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

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

doi:10.1021/acs.molpharmaceut.7b00521

Yingyue Zhang, Robert K Prud'Homme + Show 7 more

Open Access

https://doi.org/10.1021/acs.molpharmaceut.7b00521

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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.

Highlights

Clofazimine presents with a red color and is a lipophilic riminophenazine antibiotic which has been recommended by the World Health Organization (WHO) and prescribed with other medicines for the treatment of leprosy as a multidrug therapy (MDT) for over four decades
hypromellose acetate succinate (HPMCAS) is a cellulosic polymer synthesized by esterification of HPMC with acetic anhydride and succinic anhydride
Three HPMCAS polymers with different substitution ratios of succinyl and acetyl groups were studied in order to compare their ability to stabilize clofazimine nanoparticles during the flash nanoprecipitation (FNP) process

Summary

Introduction

Clofazimine presents with a red color and is a lipophilic riminophenazine antibiotic which has been recommended by the World Health Organization (WHO) and prescribed with other medicines for the treatment of leprosy as a multidrug therapy (MDT) for over four decades. Clofazimine was identified as a potential new treatment of cryptosporidiosis through a high-throughput phenotypic screen.[4] Cryptosporidiosis is a leading cause of diarrhea in children in the developing world, caused by Cryptosporidium infections in the intestine. Unlike leprosy, which is a chronic disease and long-term infection, cryptosporidiosis requires fast-acting treatment, as it leads to severe symptoms such as dehydration, vomiting, and fever, contributing to morbidity in infants and small children.[5,6] Given the relatively slow absorption of Lamprene and high interpatient variability, a faster-releasing and more bioavailable formulation of clofazimine is highly desirable.[7]

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