Snežana Savić | University of Belgrade (original) (raw)

Papers by Snežana Savić

Advanced technologies, 2020

The present study describes the release pattern of risperidone, a poorly water-soluble psychophar... more The present study describes the release pattern of risperidone, a poorly water-soluble psychopharmacological drug, from two parenteral nanoemulsions containing the mixture of medium-chain triglycerides and soybean oil as an oil phase, sodium oleate solution as an aqueous phase and lecithin alone or in combination with polysorbate 80 as emulsifiers/stabilizers. The nanoemulsions were prepared by hot highpressure homogenization, and evaluated regarding physicochemical properties-a droplet size, polydispersity index, zeta potential, and viscosity, as well as biopharmaceutical performances-in vitro drug release by employing a reverse dialysis bag technique.Physicochemical characterization revealed a favorable mean droplet size (160-210 nm), narrow size distribution (<0.15), high surface charge (around-50 mV to-60 mV) and low apparent viscosity (4-6 mPa.s) of developed nanoemulsions, thus proving their suitability for parenteral administration of poorly water-soluble actives. The in vitro drug release study showed biphasic release profiles of risperidone, with significant differences between two investigated nanoemulsion formulations (differing only in the presence of polysorbate 80), indicating the influence of nanoemulsion matrix on drug release kinetics. However, the release of risperidone from investigated nanoemulsions was relatively rapid (more than 50% released within the first 5 min), suggesting their promising application in emergency situations. Furthermore, above 95% of the drug was released from both tested nanoemulsions within 180 min, while the kinetic release process could be described by Korsmeyer-Peppas model and supposed to be diffusion-controlled.Overall, it can be concluded that the reverse dialysis bag technique was the appropriate and enough discriminatory method to evaluate the in vitro release of risperidone from presented nanoemulsion systems.

Arhiv za farmaciju, 2019

Parenteralnim putem se primenjuju različiti tipovi farmaceutskih preparata čiji sastav može biti ... more Parenteralnim putem se primenjuju različiti tipovi farmaceutskih preparata čiji sastav može biti jednostavan (vodeni rastvori) i manje ili više kompleksan (emulzije, suspenzije, liposomi kao nosači lekovitih supstanci, čestični sistemi, čvrsti implanti/implantati). Napredak u bio-i nanotehnologiji omogućio je razvoj nove klase kompleksnih lekova, bioloških i tzv. nebioloških kompleksnih lekova (i njihovih "similara"-sličnih lekova), čiji dalji razvoj se očekuje u bliskoj budućnosti, a koji se, u velikom broju slučajeva, primenjuju parenteralnim putem. Parenteralni preparati koji u svom sastavu sadrže lekovite supstance koje su inkapsulirane u nosače tipa liposoma predstavljaju nebiološke kompleksne lekove koji su do sada najduže u upotrebi i čije su osobine i definisana svojstva kvaliteta najviše ispitivana. U radu je dat pregled obaveznih i dodatnih (specifičnih) in vitro ispitivanja liposomskih nosača lekovitih supstanci za primenu parenteralnim putem. Činjenica da postupci izvođenja ovih ispitivanja u osnovi nisu propisani u relevantnim farmakopejama (Ph. Eur., USP i JP) i da se mogu značajno razlikovati između laboratorija, doprinosi velikoj varijabilnosti dobijenih rezultata i ograničenjima u njihovom međusobnom poređenju. Regulatorna tela EMA i FDA učestvovala su u pripremi određenih dokumenata i razvoju odgovarajućih standarda i smernica u pogledu ispitivanja kvaliteta farmaceutskih oblika sa liposomskim nosačima lekovitih supstanci za parenteralnu primenu.

Savremene tehnologije, 2015

Using the experimental design methodology, we have developed and characterized nanoemulsions for ... more Using the experimental design methodology, we have developed and characterized nanoemulsions for a parenteral delivery using diazepam as a model drug. The formulations containing 20 or 30% (w/w) of medium chain triglycerides or the mixture of medium chain triglycerides and soybean oil as the oil phase, soybean lecithin and polysorbate 80 as emulsifiers, and a phosphate buffer solution as the aqueous phase were prepared by cold high pressure homogenization. The obtained nanoemulsions were evaluated in terms of droplet size, size distribution, surface charge, drug-vehicle interactions and physical stability. To evaluate the effects of the oil phase type, oil content and drug presence, as well as their interactions on critical quality attributes of nanoemulsions, a three-factor two-level full factorial design was applied. After the preparation, all nanoemulsions revealed small spherical droplets in the range 170-210 nm, with the narrow droplet size distribution (< 0.15) and the surface charge about-60 mV. The experimental design results indicated that not only factors alone (oil type, oil content, presence of drug), but their interactions also had a significant effect on the nanoemulsion droplet size, polydispersity index, and zeta potential. During two months of storage at 25 °C, all nanoemulsions formulated with the medium chain triglycerides-soybean oil mixture (4:1, w/w) remained physically stable, without considerable changes in monitored parameters. Physicochemical characteristics and stability of these nanoemulsions demonstrated their suitability for parenteral drug delivery.

Arhiv za farmaciju, 2016

Cilj ovog istraživanja bio je da se razviju parenteralne nanoemulzije sa rastućom koncentracijom ... more Cilj ovog istraživanja bio je da se razviju parenteralne nanoemulzije sa rastućom koncentracijom uljane faze (20, 30 i 40% smeše triglicerida srednje dužine lanca i sojinog ulja u odnosu 4:1), stabilizovane kombinacijom lecitina i polisorbata 80, i da se proceni njihova pogodnost kao nosača za slabo rastvorljive psihofarmakološke lekovite supstance. U tu svrhu, homogenizacijom pod visokim pritiskom izrađene su nanoemulzije sa diazepamom kao model lekovitom supstancom i okarakterisane u pogledu veličine kapi, indeksa polidisperznosti, površinskog naelektrisanja, viskoziteta, pH vrednosti i električne provodljivosti. Takođe, primenom reverzne tehnike sa dijaliznim vrećicama procenjena je brzina oslobađanja diazepama iz razvijenih nanoemulzija, uz karakterizaciju dobijenih profila oslobađanja primenom različitih matematičkih modela. Nakon izrade, sve formulacije imale su malu prosečnu veličinu kapi (206 ± 7 nm), sa uskom raspodelom veličina (0,116 ± 0,012) i zeta potencijalom oko-50 mV, što je u skladu sa farmakopejskim zahtevima (USP 39-NF 34) pri čemu se vrednosti navedenih parametara nisu značajno promenile nakon godinu dana čuvanja na 25 ± 2°C. In vitro ispitivanje brzine oslobađanja pokazalo je da se 40-50% diazepama oslobodi iz ispitivanih nanoemulzija tokom 1 h, pri čemu se kinetika oslobađanja može opisati Korsmeyer-Peppas modelom. Dobijeni rezultati ukazuju da formulisane parenteralne nanoemulzije predstavljaju obećavajuće nosače za brzu isporuku slabo rastvorljivih psihofarmakoloških lekovitih supstanci. Ključne reči: nanoemulzija; parenteralna primena; diazepam; stabilnost; reverzna tehnika sa dijaliznim vrećicama.

Acta Pharmaceutica, Dec 20, 2017

Alkyl polyglucoside vs. ethoxylated surfactant-based microemulsions as vehicles for two poorly wa... more Alkyl polyglucoside vs. ethoxylated surfactant-based microemulsions as vehicles for two poorly water-soluble drugs: physicochemical characterization and in vivo skin performance Two types of biocompatible surfactants were evaluated for their capability to formulate skin-friendly/non-irritant microemulsions as vehicles for two poorly water-soluble model drugs differing in properties and concentrations: alkyl polyglucosides (decyl glucoside and caprylyl/capryl glucoside) and ethoxylated surfactants (glycereth-7-caprylate/ caprate and polysorbate 80). Phase behavior, structural inversion and microemulsion solubilization potential for sertaconazole nitrate and adapalene were found to be highly dependent on the surfactants structure and HLB value. Performed characterization (polarized light microscopy, pH, electrical conductivity, rheological, FTIR and DSC measurements) indicated a formulation containing glycereth-7-caprylate/caprate as suitable for incorporation of both drugs, whereas alkyl polyglucoside-based systems did not exhibit satisfying solubilization capacity for sertaconazole nitrate. Further, monitored parameters were strongly affected by sertaconazole nitrate incorporation, while they remained almost unchanged in adapalene-loaded vehicles. In addition, results of the in vivo skin performance study supported acceptable tolerability for all investigated formulations, suggesting selected microemulsions as promising carriers worth exploring further for effective skin delivery of model drugs.

Journal of Applied Polymer Science, Jun 24, 2015

The objectives of this study were to prepare films from submicron chitosan/Eudragit V R L100-55 p... more The objectives of this study were to prepare films from submicron chitosan/Eudragit V R L100-55 polyelectrolyte complexes (CH/EL PEC) and to assess the influence of CH molecular weight and CH/EL mass ratio on their structure and drug-release properties. The films were obtained by a simple, environmentally friendly, casting/solvent evaporation method and the verapamil hydrochloride (VH) was used as model drug. Submicron size, narrow size distribution, and acceptable stability of CH/EL PECs were confirmed by DLS and laser Doppler microelectrophoresis. SEM analysis revealed nonporous inner structure and flat surface of the films. Interactions between comprising polymers and formation of CH/EL PEC were established by DSC and FT-IR spectroscopy. In vitro swelling and drug release studies revealed the pH sensitivity of the films, with burst drug release in acidic conditions (pH 1.2) and sustained release in phosphate buffers pH 5.8, 6.8, and 7.4. The slowest VH release was achieved from the films prepared from equal amounts of EL and CH of higher molecular weight, confirming the significance of the CH/EL ratio and CH molecular weight on their ability to sustain drug release. The obtained results suggested that presented, simple, and eco-friendly preparation procedure can be used to obtain pH-sensitive CH/EL PEC films with a promising potential as drug carriers. V

Arhiv za farmaciju, 2006

There are two different ways of action for sunscreens, physical sunscreens and molecular sunscree... more There are two different ways of action for sunscreens, physical sunscreens and molecular sunscreens. The presence of sunscreens on top of the horny layer can cause phototoxic and photoallergic reactions. The development of suitable products which prevent penetration of the sunscreen into the skin is a challenge for manufacturers of cosmetic products. It has been shown that solid lipid nanoparticles act as active carriers for sunscreens due to their paniculate character i.e. they represent physical sunscreens on their own. Incorporation of molececuiar sunscreens into SLN has a synergistic effect on the protective characteristics. Therefore, amount of molecular sunscreen could be decreased while maintaining the protection level (compared to a conventional emulsion). Oxybenzone (benzophenone-3) is lipophilic sunscreen is widely used in commercially available cosmetic formulations such as lotions, o/w emulsions and has been studied intensely in vitro and in vivo. The release rate of oxybenzone is decreased when using SLN formulations compared to emulsions, thus more of the active remains on the surface of the skin; this effect is desired. Titanium dioxide (TiO2) fine particles are embedded with sunscreens into the skin to effectively attenuate UV-B radiation.

Arhiv za farmaciju, 2018

Film-formers are cosmetic raw materials responsible for generating a film after their application... more Film-formers are cosmetic raw materials responsible for generating a film after their application. Recently, a certain expansion of these materials is noted, with numerous alleged functions and effects on skin or its appendages, making them a true example of multifunctional ingredients. CosIng database currently lists 965 ingredients with the recognized film-forming function. This paper offers a review of different types of film-formers as cosmetic raw materials, their properties and possible combinations in cosmetic products for skin, hair or nails. Although film-forming materials increasingly form part of contemporary cosmetic formulations, the paper mentions only the groups of cosmetic products that contain them in larger amounts, such as anti-age cosmetic products (lifting effect), sunscreens (water resistance and SPF/UVA-PF boosting), hair styling products and nail polishes. In line with the increase in their use, the Scientific Committee on Consumer Safety,operating within the European Commission, has announced recent development of scientific opinions on several cosmetic raw materials with film-forming properties.

Colloids and Surfaces A: Physicochemical and Engineering Aspects, Nov 1, 2014

Abstract The fast inverted oil-in-water (o/w) emulsions named SWOP (SWitch Oil Phase) emulsions h... more Abstract The fast inverted oil-in-water (o/w) emulsions named SWOP (SWitch Oil Phase) emulsions have been investigated with particular reference to physicochemical characteristics. Emulsions (oil-in-water (o/w) and water-in-oil (w/o)) are widely used in cosmetic and pharmaceutical formulations. Fast inverted o/w emulsions have been introduced as an alternative. The combination of appropriate w/o emulsifiers, anionic surfactants and polymeric stabilizers is essential for the formation of these emulsions. Samples of investigated, fast inverted o/w emulsion were prepared by hot–hot emulsification procedure using the combination of a w/o polymeric emulsifier (polyglyceryl-2 dipolyhydroxystearate) with a mild surfactant (sodium lauryl glucoside carboxylate (and) lauryl glucoside) in ratio 4:1.5 with addition of a stabilizing polymer (sodium polyacrylate). In the same manner, reference o/w and w/o emulsions were prepared. Investigated and reference emulsions were compared according to their physicochemical characteristics, structural characteristics, and their stability under the foreseen storage conditions and under the stress conditions employing the centrifugation test, pH, conductivity, rheological and contact angle measurements, microscopic observation, differential scanning calorimetry and thermogravimetric analysis. The samples of investigated and reference o/w emulsions were stable during three months storage at room temperature, while the samples of reference w/o emulsion showed phase separation. Only the samples of investigated emulsion remained stable in centrifugation test taken after the six freeze–thaw cycles. Oscillatory rheology indicated that the elastic modulus was dominant for both the investigated and the reference o/w emulsions due to the presence of gel structures, but the values of maximal apparent viscosity of the investigated emulsion which increased due to the temperature changes and the higher yield stress values that were obtained for the reference o/w emulsion indicated that the reference o/w emulsion had a stronger gel structure. Analysis of all the emulsions using polarization microscopy showed that the reference o/w emulsion had a more regular and a more rigid structure than the investigated emulsion. Obtained DSC and TGA results indicated that the SWOP emulsion showed a much faster evaporation of the water than the reference o/w emulsion which is in fine agreement with results from the contact angle measurements, i.e. , the inversion point for the SWOP emulsion was attained in less than 15 min in comparison with the reference o/w emulsion. Generally, the fast inverted, SWOP emulsion showed better characteristics in comparison with the reference o/w and w/o emulsions making it suitable for the wide range of applications.

European Journal of Pharmaceutical Sciences, Dec 1, 2018

This study aimed to investigate the potential of lecithin-based nanoemulsions costabilized by suc... more This study aimed to investigate the potential of lecithin-based nanoemulsions costabilized by sucrose esters, with and without skin pretreatment with stainless steel microneedles, to improve delivery of aceclofenac, as a model drug, into/across the skin. The characterization revealed favorable droplet size (about 180 nm), narrow size distribution (< 0.15), high surface charge (about −40 mV) and satisfying long-term stability (one year at 4 ± 1°C) of the formulation costabilized by sucrose palmitate, demonstrating a similar trend observed for the reference stabilized by widely used lecithin/polysorbate 80 combination. In vitro release/permeation testing and differential stripping on the porcine ear proved the superiority of the sucrose ester-over polysorbate-based nanoemulsion. However, in vitro findings were not fully indicative of the in vivo performancesno significant differences were observed between investigated formulations in pharmacokinetic profile and total amount of aceclofenac deposited in the rat skin 24 h after dosing, simultaneously pointing to delayed aceclofenac delivery into the systemic circulation. In addition, the ratio of plasma concentrations of aceclofenac and its major metabolite in rats, diclofenac, was remarkably changed after topical application of tested nanoemulsions compared to intravenous administration of aceclofenac solution. Finally, skin pretreatment with microneedles improved aceclofenac delivery into/across the rat skin from tested formulations, resulting in 1.4-2.1-fold increased bioavailability and 1.2-1.7-fold enhanced level of aceclofenac retained in the skin, as measured 24 h after administration. Moreover, the plasma concentrations of aceclofenac 24 h after application of tested formulations (lecithin/sucrose palmitate vs. lecithin/polysorbate 80) combined with microneedles (173.37 ± 40.50 ng/ml vs. 259.23 ± 73.18 ng/ml) were significantly higher than those obtained through intact skin (105.69 ± 19.53 ng/ml vs. 88.38 ± 14.46 ng/ml). However, obtained results suggest that combination of microneedles and sucrose palmitate-costabilized nanoemulsion could be useful to attain higher skin concentration, while combination of microneedles with polysorbate 80-costabilized nanoemulsion could be a preferable option for enhancing drug delivery into the bloodstream. enforced intensive research efforts towards exploring different percutaneous penetration enhancement technologies aiming to ensure effective treatment of various musculoskeletal disorders via skin. Considering that the success of topical NSAID therapy predominantly depends on the drug's capability to penetrate the stratum corneum (SC) layer in sufficiently high amount to exert its clinical effect, formulators

Journal of Thermal Analysis and Calorimetry, Feb 19, 2012

Mesomorphic behavior of the novel long-chain alkyl polyglucoside emulsifier comprising arachidyl ... more Mesomorphic behavior of the novel long-chain alkyl polyglucoside emulsifier comprising arachidyl alcohol (C 20), behenyl alcohol (C 22), and arachidyl glucoside was investigated in order to determine the prevalent stabilization mechanism and moisturizing capacity of emulsion systems based on it. For this to be accomplished thermoanalytical methods (differential scanning calorimetry and thermogravimetric analysis) coupled with microscopy, rheological, X-ray diffraction methods and a short-term in vivo study of skin hydration level were performed. Obtained results have proved that C 20 /C 22 alkyl polyglucoside mixed emulsifier is able to provide the synergism between the two main types of lamellar phases, the liquid-crystalline (La), and the gel crystalline (Lb) one, building the emulsion systems of different stability and performance. Formation of lamellar structures influenced for more than one half of water within the system to be entrapped. Conducted investigation of hydration potential in real-time conditions provided valuable information on the investigated emulsion vehicles' moisturizing potential as well as their contribution to the skin barrier improvement. Therefore, it could be expected that emulsions based on this alkyl polyglucoside emulsifier could influence the delivery of active ingredients of both the lipophilic and hydrophilic type. The employment of thermoanalytical methods in our work suggests the possibility for thermal methods to be used more frequently in the characterization of both the novel raw materials and the belonging emulsion systems.

International Journal of Pharmaceutics, Mar 1, 2004

It is known that, depending on the concentration, treatment with urea could improve skin barrier ... more It is known that, depending on the concentration, treatment with urea could improve skin barrier function, despite its penetration-enhancing properties. This controversial skin effect of urea has been explored systematically in this study in terms of the effect of vehicle on the performance of urea. In the first part, a series of four semi-solid emulsions with 5% (w/w) urea, varying in the type of emulsion, nature of emulsifier and polarity of oil ingredients, have been evaluated with regard to their skin hydrating and transepidermal water loss (TEWL)-modifying properties. Placebo samples were tested alongside the urea-containing ones. Two best performing moisturisers from the above were chosen for the second part of the study, in which sodium lauryl sulphate (SLS)-irritated skin was treated with both placebo and urea-containing samples. In addition to TEWL and skin hydration level, the erythema index (EI) was measured before, during and after the treatment. The results have shown that barrier-improving and hydrating abilities of urea are bi-directional and dependent on both the type of vehicle used for its delivery and the state of skin.

International Journal of Cosmetic Science, Aug 4, 2021

The growing consumers’ preferences and concerns regarding healthy ageing, youthful skin appearanc... more The growing consumers’ preferences and concerns regarding healthy ageing, youthful skin appearance, environmental protection and sustainability have triggered an ever‐increasing trend towards natural, eco‐friendly and ethically sourced anti‐ageing products. Accordingly, this paper describes design and evaluation of novel, safe, effective and high‐quality emulsion serums, completely based on ingredients of natural origin, intended for improving facial fine lines and wrinkles.

Tenside Surfactants Detergents, May 1, 2013

Alkyl polyglucosides (APGs) are a perfect amphiphilic structure, with excellent surface activity ... more Alkyl polyglucosides (APGs) are a perfect amphiphilic structure, with excellent surface activity and solubility feature. The aim of this study is to develop a simple system, with a relatively low emulsifier content, composed of materials mainly naturally based and with no additional fatty alcohol. Hydroxystearyl alcohol and Hydroxystearyl glucoside, prepared with Jojoba and Hazelnut oil, medium chain triglycerides with or without Xylitylglucoside and Anhydroxylitol and Xylitol, have been investigated by using microscopy, rheology, thermal analysis, pH and conductimetry. Cyclic stress and in vivo skin irritation tests were also conducted. The investigated natural APG emulsifier has a capacity to form simple and stable emulsions of desirable rheological profile with improved hydration potential and to renew damaged skin, thus it can be safely applied as stabilizer in cosmetic and prospective pharmaceutical cream-bases.

International Journal of Pharmaceutics, Nov 1, 2017

This work aimed to deepen the lately acquired knowledge about parenteral nanoemulsions as carrier... more This work aimed to deepen the lately acquired knowledge about parenteral nanoemulsions as carriers for brain delivery of risperidone, a poorly water-soluble antipsychotic drug, through establishing the prospective relationship between their physicochemical, pharmacokinetic, biodistribution, and behavioral performances. For this purpose, two optimized risperidone-loaded nanoemulsions, stabilized by lecithin or lecithin/polysorbate 80 mixture, and costabilized by sodium oleate, were produced by high-pressure homogenization. The characterization revealed the favorable droplet size, narrow size distribution, high surface charge, with proven stability to autoclaving and longterm stability for at least one year at 25 ± 2 °C. Pharmacokinetic and tissue distribution results demonstrated improved plasma, liver, and brain pharmacokinetic parameters, resulting in 1.2-1.5fold increased relative bioavailability, 1.1-1.8-fold decreased liver distribution, and about 1.3-fold improved brain uptake of risperidone active moiety following intraperitoneal administration of nanoemulsions relative to solution in rats. In behavioral study, investigated nanoemulsions showed pronounced reduction in basal and, more pertinently, amphetamine-induced locomotor activity in rats, with an early onset of antipsychotic action, and this effect lasted at least 90 min after drug injection. Together, these findings corroborate the applicability of parenteral nanoemulsions as carriers for enhanced brain delivery of risperidone, further suggesting their promise in acute psychosis treatment or other emergency situations.

Drug Development and Industrial Pharmacy, Feb 26, 2020