Biopharmaceutical Development of a Bifonazole Multiple Emulsion for Enhanced Epidermal Delivery
Abstract
:1. Introduction
2. Materials and Methods
2.1. Substances and Reagents
2.2. Preparation of Multiple Emulsions
2.3. Physicochemical Characterization and Stability
2.4. Rheological Properties
2.4.1. Rotational Measurements
2.4.2. Dynamic Oscillatory Measurements
2.5. Drug Content
2.5.1. Drug Extraction
2.5.2. UV Analysis
2.5.3. HPLC Analysis
2.5.4. Statistical Analyses
2.6. In Vitro Drug Release
2.6.1. Drug Release Equations
2.6.2. Statistical Analyses
2.7. Drug Permeation—Penetration
2.7.1. Drug Permeation
2.7.2. Drug Penetration
2.7.3. Statistical Analyses
2.8. Epidermal Histology
2.9. Skin Integrity Assessment
2.9.1. Subjects
2.9.2. Test Procedure
2.9.3. Skin Parameters
- -
- Skin elasticity. The effect of the formulation on the elasticity of the upper skin layers was tested with a Cutometer® MPA 580 (Courage and Khazaka, Electronic GmbH, Köln, Germany). This measurement generates a negative pressure, drawing the skin into a probe that leads to a vertical deformation. When the negative pressure is switched off, the skin recovery is characterized [31,32] in terms of skin biomechanical properties.
- -
- Corneum stratum hydration (SCH). It was performed with a Corneometer® 825 (Courage and Khazaka, Electronic GmbH, Köln, Germany). This measures the capacitance variation of the dielectric properties of epidermic stratum corneum due to changes in skin hydration.
- -
- Transepidermal Water Loss (TEWL). The retrograde water permeation through skin was measured with a Tewameter® TM 300 (Courage and Khazaka, Electronic GmbH, Köln, Germany). This measures the vapor density gradient across the skin combining temperature and relative humidity sensors located in a hollow cylinder applied on the skin surface.
2.9.4. Statistical Analyses
3. Results
3.1. Physicochemical Properties and Stability
3.2. Rheological Properties
3.2.1. Rotational Test
3.2.2. Oscillatory Test
3.3. Drug Content
3.4. Release Test
3.5. Skin Permeation
3.6. Histological Analysis
3.7. Skin Integrity Assessment
4. Discussion
4.1. Physicochemical Properties and Stability
4.2. Rheological Properties
4.3. Release and Skin Permeation
4.4. Histological Analyses
4.5. Skin Integrity
5. Conclusions
Author Contributions
Acknowledgments
Conflicts of Interest
References
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Components | Percentage Composition (w/w) | |
---|---|---|
JMLP01B0 | JMLP01BT | |
Oil phase (O) | ||
Bifonazole | 1.00 | 1.00 |
Capric/caprylic triglyceride (Labrafac® Lipophile 1349) | 11.00 | 11.00 |
Cetyl palmitate | 2.00 | 2.00 |
Cetyl dimethicone copolyol (Abil® EM 90) | 1.50 | 1.50 |
Sorbitan stearate (Span® 60) | 2.00 | 2.00 |
Internal aqueous phase (W1) | ||
Sodium chloride | 0.25 | 0.25 |
Purified water at pH 6.6 | 32.25 | 32.25 |
External aqueous phase (W2) | ||
Carbomer (Tego® Carbomer 341) | 0.20 | 0.20 |
Cocamidopropyl betaine (Tego® Betaine F) | 0.70 | 0.70 |
Polysorbate 80 (Tween® 80) | - | 1.00 |
Purified water at pH 6.6 | 49.10 | 48.10 |
Sample | pH | Conductivity (μm/s−1) | Droplet Size Analysis (μm) | ||||
---|---|---|---|---|---|---|---|
D[4,3] | D[3,2] | D[v,0.1] | D[v,0.5] | D[v,0.9] | |||
JMLP01B0 | 5.80 ± 0.04 6.01 ± 0.01 | 309.5 ± 6.5 336.3 ± 7.1 | 65.2 ± 0.8 75.2 ± 0.7 | 9.7 ± 0.2 10.5 ± 0.7 | 3.4 ± 0.3 4.1 ± 0.7 | 35.8 ± 0.3 33.8 ± 0.5 | 172.9 ± 6.3 189.2 ± 7.1 |
JMLP01BT | 6.11 ± 0.02 6.30 ± 0.04 | 257.3 ± 3.3 289.0 ± 3.5 | 68.5 ± 1.0 60.8 ± 0.9 | 12.8 ± 0.1 12.1 ± 0.8 | 6.0 ± 0.2 6.3 ± 0.8 | 40.4 ± 5.6 49.5 ± 1.8 | 168.1 ± 3.4 165.02 ± 4.1 |
BFZ-CF | 6.09 ± 0.04 N.A. | 199.1 ± 6.3 N.A. | 29.8 ± 9.8 N.A. | 5.8 ± 0.5 N.A. | 1.8 ± 0.2 N.A. | 18.0 ± 2.1 N.A. | 59.0 ± 13.9 N.A. |
Formulation | Frequency (s−1) | Viscosity (mPa.s) | Oscillatory Measurements (at 24 h) | |||
---|---|---|---|---|---|---|
at 24 h | 180 days | G’(Pa) | G’’(Pa) | η*(Pa.s) | ||
JMLP01B0 | 0.01 | N.A. | N.A. | 62.08 | 19.47 | 1035.00 |
10 | 1745.0 ± 16.7 | 1705.0 ± 15.7 | 85.09 | 27.45 | 1.42 | |
100 | 237.5 ± 4.7 | 205.8 ± 2.6 | N.A. | N.A. | N.A. | |
JMLP01BT | 0.01 | N.A. | N.A. | 81.99 | 30.29 | 1391 |
10 | 2176.0 ± 24.6 | 2093.5 ± 19.9 | 167.60 | 60.97 | 2.84 | |
100 | 295.8 ± 6.8 | 261.2 ± 4.1 | N.A. | N.A. | N.A. | |
BFZ-CF | 0.01 | N.A. | N.A. | 3736 | 1875 | 66,530 |
10 | 19,301.7 ± 99.7 | 19,240.5 ± 116.9 | 15,940 | 4160 | 262.20 | |
100 | 1901.3 ± 30.9 | 1963.0 ± 23.7 | N.A. | N.A. | N.A. |
Formulation | K Higuchi | AUC05/(Q5·T) | Permeation Flux | Skin Penetration | |
---|---|---|---|---|---|
(µg·h−1/2) | (h) | (µg/cm2h) | (µg/g) | (µg/cm2) | |
JMLP01B0 | 539.3 ± 71.5 | 0.644 ± 0.072 | 0.137 ± 0.008 b | 13.12 ± 1.24 b | 2.87 ± 0.36 |
JMLP01BT | 690.4 ± 97.8 a | 0.716 ± 0.026 | 0.064 ± 0.012 | 106.20 ± 8.73 | 16.60 ± 7.09 |
BFZ-CF | 780.0 ± 87.5 | 0.692 ± 0.098 | 0.132 ± 0.009 b | 4.91 ± 0.72 b | 0.38 ± 0.07 b |
Formulations | Skin Elasticity Mean Differences (AU) | Skin Hydration Mean Differences (AU) | TEWL Mean Differences (g/h·m2) |
---|---|---|---|
JMLP01B0 | 0.0521 ± 0.003 * | 8.1 ± 7.8 | 3.6 ± 1.4 |
JMLP01BT | 0.2232 ± 0.03 | 3.6 ± 1.4 | 3.6 ± 1.9 |
BFZ-CF | 0.1605 ± 0.04 | 6.0 ± 6.5 | 1.5 ± 2.3 |
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Suñer-Carbó, J.; Calpena-Campmany, A.; Halbaut-Bellowa, L.; Clares-Naveros, B.; Rodriguez-Lagunas, M.J.; Barbolini, E.; Zamarbide-Losada, J.; Boix-Montañés, A. Biopharmaceutical Development of a Bifonazole Multiple Emulsion for Enhanced Epidermal Delivery. Pharmaceutics 2019, 11, 66. https://doi.org/10.3390/pharmaceutics11020066
Suñer-Carbó J, Calpena-Campmany A, Halbaut-Bellowa L, Clares-Naveros B, Rodriguez-Lagunas MJ, Barbolini E, Zamarbide-Losada J, Boix-Montañés A. Biopharmaceutical Development of a Bifonazole Multiple Emulsion for Enhanced Epidermal Delivery. Pharmaceutics. 2019; 11(2):66. https://doi.org/10.3390/pharmaceutics11020066
Chicago/Turabian StyleSuñer-Carbó, Joaquim, Ana Calpena-Campmany, Lyda Halbaut-Bellowa, Beatriz Clares-Naveros, María José Rodriguez-Lagunas, Elena Barbolini, Joanna Zamarbide-Losada, and Antonio Boix-Montañés. 2019. "Biopharmaceutical Development of a Bifonazole Multiple Emulsion for Enhanced Epidermal Delivery" Pharmaceutics 11, no. 2: 66. https://doi.org/10.3390/pharmaceutics11020066
APA StyleSuñer-Carbó, J., Calpena-Campmany, A., Halbaut-Bellowa, L., Clares-Naveros, B., Rodriguez-Lagunas, M. J., Barbolini, E., Zamarbide-Losada, J., & Boix-Montañés, A. (2019). Biopharmaceutical Development of a Bifonazole Multiple Emulsion for Enhanced Epidermal Delivery. Pharmaceutics, 11(2), 66. https://doi.org/10.3390/pharmaceutics11020066