Izdelava in vrednotenje peroralnih liofilizatov na osnovi encimsko obdelane želatine

Tomšič, Rok (author), Ahlin Grabnar, Pegi (mentor), Bjelošević Žiberna, Maja (co-mentor)

Za zdravilne učinkovine drugega razreda po biofarmacevtski klasifikaciji zdravil (BCS) je značilno, da so slabo topne v vodi in dobro permeabilne, njihova topnost pa močno vpliva na njihovo biološko uporabnost. Za namen izboljšanja biološke uporabnosti se takšne zdravilne učinkovine vgrajujejo med drugim tudi v orodisperzibilne farmacevtske oblike, med katere spadajo tudi peroralni liofilizati. Za slednje farmacevtske oblike je značilno, da v zelo kratkem času v ustni votlini razpadejo, kjer se del učinkovine že lahko absorbira in se tako izogne metabolizmu prvega prehoda. Namen magistrskega dela je bila izdelava in vrednotenje peroralnih liofilizatov na osnovi encimsko obdelane želatine ter vgradnja zelo slabo topnih učinkovin (olanzapin in piroksikam) v le-te. Liofilizate smo izdelali iz tekočih formulacij s 6 % in 15 % (m/m) pomožnih snovi. Liofilizatom smo določili razpadni čas ter ovrednotili njihov izgled. Ugotovili smo, da so liofilizati, izdelani iz tekoče formulacije s 6 % (m/m) pomožnih snovi krhki, kar omejuje rokovanje z njimi, medtem ko so se na nekaterih liofilizatih, izdelanih iz tekoče formulacije s 15 % (m/m) pomožnih snovi pojavile razpoke med procesom liofilizacije. Kot formulaciji z ustreznim videzom in z najkrajšim razpadnim časom sta se izkazali formulaciji z masnimi razmerji encimsko obdelana želatina: PVP K25: manitol: glicin = 4: 2: 4,5: 0,5 ter encimsko obdelana želatina: PVP K25: manitol: premrežen natrijev karmelozat = 4: 2: 4,5: 0,5, ki sta bili izdelani iz tekoče formulacije s 15 % (m/m) pomožnih snovi. Z diferenčno dinamično kalorimetrijo smo določili temperature steklastega prehoda kritično koncentriranih raztopin, ki se tvorijo med zamrzovanjem in s tem potrdili agresivne pogoje sušenja. Temperature steklastega prehoda peroralnih liofilizatov pa zaradi nizke temperature razpada encimsko obdelane želatine ni bilo možno določiti. Z vrstično elektronsko mikroskopijo smo dokazali razlike v morfologiji liofilizatov, ki so vsebovali glicin oziroma premrežen natrijev karmelozat. Na podlagi rezultatov Brunauer-Emmett-Teller-jeve metode lahko zaključimo, da ni korelacije med specifično površino in razpadnim časom liofilizatov.

• Language: Slovenian
• Keywords: peroralni liofilizati, liofilizacija, encimsko obdelana želatina, olanzapin, piroksikam
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2023
• PID: 20.500.12556/RUL-144869
• Publication date in RUL: 18.03.2023

Secondary language

• Language: English
• Title: Preparation and evaluation of oral lyophilisates based on the enzyme-treated gelatin

Abstract

Active substances in class 2 of Biopharmaceutical Classification Scheme are characterized as poorly soluble water and well permeable, as their poor solubility strongly affects their bioavailability. For the purpose of improving bioavailability, such active ingredients are incorporated, among other things, into orodispersible pharmaceutical forms, which also include oral lyophilisates. It is typical for such pharmaceutical forms that they disintegrate in a very short time in the oral cavity, where part of the active ingredient can already be absorbed and thus avoids first-pass metabolism. The purpose of the master's thesis was the production and evaluation of oral lyophilisates based on enzymatically treated gelatine and the incorporation of very poorly soluble active ingredients (olanzapine and piroxicam) into them. We made lyophilized formulations with 6% and 15% (m/m) of excipients in liquid formulations for lyophilization. We determined the disintegration time of the lyophilizates and evaluated their appearance. We found that lyophilisates made from a liquid formulation with 6% (w/w) excipients are fragile, which limits their handling, while some lyophilisates made from a liquid formulation with 15% (w/w) excipients cracks appeared during the lyophilization process. Formulations with mass ratios of enzymatically treated gelatin: PVP K25: mannitol: glycine = 4: 2: 4.5: 0.5 and enzymatically treated gelatin: PVP K25: mannitol: sodium carmellose = 4: 2: 4.5: 0.5, proved to be the formulations with the appropriate appearance and the shortest disintegration time, both made from a liquid formulation with 15% (w/w) excipients. Using differential dynamic calorimetry, we determined the glass transition temperatures of critically concentrated solutions, which are formed during freezing, and thus confirmed the aggressive primary drying conditions. However, the glass transition temperature of lyophilisates could not be determined due to the low decomposition temperature of enzymatically treated gelatin. Using scanning electron microscopy, we demonstrated differences in the morphology of lyophilisates containing glycine and sodium carmellose. Based on the results of the Brunauer-Emmett-Teller method, we can conclude that there is no correlation between the specific surface area and the disintegration time of lyophilisates.

• Keywords: oral lyophilisates, lyophilisation, enzyme-treated gelatin, olanzapine, piroxicam