Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance
Аутори
Mitrović, JelenaDivović, Branka
Knutson, Daniel
Đoković, Jelena
Vulić, Predrag
Randjelović, Danijela
Dobričić, Vladimir
Čalija, Bojan
Cook, James
Savić, Miroslav M.
Savić, Snežana
Чланак у часопису (Рецензирана верзија)
Метаподаци
Приказ свих података о документуАпстракт
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.
Кључне речи:
Pyrazoloquinolinones / Nanosuspension / Wet ball milling / Pharmacokinetics / Biodistribution / PharmacodynamicsИзвор:
European Journal of Pharmaceutical Science, 2020, 152, 105432-Издавач:
- Elsevier
Финансирање / пројекти:
- Развој микро- и наносистема као носача за лекове са антиинфламаторним деловањем и метода за њихову карактеризацију (RS-MESTD-Technological Development (TD or TR)-34031)
- Бихејвиорални ефекти понављане примене новосинтетисаних супстанци селективних за поједине подтипове бензодиазепинског места везивања ГАБА А рецептора: поређење са стандардним психофармаколошким лековима (RS-MESTD-Basic Research (BR or ON)-175076)
Напомена:
- This is the peer-reviewed version of the article: Jelena R. Mitrovic et. al. Nanocrystal dispersion of DK-I-56-1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: formulation approach toward improved in vivo performance, European Journal of Pharmaceutical Science, 2020, 152, 105432, doi: https://doi.org/10.1016/j.ejps.2020.105432
- The published version: https://cer.ihtm.bg.ac.rs/handle/123456789/3635
DOI: 10.1016/j.ejps.2020.105432
ISSN: 0928-0987
WoS: 000555462800006
Scopus: 2-s2.0-85086705529
Институција/група
IHTMTY - JOUR AU - Mitrović, Jelena AU - Divović, Branka AU - Knutson, Daniel AU - Đoković, Jelena AU - Vulić, Predrag AU - Randjelović, Danijela AU - Dobričić, Vladimir AU - Čalija, Bojan AU - Cook, James AU - Savić, Miroslav M. AU - Savić, Snežana PY - 2020 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/3714 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 T2 - European Journal of Pharmaceutical Science 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 SP - 105432 DO - 10.1016/j.ejps.2020.105432 ER -
@article{ author = "Mitrović, Jelena and Divović, Branka and Knutson, Daniel and Đoković, Jelena and Vulić, Predrag and Randjelović, Danijela and Dobričić, Vladimir and Čalija, Bojan and Cook, James and Savić, Miroslav M. 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", journal = "European Journal of Pharmaceutical Science", 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", pages = "105432", doi = "10.1016/j.ejps.2020.105432" }
Mitrović, J., Divović, B., Knutson, D., Đoković, J., Vulić, P., Randjelović, D., Dobričić, V., Čalija, B., Cook, J., Savić, M. 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 Science Elsevier., 152, 105432. https://doi.org/10.1016/j.ejps.2020.105432
Mitrović J, Divović B, Knutson D, Đoković J, Vulić P, Randjelović D, Dobričić V, Čalija B, Cook J, Savić MM, 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 Science. 2020;152:105432. doi:10.1016/j.ejps.2020.105432 .
Mitrović, Jelena, Divović, Branka, Knutson, Daniel, Đoković, Jelena, Vulić, Predrag, Randjelović, Danijela, Dobričić, Vladimir, Čalija, Bojan, Cook, James, Savić, Miroslav M., 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 Science, 152 (2020):105432, https://doi.org/10.1016/j.ejps.2020.105432 . .