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

Abstract

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 pain at the subcutaneous (SC) infusion site or fatal catheter-associated intravenous (IV) infections with external or implanted pump systems. 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 the drug's residence at the injection site, increased the half-life of elimination, and lowered the maximal plasma concentration. One injection induced pulmonary vasodilation lasting 3–4 d, improved hemodynamics, and reduced pulmonary vascular remodeling. A safety evaluation showed favorable biocompatibility and local tolerability, with a mild local inflammatory response resolving within 1 week. In conclusion, the injectable TRE depot is a promising alternative to pump delivery, reducing the administration burden and improving compliance and quality of life.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (Nos. 82073782 and 82241002).

Ethical statements

The animals used in all experiments followed the Regulations on the Management of Laboratory Animals and the Jiangsu Province Measures for the Management of Laboratory Animals, as well as the China Pharmaceutical University Institutional Animal Care and Use Committee (No. 202407033).

Author contributions

The authors confirm contribution to the work as follows: study conception and design: Yang P, He W; data collection: Li Z, Xie B; analysis and interpretation of results: Li Z, Xie B, Zou J, He X; draft manuscript preparation: Li Z, Xie B; manuscript revision and editing: Yang P, He W. All authors reviewed the results and approved the final version of the manuscript.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflict of interest

The authors have no conflicts of interest to declare.

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