Desenvolvimento de cristais líquidos e hidrogéis para administração cutânea de metotrexato para tratamento de psoríase

Abstract

Introduction: Psoriasis is an autoimmune, inflammatory and chronic skin disease in which there is an acceleration of cell growth and proliferation, resulting in erythema and ill-defined lesions, with white and red stains and peeling of the epidermis. Methotrexate (MTX) is one of the drugs for the treatment of systemic use, but there are several side effects. Topical administration may be a strategy to vectorize the release of this drug at the site of action, but as the stratum corneum epidermis is a permeation barrier for hydrophilic drugs, it is necessary to develop vehicles that promote its penetration into the skin. Objective: To evaluate the topical effect of MTX in psoriasis using liquid- crystalline systems (CLs) and hydrogels as vehicles. Method: Study of phase behavior by constructing the ternary phase diagram combining polysorbate 80 (Tween® 80), isopropyl myristate (MIP) and MiliQ water to obtain CLs. The hydrogels tested were based on chitosan (HQS), hydroxypropylmethylcellulose phthalate (HHPMC) and alkylated carbomer (HCA). The samples were characterized by polarized light microscopy (MLP), oscillatory rheology, texture analysis (TPA), solubility of MTX, obtaining the release profile, ex vivo bioadhesion studies and in vivo tests in mice with induction of psoriatic dermatitis. Results: Systems containing surfactant / oil / water in the proportions 60/10/30 and 60/20/20 were characterized as lamellar phases (L1 and L2, respectively) and 50/10/40 and 50/20/30 as hexagonal phases ( H1 and H2, respectively). It was possible to solubilize MTX at a concentration of 2 mg / mL in the CLs and in the HCA hydrogel (pH = 7.4), and 0.1 mg / mL in the HQS hydrogel (pH = 3.5) and not solubilized in HPMCP ( pH = 4.5). Oscillatory rheology showed that hexagonal phases are more elastic than lamellar phases, and HCA with behavior similar to lamellar phases. The TPA test correlated with rheology, but ex vivo bioadhesion showed a better interaction of HCA with swine skin in relation to CLs. The release profile showed that H1 and H2 retained MTX more than L1 and L2, due to their more rigid and organized structure. HCA released more MTX showing that the gelled polymer network retains the drug less. The release profile adjusted for the Weibull mathematical model indicated that the release kinetics is fast and complex. As a proof of principle, in vivo tests showed that CLs promoted a more exacerbated inflammatory effect, but the HCA hydrogel had similar efficacy to dexamethasone. Conclusion: Although studies are still needed to understand the toxicity and safety of the systems, in in vivo tests in mice with imiquimod-induced psoriatic dermatitis, topical application of MTX may be a new approach for the treatment of psoriasis with less side effects and proven efficacy.