title: Carbopol-mediated paracellular transport enhancement in Calu-3 cell layers.
abstract: 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 C(max) 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 Ca(2+) by charged polymer carboxylate groups that leads to temporary disruption of tight-junctions, thereby facilitating paracellular transport.
authors.affiliation: Exploratory Biopharmaceutics and Stability Department, Bristol-Myers Squibb Pharmaceutical Research Institute, New Brunswick, New Jersey 08903, USA. neil.mathias@bms.com
authors.forename: Lianli
authors.initials: L
authors.lastname: Li
authors.forename: Neil R
authors.initials: NR
authors.lastname: Mathias
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Heran
authors.forename: Paul
authors.initials: P
authors.lastname: Moench
authors.forename: Doris A
authors.initials: DA
authors.lastname: Wall
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Smith
mesh_terms: D000180:Acrylic Resins; D000281:Administration, Intranasal; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001980:Bronchi / Q000166:cytology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects; D005782:Gels; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009297:Nasal Mucosa / Q000166:cytology / Q000187:drug effects*; D011145:Polyvinyls / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity*; D011817:Rabbits
chemical_list: D000180:Acrylic Resins; D004337:Drug Carriers; D005782:Gels; D011145:Polyvinyls; C006912:carboxypolymethylene