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V diplomskem delu sem opisala, kaj je zeta potencial, naštela njegove lastnosti in vplive, ki nanj delujejo. Z računi sem podala načine, s katerimi ga lahko izmerimo in posledično izračunamo, ter kje ga uporabljamo. Nato sem na splošno opisala kaj so mikoemulzije, podala njihove lastnosti in v čem se razlikujejo od emulzij. Naštela sem tudi njihove prednosti in slabosti, opisala njihovo uporabo, ter opisala kako se zeta potencial uporablja za določevanje stabilnosti v farmacevtski industriji. In my bachelor’s thesis, I explained what zeta potential is, described its properties and explained the factors that can have an impact on it. With equations I described methods of how we can measure and calculate zeta potential and added uses of zeta potential. Furthermore, I described the meaning and properties of microemulsions and described differences with emulsions. Moreover, I described their advantages and disadvantages and explained their use and how zeta potential is used to describe the stability of microemulsions in the field of pharmacy.

Postopki čiščenja predmetov kulturne dediščine se z leti razvijajo. Nekoč so bila poglavitno uporabljena organska topila, ki so okolju in človeku škodljiva. Sedaj je pri konservacijsko-restavracijskih postopkih najbolj razširjena raba koloidnih sistemov, ki minimizirajo porabo toksičnih topil in zmanjšajo nevarnost poškodb čiščenih predmetov. Primer koloidnih sistemov so geli, ki jih sestavljata vsaj dve komponenti: polimer in tekočina, ki zapolnjuje polimerno mrežo. Ta tekočina je lahko navadno topilo ali pa mikroemulzija, ki je stabilna koloidna disperzija dveh tekočin, ki se med seboj ne mešata in je ena razpršena v drugi. Tip čistilnega sredstva je določen na podlagi lastnosti čiščenega predmeta. Pomembno je, da slednji ostane nepoškodovan in da na njegovi površini ne ostajajo delci gela oz. druge vrste čistila. Posebna vrsta gelov so poli(vinil) alkohol hidrogeli. Njihove lastnosti so prilagojene posameznemu artefaktu z različnimi načini sinteze, ki so lahko sušenje v kalupu ali zamrzovanje in odtajanje v enem ali več ciklih. Poleg načina sinteze, ki vpliva na zamrežitev gela in s tem na njegove visko-elastične lastnosti in sproščanje tekočine, lahko na te lastnosti vplivamo tudi z dodatkom poli(vinil) pirolidona, ki hidrogelu poveča poroznost. The procedures of cleaning cultural heritage objects are evolving each year. In the past, the primary method of cleaning involved the use of organic solvents, which are harmful to the environment and people. Presently the use of colloidal systems is the main method in the conservation-restoration procedures. These systems minimize the usage of toxic solvents and decrease the chance of damaging the objects we clean. An example of colloidal systems are gels. These are systems of at least two components: a polymer and a fluid that fills the polymer mesh. The fluid can either be a solvent or a microemulsion, which is a stable colloid dispersion of two fluids that don’t mix, where one is dispersed in the other. Gels, solvents and microemulsion are chosen specifically for each cleaned object. It is crucial that the object stays undamaged and that no residues of gel remain on its surface. A special type of gel is poly(vinyl) alcohol hydrogel. Its characteristics can be modified by different methods of synthesis, which are cast-drying and freeze-thawing by one or more cycles. Besides different synthesis methods, the addition of poly(vinyl) pyrrolidone also affects viscoelastic characteristics and the release of fluid. Poly(vinyl) pyrrolidone increases the porosity of the hydrogel.

The novel role of oxidants and antioxidants in skin ageing as well as in various skin disorders and diseases has opened new research areas in several disease states and their therapeutic strategies. Successful prophylaxis and therapy of reactive-oxygen mediated skin ageing and phatogenesis would necessitate control of oxidant/antioxidant balance in the affected site, which can be achieved by external supply of skin endogenous antioxidants. However, antioxidants’ skin biovailability is usually low, mainly due to their poor aqueous solubility, inefficient permeability or instability during the storage. Colloidal drug delivery systems, like microemulsions (ME), nanoparticles or liposomes, are applicable to overcome the stability and pharmacokinetic problems associated with antioxidant delivery. These systems offer better targeting to upper skin layers, with faster onset and lower concentrations of the antioxidants needed. Moreover, liposomes and ME have a unique ability to simultaneously deliver both lipid- and water-soluble antioxidants. The thesis focuses on topical ME simultaneously loaded with lipophilic vitamin E, skin’s major membrane antioxidant and hydrophilic vitamin C, the main component of skin water-soluble antioxidant defence. Initially, viscosity of liquid o/w and w/o ME both composed of the same ingredients has been optimized for topical application. Among thickening agents tested carbomer, colloidal silica and mixture of xanthan and alginate revealed as suitable thickeners for o/w ME and white wax and colloidal silica for w/o ME. Transparent microemulsion gel (gel-like ME) that has been formed upon the addition of specific amounts of water to liquid o/w ME has been investigated as an alternative solution to viscosity problem. Gel-like ME was found to offer the best protection for both vitamins, although other ME also significantly increased their stability compared to solution. In the presence of vitamin C no decrease in vitamin E content occurred. The addition of thickeners to ME changed the stability of at least one vitamin, but the systems still protected vitamins better than solutions, the exception being o/w ME thickened with mixture of xanthan and alginate. By varying the composition of ME, absorption of vitamins C and E in reconstructed human epidermis was significantly modulated. The absorption of vitamins C and E in epidermal and collagen layer was in general enhanced by ME when compared to solutions. The location of the antioxidants in the ME and affinity for the vehicle appeared to be crucial in the case of non-thickened ME. Addition of collidal silica to ME enhanced the deposition of vitamins E and C in the reconstructed human epidermis. The addition of colloidal silica to either o/w or w/o ME also increased skin bioavailability of both vitamins. Dual influence of colloidal silica on skin delivery of vitamins C and E from topical ME was confirmed: it affected formulation characteristics and had a direct impact on the skin. The temperature-driven changes in the microstructure of gel-like ME together with their influence on skin deposition of vitamins C and E were confirmed by rotational rheometry, viscosity measurements, droplet size determination and pig ear permeation studies. The release studies have shown that the vitamins’ release at skin temperature from gel-like ME were comparable to those from o/w ME and were much faster and more complete than from o/w ME conventionally thickened with polymer (o/w ME carbomer). Concerning effectiveness in skin delivery of both vitamins o/w ME was found the most appropriate, followed by gel-like ME and by o/w ME carbomer. Finally, the irritation potential of ME was assessed in comparison to commercially available ME. Two different models were used: reconstructed human epidermis as ECVAM validated model for skin irritation testing and NCTC 2544 human keratinocyte cell cultures. Both models confirmed our ME less irritant than commercial product. In summary, ME have been proved effective and non-irritant vehicles with functionally suitable consistency for simultaneous topical delivery of a hydrophilic vitamin C and a lipophilic vitamin E. Mikroemulzije so bistre, termodinamsko stabilne disperzije vodne in oljne faze, stabilizirane z medfaznim filmom emulgatorja. Kot nosilni sistemi za dermalno dostavo učinkovin izkazujejo številne prednosti, saj lahko vanje zaradi njihove specifične zgradbe vgradimo tako vodotopne kot tudi lipofilne in/ali amfifilne učinkovine z namenom povečanja topnosti, hitrosti in obsega absorpcije učinkovine, doseganja prirejenega sproščanja, zaščite nestabilne učinkovine, zmanjšanja variabilnosti biološke uporabnosti ter zakrivanja neprijetnega vonja. Kljub naštetim prednostim je število registriranih mikroemulzij majhno, in sicer predvsem zaradi velikega deleža emulgatorjev, ki so potencialno toksične snovi. Mikroemulzije so pogosto Newtonske tekočine z nizko viskoznostjo, ki so neprimerne za direkten nanos na kožo. Viskoznost mikroemulzij lahko povečamo z dodajanjem zgoščeval, ki ustrezno spremenijo reološko obnašanje sistema, ne da bi pri tem vplivala na druge lastnosti mikroemulzij, kot so stabilnost, bistrost in spontan nastanek. Druga možnost prirejanja viskoznosti je izdelava mikroemulzijskih gelov z izbiro ustreznih sestavin mikroemulzij in določitvijo koncentracij, kjer spontano tvorijo lamelarne strukture, za katere je značilna povečana viskoznost. Koža, radikali in antioksidanti Pri prekomerni izpostavitvi kože UV-svetlobi pride poleg povečanega nastajanja radikalov istočasno tudi do zaviranja delovanja pomembnejših encimov, ki odstranjujejo radikale. Porušenje ravnotežja med nastajanjem radikalov in antioksidativno obrambo v prid prvih lahko privede do poškodb organizma. Tako stanje imenujemo oksidativni stres, ki je eden glavnih dejavnikov pri fotostaranju, vnetjih in celo rakavih spremembah kože. Telo je razvilo številne obrambne sisteme, ki celice varujejo pred presežnimi radikali. Med najpomembnejše obrambne mehanizme štejemo encimski (npr. superoksid dizmutaza, katalaza, peroksidaza) in neencimski (npr. glutation, vitamin E – α-tokoferol, vitamin C – askorbinska kislina, β-karoten, ubikinon) antioksidativni sistem. Obetaven pristop k zaščiti kože pred škodljivimi vplivi radikalov je krepitev endogenega obrambnega sistema. V terapiji se najpogosteje uporabljajo vitamin C, vitamin E in β-karoten. Vitamin C, ki neposredno reagira z vsemi pomembnimi kisikovimi radikali, je glavni in edini življenjsko potreben vodotopen antioksidant, medtem ko je vitamin E najpomembnejši lipofilni antioksidant, ki zagotavlja zaščito pred oksidativno poškodbo membran in je dokazano učinkovit pri preprečevanju lipidne peroksidacije in tvorbe tumorjev kože. Čeprav sta vitamina C in E prisotna v različnih predelih celice, vse več dejstev dokazuje, da je njuno delovanje sinergistično. Vitamin C potencira antioksidativno učinkovitost vitamina E preko regeneracije tokoferoksilnega radikala v aktivno obliko vitamina E. Antioksidativni obrambni mehanizmi so torej medsebojno prepleteni, zato je ravnovesje med posameznimi kožnimi antioksidanti zelo pomembno. Ker oksidiran vitamin E za svoje obnavljanje troši druge antioksidante, je priporočljivo kombinirano dajanje vitamina E z antioksidantom, ki sodeluje pri njegovi obnovi, npr. vitaminom C, glutationom ali karotenoidi. Vloga nosilnega sistema pri dostavi antioksidantov v kožo Na trgu obstaja veliko formulacij z antioksidanti, najpogosteje z vitamini, ki pa so vgrajeni v klasične farmacevtske oblike, saj so le-te praviloma enostavne za izdelavo in relativno poceni. Učinkovitost teh pripravkov je pogosto vprašljiva zaradi slabih fizikalno-kemijskih in biofarmacevtskih lastnosti antioksidantov, kot so nizka topnost, slaba permeabilnost in/ali visoka nestabilnost. Eden od načinov zaščite antioksidantov in izboljšane dostave na mesto delovanja je njihova vgraditev v različne koloidne nosilce: micele, mikroemulzije, nanodelce, liposome. Za doseganje ustreznih koncentracij antioksidantov v koži peroralno jemanje običajno ne zadostuje, nasprotno pa sta se dermalna dostava in kombinacija dermalne in per os dostave antioksidantov, vgrajenih v ustrezne nosilne sisteme, pokazali kot učinkoviti. V zadnjih letih so antioksidanti postali marketinški hit v kozmetični industriji. Uporabljajo se predvsem z namenom upočasnjevanja staranja kože. V tabeli 1 so navedeni nekateri primeri komercialnih izdelkov, ki vsebujejo kot aktivne učinkovine antioksidante, vgrajene v koloidne nosilne sisteme.

U ovom radu proveden je postupak optimiranja pripreme mikroemulzija ulje u vodi i ulje i vodenom ekstraktu mente u mikroprotočnom sustavu uz emulgator polietilen glikol (PEG1500, 6000 i 20000). Ispitan je utjecaj količine emulgatora, količine ulja i ukupnih protoka na stabilnost mikroemulzija koja je izražena zeta potencijalom i Feretovim promjerom te su određeni optimalni procesni uvjeti za 6 sustava pripreme mikroemulzija. Na temelju dobivenih vrijednosti zeta potencijala kao najstabilnije su se pokazale emulzije pripremljene s vodom kao kontinuiranom fazom i emulgatorom PEG1500 te je uočeno da vrijednost zeta potencijala opada porastom molekulske mase upotrijebljenog emulgatora. Nadalje izabrani emulgatori ne osiguravaju zadovoljavajuću stabilnost emulzija ako se kao kontinuirana faza upotrijebi vodeni ekstrakt mente. Umjetne neuronske mreže pokazale su se pouzdanima u predviđanju Feretovog promjera kapljica emulzija ulje u vodi za sve analizirane sustave. In this work, optimisation of oil in water and oil in peppermint extract microemulsion preparation in microfluidic system using polyethylene glycol as emulsifier (PEG 1500, 6000 and 20000) was performed. The effect of the emulsifier amount, oil amount and total flow rate on the microemulsion stability expressed as zeta potential and Feret diameter was analysed. Optimal process conditions for microemulsion preparations were estimated for all 6 analysed systems. Based on the zeta potential, the most stable emulsions were prepared with water as continuous phase and using PEG 1500 as emulsifier. It was observed that with the increase of emulsifier molecular weight value of zeta potential decreases. Furthermore, the selected emulsifiers did not ensure satisfactorily stability for emulsions when the aqueous extract of mint was used as the continuous phase. Artificial neural networks (ANNs) were shown reliable for prediction of Feret diameter of droplets in oil in water emulsions for all analysed systems.

Primarni cilj istraživanja ove doktorske disertacije je bila procena mogućnosti da se razvojem i primenom mikroemulzija (kao opcije hemijskog inhensera penetracije) poboljša dermalna isporuka slabo rastvorljivih lekovitih supstanci – adapalena (ADA) i sertakonazol-nitrata (SN), koje pripadaju različitim farmakoterapijskim grupama, imaju različite fizičkohemijske osobine i primenjuju se u različitim terapijskim koncentracijama. Mikroemulzije su stabilizovane nejonskim surfaktantima novije generacije – alkil poligukozidima (APG) ili polioksietilen(glicerol) estrima masnih kiselina. U cilju komparativne procene doprinosa različitih vrsta nosača dermalnoj raspoloživosti model leka, posebna pažnja je posvećena analizi sposobnosti različitih vrsta mikroigala (fizički inhenseri penetracije) da pojačaju isporuku SN u kožu (čvrste silikonske vs. rastvorljive mikroigle). Rezultati su ukazali da se još uvek nedovoljno korišćeni APG surfaktanti i gliceret-7- kaprilat/kaprat mogu uspešno primeniti u formulaciji mikroemulzija. Razvijene (invertne) bikontinuirane mikroemulzije su se pokazale kao pogodni nosači za solubilizovanje ADA i SN, u pogledu njihovih fizičkohemijskih osobina, bezbednosti i stabilnosti, i, najvažnije, u pogledu njihovog potencijala za poboljšanje dermalne isporuke ovih lekova in vitro. Dodatno, rastvorljive mikroigle su uspešno formulisane kao nosači za dermalnu isporuku teško rastvorljivog SN i obezbedile komparabilno deponovanje leka u koži kao mikroemulzije, međutim uz prisustvo in vitro transdermalne isporuke dela primenjene doze leka. Sinergističko delovanje mikroigala i mikroemulzija bilo je superiorno u odnosu primenu samog fizičkog i samog hemijskog premošćivača barijere stratum corneum-a, bez značajnog povećanja permeacije leka. The aim of this doctoral dissertation was to evaluate the possibility of using microemulsions (as chemical penetration inerters) for improvment of dermal delivery of a poorly soluble model dugs having different physicochemical characteristics, belonging to different pharmacotherapeutic groups, i.e. applied in different therapeutic concentrations (adapalene (ADA) and sertaconazole nitrate (SN)). Microemulsions were stabilized with newer nonionic surfactants - alkyl polygucosides (APG) or polyoxyethylene (glycerol) fatty acid esters. In order to compare the contribution of different types of carriers to the enhancement of dermal availability of the model drug, a special attention has been paid to the assessment of microneedles ability to significantly improve delivery of SN into the skin (dissolvable vs. solid silicone microneedles). The obtained results showed that newer and so far insufficiently used APG surfactants and glycereth-7-caprylate/caprate can be successfully applied in the formulation of microemulsions. The developed (invert) bicontinuous microemulsion formulations have proved to be suitable carriers for solubilizing the investigated model drugs, in terms of their physicochemical properties, safety profile and stability, and, most importantly, their great potential of improving dermal delivery of ADA and SN in vitro. In addition, dissolvable microneedles were successfully fabricated as carriers for dermal delivery o highly lipophilic SN and provided comparable drug deposition in the skin as microemulsions, but coupled with transdermal delivery of a portion of the administered drug dose. The synergistic action of microneedles and microemulsions was superior over the application either of physical or chemical enhancer alone, without reaching a significant increase in drug permeation as compared to the use of dissolvable microneedles.

Eterična ulja prisutna su u topikalnoj primjeni zbog svojih antimikrobnih, antioksidacijskih, protuupalnih i drugih pozitivnih učinaka. Posebno je ineresantna njihova primjena kao promotora penetracije. Upotrebom nanotehnoloških nosača, kao što su nanoemulzije, mikroemulzije, nanogelovi i nanočestice, omogućuje se primjena nestabilnih i teško topljivih djelatnih tvari, poboljšava se dermalna raspoloživost i omogućava kontrolirano oslobađanje djelatnih tvari. Primjenom eteričnih ulja u nanotehnološkim pripravcima s uklopljenom djelatnom tvari, dobivaju se sustavi jedinstvenih svojstava. Eterična ulja dodatno poboljšavaju fizičku stabilnost uklopljene djelatne tvari, njenu permeaciju i raspodjelu u koži, a posljedično i biološku aktivnost djelatne tvari. Upotrebom eteričnih ulja moguće je pripremiti nanotehnološke nosače s boljim kapacitetom uklapanja za određene djelatne tvari. Nadalje, eterična ulja u nanotehnološkim pripravcima zadržavaju svoja farmakološka svojstva i djelujući sinergistički poboljšavaju učinak uklopljene djelatne tvari. Brojna su in vitro ispitivanja pokazala sigurnost i učinkovitost nanotehnoloških formulacija s uklopljenim eteričnim uljima i djelatnim tvarima. Stoga, takve formulacije predstavljaju veliki potencijal za daljnje istraživanje. Prije svega, potrebno je utvrditi njihovu sigurnost i učinkovitost u kliničkoj primjeni. Essential oils are used for topical application because of their antimicrobial, antioxidant, anti-inflammatory, and other beneficial effects. Their use as penetration enhancers is particularly interesting. Nanotechnological carriers, such as nanoemulsions, microemulsions, nanogels and nanoparticles, enable application of unstable and poorly soluble active ingredients, improve dermal availability and enable sustained release of active ingredients. Use of essential oils in nanotechnological carriers with encapsulated active ingredients enables production of formulations with unique properties. Essential oils further improve active ingredient physical stability, improve active ingredient permeation and skin distribution, and consequently its biological activity. Using essential oils, it is possible to prepare nanotechnological carriers with better encapsulation efficiency for some active ingredients. Furthermore, essential oils in nanotechnological carriers retain their pharmacological properties and acting synergistically, improve the effect of encapsulated active ingredient. Numerous in vitro researches show nanotechnological formulations with encapsulated essential oils safety and efficiency. Therefore, there is a huge potential for further research of such formulations. Especially, their safety and efficiency in clinical trials should be determined.

Mikroemulzije su se u proteklih nekoliko godina pojavile kao novi dozirni oblik kojim se omogućuje povećanje apsorpcije djelatne tvari u organizam. To su termodinamički stabilni, optički izotropni sustavi sastavljeni od ulja, vode, surfaktanata i kosurfaktanata. Zbog postojanja hidrofilnih i lipofilnih domena pokazuju poboljšanu topljivost djelatne tvari. Prema strukturi dijele se na mikroemulzije ulja u vodi, mikroemulzije vode u ulju te bikontinuirane strukture. U eksperimentalnom su istraživanju formirane samoorganizirajuće mikroemulzije s uklopljenim dronedaron-hidrokloridom. Dronedaron-hidroklorid otopljen je u etanolu koji je uklonjen isparavanjem u rotacijskom isparivaču i vakuumskom sušioniku. Korištena su dva stabilizatora, Kolliphor EL i Kolliphor RH40. In vitro metodom ispitana je brzina oslobađanja dronedaron-hidroklorida iz mikroemulzija. Promjena koncentracije dronedarona određena je pomoću UV/Vis spektrofotometra mjerenjem apsorbancije te su dobiveni profili oslobađanja dronedaron-hidroklorida. Mikrografijama je potvrđeno da dodatkom pripremljenog sustava u fosfatni pufer nastaju mikroemulzije. In vitro metoda ispitivanja pokazala je izuzetno brzo oslobađanje dronedaron-hidroklorida iz mikroemulzija, već 90 % nakon 10 minuta. In last few years, microemulsions have been recognized as new alternative dosage form which allows increase in the absorption of active substance. They are thermodynamically stable, optically isotropic systems of oil, water, surfactants and cosurfactants. Due to the existence of hydrophilic and lipophilic domains better solubility of active substances is possible. Structurally, they are divided into oil in water, water in oil and bicontinuous microemulsions. Self-microemulsifying drug delivery systems containing dronedarone hidrochloride were prepared in this study. Dronedarone hydrochloride was dissolved in ethanol and then removed by evaporation in rotational evaporator and vacuum dryer. Two stabilizers were used, Kolliphor EL i Kolliphor RH40. In vitro method was used to determine the release rate of dronedarone hydrochloride from microemulsions. The change of dronedarone concentration was determined measuring the absorbance by UV/Vis spectrophotometer. Also, dronedarone hydrochloride dissolution profiles were obtained. Micrographs confirmed self-formation of microemulsions when prepared mixtures were added into phosphate buffer. In vitro method showed instant release of dronedarone hydrochloride from microemulsions, 90% after 10 minutes.

Pt-based nanocatalysts supported on Vulcan XC-72R carbon, were prepared by water-in-oil microemulsion method, with addition of various amounts of HCl in the water phase. Polyethileneglycoldodecylether (BRIJ 30) was used as a surfactant, which influenced the Pt surface structure, along with HCl. Catalysts prepared with addition of 0, 15, 25 and 35 % of HCl during the synthesis, were electrochemically characterised in 0,5 M H2SO4 using cyclic voltammetry and CO oxidation. Formic acid electrooxidation was examined on all investigated catalysts, in terms of their electrocatalytic activity and stability. Platinum loading on carbon support was examined by Thermogravimetric analysis. Catalysts showed different features in hydrogen region, and slight differences in formic acid oxidation mechanisms. Platinski nano-katalizatori na ugljeničnom nosaču Vulcan XC-72R sintetizovani su mikroemulzionom metodom, sa različitim sadržajem HCl u vodenoj fazi mikroemulzije. Kao surfaktant korišćen je polietilenglikol-dodeciletar (BRIJ30), čija je uloga da, zajedno sa HCl, utiče na strukturu površine platine. Katalizatori, koji su pripremljeni sa 0, 15, 25 i 35 % HCl u vodenoj fazi, okarakterisani su elektrohemijski u 0,5 M H2SO4, cikličnom voltametrijom i oksidacijom CO. Aktivnost i stabilnost sva četiri katalizatora ispitana je za oksidaciju mravlje kiseline. Udeo platine u prahu pripremljenih katalizatora određen je termogravimetrijskom analizom. Katalizatori su pokazali različito ponašanje u vodoničnoj oblasti osnovnih voltamograma, kao i različitu aktivnost i stabilnost za oksidaciju mravlje kiseline.

Nesteroidni antiinflamatorni lekovi (NSAIL) su heterogena grupa lekovitih supstanci sa antiinflamatornim, antipiretičkim i analgetskim delovanjem. Iako postoji više od 50 različitih NSAIL na svetskom tržištu, stalno istraživanje i razvoj novih lekovitih supstanci ove terapijske grupe je posledica njihovog nepovoljnog farmakokinetičkog profila (npr. kratko poluvreme eliminacije) i/ili ispoljavanja neželjenih efekata (npr. na nivou gastrointestinalnog trakta). Aceklofenak je indikovan za oralnu primenu u terapiji reumatoidnih bolesti, kao i u terapiji drugih upalnih i bolnih stanja. I pored prednosti u odnosu na ostale lekovite supstance iz ove grupe, hronična oralna primena aceklofenaka može dovesti do pojave neželjenih efekata koji su karakteristični i za ostale NSAIL, te se nameće potreba za prevazilaženjem ovih problema primenom farmaceutsko-tehnoloških pristupa i/ili drugim putem primene. Jedan od načina za smanjenje neželjenih efekata i zaobilaženje metabolizma prvog prolaza je lokalna primena aceklofenaka u terapiji reumatoidnih bolesti. Da bi koncentracija lokalno primenjenog aceklofenaka bila dovoljna za ispoljavanje kliničkog efekta, neophodno je prevazići stratum corneum, primarnu barijeru za difuziju lekovitih supstanci u kožu. Koloidni nosači tipa mikroemulzija su perspektivni nosači lekovitih supstanci, čijom se primenom može poboljšati dermalna/transdermalna isporuka, a time i lokalna i/ili sistemska raspoloživost. Sa druge strane, neophodno je posvetiti posebnu pažnju izboru ekscipijenasa, kako sa aspekta bezbednosti/iritacije, tako i sa aspekta njihovog potencijalnog uticaja na dermalnu/transdermalnu isporuku lekovite supstance. Saharozni estri su nejonski surfaktanti, a njihove osobine poput biokompatibilnosti, biodegradabilnosti, niskog rizika da dovedu do iritacije, i potencijala da deluju kao pojačivači penetracije, predstavljaju značajne prednosti ovih surfaktanata u odnosu na tradicionalno korišćene, sintetske, etoksilovane surfaktante. Imajući to u vidu, osnovni cilj istraživanja ove doktorske disertacije predstavlja proučavanje molekularnih mehanizama kojima saharozni estri, sa različitom dužinom lipofilnog lanca, povećavaju penetraciju lekovitih supstanci... Despite the diversity of the chemical structures, non-steroidal anti-inflammatory drugs (NSAIDs) share the same activity, such as analgesic, antipyretic and anti-inflammatory. Interestingly, there are more than 50 different NSAIDs on the global market – the continuous research and development of new active substances from this therapeutic group is related to their unfavourable pharmacokinetic properties (e.g. short half-life) or is associated with a broad spectrum of adverse reactions (e.g. gastrointestinal side effects). Aceclofenac is indicated in the therapy of rheumatoid diseases, as well as in the symptomatic therapy of pain and inflammation. Although effective and relatively safe, chronic oral aceclofenac administration may cause systemic side effects typical of other NSAIDs, which warrants the search for a new route of its administration and/or implementation of pharmaceutical-technological approaches in the therapy of musculoskeletal disorders, in order to decrease the incidence of adverse reactions, as well as to avoid the first-pass metabolism. The crucial step during any topical NSAID therapy is the ability of drug to overcome the outermost layer of the skin – stratum corneum, as a critical barrier for penetration of an active through the skin in sufficiently high amount to exert its clinical effect. Microemulsions are colloidal systems that are currently of pharmaceutical interest as promising vehicles which can improve dermal/transdermal drug delivery, and thus, its local/systemic bioavailability. However, the choice of excipient is one of the key factors in preformulation studies, due to their potential influence on skin tolerability, as well as their ability to act as penetration enhancers. Described as very mild and nonirritant with regard to dermatological properties, sucrose esters are of growing research interest, with promising features of low skin sensitization potential and enhancing skin penetration effect, as well as with a high environmental compatibility, all of which may be distinct advantages when compared to traditionally used synthetic ethoxylated surfactants...

Maslinovo ulje je jedna od najvažnijih namirnica u čovjekovoj svakodnevnoj prehrani zbog visoko vrijednih sastojaka koji potpomažu u očuvanju ljudskog zdravlja zbog uravnoteženog sastava masnih kiselina. Također, maslinovo ulje ima visok sadržaj vitamina E i polifenola koji imaju zaštitnu i antioksidacijsku ulogu. Riblje ulje je u posljednje vrijeme vrlo korištena namirnica zbog visokog sadržaja nezasićenih masnih kiselina, no ono je isto kao i maslinovo ulje podložno oksidaciji. Skvalen je polunezasićeni ugljikovodik koji ima značajan antioksidacijski učinak i mnoga biološka djelovanja, te zaštitno djeluje na nekoliko vrsta tumora. U ovom završnom radu se istraživao utjecaj dodatka skvalena na oksidacijsku stabilnost ribljeg i maslinovog ulja. Rezultati su potvrdili da skvalen nema utjecaj na produljenje oksidacijske stabilnosti ekstra djevičanskog maslinovog ulja niti ribljeg ulja. S druge strane, korištenje emulzijskog sustava može povećati utjecaj skvalena na produljenje oksidacijske stabilnosti. Olive oil is one of the most important foods in human daily diet because of high-value ingredients that affect the preservation of human health due to a balanced fat composition. Also, olive oil has a high vitamin E precentage that has a protective and antioxidant role. Fish oil has been a very useful food for the last time due to the high content of unsaturated fatty acids, but it is like olive oil an inadequate oxidation. Squalen is a semi-saturated hydrocarbon having a significant antioxidant effect and many biological effects, and protects against several types of tumors. In this final paper, the effect of squalene on the oxidative stability of fish and olive oil was investigated. Results showed that squalene had no effect on the prolongation of the oxidative stability of olive oil and fish oil. On the other hand, the use of emulsions system with incorporated squalene showed the prolongation of the olive oil and fish oil oxidative stability.

Nanoemulzije zbog svojih su svojstava zanimljive kao formulacije namijenjene oftalmičkoj primjeni. Mogu biti izrađene niskoenergetskim i visokoenergetskim metodama. Za potrebe ovog rada korištene su dvije visokoenergetske metode, visokotlačna homogenizacija i mikrofluidizacija. Nanoemulzije su pripremljene tako da se najprije izradila primarna emulzija, koja je zatim prošla kroz jedan, tri i pet ciklusa visokotlačne homogenizacije, odnosno mikrofluidizacije. Veličina kapljica, PDI i zeta-potencijal određeni su nakon izrade i dva tjedna nakon izrade kako bi se mogla procijeniti stabilnost nanoemulzija. Dobivene nanoemulzije bile su mliječno bijele boje i nisu pokazale odvajanje faza tijekom dva tjedna. Općenito su pri većem tlaku i pri većem broju ciklusa izmjerene najmanje veličine kapljica, dok je najmanja veličina kapljica izmjerena za nanoemulziju izrađenu nakon pet ciklusa mikrofluidizacije pri tlaku od 1300 bara. PDI nijednom nije bio manji od 0,1. Zeta-potencijal bio je približno sličan kod svakog uređaja, pri svakom tlaku i broju ciklusa. Bitno je naglasiti da su izmjerene vrijednosti (~4 mV) daleko od očekivanih vrijednosti (~30 mV). Nijedna formulacija nije pokazala željena svojstva. Nanoemulsions are interesting as pharmaceutical formulations for ophthalmic use because of their specific properties. They can be made with low-energy and high-energy methods. High-pressure homogenization and microfluidization were two high-energy methods used in this research. Nanoemulsions were prepared as follows: firstly, the primary emulsion was made, which was then passed through one, three and five cycles of high-pressure homogenization or microfluidization. Droplet size, PDI and zeta-potential were measured one day after preparation and two weeks after preparation to assess the stability of nanoemulsions. Prepared nanoemulsions were milky white and phase separation did not occur in two weeks. In general, using higher pressure and greater number of cycles resulted with smaller droplet size, with the smallest droplet size measured for nanoemulsion produced after five microfluidization cycles at 1300 bar. PDI was never less than 0.1. The zeta-potential was approximately the same in nanoemulsions prepared using both devices, regardless of pressure and number of cycles. It is important to note that the measured values (~ 4 mV) are far from the expected values (~ 30 mV). None of the formulations showed the desired properties.

Tinkture su alkoholne ili hidroalkoholne otopine pripremljene od biljnih ili kemijskih tvari. Tinkture su veoma korisne u industriji parfema , jer sadrže etanol koji je dobro otapalo mirisnih spojeva. U ovom istraživanju titracijskom metodom je određeno monofazno područje u trokomponentnom sustavu citral - etanol-voda . Stabilnost mikroemulzijskih agregata ispitana je mjerenjem zeta - potencijala . Tinctures are alcoholic or hydroalcoholic solutions prepared from vegetable or chemical substances. Tinctures are very useful in the perfume industry, because they contain ethanol, which is a good solvent of aromatic compounds. In this study titration method is used for the determination of single-phase area in three-component system citral - a water-ethanol. The stability of the microemulsion of aggregates was tested by measuring the zeta – potential.

Pt-based nanocatalysts supported on Vulcan XC-72R carbon, were prepared by water-in-oil microemulsion method, with addition of various amounts of HCl in the water phase. Polyethileneglycoldodecylether (BRIJ 30) was used as a surfactant, which influenced the Pt surface structure, along with HCl. Catalysts prepared with addition of 0, 15, 25 and 35 % of HCl during the synthesis, were electrochemically characterised in 0,5 M H2SO4 using cyclic voltammetry and CO oxidation. Formic acid electrooxidation was examined on all investigated catalysts, in terms of their electrocatalytic activity and stability. Platinum loading on carbon support was examined by Thermogravimetric analysis. Catalysts showed different features in hydrogen region, and slight differences in formic acid oxidation mechanisms. Platinski nano-katalizatori na ugljeničnom nosaču Vulcan XC-72R sintetizovani su mikroemulzionom metodom, sa različitim sadržajem HCl u vodenoj fazi mikroemulzije. Kao surfaktant korišćen je polietilenglikol-dodeciletar (BRIJ30), čija je uloga da, zajedno sa HCl, utiče na strukturu površine platine. Katalizatori, koji su pripremljeni sa 0, 15, 25 i 35 % HCl u vodenoj fazi, okarakterisani su elektrohemijski u 0,5 M H2SO4, cikličnom voltametrijom i oksidacijom CO. Aktivnost i stabilnost sva četiri katalizatora ispitana je za oksidaciju mravlje kiseline. Udeo platine u prahu pripremljenih katalizatora određen je termogravimetrijskom analizom. Katalizatori su pokazali različito ponašanje u vodoničnoj oblasti osnovnih voltamograma, kao i različitu aktivnost i stabilnost za oksidaciju mravlje kiseline.

Development of self-dispersing drug delivery systems (SMEDDS) is a modern strategy for oral delivery improvement of poorly soluble drugs. Self-microemulsifying drug delivery systems (SMEDDS) are isotropic mixtures of oils and hydrophilic surfactants, which form oil-in-water (o/w) microemulsions by dilution in aqueous media (e.g., gastrointestinal fluids). Formulation of SMEDDS carriers requires consideration of a large number of formulation parameters and their influences on process of self-microemulsifying and releasing of drug. The aim of this work was formulation and characterization of SMEDDS for oral administration of ibuprofen. In the experimental work, two series of potential SMEDDS were prepared (M1-M10), using surfactant (Labrasol®, Gattefosse), cosurfactant (PEG­40 hydrogenated castor (Cremophor® RH40), and oil (medium chain triglycerides (Crodamol® GTCC) and olive oil (Cropur® Olive)), at surfactant-to-cosurfactant mass ratios (Km) 9:1, 7:3, 5:5, 3:7, and 1:9, and 10 or 20% of the oil phase. Ibuprofen was dissolved in formulations in concentration of 10%. Characterization of the investigated formulations included evaluation of physical stability, self-microemulsification ability in 0.1 M HCl (pH 1.2) and phosphate buffer pH 7.2 (USP) and in vitro drug release. Formation of o/w microemulsions with the average droplet size (Z-ave) up to 100 nm, was observed in dispersions of formulations prepared with 10 mass% of medium chain triglycerides, within the entire investigated range of the Km values (M1-M5). These formulations were selected as SMEDDS. Results of characterization pointed out the importance of the type and concentration of the oil as well as the Km value for the self-microemulsing ability, as well as drug release kinetics from the investigated SMEDDS. Ibuprofen release was in accordance with the request of USP 30-NF 25 (at least 80% after 60 min) from the formulations M1 (Km 9:1) and M5 (Km 1:9). Furthermore, the ibuprofen release was completed after 10 min from formulation M1, while the release from the carrier M5 (~30%) as well as from the commercial tablets Brufen® (~55%) and soft capsules Rapidol® (~65%), examined under the same conditions, was significantly slower. The present study revealed that the formulation M1 represents a potential SMEDDS which efficiently dissolves ibuprofen in acidic media, with potential to minimize the side effects, while on introduction into alkaline intestinal environment, the drug may rapidly release from the carrier and undergo absorption. Razvoj samo-mikroemulgujućih nosača je značajna savremena strategija za unapređenje peroralne primene teško rastvorljivih aktivnih supstanci. Cilj rada bio je formulacija i karakterizacija samo-mikroemulgujućih nosača na bazi smeše biokompatibilnih nejonskih surfaktanata (PEG-8 kaprilno/kaprinski gliceridi (Labrasol®) i PEG-40 hidrogenizovano ricinusovo ulje (Cremophor® RH40)) za peroralnu primenu ibuprofena i in vitro karakterizacija njihove fizičke stabilnosti i veličine kapi nakon dispergovanja u vodenim medijumima različite pH vrednosti i in vitro profila oslobađanja lekovite supstance iz nosača. Rezultati karakterizacije ukazali su na značaj vrste i koncentracije ulja i masenog odnosa upotrebljenih surfaktanata za sposobnost samo-mikroemulgovanja, kapacitet za solubilizaciju ibuprofena i njegovu brzinu oslobađanja iz nosača.

The development of innovative dermatocosmetic products is based on the integration of nanoparticles. The increased usage of nanopartides in cosmetic products is indicative of their huge potential for the futher improvments in the cosmetics industry. These innovative dermatocosmetic products maintain or enhance the appearance of the skin, and can be based on various nanotechnological approaches. Nanopartides in dermatocosmetic products are mainly used as nanosystems for the delivery of active ingredients. Delivery nanosystems incorporated into fina! dermatocosmetic products - such as liposomes, microemulsion droplets, polymeric micelles - have been shown to enhance skin hydration and bioavailability of active ingredients, improve stability of the encapsulated cosmeceuticals and allow for controlled delivery of cosmeceuticals. In 2006, the European Commission estimated that 5% of cosmetic products in Europe contained nanoparticles and predicted that number will exponentially increase over time. The cosmetic industry leads in the number of patents for various nanoparticles.