title: Development and in vivo evaluation of child-friendly lopinavir/ritonavir pediatric granules utilizing novel in situ self-assembly nanoparticles.
abstract: 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 158nm with mono-dispersed distribution, over 95% entrapment efficiency for both LPV and RTV and stability over 8h 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 6months. 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.
authors: Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA.
authors: Kevin
authors: K
authors: Pham
authors: Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA.
authors: Diana
authors: D
authors: Li
authors: State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Shujie
authors: S
authors: Guo
authors: Department of Pharmacotherapy, University of North Texas Health Science Center, Fort Worth, TX, USA.
authors: Scott
authors: S
authors: Penzak
authors: Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA. Electronic address: Xiaowei.Dong@unthsc.edu.
authors: Xiaowei
authors: X
authors: Dong
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D002648:Child; D004337:Drug Carriers / Q000737:chemistry*; D004338:Drug Combinations; D062609:Electronic Nose; D006801:Humans; D061466:Lopinavir / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility; D013649:Taste
chemical_list: D019380:Anti-HIV Agents; D004337:Drug Carriers; D004338:Drug Combinations; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; D019438:Ritonavir
keywords: Drug loading; Fixed-dose combinations; HIV; Pediatric formulation; Stability; Taste