Tomono Takumi, Yagi Haruya, Ukawa Masami, Ishizaki Seiya, Miwa Takahiro, Nonomura Mao, Igi Ryoji, Kumagai Hironori, Miyata Kohei, Tobita Etsuo, Kobayashi Hideo, Sakuma Shinji
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan; Life Science Materials Laboratory, ADEKA Co., 7-2-34, Higashiogu, Arakawa-ku, Tokyo 116-8553, Japan.
Eur J Pharm Biopharm. 2020 Sep;154:186-194. doi: 10.1016/j.ejpb.2020.07.003. Epub 2020 Jul 15.
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.
我们之前的小鼠研究表明，艾塞那肽-4（一种注射用胰高血糖素样肽-1（GLP-1）类似物，其分子量（Mw）和等电点（pI）分别约为4.2 kDa和4.5）与携带典型细胞穿透肽D-八聚精氨酸的聚（N-乙烯基乙酰胺-共-丙烯酸）（PNVA-共-AA）一起经鼻给药时，相对于皮下给药，其平均生物利用度为20%，尽管单独经鼻给予艾塞那肽-4时生物利用度不到1%。研究还表明，D-八聚精氨酸连接的PNVA-共-AA对艾塞那肽-4的吸收增强能力在统计学上与水杨酸盐（SNAC）相当，SNAC是一种吸收增强剂，最近被用于司美格鲁肽片剂中，司美格鲁肽是一种口服可用的GLP-1类似物。从我们技术的临床应用角度来看，我们已经分别开发了通过四甘氨酸间隔基用L-八聚精氨酸修饰的透明质酸，该间隔基在生物条件下会降解。本研究表明，四甘氨酸-L-八聚精氨酸连接的透明质酸与D-八聚精氨酸连接的PNVA-共-AA一样，可增强小鼠体内艾塞那肽-4的经鼻吸收。当使用奥曲肽（Mw：约1.0 kDa，pI：8.3）和利司那肽（Mw：约4.9 kDa，pI：9.5）作为模型蛋白药物时，透明质酸衍生物与SNAC之间的吸收增强能力没有显著差异。另一方面，与无吸收增强剂的情况相比，SNAC并没有显著增强生长激素（Mw：约22.1 kDa，pI：5.3）的经鼻吸收。用四甘氨酸-L-八聚精氨酸连接的透明质酸替代SNAC后，生长激素的绝对生物利用度提高了5倍，具有统计学意义。似乎pI几乎不会影响这两种增强剂的吸收增强能力。结果表明，我们的多糖衍生物将是一种有前途的吸收增强剂，可将应用于鼻黏膜的生物制品输送到体循环中，并且在增强较大Mw的蛋白药物经鼻吸收方面比SNAC具有更大优势。
