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

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

JS403, Carbamoylphosphonate molecule, is a promising drug candidate with anti-metastatic activity. The polarity and water solubility of JS403 evolve from the phosphonate moiety that is ionized at physiologic pH. JS403 is regarded as a BCS class III molecule, and exhibit poor absolute oral bioavailability of less than 1%. The aim of this investigation is to identify proper chitosan based absorption enhancer compound(s) that upon oral co-administration with 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 intestinal permeability of JS403 was examined in-vitro using the CaCO₂ monolayer model. Then, the oral bioavailability of JS403 coadministered with the selected CD was examined in the freely moving rat model. The in-vitro study identified two leading trimethyl CD, KC13, (85% deacetylation, MW 20,000 g/mol and 66% trimethylation) and a novel derivative 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 coadministered with atenolol, another BSCIII drug. The paracellular absorption mechanism of these BCS III compounds was ascertained using palmitoyl carnitine as positive control. The pharmacokinetic investigation, following gavage coadministration with either KC13 or KHC2, showed a significant increase in JS403 oral AUC of 200%. The in-vitro permeation 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 of multiple treatment.