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Enhanced intranasal insulin delivery by formulations and tumor protein-derived protein transduction domain as an absorption enhancer

Title
Enhanced intranasal insulin delivery by formulations and tumor protein-derived protein transduction domain as an absorption enhancer
Authors
Kim N.A.Thapa R.Jeong S.H.Bae H.-D.Maeng J.Lee K.Park K.
Ewha Authors
이경림
SCOPUS Author ID
이경림scopus
Issue Date
2019
Journal Title
Journal of Controlled Release
ISSN
0168-3659JCR Link
Citation
Journal of Controlled Release vol. 294, pp. 226 - 236
Keywords
CarbohydratesInsulin formulationIntranasal absorptionProtein aggregationProtein transduction domain
Publisher
Elsevier B.V.
Indexed
SCI; SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
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. © 2018 Elsevier B.V.
DOI
10.1016/j.jconrel.2018.12.023
Appears in Collections:
약학대학 > 약학과 > Journal papers
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