A new drug-drug co-amorphous system of imipramine and celecoxib with improved solubility and synergistic antinociceptive effects

Because the monotherapy of currently available pain killers often shows serious adverse effects or limited efficacy for treating neuropathic pain, multimodal analgesia has been highly recommended to gain improved antinociceptive effects and reduce dose-dependent side effects. Drug-drug co-amorphous systems emerge as a useful strategy for ameliorating the physicochemical properties of drug substances and achieving clinical benefits compared with individual components. New drug-drug co-amorphous products IMI-CEL at different ratios were prepared from imipramine hydrochloride (IMI) and a poorly water-soluble anti-inflammatory drug–celecoxib (CEL) by melt-quenching method, which were characterized by XRPD, DSC and IR. Co-amorphous product IMI-CEL (1:1) displayed notable improvement in the solubility (64.4 times) and dissolution rate (3.1 times) than crystalline CEL in pH 6.8 buffer, and IMI-CEL exhibited good physical stability under long-term storage conditions. Isobolographic analysis demonstrated that IMI-CEL (1:1) showed synergistic analgesic effects in paclitaxel-induced neuropathic pain in mice. Moreover, the oral bioavailability of 1:1 IMI-CEL was improved 1.396 times in rats when compared to the single drug. Above results suggested the potential of IMI-CEL to produce synergistic analgesic effects through developing drug-drug co-amorphous systems.