利用溶媒揮發法製備蘭索拉唑微粒緩釋劑型之研究

Abstract

蘭索拉唑是一種質子幫浦抑制劑(proton pump inhibitor)，其作用可專一性的抑制H+/K+-ATPase，常用於治療消化性潰瘍的相關疾病。但由於本身的血中半衰期短，因此無法有效控制夜間酸突破現象(nocturnal acid breakthrough)，本研究乃以緩釋微球之處方研究尋求改善。 本實驗利用油/水溶媒揮發法製作RS-100緩釋微球，並且針對三個影響緩釋微球的因子進行評估，即均質化速度、Eudragit® RS-100的濃度及Eudragit® RS-100/蘭索拉唑比例。接著使用水/油溶媒揮發法，對RS-100緩釋微球進行第二層腸溶性膜衣包覆，並且探討硬脂酸鎂的含量和Eudragit® L100-55/緩釋微粒的比例的影響。 實驗結果顯示，在RS-100緩釋微球方面，增加均質化速度會使平均粒徑、藥品包覆率和產率降低；增加Eudragit® RS-100的濃度可使平均粒徑、藥品包覆率、藥品含量及產率增加；Eudragit® RS-100/蘭索拉唑比例與藥品包覆率及產率呈正相關，對藥品含量則是10/10與10/5相等，而大於10/1。在SEM的觀察下可看出各組緩釋微球均具有良好的球狀外觀。藉由FT-IR與DSC測定可得知，蘭索拉唑是以非結晶態物理性包覆於Eudragit® RS-100。在體外溶離試驗中，可以知道當均質速度愈小或Eudragit® RS-100濃度愈高時，蘭索拉唑的釋離速度會下降；而Eudragit® RS-100/蘭索拉唑比例提高時，釋離速度會上升，但R2000-1010會大於R2000-1005。 在雙層包覆微球的實驗方面，添加硬脂酸鎂可使平均粒徑、產率提高，而不會對藥品包覆率及藥品含量造成影響；且經由SEM可得知，加入硬脂酸鎂亦會使雙層包覆微球表面變得粗糙。增加Eudragit® L100-55/緩釋微粒的比例時，平均粒徑會上升，藥品含量會下降，但不會影響產率及藥品包覆率的大小。在體外溶離試驗可得知，雙層包覆的過程中，部分蘭索拉唑從緩釋微粒中釋放出來，因此造成雙層包覆微球釋離速率上升及累積釋離量提高。

Lansoprazole is a proton pump inhibitor which selectively inhibits H+/K+-ATPase. It is usually used for gastric ulcer diseases. However, due to its short half life in plasma, lansoprazole cannot control nocturnal acid breakthrough. This study was aimed to improve this situation by preparing sustained-release lansoprazole microparticles. In this study, the RS-100 sustained release microparticles were made by the oil/water solvent evaporation method. Three responses (homogenization rate, concentration of Eudragit®® RS-100 and Eudragit®® RS-100/lansoprazole ratio) that would affect the sustained release microparticles were further evaluated. By using the oil/water solvent method, the RS-100 sustained release micorparticles were covered with the second layer enteric coating. The content of the Mg stearate and the ratio of the Eudragit®® L100-55/RS-100 microparticles were also discussed. The result showed that increasing homogenization rate would decrease particle size, encapsulation efficiency and yield of RS-100 sustained release microparticles. Increasing concentration of Eudragit®® RS-100 would increase particle size, encapsulation efficiency, drug loading and yield. Increasing Eudragit®® RS-100/lansoprazole ratio would increase encapsulation efficiency and yield; for drug loading, the ratio 10/10 was equal to 10/5 and both larger than 10/1. The SEM micrographs showed the sustained release microparticles with good spherical shape. Based on FT-IR and DSC data, lansoprazole was physically wrapped by Eudragit®® RS-100 as non-crystal form. In vitro release showed that reduction of homogenization rate or increased in concentration of Eudragit®® RS-100, decreased release rate of lansoprazole. Increasing Eudragit®® RS-100/lansoprazole ratio would increase release rate, but R2000-1010 was faster than R2000-1005. In the study of enteric coated microparticles, adding Mg stearate would increase particle size and yield, but did not affect the encapsulation efficiency and drug loading; however, the surface of double coated microparticles became rough based on SEM micrographs. While increasing the ratio of Eudragit® L100-55/RS-100 microparticles, increased particle size and decreased drug loading, but did not affect the yield and encapsulation efficiency. According to in vitro release study, some lansoprazole was released from sustained release microparticles during the process of double coating, causing increase of release rate and cumulative release amount of drug from enteric coated microparticles.