GastroPlus- and HSPiP-Oriented Predictive Parameters as the Basis of Valproic Acid-Loaded Mucoadhesive Cationic Nanoemulsion Gel for Improved Nose-to-Brain Delivery to Control Convulsion in Humans
Abstract
:1. Introduction
2. Results and Discussion
2.1. Prediction and Simulation Study Using GastroPlus
2.1.1. Prediction of Plasma Drug Concentration Time Profile
2.1.2. Regional Compartmental Absorption of Both Tablets
2.1.3. PSA (Parameter Sensitivity Analysis) Assessment
2.1.4. Hansen Solubility Parameters for VA and Excipients
2.1.5. Solubility of Valproate (VA) in Various Excipients
2.1.6. VA Loaded Cationic Nanoemulsions Prepared
2.1.7. Freeze–Thaw Cycle and Ultracentrifugation of Nanoemulsions
2.2. Evaluation of Cationic and Anionic Nanoemulsions Gels
2.2.1. Morphological Evaluation of the Optimized Cationic Nanoemulsion and Respective Gel
2.2.2. Drug Content Estimation
2.2.3. In Vitro Drug Release Profile
2.2.4. Ex Vivo Drug Permeation and Drug Deposition Using Goat Nasal Mucosal Tissue
2.2.5. Confocal Laser Scanning Microscopy (CLSM)
3. Conclusions
4. Materials and Methods
4.1. Materials
4.2. Methods
4.2.1. Prediction and Simulation Study Using GastroPlus for Oral Tablet
Hansen Solubility Parameters for VA and Excipients
Solubility of Valproate Sodium in Various Excipients
Pseudo Ternary Phase Diagram, Cationic Nanoemulsions, and Nanoemulsion Gel
Thermodynamic Stability of Cationic Nanoemulsion: Freeze–Thaw Cycle and Ultracentrifugation
4.2.2. Evaluation of Cationic Nanoemulsions and Gels
Morphological Evaluation of the Optimized Cationic Nanoemulsion and Respective Gel
Drug Content Estimation
4.2.3. In Vitro Drug Release Profile
4.2.4. Ex Vivo Drug Permeation and Drug Deposition Using a Goat Nasal Mucosa
4.2.5. Confocal Laser Scanning Microscopy (CLSM)
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameter | Values |
---|---|
Molecular formula | C8H15NaO2 |
Molecular weight (g/mol) | 166.19 |
Melting point (°C) | 300 |
Aqueous solubility (mg/mL) at 25 °C | <1 |
Density (g/mL) | 0.9 |
Pka | 5.14 |
Log p | 3.08 |
Apparent permeability coefficient (cm/h) across hCMEC/D3 and CC-2565 of in vitro blood brain barrier | 0.625 |
Dose (mg) | 200 |
Body weight (kg) | 70 |
Dosing volume (mL) | 1 |
Mean precipitation time (s) | 30 |
AUC (µg. h/mL) | 10–160 |
Cmax (mg/L) | ~120 |
Tmax (h) (mean) | 5 |
Elimination half-life (h) | 8–15 |
Clearance (L/h) | 0.206–1.154 |
Plasma protein binding (%) | 90–95 |
Vd (L) | 8.4–23.3 |
pH for reference solubility | 7.0 |
Simulation time (h) | 24 |
Drug and Excipient | δd (MPa1/2) | δp (MPa1/2) | δh (MPa1/2) |
---|---|---|---|
AV | 16.1 | 4.3 | 9.0 |
Safflower seed oil (87%) * | 14.5 | 2.7 | 5.3 |
Grape seed oil (70%) * | 11.69 | 2.17 | 4.27 |
Flaxseed oil (60%) * | 10.02 | 1.86 | 3.66 |
Tween 80 | 16.6 | 5.3 | 7.5 |
Span 80 | 16.7 | 6.1 | 12.4 |
Lecithin (PC as 20%) * | 3.2 | 0.54 | 0.64 |
Linoleic acid * | 16.7 | 3.1 | 6.1 |
Transcutol HP | 16.0 | 2.8 | 6.2 |
PG ϕ | 16.8 | 10.4 | 21.3 |
PC * | 16 | 2.7 | 3.2 |
Code | SO (%) | Smix (%) | Water (%) | Smix Ratio | ST (%) | Size (nm) | PDI | ZP (mV) | %T | Product Strength (% w/w) |
---|---|---|---|---|---|---|---|---|---|---|
CVE1 | 16.46 | 30.21 | 48.59 | 1:2 | 0.04 | 162 | 0.27 | +24.7 | 98.5 | 0.4 |
CVE2 | 20.75 | 23.5 | 50.22 | 1:3 | 0.05 | 189 | 0.32 | +26.8 | 96.8 | 0.5 |
CVE3 | 14.72 | 21.67 | 57.12 | 1:2 | 0.06 | 185 | 0.31 | +31.6 | 97.2 | 0.6 |
CVE4 | 19.88 | 43.51 | 32.16 | 1:2 | 0.04 | 148 | 0.18 | +23.9 | 96.9 | 0.4 |
CVE5 | 9.8 | 21.84 | 63.04 | 2:1 | 0.05 | 79 | 0.11 | +27.1 | 95.3 | 0.5 |
CVE6 | 14.46 | 17.15 | 60.99 | 3:1 | 0.07 | 113 | 0.26 | +34.7 | 97.8 | 0.7 |
AVE6 | 14.46 | 17.15 | 60.92 | 3:1 | 0.0 | 126 | 0.29 | −22.8 | 95.6 | 0.7 |
Nanoemulsion gel (0.5% w/w) composition (VA strength) | Evaluated parameters | |||||||||
0.5% VE gel | NE (g) | Gel-blank (g) | Triethanolamine (g) | CVE6:gel ratio | Size (nm) | PDI | ZP (mV) | Viscosity (cP) | pH | |
CVE6 gel (0.35%) | 1 | 0.95 | 0.05 g | 1:1 | 129 | 0.24 | +21.9 | 1837.3 | 6.8 | |
AVE6 gel (0.35%) | 1 | 0.95 | 0.05 g | 1:1 | 142 | 0.31 | −26.5 | 1907.1 | 7.1 |
Formulations | Freezing (−21 °C) | Room Temperature | Thaw (40 °C) | Centrifugation | Inference * |
---|---|---|---|---|---|
CVE1 | ✓ | ✓ | ✓ | ✓ | Stable |
CVE2 | ✓ | ✓ | ✓ | ✓ | Stable |
CVE3 | ✓ | ✓ | ✓ | ✓ | Stable |
CVE4 | ✓ | ✓ | ✓ | ✓ | Stable |
CVE5 | ✓ | ✓ | ✓ | ✓ | Stable |
CVE6 | ✓ | ✓ | ✓ | ✓ | Stable |
AVE6 | ✓ | ✓ | ✓ | ✓ | Stable |
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Hussain, A.; Altamimi, M.A.; Ramzan, M.; Mirza, M.A.; Khuroo, T. GastroPlus- and HSPiP-Oriented Predictive Parameters as the Basis of Valproic Acid-Loaded Mucoadhesive Cationic Nanoemulsion Gel for Improved Nose-to-Brain Delivery to Control Convulsion in Humans. Gels 2023, 9, 603. https://doi.org/10.3390/gels9080603
Hussain A, Altamimi MA, Ramzan M, Mirza MA, Khuroo T. GastroPlus- and HSPiP-Oriented Predictive Parameters as the Basis of Valproic Acid-Loaded Mucoadhesive Cationic Nanoemulsion Gel for Improved Nose-to-Brain Delivery to Control Convulsion in Humans. Gels. 2023; 9(8):603. https://doi.org/10.3390/gels9080603
Chicago/Turabian StyleHussain, Afzal, Mohammad A. Altamimi, Mohhammad Ramzan, Mohd Aamir Mirza, and Tahir Khuroo. 2023. "GastroPlus- and HSPiP-Oriented Predictive Parameters as the Basis of Valproic Acid-Loaded Mucoadhesive Cationic Nanoemulsion Gel for Improved Nose-to-Brain Delivery to Control Convulsion in Humans" Gels 9, no. 8: 603. https://doi.org/10.3390/gels9080603