以超臨界反溶劑沉積法進行藥物微粒化之研究

Abstract

本研究以連續式超臨界反溶劑(Supercritical Anti-Solvent, SAS)沉積法對抗生素(Sulfamethoxazole與Sulfaphenazole)與非類固醇抗發炎藥(Acetaminophen與Sulidac)進行微粒化，並與批式超臨界反溶劑沉積法得到的結果比較，發現連續式SAS操作較批式SAS操作能得到更小的藥物微粒。其後選定Sulfamethoxazole為目標藥物，利用實驗設計法，進行批式與連續式SAS操作參數效應分析。在批式操作中，乙酸乙酯為最佳溶劑，於較低溶液濃度下有利小顆粒之生成。而在連續式操作中，丙酮為最佳溶劑，於低溶液流率與高溶液濃度下操作有利小顆粒之生成。經由連續式操作得到的Sulfamethoxazole藥物之溶解速率與抗菌效果，較原始藥物分別提升約5倍與3倍。此外，本研究亦探討將Hydroxypropylcellulose加入Sulfamethoxazole藥物溶液中，進行連續式SAS操作，與藥物共沉澱之可行性。結果發現共沉澱藥物的溶解速率，較原始藥物提升約50倍。

Micronization of the antibiotics (Sulfamethoxazole and Sulfaphenazole) and the non-steroidal anti-inflammatory drugs (Acetaminophen and Sulindac) were investigated in this study using the batch and continuous supercritical carbon dioxide anti-solvent (SAS) precipitation method. Particles produced by the continuous SAS are smaller than those produced by the batch ones. Crystal structure of sulfamethoxazole analyzed by XRD showed the solid-solid transition after the batch SAS process. The effect of the process parameters were compared using sulfamethoxazole as model drug. In the batch SAS process, using ethyl acetate as solvent at low concentration favors smaller particle formation while in the continuous SAS process, acetone as solvent was suggested and operating at lower solution flow rate and higher concentration favored smaller particle formation. The micronized sulfamethoxazole exhibits a higher dissolution rate and antibacterial performance. The dissolution test demonstrated the use of additives in drug formulation can be avoided when the SAS processed drug is used. Coprecipitation of sulfamethoxazole and hydroxypropylcellulose (HPC) by the continuous SAS process was also investigated. The dissolution rate of sulfamethoxazole was dramatically enhanced after Coprecipitating with HPC.