Development of Piperine-Loaded Solid Self-Nanoemulsifying Drug Delivery System: Optimization, In-Vitro, Ex-Vivo, and In-Vivo Evaluation
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Methods
2.2.1. Screening of Formulation Materials
2.2.2. Construction of Pseudo Ternary Phase Diagram
2.3. Optimization
2.4. Development of PE Loaded SNEDDS
2.5. Characterization
2.5.1. Globule Characterization
2.5.2. Self-Nano Emulsification Time
2.5.3. Percentage Transmittance
2.6. Evaluation of Optimized PE-SNEDDS (OF3)
2.7. Drug Release Study
2.8. Permeation Study
2.9. Formulation of Solid PE-SNEDDS (S-PE-SNEDDS)
2.10. Evaluation of S-PE-SNEDDS
2.10.1. Globule Size, PDI, and Zeta Potential
2.10.2. Morphological Study
2.10.3. Thermal Analysis
2.10.4. Drug Content
2.10.5. Drug Release Study
2.10.6. In-Vitro Antioxidant Study
2.10.7. Anti-Microbial Study
2.11. In-Vivo Study
2.11.1. Pharmacodynamic Study
2.11.2. Pharmacokinetic Study
2.11.3. Histological Study
2.12. Stability Study
2.13. Statistical Analysis
3. Results and Discussion
3.1. Screening of Formulation Materials
3.2. Pseudo Ternary Phase Diagram
3.3. Optimization
3.3.1. Effect of Variables over Globule Size (Y1)
3.3.2. Effect of Variables over Percentage Transmittant (Y2)
3.3.3. Effect of Independent Variables over Emulsification Time (Y3)
3.4. Point prediction
3.5. SNEDDS Characterization
3.6. Stability Study
3.7. Viscosity and Refractive Index Measurement
3.8. Drug Release
3.9. Permeation Study
3.10. Development of Solid PE-SNEDDS
3.11. Characterization
3.11.1. Globule Size, PDI, Zeta potential
3.11.2. Scanning Electron Microscopy (SEM)
3.11.3. Thermal Analysis
3.11.4. Drug Release Study
3.11.5. Antioxidant Study
3.11.6. Anti-Microbial Activity
3.12. In Vivo Study
3.12.1. Pharmacodynamic Activity
3.12.2. Pharmacokinetic Study
3.12.3. Histological Examination
3.13. Stability Study
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Formulation Variables | Level (Coded Value) | ||
---|---|---|---|
Low (−1) | Medium (0) | High (+1) | |
Oil (%) | 15 | 37.5 | 60 |
Surfactant (%) | 25 | 47.5 | 70 |
Co-surfactant (%) | 10 | 25 | 40 |
Responses | Goal | ||
Globule size (nm) | Minimum | ||
Transmittance (%) | Maximum | ||
Emulsification time (Second) | Minimum |
Code | Oil Concentration (%) | Conc of Surfactant (%) | Conc of Co-Surfactant (%) | Globule Size (nm) | Transmittant (%) | Emulsification Time (S) | |||
---|---|---|---|---|---|---|---|---|---|
Actual Value * | Predicted Value | Actual Value * | Predicted Value | Actual Value * | Predicted Value | ||||
F1 | 15 | 25 | 25 | 62.03 ± 3.54 | 63.05 | 97.28 ± 1.23 | 97.17 | 59 ± 2 | 60 |
F2 | 60 | 25 | 25 | 200.34 ± 4.23 | 201.70 | 85.23 ± 2.42 | 85.22 | 144 ± 3 | 143 |
F3 | 15 | 70 | 25 | 30.52 ± 5.12 | 28.30 | 98.00 ± 2.12 | 98.01 | 46 ± 2 | 48 |
F4 | 60 | 70 | 25 | 117.91 ± 3.65 | 116.89 | 96.15 ± 3.65 | 96.26 | 81 ± 2 | 80 |
F5 | 15 | 47.5 | 10 | 65.54 ± 5.61 | 66.14 | 93.30 ± 1.42 | 93.37 | 62 ± 3 | 63 |
F6 | 60 | 47.5 | 10 | 178.78 ± 5.43 | 179.24 | 89.10 ± 1.23 | 89.07 | 135 ± 2 | 136 |
F7 | 15 | 47.5 | 40 | 25.16 ± 6.17 | 24.70 | 99.89 ± 2.46 | 99.92 | 33 ± 3 | 32 |
F8 | 60 | 47.5 | 40 | 140.54 ± 5.32 | 138.86 | 90.57 ± 1.76 | 90.50 | 75 ± 2 | 77 |
F9 | 37.5 | 25 | 10 | 170.76 ± 7.43 | 167.84 | 88.54 ± 1.27 | 88.58 | 106 ± 2 | 107 |
F10 | 37.5 | 70 | 10 | 95.23 ± 6.76 | 95.56 | 96.23 ± 1.65 | 96.15 | 42 ± 2 | 43 |
F11 | 37.5 | 25 | 40 | 115.43 ± 3.65 | 114.44 | 94.12 ± 1.61 | 94.20 | 35 ± 2 | 35 |
F12 | 37.5 | 70 | 40 | 65.65 ± 3.87 | 67.16 | 98.56 ± 1.46 | 98.52 | 23 ± 3 | 24 |
F13 * | 37.5 | 47.5 | 25 | 109.21 ± 6.32 | 103.12 | 97.56 ± 2.43 | 97.79 | 62 ± 2 | 62 |
F14 * | 37.5 | 47.5 | 25 | 101.54 ± 5.32 | 103.54 | 97.98 ± 1.43 | 97.79 | 61 ± 3 | 62 |
F15 * | 37.5 | 47.5 | 25 | 104.24 ± 3.54 | 103.76 | 97.76 ± 1.65 | 97.79 | 63 ± 2 | 62 |
F16 * | 37.5 | 47.5 | 25 | 100.76 ± 5.36 | 103.63 | 97.76 ± 1.67 | 97.79 | 63 ± 3 | 62 |
F17 * | 37.5 | 47.5 | 25 | 101.71 ± 4.58 | 103.21 | 97.89 ± 1.87 | 97.79 | 62 ± 2 | 62 |
Statistical Term | Globule Size (Y1) | % Transmittant (Y2) | Emulsification Time (Y3) |
---|---|---|---|
R2 | 0.9980 | 0.9995 | 0.9996 |
Adjusted R2 | 0.9954 | 0.9988 | 0.9991 |
Model F-Value | 388.10 | 1476.83 | 1936.34 |
Model p-value | <0.0001 | <0.0001 | <0.0001 |
Lack of fit F-value | 0.51 | 0.67 | 0.39 |
Lack of fit p-value | 0.6945 * | 0.6129 * | 0.7693 * |
Adequate Precision | 70.594 | 130.299 | 169.586 |
Code | Composition of SNEDDS | Actual Value | Predicted Value | ||||
---|---|---|---|---|---|---|---|
Oil | Globule Size (nm) | Transmittant (%) | Emulsification Time (Sec) | Globule Size (nm) | Transmittant (%) | Emulsification Time (Sec) | |
OF1 | 37.50:47.50:25.00 | 104.23 ± 2.54 | 97.87 ± 2.12 | 61 ± 1 | 103 | 97.79 | 62 |
OF2 | 30.00:46.28:25.00 | 86.54 ± 3.65 | 98.65 ± 2.17 | 55 ± 2 | 84.93 | 98.55 | 56 |
OF3 | 25.00:46.28:25.00 | 70.34 ± 3.27 | 99.02 ± 2.02 | 53 ± 2 | 71.21 | 98.87 | 54 |
Ingredients | Concentration (mg) | Composition (%) |
---|---|---|
Piperine | 20 | 7.51 |
GML | 25 | 9.39 |
Poloxamer 188 | 46.28 | 17.38 |
Transcutol HP | 25 | 9.39 |
Avicel | 150 mg | 56.33 |
S.No. | Kinetic Model | Plot | R2 |
---|---|---|---|
1 | Zero order | % cumulative amount of drug released versus time | 0.9891 |
2 | First order | Log % cumulative drug remaining versus time | 0.8142 |
3 | Higuchi’s model | % cumulative amount of drug released versus square root of time | 0.9631 |
4 | Korsmeyer-Peppas model | Log of fraction of drug released/ Log cumulative % drug released versus log time | 0.9352 n = 0.2096 |
Parameters | Pure PE | S-PE-SNEDDS |
---|---|---|
Cmax (µg/mL) | 149.18 ± 25.29 | 585.14 ± 39.47 |
Tmax (h) | 1 | 2 |
Ke (h−1) | 0.11 ± 0.009 | 0.0958 ± 0.006 |
T1/2 (h) | 5.81 ± 0.57 | 7.23 ± 0.39 |
AUC0–12 (µg·h/mL) | 667.14 ± 27.39 | 3718.99 ± 83.72 |
AUC0–α (µg·h/mL) | 866.14 ± 43.91 | 5177.43 ± 157.36 |
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Zafar, A.; Imam, S.S.; Alruwaili, N.K.; Alsaidan, O.A.; Elkomy, M.H.; Ghoneim, M.M.; Alshehri, S.; Ali, A.M.A.; Alharbi, K.S.; Yasir, M.; et al. Development of Piperine-Loaded Solid Self-Nanoemulsifying Drug Delivery System: Optimization, In-Vitro, Ex-Vivo, and In-Vivo Evaluation. Nanomaterials 2021, 11, 2920. https://doi.org/10.3390/nano11112920
Zafar A, Imam SS, Alruwaili NK, Alsaidan OA, Elkomy MH, Ghoneim MM, Alshehri S, Ali AMA, Alharbi KS, Yasir M, et al. Development of Piperine-Loaded Solid Self-Nanoemulsifying Drug Delivery System: Optimization, In-Vitro, Ex-Vivo, and In-Vivo Evaluation. Nanomaterials. 2021; 11(11):2920. https://doi.org/10.3390/nano11112920
Chicago/Turabian StyleZafar, Ameeduzzafar, Syed Sarim Imam, Nabil K. Alruwaili, Omar Awad Alsaidan, Mohammed H. Elkomy, Mohammed M. Ghoneim, Sultan Alshehri, Ahmed Mahmoud Abdelhaleem Ali, Khalid Saad Alharbi, Mohd Yasir, and et al. 2021. "Development of Piperine-Loaded Solid Self-Nanoemulsifying Drug Delivery System: Optimization, In-Vitro, Ex-Vivo, and In-Vivo Evaluation" Nanomaterials 11, no. 11: 2920. https://doi.org/10.3390/nano11112920