Curcumin-loaded parenteral nanoemulsions: the impact of PEGylated phospholipids on physicochemical characteristics, long-term stability and in vitro/in vivo performance

[J. B. Đoković]

110 str.

Farmacija - Farmacutska tehnologija / Pharmacy - Pharmaceutical technology

Upotreba nanotehnologije u medicini je do sada uglavnom bila fokusirana na terapiju kancera, pa je njen pun potencijal u lečenju infektivnih oboljenja, genetskih bolesti, bolesti oka, ali i različitih stanja koja zahvataju nervni sistem tek potrebno istražiti. Kako bi se omogućilo da lekovita supstanca dospe do centralnog nervnog sistema, odnosno uspešno prođe krvno-moždanu barijeru, pre svega treba odabrati adekvatan put primene, ali i modifikovati sistem za njenu isporuku. PEGilovanje je strategija koja podrazumeva pokrivanje površine nanonosača lancima polietilenglikola koji smanjuju interakciju sa proteinima plazme i produžavaju vreme cirkulacije, dajući nosaču dovoljno vremena da dođe do ciljnog mesta delovanja. Kao model aktivna supstanca u ovom istraživanju je korišćen kurkumin, supstanca koja ima potencijal za lečenje različitih stanja i bolesti, ali i nepovoljne fizičkohemijske i farmakokinetičke osobine koje onemogućavaju dostizanje ciljnog mesta delovanja. Osnovni cilj ove disertacije je razvoj PEGilovanih nanoemulzija sa kurkuminom za parenteralnu primenu, njihova detaljna fizičkohemijska i strukturna analiza, kao i dugoročno praćenje stabilnosti. Radi sveobuhvatne procene uticaja procesnih parametara i faktora formulacije na karakteristike dobijenih nanoemulzija korišćena je metodologija eksperimentalnog dizajna. Posebna pažnja je posvećena određivanju uticaja izbora masne faze (sojinog ili ribljeg ulja) na karakteristike razvijenih formulacija, kao i proceni efikasnosti PEGilovanja, odnosno određivanju koncentracije PEGilovanih fosfolipida koja obezbeđuje optimalnu zaštitu površine kapi. Na kraju je procenjena neškodljivost i efikasnost razvijenih formulacija na ćelijskim kulturama, kao i uticaj PEGilovanja na sudbinu kurkumina nakon intravenske primene formulacija na eksperimentalnim životinjama. U sprovedenim istraživanjima je pokazano da je PEGilovanje poboljšalo dugoročnu stabilnost razvijenih nanoemulzija, bez negativnih uticaja na fizičkohemijske karakteristike ili antioksidativnu aktivnost. Dodatno je pokazano da kurkumin deluje kao stabilizator formulacija sa ribljim uljem, ali da upotreba ribljeg ulja ne doprinosi povećanju ukupnog antioksidativnog efekta formulacija. U analizama na ćelijskim kulturama je potvrđena njihova neškodljivost i efikasnost. Pilot studija farmakokinetike je pokazala da PEGilovanje pruža povećanje koncentracije kurkumina u plazmi i da može biti dobra opcija za povećanje isporuke u mozak.

but its full potential in the treatment of infectious, genetic, and eye diseases, as well as various conditions affecting the nervous system is yet to be fully explored. In order for the active substance to reach the central nervous system, and pass through the blood-brain barrier, a suitable route of administration must first be selected, and the drug delivery system should also be modified. PEGylation is a strategy in which the surface of a nanocarrier is covered with polyethylene glycol chains that reduce the carrier's interaction with plasma proteins and prolong its circulation time enabling sufficient opportunuties to reach the site of action. Curcumin, a model drug used in this research, has the potential to treat various conditions and diseases, but also possesses unfavourable physicochemical and pharmacokinetic properties that prevent it from reaching the target site of action. The main objective of this dissertation is the development of PEGylated nanoemulsions containing curcumin for parenteral administration, their detailed physicochemical and structural analysis and monitoring of long-term stability. A design of experiments methodology was used to comprehensively evaluate the influence of process parameters and formulation factors on the properties of the nanoemulsions obtained. Particular attention was paid to determining the influence of the oil phase selection (soybean or fish oil) on the properties of the developed formulations and to evaluating the effectiveness of PEGylation, i.e. determining the concentration of PEGylated phospholipids that ensures optimum protection of the droplet surface. Finally, the safety and efficacy of the developed formulations on different cell cultures and the influence of PEGylation on the fate of curcumin after intravenous administration to animal models were evaluated. The results showed that PEGylation improved the long-term stability of the developed nanoemulsions without any negative effects on their physicochemical properties or antioxidant activity. In addition, it was shown that curcumin acts as a stabiliser of formulations containing fish oil, but that the use of fish oil does not contribute to increasing the overall antioxidant activity of the formulations. Analyses on cell cultures confirmed its safety and efficacy. A pilot pharmacokinetic study showed that PEGylation leads to an increase in curcumin concentration in plasma and could be a good option for improving brain delivery.

kurkumin, PEGilovane nanoemulzije, parenteralna primena, eksperimentalni dizajn, efikasnost PEGilovanja, elektron paramagnetna rezonantna spektroskopija, injektabilnost, antioksidativna aktivnost, dugoročna stabilnost, pilot studija farmakokinetike

curcumin, PEGylated nanoemulsions, parenteral administration, experimental design, PEGylation efficacy, electron paramagnetic resonance spectroscopy, injectability, antioxidant activity, long-term stability, pilot study of pharmacokinetics

615.015(043.3)

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