Suspensão de nanocápsulas de poli(ԑ-caprolactona) contendo tacrolimus como sistema de liberação cutânea: estudo de estabilidade, perfil de permeação e efeito anti-inflamatório.

Abstract

Tacrolimus (TAC) is a drug of natural origin used in conventional topical application to control autoimmune skin diseases such as atopic dermatitis, psoriasis and vitiligo. However, topical application of the drug often causes significant adverse effects in some patients, leading to lower adherence to treatment. Thus, the development of modified delivery systems can be used to enhance skin permeation, reduce the dose applied topically, decrease adverse effects and increase drug biodistribution. Based on this, the aim of the present study was to evaluate in vitro and in vivo TAC-loaded poly(ԑ-caprolactone) nanocapsules developed, characterized and quantified previously. Stability studies of PCL nanocapsules was conducted using Raman spectroscopy. In vitro drug release mechanism was performed from in vitro drug release experiments, evaluating the release kinetics by mathematical models of zero order, first order, Higuchi, Korsmeyer-Peppas and Hixson-Crowell. In vitro skin permeation was analyzed using vertical Franz diffusion cells and photoacoustic spectroscopy. Anti-inflammatory activity was evaluated in vivo according to the model of induction of ear edema in male Balb/c mice. Raman results showed that the mechanism of degradation of the nanocapsules occurred mainly in amorphous domains of the PCL and resulted in an increase in the crystallinity of the polymer, concluding that the nanoparticles had adequate stability up to 60 days after preparation. In vitro drug dissolution experiments showed a controlled release of TAC. The release kinetics showed zero-order kinetics. As per the Korsmeyer–Peppas model, anomalous transport features were observed. In vitro permeation study by Franz cell model demonstrates that pure TAC and TAC-loaded poly(ԑ-caprolactone) nanocapsules remained retained in the membranes, which is desirable for topical application. Photoacoustic spectroscopy assay revealed that nanocapsules were able to reduce the cutaneous permeation of the TAC through skin layers, improving the biodistribution and accumulating the highest concentration of the nanoparticles in the stratum corneum, viable epidermis and in the dermal region. TAC-loaded PCL nanocapsules exhibited excellent anti-inflammatory activity when compared to the free drug. TAC-loaded PCL nanocapsules can be suitably used as a novel nano-based dosage form to control of cutaneous autoimmune diseases and the results provide an experimental basis for formulations both as a viable topical and alternative administration strategy, which may appear as an alternative to the commercial form currently employed.