Modelling intramuscular drug fate in vitro with tissue-relevant biomimetic hydrogels.
Modelling intramuscular drug fate in vitro with tissue-relevant biomimetic hydrogels.
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DOI：
10.1016/j.ijpx.2022.100125
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发表时间：
2022-12
影响因子：
4.7
通讯作者：
Mrsny, Randall J.
中科院分区：
文献类型：
--
作者：
McCartan, Adam;Mackay, Julia;Curran, David;Mrsny, Randall J.
肠外给药是临床给药的主要手段。肌肉内注射(IM)直接将药物沉积到骨骼肌腹中，由于该部位高度血管化的性质，提供了快速的全身摄取。注射微粒或非水材料的可能性也使IM注射对长效制剂很有用。这些属性支持过多的药物被批准用于IM管理。尽管有多个药物类别的许多批准，但控制药物从注射部位释放的机制，以及因此其药代动力学特性，仍然知之甚少。一些临床前的活体动物已经被用来模拟IM药物在患者身上的命运，但这些方法并没有一致地预测临床结果。缺乏可预测的体内模型和标准化的体外工具限制了制药科学家合理设计IM给药配方的选择。在这里，我们描述了一种新的、易处理的体外模型，该模型由IM注射部位存在的主要细胞外基质(ECM)成分提供信息。在这个体外模型的初步测试中，研究了绿色荧光蛋白(GFP)的三种电荷变体以及三种常见配方成分的影响。与标准GFP和强负电荷GFP相比，强正电荷GFP在由ECM成分、I型胶原和透明质酸组成的水凝胶中的释放受到限制。引入常用的缓冲液(组氨酸或醋酸酯)或非离子表面活性剂聚山梨酸酯20以依赖于ECM元件组成的方式改变了这些GFP变体的释放特性。总之，这种名为SIMI的肌肉内注射模拟器展示了一种蛋白质生物制药替代品的独特释放曲线，可用于询问配方成分的影响，以加快新药开发并减少目前对潜在的非预测性临床前体内模型的依赖。描述了一种模拟肌肉注射(IM)部位药物释放参数的初始体外格式。在半透性小室中测试了1型胶原(COL1)和透明质酸的混合物。不同电荷分布的绿色荧光蛋白被用来模拟不同的生物制药性质。以Col1为主的水凝胶形式提供了这种体外IM注射部位方法的初步验证
Parenteral administrations are a mainstay of clinical drug delivery. Intramuscular (IM) injections deposit drug directly into skeletal muscle bellies, providing rapid systemic uptake due to the highly vascularized nature of this site. The potential to inject particulate or non-aqueous materials have also made IM injections useful for long-acting formulations. These attributes have supported a plethora of medicines being approved for IM administration. Despite these many approvals across multiple pharmaceutical categories, mechanisms that control drug release from the injection site, and thus its pharmacokinetic properties, remain poorly understood. Several pre-clinical in vivo animals have been used to model IM drug fate in patients, but these approaches have not consistently predicted clinical outcomes. This lack of a predictive in vivo model and no standardized in vitro tools have limited the options of pharmaceutical scientists to rationally design formulations for IM delivery. Here, we describe a novel, tractable in vitro model informed by dominant extracellular matrix (ECM) components present at the IM injection site. Three charge variants of green florescent protein (GFP) and the impact of three common formulation components were examined in an initial test of this in vitro model. A strongly positively charged GFP was restricted in its release from hydrogels composed of ECM components type I collagen and hyaluronic acid compared to standard and strongly negatively charged GFP. Introduction of commonly used buffers (histidine or acetate) or the non-ionic surfactant polysorbate 20 altered the release properties of these GFP variants in a manner that was dependent upon ECM element composition. In sum, this Simulator of IntraMuscular Injections, termed SIMI, demonstrated distinct release profiles of a protein biopharmaceutical surrogate that could be exploited to interrogate the impact of formulation components to expedite novel drug development and reduce current dependence on potentially non-predictive pre-clinical in vivo models. An initial in vitro format to model drug release from the intramuscular (IM) injection site release parameters is described. Mixtures of collagen type 1 (Col1) and hyaluronic acid within a semi-permeable chamber were tested. Green fluorescent proteins with varied charge profiles were used to model different biopharmaceutical properties. A Col1-dominated hydrogel format provided an initial validation of this in vitro IM injection site approach
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