口腔崩散製劑的研究

1. 口腔崩散製劑的研究 • 口腔崩散製劑是一種固體製劑，可在口腔內藉由唾液的渗入作用，於數十秒內崩散或溶解開來。它最主要的效果是促進患者口服藥品的便利性，尤其是某些族群的病患，如老人或嬰幼兒等，往往因為吞嚥藥物不易，使得病人的順從性較差，影響治療效果。本篇論文主要以一般錠劑所使用的功能性材料，來組成一組可以達到前述口腔崩散效果的錠劑。首先各以Lactose granule及Lactose monohydrate作基劑，輔以崩散劑Croscarmellose Na、Low-substituted Hydroxypropyl cellulose (L-HPC)，潤滑劑Magnesium Stearate、Talc、Sodium Dodecyl Sulfate (SDS)、結合劑Polyvinylpyrrolidone (PVP)來組成錠劑配方，混合後以單沖模油壓計，以100kg/cm2壓製成直徑10mm的圓形雙平面錠劑，其後分別測量硬度及崩散時間，從其中挑選表現較佳的材料，進一步組成實驗設計的方式，來求取最佳化的處方比例及條件。在實驗變數PVP比例、L-HPC比例、壓錠力比例各為5-15%，10-30%，50-110 kg/cm2，來壓製出口腔崩散劑試製品。經由上述過程，可得到一組5%PVP，20% L-HPC，及60 kg/cm2壓錠力的參數條件，符合較高的硬度 4.3±0.3 kg 及較短的崩散時間6.0±1.0 秒，而流動性之安息角為42°。同時進一步測試人體口腔內的崩散時間約為0.5至1.5分鐘之間，先不以水或以水潤溼口腔時平均崩散時間分別為77±12及58±17秒。而後以naloxone HCl作為小分子模式藥品，可以得到較快的溶離速率，即於2分鐘內釋放80% 的藥品，高於一般錠劑在10分鐘方可釋放80%。另進行有熱分析試驗，顯示naloxone HCl與PVP、lactose monohydrate有較大之交互作用，而與talc、L-HPC則不明顯。綜合前述之各項實驗，可以藉由一般賦型劑的材料：lactose monohydrate，L-HPC，talc，PVP來製成口腔崩散錠，得到較高硬度、較快崩散效果外，也使得溶離速率提昇很多。日後可進一步藉由不同的模式藥品，來進行更多的應用試驗。

2. Study of Orally Disintegrating Tablet • The purpose of this study is to develop a orally disintegrating tablet (ODT) , which disintegrating or dissolving in oral cavity within one minute without drinking water, then swallowing the suspension or dissolved liquid. The ODT dosage form provides convenience to reduce the difficult of swallowing tablets and hard gelatin capsules for the elderly and children, increasing the compliance and therapeutic effect. First, lactose granule、lactose monohydrate、 croscarmellose Na、low-substituted hydroxypropylcellulose(L-HPC) LH-11、magnesium stearate、talc、Sodium Dodecyl Sulfate (SDS) and Polyvinyl-pyrrolidone (PVP) K-30, were used to formulated a effective ODT by 100 kg/cm2 compression force. Crushing strength and disintegrating time were evaluated to estimate proper excipients for a candidate ODT. The three main factors of L-HPC (10-30%), PVP (5-15%) and compression force (50-110 kg/cm2) were evaluated by central composite design (CCD). The optimal value was observed for crushing strength, disintegrating time and angle of repose, 4.3±0.3 kg, 6.0±1.0 seconds and 42 degree, respectively, under the parameters of 40mg L-HPC, 10mg PVP and 60 kg/cm2 compression force. In addition, the disintegrating time in oral cavity were between 0.5-1.5 min (average 77±12, 58±17 seconds without and with water) in seven volunteers. Furthermore, naloxone HCl (MW 363.84) were formulated as small molecules model drug of ODT. Apparently, naloxone ODT release faster ( 80% released within 2min) than conventional tablet (80% released within 10min) by dissolution apparatus. Differential scanning calorimetry (DSC) revealed that naloxone HCl and PVP, lactose monohydrate had significant interaction. In conclusion, a proper ODT can be formulated by lactose monohydrate, L-HPC, talc, PVP. The ODT appeared enough hardness, shorter disintegrating time and fast release rate than conventional tablet.