@phdthesis{
author = "Lavrič, Olivera Lj.",
year = "2019",
abstract = "Cilj ovog istraživanja bio je razvoj tableta sa pulsnim oslobađanjem karvedilola,pogodnih za korišćenje u hronoterapiji, korišćenjem tehnika elektropredenja i oblaganjakompresijom. Istraživanje se sastojalo iz četiri dela.U prvom delu istraživanja vršeno je ispitivanje stepena mešanja karvedilola i Soluplus®polimera korišćenjem dve metode. Najpre, određivanjem razlike ukupnih parametararastvorljivosti ove dve komponente, a potom i određivanjem Flory-Hugginsinterakcionog parametra. Parcijalni i ukupni parametar rastvorljivosti karvediloladobijeni su Stefanis-Panayiotou metodom, a potom je određena razlika ukupnogparametra rastvorljivosti karvedilola i polimera. Izračunata vrednost iznosila je 5,1MPa1/2, i ukazala je da u sistemu ove dve komponente najverovatnije dolazi do mešanja.Rezultati druge metode, tj. određena vrednost interakcionog parametra, koja je iznosila -2,3054; ukazala je na veliku verovatnoću da se karvedilol i Soluplus® mešaju.U drugoj fazi eksperimentalnog istraživanja vršen je razvoj formulacije nanovlakanaSoluplus®-a tehnikom elektropredenja. Određen je region rastvorljivosti za polimerSoluplus® na ternernom grafiku, koristeći frakcione parametre rastvorljivosti odabranihrastvarača. Potom su rastvarači iz definisanog regiona rastvorljivosti kategorisani naosnovu njihove dielektrične konstante, kao i sa aspekta mogućnosti rastvaranjakarvedilola, u cilju procene njihove pogodnosti za proces elektropredenja. Upreliminarnoj fazi, izvršeno je elektropredenje Soluplus®-a u različitim rastvaračima, gdeje na osnovu posmatranja morfologije dobijenih vlakana pod optičkim mikroskopom, kaoi na osnovu stabilnosti procesa (pojavom Taylor-ove kupe), definisan optimalan rastvaračza dobijanje nanovlakana Soluplus®-a impregniranih karvedilolom. Definisane suformulacije sa različitim udelom karvedilola (5-50% m/m u odnosu na suvu masuvlakana) u 20% rastvoru Soluplus®-a, u smeši rastvarača aceton-hloroform (90:10(m/m)), i izvršena je karakterizacija dobijenih nanovlakana. Rezultati su pokazali da jeprocenat inkorporiranog karvedilola u vlaknima bio od 84 do 93%. Skenirajućaelektronska mikroskopija je pokazala da su dobijena vlakna uniformne, glatke strukture,pri čemu se sa povećanjem udela karvedilola smanjuje broj proširenja na vlaknima.Pokazano je da nema kristala karvedilola na površini vlakana, čime je pretpostavljeno daje inkorporiran u vlakna, a diferencijalna skenirajuća kalorimetrija je ukazala na odsustvokristalnog oblika karvedilola u svim formulacijama. Infracrvena spektroskopija saFurijeovom transformacijom je pokazala odsustvo karakterističnih pikova karvedilola unanovaknima. Brzina rastvaranja karvedilola iz nanovlakana bila je veća u odnosu nakristalni oblik čiste supstance (karvedilola).U trećoj fazi eksperimentalnog istraživanja cilj je bio razvoj formulacija tableta satrenutnim oslobađanjem karvedilola koršćenjem direktne kompresije. Ispitivano jepostojanje razlike u brzini rastvaranja karvedilola između tableta koje su sadržalekonvencionalne ekscipijense i tableta dobijenih kompresijom nanovlakana Soluplus®-aimpregniranih karvedilolom. Brzina rastvaranja karvedilola se značajno razlikovala samou prvih 15 minuta..., The aim of this work was the development of tablets with pulse release profile ofcarvedilol, suitable for chronotherapy. Electrospinning and compression coating wereused in the preparation of tablets. The research activities were divided in four parts.In the first part, the degree of miscibility of carvedilol with polymers was studied usingtwo methods. Using the first method, the difference of total solubility parameters of thetwo components of mixture was determined, while for the second method, the calculationof Flory-Huggins interaction parameter was made. Partial and total solubility parametersof carvedilol were calculated according to the method developed by Stefanis-Panayiotouwhich was followed by calculating the difference of total solubility parameters ofcarvedilol and polymer. The calculated value was 5.1MPa1/2 suggesting that mixing ofthe two components would most likely occur. The determination of Flory-Hugginsinteraction parameter resulted in the value of interaction parameter of -2.3054, implying,with high likelihood, that carvedilol and Soluplus® would form a mixture.In the second part of research activities Soluplus® nanofibers were developed usingelectrospinning technique. The solubility region of Soluplus® polymer in selectedsolvents was determined by using ternary diagram constructed by employing fractionalsolubility parameters. Solvents from the defined solubility region were then categorizedaccording to their dielectric constants as well as their ability to dissolve carvedilol in orderto evaluate their suitability for the electrospinning process. In the preliminary steps,Soluplus® was dissolved in different selected solvents and then electrospinned. Processstability, assessed by observing the occurrence (or absence) of Taylor cone, and theresulting fiber morphology, assessed by optical microscopy, were used to define theoptimal solvent for Soluplus® nanofibers with impregnated carvedilol. 20% solutions ofSoluplus® in a mixture of acetone-chlorophorm (90:10 (m/m)) with added carvedilol (5-50% of total dry mass) were electrosprayed and the resulting nanofibers subsequentlycharacterized. Encapsulation efficiency of carvedilol in Soluplus® nanofibers was foundto be 84% to 93%. Scanning electron microscopy of electrospun samples revealeduniform nanofibers with smooth surfaces, where increasing mass percentage of carvediloldecreased the number and occurrence of beads. Absence of crystalline particles ofcarvedilol on the surface of nanofibers implied full incorporation into nanofibers whilethe results of differential scanning calorimetry revealed the absence of crystallinecarvedilol for all formulation. Spectra of nanofibers measured by infrared spectroscopy(with fast Fourirer transform) revealed absence of characteristic peaks of carvedilol.Dissolution rate Soluplus® nanofibers with carvedilol was higher relative to thecrystalline form of pure carvedilol.In the third part, the goal was the development of tablet formulation with instant releaseof carvedilol prepared by direct compression. Dissolution rates of carvedilol from tabletsprepared from conventional excipients were compared to those determined for tabletsprepared by compressing Soluplus® nanofibers with carvedilol.",
publisher = "Универзитет у Београду, Фармацеутски факултет",
journal = "Универзитет у Београду",
title = "Farmaceutski razvoj tableta sa pulsnim oslobađanjem karvedilola tehnikama elektropredenja i oblaganja kompresijom",
url = "https://hdl.handle.net/21.15107/rcub_nardus_12128"
}
