In situ gel technology was employed for controlled delivery of curcumin and piperine in the local treatment of inflammatory and degenerative joint disease, such as osteoarthritis and rheumatoid arthritis. Particularly, glyceryl monooleate was used in association with phosphatidylcholine and ethanol. To obtain a liquid form suitable for subcutaneous injection, reaching a semisolid consistency in contact with biological fluids, different ratios between excipients were evaluated. A formulative study was conducted to evaluate the composition effect on the structural properties of the formulations, particularly focusing on injectability and phase transition. Curcumin and piperine were loaded, singularly or jointly, in selected in situ forming gels. Structural characterization, performed by X-ray scattering, revealed disordered reverse micellar phases, undergoing transition to hexagonal and cubic Pn3m phases upon hydration. In vitro dialysis demonstrated a sustained release of both drugs over 96 h, and faster release in the case of jointly loaded drugs. Mechanistic analysis and water uptake studies indicated a drug release governed by both diffusion and swelling/erosion of the lipid supramolecular structure. Furthermore, an ex vivo release analysis performed using human skin explants suggested the formulation suitability for subcutaneous injection, indicating that the presence of piperine in the in situ formed gel allowed for double the curcumin release with respect to the simple curcumin-loaded gel. The system's unique transition—from micellar to hexagonal and cubic semisolid phases upon contact with water—resulted in a swellable matrix that provided sustained drug release. Further studies will be conducted to validate the therapeutic efficacy of the curcumin–piperine-loaded gel against inflammatory and degenerative joint disorders.

Pula, W., Pepe, A., Ferrara, F. et al. In situ forming gels as subcutaneous delivery systems of curcumin and piperine. Sci Rep 15, 3046 (2025). https://doi.org/10.1038/s41598-025-87750-w