Kinetika oslobađanja slabo vodorastvornih aktivnih supstanci iz nosača na bazi poli(metakrilne kiseline), kazeina i lipozoma

Abstract

Hidrogelovi na bazi poli(metakrilne kiseline) - PMAA imaju veliku primenu u sistemima za ciljano otpuštanje aktivnih supstanci zato što su pH osetljivi, netoksični i biokompatibilni. Ipak zbog izrazite hidrofilnosti ovi hidrogelovi se mogu koristiti samo za kontrolisano otpuštanje hidrofilnih supstanci. U ovoj disertaciji predstavljena je modifikacija PMAA hidrogelova amfifilnim supstancama: proteinom - kazeinom i fosfolipidnim nanočesticama - lipozomima, kako bi se dobio nosač slabo vodorastvorne aktivne supstance (SVAS). Opisana je sinteza nosača, njihova karakterizacija primenom infracrvene spektroskopije sa Furijeovom transformacijom (FTIR) i skenirajućom elektronskom mikroskopijom (SEM) i karakterizacija lipozoma primenom dinamičkog rasipanja svetlosti (DLS) i metodom elektroforetskog rasipanja svetlosti (ELS). FTIR spektri su pokazali da su hidrofobne interakcije uspostavljene između SVAS model leka – kofeina i kazeina omogućile inkapsulaciju kofeina i njegovo kontrolisano oslobađanje, dok su prisutni lipozomi omogućili bolju kontrolu brzine oslobađanja kofeina. Ispitan je i uticaj parametara sinteze (stepen neutralizacije metakrilne kiseline, koncentracija umreživača i kofeina, prisustvo itakonske kiseline i lipozoma, udeo i oblik lipozomne formulacije) na morfološke karakteristike nosača, njihovo bubrenje i kinetiku oslobađanja kofeina u dve sredine različitih pH vrednosti koje su simulirale uslove prisutne u gastrointestinalnom traktu čoveka. Praćenje oslobađanja kofeina iz nosača u ovim sredinama izvršeno je primenom ultraljubičaste spektroskopije (UV). Izvedena je detaljna analiza dobijenih eksperimentalnih podataka otpuštanja kofeina u in vitro uslovima, primenom nekoliko matematičkih modela. Najbolja kinetika otpuštanja kofeina postignuta je iz nosača sa potpuno neutralizovanom metakrilnom kiselinom, 1,6mol% umreživača i inkorporiranim lipozomima u kojima je inkapsuliran kofein. Ovaj nosač je odabran za dalje analize - ispitano je njegovo ponašanje u uslovima koji su simulirali put nosača kroz gastrointestinalni trakt čoveka. Rezultati su pokazali da kofein može da se inkapsulira u izabrani nosač u koncentracijama koje su više od njegove maksimalne rastvorljivosti i da se postigne njihovo ciljano otpuštanje. Inkapsulacija kofeina u koncentracijama ovih vrednosti, postignuta je dodatkom nikotin-amida koji sa kofeinom gradi stabilni kompleks. Dobijeni rezultati pokazuju da sintetisani nosači imaju veliki potencijal za ciljanu dostavu slabo vodorastvotnih supstanci.

Hydrogels based on poly(methacrylic acid) (PMAA) have been extensively used in systems for targeted delivery of active substances because they are pH-sensitive, non-toxic and biocompatible. However, being highly hydrophilic, these hydrogels are able to deliver only hydrophilic active substances. In this dissertation, modification of PMAA hydrogels with amphiphilic substances: protein - casein and phospholipidic nanoparticles - liposomes in order to design a hydrophilic carrier for a poorly water-soluble substance (PWSS) are presented. The synthesis of the carriers and their characterization using the Fourier Transform Infrared Spectroscopy (FTIR) and the Scanning Electron Microscopy (SEM) and the characterization of the liposomes using the Dynamic Light Scattering (DLS) and the method of the Electrophoretic Light Scattering (ELS) are described. The FTIR spectra showed that hydrophobic interactions were established between PWSS model drug - caffeine and casein and enabled caffeine encapsulation in the carrier and its controlled release, while the presence of the liposomes enabled better control of caffeine release rate. The morphological characteristics of the carriers, their swelling behavior and the caffeine release kinetics were investigated depending on the changes in the synthesis parameters (neutralization degree of methacrylic acid, crosslinker and caffeine concentrations, introduction of itaconic acid and liposomes, volume ratio and form of liposomal formulation) in two media with different pH values that simulated the environment in human gastrointestinal tract. Ultraviolet (UV) Spectroscopy was used to monitor caffeine release from these carriers. Data from caffeine in vitro release experiments were analyzed in detail using several mathematical models. The best kinetic of caffeine release was achieved form the carrier in which methacrylic acid was complitely neutralized and which had 1,6mol% of crosslinker and incorporated liposomes with encapsulated caffeine. The behavior of this carrier was further investigated in the environment which simulated the conditions in the human gastrointestinal tract. Results showed that this carrier could be used for the encapsulation of caffeine in concentrations which were higher than its solubility and for targeted delivery of these concentrations. Encapsulation of caffeine in these values of concentration was achieved by adding nicotinamide, which forms stable complex with caffeine. Presented results showed that synthesized carriers have great potential for targeted delivery of poorly water-soluble substances.