TY  - CONF
AU  - Stanković, Tijana
AU  - Ilić, Tanja
AU  - Pantelić, Ivana
AU  - Tošić, Anđela
AU  - Mitrović, Jelena
AU  - Cook, James M.
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5000
AB  - Design of tailor-made biocompatible nanocarrier for novel pyrazoloquinolinone ligand (CW-02-79) based on comprehensive evaluation of critical physicochemical descriptors 

Tijana Stanković1, Tanja Ilić1, Ivana Pantelić1, Anđela Tošić1, Jelena Mitrović1, James M. Cook2, Miroslav Savić3, Snežana Savić1

1 University of Belgrade-Faculty of Pharmacy, Department of Pharmaceutical Technology and Cosmetology, Vojvode Stepe 450, Belgrade, Serbia,
2 University of Wisconsin-Milwaukee, Milwaukee Institute for Drug Discovery, 3210 N. Cramer St. Milwaukee, Wisconsin, United States,
3 University of Belgrade-Faculty of Pharmacy, Department of Pharmacology, Vojvode Stepe 450, Belgrade, Serbia.

The poor water solubility of novel patent-protected ligand of the pyrazoloquinolinone chemotype (CW-02-79), with significant binding affinity for sigma-2 receptors in the brain, restricts the development of conventional parenteral formulations and consequently, extensive pharmacological studies during the preclinical investigation. Therefore, we aimed to develop a biocompatible nanocarrier tailored to specific physicochemical properties of CW-02-79, to improve its transport across the blood-brain barrier and achieve the optimal brain disposition. In this context, a detailed analysis of lipophilicity (via log P and log D determination), solubility in various solvents/excipients (using shake-flask method) and crystalline state of CW-02-07 (using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) with melt quenching approach and polarization microsocopy) was performed. After the analysis of key “input” physicochemical descriptors, based on the developed decision tree, nanoemulsions were selected as promising carriers for CW-02-79. The nanoemulsions were prepared using the high pressure homogenization method, varying the process (number of cycles, temperature and pressure) and formulation parameters (the content of the oil phase, the stabilizer mixture composition). Additionally, the influence of the sterilization process (thermal sterilization/aseptic filtration) on the nanoemulsion physicochemical properties was investigated, including droplet size and size distribution, zeta potential, pH, electrical conductivity and osmolality. The obtained results showed that it was possible to formulate CW-02-79-loaded nanoemulsions with 20% oil phase (medium chain triglycerides:castor oil at ratio 1:1), stabilized with the biocompatible emulsifiers (lecithin/polysorbate 80), exhibiting the nano-sized droplets (<200 nm) with narrow size distribution (polydispersity index < 0.2), zeta potential (> ǀ-30ǀ mV), pH (~ 5.7) and osmolality (295 mOsm/kg). The sterilization process did not remarkably affect the physiochemical properties of nanoemulsions, making them suitable for the parenteral administration. Owing to sastifying solubilization capacity for CW-02-79, physicochemical properties and preliminary stability, the nanoemulsions are the promising carriers worth exploring further to support the preclinical evalution of CW-02-79.
ACKNOWLEDGEMENT. This research was 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 — NanoCellEmoCog
PB  - International Association of Physical Chemists
C3  - 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6
T1  - Design of tailor-made biocompatible nanocarrier for novel pyrazoloquinolinone ligand (CW-02-79) based on comprehensive evaluation of critical physicochemical descriptors
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5000
ER  - 

@conference{
author = "Stanković, Tijana and Ilić, Tanja and Pantelić, Ivana and Tošić, Anđela and Mitrović, Jelena and Cook, James M. and Savić, Miroslav and Savić, Snežana",
year = "2023",
abstract = "Design of tailor-made biocompatible nanocarrier for novel pyrazoloquinolinone ligand (CW-02-79) based on comprehensive evaluation of critical physicochemical descriptors 

Tijana Stanković1, Tanja Ilić1, Ivana Pantelić1, Anđela Tošić1, Jelena Mitrović1, James M. Cook2, Miroslav Savić3, Snežana Savić1

1 University of Belgrade-Faculty of Pharmacy, Department of Pharmaceutical Technology and Cosmetology, Vojvode Stepe 450, Belgrade, Serbia,
2 University of Wisconsin-Milwaukee, Milwaukee Institute for Drug Discovery, 3210 N. Cramer St. Milwaukee, Wisconsin, United States,
3 University of Belgrade-Faculty of Pharmacy, Department of Pharmacology, Vojvode Stepe 450, Belgrade, Serbia.

The poor water solubility of novel patent-protected ligand of the pyrazoloquinolinone chemotype (CW-02-79), with significant binding affinity for sigma-2 receptors in the brain, restricts the development of conventional parenteral formulations and consequently, extensive pharmacological studies during the preclinical investigation. Therefore, we aimed to develop a biocompatible nanocarrier tailored to specific physicochemical properties of CW-02-79, to improve its transport across the blood-brain barrier and achieve the optimal brain disposition. In this context, a detailed analysis of lipophilicity (via log P and log D determination), solubility in various solvents/excipients (using shake-flask method) and crystalline state of CW-02-07 (using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) with melt quenching approach and polarization microsocopy) was performed. After the analysis of key “input” physicochemical descriptors, based on the developed decision tree, nanoemulsions were selected as promising carriers for CW-02-79. The nanoemulsions were prepared using the high pressure homogenization method, varying the process (number of cycles, temperature and pressure) and formulation parameters (the content of the oil phase, the stabilizer mixture composition). Additionally, the influence of the sterilization process (thermal sterilization/aseptic filtration) on the nanoemulsion physicochemical properties was investigated, including droplet size and size distribution, zeta potential, pH, electrical conductivity and osmolality. The obtained results showed that it was possible to formulate CW-02-79-loaded nanoemulsions with 20% oil phase (medium chain triglycerides:castor oil at ratio 1:1), stabilized with the biocompatible emulsifiers (lecithin/polysorbate 80), exhibiting the nano-sized droplets (<200 nm) with narrow size distribution (polydispersity index < 0.2), zeta potential (> ǀ-30ǀ mV), pH (~ 5.7) and osmolality (295 mOsm/kg). The sterilization process did not remarkably affect the physiochemical properties of nanoemulsions, making them suitable for the parenteral administration. Owing to sastifying solubilization capacity for CW-02-79, physicochemical properties and preliminary stability, the nanoemulsions are the promising carriers worth exploring further to support the preclinical evalution of CW-02-79.
ACKNOWLEDGEMENT. This research was 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 — NanoCellEmoCog",
publisher = "International Association of Physical Chemists",
journal = "10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6",
title = "Design of tailor-made biocompatible nanocarrier for novel pyrazoloquinolinone ligand (CW-02-79) based on comprehensive evaluation of critical physicochemical descriptors",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5000"
}

Stanković, T., Ilić, T., Pantelić, I., Tošić, A., Mitrović, J., Cook, J. M., Savić, M.,& Savić, S.. (2023). Design of tailor-made biocompatible nanocarrier for novel pyrazoloquinolinone ligand (CW-02-79) based on comprehensive evaluation of critical physicochemical descriptors. in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6
International Association of Physical Chemists..
https://hdl.handle.net/21.15107/rcub_farfar_5000

Stanković T, Ilić T, Pantelić I, Tošić A, Mitrović J, Cook JM, Savić M, Savić S. Design of tailor-made biocompatible nanocarrier for novel pyrazoloquinolinone ligand (CW-02-79) based on comprehensive evaluation of critical physicochemical descriptors. in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_5000 .

Stanković, Tijana, Ilić, Tanja, Pantelić, Ivana, Tošić, Anđela, Mitrović, Jelena, Cook, James M., Savić, Miroslav, Savić, Snežana, "Design of tailor-made biocompatible nanocarrier for novel pyrazoloquinolinone ligand (CW-02-79) based on comprehensive evaluation of critical physicochemical descriptors" in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6 (2023),
https://hdl.handle.net/21.15107/rcub_farfar_5000 .

TY  - JOUR
AU  - Stanković, Tijana
AU  - Ilić, Tanja
AU  - Dobričić, Vladimir
AU  - Tošić, Anđela
AU  - Pantelić, Ivana
AU  - Savić, Snežana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5386
AB  - In order to improve the delivery of topical corticosteroids into inflammatory skin lesions
while reducing the likelihood of adverse effects, lipid nanocarriers have received increasing
attention. Hence, this study aimed to develop biocompatible nanoemulsions (NEs) and
nanostructured lipid carriers (NLCs) as carriers for fluocinolone acetonide (FA) by carefully
optimizing the formulation and process parameters. After an analysis of the relevant
physicochemical parameters and stability testing, in vitro release and permeation tests were
performed to evaluate whether the nanocarriers affected the penetration of FA into/through the
skin compared to a conventional reference product (Sinoderm® cream). The developed NEs
exhibited satisfactory physicochemical properties (droplet size <200 nm, PDI<0.2, ZP>ǀ-30ǀ mV,
pH ~ 4.75) and long-term stability. Although the developed NLCs initially had satisfactory
properties, gelation was observed within 3 months of storage, implying that further formulation
testing is required to resolve the limited stability of these systems. In vitro release/permeation
findings suggest that the developed nanocarriers (especially NEs) provide better delivery of FA
into/though the skin compared to the Sinoderm® cream. Therefore, a lecithin-based NE with a
10% lipid phase (medium-chain triglycerides/oleic acid 3:1) is a promising strategy for improved
delivery of FA to the inflamed skin, allowing for ease of application, especially to larger skin
surfaces and hairy regions.
AB  - Kako bi se poboljšala topikalna isporuka kortikosteroida u inflamatorne lezije kože i
istovremeno smanjila učestalost neželjenih efekata, posebna pažnja je usmerena ka razvoju
lipidnih nanonosača. Stoga, cilj ovog rada je bio razvoj biokompatibilnih nanoemulzija (NEs) i
nanostrukturiranih lipidnih nosača (NLCs) kao nosača za fluocinolonacetonid (FA) pažljivom
optimizacijom formulacionih i procesnih parametara. Nakon analize relevantnih fizičko-
hemijskih parametara i studije stabilnosti, in vitro ispitivanje oslobađanja i permeacije je
sprovedeno kako bi se dobio uvid u to da li razvijeni nanonosači utiču na penetraciju FA u/kroz
kožu, u poređenju sa konvencionalnim referentnim preparatom (Sinoderm® krem). Uspešno su
razvijene NEs zadovoljavajućih fizičko-hemijskih osobina (veličina kapi<200 nm, PDI<0,2,
ZP>ǀ-30ǀ mV, pH~4,75) i dugoročne stabilnosti. Iako su inicijalno posedovali zadovoljavajuće
karakteristike, NLCs su gelirali tokom tri meseca čuvanja, što ukazuje na potrebu za daljim radom
na razvoju formulacije, u cilju rešavanja problema ograničene stabilnosti ovih sistema. Nalazi in
vitro ispitivanja oslobađanja/permeacije upućuju na činjenicu da razvijeni lipidni nanonosači
(prevashodno NEs) obezbeđuju bolju isporuku FA u/kroz kožu u poređenju sa Sinoderm®
kremom. Nanoemulzije bazirane na lecitinu sa 10% uljane faze (smeša triglicerida srednje dužine
lanaca i oleinske kiseline 3:1) predstavljaju obećavajuću strategiju za poboljšanu isporuku FA u
inflamatorne promene na koži, omogućavajući laku primenu, posebno na većim površinama i
kosmatim delovima tela.
PB  - Savez farmaceutskih udruženja Srbije
T2  - Arhiv za farmaciju
T1  - Biocompatible lipid nanocarriers for improved skin delivery of fluocinolone acetonide: physicochemical and in vitro performances
T1  - Biokompatibilni lipidni nanonosači za poboljšanu isporuku fluocinolonacetonida u kožu: fizičko- hemijske osobine i in vitro učinak
VL  - 73
IS  - 5
SP  - 423
EP  - 439
DO  - 10.5937/arhfarm73-46312
ER  - 

@article{
author = "Stanković, Tijana and Ilić, Tanja and Dobričić, Vladimir and Tošić, Anđela and Pantelić, Ivana and Savić, Snežana",
year = "2023",
abstract = "In order to improve the delivery of topical corticosteroids into inflammatory skin lesions
while reducing the likelihood of adverse effects, lipid nanocarriers have received increasing
attention. Hence, this study aimed to develop biocompatible nanoemulsions (NEs) and
nanostructured lipid carriers (NLCs) as carriers for fluocinolone acetonide (FA) by carefully
optimizing the formulation and process parameters. After an analysis of the relevant
physicochemical parameters and stability testing, in vitro release and permeation tests were
performed to evaluate whether the nanocarriers affected the penetration of FA into/through the
skin compared to a conventional reference product (Sinoderm® cream). The developed NEs
exhibited satisfactory physicochemical properties (droplet size <200 nm, PDI<0.2, ZP>ǀ-30ǀ mV,
pH ~ 4.75) and long-term stability. Although the developed NLCs initially had satisfactory
properties, gelation was observed within 3 months of storage, implying that further formulation
testing is required to resolve the limited stability of these systems. In vitro release/permeation
findings suggest that the developed nanocarriers (especially NEs) provide better delivery of FA
into/though the skin compared to the Sinoderm® cream. Therefore, a lecithin-based NE with a
10% lipid phase (medium-chain triglycerides/oleic acid 3:1) is a promising strategy for improved
delivery of FA to the inflamed skin, allowing for ease of application, especially to larger skin
surfaces and hairy regions., Kako bi se poboljšala topikalna isporuka kortikosteroida u inflamatorne lezije kože i
istovremeno smanjila učestalost neželjenih efekata, posebna pažnja je usmerena ka razvoju
lipidnih nanonosača. Stoga, cilj ovog rada je bio razvoj biokompatibilnih nanoemulzija (NEs) i
nanostrukturiranih lipidnih nosača (NLCs) kao nosača za fluocinolonacetonid (FA) pažljivom
optimizacijom formulacionih i procesnih parametara. Nakon analize relevantnih fizičko-
hemijskih parametara i studije stabilnosti, in vitro ispitivanje oslobađanja i permeacije je
sprovedeno kako bi se dobio uvid u to da li razvijeni nanonosači utiču na penetraciju FA u/kroz
kožu, u poređenju sa konvencionalnim referentnim preparatom (Sinoderm® krem). Uspešno su
razvijene NEs zadovoljavajućih fizičko-hemijskih osobina (veličina kapi<200 nm, PDI<0,2,
ZP>ǀ-30ǀ mV, pH~4,75) i dugoročne stabilnosti. Iako su inicijalno posedovali zadovoljavajuće
karakteristike, NLCs su gelirali tokom tri meseca čuvanja, što ukazuje na potrebu za daljim radom
na razvoju formulacije, u cilju rešavanja problema ograničene stabilnosti ovih sistema. Nalazi in
vitro ispitivanja oslobađanja/permeacije upućuju na činjenicu da razvijeni lipidni nanonosači
(prevashodno NEs) obezbeđuju bolju isporuku FA u/kroz kožu u poređenju sa Sinoderm®
kremom. Nanoemulzije bazirane na lecitinu sa 10% uljane faze (smeša triglicerida srednje dužine
lanaca i oleinske kiseline 3:1) predstavljaju obećavajuću strategiju za poboljšanu isporuku FA u
inflamatorne promene na koži, omogućavajući laku primenu, posebno na većim površinama i
kosmatim delovima tela.",
publisher = "Savez farmaceutskih udruženja Srbije",
journal = "Arhiv za farmaciju",
title = "Biocompatible lipid nanocarriers for improved skin delivery of fluocinolone acetonide: physicochemical and in vitro performances, Biokompatibilni lipidni nanonosači za poboljšanu isporuku fluocinolonacetonida u kožu: fizičko- hemijske osobine i in vitro učinak",
volume = "73",
number = "5",
pages = "423-439",
doi = "10.5937/arhfarm73-46312"
}

Stanković, T., Ilić, T., Dobričić, V., Tošić, A., Pantelić, I.,& Savić, S.. (2023). Biocompatible lipid nanocarriers for improved skin delivery of fluocinolone acetonide: physicochemical and in vitro performances. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije., 73(5), 423-439.
https://doi.org/10.5937/arhfarm73-46312

Stanković T, Ilić T, Dobričić V, Tošić A, Pantelić I, Savić S. Biocompatible lipid nanocarriers for improved skin delivery of fluocinolone acetonide: physicochemical and in vitro performances. in Arhiv za farmaciju. 2023;73(5):423-439.
doi:10.5937/arhfarm73-46312 .

Stanković, Tijana, Ilić, Tanja, Dobričić, Vladimir, Tošić, Anđela, Pantelić, Ivana, Savić, Snežana, "Biocompatible lipid nanocarriers for improved skin delivery of fluocinolone acetonide: physicochemical and in vitro performances" in Arhiv za farmaciju, 73, no. 5 (2023):423-439,
https://doi.org/10.5937/arhfarm73-46312 . .

TY  - JOUR
AU  - Tošić, Anđela
AU  - Stanković, Tijana
AU  - Ilić, Tanja
AU  - Savić, Snežana
AU  - Pantelić, Ivana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4770
AB  - Tribology investigates the events that happen on the surfaces of two substances/objects that 
are in direct or indirect contact through assessing friction, lubrication and/or wear. In particular, 
friction measurements could provide the information on the textural characteristics of (per)oral 
pharmaceutical  preparations  and  contribute  to  the  understanding  of  palatability.  On  the  other  
hand,  tribological  tests  have  been  more  intensively  used  to  characterize  topical  preparations  
(pharmaceutical,  cosmetic),  giving  a  thorough  insight  into  the  tactile  and  texture  properties  of  
these preparations. However, these tests are often combined with rheological, textural, and certain 
biophysical  approa
ches.  Additionally,  the  materials  used  for  constructing  artificial  joints  and  
articular  cartilages  are  true  tribological  systems,  developed  and  optimized  in  order  to  have  
properties that resemble the natural ones. Since tribological studies can be used to assess a wide 
range of drug dosage forms and products in general, the equipment used may be quite diverse. 
Accordingly,  a  special  section  of  this  work  is  committed  to  the  description  of  the  testing  
equipment’s  specifications  and  the  applied  protocols.  The  investigation  of  recently  regulatory  
discovered  phenomena,  such  as  transformation/metamorphosis  of  the  vehicle/base  of  topical  
preparations, have brought tribology back into focus as a potential assessment method.
AB  - Tribologija se bavi izučavanjem uticaja i 
događaja koji se dešavaju na površinama dveju 
materija/objekata  koji  su  u  direktnom  ili  indirektnom  kontaktu,  uključujući  procese  trenja, 
podmazivanja i/ili habanja (trošenja). Naime, primećeno je da je merenjem frikcije moguće 
ispitati teksturna svojstva 
(per)oralnih farmaceutskih preparata i doprineti razumevanju njihove 
palatabilnosti.  S  druge  strane,  nešto  duži  niz  godina  se  tribološka  ispitivanja  izvode  u  cilju  
karakterizacije preparata (farmaceutskih, kozmetičkih) koji se primenjuju na koži, dajući ti
me 
kompletniju sliku o taktilnim i teksturnim osobinama ovih preparata. Ipak, dobijeni rezultati se 
uobičajeno razmatraju zajedno sa onim dobijenim tokom reoloških, teksturnih i/ili biofizičkih 
studija. Takođe, materijali od kojih su napravljeni veštački z
globovi i zglobne hrskavice su primer 
triboloških  sistema  koji  su  razvijani  i  optimizovani  na  način  da  imaju  slične  karakteristike 
prirodnim sistemima, a za čiji je razvoj i karakterizaciju neophodno ispitivanje frikcije, lubrikacije 
i trošenja. Kako je po
lje primene triboloških ispitivanja široko i provlači se kroz, u tehnološkom 
smislu, izrazito različite farmaceutske oblike, posledično će i aparatura koja se koristi u te svrhe 
pokazivati veliki diverzitet, te je deo ovog rada posvećen i pregledu specifič
nosti uređaja za 
ispitivanje triboloških parametara, sa posebnim osvrtom na primenjene protokole ispitivanja. Na 
kraju,  dat  je  osvrt  na  potencijalne  primene  triboloških  studija  za  ispitivanje  novootkrivenih  
fenomena, poput transformacije/metamorfoze vehikuluma/podloge topikalnih preparata.
PB  - Savez farmaceutskih udruženja Srbije, Beograd
T2  - Arhiv za farmaciju
T1  - Current role of tribological tests: striving for full  characterization of medicinal and cosmetic  products
T1  - Doprinos triboloških testova sveobuhvatnoj 
karakterizaciji medicinskih i kozmetičkih 
proizvoda
VL  - 73
IS  - 2
SP  - 126
EP  - 145
DO  - 10.5937/arhfarm73- 43515
ER  - 

@article{
author = "Tošić, Anđela and Stanković, Tijana and Ilić, Tanja and Savić, Snežana and Pantelić, Ivana",
year = "2023",
abstract = "Tribology investigates the events that happen on the surfaces of two substances/objects that 
are in direct or indirect contact through assessing friction, lubrication and/or wear. In particular, 
friction measurements could provide the information on the textural characteristics of (per)oral 
pharmaceutical  preparations  and  contribute  to  the  understanding  of  palatability.  On  the  other  
hand,  tribological  tests  have  been  more  intensively  used  to  characterize  topical  preparations  
(pharmaceutical,  cosmetic),  giving  a  thorough  insight  into  the  tactile  and  texture  properties  of  
these preparations. However, these tests are often combined with rheological, textural, and certain 
biophysical  approa
ches.  Additionally,  the  materials  used  for  constructing  artificial  joints  and  
articular  cartilages  are  true  tribological  systems,  developed  and  optimized  in  order  to  have  
properties that resemble the natural ones. Since tribological studies can be used to assess a wide 
range of drug dosage forms and products in general, the equipment used may be quite diverse. 
Accordingly,  a  special  section  of  this  work  is  committed  to  the  description  of  the  testing  
equipment’s  specifications  and  the  applied  protocols.  The  investigation  of  recently  regulatory  
discovered  phenomena,  such  as  transformation/metamorphosis  of  the  vehicle/base  of  topical  
preparations, have brought tribology back into focus as a potential assessment method., Tribologija se bavi izučavanjem uticaja i 
događaja koji se dešavaju na površinama dveju 
materija/objekata  koji  su  u  direktnom  ili  indirektnom  kontaktu,  uključujući  procese  trenja, 
podmazivanja i/ili habanja (trošenja). Naime, primećeno je da je merenjem frikcije moguće 
ispitati teksturna svojstva 
(per)oralnih farmaceutskih preparata i doprineti razumevanju njihove 
palatabilnosti.  S  druge  strane,  nešto  duži  niz  godina  se  tribološka  ispitivanja  izvode  u  cilju  
karakterizacije preparata (farmaceutskih, kozmetičkih) koji se primenjuju na koži, dajući ti
me 
kompletniju sliku o taktilnim i teksturnim osobinama ovih preparata. Ipak, dobijeni rezultati se 
uobičajeno razmatraju zajedno sa onim dobijenim tokom reoloških, teksturnih i/ili biofizičkih 
studija. Takođe, materijali od kojih su napravljeni veštački z
globovi i zglobne hrskavice su primer 
triboloških  sistema  koji  su  razvijani  i  optimizovani  na  način  da  imaju  slične  karakteristike 
prirodnim sistemima, a za čiji je razvoj i karakterizaciju neophodno ispitivanje frikcije, lubrikacije 
i trošenja. Kako je po
lje primene triboloških ispitivanja široko i provlači se kroz, u tehnološkom 
smislu, izrazito različite farmaceutske oblike, posledično će i aparatura koja se koristi u te svrhe 
pokazivati veliki diverzitet, te je deo ovog rada posvećen i pregledu specifič
nosti uređaja za 
ispitivanje triboloških parametara, sa posebnim osvrtom na primenjene protokole ispitivanja. Na 
kraju,  dat  je  osvrt  na  potencijalne  primene  triboloških  studija  za  ispitivanje  novootkrivenih  
fenomena, poput transformacije/metamorfoze vehikuluma/podloge topikalnih preparata.",
publisher = "Savez farmaceutskih udruženja Srbije, Beograd",
journal = "Arhiv za farmaciju",
title = "Current role of tribological tests: striving for full  characterization of medicinal and cosmetic  products, Doprinos triboloških testova sveobuhvatnoj 
karakterizaciji medicinskih i kozmetičkih 
proizvoda",
volume = "73",
number = "2",
pages = "126-145",
doi = "10.5937/arhfarm73- 43515"
}

Tošić, A., Stanković, T., Ilić, T., Savić, S.,& Pantelić, I.. (2023). Current role of tribological tests: striving for full  characterization of medicinal and cosmetic  products. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije, Beograd., 73(2), 126-145.
https://doi.org/10.5937/arhfarm73- 43515

Tošić A, Stanković T, Ilić T, Savić S, Pantelić I. Current role of tribological tests: striving for full  characterization of medicinal and cosmetic  products. in Arhiv za farmaciju. 2023;73(2):126-145.
doi:10.5937/arhfarm73- 43515 .

Tošić, Anđela, Stanković, Tijana, Ilić, Tanja, Savić, Snežana, Pantelić, Ivana, "Current role of tribological tests: striving for full  characterization of medicinal and cosmetic  products" in Arhiv za farmaciju, 73, no. 2 (2023):126-145,
https://doi.org/10.5937/arhfarm73- 43515 . .

TY  - CONF
AU  - Tošić, Anđela
AU  - Ilić, Tanja
AU  - Savić, Snežana
AU  - Pantelić, Ivana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4592
AB  - INTRODUCTION The metamorphosis of topical products is a relatively new concept that has grown in importance during the past few years [1]. It is defined by the phenomenon in which the primary packaged formulation changes its composition and/or microstructure during application. This change could be caused by different internal/external stimuli, most commonly, but not limited to the evaporation of highly volatile ingredients. As a consequence, there is a high possibility of a discrepancy between the desired release profile of the active substance and the obtained one. In addition to the pharmacokinetic profile changes, metamorphosis can also cause changes in the rheological, texture and cosmetic properties of the preparation [2,3]. According to the most recent EMA Draft Guideline on quality and equivalence of topical products from 2018, it is necessary to examine metamorphosis when assessing the bioequivalence of (trans)dermal products [1]. At this moment, a part of the scientific community suggests only two methods for metamorphosis assessment: nanothermal analysis and photothermal microspectroscopy. Both methods use probes to detect crystals of the drug substance in the deeper layers of the stratum corneum [4]. However, these methods require very expensive, sophisticated equipment, and they have not yet been formalized as methodologies used for this purpose. The aim of this work was to evaluate the possibility of using rheological, tribological and mass loss testing as single or combined methods for the assessment of metamorphosis of topical hydrogels. MATERIALS AND METHODS Materials Carbopol® 934 was obtained from Lubrizol (USA), while propylene glycol, triethanolamine, isopropanol, sodium hydroxide, methyl and propyl paraben were purchased from Sigma Aldrich (Germany). A model substance, diclofenac-sodium, was kindly donated by Hemofarm (Serbia). Sample preparation The concentration of isopropanol, as a model easily volatile ingredient, was varied in the range 0-15% (w/w). In the sample F1 (Table 1), the concentration of the gelling agent was also varied, as another parameter of interest for valid transformation analysis. The gels were prepared in accordance with the usual compendial guidelines (DAC/NRF). Rheological characterization Measurements were preformed using a Rheolab MC 120 rotational rheometer (Paar Physica, Germany), with a cone/plate system with a diameter of 50 mm, at an angle of 1° and a sample thickness of 0.05 mm, at a temperature of 20±0.1°C. Tribological study Test was performed in vivo in 4 female healthy volunteers, at the forearm skin, using Frictiometer® FR700 (Courage+Khazaka, Germany) equipped with a plain, smooth Teflon (PTFE) disk. Study was performed both in finite and infinite dosing conditions. Measurements were performed at 90 rpm for 100 s, with one measurement taken per second. Mass loss analysis The test was performed at a temperature of 32±0.1°C in a closed system of the device Orbital Shaker Incubator ES 20 (Biosan, Latvia). Each sample was applied in the quantity of 1 g, in a thin layer on the glass substrate and placed in a closed chamber system. The mass of the samples was measured on the ABJ 120-4M analytical scale (Kern & Sohn GmbH, Germany) during two hours in 15-minute intervals. RESULTS AND DISCUSSION The greatest potential for instrumental transformation analysis has been demonstrated by the simple mass loss study. In Figure 1, it can be clearly seen that samples F3-F6, which contain isopropanol, have reached the "plateau" sooner than samples F1-F2. The slope of the curve (transformation rate) between 45 and 60 min of drying is also significantly different for the samples F1- F2 and F3-F6. This method additionally allows discerning regions that represent the secondary and third (residual) formulations. Part of the curve between 15 and 45 min, when the mass loss is the most significant, correlates with forming the secondary formulation. The region between 45 and 120 min, depending on the very sample, represents the process of forming the residual formulation, after all the volatile ingredients have evaporated. On the other hand, rheological test has shown somewhat different results. Flow curves (Figure 2) represent changes in the microstructure that formulations go through during the test. Expectedly, gels that contain isopropanol go through more drastic changes. In the descending part of the curve unsymmetrical regions could be spotted, relative to the ascending part. This phenomenon could not be noted in the flow curves of the formulations F1 and F2. Furthermore, maximal and minimal viscosities and hysteresis area were the parameters that failed to show great potential for in depth assessment of a vehicle’s metamorphosis.A tribological study carried out under finite dosing conditions (3 mg/cm2 ; Figure 3a) provided more informative results, especially for the samples’ F3-F6 process of metamorphosis. The levels of changes in the friction value correlate well with the concentration of isopropyl alcohol. Therefore, it can be seen that the changes of this parameter are more intensive for formulations F5-F6 compared to formulations F3-F4, that contained isopropyl alcohol in lower concentrations. The same study, performed under infinite dosing conditions (10 mg/cm2 ; Figure 3b), showed no apparent potential for these purposes.CONSLUSION The results have showed that all three methods in a certain sense contribute to the examination of the metamorphosis of carbomer gels. Certain time points during mass loss and friction tests correlate well in terms of the exact onset of each transformation phase.
C3  - 4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France
T1  - Contribution of various instrumental methods to  transformation/metamorphosis assessment of  hydrophilic gels during skin application
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4592
ER  - 

@conference{
author = "Tošić, Anđela and Ilić, Tanja and Savić, Snežana and Pantelić, Ivana",
year = "2023",
abstract = "INTRODUCTION The metamorphosis of topical products is a relatively new concept that has grown in importance during the past few years [1]. It is defined by the phenomenon in which the primary packaged formulation changes its composition and/or microstructure during application. This change could be caused by different internal/external stimuli, most commonly, but not limited to the evaporation of highly volatile ingredients. As a consequence, there is a high possibility of a discrepancy between the desired release profile of the active substance and the obtained one. In addition to the pharmacokinetic profile changes, metamorphosis can also cause changes in the rheological, texture and cosmetic properties of the preparation [2,3]. According to the most recent EMA Draft Guideline on quality and equivalence of topical products from 2018, it is necessary to examine metamorphosis when assessing the bioequivalence of (trans)dermal products [1]. At this moment, a part of the scientific community suggests only two methods for metamorphosis assessment: nanothermal analysis and photothermal microspectroscopy. Both methods use probes to detect crystals of the drug substance in the deeper layers of the stratum corneum [4]. However, these methods require very expensive, sophisticated equipment, and they have not yet been formalized as methodologies used for this purpose. The aim of this work was to evaluate the possibility of using rheological, tribological and mass loss testing as single or combined methods for the assessment of metamorphosis of topical hydrogels. MATERIALS AND METHODS Materials Carbopol® 934 was obtained from Lubrizol (USA), while propylene glycol, triethanolamine, isopropanol, sodium hydroxide, methyl and propyl paraben were purchased from Sigma Aldrich (Germany). A model substance, diclofenac-sodium, was kindly donated by Hemofarm (Serbia). Sample preparation The concentration of isopropanol, as a model easily volatile ingredient, was varied in the range 0-15% (w/w). In the sample F1 (Table 1), the concentration of the gelling agent was also varied, as another parameter of interest for valid transformation analysis. The gels were prepared in accordance with the usual compendial guidelines (DAC/NRF). Rheological characterization Measurements were preformed using a Rheolab MC 120 rotational rheometer (Paar Physica, Germany), with a cone/plate system with a diameter of 50 mm, at an angle of 1° and a sample thickness of 0.05 mm, at a temperature of 20±0.1°C. Tribological study Test was performed in vivo in 4 female healthy volunteers, at the forearm skin, using Frictiometer® FR700 (Courage+Khazaka, Germany) equipped with a plain, smooth Teflon (PTFE) disk. Study was performed both in finite and infinite dosing conditions. Measurements were performed at 90 rpm for 100 s, with one measurement taken per second. Mass loss analysis The test was performed at a temperature of 32±0.1°C in a closed system of the device Orbital Shaker Incubator ES 20 (Biosan, Latvia). Each sample was applied in the quantity of 1 g, in a thin layer on the glass substrate and placed in a closed chamber system. The mass of the samples was measured on the ABJ 120-4M analytical scale (Kern & Sohn GmbH, Germany) during two hours in 15-minute intervals. RESULTS AND DISCUSSION The greatest potential for instrumental transformation analysis has been demonstrated by the simple mass loss study. In Figure 1, it can be clearly seen that samples F3-F6, which contain isopropanol, have reached the "plateau" sooner than samples F1-F2. The slope of the curve (transformation rate) between 45 and 60 min of drying is also significantly different for the samples F1- F2 and F3-F6. This method additionally allows discerning regions that represent the secondary and third (residual) formulations. Part of the curve between 15 and 45 min, when the mass loss is the most significant, correlates with forming the secondary formulation. The region between 45 and 120 min, depending on the very sample, represents the process of forming the residual formulation, after all the volatile ingredients have evaporated. On the other hand, rheological test has shown somewhat different results. Flow curves (Figure 2) represent changes in the microstructure that formulations go through during the test. Expectedly, gels that contain isopropanol go through more drastic changes. In the descending part of the curve unsymmetrical regions could be spotted, relative to the ascending part. This phenomenon could not be noted in the flow curves of the formulations F1 and F2. Furthermore, maximal and minimal viscosities and hysteresis area were the parameters that failed to show great potential for in depth assessment of a vehicle’s metamorphosis.A tribological study carried out under finite dosing conditions (3 mg/cm2 ; Figure 3a) provided more informative results, especially for the samples’ F3-F6 process of metamorphosis. The levels of changes in the friction value correlate well with the concentration of isopropyl alcohol. Therefore, it can be seen that the changes of this parameter are more intensive for formulations F5-F6 compared to formulations F3-F4, that contained isopropyl alcohol in lower concentrations. The same study, performed under infinite dosing conditions (10 mg/cm2 ; Figure 3b), showed no apparent potential for these purposes.CONSLUSION The results have showed that all three methods in a certain sense contribute to the examination of the metamorphosis of carbomer gels. Certain time points during mass loss and friction tests correlate well in terms of the exact onset of each transformation phase.",
journal = "4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France",
title = "Contribution of various instrumental methods to  transformation/metamorphosis assessment of  hydrophilic gels during skin application",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4592"
}

Tošić, A., Ilić, T., Savić, S.,& Pantelić, I.. (2023). Contribution of various instrumental methods to  transformation/metamorphosis assessment of  hydrophilic gels during skin application. in 4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France.
https://hdl.handle.net/21.15107/rcub_farfar_4592

Tošić A, Ilić T, Savić S, Pantelić I. Contribution of various instrumental methods to  transformation/metamorphosis assessment of  hydrophilic gels during skin application. in 4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_4592 .

Tošić, Anđela, Ilić, Tanja, Savić, Snežana, Pantelić, Ivana, "Contribution of various instrumental methods to  transformation/metamorphosis assessment of  hydrophilic gels during skin application" in 4th European Conference on Pharmaceutics, 20 - 21 March 2023, Marseille, France (2023),
https://hdl.handle.net/21.15107/rcub_farfar_4592 .

TY  - JOUR
AU  - Vukašinović, Mila
AU  - Pantelić, Ivana
AU  - Savić, Sanela
AU  - Cekić, Nebojša
AU  - Vukašinović Sekulić, Maja
AU  - Antić-Stanković, Jelena
AU  - Božić, Dragana
AU  - Tošić, Anđela
AU  - Tamburić, Slobodanka
AU  - Savić, Snežana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5311
AB  - Bioactive peptides are promising cosmetic active ingredients that can improve skin health
and appearance. They exhibit a broad spectrum of activity, including anti-aging, antioxidant, an-
timicrobial, and anti-inflammatory effects. The aim of this study was to develop a safe, stable, and
efficacious environmentally friendly (“green”) emulsion using a milk protein hydrolysate as a model
active ingredient. Potential emulsions were formulated with biodegradable emollients, stabilized
with naturally derived mixed emulsifier, and prepared by cold process. They were evaluated for
rheological behavior (continuous rotation and oscillation tests), physical stability (dynamic me-
chanical thermal analysis—DMTA test), and texture profiles, as well as cytotoxic, antioxidant, and
antimicrobial effects. Rheological characterization revealed shear-thinning flow behavior with yield
point from continuous rotation tests and predominantly elastic character from oscillation (amplitude
and frequency sweep) tests, with small structural change detected in the DMTA test. These results
implied satisfactory rheological properties and good stability. Texture analysis revealed acceptable
spreadability and substantivity of the emulsions. The protein hydrolysate showed antioxidant activity.
The developed emulsions showed low antibacterial activity against selected microorganisms, but
this was due to the action of preservatives, not peptides. All potential emulsions showed a desirable
safety profile. The results obtained provide the basis for the next stage of formulation development,
i.e., in vivo efficacy tests.
PB  - MDPI
T2  - Cosmetics
T1  - Development of a “Green” Emulsion with a Milk Protein Hydrolysate: An Evaluation of Rheology, Texture, In Vitro Bioactivity, and Safety
VL  - 10
IS  - 6
DO  - 10.3390/cosmetics10060162
ER  - 

@article{
author = "Vukašinović, Mila and Pantelić, Ivana and Savić, Sanela and Cekić, Nebojša and Vukašinović Sekulić, Maja and Antić-Stanković, Jelena and Božić, Dragana and Tošić, Anđela and Tamburić, Slobodanka and Savić, Snežana",
year = "2023",
abstract = "Bioactive peptides are promising cosmetic active ingredients that can improve skin health
and appearance. They exhibit a broad spectrum of activity, including anti-aging, antioxidant, an-
timicrobial, and anti-inflammatory effects. The aim of this study was to develop a safe, stable, and
efficacious environmentally friendly (“green”) emulsion using a milk protein hydrolysate as a model
active ingredient. Potential emulsions were formulated with biodegradable emollients, stabilized
with naturally derived mixed emulsifier, and prepared by cold process. They were evaluated for
rheological behavior (continuous rotation and oscillation tests), physical stability (dynamic me-
chanical thermal analysis—DMTA test), and texture profiles, as well as cytotoxic, antioxidant, and
antimicrobial effects. Rheological characterization revealed shear-thinning flow behavior with yield
point from continuous rotation tests and predominantly elastic character from oscillation (amplitude
and frequency sweep) tests, with small structural change detected in the DMTA test. These results
implied satisfactory rheological properties and good stability. Texture analysis revealed acceptable
spreadability and substantivity of the emulsions. The protein hydrolysate showed antioxidant activity.
The developed emulsions showed low antibacterial activity against selected microorganisms, but
this was due to the action of preservatives, not peptides. All potential emulsions showed a desirable
safety profile. The results obtained provide the basis for the next stage of formulation development,
i.e., in vivo efficacy tests.",
publisher = "MDPI",
journal = "Cosmetics",
title = "Development of a “Green” Emulsion with a Milk Protein Hydrolysate: An Evaluation of Rheology, Texture, In Vitro Bioactivity, and Safety",
volume = "10",
number = "6",
doi = "10.3390/cosmetics10060162"
}

Vukašinović, M., Pantelić, I., Savić, S., Cekić, N., Vukašinović Sekulić, M., Antić-Stanković, J., Božić, D., Tošić, A., Tamburić, S.,& Savić, S.. (2023). Development of a “Green” Emulsion with a Milk Protein Hydrolysate: An Evaluation of Rheology, Texture, In Vitro Bioactivity, and Safety. in Cosmetics
MDPI., 10(6).
https://doi.org/10.3390/cosmetics10060162

Vukašinović M, Pantelić I, Savić S, Cekić N, Vukašinović Sekulić M, Antić-Stanković J, Božić D, Tošić A, Tamburić S, Savić S. Development of a “Green” Emulsion with a Milk Protein Hydrolysate: An Evaluation of Rheology, Texture, In Vitro Bioactivity, and Safety. in Cosmetics. 2023;10(6).
doi:10.3390/cosmetics10060162 .

Vukašinović, Mila, Pantelić, Ivana, Savić, Sanela, Cekić, Nebojša, Vukašinović Sekulić, Maja, Antić-Stanković, Jelena, Božić, Dragana, Tošić, Anđela, Tamburić, Slobodanka, Savić, Snežana, "Development of a “Green” Emulsion with a Milk Protein Hydrolysate: An Evaluation of Rheology, Texture, In Vitro Bioactivity, and Safety" in Cosmetics, 10, no. 6 (2023),
https://doi.org/10.3390/cosmetics10060162 . .