Presentation Title

Hidetoshi Arima1, Taishi Higashi1, Keiichi Motoyama1

1Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University.

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1. Bah S., Grand E., Maury S. Journal name, vol, pp-pp(2008).

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

Naoko Ohshita1, Anna Tajima1, Taishi Higashi1, Keiichi Motoyama1, Sawako Koyama2, Ruriko Iibuchi2, Shiuhei Mieda2, Kenji Handa2, Hidetoshi Arima1, 3

1Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2Terumo Corporation,R&D Headquarters,3Program for Leading Graduate Schools “HIGO Program”, Kumamoto University.

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(Purpose)Recently, various kinds of protein drugs have been formulated as the recombinant DNA technologiesadvance. Particularly, the subcutaneous formulation, which is available for the self-administration,has been expected to apply for protein drugs represented by an antibody. Because a subcutaneous formulation has less administration capacity than an intravenous one, it becomes necessary to concentrate anantibody in the subcutaneous formulation. However, the highly-concentrated antibody is likely to form an aggregate during the storage and transportation, and concerns about the loss of pharmacological activity and the immunogenicity are raised. Meanwhile, we previously reported the potential use of polypseudorotaxane (PPRX) hydrogels prepared by cyclodextrins (CyDs) and polyethylene glycol (PEG, MW20,000) as sustained release systems for protein drugs such as insulin. Therefore, in the present study, we designed and evaluated the highly-concentrated human IgG formulation using PEG/CyDs PPRX hydrogels.

(Materials and Method)The-CyD solution (145 mg/mL) or -CyD solution (232 mg/mL)containing human IgG (130 mg/mL) was mixed with PEG solution (0.02 M, MW20,000). The mixture was kept in a refrigerator at 4°C for 12 h to form a viscous gel. The threading of CyDs onto the PEG chains and formation of their supramolecular self-assembly in the hydrogels were confirmed by X-ray diffraction pattern. The stability of human IgG encapsulated into the hydrogel was evaluated after heating (60°C, 30 min) or shaking (500 rpm, 1 week) by a UV spectrometer (280 nm).

(Results and Discussion)The X-ray diffraction patterns of human IgG/CyD hydrogels were different from those of physical mixtures, but the same as those of CyD PPRX hydrogels. These results suggest that PEG/-CyD and PEG/-CyD PPRXssuccessfully formedthe hydrogels containing highly-concentrated human IgG (130 mg/mL). Human IgG encapsulated into the hydrogels were released in accordance with non-Fickian diffusion model. In addition, the stability of human IgGencapsulated intoPEG/CyDs PPRX hydrogelsagainstthe heat and shaking stress were markedlyimproved.

(Conclusion)These results suggest that PEG/CyDs PPRX hydrogels have the potential for the preparation of highly-concentrated human IgG.