Ruponen Marika, Kettunen Konsta, Santiago Pires Monica, Laitinen Riikka
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Escola Superior de Tecnologia da Saúde de Lisboa, 1990-094 Lisbon, Portugal.
Pharmaceutics. 2021 Jan 27;13(2):171. doi: 10.3390/pharmaceutics13020171.
In this study, the amino acid arginine (ARG) and P-glycoprotein (P-gp) inhibitors verapamil hydrochloride (VER), piperine (PIP) and quercetin (QRT) were used as co-formers for co-amorphous mixtures of a Biopharmaceutics classification system (BCS) class IV drug, furosemide (FUR). FUR mixtures with VER, PIP and QRT were prepared by solvent evaporation, and mixtures with ARG were prepared by spray drying in 1:1 and 1:2 molar ratios. The solid-state properties of the mixtures were characterized with X-ray powder diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) in stability studies under different storage conditions. Simultaneous dissolution/permeation studies were conducted in side-by-side diffusion cells with a PAMPA (parallel artificial membrane permeability assay) membrane as a permeation barrier. It was observed with XRPD that ARG, VER and PIP formed co-amorphous mixtures with FUR at both molar ratios. DSC and FTIR revealed single glass transition values for the mixtures (except for FUR:VER 1:2), with the formation of intermolecular interactions between the components, especially salt formation between FUR and ARG. The co-amorphous mixtures were found to be stable for at least two months under an elevated temperature/humidity, except FUR:ARG 1:2, which was sensitive to humidity. The dissolution/permeation studies showed that only the co-amorphous FUR:ARG mixtures were able to enhance both the dissolution and permeation of FUR. Thus, it is concluded that formulating co-amorphous salts with ARG may be a promising option for poorly soluble/permeable FUR.
在本研究中，氨基酸精氨酸（ARG）以及P-糖蛋白（P-gp）抑制剂盐酸维拉帕米（VER）、胡椒碱（PIP）和槲皮素（QRT）被用作生物药剂学分类系统（BCS）IV类药物呋塞米（FUR）共无定形混合物的共形成剂。通过溶剂蒸发法制备了FUR与VER、PIP和QRT的混合物，通过喷雾干燥法以1:1和1:2的摩尔比制备了FUR与ARG的混合物。在不同储存条件下的稳定性研究中，采用X射线粉末衍射（XRPD）、傅里叶变换红外光谱（FTIR）和差示扫描量热法（DSC）对混合物的固态性质进行了表征。在以PAMPA（平行人工膜通透性测定）膜作为渗透屏障的并排扩散池中进行了同步溶解/渗透研究。通过XRPD观察到，ARG、VER和PIP在两种摩尔比下均与FUR形成了共无定形混合物。DSC和FTIR显示混合物具有单一的玻璃化转变值（FUR:VER 1:2除外），各组分之间形成了分子间相互作用，特别是FUR与ARG之间形成了盐。发现共无定形混合物在高温/高湿条件下至少稳定两个月，但FUR:ARG 1:2对湿度敏感。溶解/渗透研究表明，只有共无定形的FUR:ARG混合物能够提高FUR的溶解和渗透能力。因此，得出结论，用ARG配制共无定形盐可能是提高难溶性/难渗透性FUR溶解度的一个有前景的选择。
