Nanocompósitos à base de poli(uretano-ureia)s dispersos em água e diferentes cargas inorgânicas para liberação transdérmica de progesterona

Abstract

In this work, waterborne poly(urethane-urea)s (WPUU) and respective nanocomposites (NWPUU) based on hydrophilic montmorillonite (MMT-Na+) sodium clay, reduced graphene oxide (rGO) or MMT/rGO hybrids were produced by a green synthesis method, aiming at obtaining biocompatible films, applied as transdermal drug delivery systems (TDDS). The monomers used were isophorone diisocyanate (IPDI), dimethylolpropionic acid (DMPA), poly(propylene glycol) (homoPPG), copolymers based on poly(ethylene glycol-block-propylene glycol) (PEG-b-PPG), with different PEG-segments ratio (7% and 38%, in terms of copolymer molar mass), and hydrazine as a chain extender. The ratio between soft and hard segments was kept the same (NCO/OH=2.3) to all systems. The nanoload content for the preparation of nanocomposites was 0.5% for MMT or rGO, and 0.25/0.25% for the hybrid MMT/rGO, in relation to prepolymer mass. Progesterone (P4), a steroidal hormone, was used as model drug and incorporated into the aqueous dispersions to obtain cast films. Aqueous dispersions were characterized in terms of solids content, pH, apparent viscosity, average hydrodynamic diameter (DH) particles and polydispersity index (PDI) by dynamic light scattering (DLS) measurements. The cast films were characterized by X-ray diffraction (XRD), low-field nuclear magnetic resonance (NMR) by nuclear relaxometry method, Fourier-Transform infrared spectrometry (FTIR), thermogravimetric analysis (TGA) and mechanical tests. In vitro release tests, using cellulosic membrane, and ex vivo permeation and retention assays, using biological membrane of pig ear skin, were performed at 37±0.5°C in a Franz diffusion cell system, employing phosphate-buffered saline (PBS)/propylene glycol solution (3:2, v/v) (pH 7.4) as the receiving solution. The content of the released drug in vitro was determined by ultraviolet-visible (UV-Vis) spectroscopy, and, in the ex vivo assays, the permeated drug content was quantified by high performance liquid chromatography (HPLC). Pseudoplastic dispersions with DH<200 nm were stable for more than twelve months. The formation of exfoliated structures suggested the homogeneous nanodispersion of MMT silicate layers and rGO nanosheets. MMT/rGO synergism and layer-to-layer interactions suggested segregation of phases. Hydrogen bonds between polar groups of nanoloads and rigid segments of polymer chains influenced the structure and molecular dynamics of the chains, as well as increasing the thermal and mechanical properties of materials. WPUU/P4 films showed high amount and higher in vitro release rates and ex vivo drug permeation in relation to the nanocomposite series. P4-loaded NWPUU (MMT, rGO and MMT/rGO) films exhibited sustained release of the drug in the ex vivo permeation tests, and low drug retention in skin extracts (epidermis and dermis). The results obtained show that NWPUU systems based on MMT, rGO and MMT/rGO particles can potentially be applied as new transdermal drug delivery systems.