Cyclodextrin–Amphiphilic Copolymer Supramolecular Assemblies for the Ocular Delivery of Natamycin
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Micelles Preparation and Characterization
2.3. Solubility of Natamycin in Micelle Dispersions
2.4. Solubility of Natamycin in αCD
2.5. Preparation of Poly(pseudo)rotaxanes
2.6. Rheological Characterization
2.7. Diffusion Assays
2.8. Ocular Tolerance Test (HET-CAM Test)
2.9. Ex-Vivo Corneal and Sclera Permeability Study
2.10. Statistical Analysis
3. Results and Discussion
3.1. Micelles Preparation and Natamycin Solubilization
3.2. Poly(pseudo)rotaxane Formation
3.3. HET-CAM Assay
3.4. Natamycin Diffusion
3.5. Ex Vivo Permeation Assay
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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0.9% NaCl | ||||
Copolymer (%w/v) | pH | Diameter (nm) | PDI | Zeta Potential (mV) |
Soluplus (10%) | 3.34 | 90.0 ± 1.3 | 0.168 ± 0.010 | −0.40 ± 0.19 |
Pluronic (10%) | 6.34 | 20.5 ± 0.6 | 0.238 ± 0.003 | 1.03 ± 0.47 |
Soluplus/Pluronic P103 (1:4) | 4.67 | 129.6 ± 2.9 | 0.246 ± 0.019 | −0.66 ± 0.20 |
Soluplus/Pluronic P103 (2:3) | 3.89 | 131.0 ± 3.0 | 0.214 ± 0.011 | −0.81 ± 0.08 |
Soluplus/Pluronic P103 (3:2) | 3.70 | 121.7 ± 1.0 | 0.190 ± 0.017 | −1.49 ± 0.46 |
Soluplus/Pluronic P103 (4:1) | 3.52 | 110.7 ± 1.8 | 0.209 ± 0.008 | −0.56 ± 0.41 |
Buffer pH 6.4 | ||||
Copolymer (%w/v) | pH | Diameter (nm) | PDI | Zeta Potential (mV) |
Soluplus (10%) | 6.08 | 102.8 ± 1.0 | 0.189 ± 0.018 | −0.14 ± 0.36 |
Pluronic (10%) | 6.36 | 16.1 ± 0.4 | 0.226 ± 0.018 | 1.15 ± 0.28 |
Soluplus/Pluronic P103 (1:4) | 6.49 | 150.8 ± 4.5 | 0.217 ± 0.011 | 0.48 ± 0.06 |
Soluplus/Pluronic P103 (2:3) | 6.47 | 140.5 ± 0.7 | 0.176 ± 0.008 | −0.02 ± 0.15 |
Soluplus/Pluronic P103 (3:2) | 6.20 | 127.8 ± 0.9 | 0.171 ± 0.011 | −0.12 ± 0.01 |
Soluplus/Pluronic P103 (4:1) | 6.48 | 114.7 ± 2.4 | 0.170 ± 0.011 | −0.18 ± 0.13 |
Copolymer (% w/w) | Soluplus (M) | NAT (M) | NAT (µg/mL) | χ | P | PM | ΔG (KJ/mol) | mf |
---|---|---|---|---|---|---|---|---|
0.1 | 0.87 × 10−5 | 0.71 × 10−4 | 46.99 | 0.52 | 0.07 | 7869.6 | −22,227.0 | 0.06 |
1 | 8.70 × 10−5 | 1.04 × 10−4 | 69.31 | 0.44 | 0.58 | 6619.2 | −21,798.2 | 0.37 |
2 | 1.74 × 10−4 | 1.26 × 10−4 | 84.03 | 0.35 | 0.91 | 5233.1 | −21,216.1 | 0.48 |
3 | 2.61 × 10−4 | 1.47 × 10−4 | 97.93 | 0.31 | 1.23 | 4700.0 | −20,949.8 | 0.55 |
4 | 3.48 × 10−4 | 1.84 × 10−4 | 122.51 | 0.34 | 1.78 | 5131.2 | −21,167.3 | 0.64 |
5 | 4.35 × 10−4 | 2.03 × 10−4 | 135.23 | 0.31 | 2.07 | 4769.5 | −20,986.2 | 0.67 |
10 | 8.70 × 10−4 | 2.98 × 10−4 | 198.49 | 0.27 | 3.51 | 4038.0 | −20,573.7 | 0.78 |
10 (buffer) * | 8.70 × 10−4 | 3.96 × 10−4 | 263.73 | 0.38 | 4.99 | 5743.2 | −21,446.5 | 0.83 |
Copolymer (% w/w) | Pluronic P103 (M) | NAT (M) | NAT (µg/mL) | χ | P | PM | ΔG (KJ/mol) | mf |
---|---|---|---|---|---|---|---|---|
0.1 | 0.20 × 10−3 | 0.70 × 10−4 | 46.27 | 5.59 × 10−2 | 0.05 | 845.5 | −16,699.6 | 0.05 |
1 | 2.02 × 10−3 | 0.84 × 10−4 | 56.00 | 9.59 × 10−3 | 0.27 | 145.1 | −12,332.5 | 0.21 |
2 | 4.04 × 10−3 | 0.95 × 10−4 | 63.21 | 7.40 × 10−3 | 0.44 | 112.0 | −11,690.4 | 0.30 |
3 | 6.06 × 10−3 | 1.12 × 10−4 | 74.37 | 7.71 × 10−3 | 0.69 | 116.6 | −11,790.1 | 0.41 |
4 | 8.08 × 10−3 | 1.24 × 10−4 | 82.63 | 7.31 × 10−3 | 0.88 | 110.6 | −11,659.3 | 0.47 |
5 | 1.01 × 10−2 | 1.37 × 10−4 | 91.06 | 7.10 × 10−3 | 1.07 | 107.4 | −11,586.3 | 0.52 |
10 | 2.02 × 10−2 | 2.16 × 10−4 | 143.49 | 7.45 × 10−3 | 2.27 | 112.7 | −11,706.4 | 0.69 |
10 (buffer) * | 2.02 × 10−2 | 2.15 × 10−4 | 143.39 | 7.44 × 10−3 | 2.26 | 112.6 | −11,704.0 | 0.69 |
Formulation | 0.9% NaCl | Buffer pH 6.4 | ||
---|---|---|---|---|
D × 106 (cm2/min) | R2 | D × 106 (cm2/min) | R2 | |
Pluronic P103 10% | 49.46 (3.99) | 0.992 | 65.14 (0.96) | 0.992 |
Pluronic P103 + αCD 10% | 32.66 (4.73) | 0.990 | 50.30 (11.57) | 0.990 |
Soluplus 10% | 5.56 (1.62) | 0.992 | 10.58 (0.53) | 0.982 |
Soluplus 10% + αCD 10% | 3.72 (0.24) | 0.982 | 9.92 (2.38) | 0.992 |
Soluplus/Pluronic P 103 (4:1) | 18.31 (1.24) | 0.998 | 45.68 (4.10) | 0.989 |
Soluplus/Pluronic P 103 (4:1) + αCD 10% | 8.21 (1.22) | 0.970 | 16.14 (2.00) | 0.996 |
Formulation | 0.9% NaCl | Buffer pH 6.4 | ||
---|---|---|---|---|
J (µg/(cm2·h)) | Papp × 106 (cm/s) | J (µg/(cm2·h)) | Papp × 106 (cm/s) | |
Pluronic P103 10% | 0.724 (0.042) | 1.67 (0.09) | 0.774 (0.032) | 1.79 (0.07) |
Pluronic P103 + αCD 10% | 0.496 (0.023) | 1.15 (0.05) | 0.449 (0.012) | 1.04 (0.03) |
Soluplus 10% | 0.403 (0.006) | 0.93 (0.01) | 0.466 (0.024) | 1.08 (0.05) |
Soluplus 10% + αCD 10% | 0.174 (0.018) | 0.40 (0.04) | 0.090 (0.008) | 0.27 (0.02) |
Soluplus/Pluronic P 103 (4:1) | 0.623 (0.065) | 1.44 (0.15) | 0.543 (0.021) | 1.26 (0.05) |
Soluplus/Pluronic P 103 (4:1) + αCD 10% | 0.391 (0.023) | 0.91 (0.05) | 0.313 (0.016) | 0.73 (0.04) |
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Lorenzo-Veiga, B.; Sigurdsson, H.H.; Loftsson, T.; Alvarez-Lorenzo, C. Cyclodextrin–Amphiphilic Copolymer Supramolecular Assemblies for the Ocular Delivery of Natamycin. Nanomaterials 2019, 9, 745. https://doi.org/10.3390/nano9050745
Lorenzo-Veiga B, Sigurdsson HH, Loftsson T, Alvarez-Lorenzo C. Cyclodextrin–Amphiphilic Copolymer Supramolecular Assemblies for the Ocular Delivery of Natamycin. Nanomaterials. 2019; 9(5):745. https://doi.org/10.3390/nano9050745
Chicago/Turabian StyleLorenzo-Veiga, Blanca, Hakon Hrafn Sigurdsson, Thorsteinn Loftsson, and Carmen Alvarez-Lorenzo. 2019. "Cyclodextrin–Amphiphilic Copolymer Supramolecular Assemblies for the Ocular Delivery of Natamycin" Nanomaterials 9, no. 5: 745. https://doi.org/10.3390/nano9050745