preparations and storage conditions using a 23 factorial study design. Captopril aqueous solutions of 1 mg/mL or 0.5 mg/mL were prepared and stored in plastic bottles at 4℃ or 25℃, and protected from light or not based on the study design. Samples were taken out from these storage conditions after 0, 1, 3, 5, 7, 10, 14, 21 and 28 days to assay captopril and captopril disulfide contents by a stability-indicating high performance liquid chromatography method. Physical and microbiological stabilities were also evaluated during study period.
The results of study revealed that captopril contents in samples stored in the refrigerator and protected from light were higher than 90 % for 14 to 28 days, and relative content of captopril disulfide in most samples were lower than 3 %. The appearance and odor of captopril solutions were recorded, and the results showed that samples were physically stable under a refrigerator condition during storage period. The captopril solutions was microbiologically stable for 28 days when refrigerated, and for 10 days when stored at 25℃. To summarize, captopril solutions stored in tightly closed container and in the refrigerator were stable for 10 days. A conservative “beyond-use date” of 7 days was suggested when captopril solution was used clinically.
In order to simulate the patients or their family members while preparing captopril solution at home, a study was designed to observe the variation of the preparations. The variation of preparing solutions was evaluated through pouring water into a graduated plastic bottle up to the 50-mL scale. Eleven people had participated in this study. The results indicated that intra-subject or inter-subject variations were found to be lower than 2 %. The variation of sampling volume was also evaluated through pouring 5-mL water in a graduated plastic cup. Fifteen people had participated in this study. It was found that the intra-subject variations were 1.86 to 10.03 % and the inter-subject variation was 4.77 %.
From this study, it is concluded that captopril solution is easily prepared and stored. In conjunction with an appropriate and clear patient education about the accurate preparation and measuring procedure for captopril solution, the design from the study can be applied clinically for pediatric patient usage. Most importantly, captopril solution should be refrigerated to ensure its stability. This study also provides an evaluation model for quality assurance for pharmacy practice.

第一章 前言..............................................1
第二章 文獻探討..........................................4
 第一節 調製藥品之介紹及相關法規規定....................4
 第二節 小兒用藥之調製..................................9
 第三節 藥品安定性之簡介................................18
第三章 研究目的..........................................22
第四章 材料與方法 ........................................23
 第一節 材料............................................23
 第二節 研究方法........................................25
第五章 結果..............................................37
 第一節 分析方法之確效..................................37
 第二節 Captopril錠劑單位劑量含量均一度試驗.............45
 第三節 Captopril水溶液劑安定性試驗.....................48
 第四節 人為之溶液配製及取量誤差........................75
第六章 討論..............................................80
第七章 結論..............................................96
參考文獻.................................................101

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