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N-Trimethylated Chitosan Chloride (TMC) Improves the Intestinal Permeation of the Peptide Drug Buserelin In Vitro (Caco-2 Cells) and In Vivo (Rats)

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Abstract

Purpose. To evaluate N-trimethyl chitosan chloride (TMC) of highdegrees of substitution as intestinal permeation enhancers for thepeptide drug buserelin in vitro using Caco-2 cell monolayers, and toinvestigate TMCs as enhancers of the intestinal absorption of buserelinin vivo, in rats.

Methods. TMCs were tested on Caco-2 cells for their efficiency toincrease the paracellular permeability of the peptide buserelin. For thein vivo studies male Wistar rats were used and buserelin wasadministered with or without the polymers intraduodenally. Both types ofexperiments were performed at pH 7.2.

Results. Transport studies with Caco-2 cell monolayers confirmed thatthe increase in buserelin permeation is dependent on the degree oftrimethylation of TMC. In agreement with the in vitro results, in vivodata revealed highly increased bioavailability of buserelin followingintraduodenal co-administration with 1.0% (w/v) TMCs.Intraduodenally applied buserelin resulted in 0.8% absolute bioavailability,whereas co-administrations with TMCs resulted in mean bioavailabilityvalues between 6 and 13 %. Chitosan HCl (1.0% pH = 7.2) did notsignificantly increase the intestinal absorption of buserelin.

Conclusions. Both the in vitro and in vivo results indicate that TMCsare potent mucosal permeation enhancers of the peptide drug buserelinat neutral pH values.

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Authors and Affiliations

  1. Division of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300RA, Leiden, The Netherlands

    M. Thanou, B. I. Florea & J. C. Verhoef

  2. Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9503, 2300RA, Leiden, The Netherlands

    M. W. E. Langemeÿer

  3. Division of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300RA, Leiden, The Netherlands

    H. E. Junginger

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  1. M. Thanou
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  2. B. I. Florea
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  3. M. W. E. Langemeÿer
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  4. J. C. Verhoef
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  5. H. E. Junginger
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Thanou, M., Florea, B.I., Langemeÿer, M.W.E. et al. N-Trimethylated Chitosan Chloride (TMC) Improves the Intestinal Permeation of the Peptide Drug Buserelin In Vitro (Caco-2 Cells) and In Vivo (Rats). Pharm Res 17, 27–31 (2000). https://doi.org/10.1023/A:1007558206506

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