Design and Solidification of Fast-Releasing Clofazimine Nanoparticles for Treatment of Cryptosporidiosis

Yingyue Zhang, Jie Feng, Simon A. McManus, Hoang D. Lu, Kurt D. Ristroph, Eugene J. Cho, Ellen L. Dobrijevic, Hak Kim Chan, Robert K. Prud'Homme

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Clofazimine, a lipophilic (log P = 7.66) riminophenazine antibiotic approved by the US Food and Drug Administration (FDA) with a good safety record, was recently identified as a lead hit for cryptosporidiosis through a high-throughput phenotypic screen. Cryptosporidiosis requires fast-acting treatment as it leads to severe symptoms which, if untreated, result in morbidity for infants and small children. Consequently, a fast-releasing oral formulation of clofazimine in a water-dispersible form for pediatric administration is highly desirable. In this work, clofazimine nanoparticles were prepared with three surface stabilizers, hypromellose acetate succinate (HPMCAS), lecithin, and zein, using the flash nanoprecipitation (FNP) process. Drug encapsulation efficiencies of over 92% were achieved. Lyophilization and spray-drying were applied and optimized to produce redispersible nanoparticle powders. The release kinetics of these clofazimine nanoparticle powders in biorelevant media were measured and compared with those of crystalline clofazimine and the currently marketed formulation Lamprene. Remarkably improved dissolution rates and clofazimine supersaturation levels up to 90 times equilibrium solubility were observed with all clofazimine nanoparticles tested. Differential scanning calorimetry indicated a reduction of crystallinity of clofazimine in nanoparticles. These results strongly suggest that the new clofazimine nanoparticles prepared with affordable materials in this low-cost nanoparticle formulation process can be used as viable cryptosporidiosis therapeutics.

Original languageEnglish (US)
Pages (from-to)3480-3488
Number of pages9
JournalMolecular Pharmaceutics
Volume14
Issue number10
DOIs
StatePublished - Oct 2 2017

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Keywords

  • clofazimine
  • cryptosporidiosis
  • flash nanoprecipitation
  • hypromellose acetate succinate
  • lecithin
  • lyophilization
  • spray-drying
  • zein

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    Zhang, Y., Feng, J., McManus, S. A., Lu, H. D., Ristroph, K. D., Cho, E. J., Dobrijevic, E. L., Chan, H. K., & Prud'Homme, R. K. (2017). Design and Solidification of Fast-Releasing Clofazimine Nanoparticles for Treatment of Cryptosporidiosis. Molecular Pharmaceutics, 14(10), 3480-3488. https://doi.org/10.1021/acs.molpharmaceut.7b00521