Hemijski i fizički pojačivači dermalne isporuke slabo rastvorljivih lekovitih supstanci: uporedna ispitivanja mikroemulzija, čvrstih i rastvorljivih mikroigala
Chemical and physical enharcens for dermal delivery of poorly soluble drugs: comparative study of microemulsions, solid and dissolvable microneedles
Докторанд
Bubić Pajić, NatašaМентор
Savić, SnežanaЧланови комисије
Vučen, SonjaPantelić, Ivana
Škrbić, Ranko
Метаподаци
Приказ свих података о дисертацијиСажетак
Primarni cilj istraživanja ove doktorske disertacije je bila procena mogućnosti da se razvojem
i primenom mikroemulzija (kao opcije hemijskog inhensera penetracije) poboljša dermalna
isporuka slabo rastvorljivih lekovitih supstanci – adapalena (ADA) i sertakonazol-nitrata (SN), koje
pripadaju različitim farmakoterapijskim grupama, imaju različite fizičkohemijske osobine i
primenjuju se u različitim terapijskim koncentracijama. Mikroemulzije su stabilizovane nejonskim
surfaktantima novije generacije – alkil poligukozidima (APG) ili polioksietilen(glicerol) estrima
masnih kiselina. U cilju komparativne procene doprinosa različitih vrsta nosača dermalnoj
raspoloživosti model leka, posebna pažnja je posvećena analizi sposobnosti različitih vrsta
mikroigala (fizički inhenseri penetracije) da pojačaju isporuku SN u kožu (čvrste silikonske vs.
rastvorljive mikroigle).
Rezultati su ukazali da se još uvek nedovoljno korišćeni APG surfaktanti i gliceret-7-
kaprilat/kaprat mogu uspeš...no primeniti u formulaciji mikroemulzija. Razvijene (invertne)
bikontinuirane mikroemulzije su se pokazale kao pogodni nosači za solubilizovanje ADA i SN, u
pogledu njihovih fizičkohemijskih osobina, bezbednosti i stabilnosti, i, najvažnije, u pogledu
njihovog potencijala za poboljšanje dermalne isporuke ovih lekova in vitro. Dodatno, rastvorljive
mikroigle su uspešno formulisane kao nosači za dermalnu isporuku teško rastvorljivog SN i
obezbedile komparabilno deponovanje leka u koži kao mikroemulzije, međutim uz prisustvo in
vitro transdermalne isporuke dela primenjene doze leka. Sinergističko delovanje mikroigala i
mikroemulzija bilo je superiorno u odnosu primenu samog fizičkog i samog hemijskog
premošćivača barijere stratum corneum-a, bez značajnog povećanja permeacije leka.
The aim of this doctoral dissertation was to evaluate the possibility of using microemulsions
(as chemical penetration inerters) for improvment of dermal delivery of a poorly soluble model
dugs having different physicochemical characteristics, belonging to different pharmacotherapeutic
groups, i.e. applied in different therapeutic concentrations (adapalene (ADA) and sertaconazole
nitrate (SN)). Microemulsions were stabilized with newer nonionic surfactants - alkyl
polygucosides (APG) or polyoxyethylene (glycerol) fatty acid esters. In order to compare the
contribution of different types of carriers to the enhancement of dermal availability of the model
drug, a special attention has been paid to the assessment of microneedles ability to significantly
improve delivery of SN into the skin (dissolvable vs. solid silicone microneedles).
The obtained results showed that newer and so far insufficiently used APG surfactants and
glycereth-7-caprylate/caprate can be successfully applie...d in the formulation of microemulsions. The
developed (invert) bicontinuous microemulsion formulations have proved to be suitable carriers for
solubilizing the investigated model drugs, in terms of their physicochemical properties, safety
profile and stability, and, most importantly, their great potential of improving dermal delivery of
ADA and SN in vitro. In addition, dissolvable microneedles were successfully fabricated as carriers
for dermal delivery o highly lipophilic SN and provided comparable drug deposition in the skin as
microemulsions, but coupled with transdermal delivery of a portion of the administered drug dose.
The synergistic action of microneedles and microemulsions was superior over the application either
of physical or chemical enhancer alone, without reaching a significant increase in drug permeation
as compared to the use of dissolvable microneedles.