Drug Res (Stuttg) 2018; 68(11): 605-614
DOI: 10.1055/s-0044-100374
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

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

Franziska G. Leifer
1   Insmed Incorporated, Bridgewater, NJ, USA
1   Insmed Incorporated, Bridgewater, NJ, USA
2   IPS Therapeutique Inc., Sherbrooke, QC, Canada
,
Donna M. Konicek
1   Insmed Incorporated, Bridgewater, NJ, USA
1   Insmed Incorporated, Bridgewater, NJ, USA
2   IPS Therapeutique Inc., Sherbrooke, QC, Canada
,
Kuan-Ju Chen
1   Insmed Incorporated, Bridgewater, NJ, USA
,
Adam J. Plaunt
1   Insmed Incorporated, Bridgewater, NJ, USA
,
Dany Salvail
2   IPS Therapeutique Inc., Sherbrooke, QC, Canada
,
Charles E. Laurent
2   IPS Therapeutique Inc., Sherbrooke, QC, Canada
,
Michel R. Corboz
1   Insmed Incorporated, Bridgewater, NJ, USA
,
Zhili Li
1   Insmed Incorporated, Bridgewater, NJ, USA
,
Richard W. Chapman
1   Insmed Incorporated, Bridgewater, NJ, USA
,
Walter R. Perkins
1   Insmed Incorporated, Bridgewater, NJ, USA
,
Vladimir S. Malinin
1   Insmed Incorporated, Bridgewater, NJ, USA
› Author Affiliations
Further Information

Publication History

received 22 September 2017

accepted 04 January 2018

Publication Date:
23 May 2018 (online)

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.

# These authors contributed equally to this work.


* Franziska G. Leifer and Donna M. Konicek are co-first authors.


Supplementary Material

 
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