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Encapsulation of OZ439 into Nanoparticles for Supersaturated Drug Release in Oral Malaria Therapy.
ACS Infectious Diseases ( IF 5.3 ) Pub Date : 2018-04-12 , DOI: 10.1021/acsinfecdis.7b00278
Hoang D Lu 1 , Kurt D Ristroph 1 , Ellen L K Dobrijevic 1 , Jie Feng 1 , Simon A McManus 1 , Yingyue Zhang 1 , William D Mulhearn 1 , Hanu Ramachandruni 2 , Anil Patel 2 , Robert K Prud'homme 1
Affiliation  

Malaria poses a major burden on human health and is becoming increasingly difficult to treat due to the development of antimalarial drug resistance. The resistance issue is further exacerbated by a lack of patient adherence to multi-day dosing regimens. This situation motivates the development of new antimalarial treatments that are less susceptible to the development of resistance. We have applied Flash NanoPrecipitation (FNP), a polymer-directed self-assembly process, to form stable, water-dispersible nanoparticles (NPs) of 50-400 nm in size containing OZ439, a poorly orally bioavailable but promising candidate for single-dose malaria treatment developed by Medicines for Malaria Venture (MMV). During the FNP process, a hydrophobic OZ439 oleate ion paired complex was formed and was encapsulated into NPs. Lyophilization conditions for the NP suspension were optimized to produce a dry powder. The in vitro release rates of OZ439 encapsulated in this powder were determined in biorelevant media and compared with the release rates of the unencapsulated drug. The OZ439 NPs exhibit a sustained release profile and several-fold higher release concentrations compared to that of the unencapsulated drug. In addition, XRD suggests the drug was stabilized into an amorphous form within the NPs, which may explain the improvement in dissolution kinetics. Formulating OZ439 into NPs in this way may be an important step toward developing a single-dose oral malaria therapeutic, and offers the possibility of reducing the amount of drug required per patient, lowering delivery costs, and improving dosing compliance.

中文翻译:

OZ439封装到纳米颗粒中以用于口服疟疾治疗中的过饱和药物释放。

疟疾给人类健康带来了沉重负担,并且由于抗疟疾药物耐药性的发展,使其变得越来越难以治疗。患者缺乏对多日给药方案的依从性进一步加剧了耐药性问题。这种情况激发了新的抗疟疾治疗方法的发展,这种抗疟药治疗方法不易产生耐药性。我们已经应用了Flash-Nanoprecipitation(FNP)(一种由聚合物控制的自组装过程)来形成尺寸为50-400 nm的稳定,水分散性纳米颗粒(NPs),其中含有OZ439,口服生物利用度较差,但有望成为单剂量的候选药物药物用于疟疾事业(MMV)开发的疟疾治疗。在FNP过程中,形成了疏水的OZ439油酸根离子配对复合物,并将其封装到NP中。优化NP悬浮液的冻干条件以产生干粉。在生物相关介质中测定包封在该粉末中的OZ439的体外释放速率,并将其与未包囊药物的释放速率进行比较。与未包囊药物相比,OZ439 NPs表现出持续释放特性,且释放浓度高出几倍。另外,X射线衍射表明该药物在NPs内稳定为无定形形式,这可以解释溶出动力学的改善。以这种方式将OZ439配制成NP可能是开发单剂量口服疟疾治疗剂的重要步骤,并提供了减少每位患者所需药物量,降低递送成本并改善剂量依从性的可能性。在生物相关介质中测定包封在该粉末中的OZ439的体外释放速率,并将其与未包囊药物的释放速率进行比较。与未包囊药物相比,OZ439 NPs表现出持续释放特性,且释放浓度高出几倍。另外,X射线衍射表明该药物在NPs内稳定为无定形形式,这可以解释溶出动力学的改善。以这种方式将OZ439配制成NP可能是开发单剂量口服疟疾治疗剂的重要步骤,并提供了减少每位患者所需药物量,降低递送成本并改善剂量依从性的可能性。在生物相关介质中测定包封在该粉末中的OZ439的体外释放速率,并将其与未包囊药物的释放速率进行比较。与未包囊药物相比,OZ439 NPs表现出持续释放特性,且释放浓度高出几倍。另外,X射线衍射表明该药物在NPs内稳定为无定形形式,这可以解释溶出动力学的改善。以这种方式将OZ439配制成NP可能是开发单剂量口服疟疾治疗剂的重要步骤,并提供了减少每位患者所需药物量,降低递送成本并改善剂量依从性的可能性。
更新日期:2018-03-26
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