Optimization of a Mucoadhesive Vaginal Gel Containing Clotrimazole Using a D-Optimal Experimental Design and Multivariate Analysis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Design of Experiments (DoE) and Preparation of CLT-MVG Formulations
2.3. Determination of the Pharmaceutical Characteristics of CLT-MVG Formulations Used as DoE Responses
2.3.1. Determination of Spreading Capacity
2.3.2. Determination of Detachment Force
2.3.3. Determination of Thixotropy Index, Yield Stress, Apparent Viscosity, and Consistency Index
- τ = shear stress (Pa);
- γ = shear rate (s−1), n is the non-Newtonian index (0 < n < 1);
- K (consistency index) is a factor related to the apparent viscosity of the gel.
2.3.4. In Vitro Drug Release and Kinetic Release Evaluation
2.4. Optimization Procedure and Multivariate Analysis
- bi represents the estimation of the main effects of the factors Xijk;
- bii represents the estimation of the second-order effects, and
- bij and bijk are the estimations of the interactions between Xi and Xj.
2.5. Additional Characterization of the Optimized CLT-MVG Formulation
2.5.1. FT-ATR-IR Spectroscopy
2.5.2. CLT Particle Size
2.5.3. pH Determination
2.5.4. Ex Vivo Mucoadhesion Time
2.5.5. In Vitro Antifungal Activity Evaluation
3. Results
3.1. Design of Experiments (DoE) Analysis
3.2. In Vitro Clotrimazole Release from Mucoadhesive Vaginal Gels
3.3. Multivariate Analysis
3.4. Experimental Design Validation and Similarity of the Dissolution Profiles
3.5. Additional Characterization of the Optimized Formulation
3.5.1. FT-ATR-IR Studies
3.5.2. CLT Particle Size, pH, and Ex Vivo Mucoadhesion Time
3.5.3. In Vitro Antifungal Activity of the Optimized CLT-MVG Formulation
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Independent Variables (Formulation Factors of DoE) | ||||||
---|---|---|---|---|---|---|
No. | Name | Symbol | Levels | |||
–1 | 0 | +1 | ||||
1 | Carbopol 940 ratio | X1 | 0.5 | 0.75 | 1 | |
2 | PEO type | X2 | PEO1105 | PEO750 | ||
3 | PEO ratio | PEO1105 | X3 | 1 | 2 | 3 |
PEO750 | 3 | 4.5 | 6 | |||
The dependent variables (Response of DoE and characteristics of the mucoadhesive vaginal gel) | ||||||
No. | Name | Symbol | ||||
1 | Spreading capacity (cm2) | Y1 | ||||
2 | Detachment force (mN) | Y2 | ||||
3 | Thixotropy index | Y3 | ||||
4 | Yield stress (Pa) | Y4 | ||||
5 | Viscosity at 20 s−1 (Pa.s) | Y5 | ||||
6 | Consistency index (Pa.s) | Y6 | ||||
7 | K–Peppas (h−1) | Y7 | ||||
8 | Clotrimazole released at 2 h (%) | Y8 | ||||
9 | Clotrimazole released at 5 h (%) | Y9 | ||||
10 | Clotrimazole released at 8 h (%) | Y10 | ||||
The matrix experimental design | ||||||
Exp. Name | X1 | X2 | X3 | |||
F1 | 0.5 | PEO1105 | 1 | |||
F2 | 1 | PEO1105 | 1 | |||
F3 | 0.5 | PEO750 | 3 | |||
F4 | 1 | PEO750 | 3 | |||
F5 | 0.5 | PEO1105 | 3 | |||
F6 | 1 | PEO1105 | 3 | |||
F7 | 0.5 | PEO750 | 6 | |||
F8 | 1 | PEO750 | 6 | |||
F9 | 0.75 | PEO1105 | 2 | |||
F10 | 0.75 | PEO1105 | 2 |
Exp. Name | Spreadability (cm2) | Detachment Force (mN) | Thixotropy Index | Yield Stress (Pa) | Viscosity at 20 s−1 (Pa·s) | Consistency Index (Pa·s) | KKP Peppas (h−1) | CLT Released at 2 h (%) | CLT Released at 5 h (%) | CLT Released at 8 h (%) |
---|---|---|---|---|---|---|---|---|---|---|
Y1 | Y2 | Y3 | Y4 | Y5 | Y6 | Y7 | Y8 | Y9 | Y10 | |
F1 | 25.50 ± 1.86 | 90 ± 2.12 | 10.20 ± 1.21 | 100.70 ± 22 | 2412.9 ± 98 | 10796 ± 201 | 19.441 ± 11 | 36.11 ± 2.31 | 64.33 ± 3.10 | 92.55 ± 8.11 |
F2 | 18.85 ± 0.98 | 120 ± 10.40 | 11.40 ± 2.34 | 155.30 ± 17 | 2684.7 ± 23 | 8099 ± 332 | 13.621 ± 22 | 20.55 ± 1.67 | 50.11 ± 2.22 | 78.16 ± 7.45 |
F3 | 26.00 ± 0.78 | 110 ± 12.01 | 9.21 ± 0.98 | 89.20 ± 12 | 3162.3 ± 45 | 17664 ± 203 | 22.540 ± 18 | 39.74 ± 1.34 | 67.25 ± 3.01 | 96.70 ± 9.01 |
F4 | 21.22 ± 0.97 | 125 ± 11.02 | 9.77 ± 1.13 | 169.10 ± 13 | 4290.5 ± 56 | 19019 ± 123 | 15.568 ± 77 | 22.32 ± 0.98 | 55.32 ± 0.76 | 82.33 ± 5.08 |
F5 | 20.41 ± 0.87 | 140 ± 12.83 | 9.94 ± 0.88 | 45.13 ± 0.28 | 4471.7 ± 25 | 35576 ± 350 | 14.231 ± 58 | 19.43 ± 0.65 | 46.52 ± 1.08 | 74.55 ± 4.56 |
F6 | 17.71 ± 1.03 | 250 ± 13.68 | 11.80 ± 1.25 | 145.10 ± 11 | 7691.7 ± 79 | 28649 ± 284 | 10.814 ± 87 | 16.54 ± 0.78 | 41.28 ± 1.12 | 62.41 ± 3.44 |
F7 | 22.00 ± 1.11 | 170 ± 2.27 | 8.82 ± 0.76 | 200.80 ± 14 | 4924.7 ± 88 | 14846 ± 180 | 14.725 ± 91 | 25.66 ± 1.38 | 57.48 ± 0.77 | 87.88 ± 6.86 |
F8 | 15.55 ± 1.21 | 180 ± 9.89 | 8.88 ± 1.03 | 391.50 ± 10 | 5921.1 ± 96 | 8923 ± 210 | 14.235 ± 67 | 21.32 ± 1.11 | 52.44 ± 1.04 | 77.71 ± 8.02 |
F9 | 25.05 ± 1.35 | 160 ± 11 | 10.40 ± 1.83 | 128 ± 5.41 | 3788.2 ± 55 | 34645 ± 198 | 13.173 ± 39 | 17.22 ± 1.09 | 44.28 ± 1.78 | 70.22 ± 6.76 |
F10 | 25.10 ± 1.92 | 159 ± 3.89 | 10.80 ± 1.23 | 120 ± 6.22 | 3756.2 ± 48 | 34520 ± 205 | 12.926 ± 45 | 17.06 ± 1.33 | 43.99 ± 3.01 | 69.77 ± 4.92 |
Response | R2 | Q2 | p-Value | p-Error | F-Value | Model Validity | Reproducibility |
---|---|---|---|---|---|---|---|
Y1 | 0.79 | 0.47 | 0.018 | 0.448 | 7,64 | 0.80 | 0.86 |
Y2 | 0.97 | 0.69 | 0.002 | 0.439 | 34.39 | 0.79 | 0.97 |
Y3 | 0.95 | 0.83 | 0.010 | 0.525 | 15.91 | 0.84 | 0.92 |
Y4 | 0.99 | 0.88 | <0.001 | 0.500 | 63.87 | 0.83 | 0.98 |
Y5 | 0.93 | 0.60 | 0.005 | 0.521 | 15.44 | 0.84 | 0.91 |
Y6 | 0.83 | 0.45 | 0.029 | 0.170 | 2.85 | 0.37 | 0.99 |
Y7 | 0.90 | 0.48 | 0.011 | 0.381 | 10.74 | 0.76 | 0.94 |
Y8 | 0.87 | 0.70 | 0.046 | 0.355 | 20.95 | 0.60 | 0.97 |
Y9 | 0.99 | 0.85 | 0.004 | 0.443 | 53.99 | 0.55 | 0.97 |
Y10 | 0.87 | 0.63 | 0.020 | 0.453 | 8.29 | 0.80 | 0.89 |
Kinetic Models | Parameter | Formulation | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
F1 | F2 | F3 | F4 | F5 | F6 | F7 | F8 | F9 | F10 | ||
Korsmeyer–Peppas model | KKP | 19.441 | 13.621 | 22.40 | 15.568 | 14.231 | 10.814 | 14.725 | 14.235 | 13.173 | 12.926 |
n | 0.7474 | 0.8219 | 0.6946 | 0.7832 | 0.7616 | 0.8304 | 0.8536 | 0.8128 | 0.7769 | 0.7831 | |
R2 | 0.9976 | 0.9974 | 0.9933 | 0.9949 | 0.9930 | 0.9984 | 0.9988 | 0.9976 | 0.9923 | 0.9926 | |
Higuchi model | KH | 29.223 | 24.894 | 31.023 | 26.426 | 24.289 | 21.301 | 26.791 | 25.848 | 23.418 | 23.065 |
R2 | 0.9626 | 0.9485 | 0.9689 | 0.9535 | 0.9562 | 0.9485 | 0.9454 | 0.9536 | 0.9558 | 0.9516 | |
First-order model | K1 | 0.2214 | 0.1612 | 0.2479 | 0.1796 | 0.1523 | 0.1207 | 0.1885 | 0.1720 | 0.1415 | 0.1388 |
R2 | 0.9869 | 0.9851 | 0.9769 | 0.9838 | 0.9873 | 0.9896 | 0.9840 | 0.9860 | 0.9883 | 0.9880 | |
Zero-order model | K0 | 12.384 | 9.5326 | 13.083 | 10.086 | 8.4698 | 7.4706 | 11.2679 | 9.7311 | 8.0722 | 8.0588 |
R2 | 0.9748 | 0.9879 | 0.9558 | 0.9794 | 0.9733 | 0.9900 | 0.9935 | 0.9882 | 0.9774 | 0.9771 |
Composition | Responses | |||
---|---|---|---|---|
Name | Predicted Values | Obtained Values | Bias (%) | |
X1: C940—0.89% | Y1 (Spreading surface) | 26.1183 cm2 | 23.22 ± 4.22 cm2 | −11.10 |
X2: PEO1105 | Y2 (Detachment force) | 141.72 mN | 150.91 ± 8.92 mN | 6.48 |
X3: PEO1105—1.39% | Y3 (Thixotropy index) | 11.29 | 10.72 ± 2.19 | −5.05 |
Y4 (Yield stress) | 133.83 Pa | 142.87 ± 7.18 Pa | 6.75 | |
Y5 (Viscosity at 20 s−1) | 3170 Pa·s | 3834 ± 109 Pa·s | 20.95 |
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Dinte, E.; Iovanov, R.I.; Bodoki, A.E.; Colosi, I.A.; Colosi, H.A.; Tosa, N.; Vostinaru, O.; Tomuta, I. Optimization of a Mucoadhesive Vaginal Gel Containing Clotrimazole Using a D-Optimal Experimental Design and Multivariate Analysis. Polymers 2023, 15, 2023. https://doi.org/10.3390/polym15092023
Dinte E, Iovanov RI, Bodoki AE, Colosi IA, Colosi HA, Tosa N, Vostinaru O, Tomuta I. Optimization of a Mucoadhesive Vaginal Gel Containing Clotrimazole Using a D-Optimal Experimental Design and Multivariate Analysis. Polymers. 2023; 15(9):2023. https://doi.org/10.3390/polym15092023
Chicago/Turabian StyleDinte, Elena, Rares Iuliu Iovanov, Andreea Elena Bodoki, Ioana Alina Colosi, Horatiu Alexandru Colosi, Nicoleta Tosa, Oliviu Vostinaru, and Ioan Tomuta. 2023. "Optimization of a Mucoadhesive Vaginal Gel Containing Clotrimazole Using a D-Optimal Experimental Design and Multivariate Analysis" Polymers 15, no. 9: 2023. https://doi.org/10.3390/polym15092023
APA StyleDinte, E., Iovanov, R. I., Bodoki, A. E., Colosi, I. A., Colosi, H. A., Tosa, N., Vostinaru, O., & Tomuta, I. (2023). Optimization of a Mucoadhesive Vaginal Gel Containing Clotrimazole Using a D-Optimal Experimental Design and Multivariate Analysis. Polymers, 15(9), 2023. https://doi.org/10.3390/polym15092023