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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| Format: | Article |
| Language: | English |
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MDPI AG
2021-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/2/548 |
| _version_ | 1797415171965059072 |
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| author | Adam J. Plaunt Sadikul Islam Tony Macaluso Helena Gauani Thomas Baker Donald Chun Veronica Viramontes Christina Chang Michel R. Corboz Richard W. Chapman Zhili Li David C. Cipolla Walter R. Perkins Vladimir S. Malinin |
| author_facet | Adam J. Plaunt Sadikul Islam Tony Macaluso Helena Gauani Thomas Baker Donald Chun Veronica Viramontes Christina Chang Michel R. Corboz Richard W. Chapman Zhili Li David C. Cipolla Walter R. Perkins Vladimir S. Malinin |
| author_sort | Adam J. Plaunt |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T05:44:00Z |
| format | Article |
| id | doaj.art-4c4d58c1a0184939b9ca33128da7d82b |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T05:44:00Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4c4d58c1a0184939b9ca33128da7d82b2023-12-03T12:22:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-0122254810.3390/ijms22020548Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial HypertensionAdam J. Plaunt0Sadikul Islam1Tony Macaluso2Helena Gauani3Thomas Baker4Donald Chun5Veronica Viramontes6Christina Chang7Michel R. Corboz8Richard W. Chapman9Zhili Li10David C. Cipolla11Walter R. Perkins12Vladimir S. Malinin13Insmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USATreprostinil 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.https://www.mdpi.com/1422-0067/22/2/548treprostinil palmitilmetered-dose inhalerprodruginhalation aerosolpulmonary hypertensionpulmonary arterial hypertension |
| spellingShingle | Adam J. Plaunt Sadikul Islam Tony Macaluso Helena Gauani Thomas Baker Donald Chun Veronica Viramontes Christina Chang Michel R. Corboz Richard W. Chapman Zhili Li David C. Cipolla Walter R. Perkins Vladimir S. Malinin Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension International Journal of Molecular Sciences treprostinil palmitil metered-dose inhaler prodrug inhalation aerosol pulmonary hypertension 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 | treprostinil palmitil metered-dose inhaler prodrug inhalation aerosol pulmonary hypertension pulmonary arterial hypertension |
| url | https://www.mdpi.com/1422-0067/22/2/548 |
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