Purpose: The number of active pharmaceutical compounds from Class II and IV, having low solubility have significantly increased in last 10 years. These compounds have high therapeutic potential but difficult to formulate as oral dosage forms due to poor aqueous solubility. The solubility and dissolution and hence, potentially the bioavailability, of these poorly water-soluble drugs can be increased by formulating the amorphous solid dispersion, as this technique directly deals with the intermolecular interaction of the compounds and works at molecular level. Dibenzoylmethane(DBM), curcumin(CUR) and resveratrol(RES) are some antioxidants having synergistic/additive effects but having poor solubility, limiting its absorption and overall bioavailability. However, ternary amorphous solid complexes can be successfully used in fixed dose combinations or combinations of the compounds having synergistic/additive effects. The objective of the study is to design soluble and stable amorphous combinations of these compounds with suitable polymer to harness their pharmacological potential.
Methods: Polymers like Hydroxypropyl-β-cyclodextrin(HPβ-CD), Polyvinylpyrrolidone(PVP), and Eudragit EPO®(EPO) were screened to select the most suitable and compatible polymer for designing amorphous complexes (binary complexes of each drug with each polymer in 50:50 by weight ratio and ternary complexes of the combinations of two drugs with each polymer in 25:25:50 by weight ratio). Briefly, DBM, CUR and RES were dissolved in acetone and incorporated into different polymer to get homogeneous dispersions. These mixtures were dried by solvent evaporation using rota-vapor (at 100 rpm and 50-550 C) leading to solid complex formation. Pure compounds, their physical mixtures(PM) and complexes were characterized by Infrared Spectroscopy(IR), X-ray diffraction(XRD), Modulated Differential Scanning (MDSC). The formulations were also studied for the binding interactions, between the polymers and the drugs, by molecular modelling. Compounds were sequentially docked to polymers using default settings in MOE with one change. Ultraviolet-Visible method was developed for simultaneous quantification of Curcumin-Resveratrol and Curcumin-Dibenzoylmethane. Solubility studies were carried out for Curcumin-resveratrol-EPO and Curcumin-Dibenzoylmethane-EPO in aqueous solutions at room temperatures using UV method as analytical tool for determining the concentration of compounds. Dissolution studies over 12 hours, using USP apparatus II, of the two combinations (formulations) were done in phosphate buffer (pH 7.4) to determine the bioavailability of the drugs and the concentrations were determined using developed UV method. Stability of amorphous complexes were evaluated over a period of 5 months at room temperature.
Results: EPO showed good miscibility with DBM, CUR and RES and was found to be most suitable polymer for amorphous complexes. By comparing the XRD data of binary complexes, ternary complexes and, physical mixtures it was confirmed that the combination of two drugs with EPO in the ratio of 25:25:50w/w/w [(CUR:DBM:EPO)and(CUR:RES:EPO)] are amorphous and the sharp peaks were observed in the XRD plots of binary complexes and physical mixtures of drugs with polymer representing their crystallinity. In IR studies, the specific peaks for the functional group of each drugs the physical mixtures and ternary complexes confirmed the presence of drugs in the amorphous complexes. No interactions between compounds with polymers were found in PM while ternary amorphous complexes showed the interaction between the compounds. Hydrogen bonding between the polymer and drugs was observed in the IR data of the ternary complexes when compared to the physical mixtures of the components. Molecular modeling showed that there is non-covalent bonding between the combination of the drugs and EPO. Aqueous solubility study showed that there is an increase in solubility of CUR, RES and, DBM. Dissolution study over 12 hours in the phosphate buffer showed 36-folds, 6-folds and 8-folds increase in solubility of CUR, RES and, DBM respectively. The ternary complexes were stored at room temperature in the closed container and tested for the stability using XRD and IR and showed that formulations were amorphous for the period of 5 months.
Conclusion: EPO was found to be working excellent with combination of drugs and enhances the aqueous solubility and stability (for 180 days) of combination of drugs.
Harsh Chauhan– Associate Professor, Creighton University, Omaha, Nebraska