Long-acting injectable in situ treprostinil depot for the targeted treatment of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a fatal, progressive cardiovascular disease. Treprostinil (TRE) is a first-line drug for PAH treatment. However, the use of TRE for severe PAH is often limited by the risks and complexities of subcutaneous (SC) infusion site pain or fatal catheter-associated intravenous (IV) infection with external or implanted pump system. Herein, we engineered an injectable in situ-forming TRE depot at physiological temperature to prolong vasodilation by loading drug microparticles into a methylcellulose-based gel. A single intramuscular (IM) injection significantly prolonged drug residence at the injection site, increased elimination half-life, and lowered the maximal plasma concentration. One injection induced pulmonary vasodilation lasting 3–4 days, improved hemodynamics, and reduced pulmonary vascular remodeling. Safety evaluation showed favorable biocompatibility and local tolerability, with mild local inflammatory response resolving within one week. In conclusion, the injectable TRE depot is a promising alternative to pump delivery, reducing administration burden and improving compliance and quality of life.