利用超臨界反溶劑法進行安樂普利諾及氨苯碸之微粒化研究

Abstract

本研究利用超臨界反溶劑法對兩種低水溶性的藥物進行微粒化之研究，目的為增加其溶離速率，增加藥物在人體的生體可用率。選用的目標藥物為控制尿酸的痛風藥物安樂普利諾(Allopurinol)及用來大量用來治療痲瘋病的抗生素藥物氨苯碸(Dapsone)，此兩種藥物水溶性皆非常的低，幾乎不溶於水。因此，本研究使用超臨界反溶劑法對此兩種藥物進行微粒化，以超臨界二氧化碳當作反溶劑，探討不同參數，如溶劑種類、溫度、壓力、溶液流速、噴嘴內徑及溶液濃度等，對於微粒化結果的影響，以得到最佳化操作條件，進而提升其溶離速率。此外，本研究也將微粒化前後之藥物加入模擬人體腸液後進行溶離速率測試，以觀察藥物經過微粒化後，是否有較高的溶離速率。 在安樂普利諾的微粒化研究中，最佳化操作條件下可將原始藥物的平均粒徑8.9微米降至操作後的0.8微米。且由分析儀器XRD、DSC及FTIR可知，藥物並沒有晶型的轉變也沒有發生變質或是溶劑殘留的情況發生。溶離速率實驗方面，經過SAS處理過後的藥物溶離速率較未處理的藥物快，且經過Weibull model回歸後，原始藥物溶離速率係數kw為0.47 min-1，微粒化後藥物之溶離速率係數kw為0.64 min-1，溶離速率提升約1.35倍。 在氨苯碸的微粒化研究中，最佳化操作條件下可將原始藥物的平均粒徑由40.8微米降至操作後的2.2微米。且由分析儀器XRD、DSC及FTIR可知，藥物經過操作後，部分藥物晶型發生轉變，由單晶型轉變成兩種晶型的混合，但是沒有變質或是溶劑殘留的情況發生。溶離速率實驗方面，結果顯示經過SAS處理過後的藥物溶離速率比未處理的還要快，且經過Weibull model回歸後原始藥物溶離速率係數kw為0.00461 min-1，微粒化後藥物之溶離速率係數kw為0.01876 min-1，較原始藥物提升約4.07倍。

In order to enhance the dissolution rate and bioavailability in human beings, this study focused on the micronization of poor water soluble pharmaceuticals by using supercritical antisolvent method (SAS). The target pharmaceuticals used in this research are Allopurinol and Dapsone. Allopurinol is an oral drug for gout treatment and Dapsone is an oral durg for leprosy. Both two drugs have poor water solubility and low dissolution rate. Therefore, the purpose of this study is trying to make these two drugs micronized and enhance their dissolution rate. In this study, supercritical carbon dioxide was used as antisolvent. Different experimental results were obtained by different effect parameters, including solvent, operation temperature, pressure, solution flow rate, nozzle diameter and solution concentration. About the micronization of Allopurinol, it could be successfully micronized from 8.9 μm to 0.8 μm at the optimal operating conditions. About the micronization of Dapsone, it could also be successfully micronized from 40.9 μm to 2.2 μm at the optimal operating conditions. From the DSC result we can find another crystalline form after SAS processed. After the micronization process, the processed and unprocessed pharmaceuticals were tested by using a dissolution tester. The results of dissolution rate test, both the processed drugs have higher dissolution rate than the original drugs.