Preparation of Carrier-Free Inhalable Dry Powder of Rivaroxaban Using Two-Step Milling for Lung-Targeted Delivery
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Preparation of Milled Rivaroxaban for Dry Powder Inhalation
2.3. Physicochemical Characterization
2.3.1. Morphology of Milled RVX Dry Powder
2.3.2. X-Ray Diffraction (XRD)
2.3.3. Differential Scanning Calorimetry (DSC)
2.4. Particle Image Velocimetry
2.5. In-Vitro Aerodynamic Performance
2.6. Ex-Vivo Plasma Anticoagulation Effect Tests
2.7. In-Vivo Study of Rivaroxaban
2.7.1. Pharmacokinetic Studies of Rivaroxaban
2.7.2. Lung and Heart Distribution of Rivaroxaban
2.8. Statistical Analysis
3. Results and Discussion
3.1. Preparation and Characterization of Milled Rivaroxaban Dry Powder
3.2. Comparison of Particle Dispersion and Aerodynamic Performance of RVX Formulations Prepared by Different Milling Methods
3.3. Effect of Leucine Concentration on Aerodynamic Performance in Two-Step Milling Method
3.4. Ex-Vivo Plasma Anticoagulation Effect
3.5. Pharmacokinetic Studies
3.6. Lung and Heart Distribution
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
PE | Pulmonary embolism |
VTE | Venous thromboembolism |
NOACs | Non-vitamin K antagonist oral anticoagulants |
LEU or L | L-leucine |
FCA | Force control agent |
BM | Bead milling |
JM | Jet milling |
RVX | Rivaroxaban |
DPI | Dry powder inhalation |
SEM | Scanning electron microscope |
XRD | X-ray diffraction |
DSC | Differential scanning calorimetry |
PIV | Particle image velocimetry |
HPLC | High-performance liquid chromatography |
NGI | Next-generation impactor |
ED | Emitted dose |
FPF | Fine particle fraction |
FPD | Fine particle dose |
MMAD | Mass median aerodynamic diameter |
GSD | Geometric standard deviation |
PBS | Phosphate-buffered saline |
PK | Pharmacokinetic |
ANOVA | Analysis of variance |
AUC | Area under the curve |
Cmax | Maximum plasma concentration |
Tmax | Time to maximum concentration |
T1/2 | Half-life |
CL/F | Clearance |
BA | Bioavailability |
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Formulation | |||
---|---|---|---|
Code | Component | Process | |
Rivaroxaban | L-leucine | ||
BM only | 3 | - | Bead milling |
JM-only | - | Jet milling | |
BM-JM | - | Bead and Jet milling | |
BM-JM-1L | 0.03 | ||
BM-JM-5L | 0.15 | ||
BM-JM-10L | 0.3 | ||
Milling condition | |||
Bead milling | Jet milling | ||
Bead | Zirconium beads 1 mm | Grinding pressure | 0.45 MPa |
Speed | 650 rpm | Pushing pressure | 0.50 MPa |
Cycle | 5 cycles Rotation time 12 min Interval time 3 min | Feed rate | 40 Hz |
Drying | 50 °C, 12 hours |
Formulations | Dv 10 (μm) | Dv 50 (μm) | Dv 90 (μm) | Span |
---|---|---|---|---|
Raw-RVX | 3.67 ± 0.00 ##,††,!! | 8.27 ± 0.05 ##,††,!! | 16.74 ± 0.40 ##,††,!! | 1.58 ± 0.03 ##.††,!! |
BM-only | 4.82 ± 0.16 **,††,!! | 45.9 ± 0.36 **,††, !! | 86.88 ± 0.13 **,††, !! | 1.78 ± 0.01 ††,!! |
JM-only | 2.16 ± 0.01 **,##,!! | 6.12 ± 0.04 **,##,!! | 13.94 ± 0.20 **,##,†† | 1.92 ± 0.02 **,##,!! |
BM-JM | 0.89 ± 0.01 **,##,†† | 2.84 ± 0.08 **,##,†† | 21.46 ± 1.75 **,##,†† | 7.21 ± 0.39 **,##,†† |
BM-JM-1L | 0.58 ± 0.01 **,##,†† | 1.22 ± 0.01 **,##,†† | 7.39 ± 0.20 **,##,††,!! | 5.57 ± 0.15 **,##,††,!! |
BM-JM-5L | 0.87 ± 0.01 **,##,†† | 2.58 ± 0.01 **,##,†† | 9.25 ± 0.08 **,##,††,!! | 3.23 ± 0.03 **,##,††,!! |
BM-JM-10L | 0.89 ± 0.00 **,##,††,!! | 2.82 ± 0.01 **,##,††,!! | 7.56 ± 0.08 **,##,††,!! | 2.35 ± 0.02 **,##,!! |
Properties | Raw-RVX | BM-Only | JM-Only | BM-JM | |
---|---|---|---|---|---|
PIV | Arrival time (ms) | 161.67 ± 46.12 | 75.83 ± 10.10 | 158.67 ± 91.11 | 146.67 ± 25.9 |
Mean speed (mm/ms) | 0.95 ± 0.08 ## | 0.77 ± 0.08 **,†† | 1.05 ± 0.02 ## | 1.00 ± 0.05 ## | |
Maximum speed (mm/ms) | 3.00 ± 0.06 # | 6.22 ± 0.09 *,†† | 2.93 ± 0.08 ## | 2.82 ± 0.11 ## | |
NGI | ED (%) | - | 69.69 ± 19.91 | 84.02 ± 6.17 | 78.60 ± 1.48 |
FPF (%) | - | 15.69 ± 1.91 †† | 27.71 ± 2.49 ## | 45.55 ± 4.90 ##,†† | |
MMAD (μm) | - | N/A | 7.71 ± 0.03 | 6.56 ± 1.31 | |
GSD | - | N/A | 1.66 ± 0.02 | 2.61 ± 0.18 |
Parameters | Oral (5 mg/kg) | BM-JM-5L (2 mg/kg) | BM-JM-5L (5 mg/kg) | BM-JM-5L (10 mg/kg) |
---|---|---|---|---|
t1/2 (h) | 3.85 ± 1.29 | 6.27 ± 1.82 | 8.76 ± 1.54 | 10.46 ± 3.29 |
Tmax (h) | 4.00 ± 0.01 | 2.80 ± 0.45 | 3.80 ± 0. 45 | 3.80 ± 2.68 |
Cmax (ng/mL) | 770.26 ± 64.46 | 566.61 ± 134.22 | 1029.48 ± 256.54 | 1334.64 ± 465.97 |
AUC0–24 (ng·hr/mL) | 4006.47 ± 1124.41 | 3945.45 ± 666.26 | 10,272.88 ± 2516.56 ** | 12,880.85 ± 565.1 **,†† |
CL/F (L/h/kg) | 1.31 ± 0.28 | 0.45 ± 0.07 | 0.42 ± 0.11 | 0.30 ± 0.04 |
Relative BA | - | 2.46 | 2.56 | 1.61 |
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Kim, Y.-J.; Son, J.; Han, C.-S.; Park, C.-W. Preparation of Carrier-Free Inhalable Dry Powder of Rivaroxaban Using Two-Step Milling for Lung-Targeted Delivery. Pharmaceutics 2025, 17, 634. https://doi.org/10.3390/pharmaceutics17050634
Kim Y-J, Son J, Han C-S, Park C-W. Preparation of Carrier-Free Inhalable Dry Powder of Rivaroxaban Using Two-Step Milling for Lung-Targeted Delivery. Pharmaceutics. 2025; 17(5):634. https://doi.org/10.3390/pharmaceutics17050634
Chicago/Turabian StyleKim, Young-Jin, Jaewoon Son, Chang-Soo Han, and Chun-Woong Park. 2025. "Preparation of Carrier-Free Inhalable Dry Powder of Rivaroxaban Using Two-Step Milling for Lung-Targeted Delivery" Pharmaceutics 17, no. 5: 634. https://doi.org/10.3390/pharmaceutics17050634
APA StyleKim, Y.-J., Son, J., Han, C.-S., & Park, C.-W. (2025). Preparation of Carrier-Free Inhalable Dry Powder of Rivaroxaban Using Two-Step Milling for Lung-Targeted Delivery. Pharmaceutics, 17(5), 634. https://doi.org/10.3390/pharmaceutics17050634