Phenolic Preservative Removal from Commercial Insulin Formulations Reduces Tissue Inflammation while Maintaining Euglycemia,ACS Pharmacology & Translational Science

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Phenolic Preservative Removal from Commercial Insulin Formulations Reduces Tissue Inflammation while Maintaining Euglycemia
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2021-04-26 , DOI: 10.1021/acsptsci.1c00047
Adam Mulka ₁ , Brianne E Lewis ₁ , Li Mao ₁ , Roshanak Sharafieh ₂ , Shereen Kesserwan ₁ , Rong Wu ₃ , Donald L Kreutzer ₂ , Ulrike Klueh ₁

Affiliation

Background: Exogenous insulin therapy requires stabilization of the insulin molecule, which is achieved through the use of excipients (e.g., phenolic preservatives (PP)) that provide protein stability, sterility and prolong insulin shelf life. However, our laboratory recently reported that PP, (e.g., m-creosol and phenol) are also cytotoxic, inducing inflammation and fibrosis. Optimizing PP levels through filtration would balance the need for insulin preservation with PP-induced inflammation. Method: Zeolite Y (Z-Y), a size-exclusion-based resin, was employed to remove PP from commercial insulin formulations (Humalog) before infusion. Results: PP removal significantly decreased cell toxicity in vitro and inflammation in vivo. Infusion site histological analysis after a 3 day study demonstrated that leukocyte accumulation increased with nonfiltered preparations but decreased after filtration. Additional studies demonstrated that a Z-Y fabricated filter effectively removed excess PP such that the filtered insulin solution achieved equivalent glycemic control in diabetic mice when compared to nonfiltered insulin. Conclusion: This approach represents the proof of concept that using Z-Y for in-line PP removal assists in lowering inflammation at the site of insulin infusion and thus could lead to extending the functional lifespan of insulin infusion sets in vivo.

中文翻译：

从商业胰岛素制剂中去除酚类防腐剂可减少组织炎症，同时保持血糖正常

背景：外源性胰岛素治疗需要稳定胰岛素分子，这是通过使用提供蛋白质稳定性、无菌性和延长胰岛素保质期的赋形剂（例如，酚类防腐剂 (PP)）来实现的。然而，我们实验室最近报道，PP（例如，间甲酚和苯酚）也具有细胞毒性，可诱导炎症和纤维化。通过过滤优化 PP 水平将平衡胰岛素保存的需要和 PP 引起的炎症。方法：在输注之前，使用基于尺寸排阻的树脂沸石 Y (ZY) 从商业胰岛素制剂 (Humalog) 中去除 PP。结果：去除 PP 显着降低了体外细胞毒性和炎症在体内。3 天研究后的输注部位组织学分析表明，白细胞积累随着未过滤制剂的增加而增加，但在过滤后减少。其他研究表明，与未过滤的胰岛素相比，ZY 制造的过滤器有效地去除了过量的 PP，因此过滤的胰岛素溶液在糖尿病小鼠中实现了等效的血糖控制。结论：这种方法证明了使用 ZY 在线去除 PP 有助于降低胰岛素输注部位的炎症，从而可以延长体内胰岛素输注装置的功能寿命。

更新日期：2021-06-11

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