目前常見的藥物製劑以口服劑型最為廣泛被使用，而口服控釋製劑中又以間質性系統 (Matrix system) 與貯藏式系統(Reservoir system) 這兩種機轉最常被用來製備控制釋放之製劑。因此本研究中將應用此兩種系統來製備高水溶性鹽類藥物的控制釋放錠劑，並進一步探討影響藥物釋放的可能因素以及藥物釋放機轉。
本研究中所使用的模式藥物為檸檬酸鉀，臨床上常用來治療腎結石。在間質性系統方面，是使用巴西棕櫚蠟(Carnauba wax)來作為控釋材質，並以乾式造粒法及直接打錠法來製備疏水性間質錠劑。錠劑的硬度控制在8-10 kg/cm2。在貯藏式系統方面，乃使用不同乙基纖維素(Ethylcellulose, EC)/羥丙基甲基纖維素(Hydroxypropylmethylcellulose, HPMC)比例之高分子，來執行疏水性間質錠劑的膜衣包覆，使製備成2%、4%和6%(w/w)膜衣包覆率之錠劑。溶離試驗之方法乃是依據美國藥典(USP)的槳式(paddle)模式(900 ml溶離液，37 ± 0.5℃和50 rpm的轉速)。檸檬酸鉀的含量分析方面是使用原子吸收光譜儀(Atomic absorption spectrophotometer)。
對疏水性間質錠劑而言，增加巴西棕櫚蠟(Carnauba wax)和潤滑劑的使用量，或是降低檸檬酸鉀的顆粒大小，皆會降低藥物溶離的速率，而製備錠劑方法及製程的改變也會影響藥物的溶離速率。在藥物釋放機轉方面，疏水性間質錠劑之藥物釋放百分比和時間的平方根成正比(R2=0.9986)，且釋放後的錠劑表面及內部均有釵h孔洞產生，因此由上述線性回歸及觀察的結果中可得知，疏水性間質錠劑中其釋放機轉，主要為藥物藉由溶解後經擴散的方式，通過錠劑中疏水性基質間的裂縫或孔洞而釋放出來。
對包衣型間質錠劑而言，藥物的釋放受到乙基纖維素和羥丙甲纖維素之比率以及包覆膜衣的重量百分比所影響，當增加膜衣中乙基纖維素的含量或是包覆膜衣的重量百分比時，均會降低藥物的釋放速率。在藥物釋放機轉方面，包衣型間質錠劑其藥物釋放百分比和時間成正比(R2=0.9974)，且釋放前或釋放後的錠劑表面皆有一層完整膜衣包覆住，因此由上述線性回歸及觀察的結果中可得知，包衣型間質錠劑其藥物釋放的機轉，主要是藉由藥物溶解後經擴散通過控釋膜衣的方式釋放出來。
由上述研究內容顯示，應用間質性系統(Matrix system) 以及貯藏式系統(Reservoir system)的方式來製備具有控制釋放效果的口服檸檬酸鉀製劑是確實可行的。 Matrix and reservoir systems are commonly used in manufacturing controlled release dosage forms. The objective of this study is to prepare and evaluate release characteristics of controlled-release tablets based on matrix and matrix-coating systems for a highly soluble salt. The release mechanism and factors affecting drug release are also studied.
The model drug, potassium citrate, is used clinically to treat nephrolithiasis. The controlling material used in matrix tablets was carnauba wax. Both dry granulation and direct compression methods were utilized to prepare lipophilic matrix tablets. The hardness of tablets were controlled within 8-10 kg/cm2. For the matrix coating, the controlling polymers were different ratios of Ethylcellulose (EC) and Hydroxypropylmethylcellulose (HPMC). Coating percentages (w/w) of lipophilic matrix tablets were 2%, 4% and 6%. Dissolution tests were performed according to the USP paddle method (900 ml medium, 37 ± 0.5℃ and 50 rpm). Potassium citrate concentrations were determined using atomic absorption spectrophotometer.
For matrix tablets, the results indicate that drug release rates can be decreased by increasing amount of carnauba wax and lubricant, or by reducing particle size of drug. Manufacturing process/methods also affect drug release rate. When the regression analysis was performed on release percentage versus square root of time, the relationship exhibit excellent diffusional release kinetics (R2=0.9986). From the regression analysis and image observations, drug diffusion through channels/pores and cracks of the lipophilic matrix is the predominant mechanism in controlling drug release. For matrix-coating systems, the results indicate that drug release rates can be decreased by increasing amount of EC and coating percentage. When the regression analysis was performed on release percentage versus time, the profiles exhibit excellent zero-order release kinetics (R2=0.9974). From the above regression analysis and image observations, drug diffusion through the film coating of tablets is the predominant mechanism in controlling drug release. The study demonstrates controlled release of potassium citrate is feasible using matrix and matrix-coating systems.
