Vpliv deaktivacije površine poroznih nosilcev na proces izdelave in lastnosti trdnih samo-(mikro)emulgirajočih sistemov s karvedilolom

Ban, Pia (avtor), Zvonar Pobirk, Alenka (mentor)

Med novo odkritimi zdravilnimi učinkovinami (ZU) prevladujejo slabo vodotopne učinkovine. Slaba vodotopnost negativno vpliva na absorpcijo teh učinkovin, kar ima za posledico nizko biološko uporabnost (BU). Da dosežemo terapevtske koncentracije tovrstnih ZU v sistemskem krvnem obtoku, je potrebna bodisi aplikacija večjega odmerka ZU, kar lahko vodi do neželenih učinkov, ali izboljšanje njene vodotopnosti s pomočjo različnih pristopov. Eden izmed tehnoloških pristopov je vgradnja ZU v na lipidnih osnovane dostavne sisteme, med katerimi so najbolj proučevani samo-(mikro)emulgirajoči sistemi (SMES). V njih je ZU raztopljena, po zaužitju pa v prebavnem traktu v prisotnosti vodne faze pride do spontane tvorbe (mikro)emulzije tipa olje v vodi. Ker so SMES v tekoči obliki, je v zadnjih desetih letih veliko pozornosti usmerjene v postopek njhove pretvorbe v trdno obliko, v kateri bi bile prednosti tekočih SMES združene s prednostmi bolj zaželenih trdnih farmacevtskih oblik. V magistrski nalogi smo se osredotočili na pretvorbo tekočega SMES v trdno obliko z metodama direktne adsorpcije in sušenja z razprševanjem z uporabo trdnih poroznih nosilcev ter ovrednotenje dobljenih produktov. Kot modelno učinkovino smo uporabili karvedilol, ki spada v II. razred po biofarmacevtskem klasifikacijskem sistemu (slabo topna v vodi in dobro permeabilna ZU). V procesu izdelave trdnih samo-(mikro)emulgirajočih prahov smo tekoči SMES z ZU adsorbirali na oziroma v porozne nosilce (Aeroperl® 300 Pharma, Florite® R, Neusilin® US2, Syloid® 244 FP in Syloid® XDP 3050), pri čemer smo spreminjali razmerje med tekočim SMES z ZU in nosilcem (1:1 in 2:1). V literaturi je opisano nepopolno sproščanje ZU iz nosilcev, zato smo za dosego popolnega sproščanja površino slednjim delno deaktivirali z delno zapolnitvijo por. Za to smo uporabili polimere Pharmacoat® 606, PVP K30 in PVP K90. Tako metoda direktne adsorpcije kot sušenje z razprševanjem sta se izkazali kot primerni za pripravo trdnih SMES (ang. »solid« SMES oziroma S-SMES), pri čemer je delna deaktivacija površine nosilcev nekoliko znižala kapaciteto slednjih za adsorpcijo SMES, a povečala obseg sproščene ZU tako v mediju s pH=1,2 kot tudi v pH=6,8. Samo-(mikro)emulgirajočim prahovom smo določili tudi pretočne lastnosti, ki bi jih bilo pred postopkom tabletiranja ali kapsuliranja potrebno izboljšati z dodatkom drsil. Proučevali smo tudi močenje nosilcev pred in po deaktivaciji površine ter trdnih produktov z vodo, SMES ter vodno disperzijo SMES z metodo merjenja stičnega kota sedeče kapljice. Zanimalo nas je, ali obstaja korelacija med močenjem nosilcev z izbranimi tekočinami in določenimi lastnostmi S-SMES (deaktivacija površine, hitrost sproščanja ZU, izkoristek procesa sušenja z razprševanjem). V skladu s pričakovanji je bil stični kot vode nižji na produktih z večjim deležem SMES, kar potrjuje večjo adsorpcijo slednjega na površino nosilcev. Delna deaktivacija površine je vplivala na povečanje kota močenja, kar nakazuje na nalaganje polimera na površino nosilcev. Z metodo diferenčne dinamične kalorimetrije smo potrdili, da ZU v S-SMES ne kristalizira. Zaradi hitre sprostitve ZU iz S-SMES, ki smo jo opazili pri in vitro testu sproščanja, lahko predvidevamo tudi povečano BU. Z veliko količino hkrati sproščene ZU bi lahko nasitili jetrne encime in s tem zmanjšali obseg predsistemskega metabolizma, ki je v primeru karvedilola en od poglavitnih razlogov za slabo BU.

• Jezik: Slovenski jezik
• Ključne besede: samo-(mikro)emulgirajoči sistemi (SMES), trdni samo-(mikro)emulgirajoči sistemi (S-SMES), sušenje z razprševanjem, metoda direktne adsorpcije, delno zapolnjene pore, karvedilol
• Vrsta gradiva: Magistrsko delo/naloga
• Organizacija: FFA - Fakulteta za farmacijo
• Leto izida: 2021
• PID: 20.500.12556/RUL-124667
• Datum objave v RUL: 06.02.2021

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Porous carriers' surface deactivation influence on manufacturing process and characteristics of solid carvedilol-loaded self-(micro)emulsifying systems

Izvleček

Many newly discovered pharmacologically active ingredients are poorly water-soluble. Consequently, the absorption and bioavailability of such drugs are compromised and higher dosages are required to achieve desired therapeutic concentrations. To reduce adverse effects related to higher administered dosages, it is possible to improve the drug solubility by incorporating the active pharmaceutical ingredients (APIs) into lipid formulations. Among the most studied are self-(micro)emulsifying drug delivery systems (S(M)EDDS), where API is already present in the dissolved state. S(M)EDDS spontaneously form oil-in-water (micro)emulsion in an aqueous medium of our gastrointestinal tract after oral intake. During the last ten years, research was widely focused on the S(M)EDDS solidification to optimize advantages of preferred solid pharmaceutical dosage forms while keeping their desired properties. The aim of our work was the transformation of liquid S(M)EDDS into solid state by direct adsorption method and spray drying with the use of solid porous carriers, followed by evaluation of products. Carvedilol was used as a model of poorly soluble drug; it belongs to the Class II according to Biopharmaceutical Classification System because of its poor solubility and good permeability. In the process of making solid S(M)EDDS (S-S(M)EDDS), carvedilol loaded S(M)EDDS were adsorbed onto porous carriers (Aeroperl® 300 Pharma, Florite® R, Neusilin® US2, Syloid® 244 FP and Syloid® XDP 3050) in different ratios (1:1 and 2:1). Since incomplete desorption of API from carriers was reported in literature, the surface of used carriers was partially deactivated with partial pre-filling of pores with polymers (Pharmacoat® 606, PVP K30 and PVP K90) to achieve a higher API desorption from S-S(M)EDDS after redispersion. S-S(M)EDDS were successfully produced with both solidification methods. Pre-filling of the pores lowered the capacity for adsorption of S(M)EDDS onto carrier but allowed a higher desorption of API in the medium with pH=1,2 and pH=6,8. The flowability of the products would have to be improved by addition of lubricants prior to compressing into tablets or filling into capsules. The wettability was determined by sessile drop method with water, S(M)EDDS and S(M)EDDS dissolution before and after the deactivation of carrier’s surface. Additionally, the wettability was measured on S-S(M)EDDS. The correlation between wettability of the carriers and S-S(M)EDDS characteristics was assessed by comparing deactivation of the surface, the rate of API desorption and yield of spray drying method. The wetting angle of water on S-S(M)EDDS was lower when the ratio between S(M)EDDS and carriers was higher, which suggests that more S(M)EDDS was adsorbed onto the surface. Partial deactivation of carrier’s surface resulted in a higher wetting angle, which shows that polymer was also adsorbed on the surface. API did not crystalize in S-S(M)EDDS according to our analysis with differential scanning calorimetry. A desorption rate of API from S-S(M)EDDS observed by performing in vitro dissolution tests was fast, indicating the possibility of achieving a higher bioavailability using such systems. Because of a high dose of API released over a short period of time after oral intake, the drug metabolizing enzymes in the liver could be saturated, resulting in a lower first pass metabolism of carvedilol and subsequently, a higher bioavailability of the drug after oral intake.

• Ključne besede: self-(micro)emulsifying drug delivery systems (S(M)EDDS), solid self-(micro)emulsifying drug delivery systems (S-S(M)EDDS), spray drying, direct adsorption methode, partial pre-filling of the pores, carvedilol