Effect of Cyclodextrin Complex Formation on Solubility Changes of Each Drug Due to Intermolecular Interactions between Acidic NSAIDs and Basic H2 Blockers

IF 4.5 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Pharmaceutics Pub Date : 2023-09-09 DOI:10.1021/acs.molpharmaceut.3c00291

Chihiro Tsunoda, Kanji Hasegawa, Ryosuke Hiroshige, Takahiro Kasai, Hideshi Yokoyama and Satoru Goto*,

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Abstract

One of the solubilization of poorly water-soluble drugs is the use of cyclodextrin (CD)-based inclusion complexes. On the other hand, few studies have investigated how CD functions on the solubility of drugs in the presence of multiple drugs that interact with each other. In this study, we used indomethacin (IND) and diclofenac (DIC) as acidic drugs, famotidine (FAM) and cimetidine (CIM) as basic drugs, and imidazole (IMZ), histidine (HIS), and arginine (ARG) as compounds structurally similar to basic drugs. We attempted to clarify the effect of β-CD on the solubility change of each drug in the presence of multiple drugs. IND and DIC formed a eutectic mixture in the presence of CIM, IMZ, and ARG, which greatly increased the intrinsic solubility of the drugs as well as their affinity for β-CD. Furthermore, the addition of high concentrations of β-CD to the DIC–FAM combination, which causes a decrease in solubility due to the interaction, improved the solubility of FAM, which was decreased in the presence of DIC. These results indicate that β-CD synergistically improves the solubility of drugs in drug–drug combinations, where the solubility is improved, whereas it effectively improves the dissolution rate of drugs in situations where the solubility is reduced by drug–drug interactions, such as FAM–DIC. This indicates that β-CD can be used to improve the physicochemical properties of drugs, even when they are administered in combination with drugs that interact with each other.

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酸性非甾体抗炎药和碱性H2阻断剂分子间相互作用导致环糊精复合物形成对每种药物溶解度变化的影响

水溶性差的药物的增溶作用之一是使用基于环糊精（CD）的包合物。另一方面，很少有研究调查CD在多种药物相互作用的情况下如何影响药物的溶解度。在本研究中，我们使用吲哚美辛（IND）和双氯芬酸（DIC）作为酸性药物，法莫替丁（FAM）和西咪替丁（CIM）作为碱性药物，咪唑（IMZ）、组氨酸（HIS）和精氨酸（ARG）作为结构类似于碱性药物的化合物。我们试图阐明在多种药物存在的情况下，β-CD对每种药物溶解度变化的影响。IND和DIC在CIM、IMZ和ARG存在下形成共晶混合物，这大大增加了药物的内在溶解度以及它们对β-CD的亲和力。此外，在DIC–FAM组合中添加高浓度的β-CD，由于相互作用导致溶解度降低，从而提高了在DIC存在时降低的FAM的溶解度。这些结果表明，β-CD协同提高了药物在药物-药物组合中的溶解度，其中溶解度得到了提高，而在药物相互作用（如FAM–DIC）降低溶解度的情况下，它有效地提高了药物的溶解速率。这表明β-CD可用于改善药物的物理化学性质，即使是与相互作用的药物联合用药。

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来源期刊

Molecular Pharmaceutics 医学-药学

CiteScore

8.00

自引率

6.10%

发文量

391

审稿时长

2 months

期刊介绍： Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.