Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Nov;68(11):605-614.
doi: 10.1055/s-0044-100374. Epub 2018 May 23.

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

Franziska G Leifer  1   1   2 , Donna M Konicek  1   1   2 , Kuan-Ju Chen  1 , Adam J Plaunt  1 , Dany Salvail  2 , Charles E Laurent  2 , Michel R Corboz  1 , Zhili Li  1 , Richard W Chapman  1 , Walter R Perkins  1 , Vladimir S Malinin  1
Affiliations

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

Franziska G Leifer et al. Drug Res (Stuttg). 2018 Nov.

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 Cmax 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 Cmax-associated adverse events which could provide patients with an improved treprostinil therapy.

PubMed Disclaimer

Conflict of interest statement

All authors of this work as well as the work presented in this manuscript were funded by Insmed Incorporated.

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

MeSH terms

-