Abstract
The aim of this work was to investigate alternative safe and effective permeation enhancers for buccal peptide delivery. Basic amino acids improved insulin solubility in water while 200 and 400 μg/mL lysine significantly increased insulin solubility in HBSS. Permeability data showed a significant improvement in insulin permeation especially for 10 μg/mL of lysine (p < 0.05) and 10 μg/mL histidine (p < 0.001), 100 μg/mL of glutamic acid (p < 0.05) and 200 μg/mL of glutamic acid and aspartic acid (p < 0.001) without affecting cell integrity; in contrast to sodium deoxycholate which enhanced insulin permeability but was toxic to the cells. It was hypothesized that both amino acids and insulin were ionised at buccal cavity pH and able to form stable ion pairs which penetrated the cells as one entity; while possibly triggering amino acid nutrient transporters on cell surfaces. Evidence of these transport mechanisms was seen with reduction of insulin transport at suboptimal temperatures as well as with basal-to-apical vectoral transport, and confocal imaging of transcellular insulin transport. These results obtained for insulin are the first indication of a possible amino acid mediated transport of insulin via formation of insulin-amino acid neutral complexes by the ion pairing mechanism.
Highlights
Low toxicity/irritant and high stability alternative[6]
There is a lack of consensus on solubility of insulin in water as different authors have either reported it as soluble/hydrophilic[15] or insoluble/hydrophobic[16]
Our results show that insulin remained only slightly soluble in deionised water (
Summary
Low toxicity/irritant and high stability alternative[6]. the availability of amino acid transport across cells may enhance facilitated transport of drug-amino acid complexes (after ion pair formation), leading to enhanced permeation[7]. Various studies have investigated the use of amino acids as ion pairs to improve solubility/permeability of small molecules[4,8,9,10,11]. The use of amino acids as ion pairs to enhance solubility/permeability has not been extensively reported for proteins and macromolecules. That ionised insulin molecules could form ion pairs with opposite charges provided by basic and acidic amino acids to form an insulin-amino acid neutral complex with enhanced lipophilicity, which could permeate the buccal membrane via transcellular passive diffusion. The aim of this work was to investigate the ion pairing effect of basic and acidic amino acids on the solubility, permeability, mechanism and the transport route of insulin across TR146 buccal cell layers
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