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dc.creatorMitrović, Jelena
dc.creatorDivović, Branka
dc.creatorKnutson, Daniel
dc.creatorĐoković, Jelena
dc.creatorVulić, Predrag
dc.creatorRanđelović, Danijela
dc.creatorDobričić, Vladimir
dc.creatorČalija, Bojan
dc.creatorCook, James
dc.creatorSavić, Miroslav M.
dc.creatorSavić, Snežana
dc.date.accessioned2020-08-26T11:02:21Z
dc.date.available2020-08-26T11:02:21Z
dc.date.issued2020
dc.identifier.issn0928-0987
dc.identifier.urihttp://cer.ihtm.bg.ac.rs/handle/123456789/3635
dc.description.abstractDK-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.sr
dc.language.isoensr
dc.publisherElseviersr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Technological Development (TD or TR)/34031/RS//sr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/175076/RS//sr
dc.rightsrestrictedAccesssr
dc.sourceEuropean Journal of Pharmaceutical Sciencesr
dc.subjectPyrazoloquinolinonessr
dc.subjectNanosuspensionsr
dc.subjectWet ball millingsr
dc.subjectPharmacokineticssr
dc.subjectBiodistributionsr
dc.subjectPharmacodynamicssr
dc.titleNanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performancesr
dc.typearticlesr
dc.rights.licenseARRsr
dcterms.abstractСавић, Мирослав; Ранђеловић, Данијела; Митровић, Јелена; Дивовић, Бранка; Кнутсон, Даниел; Ђоковић, Јелена; Вулић, Предраг; Добричић, Владимир; Чалија, Бојан; Цоок, Јамес; Савић, Снежана;
dc.rights.holderElseviersr
dc.citation.volume152
dc.citation.spage105432
dc.citation.rankM21~
dc.description.otherThe peer-reviewed version: [https://cer.ihtm.bg.ac.rs/handle/123456789/3714]
dc.identifier.doi10.1016/j.ejps.2020.105432
dc.identifier.scopus2-s2.0-85086705529
dc.identifier.wos000555462800006
dc.type.versionpublishedVersionsr


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