Title:Polymer Hydrophobicity Has a Positive Effect on the Oral Absorption of Cyclosporine A from Poly(ethylenimine) Based Nanomedicines
VOLUME: 1 ISSUE: 1
Author(s):Hang T.B Le, Andreas G. Schätzlein and Ijeoma F. Uchegbu
Affiliation:UCL School of Pharmacy, London WC1N 1AX, UK.
Keywords:Bioavailability, cyclosporine A, nanomedicines, nanoparticles, oral absorption, poly(ethylenimine).
Abstract:Hydrophobic drugs are problematic to deliver. We have previously shown that poly(ethylenimine) (PEI) amphiphile
nanoparticles facilitate the oral absorption of the model drug cyclosporine A (CsA). We hypothesised that polymer
molecular features (molecular weight, a branched or linear polymer architecture, polymer hydrophobicity) would
drive this oral absorption enhancement. To test this hypothesis, we synthesised five linear PEI amphiphiles (Mn ~ 1.3 kDa
or 13 kDa) and two branched PEI amphiphiles (Mn ~ 4 kDa or 10 kDa) by cetylation of PEI, followed by methylation to
give N-cetyl, N-methyl, N,N-dimethyl, N,N,N-trimethyl poly(ethylenimines). Polymer aggregation, CsAencapsulation,
polymer in vitro cytotoxicity and polymer enabled oral drug absorption were all studied. The polymers aggregated in
aqueous media, with critical micellar concentrations (CMCs) ranging from 0.2 – 0.9 mg mL-1. The polymer CMCs, CsA
encapsulation (up to 0.36 g CsA per g of PEI amphiphile) within the 60 – 200 nm nanoparticles and rat oral drug absorption
after a 7.5 mg kg-1 dose of CsA, polymer nanoparticles (polymer, drug weight ratio – 5: 1) all increased with polymer
hydrophobicity, although these parameters were not affected by polymer molecular weight or polymer branching. Release
of CsA from a tablet dosage form was enhanced in the presence of the more hydrophilic branched polymer, however, as
the more hydrophobic polymers endowed the tablets with longer disintegration times. Cell cytotoxicity (A431 cells and rat
erythrocytes) was similar for all polymers (A431 IC50 = 10 – 50 μg mL-1 and 50% haemolysis = 30 – 55 μg mL-1).We
conclude that the most important parameter controlling amphiphilic polymer nanoparticle enabled oral drug absorption is
the hydrophobicity of the polymer amphiphile.
