Optimizacija procesa pretvorbe samomikroemulgirajočega sistema s karvedilolom v trdno obliko z metodo vrtinčnoslojnega granuliranja : industrijska farmacija

Pirnat, Vesna (author), Zvonar Pobirk, Alenka (mentor), Luštrik, Matevž (co-mentor)

V farmaciji narašča število slabo vodotopnih zdravilnih učinkovin (ZU) z nizko biološko uporabnostjo po peroralni uporabi. Eden izmed pristopov za izboljšanje njihove biološke uporabnosti je uporaba samo(mikro)emulgirajočih sistemov (S(M)ES), v katerih je ZU raztopljena. SMES so zmesi lipidov, površinsko aktivnih snovi, koemulgatorjev, sotopil in ZU v tekočem agregatnem stanju, ki ob stiku z vodnim medijem že ob rahlem stresanju tvorijo mikroemulzije tipa olje v vodi. Zaradi številnih prednosti uporabe trdnih farmacevtskih oblik pred tekočimi, se v zadnjem času intenzivno proučujejo metode za pretvorbo tekočih SMES v trdno obliko. V sklopu magistrske naloge smo v predhodno razvit SMES vključili slabo vodotopno ZU karvedilol in ga s pomočjo tehnologije vrtinčnoslojnega granuliranja pretvorili v trdno obliko. Pri tem smo preizkusili različne trdne nosilce, veziva in nastavitve procesnih spremenljivk. Kot najprimernejši trdni nosilec se je izkazal Neusilin® US2, ki je omogočal doseganje visokih izkoristkov procesa granuliranja in izdelavo granulatov z visoko vsebnostjo karvedilola. Kot potencialno primerna se je izkazala tudi fizikalna zmes Avicela® PH 101 in Aerosila® 200 v masnem razmerju 1 : 1, ki je omogočala izdelavo granulatov s takojšnjim sproščanjem karvedilola, toda zaradi zelo majhne velikosti delcev Aerosila® 200 smo na uporabljeni vrtinčnoslojni napravi dosegali nizke izkoristke procesa granuliranja. Med optimizacijo sestave disperzije za granuliranje smo dokazali, da vsa uporabljena veziva, ob ustreznih razmerjih med posameznimi sestavinami formulacije, omogočajo izdelavo granulatov z ustreznimi proučevanimi lastnostmi. Vezivi PVP K90 in Pharmacoat® 606 sta omogočali dober nadzor nad procesom granuliranja, medtem ko je PVP K30 učinkovito inhibiral obarjanje karvedilola. Izdelanim granulatom smo najprej določili pretočne lastnosti. Potrdili smo, da obstaja mejna vrednost adsorpcije olj v/na posamezne nosilce, ki je ne smemo preseči, saj se v tem primeru pretočne lastnosti granulatov bistveno poslabšajo. Uspešnost pretvorbe tekočega SMES v trdno obliko z ohranjenimi samo(mikro)emulgirajočimi lastnostmi smo preverjali z diferenčno dinamično kalorimetrijo, s katero smo potrdili odsotnost kristalinične oblike karvedilola v testiranih granulatih in s fotonsko korelacijsko spektroskopijo, s katero smo potrdili, da po redispergiranju iz izbranih granulatov spontano nastanejo (mikro)emulzije. S preskusi sproščanja karvedilola iz izbranih granulatov smo tudi dokazali, da njegova vgradnja v samomikroemulgirajoči granulat omogoča bistveno izboljšanje raztapljanja karvedilola v primerjavi z njegovo kristalinično obliko. Rezultati vrednotenja izdelanih granulatov nakazujejo, da smo uspeli izdelati več samomikroemulgirajočih granulatov, ki bi lahko bili primerni za nadaljnje polnjenje v kapsule ali izdelavo tablet. Z uporabo izdelanih granulatov bi se biološka uporabnost karvedilola, v primerjavi z uporabo kristalinične oblike, najverjetneje izboljšala; ne le zaradi hitrega sproščanja, temveč tudi zaradi inhibicije metabolnih encimov in sekretornih prenašalcev s sestavinami SMES.

• Language: Slovenian
• Keywords: samomikroemulgirajoči sistem samomikroemulgirajoči granulat, vrtinčnoslojno granuliranje karvedlol izdelava tablet vodotopnost tablet
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [V. Pirnat]
• Year: 2017
• Number of pages: XII, 79 f.
• PID: 20.500.12556/RUL-97870
• UDC: 615.4:661.12(043.3)
• COBISS.SI-ID: 4335985
• Publication date in RUL: 05.01.2018

Secondary language

• Language: English
• Title: Optimization of the fluid bed granulation process for solidification of the carvedilol-loaded self-microemulsifying system

Abstract

In pharmacy there has been an increase of active pharmaceutical ingredients (API) with poor solubility and therefore low bioavailability after oral use. One of the approaches to improve their bioavailability is the use of self-(micro)emulsifying systems (S(M)ES) in which API is dissolved. SMES are mixtures of lipids, surfactants, co-surfactants, co-solvents and API in liquid physical state. In contact with water media and only with a gentle stirring microemulsion type oil-in-water is formed. Due to numerous advantages of solid dosage forms before the liquid ones, methods to transform liquid SMES into a solid form are currently being intensely studied. Within this master thesis, carvedilol, API with low solubility, was incorporated into a previously developed SMES and transformed into solid form by fluid bed granulation process. Different solid carriers, binders and process related variables were tested. The most appropriate solid carrier turned out to be Neusilin® US2 which enabled high granulation process yield and the production of granulates with high content of carvedilol. The physical mixture of Avicel® PH 101 and Aerosil® 200 in mass proportion 1 : 1 also turned out to be potentially appropriate as it enabled the preparation of granulates with immediate carvedilol release but because of very small size of Aerosil® 200 particles low granulation process yield was achieved on fluid bed equipment. During optimization of dispersion composition it was proven that the production of granulates with appropriate studied properties can be produced by all used binders with appropriate ratio between individual formulation components. PVP K90 and Pharmacoat® 606 binders enabled good control over the granulation process while PVP K30 effectively inhibited carvedilol precipitation. First, flow properties were defined for produced granulates. It was confirmed that there is some limit value of oil adsorption on carriers that should not be exceeded because otherwise flow properties of granulates considerably worsen. Efficiency of transforming liquid SMES into solid form with preserved self-(micro)emulsifying properties was tested by differential scanning calorimetry which confirmed the absence of crystalline form of carvedilol in tested granulates, and with photon correlation spectroscopy which confirmed that after re-dispersion from selected granulates (micro)emulsions occur spontaneously. With carvedilol dissolution tests it was proven that its incorporation into self-(micro)emulsifying granulate enables considerable improvement of carvedilol dissolution rate (and extent) in comparison with its crystalline form. The results of evaluation of produced granulates suggest that we managed to produce more self-microemulsifying granulates which could be appropriate for further capsule filling or tablet production. By using produced granulates, carvedilol bioavailability would most probably improve in comparison with the use of its crystalline form not only due to rapid dissolution but also due to inhibition of matabolic enzymes and efflux transport systems by SMES components.

• Keywords: self-(micro)emulsifying system (SMES) self-microemulsifying granulate fluid bed granulation and carvedilol