<br>用于评估口服肽制剂的 Caco-2 Transwell 和 Gut-on-a-Chip 模型的头对头比较,Molecular Pharmaceutics

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用于评估口服肽制剂的 Caco-2 Transwell 和 Gut-on-a-Chip 模型的头对头比较
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2024-06-28 , DOI: 10.1021/acs.molpharmaceut.4c00210
John P Gleeson ₁ , Stephanie Y Zhang ₁ , Natalia Subelzu ₂ , Jing Ling ₁ , Becky Nissley ₁ , Whitney Ong ₂ , Rebecca Nofsinger _{1,

3} , Filippos Kesisoglou ₁

Affiliation

强效肽药物的口服给药给制药行业带来了关键的制剂挑战：稳定性、溶解度和渗透性。肠道渗透增强剂（PE）可以通过提高药物渗透性来克服口服生物利用度低的问题。用于评估 PE 的传统体外和离体模型无法预测体内功效。在这里，我们将传统静态 Transwell 模型中培养的 Caco-2 细胞与市售的连续流微流控芯片肠道模型进行了比较。我们确定了 Transwell (5.3 ± 0.8 × 10 ^–8 cm/s) 与 Chip (3.2 ± 1.8 × 10 ^–7 cm/s) 中 FITC-Dextan 3 kDa (FD3) 的基线渗透性。我们筛选了两种已建立的 PE 癸酸钠和蔗糖单月桂酸酯的浓度影响，并指出在 Chip 模型中需要更高的增强剂浓度才能获得相同的功效，例如，Transwell 中的 10 mM 癸酸钠与 Chips 中的 25 mM 相比。将禁食和进食状态模拟肠液 (FaSSIF/FeSSIF) 引入芯片中，使基础 FD3 渗透性分别增加 3 倍和 20 倍，而 Transwell 中为 4 倍和 4000 倍。我们评估了该模型对含有 PE 的肽（胰岛素和奥曲肽）的效用，并在 Chip 模型中观察到更适度的通透性增强，这与离体和体内临床前模型的观察结果一致。这些数据表明微流控芯片模型非常适合弥合传统体外和体内模型之间的差距。

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Head-to-Head Comparison of Caco-2 Transwell and Gut-on-a-Chip Models for Assessing Oral Peptide Formulations

Oral delivery of potent peptide drugs provides key formulation challenges in the pharmaceutical industry: stability, solubility, and permeability. Intestinal permeation enhancers (PEs) can overcome the low oral bioavailability by improving the drug permeability. Conventional in vitro and ex vivo models for assessing PEs fail to predict efficacy in vivo. Here, we compared Caco-2 cells cultured in the conventional static Transwell model to a commercially available continuous flow microfluidic Gut-on-a-Chip model. We determined baseline permeability of FITC-Dextan 3 kDa (FD3) in Transwell (5.3 ± 0.8 × 10^–8 cm/s) vs Chip (3.2 ± 1.8 × 10^–7 cm/s). We screened the concentration impact of two established PEs sodium caprate and sucrose monolaurate and indicated a requirement for higher enhancer concentration in the Chip model to elicit equivalent efficacy e.g., 10 mM sodium caprate in Transwells vs 25 mM in Chips. Fasted and fed state simulated intestinal fluids (FaSSIF/FeSSIF) were introduced into the Chip and increased basal FD3 permeability by 3-fold and 20-fold, respectively, compared to 4-fold and 4000-fold in Transwells. We assessed the utility of this model to peptides (Insulin and Octreotide) with PEs and observed much more modest permeability enhancement in the Chip model in line with observations in ex vivo and in vivo preclinical models. These data indicate that microfluidic Chip models are well suited to bridge the gap between conventional in vitro and in vivo models.

更新日期：2024-06-28

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