Caltech Optical Imaging Laboratory, Andrew and Peggy Cherng Department of Medical Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Mol Metab. 2022 Aug;62:101522. doi: 10.1016/j.molmet.2022.101522. Epub 2022 Jun 4.
Ultra-rapid insulin formulations control postprandial hyperglycemia; however, inadequate understanding of injection site absorption mechanisms is limiting further advancement. We used photoacoustic imaging to investigate the injection site dynamics of dye-labeled insulin lispro in the Humalog® and Lyumjev® formulations using the murine ear cutaneous model and correlated it with results from unlabeled insulin lispro in pig subcutaneous injection model.
We employed dual-wavelength optical-resolution photoacoustic microscopy to study the absorption and diffusion of the near-infrared dye-labeled insulin lispro in the Humalog and Lyumjev formulations in mouse ears. We mathematically modeled the experimental data to calculate the absorption rate constants and diffusion coefficients. We studied the pharmacokinetics of the unlabeled insulin lispro in both the Humalog and Lyumjev formulations as well as a formulation lacking both the zinc and phenolic preservative in pigs. The association state of insulin lispro in each of the formulations was characterized using SV-AUC and NMR spectroscopy.
Through experiments using murine and swine models, we show that the hexamer dissociation rate of insulin lispro is not the absorption rate-limiting step. We demonstrated that the excipients in the Lyumjev formulation produce local tissue expansion and speed both insulin diffusion and microvascular absorption. We also show that the diffusion of insulin lispro at the injection site drives its initial absorption; however, the rate at which the insulin lispro crosses the blood vessels is its overall absorption rate-limiting step.
This study provides insights into injection site dynamics of insulin lispro and the impact of formulation excipients. It also demonstrates photoacoustic microscopy as a promising tool for studying protein therapeutics. The results from this study address critical questions around the subcutaneous behavior of insulin lispro and the formulation excipients, which could be useful to make faster and better controlled insulin formulations in the future.
超快速胰岛素制剂可控制餐后高血糖；然而，对注射部位吸收机制的理解不足限制了其进一步发展。我们使用光声成像技术，通过鼠耳皮肤模型研究了 Humalog®和 Lyumjev®制剂中染料标记的胰岛素赖脯氨酸的注射部位动力学，并将其与猪皮下注射模型中未标记的胰岛素赖脯氨酸的结果进行了关联。
我们采用双波长光分辨率光声显微镜研究了近红外染料标记的胰岛素赖脯氨酸在 Humalog 和 Lyumjev 制剂中的吸收和扩散。我们对实验数据进行了数学建模，以计算吸收速率常数和扩散系数。我们研究了 Humalog 和 Lyumjev 制剂以及缺乏锌和酚防腐剂的制剂中未标记的胰岛素赖脯氨酸的药代动力学。使用 SV-AUC 和 NMR 光谱学来表征每种制剂中胰岛素赖脯氨酸的缔合状态。
通过使用鼠和猪模型进行的实验，我们表明胰岛素赖脯氨酸的六聚体解离速率不是吸收速率限制步骤。我们证明 Lyumjev 制剂中的赋形剂会导致局部组织扩张，从而加速胰岛素扩散和微血管吸收。我们还表明，注射部位的胰岛素赖脯氨酸扩散驱动其初始吸收；然而，胰岛素赖脯氨酸穿过血管的速度是其整体吸收速率限制步骤。
这项研究提供了对胰岛素赖脯氨酸注射部位动力学和制剂赋形剂影响的深入了解。它还展示了光声显微镜作为研究蛋白质治疗剂的有前途的工具。这项研究的结果解决了有关胰岛素赖脯氨酸和制剂赋形剂在皮下行为的关键问题，这对于未来更快更好控制胰岛素制剂可能是有用的。
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