- 學位論文
運用KollidonR SR作為藥物控釋劑之Trimetazidine Dihydrochloride基質型錠片的處方開發研究
Formulation Design for Trimetazidine Dihydrochloride Matrix Tablet Using KollidonR SR as Releasing Controller
摘要
近年來，在藥物釋放劑型 (drug release dosage form) 之研究上，改良釋放劑型 (modified release dosage form, MR) 倍受矚目，因其能達成延長藥物釋放時間的需求。 本研究中主要探討的是將心絞痛用藥Trimetazidine dihydrochloride 以基質系統 (Matrix tablet) 為骨架，製程方式為直接壓錠來製得錠片；錠劑中利用聚醋酸乙烯酯 (Polyvinyl acetate, PVA)和聚维酮 (Povidone) 所組成之適合緩釋直打錠使用之賦形劑KollidonR SR，作為改良釋放劑型中控制釋放藥物 (control releaser) 之角色，配合設計不同的處方以求達到劑型之控釋效果，並探究其釋放溶離機轉。 首先由錠劑之物理外觀及孔隙度觀察其基本特性，接著錠劑在體外溶離試驗過程中不同pH值溶離液環境下，探討藥物釋放的情形，並且以掃描式電子顯微鏡 (Scanning Electron Microscope) 觀察溶離過程前後錠劑外觀及剖面的變化進而討論藥物釋出可能之機轉。藥物釋放情形依處方中KollidonR SR及稀釋劑：微晶纖維素 (MCC-PH102，microcristalline cellulose)、無水乳糖 (lactose anhydrous)、無水磷酸氫鈣 (FujicalinR, dibasic calcium phosphate anhydrous) 之比例不同而釋放情形不一，再利用公式函數計算出之ƒ1 及ƒ2 值探討不同處方間藥物釋放情形之差異性，再挑選與市售藥品最相似的KM系列處方進行生體可用率試驗 (bioavailability study)。 本研究中發現，在直打錠中以 KollidonR SR取代傳統劑型中常用的控釋劑：具有遇水而有黏膠性特性之高分子材料 hydroxy propyl methyl cellulose (HPMC) 也具有良好的控釋效果，但是在處方之設計上對於不同賦形劑之間混合使用，在藥物釋放情形之機轉及原理之間或有差異，因此欲達到想要之控釋效果仍須考量聚合物共同混和後 (polymer combination) 之特性以期藉由處方的調配而達成控制藥品穩定釋出之目標，並使藥品達到長期釋放的效果。
並列摘要
Nowadays, the modified release dosage form has getting much more attention in researches on drug release dosage form. Prolonging drug release time is in demand of researches and selections of the modified release dosage forms. This study mainly discuss using matrix system as drug's skeleton to form the antiangina agent, Trimetazidine dihydrochloride, and the process of making the agent is by direct compression to form the tablet. KollidonR SR is a polyvinyl acetate (PVA) and povidone based matrix retarding agent. It is particularly suitable for the manufacture of sustained-release matrix tablets by direct compression, and it also is a nice drug control releaser to be used in different formulations in order to achieve the effect of controlled release dosage forms, and the study also wants to explore its release mechanism. Firstly, by observing the physical appearance and porosity degree of the tablets to understand the basic characteristics of the tablets. Secondly, during the in vitro dissolution testing, discussing drug release situation in pH 1.2 simulated gastric fluid (SGF) and pH 6.8 simulated intestinal fluid (SIF) for 12 hours. Thirdly, using the scanning electron microscope to observe the appearance and the cross–section of the tablets before and after the dissolution testing, discussed the possible mechanism of drug release. Different ratio of KollidonR SR to different diluents such as microcrystalline cellulose, anhydrous lactose and anhydrous calcium hydrogen phosphate can cause different drug release conditions. In the circumstances of different formulations, using formulas to calculate the values of ƒ1 and ƒ2, and know the differences of drug release between defferent formulations. In this study, KollidonR SR has substituted hydroxy propyl methyl cellulose (HPMC) to be the main ingredient with a good controlled release effect. Applying kinetic equation models, the mechanism of release of the drug from KM and KD formulations were found to be followed Higuchi model, which shows the formulated sustained release matrix tablets deliver the drug through a diffusion controlled mechanism. On the other hand, the mechanism of release of the drug from KL formulations were found to be followed Korsmeyer–Peppas model and the “n” value lies between n < 0.45, demonstrating that the mechanism controlling the drug release was the diffusion release. In this study, we found that KM formulations is the most similar to commercial drug VastarelR 35 mg MR (Trimetazidine dihydrochloride) in the in vitro dissolution, so we choose KM formulations and the commercial drug VastarelR 35 mg MR to be the generic drug and comparison drug in a bioavailability study (KM formulations are manufacturing in a cGMP pharmaceutical company) to see if there is correlation between in vivo and in vitro study. The controlled–release matrix tablet we developed has a better economic benefits in manufacturing by direct compession and also has a good controlled–release results in the dissolution. In order to achieve the desired controlled–release effect we can proceed with the clinical trial in the future to improve the long–term treatment of angina pectoris patient’s condition .