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Design of efficient drug delivery system which can protect drug, preserve its activity, improve its bioavailability, and release it in control manner still presents quite challenge. Encapsulation of drug during the synthesis of drug delivery system is especially complex part. In our previous research we have developed simple and eco-friendly synthesis of hydrogels based on poly(methacrylic acid) that employing hydrogen peroxide and vitamin C (H2O2/VC) as initiator. Present study investigates if the encapsulation of lidocaine hydrochloride during the synthesis of hydrogel and later its con-trolled release, can be achieved by using this method. Results show that mild synthesis conditions enable efficient encapsulation of lidocaine hydrochloride and synthesis of hydrogels based on poly(methacrylic acid) (PMAAL). Lidocaine hydrochloride is local anesthetic which is used in anesthesia and in antiarrhythmic therapy, and it is usually applied by injection. Its encapsulation and controlled release from the hydrogels present good solution to overcome unpleasantness during its application and to reduce required number of dosages. Obtained PMAAL hydrogels are further char-acterized by employing FTIR and SEM analysis, as well as single compression tests. PMAAL swelling and controlled release of the drug are analyzed in two environments with pH 1 and pH 6.8 simulating pH environments in human stomach and intestines. The results show that around eight times higher amount of lidocaine hydrochloride is released in environment with pH 6.8 due to the pH dependent swelling of the PMAAL hydrogels. The change in crosslinker amount on the PMAAL swelling and drug release are also investigated. The increase in the crosslinker amount lead to the decrease of amount of drug released from the PMAAL hydrogels. This study shows that the method which employing H2O2/VC as initiator can be used for efficient encapsulation of lidocaine hydrochloride. Also, this drug can be released in controlled man, Razvoj efikasnog sistema za dostavu lekova koji može da zaštiti lek, sačuva njegovu aktivnost, poboljša njegovu biodostupnost i kontrolisano ga otpušta predstavlja još uvek pravi izazov. Inkapsu-lacija leka tokom sinteze sistema za otpuštanje leka je posebno zahtevan deo. U našem prethodnom radu razvili smo jednostavnu i ekološki prihvatljivu sintezu hidrogelova na bazi poli(metakrilne kise-line) kod koje se kao inicijator koristi sistem vodonik peroksid i vitamin C (H2O2/VC). U sadašnjem istraživanju se ispituje da li se može postići inkapsulacija lidokain hidrohlorida tokom sinteze hidro-gela i kasnije njegovo kontrolisano oslobađanje. Rezultati su pokazali da su blagi uslovi sinteze o-mogućili efikasnu inkapsulaciju lidokain hidrohlorida i sintezu hidrogelova na bazi poli(metakrilne kiseline) (PMAAL). Lidokain hidrohlorid je lokalni anestetik koji se koristi kod anestezije i kod tera-pije aritmije, a najčešće se pacijentima daje injekcijom. Njegovo inkapsuliranje i kontrolisano oslo-bađanje iz hidrogelova predstavljaju dobro rešenje kako bi se sprečile neprijatnosti do kojih dolazi tokom njegove administracije i kako bi se smanjio broj doza potrebnih za terapiju. Karakterizacija dobijenih PMAAL hidrogelova je zatim izvedena primenom FTIR i SEM analize, kao i ispitivanjem otpornosti ovih materijala na kompresiju. Bubrenje PMAAL hidrogelova i kontrolisano oslobađanje leka analizirani su u dve sredine sa pH 1 i pH 6,8, koje su simulirale pH sredine u ljudskom želucu i crevima. Rezultati pokazuju da se oko osam puta veća količina lidokain hidrohlorida oslobađa u sredini sa pH 6,8 zbog pH osetljivog bubrenja PMAAL hidrogelova. Takođe je ispitan uticaj promene količine umreživača na bubrenje PMAAL hidrogelova i otpuštanje leka. Povećanje količine umreži-vača dovodi do smanjenja otpuštene količine. Ovo istraživanje pokazuje da metoda kod koje se koristi H2O2/VC kao inicijator može da se koristi za efikasnu inkapsulaciju lidokain hidrohlorida. Takođe, ovaj lek se može ko

Controlled release of drugs is a promising tool for improvement of therapy for many diseases because drug concentration for long period of time is kept constant, whereas number of drug doses and side effects are reduced. pH sensitive hydrogels, such as hydrogels based on poly(methacrylic acid) (PMAA), are extensively employed for drug delivery. The synthesis of the hydrogel is one of the most important factors which affect encapsulation of drug and its bioactivity. In present study, we investigate if the encapsulation of poorly water-soluble active substance (caffeine) during the synthesis of PMAA hydrogels, and later its controlled release from the PMAA hydrogels, can be achieved by applying novel ”green” method for the hydrogels preparation. The PMAA hydrogels with encapsulated caffeine and various amount of crosslinker are prepared by free radical polymerisation in aqueous solution and ambient conditions by using novel initiation system based on hydrogen peroxide and vitamin C. The swelling behaviour of the PMAA hydrogels and controlled release of caffeine are investigated in two media with pH 1 and pH 6.8 as simulation of human stomach and intestines, respectively. The SDeq values of the PMAA hydrogels are eight times higher in the medium with pH 6.8 and as a consequence, three times higher amount of caffeine is released in that medium. The increase in the crosslinker amount leads to the decrease of SDeq values of the PMAA hydrogels and amount of released caffeine. The results show that the PMAA hydrogels have great potential for controlled release of poorly water-soluble drugs.

Everyday struggle of humanity with novel diseases and present once, urge researchers to find novel and improve existing therapies to enhance their efficiency and safety. One of the promising approaches to overcome these challenges is controlled release of drugs. Biomaterials based on poly(methacrylic acid) (PMAA) are excellent drug delivery systems because they can control release rate and released amount of drug. Also, due to their pH sensitivity the PMAA hydrogels can release drug at the site of action. Namely, these nontoxic and biocompatible hydrogels swell in the environment with pH value higher than pKa of PMAA (4.6) and release encapsulated drug during the process. In present study, PMAA hydrogels are synthetized under ambient conditions by simple, cost effective and eco-friendly synthesis. Novel initiation system based on hydrogen peroxide, potato peel peroxidase and vitamin C (VC) is used for the first time for free radical polymerization of PMAA hydrogel. In accordance with the principles of circular economy, peroxidase was isolated from potato peel waste by water extraction for 12 h at 4 ℃. Four PMAA hydrogels were prepared by using potato peel peroxidase with various enzyme activity (0.4; 0.8; 1.2 and 1.8 IU), whereas the amounts of H2O2 (30 mL) and VC (10 mg) have been kept constant. The composition of the PMAA hydrogels was confirmed by FTIR analysis, whereas their porous structure was revealed by SEM. The swelling of the PMAA hydrogels was monitored in two media: 0.1M HCl (as simulation of human stomach) and phosphate buffer with pH 7.4 (as simulation of human intestines). In order to encapsulate anti-inflammatory drug – dexamethasone into the PMAA hydrogels, the hydrogels were immersed into the dexamethasone aqueous solution (5 mg/ml) and left to swell to the equilibrium, after which they were dried at room temperature. Dexamethasone release from the PMAA hydrogels was monitored in the same environments as was the PMAA swelling. The results showed th

Liposome-encapsulated folic acid is incorporated into the films made from sodium carboxymethyl cellulose (CMC) (2 mas%) and a mixture of CMC and solagum (9:1 w/w) using the film-forming cast solution method. Histidine is used to increase solubility for folic acid in liposomes (1–5 mg mL−1), and propylene glycol is used as a film plasticizer (2.6 mas%). The obtained films (50–60 µm tick) containing 3.12–20.19 mg of folic acid per gram of film are envisaged to be used as patches for transdermal delivery of folic acid. Therefore, some physical, mechanical, release and structural attributes of the films are scrutinized. Folic acid gives yellow color to the films and contributes to stronger chemical bonds which result in improved strength of the film. Liposomes prolong the release of folic acid from films to 24 h without adverse effects on mechanical properties of the films, but degrade homogeneity of the films, which can be ascribed to its agglomeration within the film matrix as revealed by atomic force microscopy. According to the release at pH 5.5, the film formulation based on a blend of CMC and solagum containing 3 mg mL−1 liposome-encapsulated folic acid is recommended. Practical Application: Folic acid is effective in reducing oxidative stress levels in the skin and neutralizing the harmful free radicals and is also essential for various metabolic reactions in the body. However, the limited solubility of folic acid linked with its poor absorption in an organism, low storage stability, short half-life upon oral consumption, specific food preferences of some people, extensive liver metabolism, and pregnancy-induced vomiting point to a large potential in transdermal usage of folic acid. This has motivated us to design new multicomponent polymer-lipid systems as an alternative solution to overcome some of these drawbacks. The results obtained for these multicomponent films pointed to their potential for prolonged release of folic acid to 24 h, which can also be useful

Summary Sjögren's syndrome (SS) is a rheumatic autoimmune disease of salivary and lacrimal gland. The disease has a heterogenous character, therefore multiple organ manifestations can occur next to dryness, fatigue and pain. The most common manifestations of the disease are dryness of the mouth and eyes, the sicca symptoms. In our study, we investigated the occurrence of sicca symptoms and secondary SS in patients with rheumatoid arthritis (RA). Patients with higher disease activity of RA had more often sicca complaints and secondary SS. We showed that the presence of and changes in organ involvement of SS can be studied with ESSDAI, a systemic disease activity score. Furthermore, joint involvement can be assessed in more detail by DAS-28 score. In this thesis, the diagnosis and treatment of SS in elderly patients was discussed. It is known that 5-10% of SS patients develop lymphomas. We found that serum levels of free light chains can be suitable as biomarker for systemic disease activity and MALT lymphoma in SS patients. Finally, an overview was given of different treatments of sicca complaints and extraglandular disease manifestations. Most patients experience fatigue as most important symptom. Treatment with rituximab resulted in significant improvement of physical fatigue, but the majority of patients still experienced a substantial level of fatigue. The findings from this thesis give an overview of clinical manifestations, biomarkers and effect of the treatment and can tribute to monitoring and treatment of SS patients in daily clinical practice.

Materials sensitive to external stimuli are recognized as safe and effective tool able to respond to specific demands in the therapy of various diseases. Thermo sensitive hydrogels based on poly(N-isopropylacrylamide) (P(NIPAAM)) are widely investigated for targeted drug delivery. Still, the abundance of the stimuli in the human body often requires more than one responsive group able to act simultaneously to achieve optimal therapeutic effects. Due to its pH sensitivity and bio-based production, crotonic acid (CA) was a monomer of choice for preparation of eco-friendly copolymer hydrogels based on NIPAAM and CA (P(NIPAAMcoCA)), which turned to be thermo and pH sensitive at the same time. The potential of the P(NIPAAMcoCA) system for encapsulation and controlled release of drugs with different solubility was investigated engaging water-soluble lidocaine hydrochloride and poorly water-soluble ibuprofen as model drugs. The hydrogels were characterized by various technics: FTIR, DSC, SEM and single compressive tests, while swelling behavior and controlled release of the drugs were analyzed with respect to the CA amount in two environments with different pH values at 25 °C and 37 °C. It was demonstrated that due to their dual responsiveness the P(NIPAAMcoCA) hydrogels have potential for controlled release of drugs with different solubility.

Everyday demands for safer and more efficient therapy for many diseases, especially serious ones such as various types of cancer, put various challenges in front of modern science. One of them lies in the fact that numerous anticancer drugs are poorly-water soluble and therefore their encap-sulation and controlled release are quite demanding processes. In the present study, we deepened our research of carrier based on hydrophilic poly(methacrylic acid) modified with amphiphilic ca-sein, in which poorly water-soluble model drug caffeine was encapsulated (PMAC-Caf hydrogels). It was investigated how neutralization degree of methacrylic acid (MAA) and amount of encapsulated caffeine affected swelling behavior of the PMAC-Caf hydrogels and caffeine release. Easy, one pot, simultaneous synthesis of the carrier and the encapsulation of caffeine is presented, obtaining thereby as prepared PMAC-Caf drug delivery system that could respond to the specific demands of the tar-geted delivery of the poorly water-soluble drug - protecting it in the environment which simulated human stomach and releasing it in the environment which simulated human intestines. Changing the synthesis parameters (neutralization degree of MAA and/or amount of encapsulated caffeine) we achieved controlled release of caffeine, indicating that the number of the required doses of the drug in the treatment and its side effects could be reduced. Results showed that the PMAC-Caf drug deliv-ery systems have huge potential for controlled release of poorly water-soluble drugs.

Researchers are making everyday efforts to develop new drugs or improve present ones in order to enhance therapies of various diseases, especially serious ones like cancer. Drug delivery systems (DDS) are one of the solutions for safer and more efficient therapy. Hydrogels based on poly(methacrylic acid) (PMAA) are extensively investigated as DDS due to their nontoxicity, biocompatibility and pH sensitivity. Many chemotherapeutics are poorly watersoluble, so it is quite challenging to encapsulate them into highly hydrophilic PMAA. In our previous study we overcome this limitation by modifying PMAA with amphiphilic casein and demonstrated that poorly water-soluble model drug – caffeine can be successfully encapsulated and released in control manner from these samples (H hydrogels). In present study we go step forward and investigated how the change in the amount of encapsulated caffeine affect the mechanism of caffeine release from the H hydrogels in medium with pH of 6.8 (which simulates the environment in human intestines). Commonly used models for the analysis of kinetics of drug release from hydrogels: Ritger-Peppas, Higuchi and Kopcha model are employed for the analysis of the mechanism of caffeine release. Presented results indicate that it is possible to adjust the manner and mechanism of drug release by changing the amount of encapsulated drug, due to which the H hydrogels can adapt to the unique requirements of the therapy.

Drug delivery system is an amazing tool which is widely used for drug protection and its controlled release in order to enhance drug bioavailability, reduce side effects and therefore to improve overall therapy. Hydrogels have been attracted great attention as drug carriers due to their great physicochemical properties, similarity to the living tissues and biocompatibility. One group of pH sensitive hydrogels are based on poly(methacrylic acid) (PMAA). These non-toxic hydrogels are used as drug delivery system because they swell as a response to the change in pH of external environment and drug is being released during the process. In present study, in order to improve the control of drug release rate, caffeine was encapsulated in liposomes which were further embedded into PMC hydrogel (PMCL). It was investigated how the change in neutralization degree of methacrylic acid affect the swelling degree of PMCL hydrogels and caffeine release in two environments at 37 °C for 24 h: 0.1 M hydrochloride acid (pH 1) and phosphate buffer with pH value of 6.8 (pH 6.8), as a simulation of pH environment in human stomach and intestines, respectively. Obtained results show that PMCL hydrogels have great potential for controlled release of poorly water-soluble drugs in human intestines.

Targeted drug delivery is powerful tool which researchers use to achieve safer and more efficient therapy of many diseases, including various types of cancer. Many chemotherapeutics are poorly watersoluble, so their encapsulation and targeted delivery remain quite challenge. Hydrogels based on poly(methacrylic acid) (PMAA) are widely investigated for targeted drug delivery due to their pH sensitivity, non-toxicity and biocompatibility. Still, due to the PMAA highly hydrophilic nature, PMAA can only be used for encapsulation and targeted delivery of water-soluble drugs. Our previous research was directed towards overcoming this limitation: PMAA was modified with amphiphilic protein – casein and poorly-water soluble model drug – caffeine – was encapsulated (PMAC). Present study is focused on investigation how variation of amount of one of the most important hydrogels network parameter such as crosslinker affect PMAC swelling properties and caffeine release. The group of hybrid hydrogels – PMAC – was synthesized with various amount of crosslinker: 0.4mol%, 0.8mol%, 1.6mol% and 3.2mol% with respect to methacrylic acid. Swelling behavior of hybrid hydrogels and caffeine release was investigated in two environments which simulated human stomach and intestines. Obtained results showed that targeted delivery of poorly water-soluble model drug was achieved and that its release can be prolonged up to 24h. Also, kinetic of poorly water-soluble drug release can be easily modified only by changing crosslinker amount. PMAC hybrid hydrogels have huge potential for targeted delivery of poorly water-soluble active substances.

Polymeric carriers for targeted delivery of poorly water-soluble active substances (PWSAS) are facing two challenges. First, encapsulation of PWSAS depends on structure of the carrier. Second limitation is caused by the phenomenon of burst drug release. Despite the fact that the fast release of drug in a burst stage is utilized in certain drug administration strategies, the negative effects brought about by burst can be pharmacologically dangerous and economically inefficient. This study presents a novel strategy for encapsulation and targeted delivery of PWSAS - caffeine without the possibility of burst effect. Hydrophilic carrier based on poly(methacylic acid) was modified by amphiphilic substances - casein and centrifuged liposomes to ensure caffeine encapsulation. The caffeine was encapsulated in liposomes which further were incorporated into the carrier networks during the synthesis of the carriers. The release kinetic of caffeine was analyzed with respect to morphology of the carriers and interactions that could be established between the components of the carrier. The swelling of carriers and release of caffeine were further investigated depending on the neutralization degree of methacrylic acid in two media with different pH simulating the path of the carrier through the upper and lower human gastrointestinal tract. Synthesized carriers showed significant potential for encapsulation and targeted delivery of PWSAS., Kod razvoja polimernih nosača za ciljano otpuštanje slabo vodorastvornih aktivnih supstanci (SVAS) postoje dva ograničenja. Prvo, inkapsulacija SVAS zavisi od strukture nosača. Drugo ograničenje je vezano za naglo oslobađanje leka. Uprkos činjenici da je naglo oslobađanje leka, tzv. burst efekat poželjno kod nekih sistema, negativni efekti naglog oslobađanja leka u većini slučajeva mogu biti farmakološki opasni i ekonomski neefikasni. U ovom radu je prikazana nova strategija za inkapsulaciju i ciljano otpuštanje SVAS – kofeina bez burst efekta. Hidrofilni nosač na bazi poli(metakrilne kiseline) je modifikovan amfifilnim supstancama – kazeinom i centrifugiranim lipozomima kako bi se postigla inkapsulacija kofeina. Kofein je inkapsuliran u lipozome koji su zatim inkorporirani u mrežu nosača tokom sinteze nosača. Analiziran je uticaj morfologije nosača i interakcija koje su se uspostavile između njegovih komponenti na kinetiku otpuštanja kofeina. Zatim je analiziran uticaj stepen neutralizacije metakrilne kiseline na bubrenje nosača i otpuštanje kofeina u dve sredine različitih pH vrednosti koje su simulirale pH sredinu u gastrointestinalnom traktu čoveka. Pokazano je da sintetisani nosači imaju veliki potencijal za inkapsulaciju i ciljano otpuštanje SVAS