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 sistemimaza ciljano otpuštanje aktivnih supstanci zato što su pH osetljivi, netoksični i biokompatibilni.Ipak zbog izrazite hidrofilnosti ovi hidrogelovi se mogu koristiti samo za kontrolisano otpuštanjehidrofilnih supstanci. U ovoj disertaciji predstavljena je modifikacija PMAA hidrogelovaamfifilnim supstancama: proteinom - kazeinom i fosfolipidnim nanočesticama - lipozomima,kako bi se dobio nosač slabo vodorastvorne aktivne supstance (SVAS). Opisana je sintezanosača, njihova karakterizacija primenom infracrvene spektroskopije sa Furijeovomtransformacijom (FTIR) i skenirajućom elektronskom mikroskopijom (SEM) i karakterizacijalipozoma primenom dinamičkog rasipanja svetlosti (DLS) i metodom elektroforetskog rasipanjasvetlosti (ELS). FTIR spektri su pokazali da su hidrofobne interakcije uspostavljene izmeđuSVAS model leka – kofeina i kazeina omogućile inkapsulaciju kofeina i njegovo kontrolisanooslobađanje, dok su prisutni lipozomi omogućili bolju kontrolu brzine oslobađanja kofeina.Ispitan je i uticaj parametara sinteze (stepen neutralizacije metakrilne kiseline, koncentracijaumreživača i kofeina, prisustvo itakonske kiseline i lipozoma, udeo i oblik lipozomneformulacije) na morfološke karakteristike nosača, njihovo bubrenje i kinetiku oslobađanjakofeina u dve sredine različitih pH vrednosti koje su simulirale uslove prisutne ugastrointestinalnom traktu čoveka. Praćenje oslobađanja kofeina iz nosača u ovim sredinamaizvršeno je primenom ultraljubičaste spektroskopije (UV). Izvedena je detaljna analiza dobijeniheksperimentalnih podataka otpuštanja kofeina u in vitro uslovima, primenom nekolikomatematičkih modela. Najbolja kinetika otpuštanja kofeina postignuta je iz nosača sa potpunoneutralizovanom metakrilnom kiselinom, 1,6mol% umreživača i inkorporiranim lipozomima ukojima je inkapsuliran kofein. Ovaj nosač je odabran za dalje analize - ispitano je njegovoponašanje u uslovima koji su simulirali put nosača kroz gastrointestinalni trakt čoveka. Rezultatisu pokazali da kofein može da se inkapsulira u izabrani nosač u koncentracijama koje su više odnjegove maksimalne rastvorljivosti i da se postigne njihovo ciljano otpuštanje. Inkapsulacijakofeina u koncentracijama ovih vrednosti, postignuta je dodatkom nikotin-amida koji sakofeinom gradi stabilni kompleks. Dobijeni rezultati pokazuju da sintetisani nosači imaju velikipotencijal za ciljanu dostavu slabo vodorastvotnih supstanci.

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