Hyaluronic Acid in the Intestinal Tract: Influence of Structure, Rheology, and Mucoadhesion on the Intestinal Uptake in Rats

Oral hyaluronic acid (HA) is a ubiquitous biopolymer that has gained attention as a treatment for local or systemic diseases. Here, we prepared and characterized structures of free HA (f-HA) with a high (>10(5) Da), intermediate (≤10(5) Da), and low (≤10(4) Da) average molar mass (MM); nanoparticles crosslinked with adipic dihydrazide (n-HA); and mixed formulations (mixed-HA) containing f-HA and n-HA. MM distribution determined the structure, hydrodynamic diameter, and zeta potential of the f-HAs. Crosslinking changed the physicochemical properties in n-HA. In vitro tack adhesion assays, using mucin tablets or a viable rat intestinal mucosa, showed better mucoadhesion with f-HA (intermediate MM) and mixed-HA (25% n-HA), especially in the jejunum segment. High MM f-HA presented negligible mucoadhesion. n-HA showed the deepest diffusion into the porous of the membranes. In vivo results showed that, except for high MM f-HA, there is an inverse relationship between rheological changes in the intestinal membrane macerates resulting from mucoadhesion and the effective intestinal permeability that led to blood clearance of the structures. We conclude that the n-HA formulations are promising for targeting other tissues, while formulations of f-HA (intermediate MM) and mixed-HA are better for treating dysbiosis.