- 學位論文
利用控釋型膜衣製備多單元顆粒之脈衝式藥物傳輸系統探討
Evaluation of controlled release membrane in multiparticulate pulsatile drug delivery system
摘要
控釋劑型 (controlled release dosage form)的發展延長了藥效持續時間，進而使疾病治療的效果有所提升，而隨著更多節律性相關疾病的發現，在其容易發作的時段給予足夠的藥物濃度勢必能夠帶來更精確、有效的治療效果，因此利用脈衝式藥物傳輸系統 (pulsatile drug delivery system)來達到節律性治療 (chronotherapy)的給藥方式便被發展出來。 利用一般錠片來達到脈衝式給藥的方法為近期常被探討的題材， 但如以多單元顆粒 (multiparticulate)劑型來達到脈衝式藥物控釋效果而言，確實是較少見的；因此本研究主要探討不同含量的滲透壓物質(NaCl)之多單元顆粒劑型，改變其外層膜衣 (Eudragit® RS 30D)厚度、塑化劑 (TEC)添加量，並觀察對藥物釋放造成的影響，最後利用體外溶離試驗及掃描式電子顯微鏡探討此多單元顆粒之脈衝式藥物釋放機轉。 首先，在模式藥物選擇上為皆具有節律性治療意義之降血壓藥物 propranolol HCl以及胃酸抑制劑omeprazole basic、omeprazole sodium，利用擠壓搓圓法各製備出含4%、20% NaCl 的滲透壓物質核心圓粒(core)，且包覆上添加含量為TEC 15%、20%之四種膜衣厚度 (10、 20、30、40%)的Eudragit® RS 30D 膜衣，藉由體外溶離試驗，可以觀察出不同滲透壓物質添加量及膜衣含量比率對藥物釋放造成的影響，並利用掃描式電子顯微鏡觀察出因核心圓粒滲透壓而造成膜衣破裂之情形。 研究結果可因三種不同特性之模式藥物而分為三種趨勢，以藥物延遲釋放時間及藥物釋放速率做為脈衝式給藥的判斷基準而言，達到脈衝式藥物釋放趨勢之顯著性為：propranolol HCl > omeprazole sodium >omeprazole basic。由上述結果可以得到兩個結論，第一、利用滲透壓系統 (NaCl)配合控釋型膜衣 (Eudragit® RS 30D)是為製備多單元顆粒脈衝劑型之可行處方設計；第二、因Eudragit® RS 30D 膜衣上含有3%且帶正電之四級銨基基團，藥物釋放量即會隨著模式藥物特性的不同而改變，其中帶負電、低溶解度的omeprazole basic 會和膜衣上帶正電性的銨基產生離子交換作用而導致釋放量降低，而帶負電、高溶解度的omeprazolesodium 則為次之，最後則是帶正電、高溶解度且不與膜衣產生作用的propranolol HCl 會有最佳的藥物釋放效果；第三、在以上述膜衣處方設計的前提下，利用三種不同特性模式藥物之比較結果，其可做為以控釋型膜衣製備多單元顆粒脈衝式劑型之篩選帄台。
並列摘要
The development of controlled-release drug delivery system bringsbenefits to the treatment of diseases by prolong the duration of drug release. As the discovery of diseases with circadian rhythms, it will be more accuracy and efficiency in the treatment of such diseases when the drug is released at special time point. Therefore the concept of pulsatile drug delivery system is studied to achieve the goal of chronotherapy. It is frequently-discussed in the usage of a tablet to achieve pulsatile drug delivery system compared to the usage of the multiparticulate in recent years. The purpose of this research is to compare the drug release in different amount of osmogent inside the multiparticulate core which is coated by polymer membrane with various coating level and amount of plastizer. The mechanism of drug release is also evaluated by using the scanning electron microscopy and the dissolution test. At first, an anti-hypertension dug: propranolol HCl, two anti-acid secretion drugs with different salt forms: omeprazole basic and omeprazole sodium were chosen as model drugs. Each types of model drugs contained 4% or 20% of osmogent (NaCl) was formulated by extrusion-spheronization, and coated by Eudragit® RS 30D membrane with 15%, 20% of triethylcitrate as plasticizer at 10, 20, 30, 40% coating level. Finally, it is obvious to distinguish three different types of release patterns based on the different characteristics of model drugs by the resultof dissolution test in pH 6.8 medium and SEM. The pulsatile drug release pattern was achieved as the order of propranolol HCl > omeprazole sodium > omeprazole basic, based on the judgment of lag-time and drug release rate after a lag-time period. In conclusion, it is an applicable formulation design to combine osmotic system (NaCl) with controlled released membrane (Eudragit® RS30D) in multiparticulate pulsatile drug delivery dosage form activated by membrane rupture. Second, it is possible that there is an ion-ion interaction between Eudragit® RS 30D polymer which possess an quaternary ammonium group with positive charge. With different characteristics of : omeprazole basic, which possess negative charge and slightly soluble solubility. Omeprazole sodium, which possess negative charge and freely soluble solubility. Propranolol HCl, which possess positive charge and freely soluble solubility. Consequently, the order of pulsatile drug release pattern is: propranolol HCl > omeprazole sodium > omeprazole basic. Finally, it can be a preliminary screening tool to estimate the pulsatile drug release pattern according to the comparison of three different types of model drugs based on this formulation design.