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

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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.

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          Most cited references41

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          Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability

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            Revisiting the method of cumulants for the analysis of dynamic light-scattering data.

            The method of cumulants is a standard technique used to analyze dynamic light-scattering data measured for polydisperse samples. These data, from an intensity-intensity autocorrelation function of the scattered light, can be described in terms of a distribution of decay rates. The method of cumulants provides information about the cumulants and the moments of this distribution. However, the method does not permit independent determination of the long-time baseline of the intensity correlation function and can lead to inconsistent results when different numbers of data points are included in the fit. The method is reformulated in terms of the moments about the mean to permit more robust and satisfactory fits. The different versions of the method are compared by analysis of the data for polydisperse-vesicle samples.
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              Clofazimine: current status and future prospects.

              Clofazimine, a lipophilic riminophenazine antibiotic, possesses both antimycobacterial and anti-inflammatory activities. However, its efficacy has been demonstrated only in the treatment of leprosy, not in human tuberculosis, despite the fact that this agent is impressively active in vitro against multidrug-resistant strains of Mycobacterium tuberculosis. Recent insights into novel targets and mechanisms of antimicrobial and anti-inflammatory activity coupled with the acquisition of innovative drug delivery technologies have, however, rekindled interest in clofazimine as a potential therapy for multidrug- and extensively multidrug-resistant tuberculosis in particular, as well as several autoimmune diseases. The primary objective of this review is to critically evaluate these recent developments and to assess their potential impact on improving the therapeutic efficacy and versatility of clofazimine.
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                Author and article information

                Journal
                Mol Pharm
                Mol. Pharm
                mp
                mpohbp
                Molecular Pharmaceutics
                American Chemical Society
                1543-8384
                1543-8392
                20 September 2017
                02 October 2017
                : 14
                : 10
                : 3480-3488
                Affiliations
                []Department of Chemical and Biological Engineering, Princeton University , Princeton, New Jersey 08854, United States
                []School of Pharmacy, University of Sydney , Sydney, New South Wales 2006, Australia
                Author notes
                Article
                10.1021/acs.molpharmaceut.7b00521
                5627342
                28929769
                519068c1-8163-41ec-95a4-301dd960ea3e
                Copyright © 2017 American Chemical Society

                This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.

                History
                : 20 June 2017
                : 09 August 2017
                : 03 August 2017
                Categories
                Article
                Custom metadata
                mp7b00521
                mp-2017-00521a

                Pharmacology & Pharmaceutical medicine
                clofazimine,flash nanoprecipitation,cryptosporidiosis,hypromellose acetate succinate,lecithin,zein,lyophilization,spray-drying

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