Vpliv polimernih zaviralcev obarjanja na lastnosti samo-mikroemulgirajočega sistema s karvedilolom in njegova pretvorba v trdno formulacijo

Kolenc, Matej (author), Zvonar Pobirk, Alenka (mentor)

Ker velik delež novo odkritih zdravilnih učinkovin (ZU) uvrščamo v II. in IV. razred biofarmacevtskega klasifikacijskega sistema ter izkazuje slabo topnost v vodnih medijih, je povečevanje topnosti eden od velikih izzivov v farmacevtskem razvoju. Med pristopi za izboljševanje topnosti so tudi na lipidih osnovani sistemi, med njimi tudi samomikroemulgirajoči dostavni sistemi (S(M)ES). Le-ti so sestavljeni iz lipidov, površinsko aktivnih snovi in sotopil. Za njih je značilno, da po razredčitvi v vodnem mediju spontano tvorijo mikroemulzijo tipa olje v vodi, kar pripomore k povečevanju topnosti zdravilne učinkovine, posledično pa tudi k boljši absorpciji in višji biološki uporabnosti. Številne ZU so v gastrointestinalnem traktu (GIT) podvržene obarjanju, zato smo tekom eksperimentalnega dela raziskovali, kako uporaba različnih inhibitorjev obarjanja zavira obarjanje ZU in s tem skozi daljše časovno obdobje vzdržuje večji delež slednje v raztopljeni obliki. Tako smo najprej pripravili tekoči S(M)ES z modelno učinkovino karvedilol in po dodatku različnih koncentracij različnih tipov inhibitorjev obarjanja (Pharmacoat® 606, PVP K30 in Soluplus®) spremljali profil sproščanja ter čas, ko pride do obarjanja ZU. Dokazali smo, da z uporabo inhibitorjev obarjanja zelo učinkovito zaviramo proces obarjanja ZU. Ker imajo trdne farmacevtske oblike (FO) številne prednosti pred tekočimi (stabilnost, lažja in cenejša proizvodnja), smo tekoče S(M)ES pretvorili v trdno obliko z vlažnim granuliranjem. Pri tem smo uporabili mezoporozna nosilca Syloid® 244 FP in Neusilin® US2. Izdelanim granulatom smo ovrednotili pretočne lastnosti, velikost in porazdelitev velikosti ter profil sproščanja. Najboljšo formulacijo glede na omenjene lastnosti smo granulirali še v hitrovrtečem mešalniku in primerjali ta zrnca z ročno izdelanimi zrnci (v pateni). Pri pretvorbi v trdno obliko je zelo pomembno, da formulacija ohrani samomikroemulgirajoče lastnosti, kar smo preverili in potrdili tudi s fotonsko korelacijsko spektroskopijo.

• Language: Slovenian
• Keywords: inhibitorji precipitacije, samomikroemulgirajoči sistemi (SMES), vlažno granuliranje, solidifikacija, karvedilol
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2021
• PID: 20.500.12556/RUL-131739
• Publication date in RUL: 02.10.2021

Secondary language

• Language: English
• Title: The influence of polymeric precipitation inhibitors on carvedilol loaded self(micro)emulsifying system characteristics and its transformation into a solid formulation

Abstract

As a large proportion of newly discovered active pharmaceutical ingrediants (API) belong to II. and IV. class of the biopharmaceutical classification system and show poor solubility in aqueous media, increasing solubility is one of the major challenges in pharmaceutical development. Approaches to improving solubility also include lipid-based systems, including self-microemulsifying drug delivery systems (SMEDDS). These are composed of lipids, surfactants and co-solvents. They are characterized by the spontaneous formation of an oil-in-water microemulsion after dilution in an aqueous medium, which helps to increase the solubility of the active substance and, consequently, to improve absorption and higher bioavailability. Many API’s are in the gastrointestinal tract (GIT) subject to precipitation, so during the experimental work we investigated how the use of various precipitation inhibitors inhibits precipitation in order to keep API in the dissolution medium in dissolved form. Thus, we first prepared a liquid SMEDDS with the model active ingredient carvedilol and with the addition of different precipitation inhibitors (Pharmacoat® 606, PVP K30 and Soluplus®) in different concentrations, we monitored the release profile and the time when API precipitation occurs. We have proven that using precipitation inhibitors is very effective in inhibiting the process of precipitation of API. Because solid pharmaceutical forms have many advantages over liquid ones (stability, easier and cheaper production), we have converted liquid SMEDDS into a solid form by wet granulation in a paten. Mesoporous carriers Syloid® 244 FP and Neusilin® US2 were used. The flow properties, size, size distribution and release profile were evaluated with the produced granules. The best formulation according to the mentioned properties was granulated in a high-shear mixer and these granules were compared with hand-made granules. When converting to a solid form, it is very important that the formulation retains its self-microemulsifying properties, which was also verified and confirmed by photon correlation spectroscopy.

• Keywords: precipitation inhibitors, self-microemulsifying drug delivery systems (SMEDDS), wet granulation, solidification, carvedilol