TY - JOUR
T1 - Encapsulation of OZ439 into Nanoparticles for Supersaturated Drug Release in Oral Malaria Therapy
AU - Lu, Hoang D.
AU - Ristroph, Kurt D.
AU - Dobrijevic, Ellen L.K.
AU - Feng, Jie
AU - McManus, Simon A.
AU - Zhang, Yingyue
AU - Mulhearn, William D.
AU - Ramachandruni, Hanu
AU - Patel, Anil
AU - Prud'Homme, Robert K.
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/6/8
Y1 - 2018/6/8
N2 - 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.
AB - 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.
KW - drug delivery
KW - hydrophobic ion pairing
KW - malaria
KW - nanocarrier
KW - oral therapeutic
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U2 - 10.1021/acsinfecdis.7b00278
DO - 10.1021/acsinfecdis.7b00278
M3 - Article
C2 - 29575888
AN - SCOPUS:85048283202
SN - 2373-8227
VL - 4
SP - 970
EP - 979
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 6
ER -