Quality-by-Design-Based Development of n-Propyl-Gallate-Loaded Hyaluronic-Acid-Coated Liposomes for Intranasal Administration
Abstract
:1. Introduction
2. Results
2.1. Initial Knowledge Space Development
2.2. Results of Risk Assessment
2.3. Design of Experiments: Box–Behnken Design
2.4. Influence of Investigated Parameters on the Z-Average, PDI, and Zeta Potential
2.5. Characterization of Z-Average, PDI, and Zeta Potential and Analysis of Coated and Uncoated Liposomes
2.6. Determination of Acetone Residual in the Formulations
2.7. Encapsulation Efficiency, Percentage Yield, and Drug-Loading Analysis
2.8. Fourier-Transform Infrared Spectroscopy (FTIR) Spectroscopy Analysis
2.9. Differential Scanning Calorimetry (DSC) Analysis Results
2.10. X-ray Powder Diffraction (XRPD) Analysis Results
2.11. Morphology of Liposomes
2.12. In Vitro Release Studies
2.13. In Vitro Permeability Study
2.14. Antioxidant Activity Measurement with Hydrogen Peroxide (H2O2)-Scavenging Assay
2.15. Accelerated Stability Studies
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Initial Knowledge Space Development and Collection of Influencing Factors of PG-Lipo
4.3. Risk Assessment (RA)
4.4. Design of Experiments by the Box–Behnken Design (BBD) for Optimizing the Composition of Coated Liposomes (C-Lipo)
4.5. Preparation of Liposomes via the DPM and Coating of the Lyophilized NPs with HA Polymer Solution
4.6. Average Hydrodynamic Diameter, Surface Charge, and Polydispersity Index
4.7. Residual Solvent Determination with Gas Chromatography-Mass Spectrometry (GC-MS)
4.8. Encapsulation Efficiency, Percentage Yield, and Drug-Loading Determination
4.9. Fourier-Transform Infrared Spectroscopy (FTIR)
4.10. Differential Scanning Calorimetry (DSC)
4.11. X-ray Powder Diffraction (XRPD)
4.12. Surface Morphology
4.13. In Vitro Release Test
4.14. In Vitro Permeability Study
4.15. Hydrogen Peroxide (H2O2)-Scavenging Assay
4.16. Stability Studies of Coated and Uncoated Liposomes
4.17. Statistical Analysis
5. Conclusions and Future Perspectives
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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QTPP | Target | Justification |
---|---|---|
Therapeutic effect | The CNS (the model API is PG) | Circumvention of the blood–brain barrier (BBB). PG has antioxidant and anti-inflammatory activity that are essential in the treatment of cancer [26]. |
Administration route | Nasal administration (nose-to-brain delivery) | Non-invasive, direct, and more effective route of administration than other invasive routes. Nanoparticles are transported from endothelial cells to the olfactory neurons via endocytosis or pinocytosis and move along the axon or follow the trigeminal nerve pathway [27,28]. |
Dosage form | Liquid nano-formulation | Enhanced biocompatibility, high scalability, safety, and efficacy of lipid nanoparticles. A liquid formulation is more feasible for nose-to-brain administration [29]. |
Coated lipid nanoparticles | Enhanced stability | The hyaluronic acid (HA) coating will enhance the stay time within the nasal mucosa. Active target delivery at the CD44 receptor is possible via coating with HA. Additionally, it will synergize stability [30]. |
Targeting pathway | Preferred particle size range 100–700 nm | Nanoparticles within the range of 20–200 nm can follow clathrin-coated pits, and nanoparticles in the size range of 200–1000 nm can be transported via caveolae-mediated endocytosis. |
Number of Runs | Temperature (°C) | Amount of Phospholipids (mg) | Amount of Cholesterol (mg) | Z-Average (nm) * | PDI * | Zeta Potential (mV) * |
---|---|---|---|---|---|---|
1 | 50 | 16 | 16 | 150 ± 10 | 0.27 ± 0.01 | −22 ± 8.4 |
2 | 70 | 16 | 16 | 155 ± 5.5 | 0.28 ± 0.02 | −18 ± 6.5 |
3 | 50 | 32 | 16 | 145 ± 4.5 | 0.29 ± 0.02 | −23 ± 8.4 |
4 | 70 | 32 | 16 | 140 ± 5.5 | 0.28 ± 0.05 | −24 ± 8.4 |
5 | 50 | 24 | 8 | 125 ± 6.6 | 0.25 ± 0.07 | −27 ± 7.5 |
6 | 70 | 24 | 8 | 125 ± 7.8 | 0.22 ± 0.01 | −28 ± 8.5 |
7 | 50 | 24 | 24 | 400 ± 8.8 | 0.40 ± 0.08 | −8 ± 10.2 |
8 | 70 | 24 | 24 | 450 ± 22 | 0.45 ± 0.09 | −7 ± 12 |
9 | 60 | 16 | 8 | 121 ± 2.3 | 0.24 ± 0.08 | −33 ± 5.5 |
10 | 70 | 32 | 8 | 123 ± 2.4 | 0.25 ± 0.06 | −28 ± 6.5 |
11 | 60 | 16 | 24 | 430 ± 40 | 0.55 ± 0.08 | −6 ± 10 |
12 | 60 | 32 | 24 | 420 ± 20 | 0.49 ± 0.05 | −8 ± 10.2 |
13 | 60 | 24 | 16 | 130 ± 12 | 0.21 ± 0.01 | −29 ± 3.3 |
14 | 80 | 24 | 16 | 135 ± 10 | 0.22 ± 0.02 | −26 ± 5.5 |
15 | 70 | 24 | 16 | 142 ± 8 | 0.27 ± 0.02 | −25 ± 6.2 |
Formulation | Z-Average * (nm) | PDI * | Zeta Potential * (mV) |
---|---|---|---|
Uncoated liposomes | 135.2 ± 5.2 | 0.094 ± 0.001 | −29.9 ± 5.8 |
Coated liposomes | 167.9 ± 3.5 | 0.129 ± 0.002 | −33.6 ± 4.5 |
Formulation | Acetone (ppm) | Maximum Residual Level * (ppm) |
---|---|---|
Uncoated liposomes | 442 ppm | 5000 |
Coated liposomes | 47 ppm |
Kinetic Model | Zero Order | First Order | Korsmeyer–Peppas | Higuchi | Hixson–Crowel |
---|---|---|---|---|---|
R2 value of uncoated liposomes | 0.7211 | 0.8922 | 0.8656 | 0.9238 | 0.8691 |
R2 value of coated liposomes | 0.745 | 0.8935 | 0.8662 | 0.9073 | 0.8488 |
Formulation | Time (Months) | Decrease in EE * (%) | Z-Average * (nm) | PDI * | Z.P. * (mV) | P.A. |
---|---|---|---|---|---|---|
Uncoated liposomes | 0 3 6 | N.C. 10 ± 2.0 30 ± 3.0 | N.C. N.C. 550 ± 10 | 0.094 ± 0.03 0.095 ± 0.01 0.511 ± 0.54 | −29.9 ± 2.3 −27.7 ± 3.3 −15.6 ± 4.5 | Milky dispersion Milky dispersion Milky dispersion |
Coated liposomes | 0 3 6 | N.C. N.C. 5 ± 2 | N.C. ~170.2 ± 5.5 180 ± 7.6 | N.C. 0.130 ± 0.02 0.222 ± 0.03 | −33.6 ± 3.5 −29.9 ± 5.5 −27.7 ± 6.4 | Milky dispersion Milky dispersion Milky dispersion |
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Sabir, F.; Katona, G.; Pallagi, E.; Dobó, D.G.; Akel, H.; Berkesi, D.; Kónya, Z.; Csóka, I. Quality-by-Design-Based Development of n-Propyl-Gallate-Loaded Hyaluronic-Acid-Coated Liposomes for Intranasal Administration. Molecules 2021, 26, 1429. https://doi.org/10.3390/molecules26051429
Sabir F, Katona G, Pallagi E, Dobó DG, Akel H, Berkesi D, Kónya Z, Csóka I. Quality-by-Design-Based Development of n-Propyl-Gallate-Loaded Hyaluronic-Acid-Coated Liposomes for Intranasal Administration. Molecules. 2021; 26(5):1429. https://doi.org/10.3390/molecules26051429
Chicago/Turabian StyleSabir, Fakhara, Gábor Katona, Edina Pallagi, Dorina Gabriella Dobó, Hussein Akel, Dániel Berkesi, Zoltán Kónya, and Ildikó Csóka. 2021. "Quality-by-Design-Based Development of n-Propyl-Gallate-Loaded Hyaluronic-Acid-Coated Liposomes for Intranasal Administration" Molecules 26, no. 5: 1429. https://doi.org/10.3390/molecules26051429