Title Razvoj novih dozirnih oblika dronedaron-hidroklorida za oralnu primjenu Title (english) Development of new oral dosage forms of dronedarone hydrochloride Author Matija Gretić Mentor Gordana Matijašić (mentor)Committee member Krunoslav Žižek (predsjednik povjerenstva)Committee member Vesna Tomašić (član povjerenstva)Committee member Ivo Crnolatac (član povjerenstva)Granter University of Zagreb Defense date and country 2021-04-23, Croatia Scientific / art field, TECHNICAL SCIENCES Universal decimal classificationUDC ) 66 - Chemical technology. Chemical and related industries 615 - Pharmacology. Therapeutics. Toxicology Abstract Metode priprave dozirnih oblika, uvjeti provedbe procesa te dodatak različitih pomoćnih tvari u velikoj mjeri utječu na fizikalno-kemijska svojstva i oslobađanje djelatne tvari iz dozirnog oblika. Ugradnja djelatne tvari u novi dozirni oblik može znatno doprinijeti njegovoj sigurnosti, prikladnom doziranju i smanjenu nuspojava. Istraživanje uključuje pripravu četiri dozirna oblika djelatne tvari dronedaronhidroklorid (DNR) koji se koristi u liječenju srčane aritmije. Dozirni oblici pripravljeni su peletiranjem, mikrokapsuliranjem i 3D-tiskanjem. Pelete su pripravljene postupkom ekstrudiranja i sferoniziranja. DNR je ugrađen u porozne pelete u obliku suspenzije vakuum impregnacijom i direktnom ugradnjom u procesu ekstrudiranja. Pripravljene pelete oblagane su hidroksipropil-metil-celulozom u fluidiziranom sloju. Pripravljenim peletama je određena specifična površina, raspodjela veličina čestica i morfologija te je određen sadržaj DNR-a. Mikrokapsule su pripravljene u laboratorijskom sušioniku s raspršivanjem pri četiri različita protoka zraka za raspršivanje. Otopine DNR-a i poli(vinil-alkohola) te DNR-a i metakrilatnog kopolimera pripremljene su u različitim masenim omjerima 1:1, 1:2 i 1:3. Pripravljenim mikrokapsulama ispitana je morfologija. Filamenti poli(vinil-alkohola) korišteni su za 3D-tiskanje kapsula različitih debljina stjenke (0,25 mm, 0,50 mm, 0,75 mm i 1 mm), postupkom taložnog srašćivanja. Kapsula se sastoji od dva poklopca i unutarnjeg dijela. Kvaliteta 3D-tiskanih kapsula ispitana je pomoću pretražnog elektronskog mikroskopa i steromikroskopa. Kako bi se uspješno 3D-tiskala tableta u PVA filament je ugrađena djelatna tvari DNR. Filamenti su pripravljeni ekstrudiranjem taljenjem pri 170 ℃. Istražen je optimalan maseni udio i postupak ugradnje DNR-a te utjecaj dva različita plastifikatora na kvalitetu filamenta. Dobiveni filamenti korišteni su za 3D-tiskanje tableta različitih gustoća ispune. Provedena je toplinska karakterizacija materijala i filamenata, određen je sadržaj DNR-a u filamentima i provjerena je morfologija filamenata i tableta. Na svim dozirnim oblicima ispitano je in vitro oslobađanje DNR-a i stabilnost. Opisana je kinetika oslobađanja, a korelacije in vitro – in vivo primijenjene su za predviđanje ponašanja pripravljenih dozirnih oblika in vivo. Rezultati su pokazali da načini ugradnje DNR-a u pelete i filamente, protoka zraka za raspršivanje i omjer DNR-a i polimera kod mikrokapsula, debljina stijenke 3D-tiskanih kapsula i gustoća ispune 3Dtiskanih tableta imaju značajan utjecaj na oslobađanje djelatne tvari DNR iz dozirnih oblika. Opis kinetike oslobađanja ukazuje na brzinu i mehanizam oslobađanja. Korelacije in vitro – in vivo pokazale su dobro slaganje farmakokinetičkih parametara dobivenih simulacijom i konvolucijom podataka za uzorke peleta, 3D-tiskanih kapsula debljine stijenke 0,50 mm te mikrokapsula metakrilatnog kopolimera.
Abstract (english) Physicochemical properties and release of the active ingredient from the dosage form are influenced by the methods of preparation of the dosage forms, the process conditions, and the addition of the various excipients. Embedding of the active pharmaceutical ingredient into a new dosage form can significantly contribute to its efficiency, safety, dosage suitability, and reduction of the side effects. Research involves the preparation of four dosage forms of the active pharmaceutical ingredient, dronedarone hydrochloride, used as a drug for cardiac arrhythmias. Dosage forms are prepared by pelletization, microencapsulation and 3D printing. The pellets were prepared by extrusion/spheronization process. DNR is loaded into the porous pellets in the form of the drug suspension by vacuum impregnation and direct loading in the extrusion process. The prepared pellets were coated with hydroxypropyl methylcellulose in a fluidized bed. The microcapsules were prepared in a laboratory spray dryer at four different atomization air flowrates. Solutions of DNR and poly (vinyl alcohol) and DNR and methacrylate copolymers were prepared in different weight ratios of 1:1, 1:2 and 1:3. The morphology of the prepared microcapsules was examined by scanning electron microscope. Poly (vinyl alcohol) filaments were used for 3D printing of the capsules with different wall thicknesses (0.25 mm, 0.50 mm, 0.75 mm and 1 mm), by the fused deposition modeling. The capsule comprises two caps and an inner part. The quality of 3D-printed capsules was examined using a scanning electron microscope and stereomicroscope. In order to successfully 3D print the tablet, the active ingredient DNR is loaded into the PVA filament. Hot melt extrusion at 170 °C was used to prepare the filaments. The optimal mass fraction process of the DNR loading and the influence of two different plasticizers on filament quality were investigated. The obtained filaments were used for 3D printing of tablets with different infill densities. Thermal characterization of the materials and filaments was performed, DNR content in filaments was determined and morphology of filaments and tablets was checked. All dosage forms were tested for in vitro DNR release and stability. Release kinetics was described, while in vitro – in vivo correlations were used to predict the in vivo behavior of prepared dosage forms. The results showed that loading technique of the DNR into the pellets and filaments, atomization air flowrates and the ratio of the DNR to polymer in the microcapsules, the various wall thickness of the 3D printed capsules and infill density of the 3D printed tablets have a significant influence on the release of DNR from dosage forms. The description of the released kinetics indicates the rate and mechanism of drug release. In vitro – in vivo correlations showed good agreement of the pharmacokinetic parameters obtained by simulation and convolution for samples of pellet, 3D-printed capsules with a wall thickness of 0.50 mm and microcapsules of methacrylate copolymer.
Keywords
dozirni oblik
dronedaron-hidroklorid
peleta
mikrokapsula
3D-tiskanje
filament
oslobađanje in vitro
kinetički modeli
korelacije in vitro – in vivo
Keywords (english)
dosage form
dronedarone hydrochloride
pellet
microcapsule
3D printing
filament
in vitro release
kinetic models
in vitro – in vivo correlations
Language croatian URN:NBN urn:nbn:hr:149:153609 Promotion 2021 Study programme Title: Chemical Engineering and Applied Chemistry - Doctoral course Type of resource Text Extent 212, [43] str. ; 30 cm File origin Born digital Access conditions Access restricted to students and staff of home institution Terms of use Created on 2023-06-02 11:14:05
