An Enteric-Coated Polyelectrolyte Nanocomplex Delivers Insulin in Rat Intestinal Instillations When Combined with a Permeation Enhancer
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Synthesis of Insulin-Associated Polyelectrolyte Nanoparticle Complexes (PECs)
2.3. Physicochemical Properties of PECs
2.4. Measurements of Insulin Loading in PECs and HPLC Analysis
2.5. Colloidal Stability of PECs
2.6. PEC Release Studies in Simulated Intestinal Fluids and Proteolytic Sensitivity
2.7. Cytotoxicity Assays of Uncoated Unloaded PECs: (3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) MTS, ATP, and Neutral Red Uptake Assays
2.8. Mucoadhesion of Uncoated, Unloaded Anionic and Cationic PECs
2.9. Rat Jejunal Instillations of Insulin-Associated PECs
2.10. Statistical Analysis
3. Results
3.1. Selection of the Unloaded PEC Prototype
3.2. Cytotoxicity Assays in Caco-2 Cells
3.3. Mucoadhesion Studies
3.4. Insulin Loading of Uncoated and Coated PECs
3.5. Colloidal Stability of Uncoated and Coated PECs
3.6. PEC Release of Insulin: Studies in FaSSIF-V2
3.7. Proteolytic Sensitivity
3.8. Rat Intra-Jejunal Instillations of Insulin-Loaded PECs
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
References
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PEC | Loading (µg/mL) | Diameter (nm) | PdI | ZP (mV) | AE (%) | PL (%) | FL (µg/mg) |
---|---|---|---|---|---|---|---|
Uncoated | 100 | 232 ± 36 | 0.15 ± 0.06 | −33 ± 5 | 82 ± 6 | 8 ± 1 | 83 ± 7 |
500 | 295 ± 58 | 0.28 ± 0.13 | −36 ± 3 | 80 ± 2 | 31 ± 1 | 285 ± 13 | |
Coated | 100 | 154 ± 27 | 0.16 ± 0.07 | −26 ± 8 | 95 | 1.5 | 17 |
500 | 116 ± 28 | 0.21 ± 0.04 | −23 ± 3 | 97 ± 1 | 6 ± 0 | 58 ± 5 |
PEC | Batches | Particle Diameter (nm) | PdI | ZP (mV) | Cf | |||
---|---|---|---|---|---|---|---|---|
Before | After | Before | After | Before | After | |||
Unloaded | 1 | 175 | 298 | 0.16 | 0.16 | −48 | −53 | 6.71 |
500 µg/mL insulin, uncoated | 4 | 200 (± 24) | 307 (± 74) | 0.23 (± 0.04) | 0.25 (± 0.05) | −49 (± 1) | −54 (± 2) | 3.17 (± 1.48) |
500 µg/mL insulin, coated | 2 | 87 | 105 | 0.15 | 0.24 | −37 | −59 | 4.05 |
Treatment | AUC (0–120 min) | Tmax (min) | Cmax (mU/L) | %F(0–120min) |
---|---|---|---|---|
Insulin (s.c.) | 6936 ± 2436 | 20 ± 0 | 111 ± 26 | - |
Coated PECs | 1725 ± 411 | 30 ± 10 | 45 ± 14 | 0.5 |
Uncoated PECs + SL | 3301 ± 784 | 23 ± 3 | 66 ± 16 | 1.0 |
Coated PECs + SL | 4001 ± 2031 | 23 ± 3 | 142 ± 39 | 1.2 |
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Sladek, S.; McCartney, F.; Eskander, M.; Dunne, D.J.; Santos-Martinez, M.J.; Benetti, F.; Tajber, L.; Brayden, D.J. An Enteric-Coated Polyelectrolyte Nanocomplex Delivers Insulin in Rat Intestinal Instillations When Combined with a Permeation Enhancer. Pharmaceutics 2020, 12, 259. https://doi.org/10.3390/pharmaceutics12030259
Sladek S, McCartney F, Eskander M, Dunne DJ, Santos-Martinez MJ, Benetti F, Tajber L, Brayden DJ. An Enteric-Coated Polyelectrolyte Nanocomplex Delivers Insulin in Rat Intestinal Instillations When Combined with a Permeation Enhancer. Pharmaceutics. 2020; 12(3):259. https://doi.org/10.3390/pharmaceutics12030259
Chicago/Turabian StyleSladek, Svenja, Fiona McCartney, Mena Eskander, David J. Dunne, Maria Jose Santos-Martinez, Federico Benetti, Lidia Tajber, and David J. Brayden. 2020. "An Enteric-Coated Polyelectrolyte Nanocomplex Delivers Insulin in Rat Intestinal Instillations When Combined with a Permeation Enhancer" Pharmaceutics 12, no. 3: 259. https://doi.org/10.3390/pharmaceutics12030259