| 摘要: | 在製藥時由於製造方式所加的賦形劑及儲存時的環境因素(如：光照、溫度、濕度、氧氣…等)，都可能使藥物產生各種物理化學之變化並可能使藥物產生各類不純物，這些不純物有其不容忽視的潛在危險，因而藥物之安定性議題漸受重視。在本實驗所用到的藥物為fluvastatin。由之前的文獻可知statin類藥物在光照之下會產生降解。故本實驗主要目的在了解fluvastatin在不同的耐受性試驗情況下的分解變化，並探討在製作控制釋放劑型後不同的處方配製對fluvastatin化學安定性的影響。
本實驗共分成兩部分，第一部份的耐受性試驗包括使用0.1N HCl之酸性試液，0.1N NaOH之鹼性試液，3% H2O2之氧化試液，以及在黑暗中隔水加熱至80℃和使用UV光照試驗。第二部份的實驗為評估控釋處方上的設計對安定性之影響。共有四種處方，分別為添加酸性、鹼性和氧化賦形劑之處方，及以使用不添加任何酸鹼賦形劑之處方做對照，並探討製作錠劑及儲存於60℃，75%RH下及各項製造過程等對fluvastatin可能造成之不純物。本實驗中分析方法乃採用高效能液相層析儀(HPLC)配合紫外光(UV)偵測儀作為主要分析儀器。
第一部分耐受性試驗的結果與文獻相呼應：在UV光照之下會有降解之情形，其共有三支主要的降解片段。在酸性試液下，其亦具有三支波峰出現。在高溫之下也會有產生降解，且降解片段具相近的滯留時間。在鹼性試液和氧化試液中相對較安定，幾乎沒有變化。由第二部份研究結果得知萃取混合之過程不會使主成分和不純物增減；經由製備錠劑之後主成分會有1~4%之增減，而在不純物之部分則與耐受性試驗之結果具一致性。錠劑經包覆膜衣後進行24小時光照試驗，得知包覆添加阻光劑之膜衣材質的錠劑確實能夠使錠劑免於光照之降解反應。而由溶離試驗可得知添加鹼性賦形劑之處方錠劑具有較快之藥物溶離，而添加酸性賦形劑之處方錠劑，其溶離則較慢。但不論添加酸或鹼性質之賦形劑，其在加速試驗後皆具有溶離之安定性。
綜合以上實驗結果得知fluvastatin在酸及光照之下較易降解，因此在製作劑型時必須注意添加阻光劑及膜衣材質並避光，此外應避免使用酸性的賦型劑，以增加其固體藥物製劑的安定性。
During the storage process of drug substances and/or drug products, the chemical structure integrity may vary with time under the influence of different factors such as acid, base, temperature, humidity, oxygen, light, as well as excipients. These factors may result in chemical impurities due to degradation of bulk drugs, causing potential pharmacological problems that cannot be ignored.
The present work will focus on investigating the degradation behavior of fluvastatin in various stress conditions and in its controlled-release formulations. Previous studies showed that statins were easily transformed in water by photo irradiation. Literature results also indicated that statins were sensitive to acid stress.
In the first part of the experiment, fluvastatin solutions were subjected to oxidation (in 3% H2O2), acid (in 0.1N HCl), alkaline (in 0.1N NaOH), photolysis (UV at 254 nm) and heat (on a bath water at 80◦C, in the dark) in stressed conditions. A reverse phase high performance liquid chromatographic (HPLC) method with UV detection was developed to study the stability of fluvastatin. The second part of the experiment was to evaluate the stability profile of fluvastatin in its controlled-release formulations. Four formulations were studied: formulation with acid excipient, formulation with alkaline excipient, and formulation with excipient having oxidization potential. The experiment also evaluated possible impurities during the manufacturing of tablets and its preservation under two weeks of 60◦C, 75%RH conditions. The dissolution stability for the four formulations was also studied.
The result of the first experiment agreed with previous studies that fluvastatin was degraded by photo-irradiation in water when exposed to UV. Under 0.1N HCl, three degradation peaks appeared after the active ingredient. Degradation was also seen under heat stress. Fluvastatin was found to be more stable under alkaline and oxidative stress conditions. From the result of the second experiment, the process of mixing and extracting did not significantly change the amount of the active ingredient and impurities. Through tablet compression, active ingredient changed 1~4%, while the impurities were consistent to the impurities after heat stress. For coated tablet after UV irradiation for 24 hours, the tablets with TiO2 in HPMC-based coating may decrease the degradation caused by photo-irradiation. The dissolution study demonstrated that the dissolution was faster for tablets with alkaline excipient, and the dissolution was slower when acid excipient was added. The dissolution was stable for all formulation after the accelerated stability studies.
In summary, the stability profiles of fluvastatin and its controlled-release formulations were studied. The results suggest that, since fluvastatin can easily degrades under acid or lighting environment, acidic excipients should be avoided; TiO2 in HPMC-based coating should be also added to prevent photodegradation of fluvastatin tablets. |
