Tioconazole-Loaded Transethosomal Gel Using Box–Behnken Design for Topical Applications: In Vitro, In Vivo, and Molecular Docking Approaches
Abstract
:1. Introduction
2. Results and Discussion
2.1. Box–Behnken Design
2.1.1. Effects of Independent Variables on Vesicle Size (Y1)
2.1.2. Effects of Independent Variables on % Entrapment Efficiency (Y2)
2.1.3. Effects of Independent Variables on % Drug Release (Y3)
2.1.4. Effects of Independent Variables on Zeta Potential (Y4)
2.2. FTIR Studies
2.3. Transmission Electron Microscopy (TEM)
2.4. X-ray Diffraction (XRD) Analysis
2.5. DSC Studies
2.6. Characterization of Fabricated TCZ-Loaded Transethosomal Gels
2.6.1. Physical Appearance, pH, and Conductivity
2.6.2. Drug Content, Spreadability, and Extrudability
2.6.3. Rheological Studies
2.7. In Vitro Drug Release
2.8. Ex Vivo Permeation Studies
2.9. In Vitro Drug Release Kinetics
2.10. In Vitro Antifungal Activity
2.11. Stability Study
2.12. In Vivo Antifungal Activity
2.13. Histopathological Examination
2.14. Molecular Modeling
3. Conclusions
4. Materials and Methods
4.1. Materials
4.2. Fabrication of TCZ-Loaded TEs
4.3. Box–Behnken Composite Design
4.4. Characterization of Fabricated TCZ-Loaded TEs
4.4.1. Particle Size, Zeta Potential, and Polydispersity Index (PDI)
4.4.2. Fourier Transform Infrared Spectroscopy
4.4.3. % Entrapment Efficiency (% EE)
4.4.4. In Vitro Drug Release
4.4.5. Optical Microscopy
4.4.6. Transmission Electron Microscopy (TEM)
4.4.7. Differential Scanning (DSC)
4.4.8. X-ray Powder Diffraction (XRD)
4.4.9. Storage Stability of Transethosomes
4.5. Preparation of TE Gel
4.5.1. Physical Appearance, Conductivity, and pH Measurement
4.5.2. Extrudability and Spreadability
4.5.3. % Drug Content
4.5.4. Rheological Studies
4.6. Ex Vivo Permeation Studies
4.7. Drug Release Kinetics
4.8. In Vitro Antifungal Activity
4.9. In Vivo Antifungal Activity
4.10. Molecular Modeling
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Independent Variables | Dependent Variables | |||||||
---|---|---|---|---|---|---|---|---|
Run | Code | X1 (% w/v) | X2 (% v/v) | X3 (% w/w) | Y1 (nm) | Y2 (%) | Y3 (%) | Y4 mV |
01 | TE01 | 3.5 | 30 | 17.5 | 254.4 ± 2.13 | 80.71 ± 0.21 | 85.12 ± 0.54 | −21.2 ± 0.23 |
02 | TE02 | 05 | 30 | 10.0 | 314.4 ± 3.21 | 65.12 ± 0.84 | 81.23 ± 0.35 | −25.8 ± 0.34 |
03 | TE03 | 3.5 | 40 | 10.0 | 610.3 ± 1.14 | 67.34 ± 0.54 | 90.14 ± 0.45 | −18.2 ± 0.56 |
04 | TE04 | 3.5 | 20 | 25.0 | 229.5 ± 2.19 | 86.13 ± 0.46 | 92.03 ± 0.67 | −1.50 ± 0.23 |
05 | TE05 | 05 | 20 | 17.5 | 432.1 ± 3.26 | 82.34 ± 0.35 | 90.04 ± 0.41 | −7.19 ± 0.56 |
06 | TE06 | 02 | 20 | 17.5 | 402.7 ± 3.98 | 68.24 ± 0.45 | 79.12 ± 0.37 | −13.9 ± 0.21 |
07 | TE07 | 02 | 30 | 10.0 | 235.3 ± 2.24 | 63.34 ± 0.97 | 77.01 ± 0.59 | −24.3 ± 0.56 |
08 | TE08 | 3.5 | 40 | 25.0 | 757.1 ± 2.54 | 70.35 ± 0.54 | 82.24 ± 0.61 | −15.8 ± 0.43 |
09 | TE09 | 3.5 | 20 | 10.0 | 522.8 ± 3.65 | 60.56 ± 0.21 | 85.43 ± 0.54 | −28.5 ± 0.23 |
10 | TE10 | 3.5 | 30 | 17.5 | 219.1 ± 4.21 | 63.43 ± 0.56 | 84.02 ± 0.71 | −3.79 ± 0.67 |
11 | TE11 | 3.5 | 30 | 17.5 | 219.1 ± 2.45 | 63.43 ± 0.24 | 84.02 ± 0.34 | −3.79 ± 0.98 |
12 | TE12 | 05 | 40 | 17.5 | 227.8 ± 3.43 | 73.43 ± 0.56 | 85.21 ± 0.67 | −1.27 ± 0.43 |
13 | TE13 | 02 | 30 | 25.0 | 248.5 ± 1.54 | 74.87 ± 0.23 | 81.24 ± 0.23 | −23.8 ± 0.78 |
14 | TE14 | 05 | 30 | 25.0 | 378.5 ± 5.23 | 83.39 ± 0.54 | 85.21 ± 0.56 | −14.8 ± 0.23 |
15 | TE15 | 02 | 40 | 17.5 | 239.3 ± 2.45 | 69.3 ± 0.35 | 79.29 ± 0.32 | −1.04 ± 0.43 |
Fit Model | Response | R2 | Adjusted R2 | Predicted R2 | SD | % CV |
---|---|---|---|---|---|---|
Quadratic | Vesicle size (Y1) | 0.6547 | 0.0331 | −4.4953 | 162.73 | 46.13 |
Linear | % EE (Y2) | 0.5842 | 0.4708 | −0.3307 | 6.04 | 8.47 |
Quadratic | % Drug release (Y3) | 0.9198 | 0.7755 | −0.2474 | 2.05 | 2.44 |
Quadratic | Zeta potential (Y4) | 0.7749 | 0.3697 | −0.5651 | 7.84 | 57.38 |
No. | Code | pH | Conductivity (µs/cm) | % Drug Content | Spreadability (g/s) | Extrudability (g/cm2) |
---|---|---|---|---|---|---|
01 | TEG01 | 6.79 ± 0.03 | 913± 0.03 | 98.15 ± 0.21 | 5.28 ± 0.15 | 8.35 ± 0.05 |
02 | TEG04 | 6.73 ± 0.01 | 974± 0.02 | 99.24 ± 0.31 | 5.75 ± 0.15 | 8.64 ± 0.01 |
03 | TEG06 | 6.61 ± 0.04 | 975± 0.03 | 98.64 ± 0.15 | 5.22 ± 0.15 | 8.53 ± 0.05 |
04 | TEG13 | 6.82± 0.03 | 912± 0.01 | 98.86 ± 0.15 | 5.34 ± 0.15 | 8.44 ± 0.07 |
Formulation Code | Jmax (µg cm−2 h−1) | Kp (cm h−1) | ER |
---|---|---|---|
TCZ gel | 6.8 | 0.53 | 5.2 |
TEG04 | 24.1 | 3.1 |
Fungal Species | Code | MIC (µg/mL) | MFC (µg/mL) |
---|---|---|---|
Aspergillus fumigatus | TCZ | 5.8 ± 0.12 | 34.2 ± 0.14 |
TE04 | 4.3 ± 0.54 | 21.6 ± 0.25 | |
TEG04 | 5.3 ± 0.98 | 24.1 ± 0.37 | |
Candida albicans | TCZ | 2.8 ± 0.23 | 24.4 ± 0.45 |
TE04 | 1.9 ± 0.34 | 17.2 ± 0.67 | |
TEG04 | 2.3 ± 0.18 | 19.8 ± 0.21 |
Time | Drug Content | Particle Size |
---|---|---|
Initial | 99.54 ± 0.14 | 229.5 ± 2.34 |
After 2 months | 98.53 ± 0.32 | 234.5 ± 3.12 |
After 4 months | 98.10 ± 0.21 | 238.1 ± 4.41 |
After 6 months | 98.21 ± 0.15 | 240.4 ± 3.64 |
Time | Drug Content | pH | Homogeneity |
---|---|---|---|
Initial | 99.24 ± 0.26 | 6.8 ± 0.25 | Homogeneous |
After 2 months | 98.53 ± 0.53 | 6.5 ± 0.04 | Homogeneous |
After 4 months | 98.10 ± 0.64 | 6.9 ± 0.19 | Homogeneous |
After 6 months | 98.21 ± 0.35 | 7.1 ± 0.31 | Homogeneous |
Group | Fungal Hyphae | Hyperkeratosis | Acanthosis | Interface Dermatitis | Inflammation | Dermis |
---|---|---|---|---|---|---|
Group 1 (Negative control) | 0 | 0 | 0 | 0 | 0 | 0 |
Group 2 (Positive control) | 1 | 1 | 1 | 1 | 2 | 1 |
Group 3 (Experimental drug) | 0 | 0 | 0 | 0 | 0 | 0 |
Group 4 (Market drug) | 0 | 0 | 1 | 0 | 0 | 0 |
Variables | Level | |
---|---|---|
Low | High | |
Independent variables | ||
X1: Phospholipids (Lipoid S100) % w/v | 2 | 5 |
X2: Ethanol % v/v | 20 | 40 |
X3: Surfactant (Tween 80) % w/w of total Lipoid S100 | 10 | 25 |
Dependent Variables | ||
Y1: Vesicle size (nm) | ||
Y2: % Entrapment Efficiency | ||
Y3: % Drug release | ||
Y4: Zeta potential (mV) |
Run | Phospholipids % w/v | Ethanol % v/v | Surfactant % w/w of Total Lipids | Cholesterol % w/v | Drug % w/v |
---|---|---|---|---|---|
01 | 3.5 | 30 | 17.5 | 0.5 | 1 |
02 | 05 | 30 | 10.0 | 0.5 | 1 |
03 | 3.5 | 40 | 10.0 | 0.5 | 1 |
04 | 3.5 | 20 | 25.0 | 0.5 | 1 |
05 | 05 | 20 | 17.5 | 0.5 | 1 |
06 | 02 | 20 | 17.5 | 0.5 | 1 |
07 | 02 | 30 | 10.0 | 0.5 | 1 |
08 | 3.5 | 40 | 25.0 | 0.5 | 1 |
09 | 3.5 | 20 | 10.0 | 0.5 | 1 |
10 | 3.5 | 30 | 17.5 | 0.5 | 1 |
11 | 3.5 | 30 | 17.5 | 0.5 | 1 |
12 | 05 | 40 | 17.5 | 0.5 | 1 |
13 | 02 | 30 | 25.0 | 0.5 | 1 |
14 | 05 | 30 | 25.0 | 0.5 | 1 |
15 | 02 | 40 | 17.5 | 0.5 | 1 |
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Qureshi, M.I.; Jamil, Q.A.; Usman, F.; Wani, T.A.; Farooq, M.; Shah, H.S.; Ahmad, H.; Khalil, R.; Sajjad, M.; Zargar, S.; et al. Tioconazole-Loaded Transethosomal Gel Using Box–Behnken Design for Topical Applications: In Vitro, In Vivo, and Molecular Docking Approaches. Gels 2023, 9, 767. https://doi.org/10.3390/gels9090767
Qureshi MI, Jamil QA, Usman F, Wani TA, Farooq M, Shah HS, Ahmad H, Khalil R, Sajjad M, Zargar S, et al. Tioconazole-Loaded Transethosomal Gel Using Box–Behnken Design for Topical Applications: In Vitro, In Vivo, and Molecular Docking Approaches. Gels. 2023; 9(9):767. https://doi.org/10.3390/gels9090767
Chicago/Turabian StyleQureshi, Muhammad Imran, Qazi Adnan Jamil, Faisal Usman, Tanveer A. Wani, Mudassir Farooq, Hamid Saeed Shah, Hassan Ahmad, Ruqaiya Khalil, Muhammad Sajjad, Seema Zargar, and et al. 2023. "Tioconazole-Loaded Transethosomal Gel Using Box–Behnken Design for Topical Applications: In Vitro, In Vivo, and Molecular Docking Approaches" Gels 9, no. 9: 767. https://doi.org/10.3390/gels9090767