TY - JOUR
T1 - Development and in vivo evaluation of child-friendly lopinavir/ritonavir pediatric granules utilizing novel in situ self-assembly nanoparticles
AU - Pham, Kevin
AU - Li, Diana
AU - Guo, Shujie
AU - Penzak, Scott
AU - Dong, Xiaowei
PY - 2016/3/28
Y1 - 2016/3/28
N2 - The aim of this study was to develop a nanotechnology to formulate a fixed-dose combination of poorly water-soluble drugs in a children-friendly, flexible solid dosage form. For diseases like HIV, pediatric patients are taking multiple drugs for effective treatments. Fixed-dose combinations could reduce pill burdens and costs as well as improving patient adherence. However, development of fixed-dose combinations of poorly water-soluble drugs for pediatric formulations is very challenging. We discovered a novel nanotechnology that produced in situ self-assembly nanoparticles (ISNPs) when the ISNP granules were introduced to water. In this study, antiretroviral drug granules, including lopinavir (LPV) ISNP granules and a fixed-dose combination of LPV/ritonavir (RTV) ISNP granules, were prepared using the ISNP nanotechnology, which spontaneously produced drug-loaded ISNPs in contact with water. Drug-loaded ISNPs had particle size less than 158 nm with mono-dispersed distribution, over 95% entrapment efficiency for both LPV and RTV and stability over 8 h in simulated physiological conditions. Drug-loaded ISNP granules with about 16% of LPV and 4% of RTV were palatable and stable at room temperature over 6 months. Furthermore, LPV/RTV ISNP granules displayed a 2.56-fold increase in bioavailability and significantly increased LPV concentrations in tested tissues, especially in HIV sanctuary sites, as compared to the commercial LPV/RTV tablet (Kaletra®) in rats. Overall, the results demonstrated that the novel ISNP nanotechnology is a promising platform to manufacture palatable, "heat" stable, and flexible pediatric granules for fixed-dose combinations that can be used as sachets and sprinkles. To the best of our knowledge, this is the first report on this kind of novel nanotechnology for pediatric fixed-dose combinations of poorly water-soluble drugs.
AB - The aim of this study was to develop a nanotechnology to formulate a fixed-dose combination of poorly water-soluble drugs in a children-friendly, flexible solid dosage form. For diseases like HIV, pediatric patients are taking multiple drugs for effective treatments. Fixed-dose combinations could reduce pill burdens and costs as well as improving patient adherence. However, development of fixed-dose combinations of poorly water-soluble drugs for pediatric formulations is very challenging. We discovered a novel nanotechnology that produced in situ self-assembly nanoparticles (ISNPs) when the ISNP granules were introduced to water. In this study, antiretroviral drug granules, including lopinavir (LPV) ISNP granules and a fixed-dose combination of LPV/ritonavir (RTV) ISNP granules, were prepared using the ISNP nanotechnology, which spontaneously produced drug-loaded ISNPs in contact with water. Drug-loaded ISNPs had particle size less than 158 nm with mono-dispersed distribution, over 95% entrapment efficiency for both LPV and RTV and stability over 8 h in simulated physiological conditions. Drug-loaded ISNP granules with about 16% of LPV and 4% of RTV were palatable and stable at room temperature over 6 months. Furthermore, LPV/RTV ISNP granules displayed a 2.56-fold increase in bioavailability and significantly increased LPV concentrations in tested tissues, especially in HIV sanctuary sites, as compared to the commercial LPV/RTV tablet (Kaletra®) in rats. Overall, the results demonstrated that the novel ISNP nanotechnology is a promising platform to manufacture palatable, "heat" stable, and flexible pediatric granules for fixed-dose combinations that can be used as sachets and sprinkles. To the best of our knowledge, this is the first report on this kind of novel nanotechnology for pediatric fixed-dose combinations of poorly water-soluble drugs.
KW - Drug loading
KW - Fixed-dose combinations
KW - HIV
KW - Pediatric formulation
KW - Stability
KW - Taste
UR - http://www.scopus.com/inward/record.url?scp=84959441486&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2016.02.001
DO - 10.1016/j.jconrel.2016.02.001
M3 - Article
C2 - 26849919
AN - SCOPUS:84959441486
SN - 0168-3659
VL - 226
SP - 88
EP - 97
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -