Razvoj hidrofilnih nanovlaken za izboljšanje raztapljanja lovastatina

Strle, Maja (author), Kocbek, Petra (mentor), Kajdič, Saša (co-mentor)

Izdelava hidrofilnih polimernih nanovlaken predstavlja sodoben pristop za izboljšanje topnosti in hitrosti raztapljanja slabo topnih učinkovin, kot je lovastatin. Tako smo v okviru magistrske naloge z metodo elektrostatskega sukanja etanolnih raztopin polimerov izdelali nanovlakna z lovastatinom. Njihove lastnosti smo primerjali s polimernimi filmi ter fizikalnimi zmesmi z enako kvalitativno in kvantitativno sestavo. Uporabili smo različne hidrofilne polimere, in sicer polietilenoksid, poloksamer 407, poloksamer 188 in Soluplus. Uspešnost izdelave ter morfologijo izdelanih nanovlaken in polimernih filmov smo vrednotili s pomočjo vrstične elektronske mikroskopije. Ugotavljali smo hitrost sproščanja lovastatina v fosfatnem pufru in njegove koncentracije v vzorcih določali s pomočjo tekočinske kromatografije ultra visoke ločljivosti. Pri formulacijah s poloksamerom 407 in poloksamerom 188 nismo dosegli zastavljenega cilja, da bi z izdelavo nanovlaken pospešili hitrost raztapljanja lovastatina, v primerjavi s polimernim filmom. S fotonsko korelacijsko spektroskopijo smo izmerili velikost delcev, ki nastanejo po dispergiranju vzorcev v prečiščeni vodi in ugotovili, da so tisti, ki so nastali z dispergiranjem nanovlaken s poloksamerom 188, večji od tistih, nastalih z dispergiranjem polimernega filma. Posledično je bila hitrost raztapljanja lovastatina v obliki filma večja kot v obliki nanovlaken. Zamenjava poloksamerov s Soluplusom v sestavi nanovlaken, je povečala hitrost sproščanja lovastatina. Topnost lovastatina smo z izdelavo polimernega filma povečali za več kot 2-krat, z izdelavo nanovlaken pa za več kot 3-krat, glede na njegovo topnost v obliki fizikalne zmesi. Ker je lovastatin pri višjih temperaturah in ob prisotnosti vode in kisika precej nestabilen, smo v vse formulacije dodali antioksidante, askorbinsko kislino in butil hidroksianizol ter tako v vzorcih takoj po izdelavi dosegli skoraj 100 % vsebnost lovastatina. Med pospešeno stabilnostno študijo smo nanovlakna izbrane formulacije s Soluplusom, z in brez dodanih antioksidantov, izpostavili temperaturi 40 °C in relativni vlažnosti 75 %, ter tekom 56 dni spremljali vsebnost lovastatina. Ta je v nanovlaknih brez antioksidantov v 56 dneh padla na 82 %, v nanovlaknih z antioksidanti pa na 91 %. Z zmanjševanjem vsebnosti lovastatina se je v vzorcih povečevala količina lovastatinske kisline, glavnega produkta hidrolize. Izdelava hidrofilnih nanovlaken se je v naši raziskavi izkazala za učinkovit pristop za izboljšanje topnosti in hitrosti raztapljanja lovastatina. Dodani antioksidanti so lovastatin uspešno zaščitili pred oksidacijo med izdelavo nanovlaken, medtem ko v stresnih pogojih testiranja ta učinkovina ni bila popolnoma zaščitena pred oksidacijo.

• Language: Slovenian
• Keywords: lovastatin, topnost, nanovlakna, polimerni film, hitrost raztapljanja, stabilnost
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-111155
• Publication date in RUL: 25.09.2019

Secondary language

• Language: English
• Title: Development of hydrophilic nanofibers for enhanced dissolution of lovastatin

Abstract

The preparation of hydrophilic polymer nanofibers represents a modern approach to improve the solubility and dissolution rate of poorly soluble drugs such as lovastatin. Thus, in the scope of the master's thesis, nanofibers with lovastatin were prepared by electrospinning of ethanol polymer solutions. Their properties were compared to polymer films and physical mixtures with the same qualitative and quantitative composition. We used hydrophilic polymers, namely polyethylene oxide, poloxamer 407, poloxamer 188 and Soluplus. The fabrication performance and morphology of nanofibers and polymer films were evaluated by scanning electron microscopy. Dissolution rate and the concentration of lovastatin released in phosphate buffer with SDS were determined by ultra performance liquid chromatography analysis. The formulations with poloxamer 407 and poloxamer 188 did not meet the goal to increase the dissolution rate of lovastatin from nanofibers compared to the polymer film. Using photon correlation spectroscopy, we measured the particle size of samples dispersed in purified water. The particles in the dispersion of poloxamer 188 nanofibers were larger than those in the dispersion of polymer film. Thus, the dissolution rate of lovastatin in polymer film was higher than that of nanofibers. Replacement of poloxamers with Soluplus in nanofibers increased the rate of lovastatin release. The solubility of lovastatin was increased more than 2 times by the preparation of polymer film and more than 3 times by the preparation of nanofibers, compared to its solubility in the form of a physical mixture. Lovastatin is quite unstable at high temperatures in the presence of water and oxygen, therefore, the antioxidants, namely ascorbic acid and butylated hydroxyanisole, were added to all formulations to achieve almost 100% lovastatin content in samples immediately after preparation. During the accelerated stability study, the selected formulation of nanofibers with Soluplus, with and without added antioxidants, was exposed to a temperature of 40 ° C and a relative humidity of 75 %. The drug content was monitored for 56 days. The lovastatin content decreased to 82% in 56 days in nanofibers without added antioxidants and to 91% in nanofibers with antioxidants. As the lovastatin content in the samples decreased, the amount of its main product of hydrolysis, namely lovastatin acid, increased. The preparation of hydrophilic nanofibers was shown in our study to be an effective approach to improve the solubility and dissolution rate of lovastatin. The antioxidants added successfully protected lovastatin from oxidation during nanofiber preparation, whereas under stress test conditions lovastatin was not completely protected from oxidation.

• Keywords: lovastatin, solubility, nanofiber, polymer film, dissolution rate, stability