TY  - JOUR
AU  - Demisli, Sotiria
AU  - Galani, Eleni
AU  - Goulielmaki, Maria
AU  - Kyrilis, Fotios
AU  - Ilić, Tanja
AU  - Hamdi, Farzad
AU  - Crevar, Milkica
AU  - Kastritis, Panagiotis
AU  - Pletsa, Vasiliki
AU  - Nallet, Frédéric
AU  - Savić, Snežana
AU  - Xenakis, Aristotelis
AU  - Papadimitriou, Vassiliki
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4384
AB  - Hypothesis: Lipophilic cannabidiol can be solubilized in oil-in water nanoemulsions, which can then be impregnated into chitosan hydrogels forming another colloidal system that will facilitate cannabidiol's release. The delivery from both systems was compared, alongside structural and biological studies, to clarify the effect of the two carriers' structure on the release and toxicity of the systems. Experiments: Oil-in-water nanoemulsions (NEs) and the respective nanoemulsion-filled chitosan hydrogels (NE/HGs) were formulated as carriers of cannabidiol (CBD). Size, polydispersity and stability of the NEs were evaluated and then membrane dynamics, shape and structure of both systems were investigated with EPR spin probing, SAXS and microscopy. Biocompatibility of the colloidal delivery systems was evaluated through cytotoxicity tests over normal human skin fibroblasts. An ex vivo permeation protocol using porcine ear skin was implemented to assess the release of CBD and its penetration through the skin. Findings: Incorporation of the NEs in chitosan hydrogels does not significantly affect their structural properties as evidenced through SAXS, EPR and confocal microscopy. These findings indicate the successful development of a novel nanocarrier that preserves the NE structure with the CBD remaining encapsulated in the oil core while providing new rheological properties advantageous over NEs. Moreover, NE/HGs proved to be more efficient as a carrier for the release of CBD. Cell viability assessment revealed high biocompatibility of the proposed colloids.
PB  - Academic Press Inc.
T2  - Journal of Colloid and Interface Science
T1  - Encapsulation of cannabidiol in oil-in-water nanoemulsions and nanoemulsion-filled hydrogels: A structure and biological assessment study
VL  - 634
SP  - 300
EP  - 313
DO  - 10.1016/j.jcis.2022.12.036
ER  - 

@article{
author = "Demisli, Sotiria and Galani, Eleni and Goulielmaki, Maria and Kyrilis, Fotios and Ilić, Tanja and Hamdi, Farzad and Crevar, Milkica and Kastritis, Panagiotis and Pletsa, Vasiliki and Nallet, Frédéric and Savić, Snežana and Xenakis, Aristotelis and Papadimitriou, Vassiliki",
year = "2023",
abstract = "Hypothesis: Lipophilic cannabidiol can be solubilized in oil-in water nanoemulsions, which can then be impregnated into chitosan hydrogels forming another colloidal system that will facilitate cannabidiol's release. The delivery from both systems was compared, alongside structural and biological studies, to clarify the effect of the two carriers' structure on the release and toxicity of the systems. Experiments: Oil-in-water nanoemulsions (NEs) and the respective nanoemulsion-filled chitosan hydrogels (NE/HGs) were formulated as carriers of cannabidiol (CBD). Size, polydispersity and stability of the NEs were evaluated and then membrane dynamics, shape and structure of both systems were investigated with EPR spin probing, SAXS and microscopy. Biocompatibility of the colloidal delivery systems was evaluated through cytotoxicity tests over normal human skin fibroblasts. An ex vivo permeation protocol using porcine ear skin was implemented to assess the release of CBD and its penetration through the skin. Findings: Incorporation of the NEs in chitosan hydrogels does not significantly affect their structural properties as evidenced through SAXS, EPR and confocal microscopy. These findings indicate the successful development of a novel nanocarrier that preserves the NE structure with the CBD remaining encapsulated in the oil core while providing new rheological properties advantageous over NEs. Moreover, NE/HGs proved to be more efficient as a carrier for the release of CBD. Cell viability assessment revealed high biocompatibility of the proposed colloids.",
publisher = "Academic Press Inc.",
journal = "Journal of Colloid and Interface Science",
title = "Encapsulation of cannabidiol in oil-in-water nanoemulsions and nanoemulsion-filled hydrogels: A structure and biological assessment study",
volume = "634",
pages = "300-313",
doi = "10.1016/j.jcis.2022.12.036"
}

Demisli, S., Galani, E., Goulielmaki, M., Kyrilis, F., Ilić, T., Hamdi, F., Crevar, M., Kastritis, P., Pletsa, V., Nallet, F., Savić, S., Xenakis, A.,& Papadimitriou, V.. (2023). Encapsulation of cannabidiol in oil-in-water nanoemulsions and nanoemulsion-filled hydrogels: A structure and biological assessment study. in Journal of Colloid and Interface Science
Academic Press Inc.., 634, 300-313.
https://doi.org/10.1016/j.jcis.2022.12.036

Demisli S, Galani E, Goulielmaki M, Kyrilis F, Ilić T, Hamdi F, Crevar M, Kastritis P, Pletsa V, Nallet F, Savić S, Xenakis A, Papadimitriou V. Encapsulation of cannabidiol in oil-in-water nanoemulsions and nanoemulsion-filled hydrogels: A structure and biological assessment study. in Journal of Colloid and Interface Science. 2023;634:300-313.
doi:10.1016/j.jcis.2022.12.036 .

Demisli, Sotiria, Galani, Eleni, Goulielmaki, Maria, Kyrilis, Fotios, Ilić, Tanja, Hamdi, Farzad, Crevar, Milkica, Kastritis, Panagiotis, Pletsa, Vasiliki, Nallet, Frédéric, Savić, Snežana, Xenakis, Aristotelis, Papadimitriou, Vassiliki, "Encapsulation of cannabidiol in oil-in-water nanoemulsions and nanoemulsion-filled hydrogels: A structure and biological assessment study" in Journal of Colloid and Interface Science, 634 (2023):300-313,
https://doi.org/10.1016/j.jcis.2022.12.036 . .

TY  - CONF
AU  - Đoković, Jelena
AU  - Demisli, Sotiria
AU  - Papadimitriou, Vassiliki
AU  - Savić, Snežana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4572
AB  - INTRODUCTION
Nanoemulsions (NEs) offer a flexible platform for drug delivery via several administration routes. Rapid plasma clearance brought on by interactions with plasma proteins and the activation of the mononuclear phagocytic system is the greatest challenge NEs face after parenteral administration. PEGylation, or adding PEGylated phospholipids to the stabilizing layer of the NEs, is one method for ensuring that droplets circulate for a longer period of time. It is crucial to select the optimum concentration of the PEGylated in order to maintain the necessary physicochemical properties of NEs while providing appropriate surface coverage with the PEG chains. Curcumin is a model active that has been found to be localized in the stabilizing layer of NEs (1-3) and offers a wide range of potential health benefits, but due to its short plasma half-life, new strategies for enhancing bioavailability are required. The purpose of this study is to investigate the effects of various PEGylated phospholipid (PEG2000-DSPE) concentrations on the structural properties of NEs with an active placed in the stabilizing layer.
PREPARATION OF NANOEMULSIONS
All the NEs were prepared using the high pressure homogenization technique. The aqueous phase (glycerol, polysorbate 80, sodium oleate and highly purified water) was added to the oil phase (soybean oil, medium chain triglycerides, soybean lecithin, buthylhydroxytoluene, curcumin and 0.1%/0.3%/0.6% PEG2000-DSPE) and mixed at 11000rpm for 1 min on rotor stator homogenizer (IKA Ultra-Turrax T25 digital, IKA-Werke GmbH & Co. KG, Staufen, Germany), and then further processed at 800 bar for 10 discontinued cycles (EmulsiFlex-C3, Avestin Inc., Ottawa,ON, Canada) to obtain CS21, CS23 and CS26 formulations.
NANOEMULSION DROPLET SIZE
The droplet size was assessed through the dynamic light scattering method and presented as mean droplet size (Z-ave) and polydispersity index (PDI), after diluting the NEs 1:500 (v/v) in highly purified water.
ELECTRON PARAMAGNETIC RESONANCE (EPR) SPECTROSCOPY
For this study three amphiphilic fatty acid derivatives labeled at different positions of the aliphatic chain (5-DSA, 12-DSA and 16-DSA) were used to probe the dynamics of the membrane at different depths. Stock solutions of the spin probes were prepared in absolute ethanol at 1mM concentration. Subsequently, 15 µl of the stock solutions were evaporated and then incubated with 1 ml of the NE sample in final concentration of 0.015 mM. The resulting spectra was analyzed in terms of rotational correlation time (τR), order parameter (S) and isotropic hyperfine constant (αN).
RESULTS AND DISCUSION
All of the formulations had average droplet sizes between 95 and 103 nm and PDI values under 0.25, which indicated that they were suitable for parenteral administration.
The results of the EPR investigation showed that the stabilizing layer changed as the amount of PEGylated phospholipids increased, indicating that the PEGylation threshold has not yet been reached in the stabilizing layer.
The EPR research also showed that the 5-DSA spin probe's spectra were significantly affected by the addition of various PEGylated phospholipid concentrations (Figure 1). This indicates that the portion of the stabilizing layer nearest to the aqueous phase was the one most affected by the increase in the PEGylated phospholipid concentration. Table 1 provides the calculated values for the spectrum parameters. The mobility of the spin-probe and the time it takes for the spin-probe to make a full rotation is reflected in the τR parameter, which was changed the most, compared to the other parameters, by the variations in the PEGylated phospholipid content. A formulation with the most rigid stabilizing layer had the largest τR values, which, in this instance, was the formulation with 0.1% PEG2000-DSPE. It's interesting to note that the addition of PEGylated phospholipid had the opposite effect of strengthening the stabilizing layer. Further PEG2000-DSPE addition appeared to result in nanoemulsions with a less rigid stabilizing layer, possibly indicating that larger concentrations of the PEGylating agent lead to interface destabilization. The interactions between the curcumin, a symmetrical molecule with two aromatic ring systems and a bent conformation located in the stabilizing layer and the extra stabilizer are likely responsible for this.
The other two spin probes (12-DSA and 16-DSA) provide information about the stabilizing layer located closer to the oil core. Based on the data provided in Table 1 it can be inferred that the PEGylation mostly affects the stabilizing layer's areas closest to the aqueous interface, leaving the parts closer to the oil core largely not impacted.
CONCLUSION
This study demonstrates that one of the key elements in assessing how PEGylation affects the NE system is the active's localization. To pick the concentration of the PEGylated phospholipid that will offer the best surface coverage without compromising the integrity of the interface, additional considerations must be addressed in the event of an active situated in the stabilizing layer. In this instance, it may be hypothesized that the lowest PEG2000-DSPE concentration of 0.1%, CS21, will produce NEs that can slow down curcumin release the most compared to the other two formulations. Additionally, given that further addition of the PEGylated phospholipid causes the formation of less rigid stabilizing layer, further inquiries should be made to see the impact of these changes on the interactions with plasma proteins and biological fate of the droplets upon administration.
C3  - 4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France
T1  - Structural analysis of PEGylated nanoemulsions using EPR spectroscopy – the impact of an active compound incorporated in stabilizing layer
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4572
ER  - 

@conference{
author = "Đoković, Jelena and Demisli, Sotiria and Papadimitriou, Vassiliki and Savić, Snežana",
year = "2023",
abstract = "INTRODUCTION
Nanoemulsions (NEs) offer a flexible platform for drug delivery via several administration routes. Rapid plasma clearance brought on by interactions with plasma proteins and the activation of the mononuclear phagocytic system is the greatest challenge NEs face after parenteral administration. PEGylation, or adding PEGylated phospholipids to the stabilizing layer of the NEs, is one method for ensuring that droplets circulate for a longer period of time. It is crucial to select the optimum concentration of the PEGylated in order to maintain the necessary physicochemical properties of NEs while providing appropriate surface coverage with the PEG chains. Curcumin is a model active that has been found to be localized in the stabilizing layer of NEs (1-3) and offers a wide range of potential health benefits, but due to its short plasma half-life, new strategies for enhancing bioavailability are required. The purpose of this study is to investigate the effects of various PEGylated phospholipid (PEG2000-DSPE) concentrations on the structural properties of NEs with an active placed in the stabilizing layer.
PREPARATION OF NANOEMULSIONS
All the NEs were prepared using the high pressure homogenization technique. The aqueous phase (glycerol, polysorbate 80, sodium oleate and highly purified water) was added to the oil phase (soybean oil, medium chain triglycerides, soybean lecithin, buthylhydroxytoluene, curcumin and 0.1%/0.3%/0.6% PEG2000-DSPE) and mixed at 11000rpm for 1 min on rotor stator homogenizer (IKA Ultra-Turrax T25 digital, IKA-Werke GmbH & Co. KG, Staufen, Germany), and then further processed at 800 bar for 10 discontinued cycles (EmulsiFlex-C3, Avestin Inc., Ottawa,ON, Canada) to obtain CS21, CS23 and CS26 formulations.
NANOEMULSION DROPLET SIZE
The droplet size was assessed through the dynamic light scattering method and presented as mean droplet size (Z-ave) and polydispersity index (PDI), after diluting the NEs 1:500 (v/v) in highly purified water.
ELECTRON PARAMAGNETIC RESONANCE (EPR) SPECTROSCOPY
For this study three amphiphilic fatty acid derivatives labeled at different positions of the aliphatic chain (5-DSA, 12-DSA and 16-DSA) were used to probe the dynamics of the membrane at different depths. Stock solutions of the spin probes were prepared in absolute ethanol at 1mM concentration. Subsequently, 15 µl of the stock solutions were evaporated and then incubated with 1 ml of the NE sample in final concentration of 0.015 mM. The resulting spectra was analyzed in terms of rotational correlation time (τR), order parameter (S) and isotropic hyperfine constant (αN).
RESULTS AND DISCUSION
All of the formulations had average droplet sizes between 95 and 103 nm and PDI values under 0.25, which indicated that they were suitable for parenteral administration.
The results of the EPR investigation showed that the stabilizing layer changed as the amount of PEGylated phospholipids increased, indicating that the PEGylation threshold has not yet been reached in the stabilizing layer.
The EPR research also showed that the 5-DSA spin probe's spectra were significantly affected by the addition of various PEGylated phospholipid concentrations (Figure 1). This indicates that the portion of the stabilizing layer nearest to the aqueous phase was the one most affected by the increase in the PEGylated phospholipid concentration. Table 1 provides the calculated values for the spectrum parameters. The mobility of the spin-probe and the time it takes for the spin-probe to make a full rotation is reflected in the τR parameter, which was changed the most, compared to the other parameters, by the variations in the PEGylated phospholipid content. A formulation with the most rigid stabilizing layer had the largest τR values, which, in this instance, was the formulation with 0.1% PEG2000-DSPE. It's interesting to note that the addition of PEGylated phospholipid had the opposite effect of strengthening the stabilizing layer. Further PEG2000-DSPE addition appeared to result in nanoemulsions with a less rigid stabilizing layer, possibly indicating that larger concentrations of the PEGylating agent lead to interface destabilization. The interactions between the curcumin, a symmetrical molecule with two aromatic ring systems and a bent conformation located in the stabilizing layer and the extra stabilizer are likely responsible for this.
The other two spin probes (12-DSA and 16-DSA) provide information about the stabilizing layer located closer to the oil core. Based on the data provided in Table 1 it can be inferred that the PEGylation mostly affects the stabilizing layer's areas closest to the aqueous interface, leaving the parts closer to the oil core largely not impacted.
CONCLUSION
This study demonstrates that one of the key elements in assessing how PEGylation affects the NE system is the active's localization. To pick the concentration of the PEGylated phospholipid that will offer the best surface coverage without compromising the integrity of the interface, additional considerations must be addressed in the event of an active situated in the stabilizing layer. In this instance, it may be hypothesized that the lowest PEG2000-DSPE concentration of 0.1%, CS21, will produce NEs that can slow down curcumin release the most compared to the other two formulations. Additionally, given that further addition of the PEGylated phospholipid causes the formation of less rigid stabilizing layer, further inquiries should be made to see the impact of these changes on the interactions with plasma proteins and biological fate of the droplets upon administration.",
journal = "4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France",
title = "Structural analysis of PEGylated nanoemulsions using EPR spectroscopy – the impact of an active compound incorporated in stabilizing layer",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4572"
}

Đoković, J., Demisli, S., Papadimitriou, V.,& Savić, S.. (2023). Structural analysis of PEGylated nanoemulsions using EPR spectroscopy – the impact of an active compound incorporated in stabilizing layer. in 4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France.
https://hdl.handle.net/21.15107/rcub_farfar_4572

Đoković J, Demisli S, Papadimitriou V, Savić S. Structural analysis of PEGylated nanoemulsions using EPR spectroscopy – the impact of an active compound incorporated in stabilizing layer. in 4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_4572 .

Đoković, Jelena, Demisli, Sotiria, Papadimitriou, Vassiliki, Savić, Snežana, "Structural analysis of PEGylated nanoemulsions using EPR spectroscopy – the impact of an active compound incorporated in stabilizing layer" in 4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France (2023),
https://hdl.handle.net/21.15107/rcub_farfar_4572 .

TY  - CONF
AU  - Đoković, Jelena
AU  - Demisli, Sotiria
AU  - Papadimitriou, Vassiliki
AU  - Xenakis, Aristotelis
AU  - Savić, Snežana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4284
AB  - ANALYZING THE IMPACT OF THE OIL PHASE SELECTION AND CURCUMIN
PRESENCE ON THE NANOEMULSION STABILIZING LAYER USING ELECTRON
PARAMAGNETIC RESONANCE SPECTROSCOPY
Jelena	Đoković1*, Sotiria Demisli2, Vassiliki Papadimitriou2,		
Aristotelis Xenakis2, Snežana Savić1
1University of Belgrade – Faculty of Pharmacy, Department of Pharmaceutical
Technology and Cosmetology, Belgrade, Serbia
2National Hellenic Research Foundation – Institute of Chemical Biology, Athens,
Greece
*jelenadj@pharmacy.bg.ac.rs
The stabilizing layer of nanoemulsions impacts their stability and destiny upon in vivo
administration (1). The aim of this work was to gain information about the dynamics of the
surfactants’ monolayer when different oils (soybean / fish) were used, and obtain data
regarding the localization of curcumin (2), an active compound with many potential health
benefits, using electron paramagnetic resonance (EPR) spectroscopy. Formulations were
analysed using EPR technique with three different spin probes: 5-, 12- and 16-doxyl stearic
acid (DSA), to investigate membrane dynamics at different depths. The results indicated that
the oil type played a crucial role, not only on the structure, but also in the localization of the
bioactive compound. The addition of curcumin changed the rotational correlation time (τR)
values, most notably for 5-DSA, both in soybean oil and fish oil nanoemulsions, indicating its
localization in the stabilizing layer, but with opposite effects. In the soybean oil
nanoemulsion the addition of curcumin increased spin probe mobility, with τR decreasing
from 2.18±0.60 ns to 1.66±0.61 ns, indicating a less rigid stabilizing structure, while in the
fish oil formulations it resulted in a more rigid structure reflected in τR increase from
1.19±0.10 ns to 2.96±0.81 ns and 1.63±0.13 ns to 2.27±0.19 ns, for 5-DSA and 12-DSA,
respectively. This study concluded that the curcumin is located in the stabilizing layer of
nanoemulsions, but its impact on stabilizing layer structure depended on the oil phase
selection, with particular stabilizing effects on fish oil nanoemulsions.
References
1. Nikolic, I. et al. Curcumin-loaded low‐energy nanoemulsions: Linking EPR spectroscopy‐
analysed microstructure and antioxidant potential with in vitro evaluated biological activity.
J. Mol. Liq. 2020, 301, 112479.
2. Griffith, O.H. and Jost, P.C. Lipid Spin Labels in Biological Membrane. In Spin Labeling,
Theory and Applications; Berliner, L.J., Eds.; Academic Press: New York, NY, USA, 1976;
pp 454–484
Acknowledgements
This research was funded by the MESDT, Republic of Serbia through Grant Agreement
with University of Belgrade – Faculty of Pharmacy No: 451-03-68/2022-14/200161 and
supported by the Science Fund of the Republic of Serbia, GRANT No 7749108, Neuroimmune
aspects of mood, anxiety and cognitive effects of leads/drug candidates acting at GABAA
and/or sigma‐2 receptors: In vitro/in vivo delineation by nano‐	 and hiPSC‐based platform -
NanoCellEmоCog
C3  - 8. Kongres farmaceuta Srbije; 12.-15. oktobar, Beograd, Srbija
T1  - Analyzing the impact of the oil phase selection and curcumin presence on the nanoemulsion stabilizing layer using electron paramagnetic resonance spectroscopy
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4284
ER  - 

@conference{
author = "Đoković, Jelena and Demisli, Sotiria and Papadimitriou, Vassiliki and Xenakis, Aristotelis and Savić, Snežana",
year = "2022",
abstract = "ANALYZING THE IMPACT OF THE OIL PHASE SELECTION AND CURCUMIN
PRESENCE ON THE NANOEMULSION STABILIZING LAYER USING ELECTRON
PARAMAGNETIC RESONANCE SPECTROSCOPY
Jelena	Đoković1*, Sotiria Demisli2, Vassiliki Papadimitriou2,		
Aristotelis Xenakis2, Snežana Savić1
1University of Belgrade – Faculty of Pharmacy, Department of Pharmaceutical
Technology and Cosmetology, Belgrade, Serbia
2National Hellenic Research Foundation – Institute of Chemical Biology, Athens,
Greece
*jelenadj@pharmacy.bg.ac.rs
The stabilizing layer of nanoemulsions impacts their stability and destiny upon in vivo
administration (1). The aim of this work was to gain information about the dynamics of the
surfactants’ monolayer when different oils (soybean / fish) were used, and obtain data
regarding the localization of curcumin (2), an active compound with many potential health
benefits, using electron paramagnetic resonance (EPR) spectroscopy. Formulations were
analysed using EPR technique with three different spin probes: 5-, 12- and 16-doxyl stearic
acid (DSA), to investigate membrane dynamics at different depths. The results indicated that
the oil type played a crucial role, not only on the structure, but also in the localization of the
bioactive compound. The addition of curcumin changed the rotational correlation time (τR)
values, most notably for 5-DSA, both in soybean oil and fish oil nanoemulsions, indicating its
localization in the stabilizing layer, but with opposite effects. In the soybean oil
nanoemulsion the addition of curcumin increased spin probe mobility, with τR decreasing
from 2.18±0.60 ns to 1.66±0.61 ns, indicating a less rigid stabilizing structure, while in the
fish oil formulations it resulted in a more rigid structure reflected in τR increase from
1.19±0.10 ns to 2.96±0.81 ns and 1.63±0.13 ns to 2.27±0.19 ns, for 5-DSA and 12-DSA,
respectively. This study concluded that the curcumin is located in the stabilizing layer of
nanoemulsions, but its impact on stabilizing layer structure depended on the oil phase
selection, with particular stabilizing effects on fish oil nanoemulsions.
References
1. Nikolic, I. et al. Curcumin-loaded low‐energy nanoemulsions: Linking EPR spectroscopy‐
analysed microstructure and antioxidant potential with in vitro evaluated biological activity.
J. Mol. Liq. 2020, 301, 112479.
2. Griffith, O.H. and Jost, P.C. Lipid Spin Labels in Biological Membrane. In Spin Labeling,
Theory and Applications; Berliner, L.J., Eds.; Academic Press: New York, NY, USA, 1976;
pp 454–484
Acknowledgements
This research was funded by the MESDT, Republic of Serbia through Grant Agreement
with University of Belgrade – Faculty of Pharmacy No: 451-03-68/2022-14/200161 and
supported by the Science Fund of the Republic of Serbia, GRANT No 7749108, Neuroimmune
aspects of mood, anxiety and cognitive effects of leads/drug candidates acting at GABAA
and/or sigma‐2 receptors: In vitro/in vivo delineation by nano‐	 and hiPSC‐based platform -
NanoCellEmоCog",
journal = "8. Kongres farmaceuta Srbije; 12.-15. oktobar, Beograd, Srbija",
title = "Analyzing the impact of the oil phase selection and curcumin presence on the nanoemulsion stabilizing layer using electron paramagnetic resonance spectroscopy",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4284"
}

Đoković, J., Demisli, S., Papadimitriou, V., Xenakis, A.,& Savić, S.. (2022). Analyzing the impact of the oil phase selection and curcumin presence on the nanoemulsion stabilizing layer using electron paramagnetic resonance spectroscopy. in 8. Kongres farmaceuta Srbije; 12.-15. oktobar, Beograd, Srbija.
https://hdl.handle.net/21.15107/rcub_farfar_4284

Đoković J, Demisli S, Papadimitriou V, Xenakis A, Savić S. Analyzing the impact of the oil phase selection and curcumin presence on the nanoemulsion stabilizing layer using electron paramagnetic resonance spectroscopy. in 8. Kongres farmaceuta Srbije; 12.-15. oktobar, Beograd, Srbija. 2022;.
https://hdl.handle.net/21.15107/rcub_farfar_4284 .

Đoković, Jelena, Demisli, Sotiria, Papadimitriou, Vassiliki, Xenakis, Aristotelis, Savić, Snežana, "Analyzing the impact of the oil phase selection and curcumin presence on the nanoemulsion stabilizing layer using electron paramagnetic resonance spectroscopy" in 8. Kongres farmaceuta Srbije; 12.-15. oktobar, Beograd, Srbija (2022),
https://hdl.handle.net/21.15107/rcub_farfar_4284 .

TY  - JOUR
AU  - Đoković, Jelena
AU  - Demisli, Sotiria
AU  - Savić, Sanela
AU  - Marković, Bojan
AU  - Cekić, Nebojša D.
AU  - Ranđelović, Danijela V.
AU  - Mitrović, Jelena
AU  - Lunter, Dominique Jasmin
AU  - Papadimitriou, Vassiliki
AU  - Xenakis, Aristotelis
AU  - Savić, Snežana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4265
AB  - A nanotechnology-based approach to drug delivery presents one of the biggest trends in biomedical science that can provide increased active concentration, bioavailability, and safety compared to conventional drug-delivery systems. Nanoemulsions stand out amongst other nanocarriers for being biodegradable, biocompatible, and relatively easy to manufacture. For improved drug-delivery properties, longer circulation for the nanoemulsion droplets should be provided, to allow the active to reach the target site. One of the strategies used for this purpose is PEGylation. The aim of this research was assessing the impact of the oil phase selection, soybean or fish oil mixtures with medium chain triglycerides, on the physicochemical characteristics and injectability of curcumin-loaded PEGylated nanoemulsions. Electron paramagnetic resonance spectroscopy demonstrated the structural impact of the oil phase on the stabilizing layer of nanoemulsions, with a more pronounced stabilizing effect of curcumin observed in the fish oil nanoemulsion compared to the soybean oil one. The design of the experiment study, employed to simultaneously assess the impact of the oil phase, different PEGylated phospholipids and their concentrations, as well as the presence of curcumin, showed that not only the investigated factors alone, but also their interactions, had a significant influence on the critical quality attributes of the PEGylated nanoemulsions. Detailed physicochemical characterization of the NEs found all formulations were appropriate for parenteral administration and remained stable during two years of storage, with the preserved antioxidant activity demonstrated by DPPH and FRAP assays. In vitro release studies showed a more pronounced release of curcumin from the fish oil NEs compared to that from the soybean oil ones. The innovative in vitro injectability assessment, designed to mimic intravenous application, proved that all formulations tested in selected experimental setting could be employed in prospective in vivo studies. Overall, the current study shows the importance of oil phase selection when formulating PEGylated nanoemulsions
PB  - MDPI
T2  - Pharmaceutics
T1  - The Impact of the Oil Phase Selection on Physicochemical Properties, Long-Term Stability, In Vitro Performance and Injectability of Curcumin-Loaded PEGylated Nanoemulsions
VL  - 14
IS  - 8
DO  - 10.3390/pharmaceutics14081666
ER  - 

@article{
author = "Đoković, Jelena and Demisli, Sotiria and Savić, Sanela and Marković, Bojan and Cekić, Nebojša D. and Ranđelović, Danijela V. and Mitrović, Jelena and Lunter, Dominique Jasmin and Papadimitriou, Vassiliki and Xenakis, Aristotelis and Savić, Snežana",
year = "2022",
abstract = "A nanotechnology-based approach to drug delivery presents one of the biggest trends in biomedical science that can provide increased active concentration, bioavailability, and safety compared to conventional drug-delivery systems. Nanoemulsions stand out amongst other nanocarriers for being biodegradable, biocompatible, and relatively easy to manufacture. For improved drug-delivery properties, longer circulation for the nanoemulsion droplets should be provided, to allow the active to reach the target site. One of the strategies used for this purpose is PEGylation. The aim of this research was assessing the impact of the oil phase selection, soybean or fish oil mixtures with medium chain triglycerides, on the physicochemical characteristics and injectability of curcumin-loaded PEGylated nanoemulsions. Electron paramagnetic resonance spectroscopy demonstrated the structural impact of the oil phase on the stabilizing layer of nanoemulsions, with a more pronounced stabilizing effect of curcumin observed in the fish oil nanoemulsion compared to the soybean oil one. The design of the experiment study, employed to simultaneously assess the impact of the oil phase, different PEGylated phospholipids and their concentrations, as well as the presence of curcumin, showed that not only the investigated factors alone, but also their interactions, had a significant influence on the critical quality attributes of the PEGylated nanoemulsions. Detailed physicochemical characterization of the NEs found all formulations were appropriate for parenteral administration and remained stable during two years of storage, with the preserved antioxidant activity demonstrated by DPPH and FRAP assays. In vitro release studies showed a more pronounced release of curcumin from the fish oil NEs compared to that from the soybean oil ones. The innovative in vitro injectability assessment, designed to mimic intravenous application, proved that all formulations tested in selected experimental setting could be employed in prospective in vivo studies. Overall, the current study shows the importance of oil phase selection when formulating PEGylated nanoemulsions",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "The Impact of the Oil Phase Selection on Physicochemical Properties, Long-Term Stability, In Vitro Performance and Injectability of Curcumin-Loaded PEGylated Nanoemulsions",
volume = "14",
number = "8",
doi = "10.3390/pharmaceutics14081666"
}

Đoković, J., Demisli, S., Savić, S., Marković, B., Cekić, N. D., Ranđelović, D. V., Mitrović, J., Lunter, D. J., Papadimitriou, V., Xenakis, A.,& Savić, S.. (2022). The Impact of the Oil Phase Selection on Physicochemical Properties, Long-Term Stability, In Vitro Performance and Injectability of Curcumin-Loaded PEGylated Nanoemulsions. in Pharmaceutics
MDPI., 14(8).
https://doi.org/10.3390/pharmaceutics14081666

Đoković J, Demisli S, Savić S, Marković B, Cekić ND, Ranđelović DV, Mitrović J, Lunter DJ, Papadimitriou V, Xenakis A, Savić S. The Impact of the Oil Phase Selection on Physicochemical Properties, Long-Term Stability, In Vitro Performance and Injectability of Curcumin-Loaded PEGylated Nanoemulsions. in Pharmaceutics. 2022;14(8).
doi:10.3390/pharmaceutics14081666 .

Đoković, Jelena, Demisli, Sotiria, Savić, Sanela, Marković, Bojan, Cekić, Nebojša D., Ranđelović, Danijela V., Mitrović, Jelena, Lunter, Dominique Jasmin, Papadimitriou, Vassiliki, Xenakis, Aristotelis, Savić, Snežana, "The Impact of the Oil Phase Selection on Physicochemical Properties, Long-Term Stability, In Vitro Performance and Injectability of Curcumin-Loaded PEGylated Nanoemulsions" in Pharmaceutics, 14, no. 8 (2022),
https://doi.org/10.3390/pharmaceutics14081666 . .

TY  - JOUR
AU  - Theochari, Ioanna
AU  - Mitsou, E.
AU  - Nikolić, Ines
AU  - Ilić, Tanja
AU  - Dobričić, Vladimir
AU  - Pletsa, V.
AU  - Savić, Snežana
AU  - Xenakis, Aristotelis
AU  - Papadimitriou, Vassiliki
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3821
AB  - Colloidal liquid-in-liquid nanodispersions such as micro- and nanoemulsions were developed, characterized and compared as potential carriers for the topical administration of ibuprofen. Both colloidal systems were based on water as the continuous phase, limonene as the dispersed phase and a mixture of pharmaceutically acceptable surfactants (Pluronic® L-35, Labrasol®, Tween 80). To improve their properties regarding penetration efficacy, an aqueous solution of chitosan was used as continuous phase in both systems. Micro- and nanoemulsions were structurally studied applying Dynamic Light Scattering (DLS), Electron Paramagnetic Resonance (EPR) spectroscopy and viscometry. Microemulsions with mean droplet diameter of 41 nm and PdI < 0.3 were obtained in the absence and presence of either chitosan or ibuprofen. Nanoemulsions were developed by high-pressure homogenization using the same ingredients at different concentrations. Unlike thermodynamically stable microemulsions, nanoemulsions showed storage stability for 2 months, higher droplet size (174 nm) and lower PdI (<0.15). In the presence of Ibuprofen droplet size and stability of the nanoemulsions were not affected. EPR spectroscopy revealed ibuprofen’s location in the oil cores and gave information about the rigidity of the surfactants’ monolayer. In both cases an outer compact configuration of the interfacial layer and a more flexible inner one was observed. The cytotoxicity of both systems towards human melanoma cell line WM 164 was relatively low. Interestingly, ibuprofen was released more promptly from the microemulsions (prospectively, systemic exposure increase), however the ex vivo studies, regarding skin uptake and penetration, revealed that the nanoemulsions are more appropriate as nanocarriers for the topical administration of ibuprofen.
PB  - Elsevier B.V.
T2  - Journal of Molecular Liquids
T1  - Colloidal nanodispersions for the topical delivery of Ibuprofen: Structure, dynamics and bioperformances
VL  - 334
DO  - 10.1016/j.molliq.2021.116021
ER  - 

@article{
author = "Theochari, Ioanna and Mitsou, E. and Nikolić, Ines and Ilić, Tanja and Dobričić, Vladimir and Pletsa, V. and Savić, Snežana and Xenakis, Aristotelis and Papadimitriou, Vassiliki",
year = "2021",
abstract = "Colloidal liquid-in-liquid nanodispersions such as micro- and nanoemulsions were developed, characterized and compared as potential carriers for the topical administration of ibuprofen. Both colloidal systems were based on water as the continuous phase, limonene as the dispersed phase and a mixture of pharmaceutically acceptable surfactants (Pluronic® L-35, Labrasol®, Tween 80). To improve their properties regarding penetration efficacy, an aqueous solution of chitosan was used as continuous phase in both systems. Micro- and nanoemulsions were structurally studied applying Dynamic Light Scattering (DLS), Electron Paramagnetic Resonance (EPR) spectroscopy and viscometry. Microemulsions with mean droplet diameter of 41 nm and PdI < 0.3 were obtained in the absence and presence of either chitosan or ibuprofen. Nanoemulsions were developed by high-pressure homogenization using the same ingredients at different concentrations. Unlike thermodynamically stable microemulsions, nanoemulsions showed storage stability for 2 months, higher droplet size (174 nm) and lower PdI (<0.15). In the presence of Ibuprofen droplet size and stability of the nanoemulsions were not affected. EPR spectroscopy revealed ibuprofen’s location in the oil cores and gave information about the rigidity of the surfactants’ monolayer. In both cases an outer compact configuration of the interfacial layer and a more flexible inner one was observed. The cytotoxicity of both systems towards human melanoma cell line WM 164 was relatively low. Interestingly, ibuprofen was released more promptly from the microemulsions (prospectively, systemic exposure increase), however the ex vivo studies, regarding skin uptake and penetration, revealed that the nanoemulsions are more appropriate as nanocarriers for the topical administration of ibuprofen.",
publisher = "Elsevier B.V.",
journal = "Journal of Molecular Liquids",
title = "Colloidal nanodispersions for the topical delivery of Ibuprofen: Structure, dynamics and bioperformances",
volume = "334",
doi = "10.1016/j.molliq.2021.116021"
}

Theochari, I., Mitsou, E., Nikolić, I., Ilić, T., Dobričić, V., Pletsa, V., Savić, S., Xenakis, A.,& Papadimitriou, V.. (2021). Colloidal nanodispersions for the topical delivery of Ibuprofen: Structure, dynamics and bioperformances. in Journal of Molecular Liquids
Elsevier B.V.., 334.
https://doi.org/10.1016/j.molliq.2021.116021

Theochari I, Mitsou E, Nikolić I, Ilić T, Dobričić V, Pletsa V, Savić S, Xenakis A, Papadimitriou V. Colloidal nanodispersions for the topical delivery of Ibuprofen: Structure, dynamics and bioperformances. in Journal of Molecular Liquids. 2021;334.
doi:10.1016/j.molliq.2021.116021 .

Theochari, Ioanna, Mitsou, E., Nikolić, Ines, Ilić, Tanja, Dobričić, Vladimir, Pletsa, V., Savić, Snežana, Xenakis, Aristotelis, Papadimitriou, Vassiliki, "Colloidal nanodispersions for the topical delivery of Ibuprofen: Structure, dynamics and bioperformances" in Journal of Molecular Liquids, 334 (2021),
https://doi.org/10.1016/j.molliq.2021.116021 . .

TY  - JOUR
AU  - Theochari, Ioanna
AU  - Ilić, Tanja
AU  - Nikolić, Ines
AU  - Dobričić, Vladimir
AU  - Tenchiou, Alia
AU  - Papahatjis, Demetris
AU  - Savić, Snežana
AU  - Xenakis, Aristotelis
AU  - Papadimitriou, Vassiliki
AU  - Pletsa, Vasiliki
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3801
AB  - During the last decade, many studies have been reported on the design and formulation of novel drug delivery systems proposed for dermal or transdermal administration. The efforts focus on the development of biocompatible nanodispersions that can be delivered to the skin and treat severe skin disorders, including cancer. In this context, oil-in-water (O/W) microemulsions have been developed to encapsulate and deliver lipophilic bioactive molecules for dermal application. An O/W biocompatible microemulsion composed of PBS buffer, Tween 80, and triacetin was assessed for its efficacy as a drug carrier of DPS-2, a lead compound, initially designed in-house to inhibit BRAFV600E oncogenic kinase. The system was evaluated through both in vitro and ex vivo approaches. The cytotoxic effect, in the presence and absence of DPS-2, was examined through the thiazolyl blue tetrazolium bromide (MTT) cell proliferation assay using various cell lines. Further investigation through Western blotting revealed that cells died of necrosis. Porcine ear skin was used as a skin model to evaluate the degree of permeation of DPS-2 through skin and assess its retention. Through the ex vivo experiments, it was clarified that encapsulated DPS-2 was distributed within the full thickness of the stratum corneum (SC) and had a high affinity to hair follicles.
PB  - MDPI AG
T2  - Biomimetics
T1  - Biological evaluation of oil-in-water microemulsions as carriers of benzothiophene analogues for dermal applications
VL  - 6
IS  - 1
SP  - 1
EP  - 15
DO  - 10.3390/biomimetics6010010
ER  - 

@article{
author = "Theochari, Ioanna and Ilić, Tanja and Nikolić, Ines and Dobričić, Vladimir and Tenchiou, Alia and Papahatjis, Demetris and Savić, Snežana and Xenakis, Aristotelis and Papadimitriou, Vassiliki and Pletsa, Vasiliki",
year = "2021",
abstract = "During the last decade, many studies have been reported on the design and formulation of novel drug delivery systems proposed for dermal or transdermal administration. The efforts focus on the development of biocompatible nanodispersions that can be delivered to the skin and treat severe skin disorders, including cancer. In this context, oil-in-water (O/W) microemulsions have been developed to encapsulate and deliver lipophilic bioactive molecules for dermal application. An O/W biocompatible microemulsion composed of PBS buffer, Tween 80, and triacetin was assessed for its efficacy as a drug carrier of DPS-2, a lead compound, initially designed in-house to inhibit BRAFV600E oncogenic kinase. The system was evaluated through both in vitro and ex vivo approaches. The cytotoxic effect, in the presence and absence of DPS-2, was examined through the thiazolyl blue tetrazolium bromide (MTT) cell proliferation assay using various cell lines. Further investigation through Western blotting revealed that cells died of necrosis. Porcine ear skin was used as a skin model to evaluate the degree of permeation of DPS-2 through skin and assess its retention. Through the ex vivo experiments, it was clarified that encapsulated DPS-2 was distributed within the full thickness of the stratum corneum (SC) and had a high affinity to hair follicles.",
publisher = "MDPI AG",
journal = "Biomimetics",
title = "Biological evaluation of oil-in-water microemulsions as carriers of benzothiophene analogues for dermal applications",
volume = "6",
number = "1",
pages = "1-15",
doi = "10.3390/biomimetics6010010"
}

Theochari, I., Ilić, T., Nikolić, I., Dobričić, V., Tenchiou, A., Papahatjis, D., Savić, S., Xenakis, A., Papadimitriou, V.,& Pletsa, V.. (2021). Biological evaluation of oil-in-water microemulsions as carriers of benzothiophene analogues for dermal applications. in Biomimetics
MDPI AG., 6(1), 1-15.
https://doi.org/10.3390/biomimetics6010010

Theochari I, Ilić T, Nikolić I, Dobričić V, Tenchiou A, Papahatjis D, Savić S, Xenakis A, Papadimitriou V, Pletsa V. Biological evaluation of oil-in-water microemulsions as carriers of benzothiophene analogues for dermal applications. in Biomimetics. 2021;6(1):1-15.
doi:10.3390/biomimetics6010010 .

Theochari, Ioanna, Ilić, Tanja, Nikolić, Ines, Dobričić, Vladimir, Tenchiou, Alia, Papahatjis, Demetris, Savić, Snežana, Xenakis, Aristotelis, Papadimitriou, Vassiliki, Pletsa, Vasiliki, "Biological evaluation of oil-in-water microemulsions as carriers of benzothiophene analogues for dermal applications" in Biomimetics, 6, no. 1 (2021):1-15,
https://doi.org/10.3390/biomimetics6010010 . .

TY  - JOUR
AU  - Nikolić, Ines
AU  - Mitsou, Evgenia
AU  - Damjanović, Ana
AU  - Papadimitriou, Vassiliki
AU  - Antić-Stanković, Jelena
AU  - Stanojević, Boban
AU  - Xenakis, Aristotelis
AU  - Savić, Snežana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3528
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 < 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 B.V.
T2  - Journal of Molecular Liquids
T1  - Curcumin-loaded low-energy nanoemulsions: Linking EPR spectroscopy-analysed microstructure and antioxidant potential with in vitro evaluated biological activity
VL  - 301
DO  - 10.1016/j.molliq.2020.112479
ER  - 

@article{
author = "Nikolić, Ines and Mitsou, Evgenia and Damjanović, Ana and Papadimitriou, Vassiliki and Antić-Stanković, Jelena and Stanojević, Boban and Xenakis, Aristotelis and Savić, Snežana",
year = "2020",
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 < 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 B.V.",
journal = "Journal of Molecular Liquids",
title = "Curcumin-loaded low-energy nanoemulsions: Linking EPR spectroscopy-analysed microstructure and antioxidant potential with in vitro evaluated biological activity",
volume = "301",
doi = "10.1016/j.molliq.2020.112479"
}

Nikolić, I., Mitsou, E., Damjanović, A., Papadimitriou, V., Antić-Stanković, J., Stanojević, B., Xenakis, A.,& Savić, S.. (2020). Curcumin-loaded low-energy nanoemulsions: Linking EPR spectroscopy-analysed microstructure and antioxidant potential with in vitro evaluated biological activity. in Journal of Molecular Liquids
Elsevier B.V.., 301.
https://doi.org/10.1016/j.molliq.2020.112479

Nikolić I, Mitsou E, Damjanović A, Papadimitriou V, Antić-Stanković J, Stanojević B, Xenakis A, Savić S. Curcumin-loaded low-energy nanoemulsions: Linking EPR spectroscopy-analysed microstructure and antioxidant potential with in vitro evaluated biological activity. in Journal of Molecular Liquids. 2020;301.
doi:10.1016/j.molliq.2020.112479 .

Nikolić, Ines, Mitsou, Evgenia, Damjanović, Ana, Papadimitriou, Vassiliki, Antić-Stanković, Jelena, Stanojević, Boban, Xenakis, Aristotelis, Savić, Snežana, "Curcumin-loaded low-energy nanoemulsions: Linking EPR spectroscopy-analysed microstructure and antioxidant potential with in vitro evaluated biological activity" in Journal of Molecular Liquids, 301 (2020),
https://doi.org/10.1016/j.molliq.2020.112479 . .

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  - 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  - Savić, Vedrana
AU  - Todosijević, Marija N.
AU  - Ilić, Tanja
AU  - Lukić, Milica
AU  - Mitsou, Evgenia
AU  - Papadimitriou, Vassiliki
AU  - Avramiotis, Spyridon
AU  - Marković, Bojan
AU  - Cekić, Nebojša
AU  - Savić, Snežana
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2823
AB  - In order to improve skin penetration of tacrolimus we aimed to develop potentially non-irritant, lecithin-based microemulsions containing ethanol, isopropanol and/or propylene glycol as cosurfactants, varying caprylic/capric triglycerides and propylene glycol monocaprylate as oil phase. The influence of excipients on the size of microemulsion region in pseudo-ternary phase diagrams and their ability to form different types of microemulsions was evaluated. The comprehensive physicochemical characterization of microemulsions and the evaluation of their structure was performed, while the localization of tacrolimus in microemulsions was further investigated using electron paramagnetic resonance spectroscopy. Moreover, stability studies proved no change in tacrolimus content during one year of storage at room temperature. In addition, in vivo skin performance indicated no skin irritation potential of blank microemulsions, whereas in vitro release testing using Franz diffusion cells showed superior release rate of tacrolimus from microemulsions (0.98 +/- 0.10 and 0.92 +/- 0.11 mu g/cm(2)/h for two bicontinuous and 1.00 +/- 0.24 mu g/cm(2)/h for oil-in-water microemulsion) compared to referent Protopic ointment (0.15 +/- 0.08 mu g/cm(2)/h). Furthermore, ex vivo penetration assessed through porcine ear skin using tape stripping, confirmed superiority of two microemulsions related to the reference, implying developed microemulsions as promising carriers for dermal delivery of tacrolimus.
PB  - Elsevier Science BV, Amsterdam
T2  - International Journal of Pharmaceutics
T1  - Tacrolimus loaded biocompatible lecithin-based microemulsions with improved skin penetration: Structure characterization and in vitro/in vivo performances
VL  - 529
IS  - 1-2
SP  - 491
EP  - 505
DO  - 10.1016/j.ijpharm.2017.07.036
ER  - 

@article{
author = "Savić, Vedrana and Todosijević, Marija N. and Ilić, Tanja and Lukić, Milica and Mitsou, Evgenia and Papadimitriou, Vassiliki and Avramiotis, Spyridon and Marković, Bojan and Cekić, Nebojša and Savić, Snežana",
year = "2017",
abstract = "In order to improve skin penetration of tacrolimus we aimed to develop potentially non-irritant, lecithin-based microemulsions containing ethanol, isopropanol and/or propylene glycol as cosurfactants, varying caprylic/capric triglycerides and propylene glycol monocaprylate as oil phase. The influence of excipients on the size of microemulsion region in pseudo-ternary phase diagrams and their ability to form different types of microemulsions was evaluated. The comprehensive physicochemical characterization of microemulsions and the evaluation of their structure was performed, while the localization of tacrolimus in microemulsions was further investigated using electron paramagnetic resonance spectroscopy. Moreover, stability studies proved no change in tacrolimus content during one year of storage at room temperature. In addition, in vivo skin performance indicated no skin irritation potential of blank microemulsions, whereas in vitro release testing using Franz diffusion cells showed superior release rate of tacrolimus from microemulsions (0.98 +/- 0.10 and 0.92 +/- 0.11 mu g/cm(2)/h for two bicontinuous and 1.00 +/- 0.24 mu g/cm(2)/h for oil-in-water microemulsion) compared to referent Protopic ointment (0.15 +/- 0.08 mu g/cm(2)/h). Furthermore, ex vivo penetration assessed through porcine ear skin using tape stripping, confirmed superiority of two microemulsions related to the reference, implying developed microemulsions as promising carriers for dermal delivery of tacrolimus.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "International Journal of Pharmaceutics",
title = "Tacrolimus loaded biocompatible lecithin-based microemulsions with improved skin penetration: Structure characterization and in vitro/in vivo performances",
volume = "529",
number = "1-2",
pages = "491-505",
doi = "10.1016/j.ijpharm.2017.07.036"
}

Savić, V., Todosijević, M. N., Ilić, T., Lukić, M., Mitsou, E., Papadimitriou, V., Avramiotis, S., Marković, B., Cekić, N.,& Savić, S.. (2017). Tacrolimus loaded biocompatible lecithin-based microemulsions with improved skin penetration: Structure characterization and in vitro/in vivo performances. in International Journal of Pharmaceutics
Elsevier Science BV, Amsterdam., 529(1-2), 491-505.
https://doi.org/10.1016/j.ijpharm.2017.07.036

Savić V, Todosijević MN, Ilić T, Lukić M, Mitsou E, Papadimitriou V, Avramiotis S, Marković B, Cekić N, Savić S. Tacrolimus loaded biocompatible lecithin-based microemulsions with improved skin penetration: Structure characterization and in vitro/in vivo performances. in International Journal of Pharmaceutics. 2017;529(1-2):491-505.
doi:10.1016/j.ijpharm.2017.07.036 .

Savić, Vedrana, Todosijević, Marija N., Ilić, Tanja, Lukić, Milica, Mitsou, Evgenia, Papadimitriou, Vassiliki, Avramiotis, Spyridon, Marković, Bojan, Cekić, Nebojša, Savić, Snežana, "Tacrolimus loaded biocompatible lecithin-based microemulsions with improved skin penetration: Structure characterization and in vitro/in vivo performances" in International Journal of Pharmaceutics, 529, no. 1-2 (2017):491-505,
https://doi.org/10.1016/j.ijpharm.2017.07.036 . .