In Situ Gelling Ophthalmic Drug Delivery System for the Optimization of Diagnostic and Preoperative Mydriasis: In Vitro Drug Release, Cytotoxicity and Mydriasis Pharmacodynamics
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. In Situ Gelling Formulations
2.3. High Performance Liquid Chromatography (HPLC) Analysis of Phenylephrine Hydrochloride and Tropicamide
2.4. In Vitro Drug Release Study Using the USP 4 Apparatus
2.4.1. In Vitro Drug Release Evaluation Using the Standard Flow-Through Cells
2.4.2. In Vitro Drug Release Evaluation Using the Semisolid Adapter
2.5. Mathematic Modeling of Drug Release Kinetics
2.6. Polymer Network Microstructure
2.7. Cytotoxicity Assay on Human Corneal Epithelial Cells
2.7.1. Cell Culture
2.7.2. Cell Incubation
2.7.3. Cell Viability
2.8. In Vivo Evaluation of the Mydriasis
2.9. Statistical Analysis
3. Results and Discussion
3.1. In Vitro Drug Release
3.1.1. In Vitro Drug Release Evaluation Using the Standard Flow-Through Cells
3.1.2. In Vitro Drug Release Evaluation Using the Semisolid Adapter
3.2. Polymer Network Microstructure
3.3. Cytotoxicity Assay on Human Corneal Epithelial Cells
3.4. In Vivo Evaluation of the Mydriasis
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Formulation | Gellan Gum (% w/v) | Hydroxyethylcellulose (% w/v) | Sodium Citrate (% w/v) | Phenylephrine (% w/v) | Tropicamide (% w/v) |
---|---|---|---|---|---|
A | 0.15 | 0 | 0.09 | 5.0 | 0.5 |
B | 0.15 | 0.25 | 0.09 | 5.0 | 0.5 |
C | 0.15 | 0.5 | 0.09 | 5.0 | 0.5 |
Model | Equation | Description |
---|---|---|
Higuchi | Diffusion as release mechanism | |
Korsmeyer-Peppas | 0.3 < n < 0.5, Fickian/diffusion-controlled release; n = 1.0, zero-order release; 0.5 < n < 1.0, anomalous/co-existence of diffusion and erosion | |
Peppas-Sahlin | Separation of diffusion part and erosion parts | |
Weibull | β < 0.75, Fickian/diffusion-controlled release; 0.75 < β < 1.0, anomalous/co-existence of diffusion and erosion | |
Hopfenberg | Erosion dependent release, not influenced by diffusion | |
Makoïd-Banakar | c = 0.0, Korsmeyer-Peppas power law; If c ≈ 0.0, same interpretation of n as in Korsmeyer-Peppas model with a better fit to experimental values |
Drug Release Profile | Formulation | f2 Values (3 mL/min) | f2 Values (8 mL/min) | f2 Values (15 mL/min) |
---|---|---|---|---|
PHE; TPC | PHE A; TPC A | 60 | 66.8 | 84.4 |
PHE B; TPC B | 58.7 | 63.8 | 80.0 | |
PHE C; TPC C | 57.2 | 63.4 | 68.9 | |
PHE; PHE | PHE A; PHE B | 93.9 | 63.2 | 64.1 |
PHE A; PHE C | 95.6 | 48.9 | 35.0 | |
PHE B; PHE C | 93.3 | 72.8 | 39.9 | |
TPC; TPC | TPC A; TPC B | 89.7 | 59.9 | 62.7 |
TPC A; TPC C | 90.2 | 49.4 | 32.6 | |
TPC B; TPC C | 96.9 | 72.3 | 37.7 |
Flow Rates Comparisons (mL/min) | f2 Values | |||||
---|---|---|---|---|---|---|
PHE A | PHE B | PHE C | TPC A | TPC B | TPC C | |
3 vs 8 | 49.0 | 62.9 | 86.1 | 46.5 | 57.6 | 72.2 |
3 vs 15 | 27.7 | 30.8 | 87.2 | 24.3 | 27.7 | 72.6 |
8 vs 15 | 36.1 | 35.8 | 89.7 | 32.8 | 33.3 | 79.4 |
Flow Rate | F | Peppas-Sahlin | Makoïd-Banakar | Weibull | Hopfenberg | |||||
---|---|---|---|---|---|---|---|---|---|---|
R2adj | k1 | k2 | R2adj | n | C | R2adj | β | R2adj | ||
3 mL/min | A | 0.999 | 10.48 | 0.254 | 0.999 | 0.46 | 0.001 | 0.999 | 0.61 | 0.898 |
B | 0.999 | 10.11 | 0.222 | 1.000 | 0.45 | 0.001 | 0.999 | 0.61 | 0.899 | |
C | 0.999 | 10.59 | 0.280 | 0.999 | 0.47 | 0.002 | 0.999 | 0.59 | 0.889 | |
8 mL/min | A | 0.999 | 12.90 | 0.334 | 0.999 | 0.41 | 0.001 | 0.998 | 0.65 | 0.941 |
B | 0.999 | 12.36 | 0.425 | 1.000 | 0.34 | 0.002 | 0.998 | 0.56 | 0.893 | |
C | 0.999 | 10.66 | 0.235 | 1.000 | 0.39 | 0.002 | 0.998 | 0.61 | 0.898 | |
15 mL/min | A | 0.984 | 13.03 | 0.63 | 0.999 | 0.85 | 0.019 | 0.999 | 0.95 | 0.998 |
B | 0.978 | 9.99 | 1.02 | 0.998 | 1.01 | 0.025 | 0.997 | 0.99 | 0.998 | |
C | 0.996 | 10.56 | 0.22 | 0.998 | 0.58 | 0.008 | 0.998 | 0.58 | 0.793 |
Flow Rate | Formulation | T25 (min) | T50 (min) | T80 (min) | |||
---|---|---|---|---|---|---|---|
PHE | TPC | PHE | TPC | PHE | TPC | ||
3 mL/min | A | 6.5 | 10.4 | 30.3 | 42.3 | 102.1 | 110.6 |
B | 6.9 | 10.9 | 31.9 | 45.3 | 103.9 | 121.4 | |
C | 6.4 | 10.6 | 30.6 | 45.2 | 108.6 | 125.3 | |
8 mL/min | A | 4.2 | 5.6 | 19.1 | 24.2 | 60.2 | 68.8 |
B | 4.8 | 6.4 | 23.6 | 31.7 | 94.7 | 125.7 | |
C | 6.2 | 8.4 | 28.2 | 37.4 | 89.9 | 113.5 | |
15 mL/min | A | 3.1 | 3.5 | 10.9 | 11.8 | 24.5 | 25.5 |
B | 4.3 | 4.9 | 13.3 | 14.4 | 27.2 | 28.7 | |
C | 6.2 | 8.6 | 28.4 | 34.7 | 89.2 | 108.9 |
Formulation | T25 (h) | T50 (h) | T80 (h) | |
---|---|---|---|---|
PHE | A | 0.8 | 3.1 | 7.9 |
B | 0.9 | 3.6 | 9.2 | |
C | 1.0 | 4.2 | 10.6 | |
Ctrl | 0.3 | 1.5 | 3.7 | |
TPC | A | 0.9 | 3.9 | 10.0 |
B | 1.3 | 5.1 | 13.1 | |
C | 1.5 | 6.1 | 15.6 | |
Ctrl | 0.4 | 1.6 | 3.9 |
Formulation | AUC0–300 min (mm min) |
---|---|
A | 1781.6 ± 121.7 |
B | 1618.8 ± 151.8 |
C | 1586.2 ± 120.9 |
CTRL | 1080.5 ± 169.1 |
CED | 1690.6 ± 97.6 |
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Destruel, P.-L.; Zeng, N.; Brignole-Baudouin, F.; Douat, S.; Seguin, J.; Olivier, E.; Dutot, M.; Rat, P.; Dufaÿ, S.; Dufaÿ-Wojcicki, A.; et al. In Situ Gelling Ophthalmic Drug Delivery System for the Optimization of Diagnostic and Preoperative Mydriasis: In Vitro Drug Release, Cytotoxicity and Mydriasis Pharmacodynamics. Pharmaceutics 2020, 12, 360. https://doi.org/10.3390/pharmaceutics12040360
Destruel P-L, Zeng N, Brignole-Baudouin F, Douat S, Seguin J, Olivier E, Dutot M, Rat P, Dufaÿ S, Dufaÿ-Wojcicki A, et al. In Situ Gelling Ophthalmic Drug Delivery System for the Optimization of Diagnostic and Preoperative Mydriasis: In Vitro Drug Release, Cytotoxicity and Mydriasis Pharmacodynamics. Pharmaceutics. 2020; 12(4):360. https://doi.org/10.3390/pharmaceutics12040360
Chicago/Turabian StyleDestruel, Pierre-Louis, Ni Zeng, Françoise Brignole-Baudouin, Sophie Douat, Johanne Seguin, Elodie Olivier, Melody Dutot, Patrice Rat, Sophie Dufaÿ, Amélie Dufaÿ-Wojcicki, and et al. 2020. "In Situ Gelling Ophthalmic Drug Delivery System for the Optimization of Diagnostic and Preoperative Mydriasis: In Vitro Drug Release, Cytotoxicity and Mydriasis Pharmacodynamics" Pharmaceutics 12, no. 4: 360. https://doi.org/10.3390/pharmaceutics12040360
APA StyleDestruel, P. -L., Zeng, N., Brignole-Baudouin, F., Douat, S., Seguin, J., Olivier, E., Dutot, M., Rat, P., Dufaÿ, S., Dufaÿ-Wojcicki, A., Maury, M., Mignet, N., & Boudy, V. (2020). In Situ Gelling Ophthalmic Drug Delivery System for the Optimization of Diagnostic and Preoperative Mydriasis: In Vitro Drug Release, Cytotoxicity and Mydriasis Pharmacodynamics. Pharmaceutics, 12(4), 360. https://doi.org/10.3390/pharmaceutics12040360