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Clofazimine-Loaded Mucoadhesive Nanoparticles Prepared by Flash Nanoprecipitation for Strategic Intestinal Delivery

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Abstract

Purpose

This study was undertaken to develop novel mucoadhesive formulations of clofazimine (CFZ), a drug candidate for the treatment of cryptosporidiosis, with the aim of strategic delivery to the small intestine, the main site of the disease parasites.

Methods

CFZ-loaded nanoparticles (nCFZ) coated with non-biodegradable anionic polymer (nCFZ/A) and biodegradable anionic protein complex (nCFZ/dA) were prepared by Flash NanoPrecipitation (FNP) and evaluated for their physicochemical and biopharmaceutical properties.

Results

The mean diameters of nCFZ/A and nCFZ/dA were ca. 90 and 240 nm, respectively, and they showed narrow size distributions and negative ζ-potentials. Both formulations showed higher solubility of CFZ in aqueous solution than crystalline CFZ. Despite their improved dispersion behaviors, both formulations exhibited significantly lower diffusiveness than crystalline CFZ in a diffusion test using artificial mucus (AM). Quartz crystal microbalance analysis showed that both formulations clearly interacted with mucin, which appeared to be responsible for their reduced diffusiveness in AM. These results suggest the potent mucoadhesion of nCFZ/A and nCFZ/dA. After the oral administration of CFZ samples (10 mg-CFZ/kg) to rats, nCFZ/dA and nCFZ/A exhibited a prolongation in Tmax by 2 and >9 h, respectively, compared with crystalline CFZ. At 24 h after oral doses of nCFZ/A and nCFZ/dA with mucoadhesion, there were marked increases in the intestinal CFZ concentration (4–7 fold) compared with Lamprene®, a commercial CFZ product, indicating enhanced CFZ exposure in the small intestine.

Conclusion

The use of FNP may produce mucoadhesive CFZ formulations with improved intestinal exposure, possibly offering enhanced anti-cryptosporidium therapy.

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Funding

This work was financially supported by JSPS KAKENHI [a Grant-in-Aid for Scientific Research (C) (No. 20 K07158: S. Onoue, No. 20 K07180: H. Sato)]. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship under Grant No. #DGE-1656466 awarded to KDR.

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Authors and Affiliations

  1. Laboratory of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Kohei Yamada, Yuki Kaneko, Hideyuki Sato & Satomi Onoue

  2. Department of Chemical & Biological Engineering, A301 EQUAD, Princeton University, Princeton, NJ, 08544, USA

    Kurt D. Ristroph, Hoang D. Lu & Robert K. Prud’homme

Authors
  1. Kohei Yamada
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  2. Kurt D. Ristroph
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  3. Yuki Kaneko
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  4. Hoang D. Lu
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  5. Hideyuki Sato
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  6. Robert K. Prud’homme
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  7. Satomi Onoue
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Correspondence to Robert K. Prud’homme or Satomi Onoue.

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Yamada, K., Ristroph, K.D., Kaneko, Y. et al. Clofazimine-Loaded Mucoadhesive Nanoparticles Prepared by Flash Nanoprecipitation for Strategic Intestinal Delivery. Pharm Res 38, 2109–2118 (2021). https://doi.org/10.1007/s11095-021-03144-3

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