Micronization of SMZ Drug Using High-gravity Precipitation Process

摘要 近年來，生技製藥產業成為我國生物科技的主流，但在新開發出來的藥物中，卻有近40%的藥物因溶解度與溶解速率過低，不易被生物體利用，為了解決這個問題，將藥物微粒化是提升藥物溶解度與溶解速率最普遍與有效的方法之一。本研究於超重力系統中分別採用反應沉澱法以及反溶劑沉澱法進行藥物的微粒化。 本實驗所選取的藥品為SMZ(sulfamethoxazole)，此藥物為磺胺類(Sulfonamide)抗生素的一種，主要用作抗菌，常用於呼吸系統感染、泌尿系統感染、腸道感染等。此外，用於眼用製劑時，可治療結膜炎、砂眼等眼疾。 本研究中，於反應沉澱法下討論添加劑效應、噴嘴效應、盤面大小效應、轉速效應、靜置時間效應、溫度效應、流量效應、產物研磨後的影響以及再現性，並測量產物溶解度及溶解速率。於反溶劑沉澱法下討論添加劑效應、溫度效應、轉速效應、噴嘴效應、連續式改為循環式的影響，並測量產物溶解度及溶解速率。最後，將兩種方法所得結果加以比較及討論。 本研究所用原料藥大小約在10~25μm之間，而觀察實驗結果，採用反應沉澱法時，粒徑約在1~5μm，僅有少數大顆粒的粒子存在，加入Tween80作為添加劑可避免產物黏附於盤面上，產率最高可達88%。採用反溶劑沉澱法時，粒徑也約在1~5μm之間，但分布較為均勻，幾乎無大顆粒的粒子存在，加入Tween80後產率最高可達77%，其中若將連續式操作改為循環式操作則可達83%。 比較兩種實驗方法，反應沉澱法與反溶劑沉澱法所得粒子大小相近，但反溶劑沉澱法所得粒子分布較為均勻。在pH=1.12時測量溶解速率，反應沉澱法約在25分鐘達90%的溶解，反溶劑沉澱法則約在13分鐘時即可達到90%的溶解，顯現了採用反溶劑沉澱法較有助於提升藥物的溶解速率。而加入HPC則可有效提升產物的溶解速率，在這兩種實驗方法中添加至與SMZ相對量為10~15wt%的HPC時，在5到6分鐘內即可達到95%的溶解。Abstract In recent years, pharmaceutical industry becomes the main stream of biotechnology in Taiwan. However, 40% of new drugs have two problems: low solubility and low dissolution rate, and thus low bioavailability. In order to overcome these two problems, one of the most common and effective method was to reduce the drug size. In this research, reaction precipitation method and anti-solvent precipitation method were adopted to reduce the particle size of the drugs in a high-gravity system. Sulfamethoxazole(SMZ) was chosen as the model drug, which was one kind of sulfonamide antibiotics. It was used as antiseptic to treat respiratory system infection, urinary system infection and intestines infection. Moreover, when it was used as eyewash agent, it could treat conjunctivitis and sand holes. In this study, when using reaction precipitation method, the effect of operating variables, including additive, nozzle size, disk diameter, rotating speed, aging time, temperature, flow rate, milling condition and reappearance were studied, also solubility and dissolution rate of product were measured. Moreover, when using anti-solvent precipitation method, the effect of operating variables, including additive, temperature, rotating speed, nozzle size and the operation mode, i.e, continuous vs. recycle were studied, also solubility and dissolution rate were measured. Finally, the results obtained from the two methods were compared and discussed. The particle size of original drugs in this study was about 10~25μm. The particle size of product obtained in the reaction precipitation experiment was between 1~5μm, and a few particles of larger size were present. Adding Tween80 as additive could prevent products from adhering on the surface of disk, and the yield of this method reached 88%. In the anti-solvent precipitation experiment, particle size was also between 1~5μm. The distribution was more uniform because large particles were almost disappeared. When adding Tween80 as additive, the yield of the anti-solvent precipitation method reached 77%. When the operation mode was changed from continuous to recycle mode, the yield reached 83%. Comparing the samples from the two methods, the particle size were similar to each other, but the particle size distribution was more uniform for anti-solvent precipitation method. Under pH of 1.12, the 90% SMZ from reaction precipitation method were dissolved in 25 minutes, and the 90% SMZ from anti-solvent precipitation method were dissolved in 13 minutes. It showed that anti-solvent precipitation method was better for promoting dissolution rate of SMZ. Addition of HPC to SMZ could raise products dissolution rate. When the amount of HPC added was 10~15wt% of SMZ, 95% SMZ were dissolved in 5 to 6 minutes for both samples.目錄 口試委員會審定書………………………………………………………i 誌謝………………………………………...…………….…………..ii 中文摘要………………………………,,,……………….………….iii 英文摘要……………………………………………………..………….v 目錄………………………………………………………..……...…vii 圖索引……………………………………………………….………….xi 表索引……………………………………………………....……….xvi 第一章、 緒論………………………………………………………...1 第二章、 文獻回顧…………………………………………………...3 2-1 目標藥物SMZ………...……………………………………………3 2-2 藥物的微粒化………………………………………………………6 2-3 藥物的溶解…………………………………………………………11 2-4 藥物的制放技術…………………………………………………..14 2-5 結晶動力學………………………………….…………………….18 2-5-1 過飽和度與結晶方式………………...………………………18 2-5-2 微觀混合對結晶的影響……………………...………………21 2-6 超重力系統……………………………………………….……….24 2-6-1 超重力系統之誕生……………………………………...……24 2-6-2 超重力系統之構造與原理………………………………...…25 2-7 超重力系統的應用…………………………………………….….28 2-7-1 脫氧…………………………………………………….....…28 2-7-2 精餾…………………………………………………………...31 2-7-3 吸附…………………………………………………………...32 2-7-4 吸收………………………………………………………...…33 2-7-5 結晶…………………………………………………………...36 第三章、 實驗裝置與步驟………………….……………………….43 3-1 實驗藥品………………………………………………………….43 3-2 實驗儀器………………………………………………………….43 3-3 分析儀器………………………………………………………….44 3-4 實驗方法與步驟……………………………………………………44 3-4-1 SMZ溶解度的測量………………………………......………44 3-4-2 反應沉澱法………………………………………………...…45 3-4-3 反溶劑沉澱法-連續式……………………………………....46 3-4-4 反溶劑沉澱法-循環式……………………………………....47 3-5 分析方法與步驟…………………………………………………..49 3-5-1 顆粒型態………………………………………………....….49 3-5-2 結晶特性…………………………………………………..….49 3-5-3 溶解速率測試………………………………………………...49 第四章、 結果與討論…………………………………………….….56 4-1 以反應沉澱法製備SMZ藥品之探討………………………………56 4-1-1 尋找適合的操作條件……………………………………..…56 4-1-2 添加劑效應…………………………………………………..61 4-1-3 噴嘴效應……………………………………………..………67 4-1-4 盤面大小效應…………………………………………..……70 4-1-5 轉速效應…………………………………………………..…71 4-1-6 靜置時間對粒子之影響…………………………………..…75 4-1-7 溫度效應…………………………………………………..…77 4-1-8 流量效應………………………………………………..……80 4-1-9 研磨後對產率及粒徑之影響……………………………..…82 4-1-10溶解度以及溶解速率之比較……………….......………….87 4-1-11 再現性實驗…….……………………………………........91 4-2 以反溶劑沉澱法製備SMZ藥品之探討………………………….…93 4-2-1 尋找適合的操作條件………………………………...………93 4-2-2 添加劑效應………………………………………………...…94 4-2-3 溫度效應…………………………………………...…………99 4-2-4 轉速效應………………………………………………...….103 4-2-5 噴嘴效應…………………………………………...……….107 4-2-6 操作方式的影響………………………………………...….109 4-2-7 溶解度以及溶解速率之比較…………………........…….113 4-3反應沉澱法及反溶劑沉澱法之比較………………………….….115 4-4 與文獻結果之比較…………………………………………….…120 第五章、 結論……………………………………………………...124 參考文獻……………………………………………………………...126 附錄……………………………………………………………..…….13