Formation of a pulmonary drug-depot by a double-ester treprostinil prodrug enables sustained lung-selective delivery.

Prostacyclin analogues are effective treatments in pulmonary arterial hypertension (PAH), especially in advanced stages. Treprostinil, a stable prostacyclin analogue, can be administered as subcutaneous and intravenous infusions, oral extended-release tablets and inhalation. Inhalation offers several advantages over other routes of administration, including direct access to the lungs for localized therapy, reduced infection risk, and a painless, convenient mode of delivery. However, small lipophilic molecules like treprostinil are absorbed into the bloodstream within minutes after inhalation, resulting in a short duration of action in the lungs and systemic side effects. To address these limitations, we developed a novel strategy involving a double treprostinil prodrug tailored for pulmonary delivery. The prodrug consists of treprostinil di-esterified at its carboxylic acid with a polyethylene glycol (PEG) chain, and at its C11 hydroxyl group with butyric acid. The prodrug exhibited sustained treprostinil release in bronchoalveolar lavage fluid and serum, supporting its suitability for pulmonary delivery. It was cleaved by initial hydrolysis of the PEG chain, followed by subsequent cleavage of the short-chain fatty acid. Ex vivo studies in isolated pulmonary artery rings showed a delayed and prolonged vasorelaxation effect of the conjugate compared to the free drug. In vivo studies demonstrated significant lung retention, with detectable quantities of the compound remaining in the lungs 24 h after administration, and a markedly reduced peak serum concentration following inhalation. This double-prodrug approach represents a promising strategy for improving PAH treatment by optimizing local, sustained treprostinil delivery while minimizing systemic exposure.