具有降低在模擬胃腸道溶液酸鹼值影響的 Propranolol 脈衝式傳遞控釋膜系統之研發   全文下載

Development of Timely Controlled-Release Systems for Chronotherapy of Propranolol with Minimization of the pH Effect in the Simulated Gastrointestinal Medium

本研究開發具有降低藥物胃腸道時間與酸鹼值影響性之及時控釋劑型。以 Propranolol 為模式藥物與 Innopran XL 為對照商品，並將藥物直接包覆於糖蕊或以間質型材料添加滲透劑利用擠出搓圓法製備藥物圓粒，選用水不溶性乙基纖維素與速率控制非酸鹼值依賴性 Eudragit(R) RS 之聚合物材料作為控釋膜衣並包覆於藥物圓粒上。實驗結果顯示，於 Eudragit(R) RS 添加 30% 檸檬酸三乙酯且包覆量為 15% 時，其滯後時間與對照商品接近但其釋放速率較慢；而利用乙基纖維素作為控釋膜衣並添加羥丙基甲基纖維素作為塑化劑，雖未觀察到藥物有滯後時間，但其與對照商品有相似之釋放曲線。再者，利用擠壓搓圓法製備的藥物圓粒以不同包覆量的乙基纖維素添加乳糖之控釋膜衣可調整滯後時間，隨著滯後時間的增加，釋放速率減慢，比起對照商品其滯後時間更短且釋放速率更慢。換言之，以包覆不同量之 Eudragit(R) RS 作為控釋膜衣之間質型藥物圓粒，可調節脈衝式預期釋藥的滯後時間，並達成不受酸鹼值改變之及時控釋作用，然而，基於此滯後時間只在5小時範圍之內，並無法滿足臨床使用上之需求性。若添加滲透劑（氯化鈉或乳糖）於間質型藥物圓粒，並利用 Eudragit(R) RS 包覆不同量之膜衣，則能有效地延長脈衝式預期之釋藥曲線滯後時間達 15 小時且不受酸鹼值改變之時間控釋作用。預期在臨床上可滿足實際需要並降低藥物通過胃腸道時間與酸鹼值之影響性。

A timely controlled release dosage form with minimization of transit time and pH effects of gastrointestinal tract for chronotherapy of propranolol was developed. Ethylcellulose (EC) and Eudragit RS selected as the controlling membrane for drug-layering non-pareil seeds (NP) or extrusion-spheronized pellets incorporated with matrix materials or osmogents were characterized in the simulated gastric fluid (SGF) and pH change medium. Results demonstrated that when propranolol was layered on NP, Eudragit RS plasticized with 30% triethylcitrate (TEC) coated at 15% level could adjust a lag time close to the reference but with a slower release rate after then, while EC plasticized with HPMC could not delay drug release at a lag time close to the reference. Furthermore, EC incorporated with lactose coated on the extrusion-spheronized pellets could adjust the lag time, but a release rate correspondingly decreased with increasing lag time. Never-theless, coating Eudragit RS on matrix pellets as controlling membrane at different levels could adjust a desired lag time with a pulsatile release pattern. However, the lag time adjusted was only within a 5 h range. Finally, coating Eudragit RS at different level on matrix pellets containing various ratio of osmogent, NaCl or lactose, could effectively adjust a desired lag time as long as 15 h with a pulsatile release pattern to accomplish the timely controlled release with minimization of the pH effects of gastrointestinal tract that could meet the clinical need for chronotherapy of propranolol.