Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach
Authors
Mitrović, JelenaDivović-Matović, Branka
Knutson, Daniel
Đoković, Jelena
Kremenović, Aleksandar
Dobričić, Vladimir
Ranđelović, Danijela
Pantelić, Ivana
Cook, James
Savić, Miroslav
Savić, Snežana
Article (Published version)
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Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differ...ential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain.
Keywords:
Fasted/fed bioavailability / Nanocrystals / Pyrazoloquinolinones / Wet media millingSource:
Pharmaceutics, 2021, 13, 8Publisher:
- MDPI AG
Funding / projects:
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200161 (University of Belgrade, Faculty of Pharmacy) (RS-200161)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200126 (University of Belgrade, Faculty of Mining and Geology) (RS-200126)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200026 (University of Belgrade, Institute of Chemistry, Technology and Metallurgy - IChTM) (RS-200026)
- National Institutes of Health, USA through grants R01 NS076517 and R01 MH096463 and National Science Foundation
- Division of Chemistry through grant CHE-1625735 to JC. The APC was funded by the Ministry of Education, Science and Technological, Development, the Republic of Serbia
DOI: 10.3390/pharmaceutics13081188
ISSN: 1999-4923
WoS: 000689833500001
Scopus: 2-s2.0-85112101400
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Institution/Community
PharmacyTY - JOUR AU - Mitrović, Jelena AU - Divović-Matović, Branka AU - Knutson, Daniel AU - Đoković, Jelena AU - Kremenović, Aleksandar AU - Dobričić, Vladimir AU - Ranđelović, Danijela AU - Pantelić, Ivana AU - Cook, James AU - Savić, Miroslav AU - Savić, Snežana PY - 2021 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3934 AB - Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain. PB - MDPI AG T2 - Pharmaceutics T1 - Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach VL - 13 IS - 8 DO - 10.3390/pharmaceutics13081188 ER -
@article{ author = "Mitrović, Jelena and Divović-Matović, Branka and Knutson, Daniel and Đoković, Jelena and Kremenović, Aleksandar and Dobričić, Vladimir and Ranđelović, Danijela and Pantelić, Ivana and Cook, James and Savić, Miroslav and Savić, Snežana", year = "2021", abstract = "Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain.", publisher = "MDPI AG", journal = "Pharmaceutics", title = "Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach", volume = "13", number = "8", doi = "10.3390/pharmaceutics13081188" }
Mitrović, J., Divović-Matović, B., Knutson, D., Đoković, J., Kremenović, A., Dobričić, V., Ranđelović, D., Pantelić, I., Cook, J., Savić, M.,& Savić, S.. (2021). Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach. in Pharmaceutics MDPI AG., 13(8). https://doi.org/10.3390/pharmaceutics13081188
Mitrović J, Divović-Matović B, Knutson D, Đoković J, Kremenović A, Dobričić V, Ranđelović D, Pantelić I, Cook J, Savić M, Savić S. Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach. in Pharmaceutics. 2021;13(8). doi:10.3390/pharmaceutics13081188 .
Mitrović, Jelena, Divović-Matović, Branka, Knutson, Daniel, Đoković, Jelena, Kremenović, Aleksandar, Dobričić, Vladimir, Ranđelović, Danijela, Pantelić, Ivana, Cook, James, Savić, Miroslav, Savić, Snežana, "Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach" in Pharmaceutics, 13, no. 8 (2021), https://doi.org/10.3390/pharmaceutics13081188 . .