以連續式超臨界反溶劑沉積法進行藥物微粒化及包覆之研究

Micronization and Encapsulation of Pharmaceutical Compounds Using Supercritical Anti-Solvent Precipitation Process

陳鈞振(Jiun-Jen Chen)

指導教授 ： 陳延平

國立臺灣大學/工學院/化學工程學研究所/碩士(2006年)

https://doi.org/10.6342/NTU.2006.01389

摘要

本研究以超臨界反溶劑法(SAS)法，進行高分子及藥物微粒化，超臨界CO2扮演反溶劑的角色，使得溶液體積膨脹，溶液迅速達過飽和而析出溶質。本研究利用超臨界反溶劑法，成功地將PMMA, CA, HPC等高分子微粒化。Hydrochlorothiazide (HCT, 利尿劑), Tolazamide, Succinic acid, Naringin等藥物經過SAS操作，亦得到良好的微粒化效果。

在本研究選定利尿劑HCT進行操作參數的探討，在不同的壓力、溫度、溶液濃度、溶液流速下進行實驗，探討各參數對粒徑及晶貌的影響。研究結果顯示，在壓力為120bar，溫度為45℃，溶液濃度為10%飽和濃度及溶液流率為0.25mL/min時，可得最小的HCT粒徑為0.67µm。

本研究又以利尿劑HCT為核心藥物，生物可分解性高分子PLA為殼層物質進行包覆，並探討原始藥物、微粒化藥物及包覆後藥物的溶離速率情形。經由本研究SAS操作得到的微粒化HCT藥物之溶離速率，較原始藥物提升了3倍，而包覆後的微囊，具有延長釋放的效果，且其釋放動態模式，符合Higuchi釋放動力模式。

關鍵字

微粒化 ； 包覆 ； 超臨界反溶劑法

並列摘要

The purpose of this study was to apply the technique, supercritical anti-solvent (SAS) to the preparation of micronized polymers and drugs. In the SAS process, supercritical CO2 acts as an anti-solvent for the solution. The supercritical CO2 causes supersaturation of the solution, leading to nucleation and precipitation of the solute rapidly. The polymers such as PMMA, CA, HPC were successfully micronized using the SAS process. At the same time, the size of drugs such as Hydrochlorothiazide (HCT), Tolazamide, Succinic acid and Naringin were also greatly reduced after the SAS process.
In this research, the effect of the process parameters was discussed using HCT as model drug. The operating parameters that have an effect on the size of the drug, such as pressure, temperature, concentration of solution and flow rate of solution, were systematically studied to find the optimum operating parameters. We got the smallest average particle size, 0.67µm of HCT at the condition that P=120bar, T=45℃,solution concentration=10% sat., solution flow rate=0.25mL/min.
Encapsulation of fine particles with polymer using the supercritical antisolvent coating process was also investigated in this research. The diuretic drug, HCT particles were used as host particles and PLA, a biodegradable polymer used for controlled release of drugs, was chosen as the coating material. This study also discussed the dissolution rates of original, micronized and encapsulated drugs. The dissolution rate of micronized HCT which were obtained after continuous SAS was 3 times greater than that of the original drug. The encapsulated drug allows a slow and prolonged drug release and the release profile of the encapsules matches the Higuchi matrix release kinetic model.

並列關鍵字

Micronization ； Encapsulation ； Supercritical antisolvent

參考文獻

吳漢鍾，超臨界二氧化碳製備微奈米阿司匹靈膠囊粒子及控制釋放之

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Carretier, E., Badens, E., Guichardon, P., Boutin, O., Charbit, G., Hydrodynamics of supercritical antisolvent precipitation: characterization and influence on particle morphology, Ind. Eng. Chem. Res, 42, 2003, 331-338

Calderone, M., Rodier, E., Freiss, B., Letourneau, J.J., and Fages, J., Coating of nanoparicles using a supercritical antisolvent(SAS) process, 7th Italian Conference on Supercritical Fluids and Their Applications, Italy, 2004