Effect of Inhalation Profile on Delivery of Treprostinil Palmitil Inhalation Powder
Abstract
:1. Introduction
2. Materials and Methods
2.1. DPI Device
2.2. Compounds and Materials
2.3. Aerosol Characterization Using the Next Generation Impactor (NGI) and Breathing Simulator
2.4. Quantitation of TP
2.5. Determination of ED, MMAD, GSD, FPF and FPD
2.6. Data Analyses and Statistics
3. Results
3.1. Evaluation of the Inhalation Acceleration Rates for the 16 and 32 mg TPIP Capsule Doses at 60 LPM Inspiratory Flow Rate and 4 L Inhalation Volume
3.2. Evaluation of the Inhalation Volume for the 16 and 32 mg TPIP Capsule Doses at 60 LPM Inspiratory Flow Rate
3.3. Evaluation of the Inhalation Volume for the 16 mg TPIP Capsule Doss at 30 LPM Inspiratory Flow Rate
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Inhalation Ramp Time | n | Emitted Dose | MMAD | GSD | FPF (<5 µm) | FPD (<5 µm) | ||
---|---|---|---|---|---|---|---|---|
% | µg, TP | µm | % of Emitted Dose | % of Loaded Dose | µg, TP | |||
16 mg capsule containing 160 µg TP | ||||||||
50 ms | 3 | 79.8 ± 1.1 | 127.68 ± 1.70 | 1.27 ± 0.08 | 3.54 ± 0.11 | 78.1 ± 1.1 | 62.3 ± 1.7 | 99.71 ± 2.76 |
170 ms | 3 | 81.3 ± 1.2 | 130.11 ± 1.95 | 1.18 ± 0.03 | 3.71 ± 0.05 | 77.6 ± 1.1 | 63.1 ± 0.8 | 100.89 ± 1.30 |
500 ms | 3 | 79.8 ± 0.9 | 127.69 ± 1.46 | 1.04 ± 0.03 | 3.83. ± 0.05 | 80.0 ± 0.4 | 63.8 ± 1.0 | 102.11 ± 1.64 |
1000 ms | 3 | 80.3 ± 2.7 | 128.47 ± 4.24 | 1.05 ± 0.05 | 3.93 ± 0.10 | 80.4 ± 0.3 | 64.5 ± 2.4 | 103.23 ± 3.80 |
2000 ms | 3 | 81.8 ± 0.6 | 130.88 ± 1.00 | 1.06 ± 0.02 | 3.97 ± 0.10 | 79.6 ± 1.4 | 65.1 ± 1.6 | 104.23 ± 2.57 |
32 mg capsule containing 320 µg TP | ||||||||
50 ms | 3 | 81.3 ± 1.7 | 260.10 ± 5.55 | 1.66 ± 0.07 | 4.30 ± 0.21 | 67.6 ± 1.3 | 54.9 ± 1.3 | 175.81 ± 4.14 |
170 ms | 3 | 82.7 ± 1.3 | 264.76 ± 4.01 | 1.51 ± 0.02 | 4.35 ± 0.10 | 68.6 ± 3.3 | 56.8 ± 3.5 | 181.59 ± 11.15 |
500 ms | 3 | 81.3 ± 0.3 | 260.04 ± 1.07 | 1.38 ± 0.10 | 4.59 ± 0.26 | 70.7 ± 1.6 | 57.5 ± 1.1 | 183.93 ± 3.48 |
1000 ms | 3 | 82.9 ± 0.4 | 265.20 ± 1.12 | 1.40 ± 0.13 | 4.57 ±0.23 | 71.3 ± 2.4 | 59.1 ± 2.3 | 189.18 ± 7.19 |
2000 ms | 3 | 89.4 ± 2.2 | 286.14 ± 7.08 | 1.33 ± 0.10 | 4.32 ± 0.09 | 72.9 ± 2.0 | 65.2 ± 3.3 | 208.75 ± 10.62 |
Ramp Time | FPD (<5 µm) t-Test 2-Tailed p-Values | ||||
---|---|---|---|---|---|
vs. 50 ms | vs. 170 ms | vs. 500 ms | vs. 1000 ms | vs. 2000 ms | |
16 mg capsule containing 160 µg TP | |||||
50 ms | - | 0.540 | 0.265 | 0.265 | 0.106 |
170 ms | 0.540 | - | 0.370 | 0.371 | 0.115 |
500 ms | 0.265 | 0.370 | - | 0.664 | 0.294 |
1000 ms | 0.265 | 0.371 | 0.664 | - | 0.724 |
2000 ms | 0.106 | 0.115 | 0.294 | 0.724 | - |
Overall p-value (ANOVA: single factor) | 0.282 | ||||
32 mg capsule containing 320 µg TP | |||||
50 ms | - | 0.447 | 0.060 | 0.049 | 0.007 |
170 ms | 0.447 | - | 0.747 | 0.378 | 0.038 |
500 ms | 0.060 | 0.747 | - | 0.318 | 0.018 |
1000 ms | 0.049 | 0.378 | 0.318 | - | 0.057 |
2000 ms | 0.007 | 0.038 | 0.018 | 0.057 | - |
Overall p-value (ANOVA: single factor) | 0.005 |
Inhalation Parameters: Ramp Time, Inhaled Volume | n | Emitted Dose | MMAD | GSD | FPF (<5 µm) | FPD (<5 µm) | ||
---|---|---|---|---|---|---|---|---|
% | µg, TP | µm | % of Emitted Dose | % of Loaded Dose | µg, TP | |||
16 mg capsule containing 160 µg TP at 60 LPM (50 and 2000 ramp times corresponding to 20 and 0.5 L/s2 acceleration rates, respectively) | ||||||||
50 ms, 1 L | 3 | 81.1 ± 0.6 | 129.81 ± 0.96 | 1.24 ± 0.02 | 3.80 ± 0.07 | 76.0 ± 1.5 | 61.7 ± 0.7 | 98.70 ± 1.19 |
50 ms, 2 L | 3 | 79.1 ± 1.9 | 126.53 ± 3.07 | 1.28 ± 0.01 | 3.68 ± 0.13 | 76.9 ± 1.0 | 60.8 ± 0.7 | 97.28 ± 1.12 |
* 50 ms, 4 L | 3 | 79.8 ± 1.1 | 127.68 ± 1.70 | 1.27 ± 0.08 | 3.54 ± 0.11 | 78.1 ± 1.1 | 62.3 ± 1.7 | 99.71 ± 2.76 |
2000 ms, 1 L | 3 | 82.3 ± 1.2 | 131.71 ± 1.92 | 1.19 ± 0.05 | 4.16 ± 0.05 | 76.8 ± 1.0 | 63.2 ± 1.0 | 101.13 ± 1.61 |
2000 ms, 2 L | 3 | 82.5 ± 2.3 | 131.94 ± 3.63 | 1.06 ± 0.03 | 3.95 ± 0.05 | 78.6 ± 0.7 | 64.8 ± 2.4 | 103.68 ± 3.81 |
* 2000 ms, 4 L | 3 | 81.8 ± 0.6 | 130.88 ± 1.00 | 1.06 ± 0.02 | 3.97 ± 0.10 | 79.6 ± 1.4 | 65.1 ± 1.6 | 104.23 ± 2.57 |
32 mg capsule containing 320 µg TP at 60 LPM (50 and 2000 ramp times corresponding to 20 and 0.5 L/s2 acceleration rates, respectively) | ||||||||
50 ms, 1 L | 3 | 84.1 ± 0.5 | 269.01 ± 1.62 | 1.68 ± 0.03 | 4.51 ± 0.07 | 63.0 ± 1.0 | 53.0 ± 0.8 | 169.43 ± 2.45 |
50 ms, 2 L | 3 | 84.7 ± 1.3 | 271.12 ± 3.99 | 1.65 ± 0.02 | 4.30 ± 0.14 | 65.6 ± 1.0 | 55.6 ± 0.9 | 177.94 ± 2.73 |
* 50 ms, 4 L | 3 | 81.3 ± 1.7 | 260.10 ± 5.55 | 1.66 ± 0.07 | 4.30 ± 0.21 | 67.6 ± 1.3 | 54.9 ± 1.3 | 175.81 ± 4.14 |
50 ms, 4 L | 3 | 83.9 ± 0.5 | 268.37 ± 1.53 | 1.69 ± 0.07 | 4.35 ± 0.08 | 64.6 ± 1.5 | 54.2 ± 1.3 | 173.38 ± 4.28 |
2000 ms, 1 L | 3 | 81.2 ± 1.3 | 259.99 ± 4.08 | 1.27 ± 0.08 | 4.37 ± 0.16 | 72.1 ± 1.4 | 58.6 ± 0.3 | 187.40 ± 0.88 |
2000 ms, 2 L | 3 | 86.8 ± 0.6 | 277.59 ± 2.00 | 1.34 ± 0.03 | 4.25 ± 0.10 | 72.6 ± 1.4 | 63.0 ± 1.1 | 201.61 ± 3.49 |
* 2000 ms, 4 L | 3 | 89.4 ± 2.2 | 286.14 ± 7.08 | 1.33 ± 0.10 | 4.32 ± 0.09 | 72.9 ± 2.0 | 65.2 ± 3.3 | 208.75 ± 10.62 |
2000 ms, 4 L | 3 | 87.6 ± 0.9 | 280.22 ± 2.81 | 1.35 ± 0.03 | 4.33 ± 0.01 | 72.2 ± 0.2 | 63.2 ± 0.6 | 202.20 ± 1.96 |
Ramp Time, Volume | FPD (<5 µm) t-Test 2-Tailed p-Values | |||||
---|---|---|---|---|---|---|
vs. 50 ms 1 L | vs. 50 ms 2 L | vs. 50 ms 4 L | vs. 2000 ms 1 L | vs. 2000 ms 2 L | vs. 2000 ms 4 L | |
16 mg capsule containing 160 µg TP at 60 LPM (50 and 2000 ramp times corresponding to 20 and 0.5 L/s2 acceleration rates, respectively) | ||||||
50 ms, 1 L | - | 0.206 | 0.588 | 0.103 | 0.097 | 0.028 |
50 ms, 2 L | 0.206 | - | 0.229 | 0.027 | 0.049 | 0.013 |
50 ms, 4 L | 0.588 | 0.229 | - | 0.485 | 0.218 | 0.106 |
2000 ms, 1 L | 0.103 | 0.027 | 0.485 | - | 0.345 | 0.151 |
2000 ms, 2 L | 0.097 | 0.049 | 0.218 | 0.345 | - | 0.846 |
2000 ms, 4 L | 0.028 | 0.013 | 0.106 | 0.151 | 0.846 | - |
(ANOVA: single factor) | 0.336 | 0.409 | ||||
Overall p-value (ANOVA: single factor) | 0.022 | |||||
32 mg capsule containing 320 µg TP at 60 LPM (50 and 2000 ramp times corresponding to 20 and 0.5 L/s2 acceleration rates, respectively) | ||||||
50 ms, 1 L | - | 0.016 | 0.237 | 0.000 | 0.000 | 0.000 |
50 ms, 2 L | 0.016 | - | 0.194 | 0.005 | 0.001 | 0.000 |
50 ms, 4 L | 0.237 | 0.194 | - | 0.005 | 0.001 | 0.000 |
2000 ms, 1 L | 0.000 | 0.005 | 0.005 | - | 0.002 | 0.000 |
2000 ms, 2 L | 0.000 | 0.001 | 0.001 | 0.002 | - | 0.811 |
2000 ms, 4 L | 0.000 | 0.000 | 0.000 | 0.000 | 0.811 | - |
p-value (ANOVA: single factor) | 0.050 | 0.004 | ||||
Overall p-value (ANOVA: single factor) | 0.000 |
Inhalation Parameters: Ramp Time, Inhaled Volume | n | Emitted Dose | MMAD | GSD | FPF (<5 µm) | FPD (<5 µm) | ||
---|---|---|---|---|---|---|---|---|
% | µg, TP | µm | % of Emitted Dose | % of Loaded Dose | µg, TP | |||
16 mg capsule containing 160 µg TP at 30 LPM (25 and 1000 ramp times corresponding to 20 and 0.5 L/s2 acceleration rates, respectively) | ||||||||
25 ms, 1 L | 3 | 76.4 ± 0.7 | 122.30 ± 1.04 | 2.19 ± 0.11 | 2.34 ± 0.05 | 76.2 ± 1.7 | 58.2 ± 0.9 | 93.13 ± 1.45 |
25 ms, 2 L | 3 | 76.1 ± 2.3 | 121.79 ± 3.61 | 2.25 ± 0.08 | 2.31 ± 0.10 | 75.6 ± 1.4 | 57.5 ± 0.9 | 92.08 ± 1.40 |
25 ms, 4 L | 3 | 76.1 ± 1.8 | 121.83 ± 2.95 | 2.16 ± 0.08 | 2.40 ± 0.06 | 75.9 ± 1.8 | 57.7 ± 1.0 | 92.39 ± 1.60 |
1000 ms, 1 L | 3 | 71.7 ± 1.8 | 114.73 ± 2.83 | 1.90 ± 0.11 | 2.58 ± 0.07 | 76.0 ± 1.3 | 54.5 ± 0.8 | 87.16 ± 1.27 |
1000 ms, 2 L | 3 | 72.7 ± 1.1 | 116.30 ± 1.71 | 1.88 ± 0.08 | 2.67 ± 0.03 | 74.2 ± 1.1 | 53.9 ± 0.9 | 86.26 ± 1.44 |
1000 ms, 4 L | 3 | 74.8 ± 2.3 | 119.67 ± 3.75 | 1.95 ± 0.11 | 2.54 ± 0.09 | 74.9 ± 0.6 | 56.0 ± 2.1 | 89.61 ± 3.29 |
Ramp Time, Volume | FPD (< 5 µm) t-Test 2-Tailed p-Values | |||||
---|---|---|---|---|---|---|
vs. 25 ms 1 L | vs. 25 ms 2 L | vs. 25 ms 4 L | vs. 1000 ms 1 L | vs. 1000 ms 2 L | vs. 1000 ms 4 L | |
16 mg capsule containing 160 µg TP at 30 LPM (25 and 1000 ramp times corresponding to 20 and 0.5 L/s2 acceleration rates, respectively) | ||||||
25 ms, 1 L | - | 0.415 | 0.581 | 0.006 | 0.004 | 0.165 |
25 ms, 2 L | 0.415 | - | 0.813 | 0.011 | 0.007 | 0.298 |
25 ms, 4 L | 0.581 | 0.813 | - | 0.011 | 0.008 | 0.259 |
1000 ms, 1 L | 0.006 | 0.011 | 0.011 | - | 0.463 | 0.296 |
1000 ms, 2 L | 0.004 | 0.007 | 0.008 | 0.463 | - | 0.182 |
1000 ms, 4 L | 0.165 | 0.298 | 0.259 | 0.296 | 0.182 | - |
(ANOVA: single factor) | 0.686 | 0.235 | ||||
Overall p-value (ANOVA: single factor) | 0.003 |
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Gauani, H.; Baker, T.; Li, Z.; Malinin, V.S.; Perkins, W.R.; Sullivan, E.J.; Cipolla, D. Effect of Inhalation Profile on Delivery of Treprostinil Palmitil Inhalation Powder. Pharmaceutics 2023, 15, 934. https://doi.org/10.3390/pharmaceutics15030934
Gauani H, Baker T, Li Z, Malinin VS, Perkins WR, Sullivan EJ, Cipolla D. Effect of Inhalation Profile on Delivery of Treprostinil Palmitil Inhalation Powder. Pharmaceutics. 2023; 15(3):934. https://doi.org/10.3390/pharmaceutics15030934
Chicago/Turabian StyleGauani, Helena, Thomas Baker, Zhili Li, Vladimir S. Malinin, Walter R. Perkins, Eugene J. Sullivan, and David Cipolla. 2023. "Effect of Inhalation Profile on Delivery of Treprostinil Palmitil Inhalation Powder" Pharmaceutics 15, no. 3: 934. https://doi.org/10.3390/pharmaceutics15030934