Formulation and In Vitro and In Silico Characterization of “Nano-in-Micro” Dry Powder Inhalers Containing Meloxicam
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Preparation Method
2.2.1. Wet Milling
2.2.2. Co-Spray Drying
2.2.3. Physical Mixtures
2.3. Determination of Particle Size and Distribution
2.4. Investigation of Morphology
2.5. Density Measurement
2.6. Determination of the Interparticle Interactions
2.7. Structural Analysis
2.8. Thermoanalitycal Analysis
2.9. In Vitro Dissolution Test
2.10. In Vitro Diffusion Test
2.11. In Vitro Aerodynamic Measurements
2.12. In Silico Characterization
3. Results
3.1. Particle Size Distribution
3.2. Particle Morphology
3.3. Powder Rheology
3.4. Interparticular Interactions
3.5. X-ray Powder Diffraction Results
3.6. Thermoanalytical Results
3.7. In Vitro Dissolution Results
3.8. In Vitro Permeability Results
3.9. In Vitro Aerodynamic Results
3.10. In Silico Aerodynamic Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Samples | MX (g/L) | PVA (g/L) | LEU (g/L) | Yield * (%) |
---|---|---|---|---|
nanoMX1_LEU0 | 4.00 | 0.90 | 0.00 | 45.41 ± 5.10 |
nanoMX1_LEU0.5 | 4.00 | 0.90 | 2.00 | 57.56 ± 1.36 |
nanoMX1_LEU1 | 4.00 | 0.90 | 4.00 | 58.43 ± 6.36 |
Samples | MX (g) | PVA (g) | LEU (g) |
---|---|---|---|
pmMX1_LEU0 | 4.00 | 0.90 | 0.00 |
pmMX1_LEU0.5 | 4.00 | 0.90 | 2.00 |
pmMX1_LEU1 | 4.00 | 0.90 | 4.00 |
ACI Stages | Cut-Off Diameter at 28.3 L/min (µm) |
---|---|
0 | 9.0–10.0 |
1 | 5.8–9.0 |
2 | 4.7–5.8 |
3 | 3.3–4.7 |
4 | 2.1–3.3 |
5 | 1.1–2.1 |
6 | 0.7–1.1 |
7 | 0.4–0.7 |
Filter | <0.4 |
Samples | D[0.1] * (µm) | D[0.5] * (µm) | D[0.9] * (µm) | Span * | SSA * (m2/g) |
---|---|---|---|---|---|
raw MX | 2.719 ± 0.057 | 9.913 ± 0.371 | 29.49 ± 0.630 | 2.70 ± 0.043 | 1.09 ± 0.028 |
MX suspension | 0.067 ± 0.001 | 0.138 ± 0.005 | 0.555 ± 0.310 | 3.584 ± 2.056 | 43.65 ± 5.318 |
pmMX1_LEU0 | 3.073 ± 0.030 | 13.10 ± 0.500 | 349.92 ± 34.86 | 26.47 ± 1.649 | 0.88 ± 0.025 |
pmMX1_LEU0.5 | 5.426 ± 0.631 | 91.22 ± 17.90 | 357.57 ± 168.2 | 3.86 ± 1.101 | 0.40 ± 0.066 |
pmMX1_LEU1 | 7.983 ± 0.092 | 110.67 ± 0.261 | 353.25 ± 47.24 | 3.12 ± 0.433 | 0.27 ± 0.002 |
nanoMX1_LEU0 | 1.497 ± 0.046 | 3.186 ± 0.019 | 6.481 ± 0.193 | 1.56 ± 0.068 | 2.22 ± 0.031 |
nanoMX1_LEU0.5 | 1.834 ± 0.007 | 3.800 ± 0.014 | 7.389 ± 0.030 | 1.46 ± 0.004 | 1.88 ± 0.024 |
nanoMX1_LEU1 | 1.977 ± 0.093 | 4.396 ± 0.032 | 8.903 ± 0.186 | 1.58 ± 0.075 | 1.71 ± 0.051 |
Samples | D * (nm) | SEM Pictures | ||
---|---|---|---|---|
nanoMX1_LEU0 | 134.30 ± 23.07 | | | |
nanoMX1_LEU0.5 | 126.57 ± 27.26 | | | |
nanoMX1_LEU1 | 138.27 ± 42.57 | | | |
Samples | Bulk Density * (g/cm3) | Tapped Density * (g/cm3) | Hausner Ratio * | Carr Index * | Flowability |
---|---|---|---|---|---|
nanoMX1_LEU0 | 0.177 ± 0.020 | 0.262 ± 0.001 | 1.488 ± 0.048 | 32.39 ± 7.232 | Very poor |
nanoMX1_LEU0.5 | 0.156 ± 0.009 | 0.274 ± 0.004 | 1.759 ± 0.084 | 43.09 ± 2.704 | Very, very poor |
nanoMX1_LEU1 | 0.147 ± 0.013 | 0.204 ± 0.012 | 1.398 ± 0.209 | 27.65 ± 10.82 | Very poor |
Samples | γd * [mN/m] | γp * [mN/m] | γ * [mN/m] | Wc * [mN/m] | Pol * [%] |
---|---|---|---|---|---|
MX | 45.49 ± 0.09 | 13.89 ± 0.13 | 59.38 ± 0.22 | 118.76 ± 0.44 | 23.39 ± 0.15 |
PVA | 45.65 ± 0.10 | 36.89 ± 0.20 | 82.54 ± 0.30 | 165.08 ± 0.60 | 44.69 ± 0.11 |
LEU | 30.00 ± 0.07 | 0.50 ± 0.17 | 30.50 ± 0.24 | 61.00 ± 0.48 | 1.639 ± 0.20 |
pmMX1_LEU0 | 42.62 ± 0.12 | 30.65 ± 0.48 | 73.27 ± 0.60 | 146.54 ± 1.20 | 41.83 ± 0.56 |
pmMX1_LEU0.5 | 36.57 ± 0.34 | 25.63 ± 0.27 | 62.20 ± 0.61 | 124.40 ± 1.22 | 41.21 ± 0.84 |
pmMX1_LEU1 | 34.01 ± 0.55 | 16.57 ± 0.36 | 50.58 ± 0.91 | 101.16 ± 1.82 | 32.76 ± 0.44 |
nanoMX1_LEU0 | 42.34 ± 0.08 | 31.03 ± 0.62 | 73.38 ± 0.70 | 146.76 ± 1.40 | 42.29 ± 0.44 |
nanoMX1_LEU0.5 | 36.15 ± 0.95 | 25.69 ± 0.45 | 61.84 ± 0.51 | 123.68 ± 1.02 | 41.54 ± 1.07 |
nanoMX1_LEU1 | 33.39 ± 0.86 | 16.59 ± 0.11 | 49.98 ± 0.97 | 99.96 ± 1.94 | 33.19 ± 0.43 |
Samples | J (µg/cm2/h) | Kp (cm/h) |
---|---|---|
rawMX | 28.23 | 0.1394 |
pmMX1_LEU0 | 34.69 | 0.2081 |
pmMX1_LEU0.5 | 37.45 | 0.2247 |
pmMX1_LEU1 | 33.25 | 0.1995 |
nanoMX1_LEU0 | 61.80 | 0.3708 |
nanoMX1_LEU0.5 | 86.90 | 0.5214 |
nanoMX1_LEU1 | 73.58 | 0.4415 |
Samples | MMAD * (µm) | FPD * (mg) | FPF * (%) | ED * (mg) | EF * (%) | Loaded API * (mg) | API content * (%) |
---|---|---|---|---|---|---|---|
nanoMX1_LEU0 | 2.33 ± 0.08 | 4.52 ± 0.33 | 75.67 ± 3.46 | 5.98 ± 0.22 | 72.42 ± 3.05 | 8.26 ± 0.14 | 93.81 ± 2.99 |
nanoMX1_LEU0.5 | 1.74 ± 0.35 | 3.09 ± 0.31 | 72.81 ± 1.46 | 4.24 ± 0.34 | 83.47 ± 1.33 | 5.07 ± 0.33 | 55.48 ± 0.78 |
nanoMX1_LEU1 | 1.55 ± 0.06 | 2.51 ± 0.04 | 73.63 ± 0.96 | 3.40 ± 0.10 | 75.22 ± 1.75 | 4.53 ± 0.23 | 51.46 ± 0.66 |
Samples | Deposited Fraction * (%) | |||
---|---|---|---|---|
Extrathoracic | Lung | Bronchial | Acinar | |
nanoMX1_LEU0 | 21.41 ± 2.79 | 46.73 ± 2.21 | 17.92 ± 2.93 | 28.81 ± 2.22 |
nanoMX1_LEU0.5 | 14.45 ± 0.95 | 27.55 ± 0.99 | 10.72 ± 1.30 | 16.83 ± 1.34 |
nanoMX1_LEU1 | 10.07 ± 0.47 | 22.44 ± 0.31 | 8.64 ± 0.54 | 13.80 ± 0.35 |
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Party, P.; Bartos, C.; Farkas, Á.; Szabó-Révész, P.; Ambrus, R. Formulation and In Vitro and In Silico Characterization of “Nano-in-Micro” Dry Powder Inhalers Containing Meloxicam. Pharmaceutics 2021, 13, 211. https://doi.org/10.3390/pharmaceutics13020211
Party P, Bartos C, Farkas Á, Szabó-Révész P, Ambrus R. Formulation and In Vitro and In Silico Characterization of “Nano-in-Micro” Dry Powder Inhalers Containing Meloxicam. Pharmaceutics. 2021; 13(2):211. https://doi.org/10.3390/pharmaceutics13020211
Chicago/Turabian StyleParty, Petra, Csilla Bartos, Árpád Farkas, Piroska Szabó-Révész, and Rita Ambrus. 2021. "Formulation and In Vitro and In Silico Characterization of “Nano-in-Micro” Dry Powder Inhalers Containing Meloxicam" Pharmaceutics 13, no. 2: 211. https://doi.org/10.3390/pharmaceutics13020211