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

Author(s): Zhang, Y; Feng, J; McManus, SA; Lu, HD; Ristroph, KD; et al

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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.
Publication Date: 2017
Citation: Zhang, Y, Feng, J, McManus, SA, Lu, HD, Ristroph, KD, Cho, EJ, Dobrijevic, EL, Chan, H-K, Prud Homme, RK. (2017). Design and Solidification of Fast-Releasing Clofazimine Nanoparticles for Treatment of Cryptosporidiosis. Molecular Pharmaceutics, 14 (3480 - 3488. doi:10.1021/acs.molpharmaceut.7b00521
DOI: doi:10.1021/acs.molpharmaceut.7b00521
Pages: 3480 - 3488
Type of Material: Journal Article
Journal/Proceeding Title: Molecular Pharmaceutics
Version: Final published version. This is an open access article.

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