TY  - CONF
AU  - Mitrović, Jelena
AU  - Petković, Miloš
AU  - Randjelović, Danijela
AU  - Đoković, Jelena
AU  - Knutson, Daniel
AU  - Cook, James
AU  - Savić, Vladimir
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2022
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/5259
AB  - Poster presented at 13th World meeting on pharmaceutics, biopharmaceutics and pharmaceutical technology, 28-31 March 2022, Rotterdam, Netherlands
T1  - Physicochemical/structural investigation of lipid nanoparticles with high lecithin amounts loaded with patent protected pyrazoloquinolinone ligand DK-I-60-3
UR  - https://hdl.handle.net/21.15107/rcub_cer_5259
ER  - 

@conference{
author = "Mitrović, Jelena and Petković, Miloš and Randjelović, Danijela and Đoković, Jelena and Knutson, Daniel and Cook, James and Savić, Vladimir and Savić, Miroslav and Savić, Snežana",
year = "2022",
abstract = "Poster presented at 13th World meeting on pharmaceutics, biopharmaceutics and pharmaceutical technology, 28-31 March 2022, Rotterdam, Netherlands",
title = "Physicochemical/structural investigation of lipid nanoparticles with high lecithin amounts loaded with patent protected pyrazoloquinolinone ligand DK-I-60-3",
url = "https://hdl.handle.net/21.15107/rcub_cer_5259"
}

Mitrović, J., Petković, M., Randjelović, D., Đoković, J., Knutson, D., Cook, J., Savić, V., Savić, M.,& Savić, S.. (2022). Physicochemical/structural investigation of lipid nanoparticles with high lecithin amounts loaded with patent protected pyrazoloquinolinone ligand DK-I-60-3. .
https://hdl.handle.net/21.15107/rcub_cer_5259

Mitrović J, Petković M, Randjelović D, Đoković J, Knutson D, Cook J, Savić V, Savić M, Savić S. Physicochemical/structural investigation of lipid nanoparticles with high lecithin amounts loaded with patent protected pyrazoloquinolinone ligand DK-I-60-3. 2022;.
https://hdl.handle.net/21.15107/rcub_cer_5259 .

Mitrović, Jelena, Petković, Miloš, Randjelović, Danijela, Đoković, Jelena, Knutson, Daniel, Cook, James, Savić, Vladimir, Savić, Miroslav, Savić, Snežana, "Physicochemical/structural investigation of lipid nanoparticles with high lecithin amounts loaded with patent protected pyrazoloquinolinone ligand DK-I-60-3" (2022),
https://hdl.handle.net/21.15107/rcub_cer_5259 .

TY  - JOUR
AU  - Mitrović, Jelena
AU  - Divović-Matović, Branka
AU  - Knutson, Daniel E.
AU  - Ðoković, Jelena B.
AU  - Kremenović, Aleksandar
AU  - Dobričić, Vladimir
AU  - Randjelović, Danijela
AU  - Pantelić, Ivana
AU  - Cook, James
AU  - Savić, Miroslav M.
AU  - Savić, Snežana D.
PY  - 2021
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/4791
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
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
SP  - 1188
DO  - 10.3390/pharmaceutics13081188
ER  - 

@article{
author = "Mitrović, Jelena and Divović-Matović, Branka and Knutson, Daniel E. and Ðoković, Jelena B. and Kremenović, Aleksandar and Dobričić, Vladimir and Randjelović, Danijela and Pantelić, Ivana and Cook, James and Savić, Miroslav M. and Savić, Snežana D.",
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",
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",
pages = "1188",
doi = "10.3390/pharmaceutics13081188"
}

Mitrović, J., Divović-Matović, B., Knutson, D. E., Ðoković, J. B., Kremenović, A., Dobričić, V., Randjelović, D., Pantelić, I., Cook, J., Savić, M. M.,& Savić, S. D.. (2021). Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach. in Pharmaceutics
MDPI., 13(8), 1188.
https://doi.org/10.3390/pharmaceutics13081188

Mitrović J, Divović-Matović B, Knutson DE, Ðoković JB, Kremenović A, Dobričić V, Randjelović D, Pantelić I, Cook J, Savić MM, Savić SD. Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach. in Pharmaceutics. 2021;13(8):1188.
doi:10.3390/pharmaceutics13081188 .

Mitrović, Jelena, Divović-Matović, Branka, Knutson, Daniel E., Ðoković, Jelena B., Kremenović, Aleksandar, Dobričić, Vladimir, Randjelović, Danijela, Pantelić, Ivana, Cook, James, Savić, Miroslav M., Savić, Snežana D., "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):1188,
https://doi.org/10.3390/pharmaceutics13081188 . .

TY  - JOUR
AU  - Nikolić, Ines
AU  - Antić-Stanković, Jelena
AU  - Božić, Dragana
AU  - Randjelović, Danijela
AU  - Marković, Bojan D.
AU  - Lunter, Dominique Jasmin
AU  - Kremenović, Aleksandar
AU  - Savić, Miroslav M.
AU  - Savić, Snežana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3711
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/3720
AB  - As the number of poorly soluble drugs is increasing, nanocrystals have become very interesting due to wide range of application possibilities. Curcuminwas used as a model active ingredient in this work. Even though it has many proven positive effects, due to its physicochemical issues, its possibilities have not been fully exploited. The goal of this work was to select optimal conditions for a top-down method for curcumin nanosuspension production, and to perform their comprehensive characterization applying complementary methodologies: dynamic light scattering, polarization and atomic force microscopy, thermal analysis, X-ray powder diffraction, antioxidant activity evaluation, release kinetics assessment, and screening of potential biological effects applying cell viability assays on normal human lung fibroblasts, human melanoma and human adenomacarcinoma cells. After 30 min of milling, nanosuspensions stabilized by polysorbate 80 and by its combinations with sucrose palmitate showed good stability, while curcumin crystal structure was unaltered. Obtained nanocrystals were well defined, with average diameter 120-170 nm and PDI of about 0.25, zeta potential was below -30 mV and pH~5 for all formulations. Nanodispersions exhibited high antioxidant potential and improved dissolution rate compared to the corresponding coarse dispersions. Although curcumin nanodispersions exhibited significant antiproliferative effect to each cancer cell line, the highest effect was towards adenocarcinoma cells.
PB  - Walter de Gruyter GmbH
T2  - Reviews on Advanced Materials Science
T1  - Curcumin Nanonization Using An Alternative Small-Scale Production Unit: Selection of Proper Stabilizer Applying Basic Physicochemical Consideration and Biological Activity Assessment of Nanocrystals
VL  - 59
IS  - 1
SP  - 406
EP  - 424
DO  - 10.1515/rams-2020-0043
ER  - 

@article{
author = "Nikolić, Ines and Antić-Stanković, Jelena and Božić, Dragana and Randjelović, Danijela and Marković, Bojan D. and Lunter, Dominique Jasmin and Kremenović, Aleksandar and Savić, Miroslav M. and Savić, Snežana",
year = "2020",
abstract = "As the number of poorly soluble drugs is increasing, nanocrystals have become very interesting due to wide range of application possibilities. Curcuminwas used as a model active ingredient in this work. Even though it has many proven positive effects, due to its physicochemical issues, its possibilities have not been fully exploited. The goal of this work was to select optimal conditions for a top-down method for curcumin nanosuspension production, and to perform their comprehensive characterization applying complementary methodologies: dynamic light scattering, polarization and atomic force microscopy, thermal analysis, X-ray powder diffraction, antioxidant activity evaluation, release kinetics assessment, and screening of potential biological effects applying cell viability assays on normal human lung fibroblasts, human melanoma and human adenomacarcinoma cells. After 30 min of milling, nanosuspensions stabilized by polysorbate 80 and by its combinations with sucrose palmitate showed good stability, while curcumin crystal structure was unaltered. Obtained nanocrystals were well defined, with average diameter 120-170 nm and PDI of about 0.25, zeta potential was below -30 mV and pH~5 for all formulations. Nanodispersions exhibited high antioxidant potential and improved dissolution rate compared to the corresponding coarse dispersions. Although curcumin nanodispersions exhibited significant antiproliferative effect to each cancer cell line, the highest effect was towards adenocarcinoma cells.",
publisher = "Walter de Gruyter GmbH",
journal = "Reviews on Advanced Materials Science",
title = "Curcumin Nanonization Using An Alternative Small-Scale Production Unit: Selection of Proper Stabilizer Applying Basic Physicochemical Consideration and Biological Activity Assessment of Nanocrystals",
volume = "59",
number = "1",
pages = "406-424",
doi = "10.1515/rams-2020-0043"
}

Nikolić, I., Antić-Stanković, J., Božić, D., Randjelović, D., Marković, B. D., Lunter, D. J., Kremenović, A., Savić, M. M.,& Savić, S.. (2020). Curcumin Nanonization Using An Alternative Small-Scale Production Unit: Selection of Proper Stabilizer Applying Basic Physicochemical Consideration and Biological Activity Assessment of Nanocrystals. in Reviews on Advanced Materials Science
Walter de Gruyter GmbH., 59(1), 406-424.
https://doi.org/10.1515/rams-2020-0043

Nikolić I, Antić-Stanković J, Božić D, Randjelović D, Marković BD, Lunter DJ, Kremenović A, Savić MM, Savić S. Curcumin Nanonization Using An Alternative Small-Scale Production Unit: Selection of Proper Stabilizer Applying Basic Physicochemical Consideration and Biological Activity Assessment of Nanocrystals. in Reviews on Advanced Materials Science. 2020;59(1):406-424.
doi:10.1515/rams-2020-0043 .

Nikolić, Ines, Antić-Stanković, Jelena, Božić, Dragana, Randjelović, Danijela, Marković, Bojan D., Lunter, Dominique Jasmin, Kremenović, Aleksandar, Savić, Miroslav M., Savić, Snežana, "Curcumin Nanonization Using An Alternative Small-Scale Production Unit: Selection of Proper Stabilizer Applying Basic Physicochemical Consideration and Biological Activity Assessment of Nanocrystals" in Reviews on Advanced Materials Science, 59, no. 1 (2020):406-424,
https://doi.org/10.1515/rams-2020-0043 . .

TY  - 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 . .

TY  - 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/123456789/3635
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 . .

TY  - JOUR
AU  - Rizvic, Eldina
AU  - Jankovic, Goran
AU  - Kostić Rajačić, Slađana
AU  - Savić, Miroslav M.
PY  - 2017
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2161
AB  - Lerimazoline is a sympathomimetic drug that belongs to the imidazoline class of compounds, and is used as a nasal decongestant. Studies on lerimazoline are rare, and its pharmacological profile is not completely understood. Here, we analyzed the affinity of lerimazoline for dopamine receptor D2, serotonin 5-HT1A and 5-HT2A receptors and alpha(1)-adrenoceptor, and investigated lerimazoline contractile effects in isolated rat thoracic aorta. We also determined the effect of several antagonists on the contractile response to lerimazoline, including prazosin (alpha(1)-adrenoceptor antagonist), RX 821002 and rauwolscine (alpha(2)-adrenoceptor antagonists), JP 1302 (alpha(2C)-adrenoceptor antagonist), methiothepin (non-selective 5-HT receptor antagonist), SB 224289 (5-HT1B receptor antagonist), BRL 15572 (5-HT1D receptor antagonist), and ketanserin (5-HT2A receptor antagonist). Lerimazoline displayed high affinity for the 5-HT1A receptor (Ki = 162.5 nM), similar to the previously reported affinity for the 5-HT1D receptor. Binding affinity estimates (Ki) for alpha(1), 5-HT2A, and D-2 receptors were 6656, 4202 and 3437.5 nM, respectively (the literature reported Ki for 5-HT1B receptor is 3480 nM). Lerimazoline caused concentration-dependent contractions in 70% of preparations, varying in the range between 40% and 55% of the maximal contraction elicited by phenylephrine. While prazosin reduced the maximum contractile response to lerimazoline, rauwolscine showed a non-significant trend in reduction of the response. Both ketanserin (10 nM and 1 mu M) and methiothepin strongly suppressed the maximum response to lerimazoline. Overall, our results suggest that 5-HT2A and, less distinctly, alpha(1)-adrenergic receptors are involved in the lerimazoline-induced contractions, which makes lerimazoline an "atypical" decongestant.
PB  - Association of Basic Medical Sciences of Federation of Bosnia and Herzegovina
T2  - Bosnian Journal of Basic Medical Sciences
T1  - Atypical sympathomimetic drug lerimazoline mediates contractile effects in rat aorta predominantly by 5-HT2A receptors
VL  - 17
IS  - 3
SP  - 194
EP  - 202
DO  - 10.17305/bjbms.2017.2071
ER  - 

@article{
author = "Rizvic, Eldina and Jankovic, Goran and Kostić Rajačić, Slađana and Savić, Miroslav M.",
year = "2017",
abstract = "Lerimazoline is a sympathomimetic drug that belongs to the imidazoline class of compounds, and is used as a nasal decongestant. Studies on lerimazoline are rare, and its pharmacological profile is not completely understood. Here, we analyzed the affinity of lerimazoline for dopamine receptor D2, serotonin 5-HT1A and 5-HT2A receptors and alpha(1)-adrenoceptor, and investigated lerimazoline contractile effects in isolated rat thoracic aorta. We also determined the effect of several antagonists on the contractile response to lerimazoline, including prazosin (alpha(1)-adrenoceptor antagonist), RX 821002 and rauwolscine (alpha(2)-adrenoceptor antagonists), JP 1302 (alpha(2C)-adrenoceptor antagonist), methiothepin (non-selective 5-HT receptor antagonist), SB 224289 (5-HT1B receptor antagonist), BRL 15572 (5-HT1D receptor antagonist), and ketanserin (5-HT2A receptor antagonist). Lerimazoline displayed high affinity for the 5-HT1A receptor (Ki = 162.5 nM), similar to the previously reported affinity for the 5-HT1D receptor. Binding affinity estimates (Ki) for alpha(1), 5-HT2A, and D-2 receptors were 6656, 4202 and 3437.5 nM, respectively (the literature reported Ki for 5-HT1B receptor is 3480 nM). Lerimazoline caused concentration-dependent contractions in 70% of preparations, varying in the range between 40% and 55% of the maximal contraction elicited by phenylephrine. While prazosin reduced the maximum contractile response to lerimazoline, rauwolscine showed a non-significant trend in reduction of the response. Both ketanserin (10 nM and 1 mu M) and methiothepin strongly suppressed the maximum response to lerimazoline. Overall, our results suggest that 5-HT2A and, less distinctly, alpha(1)-adrenergic receptors are involved in the lerimazoline-induced contractions, which makes lerimazoline an "atypical" decongestant.",
publisher = "Association of Basic Medical Sciences of Federation of Bosnia and Herzegovina",
journal = "Bosnian Journal of Basic Medical Sciences",
title = "Atypical sympathomimetic drug lerimazoline mediates contractile effects in rat aorta predominantly by 5-HT2A receptors",
volume = "17",
number = "3",
pages = "194-202",
doi = "10.17305/bjbms.2017.2071"
}

Rizvic, E., Jankovic, G., Kostić Rajačić, S.,& Savić, M. M.. (2017). Atypical sympathomimetic drug lerimazoline mediates contractile effects in rat aorta predominantly by 5-HT2A receptors. in Bosnian Journal of Basic Medical Sciences
Association of Basic Medical Sciences of Federation of Bosnia and Herzegovina., 17(3), 194-202.
https://doi.org/10.17305/bjbms.2017.2071

Rizvic E, Jankovic G, Kostić Rajačić S, Savić MM. Atypical sympathomimetic drug lerimazoline mediates contractile effects in rat aorta predominantly by 5-HT2A receptors. in Bosnian Journal of Basic Medical Sciences. 2017;17(3):194-202.
doi:10.17305/bjbms.2017.2071 .

Rizvic, Eldina, Jankovic, Goran, Kostić Rajačić, Slađana, Savić, Miroslav M., "Atypical sympathomimetic drug lerimazoline mediates contractile effects in rat aorta predominantly by 5-HT2A receptors" in Bosnian Journal of Basic Medical Sciences, 17, no. 3 (2017):194-202,
https://doi.org/10.17305/bjbms.2017.2071 . .

TY  - JOUR
AU  - Dordevic, Sanela M
AU  - Cekic, Nebojsa
AU  - Savić, Miroslav M.
AU  - Isailovic, Tanja M
AU  - Randjelović, Danijela
AU  - Marković, Bojan D.
AU  - Savić, Saša R.
AU  - Stamenic, Tamara Timic
AU  - Daniels, Rolf
AU  - Savić, Snežana D.
PY  - 2015
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/1697
AB  - This paper describes design and evaluation of parenteral lecithin-based nanoemulsions intended for brain delivery of risperidone, a poorly water-soluble psychopharmacological drug. The nanoemulsions were prepared through cold/hot high pressure homogenization and characterized regarding droplet size, polydispersity, surface charge, morphology, drug-vehicle interactions, and physical stability. To estimate the simultaneous influence of nanoemulsion formulation and preparation parameters-co-emulsifier type, aqueous phase type, homogenization temperature-on the critical quality attributes of developed nanoemulsions, a general factorial experimental design was applied. From the established design space and stability data, promising risperidone-loaded nanoemulsions (mean size about 160 nm, size distribution  LT 0.15, zeta potential around -50 mV), containing sodium oleate in the aqueous phase and polysorbate 80, poloxamer 188 or Solutol (R) HS15 as co-emulsifier, were produced by hot homogenization and their ability to improve risperidone delivery to the brain was assessed in rats. Pharmacokinetic study demonstrated erratic brain profiles of risperidone following intraperitoneal administration in selected nanoemulsions, most probably due to their different droplet surface properties (different composition of the stabilizing layer). Namely, polysorbate 80-costabilized nanoemulsion showed increased (1.4-7.4-fold higher) risperidone brain availability compared to other nanoemulsions and drug solution, suggesting this nanoemulsion as a promising carrier worth exploring further for brain targeting.
PB  - Elsevier
T2  - International Journal of Pharmaceutics
T1  - Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation
VL  - 493
IS  - 1-2
SP  - 40
EP  - 54
DO  - 10.1016/j.ijpharm.2015.07.007
ER  - 

@article{
author = "Dordevic, Sanela M and Cekic, Nebojsa and Savić, Miroslav M. and Isailovic, Tanja M and Randjelović, Danijela and Marković, Bojan D. and Savić, Saša R. and Stamenic, Tamara Timic and Daniels, Rolf and Savić, Snežana D.",
year = "2015",
abstract = "This paper describes design and evaluation of parenteral lecithin-based nanoemulsions intended for brain delivery of risperidone, a poorly water-soluble psychopharmacological drug. The nanoemulsions were prepared through cold/hot high pressure homogenization and characterized regarding droplet size, polydispersity, surface charge, morphology, drug-vehicle interactions, and physical stability. To estimate the simultaneous influence of nanoemulsion formulation and preparation parameters-co-emulsifier type, aqueous phase type, homogenization temperature-on the critical quality attributes of developed nanoemulsions, a general factorial experimental design was applied. From the established design space and stability data, promising risperidone-loaded nanoemulsions (mean size about 160 nm, size distribution  LT 0.15, zeta potential around -50 mV), containing sodium oleate in the aqueous phase and polysorbate 80, poloxamer 188 or Solutol (R) HS15 as co-emulsifier, were produced by hot homogenization and their ability to improve risperidone delivery to the brain was assessed in rats. Pharmacokinetic study demonstrated erratic brain profiles of risperidone following intraperitoneal administration in selected nanoemulsions, most probably due to their different droplet surface properties (different composition of the stabilizing layer). Namely, polysorbate 80-costabilized nanoemulsion showed increased (1.4-7.4-fold higher) risperidone brain availability compared to other nanoemulsions and drug solution, suggesting this nanoemulsion as a promising carrier worth exploring further for brain targeting.",
publisher = "Elsevier",
journal = "International Journal of Pharmaceutics",
title = "Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation",
volume = "493",
number = "1-2",
pages = "40-54",
doi = "10.1016/j.ijpharm.2015.07.007"
}

Dordevic, S. M., Cekic, N., Savić, M. M., Isailovic, T. M., Randjelović, D., Marković, B. D., Savić, S. R., Stamenic, T. T., Daniels, R.,& Savić, S. D.. (2015). Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation. in International Journal of Pharmaceutics
Elsevier., 493(1-2), 40-54.
https://doi.org/10.1016/j.ijpharm.2015.07.007

Dordevic SM, Cekic N, Savić MM, Isailovic TM, Randjelović D, Marković BD, Savić SR, Stamenic TT, Daniels R, Savić SD. Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation. in International Journal of Pharmaceutics. 2015;493(1-2):40-54.
doi:10.1016/j.ijpharm.2015.07.007 .

Dordevic, Sanela M, Cekic, Nebojsa, Savić, Miroslav M., Isailovic, Tanja M, Randjelović, Danijela, Marković, Bojan D., Savić, Saša R., Stamenic, Tamara Timic, Daniels, Rolf, Savić, Snežana D., "Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation" in International Journal of Pharmaceutics, 493, no. 1-2 (2015):40-54,
https://doi.org/10.1016/j.ijpharm.2015.07.007 . .

TY  - JOUR
AU  - Todosijević, Marija
AU  - Savić, Miroslav M.
AU  - Batinić, Bojan B.
AU  - Marković, Bojan D.
AU  - Gasperlin, Mirjana
AU  - Randjelović, Danijela
AU  - Lukić, Milica
AU  - Savić, Snežana D.
PY  - 2015
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/1805
AB  - To elaborate the decisive role of surfactants in promotion of aceclofenac' skin absorption, potentially avoiding irritation, we developed non-ionic microemulsions varying natural or synthetic surfactants: sucrose esters (laurate or myristate) vs. polysorbate 80. A comprehensive physicochemical characterization indicated no significant influence of the solubilized nonsteroidal anti-inflammatory drug on the bicontinuous structure of blank formulations. To evaluate skin tolerability of isopropyl alcohol, a sucrose ester-based microemulsion containing transcutol P as a cosurfactant was also developed. The measured skin parameters strongly depended on the (co)surfactant type, showing higher compatibility of the microemulsions containing sucrose ester and isopropyl alcohol. In vitro release results, in vivo tape stripping and pharmacokinetics in rats confirmed superiority of the sucrose ester-over polysorbate-based microemulsions (total amounts of aceclofenac penetrated 60.81 +/- 5.97 and 60.86 +/- 3.67 vs. 27.00 +/- 5.09 mu g/cm(2), and its maximum plasma concentrations 275.57 +/- 109.49 and 281.31 +/- 76.76 vs. 150.23 +/- 69.74 ng/ml for sucrose laurate- and myristate- vs. polysorbate 80-based microemulsions, respectively). Hence, sugar-based excipients increased delivery of aceclofenac through stratum corneum by increasing its fluidity, showing overall more satisfying safety profiles. In conclusion, sucrose ester-based microemulsions proved to be promising carriers for dermal/transdermal aceclofenac delivery.
PB  - Elsevier
T2  - International Journal of Pharmaceutics
T1  - Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance
VL  - 496
IS  - 2
SP  - 931
EP  - 941
DO  - 10.1016/j.ijpharm.2015.10.048
ER  - 

@article{
author = "Todosijević, Marija and Savić, Miroslav M. and Batinić, Bojan B. and Marković, Bojan D. and Gasperlin, Mirjana and Randjelović, Danijela and Lukić, Milica and Savić, Snežana D.",
year = "2015",
abstract = "To elaborate the decisive role of surfactants in promotion of aceclofenac' skin absorption, potentially avoiding irritation, we developed non-ionic microemulsions varying natural or synthetic surfactants: sucrose esters (laurate or myristate) vs. polysorbate 80. A comprehensive physicochemical characterization indicated no significant influence of the solubilized nonsteroidal anti-inflammatory drug on the bicontinuous structure of blank formulations. To evaluate skin tolerability of isopropyl alcohol, a sucrose ester-based microemulsion containing transcutol P as a cosurfactant was also developed. The measured skin parameters strongly depended on the (co)surfactant type, showing higher compatibility of the microemulsions containing sucrose ester and isopropyl alcohol. In vitro release results, in vivo tape stripping and pharmacokinetics in rats confirmed superiority of the sucrose ester-over polysorbate-based microemulsions (total amounts of aceclofenac penetrated 60.81 +/- 5.97 and 60.86 +/- 3.67 vs. 27.00 +/- 5.09 mu g/cm(2), and its maximum plasma concentrations 275.57 +/- 109.49 and 281.31 +/- 76.76 vs. 150.23 +/- 69.74 ng/ml for sucrose laurate- and myristate- vs. polysorbate 80-based microemulsions, respectively). Hence, sugar-based excipients increased delivery of aceclofenac through stratum corneum by increasing its fluidity, showing overall more satisfying safety profiles. In conclusion, sucrose ester-based microemulsions proved to be promising carriers for dermal/transdermal aceclofenac delivery.",
publisher = "Elsevier",
journal = "International Journal of Pharmaceutics",
title = "Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance",
volume = "496",
number = "2",
pages = "931-941",
doi = "10.1016/j.ijpharm.2015.10.048"
}

Todosijević, M., Savić, M. M., Batinić, B. B., Marković, B. D., Gasperlin, M., Randjelović, D., Lukić, M.,& Savić, S. D.. (2015). Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance. in International Journal of Pharmaceutics
Elsevier., 496(2), 931-941.
https://doi.org/10.1016/j.ijpharm.2015.10.048

Todosijević M, Savić MM, Batinić BB, Marković BD, Gasperlin M, Randjelović D, Lukić M, Savić SD. Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance. in International Journal of Pharmaceutics. 2015;496(2):931-941.
doi:10.1016/j.ijpharm.2015.10.048 .

Todosijević, Marija, Savić, Miroslav M., Batinić, Bojan B., Marković, Bojan D., Gasperlin, Mirjana, Randjelović, Danijela, Lukić, Milica, Savić, Snežana D., "Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance" in International Journal of Pharmaceutics, 496, no. 2 (2015):931-941,
https://doi.org/10.1016/j.ijpharm.2015.10.048 . .

TY  - JOUR
AU  - Dordevic, Sanela M
AU  - Cekic, Nebojsa
AU  - Savić, Miroslav M.
AU  - Isailovic, Tanja M
AU  - Randjelović, Danijela
AU  - Marković, Bojan D.
AU  - Savić, Saša R.
AU  - Stamenic, Tamara Timic
AU  - Daniels, Rolf
AU  - Savić, Snežana D.
PY  - 2015
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/3201
AB  - This paper describes design and evaluation of parenteral lecithin-based nanoemulsions intended for brain delivery of risperidone, a poorly water-soluble psychopharmacological drug. The nanoemulsions were prepared through cold/hot high pressure homogenization and characterized regarding droplet size, polydispersity, surface charge, morphology, drug-vehicle interactions, and physical stability. To estimate the simultaneous influence of nanoemulsion formulation and preparation parameters-co-emulsifier type, aqueous phase type, homogenization temperature-on the critical quality attributes of developed nanoemulsions, a general factorial experimental design was applied. From the established design space and stability data, promising risperidone-loaded nanoemulsions (mean size about 160 nm, size distribution  LT 0.15, zeta potential around -50 mV), containing sodium oleate in the aqueous phase and polysorbate 80, poloxamer 188 or Solutol (R) HS15 as co-emulsifier, were produced by hot homogenization and their ability to improve risperidone delivery to the brain was assessed in rats. Pharmacokinetic study demonstrated erratic brain profiles of risperidone following intraperitoneal administration in selected nanoemulsions, most probably due to their different droplet surface properties (different composition of the stabilizing layer). Namely, polysorbate 80-costabilized nanoemulsion showed increased (1.4-7.4-fold higher) risperidone brain availability compared to other nanoemulsions and drug solution, suggesting this nanoemulsion as a promising carrier worth exploring further for brain targeting.
PB  - Elsevier
T2  - International Journal of Pharmaceutics
T1  - Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation
VL  - 493
IS  - 1-2
SP  - 40
EP  - 54
DO  - 10.1016/j.ijpharm.2015.07.007
ER  - 

@article{
author = "Dordevic, Sanela M and Cekic, Nebojsa and Savić, Miroslav M. and Isailovic, Tanja M and Randjelović, Danijela and Marković, Bojan D. and Savić, Saša R. and Stamenic, Tamara Timic and Daniels, Rolf and Savić, Snežana D.",
year = "2015",
abstract = "This paper describes design and evaluation of parenteral lecithin-based nanoemulsions intended for brain delivery of risperidone, a poorly water-soluble psychopharmacological drug. The nanoemulsions were prepared through cold/hot high pressure homogenization and characterized regarding droplet size, polydispersity, surface charge, morphology, drug-vehicle interactions, and physical stability. To estimate the simultaneous influence of nanoemulsion formulation and preparation parameters-co-emulsifier type, aqueous phase type, homogenization temperature-on the critical quality attributes of developed nanoemulsions, a general factorial experimental design was applied. From the established design space and stability data, promising risperidone-loaded nanoemulsions (mean size about 160 nm, size distribution  LT 0.15, zeta potential around -50 mV), containing sodium oleate in the aqueous phase and polysorbate 80, poloxamer 188 or Solutol (R) HS15 as co-emulsifier, were produced by hot homogenization and their ability to improve risperidone delivery to the brain was assessed in rats. Pharmacokinetic study demonstrated erratic brain profiles of risperidone following intraperitoneal administration in selected nanoemulsions, most probably due to their different droplet surface properties (different composition of the stabilizing layer). Namely, polysorbate 80-costabilized nanoemulsion showed increased (1.4-7.4-fold higher) risperidone brain availability compared to other nanoemulsions and drug solution, suggesting this nanoemulsion as a promising carrier worth exploring further for brain targeting.",
publisher = "Elsevier",
journal = "International Journal of Pharmaceutics",
title = "Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation",
volume = "493",
number = "1-2",
pages = "40-54",
doi = "10.1016/j.ijpharm.2015.07.007"
}

Dordevic, S. M., Cekic, N., Savić, M. M., Isailovic, T. M., Randjelović, D., Marković, B. D., Savić, S. R., Stamenic, T. T., Daniels, R.,& Savić, S. D.. (2015). Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation. in International Journal of Pharmaceutics
Elsevier., 493(1-2), 40-54.
https://doi.org/10.1016/j.ijpharm.2015.07.007

Dordevic SM, Cekic N, Savić MM, Isailovic TM, Randjelović D, Marković BD, Savić SR, Stamenic TT, Daniels R, Savić SD. Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation. in International Journal of Pharmaceutics. 2015;493(1-2):40-54.
doi:10.1016/j.ijpharm.2015.07.007 .

Dordevic, Sanela M, Cekic, Nebojsa, Savić, Miroslav M., Isailovic, Tanja M, Randjelović, Danijela, Marković, Bojan D., Savić, Saša R., Stamenic, Tamara Timic, Daniels, Rolf, Savić, Snežana D., "Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation" in International Journal of Pharmaceutics, 493, no. 1-2 (2015):40-54,
https://doi.org/10.1016/j.ijpharm.2015.07.007 . .

TY  - JOUR
AU  - Todosijević, Marija
AU  - Savić, Miroslav M.
AU  - Batinić, Bojan B.
AU  - Marković, Bojan D.
AU  - Gasperlin, Mirjana
AU  - Randjelović, Danijela
AU  - Lukić, Milica
AU  - Savić, Snežana D.
PY  - 2015
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/3202
AB  - To elaborate the decisive role of surfactants in promotion of aceclofenac' skin absorption, potentially avoiding irritation, we developed non-ionic microemulsions varying natural or synthetic surfactants: sucrose esters (laurate or myristate) vs. polysorbate 80. A comprehensive physicochemical characterization indicated no significant influence of the solubilized nonsteroidal anti-inflammatory drug on the bicontinuous structure of blank formulations. To evaluate skin tolerability of isopropyl alcohol, a sucrose ester-based microemulsion containing transcutol P as a cosurfactant was also developed. The measured skin parameters strongly depended on the (co)surfactant type, showing higher compatibility of the microemulsions containing sucrose ester and isopropyl alcohol. In vitro release results, in vivo tape stripping and pharmacokinetics in rats confirmed superiority of the sucrose ester-over polysorbate-based microemulsions (total amounts of aceclofenac penetrated 60.81 +/- 5.97 and 60.86 +/- 3.67 vs. 27.00 +/- 5.09 mu g/cm(2), and its maximum plasma concentrations 275.57 +/- 109.49 and 281.31 +/- 76.76 vs. 150.23 +/- 69.74 ng/ml for sucrose laurate- and myristate- vs. polysorbate 80-based microemulsions, respectively). Hence, sugar-based excipients increased delivery of aceclofenac through stratum corneum by increasing its fluidity, showing overall more satisfying safety profiles. In conclusion, sucrose ester-based microemulsions proved to be promising carriers for dermal/transdermal aceclofenac delivery.
PB  - Elsevier
T2  - International Journal of Pharmaceutics
T1  - Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance
VL  - 496
IS  - 2
SP  - 931
EP  - 941
DO  - 10.1016/j.ijpharm.2015.10.048
ER  - 

@article{
author = "Todosijević, Marija and Savić, Miroslav M. and Batinić, Bojan B. and Marković, Bojan D. and Gasperlin, Mirjana and Randjelović, Danijela and Lukić, Milica and Savić, Snežana D.",
year = "2015",
abstract = "To elaborate the decisive role of surfactants in promotion of aceclofenac' skin absorption, potentially avoiding irritation, we developed non-ionic microemulsions varying natural or synthetic surfactants: sucrose esters (laurate or myristate) vs. polysorbate 80. A comprehensive physicochemical characterization indicated no significant influence of the solubilized nonsteroidal anti-inflammatory drug on the bicontinuous structure of blank formulations. To evaluate skin tolerability of isopropyl alcohol, a sucrose ester-based microemulsion containing transcutol P as a cosurfactant was also developed. The measured skin parameters strongly depended on the (co)surfactant type, showing higher compatibility of the microemulsions containing sucrose ester and isopropyl alcohol. In vitro release results, in vivo tape stripping and pharmacokinetics in rats confirmed superiority of the sucrose ester-over polysorbate-based microemulsions (total amounts of aceclofenac penetrated 60.81 +/- 5.97 and 60.86 +/- 3.67 vs. 27.00 +/- 5.09 mu g/cm(2), and its maximum plasma concentrations 275.57 +/- 109.49 and 281.31 +/- 76.76 vs. 150.23 +/- 69.74 ng/ml for sucrose laurate- and myristate- vs. polysorbate 80-based microemulsions, respectively). Hence, sugar-based excipients increased delivery of aceclofenac through stratum corneum by increasing its fluidity, showing overall more satisfying safety profiles. In conclusion, sucrose ester-based microemulsions proved to be promising carriers for dermal/transdermal aceclofenac delivery.",
publisher = "Elsevier",
journal = "International Journal of Pharmaceutics",
title = "Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance",
volume = "496",
number = "2",
pages = "931-941",
doi = "10.1016/j.ijpharm.2015.10.048"
}

Todosijević, M., Savić, M. M., Batinić, B. B., Marković, B. D., Gasperlin, M., Randjelović, D., Lukić, M.,& Savić, S. D.. (2015). Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance. in International Journal of Pharmaceutics
Elsevier., 496(2), 931-941.
https://doi.org/10.1016/j.ijpharm.2015.10.048

Todosijević M, Savić MM, Batinić BB, Marković BD, Gasperlin M, Randjelović D, Lukić M, Savić SD. Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance. in International Journal of Pharmaceutics. 2015;496(2):931-941.
doi:10.1016/j.ijpharm.2015.10.048 .

Todosijević, Marija, Savić, Miroslav M., Batinić, Bojan B., Marković, Bojan D., Gasperlin, Mirjana, Randjelović, Danijela, Lukić, Milica, Savić, Snežana D., "Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance" in International Journal of Pharmaceutics, 496, no. 2 (2015):931-941,
https://doi.org/10.1016/j.ijpharm.2015.10.048 . .

TY  - JOUR
AU  - Todosijević, Marija
AU  - Cekic, Nebojsa
AU  - Savić, Miroslav M.
AU  - Gasperlin, Mirjana
AU  - Randjelović, Danijela
AU  - Savić, Snežana D.
PY  - 2014
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/1411
AB  - We assessed the functionality of sucrose esters (sucrose laurate, myristate, palmitate, and stearate), relatively innocuous nonionic surfactants, in formulation of biocompatible microemulsions. The putative influence of surfactant structure on the extension of microemulsion region was explored through the construction of the pseudo-ternary phase diagrams for the isopropyl myristate/sucrose ester-isopropyl alcohol/water system, using the titration method and mixture experimental approach. Minor changes in surfactant tail length strongly affected the microemulsion area boundaries. D-optimal mixture design proved to be highly applicable in detecting the microemulsion regions. Examination of conductivity, rheology, and thermal behavior of the selected sucrose laurate and sucrose myristate-based microemulsions, upon dilution with water, indicated existence of percolation threshold and suggested the phase inversion from water-in-oil to oil-in-water via a bicontinuous structure. Atomic force micrographs confirmed the suggested type of microemulsions and were valuable in further exploring their inner structure. The solubilization capacity of aceclofenac as a model drug has decreased as the water volume fraction in microemulsion increased. High surfactant concentration and the measured solubility of aceclofenac in microemulsion components suggested that the interfacial film may mostly contribute to aceclofenac solubilization.
PB  - Springer, New York
T2  - Colloid and Polymer Science
T1  - Sucrose ester-based biocompatible microemulsions as vehicles for aceclofenac as a model drug: formulation approach using D-optimal mixture design
VL  - 292
IS  - 12
SP  - 3061
EP  - 3076
DO  - 10.1007/s00396-014-3351-4
ER  - 

@article{
author = "Todosijević, Marija and Cekic, Nebojsa and Savić, Miroslav M. and Gasperlin, Mirjana and Randjelović, Danijela and Savić, Snežana D.",
year = "2014",
abstract = "We assessed the functionality of sucrose esters (sucrose laurate, myristate, palmitate, and stearate), relatively innocuous nonionic surfactants, in formulation of biocompatible microemulsions. The putative influence of surfactant structure on the extension of microemulsion region was explored through the construction of the pseudo-ternary phase diagrams for the isopropyl myristate/sucrose ester-isopropyl alcohol/water system, using the titration method and mixture experimental approach. Minor changes in surfactant tail length strongly affected the microemulsion area boundaries. D-optimal mixture design proved to be highly applicable in detecting the microemulsion regions. Examination of conductivity, rheology, and thermal behavior of the selected sucrose laurate and sucrose myristate-based microemulsions, upon dilution with water, indicated existence of percolation threshold and suggested the phase inversion from water-in-oil to oil-in-water via a bicontinuous structure. Atomic force micrographs confirmed the suggested type of microemulsions and were valuable in further exploring their inner structure. The solubilization capacity of aceclofenac as a model drug has decreased as the water volume fraction in microemulsion increased. High surfactant concentration and the measured solubility of aceclofenac in microemulsion components suggested that the interfacial film may mostly contribute to aceclofenac solubilization.",
publisher = "Springer, New York",
journal = "Colloid and Polymer Science",
title = "Sucrose ester-based biocompatible microemulsions as vehicles for aceclofenac as a model drug: formulation approach using D-optimal mixture design",
volume = "292",
number = "12",
pages = "3061-3076",
doi = "10.1007/s00396-014-3351-4"
}

Todosijević, M., Cekic, N., Savić, M. M., Gasperlin, M., Randjelović, D.,& Savić, S. D.. (2014). Sucrose ester-based biocompatible microemulsions as vehicles for aceclofenac as a model drug: formulation approach using D-optimal mixture design. in Colloid and Polymer Science
Springer, New York., 292(12), 3061-3076.
https://doi.org/10.1007/s00396-014-3351-4

Todosijević M, Cekic N, Savić MM, Gasperlin M, Randjelović D, Savić SD. Sucrose ester-based biocompatible microemulsions as vehicles for aceclofenac as a model drug: formulation approach using D-optimal mixture design. in Colloid and Polymer Science. 2014;292(12):3061-3076.
doi:10.1007/s00396-014-3351-4 .

Todosijević, Marija, Cekic, Nebojsa, Savić, Miroslav M., Gasperlin, Mirjana, Randjelović, Danijela, Savić, Snežana D., "Sucrose ester-based biocompatible microemulsions as vehicles for aceclofenac as a model drug: formulation approach using D-optimal mixture design" in Colloid and Polymer Science, 292, no. 12 (2014):3061-3076,
https://doi.org/10.1007/s00396-014-3351-4 . .

TY  - JOUR
AU  - Dordevic, Sanela M.
AU  - Radulovic, Tamara S.
AU  - Cekic, Nebojsa
AU  - Randjelović, Danijela
AU  - Savić, Miroslav M.
AU  - Krajisnik, Danina R.
AU  - Milic, Jela R.
AU  - Savić, Snežana D.
PY  - 2013
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/1194
AB  - With the aid of experimental design, we developed and characterized nanoemulsions for parenteral drug delivery. Formulations containing a mixture of medium-chain triglycerides and soybean oil as oil phase, lecithin (soybean/egg) and polysorbate 80 as emulsifiers, and 0.1M phosphate buffer solution (pH 8) as aqueous phase were prepared by cold high-pressure homogenization. To study the effects of the oil content, lecithin type, and the presence of diazepam as a model drug and their interactions on physicochemical characteristics of nanoemulsions, a three factor two-level full factorial design was applied. The nanoemulsions were evaluated concerning droplet size and size distribution, surface charge, viscosity, morphology, drug-excipient interactions, and physical stability. The characterization revealed the small spherical droplets in the range 195-220nm with polydispersity index below 0.15 and zeta potential between -30 and -60mV. Interactions among the investigated factors, rather than factors alone, were shown to more profoundly affect nanoemulsion characteristics. In vivo pharmacokinetic study of selected diazepam nanoemulsions with different oil content (20%, 30%, and 40%, w/w) demonstrated fast and intense initial distribution into rat brain of diazepam from nanoemulsions with 20% and 30% (w/w) oil content, suggesting their applicability in urgent situations.
PB  - Wiley-Blackwell, Hoboken
T2  - Journal of Pharmaceutical Sciences
T1  - Experimental Design in Formulation of Diazepam Nanoemulsions: Physicochemical and Pharmacokinetic Performances
VL  - 102
IS  - 11
SP  - 4159
EP  - 4172
DO  - 10.1002/jps.23734
ER  - 

@article{
author = "Dordevic, Sanela M. and Radulovic, Tamara S. and Cekic, Nebojsa and Randjelović, Danijela and Savić, Miroslav M. and Krajisnik, Danina R. and Milic, Jela R. and Savić, Snežana D.",
year = "2013",
abstract = "With the aid of experimental design, we developed and characterized nanoemulsions for parenteral drug delivery. Formulations containing a mixture of medium-chain triglycerides and soybean oil as oil phase, lecithin (soybean/egg) and polysorbate 80 as emulsifiers, and 0.1M phosphate buffer solution (pH 8) as aqueous phase were prepared by cold high-pressure homogenization. To study the effects of the oil content, lecithin type, and the presence of diazepam as a model drug and their interactions on physicochemical characteristics of nanoemulsions, a three factor two-level full factorial design was applied. The nanoemulsions were evaluated concerning droplet size and size distribution, surface charge, viscosity, morphology, drug-excipient interactions, and physical stability. The characterization revealed the small spherical droplets in the range 195-220nm with polydispersity index below 0.15 and zeta potential between -30 and -60mV. Interactions among the investigated factors, rather than factors alone, were shown to more profoundly affect nanoemulsion characteristics. In vivo pharmacokinetic study of selected diazepam nanoemulsions with different oil content (20%, 30%, and 40%, w/w) demonstrated fast and intense initial distribution into rat brain of diazepam from nanoemulsions with 20% and 30% (w/w) oil content, suggesting their applicability in urgent situations.",
publisher = "Wiley-Blackwell, Hoboken",
journal = "Journal of Pharmaceutical Sciences",
title = "Experimental Design in Formulation of Diazepam Nanoemulsions: Physicochemical and Pharmacokinetic Performances",
volume = "102",
number = "11",
pages = "4159-4172",
doi = "10.1002/jps.23734"
}

Dordevic, S. M., Radulovic, T. S., Cekic, N., Randjelović, D., Savić, M. M., Krajisnik, D. R., Milic, J. R.,& Savić, S. D.. (2013). Experimental Design in Formulation of Diazepam Nanoemulsions: Physicochemical and Pharmacokinetic Performances. in Journal of Pharmaceutical Sciences
Wiley-Blackwell, Hoboken., 102(11), 4159-4172.
https://doi.org/10.1002/jps.23734

Dordevic SM, Radulovic TS, Cekic N, Randjelović D, Savić MM, Krajisnik DR, Milic JR, Savić SD. Experimental Design in Formulation of Diazepam Nanoemulsions: Physicochemical and Pharmacokinetic Performances. in Journal of Pharmaceutical Sciences. 2013;102(11):4159-4172.
doi:10.1002/jps.23734 .

Dordevic, Sanela M., Radulovic, Tamara S., Cekic, Nebojsa, Randjelović, Danijela, Savić, Miroslav M., Krajisnik, Danina R., Milic, Jela R., Savić, Snežana D., "Experimental Design in Formulation of Diazepam Nanoemulsions: Physicochemical and Pharmacokinetic Performances" in Journal of Pharmaceutical Sciences, 102, no. 11 (2013):4159-4172,
https://doi.org/10.1002/jps.23734 . .