Desenvolvimento de formulações farmacêuticas a partir de folhas e ramos de Plinia cauliflora: composições e usos

Abstract

Plinia cauliflora (DC.) Kausel, also known as Plinia peruviana, is commonly referred to as jabuticaba and is a member of the Myrtaceae family. The species is widely distributed in Brazil, and its therapeutic potential is recognized mainly through its antioxidant, anti-inflammatory, vasodilating and healing properties. However, the scientific literature has focused primarily on the study of the fruits, with limited data available on the biological activities of the less studied and underutilized parts of the plant, such as the leaves and branches. In this context, the present study aimed to evaluate the pharmacological and toxicological effects of the ethanolic extracts of the leaves (EEL) and branches (EEB) of P. cauliflora, as well as their supramolecular complexes with ꞵ-cyclodextrin (EEL/ꞵCD and EEB/ꞵCD). The study focused on their therapeutic potential, particularly in terms of anti-inflammatory and vasodilatory activities, via topical and oral administration, respectively. The formation of the complexes was confirmed by spectroscopic techniques including nuclear magnetic resonance (NMR) and Raman spectroscopy. The bioavailability of the phenolic compounds was evaluated by simulated in vitro digestion according to the INFOGEST protocol. Acute and subchronic toxicity assays were performed in Swiss mice, and in vitro cell viability was evaluated in macrophage (J774A.1) and fibroblast (L929) cell lines using the MTT assay. The anti-inflammatory activity was assessed by measuring nitric oxide (NO) production, lipid droplets (LDs) formation, and inflammatory mediators related to their biosynthesis (TGF-ꞵ and PGE2), in addition to proinflammatory interleukins (IL-1ꞵ, IL-6, IL-12, and TNF-α). The vasodilatory effects were assessed by ex vivo vascular relaxation assays using Wistar rat aortic rings. It was observed that all samples exhibited a maximal vasodilator effect (Emax) greater than 80%, possibly mediated by the NO pathway. Topical formulations were developed using the extracts and their complexes, which were incorporated into a Lanette® base. These formulations were then subjected to physicochemical and rheological characterization by FTIR spectroscopy, thermal analysis (TGA/DTA) and viscoelastic tests. The physicochemical characterizations confirmed interactions between the extract components and ꞵCD. The formulations also identified the presence of interactions between the extract or complex components and the Lanette® base. Studies using the in vitro digestion model demonstrated that complexation of EEB with ꞵCD resulted in enhanced gastric stability of the phenolic compounds and improved their intestinal absorption. In vivo toxicological studies showed no significant adverse effects for EEB and EEB/ꞵCD (LD50 > 1000 mg/Kg), and biochemical and haematological parameters suggested physiological adaptations without relevant hepatic or renal toxicity, with EEB/ꞵCD showing superior safety compared to the free extract. In the in vitro cell viability assay, EEL/ꞵCD reduced the toxicity of EEL at higher concentrations in both cell lines. The anti-inflammatory activity was particularly noteworthy, especially for EEL/ꞵCD, which reduced NO by 73.1%, LDs by 67%, TGF-ꞵ by 88%, and PGE2 by 52%. The study also demonstrated effective modulation of the cytokines IL-1ꞵ, IL-6, IL-12 and TNF-α. The Lanette® based formulations demonstrated satisfactory properties for dermatological application. P. cauliflora extracts, whether isolated or complexed with ꞵCD, exhibit pharmacological properties for managing inflammatory and cardiovascular conditions. Complexation with ꞵCD enhances phenolic compounds' stability, bioavailability, and efficacy. Further studies are recommended to validate these findings in models and to elucidate the mechanisms underlying the observed activities.