Pretvorba tekočega samomikroemulgirajočega sistema v trdno farmacevtsko obliko z vlažnim granuliranjem

Levart, Vita (author), German Ilić, Ilija (mentor), Bolko Seljak, Katarina (comentor)

Veliko novoodkritih zdravilnih učinkovin (ZU) je slabo vodotopnih, kar lahko pri razvoju zdravil predstavlja zahtevno nalogo. Eden od novejših pristopov za izboljšanje topnosti je tvorba samomikroemulgirajočih sistemov (SMES), sestavljenih iz mešanice lipidov, z vgrajeno raztopljeno ZU, sotopil in površinsko aktivnih snovi. Ob razredčitvi z vodnim medijem in blagem mešanju spontano nastane stabilna mikroemulzija olje v vodi. SMES so tekoče formulacije, zato imajo slabšo stabilnost in dražjo proizvodnjo. Rešitev predstavljajo trdni SMES, ki jih izdelamo iz tekočih SMES z različnimi tehnološkimi postopki. Namen našega raziskovalnega dela je bil pretvorba tekočega SMES-a (z vgrajenim slabo vodotopnim karvedilolom kot modelno ZU) v trdno obliko z vlažnim granuliranjem in izdelana zrnca uspešno stisniti v tableto. Za ročno granuliranje smo uporabili nosilce različne poroznosti (Aeroperl® 300, Avicel® PH-101, Fujicalin® SG, Neusilin® US2, Syloid® 244FP, Syloid® XDP 3050). V izdelanih zrncih je SMES predstavljal 35–66 % mase. Izdelana zrnca smo ovrednotili z različnimi metodami. Vsa zrnca so imela dobre pretočne lastnosti, potrdili smo ohranitev samomikroemulgirajočih lastnosti in dokazali hitrejše sproščanje karvedilola iz zrnc kot je raztapljanje kristaliničnega karvedilola. Na osnovi rezultatov vrednotenja zrnc smo izbrali dva najboljša nosilca (Neusilin® US2, Syloid® 244FP) in ju granulirali v hitro vrtečem granulatorju. Izdelana zrnca smo vrednotili po istih metodah kot ročno izdelana zrnc, s čimer smo lahko primerjali ročni in strojni način izdelave. Z vrstično elektronsko mikroskopijo smo potrdili predpostavko, da imajo zrnca iz hitro vrtečega granulatorja bolj gladko površino in bolj okroglo obliko, zaradi česar so se izboljšale pretočne lastnosti. Na koncu smo z dodatkom pomožnih snovi še stisnili samomikroemulgirajočo tableto, katere masa je bila 845 mg s vsebnostjo karvedilola 12,5 mg. Izdelane tablete so ustrezale farmakopejskemu kriteriju razpadnosti, saj so razpadle v <51 s in krušljivosti, ki je znašala <0,22 %. Iz tablet se je ZU sprostila nekoliko kasneje kot iz zrnc, predvidoma zaradi porušitve porozne strukture nosilca.

• Language: Slovenian
• Keywords: samomikroemulgirajoči sistem, trdni samomikroemulgirajoči sistem, samomikroemulgirajoča tableta, karvedilol, vlažno granuliranje
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2021
• PID: 20.500.12556/RUL-124692
• Publication date in RUL: 10.02.2021

Secondary language

• Language: English
• Title: Transformation of a liquid selfmicroemulsifying system into a solid dosage form by using wet granulation

Abstract

Many newly discovered active pharmaceutical ingredients (API) are poorly water-soluble, which can be a challenging in the development of oral dosage forms. One of the approaches to improve solubility is the formation of self-microemulsifying drug delivery systems (SMEDDS). SMEDDS are a mixture of lipids, with solubilized API, cosolvents and surfactants. Stable oil-in-water microemulsion is formed spontaneously upon dilution with aqueous media and gentle stirring. SMEEDDS are liquid formations, therefore they have lower stability and more expensive production. The solution are solid SMEDDS, which are made from liquid SMEDDS by various solidification methods. The purpose of our research work was the transformation of liquid SMEDDS (with carvedilol as a poorly water-soluble model drug) into a solid form by wet granulation and successfully compressing the produced granules into a tablet. Carriers of different porosity (Aeroperl® 300, Avicel® PH-101, Fujicalin® SG, Neusilin® US2, Syloid® 244FP, Syloid® XDP 3050) were used for granulation by hand. In the produced granules, SMEDDS represented 35-66 % of the weight. The produced granules were evaluated by various methods. All granules had good flow properties. We confirmed the preservation of self-microemulsifying properties and proved faster release of carvedilol from ganules than dissolving crystalline carvedilol. Based on the results of the granules evaluation, the two best carriers (Neusilin® US2, Syloid® 244FP) were selected and granulated in a high shear granulator. In order to compare manual and machine production methods the produced granules were evaluated by the same methods as hand-made granules. The assumption that the granules made in high shear granulator have smoother surface and more spherical shape was confirmed by scanning electron microscopy, resulting in improved flow properties. Finally, a self-microemulsifying tablet weighing 845 mg with a 12.5 mg dose of carvedilol was compressed with the addition of excipients. The produced tablets met the pharmacopoeial criteria of disintegration (<51 s) and friability (<0.22 %). In the dissolution test, due to the collapse of the porous structure of the carrier, API release rate was slightly slower than from the granules.

• Keywords: self-microemulsifying drug delivery system, solid self-microemulsifying drug delivery system, self-microemulsifying tablet, carvedilol, wet granulation