Desenvolvimento de géis contendo dispersões sólidas de rutina e seu emprego no tratamento de osteoartrite em modelo animal

Abstract

Introduction: Osteoarthritis (OA) is characterized by chronic pain and long-term disability. Rutin (RTN) is a natural flavonoid with antioxidant and anti-inflammatory properties that represents a promising alternative to reduce the indiscriminate use of non-steroidal antiinflammatory drugs (NSAIDs) in the treatment of OA. However, its local administration is limited due to its physicochemical characteristics. The preparation of solid dispersions (SDs) of RTN associated with polymers and cyclodextrins by Hot Melt Extrusion (HME), followed by their use in obtaining supramolecular gels, can overcome these limitations and significantly improve the efficacy of RTN in the local treatment of OA. Objective: To develop supramolecular gels containing RTN SDs, obtained by HME, as well as to evaluate the effects of thermomechanical processing on the microstructural properties and in-vivo performance in an animal model with OA. Methods: For HME processing, mixtures composed of Soluplus® polymer (SLP), alphacyclodextrin (αCD), polyethylene glycol 400, and RTN were used. The obtained SDs were characterized by powder X-ray diffraction, differential scanning calorimetry, and thermogravimetry. The gels were then prepared in sodium acetate buffer (pH 5.0) by dispersing the SDs (HME gels) or, alternatively, by simply dispersing the individual constituents (MF gels). The gels were characterized in terms of morphology (macro and microscopic) and rheology, and their stability, in-vitro RTN release profile, and biological safety were duly evaluated by the HETCAM. The anti-inflammatory activity of RTN in the selected gels was studied in an inflammationinduced model in female Swiss albino mice (Mus musculus). Results: HME processing promoted the loss of the crystalline structure of RTN, favoring the formation of amorphous SDs, without flavonoid degradation. Rheological analysis showed that MF gels behaved as more viscous than elastic preparations (G’’ > G’), while HME gels, both PPR-HME (with αCD) and GM-HME (without αCD), were rigid and viscous, exhibiting higher and overlapping G’ and G’’ values, indicating a complex viscoelastic behavior, which was significantly more pronounced in the PPR-HME formulation. HME gels showed a greater in-vitro release of RTN when compared to MF gels. This effect can be attributed to the greater amount of molecularly dispersed flavonoid. HET-CAM results demonstrated that HME gels have no potential for skin irritation. HME gels reduced hyperalgesia and edema, consequently promoting a significant increase in locomotor activity in the animals. The GM-HME and PPR-HME gels exhibited very similar in vivo behavior, consistent with in vitro release studies. This lack of significant difference is possibly due to the low concentration of αCD in the PPR gel. Conclusion: The results showed that HME allowed the production of gels with rheological profiles distinct from those obtained by physical mixing, demonstrating efficacy in mitigating OA in mice and highlighting its therapeutic potential