| Sažetak | Alzheimerova bolest neurodegenerativna je bolest mozga s brojem oboljelih koji ubrzano raste. Donepezil
(inhibitor acetilkolinesteraze), najčešće korišteni lijek za liječenje Alzheimerove bolesti, dostupan je u oblicima za
oralnu primjenu (samostalno i u kombinaciji s memantinom) te u obliku transdermalnog flastera. Krvno-moždana
barijera je slabo propusna pa je potrebna visoka doza lijeka kod primjene per os, što dovodi do brojnih nuspojava
uzrokovanih perifernim djelovanjem acetilkolina. Nazalna primjena donepezila osigurava dostavu lijeka izravno u
mozak, pri čemu je potrebna značajno manja doza za postizanje terapijskog učinka u usporedbi s oralno primijenjenom
dozom te se posljedično očekuje značajno smanjenje incidencije nuspojava.
Cilj ovog rada bio je pripraviti kitozanske in situ gelirajuće sustave s donepezilom te ispitati utjecaj
koncentracije kitozana na viskoznost u mirovanju (η), temperaturu (T) faznog prijelaza otopina iz sol u gel stanje te
vrijeme (t) potrebno za fazni prijelaz otopina iz sol u gel stanje pri 34 °C. In situ gelirajući sustavi donepezila (0,30 mg
mL-1 ) pripravljeni su s kitozanom (6,15-9,23 mg mL-1) i β-glicerofosfatom (β-GP; 188,46 mg mL-1
) koji osiguravaju geliranje otopine ovisno o temperaturi. Temeljem rezultata reoloških ispitivanja (η = 206,37 ± 1,46 mPa s; T = 33,7 ± 0,1 °C; t = 0,0 ± 0,0 min) i kuta raspršenja (15,5 ± 0,4°), najboljim za nazalnu primjenu pokazao se in situ gelirajući
sustav pripravljen pri koncentraciji kitozana od 9,23 mg mL-1 , stoga je taj sustav izabran za ispitivanje profila nazalne
depozicije. Profil nazalne depozicije ispitan je in vitro, pomoću višedijelnog 3D printanog modela nosne šupljine, pod
kutovima 45°, 60° i 75° u odnosu na horizontalnu ravninu te pri simuliranju zadržavanja daha. Najveći udio
formulacije dostavljen je u ciljano olfaktorno područje (58,1 ± 8,9 %) pri primjeni spreja pod kutom od 75°. Ostvareni
rezultati upućuju na potencijal kitozanskog in situ gelirajućeg sustava za nazalnu primjenu donepezila. |
| Sažetak (engleski) | Alzheimer's disease is a neurodegenerative brain disease with an increasing prevalence. Donepezil
(acetylcholinesterase inhibitor), the most commonly used drug for the treatment of Alzheimer's disease, is available in
oral dosage forms (monotherapy and in combination with memantine) and as transdermal patch formulation. The
blood-brain barrier is poorly permeable, so a high dose of the drug is required when administered per os, which leads
to numerous side effects caused by the peripheral action of acetylcholine. Nasal administration of donepezil ensures
delivery of the drug directly to the brain, where a significantly lower dose is required to achieve a therapeutic effect
when compared to an orally administered dose, and consequently a significantly reduced incidence of side effects is
expected.
The aim of this study was to prepare chitosan in situ gelling systems for donepezil nasal delivery and to
examine the influence of chitosan concentration on the zero shear viscosity (η), the temperature (T) of the phase
transition of the sample from sol to gel state and the time (t) required for the phase transition from sol to gel state at 34
°C. Donepezil loaded in situ gelling systems (0.30 mg mL-1) were prepared with chitosan (6.15-9.23 mg mL-1) and βglycerophosphate (β-GP; 188.46 mg mL-1) which ensure gelation of the solution depending on the temperature. Based on the results of the rheological tests (η = 206.37 ± 1.46 mPa s; T = 33.7 ± 0.1 °C; t = 0.0 ± 0.0 min) and spray cone
angle (15.5 ± 0.4°), in situ gelling system prepared at chitosan concentration of 9.23 mg mL-1 proved to be the best for
nasal administration, therefore it was chosen for testing the nasal deposition profile. Nasal deposition profile was
tested in vitro, using a multi-sectional 3D printed nasal cavity model, at spray administration angle of 45°, 60° and 75°
from the horizontal plane, and simulating breath holding. The largest proportion of the formulation was delivered to
the targeted olfactory area (58.1 ± 8.9 %) when the spray was applied at an angle of 75°. The obtained results indicate
the potential of the chitosan in situ gelling system for the nasal donepezil delivery. |
