Vrednotenje vpliva procesnih parametrov iztiskanja talin na fizikalne lastnosti in raztapljanje trdne disperzije hidroksipropilmetilcelulozaacetatsukcinata

Stenšak, Vanesa (avtor), Janković, Biljana (mentor), Huzjak, Tilen (komentor)

85 % zdravilnih učinkovin (ZU) na trgu je vgrajenih v peroralne farmacevtske oblike (FO). Velik delež ZU ima slabo vodotopnost, zato je izboljšanje topnosti ZU eden izmed ključnih korakov za dosego boljše biološke uporabnosti (BU). Priprava amorfnih trdnih disperzij (ASD) s tehnologijo iztiskanja talin (HME) je ena izmed najbolj uporabljenih metod za izboljšanje BU slabo topnih ZU. ASD so disperzije ene ali več ZU v trdnem inertnem nosilcu, ki med raztapljanjem upočasni in zavira nukleacijo in rast kristalov ter vzdržuje koncentracijo ZU nad ravnotežno. V sklopu magistrske naloge smo s HME pri različni procesni temperaturi, hitrosti vrtenja polžev in dovajanju vstopne zmesi pripravili 4 vzorce ASD. Uporabili smo šibko bazično ZU iz razreda BCS II, kot nosilni polimer pa šibko kisel HPMCAS tip L. Z nadaljnjimi analizami smo raziskovali vpliv procesnih parametrov na raztapljanje ASD. Vzorcem smo z diferenčno dinamično kalorimetrijo (DSC) določili temperaturo steklastega prehoda, pri čemer med posameznimi vzorci nismo zaznali razlik. Z vrstično elektronsko mikroskopijo smo spremljali proces njihovega raztapljanja v biorelevantnem mediju FaSSIF. Ob različnih časovnih točkah smo opazovali velikost, obliko in število delcev na površini ASD po raztapljanju v mediju FaSSIF pri vrednosti pH 6,5 in ugotovili, da delci s časom rastejo do ravnotežne velikosti 140–200 nm, medtem ko se njihova morfologija s časom ne spreminja. Raziskave so pokazale, da različni procesni parametri vplivajo na velikost koloidnih delcev, ki nastajajo pri raztapljanju. Pri najnižji preiskovani vrednosti pH 5,75 medija FaSSIF v času 5 minut ni bilo razvitih koloidnih delcev, pri vseh ostalih preiskovanih vrednostih pH (6,0, 6,25, 6,5) so delci že bili razviti. Z napravo MicroFLUXTM smo potrdili, da imajo manjši koloidni delci hitrejši snovni pretok skozi lipidno membrano kot večji delci. Z napravo Zetasizer Nano ZS smo ob različnih časovnih točkah določali velikost in število nastalih nanostruktur, ki so nastale med raztapljanjem ASD v mediju FaSSIF pH 6,5, vendar med posameznimi vzorci nismo opazili razlik. Ker je prisotnost micelov v mediju FaSSIF ovirala interpretacijo dobljenih rezultatov, smo jih poskusili odstraniti s centrifugiranjem in filtracijo. Rezultate analiz ASD s HPMCAS tipa L smo primerjali z ASD, ki vsebuje tip M in so bili izdelani pri primerljivih procesnih parametrih. V primeru tipa M smo po 10 minutah namakanja ASD in vrednosti pH 6,5 medija FaSSIF izmerili manjše koloidne delce kot pri tipu L.

• Jezik: Slovenski jezik
• Ključne besede: tehnologija iztiskanja talin, amorfne trdne disperzije, iztiskanec, raztapljanje, koloidni delci
• Vrsta gradiva: Magistrsko delo/naloga
• Organizacija: FFA - Fakulteta za farmacijo
• Leto izida: 2023
• PID: 20.500.12556/RUL-151778
• Datum objave v RUL: 20.10.2023

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Evaluation of hot-melt process parameters impact to physical characteristics and dissolution properties of hydroxypropylmethylcellulose acetate succinate-based solid dispersion

Izvleček

85 % of active pharmaceutical ingredients (API) on the market are incorporated into the oral pharmaceutical dosage forms. A large proportion of APIs has poor water solubility, therefore improving the solubility of API is one of the key steps to achieve better bioavailability. The preparation of amorphous solid dispersions (ASD) by hot melt extrusion (HME) technology is one of the most used methods to improve the bioavailability of poorly soluble API. ASDs are dispersions of one or more APIs in a solid inert carrier, which reduces and inhibits crystal growth and nucleation during dissolution and therefore, maintains the concentration of the API above equilibrium. As part of research work, we prepared 4 samples of ASD with HME at different process temperatures, screw rotation speeds and feeding rates of the blend. We used weakly basic API from class BCS II, and weakly acidic HPMCAS type L as carrier polymer. With further analyses, we investigated the influence of process parameters on ASD dissolution. We determined the glass transition temperature of the samples using differential dynamic calorimetry (DSC), and no differences were detected between the individual samples. The process of their dissolution in the biorelevant FaSSIF medium was monitored by scanning electron microscopy. At different time points, we observed the size, shape and number of particles on the surface of the ASDs after dissolution in the biorelevant FaSSIF medium at pH 6.5 and found that the particles grow with time to an equilibrium size of 140–200 nm, while their morphology does not change with time. The research has shown that different process parameters affect the size of the colloidal particles that are formed during dissolution. At the lowest tested pH value of 5.75 of the FaSSIF medium, no colloidal particles were developed within 5 minutes, at all other tested pH values (6.0, 6.25, 6.5) the particles were already developed. With the MicroFLUXTM device, we confirmed that smaller colloidal particles have a faster mass flow through the lipid membrane than larger particles. The Zetasizer Nano ZS device was used to determine the size and number of nanostructures formed during the dissolution of ASD in FaSSIF medium pH 6.5 at various time points, but no differences were observed between individual samples. Since the presence of micelles in the FaSSIF medium hindered the interpretation of the obtained results, we tried to remove them by centrifugation and filtration. The results of the ASD analyzes with HPMCAS type L were compared with ASD containing type M which were produced at comparable process parameters. In the case of type M, smaller colloidal particles were measured than in type L after 10 minutes of ASD soaking and a pH value of 6.5 of FaSSIF medium.

• Ključne besede: hot melt extrusion, amorphous solid dispersion, extrudate, dissolution, colloidal particles