Exploiting the potential of <i>in situ</i> forming liquid crystals: development and <i>in vitro</i> performance of long-acting depots for peptide drug thymosin alpha 1 subcutaneous administration

The fast-growing filed of long-acting depots for subcutaneous (SC) administration holds significant potential to enhance patient adherence to treatment regimens, particularly in the context of chronic diseases. Among them, injectable <i>in situ</i> forming lyotropic liquid crystals (LCCs) consisting of hexagonal mesophases represent an attractive platform due to their remarkable highly ordered microstructure enabling the sustained drug release. These systems are especially relevant for peptide drugs, as their use is limited by their short plasma half-life and inherent poor stability. In this study, we thus aimed to exploit the potential of a liquid crystalline platform for the sustained release of peptide drug thymosin alpha 1 (Tα1), characterized by a short plasma half-life and with that associated twice-weekly SC administration regimen. We initially selected specified ingredients, with ethanol serving to reduce viscosity and stabilize the peptide drug Tα1, lecithin contributing to LCCs formation and stabilization, and glycerol monooleate or glycerol monolinoleate representing the hexagonal LCCs forming matrix material. The selected studied nonaqueous precursor formulations were characterized by suitable rheological properties for SC injection. A convenient and rapid <i>in situ</i> phase transition of precursor formulations to hexagonal LCCs, triggered by water absorption, was successfully accomplished <i>in vitro.</i> Notably, <i>in situ</i> formed LCCs demonstrated sustained release kinetics of the peptide drug Tα1 for up to 2 weeks of <i>in vitro</i> release testing, offering minimized dosing frequency and thus promoting patient adherence. In summary, the newly developed <i>in situ</i> forming liquid crystalline systems represent prospective injectable long-acting depots for SC administration of the peptide drug Tα1.