Drug-drug eutectic mixtures of celecoxib with tapentadol and milnacipran which could improve analgesic and antidepressant efficacy

Abstract

Eutectic mixtures had been developed as an approach to enhance physicochemical properties and oral bioavailability of drugs. Moreover, drug-drug eutectics mixtures with synergetic effects had been used to improve pharmacodynamic properties. In this study, two eutectic mixtures of celecoxib (CEL) with milnacipran hydrochloride (MIN) and tapentadol hydrochloride (TAP) were designed and prepared. The differential scanning calorimetry (DSC) data of mixtures prepared from 0.1 to 0.9 M ratios were applied to construct binary phase diagrams to determine the eutectic molar ratio. The CEL and TAP eutectics (CEL-TAP-EU) system formed a eutectic at a CEL mole fraction of 0.6, and for CEL and MIN eutectics (CEL-MIN-EU) system was at a CEL mole fraction of 0.5. Eutectic mixtures were further characterized by powder x-ray diffraction (PXRD) Fourier Transform infrared spectroscopy(FTIR), Raman spectra, and solid-state nuclear magnetic resonance (SS-NMR) to verify the formation of the eutectic system. Scanning electron microscope (SEM) techniques depict the actual morphology difference between eutectic mixtures and CEL, TAP, and MIN. The disk intrinsic dissolution rate test (DIDR) and powder dissolution test indicated that CEL from CEL-TAP-EU and CEL-MIN-EU had improved dissolution properties comparing CEL alone and their physical mixture, while the dissolution of TAP and MIN dramatically reduced. The pharmacokinetics study suggested that the CEL in the eutectic mixtures had higher oral bioavailability and earlier plasma concentration peak time. The acetic induced writhing test of CEL-TAP-EU indicated an analgesic efficacy enhancement while the forced swimming test of CEL-MIN-EU suggested an improved antidepressant efficacy. The solubility, pharmacokinetics, and pharmacodynamic properties enhancements made the CEL-TAP-EU and CEL-MIN-EU potential candidates for further pharmaceutical products development.