Carbopol-mediated paracellular transport enhancement in Calu-3 cell layers

The interaction of Carbopol polymers with mucus producing Calu-3 human bronchial epithelial cells was evaluated to test for potential paracellular transport enhancement. Using desmopressin (1-deamino-8-arginine-vasopressin, DDAVP) as the model peptide, apical treatment with Carbopol polymer gel form...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2006-02, Vol.95 (2), p.326-335
Main Authors: Li, Lianli, Mathias, Neil R., Heran, Christopher L., Moench, Paul, Wall, Doris A., Smith, Ronald L.
Format: Article
Language:English
Subjects:
Acrylic Resins
Administration, Intranasal
Animals
Biological and medical sciences
Biological Transport - drug effects
Bronchi - cytology
Calu-3 monolayer
Carbopol
cell culture
Cell Line, Tumor
Cell Survival - drug effects
Dose-Response Relationship, Drug
Drug Carriers
Electric Impedance
Epithelial Cells - drug effects
epithelial delivery/permeability
Gels
General pharmacology
Humans
Hydrogen-Ion Concentration
Medical sciences
mucoadhesive polymer
nasal drug delivery
Nasal Mucosa - cytology
Nasal Mucosa - drug effects
paracellular transport
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Polyvinyls - administration & dosage
Polyvinyls - pharmacokinetics
Polyvinyls - pharmacology
Polyvinyls - toxicity
Rabbits
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Summary:The interaction of Carbopol polymers with mucus producing Calu-3 human bronchial epithelial cells was evaluated to test for potential paracellular transport enhancement. Using desmopressin (1-deamino-8-arginine-vasopressin, DDAVP) as the model peptide, apical treatment with Carbopol polymer gel formulations resulted in molecular size-dependent permeability enhancement with a concomitant drop in the transepithelial electrical resistance (TEER). Permeability enhancement of DDAVP was dependent on the formulation vehicle composition and polymer concentration, was noncytotoxic, and completely reversible. Carbopol 971P displayed the greatest permeability enhancement across Calu-3 cells compared to other more viscous Carbopol polymers 934P and 974P, and other mucoadhesive cellulosic polymers. The greatest enhancement was observed when C971P formulation was prepared in water at a concentration of 0.25% w/v. Enhancement was confirmed in rabbit dosed with intranasal fluorescent dextran 4400. The Cmax and absorption rate each increased by 48% in C971P formulations compared to control, while the relative exposure increased 30%. In conclusion, Carbopol polymers are potentially useful excipients to enhance intranasal peptide absorption. We hypothesize that the permeation enhancement is related to the chelation of extracellular or tight-junctional Ca2+ by charged polymer carboxylate groups that leads to temporary disruption of tight-junctions, thereby facilitating paracellular transport. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.20541