Polymer-based sustained-release dosage forms for protein drugs, challenges, and recent advances

AAPS PharmSciTech

Volumn 9, Issue 4, 2008, Pages 1218-1229

  Wu, Fei ^a   Jin, Tuo ^a  

^a SHANGHAI JIAO TONG UNIVERSITY   (China)

Author keywords

Immunogenicity; Protein; Stability; Sustained release

Indexed keywords

AMMONIUM SULFATE; AMYLOPECTIN; COLLAGEN; COPOLYMER; DEXTRAN; ERYTHROPOIETIN; FATTY ACID ESTER; FATTY ACID POLYGLYCEROL ESTER; HETASTARCH; HUMAN GROWTH HORMONE; HYALURONIC ACID; INSULIN; MACROGOL; MICROSPHERE; OCTODEX; ORGANIC SOLVENT; PEPTIDE; POLY(ETHYLENE GLYCOL) POLYHISTIDINE COPOLYMER; POLYARGININE; POLYGLYCOLIC ACID; POLYLACTIC ACID; POLYMER; POLYSACCHARIDE; PROMAXX; RECOMBINANT ALPHA2A INTERFERON; RECOMBINANT BASIC FIBROBLAST GROWTH FACTOR; UNCLASSIFIED DRUG; PROTEIN;

ACIDITY; BIOCOMPATIBILITY; BIODEGRADATION; BODY TEMPERATURE; CELL DIFFERENTIATION; CROSS LINKING; DRUG DOSAGE FORM; DRUG ELUTING STENT; EMULSION; ENERGY; ENERGY BARRIER; FREEZE DRYING; GELATION; HUMAN; HYDROPHILICITY; HYDROPHOBICITY; IMMUNOGENICITY; IMPLANT; MICROENCAPSULATION; NONHUMAN; OSMOTIC PUMP; PARTICLE SIZE; PROTEIN AGGREGATION; PROTEIN CONFORMATION; PROTEIN DENATURATION; PROTEIN STABILITY; REVIEW; ROOM TEMPERATURE; STEM CELL; SUSTAINED DRUG RELEASE; SUSTAINED RELEASE FORMULATION; TIME TO MAXIMUM PLASMA CONCENTRATION; TISSUE REGENERATION; CHEMISTRY;

DOSAGE FORMS; MICROSPHERES; POLYMERS; PROTEINS;

EID: 63649138813     PISSN: None     EISSN: 15309932     Source Type: Journal    
DOI: 10.1208/s12249-008-9148-3     Document Type: Review

References (134)

1. S. Frokjaer, and D. E. Otzen. Protein drugs stability: A formulation challenge. Nat. Rev. Drug Discov. 4:298-306 (2005).
2. W. Wang. Lyophilization and development of solid protein pharmaceuticals. Int. J. Pharm. 203:1-60 (2000).
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).
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).
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).
6. R. Langer, and J. Folkman. Polymers for sustained release of proteins and other macromolecules. Nature. 263:793-800 (1976).
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).
8. V. R. Sinha, and A. Trehan. Biodegradable microspheres for protein delivery. J. Control Release. 90:261-280 (2003).
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).
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).
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).
12. A. V. Finkelstein. Proteins: Structural, thermodynamic and kinetic aspects. EDP Sci. 77:651-692 (2003).
13. A. S. Rosenberg. Effects of protein aggregates: An immunologic perspective. AAPS J. 8(3):E501-E507 (2006).
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).
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).
16. K. A. Dill. Dominant forces in protein folding. Biochemistry. 29:7133-7155 (1990).
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.
18. M. C. Lai, and E. M. Topp. Solid-state chemical stability of proteins and peptides. J. Pharm. Sci. 88(5):489-500 (1999).
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).
20. S. Huub. Immunogenicity of therapeutic proteins. Nephrol. Dial. Transpl. 18:1257-1259 (2003).
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).
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).
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).
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).
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).
30. W. Wang. Protein aggregation and its inhibition in biopharmaceutics. Int. J. Pharm. 289:1-30 (2005).
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).
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).
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).
34. L. Li, and S. P. Schwendeman. Mapping neutral microclimate pH in PLGA microspheres. J. Control Release. 101:163-173 (2005).
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).
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).
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).
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).
39. H. V. Marc, B. Katia, and F. B. Regenmortel. Immunogenicity of biopharmaceuticals: An example from erythropoietin. BioPharm. Int. 18(8):36-47 (2005).
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).
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).
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).
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).
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).
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).
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.
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).
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).
49. H. Sah. Protein behavior at the water/methylene chloride interface. J. Pharm. Sci. 88:1320-1325 (1999).
50. P. Reisz. Free radical formation induced by ultrasound and its biological implications. Free Rad. Biol. Med. 13:247-270 (1992).
51. K. S. Suslick, D. A. Hammerton, and R. E. Cline. The sonochemical hot spot. J. Am. Chem. Soc. 108:5641-5642 (1986).
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).
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).
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).
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).
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).
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).
58. S. Huub, and C. Nicole. Immunogenicity of recombinant human proteins: causes and consequences. J. Neurol. 251(Suppl 2):1114-1119 (2004).
59. C. C. Thomas. The drug development crisis: Efficiency and safety. Annu. Rev Med. 58:1-16 (2007).
60. J. Rossert. Erythropoietin-induced, antibody-mediated pure red cell aplasia. Eur. J. Clin. Invest. 35(Suppl. 3):95-99 (2005).
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).
62. G. Schernthaner. Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care. 16(Suppl 3):155-165 (1993).
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).
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).
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).
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).
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).
68. J. F. Carpenter, and J. H. Crowe. The mechanism of cryoprotection of proteins by solutes. Cryobiology. 25:244-255 (1988).
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).
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).
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).
73. W. Wang. Instability, stabilization, and formulation of liquid protein pharmaceuticals. Int. J. Pharm. 185:129-188 (1999).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
91. N. Kumar, R. Langer, and A. J. Bomb. Polyanhydrides: An overview. Adv. Drug Del. Rev. 54:889-910 (2002).
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).
93. S. Pechenov, B. Shenoy, and M. X. Yang. Injectable controlled release formulations incorporating protein crystals. J. Control Release. 96:149-158 (2004).
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).
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).
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).
97. J. A. M. Hoogeboom, and W. E. Hennink. Degradation and release behavior of dextran-based hydrogels. Macromolecules. 30:4639-4645 (1997).
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).
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).
101. A. Hatefi. Biodegradable injectable in situ forming drug delivery systems. J. Control Release. 80:9-28 (2002).
102. B. Amsden, and E. Bravo-Grimaldo. Development of biodegradable injectable thermoplastic oligomers. Biomacromolecules. 5(2):637-642 (2004).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
115. S. Mohl, and G. Winter. Continuous release of rh-interferon α-2a from triglyceride matrices. J. Control Release. 97:67-78 (2004).
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).
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).
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).
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).
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).
121. R. R. Chen, and D. J. Mooney. Polymeric growth factor delivery strategies for tissue engineering. Pharm. Res. 20(8):1103-1112 (2003).
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).
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).
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).
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).
126. R. C. Mulligan. The basic science of gene therapy. Science. 260:926-932 (1993).
127. K. R. Cutroneo. Gene therapy for tissue regeneration. J. Cell Biochem. 88:418-425 (2003).
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).
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).
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).
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).
132. W. R. Gombotz, and D. K. Pettit. Biodegradable polymers for protein and peptide drug delivery. Bioconjugate. Chem. 6:332-351 (1995).
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).
134. T. Jin, F. Wu, and W. E. Yuan, inventors. Polysaccharide microparticles containing biological agents: Their preparation and applications. WO 2007001777. April 1, 2007.