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Razvoj posušenih emulzij s simvastatinom, z uporabo tehnologije sušenja z razprševanjem
ID Perger, Zala (Author), ID Dreu, Rok (Mentor) More about this mentor... This link opens in a new window, ID Pohlen, Mitja (Co-mentor)

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Abstract
Simvastatin spada v II. razred BCS klasifikacije zdravilnih učinkovin, kar pomeni, da ima slabo vodotopnost in dobro permeabilnost. Slaba vodotopnost simvastatina vodi do pomislekov pri kronični uporabi zaradi nižje biološke uporabnosti. Uporaba na lipidih osnovanih sistemov se je uveljavila kot eden izmed pristopov povečanja topnosti in posledično biološke uporabnosti slabo vodotopnih lipofilnih zdravilnih učinkovin. Dodatno lahko na lipidih osnovani sistemi, ob ustreznih pogojih, nudijo tudi zmanjšanje učinka metabolizma prvega prehoda z izkoriščanjem alternativne poti absorpcije preko limfnega obtoka. Tekoče emulzije nudijo številne prednosti na lipidih osnovanih sistemov, vendar imajo tudi nekatere slabosti, kot sta fizikalna nestabilnost in zmanjšana kemijska stabilnost zdravilne učinkovine. S pretvorbo tekočih emulzij v posušene emulzije smo poskušali oblikovati formulacijo za peroralno dostavo učinkovine, ki bi odpravila slabosti tekočih emulzij ter z redispergiranjem ohranila prednosti na lipidih osnovanih sistemov. S postopkom sušenja z razprševanjem smo oblikovali delce, ki so nam v vodnem mediju omogočili samodejno redispergiranje posušene emulzije. Izdelane posušene emulzije smo vrednotili z vidika porazdelitve velikosti delcev, izkoristka procesa, pretočnih lastnosti, vsebnosti vlage, stabilnosti vgrajene učinkovine, učinkovitosti redispergiranja, učinkovitosti vgradnje učinkovine in profila sproščanja. Rezultati preliminarnih testiranj v začetnih stopnjah eksperimentalnega dela so služili kot izhodišče za določitev mej neodvisnih spremenljivk in postavitev eksperimentalnega načrta. Neodvisne spremenljivke so zajemale: koncentracijo nevodnih komponent, masni delež olja in emulgatorja, geometrijo šobe in tlak na šobi. Na podlagi rezultatov izvedenih poskusov eksperimentalnega načrta smo postavili modele kvantitativnega vpliva faktorjev na odzive, z relativno visokimi koeficienti determinacije ter optimizirali tako sestavo emulzije kot procesne parametre z vidika ključnih atributov kakovosti produkta. Optimizirali smo ustreznost redispergiranja, kemijsko stabilnost simvastatina in učinkovitost vgradnje simvastatina. Ustreznost optimizacije se je izkazala v izboljšanju enomesečne stabilnosti simvastatina v posušenih emulzijah in v izboljšani rekonstituciji emulzije. S pripravo optimizirane formulacije in merjenjem odziva, modela učinkovitosti vgradnje učinkovine nismo potrdili, zato ne moremo trditi kateri parametri in v kakšni meri vplivajo na vgradnjo simvastatina v posušene emulzije. Izboljšanje profila sproščanja v primerjavi s trenutno dostopnimi produkti na tržišču nakazuje na potencial povečanja biološke uporabnosti simvastatina po peroralni aplikaciji.

Language:Slovenian
Keywords:posušene emulzije, sušenje z razprševanjem, simvastatin, statistično načrtovanje poskusov, redispergiranje
Work type:Master's thesis/paper
Organization:FFA - Faculty of Pharmacy
Year:2020
PID:20.500.12556/RUL-119768 This link opens in a new window
Publication date in RUL:11.09.2020
Views:1378
Downloads:181
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Secondary language

Language:English
Title:Development of simvastatin containing dried emulsions by using spray drying technology
Abstract:
Simvastatin is classified as a Biopharmaceutics Classification System Class – II active pharmaceutical ingredient, which means that it has low water solubility and high permeability. The poor water solubility of simvastatin leads to concerns with chronic use, due to it's lower bioavailability. The use of lipid-based drug delivery systems has emerged as one of the approaches to increase the solubility and consequently bioavailability of poorly water soluble lipophilic active pharmaceutical ingredients. In addition, lipid-based systems may, under appropriate conditions, also reduce the effect of first-pass metabolism by exploiting an alternative route of absorption through the lymphatic circulation. Liquid emulsions offer many advantages of lipid-based systems, but they also have some disadvantages, such as physical instability and reduced chemical stability of active pharmaceutical ingredient. By converting emulsions into dry emulsions, we tried to design a solid dosage form for oral application, which would eliminate the disadvantages of liquid emulsions and maintain the advantages of lipid-based systems by redispersion. Through the spray drying technology we formed particles that allowed us to automatically redisperse the dry emulsion in an aqueous medium. Dry emulsions produced were evaluated in terms of particle size distribution, process yield, flow properties, moisture content, stability of simvastatin in dry emulsion, emulsion reconstitution ability, efficiency of incorporation of the active ingredient and dissolution profile. The results of preliminary formulation development in the initial stages of experimental work served as a starting point for determining the boundaries of the independent variables and setting the experimental design. The independent variables included: concentration of non-aqueous components, oil and emulsifier mass fraction, nozzle geometry and nozzle pressure. Based on the results of the experimental design experiments, we set up models with relatively high determination coefficients and optimize both the emulsion composition and the process parameters in terms of key product quality attributes. We optimized the adequacy of redispersion, chemical stability of simvastatin, and the effectiveness of simvastatin incorporation. Optimization adequacy has been demonstrated in improving the one-month stability of simvastatin in dry emulsions and in the improved reconstitution of the emulsion. By preparing an optimized formulation and measuring the response, we have not confirmed the drug loading model, so we cannot state which parameters and to what extent affect the drug loading of simvastatin into dry emulsions. Enhanced dissolution profile, compared to currently available products on the market, indicates the potential for increased bioavailability after oral administration.

Keywords:dry emulsions, spray-drying, simvastatin, design of experiments, redispersibility

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