Razvoj na lipidih in talinah osnovanih sistemov polnjenih v mezoporozne nosilce za izboljšanje topnosti karvedilola

Kovačević, Mila (author), Zvonar Pobirk, Alenka (mentor), German Ilić, Ilija (comentor)

Within the doctoral dissertation we were focused on developing an appropriate mesoporous carriers-based delivery systems, with the aim to improve gastrointestinal solubility of carvedilol, a poorly water-soluble drug, that according to the biopharmaceutical classification belongs to group II (low solubility, high permeability). Solubility improvement was achieved by incorporation of carvedilol into a self-microemulsifying drug delivery system (SMEDDS), which was further transformed into a solid form, and by production of amorphous solid dispersions of carvedilol. Wet granulation was used for SMEDDS solidification, while solid dispersions were prepared by high-shear melt granulation and hot melt extrusion. By incorporating SMEDDS into the granules, in addition to improving the drug solubility, high liquid SMEDDS load was achieved (up to 66 % of the total granules mass). Such SMEDDS granules exhibited good flow properties, vital for further production of SMEDDS tablets or filling into capsules. Optimization of SMEDDS-based granulation dispersion, with regard to polymeric binder type and concentration, proved to be as important for achieving preferable flow properties and in vitro dissolution characteristics from SMEDDS granules. The latter were thus mixed with additional excipients and compressed into SMEDDS tablets. The tableting mixture was optimized in order to provide sufficient tablet hardness (?100 N), short disintegration time (< 3 min), while preserving self-microemulsifying properties. To prevent the drug precipitation after ingestion and keep carvedilol in dissolved state during the passage through gastrointestine, various polymeric precipitation inhibitors were added to the formulations of liquid and solid SMEDDS. Apart from SMEDDS formulation optimization, the research within the dissertation was also focused on process development within all technologies used. Ultimately, carvedilol stability was compared between produced SMEDDS granules and amorphous solid dispersions. The latter proved to be better regarding stability and achieved higher drug loading, while considering in vitro dissolution properties, SMEDDS formulations were superior.

• Language: English
• Keywords: lipid-based systems, SMEDDS, SMEDDS granules, SMEDDS tablets, amorphous solid dispersion, mesoporous carriers, precipitation inhibitors
• Work type: Doctoral dissertation
• Organization: FFA - Faculty of Pharmacy
• Year: 2023
• PID: 20.500.12556/RUL-153350
• Publication date in RUL: 23.12.2023

Secondary language

• Language: Slovenian
• Title: Development of lipid and melt based systems loaded into mesoporous carriers for improved solubility of carvedilol

Abstract

V okviru doktorske disertacije smo se osredotočili na razvoj dostavnih sistemov na osnovi mezoporoznih nosilcev za izboljšanje topnosti karvedilola po peroralni aplikaciji. Slednjega uvrščamo med slabo vodotopne zdravilne učinkovine (ZU), po biofarmacevtski klasifikaciji pa spada v II skupino, tj. med slabo topne in dobro permeabilne ZU. Izboljšanje topnosti smo dosegli z vgradnjo karvedilola v samomikroemulgirajoči sistem (SMES), ki smo ga nadalje pretvorili v trdno obliko, in z izdelavo amorfnih trdnih disperzij karvedilola. Za solidifikacijo SMES smo uporabili metodo vlažnega granuliranja, trdne disperzije pa smo pripravili z granuliranjem s talinami v hitrovrtečem mešalniku ter z iztiskanjem talin. Z vgradnjo SMES v zrnca smo poleg izboljšanja topnosti ZU dosegli tudi visoko vsebnost tekočega SMES (do 66 % skupne mase zrnc). SMES-zrnca so izkazovala dobre pretočne lastnosti, ki so ključne za nadaljnjo proizvodnjo SMES-tablet ali polnjenje v kapsule. Optimizacija sestave granulacijske disperzije na osnovi SMES z vidika vrste in koncentracije polimernega veziva, se je izkazala kot pomembna za doseganje ustreznih pretočnih lastnostih in in vitro sproščanje karvedilola iz izdelanih SMES-zrnc. Slednjim smo nato primešali ustrezne pomožne snovi in jih stisnili v tablete, pri čemer je bilo zmes za tabletiranje potrebno optimizirati, da bi dosegli ustrezno trdnost tablet (⡈100 N), kratek razpadni čas (večinoma < 3 min) in ohranili sposobnost samomikroemulgiranja. Z namenom, da bi preprečili obarjanje ZU po zaužitju in karvedilol zadržali v raztopljeni obliki tudi med prehodom skozi prebavni trakt, smo v formulacije tekočega in trdnih SMES dodajali različne polimerne zaviralce obarjanja. Poleg optimizacije formulacije SMES, smo v doktorski disertaciji optimizirali tudi procesne parametre uporabljenih tehnologij. V zadnji fazi smo primerjali stabilnost karvedilola v izdelanih trdnih SMES in amorfnih trdnih disperzijah. Slednje so se z vidika stabilnosti izkazale kot boljše, saj smo vanje smo lahko vgradili večji delež ZU, medtem ko so bile z vidika raztapljanja superiorne SMES formulacije.

• Keywords: na lipidih osnovani sistemi, SMES, SMES-zrnca, SMES-tablete, amorfne trdne disperzije, mezoporozni nosilci, zaviralci obarjanja