Abstract
Biologics have changed the management of Inflammatory Bowel Disease (IBD), but there are concerns regarding unexpected systemic toxicity and loss of therapeutic response following administration by injection. Local delivery of biologics directly to the inflamed mucosa via rectal enema administration addresses the problems associated with systemic administration. Hydrogels are potentially useful delivery vehicles enabling rectal administration of biologics. Here, we prepared a hydrogel system based on methylcellulose (MC) and hyaluronic acid (HA), which possesses mucosal healing properties, incorporating a model macromolecular drug, namely (fluorescently-labeled) bovine serum albumin (BSA). The BSA-loaded MCHA hydrogel showed temperature-dependent gelation (liquid-like at 20 °C and gel-like at 37 °C) and shear thinning behavior, with these being important and desirable characteristics for rectal application (enabling easy application and retention). BSA release from the MCHA system at 37 °C was linear, with 50% of the loaded drug released within 2 h. The system demonstrated acceptable toxicity towards intestinal (colon) Caco-2 epithelial cells, even at high concentrations. Importantly, application of the BSA-loaded MCHA hydrogel to polarized Caco-2 monolayers, with or without an exemplar absorption enhancer, resulted in transintestinal permeability of BSA. The study therefore indicates that the MCHA hydrogel shows potential for topical (rectal) delivery of biologics in IBD.
Highlights
Crohn’s Disease (CD) and Ulcerative Colitis (UC), two main forms of inflammatory bowel disease (IBD), are chronic, disabling and progressive diseases
We recently reported a hydrogel system based on a generally recognized as safe (GRAS) amphiphile known as ascorbyl palmitate (AP), incorporating a model macromolecular drug [17]
We report a simple, thermoresponsive hydrogel system based on methylcellulose (MC)—hyaluronic acid (HA) blend (MCHA) as a previously unreported candidate for rectal delivery of biologics in IBD
Summary
Crohn’s Disease (CD) and Ulcerative Colitis (UC), two main forms of inflammatory bowel disease (IBD), are chronic, disabling and progressive diseases. Biological drugs (e.g., peptides and proteins) such as infliximab (Remicade and the biosimilars Inflectra and Remsima) and adalimumab (Humira) have had a clear impact on the management of IBD They currently require injection-mediated administration, which comes with important limitations, including systemic toxicity [1], loss of sustained response to therapy with time (producing symptom flares) [2], and disadvantages associated with injections such as high costs, patient discomfort and injection site injury. We recently reported a hydrogel system based on a generally recognized as safe (GRAS) amphiphile known as ascorbyl palmitate (AP), incorporating a model macromolecular drug (fluorescently-labeled dextran) [17] The formulation of this system was inspired by a prior study [18] showing that this system displays ‘inflammation-targeting’ properties, whereby dexamethasone-incorporated AP hydrogel was delivered in a selective manner to inflammation sites as a result of charge interaction, namely negatively charged hydrogel interacting with the positively charged proteins accumulated selectively at inflammation sites [19,20].
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