改良釋放劑型(modified release)除了可以維持藥品的血中濃度，還可以改善傳統立即釋放劑型(immediately release)重複投藥的不方便，而在改良釋放劑型的技術上又可分為以下三種不同的系統：基質系統(matrix system)、儲存式系統(reservoir system)以及滲透壓幫浦系統(osmotic pump system)，而本研究中所使用的藥品risperidone為一款新型結構的抗精神症藥物，而且此藥在低劑量下即可達到良好控制精神症患者或雙極性疾患之躁症患者之症狀，若能以控制藥品釋出的長效處方來使病人每天所需服用藥品次數減少，便可有效增加病人的順從性，並可減少藥品在體內濃度不穩定所可能引發之藥品副作用或因藥品體內濃度過低而產生突發性的症狀發作，而本研究中主要探討的是將risperidone以基質系統及儲存式系統為骨架來設計不同的處方以求達到長效釋放的效果，並探究其釋放溶離機轉。
本研究主要使用risperidone為模式藥物，以卡努巴蠟(carnauba wax)為基質錠劑(matrix)的處方，而儲藏式的基質包衣錠劑則加上以聚乙烯咯酮(poly-vinyl pyrrolidone; PVP)及聚乙烯醋酸鹽(poly-vinyl acetate; PVA)為原料之膜衣包覆處方並對於藥品釋放速率及機轉上的探討，以及微粒包衣控制釋放製劑(pellets)及其以羥丙基甲基纖維素(hydroxypropyl methyl cellulose; HPMC)及乙基纖維素(ethyl cellulose; EC)等為膜衣包覆後對於藥品釋出的影響以及其機轉上面的探討，並在不同的控制釋放劑型之間找出能持續且穩定的控制藥品釋放，且接近零級釋放(zero-order release)的處方。
在以基質為基礎的處方上，藉由實驗的結果可以得到欲使藥品在不同的酸鹼值中達到穩定釋放藥品的效果時，在處方內加入檸檬酸(citric acid)便可在不同的酸鹼環境中達到穩定釋放的效果，而在基質包衣系統上以PVP和PVA為成分的膜衣後，可使藥品溶離呈現穩定釋放的效果，而在以微粒包衣製劑控制藥品的釋放上，以HPMC及EC為膜衣包覆處方上可在其比例到達一定程度後，對於藥品的釋放也可達到穩定釋放的效果。
在本研究中發現，對於不同控制釋放劑型的機轉及原理之間或有差異，但是最後都能藉由處方的調配而達到控制藥品穩定釋出，並使藥品達到長期釋放的效果。 The aim of this study is to prepare and evaluate controlled release formulations for a pH dependent, slightly soluble drug by using matrix and reservoir systems. The reservoir systems studies were matrix-coating and pellet-coating systems. Risperidone, an atypical antipsychotic agent was used as a model drug. The solubility of risperidone is pH-dependent. The factors affecting drug release and release mechanism were discussed.
In matrix system, a direct compression method was used to prepare matrix tablets. The rate-controlling excipient used to prepare the matrix tablets was carnauba wax. In matrix-coating system, the tablets were coated in a perforated pan coater. Polyvinyl acetate (PVA)-povidone (PVP) blend was applied for matrix- coating membrane. The coating percentages of matrix-coating tablets were 4% and 6%. In pellet-coating system, ethyl cellulose (EC) and hydroxypropyl cellulose (HPMC) were used in membrane was rate-controlling excipient. Pellet-coating system was prepared by spray drying method using fluidized-bed apparatus granulator.
Dissolution tests were performed according to the USP paddle and basket method under 37±0.5℃ and 50 rpm in pH1.2 HCl medium or pH6.8 phosphoric medium for 24 hours. The dissolution percentages were obtained by UV detection under 277nm.
The results indicated the amounts of carnauba wax and citric acid (an acidifying agent) affect release kinetic of matrix tablets. pH independent profiles could be obtained by addition of citric acid. The profiles exhibited diffusion release kinetics when the regression analysis was performed on release percentage versus square root of time. The matrix-coating system may approach zero order when the regression analysis was performed on release percentage versus the time. In pellet- coating systems, the results demonstrated that these pellets could be used to extend drug release until 24 hours and have a stable drug release.
This study demonstrates that sustained drug release for a slightly soluble drug with pH dependent solubility can be obtained by using matrix-coating and pellet-coating systems.
