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Preparation of peptide-loaded polymer microparticles using supercritical carbon dioxide

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Abstract

In this study, peptide-loaded microparticles were prepared using an aerosol solvent extraction system (ASES) by employing supercritical carbon dioxide as an antisolvent. The effects of the molecular weight of poly(Llactide) (PLLA), poly(ethylene glycol) (PEG), the block length of methoxy poly(ethylene glycol)-b-poly(L-lactide) (mPEG-PLLA), the blending of PLLA and PEG, and the drug-to-polymer feed ratio on the formation of leuprolide acetate (LA)-loaded microparticles and their release characteristics were investigated. Scanning electron microscope observations showed that the LA-loaded polymer particles had a spherical morphology with a smooth surface. The entrapment efficiency of LA in the ASES-processed microparticles was found to be extremely high (about 99%), whereas the initial release rate of the LA-loaded microparticles was very low for PLLA. The release rate of LA was observed to increase as the PEG block length of mPEG-PLLA and/or the drug content in the microparticles increased. When PLLA was blended with PEG, the release rate of LA from the PLLA/PEG microparticles was significantly faster compared with the corresponding mPEG-PLLA copolymer.

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References

  1. Sharifi, R., L. D. Knoll, J. Smith, and E. Kramolowsky (1998) Leuprolide acetate (30-mg depot every four months) in the treatment of advanced prostate cancer. Urol. 51: 271–276.

    Article  CAS  Google Scholar 

  2. Inada, K., T. Tominaga, M. Toi, Y. Yamamoto, M. Abe, J. Yamashita, and M. Ogawa (1996) Protective effect of leuprolide acetate on 7,12-dimehtylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in rats. Eur. J. Surg. Oncol. 22: 583–587.

    Article  CAS  Google Scholar 

  3. Covens, A., G. Thomas, P. Shaw, I. Ackerman, R. Osborne, H. Lukka, M. Carey, E. Franssen, and K. Roche (1997) A phase II study of leuprolide in advanced/recurrent endometrial cancer. Gynecol. Oncol. 64: 126–129.

    Article  CAS  Google Scholar 

  4. Lee, P. A. and J. G. Page (1989) Effects of leuprolide in the treatment of central precocious puberty. J. Pediatr. 114: 321–324.

    Article  CAS  Google Scholar 

  5. Wilson, A. C., S. V. Meethal, R. L. Bowen, and C. S. Atwood (2007) Leuprolide acetate:A drug of diverse clinical application. Experti. Opin. Investig. Drugs 16: 1–13.

    Article  Google Scholar 

  6. Qiu, Y., H. W. Johnson, T. L. Reiland, and M. -Y. F. Lu (1999) Sublingual absorption of leuprolide: comparison between human and animal models. Int. J. Pharm. 179: 27–36.

    Article  CAS  Google Scholar 

  7. Okada, H. (1997) One- and three-month release injectable microspheres of the LH-RH superagonist leuprorelin acetate. Adv. Drug Del. Rev. 28: 43–70.

    Article  CAS  Google Scholar 

  8. Woo, B. H., J. W. Kostanski, S. Gebrekidan, B. A. Dani, B. C. Thanoo, and P. P. DeLuca (2001) Preparation, characterization and in vivo evaluation of 120-day poly(d,l-lactide) leuprolide microspheres. J. Control. Rel. 75: 307–315.

    Article  CAS  Google Scholar 

  9. Ravivarapu, H. B., K. Burton, and P. P. DeLuca (2000) Polymer and microsphere blending to alter the release of a peptide from PLGA microspheres. Eur. J. Pharm. Biopharm. 50: 263–270.

    Article  CAS  Google Scholar 

  10. Alcock, R., J. A. Blair, D. J. O’Mahony, A. Raoof, and A. V. Quirk (2002) Modifying the release of leuprolide from spray dried OED microparticles. J. Control. Rel. 82: 429–440.

    Article  CAS  Google Scholar 

  11. Gref, R., A. Domb, P. Quellec, T. Blunk, R. H. Miiller, J. M. Verbavatz, and R. Langer (1995) The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres. Adv. Drug Deliv. Rev. 16: 215–233.

    Article  CAS  Google Scholar 

  12. Stolnik, S., S. E. Dunn, M. C. Garnett, M. C. Davies, A. G. A. Coombes, D. C. Taylor, M. P. Irving, S. C. Purkiss, T. F. Tadros, S. S. Davis, and L. Illum (1994) Surface modification of poly-(lactide-co-glycolide) nanospheres by biodegradable poly(lactide)-poly(ethylene glycol) copolymer. Pharm. Res. 11: 1800–1808.

    Article  CAS  Google Scholar 

  13. Robio, M., R. Gref, A. Sanchez, R. Langer, and M. J. Alonso (1998) Stealth PLA-PEG nanoparticles as protein carriers for nasal administration. Pharm. Res. 15: 270–275.

    Article  Google Scholar 

  14. Owens III, D. E. and N. A. Peppas (2006) Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. J. Pharm. 307: 93–102.

    Article  CAS  Google Scholar 

  15. Li, Y. -P., Y. -Y. Pei, X. -Y. Zhang, Z. -H. Gu, Z. -H. Zhou, W. -F. Yuan, J. -J. Zhou, J. -H. Zhu, and X. -J. Gao (2001) PEGylated PLGA nanoparticles as protein carriers: Synthesis, preparation and biodistribution in rats. J. Control. Rel. 71: 203–211.

    Article  CAS  Google Scholar 

  16. Yeo, Y., N. Baek, and K. Park (2001) Microencapsulation methods for delivery of protein drugs. Biotechnol. Bioproc. Eng. 6: 213–230.

    Article  CAS  Google Scholar 

  17. Yeo, S. D. and E. Kiran (2005) Formation of polymer particles with supercritical fluids: A review. J. Supercrit. Fluids 34: 287–308.

    Article  CAS  Google Scholar 

  18. Fages, J., H. T. Lochard, J. -J. Letourneau, M. Sauceau, and E. Rodier (2004) Particle generation for pharmaceutical applications using supercritical fluid technology. Powder Technol. 141: 219–226.

    Article  CAS  Google Scholar 

  19. Reverchon, E. (1999) Supercritical antisolvent precipitation of micro- and nano-particles. J. Supercrit. Fluids 15: 1–21.

    Article  CAS  Google Scholar 

  20. Huang, C., S. -H. Tsai, and C. -M. Chen (2006) Isothermal crystallization behavior of poly(L-lactide) in poly(L-lactide)-blockpoly( ethylene glycol) diblock copolymers. J. Polym. Sci. Part B: Polym. Phys. 44: 2438–2448.

    Article  CAS  Google Scholar 

  21. Kaihara, S., S. Matsumura, A. G. Mikos, and J. P. Fisher (2007) Synthesis of poly(L-lactide) and polyglycolide by ring-opening polymerization. Nat. Protoc. 2: 2767–2771.

    Article  CAS  Google Scholar 

  22. Gourgouillon, D. and M. Nunes da Ponte (1999) High pressure phase equilibria for poly(ethylene glycol)s + CO2: experimental results and modeling. Phys. Chem. Chem. Phys. 1: 5369–5375.

    Article  CAS  Google Scholar 

  23. Elvassore, N., A. Bertucco, and P. Caliceti (2001) Production of insulin-loaded poly(ethylene glycol)/poly(l-lactide) (PEG/PLA) nanoparticles by gas antisolvent techniques. J. Pharm. Sci. 90: 1628–1636.

    Article  CAS  Google Scholar 

  24. International Conferences on Harmonization (1997) Impurities-Guidelines for residual solvents, Q3C. Federal Register. 62: 67377–67388.

    Google Scholar 

  25. Jacobson, G. B., R. Shinde, C. H. Contag, and R. N. Zare (2008) Sustained release of drugs dispersed in polymer. Angew. Chem. Int. Ed. Engl. 47: 7880–7882.

    Article  CAS  Google Scholar 

  26. Kang, Y., C. Yang, P. Ouyang, G. Yin, Z. Huang, Y. Yao, and X. Liao (2009) The preparation of BSA-PLLA microparticles in a batch supercritical anti-solvent process. Carbohydr. Polym. 77: 244–249.

    Article  CAS  Google Scholar 

  27. Dong, Y. and S. -S. Feng (2004) Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs. Biomaterials 25: 2843–2849.

    Article  CAS  Google Scholar 

  28. Elvassor, N. and A. Bertucco (2001) Production of protein-loaded polymeric microcapsules by compressed CO2 in a mixed solvent. Ind. Eng. Chem. Res. 40: 795–800.

    Article  Google Scholar 

  29. Mehta, R. C., B. C. Thanoo, and P. P. DeLuca (1996) Peptide containing microspheres from low molecular weight and hydrophilic poly(d,l-lactide-co-glycolide). J. Control. Rel. 41: 249–257.

    Article  CAS  Google Scholar 

  30. Hyvönen, S., L. Peltonen, M. Karjalainen, and J. Hirvonen (2005) Effect of nanoprecipitation on the physicochemical properties of low molecular weight poly([scl]-lactic acid) nanoparticles loaded with salbutamol sulphate and beclomethasone dipronate, Int. J. Pharm. 295: 269–281.

    Article  Google Scholar 

  31. Wichert, B. and P. Rohdewald (1990) A new method for the preparation of drug containing polylactic acid microparticles without using organic solvents. J. Control. Rel. 14: 269–283.

    Article  CAS  Google Scholar 

  32. Palade, L. -I., H. J. Lehermeier, and J. R. Dorgan (2001) Melt rheology of high L-content poly(lactic acid). Macromol. 34: 1384–1390.

    Article  CAS  Google Scholar 

  33. López-Periago, A., C. A. García-González, and C. Domingo (2009) Solvent- and thermal-induced crystallization of poly-Llactic acid in supercritical CO2 medium. J. Appl. Pol. Sci. 111: 291–300.

    Article  Google Scholar 

  34. Westerman, D., S. P. Nalawade, G. A. Leeke, D. W. Grijpma, and R. C. D. Santos (2008) Analysis of melting point depression in biodegradable polymers using supercritical carbon dioxide by golden gate IR and high pressure DSC. Proceedings of 11th European Meeting on Supercritical Fluids. May 4–7, Barcelona, Spain.

  35. Martin, A., F. Mattea, L. Gutierrez, F. Miguel, and M. J. Cocero (2007) Co-precipitation of carotenoids and bio-polymers with the supercritical anti-solvent process. J. Supercr. Fluids 41: 138–147.

    Article  CAS  Google Scholar 

  36. Choi, Y., S. Y. Kim, M. -H. Moon, S. H. Kim, K. -S. Lee, and Y. Byun (2001) Poly(ethylene glycol)}poly(l-lactide) diblock copolymer prevents aggregation of poly(l-lactide) microspheres during ethylene oxide gas sterilization. Biomaterials 22: 995–1004.

    Article  CAS  Google Scholar 

  37. Lee, B. -C. and Y. -M. Kuk (2002) Phase behavior of poly(l-lactide) in supercritical mixtures of dichloromethane and carbon dioxide. J. Chem. Eng. Data 47: 367–370.

    Article  CAS  Google Scholar 

  38. Huang, Y. -Y., T. -W. Chung, and T. -W. Tzeng (1997) Drug release from PLA/PEG microparticulates. Int. J. Pharm. 156: 9–15.

    Article  CAS  Google Scholar 

  39. Caliceti, P., S. Salmaso, N. Elvassore, and A. Bertucco (2004) Effective protein release from PEG/PLA nano-particles produced by compressed gas anti-solvent precipitation techniques. J. Control. Rel. 94: 195–205.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul, 120-749, Korea

    In-Il Jung & Seoungjoo Haam

  2. Department of Chemical Engineering, The University of Suwon, Hwaseong, 445-743, Korea

    Giobin Lim & Jong-Hoon Ryu

Authors
  1. In-Il Jung
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  2. Seoungjoo Haam
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  3. Giobin Lim
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  4. Jong-Hoon Ryu
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Correspondence to Giobin Lim or Jong-Hoon Ryu.

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Jung, II., Haam, S., Lim, G. et al. Preparation of peptide-loaded polymer microparticles using supercritical carbon dioxide. Biotechnol Bioproc E 17, 185–194 (2012). https://doi.org/10.1007/s12257-011-0241-1

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