利用超臨界溶液快速膨脹法進行藥物鄰乙氧基苯甲醯胺、甲亢平與甲萘醌之微粒化研究

Study of the RESS Process for the Micronization of Ethenzamide, Carbimazole and Menadione

吳俊霖(Chun-Lin Wu)

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(2017年)

https://doi.org/10.6342/NTU201701635

摘要

本研究為利用超臨界溶液快速膨脹法，以超臨界二氧化碳作為系統中的溶劑，對兩種原料藥與一種食品添加劑進行微粒化實驗，其目標藥物分別為抗消炎止痛藥鄰乙氧基苯甲醯胺 (Ethenzamide)、抗甲狀腺劑甲亢平 (Carbimazole) 與維生素K3甲萘醌 (Menadione)，藉由縮小目標藥物的尺寸，以提高藥物的總表面積，並增加其溶離速率，以達到提升生物可利用度 (Bioavailability) 之目的。

在第一支藥物 Ethenzamide 的研究中，設定的操作條件為 (Text, Pext, Tpost, DN) = (338 K, 200 bar, 298 K, 1000 μm)，雖然藥物平均粒徑僅有從17.69 μm 縮小至 9.37 μm，但從最後的溶離試驗結果來看，經過微粒化程序後，目標藥物之溶離速率常數kw值從0.0254 min-1提升至0.2471 min-1，將近提高有9.73倍之多，有很顯著的提升。而從FTIR、DSC、XRD圖譜中，沒有發現藥物變質與晶型轉變的現象，雖然微粒化後的藥物結晶強度有略微下降，但在藥物的熱穩定性與熔點上並沒有太大改變。

在第二支藥物Carbimazole的研究中，設定的操作條件為 (Text, Pext, Tpost, DN) = (348 K, 220 bar, 298 K, 1000 μm)，目標藥物平均粒徑從84.58 μm縮小至3.63 μm，縮小程度有23.3倍之多。在定性分析方面，根據FTIR、DSC、XRD圖譜，雖然沒有發生藥物變質與晶型轉變的現象，但因為結晶強度有大幅度的降低，導致微粒化後的藥物在熱穩定性上並非很穩定，熔點約下降了12.77℃。在溶離試驗方面，代入 Weibull model 進行迴歸後，得到原料藥之kw值高達0.1263 min-1，可以說已經有相當良好的溶離速率，但微粒化過後藥物之kw值為1.8957 min-1，又更加提升該藥物溶離速率多達15.01倍，效果相當顯著。

在最後一支食品添加劑Menadione的研究中，使用實驗設計法中廣泛使用的因子實驗 (Factorial design)，設計一個23因子實驗，探討三種不同的操作變數萃取溫度 (Text)、萃取壓力 (Pext) 以及環境收集溫度 (Tpost)，對於超臨界溶液快速膨脹法之粒徑大小結果影響。並在完成因子實驗後，再以第四個操作變數─噴嘴內徑 (DN) 來作延伸探討。根據23因子設計與ANOVA分析的結果，微粒化後的藥物粒徑大約落在1-3 μm這區間，而環境收集溫度是影響粒徑最為顯著的操作因子，影響程度 (Contribution) 高達91.086%。本研究選用因子試驗中以1000 μm內徑之噴嘴以及最溫和的操作條件 (Run 4) 之產物作後續儀器分析，SEM圖發現藥物平均粒徑從129.14 μm縮小至1.17 μm，縮小了110.38倍之多。在定性分析方面，同樣從FTIR、DSC、XRD圖譜中，沒有發現藥物有變質與晶型轉變的現象，但結晶強度有大幅度的降低，形成了近似非晶型 (Amorphous form) 的結構，熔點略為下降了2.82℃。而在溶離試驗方面，藥物之kw值從0.0144 min-1上升至0.0631 min-1，溶離速率加快了約4.38倍。

關鍵字

超臨界溶液快速膨脹法 ； 實驗設計法 ； 2k因子設計 ； 微粒化 ； 溶離速率 ； 鄰乙氧基苯甲醯胺 ； 甲亢平 ； 甲萘醌

並列摘要

In this study, the rapid expansion of supercritical solution (RESS) process was applied to produce micronized particles of two active pharmaceutical ingredients (APIs) and one kind of food additives. They were ethenzamide, carbimazole and menadione, respectively. The solubility of APIs and food additives is usually insoluble and poorly bioavailable. Therefore, by the reduction of targeted drug particles into submicron scale, it leads to a significant increase in dissolution rate and bioavailability.

For ethenzamide, the micronized result was not found obviously under the operating condition (Text at 338 K, Pext at 200 bar, Tpost at 298 K and nozzle diameter at 1000 μm). The mean particle size was only reduced from 17.69 μm to 9.37 μm after the RESS process. However, in the dissolution rate test, the dissolution rate constant (kw) was increased from 0.0254 min-1 to 0.2471 min-1. The rate of dissolution was significantly enhanced by 9.73 times. Besides, the thermal and spectrometric properties of the ethenzamide were nearly consistent between the original and RESS processed particles.

For carbimazole, the mean particle size was reduced from 84.58 μm to 3.63 μm under the operating condition (Text at 348 K, Pext at 220 bar, Tpost at 298 K and nozzle diameter at 1000 μm). The micronized degree was up to 23.3 times. The chemical properties of carbimazole were same. However, the melting point and the enthalpy of fusion were decreased because of the lower crystallinity after the RESS process. In addition, the dissolution rate constant (kw) of original and RESS processed particles was 0.1263 min-1 and 1.8957 min-1. Although the original dissolution rate of carbimazole was decent enough, the dissolution rate still improved 15.01 times after the RESS process.

For menadione, the factorial design was applied as the design of experiment. It was for the purpose of discussing the effect of the different parameters on the value of micronized mean particle size. Three parameters, extraction temperature (Text), extraction pressure (Pext) and post-expansion temperature (Tpost), were chosen in this 23 factorial design. After finishing the 23 factorial design, nozzle diameter (DN) was selected as another parameter to discuss. Results from the analysis of variance (ANOVA) showed that post-expansion temperature was the most significantly parameter whose contribution was high to 91.086%. Then, the product in the most moderate condition (Run 4) was subsequently selected to be analyzed. The mean particle size was dramatically micronized from 129.14 μm to 1.17 μm. In qualitative analysis, there was no change of the physical and chemical properties after the RESS process. Moreover, the RESS processed menadione was closed to amorphous form because of its quite small intensity of crystallinity. In the dissolution rate test, the dissolution rate constant (kw) was changed from 0.0144 min-1 to 0.0631 min-1. As a result, the dissolution rate enhanced 4.38 times.

並列關鍵字

RESS ； design of experiment ； factorial design ； micronization ； dissolution rate ； ethemzamide ； carbimazole ； menadione

參考文獻

陳淑鈺. (2008). 利用超臨界二氧化碳進行奈米二氧化矽表面接枝之研究. 國立臺灣化學工程學研究所碩士論文

陳鈞振. (2006). 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. 國立臺灣化學工程學研究所碩士論文

方鈞顥. (2015). 利用超臨界溶液快速膨脹法進行藥物Monobenzone、Ethylparaben、Edaravone與Kojic acid之微粒化研究. 國立臺灣化學工程學研究所碩士論文

蘇至善. (2007). 藥物固體於超臨界二氧化碳中溶解度與微粒化之研究. 國立臺灣化學工程學研究所博士論文

簡豪志. (2016). 利用超臨界溶液快速膨脹法進行藥物氯貝酸與百里酚之微粒化研究. 國立臺灣化學工程學研究所碩士論文