| 摘要: | 近年來，口服固體劑型可藉由控制釋放之配方設計以改良藥物之釋放及吸收。藥物控制釋放製劑雖具有多項之優點，但因其釋放之機轉較一般製劑更為複雜，所以藥物製劑配方與製程技術對於藥物釋放影響之各項研究顯得相當重要。本實驗使用常用之氫離子幫浦抑制劑之藥物Lansoprazole (蘭索拉唑)作為模式藥物，主要研究內容分六個部份，第一部份利用0.0001N HCl之酸性試液，0.01N NaOH之鹼性試液，0.5% H2O2之氧化劑試液，以及黑暗中隔水加熱至60℃和使用UV光照來對模式藥物Lansoprazole做耐受性試驗；第二部份針對製程放大，探討最佳之製程條件。第三部份探討不同腸溶包衣厚度之微粒或錠劑在酸環境下的藥物破壞、釋放之程度。第四部份則在研究錠劑硬度高低對藥物釋放情形及對脆度、崩散的關係，以篩選出合適之參數。另添加不同比例之崩散劑，以了解其對藥物崩解、釋放速率之影響。第五部份乃對噴霧工程之活性層，比較在添加不同比例之介面活性劑Tween 80下，測試其對藥物釋放速率之關係。第六部份，針對不同包材包裝後之成品進行加速安定性試驗，分別儲存於60℃，75% RH兩週及40℃，75% RH兩個月後，探究Lansoprazole於不同包材中可能造成之降解變化，並利用溶離度試驗，評估對藥物溶離速率的影響。在第一部份的研究結果中，顯示在鹼性或光照環境下較為安定，而在酸性、加熱或氧化的環境下，Lansoprazole會有顯著之降解情形產生。第二部份的結果可得知最佳之噴霧參數，此噴霧參數在溫度、風量、流速、霧化大小適當調整後，其噴霧過程可產生較少的黏附及聚集。第三部分結果顯示，當腸溶包衣愈厚時，藥物在酸中之釋放愈少，藥物在酸保護效果愈佳。在第四部份中，對於口崩錠之硬度，發現硬度愈高，崩散時間愈慢，而脆度則隨著硬度愈高愈好；反之，硬度若愈低，崩散則變快，但脆度愈差。另對於崩散劑測試，以添加5%之Sodium Starch Glycolate (SSG)藥物在整體之釋放速率最高。在第五部份結果顯示，添加2.5%之Tween 80藥物於製程或釋放速率皆可達較佳之效果，過多或不添加，均無法達成製程之便利及增加藥物釋放。第六部份，我們發現無論使用那種包材包裝，其加速安定性試驗皆符合規範。由以上結果得知模式藥物Lansoprazole在不同環境之安定性。因此在製劑配方上應減少或避免使用酸性賦形劑及高溫製程，並減少空氣接觸。且在製劑中選擇適當之腸溶包衣厚度，口崩錠之硬度，崩散劑、介面活性劑之運用調整，來達到理想的藥物釋放速率，以增進藥物之安全性及有效性。
In recent years, oral controlled - release dosage forms are studied extensively to improve the drug release and absorption. Pharmaceutical controlled release formulation has many advantages, however, due to release mechanism is relatively complex, the studies of formulation and process technique become very important. In the present study, a frequently used PPI - lansoprazole is used as a model drug; This study is divided into six parts. First, several stress conditions of 0.0001N HCl, 0.01N NaOH, 0.5% H2O2, 60℃heat and UV light are used to perform the lansoprazole forced degradation tests. The second part is focused on the scale up process in order to reduce the levels of agglomerates during the enteric coating. The third part is to explore the effect different enteric coating thickness on the release percentage in the acid resistance test. The fourth part, is to evaluate the effect of compression on dissolution behavior, tablet friability and disintegration. The fifth part is to test the dissolution behavior for the active layer after the addition of tween 80. The sixth Part is to evaluate the stability profiles after the different packaging configuration, stored at 60℃, 75% RH for two weeks and 40℃, 75% RH for two months.The results show that lansoprazole degradation was minor in alkaline and light condition whereas more degradation was observed in acidic, heated and oxidation condition. The optimum spray parameters obtained from the second part may reduce the adhesion and aggregation. From the third part, when enteric coating increased, the formulations have more acid resistance and slower dissolution. The fourth part shows that, when increase the hardness, the disintegration time becomes longer, but may result in better friability. For disintegrating agents tested, the 5% concentration of sodium starch glycolate have the highest drug release rate. The fifth part of the results demonstrate that the addition of 2.5% Tween 80 result in faster dissolution rate and acceptable process. Finally, in both package material including PTP and bottle, stability test are in compliance with acceptable specifications.The above results show that to obtain optimum formulation and process, we should reduce or avoid the use of acidic excipients, high process temperature, and high air exposure. To select the appropriate thickness of the enteric coating, tablets hardness, disintegrating agents, surface active agents are also important in order to achieve the desired drug release rate and to improve the safety and effectiveness . |
