Proučevanje sproščanja cinarizina iz tablet v pretočnem sistemu s steklenimi kroglicami, v odvisnosti od pH in prisotnosti lipidov v mediju

Prislan, Manca (author), Bogataj, Marija (mentor), Felicijan, Tjaša (comentor)

Cinarizin je lipofilna šibko bazična učinkovina z izrazito pH odvisno topnostjo, katere biološka uporabnost je odvisna od prisotnosti hrane v prebavnem traktu. V magistrski nalogi smo želeli ovrednotiti, kako pH vrednost medija in prisotnost lipidov v mediju vplivata na sproščanje cinarizina iz tablete v in vitro sistemu. Poskuse smo izvajali v pretočnem sistemu s steklenimi kroglicami. Kot medij za raztapljanje smo uporabili štirikrat redčene McIlvaine pufre s pH vrednostmi 3, 5 in 7, prisotnost lipidov v hrani pa smo ponazorili z dodatkom lipidne emulzije SMOFlipid®. Ugotovili smo, da je hitrost sproščanja cinarizina izrazito odvisna od pH vrednosti medija. V mediju s pH 3 se je v 120 minutah sprostil celoten odmerek cinarizina iz tablete, medtem ko je v medijih s pH 5 in pH 7 večina učinkovine ostala neraztopljena. Prisotnost lipidov v mediju je izboljšala hitrost sproščanja pri vseh pH vrednostih, predvsem v medijih s pH 5 in 7, pri katerih je cinarizin slabo vodotopen. Analizirali smo tudi porazdeljevanje cinarizina med vodno in lipidno fazo medijev z dodanimi lipidi pri različnih pH vrednostih in pri različnih odmerkih tablet. Faze v vzorcu smo ločili s centrifugiranjem in določili delež sproščene učinkovine, ki se je porazdelil v posamezno fazo medija. Višji kot je pH, večji delež cinarizina je v lipidni fazi. Pri pH 5 in pH 7 je bila večina cinarizina v lipidni fazi, porazdelitev med fazama pa je ostala relativno konstantna med celotnim poskusom. V mediju s pH 3 se je porazdeljevanje med fazama spreminjalo s časom, načeloma pa je bil pri višjih koncentracijah sproščenega cinarizina v vzorcu večji delež učinkovine v vodni fazi kot pri nižjih koncentracijah. Spremljali smo tudi sproščanje in porazdeljevanje cinarizina med lipidno in vodno fazo pri poskusih z dovajanjem medijev z različnimi pH vrednostmi v zaporedju od pH 7 do pH 3. Rezultati sproščanja z dovajanjem zaporedja medijev so bili skladni z rezultati sproščanja v medijih s konstantnim pH. V mediju brez lipidov je bilo sproščanje med dovajanjem medijev s pH 7 in 5 zelo počasno, ob začetku dovajanja medija s pH 3 pa se je izrazito pospešilo. Dodatek lipidov v medij z gradientom pH je bistveno izboljšal sproščanje cinarizina predvsem pri višjih pH vrednostih. Večina učinkovine je bila pri višjih pH vrednostih pričakovano v lipidni fazi, z bližanjem pH vrednosti proti 3 pa se je porazdeljevanje v vodno fazo izrazito povečalo do okoli 45 %. Iz rezultatov sklepamo, da je porazdeljevanje cinarizina odvisno predvsem od pH vrednosti medija, ki vpliva na ionizacijo in posledično topnost učinkovine v vodni fazi medija.

• Language: Slovenian
• Keywords: cinarizin, SMOFlipid®, pretočni sistem, sproščanje, porazdeljevanje
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2024
• PID: 20.500.12556/RUL-162023
• Publication date in RUL: 18.09.2024

Secondary language

• Language: English
• Title: Evaluation of cinnarizine release from tablets in a flow-through system with glass beads in relation to pH and presence of lipids in the medium

Abstract

Cinnarizine is a lipophilic weakly basic active ingredient with pH-dependent solubility, whose biological availability is affected by the presence of food in the digestive tract. Our object was to evaluate how the pH value and the presence of lipids in the medium affect the release cinnarizine from the tablet in an in vitro system. The experiments were conducted in a flow-through system with glass beads. We used four-times diluted McIlvaine buffers with pH values 3, 5 and 7 as the dissolution medium. The presence of lipids in food was simulated by adding of lipid emulsion SMOFlipid®. The release of cinnarizine was significantly affected by the pH value of the media. In the medium with pH 3, the entire dose of the active ingredient was released during the experiments, while in media with pH 5 and 7, most of the drug remained undissolved. The presence of lipids in the medium improved the release rate at all pH values of the medium, especially in pH 5 and 7 media, where cinnarizine is poorly water-soluble. We also analysed the distribution of cinnarizine between the aqueous and lipid phase of the media with lipids at different pH values and tablet doses. The phases of the sample were separated by centrifugation, and the percentage of released cinnarizine distributed into each of the phases was determined. The higher the pH, the higher the percentage of released cinnarizine in the lipid phase. At pH values 5 and 7, most of the cinnarizine was in the lipid phase, while the distribution between the phases remained relatively constant during the experiments. In the media with pH 3, the distribution changed over time, generally as the concentration of cinnarizine in the sample increased, the percentage of cinnarizine in the aqueous phase increased as well. Release and distribution of cinnarizine were also evaluated in experiments with a sequence of media with different pH values ranging from pH 7 to pH 3. The results of the experiments with pH gradient of the media were consistent with the results of release in media with constant pH. In the media without lipids, the release during the introduction of media with pH 7 and 5 was very slow, however, it rapidly accelerated at the beginning of the introduction of media with pH 3. The addition of lipids to the media significantly improved the release of cinnarizine, especially at higher pH values. Most of cinnarizine was in the lipid phase at higher pH values, but as the pH approached 3, distribution into the aqueous phase increased rapidly to around 45 %. We conclude that the distribution of cinnarizine depends on the pH of the media, which affects the ionization and consequently the solubility of cinnarizine in the aqueous phase.

• Keywords: cinnarizine, SMOFlipid®, flow-through system, release, distribution