Impact of mucoadhesive polymeric nanoparticulate systems on oral bioavailability of a macromolecular model drug

Abstract

Nanoparticles (NP) only different in mucoadhesivity are compared for impact on drug oral bioavailability. Two polymeric NP types based on quaternary ammonium-chitosan (NP QA-Ch) and S-protected thiolated derivative thereof (NP QA-Ch-S-pro), respectively, containing the macromolecular drug model, FD4, were prepared by crosslinking each polymer with reduced MW hyaluronic acid. The structure of basic polymers was determined by HNMR analysis. NP were similar in size (371 ± 38 vs. 376 ± 82 nm); polydispersity index (0.39 ± 0.08 vs. 0.41 ± 0.10); zeta potential (13.4 ± 0.9 vs. 11.9 ± 1.2 mV); reversible interactions with drug (bound drug, 67 vs. 66%); encapsulation efficiency (23 ± 5 vs. 23 ± 8%); release properties (15% released in 15 h in both cases); and apparent permeation across excised rat intestine (P, 8.8 ± 0.8 vs. 10 ± 1 cm/s). Then the differences in NP transport ratio through mucus (TR, 0.75 vs. 0.37) and adhesion to excised rat intestinal mucosa (adsorbed fraction, 23 ± 3 vs. 45 ± 2%) were ascribed to higher mucoadhesivity of NP QA-Ch-S-pro compared to NP QA-Ch. This directly influenced drug oral bioavailability in rats (T, 1 vs. 2 h; AUC, 1.7 ± 0.3 vs. 2.9 ± 0.4 μg/mL min, for NP QA-Ch and NP QA-Ch-S-pro, respectively). Mucoadhesivity increases drug bioavailability by retaining NP at its absorption site and opposing its transit down the GI tract. Data on drug accumulation in rat liver allows the assertion that NP is absorbed by transcytosis across intestinal epithelium and transported from blood into liver by Kuppfer cells.

Antibacterial, Antibiofilm, and Antiadhesive Properties of Different Quaternized Chitosan Derivatives

“…The relevant high and low MW quaternary ammonium-Ch conjugates (QAH and QAL, respectively) were prepared as described by Zambito, et al, 2006 [54]. High and low MW multifunctional quaternary ammonium-Ch conjugates substituted with protected thiol groups (QAH-Pro and QAL-Pro, respectively) were obtained as previously described [55]. The preparation of multifunctional quaternary ammonium-Ch derivatives of high or low MW, conjugated with methyl-β-cyclodextrin (QAH-CD or QAL-CD) followed a reported protocol [19,20].…”

Improvement of Peptide Affinity and Stability by Complexing to Cyclodextrin-Grafted Ammonium Chitosan

“…Ammonium chitosan (N + -rCh) has also shown enhanced mucoadhesivity provided by the interactions with negative charges located on the mucous membrane [9][10][11]. To further improve its mucoadhesion properties, ammonium chitosan modified with free or S-protected thiol groups have been proposed [12][13][14][15][16]. Such derivatives are capable of forming covalent bonds with the cysteine-rich subdomains of mucin, which is a key component of the mucosal layers.…”

Impact of Different Mucoadhesive Polymeric Nanoparticles Loaded in Thermosensitive Hydrogels on Transcorneal Administration of 5-Fluorouracil

“…Protected thiols present on QA-Ch-S-pro chains were determined by polymer reduction and subsequent quantification of the 6-mercaptonicotinamide protecting group. Only polymers that had the same characteristics as previously obtained [20] were used in this work.…”

“…In the case of NP, the positive groups of Ch could be bound to the crosslinker and, hence, less available for 5-FU binding. This, nevertheless, should not impair the NP effectiveness in vivo, in fact, nanoparticles made of mucoahesive polymers are themselves more mucoahesive than the corresponding parent polymers, hence, likely to strongly adhere to the ocular surface [10,20,30].…”