Razvoj dobro stisljivega in pretočnega koprocesiranega mezoporoznega silicijevega dioksida za izdelavo amorfnih trdnih disperzij in orodisperzibilnih tablet

Baumgartner, Ana (avtor), Planinšek, Odon (mentor)

V zadnjem času se v farmacevtskem razvoju pogosto srečujemo s težko vodotopnimi zdravilnimi učinkovinami, kar lahko predstavlja velik izziv pri razvoju peroralnih farmacevtskih oblik. Eden izmed načinov za izboljševanje topnosti in hitrosti raztapljanja je izdelava amorfnih trdnih disperzij, pri katerih pomožno snov predstavlja mezoporozni silicijev dioksid. Glavna pomanjkljivost tega materiala so njegove slabe pretočne lastnosti in stiljivost, kar omejuje izdelavo pacientom prijaznih trdnih farmacevtskih oblik. Cilj doktorske disertacije je bil s koprocesiranjem izboljšati te lastnosti, nato pa v koprocesiran material vgraditi zdravilno učinkovino fenofibrat v amorfni obliki ter iz takšnih trdnih disperzij izdelati orodisperzibilne tablete. Zanimala nas je tudi možnost prekrivanja okusa v takšnih trdnih disperzijah. Najprej smo z visokostrižnim granuliranjem izdelali koprocesirano pomožno snov iz mezoporozne silike in izomalta. S pristopom načrtovanja eksperimentov smo ugotavljali, kateri procesni parametri so ključni za doseganje optimalnih lastnosti produkta, ter izdelali optimiziran material. Nato smo z modelno učinkovino fenofibratom in neprocesirano siliko izdelali trdne disperzije v rotacijskem uparjevalniku ter preučevali vpliv različnih procesnih dejavnikov na stopnjo amorfnosti fenoribrata, hitrost sproščanja in fizikalno stabilnost. Optimalne pogoje smo uporabili pri izdelavi trdnih disperzij s prej razvitim koprocesiranim materialom in izdelali 30 % trdno disperzijo, ki je vsebovala popolnoma amorfno učinkovino in izkazovala bistveno hitrejše sproščanje od kristalnega fenofibrata. Trdno disperzijo smo vgradili v formulacijo za orodisperzibilne tablete, ki so bile skladne z zahtevami Evropske farmakopeje ter so izkazovale izboljšano sproščanje fenofibrata. Nazadnje smo preučevali možnost prikrivanja okusa v formulacijah z mezoporozno siliko, pri čemer smo kot modelno spojino uporabili saharin, trdne disperzije pa smo izdelali s sušenjem z razprševanjem. Te trdne disperzije smo obložili s polimerom, ki je v nevtralnem pH, kakršen je v ustni votlini, netopen, medtem ko se raztopi v kislem mediju, kakršen je v želodcu. S testi sproščanja v omenjenih medijih smo dokazali, da ima naš pristop potencial za zagotavljanje prekrivanja okusa.

• Jezik: Angleški jezik
• Ključne besede: koprocesiran mezoporozni silicijev dioksid, amorfne trdne disperzije, fenofibrat, orodisperzibilne tablete, izboljševanje raztapljanja
• Vrsta gradiva: Doktorsko delo/naloga
• Organizacija: FFA - Fakulteta za farmacijo
• Leto izida: 2025
• PID: 20.500.12556/RUL-168253
• Datum objave v RUL: 06.04.2025

Sekundarni jezik

• Jezik: Slovenski jezik
• Naslov: Development of compressible and free-flowing co-processed mesoporous silica for the production of amorphous solid dispersions and orodispersible tablets

Izvleček

Poorly water-soluble drugs represent an important challenge in pharmaceutical development and industry, because it can be a major issue in the development of oral dosage forms. One approach to improving solubility and dissolution rate is the production of amorphous solid dispersions, with mesoporous silica as the excipient. The main drawback of this material is its poor flowability and compressibility, which limits the production of patient-friendly solid dosage forms. The aim of this dissertation was to improve these properties through co-processing and then incorporate the model drug fenofibrate in its amorphous form into the co-processed material to produce orodispersible tablets. We were also interested in the potential for taste masking in such solid dispersions. Initially, we produced a co-processed excipient from mesoporous silica and isomalt via high-shear granulation. Using a Design of Experiments approach, we determined the key process parameters for achieving optimal product properties and developed an optimized material. Then, we prepared solid dispersions with the fenofibrate and unprocessed silica in a rotary evaporator, where we studied the impact of various process factors on the degree of amorphicity, dissolution rate, and physical stability. The optimal conditions were applied to produce solid dispersions with the previously developed co-processed material, resulting in a 30% solid dispersion that was fully amorphous and demonstrated significantly faster release compared to the crystalline drug. This solid dispersion was incorporated into a formulation for orodispersible tablets that met the European Pharmacopoeia requirements while still showing improved release. Finally, we investigated the possibility of taste masking in mesoporous silica-based formulations, using saccharin as a model compound. The solid dispersions were prepared by spray drying and coated with a polymer that is insoluble at neutral pH, typical of the oral cavity. Release tests in acidic and neutral media confirmed that our approach has the potential to ensure taste masking.

• Ključne besede: coprocessed mesoporous silica, amorphous solid dispersions, fenofibrate, orodispersible tablets, dissolution improvement