Dermal delivery of tacrolimus - comparative formulation and preclinical evaluation of microemulsions, nanoemulsions and nanostructured lipid carriers as novel carriers for poorly water- soluble drugs

dermatitisa. Danas je na tržištu registrovan samo jedan farmaceutski oblik sa takrolimusom zaprimenu na koži - mast. Zbog nepoželjnih karakteristika masti (masna tekstura, teško razmazivanje,sporo upijanje, teško spiranje) i težnje da se poboljša njegova isporuka u kožu, sve je veća potrebaza razvojem novih, naprednih nosača sa takrolimusom, kao što su mikroemulzije, nanoemulzije ilipidne nanočestice.Usled njihove kompleksnosti, razvoj ovih nosača je dugotrajan i neizvestan proces. Stoga jecilj ove doktorske disertacije bio formulisanje mikroemulzija, nanoemulzija i nanostrukturiranihlipidnih čestica stabilizovanih lecitinom, kao nosača za dermalnu isporuku takrolimusa.Perspektivni nosači su podvrgnuti sveobuhvatnoj fizičkohemijskoj karakterizaciji i studijistabilnosti, a dermalna isporuka takrolimusa upoređena je sa referentnom mašću.Formulaciona istraživanja omogućila su skupljanje znanja o kritičnim formulacionim iprocesnim parametarima za dobijanje stabilnih nosača sa takrolimusom. U dvočasovnoj in vitrostudiji penetracije takrolimusa u kožu uha svinje korišćenjem metode sa trakama, uočeno je da surazvijeni nosači superiorniji u poređenju sa referentnom mašću i omogućavaju bolju isporukutakrolimusa u stratum corneum. Takrolimus je u značajnoj meri penetrirao u folikule dlaka, štododatno može da osigura bolju dermalnu isporuku. Ipak, rezultati 24-časovne in vitro studijepermeacije kroz kožu uha svinje pune debljine korišćenjem Franz-ovih difuzionih ćelija ukazuju nabolju permeaciju takrolimusa iz mikroemulzije i referentne masti u poređenju sa nanostrukturiranimlipidnim česticama i nanoemulzijom, što može ukazivati i na mogućnost ispoljavanja sistemskihneželjenih efekata.Generalno, rezultati ukazuju na veliki potencijal dobijenih nosača za dermalnu isporukutakrolimusa, što bi trebalo potvrditi odgovarajućim kliničkim eksperimentalnim postavkama.Tacrolimus is a potent immunosuppressive macrolide which is topically used for treatment ofatopic dermatitis. Today, there is only one pharmaceutical form for topical application of tacrolimus- tacrolimus ointment. Due to the undesirable characteristics of ointments (greasy texture, difficultyof applying and spreading onto the skin, difficulty to wash them off) and desirable enhancement indermal delivery, there is an emerging need for development of novel carriers for tacrolimus, such asmicroemulsions, nanoemulsions and lipid nanoparticles.Owing to their complexity, the development of these carriers can be a long-lasting anduncertain process. Therefore, the aim of this doctoral thesis was to formulate lecithin basedmicroemulsions, nanoemulsions and nanostructured lipid carriers as novel carriers for dermaldelivery of tacrolimus. The physicochemical characteristics and stability of promising carriers wasassessed, and dermal delivery of tacrolimus was compared to the referent ointment.The formulation evaluation acquired important knowledge about the critical parameters forobtaining stabile carriers with tacrolimus. Results of in vitro penetration of tacrolimus in porcine earskin suggested superiority of the developed carriers compared to the referent ointment.Additionally, the delivery of tacrolimus into the hair follicles was increased as well, which couldprovide better dermal delivery of tacrolimus. On the other hand, the results of 24-hour in vitropermeation study using Franz diffusion cells and full thickness porcine ear skin indicated betterpermeation of tacrolimus from the microemulsion and the referent ointment compared to thenanostructured lipid carrier and the nanoemulsion, which can also suggest a risk of systemicadverse effects by their usage.Overall, the developed carriers could be suggested as promising carriers for dermal deliveryof tacrolimus, which should be confirmed by appropriate clinical evaluation