Article
  • Stability and In-vivo Toxicity of Poly(ethylene oxide-b-caprolactone) Micelles for Injectable Drug Carriers
  • Kim DC, Yoo Y
  • 주사용 약물 담체로서의 Poly(ethylene oxide-b-caprolactone)미셀의 안전성과 체내 독성
  • 김동철, 유영태
Abstract
Amphiphilic block copolymers of ethylene oxide and caprolactone were synthesized for three compositions of 5 k-2.5 k, 5 k-5 k, and 5 k-7.5 k(PEO-b-PCL) and micellar aggregates were formed in aqueous medium with the particle size in the range of 0.045-0.118 ㎛. The feasibility of the micelle solutions was studied in terms of colloidal stability, biodegradability and in vitro toxicity for intravenous (Ⅳ) drug delivery carriers. It was found that the colloids were stable in neutral PH PBS solution for 180 days at 37 ℃ while large aggregates were formed in acidic medium of pH 1.2-3.5. Enzymatic degradation of the polycaprolactone core was evidenced in the presence of lipase and serum as monitored by carboxylic acid generation, however protease showed little activity on the degradation of the particles. The colloidal stability of the micellar aggregates was maintained at the particle concentration less than 0.025 wt/v% in serum. In the animal toxicity test, 0.7 mL of micelle solution of 5 k-7.5 k block copolymer (1, 2 wt/v% solid) was intravenously administered to 6-wk old male mice and the general symtom was observed. This study demonstrated that most of animal subjects survived showing normal weight gain after receiving six times of single dose by 1 h period.

양친매성 공중합체인 poly(ethylene oxide-b-caprolactone) (PEO-b-PCL)을 세 조성(5k-2.5k, 5k-5k, 5k-7.5k)으로 합성하여 미셀용액으로 제조한 후 정맥주사용 약물담체로서의 입자크기, 안정성, 분해성 및 체내 독성 등에 관해 연구하였다. 공중합체가 수용액에 분산되어 형성한 미셀입자의 크기는 0.045∼0.118 ㎛으로 친수성인 PEO의 상대적 조성이 높아짐에 따라 입자크기가 감소하는 경향을 나타내었다. 미셀용액은 37'c에서 180일 동안의 관찰결과 pH 6.8-7.4(in PBS)에서 입자크기 및 pH의 큰 변화가 없이 장기적인 안정성을 나타내었으나 pH 1.2-3.5에서는 입자의 크기가 증가하면서 침전이 형성되어 불안정하였다. 체외(in vitro) 분해실험에서 미셀은 lipase 존재하에서나 serum에서 효소분해로 미셀용액의 산도가 크게 증가한 반면, protease 존재하에서는 분해정도가 미약하였다. Serum에서의 미셀농도에 따른 안정성의 변화에서는 고형분 농도가 0.025wt/v% 이상일 때 agglomerate의 형성으로 인도가 급격히 증가하는 것을 발견하였다. 생체 (in vivo) 독성시험에서 5k-7.5k 미셀용액 (1, 2 wt/v%) 0.7 mL를 6주령 옹성 mouse의 정맥에 주사한 결과 사망한 예가 없었으며 1시간 간격의 반복 주사에서도 6회까지 대부분 생존하여 안전성이 우수함을 알 수 있었다.

Keywords: micelle; amphiphilic copolymer; PEO-b-PCL; parenteral drug delivery; nanoparticles; stability; toxicity

References
  • 1. Poznansky MJDrug Delivery Systems Characteristics and Biomedical Applications, R.L. Juliano Ed., p. 253-315, Oxford University Press (1980)
  •  
  • 2. Baker RW, Tuttle ME, Lonsdale HK, Aynes JW, J. Pharm. Sci., 68, 20 (1979)
  •  
  • 3. Park TG, Hoffman AS, J. Appl. Polym. Sci., 46, 659 (1992)
  •  
  • 4. Peppas LB, Peppas NA, J. Control. Release, 8, 267 (1989)
  •  
  • 5. Kost J, Horbett TA, Ratner BO, Singh M, J. Biomed. Mater. Res., 19, 1117 (1985)
  •  
  • 6. Siegel RA, Firestone BAProc. Int. Symp. Controlled Release Bioact. Mater., 156, 164 (1988)
  •  
  • 7. Dong LC, Hoffman ASProc. Int. Symp. Controlled Release Bioact. Mater., 16, 95 (1989)
  •  
  • 8. Sheppard NF, Madrid MY, Langer R, J. Appl. Polym. Sci., 46, 19 (1992)
  •  
  • 9. Barr WH, Adir J, Garrettson L, Clin. Pharmacol. Ther., 12, 779 (1971)
  •  
  • 10. Allison AC, Gregoriadis GLiposomes in Biological System, Wiley, New York (1979)
  •  
  • 11. Wheatley MA, Chane M, Park E, Langer R, J. Appl. Polym. Sci., 43, 2123 (1991)
  •  
  • 12. Goodwin JT, Somerville GRPhysical Methods for Preparing Microcapsules, in Microcapsulation Process and Applications, J.E. Vandegaer, ed., p. 119, Pelnum Press, New York (1976)
  •  
  • 13. Baillie AJ, Florence AT, Hume LR, Muirhead GT, Rogerson A, J. Pharm. Pharmacol., 37, 863 (1985)
  •  
  • 14. Knoll D, Hermans J, J. Biol. Chem., 258, 5710 (1983)
  •  
  • 15. Shalaby SW, Hoffman AS, Ratner BD, Horbett TApolymer as Biomaterials, p. 361, Plenum Press, New York (1984)
  •  
  • 16. Ammoury N, Fessi H, Devissaguet JP, Benita S, Pharma., 5, 647 (1989)
  •  
  • 17. Couvreur P, Vauthier C, J. Control. Release, 17, 187 (1991)
  •  
  • 18. Gupta PK, J. Pharm. Sci., 79, 949 (1990)
  •  
  • 19. Illum L, Khan MA, Mark E, Davis SS, Int. J. Pharm., 30, 17 (1986)
  •  
  • 20. Jani P, Halbert GW, Landridge J, Florence AT, J. Pharm. Pharmacol., 42, 821 (1990)
  •  
  • 21. Chang RK, Price JC, Hisiao C, Drug Dev. Ind. Pharm., 15, 361 (1989)
  •  
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This Article

  • 1997; 21(4): 674-681

    Published online Jul 25, 1997