Synthesis of Lactide/Hyaluronic Acid Polymer Membrane for the Application of Drug Delivery System

약물방출시스템 적용을 위한 락타이드/히아루론산 고분자 막의 제조

  • Kim, Min-Su (Department of Chemical Engineering and Nano-Bio Technology, Hannam University) ;
  • Kwon, Ji-Young (Department of Chemical Engineering and Nano-Bio Technology, Hannam University) ;
  • Cheong, Seong-Ihl (Department of Chemical Engineering and Nano-Bio Technology, Hannam University)
  • 김민수 (한남대학교 나노생명화학공학과) ;
  • 권지영 (한남대학교 나노생명화학공학과) ;
  • 정성일 (한남대학교 나노생명화학공학과)
  • Published : 2005.12.01

Abstract

The hyaluronic acid (HA) with excellent biocompatibility can be combined with lactide, the ester dimer of polylactide, with good biodegradability to produce biocompatible materials applicable to drug delivery system. By freeze drying method, HA and lactide were crosslinked with crosslinking agent, 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide. Degree of lactide and EDC reaction was determined by the analysis of nuclear magnetic resonance (NMR) spectroscopy. The degree of lactide and EDC reaction increased and swelling ratio decreased as the mole ratio of lactide to HA or crosslinking agent concentration increased or reaction temperature decreased. The drug release experiment result from membranes having different degree of lactide reaction showed that drug release rate reduced in proportion to the degree of lactide reaction. The drug release experiment result from drugs having different hyrodphobicity showed that the more hydrophobic drug was released more slowly.

생체 적합성이 우수한 히아루론산과 생분해성이 우수한 폴리 락타이드의 이량체를 결합하여 약물 방출 시스템에 적용할 수 있는 생체 재료를 제조하고자 하였다. 냉동 건조법을 이용하여 히아루론산과 락타이드를 가교제 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC)로 가교시켰다. 생성된 막을 핵자기 공명 분광법으로 분석하여 락타이드 반응도와 EDC 반응도를 결정하였다. 히아루론산에 대한 락타이드 몰비, 가교제 농도가 증가할수록 혹은 가교 온도가 감소할수록, 락타이드 반응도가 증가하였으며 팽윤도는 감소하였다. 서로 다른 락타이드 반응도를 가진 막으로 약물 방출 실험을 수행한 결과 락타이드 반응도가 증가하면 약물 방출 속도가 감소하는 경향을 보였다. 또 친수성이 다른 여러 가지 약물로 약물 방출 실험을 수행한 결과 친수성이 우수한 약물일수록 서서히 방출되었다.

Keywords

References

  1. O. Wichterle and D. Lim, Nature, 'Hydrophilic Gels for Biological Use', 185, 117-118 (1960) https://doi.org/10.1038/185117a0
  2. N. A. Peppas, Hydrogels in Medicine and Pharmacy, Boca Raton, Vol. I, II, III, CRC Press Inc., Florida (1986)
  3. G. Khang, M. S. Kim, S. H. Cho, H. B. Lee, J. H. Chang, and K. J. Kim, 'Recent Develpoment Trend of Stimuli Sensitive Hydrogels', Polym. Sci. and Tech., 14(4), 431-437 (2003)
  4. F. Lim and A. M. Sun, Science, 'Microencapsulation of islets as bioartificial endocrine pancreas', 210, 908-910 (1980) https://doi.org/10.1126/science.6776628
  5. Y. D. Park, N. Tirelli, and J. A. Hubbell, 'Photopolymerized hyaluronic acid-based hydrogels and interpenetrating networks', Biomaterials, 24, 893-900 (2003) https://doi.org/10.1016/S0142-9612(02)00420-9
  6. G. D. Prestwitch, D. M. Marecak, and J. F. Marecek, 'Controlled chemical modification of hyaluronin acid: synthesis, applications, and biodegradation of hydrazide derivatives', J. Control. Rel., 53, 93-103 (1998) https://doi.org/10.1016/S0168-3659(97)00242-3
  7. Y. Luo, K. R. Kirker, and G. D. Prestwich, 'Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery', J. Control. Rel., 69, 169-184 (2000) https://doi.org/10.1016/S0168-3659(00)00300-X
  8. S. N. Park, H. J. Lee, K. H. Lee, and H. Sub, 'Characterization of porous collagen/hyaluronic acid scaffold modified by l-ethyl- 3-(3-dimethylaminopropyl) carbodiimide cross-linking', Biomaterials, 22, 1205-1212 (2002)
  9. S. N. Park, H. J. Lee, K. H. Lee, and H. Sub, 'Biological characterization of EDC-crosslinked collagen-hyaluronic acid matrix in dermal tissue restoration', Biomaterials, 24, 1631-1641 (2003) https://doi.org/10.1016/S0142-9612(02)00550-1
  10. H. S. Nam, J. H. Kim, J. H. An, and D. J. Jung, 'Synthesis of Hyaluronic acid scaffold for tissue engineering and evaluation of its drug release behaviors', Polymer(Korea), 25(4), 476-485 (2001)
  11. Y. Tokita and A. Pkamoto, 'Degradation of hyaluronic acid-Kinetic study and thermodynamics', Eur. Polym. J., 32(8), 1011-1014 (1996) https://doi.org/10.1016/0014-3057(96)00019-5
  12. S. P. Zhong, D. Campoccia, P. J. Doherty, R. L. Willians, L. Benedetti, and D. F. Williams, 'Biodegradation of hyaluronic acid derivatives by hyaluronidase', Biomaterials, 15, 359-368 (1994) https://doi.org/10.1016/0142-9612(94)90248-8
  13. J. S. Lee, D. J. Choo, S. H. Kim, and Y. H. Kim, 'Synthesis and degradation property of star-shaped polylactide', Polymer(Korea), 22(6), 880-889 (1998)
  14. C. Grandfils, P. Flandroy, and R. Jerome, 'Control of the biodegradation rate of poly(DL-lactide) microparticles intended as chemoembolization materials', J. Control. Rel., 38, 109-122 (1996) https://doi.org/10.1016/0168-3659(95)00102-6
  15. H. Fukuzaki, M. Yoshida, M. Asano, and M. Kumakura, 'Synthesis of copoly (D,L-lactic acid) with relatively low molecular weight and in vitro degradation', Eur. Polym. J., 25(10), 1019-1026 (1989) https://doi.org/10.1016/0014-3057(89)90131-6
  16. S. Li, M. Tenon, H. Garreau, C. Braud, and M. Vert, 'Enzymatic degradation of stereocopolymers derived from L -, D,L - and meso-lactides', Polym. Deg. Stab., 67, 85-90 (2000) https://doi.org/10.1016/S0141-3910(99)00091-9
  17. J. Y. Kwon and S. I. Cheong, Membrane J. (Korea), 'Characterization of Hyaluronic Acid Membrane Containing Lactic Acid', 15(1), 8-14 (2005)
  18. J. H. Kim, J. Y. Kim, Y. M. Lee, and K. Y. Kim, 'Controlled-release drug delivery through crosslinked poly(vinyl alcohol)/chitosan blend membrane', Polymer (Korea), 15(6), 695-701 (1991)
  19. J. W. Kuo, D. Swann, and G. D. Prestwich, 'Chemical modification of hyaluronic acid by carboiimides', Bioconjugate Chem., 2, 232-241 (1991) https://doi.org/10.1021/bc00010a007
  20. K. R. Park, D. Kim, and Y. C. Nho, 'Preparation and its application for wound dressing of gelatin hydrogel and PVP/Gelatin hydrogel by radiation crosslinking', J. Korean Ind. Eng. Chem., 12(7), 718-723 (2001)
  21. L. F. Miranda, A. B. Lugao, L. D. B. Machado, and L. V. Ramanathan, 'Crosslinking and degradation of PVP hydrogels as a function of dose and PVP concentration', Radia. Phys. Chem., 55, 709712 (1999)
  22. E. K. Choi, H. I. Kim, K. R. Park, and Y. C. No, 'Preparation and charaterization of PVA/PVP/PEG/ Chitosan hydrogels by freezing/thawing and radiation crosslinking', J. Korean Ind. Eng. Chem., 14(4), 505-510 (2003)
  23. E. K. Choi, H. I. Kim, K. R. Park, and Y. C. No, 'Preparation and charaterization of PVA/PVPIPEGI Chitosan hydrogels by freezing/thawing and radiation crosslinking', J. Korean Ind. Eng. Chem., 14(4), 505-510 (2003)
  24. E. Milella, E. Brescia, C. Massaro, P. A. Ramires, M. R. Miglietta, V. Fiori, and P. Aversa, 'Physico-chemical properties and degradability of nonwoven hyaluronan benzylic esters as tissue engineering scaffolds', Biomaterials, 23, 1053-1063 (2002) https://doi.org/10.1016/S0142-9612(01)00217-4
  25. Y. L. Luo, K. R. Kirker, and G. D. Prestwich, 'Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery', J. Control. Rel., 69, 169-184 (2000) https://doi.org/10.1016/S0168-3659(00)00300-X
  26. E. Payan, J. Y. Jouzeau, F. Lapicque, K. Bordji, and P. Netter, 'In vitro drug release from HYC 141, a corticosteroid ester of high molecular weight hyaluronan', J. Control. Rel., 34, 145-153 (1995) https://doi.org/10.1016/0168-3659(95)00002-P
  27. T. Coviello, M. Dentini, G. Rambone, P. Desideri, and F. Alhaique, 'A novel co-crosslinked polysaccharide: studies for a controlled delivery matrix', J. Control. Rel., 55, 57-66 (1998) https://doi.org/10.1016/S0168-3659(98)00028-5