Cocrystal of Apixaban-Quercetin: Improving Solubility and Bioavailability of Drug Combination of Two Poorly Soluble Drugs

被引:32
作者
Zhang, Li [1 ]
Kong, Dewen [2 ]
Wang, Hongjuan [1 ]
Jiao, Lingtai [1 ]
Zhao, Xiaoyue [2 ]
Song, Junke [2 ]
Yang, Dezhi [1 ]
Yang, Haiguang [2 ]
Yang, Shiying [1 ]
Du, Guanhua [2 ]
Lu, Yang [1 ]
机构
[1] Chinese Acad Med Sci & Peking Union Med Coll, Ctr Pharmaceut Polymorphs, Inst Mat Med, Beijing City Key Lab Polymorph Drugs, Beijing 100050, Peoples R China
[2] Chinese Acad Med Sci & Peking Union Med Coll, Natl Ctr Pharmaceut Screening, Inst Mat Med, Beijing City Key Lab Drug Target & Screening Res, Beijing 100050, Peoples R China
来源
MOLECULES | 2021年 / 26卷 / 09期
基金
国家重点研发计划;
关键词
drug– drug cocrystal; apixaban; quercetin; solubility; bioavailability; FIXED-DOSE COMBINATION; PLATELET-AGGREGATION; OPEN-LABEL; PH; INHIBITION; PHARMACOKINETICS; HYPERTENSION; COMPONENTS; RIFAMPICIN; EFFICACY;
D O I
10.3390/molecules26092677
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Drug combinations have been the hotspot of the pharmaceutical industry, but the promising applications are limited by the unmet solubility and low bioavailability. In this work, novel cocrystals, consisting of two antithrombotic drugs with poor solubility and low bioavailability in vivo, namely, apixaban (Apx) and quercetin (Que), were developed to discover a potential method to improve the poor solubility and internal absorption of the drug combination. Compared with Apx, the dissolution behavior of Apx-Que (1:1) and Apx-Que-2ACN (1:1:2) was enhanced significantly, while the physical mixture of the chemicals failed to exhibit the advantages. The dissolution improvements of Apx-Que-2ACN could be explained by the fact that the solid dispersion-like structure and column-shaped cage of Que accelerated the access of the solvent to the inner layer of Apx. The fracture of the hydrogen bonds of Apx, which was the joint of the adjacent Que chains, facilitated the break-up of the structures. Besides, the bioavailability of Apx-Que was increased compared with the physical mixture and Apx, and Apx-Que remained stable in high temperature and illumination conditions. Therefore, a drug-drug cocrystal of two antithrombotic agents with poor solubility was developed, which exhibited greatly improved solubility, bioavailability and superior stability, indicating a novel method to overcome the shortages of drug combination.
引用
收藏
页数:17
相关论文
共 49 条
[1]   Apixaban for Extended Treatment of Venous Thromboembolism [J].
Agnelli, Giancarlo ;
Buller, Harry R. ;
Cohen, Alexander ;
Curto, Madelyn ;
Gallus, Alexander S. ;
Johnson, Margot ;
Porcari, Anthony ;
Raskob, Gary E. ;
Weitz, Jeffrey I. .
NEW ENGLAND JOURNAL OF MEDICINE, 2013, 368 (08) :699-708
[2]   Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome [J].
Alexander, John H. ;
Lopes, Renato D. ;
James, Stefan ;
Kilaru, Rakhi ;
He, Yaohua ;
Mohan, Puneet ;
Bhatt, Deepak L. ;
Goodman, Shaun ;
Verheugt, Freek W. ;
Flather, Marcus ;
Huber, Kurt ;
Liaw, Danny ;
Husted, Steen E. ;
Lopez-Sendon, Jose ;
De Caterina, Raffaele ;
Jansky, Petr ;
Darius, Harald ;
Vinereanu, Dragos ;
Cornel, Jan H. ;
Cools, Frank ;
Atar, Dan ;
Luis Leiva-Pons, Jose ;
Keltai, Matyas ;
Ogawa, Hisao ;
Pais, Prem ;
Parkhomenko, Alexander ;
Ruzyllo, Witold ;
Diaz, Rafael ;
White, Harvey ;
Ruda, Mikhail ;
Geraldes, Margarida ;
Lawrence, Jack ;
Harrington, Robert A. ;
Wallentin, Lars .
NEW ENGLAND JOURNAL OF MEDICINE, 2011, 365 (08) :699-708
[3]   Co-crystal of Tramadol Hydrochloride-Celecoxib (ctc): A Novel API-API Co-crystal for the Treatment of Pain [J].
Almansa, Carmen ;
Merce, Ramon ;
Tesson, Nicolas ;
Farran, Joan ;
Tomas, Jaume ;
Plata-Salaman, Carlos R. .
CRYSTAL GROWTH & DESIGN, 2017, 17 (04) :1884-1892
[4]   Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial [J].
Bakris, George L. ;
Sarafidis, Pantelis A. ;
Weir, Matthew R. ;
Dahlof, Bjorn ;
Pitt, Bertram ;
Jamerson, Kenneth ;
Velazquez, Eric J. ;
Staikos-Byrne, Linda ;
Kelly, Roxzana Y. ;
Shi, Victor ;
Chiang, Yann-Tong ;
Weber, Michael A. .
LANCET, 2010, 375 (9721) :1173-1181
[5]   ROLE OF CYCLIC-AMP IN THE INHIBITION OF HUMAN-PLATELET AGGREGATION BY QUERCETIN, A FLAVONOID THAT POTENTIATES THE EFFECT OF PROSTACYCLIN [J].
BERETZ, A ;
STIERLE, A ;
ANTON, R ;
CAZENAVE, JP .
BIOCHEMICAL PHARMACOLOGY, 1982, 31 (22) :3597-3600
[6]   INHIBITION OF AGGREGATION AND SECRETION OF HUMAN-PLATELETS BY QUERCETIN AND OTHER FLAVONOIDS - STRUCTURE ACTIVITY RELATIONSHIPS [J].
BERETZ, A ;
CAZENAVE, JP ;
ANTON, R .
AGENTS AND ACTIONS, 1982, 12 (03) :382-387
[7]   Understanding and Predicting the Effect of Cocrystal Components and pH on Cocrystal Solubility [J].
Bethune, Sarah J. ;
Huang, Neal ;
Jayasankar, Adivaraha ;
Rodriguez-Hornedo, Nair .
CRYSTAL GROWTH & DESIGN, 2009, 9 (09) :3976-3988
[8]   Asymmetric alicyclic amine-polyether amine molecular chain structure for improved energy storage density of high-temperature crosslinked polymer capacitor [J].
Chen, Siyu ;
Meng, Guodong ;
Kong, Bo ;
Xiao, Bing ;
Wang, Zhengdong ;
Jing, Ziang ;
Gao, Yushuan ;
Wu, Guanglei ;
Wang, Hong ;
Cheng, Yonghong .
CHEMICAL ENGINEERING JOURNAL, 2020, 387
[9]   Enhanced breakdown strength of aligned-sodium-titanate-nanowire/epoxy nanocomposites and their anisotropic dielectric properties [J].
Chen, Siyu ;
Cheng, Yonghong ;
Xie, Qian ;
Xiao, Bing ;
Wang, Zhengdong ;
Liu, Jingya ;
Wu, Guanglei .
COMPOSITES PART A-APPLIED SCIENCE AND MANUFACTURING, 2019, 120 :84-94
[10]   Improving the Solubility and Bioavailability of Apixaban via Apixaban-Oxalic Acid Cocrystal [J].
Chen, Yong ;
Li, Long ;
Yao, Jia ;
Ma, Yu-Yu ;
Chen, Jia-Mei ;
Lu, Tong-Bu .
CRYSTAL GROWTH & DESIGN, 2016, 16 (05) :2923-2930