Long-lasting Immunosuppressive Effects of tacrolimus-loaded Micelle NK61060 in Preclinical Arthritis and Colitis Models

Abstract

Aim: Tacrolimus (TAC) is an important drug for inflammatory diseases. However, TAC has several limitations, such as variable trough concentrations among individuals and a high medication frequency. In this study, we created NK61060, a novel micellar TAC formulation, to circumvent these disadvantages. Materials & methods: Immunosuppressive activity of NK61060 was determined in the collagen-induced arthritis rat model, mannan-induced arthritis mouse model and dextran sodium sulfate-induced colitis mouse model. The pharmacokinetics and toxicology of NK61060 were evaluated in those models. Results: In arthritis and colitis models, NK61060 exhibited superior immunosuppressive activity compared with that of TAC. Pharmacokinetic and toxicological analyses indicated that NK61060 had a wider safety margin and could be administered at a reduced medication frequency. Conclusion: NK61060 mitigates the trough concentration variability and the medication frequency and it may be a safer and more effective option for use in clinical settings. Further studies are needed to determine its clinical usefulness.

Keywords:

• drug-delivery system
• immunosuppressive agent
• micelle

Acknowledgements

The authors thank Takuo Hiwatari, Kento Hosoya, Akiomi Kunitake, Takumi Matsumoto, Akihiko Sakamoto, Kazuumi Kotake and Yuko Okonogi for their assistance with the experiments and Yoshitaka Satoh for his technical advice.

Financial & competing interests disclosure

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the preparation of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval and have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. Specifically, all animal experiments were approved by the in-house Experimental Animal Ethics Committee of Nippon Kayaku. The animals were treated ethically in accordance with the Fundamental Guidelines for Proper Conduct of Animal Experiments issued by the Science Council of Japan.

Author's contributions

T Sato, J Konno, K Yamamoto, M Niwa, K Saiga and E Ichimura designed the research. A Sekiguchi, N Yoneki, K Kawano and T Hayashi synthesized and characterized NK61060. J Konno and Y Ogawa performed pharmacological study of CIA model rats and SKG model mice. T Sato, T Aijima and A Kikitsu performed pharmacological study of DSS-induced colitis model mice. Y Takashima, Y Kobayashi and M Mori performed pharmacokinetic study. K Hara, S Hara, H Hayashi, K Fuchigami, N Igo and E Ichimura performed toxicological study. All the authors wrote the manuscript.