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Polymer-Based Sustained-Release Dosage Forms for Protein Drugs, Challenges, and Recent Advances

  • Oral Controlled Release Development and Technology
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Abstract

While the concept of using polymer-based sustained-release delivery systems to maintain therapeutic concentration of protein drugs for extended periods of time has been well accepted for decades, there has not been a single product in this category successfully commercialized to date despite clinical and market demands. To achieve successful systems, technical difficulties ranging from protein denaturing during formulation process and the course of prolonged in vivo release, burst release, and incomplete release, to low encapsulation efficiency and formulation complexity have to be simultaneously resolved. Based on this updated understanding, formulation strategies attempting to address these aspects comprehensively were reported in recent years. This review article (with 134 citations) aims to summarize recent studies addressing the issues above, especially those targeting practical industrial solutions. Formulation strategies representative of three areas, microsphere technology using degradable hydrophobic polymers, microspheres made of water soluble polymers, and hydrophilic in vivo gelling systems will be selected and introduced. To better understand the observations and conclusions from different studies for different systems and proteins, physicochemical basis of the technical challenges and the pros and cons of the corresponding formulation methods will be discussed.

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References

  1. S. Frokjaer, and D. E. Otzen. Protein drugs stability: a formulation challenge. Nat. Rev. Drug Discov. 4:298–306 (2005).

    PubMed  CAS  Google Scholar 

  2. W. Wang. Lyophilization and development of solid protein pharmaceuticals. Int. J. Pharm. 203:1–60 (2000).

    PubMed  CAS  Google Scholar 

  3. S. Marc, S. Juergen, W. E. Hennink, and J. Wim. Recombinant gelatin hydrogels for the sustained release of proteins. J. Control Release. 119:301–312 (2007).

    Google Scholar 

  4. B. Jeong, Y. H. Bae, D. S. Lee, and S. W. Kim. Biodegradable copolymers as injectable drug-delivery systems. Nature. 388(28):860–862 (1997).

    PubMed  CAS  Google Scholar 

  5. A. Jostel, A. Mukherjee, J. Alenfall, L. Smethurst, and S. M. Shalet. A new sustained-release preparation of human growth hormone and its pharmacokinetic, pharmacodynamic and safety profile. Clin. Endocrinol. 62:623–627 (2005).

    CAS  Google Scholar 

  6. R. Langer, and J. Folkman. Polymers for sustained release of proteins and other macromolecules. Nature. 263:793–800 (1976).

    Google Scholar 

  7. C. Berkland, E. Pollauf, C. Raman, R. Silverman, K. Kim, and D. W. Pack. Macromolecule release from monodisperse PLG microspheres: control of release rates and investigation of release mechanism. J. Pharm. Sci. 96(5):1176–1191 (2007).

    PubMed  CAS  Google Scholar 

  8. V. R. Sinha, and A. Trehan. Biodegradable microspheres for protein delivery. J. Control Release. 90:261–280 (2003).

    PubMed  CAS  Google Scholar 

  9. S. P. Schwendeman. Recent advances in the stabilization of proteins encapsulated in injectable PLGA delivery systems. Crit. Rev. Ther. Drug Carrier Syst. 19(1):73–98 (2002).

    PubMed  CAS  Google Scholar 

  10. U. Bilati, E. Allemanm, and E. Doelker. Strategic approaches for overcoming peptide and protein instability within biodegradable nano- and microparticles. Eur. J. Pharm. Biopharm. 59:375–388 (2005).

    PubMed  CAS  Google Scholar 

  11. L. Jorgensen, E. H. Moeller, H. M. Nielsen, and S. Frokjaer. Preparing and evaluating delivery systems for proteins. Eur. J. Pharm Sci. 29:174–182 (2006).

    PubMed  CAS  Google Scholar 

  12. A. V. Finkelstein. Proteins: structural, thermodynamic and kinetic aspects. EDP Sci. 77:651–692 (2003).

    Google Scholar 

  13. A. S. Rosenberg. Effects of protein aggregates: an immunologic perspective. AAPS J. 8(3):E501–E507 (2006).

    PubMed  Google Scholar 

  14. V. W. Marco, W. E. Hennink, and J. Wim. Protein instability in poly(lactic-co-glycolic acid) microparticles. Pharm. Res. 17(10):1159–1167 (2000).

    Google Scholar 

  15. Y. C. Eva, K. Sampathkumar, W. R. Theodore, and J. F. Carpenter. Physical stability of proteins in aqueous solution: mechanism and driving forces in nonnative protein aggregation. Pharm. Res. 20(9):1325–1336 (2003).

    Google Scholar 

  16. K. A. Dill. Dominant forces in protein folding. Biochemistry. 29:7133–7155 (1990).

    PubMed  CAS  Google Scholar 

  17. D. B. Volkin, and A. M. Klibanov. Minimizing protein inactivation. In T. E. Creighton (ed.), Protein Function A Practical Approach, Information, Oxford, UK, 1989, pp. 1–24.

    Google Scholar 

  18. M. C. Lai, and E. M. Topp. Solid-state chemical stability of proteins and peptides. J. Pharm. Sci. 88(5):489–500 (1999).

    PubMed  CAS  Google Scholar 

  19. S. J. Shire, Z. Shahrokh, and J. Liu. Challenges in the development of high protein concentration formulations. J. Pharm. Sci. 93(6):1390–1402 (2004).

    PubMed  CAS  Google Scholar 

  20. S. Huub. Immunogenicity of therapeutic proteins. Nephrol. Dial. Transpl. 18:1257–1259 (2003).

    Google Scholar 

  21. J. L. Cleland, and J. S. Andrew. Stable formulations of recombinant human growth hormone and interferon-r for microencapsulation in biodegradable microspheres. Pharm. Res. 13(10):1464–1475 (1996).

    PubMed  CAS  Google Scholar 

  22. H. W. Byung, J. Ge, W. J. Yeong, and P. P. DeLuca. Preparation and characterization of a composite PLGA and poly(acryloyl hydroxyethyl starch) microsphere system for protein delivery. Pharm. Res. 8(11):600–606 (2001).

    Google Scholar 

  23. R. J. H. Stenekes, O. Franssen, E. M. Bommel, D. J. A. Crommelin, and W. E. Hennink. The preparation of dextran microspheres in an all-aqueous system: effect of the formulation parameters on particle characteristics. Pharm. Res. 15(4):557–561 (1998).

    PubMed  CAS  Google Scholar 

  24. T. Jin, L. Chen, H. Zhu, and inventors. Stable polymer aqueous/aqueous emulsion system and uses thereof. US patent 6 805 879. October 19, 2004.

  25. T. Jin, H. Zhu, J. Zhu, and inventors. Aquespheres, their preparation and uses thereof. US patent 6 998 393. Feb 14, 2006.

  26. O. G. Nils, and R. Mats. Starch microparticles. US patent 6 692 770 B2. Feb 17, 2004.

  27. L. Timo, and R. Mats. Encapsulation method. US patent 6 861 064 B1. Mar 1, 2005.

  28. J. L. Cleland, F. L. Olu, S. P. Johnsonb, and J. S. Andrew. Recombinant human growth hormone poly(lactic-co-glycolic acid) microsphere formulation development. Adv. Drug Delivery Rev. 28:71–84 (1997).

    CAS  Google Scholar 

  29. H. K. Kim, and T. G. Park. Microencapsulation of human growth hormone within biodegradable polyester microspheres: Protein aggregation stability and incomplete release mechanism. Biotechnol. Bioeng. 65:659–667 (1999).

    PubMed  CAS  Google Scholar 

  30. W. Wang. Protein aggregation and its inhibition in biopharmaceutics. Int. J. Pharm. 289:1–30 (2005).

    PubMed  CAS  Google Scholar 

  31. H. C. Tillmann, B. Kuhn, and J. Pill. Efficacy and immunogenicity of novel erythropoietic agents and conventional rhEPO in rats with renal insufficiency. Kidney Int. 9:60–67 (2006).

    Google Scholar 

  32. Y. Shi, and L. C. Li. Current advances in sustained release systems for parenteral drug delivery. Exp. Opin. Drug Deliv. 6:1039–1058 (2005).

    Google Scholar 

  33. T. Estey, J. C. Kang, S. P. Schwendeman, and J. F. Carpenter. BSA degradation under acidic conditions: a model for protein instability during release from PLGA delivery systems. J. Pharm. Sci. 95:1626–1639 (2006).

    PubMed  CAS  Google Scholar 

  34. L. Li, and S. P. Schwendeman. Mapping neutral microclimate pH in PLGA microspheres. J. Control Release. 101:163–173 (2005).

    PubMed  CAS  Google Scholar 

  35. G. Zhu, S. R. Mallery, and S. P. Schwendeman. Stabilization of proteins encapsulated in injectable poly (lactide-co-glycolide). Nat. Biotechnol. 18:52–57 (2000).

    PubMed  CAS  Google Scholar 

  36. K. Fu, D. W. Pack, A. M. Klibanov, and R. Langer. Visual evidence of acidic environment within degrading poly(lactic-co-glycolic acid) (PLGA) Microspheres. Pharm. Res. 17(1):100–106 (2000).

    PubMed  CAS  Google Scholar 

  37. A. Shenderova, T. G. Burke, and S. P. Schwendeman. The acidic microclimate in poly(lactide-co-glycolide) microspheres stabilizes camptothecins. Pharm. Res. 16(2):241–248 (1999).

    PubMed  CAS  Google Scholar 

  38. G. Zhu, and S. P. Schwendeman. Stabilization of proteins encapsulated in cylindrical poly(lactide-co-glycolide) implants: mechanism of stabilization by basic additives. Pharm. Res. 17(3):351–357 (2000).

    PubMed  CAS  Google Scholar 

  39. H. V. Marc, B. Katia, and F. B. Regenmortel. Immunogenicity of biopharmaceuticals: An example from erythropoietin. BioPharm. Int. 18(8):36–47 (2005).

    Google Scholar 

  40. S. Vivek, C. Purohit, M. Russell, and V. Sathyamangalam. Influence of aggregation on immunogenicity of recombinant human factor VIII in hemophilia a mice. J. Pharm. Sci. 95:358–371 (2006).

    Google Scholar 

  41. X. Li, Y. Zhang, and R. Yan. Influence of process parameters on the protein stability encapsulated in poly-DL-lactide-poly(ethylene glycol) microspheres. J. Control Release. 68:41–52 (2000).

    PubMed  CAS  Google Scholar 

  42. A. Sanchez, B. Villamayor, Y. Guo, J. McIver, and M. J. Alonso. Formulation strategies for the stabilization of tetanus toxoid in poly(lactide-co-glycolide) microspheres. Int. J. Pharm. 185:255–266 (1999).

    PubMed  CAS  Google Scholar 

  43. B. Gander, P. Johansen, H. Nam-Tran, and H. P. Merkle. Thermodynamic approach to protein microencapsulation into poly(D,L-lactide) by spray drying. Int. J. Pharm. 129:51–61 (1996).

    CAS  Google Scholar 

  44. G. Jiang, B. H. Woo, F. Kang, J. Singh, and P. P. Deluca. Assessment of protein release kinetics, stability and protein polymer interaction of lysozyme encapsulated poly(D,L-lactide-co-glycolide) microspheres. J. Control Release. 79(1–3):137–145 (2002).

    PubMed  CAS  Google Scholar 

  45. S. P. Schwendeman, M. Tobio, M. J. Alonso, and R. Langer. New strategies for the microencapsulation of tetanus vaccine. J. Microencapsul. 15:299–318 (1998).

    PubMed  CAS  Google Scholar 

  46. S. P. Schwendeman, M. Cardamone, M. R. Brandon, A. Klibanov, and R. Langer. Stability of proteins and their delivery from biodegradable polymer microspheres. In S. C. H. Bernstein (ed.), Microparticulate Systems for the Delivery of Proteins and Vaccines, vol. 77, Mercel Dekker, New York, 1996, pp. 1–49.

    Google Scholar 

  47. M. Weert, R. V. Hof, M. A. Heeren, G. Posthuma, and W. E. Hennink. Lysozyme distribution and conformation in a biodegradable polymer matrix as determined by FTIR techniques. J. Control Release. 68(1):31–40 (2000).

    PubMed  Google Scholar 

  48. C. Perez, I. J. Castellanos, H. R. Costantino, and W. Al-Azzam. Recent trends in stabilizing protein structure upon encapsulation and release from bioerodible polymers. J. Pharm. Pharmacol. 54:301–313 (2002).

    PubMed  CAS  Google Scholar 

  49. H. Sah. Protein behavior at the water/methylene chloride interface. J. Pharm. Sci. 88:1320–1325 (1999).

    PubMed  CAS  Google Scholar 

  50. P. Reisz. Free radical formation induced by ultrasound and its biological implications. Free Rad. Biol. Med. 13:247–270 (1992).

    Google Scholar 

  51. K. S. Suslick, D. A. Hammerton, and R. E. Cline. The sonochemical hot spot. J. Am. Chem. Soc. 108:5641–5642 (1986).

    CAS  Google Scholar 

  52. H. K. Kim, and T. G. Park. Microencapsulation of human growth hormone within biodegradable polyester microspheres: protein aggregation, stability and incomplete release mechanism. Biotechnol. Bioeng. 65:659–667 (1999).

    PubMed  CAS  Google Scholar 

  53. M. J. Alonso, R. K. Gupta, C. Min, G. R. Siber, and R. Langer. Biodegradable microspheres as controlled-release tetanus toxoid delivery systems. Vaccine. 12:299–306 (1994).

    PubMed  CAS  Google Scholar 

  54. T. Cohen, M. Yoshioka, L. H. Lucarelli, and R. Langer. Controlled delivery systems for proteins based on poly(lactic/glycolic acid) microspheres. Pharm. Res. 8:713–720 (1991).

    PubMed  CAS  Google Scholar 

  55. T. G. Park, and W. Lu. Importance of in vitro experimental conditions on protein release kinetics, stability and polymer degradation in protein encapsulated poly(D,L-lactic acid-coglycolic acid) microspheres. J. Control Release. 33:211–222 (1995).

    CAS  Google Scholar 

  56. P. Johansen, Y. Men, R. Audran, G. Corradin, H. P. Merkle, and B. Gander. Improving stability and release kinetics of microencapsulated tetanus toxoid by co-encapsulation of additives. Pharm. Res. 15:1103–1110 (1998).

    PubMed  CAS  Google Scholar 

  57. C. Mass, S. Hermeling, B. Bouma, W. Jiskoot, and F. B. G. Martijin. A role for protein misfolding in immunogenicity of biopharmaceuticals. J. Biol. Chem. 282(4):2229–2236 (2007).

    Google Scholar 

  58. S. Huub, and C. Nicole. Immunogenicity of recombinant human proteins: causes and consequences. J. Neurol. 251(Suppl 2):1114–1119 (2004).

    Google Scholar 

  59. C. C. Thomas. The drug development crisis: efficiency and safety. Annu. Rev Med. 58:1–16 (2007).

    Google Scholar 

  60. J. Rossert. Erythropoietin-induced, antibody-mediated pure red cell aplasia. Eur. J. Clin. Invest. 35(Suppl. 3):95–99 (2005).

    PubMed  CAS  Google Scholar 

  61. A. Braun, L. Kwee, M. A. Labow, and J. Alsenz. Protein aggregates seem to play a key role among the parameters influencing the antigenicity of interferon alpha (IFN-alpha) in normal and transgenic mice. Pharm. Res. 14:1472–1478 (1997).

    PubMed  CAS  Google Scholar 

  62. G. Schernthaner. Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care. 16(Suppl 3):155–165 (1993).

    PubMed  Google Scholar 

  63. J. A. Cadee, W. Jiskoot, and W. E. Hennink. Release of recombinant human interleukin-2 from dextran-based hydrogels. J. Control Release. 78:1–13 (2002).

    PubMed  CAS  Google Scholar 

  64. W. Jiang, and S. P. Schwendeman. Stabilization and controlled release of bovine serum albumin encapsulated in poly(D, L-lactide) and poly(ethylene glycol) microsphere blends. Pharm. Res. 18(6):878–885 (2001).

    PubMed  CAS  Google Scholar 

  65. E. C. Lavelle, M. K. Yeh, and S. S. Davis. The stability and immunogenicity of a protein antigen encapsulated in biodegradable microparticles based on blends of lactide polymers and polyethylene glycol. Vaccine. 17:512–529 (1999).

    PubMed  CAS  Google Scholar 

  66. H. Gao, Y. N. Wang, Y. G. Fan, and J. B. Ma. Conjugates of poly(DL-lactide-co-glycolide) on amino cyclodextrins and their nanoparticles as protein delivery system. J. Biomed. Mater. Res—Part A. 80(1):111–122 (2007).

    Google Scholar 

  67. T. Akagi, M. Baba, and M. Akashi. Preparation of nanoparticles by the self-organization of polymers consisting of hydrophobic and hydrophilic segments: Potential applications. Polymer. 48(23):6729–6747 (2007).

    CAS  Google Scholar 

  68. J. F. Carpenter, and J. H. Crowe. The mechanism of cryoprotection of proteins by solutes. Cryobiology. 25:244–255 (1988).

    PubMed  CAS  Google Scholar 

  69. T. Morita, Y. Horikiri, H. Yamahara, T. Suzuki, and H. Yoshino. Formation and isolation of spherical fine protein microparticles through lyophilization of protein–poly(ethylene glycol) aqueous mixture. Pharm. Res. 17(11):1367–1373 (2000).

    PubMed  CAS  Google Scholar 

  70. K. J. Brodbeck, S. Pushpala, and A. J. McHugh. Sustained release of human growth hormone from PLGA solution depots. Pharm. Res. 16:1825–1829 (1999).

    PubMed  CAS  Google Scholar 

  71. S. E. Zale, P. A. Burke, H. Berstein, A. Brickner, and inventors. Composition for sustained release of non-aggregated erythropoietin. US patent 5 716 644. Feb 10, 1998.

  72. D. Rosa, D. Larobina, M. I. L. Rotonda, P. Musto, F. Quaglia, and F. Ungaro. How cyclodextrin incorporation affects the properties of protein-loaded PLGA-based microspheres: the case of insulin/hydroxypropyl-h-cyclodextrin system. J. Control Release. 102:71–83 (2005).

    PubMed  Google Scholar 

  73. W. Wang. Instability, stabilization, and formulation of liquid protein pharmaceuticals. Int. J. Pharm. 185:129–188 (1999).

    PubMed  CAS  Google Scholar 

  74. T. Jin, Y. Geng, F. Wu, and W. E. Yuan. Sustained-release system for EPO and GM-CSF, PCT/CN2007/002962.

  75. R. J. H. Stenekes, O. Franssen, E. M. G. van Bommel, D. J. A. Crommelin, and W. E. Hennink. The preparation of dextran microspheres in an all-aqueous system: effect of the formulation parameters on particle. Pharm. Res. 15(4):557–561 (1998).

    PubMed  CAS  Google Scholar 

  76. R. J. H. Stenekes, O. Franssen, E. M. G. van Bommel, D. J. A. Crommelin, and W. E. Hennink. The use of aqueous PEG:dextran phase separation for the preparation of dextran microspheres. Int. J. Pharm. 183:29–32 (1999).

    PubMed  CAS  Google Scholar 

  77. M. W. Edelman, E. V. D. Linden, and R. H. Tromp. Phase separation of aqueous mixtures of poly(ethylene oxide) and dextran. Macromolecules. 36:7783–7790 (2003).

    CAS  Google Scholar 

  78. T. Gisela, N. Bibiana, and P. Guillero. Relationship between the protein surface hydrophobicity and its partitioning behaviour in aqueous two-aqueous systems of polyethyleneglycol–dextran. J. Chromatogr. B. 799:293–301 (2004).

    Google Scholar 

  79. W. E. Yuan, and T. Jin. Aqueous–aqueous emulsion based sustained protein delivery system and its application in recombinant human growth hormone. Shanghai Jiao Tong University; 2007.

  80. T. Arakawa, S. J. Prestrelski, W. C. Kenney, and J. F. Carpenter. Factors affecting short-term and long-term stabilities of proteins. Adv. Drug Deliv. Rev. 10:1–28 (1993).

    CAS  Google Scholar 

  81. J. F. Carpenter, B. S. Chang, and T. W. Randolph. Rational design of stable lyophilized protein formulations: some practical advice. Pharm. Res. 14:969–975 (1997).

    PubMed  CAS  Google Scholar 

  82. T. Morita, and H. Yoshino. Preparation of gelatin microparticles by co-lyophilization with poly(ethylene glycol): characterization and application to entrapment into biodegradable microspheres. Int. J. Pharm. 219:127–137 (2001).

    PubMed  CAS  Google Scholar 

  83. O. G. Nils, J. Monica, R. Mats, and inventors. Microparticle preparation. US patent 7 033 609 B2. April 25, 2006.

  84. K. G. Carrasquillo, A. M. Stanley, C. J. C. Aponte, J. P. De, H. R. Costantino, C. J. Bosques, and K. Griebenow. Non-aqueous encapsulation of excipient-stabilized spray-freeze dried BSA into poly(lactide-co-glycolide) microspheres results in release of native protein. J. Control Release. 76(3):199–208 (2001).

    PubMed  CAS  Google Scholar 

  85. M. Morlock, H. Koll, G. Winter, and T. Kissel. Microencapsulation of rh-erythropoietin using biodegradable poly(D,L-lactideco-glycolide): protein stability and the effects of stabilizing excipients. Eur. J. Pharm. Biopharm. 43:29–36 (1997).

    CAS  Google Scholar 

  86. J. H. Kim, A. Taluja, K. Knutson, and Y. H. Bae. Stability of bovine serum albumin complexed with PEG-poly(l-histidine) diblock copolymer in PLGA microspheres. J. Control Release. 109:86–100 (2005).

    PubMed  CAS  Google Scholar 

  87. J. H. Kim, A. Taluja, K. Knutson, and Y. H. Bae. Role of a novel excipient poly(ethylene glycol)-b-poly(L-histidine) in retention of physical stability of insulin in aqueous solutions. Pharm. Res. 24(8):1517–1526 (2007).

    Google Scholar 

  88. J. M. Bezemer, P. J. Dijkstra, and J. Feijena. A controlled release system for proteins based on poly(ether ester) block-copolymers: polymer network characterization. J. Control Release. 62:393–405 (1999).

    PubMed  CAS  Google Scholar 

  89. J. M. Bezemer, R. Radersma, and J. Feijena. Zero-order release of lysozyme from poly(ethylene glycol)/poly(butylene terephthalate) matrices. J. Control Release. 64:179–192 (2000).

    PubMed  CAS  Google Scholar 

  90. J. M. Bezemer, R. Radersma, D. W. Grijpma, P. J. Dijkstra, and J. Feijena. Microspheres for protein delivery prepared from amphiphilic multiblock copolymers 2. Modulation of release rate. J. Control Release. 67:249–260 (2000).

    PubMed  CAS  Google Scholar 

  91. N. Kumar, R. Langer, and A. J. Bomb. Polyanhydrides: an overview. Adv. Drug Del. Rev. 54:889–910 (2002).

    CAS  Google Scholar 

  92. C. Govardhan, N. Khalaf, C. W. Jung, B. Simeone, A. Higbie, S. Qu, L. Chemmalil, S. Pechenov, S. K. Basu, and A. L. Margolin. Novel long-acting crystal formulation of human growth hormone. Pharm Res. 22(9):1461–1470 (2005).

    PubMed  CAS  Google Scholar 

  93. S. Pechenov, B. Shenoy, and M. X. Yang. Injectable controlled release formulations incorporating protein crystals. J. Control Release. 96:149–158 (2004).

    PubMed  CAS  Google Scholar 

  94. S. K. Hahn, S. J. Kim, M. J. Kim, and D. H. Kim. Characterization and in vivo study of sustained-release formulation of human growth hormone using sodium hyaluronate. Pharm. Res. 21(8):1374–1381 (2004).

    PubMed  CAS  Google Scholar 

  95. S. J. Kim, S. K. Hahn, M. J. Kim, D. H. Kim, and Y. P. Lee. Development of a novel sustained release formulation of recombinant human growth hormone using sodium hyaluronate microparticles. J. Control Release. 104:323–335 (2005).

    PubMed  CAS  Google Scholar 

  96. J. Cadee, L. A. Brouwer, J. A. Plantinga, and W. E. Hennink. In vivo biocompatibility of dextran-based hydrogels. J. Biomed. Mat. Res. 50:397–404 (2000).

    CAS  Google Scholar 

  97. J. A. M. Hoogeboom, and W. E. Hennink. Degradation and release behavior of dextran-based hydrogels. Macromolecules. 30:4639–4645 (1997).

    Google Scholar 

  98. T. L. Scott, L. R. Brown, F. J. Riske, C. D. Blizzard, S. J. Rashba, and inventors. Sustained release microspheres. US patent 6 458 387. October 1, 2002.

  99. S. Y. Cai, X. Liu, S. Zheng, and G. D. Prestwich. Injectable glycosaminoglycan hydrogels for controlled release of human basic fibroblast growth factor. Biomaterials. 26:6054–6067 (2005).

    PubMed  CAS  Google Scholar 

  100. D. Gupta, C. H. Tator, and M. S. Shoichet. Fast-gelling injectable blend of hyaluronan and methylcellulose for intrathecal, localized delivery to the injured spinal cord. Biomaterials. 27:2370–2379 (2006).

    PubMed  CAS  Google Scholar 

  101. A. Hatefi. Biodegradable injectable in situ forming drug delivery systems. J. Control Release. 80:9–28 (2002).

    PubMed  CAS  Google Scholar 

  102. B. Amsden, and E. Bravo-Grimaldo. Development of biodegradable injectable thermoplastic oligomers. Biomacromolecules. 5(2):637–642 (2004).

    PubMed  CAS  Google Scholar 

  103. A. Chenite, C. Chaput, and D. Wang. Novel injectable neutral solutions of chitosan form biodegradable gels in situ. Biomaterials. 21(21):2155–2161 (2000).

    PubMed  CAS  Google Scholar 

  104. C. S. Yong, J. S. Choi, and Q. Z. Quan. Effect of sodium chloride on the gelation temperature, gel strength and bioadhesive forces of poloxamer gels containing diclofenac sodium. Int. J. Pharm. 226(1–2):195–205 (2001).

    PubMed  CAS  Google Scholar 

  105. M. Yamamoto, Y. Takahashi, and Y. Tabata. Enhanced bone regeneration at a segmental bone defect by controlled release of bone morphogenetic protein-2 from a biodegradable hydrogel. Tissue Eng. 12:1305–1311 (2006).

    PubMed  CAS  Google Scholar 

  106. H. Park, J. S. Temenoff, T. A. Holland, Y. Tabata, and A. G. Mikos. Delivery of TGF-b1 and chondrocytes via injectable, biodegradable hydrogels for cartilage tissue engineering applications. Biomaterials. 26:7095–7103 (2005).

    PubMed  CAS  Google Scholar 

  107. M. Z. Gaylen, R. C. Ramesh, and S. Chung. Biodegradable block copolymers for delivery of proteins and water-insoluble drugs. J. Control Release. 72:203–221 (2001).

    Google Scholar 

  108. S. Choi, M. Baudys, and S. W. Kim. Control of blood glucose by novel GLP-1 delivery using biodegradable triblock copolymer of PLGA–PEG–PLGA in type 2 diabetic rats. Pharm. Res. 21(5):827–831 (2004).

    PubMed  CAS  Google Scholar 

  109. B. Jeong, Y. H. Bae, and S. W. Kim. In situ gelation of PEG–PLGA–PEG triblock copolymer aqueous solutions and degradation thereof. J. Biomed. Mater. Res. 50:171–177 (2000).

    PubMed  CAS  Google Scholar 

  110. T. Kissel, Y. X. Li, and F. Unger. ABA-triblock copolymers from biodegradable polyester A-blocks and hydrophilic poly(ethylene oxide) B-blocks as a candidate for in situ forming hydrogel delivery systems for proteins. Adv. Drug Delivery Rev. 54:99–134 (2002).

    CAS  Google Scholar 

  111. J. M. Harris. Introduction to biotechnical and biomedical applications of poly (ethylene glycol). In J. M. Harris (ed.), Poly(ethylene glycol) Chemistry, Plenum, New York, USA, 1992, pp. 1–14.

    Google Scholar 

  112. B. Qiu, S. Stefanos, J. Ma, A. Lalloo, B. A. Perry, M. J. Leibowitz, P. J. Sinko, and S. Stein. A hydrogel prepared by in situ cross-linking of a thiol containing poly(ethylene glycol)-based copolymer: a new biomaterial for protein drug delivery. Biomaterials. 24(1):11–18 (2002).

    Google Scholar 

  113. F. W. Okumu, L. N. Dao, P. J. Fielderb, N. Dybdal, D. Brooksa, S. Sane, and J. L. Cleland. Sustained delivery of human growth hormone from a novel gel system: SABER™. Biomaterials. 23:4353–4358 (2002).

    PubMed  CAS  Google Scholar 

  114. K. Griebenow, and A. M. Klibanov. On protein denaturation in aqueous–organic mixtures but not in pure organic solvents. JACS. 118:11695–11700 (1996).

    CAS  Google Scholar 

  115. S. Mohl, and G. Winter. Continuous release of rh-interferon α-2a from triglyceride matrices. J. Control Release. 97:67–78 (2004).

    PubMed  CAS  Google Scholar 

  116. S. Mohl, and G. Winter. Continuous release of rh-interferon α-2a from triglyceride implants: storage stability of the dosage forms. Pharm. Dev. Technol. 11:103–110 (2006).

    PubMed  CAS  Google Scholar 

  117. S. Surini, H. Akiyama, M. Morishita, T. Nagai, and K. Takayama. Release phenomena of insulin from an implantable device composed of a polyion complex of chitosan and sodium hyaluronate. J. Control Release. 90:291–301 (2003).

    PubMed  CAS  Google Scholar 

  118. I. C. Liao, A. C. A. Wan, E. K. F. Yim, and K. W. Leong. Controlled release from fibers of polyelectrolyte complexes. J. Control Release. 104:347–358 (2005).

    PubMed  CAS  Google Scholar 

  119. Y. Yamagata, K. Iga, and Y. Ogawa. Novel sustained-release dosage forms of proteins using polyglycerol esters of fatty acids. J. Control Release. 63:319–329 (2000).

    PubMed  CAS  Google Scholar 

  120. W. Ryu, Z. Huang, F. B. Prinz, S. B. Goodman, and R. Fasching. Biodegradable micro-osmotic pump for long-term and controlled release of basic fibroblast growth factor. J. Control Release. 124:98–105 (2007).

    PubMed  CAS  Google Scholar 

  121. R. R. Chen, and D. J. Mooney. Polymeric growth factor delivery strategies for tissue engineering. Pharm. Res. 20(8):1103–1112 (2003).

    PubMed  CAS  Google Scholar 

  122. N. Saitoa, N. Murakamib, J. Takahashib, H. Horiuchib, H. Otab, H. Katob, and K. Takaokae. Synthetic biodegradable polymers as drug delivery systems for bone morphogenetic proteins. Adv. Drug Delivery Rev. 57:1037–1048 (2005).

    Google Scholar 

  123. V. Luginbuehl, L. Meinel, H. P. Merkle, and B. Gander. Localized delivery of growth factors for bone repair. Eur. J. Pharm. Biopharm. 58:197–208 (2004).

    PubMed  CAS  Google Scholar 

  124. M. Geigera, R. H. Lib, and W. Friessc. Collagen sponges for bone regeneration with rhBMP-2. Adv. Drug Delivery Rev. 55:1613–1629 (2003).

    Google Scholar 

  125. T. A. Einhorn, R. J. Majeska, A. Mohaideen, E. M. Kagel, M. L. Bouxsein, T. J. Turek, and J. M. Wozney. A single percutaneous injection of recombinant human bone morphogenetic protein-2 accelerates fracture repair. J. Bone Joint Surg. Am. 85-A:1425–1435 (2003).

    PubMed  Google Scholar 

  126. R. C. Mulligan. The basic science of gene therapy. Science. 260:926–932 (1993).

    PubMed  CAS  Google Scholar 

  127. K. R. Cutroneo. Gene therapy for tissue regeneration. J. Cell Biochem. 88:418–425 (2003).

    PubMed  CAS  Google Scholar 

  128. C. J. McKenna, D. R. Holmes, and R. S. Schwartz. Novel stents for the prevention of restenosis. Trends Cardiovasc. Med. 7:245–249 (1997).

    Google Scholar 

  129. L. Kamol, G. W. John, G. Ronald, J. Y. Michael, and D. Arthur. Mechanisms, management, and outcome of failure of delivery of coronary stents. Am. J. Cardiol. 83:779–781 (1999).

    Google Scholar 

  130. R. K. Aggarwal, D. C. Ireland, M. A. Azrin, M. D. Ezekowitz, D. P. Bono, A. H. Gershlick, R. K. Aggrawal, and M. A. Ireland. Antithrombotic potential of polymer-coated stents eluting platelet glycoprotein IIb/IIIa receptor antibody. Circulation. 94:3311 (1996).

    PubMed  CAS  Google Scholar 

  131. R. S. Foo, A. H. Gershlick, and K. Hogrefe. Inhibition of platelet thrombosis using an activated protein C-loaded stent: in vitro and in vivo results. Thromb. Haemost. 83(3):496 (2000).

    PubMed  CAS  Google Scholar 

  132. W. R. Gombotz, and D. K. Pettit. Biodegradable polymers for protein and peptide drug delivery. Bioconjugate. Chem. 6:332–351 (1995).

    CAS  Google Scholar 

  133. E. V. Belle, T. Couffinhal, and T. Couffinhal. Stent endothelialization, time course, impact of local catheter delivery, feasibility of recombinant protein administration, and response to cytokine expedition. Circulation. 95(2):438 (1997).

    PubMed  Google Scholar 

  134. T. Jin, F. Wu, and W. E. Yuan, inventors. Polysaccharide microparticles containing biological agents: their preparation and applications. WO 2007001777. April 1, 2007.

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Acknowledgement

In preparation of this review article, data base search and other information collecting are financially supported by the National Natural Science Foundation of China (Grant No.30472096).

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  1. School of Pharmacy, Shanghai Jiaotong University, Shanghai, 200240, China

    Fei Wu & Tuo Jin

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  1. Fei Wu
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Wu, F., Jin, T. Polymer-Based Sustained-Release Dosage Forms for Protein Drugs, Challenges, and Recent Advances. AAPS PharmSciTech 9, 1218–1229 (2008). https://doi.org/10.1208/s12249-008-9148-3

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