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

Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonar...

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Autores principales: Plaunt, Adam J., Islam, Sadikul, Macaluso, Tony, Gauani, Helena, Baker, Thomas, Chun, Donald, Viramontes, Veronica, Chang, Christina, Corboz, Michel R., Chapman, Richard W., Li, Zhili, Cipolla, David C., Perkins, Walter R., Malinin, Vladimir S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828008/
https://www.ncbi.nlm.nih.gov/pubmed/33430435
http://dx.doi.org/10.3390/ijms22020548
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author Plaunt, Adam J.
Islam, Sadikul
Macaluso, Tony
Gauani, Helena
Baker, Thomas
Chun, Donald
Viramontes, Veronica
Chang, Christina
Corboz, Michel R.
Chapman, Richard W.
Li, Zhili
Cipolla, David C.
Perkins, Walter R.
Malinin, Vladimir S.
author_facet Plaunt, Adam J.
Islam, Sadikul
Macaluso, Tony
Gauani, Helena
Baker, Thomas
Chun, Donald
Viramontes, Veronica
Chang, Christina
Corboz, Michel R.
Chapman, Richard W.
Li, Zhili
Cipolla, David C.
Perkins, Walter R.
Malinin, Vladimir S.
author_sort Plaunt, Adam J.
collection PubMed
description Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonary vasoconstriction in vivo. Here, we report on re-formulation efforts to develop a more convenient solution-based metered-dose inhaler (MDI) formulation of TP, a treprostinil palmitil inhalation aerosol (TPIA) that matches the pharmacokinetic (PK) and efficacy profile of a nebulized TP formulation, treprostinil palmitil inhalation suspension (TPIS). MDI canisters were manufactured using a two-stage filling method. Aerosol performance, formulation solubility, and chemical stability assays were utilized for in vitro evaluation. For in vivo studies, TPIA formulations were delivered to rodents using an inhalation tower modified for MDI delivery. Using an iterative process involving evaluation of formulation performance in vitro (TP and excipient solubility, chemical stability, physical stability, and aerosol properties) and confirmatory testing in vivo (rat PK and efficacy, guinea pig cough), a promising formulation was identified. The optimized formulation, TPIA-W, demonstrates uniform in vitro drug delivery, a PK profile suitable for a once-daily administration, efficacy lasting at least 12 h in a hypoxic challenge model, and a significantly higher cough threshold than the parent drug treprostinil.
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spelling pubmed-78280082021-01-25 Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension Plaunt, Adam J. Islam, Sadikul Macaluso, Tony Gauani, Helena Baker, Thomas Chun, Donald Viramontes, Veronica Chang, Christina Corboz, Michel R. Chapman, Richard W. Li, Zhili Cipolla, David C. Perkins, Walter R. Malinin, Vladimir S. Int J Mol Sci Article Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonary vasoconstriction in vivo. Here, we report on re-formulation efforts to develop a more convenient solution-based metered-dose inhaler (MDI) formulation of TP, a treprostinil palmitil inhalation aerosol (TPIA) that matches the pharmacokinetic (PK) and efficacy profile of a nebulized TP formulation, treprostinil palmitil inhalation suspension (TPIS). MDI canisters were manufactured using a two-stage filling method. Aerosol performance, formulation solubility, and chemical stability assays were utilized for in vitro evaluation. For in vivo studies, TPIA formulations were delivered to rodents using an inhalation tower modified for MDI delivery. Using an iterative process involving evaluation of formulation performance in vitro (TP and excipient solubility, chemical stability, physical stability, and aerosol properties) and confirmatory testing in vivo (rat PK and efficacy, guinea pig cough), a promising formulation was identified. The optimized formulation, TPIA-W, demonstrates uniform in vitro drug delivery, a PK profile suitable for a once-daily administration, efficacy lasting at least 12 h in a hypoxic challenge model, and a significantly higher cough threshold than the parent drug treprostinil. MDPI 2021-01-07 /pmc/articles/PMC7828008/ /pubmed/33430435 http://dx.doi.org/10.3390/ijms22020548 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Plaunt, Adam J.
Islam, Sadikul
Macaluso, Tony
Gauani, Helena
Baker, Thomas
Chun, Donald
Viramontes, Veronica
Chang, Christina
Corboz, Michel R.
Chapman, Richard W.
Li, Zhili
Cipolla, David C.
Perkins, Walter R.
Malinin, Vladimir S.
Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension
title Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension
title_full Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension
title_fullStr Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension
title_full_unstemmed Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension
title_short Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension
title_sort development and characterization of treprostinil palmitil inhalation aerosol for the investigational treatment of pulmonary arterial hypertension
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828008/
https://www.ncbi.nlm.nih.gov/pubmed/33430435
http://dx.doi.org/10.3390/ijms22020548
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