Effects of Hydrophilic Additives on the Release Rate of Protein Drugs

단백질 약물 방출속도에 미치는 친수성 첨가제의 영향

  • Kwon, Young-Kwan (School of Chemical and Biological Engineering, Seoul National University) ;
  • Kim, Ji-Hyeon (Department of Chemical and Biochemical Engineering, Dongguk University) ;
  • Yoo, Young-Je (School of Chemical and Biological Engineering, Seoul National University)
  • 권영관 (서울대학교 화학생물공학부) ;
  • 김지현 (동국대학교 생명화학공학과) ;
  • 유영제 (서울대학교 화학생물공학부)
  • Published : 2007.08.30

Abstract

It has been reported that hydrophobic additives generally decrease the release rate of protein drugs from drug delivery systems (DDS) and hydrophilic additives increase the release rate. In many cases, however, the addition of hydrophilic molecule is necessary for improving the stability of protein drugs. In the present work, the effects of hydrophilic additives on the release profiles, and micelle formation of protein drug formulations were investigated to develop a novel method for protein drug delivery. For model protein drug, bovine serum albumin (BSA) was employed and several hydrophilic additives were used in the release experiments. Hydrophilic additive D-sorbitol showed the lower release rates of BSA than other hydrophobic additives due to the gel strengthening ability of the additive and the optimum concentration of D-sorbitol was 3 w/v % for the retarded release rate. In addition, it was found that the addition of D-sorbitol was very effective for obtaining homogeneous and stable DDS. The results were discussed in terms of the micelle formation and the micelle structure, i.e., the differences in gel structure and the distribution of drugs in micelles.

첨가제가 단백질 약물 방출 속도 및 약물 제제 제조 및 구조에 미치는 영향을 고찰하였다. 친수성 첨가제인 D-sorbitol의 경우 친유성 첨가제보다 단백질 약물 방출 속도를 감소시킬 수 있었으며 최적의 농도는 3% (w/v)로 나타났다. 또한 제제 제조시 점도를 낮게 유지할 뿐 아니라 상분리 없는 균일한 pluronic 용액상태를 유지하여 약물이 첨가될 경우에 균일한 약물제제를 만들 수 있었다. 한편 D-sorbitol은 pluronic 수용액의 CMC를 낮추고 마이셀 표면에 작용하여 구조를 강화하는 역할을 수행하는 것으로 보인다. 따라서 pluronic 제제에 D-sorbitol을 첨가하여 단백질 약물의 안정성을 향상시키고 효과적인 약물전달 시스템을 설계할 수 있었다.

Keywords

References

  1. Choi, C-S., S.-M. Park, W.-H. Song, C.-M. Lee, K.-Y. Lee, D.-W. Kim, and J.-C. Kim (2003), Release properties of BSA from pectin beads for colonic drug delivery, Kor. J. Biotechnol. 18, 161-164
  2. Fix, J. A. (1996), Oral controlled release technology for peptides: status and future prospects, Pharm. Res. 13, 1760-1764 https://doi.org/10.1023/A:1016008419367
  3. Kim, M. S., K. S. Sea, H. Hyun, G. Khang, S. H. Cho, and H. E. Lee (2006), Controlled Release of bovine serum albumin using MPEG-PCL diblock copolymers as implantable protein carriers, J. Appl. Pol. Sci. 102, 1561-1567 https://doi.org/10.1002/app.23528
  4. Andrianov, A. K. and L. G. payne (1998), Polymeric carriers for oral uptake of microparticulates, Adv. Drug Deliv. Rev. 24, 155-170
  5. Kabanov, A. V., E. V. Batrakova, N. S. Melik-Nubarov, N. A. Fedoseev, T. U. Dorodnich, V. Y. Alakhov, V. P. Chekhonin, I. R. Nazarova, and V. A. Kabanov (1992), A new class of drug carriers: micelles of poly(oxyethylene)-poly(oxypropylene) block copolymers as microcantainers for drug targeting from blood in brain, J. Cont. Relaease 22, 141-157 https://doi.org/10.1016/0168-3659(92)90199-2
  6. Schmolka, I. R. (1991), Poloxamers in the Pharmaceutical Industry. In Polymers for Controlled Drug Delivery, P. J. Tarcha Eds., p189, CRC Press Boca Raton
  7. Johnston, T. P., M. A. Punjabi, and C. J. Froelich (1992), Sustained delivery of interleukin-2 from a poloxamer 407 gel matrix following intraperitoneal injection in mice, Pharm. Res. 9, 425-434 https://doi.org/10.1023/A:1015815624334
  8. Miller, S. C. and M. D. Donovan (1982), Effect of poloxamer 407 gel on the miotic activity of pilocarpine nitrate in rabbits, Int. J. Pharm. 12, 147-152 https://doi.org/10.1016/0378-5173(82)90114-4
  9. Waring, G. O. and R. R. Harris (1979), Double masked evaluation of poloxamer artificial tear in keratoconjunctivitis. In Symposium on Ocular Therapy. Vol. 11, J. H. Leopold and R. P. Burnsm, Eds., p127, Wiley, N.Y.
  10. Ford, J. L. M. H. Rubinstein, F. McCaul, and J. E. Edgar (1987), Importance of drug type, tablet shape and added diluents on drug release kinetics from hydroxypropylmethylcellulose matrix tablets, Int. J. Pharm. 40, 223-224 https://doi.org/10.1016/0378-5173(87)90172-4
  11. Desai, S. D. and J. Blanchard (1998), In vitro evaluation of pluronic F127-based controlled-release ocular delivery systems for pilocarpin, Pharm. Sci. 87, 226-230 https://doi.org/10.1021/js970090e
  12. Schmolka, I. R. (1972), Artificial skin. Preparation and properties of pluronic F-127 gels for the treatment of burns, J. Biomed Mat. Res. 6, 571-582 https://doi.org/10.1002/jbm.820060609
  13. Urtti, A., M. Juslin, and O. Minalainen (1985), Pilocarpine release from hydroxypropyl-cellulose-polyvinylpyrrolidone matrices, Int. J. Pharm. 25, 165-178 https://doi.org/10.1016/0378-5173(85)90090-0
  14. Guzman, M., F. F. Garcia, and M. R. Aberturas (1992), Polyoxyethylene-polyoxypropylene block copolymer gels as sustained release vehicles for subcutaneous drug administration, Int. J. Pharm. 80, 119-127 https://doi.org/10.1016/0378-5173(92)90269-8
  15. Bhardwaj, R. and J. Blanchard (1996), Using poloxamer 407 controlled-release delivery system for the $\alpha$-MSH analogue melatan-I, J. Pharm. Sci. 85, 915-919 https://doi.org/10.1021/js960097g
  16. Alexandridis, P. and T. A. Hatton (1995), Poly(ethylene oxide)poly( propylene oxide)-poly(ethylene oxide) block copolymer surfactants in aqueous solutions and at interfaces: thermodynamics, structure, dynamics, and modeling, Colloid & Surfaces A 96, 1-46 https://doi.org/10.1016/0927-7757(94)03028-X
  17. Alexandridis, P., D. Zhou, A. Khan (1996), Lyotropic Liquid Crystallinity in Amphiphilic Block Copolymers: Temperature Effects on Phase Behavior and Structure for Poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) Copolymers, Langmuir 12, 2690-2700 https://doi.org/10.1021/la951025s
  18. Katakam, M., L. N. Bell, and A. K. Banga (1995), Effect of surfactants on the physical stability of recombinant human growth hormone, J. Pharm. Sci. 84, 713-716 https://doi.org/10.1002/jps.2600840609
  19. Joshi, A., S. Ding, and K. J. Himmelstein (1993), US Patent 5, 252318