Optimization of the Factors Affecting the Absorption of Vardenafil from Oral Disintegrating Tablets: A Clinical Pharmacokinetic Investigation
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Pre-Formulation Studies
2.2.1. Preparation of VRD-β-CDs Inclusion Complexes
2.2.2. Solubility Study
2.3. Formulation of ODTs
2.3.1. Application of Box Behnken Experimental Design
2.3.2. Preparation of ODTs
2.4. Evaluation of the Prepared VRD-ODTs
2.5. In Vitro Disintegration of VRD-ODTs
2.6. In Vitro Dissolution of VRD-ODTs
2.7. VRD-ODTs Formulation Data Analysis by BBD
2.8. In Vivo Evaluation of the Optimized VRD-ODTs on Human Volunteers
2.8.1. In Vivo Taste Masking and Disintegration Time Evaluation
2.8.2. Pharmacokinetic Parameters Evaluation
Population and Sampling
Chromatographic Conditions
Pharmacokinetic Analysis
3. Results and Discussion
3.1. Saturation Solubility Studies of the Prepared Complexes
3.2. Development of VRD–ODTs
3.3. Evaluation of VRD-ODTs
3.4. In Vitro Dissolution Studies
3.5. Quantitative Estimation of the Factors Affecting VRD-ODTs
3.5.1. Mathematical Modeling of the Data
3.5.2. Effect of the Factors on Y1 and Y2
3.6. Prediction of the Optimized Formulation
3.7. In Vivo Evaluation of the Optimized VRD-ODTs on Human Volunteers
3.7.1. In Vivo Taste Masking and Disintegration Time
3.7.2. Pharmacokinetic Parameters Evaluation
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Factors | −1 | 0 | +1 | Response | Goal | Desirability |
---|---|---|---|---|---|---|
Mannitol (%) | 30 | 35 | 40 | Hardness (N) | Maximize | 70 N |
Explotab (%) | 6 | 8 | 10 | Disintegration time (s) | Minimize | 30 s |
Avicel (%) | 15 | 20 | 25 |
Formula # | Drug Complex * | Mannitol | Explotab | Avicel | Crospovidone | Lactose | Magnesium Stearate | Talc |
---|---|---|---|---|---|---|---|---|
(mg) | ||||||||
F1 | 30 | 70 | 20 | 30 | 10 | 36 | 2 | 2 |
F2 | 30 | 70 | 20 | 50 | 10 | 16 | 2 | 2 |
F3 | 30 | 60 | 12 | 40 | 10 | 44 | 2 | 2 |
F4 | 30 | 70 | 12 | 30 | 10 | 44 | 2 | 2 |
F5 | 30 | 60 | 16 | 50 | 10 | 30 | 2 | 2 |
F6 | 30 | 80 | 16 | 30 | 10 | 30 | 2 | 2 |
F7 | 30 | 70 | 12 | 50 | 10 | 24 | 2 | 2 |
F8 | 30 | 60 | 20 | 40 | 10 | 36 | 2 | 2 |
F9 | 30 | 80 | 20 | 40 | 10 | 16 | 2 | 2 |
F10 | 30 | 80 | 16 | 50 | 10 | 10 | 2 | 2 |
F11 | 30 | 60 | 16 | 30 | 10 | 50 | 2 | 2 |
F12 | 30 | 80 | 12 | 40 | 10 | 24 | 2 | 2 |
F13 | 30 | 70 | 16 | 40 | 10 | 30 | 2 | 2 |
F14 | 30 | 70 | 16 | 40 | 10 | 30 | 2 | 2 |
F15 | 30 | 70 | 16 | 40 | 10 | 30 | 2 | 2 |
Formula # | Weight (mg) | Thickness (mm) | Hardness (N) | Friability (%) | Drug Content (%) | Disintegration Time (s) |
---|---|---|---|---|---|---|
F1 | 203.0 ± 3.06 | 2.64 ± 0.015 | 36.482 ± 0.26 | 0.635 | 97.77 ± 0.04 | 38.32 ± 5.77 |
F2 | 201.6 ± 0.57 | 2.62 ± 0.035 | 54.723 ± 0.21 | 0.496 | 101.07 ± 0.08 | 48.67 ± 7.64 |
F3 | 203.3 ± 1.15 | 2.60 ± 0.003 | 46.485 ± 0.15 | 0.147 | 100.98± 0.01 | 88.33 ± 10.4 |
F4 | 204.3 ± 0.57 | 2.60 ± 0.001 | 33.736 ± 0.10 | 0.645 | 99.37 ± 0.04 | 52.67 ± 2.51 |
F5 | 202.3 ± 1.53 | 2.69 ± 0.006 | 52.075 ± 0.21 | 0.494 | 101.7 ± 0.04 | 46.67 ± 5.77 |
F6 | 202.6 ± 0.57 | 2.69 ± 0.006 | 44.817 ± 0.31 | 0.493 | 98.7 ± 0.08 | 72.67 ± 2.51 |
F7 | 200.0 ± 1.53 | 2.60 ± 0.000 | 63.059 ± 0.12 | 0.301 | 96.84 ± 0.05 | 76.33 ± 3.21 |
F8 | 201.6 ± 1.15 | 2.60 ± 0.001 | 31.088 ± 0.06 | 0.297 | 99.86 ± 0.05 | 36.33 ± 3.21 |
F9 | 203.0 ± 1.0 | 2.57 ± 0.025 | 61.489 ± 0.50 | 0.197 | 99.73 ± 0.01 | 41.43 ± 2.88 |
F10 | 203.0 ± 1.0 | 2.59 ± 0.010 | 65.903 ± 0.06 | 0.492 | 100.09 ± 0.04 | 88.49 ± 7.63 |
F11 | 199.3 ± 0.57 | 2.60 ± 0.001 | 36.776 ± 0.21 | 0.051 | 100.45 ± 0.04 | 65.0 ± 10.0 |
F12 | 203.0 ± 2.08 | 2.60 ± 0.001 | 48.447 ± 0.38 | 0.977 | 97.59 ± 0.01 | 97.67 ± 8.73 |
F13 | 201.0 ± 1.53 | 2.60 ± 0.341 | 42.170 ± 0.16 | 0.299 | 95.43 ± 0.04 | 66.43 ± 5.13 |
F14 | 202.0 ± 1.53 | 2.60 ± 0.001 | 44.524 ± 0.11 | 0.098 | 98.84 ± 0.04 | 73.33 ± 5.77 |
F15 | 202.0 ± 1.0 | 2.61 ± 0.001 | 45.799 ± 0.10 | 0.198 | 100.36 ± 0.08 | 63.45 ± 2.88 |
Factor | Hardness (Y1) | Disintegration Time (Y2) | ||||
---|---|---|---|---|---|---|
Estimate | F-Ratio | p-Value | Estimate | F-Ratio | p-Value | |
A: Mannitol | 1.3825 | 49.05 | 0.0009 * | 15.9825 | 2.78 | 0.1565 |
B: Explotab | −0.2025 | 1.05 | 0.3520 | −37.5625 | 15.34 | 0.0112 * |
C: Avicel | 2.14 | 117.53 | 0.0001 * | 7.875 | 0.67 | 0.4490 |
AA | 0.5717 | 3.87 | 0.1063 | 12.4133 | 0.77 | 0.4195 |
AB | 1.45 | 26.98 | 0.0035 * | −2.12 | 0.02 | 0.8819 |
AC | 0.295 | 1.12 | 0.3390 | 17.075 | 1.58 | 0.2637 |
BB | −0.0183 | 0.00 | 0.9521 | −16.0067 | 1.29 | 0.3083 |
BC | −0.565 | 4.10 | 0.0989 | −6.655 | 0.24 | 0.6445 |
CC | 0.5967 | 4.22 | 0.0952 | −11.4717 | 0.66 | 0.4534 |
R2 (%) | 97.647 | 82.457 | ||||
Adjusted R2 (%) | 93.411 | 50.879 | ||||
Analysis of Variance | ||||||
F-ratio | 23.2920 | 2.6039 | ||||
p-value | 0.0015 | 0.1522 | ||||
Lack of Fit | ||||||
F ratio | 2.8493 | 11.2529 | ||||
p value | 0.2705 | 0.0827 | ||||
R2 | 0.9956 | 0.9902 |
Volunteer No. | Disintegration Time (s) | Taste Masking (0–3) |
---|---|---|
V1 | 65 | 0 |
V2 | 60 | 1 |
V3 | 62 | 1 |
V4 | 63 | 0 |
V5 | 59 | 0 |
V6 | 65 | 0 |
Mean | 62.33 ± 2.503 |
Pharmacokinetic Parameter | VRD Marketed Tablet | Optimized VRD-ODTs |
---|---|---|
Cmax (ng/mL) | 12.29383 ± 2.55 | 18.191 ± 1.95 * |
tmax (h) | 2.0 ± 0.13 | 1.0 ± 0.21 * |
AUC(0–24) (ng·h/mL) | 46.68801 ± 4.63 | 58.81263 ± 5.15 |
AUC(24–∞) (ng·h/mL) | 0.460347 ± 0.34 | 0.332505 ± 0.17 |
AUC(0–∞) (ng·h/mL) | 47.14836 ± 3.61 | 59.14514 ± 17.35 |
AUMC(0–24) ng·hr2/mL | 184.5833 | 239.0714 |
AUMC(24–end) ng·hr2/mL | 11.04833 | 7.980117 |
AUMC(0–end) ng·hr2/mL | 195.6317 | 247.0515 |
Kel (h−1) | 0.209 ± 0.01 | 0.230573 |
t1/2 (h) | 3.317 ± 0.63 | 3.005555 ± 0.53 |
MRT (h) | 4.149 ± 0.93 | 4.174615 ± 1.33 |
CL (mL/h) | 3.824974 | 2.929219 |
Relative bioavailability (%) | 100 | 125.445 |
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Al-Gethmy, H.A.; Fahmy, U.A.; Alhakamy, N.A.; Ahmed, O.A.A.; El-Say, K.M. Optimization of the Factors Affecting the Absorption of Vardenafil from Oral Disintegrating Tablets: A Clinical Pharmacokinetic Investigation. Pharmaceutics 2019, 11, 11. https://doi.org/10.3390/pharmaceutics11010011
Al-Gethmy HA, Fahmy UA, Alhakamy NA, Ahmed OAA, El-Say KM. Optimization of the Factors Affecting the Absorption of Vardenafil from Oral Disintegrating Tablets: A Clinical Pharmacokinetic Investigation. Pharmaceutics. 2019; 11(1):11. https://doi.org/10.3390/pharmaceutics11010011
Chicago/Turabian StyleAl-Gethmy, Hytham A., Usama A. Fahmy, Nabil A. Alhakamy, Osama A. A. Ahmed, and Khalid M. El-Say. 2019. "Optimization of the Factors Affecting the Absorption of Vardenafil from Oral Disintegrating Tablets: A Clinical Pharmacokinetic Investigation" Pharmaceutics 11, no. 1: 11. https://doi.org/10.3390/pharmaceutics11010011