KSBB Journal

  • 제23권5호
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  • Pages.452-459
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  • 2008
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  • 1225-7117(pISSN)
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  • 2288-8268(eISSN)
한국생물공학회 (The Korean Society for Biotechnology and Bioengineering)
권호 표지

초임계 이산화탄소를 이용한 5-FU 함유 생분해성 고분자 미세입자 제조

Preparation of Biodegradable Polymer Microparticles Containing 5-FU Using Supercritical Carbon Dioxide

  • 정주희 (수원대학교 공과대학 화공생명공학과) ;
  • 정인일 (수원대학교 공과대학 화공생명공학과) ;
  • 주현재 (수원대학교 공과대학 화공생명공학과) ;
  • 신재란 (수원대학교 공과대학 화공생명공학과) ;
  • 임교빈 (수원대학교 공과대학 화공생명공학과) ;
  • 유종훈 (수원대학교 공과대학 화공생명공학과)
  • Jung, Ju-Hee (Department of Chemical and Biochemical Engineering, The University of Suwon) ;
  • Jung, In-Il (Department of Chemical and Biochemical Engineering, The University of Suwon) ;
  • Joo, Hyun-Jae (Department of Chemical and Biochemical Engineering, The University of Suwon) ;
  • Shin, Jae-Ran (Department of Chemical and Biochemical Engineering, The University of Suwon) ;
  • Lim, Gio-Bin (Department of Chemical and Biochemical Engineering, The University of Suwon) ;
  • Ryu, Jong-Hoon (Department of Chemical and Biochemical Engineering, The University of Suwon)
  • 발행 : 2008.10.31
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초록

본 연구에서는 뛰어난 항암효과를 가지고 있지만 매우 짧은 반감기로 인한 많은 투약 빈도수와 이로 인한 부작용을 나타내는 5-FU의 부작용을 줄이고 투약의 편의성을 증대시키고자 생분해성 고분자인 L-PLA에 약물이 봉입된 미세입자를 제조하였다. 제조 방법으로는 기존의 미립자 약물전달체 제조 공정의 문제점을 상당 부분 개선시킬 수 있는 대체 공정으로 주목받고 있는 초임계 ASES 공정을 사용하였다. 고분자의 분자량 및 분자량이 다른 동일한 고분자와의 블렌딩, 용매, 약물 투입량 등의 변수가 미세입자의 형성과 약물의 회수율, 봉입효율 및 방출에 미치는 영향을 고찰하여 초임계 유체 공정의 적용 가능성 여부를 조사하였다. 5-FU와 L-PLA의 용매로 각각 MeOH와 DCM을 사용한 경우 가장 좋은 결과가 얻어졌으며, L-PLA의 분자량이 큰 경우 구형의 입자가 생성되었으며 입자의 크기도 작은 결과가 나타났다. 모든 실험에서 약물의 봉입효율이 매우 낮게 나타났는데 이는 5-FU와 L-PLA의 매우 낮은 친화도에 기인하는 것으로 판단된다. 약물과 고분자 간의 재결정화 속도의 차이를 얼마나 줄일 수 있는가가 약물 봉입효율에 가장 큰 영향을 미칠 것으로 판단되며, 약물의 봉입효율을 향상시키기 위해서는 향후 초임계 공정의 공정변수에 대한 좀 더 자세한 연구와 약물과 고분자간의 친화력을 높여 일 수 있는 첨가제에 대한 연구가 필요할 것으로 생각된다.

To obtain maximal efficacy with minimal systemic side-effects, many studies have been carried out to achieve the controlled release of 5-fluorouracil (5-FU). In this study, biodegradable poly(L-lactide) (L-PLA) microparticles containing 5-FU were prepared by a process, called aerosol solvent extraction system (ASES), utilizing supercritical carbon dioxide. The effects of various organic solvents, drug/polymer feeding ratio, polymer molecular weight, and blending with the same polymers with different molecular weights on the formation of 5-FU loaded microparticles were investigated under a predetermined operating condition from our previous study. The drug recovery, entrapment efficiency, and in vitro drug release kinetics were determined by HPLC assays. The drug recovery obtained from the ASES process was found to be very high, whereas the drug entrapment efficiency was considerably low in all the experiments due to the poor affinity between L-PLA and 5-FU. These results indicated that the precipitation rate of L-PLA might be quite different from that of 5-FU so that there was little chance to form 5-FU loaded L-PLA microparticles.

키워드

참고문헌

  1. Feng, S. S. and S. Chien (2003), Chemotherapeutic engineering: Application and further development of chemical engineering principles for chemotherapy of cancer and other diseases, Chem. Eng. Sci. 58, 4087-4114 https://doi.org/10.1016/S0009-2509(03)00234-3
  2. Langer, R. (2006), Biomaterials for drug delivery and tissue engineering, MRS Bull. 31(6), 477-485 https://doi.org/10.1557/mrs2006.122
  3. Park, J. H., M. Ye, and K. Park (2005), Biodegradable polymers for microencapsulation of drugs, Molecules 10, 146-161 https://doi.org/10.3390/10010146
  4. Kim, K. K. and D. W. Pack (2006), Microspheres for drug delivery, In Biological and Biomedical Nanotechnology, A. P. Lee and L. J. Lee, Eds., p19, Springer, New York
  5. Anderson, J. M. and M. S. Shive (1997), Biodegradation and biocompatibility of PLA and PLGA microspheres, Adv. Drug Del. Rev. 28, 5-24 https://doi.org/10.1016/S0169-409X(97)00048-3
  6. Jain, R. A. (2000), The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices, Biomaterials 21, 2475-2490 https://doi.org/10.1016/S0142-9612(00)00115-0
  7. Ghaderi, R. (2000), A supercritical fluids extraction process for the production of drug loaded biodegradable microparticles, Ph. D. Dissertation, Division of Pharmaceutics, Uppsala University, Uppsala, Sweden
  8. Yeo, S. D. and E. Kiran (2005), Formation of polymer particles with supercritical fluids: A review, J. Supercrit. Fluids 34, 287-308 https://doi.org/10.1016/j.supflu.2004.10.006
  9. Bahrami, M. and S. Ranjbarian (2007), Production of micro- and nano-composite particles by supercritical carbon dioxide, J. Supercrit. Fluids 40, 263-283 https://doi.org/10.1016/j.supflu.2006.05.006
  10. Kompella, U. B. and K. Koushik (2001), Preparation of drug delivery systems using supercritical fluid technology, Crit. Rev. Ther. Drug Carr. Syst. 18, 173-199
  11. Martin, A. and M. J. Cocero (2008), Micronization processes with supercritical fluids: fundamentals and mechanisms, Adv. Drug Del. Rev. 60, 339-350 https://doi.org/10.1016/j.addr.2007.06.019
  12. Kim, J. H., S. Y. Lee, B. Y. Kim, J. H. Ryu, and G. B. Lim (2003), Preparation of L-PLA microparticles using pure and cosolvent-modified supercritical carbon dioxide, Korean J. Biotechnol. Bioeng. 18, 385-392
  13. Longley, D. B. and P. G. Johnston (2007), 5-fluorouracil: Molecular mechanisms of cell death, In Apoptosis, Cell Signaling, and Human Diseases: Molecular Mechanisms, Vol. 1, R. Srivastava, Ed., p263, Humana Press, New Jersey
  14. Rich, T. A., R. C. Shepard, and S. T. Mosley (2004), Four decades of continuing innovation with fluorouracil: Current and future approaches to fluorouracil chemoradiation therapy, J. Clin. Oncol. 22, 2214-2232 https://doi.org/10.1200/JCO.2004.08.009
  15. Fu, Y. J., S. S. Shyu, F. H. Su, and P. C. Yu (2002), Development of biodegradable co-poly (d,l-lactide/glycolic acid) microspheres for the controlled release of 5-FU by the spray drying method, Colloids Surf. B 25, 269-279 https://doi.org/10.1016/S0927-7765(01)00205-3
  16. Guney, O. and A. Akgerman (2002), Synthesis of controlled-release products in supercritical medium, AIChE J. 48, 856-866 https://doi.org/10.1002/aic.690480419
  17. Hussain, M., G. Beale, M. Hughes, and S. Akhtar (2002), Co-delivery of an antisense oligonucleotide and 5-fluorouracil using sustained release poly (lactide-co-glycolide) microsphere formulations for potential combination therapy in cancer, Int. J. Pharm. 234, 129-138 https://doi.org/10.1016/S0378-5173(01)00950-4
  18. Faisant N., J. Akiki, F. Siepmann, J. P. Benoit, and J. Siepmann (2006), Effects of the type of release medium on drug release from PLGA-based microparticles: Experiment and theory, Int. J. Pharm. 314, 189-197 https://doi.org/10.1016/j.ijpharm.2005.07.030
  19. Hsu, L. S. F. and T. C. Marss (1980), Determination of 5-fluorouracil in human plasma by high pressure ion-exchange chromatography, Ann. Clin. Biochem. 17, 272-276 https://doi.org/10.1177/000456328001700510
  20. Mittal, G., D. K. Sahana, V. Bhardwaj, and M. N. V. R. Kumar (2007), Estradiol loaded PLGA nanoparticles for oral administration: Effect of polymer molecular weight and copolymer composition on release behavior in vitro and in vivo, J. Control. Rel. 119, 77-85 https://doi.org/10.1016/j.jconrel.2007.01.016
  21. Dorgan, J. R., J. Janzen, M. P. Clayton, S. B. Hait, and D. M. Knauss (2005), Melt rheology of variable L-content poly (lactic acid), J. Rheol. 49, 607-619 https://doi.org/10.1122/1.1896957
  22. Blanco-Prieto, M. J., K. Besseghir, O. Zerbe, D. Andris, P. Orsolini, F. Heimgartner, H. P. Merkle, and B. Gander (2000), In vitro and in vivo evaluation of a somatostatin analogue release from PLGA microspheres, J. Control. Rel. 67, 19-28 https://doi.org/10.1016/S0168-3659(99)00289-8
  23. Ritger, P. L. and N. A. Peppas (1987), A simple equation for description of solute release II. Fickian and anomalous release from swellable devices, J. Contro. Rel. 5, 37-42 https://doi.org/10.1016/0168-3659(87)90035-6
  24. Kim, C. (1999), Release kinetics of coated, donut-shaped tablets for water soluble drugs, Eur. J. Pharm. Sci. 7, 237-242 https://doi.org/10.1016/S0928-0987(98)00029-3