Abstract
Intranasal delivery of insulin is an alternative approach to treat diabetes, as it enables higher patient compliance than conventional therapy with subcutaneously injected insulin. However, the use of intranasal delivery of insulin is limited for insulin’s hydrophilicity and vulnerability to enzymatic degradation. This limitation makes optimization of formulation intranasal insulin for commercial purpose indispensable. This study evaluated bioavailability (BA) of various formulations of insulin intranasally delivered with protein transduction domain (PTD) derived from translationally controlled tumor protein. The therapeutic efficacy of newly formulated intranasal insulin + PTD was compared in vivo studies with normal and alloxan-induced diabetic rats, to those of free insulin and subcutaneously injected insulin. BA of insulin in two new formulations was, respectively, 60.71% and 45.81% of subcutaneously injected insulin, while the BA of free insulin was only 3.34%. Histological analysis of tissues, lactate dehydrogenase activity in nasal fluid, and biochemical analysis of sera revealed no detectable topical or systemic toxicity in rats and mice. Furthermore, stability analysis of newly formulated insulin + PTD to determine the optimal conditions for storage revealed that when stored at 4 °C, the delivery capacity of insulin was maintained up to 7 d. These results suggest that the new formulations of intranasal insulin are suitable for use in diabetes therapy and are easier to administer.
Highlights
Intranasal administration is a non-invasive route which has been applied to effective delivery of broad range of drugs including small molecule drugs and macromolecular drugs (Hussain, 1998; Fortuna et al, 2014; Avgerinos et al, 2018)
Current insulin formulation for subcutaneous injection has the weakness of the patient compliance because of the inconvenience of the injection, which frequently leads to non-compliance
We previously reported that the 10 amino acid sequence (MIIYRDKLISH) at the N-terminal of human translationally controlled tumor protein (TCTP) acts as a protein transduction domain (PTD) (Kim et al, 2011b)
Summary
Intranasal administration is a non-invasive route which has been applied to effective delivery of broad range of drugs including small molecule drugs and macromolecular drugs (Hussain, 1998; Fortuna et al, 2014; Avgerinos et al, 2018). Recent studies attempting to find various formulations for effective delivery of those drugs focused on nasal administration as an alternative route for biomacromolecules. Current insulin formulation for subcutaneous injection has the weakness of the patient compliance because of the inconvenience of the injection, which frequently leads to non-compliance Both increased patient compliance and exhibiting pharmacokinetics identical with that of subcutaneously delivered insulin (Frauman et al, 1987a) make this route of administration very attractive in the treatment of diabetes. There remain several issues that should be addressed before accepting the suitability of intranasal delivery of insulin in diabetes therapy These include the need for absorption enhancers and for increasing the residence time of the drug in the nasal cavity (Hinchcliffe & Illum, 1999; Arora et al, 2002; Owens et al, 2003). The use of intranasal insulin still awaits development of optimized formulations that overcome the noted limitations
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