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Development of New Microencapsulation Technology Based on Acid-Catalyzed Solvent Extraction

Development of New Microencapsulation Technology Based on Acid-Catalyzed Solvent Extraction
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대학원 생명·약학부약학전공
이화여자대학교 대학원
본 연구의 목적은 유제의 용매를 산 가수분해를 통해 제거하는 방법을 도입하여 새로운 microspheres 제조방법을 개발하는 것이다. 봉입할 약물은 약산성 약물인 케토프로펜으로 정하였고 유기용매는 에틸 아세테이트 (EA)로 정하였다. Poly-d,l-lactide-co-glycolide (PLGA)를 EA에 녹인 것을 염산을 포함한 수상에 분산시키면 수중 유형 에멀션을 형성한다. 그 중 유제로부터 수상으로 확산된 EA가 산 가수분해되어 microspheres가 만들어진다. 이 과정에서 제조 온도를 높여서 유제 경화 발생시간을 줄이고, EA의 산 가수분해 반응속도를 높일 수 있었다. 수층의 EA가 시간이 지나며 산 가수분해되어 에탄올과 아세트산으로 전환되기 때문에 수층의 EA 양이 점점 줄어든다는 것을 기체크로마토그래피로 확인하였다. 기존의 용매증발법을 사용했을 때보다, 산 가수분해 반응을 이용하여 microspheres를 제조했을 때 microspheres의 잔류용매량이 낮아진다는 것과, 제조 온도가 높아지고 제조 시간이 길어질수록, microspheres의 잔류용매량이 낮아지는 것을 확인하였다. 또한 산 가수분해 반응을 이용하여 microspheres를 제조하게 되면 수층이 산성이 되어 약산성 약물인 케토프로펜의 봉입률이 높아진다. 새로 개발한 microspheres 제조법을 사용했을 때 케토프로펜의 봉입률은 86 %였다. 액체크로마토그래피/질량분석 (LC/MS) 결과 산 가수분해 반응을 이용하여 microspheres를 만들더라도 케토프로펜의 구조는 원상태를 유지한다는 것을 알 수 있었다. 하지만 microspheres에 봉입된 케토프로펜의 양에 따라 케토프로펜의 물리적 상태가 달라진다는 것을 알 수 있었다. 본 실험에서 새롭게 개발한 microspheres 제조방법은 기존의 microspheres 제조법에 비해 많은 이점이 있기 때문에 다양한 곳에 응용될 수 있을 것이다. ;The objective of this study was to develop a new microencapsulation technology utilizing an acid-catalyzed solvent hydrolysis for solvent extraction. Ethyl acetate was selected as a dispersed solvent, whereas ketoprofen was chosen as a model drug for microencapsulation. The new microencapsulation processing consisted of dissolving poly-d,l-lactide-co-glycolide (PLGA) in ethyl acetate, emulsifying the dispersed phase in an aqueous phase, and inducing the acid catalyzed hydrolysis of the dispersed solvent by use of hydrochloric acid. The hydrolysis of ethyl acetate dissolved in the aqueous phase allowed the continual leaching of the solvent out of emulsion droplets. The ongoing acid catalyzed process resulted in the solidification of emulsion droplets into microspheres. Interestingly, the ease at which emulsion droplets became hardening microspheres was greatly influenced by the microencapsulation processing temperature. In addition, the rate of acid catalyzed hydrolysis of ethyl acetate was dependent upon temperature. Our gas chromatographic analysis demonstrated that the depletion of ethyl acetate in the aqueous phase was in sync with its hydrolytic breakdown into ethanol and acetic acid. Our acid-catalyzed microencapsulation process led to formation of microspheres having lower residual ethyl acetate than did the conventional solvent extraction process. It was also shown that reaction time and temperature were other major parameters that influenced the residual level of ethyl acetate in microspheres. Furthermore, our new microencapsulation process worked well for microencapsulating weakly acidic drugs such as ketoprofen: under our experimental conditions its microencapsulation efficiency amounted to 86 %. The LC/MS analysis proved that the structural integrity of ketoprofen remained the same before and after microencapsulation. However, the physical status of ketoprofen in microspheres was affected by its payload. In summary, our new acid catalyzed microencapsulation technique was found to have several advantages over existing solvent extraction/evaporation techniques. It might have a potential as a technology platform for the preparation of various types of nano- and micro-sized polymeric particles.
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