Development and Preclinical Investigation of Physically Cross-Linked and pH-Sensitive Polymeric Gels as Potential Vaginal Contraceptives
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Methods
2.2.1. Formulation of Physically Cross-Linked Ci-PBA Gels
2.2.2. Formulation of Chemically Cross-Linked Ci-PVA-BA Gels
2.3. Rheological Measurements
2.3.1. Storage (G′) and Loss (G″) Modulus and Tan Δ Measurements
2.3.2. Complex Viscosity
2.4. Creep Recovery Analysis
2.5. Physical Observations
2.6. Osmolality Measurements
2.7. Fourier Transform Infrared Spectroscopy (FTIR)
2.8. Stability Analysis
2.9. In Vitro Sperm Functionality Testing
2.10. Rabbit Contraceptive Efficacy Test (RCET)
3. Results and Discussion
3.1. Rheological Characterization of PBA-SHA (Control) Gel
3.2. Development of Physically Cross-Linked Ci-PBA Gels
3.2.1. Frequency Sweep Rheology and Tan Δ Measurements for Ci-PBA Gels
3.2.2. Effect of Excipients on Viscoelastic Behavior of Ci-PBA Gels
3.3. Development of pH-Dependent Chemically Cross-Linked Ci-PVA-BA Gels
Rheology of Ci-PVA-BA Gel (7P) in the Presence of Excipients
3.4. Creep Recovery Analysis of Ci-PBA and Ci-PVA-BA Gels
3.5. Osmolality Measurements of Ci-PBA and Ci-PVA-BA Gels
3.6. FTIR Analysis of Ci-PBA and Ci-PVA-BA Gels
3.7. Stability Testing
3.8. In Vitro Sperm Functionality Testing (Sperm Motility, Viability, and Penetration)
3.9. In Vivo Contraceptive Efficacy Testing of the Gels
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gel | Ci (mg/mL) | PBA (mg/mL) | Williamson Model (r2) | Zero Shear Rate Viscosity (Pa. S) | Physical Properties | G′max (Pa) | G″max (Pa) |
---|---|---|---|---|---|---|---|
1 | 20 | 33.33 | N.D. * | N.D. | Crumbly, hard, non-syringeable | 173.56 | 30.73 |
2 | 10 | 33.33 | N.D. | N.D. | Soft, syringeable with self-healing property | 43.48 | 5.70 |
3 | 5 | 30 | N.D. | N.D. | Fluidic, no gel behavior | 3.33 | 1.54 |
4 | 10 | 30 | 0.98 | 125,107 | Soft, syringeable | 34.40 | 8.65 |
5 | 20 | 30 | 0.99 | 163,155 | Hard but syringeable with self-healing property | 42.84 | 7.17 |
6 | 10 | 50 | 0.99 | 354,482 | Relatively hard with some syringeability | 72.22 | 7.63 |
7 | 8 | 20 | 0.99 | 103,782 | Extremely soft, syringeable | 28.67 | 8.81 |
Gel | Ci (mg/mL) | PVA (mg/mL) | BA (mg/mL) | KCl (mg/mL) | Cross-linking | G′max (Pa) | G″max (Pa) | ωc (rad/s) | Modulus at Crossover (Pa) |
---|---|---|---|---|---|---|---|---|---|
1P | 5 | 10 | 5 | 2.5 | No | 18.73 | 3.93 | NA | NA |
2P | 5 | 20 | 10 | 2.5 | Weak | 75.77 | 46.32 | 39.03 | 46.17 |
3P | 5 | 30 | 15 | 2.5 | Yes | 752.13 | 431.05 | 2.44 | 330.59 |
4P | 6 | 30 | 15 | 2.5 | Yes | 5020.03 | 2294.13 | 0.90 | 1570.58 |
5P | 5 | 10 | 5 | - | No | 10.14 | 4.39 | NA | NA |
6P | 9 | 30 | 10 | - | Yes | 175.97 | 125.05 | 9.49 | 122.59 |
7P | 9.5 | 30 | 10 | - | Yes | 321.93 | 444.94 | 13.42 | 388.11 |
Gel | Acidic pH | Basic pH | ||
---|---|---|---|---|
Zero-Shear Rate Viscosity (Pa·S) | Williamson r2 Value | Zero-Shear Rate Viscosity (Pa·S) | Williamson r2 Value | |
2P | 2.99 | 0.93 | 44.39 | 0.99 |
3P | 8.46 | 0.93 | 448.12 | 0.99 |
4P | 50.67 | 0.99 | 4964.79 | 0.99 |
6P | 2.23 | 0.94 | 41.59 | 0.99 |
7P | 19.16 | 0.98 | 161.85 | 0.98 |
Samples * | Polymer Composition and Gel pH | Approximate Sperm Penetration Distance (µm) ** | |
---|---|---|---|
0 min | 20 min | ||
Ci-PBA (Gel 2) | 33.33 mg/mL of PBA, 10 mg/mL of Ci, pH~4.4 | 0 ± 0 | 0 ± 0 |
Ci-PBA (Gel 4) | 30 mg/mL of PBA, 10 mg/mL of Ci, pH~4.4 | 140 ± 3.5 | 390 ± 29.2 |
Ci-PVA-BA (Gel 7P) | 30 mg/mL of PVA, 9.5 mg/mL of Ci, 10 mg/mL of BA, pH~4.8 | 150 ± 11.2 | 350 ± 35.4 |
HEC gel | 2.7% w/w, pH~4.4 | >500 µm | Spread all over |
N-9 gel | 4% w/w | 0 ± 0 *** | Not applicable |
Treatment Arms | RCET # 1 | RCET # 2 | Summary of Two RCET Studies |
---|---|---|---|
# Pregnant/Total (% Contraceptive Efficacy) | # Pregnant/Total (% Contraceptive Efficacy) | # Pregnant/Total (% Contraceptive Efficacy) | |
Sham control | 3/3 (0%) | 3/3 (0%) | 6/6 (0%) |
HEC gel (2.7% w/w) | 4/5 (20%) | 4/4 (0%) | 8/9 (~11%) |
N-9 gel (4% w/w) | 0/2 (100%) | 0/2 (100%) | 0/4 (100%) |
Ci-PBA (Gel 2) | 2/5 (60%) | Not applicable | 2/5 (60%) |
Ci-PBA (Gel 7) | Not applicable | 3/5 (40%) | 3/5 (40%) |
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Rochani, A.; Agrahari, V.; Chandra, N.; Singh, O.N.; McCormick, T.J.; Doncel, G.F.; Clark, M.R.; Kaushal, G. Development and Preclinical Investigation of Physically Cross-Linked and pH-Sensitive Polymeric Gels as Potential Vaginal Contraceptives. Polymers 2022, 14, 1728. https://doi.org/10.3390/polym14091728
Rochani A, Agrahari V, Chandra N, Singh ON, McCormick TJ, Doncel GF, Clark MR, Kaushal G. Development and Preclinical Investigation of Physically Cross-Linked and pH-Sensitive Polymeric Gels as Potential Vaginal Contraceptives. Polymers. 2022; 14(9):1728. https://doi.org/10.3390/polym14091728
Chicago/Turabian StyleRochani, Ankit, Vivek Agrahari, Neelima Chandra, Onkar N. Singh, Timothy J. McCormick, Gustavo F. Doncel, Meredith R. Clark, and Gagan Kaushal. 2022. "Development and Preclinical Investigation of Physically Cross-Linked and pH-Sensitive Polymeric Gels as Potential Vaginal Contraceptives" Polymers 14, no. 9: 1728. https://doi.org/10.3390/polym14091728