Abstract
The sublingual mucosa is an appealing route for drug administration. However, in the context of increased use of therapeutic proteins, development of protein delivery systems that will protect the protein bioactivity is needed. As proteins are fragile and complex molecules, current sublingual formulations of proteins are in liquid dosage. Yet, protein dilution and short residence time at the sublingual mucosa are the main barriers for the control of the dose that is delivered. In this work, a simple delivery scaffold based on the assembly of two polysaccharides, chitosan and hyaluronic acid, is presented. The natural polymers were assembled by the Layer-by-Layer methodology to produce a mucoadhesive and oro-dispersible freestanding membrane, shown to be innocuous for epithelial human cells. The functionalization of the membrane with proteins led to the production of a bioactive patch with efficient loading and release of proteins, and suitable mechanical properties for manipulation. Sublingual administration of the patch in mouse evidenced the absence of inflammation and an extended time of contact between the model protein ovalbumin and the mucosa compared to liquid formulation. The delivery of fluorescent ovalbumin in mouse sublingual mucosa demonstrated the penetration of the protein in the epithelium 10 min after the patch administration. Moreover, a migration assay with a chemokine incorporated into the patch showed no decrease in bioactivity of the loaded protein after enzymatic release. This study therefore provides a promising strategy to develop a sublingual protein delivery system. Statement of significanceAlthough the oral route is largely used for drug delivery, it has limitations for the delivery of proteins that can be degraded by pH or gastric enzymes. The sublingual route therefore appears as an interesting approach for protein administration. In this work, a simple delivery scaffold is presented based on the assembly of two polysaccharides by the Layer-by-Layer methodology to produce a mucoadhesive patch. The produced patch allowed efficient loading and release of proteins, as well as protection of their bioactivity. An extended time of contact between the protein and the mucosa compared to liquid formulation was highlighted in mouse model. This study provides a promising strategy to develop a sublingual protein delivery system.
Highlights
We developed a mucoadhesive patch made of a combination of two polysaccharides: CHI and hyaluronic acid (HyA) which is widely present in the human saliva
At least 50 bilayers were required for easy manipulation without any post proceeding treatments, but 100 bilayers were used for the rest of the study to ensure robustness of the membranes and thickness homogeneity for protein incorporation
Concerning the deposition time, i.e. long cycles (6 min for the polyelectrolytes and 4 min for the rinsing buffer) and short cycles (3 min for the polyelectrolytes and 2 min for the rinsing buffer), significant differences were found over the membrane thickness where an increase of around 30% was quantified when the membranes were produced under long cycles, independently of HyA molecular weight (Fig. 1C)
Summary
The exploration of alternative routes for protein delivery is a biotechnological as well as medical challenge [3]. In this context, other mucosal administration routes of therapeutic proteins, and in particular the buccal route, has been recognized as a potential alternative for the delivery of proteins such as insulin for the treatment of diabetes [4] or vaccine antigens [5]. Sublingual administration of allergens has been proven to be safe and efficient for the treatment of type I allergies but remains to be optimized by the design of platforms to improve allergen presentation to buccal dendritic cells (DCs) [6] and allow controlled protein delivery
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