Proučevanje vpliva vrednosti pH in dodatka lipidov, soli žolčnih kislin in lecitina v medij na sproščanje cinarizina iz tablet

Ahdali, Hana (author), Bogataj, Marija (mentor), Felicijan, Tjaša (comentor)

Lipofilna učinkovina cinarizin spada v II. razred biofarmacevtskega klasifikacijskega sistema. Njegova topnost je močno odvisna od pH vrednosti, zaradi česar so pogoji v gastrointestinalnem traktu bistvenega pomena za njegovo raztapljanje in posledično absorpcijo ter delovanje. Cinarizin je učinkovina, za katero je dokazan pozitivni učinek hrane na absorpcijo, namreč prisotnost različnih komponent v želodcu po zaužitju hrane, izboljša topnost in biološko uporabnost učinkovine. Namen magistrske naloge je bil raziskati, kako različna sestava medija vpliva na sproščanje cinarizina iz tablet Arlevert®. Želeli smo preučiti zgoraj omenjen pozitiven učinek hrane v in vitro modelu z uporabo biorelevantnih medijev, ki so vsebovali lipide in površinsko aktivne snovi. Pripravili smo medije s pH 3, 5 in 7. Ti so nam služili kot osnova in tudi kot mediji, v katere smo nato dodali lipide v obliki SMOFlipid®-a ali površinsko aktivne snovi (natrijev tavroholat in lecitin) ali oboje hkrati. V teh medijih smo izvajali sproščanje, pri čemer smo uporabili napravo z vesli z avtomatskim vzorčenjem. V vzorcih smo s pomočjo tekočinske kromatografije visoke ločljivosti analizirali koncentracijo sproščenega cinarizina. V medijih z dodanimi lipidi pa nas je tudi zanimalo porazdeljevanje učinkovine v vodno in lipidno fazo. Rezultati so pokazali, da dodatek lipidov in površinsko aktivnih snovi pozitivno vpliva na sproščanje cinarizina. Prisotnost lipidov je izboljšala raztapljanje cinarizina pri vseh pH vrednostih, še posebej pri pH 5 in 7, kjer je slabo topen. Površinsko aktivne snovi so prav tako prispevale k izboljšanju raztapljanja učinkovine napram mediju brez dodatka, kombinacija obojega pa je bila optimalna pri celokupnem sproščanju cinarizina iz tablet. Porazdeljevanje učinkovine v vodno in lipidno fazo je bilo odvisno od pH vrednosti medija, prisotnosti lipidov in dodatka površinsko aktivnih snovi. Ob prisotnosti lipidov se je cinarizin porazdeljeval večinoma v lipidni fazi. Porazdeljevanje učinkovine v vodno fazo se je povečalo le pri nižjem pH in pri medijih, kjer so bile dodane površinsko aktivne snovi, vendar ni preseglo večinskega porazdeljevanja. S pomočjo uporabljenih medijev in z vrednotenjem koncentracije učinkovine v posamezni fazi lahko dobimo boljši vpogled na vpliv lipidov in površinsko aktivnih snovi na sproščanje, kar pa lahko tudi odraža obnašanje učinkovine v in vivo pogojih.

• Language: Slovenian
• Keywords: cinarizin, SMOFlipid®, sproščanje, biorelevantni medij
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2025
• PID: 20.500.12556/RUL-174574
• Publication date in RUL: 04.10.2025

Secondary language

• Language: English
• Title: Evaluating the influence of pH value and lipids, bile salts, and lecithin added in the medium on the release of cinnarizine from tablets

Abstract

The lipophilic active pharmaceutical ingredient cinnarizine belongs to Class II of the Biopharmaceutical Classification System. Its solubility is highly dependent on pH, making the conditions in the gastrointestinal tract essential for its dissolution, absorption, and efficacy. Cinnarizine is an active substance with a proven positive food effect on its absorption; the presence of various components in the stomach after food intake improves the solubility and bioavailability of the substance. The purpose of this master's thesis was to investigate the release of cinnarizine from Arlevert® tablets in medium with different compositions. The goal was to study positive food effect in an in vitro model using biorelevant medium containing lipids and surfactants. We prepared media with pH values of 3, 5, and 7. These served as a medium to which we added lipids in form of SMOFlipid® and surfactants (sodium taurocholate and lecithin), or both simultaneously. Release experiments were conducted in these media using a paddle apparatus with automated sampling. In the samples, the concentration of released cinnarizine was analysed using high-performance liquid chromatography. In medium with added lipids, we also examined the distribution of the cinnarizine between the aqueous and lipid phases. The results showed that the addition of lipids and surfactants positively influenced the release of cinnarizine. The presence of lipids improved cinnarizine dissolution at all pH values, particularly at pH 5 and 7, where its solubility is otherwise poor. Surfactants also contributed to improved dissolution compared to the medium without any additives, and the combination of both was the optimal. The distribution of the drug substance between the aqueous and lipid phases depended on the pH of the medium, the presence of lipids, and the addition of surfactants. In the presence of lipids, cinnarizine predominantly distributes into the lipid phase. Greater distribution of the dissolved cinnarizine in the aqueous phase was observed at lower pH levels and in medium with added surfactants, but it is not mainly distributed in aqueous phase. Using the prepared medium and by evaluating the drug substance in each phase, we can gain better insights into the effects of lipids and surfactants on the release, which may also reflect drug behaviour in in vivo conditions.

• Keywords: cinnarizine, SMOFlipid®, dissolution, biorelevant medium