Vpliv sestave samo-mikroemulgirajočega sistema in deleža vodne faze v disperziji za granuliranje, na lastnosti zrnc izdelanih z vlažnim granuliranjem

Rugelj, Ana (author), Zvonar Pobirk, Alenka (mentor), German Ilić, Ilija (comentor)

Velik delež novo odkritih zdravilnih učinkovin (ZU) je slabo topnih v vodnem mediju, saj so le-te bolj lipofilne, kot so bile ZU odkrite v preteklosti. V primeru, ko je učinkovina slabo topna v vodi, je po peroralni aplikaciji tudi slabše biološko razpoložljiva. Peroralni način aplikacije je med bolniki najbolje sprejet, saj je najbolj enostaven, poleg tega pa je tudi najcenejši za izdelavo (npr. tablete). Med slabo topne ZU prištevamo tudi karvedilol, ki smo ga uporabili kot modelno učinkovino. Za izboljšanje topnosti zdravilnih učinkovin se poslužujemo različnih pristopov, med katere spadajo tudi na lipidih osnovane formulacije, kamor spada tudi samo-(mikro)emulgirajoč dostavni sistem (SMEDDS), na katerega smo se osredotočili v okviru magistrskega dela. Tekoči SMEDDS smo z vlažno granulacijo vgradili v zrnca na osnovi poroznih nosilcev ter ga tako pretvorili v trdno obliko in izdelali trden SMEDDS. V nalogi smo se osredotočili na iskanje optimalnega masnega razmerja med lipidno fazo in površinsko aktivno snovjo (PAS) v samo-(mikro)emulgirajočem sistemu (SMES) ter na masno razmerje med SMES-om in vodno fazo v granulacijski tekočini. Slednje vpliva tudi na vrsto disperznega sistema, zato smo z merjenjem prevodnosti in viskoznosti ovrednotili tudi mikrostrukturo sistemov, ki nastanejo med postopnim redčenjem SMES z različnim razmerjem med lipidno fazo in PAS. Opazili smo, da prevoji prvega odvoda prevodnosti sovpadajo s spremembami naklona krivulje viskoznosti, in s tem potrdili, da v območju teh točk prihaja do sprememb v notranji strukturi. Z vlažnim granuliranjem smo SMES kot granulacijsko tekočino vgradili v trden mezoporozni nosilec ter dobljena zrnca fizikalno ovrednotili glede na velikost delcev in pretočne lastnosti. Izbrali smo formulacije, kjer je bila velikost delcev največja, pretočne lastnosti pa čim boljše. Na koncu smo izvedli še preskus sproščanja modelne učinkovine iz formulacij z najboljšimi pretočnimi lastnostmi, kjer so bili profili sproščanja precej primerljivi med seboj. Potrdili pa smo, da je profil sproščanja ZU, ki ni bila vgrajena v SMEDDS, veliko slabši. S tehniko fotonske korelacijske spektroskopije smo ovrednotili morebiten vpliv procesa solidifikacije na samo-(mikro)emulgirajoče lastnosti izdelanih zrnc, kjer smo potrdili ohranitev samo-(mikro)emulgirajočih lastnosti, saj je bila povprečna velikost kapljic manjša od 100 nm. Na podlagi zbranih rezultatov smo prišli do sklepa, da sta najboljši formulaciji za oba mezoporozna nosilca, kjer je razmerje med lipidno fazo in emulgatorsko fazo 20:80 ter med vodo in SMES-om 20:80.

• Language: Slovenian
• Keywords: samo-(mikro)emulgiranje, slabo vodotopne učinkovine, biološka uporabnost, porozni nosilci, SMES, SMEDDS
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2023
• PID: 20.500.12556/RUL-146721
• Publication date in RUL: 09.06.2023

Secondary language

• Language: English
• Title: The influence of self-microemulsifying system composition and water ratio in the granulation liquid on characteristics of granules prepared by wet granulation

Abstract

Many newly discovered active ingredients are poorly soluble in aqueous media, as these are more lipophilic or have a high molecular weight. If the active substance is poorly soluble in water, it is also less bioavailable for oral administration. Therefore, this application method is the most accepted among patients, as it is the easiest and the cheapest. Poorly soluble active ingredients include carvedilol, which is our model active ingredient. To improve the solubility of the active ingredients, we can use various techniques, including lipid-based formulations, within which we will focus on SMEDDS. Liquid SMEDDS was incorporated into porous supports with wet granulation and thus converted into solid SMEDDS. We focused on finding the optimal mass ratio between the oil phase and PAS in SMES and on the mass ratio between SMES and the aqueous phase in the granulation liquid. We evaluated the microstructure of different SMES by measuring conductivity and viscosity. We observed that the bends of the first conductivity lead appear with changes in the slope of the viscosity curve and thus confirmed the changes in the internal structures in the area at these points. We built granulation liquid into porous particles with wet granulation and physically evaluated the obtained granules (particle size, flow properties). Formulations with the largest particle size and the best flow properties were chosen. At the end, we also tested dissolution of the best formulations. The release profiles were quite comparable to each other. However, we have confirmed that the release profile of the active ingredient, which was not incorporated in SMEDDS, is much worse. We also evaluated their self- (micro) emulsifying properties using the photon correlation microscopy technique. It was confirmed that self-(micro)emulsifying properties are maintained, as the average droplet size was less than 100 nm. Based on the selected results, we concluded that the best formulations for both mesoporous carriers are where the ratio between the lipid and emulsifier phases is 20:80 and ratio between water and SMES is 20:80.

• Keywords: self (micro) emulsification, poorly soluble active ingredients, bioavailability, porous carriers, SMES, SMEDDS