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Design and Solidification of Fast-Releasing Clofazimine Nanoparticles for Treatment of Cryptosporidiosis
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-09-20 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00521 Yingyue Zhang 1 , Jie Feng 1 , Simon A McManus 1 , Hoang D Lu 1 , Kurt D Ristroph 1 , Eugene J Cho 1 , Ellen L Dobrijevic 1 , Hak-Kim Chan 2 , Robert K Prud'homme 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-09-20 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00521 Yingyue Zhang 1 , Jie Feng 1 , Simon A McManus 1 , Hoang D Lu 1 , Kurt D Ristroph 1 , Eugene J Cho 1 , Ellen L Dobrijevic 1 , Hak-Kim Chan 2 , Robert K Prud'homme 1
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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.
中文翻译：
用于治疗隐孢子虫病的速释氯法齐明纳米颗粒的设计和固化
氯法齐明是一种亲脂性（log P = 7.66）丙米吩嗪抗生素，已获得美国食品和药物管理局（FDA）批准，具有良好的安全记录，最近通过高通量表型筛选被确定为治疗隐孢子虫病的主要药物。隐孢子虫病需要快速治疗，因为它会导致严重的症状，如果不治疗，会导致婴儿和幼儿发病。因此，非常需要一种用于儿科给药的水分散形式的氯法齐明快速释放口服制剂。在这项工作中，采用快速纳米沉淀 (FNP) 工艺，用三种表面稳定剂醋酸羟丙甲纤维素琥珀酸酯 (HPMCAS)、卵磷脂和玉米蛋白制备了氯法齐明纳米颗粒。药物包封率达到92%以上。应用并优化冻干和喷雾干燥来生产可再分散的纳米颗粒粉末。测量了这些氯法齐明纳米颗粒粉末在生物相关介质中的释放动力学，并与结晶氯法齐明和目前上市的制剂 Lamprene 的释放动力学进行了比较。所有测试的氯法齐明纳米颗粒均观察到溶出率显着提高，氯法齐明过饱和水平高达平衡溶解度的 90 倍。差示扫描量热法表明纳米颗粒中氯法齐明的结晶度降低。这些结果强烈表明，在这种低成本纳米颗粒配制过程中用负担得起的材料制备的新型氯法齐明纳米颗粒可用作可行的隐孢子虫病治疗剂。
更新日期：2017-09-20
中文翻译：
用于治疗隐孢子虫病的速释氯法齐明纳米颗粒的设计和固化
氯法齐明是一种亲脂性（log P = 7.66）丙米吩嗪抗生素，已获得美国食品和药物管理局（FDA）批准，具有良好的安全记录，最近通过高通量表型筛选被确定为治疗隐孢子虫病的主要药物。隐孢子虫病需要快速治疗，因为它会导致严重的症状，如果不治疗，会导致婴儿和幼儿发病。因此，非常需要一种用于儿科给药的水分散形式的氯法齐明快速释放口服制剂。在这项工作中，采用快速纳米沉淀 (FNP) 工艺，用三种表面稳定剂醋酸羟丙甲纤维素琥珀酸酯 (HPMCAS)、卵磷脂和玉米蛋白制备了氯法齐明纳米颗粒。药物包封率达到92%以上。应用并优化冻干和喷雾干燥来生产可再分散的纳米颗粒粉末。测量了这些氯法齐明纳米颗粒粉末在生物相关介质中的释放动力学，并与结晶氯法齐明和目前上市的制剂 Lamprene 的释放动力学进行了比较。所有测试的氯法齐明纳米颗粒均观察到溶出率显着提高，氯法齐明过饱和水平高达平衡溶解度的 90 倍。差示扫描量热法表明纳米颗粒中氯法齐明的结晶度降低。这些结果强烈表明，在这种低成本纳米颗粒配制过程中用负担得起的材料制备的新型氯法齐明纳米颗粒可用作可行的隐孢子虫病治疗剂。
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