| Abstract | Nazalna primjena kortikosteroida široko je zastupljena u liječenju upalnih oboljenja sluznice nosa. Farmaceutski oblici i uređaji za nazalnu primjenu osiguravaju precizno doziranje kortikosteroida u nosnu šupljinu. Lokalnom primjenom lijeka smanjuje se terapijska doza te mogućnost razvoja nuspojava i predoziranja. Uz navedene prednosti prepoznati su i ograničavajući čimbenici nazalne primjene lijekova poput mukocilijarnog klirensa koji u vremenskom intervalu od 30 minuta potpuno ukloni primijenjeni lijek iz nosne šupljine. Stoga su suvremena istraživanja dijelom usmjerena na razvoj praškastih farmaceutskih oblika poput mikrosfera temeljenih na mukoadhezivnim polimerima koji bubre i omogućuju nastanak mukoadhezivnog gela na mjestu primjene, produljeno zadržavanje lijeka u nosnoj šupljini i prilagođeni profil oslobađanja.
Cilj ovog diplomskog rada bio je ispitati prikladnost primjene pektina i hipromeloze u pripravi mikrosfera s flutikazonpropionatom metodom sušenja raspršivanjem, te ispitati utjecaj masenog omjera pektina i hipromeloze u polimernom matriksu na fizičko-kemijska svojstva mikrosfera važna za nazalnu primjenu.
Pri razvoju mikrosfera sušenjem otopine lijeka i polimera različite topljivosti ključan je odabir prikladne smjese otapala. Reološkom karakterizacijom utvrđeno je da su se otopine pektina te pektina i hipromeloze u smjesi vode i etanola u omjeru 1:1 (V/V) pri ukupnoj koncentraciji polimera od 0,1% (m/V) ponašale kao idealni sustavi. Navedena smjesa otapala pokazala se prikladnom za izradu sustava sušenih raspršivanjem. Mikrosfere s flutikazonpropionatom masenog omjera pektina i hipromeloze od 1:0, 2:1, 1:1 i 1:2 uspješno su pripravljene sušenjem raspršivanjem otopina flutikazonpropionata (pri koncentraciji 0,002%, m/V) i polimera (pri ukupnoj koncentraciji od 0,1%, m/V). Iskorištenje procesa sušenja raspršivanjem kretalo se između 30,1±3,4% i 40,7±0,9%. Srednji promjeri mikrosfera s flutikazonpropionatom kretali su se u intervalu od 1,6±0,1 μm do 2,6±0,4 μm. Najveći srednji promjer zabilježen je kod mikrosfera s najvećim sadržajem hipromeloze. Postignuta je vrlo visoka uspješnost uklapanja lijeka rezultirajući sadržajem lijeka blizu teorijske vrijednosti (2,0%, m/m). U procesu bubrenja mikrosfere su apsorbirale značajno manji volumen SNF-a po jediničnoj masi u usporedbi s pročišćenom vodom. Pri bubrenju mikrosfera u SNF-u nije uočen značajan utjecaj polimernog sastava mikrosfera na volumen apsorbiranog fluida, dok je uklapanje lijeka negativno utjecalo na opseg bubrenja. Daljnja procjena terapijskog potencijala razvijenih mikrosfera uključivat će ispitivanje profila oslobađanja flutikazonpropionata in vitro. |
| Abstract (english) | Nasal administration of corticosteroids is widely represented in the treatment of inflammatory diseases of nasal mucosa. Nasal pharmaceutical formulations and delivery devices enable precise dosing of corticosteroids into the nasal cavity. Local drug administration ensures reduction of therapeutic dose and risk for side-effects and overdosing. In addition to described advantages, some limiting factors related to nasal drug delivery have been recognized as well, such as mucocilliary clearance that in time interval of 30 minutes completely removes the applied drug from the nasal cavity. Therefore, current studies are in part focused on the development of powder drug delivery systems such as microspheres based on mucoadhesive and swellable polymers that enable formation of mucoadhesive gel on the application site, prolonged retention within the nasal cavity and appropriate drug release profile.
The aim of this study was to investigate the applicability of pectin and hypromellose in the preparation of fluticasone propionate loaded microspheres by spray-drying method and to evaluate the influence of pectin to hypromellose weight ratio in the polymeric matrix on physico-chemical properties of microspheres, important for nasal delivery.
The selection of the appropriate mixture of solvents is crucial in the development of microspheres prepared by spray-drying of solution of drug and polymer(s) differing in solubility. Rheological characterization revealed that solutions of pectin as well as pectin and hypromellose at total polymer concentration of 0.1% (w/v) in water/ethanol mixture (1:1, v/v) showed ideal fluid behavior. The developed solvent mixture was shown to be suitable for the preparation of the spray-drying feeds. Fluticasone propionate loaded microspheres with pectin to hypromellose weight ratio of 1:0, 2:1, 1:1 and 1:2 were successfully prepared by spray drying of solutions of fluticasone propionate (at concentration of 0.002%, w/v) and polymer(s) (at total concentration of 0.1%, w/v). Process yield ranged between 30.1±3.4% and 40.7±0.9%. Mean diameters of fluticasone propionate loaded microspheres were in the range from 1.6±0.1 μm to 2.6±0.4 μm. The highest mean diameter was observed for the microspheres prepared with the highest content of hypromellose. All microspheres were characterized by high entrapment efficiency resulting in drug loading close to theoretical value (2.0%, w/w). In the swelling process microspheres absorbed significantly lower volume of SNF in comparison to purified water. Polymeric composition of the microspheres showed no significant influence on the volume of absorbed SNF while drug entrapment significantly reduced swelling extent of the microspheres. Further assessment of therapeutic potential of developed microspheres will include in vitro evaluation of fluticasone propionate release profile. |
