Human Skin Permeation Studies with PPARγ Agonist to Improve Its Permeability and Efficacy in Inflammatory Processes
Abstract
:1. Introduction
2. Results
2.1. Validation of the Analytical Method
2.2. Permeation Studies in Human Skin
2.3. Cytotoxicity Studies and Skin Tolerance Studies
2.4. Efficacy Studies
2.4.1. Colorimetric Parameters
2.4.2. Histological Analysis
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Validated Analytical Method
Conditions Analyzed
- LinearityThe calibration curve was prepared from nine different concentrations of PGZ (1.5 to 110 μg/mL). Three calibration curves were prepared, evaluating the linearity according to the determination coefficient (r2) of each curve, the y-intercept, the slope of the regression line, and the residual and sum of the squares.
- PrecisionInstrument precision was determined by intermediate precision (inter-day). It was expressed according to the standard deviation (SD) and the % coefficient of variation (CV). The precision was evaluated to analyze sets of three standard samples of 3, 60, and 110 μg/mL within three intercalated days (inter-day). The selected concentrations correspond to the lowest, the intermediate, and the highest concentrations of the calibration curve.
- AccuracyThe accuracy was determined by measuring the degree of approach between the real value and the experimental data. Accuracy was assessed for concentrations of PGZ (3, 30, 60, and 110 μg/mL) and analyzed in triplicate. The margin of error was calculated for each concentration between the theoretical value () and the experimental value () by Equation (1):
- RobustnessRobustness was determined by changing experimental flow conditions and the composition of the mobile phase. The flow was varied at ±0.1 mL/min, and the concentration of the mobile phase was varied at ±3% acetonitrile and ±3% ammonium acetate. The effects of these variations on the experimental conditions were tested for retention time. Standard deviation (SD) was calculated.
- SpecificityThe specificity of the method was evaluated by analyzing the possible interferences due to the components of the skin that are released during the passing of the drug with the penetration enhancer. Four different samples were evaluated: blank of mobile phase, standard of 30 ppm, blank of skin as a control, and sample of skin permeated with PGZ-limonene. A volume of 10 μL of each sample was injected, and then the chromatogram profiles (wavelength 269 nm) were analyzed.
- SensitivitySensitivity was analyzed by the limit of detection (LOD) and the limit of quantification (LOQ). LOD is the lowest concentration of analyte that can be determined, and LOQ is the lowest concentration that can be quantified with adequate accuracy and precision. The signal-to-noise ratio was found by comparing signals from samples of known low concentrations of drug with the signals of blank samples and then establishing the lowest concentration of drug that can be reliably detected, in addition to being reliably quantified. A signal-to-noise ratio of 3:1 for LOD and 10:1 for LOQ were ultimately determined.
4.3. Permeation Studies in Human Skin
4.4. Permeation Parameters
4.5. Toxicity in HaCat Cell Line and Skin Tolerance
4.6. Efficacy Studies
4.7. Histological Analysis
4.8. Statistics
5. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
PGZ | Pioglitazone |
PPARs | Peroxisome proliferator-activated receptors |
HPLC | Liquid chromatography of high resolution |
TLR | Toll-like receptors |
IL-8 | Interleukin 8 |
IL-1β | Interleukin 1 β |
TNF-α | Tumor necrosis factor α |
LOD | Detection limit |
LOQ | limit of quantification |
Jss | Permeability flow |
kp | Permeability coefficient |
Qret | Retained drug |
Css | Steady-state plasma concentration |
GRAS | Generally regarded as safe |
ICH | International conference on harmonization |
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Permeation and Prediction Parameters | Free-PGZ | Azona | Squaleno | Linoleic Acid | Menthol | Pyrrolidone | Limonene | Cineol |
---|---|---|---|---|---|---|---|---|
Jss (µg/(h/cm2)) × 104 | 8.42 a,c,d,f,g | 19.40 b,c,d,e | 6.56 f,g | 5.38 f,g | 3.83 e,f,g | 6.89 f,g | 21.90 g | 18.00 |
(7.68–9.36) | (17.4–23.3) | (5.81–7.22) | (4.74–6.02) | (3.44–4.31) | (6.30–7.58) | (19.7–25.1) | (15.2–20.8) | |
Kp (cm/h) × 105 | 4.92 a,c,d,f,g | 12.10 b,c,d,e | 3.62 f,g | 3.21 f,g | 2.33 e,f,g | 4.21 f,g | 13.20 g | 2.53 |
(4.33–5.41) | (11.90–14.30) | (3.16–3.98) | (2.69–3.53) | (2.20–2.66) | (3.69–4.53) | (12.90–16.50) | (2.38–2.78) | |
Qret (µg/g skin/cm2) | 42.61 a,c,d,e,f,g (38.34–46.86) | 8.42 b,d,f,g (7.67–9.36) | 53.61 c,d,e,f,g (47.24–57.97) | 14.84 d,f,g (14.35–16.32) | 101.82 e,f (90.63–112.00) | 18.04 f,g (15.23–20.84) | 207.65 g (186.88–229.41) | 94.74 (85.26–105.21) |
Css (ng/mL) × 104 | 3.73 a,c,d,f,g | 8.57 b,c,d,e,g | 2.90 f,g | 2.38 f,g | 1.69 e,f,g | 3.05 f,g | 9.68 | 9.60 |
(3.45–4.20) | (7.71–9.52) | (2.41–3.29) | (2.04–2.62) | (1.44–1.96) | (2.84–3.35) | (8.81–10.50) | (8.54–11.60) |
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Silva-Abreu, M.; Espinoza, L.C.; Rodríguez-Lagunas, M.J.; Fábrega, M.-J.; Espina, M.; García, M.L.; Calpena, A.C. Human Skin Permeation Studies with PPARγ Agonist to Improve Its Permeability and Efficacy in Inflammatory Processes. Int. J. Mol. Sci. 2017, 18, 2548. https://doi.org/10.3390/ijms18122548
Silva-Abreu M, Espinoza LC, Rodríguez-Lagunas MJ, Fábrega M-J, Espina M, García ML, Calpena AC. Human Skin Permeation Studies with PPARγ Agonist to Improve Its Permeability and Efficacy in Inflammatory Processes. International Journal of Molecular Sciences. 2017; 18(12):2548. https://doi.org/10.3390/ijms18122548
Chicago/Turabian StyleSilva-Abreu, Marcelle, Lupe Carolina Espinoza, María José Rodríguez-Lagunas, María-José Fábrega, Marta Espina, María Luisa García, and Ana Cristina Calpena. 2017. "Human Skin Permeation Studies with PPARγ Agonist to Improve Its Permeability and Efficacy in Inflammatory Processes" International Journal of Molecular Sciences 18, no. 12: 2548. https://doi.org/10.3390/ijms18122548