Formulation of Polymeric Nanoparticles Loading Baricitinib as a Topical Approach in Ocular Application
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Biological Materials
2.3. Factorial Design
2.4. Preparation of the Selected Nanoparticles Loading BTB
2.5. Physicochemical Characterization of Nanoparticles
2.5.1. Encapsulation Efficiency (EE)
2.5.2. Morphological Study of Nanoparticles
2.5.3. Extensibility of Nanoparticles
2.5.4. Rheological Characterization
2.5.5. Stability of Nanoparticles
2.6. Antimicrobial Challenge Test
2.7. Ex Vivo Cornea Permeation Assays
2.8. In Vitro Tolerance Study
2.8.1. Hen’s Egg Test on the Chorioallantoic Membrane (HET-CAM)
2.8.2. Cornea Transparency
2.8.3. Cornea Histology Study
3. Results
3.1. Factorial Design
3.2. Nanoparticle Physicochemical Characterization
3.2.1. Encapsulation Efficiency
3.2.2. Morphological Study
3.2.3. Extensibility Studies
3.2.4. Rheological Characterization
3.2.5. Stability of Nanoparticles
3.3. Antimicrobial Challenge Test
3.4. Ex Vivo Permeation
3.5. In Vitro Tolerance Study
3.5.1. Hen’s Egg Test on the Chorioallantoic Membrane (HET-CAM)
3.5.2. Cornea Transparency
3.5.3. Cornea Histological Study
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Factors | ||||||
---|---|---|---|---|---|---|
Variables Levels | Polymer Amount (mg) | Surfactant Amount (mg) | Aqueous Phase Volume (mL) | Polymer Amount (mg) | Surfactant Amount (mg) | Aqueous Phase Volume (mL) |
PCL | PCL | PCL | PLGA | PLGA | PLGA | |
Low (−1) | 50 | 200 | 38 | 75 | 150 | 50 |
Centered (0) | 60 | 240 | 44 | 95 | 200 | 60 |
High (+1) | 70 | 280 | 50 | 115 | 250 | 70 |
Axial (−0.39) | 46 | 185 | 36.5 | 72 | 134 | 47 |
Axial (+1.39) | 74 | 295 | 51.5 | 118 | 266 | 73 |
Levels of Factors | |||
---|---|---|---|
Formulations | Polymer Amount (mg) | Surfactant Amount (mg) | Aqueous Phase Volume (mL) |
F1 | 0 | 0 | 0 |
F2 | 1 | 0 | 0 |
F3 | 0 | 1 | 0 |
F4 | 1 | 1 | 0 |
F5 | 0 | 0 | 1 |
F6 | 1 | 0 | 1 |
F7 | 0 | 1 | 1 |
F8 | 1 | 1 | 1 |
F9 | 0.5 | 0.5 | 0.5 |
F10 | 0.5 | 0.5 | 0.5 |
F11 | −0.39 | 0.5 | 0.5 |
F12 | 1.39 | 0.5 | 0.5 |
F13 | 0.5 | −0.39 | 0.5 |
F14 | 0.5 | 1.39 | 0.5 |
F15 | 0.5 | 0.5 | −0.39 |
F16 | 0.5 | 0.5 | 1.39 |
F17 | 0.5 | 0.5 | 0.5 |
F18 | 0.5 | 0.5 | 0.5 |
F19 | 0.5 | 0.5 | 0.5 |
Formulation | Polymer Amount (%) | Aqueous Phase (%) | Surfactant Amount P188 (%) |
---|---|---|---|
B-PLGA-95 | 0.157 | 99.511 | 0.332 |
B-PLGA-75 | 0.107 | 99.609 | 0.284 |
B-PCL | 0.100 | 99.502 | 0.398 |
Test Microorganisms | Microorganism Concentration | |||
---|---|---|---|---|
B-PCL NPs (CFU/mL) | B-PLGA-95 and B-PLGA-75 NPs (CFU/mL) | |||
Bacteria | Pseudomonas aeruginosa | ATCC 9027 (NCIMB 8626, CIP 82.118) | 1.5 × 108 | 2.3 × 108 |
Staphylococcus aureus | ATCC 6538, (NCTC 10788, NCIMB 9518) | 2.1 × 108 | 2.3 × 108 | |
Fungus | Candida albicans | ATCC 10231 (NCPF 3179, IP 48.72) | 1 × 108 | 1 × 108 |
Aspergillus brasiliensis | ATCC 16404 (IMI 149007, IP 1431.83) | 2 × 107 | 2 × 107 |
Log Reduction (CFU/mL) | ||||||
---|---|---|---|---|---|---|
Criteria | 6 h | 24 h | 7 d | 14 d | 28 d | |
Bacteria | A | 2 | 3 | - | - | NR |
B | - | 1 | 3 | - | NI | |
Fungus | A | - | - | 2 | - | NI |
B | - | - | - | 1 | NI |
Irritation Score | Irritation Classification |
---|---|
0–0.9 | Non-Irritant |
1–4.9 | Slight Irritant |
5–8.9 | Moderate Irritant |
9–21 | Severe Irritant |
Levels of Factors | Responses | ||||
---|---|---|---|---|---|
Formulations | PLGA Amount (mg) | P188Amount (mg) | Aqueous Phase Volume (mL) | Z-Ave ± SD (nm) | PDI ± SD |
F1 | 75 | 150 | 50 | 206.65 ± 2.9 | 0.303 ± 0.016 |
F2 | 115 | 150 | 50 | 245.80 ± 2.1 | 0.177 ± 0.035 |
F3 | 75 | 250 | 50 | 201.50 ± 1.8 | 0.265 ± 0.049 |
F4 | 115 | 250 | 50 | 237.55 ± 5.0 | 0.150 ± 0.001 |
F5 | 75 | 150 | 70 | 180.80 ± 4.9 | 0.213 ± 0.050 |
F6 | 115 | 150 | 70 | 209.90 ± 3.0 | 0.231 ± 0.035 |
F7 | 75 | 250 | 70 | 197.25 ± 1.2 | 0.217 ± 0.053 |
F8 | 115 | 250 | 70 | 233.05 ± 1.3 | 0.166 ± 0.079 |
F9 | 95 | 200 | 60 | 98.20 ± 0.0 | 0.090 ± 0.056 |
F10 | 95 | 200 | 60 | 118.70 ± 0.6 | 0.168 ± 0.017 |
F11 | 72 | 200 | 60 | 209.55 ± 1.8 | 0.103 ± 0.028 |
F12 | 118 | 200 | 60 | 288.20 ± 4.5 | 0.091 ± 0.051 |
F13 | 95 | 134 | 60 | 214.75 ± 3.6 | 0.218 ± 0.022 |
F14 | 95 | 266 | 60 | 225.25 ± 3.0 | 0.117 ± 0.009 |
F15 | 95 | 200 | 47 | 217.55 ± 2.2 | 0.251 ± 0.008 |
F16 | 95 | 200 | 73 | 206.40 ± 1.6 | 0.101 ± 0.038 |
F17 | 95 | 200 | 60 | 116.60 ± 0.7 | 0.184 ± 0.002 |
F18 | 95 | 200 | 60 | 104.90 ± 0.0 | 0.191 ± 0.016 |
F19 | 95 | 200 | 60 | 159.75 ± 0.8 | 0.056 ± 0.010 |
Levels of Factors | Responses | ||||
---|---|---|---|---|---|
Formulations | PCL Amount (mg) | P188 Amount (mg) | Aqueous Phase Volume (mL) | Z-Ave ± SD (nm) | PDI ± SD |
F1 | 50 | 200 | 38 | 104.20 ± 1.70 | 0.137 ± 0.004 |
F2 | 70 | 200 | 38 | 138.30 ± 5.94 | 0.165 ± 0.016 |
F3 | 50 | 280 | 38 | 109.35 ± 0.78 | 0.174 ± 0.006 |
F4 | 70 | 280 | 38 | 120.00 ± 6.93 | 0.247 ± 0.062 |
F5 | 50 | 200 | 50 | 127.50 ± 1.98 | 0.107 ± 0.037 |
F6 | 70 | 200 | 50 | 398.65 ± 15.34 | 0.159 ± 0.047 |
F7 | 50 | 280 | 50 | 366.40 ± 4.38 | 0.160 ± 0.065 |
F8 | 70 | 280 | 50 | 339.75 ± 2.76 | 0.197 ± 0.009 |
F9 | 60 | 240 | 44 | 347.50 ± 2.55 | 0.223 ± 0.015 |
F10 | 60 | 240 | 44 | 426.60 ± 6.79 | 0.029 ± 0.030 |
F11 | 46 | 240 | 44 | 403.90 ± 1.56 | 0.096 ± 0.053 |
F12 | 118 | 240 | 44 | 335.75 ± 3.32 | 0.355 ± 0.066 |
F13 | 60 | 185 | 44 | 370.60 ± 4.53 | 0.158 ± 0.031 |
F14 | 60 | 295 | 44 | 349.95 ± 6.43 | 0.182 ± 0.040 |
F15 | 60 | 240 | 36.5 | 401.35 ± 7.85 | 0.215 ± 0.011 |
F16 | 60 | 240 | 51.5 | 374.95 ± 1.06 | 0.200 ± 0.013 |
F17 | 60 | 240 | 44 | 458.10 ± 4.95 | 0.203 ± 0.027 |
F18 | 60 | 240 | 44 | 356.90 ± 2.83 | 0.181 ± 0.034 |
F19 | 60 | 240 | 44 | 309.70 ± 6.08 | 0.147 ± 0.048 |
Formulation | Z-Ave ± SD | PDI ± SD | ZP (mV) ± SD | pH ± SD | EE (%) ± SD |
---|---|---|---|---|---|
(NPs) | (nm) | ||||
B-PLGA-95 | 84.50 ± 0.72 | 0.10 ± 0.01 | −25.70 ± 2.01 | 6.9 ± 0.3 | 65.63 ± 3.87 |
B-PLGA-75 | 77.65 ± 0.03 | 0.04 ± 0.02 | −28.20 ± 0.14 | 6.8 ± 0.3 | 27.39 ± 2.05 |
B-PCL | 138.36 ± 0.92 | 0.09 ± 0.02 | −20.55 ± 0.07 | 6.8 ± 0.2 | 77.82 ± 5.33 |
Best-Fit Values | B-PCL | B-PLGA-75 | B-PLGA-95 | Water |
---|---|---|---|---|
A | 16.03 | −5.633 | 2.408 | 31.99 |
B | 0.125 | 0.562 | 0.624 | 0.812 |
C | −0.000279 | −0.002398 | −0.003030 | −0.003556 |
Std. Error | ||||
A | 0.456 | 2.849 | 3.556 | 10.720 |
B | 0.016 | 0.097 | 0.121 | 0.365 |
C | 0.000101 | 0.000629 | 0.000785 | 0.002366 |
Goodness of Fit | ||||
R2 | 0.999 | 0.994 | 0.988 | 0.960 |
NPs | Storage Condition (°C) | Z-Ave (nm) | PDI | ||||
---|---|---|---|---|---|---|---|
Time Assayed (Days) | |||||||
0 | 7 | 30 | 0 | 7 | 30 | ||
B-PLGA-95 | 25 | 80.56 ± 0.72 | 81.72 ± 0.22 | 83.03 ± 2.90 | 0.03 ± 0.01 | 0.07 ± 0.02 * | 0.07 ± 0.05 * |
4 | 82.24 ± 0.54 | 85.48 ± 0.72 | 91.07 ± 4.85 * | 0.02 ± 0.01 | 0.03 ± 0.01 | 0.07 ± 0.08 * | |
B-PLGA-75 | 25 | 71.43 ± 0.01 | 74.75 ± 2.24 | 81.42 ± 5.42 * | 0.05 ± 0.01 | 0.07 ± 0.02 | 0.08 ± 0.04 |
4 | 75.23 ± 0.15 | 77.58 ± 0.24 | 86.00 ± 5.24 * | 0.02 ± 0.01 | 0.04 ± 0.02 | 0.06 ± 0.01 * | |
B-PCL | 25 | 130.36 ± 1.82 | 134.8 ± 2.12 | 141.5 ± 5.03 * | 0.03 ± 0.01 | 0.07 ± 0.04 | 0.12 ± 0.08 * |
4 | 128.30 ± 1.23 | 131.30 ± 2.82 | 152.5 ± 7.79 * | 0.06 ± 0.02 | 0.09 ± 0.07 | 0.02 ± 0.04 * |
Microorganism | Nanoparticle | Log Reduction (CFU/mL) | ||||
---|---|---|---|---|---|---|
6 h | 24 h | 7 d | 14 d | 28 d | ||
P. aeruginosa | B-PLGA-95 | 1 | 3 | NR | NR | |
B-PLGA-75 | NR | NR | - | - | NR | |
B-PCL | 1 | NI ** | 3 | - | NR | |
S. aureus | B-PLGA-95 | 1 | NR * | NR | NR | |
B-PLGA-75 | NR * | NR | - | - | NR | |
B-PCL | - | 1 | NI (105) | - | NR | |
C. albicans | B-PLGA-95 | - | - | NI | 1 | NI |
B-PLGA-75 | - | - | 3 | NI ** | NI | |
B-PCL | - | - | NI (106) | ~1 | NI | |
A. brasiliensis | B-PLGA-95 | - | - | 1 | NI (1) | NI |
B-PLGA-75 | NR | NR | NR | |||
B-PCL | - | - | NI (105) | NI (105) | NI |
B-PLGA-95 | B-PLGA-75 | B-PCL | B-Solution | ||
---|---|---|---|---|---|
Parameters | Units | Mean ± SD | Mean ± SD | Mean ± SD | Mean ± SD |
Flux (J/cm2) | µg/h/cm2 | 20.90 ± 2.47 | 10.12 ± 1.23 A | 16.12 ± 1.92 A,B | 0.07 ± 0.01 A,B,C |
Permeability coefficient (Kp) | cm/h | 0.126 ± 0.014 | 0.071 ± 0.008 A | 0.081 ± 0.009 A | 0.004 ± 0.000 A,B,C |
Lag Time (Tl) | h | 2.90 ± 0.53 | 2.75 ± 0.37 | 2.84 ± 0.24 | 0.83 ± 0.07 A,B,C |
Partition coefficient (P1) | cm | 2.19 ± 0.02 | 1.17 ± 0.02 A | 1.38 ± 0.01 A,B | 0.03 ± 0.00 A,B,C |
Diffusion coefficient (P2) | 1/h | 0.057 ± 0.007 | 0.061 ± 0.005 | 0.059 ± 0.005 | 0.139 ± 0.014 A,B,C |
Amount of BTB in the skin (Qret) | µg/cm2 | 3.35 ± 0.29 | 0.40 ± 0.04 A | 6.09 ± 0.57 A,B | b.l.q. |
Enhancement ratio (ER) | - | 27.7 | 15.6 | 17.8 | - |
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Beirampour, N.; Bustos-Salgado, P.; Garrós, N.; Mohammadi-Meyabadi, R.; Domènech, Ò.; Suñer-Carbó, J.; Rodríguez-Lagunas, M.J.; Kapravelou, G.; Montes, M.J.; Calpena, A.; et al. Formulation of Polymeric Nanoparticles Loading Baricitinib as a Topical Approach in Ocular Application. Pharmaceutics 2024, 16, 1092. https://doi.org/10.3390/pharmaceutics16081092
Beirampour N, Bustos-Salgado P, Garrós N, Mohammadi-Meyabadi R, Domènech Ò, Suñer-Carbó J, Rodríguez-Lagunas MJ, Kapravelou G, Montes MJ, Calpena A, et al. Formulation of Polymeric Nanoparticles Loading Baricitinib as a Topical Approach in Ocular Application. Pharmaceutics. 2024; 16(8):1092. https://doi.org/10.3390/pharmaceutics16081092
Chicago/Turabian StyleBeirampour, Negar, Paola Bustos-Salgado, Núria Garrós, Roya Mohammadi-Meyabadi, Òscar Domènech, Joaquim Suñer-Carbó, María José Rodríguez-Lagunas, Garyfallia Kapravelou, María Jesús Montes, Ana Calpena, and et al. 2024. "Formulation of Polymeric Nanoparticles Loading Baricitinib as a Topical Approach in Ocular Application" Pharmaceutics 16, no. 8: 1092. https://doi.org/10.3390/pharmaceutics16081092