Hemijski i fizički pojačivači dermalne isporuke slabo rastvorljivih lekovitih supstanci: uporedna ispitivanja mikroemulzija, čvrstih i rastvorljivih mikroigala

Abstract

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 uspešno 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 applied 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.