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The Effect of Chemical Modifications of Chitosan on Intestinal Permeability and Oral Bioavailability of Carbamoylphosphonate JS403

: Bitton-Dotan, Reut; Bohrisch, Joerg; Schmidt, Christian; Tsuriel, Marina; Tulichala, RN Prasad; Breuer, Eli; Reich, Reuven; Hoffman, Amnon; Storsberg, Joachim

Fulltext urn:nbn:de:0011-n-5934566 (514 KByte PDF)
MD5 Fingerprint: 4beee33ea7b498d2b1291febd8d5918b
Created on: 2.7.2020

Journal of bioequivalence & bioavailability. Online journal 12 (2020), No.2, Art. 392, 8 pp.
ISSN: 0975-0851
Journal Article, Electronic Publication
Fraunhofer IAP ()
Absorption enhancer; Intestinal permeability; Pharmaceutical approach; Oral bioavailability; BCS Class III; Chitosan derivatives; Paracellular; Palmitoyl carnitine

JS403, Carbamoylphosphonate molecule, is a promising drug candidate with anti-metastatic activity. The polarityand water solubility of JS403 evolve from the phosphonate moiety that is ionized at physiologic pH. JS403 isregarded as a BCS class III molecule, and exhibit poor absolute oral bioavailability of less than 1%. The aim of thisinvestigation is to identify proper chitosan based absorption enhancer compound(s) that upon oral co-administrationwith JS403 which would enhance its bioavailability. To determine the optimal properties of the chitosan derivative(CD), 11 relevant compounds were synthesized, each with different attribute, and their impact on the intestinalpermeability of JS403 was examined in-vitro using the Caco-2 monolayer model. Then, the oral bioavailability ofJS403 coadministered with the selected CD was examined in the freely moving rat model. The in-vitro study identifiedtwo leading trimethyl CD, KC13, (85% deacetylation, MW 20,000 gr/mol and 66% trimethylation) and a novelderivative of hydroxypropyl chitosan KHC2 (trimethylation 71%) increased JS403 permeability in 2 and 10 folds,respectively. Similar permeability results were obtained when the same chitosan derivatives were coadministeredwith atenolol, another BSCIII drug. The paracellular absorption mechanism of these BCS III compounds wasascertained using palmitoyl carnitine as positive control. The pharmacokinetic investigation, following gavage coadministrationwith either KC13 or KHC2, showed a significant increase in JS403 oral AUC of 200%. The in-vitropermeation data correlated with the oral bioavailability outcomes. The relatively modest enhancement (~2 folds)of the chitosan derivatives in-vivo is anticipated as their effect on the enterocytes integrity and tight junction (TJ)need to be moderate. This is required because their noninvasive and reversible impact that is demanded in case ofmultiple treatment.