1. Nasal absorption enhancement of protein drugs independent to their chemical properties in the presence of hyaluronic acid modified with tetraglycine-L-octaarginine.
- Author
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Tomono T, Yagi H, Ukawa M, Ishizaki S, Miwa T, Nonomura M, Igi R, Kumagai H, Miyata K, Tobita E, Kobayashi H, and Sakuma S
- Subjects
- Administration, Intranasal, Animals, Exenatide administration & dosage, Exenatide chemistry, Exenatide pharmacokinetics, Human Growth Hormone administration & dosage, Human Growth Hormone chemistry, Human Growth Hormone pharmacokinetics, Hyaluronic Acid chemistry, Hyaluronic Acid pharmacokinetics, Mice, Nasal Absorption physiology, Nasal Mucosa drug effects, Nasal Mucosa metabolism, Octreotide administration & dosage, Octreotide chemistry, Octreotide pharmacokinetics, Oligopeptides chemistry, Oligopeptides pharmacokinetics, Peptides chemistry, Peptides pharmacokinetics, Hyaluronic Acid administration & dosage, Nasal Absorption drug effects, Oligopeptides administration & dosage, Peptides administration & dosage
- Abstract
Our previous mouse studies demonstrated that mean bioavailability of exendin-4, which is an injectable glucagon-like peptide-1 (GLP-1) analogue whose molecular weight (Mw) and isoelectric point (pI) are ca. 4.2 kDa and 4.5, respectively, administered nasally with poly(N-vinylacetamide-co-acrylic acid) (PNVA-co-AA) bearing D-octaarginine, which is a typical cell-penetrating peptide, was 20% relative to subcutaneous administration even though it was less than 1% when exendin-4 alone was given nasally. The studies also revealed that the absorption-enhancing ability of D-octaarginine-linked PNVA-co-AA for exendin-4 was statistically equivalent to that of sodium salcaprozate (SNAC), which is an absorption enhancer formulated in tablets of semaglutide approved recently as an orally available GLP-1 analogue. From a perspective of clinical application of our technology, we have separately developed hyaluronic acid modified with L-octaarginine via a tetraglycine spacer which would be degraded in biological conditions. The present study revealed that tetraglycine-L-octaarginine-linked hyaluronic acid enhanced nasal absorption of exendin-4 in mice, as did D-octaarginine-linked PNVA-co-AA. There was no significant difference in absorption-enhancing abilities between the hyaluronic acid derivative and SNAC when octreotide (Mw: ca. 1.0 kDa, pI: 8.3) and lixisenatide (Mw: ca. 4.9 kDa, pI: 9.5) were used as a model protein drug. On the other hand, SNAC did not significantly enhance nasal absorption of somatropin (Mw: ca. 22.1 kDa, pI: 5.3) when compared with absorption enhancer-free conditions. Substitution of SNAC with tetraglycine-L-octaarginine-linked hyaluronic acid resulted in a 5-fold increase in absolute bioavailability of somatropin with statistical significance. It appeared that pI hardly ever influenced absorption-enhancing abilities of both enhancers. Results indicated that our polysaccharide derivative would be a promising absorption enhancer which delivers biologics applied on the nasal mucosa into systemic circulation and was of greater advantage than SNAC for enhancing nasal absorption of protein drugs with a larger Mw., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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