An insight into the skin penetration enhancement mechanism of N-methylpyrrolidone.
This work aims to elucidate the mechanism by which N-methylpyrrolidone (NMP) enhances the skin permeation of a compound by combining experimental data with molecular dynamic (MD) simulations. The addition of 10% NMP significantly increased the propranolol (PR) permeation through the human epidermis (∼ 15 μg/cm(2) vs ∼ 30 μg/cm(2)) while resulting inefficacious on hydrocortisone (HC) diffusion. No significant alterations in the stratum corneum structure were found after the in vitro treatment of human epidermis with NMP dispersed in mineral oil or water by attenuated total reflectance Fourier transform infrared (ATR-FTIR) analyses. MD simulations revealed the formation of a complex by H-bonds and the π-π stacking interactions between the NMP's amido group and the drug's aromatic systems. The size of the depicted NMP/PR clusters was in line with the hydrodynamic radius derived by dynamic light scattering analyses (∼ 2.00 nm). Conversely, no interaction, and consequently cluster formation, between NMP and HC occurred. These results suggest that NMP is effective in enhancing the drug permeation through human epidermis by a cotransport mechanism when NMP/drug interaction occurs.
Department of Pharmaceutical Sciences, Università degli Studi di Milano , via G. Colombo, 71 20133 Milan, Italy.
Francesco
F
Cilurzo
Giulio
G
Vistoli
Francesca
F
Selmin
Chiara G M
CG
Gennari
Umberto M
UM
Musazzi
Silvia
S
Franzé
Matteo
M
Lo Monte
Paola
P
Minghetti
D000279:Administration, Cutaneous; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004058:Diffusion; D016503:Drug Delivery Systems; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D056004:Molecular Dynamics Simulation; D011433:Propranolol / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D012869:Skin Absorption / Q000187:drug effects*; D017550:Spectroscopy, Fourier Transform Infrared; D013723:Teratogens / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics
D000893:Anti-Inflammatory Agents; D011760:Pyrrolidinones; D013723:Teratogens; D014665:Vasodilator Agents; D011433:Propranolol; C038678:N-methylpyrrolidone; D006854:Hydrocortisone
ATR-FTIR; N-methylpyrrolidone; dynamic light scattering; hydrocortisone; in vitro human skin permeation; molecular dynamic simulations; penetration enhancer; propranolol