Elektrostatsko sukanje polimernih nanovlaken z lovastatinom : enoviti magistrski študijski program Farmacija

Dolinšek, Bojan (author), Kocbek, Petra (mentor)

Majhna vodotopnost in hitrost raztapljanja zdravilnih učinkovin sta dandanes velika izziva pri razvoju formulacije, saj je veliko novih učinkovin težko vodotopnih. Med takšne učinkovine spada tudi lovastatin, zato je bil namen magistrske naloge povečati njegovo topnost in hitrost raztapljanja. To smo poskušali doseči z izdelavo polimernih nanovlaken z metodo elektrostatskega sukanja. Za izdelavo nanovlaken smo uporabili dva polimera poloksamer (407 ali 188), katerega osnovna vloga je bila povečevanje topnost lovastatina in polietilenoksid, ki je služil kot tvorilec nanovlaken. Da bi karseda povečali topnost lovastatina, smo najprej optimirali formulacijo, da je le-ta vsebovala čim več poloksamera in čim manj polietilenoksida. Kot referenčno formulacijo smo z vlivanjem izdelali polimerne filme. Morfološke lastnosti nanovlaken in polimernih filmov smo opazovali z vrstično elektronsko mikroskopijo. S testom sproščanja smo vrednotili profil sproščanja učinkovine iz izdelanih formulacij in ga primerjali s hitrostjo raztapljanja same učinkovine in njene fizikalne zmesi s polimeri. Z izdelavo nanovlaken in filmov smo uspeli povečati hitrost raztapljanja lovastatina. Le-ta je bila v primeru nanovlaken hitrejša kot v primeru filmov, kar je posledica večje površine in poroznosti mreže nanovlaken, lahko pa tudi odraz amorfne oblike lovastatina v nanovlaknih. Amorfnosti učinkovine z diferenčno kalorimetrijo nismo mogli potrditi, saj se je lovastatin raztopil v talini obeh polimerov. Dodatno smo uspeli pospešiti sproščanje lovastatina iz nanovlaken še z zamenjavo poloksamera 407 v formulaciji s poloksamerom 188. Ker je lovastatin občutljiv za oksidacijo in je nestabilen že med izdelavo nanovlaken, smo v formulacijo dodali antioksidanta in sicer askorbinsko kislino in butilhidroksianizol. Tako smo uspeli popolnoma stabilizirati učinkovino med izdelavo nanovlaken. Hitrost sproščanja iz formulacij z antioksidanti je bila počasnejša kot iz nanovlaken in filmov brez antioksidantov. Ugotovili smo, da je razlog celokupna vsebnost lovastatina v nanovlaknih, ki je bila večja, če je bil lovastatin stabiliziran. Pospešena stabilnostna študija (45 °C, relativna vlažnost 75 %) vzorcev nanovlaken brez in z antioksidanti je pokazala, da se vsebnost lovastatina v nanovlaknih brez antioksidantov s časom zmanjšuje, medtem ko je v nanovlaknih z antioksidanti ostala vsebnost tekom raziskave (84 dni) nespremenjena. Rezultati kažejo, da smo z vgrajevanjem lovastatina v nanovlakna uspeli povečati njegovo topnost in hitrost raztapljanja ter pripravili kemijsko stabilno formulacijo.

• Language: Slovenian
• Keywords: elektrostatsko sukanje lovastatin nanovlakna topnost učinkovin stabilnost učinkovin
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [B. Dolinšek]
• Year: 2017
• Number of pages: IX, 50 f.
• PID: 20.500.12556/RUL-120369
• UDC: 66.017-022.532:620.3(043.3)
• COBISS.SI-ID: 4432753
• Publication date in RUL: 18.09.2020

Secondary language

• Language: English
• Title: Electrospinning of polymer nanofibers with lovastatin

Abstract

Low solubility and low dissolution rate are nowadays two of the main challenges of formulation development as many of new discovered drugs are poorly soluble in water. Lovastatin is one of them and thus the aim of the masters thesis was increasing its solubility and dissolution rate. We achieved that by preparation of electrospun nanofibers from polymer solution of poloxamer (407 or 188) and polyethylene oxide. Main role of poloxamer in the formulation was increasing solubility of lovastatin while polyethylene oxide enabled nanofiber formation. To increase solubility of lovastatin as much possible the formulation was optimized in a way that it consisted of as little polyethylene oxide as possible and as much poloxamer as possible. As a reference formulation polymer films were prepared by film casting. Morphology of nanofibers and films was observed with scanning electron microscopy. Dissolution test was used to evaluate the drug release from prepared formulations in comparison with the dissolution rate of pure drug and its physical mixture with polymers. Dissolution rate of lovastatin was increased by production of nanofibers and polymer films compared to physical mixture and lovastatin itself. Dissolution rate of lovastatin from nanofibers was higher compared to dissolution rate from films due to bigger surface area and porosity of nanofiber mats. Amorphous form of lovastatin in nanofibers could also be a reason for higher dissolution rate from nanofibers, but that could not be confirmed by differential scanning calorimetry, since the drug dissolved in polymer melt. Lovastatin release rate was increased even more by replacing poloxamer 407 in nanofiber formulation with poloxamer 188. Antioxidants butylhydroxianysole and ascorbic acid were added to the formulation to stabilize lovastatin during production of nanofibers since the drug is prone to oxidation. Dissolution rate of lovastatin from the formulations with antioxidants was lower, which was attributed to the higher quantity of lovastatin in nanofibers. Accelerated stability study (45 °C and 75 % relative humidity) showed a decrease in lovastatin content in nanofibers without antioxidants while the content of lovastatin in nanofibers with antioxidants was unchanged throughout the experiment (84 days). With this research we successfully increased solubility and dissolution rate of lovastatin by its loading in nanofibers and prepared chemically stable formulation.