Vpliv veziva na pretvorbo tekočega samo-mikroemulgirajočega sistema v trdno formulacijo z vlažnim granuliranjem

Kobe, Tadej (author), German Ilić, Ilija (mentor), Zvonar Pobirk, Alenka (comentor)

Večina novo-razvitih zdravilnih učinkovin je hidrofobnih in zato slabo vodotopnih, kar povzroča težave pri zagotavljanju ustrezne plazemske koncentracije. Na lipidih osnovani sistemi imajo velik potencial zaradi njihove sposobnosti izboljšanja vodotopnosti in biološke uporabnosti učinkovin. Samo-mikroemulgirajoči sistemi (SMES) imajo velikost kapljic < 100 nm izboljšujejo biološko uporabnost peroralno vnesenih hidrofobnih zdravilnih učinkovin. Slednje so namreč v formulaciji vgrajene v raztopljeni obliki, s čimer se izognemo procesu raztapljanja, katerega hitrost je ključni omejujoči dejavnik za absorpcijo učinkovin, ki spadajo v BCS razred II (slabo vodotopne, dobro permeabilne). Namen magistrske naloge je bil pretvoriti tekoč SMES z vgrajeno slabo vodotopno modelno učinkovino (karvedilol) v trdno formulacijo (zrnca) z metodo vlažnega granuliranja. Spreminjali in proučevali smo delež veziva in pa vrsto veziva (povidon K30, povidon K90, kopovidon) v granulacijski tekočini ((mikro)emulzija SMES/voda = 70/30). Kot nosilec smo uporabili mezoporozen silicijev dioksid Syloid® 244FP. Pri ročnem granuliranju v pateni nam je v nosilec uspelo vgraditi veliko količino SMES, saj je ta kot tekoča faza predstavljal približno 60 % mase končnih zrnc. Izdelana zrnca so imela tudi dobre pretočne lastnosti, s fotonsko korelacijsko spektroskopijo pa smo dokazali, da zrnca ohranjajo samo-mikroemulgirajoče sposobnosti. Najboljšim zrncem smo vrednotili sproščanje v kislem mediju s pH 1,2 in fosfatnem pufru s pH 6,8, kjer smo ugotovili, da vezivo povidon K30 ugodno vpliva na sproščanje zrnc v primerjavi z zrnci brez veziva, vezivo povidon K90 zaradi višje molekulske mase sproščanje upočasni, medtem ko vezivo kopovidon na sproščanje nima bistvenega vpliva. Najboljšo formulacijo z 1,85 % veziva povidon K30 smo izdelali tudi v hitrovrtečem granulatorju, ta zrnca smo nato stisnili v tableto. Uspelo nam je izdelati tablete s 25 % deležem zrnc. Tablete so uspešno prestale preskus krušljivosti (0,22 %, zahteva < 1 %) in preskus razpadnosti (50 – 55 s, zahteva < 15 min). Sproščanje karvedilola iz tablet je bilo nekoliko počasnejše kot iz zrnc, kar je bilo nezaželeno, a tudi pričakovano. Med stiskanjem je namreč SMES prodrl globje v pore nosilca in se je zaradi tega zdravilna učinkovina počasneje sproščala, poleg tega pa morajo za sproščanje tablete najprej razpasti.

• Language: Slovenian
• Keywords: karvedilol, samo-mikroemulgirajoči sistemi (SMES), vlažno granuliranje, povidon, kopovidon, tabletiranje
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2021
• PID: 20.500.12556/RUL-134144
• Publication date in RUL: 24.12.2021

Secondary language

• Language: English
• Title: The influence of binder on transformation of liquid self-microemulsifying system into solid dosage form by wet granulation method

Abstract

Most of the newly developed drugs are hydrophobic and therefore poorly soluble in water, which leads to slow drug absorption and inadequate bioavailability. Lipid-based systems have great potential due to their ability to improve water solubility and bioavailability of drugs. Self-microemulsifying drug delivery systems (SMEDDS) have a droplet size < 100 nm and improve bioavailability of orally administered hydrophobic drugs. The drug is already in dissolved form, thus avoiding the dissolution process, which is key limiting factor in the absorption of drugs belonging to BCS class II (poor solubility, good permeability). The purpose of our Master's thesis was to convert liquid SMEDDS with poorly water-soluble drug (carvedilol) into solid formulation (granules) by wet granulation. The proportion of binder and the type of binder (povidone K30, povidone K90, copovidone) in the granulation liquid ((micro)emulsion SMEDDS/water = 70/30) were varied and studied. Mesoporous silicon dioxide Syloid® 244FP was used as a carrier. We managed to incorporate a large amount of SMEDDS into the carrier in hand-made granules (in mortar), as SMEDDS represented about 60 % of the final granules. The produced granules had good flow properties and by photon correlation spectroscopy we proved, that the granules have preserved self-microemulsifying abilities. Granules with best flow properties were evaluated for release in acidic medium with pH 1.2 and phosphate buffer with pH 6.8, where we found that the binder povidone K30 has a beneficial effect on the release of granules compared to those without binder, povidone K90 due to higher molecular weight slows down release, while copovidone has no significant effect on release. The best granules with 1,85% povidone K30 were also produced in a high-shear mixer and those granules were then compressed into tablets. We managed to make tablets containing 25 % of granules. Tablets successfully passed the friability test (0,22 %, requirement < 1 %) and the disintegration test (50-55 s, requirement < 15 min). The release of drug from tablets was slightly slower in comparison to the release from granules, which was undesirable but also expected. During compression SMEDDS penetrated deeper into the pores of the carrier and as a result drug is released more slowly. In addition, tablets must first disintegrate in order for the drug to be released.

• Keywords: carvedilol, self-microemulsifying drug delivery system (SMEDDS), wet granulation, povidone, copovidone, tableting