Vpliv pogojev izdelave trdnih disperzij s fenofibratom in mezoporoznim silicijevim dioksidom na sproščanje fenofibrata in njegovo fizikalno stabilnost

Dobaj, Nina (avtor), Planinšek, Odon (mentor), Baumgartner, Ana (komentor)

Dandanes težko topne zdravilne učinkovine predstavljajo velik tehnološki izziv pri razvoju peroralnih farmacevtskih oblik. Eno izmed težko topnih predzdravil je tudi fenofibrat, ki ga uporabljamo za zdravljenje hiperlipidemije. Po razvojnem klasifikacijskem sistemu spada v IIb razred, kar pomeni, da moramo za izboljšanje njegove topnosti uporabiti kompleksnejše pristope. Fenofibrat smo vgrajevali v trdne disperzije z neurejenim mezoporoznim silicijevim dioksidom – Syloid® 244 FP. Z metodo odparevanja topila smo pripravili trdne disperzije s 30 % vsebnostjo fenofibrata, uporabili pa smo tri različna organska topila, in sicer etil acetat, aceton in izopropanol pri različnih temperaturah odparevanja – pri 40 °C in temperaturi vrelišča posameznega topila pri normalnem zračnem tlaku. Preučevali smo vpliv izbranega organskega topila in temperature na lastnosti formulacij in na sproščanje fenofibrata iz sveže pripravljenih vzorcev ter po 4 oz. 8 tednih shranjevanja pri povišani temperaturi in relativni vlažnosti zraka. Lastnosti trdnih disperzij, ki vključujejo sproščanje fenofibrata in spremembe v trdnem stanju, smo ovrednotili z različnimi metodami, rezultate pa smo primerjali s kristalnim fenofibratom in izdelano fizikalno zmesjo z ustrezno vsebnostjo fenofibrata. V primerjavi z njima smo s pripravo formulacij izboljšali njegovo raztapljanje. Ugotovili smo, da je sproščanje hitrejše pri trdnih disperzijah, pripravljenih pri višjih temperaturah. Prav tako smo ugotovili, da dobra topnost fenofibrata v topilu vpliva na njegove fizikalne lastnosti, npr. višjo stopnjo amorfnosti, in posledično na hitrejše in boljše sproščanje v kislem mediju. Na podlagi teh ugotovitev smo določili optimalne pogoje za pripravo trdnih disperzij s fenofibratom – to je bila uporaba etil acetata pri temperaturi vrelišča. Pri teh pogojih smo pripravili trdne disperzije z različnimi vsebnostmi fenofibrata – 20 %, 25 % in 35 %. Z izjemo 35 % trdne disperzije so bile vse popolnoma amorfne, profili sproščanja pa so bili primerljivi z vzorcem s 30 % vsebnostjo predzdravila. Pri karakterizaciji vzorcev po staranju smo opazili, da se kljub večjemu deležu kristalnega fenofibrata profil sproščanja po 4 in 8 tednih načeloma ne razlikuje bistveno od profila svežih vzorcev. Zanimivo je, da se pri nekaterih formulacijah profil sproščanja celo izboljša v primerjavi z začetnimi testi. Čeprav je fenofibrat nagnjen h kristalizaciji, smo uspeli pokazati, da lahko s pripravo trdnih disperzij njegovo amorfno stanje ohranimo. V primeru 20 % vsebnosti fenofibrata v formulaciji lahko to dosežemo tudi po 8 tednih staranja.

• Jezik: Slovenski jezik
• Ključne besede: amorfna trdna disperzija, mezoporozni silicijev dioksid, metoda odparevanja topila, izboljšanje raztapljanja fenofibrata, fizikalna stabilnost
• Vrsta gradiva: Magistrsko delo/naloga
• Organizacija: FFA - Fakulteta za farmacijo
• Leto izida: 2024
• PID: 20.500.12556/RUL-164760
• Datum objave v RUL: 11.11.2024

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: The impact of production conditions of solid dispersions containing fenofibrate and mesoporous silicon dioxide on fenofibrate release and its physical stability

Izvleček

Nowadays, poorly soluble active ingredients represent a major technological challenge in the development of oral dosage forms. Fenofibrate is a poorly soluble prodrug, which is used to treat hyperlipidemia and belongs to class IIb according to the developmental classification system, meaning that complex technological approaches are needed to improve its solubility. With this aim, fenofibrate was incorporated into solid dispersions with non-ordered mesoporous silicon dioxide – Syloid® 244 FP. Solid dispersions with 30 % fenofibrate content were prepared by solvent evaporation using three different organic solvents, namely ethyl acetate, acetone, and isopropanol at different evaporation temperatures – at 40 °C and at the boiling temperature of each solvent at normal air pressure. We investigated the effect of the selected organic solvent and temperature on the properties of formulations and on the release of fenofibrate from freshly prepared samples, and after 4 and 8 weeks of storage at elevated temperature and relative humidity. The properties of the solid dispersions, including changes in the solid state and fenofibrate release, were evaluated by various methods and the results were compared with the pure prodrug and the physical mixture with the same composition. By preparing solid dispersions we managed to improve the dissolution of fenofibrate. We found that the drug release rate is higher with samples prepared at higher temperatures. It was also observed that good solubility of fenofibrate in solvent affects its physical properties, e. g. higher degree of amorphicity, and consequently faster release in an acidic medium. We also determined the optimal conditions for the preparation of solid dispersions, which were ethyl acetate as a solvent, at boiling temperature. Under these conditions, solid dispersions with different fenofibrate contents (20 %, 25 % and 35 %) were prepared. Apart from 35 % solid dispersions, they were all completely amorphous and their release profiles were comparable to the 30 % content sample. In post-aging samples, it was observed that, despite the higher proportion of crystalline fenofibrate, the release profiles at 4 and 8 weeks did not differ significantly from that of fresh samples. Interestingly, for some formulations, the release profile even improved compared to the initial tests. Although fenofibrate is prone to crystallisation, we were able to show that its amorphous state can be maintained by preparing solid dispersions. In the case of a 20 % fenofibrate content in the formulation, this can be achieved even after 8 weeks of aging at elevated conditions.

• Ključne besede: amorphous solid dispersion, mesoporous silicon dioxide, solvent evaporation method, dissolution enhancement of fenofibrate, physical stability