Injectable treprostinil depot offers multiday control of pulmonary hypertension
image: Figure 1
Credit: Targetome
A research team has developed a long-acting injectable treprostinil depot that forms a drug-releasing gel inside the body, providing sustained pulmonary vasodilation for three to four days after a single intramuscular injection in rats with pulmonary arterial hypertension (PAH). The formulation prolonged drug residence, stabilized plasma concentrations, reduced pulmonary arterial pressure, and limited pulmonary vascular and right ventricular remodeling. It also showed favorable biocompatibility, with mild injection-site inflammation resolving within one week. If validated in further preclinical and clinical studies, this pump-free delivery strategy could reduce dosing frequency, simplify treprostinil administration, improve treatment adherence, and enhance quality of life for people living with PAH.
PAH is a progressive cardiovascular disease characterized by narrowing and remodeling of the small pulmonary arteries, which increases vascular resistance and can ultimately lead to right-heart failure. Treprostinil, a prostacyclin analogue and first-line treatment for severe or rapidly progressing PAH, dilates pulmonary vessels and suppresses the proliferation of pulmonary arterial smooth muscle cells. However, its short duration of action generally requires continuous subcutaneous or intravenous infusion using an external or implanted pump. Subcutaneous infusion can cause persistent injection-site pain, while intravenous delivery carries a risk of catheter-associated infection. Pump preparation, maintenance, refilling, and sterility requirements also increase treatment complexity, cost, and burden, highlighting the need for a safer, longer-acting formulation.
A study (DOI: 10.48130/targetome-0026-0029) published in Targetome on 30 June 2026 by Wei He's & Pei Yang's team, China Pharmaceutical University, reports that a thermosensitive microparticle-loaded gel sustained treprostinil exposure and improved hemodynamic and structural indicators of PAH in rats.
The researchers first prepared treprostinil microparticles by thin-film hydration, using poloxamer 188 as a stabilizer, and then dispersed the particles in a methylcellulose-based thermosensitive hydrogel. Optimization identified a 1:4 treprostinil-to-poloxamer ratio and a formulation containing polyethylene glycol 4000 as the most suitable combination. The resulting rod-shaped particles measured approximately 1.76 micrometers and achieved a drug-loading efficiency of about 97%. At physiological temperature, the injectable liquid rapidly transformed into a porous semisolid depot that restricted drug diffusion. Laboratory release tests showed that the composite system reduced early burst release 3.66-fold compared with microparticles alone. Cell experiments further indicated prolonged inhibition of PAH-associated pulmonary arterial smooth muscle cell proliferation with less acute toxicity than free treprostinil. The researchers then evaluated pharmacokinetics, tissue residence, therapeutic efficacy, and local safety in rats. Fluorescence imaging detected the optimized depot at the injection site for up to 15 days, compared with eight days for free treprostinil and 10 days for microparticles. After a single intramuscular dose, the depot increased treprostinil’s elimination half-life from 0.75 hours to 17.96 hours and its mean residence time from 0.81 hours to 23.16 hours. It also lowered the maximum plasma concentration from approximately 1,750 to 555 nanograms per milliliter, indicating reduced burst exposure. In a monocrotaline-induced rat model of PAH, one injection lowered mean pulmonary arterial pressure from 33 to 21 millimeters of mercury within one hour, with the effect lasting three to four days. Following 14 days of treatment, the formulation reduced arterial wall thickening, smooth muscle proliferation, vascular obstruction, and right ventricular hypertrophy more effectively than free drug or microparticles alone. Safety testing found only transient local inflammation, which disappeared within seven days.
Overall, the study demonstrates how treprostinil microparticles and a temperature-responsive hydrogel can work as complementary release barriers, converting a short-acting drug into a multiday injectable treatment. The formulation may offer a simpler alternative to continuous pump infusion while reducing sharp fluctuations in circulating drug concentrations. However, the results were obtained in cell experiments and a rat model, so studies in additional PAH models, longer-term toxicity assessments, manufacturing validation, and human clinical trials will be required. With further development, this in situ depot could provide a practical platform for sustained PAH therapy and potentially for delivering other hydrophobic drugs used in chronic diseases.
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References
DOI
Original Source URL
https://doi.org/10.48130/targetome-0026-0029
Funding information
This study was supported by the National Natural Science Foundation of China (Nos. 82073782 and 82241002).
About Targetome
Targetome refers to the complete collection of molecular targets (e.g., proteins, RNA or DNA) that interact with and mediate the effect of a specific biomolecule, such as a drug, toxin, metabolites, transcription factor or microRNA, within a biological system. Targetome is an open access journal publishing rigorously peer-reviewed original research articles, reviews, break-through methods, and perspectives that advance our understanding, identification and validation of molecular targets for new drug development.