Enhancing luteolin solubility through solid dispersion-based oral gels: A novel approach for periodontal disease treatment

Abstract

Luteolin (LUT) is a bioactive flavonoid with numerous pharmacological properties, such as antioxidant, antimicrobial, and anti-cancer activity. A prominent example of LUT's properties concerns its administration for the treatment of periodontal disease. However, its low water solubility poses a serious challenge regarding its formulation into an effective dosage form. To this end, the present study investigates the incorporation of LUT's solid dispersions (SDs) into oral gels, as a way to improve LUT solubility in saliva for the treatment of periodontitis. Initially, SDs of LUT were formulated at drug-to-polymer weight ratios of 1:9 and 1:12 using either polyethylene glycol 6000 (PEG) or poloxamer P188 (P188), employing both melting and solvent evaporation techniques. Subsequently, these drug-loaded SDs were integrated into oral gels designed for the local treatment of periodontal disease within the mouth. The SDs resulted in a remarkable solubility enhancement for LUT, showing up to a 16-fold increase compared to its pure crystalline form. Physicochemical characterization using differential scanning calorimetry (DSC) and powder X-ray diffractometry (pXRD), revealed that LUT was amorphously dispersed within the SDs, while ATR-FTIR spectroscopy indicated the presence of significant molecular interactions between the drug and the matrix/carriers. The gels containing the SDs of LUT displayed appropriate rheological properties for handling and storage, while the in vitro dissolution studies in simulated saliva revealed that the PEG SD-based oral gels were able to significantly enhance LUT's release. Moreover, cell viability studies, which examined two promising SDs (one with PEG and one with P188), revealed negligible cytotoxicity, suggesting that the prepared formulations exhibit favorable and non-toxic characteristics. In addition, in vitro assays demonstrated that the formulations retained LUT's anti-inflammatory effect. Finally, ex vivo permeation studies using porcine buccal tissue demonstrated that P188-based SD, incorporated into a placebo gel, enhanced the ability of LUT to partition into and accumulate within the mucosal tissue, resulting in more than three-times the accumulation compared to the gel containing the neat drug. Therefore, the preparation of SD oral gels for LUT can be regarded as a prospective technique with strong potential for the improvement of the API's solubility and hence, its administration in the oral cavity for the topical treatment against periodontitis.