TY  - JOUR
AU  - Mitrović, Jelena
AU  - Divović-Matović, Branka
AU  - Knutson, Daniel E.
AU  - Petković, Miloš
AU  - Đorović, Đorđe
AU  - Ranđelović, Danijela V.
AU  - Dobričić, Vladimir
AU  - Đoković, Jelena
AU  - Lunter, Dominique J.
AU  - Cook, James M.
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4434
AB  - Preclinical development of deuterated pyrazoloquinolinone ligands, promising drug candidates for various neuropsychiatric disorders, was hindered by unusually low solubility in water and oils. DK-I-60-3 (7-methoxy-d3- 2-(4-methoxy-d3-phenyl)-2,5-dihydro-3Hpyrazolo[4,3-c]quinolin-3-one) is one of such pyrazoloquinolinones, and we recently reported about increased oral bioavailability of its nanocrystal formulation (NC). Lipid nano- particles (LNP) with a high concentration of lecithin, which enhances loading capacity of the lipid matrix, may give rise to further improvement. After preformulation studies by differential scanning calorimetry and polarized light microscopy, LNP were prepared by the hot high pressure homogenization, and characterized in terms of particle size, morphology, and encapsulation efficacy. The layered structure visible on atomic force micrographs was confirmed by nuclear magnetic resonance. Obtained formulations were desirably stable, with small particle size (<100 nm), and high encapsulation efficacy (>99 %). Lecithin was partially fluid and most probably located in the outer shell of the particle, together with DK-I-60-3. While the hydrophobic part of polysorbate 80 was completely immobilized, its hydrophilic part was free in the aqueous phase. In oral neuropharmacokinetic study in rats, an around 1.5-fold increase of area under the curve with LNP compared to NC was noticed both in brain and plasma. In bioavailability study, F value of LNP (34.7 ± 12.4 %) was 1.4-fold higher than of NC (24.5 ± 7.8 %); however, this difference did not reach statistical significance. Therefore, employment of LNP platform in preclinical formulation of DK-I-60-3 imparted an incremental improvement of its physicochemical as well as pharmacokinetic behavior.
PB  - Elsevier B.V.
T2  - International Journal of Pharmaceutics
T1  - High amount of lecithin facilitates oral delivery of a poorly soluble pyrazoloquinolinone ligand formulated in lipid nanoparticles: Physicochemical, structural and pharmacokinetic performances
VL  - 633
DO  - 10.1016/j.ijpharm.2023.122613
ER  - 

@article{
author = "Mitrović, Jelena and Divović-Matović, Branka and Knutson, Daniel E. and Petković, Miloš and Đorović, Đorđe and Ranđelović, Danijela V. and Dobričić, Vladimir and Đoković, Jelena and Lunter, Dominique J. and Cook, James M. and Savić, Miroslav and Savić, Snežana",
year = "2023",
abstract = "Preclinical development of deuterated pyrazoloquinolinone ligands, promising drug candidates for various neuropsychiatric disorders, was hindered by unusually low solubility in water and oils. DK-I-60-3 (7-methoxy-d3- 2-(4-methoxy-d3-phenyl)-2,5-dihydro-3Hpyrazolo[4,3-c]quinolin-3-one) is one of such pyrazoloquinolinones, and we recently reported about increased oral bioavailability of its nanocrystal formulation (NC). Lipid nano- particles (LNP) with a high concentration of lecithin, which enhances loading capacity of the lipid matrix, may give rise to further improvement. After preformulation studies by differential scanning calorimetry and polarized light microscopy, LNP were prepared by the hot high pressure homogenization, and characterized in terms of particle size, morphology, and encapsulation efficacy. The layered structure visible on atomic force micrographs was confirmed by nuclear magnetic resonance. Obtained formulations were desirably stable, with small particle size (<100 nm), and high encapsulation efficacy (>99 %). Lecithin was partially fluid and most probably located in the outer shell of the particle, together with DK-I-60-3. While the hydrophobic part of polysorbate 80 was completely immobilized, its hydrophilic part was free in the aqueous phase. In oral neuropharmacokinetic study in rats, an around 1.5-fold increase of area under the curve with LNP compared to NC was noticed both in brain and plasma. In bioavailability study, F value of LNP (34.7 ± 12.4 %) was 1.4-fold higher than of NC (24.5 ± 7.8 %); however, this difference did not reach statistical significance. Therefore, employment of LNP platform in preclinical formulation of DK-I-60-3 imparted an incremental improvement of its physicochemical as well as pharmacokinetic behavior.",
publisher = "Elsevier B.V.",
journal = "International Journal of Pharmaceutics",
title = "High amount of lecithin facilitates oral delivery of a poorly soluble pyrazoloquinolinone ligand formulated in lipid nanoparticles: Physicochemical, structural and pharmacokinetic performances",
volume = "633",
doi = "10.1016/j.ijpharm.2023.122613"
}

Mitrović, J., Divović-Matović, B., Knutson, D. E., Petković, M., Đorović, Đ., Ranđelović, D. V., Dobričić, V., Đoković, J., Lunter, D. J., Cook, J. M., Savić, M.,& Savić, S.. (2023). High amount of lecithin facilitates oral delivery of a poorly soluble pyrazoloquinolinone ligand formulated in lipid nanoparticles: Physicochemical, structural and pharmacokinetic performances. in International Journal of Pharmaceutics
Elsevier B.V.., 633.
https://doi.org/10.1016/j.ijpharm.2023.122613

Mitrović J, Divović-Matović B, Knutson DE, Petković M, Đorović Đ, Ranđelović DV, Dobričić V, Đoković J, Lunter DJ, Cook JM, Savić M, Savić S. High amount of lecithin facilitates oral delivery of a poorly soluble pyrazoloquinolinone ligand formulated in lipid nanoparticles: Physicochemical, structural and pharmacokinetic performances. in International Journal of Pharmaceutics. 2023;633.
doi:10.1016/j.ijpharm.2023.122613 .

Mitrović, Jelena, Divović-Matović, Branka, Knutson, Daniel E., Petković, Miloš, Đorović, Đorđe, Ranđelović, Danijela V., Dobričić, Vladimir, Đoković, Jelena, Lunter, Dominique J., Cook, James M., Savić, Miroslav, Savić, Snežana, "High amount of lecithin facilitates oral delivery of a poorly soluble pyrazoloquinolinone ligand formulated in lipid nanoparticles: Physicochemical, structural and pharmacokinetic performances" in International Journal of Pharmaceutics, 633 (2023),
https://doi.org/10.1016/j.ijpharm.2023.122613 . .