Supersaturated polymeric micelles for oral cyclosporine A delivery |
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Affiliation: | 1. Universite Clermont Auvergne, Chu Clermont Ferrand, CNRS, Sigma Clermont, ICCF, F-63000 Clermont-Ferrand, France;2. Chu Clermont-Ferrand, Pole Pharmacie, F-63000 Clermont-Ferrand, France;3. Chu Clermont-Ferrand, Service Ophtalmologie, F-63000 Clermont-Ferrand, France |
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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. |
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Keywords: | Supersaturated polymeric micelle Cyclosporine A Soluplus® Supersaturation degree Oral bioavailability Cellular uptake and transport CsA" },{" #name" :" keyword" ," $" :{" id" :" k0035" }," $$" :[{" #name" :" text" ," _" :" cyclosporine A CsD" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" cyclosporine D P-gp" },{" #name" :" keyword" ," $" :{" id" :" k0055" }," $$" :[{" #name" :" text" ," _" :" P-glycoprotein PMs" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" polymeric micelles HPMC-AS" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" hydroxypropyl methylcellulose acetate succinate DAPI" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," _" :" 2-(4-amidinophenyl)-6-indolecarbamidine dihydrochloride LC" },{" #name" :" keyword" ," $" :{" id" :" k0095" }," $$" :[{" #name" :" text" ," _" :" loading content EE" },{" #name" :" keyword" ," $" :{" id" :" k0105" }," $$" :[{" #name" :" text" ," _" :" entrapment efficiency TEM" },{" #name" :" keyword" ," $" :{" id" :" k0115" }," $$" :[{" #name" :" text" ," _" :" transmission electron microscopy PCS" },{" #name" :" keyword" ," $" :{" id" :" k0125" }," $$" :[{" #name" :" text" ," _" :" photon correlation spectroscopy HBSS" },{" #name" :" keyword" ," $" :{" id" :" k0135" }," $$" :[{" #name" :" text" ," _" :" Hank’s balanced salt solution Rh123" },{" #name" :" keyword" ," $" :{" id" :" k0145" }," $$" :[{" #name" :" text" ," _" :" rhodamine 123 LS" },{" #name" :" keyword" ," $" :{" id" :" k0155" }," $$" :[{" #name" :" text" ," _" :" low Soluplus® concentration HS" },{" #name" :" keyword" ," $" :{" id" :" k0165" }," $$" :[{" #name" :" text" ," _" :" high Soluplus® concentration CR" },{" #name" :" keyword" ," $" :{" id" :" k0175" }," $$" :[{" #name" :" text" ," _" :" coumarin-6-loaded Cremophor RH40 micelles CS" },{" #name" :" keyword" ," $" :{" id" :" k0185" }," $$" :[{" #name" :" text" ," _" :" coumarin-6 reference solution Verap" },{" #name" :" keyword" ," $" :{" id" :" k0195" }," $$" :[{" #name" :" text" ," _" :" verapamil AP" },{" #name" :" keyword" ," $" :{" id" :" k0205" }," $$" :[{" #name" :" text" ," _" :" apical BL" },{" #name" :" keyword" ," $" :{" id" :" k0215" }," $$" :[{" #name" :" text" ," _" :" basolateral LOD" },{" #name" :" keyword" ," $" :{" id" :" k0225" }," $$" :[{" #name" :" text" ," _" :" limit of detection LOQ" },{" #name" :" keyword" ," $" :{" id" :" k0235" }," $$" :[{" #name" :" text" ," _" :" limit of quantification maximal blood concentration of the drug time taken to reach the maximum blood concentration area under the blood drug concentration–time curve RBA" },{" #name" :" keyword" ," $" :{" id" :" k0275" }," $$" :[{" #name" :" text" ," _" :" relative oral bioavailability Tf" },{" #name" :" keyword" ," $" :{" id" :" k0285" }," $$" :[{" #name" :" text" ," _" :" transport flux |
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