Effects of N-trimethyl chitosan chloride, a novel absorption enhancer, on caco-2 intestinal epithelia and the ciliary beat frequency of chicken embryo trachea.
N-trimethyl chitosan (TMC) polymers are quaternized chitosans in different degrees of trimethylation. These polymers enhance the absorption of macromolecules through mucosal epithelia by triggering the reversible opening of tight junctions and only allow for paracellular transport. To investigate the safety of these novel absorption enhancers cytotoxicity and ciliotoxicity studies have been performed. Intestinal Caco-2 cell monolayers were chosen to study possible membrane damaging effects of these polymers, using confocal laser scanning microscopy visualization of nuclear staining by a membrane impermeable fluorescent probe during transport of the paracellular marker Texas red dextran (MW 10 000). Ciliated chicken embryo trachea tissue was used to study the effect of the polymers on the ciliary beat frequency (CBF) in vitro. In both studies the TMC polymers of different degrees of substitution (20, 40 and 60%) were tested at a concentration of 1.0% (w/v). No substantial cell membrane damage could be detected on the Caco-2 cells treated with TMCs, while the effect on the CBF in vitro was found to be marginal. TMC60 and TMC40 enhance paracellular transport of Texas red dextran in Caco-2 cell monolayers, whereas TMC20 is ineffective. In conclusion, TMCs of high degrees of substitution may be effective and safe absorption enhancers for peptide and protein drug delivery.
Thanou
M M
MM
Department of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA, Leiden, Netherlands.
Verhoef
J C
JC
Romeijn
S G
SG
Nagelkerke
J F
JF
Merkus
F W
FW
Junginger
H E
HE
D000818:Animals; D018938:Caco-2 Cells / Q000187:drug effects; D002642:Chick Embryo; D002686:Chitin / Q000031:analogs & derivatives* / Q000494:pharmacology; D048271:Chitosan; D002923:Cilia / Q000187:drug effects; D004337:Drug Carriers; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects*; D018613:Microscopy, Confocal; D011108:Polymers; D013501:Surface-Active Agents / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects* / Q000196:embryology
D004337:Drug Carriers; C118071:N-trimethyl chitosan chloride; D011108:Polymers; D013501:Surface-Active Agents; D002686:Chitin; D048271:Chitosan