臺灣博碩士論文加值系統

Rosuvastatin calcium主要治療作用是減少動脈血管粥樣硬化之形成，由抑制膽固醇在肝臟內合成的速率限制步驟HMG – CoA reductase而降低血中的膽固醇，產生降血脂作用；其化學式為Bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl (methyl-sulphonyl) amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt，文獻上指出Rosuvastatin經陽光照射後，會轉化為多環化合物而降解。
本研究評估改善Rosuvastatin calcium的安定性方法為Rosuvastatin calcium分別與不同胺基酸混合，進行安定性分析，以不同的比例(1:1、1:2、1:4)放置於不同的溫度(75℃、100℃)下，比較不同胺基酸對Rosuvastatin的影響，並與文獻中所使用過的穩定化劑，如Anhydrous calcium hydrogen phosphate、Magaldrate、Silicon magnesium aluminate、Magnesium hydroxide、Calcium acetate及抗氧化劑Butylated hydroxyanisde做比較、。
本研究以HPLC來執行安定性試驗評估，HPLC分析方法經由安定性分析方法確效(Stability-Indicating Method，SIM)，此法是依行政院衛生署的現行藥品優良製造規範—分析確效作業指導手冊之方法執行。利用不同酸鹼度、氧化條件、高溫、光照及確效方法(系統適應性、直線性、專一性、準確度)進行分析。結果證實HPLC分析方法適合執行Rosuvastatin tablet的安定性試驗。
在此安定性分析方法確效(Stability-Indicating Method，SIM)中發現Rosuvastatin calcium在酸性環境下降解較明顯 ﹔在照光及加熱後的樣品粉末會有呈淡黃色的變色反應。Rosuvastatin calcium之SIM定量分析方法確效，在Rosuvastatin calcium 之濃度在83.5~124.8 l/ml 之間時，得其相關係數 R² = 0.9999，顯示濃度與波峰面積之間具有良好線性關係。
成品Crestatinâ tablets分別存放在25℃、30℃、40℃及75℃下在不同時間測量其含量，從動力學觀點可判斷為一階反應，並推得其藥品在25℃下的有效期限分別為253.3294月，因此，預估其架儲期為2年以上。
成品Crestatinâ tablets溶離試驗安定性，比較貯存於不同溫度之錠劑在不同媒液 (pH 6.6 Buffer及0.1 N HCl)中進行溶離試驗，依據FDA所提出之Scale-UP and Post-Approval Changes(SUPAC)統計手法，進行體外溶離曲線之比對。本研究是採用相似因子f2 (similarity factor)及相異因子f1(difference factor)進行比對。結果顯示其f1值及f2值都在合格範圍內，表示溶離度不受貯存時間與溫度的影響。
本研究乃藉由混合之安定性預試驗選擇穩定化劑，因此來推定安定的錠劑處方。從研究數據得知鹼基質胺基酸，L-Lysine 和 L-Tyrosine，對Rosuvastatin而言是具有防的穩定降解化劑。

Rosuvastatin calcium, bis [(E)-7 [4-(4-fluorophenyl)-6 isopropyl- 2-[methyl (methyl-sulphonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxyhept-6-enoic acid] calcium salt, was approved by the US FDA in August 2003 to reduce cholesterol levels in patients with hypercholesterolaemia. This agent is a selective, potent and competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalizing the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in cholesterol biosynthesis. In the literature, the Rosuvastatin calcium degraded after sun exposure. The major degradation products are the corresponding (3R, 5S) lactone and an oxidation product in which the hydroxy group adjacent to the carbon-carbon double bond is oxidized to a ketone functionality.
In this study, we developed a Rosuvastatin calcium bioequivalent product to stabilizing this compound by using different amino acid with different proportions (1:1, 1:2, 1:4) for stability test at different temperatures (75℃, 100 ℃). The stability test results were compared with different stabilizing agents which literature reported in the past including Anhydrous calcium hydrogen phosphate, Magaldrate, Silicon magnesium aluminate, Magnesium hydroxide, and Calcium acetate.
The amount of this compound was quantified by means of a validated high-performance liquid chromatography (HPLC) method with a C -18 column. The Stability-Indicating method validation (SIM ) requires to force decomposition studies under a variety of conditions, such as pH, light, oxidation, dry heat, and separation of drug from degradation products. The method validation criteria, system suitability, linearity, specificity, and accuracy, are reported according to the current Taiwan Department of Health, Good Manufacturing Practices guideline. The method was proved to support analysis of Rosuvastatin tablet and its degradation products.
The SIM results showed that the Rosuvastatin calcium compound had higher degradation rate under the acidic environment, and samples powder showed a yellow discoloration reaction under the sunlight and heating. Rosuvastatin calcium SIM quantitative analysis method validation obtained the correlation coefficient R² = 0.9999 at concentration linear range in the 83.5 ~ 124.8 l / ml.
The finished products, Crestatin® tablets, were stored at 25℃( 60 % ± 5% RH), 30℃( 65 % ± 5 % RH ), 40℃( 75 % ± 5 % RH) and 75℃( 75 % ± 5 % RH ) and analyzed samples at different storage times. The results showed a first-order kinetic degradation reaction and the predict expiration date was 253.3294 months at 25℃. Therefore, the shelf life of finished products is more than 2 years.
The stability dissolution test of Crestatin® tablets was conducted by comparing in different temperatures storage and different media solution (pH 6.6 Buffer or 0.1 N HCl) according to FDA Scale-UP and Post-Approval Changes (SUPAC) statistical methodology to carry out in-vitro dissolution curve ratio comparison. The dissolution curve factors are the similarity factor f2 and difference factors f1 for comparison. The results showed that the f1 value and f2 value were within the acceptable range, indicating that the dissolution rate was independent of temperature and storage times.
In this study, we tried to mix different amino acids to develop a stable formulation. Based on the results, it was found that some amino acids, L-Lysine and L-Tyrosine, containing more basic functional groups, were able to stabilize Rosuvastatin compounds.

中文摘要 I
Abstract III
誌謝 VI
表次目錄 IX
圖次目錄 XIII
壹、緒論 1
貳、文獻回顧 5
一、高血脂之治療劑簡介 5
二、Statin類簡介 5
三、Rosuvastatin之基本概述 7
五、胺基酸簡介 10
參、材料與儀器設備 15
ㄧ、實驗材料(Materials) 15
二、實驗儀器設備(Apparatus) 17
肆、實驗方法 18
一、Rosuvastatin calcium之安定性分析方法確效(SIM)研究 18
(二) Rosuvastatin calcium之定量分析方法的分析方法確效 19
(三) Rosuvastatin calcium在不同環境下之降解反應 23
二、Rosuvastatin calcium添加不同比例胺基酸之安定性研究 25
三、Rosuvastatin calcium溶離試驗--UV方法之確效 27
四、Rosuvastatin calcium錠劑之安定性分析方法 31
伍、結果 36
一、Rosuvastatin calcium之安定性分析方法確效(SIM)研究 36
二、Rosuvastatin添加不同比例胺基酸之研究 48
三、Rosuvastatin calcium--UV方法之確效 57
四、Rosuvastatin calcium錠劑之有效期限估算 73
五、Rosuvastatin calcium 溶離試驗 76
陸、討論與結論 99
柒、參考文獻 102

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