One of the key factors for successful development of an intranasal insulin formulation is an absorption enhancer that would deliver insulin efficiently across nasal membranes without causing damage to mucosa or inducing protein aggregation under physiological conditions. In the present study, a protein transduction domain (PTD1) and its L-form with the double substitution A6L and I8A (PTD4), derived from human translationally controlled tumor protein, were used as absorption enhancers. PTD4 exhibited higher compatibility with insulin in terms of biophysical properties analyzed using μDSC, DLS, and CD. In addition, thermodynamic properties indicated stable complex formation but higher propensity of protein aggregation. Arginine hydrochloride (ArgHCl) was used to suppress protein aggregation and carbohydrates (i.e., mannitol, sucrose, and glycerin) were used as osmolytes in the formulation. The relative bioavailability of insulin co-administered intranasally using PTD4, 16 mg/mL glycerin and 100 mM ArgHCl was 58% and that using PTD4, 1 w/v% sucrose, and 25 mM ArgHCl was 53% of the bioavailability obtained via the subcutaneous route. These values represented a remarkable increase in bioavailability of intranasal insulin, causing a significant decrease in blood glucose levels within one hour. The pharmacokinetic properties of intranasal absorption were dependent on the concentration of carbohydrates used. These results suggest that the newly designed formulations with PTD represent a useful platform for intranasal delivery of insulin and other biomolecules.
Bibliographical noteFunding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) ( NRF-2018R1A5A2023127 ) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education ( NRF-2018R1D1A1B07045154 ).
© 2018 Elsevier B.V.
- Insulin formulation
- Intranasal absorption
- Protein aggregation
- Protein transduction domain