| 摘要: | 藥物控制釋放技術擁有眾多優點，如：治療效果的增進、方便性、增加病患對藥物的耐受度及藥物毒性減少等，這些都將有助於醫療品質的提高。為達上述目的，藥物製劑配方及技術對藥物釋放影響之各項研究便相當重要。而對任何個別藥物製劑而言，在藥物的原料、製造時所添加的賦形劑以及藥物儲存的環境都可能使藥物產生各種物理及化學變化。然而上述各變化中皆可能造成不同種類的不純物，而這些不純物對療效及安全性均可能造成影響。所以在製劑研發中應致力於減少不純物之生成以免造成不良反應及危害。
本實驗使用phenyltriazine類的抗癲癇藥物 Lamotrigine作為一模式藥物，以了解各種儲存環境因素對Lamotrigine的分解變化。此外，也製備Lamotrigine與不同比例高分子之處方製劑，以探討在製劑中不同比例高分子對Lamotrigine釋放之影響；並探究不同特性賦形劑對Lamotrigine控釋製劑化學安定性的影響。
本研究主要分為以下三個部份來進行，首先利用0.1N HCl之酸性試液，0.1N NaOH之鹼性試液，0.3% H2O2之氧化劑試液，以及黑暗中隔水加熱至75℃和使用UV光照來對模式藥物Lamotrigine做虐待性試驗；第二部份為擬定不同高分子總量及不同比例的HPMC K4M及K100LV，利用溶離試驗研究其於不同pH媒液中之釋放變化；第三部份為Lamotrigine於控釋處方中，分別添加酸性、鹼性及氧化的賦形劑，並將處方錠劑儲存於60℃，75% RH，兩週及40℃，75% RH，3個月後，來探究Lamotrigine於各個處方中可能造成之降解變化。
在第一部份的研究結果中，顯示在鹼性的條件下，Lamotrigine會有顯著之降解情形產生，而在酸性、氧化、光照及加熱的環境下比鹼性條件較為安定。由第二部份的結果可得知高分子之總量及比例均會影響溶離的速率，且當高分子總量增加，其溶離速率減慢；而HPMC K4M的比例增加則溶離速率減緩。第三部分，在製劑中分別添加酸、鹼及氧化賦型劑於配方後，發現加入鹼性的賦型劑之製劑，其主成分會產生裂解現象，此結果和第一部份之發現相吻合。
由以上結果得知模式藥物Lamotrigine在不同環境之安定性。因此在製劑配方上應減少或避免鹼性賦形劑的使用。且在製劑中對於高分子的種類及比例之選擇上可對高分子做適當調整，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。
Controlled drug delivery technology has many advantages, such as improve effectiveness, convenience and reduce side effects. It also helps to improve quality of life. In order to obtain optimum formulation to ensure efficacy and safety profiles, the effect of formulation variables on drug release and stability are crucial.
Lamotrigine, an phenyltriazine antiepileptic drug, is used in the present study, as the model drug to evaluate its stability in various stressed environment (such as: light, temperature, oxygen ... and so on). Moreover drug formulations with different polymer amount and ratios were designed to evaluate their effects on drug release as well as chemical stability.
This study is divided into three parts. First we use 0.1N HCl, 0.1N NaOH, 0.3% H2O2, 75℃heat and UV light to perform the lamotrigine stress test. In the second part, the release profiles for formulations with different amount of total polymer and K4M/K100LV ratios are tested using dissolution apparatus. In the third part, the stability of lamotrigine controlled release formulations added with acid, alkaline and oxidative excipients were stored in 60℃, 75% RH for two weeks and 40℃, 75% RH for three months to test chemical stability.
The results show that lamotrigine degradation was minor in acidic, oxidation, light and heated condition whereas more degradation was observed in alkaline condition. Increased the total polymer amount and K4M/K100LV ratio may decrease dissolution rate. Finally, for the acidic, alkaline, oxidative excipients, the alkaline excipient may affect the lamotrigine chemical stability, which is consistent with the stressed results.
The above results have clearly demonstrated that, in order to obtain optimum efficacy and safety profiles of lamotrigine controlled release formulations, appropriate polymer amount and ratio should be used; alkaline excipients should also be avoided to ensure its chemical stability. |
