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Design and Evaluation of the Highly Concentrated Human IgG Formulation Using Cyclodextrin Polypseudorotaxane Hydrogels

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Abstract

To achieve the potent therapeutic effects of human immunoglobulin G (IgG), highly concentrated formulations are required. However, the stabilization for highly concentrated human IgG is laborious work. In the present study, to investigate the potentials of polypseudorotaxane (PPRX) hydrogels consisting of polyethylene glycol (PEG) and α- or γ-cyclodextrin (α- or γ-CyD) as pharmaceutical materials for highly concentrated human IgG, we designed the PPRX hydrogels including human IgG and evaluated their pharmaceutical properties. The α- and γ-CyDs formed PPRX hydrogels with PEG (M.W. 20,000) even in the presence of highly concentrated human IgG (>100 mg/mL). According to the results of 1H-NMR, powder X-ray diffraction, and Raman microscopy, the formation of human IgG/CyD PPRX hydrogels was based on physical cross-linking arising from their columnar structures. The release profiles of human IgG from the hydrogels were in accordance with the non-Fickian diffusion model. Importantly, the stabilities of human IgG included into the hydrogels against thermal and shaking stresses were markedly improved. These findings suggest that PEG/CyD PPRX hydrogels are useful to prepare the formulation for highly concentrated human IgG.

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References

  1. Chames P, Regenmortel MV, Weiss E, Baty D. Therapeutic antibodies: successes, limitations and hopes for the future. Br J Pharmacol. 2009;157:220–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Novaretti MC, Dinardo CL. Immunoglobulin: production, mechanisms of action and formulations. Rev Bras Hematol Hemoter. 2011;33:377–82.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Shapiro RS. Why I use subcutaneous immunoglobulin (SCIG). J Clin Immunol. 2013;33 Suppl 2:S95–8.

    Article  PubMed  Google Scholar 

  4. Daugherty AL, Mrsny RJ. Formulation and delivery issues for monoclonal antibody therapeutics. Adv Drug Deliv Rev. 2006;58:686–706.

    Article  CAS  PubMed  Google Scholar 

  5. Harris RJ, Shire SJ, Winter C. Commercial manufacturing scale formulation and analytical characterization of therapeutic recombinant antibodies. Drug Dev Res. 2004;61:137–54.

    Article  CAS  Google Scholar 

  6. Kanai S, Liu J, Patapoff TW, Shire SJ. Reversible self-association of a concentrated monoclonal antibody solution mediated by Fab-Fab interaction that impacts solution viscosity. J Pharm Sci. 2008;97:4219–27.

    Article  CAS  PubMed  Google Scholar 

  7. Shire SJ, Shahrokh Z, Liu J. Challenges in the development of high protein concentration formulations. J Pharm Sci. 2004;93:1390–402.

    Article  CAS  PubMed  Google Scholar 

  8. Saluja A, Badkar AV, Zeng DL, Kalonia DS. Ultrasonic rheology of a monoclonal antibody (IgG2) solution: implications for physical stability of proteins in high concentration formulations. J Pharm Sci. 2007;96:3181–95.

    Article  CAS  PubMed  Google Scholar 

  9. Wang W. Instability, stabilization, and formulation of liquid protein pharmaceuticals. Int J Pharm. 1999;185:129–88.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Bolli R, Woodtli K, Bartschi M, Hofferer L, Lerch P. L-Proline reduces IgG dimer content and enhances the stability of intravenous immunoglobulin (IVIG) solutions. Biologicals. 2010;38:150–7.

    Article  CAS  PubMed  Google Scholar 

  12. Charman SA, Mason KL, Charman WN. Techniques for assessing the effects of pharmaceutical excipients on the aggregation of porcine growth hormone. Pharm Res. 1993;10:954–62.

    Article  CAS  PubMed  Google Scholar 

  13. Ignatova Z, Gierasch LM. Inhibition of protein aggregation in vitro and in vivo by a natural osmoprotectant. Proc Natl Acad Sci U S A. 2006;103:13357–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Kerwin BA, Heller MC, Levin SH, Randolph TW. Effects of Tween 80 and sucrose on acute short-term stability and long-term storage at -20 degrees C of a recombinant hemoglobin. J Pharm Sci. 1998;87:1062–8.

    Article  CAS  PubMed  Google Scholar 

  15. Jorgensen L, Hostrup S, Moeller EH, Grohganz H. Recent trends in stabilising peptides and proteins in pharmaceutical formulation—considerations in the choice of excipients. Expert Opin Drug Deliv. 2009;6:1219–30.

    Article  CAS  PubMed  Google Scholar 

  16. Serno T, Carpenter JF, Randolph TW, Winter G. Inhibition of agitation-induced aggregation of an IgG-antibody by hydroxypropyl-β-cyclodextrin. J Pharm Sci. 2010;99:1193–206.

    Article  CAS  PubMed  Google Scholar 

  17. Szenczi A, Kardos J, Medgyesi GA, Závodszky P. The effect of solvent environment on the conformation and stability of human polyclonal IgG in solution. Biologicals. 2006;34:5–14.

    Article  CAS  PubMed  Google Scholar 

  18. Kiese S, Papppenberger A, Friess W, Mahler HC. Shaken, not stirred: mechanical stress testing of an IgG1 antibody. J Pharm Sci. 2008;97:4347–66.

    Article  CAS  PubMed  Google Scholar 

  19. Hillgren A, Lindgren J, Alden M. Protection mechanism of Tween 80 during freeze-thawing of a model protein, LDH. Int J Pharm. 2012;237:57–69.

    Article  Google Scholar 

  20. Mahler HC, Muller R, Friess W, Delille A, Matheus S. Induction and analysis of aggregates in a liquid IgG1-antibody formulation. Eur J Pharm Biopharm. 2005;59:407–17.

    Article  CAS  PubMed  Google Scholar 

  21. Ha E, Wang W, Wang WJ. Peroxide formation in polysorbate 80 and protein stability. J Pharm Sci. 2002;91:2252–64.

    Article  CAS  PubMed  Google Scholar 

  22. Kerwin BA. Polysorbates 20 and 80 used in the formulation of protein biotherapeutics: structure and degradation pathways. J Pharm Sci. 2008;97:2924–35.

    Article  CAS  PubMed  Google Scholar 

  23. Uekama K, Hirayama F, Irie T. Cyclodextrin drug carrier systems. Chem Rev. 1998;98:2045–76.

    Article  CAS  PubMed  Google Scholar 

  24. Higashi T, Tajima A, Motoyama K, Arima H. Cyclodextrin/poly(ethylene glycol) polypseudorotaxane hydrogels as a promising sustained-release system for lysozyme. J Pharm Sci. 2012;101:2891–9.

    Article  CAS  PubMed  Google Scholar 

  25. Harada A, Kamachi M. Complex formation between poly(ethylene glycol) and α-cyclodextrin. Macromolecules. 1990;23:2821–3.

    Article  CAS  Google Scholar 

  26. Harada A, Li J, Kamachi M. The molecular necklace: a rotaxane containing many threaded α-cyclodextrins. Nature. 1992;356:325–7.

    Article  CAS  Google Scholar 

  27. Harada A, Hashidzume A, Yamaguchi H, Takashima Y. Polymeric rotaxanes. Chem Rev. 2009;109:5974–6023.

    Article  CAS  PubMed  Google Scholar 

  28. Harada A, Li J, Kamachi M. Double-strand inclusion complexes of cyclodextrin threaded on poly(ethylene glycol). Nature. 1994;370:126–8.

    Article  CAS  Google Scholar 

  29. Li J. Cyclodextrin inclusion polymers forming hydrogels. Adv Polym Sci. 2009;222:79–112.

    Article  CAS  Google Scholar 

  30. Li J. Self-assembled supramolecular hydrogels based on polymer-cyclodextrin inclusion complexes for drug delivery. NPG Asia Mater. 2010;2:112–8.

    Article  Google Scholar 

  31. Li J, Loh XJ. Cyclodextrin-based supramolecular architectures: syntheses, structures, and applications for drug and gene delivery. Adv Drug Deliv Rev. 2008;60:1000–17.

    Article  CAS  PubMed  Google Scholar 

  32. Li JJ, Zhao F, Li J. Polyrotaxanes for applications in life science and biotechnology. Appl Microbiol Biotechnol. 2011;90:427–43.

    Article  CAS  PubMed  Google Scholar 

  33. Wenz G, Han BH, Muller A. Cyclodextrin rotaxanes and polyrotaxanes. Chem Rev. 2006;106:782–817.

    Article  CAS  PubMed  Google Scholar 

  34. Li J, Harada A, Kamachi M. Sol-gel transition during complex formation between α-cyclodextrin and high molecular weight poly(ethylene glycols) in aqueous solution. Polym J. 1994;26:1019–26.

    Article  CAS  Google Scholar 

  35. Abu IIH, Higashi T, Anno T, Motoyama K, Abd-ElGawad AE, El-Shabouri MH, et al. Potential use of γ-cyclodextrin polypseudorotaxane hydrogels as an injectable sustained release system for insulin. Int J Pharm. 2010;392:83–91.

    Article  Google Scholar 

  36. Higashi T, Hirayama F, Misumi S, Arima H, Uekama K. Design and evaluation of polypseudorotaxanes of pegylated insulin with cyclodextrins as sustained release system. Biomaterials. 2008;29:3866–71.

    Article  CAS  PubMed  Google Scholar 

  37. Harada A. Preparation and structures of supramolecules between cyclodextrins and polymers. Coord Chem Rev. 1996;148:115–33.

    Article  CAS  Google Scholar 

  38. Takeo K, Kuge T. Complexes of starchy materials with organic compounds. Part IV. X-ray diffraction of γ-cyclodextrin complexes. Agric Biol Chem. 1970;34:568–74.

    Article  CAS  Google Scholar 

  39. Topchieva IN, Tonelli AE, Panova IG, Matuchina EV, Kalashnikov FA, Gerasimov VI, et al. Two-phase channel structures based on α-cyclodextrin-polyethylene glycol inclusion complexes. Langmuir. 2004;20:9036–43.

    Article  CAS  PubMed  Google Scholar 

  40. Toropainen T, Heikkila T, Leppanen J, Matilainen L, Velaga S, Jarho P, et al. Crystal structure changes of γ-cyclodextrin after the SEDS process in supercritical carbon dioxide affect the dissolution rate of complexed budesonide. Pharm Res. 2007;24:1058–66.

    Article  CAS  PubMed  Google Scholar 

  41. Härtl E, Winter G, Besheer A. Influence of hydroxypropyl-β-cyclodextrin on the stability of dilute and highly concentrated immunoglobulin g formulations. J Pharm Sci. 2013;102:4121–31.

    Article  PubMed  Google Scholar 

  42. Li J, Ni X, Leong KW. Injectable drug-delivery systems based on supramolecular hydrogels formed by poly(ethylene oxide)s and α-cyclodextrin. J Biomed Mater Res A. 2003;65:196–202.

    Article  PubMed  Google Scholar 

  43. Ma D, Tu K, Zhang LM. Bioactive supramolecular hydrogel with controlled dual drug release characteristics. Biomacromolecules. 2010;11:2204–12.

    Article  CAS  PubMed  Google Scholar 

  44. Ma D, Zhang LM, Xie X, Liu T, Xie MQ. Tunable supramolecular hydrogel for in situ encapsulation and sustained release of bioactive lysozyme. J Colloid Interface Sci. 2011;359:399–406.

    Article  CAS  PubMed  Google Scholar 

  45. Telikepalli SN, Kumru OS, Kalonia C, Esfandiary R, Joshi SB, Middaugh RC, Volkin DB. Structural characterization of IgG1 mAb aggregates and particles generated under various stress conditions. J. Pharm. Sci. 2014; 103:796–809.

  46. Schellekens H. Factors influencing the immunogenicity of therapeutic proteins. Nephrol Dial Transplant. 2005;20 Suppl 6:vi3–9.

    CAS  PubMed  Google Scholar 

  47. Uversky VN. A GLYmmer of insight into fibril formation. Structure. 2005;13:1090–2.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Nihon Shokuhin Kako Co., Ltd. (Tokyo, Japan) for providing parent CyDs. The authors are grateful to T. Minamoto and N. Watabe, Renishaw Inc., for their assistance on a Raman microscope experiment.

Conflict of Interest

This study was funded by Terumo Corporation (Kanagawa, Japan). S. Koyama, R. Iibuchi, S. Mieda, K. Handa, and T. Kimoto are researchers of Terumo Corporation, R&D Headquarters.

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Authors and Affiliations

  1. Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan

    Taishi Higashi, Anna Tajima, Naoko Ohshita, Tatsunori Hirotsu, Irhan Ibrahim Abu Hashim, Keiichi Motoyama & Hidetoshi Arima

  2. Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program”, Kumamoto University, Kumamoto, Japan

    Tatsunori Hirotsu & Hidetoshi Arima

  3. Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Irhan Ibrahim Abu Hashim

  4. R&D Headquarters, Terumo Corporation, 1500 Inokuchi, Nakai-machi, Ashigarakami-gun, Kanagawa, 259-0151, Japan

    Sawako Koyama, Ruriko Iibuchi, Shiuhei Mieda, Kenji Handa & Tomoaki Kimoto

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  1. Taishi Higashi
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  2. Anna Tajima
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  3. Naoko Ohshita
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  12. Hidetoshi Arima
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Correspondence to Hidetoshi Arima.

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Higashi, T., Tajima, A., Ohshita, N. et al. Design and Evaluation of the Highly Concentrated Human IgG Formulation Using Cyclodextrin Polypseudorotaxane Hydrogels. AAPS PharmSciTech 16, 1290–1298 (2015). https://doi.org/10.1208/s12249-015-0309-x

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  • DOI: https://doi.org/10.1208/s12249-015-0309-x

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