Time-controlled colon-specific drug delivery system is a new type of drug delivery system based on the fact that the small intestinal transit time is relatively consistent at 3-4 h and irrespective of formulation and dietary factors, which made the drugs do not release in the stomach, duodenum, jejunum, ileum front-end but release in the colon for local or systemic treatment. The model drugs for time-controlled colon-specific delivery pellets are mostly the drugs with the molecule weight higher than 500. However, for the drugs with the molecule weight less than 300 and with good aqueous solubilities, it is very difficult to realize the time-controlled release both in-vitro and in-vivo. Matrine is a hydrophilic active compound with lower molecular weight (< 300) isolated from a commonly used Chinese medicine Radix Sophorae Flavescentis, which showed anti-inflammatory, anti-bacterial, anti-allergic, sedation and immune suppression activities. In this study, the time-controlled release pellets of Matrine with a layer of rupturable coating and a layer of controlled coating were successfully prepared by fluid bed using a single-factor and central composite design and response surface method for optimization. The following parts are included in this study: 1. Determination of Matrine by HPLC. After the determination of its UV absorption spectrum, a HPLC method was developed for analysis of Matrine in-vitro. The validation results showed that this established HPLC method was simple, reliable and repeatable. 2. Optimization of fluid bed coating conditions. Amount of loaded pellets, airflow, inlet temperature, spray rate and spray pressure are main fluid bed coating parameters, by which the coating conditions of the coating materials used in preparation of Matrine coated pellets were established. The evaluations of agglomeration rate showed that the optimized coating conditions were suitable for long-time coating with good qualities. 3. Preparation of Matrine time-controlled colon-specific drug delivery pellets by a single-factor study. The single-factor study showed that although the release of drug could be reduced by a single layer coating of Surlease, but no enough lag time could be obtained. While when using HPMC as a swelling layer and Surelease as a time-controlled layer, the coated pellets could not obtain enough lag time (e.g. 5 h) and complete release after 16 h. Therefore, pellets with two layers of coating were prepared by fluid bed. The first layer was composed by the mixture of HPMC and ethylcellulose aqueous dispersion (Surelease) as the swelling and controlled release layer. The outer layer of the pellet was coated with Surelease as the time-controlled film. The optimized condition to prepare the pellets with 3-8 h delayed release is as follows: mass ratio of swelling controlled-release layer (Surelease: HPMC) = 3:1; weight gain of swelling controlled-release layer 50% and weight gain of time-controlled layer from 10% to 30%. 4. Optimization of coating pellets using response surface methodology and statistical analysis using Design-expert®. The three formulation variables studied were the amount of Surelease outer coat, amount of Surelease-HPMC inner coat, and the ratio of Surelease-HPMC inner coat. The two response variables studied were the amount of drug release in 5 h and in 16 h. Thus, the statistical design was based on three factors and two levels. The optimization region was in line with the design goals by the establishment of a quadratic polynomial mathematical model, analysis of variance, the portrayals of the effects of surface maps and contour map by contour lines overlap. In this study, coating pellets release in the line with the principle of double-layer membrane by microscope and scanning electron microscopy study. As mathematic model fitting results suggested, zero order equation could explain the drug release from Matrine delayed release pellets. The coating pellets were chemically stable in accelerated stability experiments in 3 months. However, the lag time of the drug in the pellets significantly reduced during the accelerated stability tests.

摘要 苦參城時控型結腸定位給藥微丸的製備和體外評價 徐樹明 指導老師:鄭穎 博士 中華醫藥研究院 時控型結腸定位給藥系統是根據藥物在小腸的轉運時間相對固定,約3-4小時, 受食物的影響較少,所以可利用此特點設計階段控制的藥物轉運系統,使藥物口服後 在胃、十二指腸、空腸、回腸前端不釋放,運送到回盲部後而發揮局部或全身治療 作用的一種新型定位給藥系統。目前遲釋時控給藥微丸的模型藥物絕大多數為分子 量大於500的化藥,而分子量小於300且水溶性好的藥物的時控釋藥較大分子藥物 難實現。苦參城是中藥苦參的小分子水溶性活性成分之一,分子量為248,水溶 性好,具有抗炎、抗菌、抗過敏、鎮靜、免疫抑制以及抗癌等多種藥理作用。本文 以苦參城為模型藥物,利用雙層膜控崩解原理,採用流化床包衣技術成功製備了時 控釋藥微丸,並進行單因素考察和應用星點設計-效應面法優化其處方,最後對最優 處方作了體外質量評價。 本論文主要包括以下內容: 1、苦參城的HPLC 測定方法的建立。通過測定吸收波長、排除輔料對苦參城吸 收的干擾等實驗,建立了苦參城體外含量的HPLC 測定方法,並進行了方法學考察。 2、流化床包衣工藝的優化。通過優化投料量、進風量、進風溫度、噴霧壓力等 流化床包衣參數,確定了製備苦參城包衣微丸所需包衣材料的包衣工藝。利用微丸 的粘連率評價包衣工藝,結果的微丸衣膜均勻、緻密,衣膜厚度符合要求。 澳門大學碩士學位論文 3、苦參城時控型結腸定位給藥微丸的製備和單因素考察。採用流化床包衣工 藝,選用 HPMC 和乙基纖維素水分散體 Surelease 聯用為溶脹控釋層,以 Surelease 為 時控層材料,製備雙層包衣微丸。單因素考察顯示:只有單層 Surelease 衣膜時,雖 然能夠延遲藥物釋放,但是不能滿足藥物在釋放時滯後快速釋放的要求;而以低黏 度的HPMC 作為單層溶服層,Surelease 為時控層,不能同時獲得既有5小時時滯又有 在16小時內釋放完全的效果 固定溶脹控釋層處方為Surelease: HPMC=3:1(重量比), 增重50%,通過調整外層 Surelease 時控層增重(10%~30%),可以得到3~8h 釋 放時滯的苦參城結腸定位給藥微丸。 4、運用星點設計-回應面法優化包衣微丸處方,通過 Design-expert 實驗設計軟 體進行統計分析。以時控層 Surelease 增重、溶脹控釋層 Surelease-HPMC 增重和質 量比為影響微丸釋放的三個主要因素,5h 和16 h 的藥物累積釋藥量為效應值, 進行3因素2水準星點設計。通過建立二次多項式數學模型,方差分析,描繪出效 應面圖和等高線圖。通過等高線重疊,得到符合苦參城包衣微丸釋放度設計目標的 優化區域。在優化區內隨機選擇幾個條件進行試驗驗證,實驗值與處方釋放度預測 結果相符。接著通過顯微鏡觀察微丸釋放藥物過程、掃描電鏡考察微丸的包衣質量 和數學模型擬合釋藥曲線等方法對優化後的處方進行體外評價。結果表明,本研究 製備的包衣微丸釋放藥物符合雙層膜崩解原理,經過約5h小時的釋放時滯後,苦 參城以零級動力學方式從微丸中釋放;包衣微丸在3個月的加速穩定性實驗中,藥 物外觀性狀、主藥含量無顯著變化,但釋藥時滯明顯縮短。 關鍵字:苦參城;時控;結腸定位給藥;微丸;星點設計;乙基纖維素水分散體 (Surelease)