Although hydrophilic drugs represent a large proportion of all therapeutics used to treat and manage chronic diseases, achieving their ultra-long-term delivery via an injectable system remains a major challenge. Implants have demonstrated potential for long term delivery of both hydrophobic and hydrophilic drugs; however, they require invasive insertion process in a sterile setting, which restricts their suitability for resource limited settings. Furthermore, implants tend to be more susceptible to local inflammation when compared to injectable alternatives. Here we report a solvent free, injectable, biodegradable, and in situ crosslinking depot (ISCD) platform for ultra-long term release of hydrophilic drugs. ISCD consists of a low molecular weight liquid pre polymer methacrylated polycaprolactone (PCL). Both hydrophilic and hydrophobic drugs can be suspended/dissolved in the liquid polymer, and when injected along with a radical initiator and an accelerator, the polymer crosslinks in situ, resulting in a solid monolithic and degradable depot, integrating the unique advantages of injectability and retrievability. Low molecular weight PCL forms a dense mesh, which limits water influx/efflux and hence reduces the drug release. Liquid state of the polymer obviates the need for solvent, minimizing initial burst release due to the solvent exchange process, as observed with in situ forming implants. Drug release and ISCD degradation can be tailored by modifying their polymer network via altering the concentration of accelerator and initiator, molecular weight  of methacrylated PCL, or by incorporation of a hydrophilic polymer or a non crosslinking polymer. We demonstrated sustained release of seven hydrophilic drugs with varying solubility or drug combinations for over seven months in vitro. Ultra long term drug release and depot degradation was also demonstrated in rats for at least six months without any evidence of local inflammation or fibrosis. Excitingly, the platform also enabled ultra-long term release of a model hydrophobic drug (tacrolimus) for at least six months.  To the best of our knowledge, this marks the first successful demonstration of an ultra long term delivery of hydrophilic drugs using an injectable formulation. This platform holds promise for developing ultra long acting therapies across a wide range of diseases.

An injectable in situ crosslinkable platform for ultra-long-acting delivery of hydrophilic therapeutics