TY - JOUR
T1 - Enhanced intranasal insulin delivery by formulations and tumor protein-derived protein transduction domain as an absorption enhancer
AU - Kim, Nam Ah
AU - Thapa, Ritu
AU - Jeong, Seong Hoon
AU - Bae, Hae duck
AU - Maeng, Jeehye
AU - Lee, Kyunglim
AU - Park, Kinam
N1 - Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2019/1/28
Y1 - 2019/1/28
N2 - 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.
AB - 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.
KW - Carbohydrates
KW - Insulin formulation
KW - Intranasal absorption
KW - Protein aggregation
KW - Protein transduction domain
UR - http://www.scopus.com/inward/record.url?scp=85058945034&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2018.12.023
DO - 10.1016/j.jconrel.2018.12.023
M3 - Article
C2 - 30557648
AN - SCOPUS:85058945034
SN - 0168-3659
VL - 294
SP - 226
EP - 236
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -