Supersaturated polymeric micelles for oral cyclosporine A delivery

Abstract

Polymeric micelles provide a promising platform for improving oral absorption of poorly soluble drugs. However, improved understanding of how drug retention within the hydrophobic micelle core can reduce drug absorption is required. We designed supersaturated polymeric micelles (Super-PMs) to increase molecularly dissolved drug concentration and gain an insight into the effect of the degree of supersaturation on oral absorption of cyclosporine A (CsA) in rats. The drug release from Super-PMs increased with an increase in initial supersaturation degrees in micelles. The cellular uptake of coumarin-6 was reduced by the retention of drug in polymer micelles. The transport flux of CsA across Caco-2 monolayer was increased with initial supersaturation degrees of 0.81-3.53 (p < 0.05). However, increase in supersaturation to 5.64 actually resulted in decreased CsA transport. The same trend was observed in a rat in vivo absorption study, in which the highest bioavailability of 134.6 ± 24.7% (relative to a commercial product, Sandimmun Neoral®, p<0.01) was achieved when the supersaturation degree was 3.53. These results demonstrated that Super-PMs were a promising drug delivery system for compounds with low aqueous solubility. This study also provided an experimental proof for the hypothesis that moderately supersaturated formulations are valuable alternative to high supersaturation formulations, resulting in optimal in vivo performance, and the degree of supersaturation should be carefully controlled to optimize drug absorption.

Keywords: 2-(4-amidinophenyl)-6-indolecarbamidine dihydrochloride; AP; AUC(0–24h); BL; C(max); CR; CS; Cellular uptake and transport; CsA; CsD; Cyclosporine A; DAPI; EE; HBSS; HPMC-AS; HS; Hank’s balanced salt solution; LC; LOD; LOQ; LS; Oral bioavailability; P-glycoprotein; P-gp; PCS; PMs; RBA; Rh123; Soluplus®; Supersaturated polymeric micelle; Supersaturation degree; T(max); TEM; Tf; Verap; apical; area under the blood drug concentration–time curve; basolateral; coumarin-6 reference solution; coumarin-6-loaded Cremophor RH40 micelles; cyclosporine A; cyclosporine D; entrapment efficiency; high Soluplus® concentration; hydroxypropyl methylcellulose acetate succinate; limit of detection; limit of quantification; loading content; low Soluplus® concentration; maximal blood concentration of the drug; photon correlation spectroscopy; polymeric micelles; relative oral bioavailability; rhodamine 123; time taken to reach the maximum blood concentration; transmission electron microscopy; transport flux; verapamil.