| Abstract | Melatonin je neurohormon koji se istražuje u liječenju brojnih bolesti i stanja zbog svojih hipnotičkih, antioksidativnih, protuupalnih
i imunomodulatornih svojstava. Slaba topljivost u vodi, kratko vrijeme polueliminacije, intenzivni metabolizam i otežani prolazak
krvno-moždane barijere nepovoljna su svojstva melatonina zbog kojih se intenzivno istražuju inovativni oblici i putovi njegove
primjene. Nazalna primjena osigurava sistemsku raspoloživost melatonina izbjegavajući razgradnju u probavnom sustavu i prvi
prolazak kroz jetru te pruža mogućnost izravne dostave u mozak zaobilazeći krvno-moždanu barijeru. Nanosuspenzije predstavljaju
prikladan farmaceutski oblik za nazalnu primjenu slabo topljivog melatonina. Vlažno mljevenje prikladna je metoda priprave
nanosuspenzija zbog dobre reproducibilnosti i kontrole veličine čestica, izbjegavanja organskih otapala i ekonomske isplativosti. Cilj
ovog rada bio je ispitati mogućnost priprave in situ gelirajuće nanosuspenzije melatonina koristeći polisorbat 80 kao surfaktant i
pektin kao gelirajući mukoadhezivni polimer te metodu vlažnog mljevenja za usitnjavanje kristala melatonina. Pripravljene su
nanosuspenzije melatonina pri koncentraciji polisorbata 80 od 0,286 % (m/V) i različitoj koncentraciji melatonina (0,140-2,860 %,
m/V), rezultirajući rasponom masenog omjera melatonina i polisorbata 80 od 1:10 do 2:1. Veličina čestica i indeks polidisperznosti
ispitani su nakon 24-satnog mljevenja metodom fotonske korelacijske spektroskopije. Veličina nanokristala melatonina kretala se
između 99,3 ± 2,0 nm i 381,3 ± 25,8 nm, a indeks polidisperznosti između 0,145 ± 0,032 i 0,478 ± 0,016. Nanosuspenzija melatonina
s masenim omjerom melatonina i polisorbata 80 od 1:2 karakterizirana je prikladnom veličinom čestica i relativno malim indeksom
polidisperznosti te odgovarajućom fizičkom stabilnošću tijekom 14 dana skladištenja. Maseni omjer melatonina i polisorbata 80 od
1:2 stoga je odabran za daljnju pripravu in situ gelirajućih nanosuspenzija melatonina. Navedeni sustavi pripravljeni su pri
koncentraciji melatonina od 0,143 % i 0,286 % (m/V) uz korištenje neionskog surfaktanta polisorbata 80 u koncentraciji redom od
0,286 % i 0,572 % (m/V) te in situ gelirajućeg mukoadhezivnog polimera pektina u koncentraciji od 0,7 % ili 0,8 % (m/V). Pripravljeni
in situ gelirajući sustavi gelirali su u prisustvu umjetnog nosnog fluida. Provedenim reološkim ispitivanjima utvrđeno je da prisustvo
nanokristala melatonina i polisorbata 80 nije značajno utjecalo na vrijeme geliranja niti svojstva formiranog pektinskog gela. |
| Abstract (english) | Melatonin is a neurohormone which is being investigated in the treatment of numerous diseases and medical states due to its hypnotic,
antioxidative, anti-inflammatory and immunomodulatory properties. Poor water solubility, short half-life, intense metabolism and
difficult passage through the blood-brain barrier are unfavorable properties of melatonin, hence innovative forms and routes of its
application are being intensely researched. Nasal administration ensures the systemic availability of melatonin avoiding
gastrointestinal and first-pass metabolism, and provides the possibility of direct drug delivery to the brain, bypassing the blood-brain
barrier. Nanosuspensions present a suitable pharmaceutical form for nasal administration of poorly water-soluble melatonin. Wet
milling is a suitable method for the preparation of nanosuspensions due to good reproducibility and control of particle size, avoidance
of organic solvents, and cost-effectiveness. The aim of this study was to examine the possibility of preparing an in situ gelling
nanosuspension of melatonin using polysorbate 80 as a surfactant and pectin as a gelling mucoadhesive polymer, and the wet milling
method for reducing the size of melatonin crystals. Melatonin nanosuspensions were prepared at a polysorbate 80 concentration of
0.286% (w/v) and different melatonin concentrations (0.140-2.860%, w/v), resulting in a range of melatonin to polysorbate 80 weight
ratios from 1:10 to 2:1. Particle size and polydispersity index were examined after 24-hour milling using the photon correlation
spectroscopy method. The size of melatonin nanocrystals ranged between 99.3 ± 2.0 nm and 381.3 ± 25.8 nm, and the polydispersity
index between 0.145 ± 0.032 and 0.478 ± 0.016. The melatonin nanosuspension with a weight ratio of melatonin to polysorbate 80
of 1:2 is characterized by a suitable particle size and a relatively low polydispersity index, as well as adequate physical stability during
14 days of storage. A weight ratio of melatonin to polysorbate 80 of 1:2 was therefore chosen for the further preparation of in situ
gelling nanosuspensions of melatonin. The mentioned systems were prepared at a concentration of melatonin of 0.143% and 0.286%
(w/v) with the use of nonionic surfactant polysorbate 80 at a concentration of 0.286% and 0.572% (w/v), respectively, and in situ
gelling mucoadhesive polymer pectin at a concentration of 0.7 % or 0.8 % (w/v). The prepared in situ gelling systems formed gel in
the presence of simulated nasal fluid. The conducted rheological tests determined that the presence of melatonin nanocrystals and
polysorbate 80 showed no significant effect on the gelation time or the properties of the formed pectin gel. |
