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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-7828008 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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