Temperature-responsive nanogel multilayers of poly(N-vinylcaprolactam) for topical drug delivery

We report nanothin temperature-responsive hydrogel films of poly(N-vinylcaprolactam) nanoparticles (vPVCL) with remarkably high loading capacity for topical drug delivery. Highly swollen (vPVCL)(n) multi layer hydrogels, where n denotes the number of nanoparticle layers, are produced by layer-by-layer hydrogen-bonded assembly of core-shell PVCL-co-acrylic acid nanoparticles with linear PVPON followed by cross-linking of the acrylic acid shell with either ethylene diamine (EDA) or adipic acid dihydrazide (AAD). We demonstrate that a (vPVCL)(5) film undergoes dramatic and reversible swelling up to 9 times its dry thickness at pH = 7.5, indicating 89 v/v % of water inside the network. These hydrogels exhibit highly reversible similar to 3-fold thickness changes with temperature variations from 25 to 50 degrees C at pH = 5, the average pH of human skin. We also show that a (vPVCL)(30) hydrogel loaded with similar to 120 mu g cm(-2) sodium diclofenac, a non-steroidal anti-inflammatory drug used for osteoarthritis pain management, provides sustained permeation of this drug through an artificial skin membrane for up to 24 h at 32 degrees C (the average human skin surface temperature). The cumulative amount of diclofenac transported at 32 degrees C from the (vPVCL)(30) hydrogel after 24 h is 12 times higher than that from the (vPVCL)(30) hydrogel at 22 degrees C. Finally, we demonstrate that the (vPVCL) hydrogels can be used for multiple drug delivery by inclusion of Nile red, fluorescein and DAPI dyes within the vPVCL nanoparticles prior to hydrogel assembly. Using confocal microscopy we observed the presence of separate dye-loaded vPVCL compartments within the hydrogel matrix with all three dyes confined to the nanogel particles without intermixing between the dyes. Our study provides opportunity for development of temperature-responsive multi layer hydrogel coatings made via the assembly of core-shell nanogel particles which can be used for skin-sensitive materials for topical drug delivery. (C) 2017 Elsevier Inc. All rights reserved.