| Abstract | Donepezil je reverzibilni inhibitor acetilkolinesteraze koji se koristi u liječenju Alzheimerove bolesti. Nedostatci
oralne primjene donepezila su gastrointestinalne nuspojave te mala bioraspoloživost u mozgu zbog slabog prolaska
kroz krvno-moždanu barijeru. Nazalnom primjenom zaobilazi se krvno-moždana barijera, što omogućuje izravnu
dostavu lijeka u mozak. Suvremena istraživanja usmjerena su na razvoj praškastih farmaceutskih oblika za nazalnu
primjenu temeljenih na mukoadhezivnim polimerima kao što je kitozan. Pokazano je da molekulska masa kitozana
može utjecati na svojstva farmaceutskih oblika. Cilj ovog rada bio je ispitati utjecaj molekulske mase kitozana na
svojstva kitozansko-manitolskih mikrosfera s donepezilom za nazalnu primjenu, pripravljenih sušenjem
raspršivanjem. U korištenim otopinama variran je tip kitozana (visokomolekulski, srednjemolekulski i
niskomolekulski) i koncentracija manitola (4 % i 6 %, m/V). Iskorištenje procesa sušenja raspršivanjem kretalo se
od 36,8 % do 65,2 %. Uspješnost uklapanja donepezila bila je visoka (96,1±1,7-101,2±0,7 %) te je sadržaj lijeka
u mikrosferama prikladan za nazalnu primjenu. Volumni promjeri pripravljenih mikrosfera s donepezilom, Dv10,
Dv50 i Dv90, redom su iznosili 7,00±0,07-12,0±0,92 μm, 23,2±0,16–28,8±1,02 μm i 55,5±0,28–73,9±3,02 μm.
Najveći Dv10 zabilježen je za mikrosfere pripravljene sušenjem raspršivanjem otopine koja je sadržavala
visokomolekulski kitozan i manitol u većoj koncentraciji. Uzorci s niskomolekulskim kitozanom imali su bolja
svojstva tečenja od ostalih uzoraka. Izmjereni su kutovi raspršenja 17,1±1,5-19,9±0,3° prikladni za nazalnu
primjenu. Ostatak u kapsuli nakon aktivacije raspršivača iznosio je 0,0±0,7-2,0±1,3 % od početne doze u kapsuli.
Mikrosfere su karakterizirane pozitivnim zeta potencijalom (16,1±0,9-38,8±3,9 mV) što upućuje na
mukoadhezivnost i potencijal poboljšanja permeacije uklopljenog lijeka. Primijećen je porast zeta potencijala s
porastom molekulske mase kitozana za uzorke s manjim sadržajem manitola. |
| Abstract (english) | Donepezil is a reversible inhibitor of the acetylcholinesterase enzyme, used in the treatment of Alzheimer's disease. The disadvantages
of oral administration of donepezil are adverse effects in the gastrointestinal system and low bioavailability in the brain due to the
drug’s poor ability to penetrate the blood–brain barrier. The intranasal route enables the delivery of drug directly to the brain by
bypassing the blood-brain barrier. Modern research has been focused on the development of dry powder formulations for intranasal
administration based on mucoadhesive polymers such as chitosan. It has been shown that the molecular weight of chitosan can
influence the properties of drug formulations. The aim of this study was to examine the influence of chitosan molecular weight on
the properties of chitosan/mannitol based donepezil-loaded microspheres for intranasal administration, prepared by spray drying. In
the solutions used, the type of chitosan (high molecular weight, medium molecular weight and low molecular weight) and the
concentration of mannitol (4% and 6%, w/v) were varied. The yield of the spray drying process ranged from 36.8% to 65.2%.
Entrapment efficiency was high (96.1±1.7-101.2±0.7%) and drug loading was suitable for intranasal administration. The volume
diameters of the prepared donepezil-loaded microspheres, Dv10, Dv50 and Dv90, were 7.00±0.07-12.0±0.92 μm, 23.2±0.16–
28.8±1.02 μm and 55.5±0.28–73.9±3.02 μm, respectively. The highest Dv10 was recorded for microspheres prepared by spray drying
of the solution containing high molecular weight chitosan and mannitol in a higher concentration. Samples with low molecular weight
chitosan had better flow properties than other samples. The measured spray cone angles 17.1±1.5-19.9±0.3° are suitable for nasal
administration. Powder retention within the capsule upon activation ranged from 0.0±0.7% to 2.0±1.3% of the initial dose in the
capsule. The microspheres had a positive zeta potential (16.1±0.9-38.8±3.9 mV), which indicates possible mucoadhesion and the
potential to enhance the permeation of the encapsulated drug. Zeta potential increased with an increase in chitosan molecular weight
in samples with lower mannitol content. |
