Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Methods
2.2.1. Preformulation Studies
Solubility of DK-I-60-3
Melt-Quenching
2.2.2. Nanocrystal Dispersions Preparation
2.2.3. Physicochemical Characterization
Particle Size Measurements
Zeta Potential Measurements
Atomic Force Microscopy (AFM)
Differential Scanning Calorimetry (DSC)
X-ray Powder Diffraction Analysis (XRPD)
Dissolution Study
Solubility of Nanocrystals
2.2.4. In Vivo Pharmacokinetic and Biodistribution Studies
2.2.5. Analytical Method
2.2.6. Statistical Analysis
3. Results and Discussion
3.1. Preformulation Studies
3.2. Nanocrystal Dispersions Preparation and Physicochemical Characterization
3.2.1. Process Parameters
3.2.2. Formulation Parameters
3.2.3. Stability Study
3.2.4. Atomic Force Microscopy (AFM)
3.2.5. Differential Scanning Calorimetry (DSC) and X-ray Powder Diffraction Analysis (XRPD)
3.2.6. Dissolution Study and Solubility of Nanocrystals
3.2.7. In Vivo Pharmacokinetic and Biodistribution Studies
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Formulation | DK-I-60-3 (% w/w) | SLS (% w/w) | PVP (% w/w) | Water (% w/w) | SLS:PVP Ratio |
---|---|---|---|---|---|
F1 | 0.20 | 0.02 | 0.20 | to 100 | 1:10 |
F2 | 0.20 | 0.02 | 0.08 | to 100 | 1:4 |
F3 | 0.20 | 0.02 | 0.04 | to 100 | 1:2 |
F4 | 0.20 | 0.02 | 0.02 | to 100 | 1:1 |
F5 | 0.20 | 0.05 | 0.50 | to 100 | 1:10 |
F6 | 0.20 | 0.05 | 0.20 | to 100 | 1:4 |
F7 | 0.20 | 0.05 | 0.10 | to 100 | 1:2 |
F8 | 0.20 | 0.05 | 0.05 | to 100 | 1:1 |
Solvent | Solubility (µg/mL) |
---|---|
Water (pH 5.23) | 6.34 ± 1.14 |
0.1 M HCl (pH 1.2) | 7.21 ± 0.40 |
Phosphate buffer (pH 6.8) | 7.75 ± 1.09 |
Medium-chain tryglycerides | 50.33 ± 7.19 |
Soybean oil | 13.81 ± 0.69 |
Castor oil | 57.96 ± 1.79 |
Benzyl alcohol | 10,373.53 ± 371.41 |
Polyethylene glycol 400 | 8224.72 ± 103.20 |
Isopropanol | 1009.41 ± 19.50 |
Methanol | 802.86 ± 103.43 |
Ethanol, 96%, v/v | 1807.70 ± 21.67 |
Dimethyl sulfoxide | 166,495.77 ± 4075.05 |
Formulation | Milling Media Volume (%, v/v) | z-Ave (nm) | PDI | ZP (mV) |
---|---|---|---|---|
60 | 195.8 ± 1.7 | 0.238 ± 0.029 | ||
F1 | 40 | 236.7 ± 1.9 | 0.208 ± 0.002 | −17.5 ± 1.6 |
20 | 233.6 ± 2.7 | 0.260 ± 0.007 | ||
F2 | 60 | 137.7 ± 2.2 | 0.226 ± 0.015 | |
40 | 165.5 ± 4.3 | 0.226 ± 0.011 | −16.8 ± 0.5 | |
20 | 229.9 ± 4.9 | 0.205 ± 0.012 | ||
F3 | 60 | 235.1 ± 4.2 | 0.273 ± 0.044 | |
40 | 239.3 ± 3.3 | 0.251 ± 0.017 | −28.0 ± 1.2 | |
20 | 298.6 ± 9.1 | 0.301 ± 0.019 | ||
F4 | 60 | 155.6 ± 2.3 | 0.258 ± 0.040 | |
40 | 176.0 ± 3.1 | 0.250 ± 0.040 | −19.2 ± 0.7 | |
20 | 233.1 ± 6.2 | 0.277 ± 0.016 | ||
F5 | 60 | 148.7 ± 2.5 | 0.231 ± 0.010 | |
40 | 174.1 ± 0.6 | 0.231 ± 0.015 | −21.8 ± 5.6 | |
20 | 222.8 ± 3.3 | 0.253 ± 0.021 | ||
F6 | 60 | 138.7 ± 2.3 | 0.225 ± 0.011 | |
40 | 153.1 ± 1.8 | 0.197 ± 0.021 | −31.9 ± 1.8 | |
20 | 185.3 ± 1.5 | 0.179 ± 0.012 | ||
F7 | 60 | 151.6 ± 4.3 | 0.206 ± 0.012 | |
40 | 170.2 ± 2.4 | 0.220 ± 0.008 | −36.8 ± 1.1 | |
20 | 214.2 ± 5.5 | 0.205 ± 0.022 | ||
F8 | 60 | 143.6 ± 1.4 | 0.231 ± 0.006 | |
40 | 160.4 ± 3.1 | 0.208 ± 0.014 | −38.1 ± 1.9 | |
20 | 182.7 ± 1.2 | 0.202 ± 0.011 |
Formulation | z-Ave (nm) | PDI | ZP (mV) | |||
---|---|---|---|---|---|---|
1 Month | 3 Months | 1 Month | 3 Months | 1 Month | 3 Months | |
F5 | 183.5 ± 4.2 | 181.2 ± 3.3 | 0.227 ± 0.024 | 0.212 ± 0.008 | −18.0 ± 0.3 | −20.7 ± 1.5 |
F6 | 162.2 ± 4.2 | 161.8 ± 5.1 | 0.204 ± 0.007 | 0.212 ± 0.010 | −35.3 ± 1.2 | −30.4 ± 0.8 |
F7 | 212.0 ± 5.3 | 214.2 ± 5.9 | 0.238 ± 0.004 | 0.220 ± 0.005 | −36.7 ± 1.1 | −40.7 ± 1.1 |
F8 | 175.4 ± 4.1 | 175.8 ± 5.2 | 0.208 ± 0.021 | 0.257 ± 0.081 | −41.8 ± 2.6 | −38.3 ± 1.0 |
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Mitrović, J.R.; Divović-Matović, B.; Knutson, D.E.; Đoković, J.B.; Kremenović, A.; Dobričić, V.D.; Randjelović, D.V.; Pantelić, I.; Cook, J.M.; Savić, M.M.; et al. Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach. Pharmaceutics 2021, 13, 1188. https://doi.org/10.3390/pharmaceutics13081188
Mitrović JR, Divović-Matović B, Knutson DE, Đoković JB, Kremenović A, Dobričić VD, Randjelović DV, Pantelić I, Cook JM, Savić MM, et al. Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach. Pharmaceutics. 2021; 13(8):1188. https://doi.org/10.3390/pharmaceutics13081188
Chicago/Turabian StyleMitrović, Jelena R., Branka Divović-Matović, Daniel E. Knutson, Jelena B. Đoković, Aleksandar Kremenović, Vladimir D. Dobričić, Danijela V. Randjelović, Ivana Pantelić, James M. Cook, Miroslav M. Savić, and et al. 2021. "Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach" Pharmaceutics 13, no. 8: 1188. https://doi.org/10.3390/pharmaceutics13081188
APA StyleMitrović, J. R., Divović-Matović, B., Knutson, D. E., Đoković, J. B., Kremenović, A., Dobričić, V. D., Randjelović, D. V., Pantelić, I., Cook, J. M., Savić, M. M., & Savić, S. D. (2021). Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach. Pharmaceutics, 13(8), 1188. https://doi.org/10.3390/pharmaceutics13081188