Preparation and evaluation of ibuprofen-loaded nanocellulose-based orodispersible films

Orodisperzibilni filmi (ODF) predstavljajo inovativen dostavni sistem, v katerega lahko vgrajujemo zdravilne učinkovine za lokalno in sistemsko dostavo. Zdravilna učinkovina se v nekaj sekundah po aplikaciji ODF sprosti v ustno votlino, s čimer dosežemo hiter začetek delovanja. V ODF lahko vgrajujemo različno velike odmerke, ki jih tako prilagodimo pediatrični populaciji ali pa predstavljajo alternativo tabletam zlasti za geriatrično populacijo, ki se sooča z oteženim požiranjem. V okviru magistrske naloge smo razvijali in vrednotili ODF z vgrajenim ibuprofenom (IBU) kot modelno učinkovino. ODF so izdelani na osnovi nanokristalne celuloze (NCC) dveh različnih proizvajalcev (NCC v prahu in gelu) v kombinaciji s tremi različnimi naravnimi polimeri (nizko viskozen hitosan, pektin in alginat) in glicerolom. NCC je naraven polimer, ki v vsaj eni dimenziji ne presega 100 nm, naravni polimeri pa povečajo premreženost polimernih verig in izboljšajo mehanske lastnosti hidrogelske rešetke. V prvem delu smo se osredotočili na vgradnjo IBU kot modelne slabo vodotopne zdravilne učinkovine (ZU) v hidrogele. Slabo topnost smo rešili s predhodno vgradnjo IBU v samo(mikro)emulgirajoči sistem, tj. zmes površinsko aktivne snovi in olja. Izdelane hidrogele smo nato reološko ovrednotili z vidika vpliva naravnega polimera ter vgrajene ZU na viskoznost in vrednosti elastičnega/plastičnega modula. Iz hidrogelov smo nadalje izdelali ODF z metodo izhlapevanja topila, kot najprimernejši za izdelavo so se izkazali filmi narejeni s pomočjo naravnega polimera alginata. Izdelanim filmom smo določili totalno vsebnost in ugotovili, da je v filmih, izdelanih na osnovi NCC v gelu, vsebnost IBU višja, kar nakazuje na večjo sposobnost vezave IBU z NCC v gelu. Z DSC smo potrdili, da je IBU v ODF prisoten v raztopljeni obliki. Čas razpadnosti filmov smo določali s pomočjo dveh različnih metod, klasično farmakopejsko metodo in kapljično metodo, novejšim pristopom za določanje časa razpadnosti. Daljše čase pri kapljični metodi pripisujemo temu, da ODF najprej počasi nabreka in šele nato razpade. V obeh primerih se je nakazal enak trend, in sicer da ODF na osnovi NCC v gelu razpadajo hitreje od paralel na osnovi NCC v prahu, ter da so časi razpadnosti najkrajši pri pektinu, sledi alginat, medtem ko ODF, narejeni s pomočjo hitosana, zaradi njegove netopnosti pri nevtralnem pH v vodi ne razpadajo. Na podlagi vseh zbranih rezultatov, lahko zaključimo, da so ODF s pektinom in alginatom primerni za vgradnjo IBU, smiselno pa bi bilo raziskati še sproščanje iz teh filmov.Orodispersible films (ODF) represent an innovative drug delivery system in which active pharmaceutical ingredients for local or system delivery can be incorporated. The active pharmaceutical substance is released into the oral cavity within a few seconds after the application of ODFs, thus achieving a rapid onset of action. A range of doses can be incorporated into ODFs, i.e. adapted for the pediatric population. At the same time, the ODFs represent an alternative to tablets within the geriatric population who have difficulties with swallowing. Within the master\u27s thesis, ibuprofen-loaded nanocellulose-based ODFs were developed and evaluated. ODFs are based on nanocrystalline cellulose (NCC) from two different manufactures (i.e. powder or gel NCC) in combination with three various natural polymers (low viscosity chitosan, alginate, and pectin) and glycerol. NCC is a natural polymer that does not exceed 100 nm in at least one dimension, while natural polymers do increase crosslinking of the polymer chains and improve the mechanical properties of the hydrogel network. In the first part of the thesis, we focused on the incorporation of ibuprofen as a model for poorly water-soluble active pharmaceutical ingredient into hydrogels. Poor solubility was resolved with pre-incorporation of ibuprofen into the self-microemulsifying system, consisting of surfactant and oil. Hydrogels were rheologically evaluated in terms of natural polymer and integrated active pharmaceutical ingredients influence on the viscosity and values of the elastic/plastic module. ODFs were then produced from hydrogels by the solvent casting method. Films made with natural polymer alginate proved to be the most suitable for production. Total content of the the produced ODFs was determined with the higher ibuprofen content in ODFs based on gel NCC, which indicated a higher ability to bind ibuprofen with gel NCC. As confirmed by DSC method the ibuprofen is present in dissolved form in the ODFs. The disintegration time of the films was determined using two methods: the classical pharmacopeia method and the drop method, a newer approach for determining disintegration time. The longer times in the droplet method are attributed to the fact that ODFs at first slowly swell and then disintegrate. With both methods, the same trend was observed, namely thet gel NCC based ODFs disintegrate faster than their powder NCC based ODFs parallels. The disintegration times are the shortest for pectin, followed by alginate, while ODFs made with chitosan, which is insoluble at neutral pH, do not disintegrate in water. Based on all the obtained results, we can conclude that ODFs with pectin and alginate are suitable for ibuprofen incorporation, and it would be reasonable to explore the release from these ODFs as well