Inhaled Treprostinil-Prodrug Lipid Nanoparticle Formulations Provide Long-Acting Pulmonary Vasodilation

Abstract

Treprostinil (TRE), a prostanoid analogue approved in the USA for the treatment of pulmonary arterial hypertension, requires continuous infusion or multiple dosing sessions per day for inhaled and oral routes of administration due to its short half-life. The inhaled drug is known to induce adverse systemic and local effects including headache, nausea, cough, and throat irritation which may be due at least in part to transiently high drug concentrations in the lungs and plasma immediately following administration [1]. To ameliorate these side effects and reduce dosing frequency we designed an inhaled slow-release TRE formulation. TRE was chemically modified to be an alkyl prodrug (TPD) which was then packaged into a lipid nanoparticle (LNP) carrier. Preclinical screening in a rat model of hypoxia-induced pulmonary vasoconstriction led to selection of a 16-carbon alkyl ester derivative of TRE. The TPD-LNP demonstrated approximately 10-fold lower TRE plasma C compared to inhaled TRE solution while maintaining an extended vasodilatory effect. The favorable PK profile is attributed to gradual dissociation of TPD from the LNP and subsequent conversion to TRE. Together, this sustained presentation of TRE to the lungs and plasma is consistent with a once- or twice-daily dosing schedule in the absence of high C-associated adverse events which could provide patients with an improved treprostinil therapy.

Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug

“…When the prodrug C16TR is cleaved by lung esterases (Leifer et al, , 2017, it also produces hexadecanol, which is expected to be readily metabolized by pulmonary pneumocytes (Frenkel et al, 1993); note that hexadecanol was a constituent of the artificial pulmonary surfactant Exosurf (colfosceril palmitate) (Durand et al, 1985).…”

“…The other formulation contains C16TR and squalane, but with 1,2-dioleoyl-sn-glycero-3phosphocholine (DOPC) and cholesterol-PEG2000; the molar ratio of these four ingredients was 40:40:10:10. This formulation has been previously termed T623 (Leifer et al, , 2017Malinin et al, 2014). Two additional TRE prodrugs were evaluated in dogs and consisted of C14TR or C12TR, which were formulated in LNP containing squalane, DOPC, and cholesterol-PEG2000 in the ratio of 40:40:10:10.…”

Current Treatment Strategies and Nanoparticle-Mediated Drug Delivery Systems for Pulmonary Arterial Hypertension

“…Prostacyclin (PGI 2 ) analogue [27,28,29,30], PDE5 inhibitors [31,32], ERA [33], oligonucleotides [34,35], pitavastatin [36,37], imatinib [38], rapamycin [39], and fasudil [40]-loaded NPs have been reported to be effective in animal PAH models and in vitro studies (Table 1). All of the data in the studies were obtained in animal models of PAH or in vitro studies and have not yet been translated to human trials.…”

“…Treprostinil-loaded NPs: Trepostinil was also chemically modified to be an alkyl prodrug (TPD) which was then packaged into a lipid nanoparticle (LNP) carrier. The TPD-LNP demonstrated approximately lower treprostinil plasma concentration compared to inhaled treprostinil solution while maintaining an extended vasodilatory effect in a rat model of hypoxia-induced pulmonary vasoconstriction [29].…”

Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension

“…Insmed has developed treprostinil palmitil (TP), an ester prodrug of TRE, which hydrolyzes slowly to provide sustained release of TRE over an extended period [ 15 ]. The chemical structures of TP and TRE are shown in Figure 1 .…”