Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology, University of Greifswald, Felix-Hausdorff-Strasse 3, 17489 Greifswald, Germany; Pharmaceutical Technologies, Chemical and Pharmaceutical Development, Merck Healthcare KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
Pharmaceutical Technologies, Chemical and Pharmaceutical Development, Merck Healthcare KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
Int J Pharm. 2019 Jun 30;565:458-471. doi: 10.1016/j.ijpharm.2019.05.028. Epub 2019 May 11.
The majority of NCEs are weakly basic drugs. Consequently, their solubility is highly pH-dependent, with higher solubility in the acidic stomach and poor solubility in the neutral intestinal environment. The gastric emptying of dissolved drug can lead to the intestinal precipitation of the drug. One option of reducing this process is to formulate the drug together with a precipitation inhibitor (PI). The aim of this study was to investigate the effects of different PIs on the intestinal concentrations of ketoconazole and five orally administered kinase inhibitors (i.e. pazopanib, gefitinib, lapatinib, vemurafenib, and a Merck KGaA research compound, MSC-A) with the aid of a predictive small-scale in vitro transfer model. This screening revealed that HPMCAS and Soluplus® were the most effective PIs. Whereas all other drugs precipitated within several minutes, gefitinib expressed highly variable amorphous precipitation which was confirmed by PXRD. During the transfer model experiments, this intermediate supersaturated state was stabilized using HPMCAS and Soluplus®. The PI screening protocol described herein allows to study the effect of PIs for solubility and potential bioavailability improvement of poorly soluble drugs to support formulation development already in early stages.
大多数 NCEs 是弱碱性药物。因此，它们的溶解度高度依赖于 pH 值，在酸性胃中溶解度较高，而在中性肠道环境中溶解度较低。溶解药物的胃排空会导致药物在肠道中沉淀。减少这一过程的一种方法是将药物与沉淀抑制剂 (PI) 一起配制。本研究的目的是借助预测性小型体外传递模型，研究不同 PI 对酮康唑和五种口服激酶抑制剂（即帕唑帕尼、吉非替尼、拉帕替尼、维莫非尼和默克公司的一种研究化合物 MSC-A）在肠道中的浓度的影响。该筛选显示 HPMCAS 和 Soluplus®是最有效的 PI。虽然所有其他药物在几分钟内都发生了沉淀，但吉非替尼表现出高度可变的无定形沉淀，这通过 PXRD 得到了证实。在传递模型实验中，使用 HPMCAS 和 Soluplus®稳定了这种中间过饱和状态。本文描述的 PI 筛选方案可用于研究 PI 对溶解度和潜在生物利用度改善的影响，以支持在早期阶段的制剂开发。
