Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance
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2020
Authors
Mitrović, JelenaDivović, Branka
Knutson, Daniel E.
Đoković, Jelena
Vulić, Predrag
Ranđelović, Danijela
Dobričić, Vladimir
Čalija, Bojan
Cook, James M.
Savić, Miroslav
Savić, Snežana
Article (Published version)
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DK-I-56–1 (7‑methoxy‑2-(4‑methoxy‑d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one), a recently developed deuterated pyrazoloquinolinone, has been recognized as a lead candidate for treatment of various neuropsychiatric disorders. During preclinical investigation of poorly water-soluble compounds such as DK-I-56–1, the application of nanotechnology could be advantageous due to improved safety and possibly increased bioavailability of nanosized formulation. DK-I-56–1 nanosuspensions stabilized by polysorbate 80, alone or in combination with poloxamers 188 i.e. 407 or d-α-tocopheryl polyethylene glycol 1000 succinate, were prepared using a small-scale media milling device. With particle size 208.7–250.6 nm and polydispersity index <0.250, selected nanodiseprsions were stable for three weeks. Pharmacokinetic and biodistribution studies following intraperitoneal administration of three types of formulation in mice indicated high plasma DK-I-56–1 levels after solution (10,228.6 ± 103...7.2 ngh/ml) and nanosuspension (6770.4 ± 770.7 ngh/ml) but not suspension administration (966.0 ± 58.1 ngh/ml). However, distribution of DK-I-56–1 after solution was heavily influenced by its composition, and brain availability of nanosuspension was superior to that of solution formulation. In spontaneous locomotor activity test, the expected hyperlocomotor effect was observed after nanosuspension administration, without compromising impact of the vehicle/excipients used. Therefore, nanonization of drug compound assembled with proper selection of stabilizers may seemingly contribute further thorough testing of DK-I-56–1 preclinical efficacy.
Keywords:
Biodistribution / Nanosuspension / Pharmacodynamics / Pharmacokinetics / Pyrazoloquinolinones / Wet ball millingSource:
European Journal of Pharmaceutical Sciences, 2020, 152Publisher:
- Elsevier B.V.
Funding / projects:
- Development of micro- and nanosystems as carriers for drugs with anti-inflammatory effect and methods for their characterization (RS-MESTD-Technological Development (TD or TR)-34031)
- Behavioral ?ffects following repeated administration of newly synthesized ligands selective for distinct subtypes of GABAA receptor benzodiazepine binding site: comparison with standard psychopharmacologic drugs (RS-MESTD-Basic Research (BR or ON)-175076)
DOI: 10.1016/j.ejps.2020.105432
ISSN: 0928-0987
WoS: 000555462800006
Scopus: 2-s2.0-85086705529
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Institution/Community
PharmacyTY - JOUR AU - Mitrović, Jelena AU - Divović, Branka AU - Knutson, Daniel E. AU - Đoković, Jelena AU - Vulić, Predrag AU - Ranđelović, Danijela AU - Dobričić, Vladimir AU - Čalija, Bojan AU - Cook, James M. AU - Savić, Miroslav AU - Savić, Snežana PY - 2020 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3640 AB - DK-I-56–1 (7‑methoxy‑2-(4‑methoxy‑d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one), a recently developed deuterated pyrazoloquinolinone, has been recognized as a lead candidate for treatment of various neuropsychiatric disorders. During preclinical investigation of poorly water-soluble compounds such as DK-I-56–1, the application of nanotechnology could be advantageous due to improved safety and possibly increased bioavailability of nanosized formulation. DK-I-56–1 nanosuspensions stabilized by polysorbate 80, alone or in combination with poloxamers 188 i.e. 407 or d-α-tocopheryl polyethylene glycol 1000 succinate, were prepared using a small-scale media milling device. With particle size 208.7–250.6 nm and polydispersity index <0.250, selected nanodiseprsions were stable for three weeks. Pharmacokinetic and biodistribution studies following intraperitoneal administration of three types of formulation in mice indicated high plasma DK-I-56–1 levels after solution (10,228.6 ± 1037.2 ngh/ml) and nanosuspension (6770.4 ± 770.7 ngh/ml) but not suspension administration (966.0 ± 58.1 ngh/ml). However, distribution of DK-I-56–1 after solution was heavily influenced by its composition, and brain availability of nanosuspension was superior to that of solution formulation. In spontaneous locomotor activity test, the expected hyperlocomotor effect was observed after nanosuspension administration, without compromising impact of the vehicle/excipients used. Therefore, nanonization of drug compound assembled with proper selection of stabilizers may seemingly contribute further thorough testing of DK-I-56–1 preclinical efficacy. PB - Elsevier B.V. T2 - European Journal of Pharmaceutical Sciences T1 - Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance VL - 152 DO - 10.1016/j.ejps.2020.105432 ER -
@article{ author = "Mitrović, Jelena and Divović, Branka and Knutson, Daniel E. and Đoković, Jelena and Vulić, Predrag and Ranđelović, Danijela and Dobričić, Vladimir and Čalija, Bojan and Cook, James M. and Savić, Miroslav and Savić, Snežana", year = "2020", abstract = "DK-I-56–1 (7‑methoxy‑2-(4‑methoxy‑d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one), a recently developed deuterated pyrazoloquinolinone, has been recognized as a lead candidate for treatment of various neuropsychiatric disorders. During preclinical investigation of poorly water-soluble compounds such as DK-I-56–1, the application of nanotechnology could be advantageous due to improved safety and possibly increased bioavailability of nanosized formulation. DK-I-56–1 nanosuspensions stabilized by polysorbate 80, alone or in combination with poloxamers 188 i.e. 407 or d-α-tocopheryl polyethylene glycol 1000 succinate, were prepared using a small-scale media milling device. With particle size 208.7–250.6 nm and polydispersity index <0.250, selected nanodiseprsions were stable for three weeks. Pharmacokinetic and biodistribution studies following intraperitoneal administration of three types of formulation in mice indicated high plasma DK-I-56–1 levels after solution (10,228.6 ± 1037.2 ngh/ml) and nanosuspension (6770.4 ± 770.7 ngh/ml) but not suspension administration (966.0 ± 58.1 ngh/ml). However, distribution of DK-I-56–1 after solution was heavily influenced by its composition, and brain availability of nanosuspension was superior to that of solution formulation. In spontaneous locomotor activity test, the expected hyperlocomotor effect was observed after nanosuspension administration, without compromising impact of the vehicle/excipients used. Therefore, nanonization of drug compound assembled with proper selection of stabilizers may seemingly contribute further thorough testing of DK-I-56–1 preclinical efficacy.", publisher = "Elsevier B.V.", journal = "European Journal of Pharmaceutical Sciences", title = "Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance", volume = "152", doi = "10.1016/j.ejps.2020.105432" }
Mitrović, J., Divović, B., Knutson, D. E., Đoković, J., Vulić, P., Ranđelović, D., Dobričić, V., Čalija, B., Cook, J. M., Savić, M.,& Savić, S.. (2020). Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance. in European Journal of Pharmaceutical Sciences Elsevier B.V.., 152. https://doi.org/10.1016/j.ejps.2020.105432
Mitrović J, Divović B, Knutson DE, Đoković J, Vulić P, Ranđelović D, Dobričić V, Čalija B, Cook JM, Savić M, Savić S. Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance. in European Journal of Pharmaceutical Sciences. 2020;152. doi:10.1016/j.ejps.2020.105432 .
Mitrović, Jelena, Divović, Branka, Knutson, Daniel E., Đoković, Jelena, Vulić, Predrag, Ranđelović, Danijela, Dobričić, Vladimir, Čalija, Bojan, Cook, James M., Savić, Miroslav, Savić, Snežana, "Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance" in European Journal of Pharmaceutical Sciences, 152 (2020), https://doi.org/10.1016/j.ejps.2020.105432 . .