TY  - CONF
AU  - Nikolić, Ines
AU  - Petrović, Marija
AU  - Krupnik, Leondard
AU  - Ranđelović, Danijela
AU  - Avaro, Jonathan
AU  - Neels, Antonia
AU  - Borchard, Gerrit
AU  - Jordan, Olivier
AU  - Đoković, Jelena
AU  - Savić, Snežana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4571
AB  - INTRODUCTION
Physicochemical properties of many active ingredients jeopardize their pharmacological activity. To overcome identified obstacles, nanosystems as carriers for delivery of actives have been recognized as promising tools. Increasing number of applications for registration of nanotechnology-enabled pharmaceuticals and many more currently in preclinical or clinical studies raised some questions not only in the field of research and development, but also for regulators. Given the complexity of nanosystems, some specific challenges have been encountered in their characterization, which have not been fully addressed despite respectable research tradition in this field.  Particle size and aggregation potential (especially in complex biological fluids) are some of the critical quality attributes of nanomedicines, being important in the context of physical stability of the colloidal system, and in terms of its safety profile and in vivo performance. Even though a bright future has been predicted for nanomedicines, some of the posted expectations have not been fully met so far. This might be reflected, at least at some points, in the certain methodological issues that commonly result in in vitro to in vivo translational gaps. This aspect underlines the importance of quality and safety assessment of nanomedicines which has also been recognized by globally leading research and regulatory bodies [1,2]. Therefore, the aim of the presented research was to perform a thorough analysis of the selected nanosystem (nanoemulsion) focusing on size estimation and particle-protein interaction applying several techniques, highlighting important factors for a reliable analysis.
METHODLOGY
Materials
As a model nanosystem, previously developed nanoemulsion was used, containing medium-chain triglycerides (Mygliol 812, Fagron) as the oil phase, combination of polysorbate 80 (Acros Organics) and soybean lecithin (Lipoid S-75, Lipoid) as stabilizes, and highly purified water as the water phase. For protein interaction assessment, human serum albumin was used (HSA, Sigma Aldrich).
Methods
Nanoemulsion preparation
Nanoemulsion was prepared via spontaneous emulsification, by dropwise addition of the mixture of the oil and stabilizers to the water phase under constant stirring. For nanoparticle-protein interaction assesment, nanoemulsion was incubated (1h, 37 °C) with HSA in the final concentration of 2.5 mg/ml. 
Sizing experiments – dynamic light scattering
Size and size distribution (per se and in biorelevant environment) were evaluated applying batch mode dynamic light scattering (DLS, Zetasizer Nano ZS90, Malvern Instruments, UK), following the NCL guidance [3]. Intensity-based average hydrodynamic diameter (Z-ave) and polydispersity index (PDI) were analysed in line with relevant parameters of the method. 
Atomic force microscopy (AFM)
Additional sizing analysis and morphological evaluation of the sample were performed applying AFM as a high-resolution technique. AFM analysis of the samples was performed by NTEGRA Prima atomic force microscope (NT-MDT, Moscow, Russia). Intermittent-contact AFM mode was applied using NT-MDT NSGO1 silicon, N-type, antimony doped cantilevers with Au reflective coating. Sample dilution corresponded to the optimal one selected for DLS, and 10 μl of the dilution was placed to the high-quality silica discs (Highest Grade V1 Mica Discs, Ted Pella Inc.) and dried in vacuum. Experiments were performed in the air, in contactless mode. Topographic images and “signal-error” images were collected, AFM images were created and analyzed with the software Image Analysis 2.2.0 (NT-MDT) and Gwyddion 2.60 (Free and Open Source software, Department of Nanometrology, Czech Metrology Institute).
Small angle X-ray scattering (SAXS)
SAXS experiments were performed with the general idea to analyze the structure of the dispersed nanodroplets more profoundly, and especially interactions in biorelevant surrounding (in contact with HSA). A laboratory X-ray setup was applied (Bruker Nanostar, Bruker AXS GmbH, Karlsruhe, Germany). Here, the Kα-line of a X-ray Cu source with a wavelength of 1.541 Å was used and further monochromated by a X-ray mirror. The beam was collimated to a beam diameter of approximately 0.4 mm using three pinholes. The sample-detector distance was set to 107 cm, which lead to a q-range of 0.07 ≤ q ≤ 2.3 nm-1. Calibration of the scattering vector q and estimation of the instrumental resolution of Δq = 0.25 nm-1 was done by measuring the first diffraction peak of a silver behenate sample. The scattered intensity was measured with an avalanche-based detector (VÅNTEC-2000, Bruker AXS). The transmitted part of the beam was determined using a home-made semi-transparent beam stop. The scattered intensity was extracted, radially averaged and integrated over all q-values using the Bruker software DIF-FRAC.EVA (Bruker AXS, version 4.1). The 1D data was transmission corrected and then background subtracted from the scattering of the solvent and the capillary using Matlab 2022.
RESULTS AND DISCUSSION
When applying DLS, as a preliminary technique, primary attention was put on the selection of optimal dilution level for the measurement, analyzing attenuation factor, count rate and intercept of the correlation function in different dilution ratios and with different dilution media (water, PBS 7.4 and 10 mM NaCl), and dilution 1:100 (v/v) was marked as the optimal one. However, significant differences in obtained nanodroplet size was observed depending on the type of medium. When water was used as a dilution medium, significantly higher Z-ave values were obtained (83.71±0.86 nm) compared to the situations where PBS 7.4 (73.50±0.75nm) or 10 mM NaCl (76.59±0.50nm) were used as dilution medium, indicating how sample preparation protocol might be crucial. Even though DLS was not sensitive enough to detect any interaction with HSA (no significant difference in terms of Z-ave and PDI compared to the results obtained in the same dilution medium without HSA), AFM captured qualitative difference in the droplet topography (Figure 1), raising ides on nanoemulsion interfacial interaction with HSA and increased aggregation potential. Further on, SAXS confirmed the existence of a bilayer structure as indicated by a prominent correlation peak at around 1 nm-1, which corresponds to a bilayer thickness of around 6.2 nm. SAXS (Figure 2; probably corresponding to the lecithin formations at the interface). It may be assumed that the bilayer structure changes its structure when mixed with HSA. 
CONCLUSION
In this research, it has been demonstrated how important is to carefully select measurement conditions even for DLS -commonly used and the only standardized methods, in order to keep the measurements meaningful. Further on, not every method is capable of detecting some specific bio-nano interactions. Aiming to generate reliable datasets, condition sine qua non is to perform complementary techniques with increasing complexity. Further experimental segments should cover additional evaluation (e.g. analytical ultracentrifugation, thermal analysis, interfacial properties assessment, electron microscopy) that would shed light on bio-nano interactions important for in vivo fate of the nanosystems.
C3  - 4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France
T1  - Sizing experiments and bio-nano interactions: method matters
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4571
ER  - 

@conference{
author = "Nikolić, Ines and Petrović, Marija and Krupnik, Leondard and Ranđelović, Danijela and Avaro, Jonathan and Neels, Antonia and Borchard, Gerrit and Jordan, Olivier and Đoković, Jelena and Savić, Snežana",
year = "2023",
abstract = "INTRODUCTION
Physicochemical properties of many active ingredients jeopardize their pharmacological activity. To overcome identified obstacles, nanosystems as carriers for delivery of actives have been recognized as promising tools. Increasing number of applications for registration of nanotechnology-enabled pharmaceuticals and many more currently in preclinical or clinical studies raised some questions not only in the field of research and development, but also for regulators. Given the complexity of nanosystems, some specific challenges have been encountered in their characterization, which have not been fully addressed despite respectable research tradition in this field.  Particle size and aggregation potential (especially in complex biological fluids) are some of the critical quality attributes of nanomedicines, being important in the context of physical stability of the colloidal system, and in terms of its safety profile and in vivo performance. Even though a bright future has been predicted for nanomedicines, some of the posted expectations have not been fully met so far. This might be reflected, at least at some points, in the certain methodological issues that commonly result in in vitro to in vivo translational gaps. This aspect underlines the importance of quality and safety assessment of nanomedicines which has also been recognized by globally leading research and regulatory bodies [1,2]. Therefore, the aim of the presented research was to perform a thorough analysis of the selected nanosystem (nanoemulsion) focusing on size estimation and particle-protein interaction applying several techniques, highlighting important factors for a reliable analysis.
METHODLOGY
Materials
As a model nanosystem, previously developed nanoemulsion was used, containing medium-chain triglycerides (Mygliol 812, Fagron) as the oil phase, combination of polysorbate 80 (Acros Organics) and soybean lecithin (Lipoid S-75, Lipoid) as stabilizes, and highly purified water as the water phase. For protein interaction assessment, human serum albumin was used (HSA, Sigma Aldrich).
Methods
Nanoemulsion preparation
Nanoemulsion was prepared via spontaneous emulsification, by dropwise addition of the mixture of the oil and stabilizers to the water phase under constant stirring. For nanoparticle-protein interaction assesment, nanoemulsion was incubated (1h, 37 °C) with HSA in the final concentration of 2.5 mg/ml. 
Sizing experiments – dynamic light scattering
Size and size distribution (per se and in biorelevant environment) were evaluated applying batch mode dynamic light scattering (DLS, Zetasizer Nano ZS90, Malvern Instruments, UK), following the NCL guidance [3]. Intensity-based average hydrodynamic diameter (Z-ave) and polydispersity index (PDI) were analysed in line with relevant parameters of the method. 
Atomic force microscopy (AFM)
Additional sizing analysis and morphological evaluation of the sample were performed applying AFM as a high-resolution technique. AFM analysis of the samples was performed by NTEGRA Prima atomic force microscope (NT-MDT, Moscow, Russia). Intermittent-contact AFM mode was applied using NT-MDT NSGO1 silicon, N-type, antimony doped cantilevers with Au reflective coating. Sample dilution corresponded to the optimal one selected for DLS, and 10 μl of the dilution was placed to the high-quality silica discs (Highest Grade V1 Mica Discs, Ted Pella Inc.) and dried in vacuum. Experiments were performed in the air, in contactless mode. Topographic images and “signal-error” images were collected, AFM images were created and analyzed with the software Image Analysis 2.2.0 (NT-MDT) and Gwyddion 2.60 (Free and Open Source software, Department of Nanometrology, Czech Metrology Institute).
Small angle X-ray scattering (SAXS)
SAXS experiments were performed with the general idea to analyze the structure of the dispersed nanodroplets more profoundly, and especially interactions in biorelevant surrounding (in contact with HSA). A laboratory X-ray setup was applied (Bruker Nanostar, Bruker AXS GmbH, Karlsruhe, Germany). Here, the Kα-line of a X-ray Cu source with a wavelength of 1.541 Å was used and further monochromated by a X-ray mirror. The beam was collimated to a beam diameter of approximately 0.4 mm using three pinholes. The sample-detector distance was set to 107 cm, which lead to a q-range of 0.07 ≤ q ≤ 2.3 nm-1. Calibration of the scattering vector q and estimation of the instrumental resolution of Δq = 0.25 nm-1 was done by measuring the first diffraction peak of a silver behenate sample. The scattered intensity was measured with an avalanche-based detector (VÅNTEC-2000, Bruker AXS). The transmitted part of the beam was determined using a home-made semi-transparent beam stop. The scattered intensity was extracted, radially averaged and integrated over all q-values using the Bruker software DIF-FRAC.EVA (Bruker AXS, version 4.1). The 1D data was transmission corrected and then background subtracted from the scattering of the solvent and the capillary using Matlab 2022.
RESULTS AND DISCUSSION
When applying DLS, as a preliminary technique, primary attention was put on the selection of optimal dilution level for the measurement, analyzing attenuation factor, count rate and intercept of the correlation function in different dilution ratios and with different dilution media (water, PBS 7.4 and 10 mM NaCl), and dilution 1:100 (v/v) was marked as the optimal one. However, significant differences in obtained nanodroplet size was observed depending on the type of medium. When water was used as a dilution medium, significantly higher Z-ave values were obtained (83.71±0.86 nm) compared to the situations where PBS 7.4 (73.50±0.75nm) or 10 mM NaCl (76.59±0.50nm) were used as dilution medium, indicating how sample preparation protocol might be crucial. Even though DLS was not sensitive enough to detect any interaction with HSA (no significant difference in terms of Z-ave and PDI compared to the results obtained in the same dilution medium without HSA), AFM captured qualitative difference in the droplet topography (Figure 1), raising ides on nanoemulsion interfacial interaction with HSA and increased aggregation potential. Further on, SAXS confirmed the existence of a bilayer structure as indicated by a prominent correlation peak at around 1 nm-1, which corresponds to a bilayer thickness of around 6.2 nm. SAXS (Figure 2; probably corresponding to the lecithin formations at the interface). It may be assumed that the bilayer structure changes its structure when mixed with HSA. 
CONCLUSION
In this research, it has been demonstrated how important is to carefully select measurement conditions even for DLS -commonly used and the only standardized methods, in order to keep the measurements meaningful. Further on, not every method is capable of detecting some specific bio-nano interactions. Aiming to generate reliable datasets, condition sine qua non is to perform complementary techniques with increasing complexity. Further experimental segments should cover additional evaluation (e.g. analytical ultracentrifugation, thermal analysis, interfacial properties assessment, electron microscopy) that would shed light on bio-nano interactions important for in vivo fate of the nanosystems.",
journal = "4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France",
title = "Sizing experiments and bio-nano interactions: method matters",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4571"
}

Nikolić, I., Petrović, M., Krupnik, L., Ranđelović, D., Avaro, J., Neels, A., Borchard, G., Jordan, O., Đoković, J.,& Savić, S.. (2023). Sizing experiments and bio-nano interactions: method matters. in 4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France.
https://hdl.handle.net/21.15107/rcub_farfar_4571

Nikolić I, Petrović M, Krupnik L, Ranđelović D, Avaro J, Neels A, Borchard G, Jordan O, Đoković J, Savić S. Sizing experiments and bio-nano interactions: method matters. in 4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_4571 .

Nikolić, Ines, Petrović, Marija, Krupnik, Leondard, Ranđelović, Danijela, Avaro, Jonathan, Neels, Antonia, Borchard, Gerrit, Jordan, Olivier, Đoković, Jelena, Savić, Snežana, "Sizing experiments and bio-nano interactions: method matters" in 4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France (2023),
https://hdl.handle.net/21.15107/rcub_farfar_4571 .

TY  - CONF
AU  - Mitrović, Jelena
AU  - Petković, Miloš
AU  - Ranđelović, Danijela
AU  - Đoković, Jelena
AU  - Knutson, Daniel
AU  - Cook, James
AU  - Savić, Vladimir
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4097
AB  - Lipid nanoparticles are being intensively investigated for
the formulation of the drugs with poor solubility substances
(1). They represent colloid dispersions of the particles with
lipid matrix that is solid at room and body temperature.
Because of the low capacity of triglycerides for the drug
substances incorporation, alternatively, high amounts of
lecithin could be added to increase the solubilization (2).
This was used for the incorporation of DK-I-60-3 (7-
methoxy-d3-2-(4-methoxyd3-phenyl)-2,5-dihydro-
3Hpyrazolo[4,3-c]quinolin-3-one), novel deuterated
pyrazoloquinolinone ligand, with very low solubility in
water as well as in oils (3,4). However, because of
amphiphilic nature of lecithin, its localization within
nanoparticles should be analyzed, especially with respect
to stability, drug loading capacity and drug localization,
because it may additionally influence the drug release
mechanism (2).
C3  - 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_farfar_4097
ER  - 

@conference{
author = "Mitrović, Jelena and Petković, Miloš and Ranđelović, Danijela and Đoković, Jelena and Knutson, Daniel and Cook, James and Savić, Vladimir and Savić, Miroslav and Savić, Snežana",
year = "2022",
abstract = "Lipid nanoparticles are being intensively investigated for
the formulation of the drugs with poor solubility substances
(1). They represent colloid dispersions of the particles with
lipid matrix that is solid at room and body temperature.
Because of the low capacity of triglycerides for the drug
substances incorporation, alternatively, high amounts of
lecithin could be added to increase the solubilization (2).
This was used for the incorporation of DK-I-60-3 (7-
methoxy-d3-2-(4-methoxyd3-phenyl)-2,5-dihydro-
3Hpyrazolo[4,3-c]quinolin-3-one), novel deuterated
pyrazoloquinolinone ligand, with very low solubility in
water as well as in oils (3,4). However, because of
amphiphilic nature of lecithin, its localization within
nanoparticles should be analyzed, especially with respect
to stability, drug loading capacity and drug localization,
because it may additionally influence the drug release
mechanism (2).",
journal = "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_farfar_4097"
}

Mitrović, J., Petković, M., Ranđelović, 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. in 13th World meeting on pharmaceutics, biopharmaceutics and pharmaceutical technology, 28-31 March 2022, Rotterdam, Netherlands.
https://hdl.handle.net/21.15107/rcub_farfar_4097

Mitrović J, Petković M, Ranđelović 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. in 13th World meeting on pharmaceutics, biopharmaceutics and pharmaceutical technology, 28-31 March 2022, Rotterdam, Netherlands. 2022;.
https://hdl.handle.net/21.15107/rcub_farfar_4097 .

Mitrović, Jelena, Petković, Miloš, Ranđelović, 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" in 13th World meeting on pharmaceutics, biopharmaceutics and pharmaceutical technology, 28-31 March 2022, Rotterdam, Netherlands (2022),
https://hdl.handle.net/21.15107/rcub_farfar_4097 .

TY  - CONF
AU  - Nikolić, Ines
AU  - Ranđelović, Danijela
AU  - Savić, Snežana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4493
AB  - Physicochemical properties of many active ingredients jeopardize their
pharmacological activity. To overcome identified obstacles, nanosystems as carriers for
delivery of actives have been recognized as promising tools, with highly posted expectations.
The nanotechnology-based approach in drug formulation is much more than just another
step in size miniaturization. Given the complexity of nanosystems, challenges encountered in
their characterization, and evident lack of testing protocols, relevant European
research/regulatory bodies have issued guidelines, summarizing important parameters for
nanosystem characterization. Size/size distribution (per se and in biorelevant environment)
are essentially important, representing critical quality attributes (1). The aim was to show
how significantly different results could be obtained under different measurement
conditions/sample preparation methods, offering optimal protocol for size estimation
applying dynamic light scattering (DLS), with complementary analysis through atomic force
microscopy. Hydrophilic nanoemulsion and aqueous dispersion of polymeric nanoparticles
were used as test samples. Ultrapurified water, phosphate buffer saline (PBS, pH 7.4) and
biorelevant medium with serum proteins were used for dilution. Measurements were
performed applying batch-mode DLS (ZetasizerNano), and AutoProbe CP-Research
microscope. Significant differences in obtained nanodroplet/nanoparticle size were
observed depending on the type of medium and dilution level. Protein corona formation
could not be confirmed with certainty. Preference was given to PBS as dispersant. The
optimal level of dilution for nanoparticles was 1:10 (Z‐ave=59.16±0.46nm), and for
nanoemulsion 1:100 (Z‐ave=73.5±0.75nm). For proper interpretation, it is necessary that the
DLS measurement report, in addition to the Z‐ave and the polydispersity index, contains at
least the data on the attenuation and correlation function intercept.
AB  - Fizičkohemijske osobine mnogih aktivnih supstanci otežavaju ostvarivanje
farmakoloških efekata. Kako bi se identifikovane prepreke prevazišle, visoka očekivanja
postavljena su pred nanosisteme - nosače za isporuku aktivnih supstanci, uz značajna
ulaganja u njihov razvoj. Nanotehnološki pristup formulaciji leka mnogo je više od pukog
smanjenja veličine. Imajući u vidu kompleksnost nanosistema, izazove koji se sreću u
njihovoj karakterizaciji, te evidentan nedostatak protokola ispitivanja, relevanta evropska
istraživačka/regulatorna tela izdala su vodiče, sumirajući značajne parametre karakterizacije
nanosistema. Veličina/distribucija veličina (per se i u biorelevantnim uslovima) od suštinske
su važnosti za postizanje očekivanih performansi, predstavljajući kritične atribute kvaliteta
(1). Cilj rada bio je pokazati kako se pri različitim uslovima merenja/načinima pripreme
istog uzorka dobijaju značajno različiti rezultati procene veličine, te ponuditi optimalan
protokol merenja dinamičkim rasipanjem svetlosti (DLS), uz komplementarno ispitivanje
mikroskopijom atomskih sila. Kao test uzorci korišćeni su hidrofilna nanoemulzija i vodena
disperzija polimernih nanočestica, a kao medijumi za razblaživanje visokoprečišćena voda,
izotonični fosfatni pufer (PBS, pH 7,4) i biorelevantni medijum obogaćen proteinima seruma.
Merenja su sprovedena primenom batch‐mode DLS, (ZetasizerNano), i na mikroskopu
AutoProbe CP-Research. Primećene su značajne razlike u vrednostima veličine
nanokapi/nanočestica zavisno od tipa medijuma i nivoa razblaženja. Nije se moglo sa
sigurnošću potvrditi formiranje protein korone nakon inkubacije u biorelevantnom
medijumu. Za procenu veličine per se, prednost je data PBS-u kao disperzantu. Optimalan
nivo razblaženja za nanočestice bio je 1:10 (Z‐ave=59,16±0,46nm), a za nanoemulziju 1:100
(Z‐ave=73,5±0,75nm). Radi adekvatnog tumačenja, potrebno je da izveštaj DLS merenja,
pored Z-ave i indeksa polidisperznosti, sadrži barem još podatke o atenuaciji i odsečku
korelacione funkcije.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Towards Proper Sizing Experiments: Analysis of the Impact of Measurement Conditions and Sample Preparation on the Size Estimation of the Nanodroplets and Nanoparticles
T1  - U susret pravilnom određivanju veličine nanostruktura: analiza uticaja uslova merenja i pripreme uzorka na razultate procene veličine nanokapi i nanočestica
VL  - 72
IS  - 4 suplement
SP  - S192
EP  - S193
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4493
ER  - 

@conference{
author = "Nikolić, Ines and Ranđelović, Danijela and Savić, Snežana",
year = "2022",
abstract = "Physicochemical properties of many active ingredients jeopardize their
pharmacological activity. To overcome identified obstacles, nanosystems as carriers for
delivery of actives have been recognized as promising tools, with highly posted expectations.
The nanotechnology-based approach in drug formulation is much more than just another
step in size miniaturization. Given the complexity of nanosystems, challenges encountered in
their characterization, and evident lack of testing protocols, relevant European
research/regulatory bodies have issued guidelines, summarizing important parameters for
nanosystem characterization. Size/size distribution (per se and in biorelevant environment)
are essentially important, representing critical quality attributes (1). The aim was to show
how significantly different results could be obtained under different measurement
conditions/sample preparation methods, offering optimal protocol for size estimation
applying dynamic light scattering (DLS), with complementary analysis through atomic force
microscopy. Hydrophilic nanoemulsion and aqueous dispersion of polymeric nanoparticles
were used as test samples. Ultrapurified water, phosphate buffer saline (PBS, pH 7.4) and
biorelevant medium with serum proteins were used for dilution. Measurements were
performed applying batch-mode DLS (ZetasizerNano), and AutoProbe CP-Research
microscope. Significant differences in obtained nanodroplet/nanoparticle size were
observed depending on the type of medium and dilution level. Protein corona formation
could not be confirmed with certainty. Preference was given to PBS as dispersant. The
optimal level of dilution for nanoparticles was 1:10 (Z‐ave=59.16±0.46nm), and for
nanoemulsion 1:100 (Z‐ave=73.5±0.75nm). For proper interpretation, it is necessary that the
DLS measurement report, in addition to the Z‐ave and the polydispersity index, contains at
least the data on the attenuation and correlation function intercept., Fizičkohemijske osobine mnogih aktivnih supstanci otežavaju ostvarivanje
farmakoloških efekata. Kako bi se identifikovane prepreke prevazišle, visoka očekivanja
postavljena su pred nanosisteme - nosače za isporuku aktivnih supstanci, uz značajna
ulaganja u njihov razvoj. Nanotehnološki pristup formulaciji leka mnogo je više od pukog
smanjenja veličine. Imajući u vidu kompleksnost nanosistema, izazove koji se sreću u
njihovoj karakterizaciji, te evidentan nedostatak protokola ispitivanja, relevanta evropska
istraživačka/regulatorna tela izdala su vodiče, sumirajući značajne parametre karakterizacije
nanosistema. Veličina/distribucija veličina (per se i u biorelevantnim uslovima) od suštinske
su važnosti za postizanje očekivanih performansi, predstavljajući kritične atribute kvaliteta
(1). Cilj rada bio je pokazati kako se pri različitim uslovima merenja/načinima pripreme
istog uzorka dobijaju značajno različiti rezultati procene veličine, te ponuditi optimalan
protokol merenja dinamičkim rasipanjem svetlosti (DLS), uz komplementarno ispitivanje
mikroskopijom atomskih sila. Kao test uzorci korišćeni su hidrofilna nanoemulzija i vodena
disperzija polimernih nanočestica, a kao medijumi za razblaživanje visokoprečišćena voda,
izotonični fosfatni pufer (PBS, pH 7,4) i biorelevantni medijum obogaćen proteinima seruma.
Merenja su sprovedena primenom batch‐mode DLS, (ZetasizerNano), i na mikroskopu
AutoProbe CP-Research. Primećene su značajne razlike u vrednostima veličine
nanokapi/nanočestica zavisno od tipa medijuma i nivoa razblaženja. Nije se moglo sa
sigurnošću potvrditi formiranje protein korone nakon inkubacije u biorelevantnom
medijumu. Za procenu veličine per se, prednost je data PBS-u kao disperzantu. Optimalan
nivo razblaženja za nanočestice bio je 1:10 (Z‐ave=59,16±0,46nm), a za nanoemulziju 1:100
(Z‐ave=73,5±0,75nm). Radi adekvatnog tumačenja, potrebno je da izveštaj DLS merenja,
pored Z-ave i indeksa polidisperznosti, sadrži barem još podatke o atenuaciji i odsečku
korelacione funkcije.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Towards Proper Sizing Experiments: Analysis of the Impact of Measurement Conditions and Sample Preparation on the Size Estimation of the Nanodroplets and Nanoparticles, U susret pravilnom određivanju veličine nanostruktura: analiza uticaja uslova merenja i pripreme uzorka na razultate procene veličine nanokapi i nanočestica",
volume = "72",
number = "4 suplement",
pages = "S192-S193",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4493"
}

Nikolić, I., Ranđelović, D.,& Savić, S.. (2022). Towards Proper Sizing Experiments: Analysis of the Impact of Measurement Conditions and Sample Preparation on the Size Estimation of the Nanodroplets and Nanoparticles. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S192-S193.
https://hdl.handle.net/21.15107/rcub_farfar_4493

Nikolić I, Ranđelović D, Savić S. Towards Proper Sizing Experiments: Analysis of the Impact of Measurement Conditions and Sample Preparation on the Size Estimation of the Nanodroplets and Nanoparticles. in Arhiv za farmaciju. 2022;72(4 suplement):S192-S193.
https://hdl.handle.net/21.15107/rcub_farfar_4493 .

Nikolić, Ines, Ranđelović, Danijela, Savić, Snežana, "Towards Proper Sizing Experiments: Analysis of the Impact of Measurement Conditions and Sample Preparation on the Size Estimation of the Nanodroplets and Nanoparticles" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S192-S193,
https://hdl.handle.net/21.15107/rcub_farfar_4493 .

TY  - 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 . .

TY  - JOUR
AU  - Đoković, Jelena
AU  - Savić, Sanela
AU  - Mitrović, Jelena
AU  - Nikolić, Ines
AU  - Marković, Bojan
AU  - Ranđelović, Danijela
AU  - Antić-Stanković, Jelena
AU  - Božić, Dragana
AU  - Cekić, Nebojša
AU  - Stevanović, Vladimir
AU  - Batinić, Bojan
AU  - Aranđelović, Jovana
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5541
AB  - The current study describes the experimental design guided development of PEGylated nanoemulsions as parenteral delivery systems for curcumin, a powerful antioxidant, as well as the evaluation of their physicochemical characteristics and antioxidant activity during the two years of storage. Experimental design setup helped development of nanoemulsion templates with critical quality attributes in line with parenteral application route. Curcumin-loaded nanoemulsions showed mean droplet size about 105 nm, polydispersity index <0.15, zeta potential of −40 mV, and acceptable osmolality of about 550 mOsm/kg. After two years of storage at room temperature, all formulations remained stable. Moreover, antioxidant activity remained intact, as demonstrated by DPPH (IC50 values 0.078–0.075 mg/mL after two years) and FRAPS assays. In vitro release testing proved that PEGylated phospholipids slowed down the curcumin release from nanoemulsions. The nanoemulsion carrier has been proven safe by the MTT test conducted with MRC-5 cell line, and effective on LS cell line. Results from the pharmacokinetic pilot study implied the PEGylated nanoemulsions improved plasma residence of curcumin 20 min after intravenous administration, compared to the non-PEGylated nanoemulsion (two-fold higher) or curcumin solution (three-fold higher). Overall, conclusion suggests that developed PEGylated nanoemulsions present an acceptable delivery system for parenteral administration of curcumin, being effective in preserving its stability and antioxidant capacity at the level highly comparable to the initial findings.
PB  - MDPI
T2  - International Journal of Molecular Sciences
T1  - Curcumin loaded pegylated nanoemulsions designed for maintained antioxidant effects and improved bioavailability: A pilot study on rats
VL  - 22
IS  - 15
DO  - 10.3390/ijms22157991
ER  - 

@article{
author = "Đoković, Jelena and Savić, Sanela and Mitrović, Jelena and Nikolić, Ines and Marković, Bojan and Ranđelović, Danijela and Antić-Stanković, Jelena and Božić, Dragana and Cekić, Nebojša and Stevanović, Vladimir and Batinić, Bojan and Aranđelović, Jovana and Savić, Miroslav and Savić, Snežana",
year = "2021",
abstract = "The current study describes the experimental design guided development of PEGylated nanoemulsions as parenteral delivery systems for curcumin, a powerful antioxidant, as well as the evaluation of their physicochemical characteristics and antioxidant activity during the two years of storage. Experimental design setup helped development of nanoemulsion templates with critical quality attributes in line with parenteral application route. Curcumin-loaded nanoemulsions showed mean droplet size about 105 nm, polydispersity index <0.15, zeta potential of −40 mV, and acceptable osmolality of about 550 mOsm/kg. After two years of storage at room temperature, all formulations remained stable. Moreover, antioxidant activity remained intact, as demonstrated by DPPH (IC50 values 0.078–0.075 mg/mL after two years) and FRAPS assays. In vitro release testing proved that PEGylated phospholipids slowed down the curcumin release from nanoemulsions. The nanoemulsion carrier has been proven safe by the MTT test conducted with MRC-5 cell line, and effective on LS cell line. Results from the pharmacokinetic pilot study implied the PEGylated nanoemulsions improved plasma residence of curcumin 20 min after intravenous administration, compared to the non-PEGylated nanoemulsion (two-fold higher) or curcumin solution (three-fold higher). Overall, conclusion suggests that developed PEGylated nanoemulsions present an acceptable delivery system for parenteral administration of curcumin, being effective in preserving its stability and antioxidant capacity at the level highly comparable to the initial findings.",
publisher = "MDPI",
journal = "International Journal of Molecular Sciences",
title = "Curcumin loaded pegylated nanoemulsions designed for maintained antioxidant effects and improved bioavailability: A pilot study on rats",
volume = "22",
number = "15",
doi = "10.3390/ijms22157991"
}

Đoković, J., Savić, S., Mitrović, J., Nikolić, I., Marković, B., Ranđelović, D., Antić-Stanković, J., Božić, D., Cekić, N., Stevanović, V., Batinić, B., Aranđelović, J., Savić, M.,& Savić, S.. (2021). Curcumin loaded pegylated nanoemulsions designed for maintained antioxidant effects and improved bioavailability: A pilot study on rats. in International Journal of Molecular Sciences
MDPI., 22(15).
https://doi.org/10.3390/ijms22157991

Đoković J, Savić S, Mitrović J, Nikolić I, Marković B, Ranđelović D, Antić-Stanković J, Božić D, Cekić N, Stevanović V, Batinić B, Aranđelović J, Savić M, Savić S. Curcumin loaded pegylated nanoemulsions designed for maintained antioxidant effects and improved bioavailability: A pilot study on rats. in International Journal of Molecular Sciences. 2021;22(15).
doi:10.3390/ijms22157991 .

Đoković, Jelena, Savić, Sanela, Mitrović, Jelena, Nikolić, Ines, Marković, Bojan, Ranđelović, Danijela, Antić-Stanković, Jelena, Božić, Dragana, Cekić, Nebojša, Stevanović, Vladimir, Batinić, Bojan, Aranđelović, Jovana, Savić, Miroslav, Savić, Snežana, "Curcumin loaded pegylated nanoemulsions designed for maintained antioxidant effects and improved bioavailability: A pilot study on rats" in International Journal of Molecular Sciences, 22, no. 15 (2021),
https://doi.org/10.3390/ijms22157991 . .

TY  - JOUR
AU  - Gledović, Ana
AU  - Janošević-Ležaić, Aleksandra
AU  - Nikolić, Ines
AU  - Tasić-Kostov, Marija
AU  - Antić-Stanković, Jelena
AU  - Krstonošić, Veljko
AU  - Ranđelović, Danijela
AU  - Božić, Dragana
AU  - Ilić, Dušan
AU  - Tamburić, Slobodanka
AU  - Savić, Snežana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3777
AB  - This study focuses on the development of biocompatible oil-in-water (O/W) nanoemulsions based on polyglycerol esters, as promising carriers for natural actives: red raspberry seed oil—RO and hydro-glycolic fruit extracts from red raspberry—RE and French oak—FE. Nanoemulsions were obtained via phase inversion composition (PIC) method at room temperature by dilution of microemulsion phase, confirmed by visual appearance, percentage of transmittance, microscopic, rheological and Differential Scanning Calorimetry (DSC) investigations. The results have shown that the basic RO-loaded formulation could be further enriched with hydro-glycolic fruit extracts from red raspberry or French oak, while keeping a semi-transparent appearance due to the fine droplet size (Z-ave: 50 to 70 nm, PDI value ≤ 0.1). The highest antioxidant activity (~92% inhibition of the DPPH radical) was achieved in the formulation containing both lipophilic (RO) and hydrophilic antioxidants (FE), due to their synergistic effect. The nanoemulsion carrier significantly increased the selective cytotoxic effect of RO towards malignant melanoma (Fem-X) cells, compared to normal human keratinocytes (HaCaT). In vivo study on human volunteers showed satisfactory safety profiles and significant improvement in skin hydration during 2 h after application for all nanoemulsions. Therefore, polyglycerol ester-based nanoemulsions can be promoted as effective carriers for red raspberry seed oil and/or hydro-glycolic fruit extracts in topical formulations intended for skin protection and hydration.
PB  - MDPI AG
T2  - Nanomaterials
T1  - Polyglycerol ester-based low energy nanoemulsions with red raspberry seed oil and fruit extracts: Formulation development toward effective in vitro/in vivo bioperformance
VL  - 11
IS  - 1
SP  - 1
EP  - 21
DO  - 10.3390/nano11010217
ER  - 

@article{
author = "Gledović, Ana and Janošević-Ležaić, Aleksandra and Nikolić, Ines and Tasić-Kostov, Marija and Antić-Stanković, Jelena and Krstonošić, Veljko and Ranđelović, Danijela and Božić, Dragana and Ilić, Dušan and Tamburić, Slobodanka and Savić, Snežana",
year = "2021",
abstract = "This study focuses on the development of biocompatible oil-in-water (O/W) nanoemulsions based on polyglycerol esters, as promising carriers for natural actives: red raspberry seed oil—RO and hydro-glycolic fruit extracts from red raspberry—RE and French oak—FE. Nanoemulsions were obtained via phase inversion composition (PIC) method at room temperature by dilution of microemulsion phase, confirmed by visual appearance, percentage of transmittance, microscopic, rheological and Differential Scanning Calorimetry (DSC) investigations. The results have shown that the basic RO-loaded formulation could be further enriched with hydro-glycolic fruit extracts from red raspberry or French oak, while keeping a semi-transparent appearance due to the fine droplet size (Z-ave: 50 to 70 nm, PDI value ≤ 0.1). The highest antioxidant activity (~92% inhibition of the DPPH radical) was achieved in the formulation containing both lipophilic (RO) and hydrophilic antioxidants (FE), due to their synergistic effect. The nanoemulsion carrier significantly increased the selective cytotoxic effect of RO towards malignant melanoma (Fem-X) cells, compared to normal human keratinocytes (HaCaT). In vivo study on human volunteers showed satisfactory safety profiles and significant improvement in skin hydration during 2 h after application for all nanoemulsions. Therefore, polyglycerol ester-based nanoemulsions can be promoted as effective carriers for red raspberry seed oil and/or hydro-glycolic fruit extracts in topical formulations intended for skin protection and hydration.",
publisher = "MDPI AG",
journal = "Nanomaterials",
title = "Polyglycerol ester-based low energy nanoemulsions with red raspberry seed oil and fruit extracts: Formulation development toward effective in vitro/in vivo bioperformance",
volume = "11",
number = "1",
pages = "1-21",
doi = "10.3390/nano11010217"
}

Gledović, A., Janošević-Ležaić, A., Nikolić, I., Tasić-Kostov, M., Antić-Stanković, J., Krstonošić, V., Ranđelović, D., Božić, D., Ilić, D., Tamburić, S.,& Savić, S.. (2021). Polyglycerol ester-based low energy nanoemulsions with red raspberry seed oil and fruit extracts: Formulation development toward effective in vitro/in vivo bioperformance. in Nanomaterials
MDPI AG., 11(1), 1-21.
https://doi.org/10.3390/nano11010217

Gledović A, Janošević-Ležaić A, Nikolić I, Tasić-Kostov M, Antić-Stanković J, Krstonošić V, Ranđelović D, Božić D, Ilić D, Tamburić S, Savić S. Polyglycerol ester-based low energy nanoemulsions with red raspberry seed oil and fruit extracts: Formulation development toward effective in vitro/in vivo bioperformance. in Nanomaterials. 2021;11(1):1-21.
doi:10.3390/nano11010217 .

Gledović, Ana, Janošević-Ležaić, Aleksandra, Nikolić, Ines, Tasić-Kostov, Marija, Antić-Stanković, Jelena, Krstonošić, Veljko, Ranđelović, Danijela, Božić, Dragana, Ilić, Dušan, Tamburić, Slobodanka, Savić, Snežana, "Polyglycerol ester-based low energy nanoemulsions with red raspberry seed oil and fruit extracts: Formulation development toward effective in vitro/in vivo bioperformance" in Nanomaterials, 11, no. 1 (2021):1-21,
https://doi.org/10.3390/nano11010217 . .

TY  - 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 . .

TY  - JOUR
AU  - Gledović, Ana
AU  - Janošević-Ležaić, Aleksandra
AU  - Krstonošić, Veljko
AU  - Đoković, Jelena
AU  - Nikolić, Ines
AU  - Bajuk-Bogdanović, Danica
AU  - Antić-Stanković, Jelena
AU  - Ranđelović, Danijela
AU  - Savić, Sanela M.
AU  - Filipović, Mila
AU  - Tamburić, Slobodanka
AU  - Savić, Snežana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3581
AB  - Considering a growing demand for medicinal/cosmetic products with natural actives, this study focuses on the low-energy nanoemulsions (LE-NEs) prepared via the Phase inversion composition (PIC) method at room temperature as potential carriers for natural oil. Four different red raspberry seed oils (ROs) were tested, as follows: cold-pressed vs. CO2- extracted, organic vs. non-organic, refined vs. unrefined. The oil phase was optimized with Tocopheryl acetate and Isostearyl isostearate, while water phase was adjusted with either glycerol or an antioxidant hydro-glycolic extract. This study has used a combined approach to formulation development, employing both conventional methods (pseudo-ternary phase diagram - PTPD, electrical conductivity, particle size measurements, microscopical analysis, and rheological measurements) and the methods novel to this area, such as textural analysis and Raman spectroscopy. Raman spectroscopy has detected fine differences in chemical composition among ROs, and it detected the interactions within nanoemulsions. It was shown that the cold-pressed, unrefined, organic grade oil (RO2) with 6.62% saturated fatty acids and 92.25% unsaturated fatty acids, was optimal for the LE-NEs. Textural analysis confirmed the existence of cubic gel-like phase as a crucial step in the formation of stable RO2-loaded LE-NEs, with droplets in the narrow nano-range (125 to 135 nm; PDI ≤ 0.1). The DPPH test in methanol and ABTS in aqueous medium have revealed a synergistic free radical scavenging effect between lipophilic and hydrophilic antioxidants in LE-NEs. The nanoemulsion carrier has improved the biological effect of raw materials on HeLa cervical adenocarcinoma cells, while exhibiting good safety profile, as confirmed on MRC-5 normal human lung fibroblasts. Overall, this study has shown that low-energy nanoemulsions present very promising carriers for topical delivery of natural bioactives. Raman spectroscopy and textural analysis have proven to be a useful addition to the arsenal of methods used in the formulation and characterization of nanoemulsion systems.
PB  - Public Library of Science
T2  - PLoS ONE
T1  - Low-energy nanoemulsions as carriers for red raspberry seed oil: Formulation approach based on Raman spectroscopy and textural analysis, physicochemical properties, stability and in vitro antioxidant/ biological activity
VL  - 15
IS  - 4
DO  - 10.1371/journal.pone.0230993
ER  - 

@article{
author = "Gledović, Ana and Janošević-Ležaić, Aleksandra and Krstonošić, Veljko and Đoković, Jelena and Nikolić, Ines and Bajuk-Bogdanović, Danica and Antić-Stanković, Jelena and Ranđelović, Danijela and Savić, Sanela M. and Filipović, Mila and Tamburić, Slobodanka and Savić, Snežana",
year = "2020",
abstract = "Considering a growing demand for medicinal/cosmetic products with natural actives, this study focuses on the low-energy nanoemulsions (LE-NEs) prepared via the Phase inversion composition (PIC) method at room temperature as potential carriers for natural oil. Four different red raspberry seed oils (ROs) were tested, as follows: cold-pressed vs. CO2- extracted, organic vs. non-organic, refined vs. unrefined. The oil phase was optimized with Tocopheryl acetate and Isostearyl isostearate, while water phase was adjusted with either glycerol or an antioxidant hydro-glycolic extract. This study has used a combined approach to formulation development, employing both conventional methods (pseudo-ternary phase diagram - PTPD, electrical conductivity, particle size measurements, microscopical analysis, and rheological measurements) and the methods novel to this area, such as textural analysis and Raman spectroscopy. Raman spectroscopy has detected fine differences in chemical composition among ROs, and it detected the interactions within nanoemulsions. It was shown that the cold-pressed, unrefined, organic grade oil (RO2) with 6.62% saturated fatty acids and 92.25% unsaturated fatty acids, was optimal for the LE-NEs. Textural analysis confirmed the existence of cubic gel-like phase as a crucial step in the formation of stable RO2-loaded LE-NEs, with droplets in the narrow nano-range (125 to 135 nm; PDI ≤ 0.1). The DPPH test in methanol and ABTS in aqueous medium have revealed a synergistic free radical scavenging effect between lipophilic and hydrophilic antioxidants in LE-NEs. The nanoemulsion carrier has improved the biological effect of raw materials on HeLa cervical adenocarcinoma cells, while exhibiting good safety profile, as confirmed on MRC-5 normal human lung fibroblasts. Overall, this study has shown that low-energy nanoemulsions present very promising carriers for topical delivery of natural bioactives. Raman spectroscopy and textural analysis have proven to be a useful addition to the arsenal of methods used in the formulation and characterization of nanoemulsion systems.",
publisher = "Public Library of Science",
journal = "PLoS ONE",
title = "Low-energy nanoemulsions as carriers for red raspberry seed oil: Formulation approach based on Raman spectroscopy and textural analysis, physicochemical properties, stability and in vitro antioxidant/ biological activity",
volume = "15",
number = "4",
doi = "10.1371/journal.pone.0230993"
}

Gledović, A., Janošević-Ležaić, A., Krstonošić, V., Đoković, J., Nikolić, I., Bajuk-Bogdanović, D., Antić-Stanković, J., Ranđelović, D., Savić, S. M., Filipović, M., Tamburić, S.,& Savić, S.. (2020). Low-energy nanoemulsions as carriers for red raspberry seed oil: Formulation approach based on Raman spectroscopy and textural analysis, physicochemical properties, stability and in vitro antioxidant/ biological activity. in PLoS ONE
Public Library of Science., 15(4).
https://doi.org/10.1371/journal.pone.0230993

Gledović A, Janošević-Ležaić A, Krstonošić V, Đoković J, Nikolić I, Bajuk-Bogdanović D, Antić-Stanković J, Ranđelović D, Savić SM, Filipović M, Tamburić S, Savić S. Low-energy nanoemulsions as carriers for red raspberry seed oil: Formulation approach based on Raman spectroscopy and textural analysis, physicochemical properties, stability and in vitro antioxidant/ biological activity. in PLoS ONE. 2020;15(4).
doi:10.1371/journal.pone.0230993 .

Gledović, Ana, Janošević-Ležaić, Aleksandra, Krstonošić, Veljko, Đoković, Jelena, Nikolić, Ines, Bajuk-Bogdanović, Danica, Antić-Stanković, Jelena, Ranđelović, Danijela, Savić, Sanela M., Filipović, Mila, Tamburić, Slobodanka, Savić, Snežana, "Low-energy nanoemulsions as carriers for red raspberry seed oil: Formulation approach based on Raman spectroscopy and textural analysis, physicochemical properties, stability and in vitro antioxidant/ biological activity" in PLoS ONE, 15, no. 4 (2020),
https://doi.org/10.1371/journal.pone.0230993 . .

TY  - JOUR
AU  - Nikolić, Ines
AU  - Mitsou, Evgenia
AU  - Pantelić, Ivana
AU  - Ranđelović, Danijela
AU  - Marković, Bojan
AU  - Papadimitriou, Vassiliki
AU  - Xenakis, Aristotelis
AU  - Lunter, Dominique Jasmin
AU  - Žugić, Ana
AU  - Savić, Snežana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3507
AB  - The objective of this work was to develop low-energy nanoemulsions for enhanced dermal delivery of curcumin, using monoterpene compounds eucalyptol (EUC) and pinene (PIN) as chemical penetration enhancers. Spontaneous emulsification was the preparation method. All formulations contained 10% of the oil phase (medium-chain triglycerides (MCT), or their mixture with EUC or PIN). Formulations were stabilized by the combination of polysorbate 80 and soybean lecithin (surfactant-to-oil-ratio=1). Concentration of curcumin was set to 3 mg/ml. Average droplet diameter of all tested formulations ranged from 102 nm to 132 nm, but the ones containing monoterpenes had significantly smaller size compared to the MCT formulation. Such finding was profoundly studied through electron paramagnetic resonance spectroscopy, which proved that the presence of monoterpenes modified the nanoemulsions’ interfacial environment, resulting in droplet size reduction. The release study of curcumin (using Franz cells) demonstrated that the cumulative amount released after 6 h of the experiment was 10.1 ± 0.2% for the MCT nanoemulsions, 13.9 ± 0.1% and 14.0 ± 0.2% for PIN and EUC formulations, respectively. In vivo tape stripping revealed their performances in delivering curcumin into the skin, indicating the following order: EUC>MCT>PIN. The formulation with EUC was clearly the most successful, giving the highest cumulative amount of curcumin that penetrated per surface unit: 34.24±5.68 µg/cm2. The MCT formulation followed (30.62±2.61 µg/cm2) and, finally, the one with PIN (21.61±0.11 µg/cm2). These results corelated with curcumin's solubility in the chosen oils: 4.18±0.02 mg/ml for EUC, 1.67±0.04 mg/ml for MCT and 0.21±0.01 mg/ml for PIN. Probably, higher solubility in the oil phase of the nanoemulsion promoted curcumin's solubility in the superficial skin layers, providing enhanced penetration.
PB  - Elsevier B.V.
T2  - European Journal of Pharmaceutical Sciences
T1  - Microstructure and biopharmaceutical performances of curcumin-loaded low-energy nanoemulsions containing eucalyptol and pinene: Terpenes’ role overcome penetration enhancement effect?
VL  - 142
DO  - 10.1016/j.ejps.2019.105135
ER  - 

@article{
author = "Nikolić, Ines and Mitsou, Evgenia and Pantelić, Ivana and Ranđelović, Danijela and Marković, Bojan and Papadimitriou, Vassiliki and Xenakis, Aristotelis and Lunter, Dominique Jasmin and Žugić, Ana and Savić, Snežana",
year = "2020",
abstract = "The objective of this work was to develop low-energy nanoemulsions for enhanced dermal delivery of curcumin, using monoterpene compounds eucalyptol (EUC) and pinene (PIN) as chemical penetration enhancers. Spontaneous emulsification was the preparation method. All formulations contained 10% of the oil phase (medium-chain triglycerides (MCT), or their mixture with EUC or PIN). Formulations were stabilized by the combination of polysorbate 80 and soybean lecithin (surfactant-to-oil-ratio=1). Concentration of curcumin was set to 3 mg/ml. Average droplet diameter of all tested formulations ranged from 102 nm to 132 nm, but the ones containing monoterpenes had significantly smaller size compared to the MCT formulation. Such finding was profoundly studied through electron paramagnetic resonance spectroscopy, which proved that the presence of monoterpenes modified the nanoemulsions’ interfacial environment, resulting in droplet size reduction. The release study of curcumin (using Franz cells) demonstrated that the cumulative amount released after 6 h of the experiment was 10.1 ± 0.2% for the MCT nanoemulsions, 13.9 ± 0.1% and 14.0 ± 0.2% for PIN and EUC formulations, respectively. In vivo tape stripping revealed their performances in delivering curcumin into the skin, indicating the following order: EUC>MCT>PIN. The formulation with EUC was clearly the most successful, giving the highest cumulative amount of curcumin that penetrated per surface unit: 34.24±5.68 µg/cm2. The MCT formulation followed (30.62±2.61 µg/cm2) and, finally, the one with PIN (21.61±0.11 µg/cm2). These results corelated with curcumin's solubility in the chosen oils: 4.18±0.02 mg/ml for EUC, 1.67±0.04 mg/ml for MCT and 0.21±0.01 mg/ml for PIN. Probably, higher solubility in the oil phase of the nanoemulsion promoted curcumin's solubility in the superficial skin layers, providing enhanced penetration.",
publisher = "Elsevier B.V.",
journal = "European Journal of Pharmaceutical Sciences",
title = "Microstructure and biopharmaceutical performances of curcumin-loaded low-energy nanoemulsions containing eucalyptol and pinene: Terpenes’ role overcome penetration enhancement effect?",
volume = "142",
doi = "10.1016/j.ejps.2019.105135"
}

Nikolić, I., Mitsou, E., Pantelić, I., Ranđelović, D., Marković, B., Papadimitriou, V., Xenakis, A., Lunter, D. J., Žugić, A.,& Savić, S.. (2020). Microstructure and biopharmaceutical performances of curcumin-loaded low-energy nanoemulsions containing eucalyptol and pinene: Terpenes’ role overcome penetration enhancement effect?. in European Journal of Pharmaceutical Sciences
Elsevier B.V.., 142.
https://doi.org/10.1016/j.ejps.2019.105135

Nikolić I, Mitsou E, Pantelić I, Ranđelović D, Marković B, Papadimitriou V, Xenakis A, Lunter DJ, Žugić A, Savić S. Microstructure and biopharmaceutical performances of curcumin-loaded low-energy nanoemulsions containing eucalyptol and pinene: Terpenes’ role overcome penetration enhancement effect?. in European Journal of Pharmaceutical Sciences. 2020;142.
doi:10.1016/j.ejps.2019.105135 .

Nikolić, Ines, Mitsou, Evgenia, Pantelić, Ivana, Ranđelović, Danijela, Marković, Bojan, Papadimitriou, Vassiliki, Xenakis, Aristotelis, Lunter, Dominique Jasmin, Žugić, Ana, Savić, Snežana, "Microstructure and biopharmaceutical performances of curcumin-loaded low-energy nanoemulsions containing eucalyptol and pinene: Terpenes’ role overcome penetration enhancement effect?" in European Journal of Pharmaceutical Sciences, 142 (2020),
https://doi.org/10.1016/j.ejps.2019.105135 . .

TY  - JOUR
AU  - Nikolić, Ines
AU  - Lunter, Dominique
AU  - Ranđelović, Danijela
AU  - Žugić, Ana R.
AU  - Tadić, Vanja M.
AU  - Marković, Bojan
AU  - Cekić, Nebojša
AU  - Živković, Lada
AU  - Topalović, Dijana
AU  - Potparević, Biljana
AU  - Daniels, Rolf
AU  - Savić, Snežana
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3084
AB  - The objective of this work was to investigate and profoundly characterize low-energy nanoemulsions as multifunctional carriers, with slight reference to dermal administration. An evidence-based approach was offered for deepening the knowledge on their formation via spontaneous emulsification. Curcumin, a compound of natural origin, potentially powerful therapeutic, was chosen as a model API. Due to curcumin's demanding properties (instability, poor solubility, low permeability), its potentials remain unreached. Low-energy nanoemulsions were considered carriers capable of overcoming imposed obstacles. Formulation consisting of Polysorbate 80 and soybean lecithin as stabilizers (9:1, 10%), medium-chain triglycerides as the oil phase (10%) and ultrapure water was selected for curcumin incorporation in 3 different concentrations (1, 2 and 3 mg/mL). Physicochemical stability was demonstrated during 3 months of monitoring (mean droplet size: 111.3-146.8 nm; PDI  lt  0.2; pH: 4.73-5.73). Curcumin's release from developed vehicles followed Higuchi's kinetics. DPPH (IC50 = 0.1187 mg/ mL) and FRAP (1.19 +/- 0.02 mmol/g) assays confirmed that curcumin acts as a potent antioxidant through different mechanisms, with no alterations after incorporation in the formulation. High biocompatibility in line with antigenotoxic activity of curcumin-loaded formulations (protective and reparative) was estimated through Comet assay. A multidisciplinary approach is needed to fully characterize developed systems, directing them to more concrete application possibilities.
PB  - Elsevier Science BV, Amsterdam
T2  - International Journal of Pharmaceutics
T1  - Curcumin-loaded low-energy nanoemulsions as a prototype of multifunctional vehicles for different administration routes: Physicochemical and in vitro peculiarities important for dermal application
VL  - 550
IS  - 1-2
SP  - 333
EP  - 346
DO  - 10.1016/j.ijpharm.2018.08.060
ER  - 

@article{
author = "Nikolić, Ines and Lunter, Dominique and Ranđelović, Danijela and Žugić, Ana R. and Tadić, Vanja M. and Marković, Bojan and Cekić, Nebojša and Živković, Lada and Topalović, Dijana and Potparević, Biljana and Daniels, Rolf and Savić, Snežana",
year = "2018",
abstract = "The objective of this work was to investigate and profoundly characterize low-energy nanoemulsions as multifunctional carriers, with slight reference to dermal administration. An evidence-based approach was offered for deepening the knowledge on their formation via spontaneous emulsification. Curcumin, a compound of natural origin, potentially powerful therapeutic, was chosen as a model API. Due to curcumin's demanding properties (instability, poor solubility, low permeability), its potentials remain unreached. Low-energy nanoemulsions were considered carriers capable of overcoming imposed obstacles. Formulation consisting of Polysorbate 80 and soybean lecithin as stabilizers (9:1, 10%), medium-chain triglycerides as the oil phase (10%) and ultrapure water was selected for curcumin incorporation in 3 different concentrations (1, 2 and 3 mg/mL). Physicochemical stability was demonstrated during 3 months of monitoring (mean droplet size: 111.3-146.8 nm; PDI  lt  0.2; pH: 4.73-5.73). Curcumin's release from developed vehicles followed Higuchi's kinetics. DPPH (IC50 = 0.1187 mg/ mL) and FRAP (1.19 +/- 0.02 mmol/g) assays confirmed that curcumin acts as a potent antioxidant through different mechanisms, with no alterations after incorporation in the formulation. High biocompatibility in line with antigenotoxic activity of curcumin-loaded formulations (protective and reparative) was estimated through Comet assay. A multidisciplinary approach is needed to fully characterize developed systems, directing them to more concrete application possibilities.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "International Journal of Pharmaceutics",
title = "Curcumin-loaded low-energy nanoemulsions as a prototype of multifunctional vehicles for different administration routes: Physicochemical and in vitro peculiarities important for dermal application",
volume = "550",
number = "1-2",
pages = "333-346",
doi = "10.1016/j.ijpharm.2018.08.060"
}

Nikolić, I., Lunter, D., Ranđelović, D., Žugić, A. R., Tadić, V. M., Marković, B., Cekić, N., Živković, L., Topalović, D., Potparević, B., Daniels, R.,& Savić, S.. (2018). Curcumin-loaded low-energy nanoemulsions as a prototype of multifunctional vehicles for different administration routes: Physicochemical and in vitro peculiarities important for dermal application. in International Journal of Pharmaceutics
Elsevier Science BV, Amsterdam., 550(1-2), 333-346.
https://doi.org/10.1016/j.ijpharm.2018.08.060

Nikolić I, Lunter D, Ranđelović D, Žugić AR, Tadić VM, Marković B, Cekić N, Živković L, Topalović D, Potparević B, Daniels R, Savić S. Curcumin-loaded low-energy nanoemulsions as a prototype of multifunctional vehicles for different administration routes: Physicochemical and in vitro peculiarities important for dermal application. in International Journal of Pharmaceutics. 2018;550(1-2):333-346.
doi:10.1016/j.ijpharm.2018.08.060 .

Nikolić, Ines, Lunter, Dominique, Ranđelović, Danijela, Žugić, Ana R., Tadić, Vanja M., Marković, Bojan, Cekić, Nebojša, Živković, Lada, Topalović, Dijana, Potparević, Biljana, Daniels, Rolf, Savić, Snežana, "Curcumin-loaded low-energy nanoemulsions as a prototype of multifunctional vehicles for different administration routes: Physicochemical and in vitro peculiarities important for dermal application" in International Journal of Pharmaceutics, 550, no. 1-2 (2018):333-346,
https://doi.org/10.1016/j.ijpharm.2018.08.060 . .

TY  - JOUR
AU  - Bubić-Pajić, Nataša
AU  - Nikolić, Ines
AU  - Mitsou, Evgenia
AU  - Papadimitriou, Vassiliki
AU  - Xenakis, Aristotelis
AU  - Ranđelović, Danijela
AU  - Dobričić, Vladimir
AU  - Smitran, Aleksandra
AU  - Cekić, Nebojša
AU  - Čalija, Bojan
AU  - Savić, Snežana
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3062
AB  - The aim of this study was development of biocompatible topical microemulsions (MEs) for incorporation and improved dermal delivery of sertaconazole nitrate (SN). For this purpose, phase behavior and microstructure of pseudo-ternary glycereth-7-caprylate/caprate (Emanon EV-E, EV)/cosurfactant/Capryol (TM) 90/water systems were investigated. Furhermore, the influence of these properties on the drug skin delivery was also assessed. Expansion of ME single-phase regions with the use of short chain alcohols was a consequence of the more fluid interface when compared to other investigated systems, which was confirmed by electron paramagnetic resonance spectroscopy-EPR. The chosen bicontinuous to inverted bicontinuous formulations were assessed against the ME based on polysorbate 80 as referent sample. Despite incorporation of SN within the selected formulations induced similar alternations in electrical conductivity, viscosity and pH values, obtained EPR spectra suggested different SN localization: within the oil phase (for most of the EV based formulations), or interacting with the interface (polysorbate 80 based formulation). Due to higher in vitro drug release (12.24%-18.53%), ex vivo SN penetration into porcine ear skin (dermal retention Enhancement Ratio (ERO) ranged from 2.66 to 4.25) and pronounced antifungal activity, the chosen MEs represent promising vehicles for dermal delivery of SN in treatment of cutaneous fungal infections. The biopharmaceutical and skin performance differences obtained with different formulations were possible to be explained on the basis of their physicochemical characteristics.
PB  - Elsevier Science BV, Amsterdam
T2  - Journal of Molecular Liquids
T1  - Biocompatible microemulsions for improved dermal delivery of sertaconazole nitrate: Phase behavior study and microstructure influence on drug biopharamaceutical properties
VL  - 272
SP  - 746
EP  - 758
DO  - 10.1016/j.molliq.2018.10.002
ER  - 

@article{
author = "Bubić-Pajić, Nataša and Nikolić, Ines and Mitsou, Evgenia and Papadimitriou, Vassiliki and Xenakis, Aristotelis and Ranđelović, Danijela and Dobričić, Vladimir and Smitran, Aleksandra and Cekić, Nebojša and Čalija, Bojan and Savić, Snežana",
year = "2018",
abstract = "The aim of this study was development of biocompatible topical microemulsions (MEs) for incorporation and improved dermal delivery of sertaconazole nitrate (SN). For this purpose, phase behavior and microstructure of pseudo-ternary glycereth-7-caprylate/caprate (Emanon EV-E, EV)/cosurfactant/Capryol (TM) 90/water systems were investigated. Furhermore, the influence of these properties on the drug skin delivery was also assessed. Expansion of ME single-phase regions with the use of short chain alcohols was a consequence of the more fluid interface when compared to other investigated systems, which was confirmed by electron paramagnetic resonance spectroscopy-EPR. The chosen bicontinuous to inverted bicontinuous formulations were assessed against the ME based on polysorbate 80 as referent sample. Despite incorporation of SN within the selected formulations induced similar alternations in electrical conductivity, viscosity and pH values, obtained EPR spectra suggested different SN localization: within the oil phase (for most of the EV based formulations), or interacting with the interface (polysorbate 80 based formulation). Due to higher in vitro drug release (12.24%-18.53%), ex vivo SN penetration into porcine ear skin (dermal retention Enhancement Ratio (ERO) ranged from 2.66 to 4.25) and pronounced antifungal activity, the chosen MEs represent promising vehicles for dermal delivery of SN in treatment of cutaneous fungal infections. The biopharmaceutical and skin performance differences obtained with different formulations were possible to be explained on the basis of their physicochemical characteristics.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Journal of Molecular Liquids",
title = "Biocompatible microemulsions for improved dermal delivery of sertaconazole nitrate: Phase behavior study and microstructure influence on drug biopharamaceutical properties",
volume = "272",
pages = "746-758",
doi = "10.1016/j.molliq.2018.10.002"
}

Bubić-Pajić, N., Nikolić, I., Mitsou, E., Papadimitriou, V., Xenakis, A., Ranđelović, D., Dobričić, V., Smitran, A., Cekić, N., Čalija, B.,& Savić, S.. (2018). Biocompatible microemulsions for improved dermal delivery of sertaconazole nitrate: Phase behavior study and microstructure influence on drug biopharamaceutical properties. in Journal of Molecular Liquids
Elsevier Science BV, Amsterdam., 272, 746-758.
https://doi.org/10.1016/j.molliq.2018.10.002

Bubić-Pajić N, Nikolić I, Mitsou E, Papadimitriou V, Xenakis A, Ranđelović D, Dobričić V, Smitran A, Cekić N, Čalija B, Savić S. Biocompatible microemulsions for improved dermal delivery of sertaconazole nitrate: Phase behavior study and microstructure influence on drug biopharamaceutical properties. in Journal of Molecular Liquids. 2018;272:746-758.
doi:10.1016/j.molliq.2018.10.002 .

Bubić-Pajić, Nataša, Nikolić, Ines, Mitsou, Evgenia, Papadimitriou, Vassiliki, Xenakis, Aristotelis, Ranđelović, Danijela, Dobričić, Vladimir, Smitran, Aleksandra, Cekić, Nebojša, Čalija, Bojan, Savić, Snežana, "Biocompatible microemulsions for improved dermal delivery of sertaconazole nitrate: Phase behavior study and microstructure influence on drug biopharamaceutical properties" in Journal of Molecular Liquids, 272 (2018):746-758,
https://doi.org/10.1016/j.molliq.2018.10.002 . .

TY  - JOUR
AU  - Isailović, Tanja
AU  - Đorđević, Sanela
AU  - Marković, Bojan
AU  - Randelović, Danijela
AU  - Cekić, Nebojša
AU  - Lukić, Milica
AU  - Pantelić, Ivana
AU  - Daniels, Rolf
AU  - Savić, Snežana
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2716
AB  - We aimed to develop lecithin-based nanoemulsions intended for effective aceclofenac (ACF) skin delivery utilizing sucrose esters [sucrose palmitate (SP) and sucrose stearate (SS)] as additional stabilizers and penetration enhancers. To find the suitable surfactant mixtures and levels of process variables (homogenization pressure and number of cycles-high pressure homogenization manufacturing method) that result in drug-loaded nanoemulsions with minimal droplet size and narrow size distribution, a combined mixture-process experimental design was employed. Based on optimization data, selected nanoemulsions were evaluated regarding morphology, surface charge, drug-excipient interactions, physical stability, and in vivo skin performances (skin penetration and irritation potential). The predicted physicochemical properties and storage stability were proved satisfying for ACF-loaded nanoemulsions containing 2% of SP in the blend with 0%-1% of SS and 1%-2% of egg lecithin (produced at 50 degrees C/20 cycles/800 bar). Additionally, the in vivo tape stripping demonstrated superior ACF skin absorption from these nanoemulsions, particularly from those containing 2% of SP, 0.5% of SS, and 1.5% of egg lecithin, when comparing with the sample costabilized by conventional surfactant-polysorbate 80. In summary, the combined mixture-process experimental design was shown as a feasible tool for formulation development of multisurfactant-based nanosized delivery systems with potentially improved overall product performances.
PB  - Elsevier Science Inc, New York
T2  - Journal of Pharmaceutical Sciences
T1  - Biocompatible Nanoemulsions for Improved Aceclofenac Skin Delivery: Formulation Approach Using Combined Mixture-Process Experimental Design
VL  - 105
IS  - 1
SP  - 308
EP  - 323
DO  - 10.1002/jps.24706
ER  - 

@article{
author = "Isailović, Tanja and Đorđević, Sanela and Marković, Bojan and Randelović, Danijela and Cekić, Nebojša and Lukić, Milica and Pantelić, Ivana and Daniels, Rolf and Savić, Snežana",
year = "2016",
abstract = "We aimed to develop lecithin-based nanoemulsions intended for effective aceclofenac (ACF) skin delivery utilizing sucrose esters [sucrose palmitate (SP) and sucrose stearate (SS)] as additional stabilizers and penetration enhancers. To find the suitable surfactant mixtures and levels of process variables (homogenization pressure and number of cycles-high pressure homogenization manufacturing method) that result in drug-loaded nanoemulsions with minimal droplet size and narrow size distribution, a combined mixture-process experimental design was employed. Based on optimization data, selected nanoemulsions were evaluated regarding morphology, surface charge, drug-excipient interactions, physical stability, and in vivo skin performances (skin penetration and irritation potential). The predicted physicochemical properties and storage stability were proved satisfying for ACF-loaded nanoemulsions containing 2% of SP in the blend with 0%-1% of SS and 1%-2% of egg lecithin (produced at 50 degrees C/20 cycles/800 bar). Additionally, the in vivo tape stripping demonstrated superior ACF skin absorption from these nanoemulsions, particularly from those containing 2% of SP, 0.5% of SS, and 1.5% of egg lecithin, when comparing with the sample costabilized by conventional surfactant-polysorbate 80. In summary, the combined mixture-process experimental design was shown as a feasible tool for formulation development of multisurfactant-based nanosized delivery systems with potentially improved overall product performances.",
publisher = "Elsevier Science Inc, New York",
journal = "Journal of Pharmaceutical Sciences",
title = "Biocompatible Nanoemulsions for Improved Aceclofenac Skin Delivery: Formulation Approach Using Combined Mixture-Process Experimental Design",
volume = "105",
number = "1",
pages = "308-323",
doi = "10.1002/jps.24706"
}

Isailović, T., Đorđević, S., Marković, B., Randelović, D., Cekić, N., Lukić, M., Pantelić, I., Daniels, R.,& Savić, S.. (2016). Biocompatible Nanoemulsions for Improved Aceclofenac Skin Delivery: Formulation Approach Using Combined Mixture-Process Experimental Design. in Journal of Pharmaceutical Sciences
Elsevier Science Inc, New York., 105(1), 308-323.
https://doi.org/10.1002/jps.24706

Isailović T, Đorđević S, Marković B, Randelović D, Cekić N, Lukić M, Pantelić I, Daniels R, Savić S. Biocompatible Nanoemulsions for Improved Aceclofenac Skin Delivery: Formulation Approach Using Combined Mixture-Process Experimental Design. in Journal of Pharmaceutical Sciences. 2016;105(1):308-323.
doi:10.1002/jps.24706 .

Isailović, Tanja, Đorđević, Sanela, Marković, Bojan, Randelović, Danijela, Cekić, Nebojša, Lukić, Milica, Pantelić, Ivana, Daniels, Rolf, Savić, Snežana, "Biocompatible Nanoemulsions for Improved Aceclofenac Skin Delivery: Formulation Approach Using Combined Mixture-Process Experimental Design" in Journal of Pharmaceutical Sciences, 105, no. 1 (2016):308-323,
https://doi.org/10.1002/jps.24706 . .

TY  - JOUR
AU  - Đorđević, Sanela
AU  - Cekić, Nebojša
AU  - Savić, Miroslav
AU  - Isailović, Tanja
AU  - Ranđelović, Danijela
AU  - Marković, Bojan
AU  - Savić, Saša R.
AU  - Timić-Stamenić, Tamara
AU  - Daniels, Rolf
AU  - Savić, Snežana
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2346
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 Science BV, Amsterdam
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 = "Đorđević, Sanela and Cekić, Nebojša and Savić, Miroslav and Isailović, Tanja and Ranđelović, Danijela and Marković, Bojan and Savić, Saša R. and Timić-Stamenić, Tamara and Daniels, Rolf and Savić, Snežana",
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 Science BV, Amsterdam",
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"
}

Đorđević, S., Cekić, N., Savić, M., Isailović, T., Ranđelović, D., Marković, B., Savić, S. R., Timić-Stamenić, T., Daniels, R.,& Savić, S.. (2015). Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation. in International Journal of Pharmaceutics
Elsevier Science BV, Amsterdam., 493(1-2), 40-54.
https://doi.org/10.1016/j.ijpharm.2015.07.007

Đorđević S, Cekić N, Savić M, Isailović T, Ranđelović D, Marković B, Savić SR, Timić-Stamenić T, Daniels R, Savić S. 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 .

Đorđević, Sanela, Cekić, Nebojša, Savić, Miroslav, Isailović, Tanja, Ranđelović, Danijela, Marković, Bojan, Savić, Saša R., Timić-Stamenić, Tamara, Daniels, Rolf, Savić, Snežana, "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 N.
AU  - Savić, Miroslav
AU  - Batinić, Bojan
AU  - Marković, Bojan
AU  - Gasperlin, Mirjana
AU  - Ranđelović, Danijela
AU  - Lukić, Milica
AU  - Savić, Snežana
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2362
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 Science BV, Amsterdam
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 N. and Savić, Miroslav and Batinić, Bojan and Marković, Bojan and Gasperlin, Mirjana and Ranđelović, Danijela and Lukić, Milica and Savić, Snežana",
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 Science BV, Amsterdam",
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. N., Savić, M., Batinić, B., Marković, B., Gasperlin, M., Ranđelović, D., Lukić, M.,& Savić, S.. (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 Science BV, Amsterdam., 496(2), 931-941.
https://doi.org/10.1016/j.ijpharm.2015.10.048

Todosijević MN, Savić M, Batinić B, Marković B, Gasperlin M, Ranđelović D, Lukić M, Savić S. 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 N., Savić, Miroslav, Batinić, Bojan, Marković, Bojan, Gasperlin, Mirjana, Ranđelović, Danijela, Lukić, Milica, Savić, Snežana, "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 N.
AU  - Cekić, Nebojša
AU  - Savić, Miroslav
AU  - Gasperlin, Mirjana
AU  - Ranđelović, Danijela
AU  - Savić, Snežana
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2125
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 N. and Cekić, Nebojša and Savić, Miroslav and Gasperlin, Mirjana and Ranđelović, Danijela and Savić, Snežana",
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. N., Cekić, N., Savić, M., Gasperlin, M., Ranđelović, D.,& Savić, S.. (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 MN, Cekić N, Savić M, Gasperlin M, Ranđelović D, Savić S. 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 N., Cekić, Nebojša, Savić, Miroslav, Gasperlin, Mirjana, Ranđelović, Danijela, Savić, Snežana, "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  - Đorđević, Sanela
AU  - Radulović, Tamara
AU  - Cekić, Nebojša
AU  - Ranđelović, Danijela
AU  - Savić, Miroslav
AU  - Krajišnik, Danina
AU  - Milić, Jela
AU  - Savić, Snežana
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1873
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 = "Đorđević, Sanela and Radulović, Tamara and Cekić, Nebojša and Ranđelović, Danijela and Savić, Miroslav and Krajišnik, Danina and Milić, Jela and Savić, Snežana",
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"
}

Đorđević, S., Radulović, T., Cekić, N., Ranđelović, D., Savić, M., Krajišnik, D., Milić, J.,& Savić, S.. (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

Đorđević S, Radulović T, Cekić N, Ranđelović D, Savić M, Krajišnik D, Milić J, Savić S. 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 .

Đorđević, Sanela, Radulović, Tamara, Cekić, Nebojša, Ranđelović, Danijela, Savić, Miroslav, Krajišnik, Danina, Milić, Jela, Savić, Snežana, "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 . .