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研究生:康吳維
研究生(外文):Wu-Way Kang
論文名稱:用熱熔融包覆法製備聚己內酯微球之研究
論文名稱(外文):Studies on Poly(ε-Caprolactone) Microparticles Prepared by Hot-melt Encapsulation Technique
指導教授:林文貞
指導教授(外文):Wen-Jen Lin
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:158
中文關鍵詞:聚己內酯微球熱熔融包覆法
外文關鍵詞:MicroparticlesPoly(ε-Caprolactone)Hot-melt Encapsulation Technique
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在近二十年來的藥劑學發展上,由於新聚合物的發明與製劑方式的演進,利用微包覆技術來製備新一代的遞送系統因而被廣泛地研究,例如:運用生分解性聚合物包藥製成微粒控釋劑型。根據新劑型的特性來改進藥物原本的療效,可使病人服藥次數降低、副作用減小。然而,微包覆技術的製備過程卻相當繁瑣且需有機溶劑去溶解聚合物,反而進一步造成環境的污染。
本實驗的目的在研發簡易製備微球劑型的方法。選擇聚己內酯作為包覆藥品的聚合物,並配合聚己內酯低融點的特性而採用熱熔融包覆法來製備微球,所包覆的藥品是美洒辛。
熔融包覆法的優點在於製備過程簡易且可以完全避免使用有機溶劑,將聚己內酯與藥品置於65℃水浴鍋中加熱至呈熔融態時,運用探針式超音波打碎機於短時間內作均質化處理,而後冷凝可得微球。實驗設計在改變外相與界面活性劑的種類,並調整藥品初始添加量、超音波打碎機功率與微球粒徑,以冀得一種高產率與高包覆率的微球劑型。
在掃描式電子顯微鏡下,經由熱熔融包覆法製備出的微球呈現圓形、光滑、無孔洞的球體外觀,也無嚴重的凝聚現象產生,以產物重量分率來區分,粒徑主要集中在250~420 mm,以(油為外相/界面活性劑L61)的微球產率與包覆率為83.18 %與26.17 %,而以(水為外相/界面活性劑PVA)的微球產率與包覆率可增加至91.15 %與91.39 %。此外,經由高性能液相層析法與示差掃描熱分析儀的分析結果顯示,熱熔融包覆法並不會對藥物安定性造成的影響。在體外溶離實驗中,美洒辛經由粒徑較大的微球( >250 mm)緩慢地釋出可達24小時,其溶離模式為兩段式釋離模式,且經由幾丁聚醣與明膠膜衣包覆後可降低突釋效應與延緩釋離。
根據本實驗所得結果,熔融包覆法的確可以簡易的製備出高產率、高包覆率的微球劑型。
In the recent two decades, due to new polymers developed and advanced techniques applied in pharmaceutics, microencapsulation of desired drugs for preparation of controlled-release dosage form is being widely investigated. By using controlled-release dosage forms, the dosing frequency is significantly reduced, and the therapeutic effect is also improved. However, the processes of microencapsulation often involve complicated procedures and also need organic solvents to dissolve polymers, which may further cause the contamination of manufacturing environments.
The aim of this study was to explore a simple method of preparing microparticles. Poly(ε-caprolactone) was chosen as the material to encapsulate the model drug, indomethacin, and the hot-melt encapsulation technique was applied because of the low melting point of poly(ε-caprolactone).
Two major advantages of hot-melt encapsulation technique were simple manufacturing process and completely abandoning of organic solvents. By changing types of the external phase and surfactants, adjusting drug initial loading、probe sonicator output power and particle size, the microparticles with a high loading efficiency and a high yield characteristics were obtained.
Surface morphology of microparticles was examined by using a scanning electronic microscopy. The results showed that the surface of microparticles was smooth, non-porous, and possessed spherical shape. No obvious aggregation was observed. According to the weight fraction of microparticles, the particle size mainly distributed in the range of 250~420 μm. Using oil as external phase with surfactant L61, the yield and loading efficiency were 83.18 % and 26.17 %, respectively, but they were increased up to 91.15 % and 91.39 %, respectively, while using water as external phase with surfactant PVA. In addition, high performance liquid chromatography and differential scanning calorimeter analysis data showed that hot-melt encapsulation technique does not influence the stability of indomethacin. In the In vitro release study, the release of indomethacin from larger microparticles ( > 250 μm) was prolonged for 24 hours, and its release profile followed a biphasic release pattern. After coating with chitosan and gelatin, the extent of burst effect and release rate were decreased significantly.
第一章 緒論
一、生分解性材料
二、聚合物遞送系統
三、微粒包覆法
(1)溶媒揮發法
(2)沈澱法
(3)化學交聯法
(4)噴霧乾燥法
(5)熱熔融包覆法
(6)熱變性法
第二章 試劑介紹
一、聚己內酯 (PCL, poly(e-caprolactone ))
二、美洒辛 (Indomethacin)
三、聚乙烯醇 Poly(vinyl alcohol)
四、聚氧乙烯-聚氧丙烯共聚合物
(Polyoxyethylene-polyoxypropylene copolymer)
五、幾丁聚醣 (Chitosan)
六、明膠 (Gelatin)
七、棉子油 (Cottonseed oil)
第三章 實驗動機與目的
第四章 實驗試劑與儀器
一、試劑
二、儀器
三、藥品溶液及緩衝液之配製
第五章 實驗方法
一、未包衣微球
1.1.熱融熔包覆法
1.1.1. 改變外相與界面活性劑
1.1.1.1. 油為外相/界面活性劑L61
1.1.1.2. 水為外相/界面活性劑F127
1.1.1.3. 水為外相/界面活性劑PVA
1.1.2. 改變探針式超音波打碎機功率
1.1.3. 改變藥品初始添加量
1.2. 美洒辛定量方法
1.2.1. 校正曲線之建立
1.2.2. 同日內精密度、準確度試驗
1.2.3. 異日間精密度、準確度試驗
1.3. 微球物性分析
1.3.1. 形態觀察
1.3.2. 粒徑分佈
1.3.3. 產率
1.3.4. 藥品包覆率
1.3.5. 體外溶離試驗
二、包覆膜衣之微球
2.1. 包覆幾丁聚醣膜衣
2.2. 包覆明膠膜衣
2.3. 微球物性分析
2.3.1. 形態觀察
2.3.2. 粒徑分佈
2.3.3. 產率
2.3.4. 藥品包覆率
2.3.5. 體外溶離試驗
三、藥品安定性試驗
3.1. 示差掃瞄熱分析儀(DSC)
3.2. 高性能液相層析法(HPLC)
四、分配(partition)試驗
五、微球表面的藥品含量分析
六、傅立葉轉換紅外線光譜儀(FT-IR)
七、聚己內酯微球的大量製備
第六章 結果與討論
一、精密度試驗結果
二、熱熔融包覆法製備聚己內酯微球
2.1. 探討不同外相與界面活性劑對微球的影響
2.1.1. 形態觀察
2.1.2. 粒徑分佈
2.1.3. 產率
2.1.4. 藥品包覆率
2.1.5. 體外溶離試驗
2.2. 探討不同微球粒徑對藥品釋離的影響
2.2.1. 產率與藥品包覆率
2.2.2. 粒徑分佈
2.2.3. 體外溶離試驗
2.3. 改變超音波打碎機功率對微球的影響
2.3.1. 產率及藥品包覆率.
2.3.2. 粒徑分佈
2.4. 探討藥品初始添加量對微球的影響
2.4.1. 產率及藥品包覆率
2.4.2. 粒徑分佈
2.4.3. 體外溶離試驗
三、藥品安定性試驗
3.1. 示差掃描熱分析儀(DSC)
3.2. 高性能液相層析法(HPLC)
四、影響突釋效應的可能因子
4.1. 微球表面的藥品含量
4.2. 粒徑大小
4.3. 分配係數(Partition Coefficiency)
4.4. 傅立葉轉換紅外線光譜儀(FT-IR)
4.5. 綜合討論
五、包覆幾丁聚醣膜衣與包覆明膠膜衣之微球
5.1. 微球外觀
5.2. 產率與藥品包覆率
5.3. 粒徑
5.4. 包覆幾丁聚醣膜衣的微球體外溶離試驗
5.5. 包覆明膠膜衣的微球體外溶離試驗
5.6. 不同包覆材質對微球體外溶離試驗之影響
六、聚己內酯微球的大量製備
6.1. 產率及藥品包覆率
6.2. 粒徑分佈
6.3. 體外溶離試驗
第七章 結論
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