Effect of Sulfobutyl ether-β-cyclodextrin on Bio- availability of Insulin Glargine and Blood Glucose Level after Subcuta- neous Injection to Rats
Effect of Sulfobutyl ether-β-cyclodextrin on Bio- availability of Insulin Glargine and Blood Glucose Level after Subcuta- neous Injection to Rats
复制标题
磺丁基醚-β-环糊精对大鼠皮下注射甘精胰岛素生物利用度及血糖水平的影响
DOI：
10.1016/j.ijpharm.2011.07.018
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
H. Arima
中科院分区：
文献类型：
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作者：
K. Uehata;T. Anno;K. Hayashida;K. Motoyama;F. Hirayama;N. Ono;J.D. Pipkin;K. Uekama;H. Arima
甘精胰岛素是第一种长效基础胰岛素类似物，用于1型或2型糖尿病患者每日一次皮下给药。为了进一步获得甘精胰岛素的生物利用度和持续降糖作用，本研究考察了磺丁基醚-β-环糊精(SBE4-β-CyD)对甘精胰岛素的药学性质和大鼠皮下注射甘精胰岛素释放的影响。SBE4-β-Cyd增加了甘精胰岛素在pH为9.5的磷酸盐缓冲液中的溶解度，抑制了甘精胰岛素的聚集，这可能是由于SBE4-β-Cyd与甘精胰岛素的酪氨酸等芳香氨基酸残基相互作用所致。此外，与单独使用甘精胰岛素相比，sBE4-β-Cyd加快了甘精胰岛素从其沉淀物中的溶解速度。此外，我们还发现，皮下注射含有SBE4-β-Cyd的甘精胰岛素溶液可提高甘精胰岛素的生物利用度，并维持降糖作用，这可能是由于SBE4-β-Cyd对注射部位的酶降解有抑制作用。这些结果表明，SBE4-β-CyD可以作为甘精胰岛素缓释的辅料。
Insulin glargine is the first long-acting basal insulin analogue used for subcutaneous administration once daily in patients with type 1 or type 2 diabetes mellitus. To obtain the further bioavailability and the sustained glucose lowering effect of insulin glargine, in the present study, we investigated the effect of sulfobutyl ether-β-cyclodextrin (SBE4-β-CyD), with the degree of substitution of sulfobutyl ether group of 3.9, on pharmaceutical properties of insulin glargine and the release of insulin glargine after subcutaneous injection to rats. SBE4-β-CyD increased the solubility and suppressed aggregation of insulin glargine in phosphate buffer at pH 9.5, probably due to the interaction of SBE4-β-CyD with aromatic amino acid residues such as tyrosine of insulin glargine. In addition, SBE4-β-CyD accelerated the dissolution rate of insulin glargine from its precipitates, compared to that of insulin glargine alone. Furthermore, we revealed that subcutaneous administration of an insulin glargine solution with SBE4-β-CyD to rats enhanced the bioavailability of insulin glargine and sustained the glucose lowering effect, possibly due to the inhibitory effects of SBE4-β-CyD on the enzymatic degradation at the injection site. These results suggest that SBE4-β-CyD can be a useful excipient for sustained release of insulin glargine.