Sistemas coloidais SNEDDS carreadores de Croton cajucara Benth aplicados em modelos experimentais in vivo de antinocicepção, inflamação e cicatrização dérmica

Abstract

Life sciences-based technology has enabled new treatments including the expansion of the bioavailability of drugs with reduction of adverse effects. Chronic inflammatory diseases (ICD) and chronic wounds, for example, are widely treated effectively, but the adverse effects attributed to medications limit prolonged treatment. Among the many possibilities of drug carriers, colloidal systems stand out as an important strategy in the protection and targeted delivery of bioactive products. Systemic chronic inflammation (SCI) and chronic wounds, for example, have been widely treated, but the adverse effects attributed to medications limit prolonged treatments. In this present study Croton cajucara Benth medicinal species was applied as an alternative therapy, by using in vivo models, aiming at to analyze its nociception, inflammation and dermal wound healing. In that, were used the non-volatil oil (so called fixed oil, FO) and the diterpine trans-dehydrocrotonin, obtained from this herbal stem bark, were loaded into a colloidal self-nanoemulsion drug delivery system (SNEDDS-type). The study was conducted aiming at the reduction of therapeutic doses and toxic risks, maintenance of the constant level of the drug in the blood (by slow and controlled release), and prolonged efficacy of therapeutic effects. The experimental study was carried out in different stages, such as: chromatographic study to obtain the bioactives OF and t-DCTN, development of a polar colloidal nanosystem O/A (oil in water), cotensoactive free, based on surfactant mixture of Tween 80 and 40, a vegetable oil of food use (as the oil phase), and the bioactives FO and t-DCTN, and then pharmacological applications. The SNEDDS-derivatives were so called SNEDDS-OFCC (15 mg of fixed oil, rich in sesquiterpenes) and SNEDDS-DCTN (5 mg of t-DCTN). The target SNEDDS system (bioactives free) was characterized by physicochemical analyses and showed droplet diameter with reduced scale (11 nm). These nanobioproducts were administered orally in experimental pain models through abdominal contortions and formalin tests. In the models of inflammation (paw edema and peritonitis) dexamethasone (0.5 mg/kg, s.c.) was used as positive control. SNEDDS-DCTN was assayed on experimental healing model, administered topically in Wistar rat lesions (7, 14 and 21 days). For each experimental group, the retraction index (morphometry) of the lesion and the tissue behavior (histopathological and immunohistochemical analysis) were observed. The treatment results of SNEDDS-OFCC formulation showed 40.2% inhibition in central pain (neuropathic) and 42.8% in inhibition of peripheral inflammatory pain. Meanwhile, SNEDDS-DCTN in reducing abdominal contortions was effective in 76.7%, and in the formalin test inhibited 47.9% (neuropathic pain) and 52.6% (peripheral pain). The inhibitor rates of leukocyte migration (by carrageenan-induced inflammation) showed significant reductions for the peritoneal cavity, with inhibitions 29.4% for SNEDDS-OFCC and 38% for SNEDDS-DCTN, in relation to the negative control group (vehicle). In the paw edema inhibition, 89.7% was observed for SNEDDS-DCTN. Based on these data, the SNEDDS-DCTN system was used in the experimental healing model and showed lesion retraction on the 14th day was quantitative (98.3%), compared to 43.7% for the 7th day, and also to the negative control group. The histopathological analyses sowed reduction in inflammation, with significant gains in cell proliferation and tissue maturation, compared to the control group. Since the target SNEDDS is a system of cosurfactant free, it reinforces the proposal of pharmacological application on prolonged periods, due to the reduction in the number of the carrier ingredients and also by loading minimized concentrations of the bioactives of C. cajucara. SNEDDS-OF and SNEDDS-DCTN presented associated antinociceptive and anti-inflammatory action, as well as healing (SNEDDS-DCTN), so, they may meet a specific demand from patients who are on prolonged treatments (SCI-type) to combat pain and inflammation caused by skin lesions or chronic inflammations.