Repurposing Disulfiram as an Antifungal Agent: Development of a New Disulfiram Vaginal Mucoadhesive Gel
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Antifungal Susceptibility Testing
2.3. Preparation and Optimization of the Mucoadhesive Gel
2.4. Adhesive Strength of the Gels
2.5. Viscosity of the Mucoadhesive Gels
2.6. Mucoadhesive Properties
2.7. Optimization of the Mucoadhesive Gels
2.8. Final Rheological Properties
2.9. Syringeability of the Formulations
2.10. In Vitro Release Tests of the Disulfiram Gel
2.11. Pig Vagina Permeation
2.12. Determination of the Concentration Retained in the Pig Vagina
3. Results and Discussion
3.1. Antifungal Susceptibility Testing
3.2. Preparation and Statistical Design to Evaluate the Effect of Experimental Variables on the Mucoadhesive Gel Properties
3.3. Optimization of the Mucoadhesive Gels
3.4. Rheological Properties
3.5. Syringeability of the Formulations
3.6. In Vitro Release of Disulfiram from the Gel
3.7. Pig Vagina Permeation
3.8. Disulfiram Concentration Retained in the Pig Vagina
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Factor | Lower Level | Higher Level |
---|---|---|
% PEG-90M (w/w) | 0.5 | 1.5 |
% Carrageenan (w/w) | 1.0 | 2.0 |
Rheological Model | Equation |
---|---|
Newton | |
Bingham | |
Ostwald–de Waele | |
Herschel–Bulkley | |
Casson | |
Cross |
Kinetic Model | Equation | Parameter(s) |
---|---|---|
First-Order | , K1 | |
Higuchi | KH | |
Korsmeyer–Peppas | F = KKP × tn | KKP, n |
Weibull | , α, β |
MIC (µg/mL) | ||
---|---|---|
Test Media | ||
Candida spp. | RPMI 1640 | Sabouraud Dextrose |
C. albicans | 2 | 2 |
C. glabrata | 4 | 2 |
C. parapsilosis | 8 | 8 |
Batch | PEG-90M (% w/w) | Carrageenan (% w/w) | Viscosity (cP) | Viscosity with SVF (cP) | Mucoadhesion (mN/cm2) | Mucoadhesion with SVF (mN/cm2) | Adhered Fluorescein (%) |
---|---|---|---|---|---|---|---|
LP-83 | 0.50 | 1.50 | 19,910 | 16,170 | 50.6 | 60.5 | 91.40 |
LP-84 | 2.00 | 1.50 | 61,660 | 39,350 | 65.3 | 79.3 | 99.64 |
LP-86 | 1.25 | 2.00 | 52,840 | 31,360 | 71.9 | 80.9 | 99.50 |
LP-87 | 1.25 | 1.50 | 38,000 | 27,070 | 67.3 | 70.8 | 99.52 |
LP-88 | 1.25 | 1.50 | 33,170 | 22,210 | 57.4 | 58.1 | 99.60 |
LP-89 | 1.25 | 1.50 | 27,890 | 21,730 | 59.4 | 61.8 | 99.59 |
LP-90 | 1.25 | 1.50 | 33,370 | 25,070 | 65.5 | 68.2 | 99.43 |
LP-91 | 1.25 | 1.50 | 32,260 | 23,250 | 53.6 | 63.3 | 99.60 |
LP-92 | 1.78 | 1.14 | 29,750 | 26,180 | 47.9 | 50.3 | 97.33 |
LP-93 | 0.72 | 1.85 | 20,100 | 16,790 | 48.3 | 51.9 | 98.10 |
LP-94 | 0.72 | 1.14 | 4720 | 10,490 | 34.9 | 38.8 | 90.28 |
LP-95 | 1.78 | 1.85 | 87,280 | 40,590 | 64.8 | 74.9 | 99.54 |
LP-96 | 1.25 | 1.00 | 10,000 | 13,690 | 38.4 | 47.8 | 92.42 |
Quadratic Polynomial Model Equation | R2 | Adj R2 |
---|---|---|
Y1 = −0.8 + 14.40 X1 + 29.88 X2 | 0.702 | 0.642 |
Y2 = 24,704 − 48,649 X1 − 23,052 X2 + 56,200 X1 X2 | 0.945 | 0.927 |
Y3 = 28.85 + 32.60 X1 + 56.06 X2 − 6.652 X12 − 13.21 X22 − 7.48 X1X2 | 0.987 | 0.978 |
PEG-90M | Carrageenan | Fluorescein Adhesion Fit | Mucoadhesion with SVF Fit | Viscosity Fit | Composite Desirability |
---|---|---|---|---|---|
0.866 | 2 | 98.42 | 71.46 | 33,824 | 0.76 |
Property | Theoretical Value (95% CI) | Placebo Gel | 0.5% D Gel | 1% D Gel | Bias (%) |
---|---|---|---|---|---|
Mucoadhesion (mN/cm2) | 71.5 (60.85; 82.07) | 72.9 | 68.2 | 69.4 | 1.86 |
Viscosity (cP) | 33,824 (22,885; 44,763) | 29,835 | 30,400 | 32,780 | 8.30 |
Fluorescein adhered (%) | 98.42 (97.23; 99.62) | 98.67 | 98.58 | 98.81 | 0.27 |
Rheological Model | Placebo Gel | Placebo Gel with SVF | ||
---|---|---|---|---|
Chi² | r | Chi² | r | |
Newton | 1.773 × 105 | 0.326 | 1.004 × 105 | −0.137 |
Bingham | 1.147 × 104 | 0.970 | 6127 | 0.968 |
Ostwald–de Waele | 8.997 | 1.000 | 13.18 | 0.999 |
Herschel–Bulkley | 7.020 | 1.000 | 12.900 | 0.999 |
Casson | 9.220 | 0.988 | 1791 | 0.991 |
Cross | 1.164 | 1.000 | 1.359 | 1.000 |
Cross Equation Parameter | Placebo Gel | Placebo Gel with SVF |
---|---|---|
318.7 | 141.9 | |
0.1517 | 0.1600 | |
0.0422 | 0.1235 | |
N | 0.6488 | 0.6853 |
Parameter | Formulation | Mean ± SD |
---|---|---|
G′ | Placebo gel | 129.92 ± 25.20 Pa |
Placebo gel with SVF | 149.66 ± 25.33 Pa | |
G″ | Placebo gel | 57.90 ± 4.60 Pa |
Placebo gel with SVF | 63.67 ± 4.01 Pa | |
η* | Placebo gel | 22,709 ± 3657 mPa |
Placebo gel with SVF | 25,947 ± 3649 mPa | |
δ | Placebo gel | 24.20 ± 4.46° |
Placebo gel with SVF | 23.67 ± 5.07° | |
tan(δ) | Placebo gel | 0.45 ± 0.11 |
Placebo gel with SVF | 0.44 ± 0.08 |
Formulation | Model | Parameters | Value |
---|---|---|---|
0.5% D gel | First-Order | K1 (h−1) Fmax (%) | 0.95 ± 0.48 85.79 ± 2.13 |
1% D gel | Weibull | α β Fmax (%) | 0.88 ± 0.43 0.73 ± 0.23 93.42 ± 3.21 |
Formulation | Parameter | Mean | SD |
---|---|---|---|
0.5% D gel | Jsup (µg/h·cm2) | 9.0106 | 0.6562 |
R2 | 0.9113 | 0.0445 | |
Kp (cm/h) | 0.2481 | 0.0181 | |
Tlag (h) | 2.2834 | 0.6721 | |
P (cm/h2) | 3.4376 | 1.2485 | |
Dif (1/h) | 0.0763 | 0.0225 | |
1% D gel | Jsup (µg/h·cm2) | 32.9769 | 1.1737 |
R2 | 0.9913 | 0.0001 | |
Kp (cm/h) | 0.4542 | 0.0162 | |
Tlag (h) | 1.1698 | 0.0514 | |
P (cm/h2) | 3.1851 | 0.0265 | |
Dif (1/h) | 0.1426 | 0.0063 |
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Lajarin-Reinares, M.; Naveira-Souto, I.; Mallandrich, M.; Suñer-Carbó, J.; Llagostera Casas, M.; Calvo, M.A.; Fernandez-Campos, F. Repurposing Disulfiram as an Antifungal Agent: Development of a New Disulfiram Vaginal Mucoadhesive Gel. Pharmaceutics 2023, 15, 1436. https://doi.org/10.3390/pharmaceutics15051436
Lajarin-Reinares M, Naveira-Souto I, Mallandrich M, Suñer-Carbó J, Llagostera Casas M, Calvo MA, Fernandez-Campos F. Repurposing Disulfiram as an Antifungal Agent: Development of a New Disulfiram Vaginal Mucoadhesive Gel. Pharmaceutics. 2023; 15(5):1436. https://doi.org/10.3390/pharmaceutics15051436
Chicago/Turabian StyleLajarin-Reinares, Maria, Iria Naveira-Souto, Mireia Mallandrich, Joaquim Suñer-Carbó, Montserrat Llagostera Casas, Maria Angels Calvo, and Francisco Fernandez-Campos. 2023. "Repurposing Disulfiram as an Antifungal Agent: Development of a New Disulfiram Vaginal Mucoadhesive Gel" Pharmaceutics 15, no. 5: 1436. https://doi.org/10.3390/pharmaceutics15051436
APA StyleLajarin-Reinares, M., Naveira-Souto, I., Mallandrich, M., Suñer-Carbó, J., Llagostera Casas, M., Calvo, M. A., & Fernandez-Campos, F. (2023). Repurposing Disulfiram as an Antifungal Agent: Development of a New Disulfiram Vaginal Mucoadhesive Gel. Pharmaceutics, 15(5), 1436. https://doi.org/10.3390/pharmaceutics15051436