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

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.

Chromatographic method for the simultaneous quantification of dapsone and clofazimine in nanoformulations

“…Compared to previously reported efficiency entrapment values for other formulations, similar values were obtained for DAP loaded in surfacefunctionalized solid lipid nanoparticles based on cetyl palmitate [12], but lower than those reported for theospheres [9]. Concerning CLZ, better entrapment efficiency was reported for more hydrophobic formulations, based on hypromellose acetate succinate, lecithin, and zein [13]. This is expected, considering the hydrophobic character of CLZ.…”

Impact of molecular rearrangement of amphiphilic stabilizers on physical stability of itraconazole nanoparticles prepared by flash nanoprecipitation

“…For instance, their extremely large surface area to volume ratio accounts for their significantly higher saturation solubility and dissolution rate compared to their coarse counterparts. This unique characteristic has been successfully exploited in the solubility enhancement of poorly water-soluble drugs (Zhang et al, 2017). Specifically, drug-loaded polymeric nanoparticles with particle size below 200 nm have been shown capable of crossing biological barriers (Fernandes et al, 2010), mitigating first-pass hepatic metabolism (Italia et al, 2007) and displaying enhanced permeability and retention (EPR) effect (Allen and Cullis, 2004).…”

“…However, in spite of its high efficiency and excellent reproducibility, FNP has been successfully applied to the production of stable nanoparticles for only a limited number of highly hydrophobic compounds or drugs including beta-carotene (Zhu et al, 2010), paclitaxel (Saad, 2007) and bifenthrin (Liu et al, 2008b). To ensure good nanoparticle stability, it has been suggested that the compound involved must have a log P value of over 6 (Zhang et al, 2017;Zhu, 2014). However, drugs typically have log P values between 3 and 6, which inevitably raise serious instability issue when they are prepared as nanoparticles by FNP.…”

Flash NanoPrecipitation for the Encapsulation of Hydrophobic and Hydrophilic Compounds in Polymeric Nanoparticles

“…These formulations are intended to provide access points for learning the process and consequently use non-degradable poly(styrene)-based polymers. Alternative stabilizers have been described in the literature, with a number of biocompatible commercial options available 14,23,24 .…”