CRYSTAL GROWTH & DESIGN
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2022
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IF 4.01
Chunyang Guo,Yuan Wang,Junyi Xie,Bin Zhu,Ming-Hui Qi,Minghuang Hong,Guo-Bin Ren
Lurasidone is an atypical antipsychotic drug for treating schizophrenia and bipolar disorder. The commercial form of lurasidone hydrochloride performs poor bioavailability and significant food effect owing to its poor water solubility. In this study, three novel salts of lurasidone, namely, lurasidone–ketoglutaric acid (LUD–KTA), lurasidone–trans-aconitic acid (LUD–TAA), and lurasidone–maleic acid (LUD–MA–H2O), were obtained and characterized by powder X-ray diffraction and thermal analyses. The molecular components and structures were confirmed by single-crystal X-ray diffraction. The results of the stability experiment showed that LUD–KTA and LUD–TAA exhibited satisfying physical stabilities. Based on in vitro powder dissolution experiments, the new salts achieved remarkably higher solubility than LUD-HCl. In addition, in vivo studies also showed that LUD–KTA and LUD–TAA provided superior bioavailability.
研究领域:
药学
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化学
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DOI
高影响因子
International Journal of Nanomedicine
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2025
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IF 6.5
Tingting Song,Wenyu Wang,Yan Wu,Chaolong Liu,Lu Yuan,Zhihong Sun,Jingjing Zhang,Yong Sun
Purpose Mental illness is the leading cause of the global burden of non-fatal disease. Lurasidone hydrochloride (LSD) is an important antipsychotic drug, but has poor water solubility and low oral bioavailability (9–19%). Additionally, LSD exhibits twice the positive food effect, meaning that patients need to consume 350 kcal when taking the medication, which leads to reduced adherence. In this study, we developed oral LSD liposome enteric-coated capsules to eliminate the food effect and improve the oral bioavailability of LSD.Methodsc Firstly, liposomes were prepared by cethanocl injection cmethod, and their morphology, particle size, polydispersity index, encapsulation efficiency, drug loading capacity, stability and in vitro release were characterized. Subsequently, the mucous permeability and transepithelial transport capacity of p-R8-DOCA-Lipos in intestinal epithelial cells were investigated, and the in vivo pharmacokinetics and biosafety of LSD liposome enteric-coated capsules were further studied.Results p-R8-DOCA-Lipos had uniform morphology (particle size~112 nm), high encapsulation efficiency and drug loading capacity, and good stability in SIF. Cellular studies have shown that pHPMA gradually dissolved as it penetrated the mucus layer, and exposed R8-DOCA-Lipos facilitated cellular uptake. The cellular uptake and cumulative transepithelial transport of p-R8-DOCA-Lipos were 4.96 and 3.80 times higher than those in the solution group, respectively. The endocytosis of p-R8-DOCA-Lipos were mainly mediated by clathrin, caveolin and ASBT. Intracellular tracing showed that p-R8-DOCA-Lipos could achieve lysosomal escape, and ER and GA pathways were involved in their intracellular transport. In vivo pharmacokinetic studies have shown that AUC0-t of p-R8-DOCA-Lipos under fasted and fed conditions were similar to that of LSD suspension under fed conditions, which reduced the food effect of LSD and improved patient compliance. Finally, they had good biosafety after continuous oral administration.Conclusion Therefore, p-R8-DOCA-Lipos may be a promising strategy for overcoming multiple gastrointestinal barriers to improve oral absorption of LSD.
研究领域:
药剂学
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药物代谢动力学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MASS SPECTROMETRY
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2022
·Vol. 57
·期 7
·e4871
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IF 2.394
Kathy Cheng Wang,Qiaohong Guo,Zijian Kuang,Jianyang Jin,Dan Li,Wenbin Chen,Wenquan Zhu,Min Li
Lurasidone is an antipsychotic drug clinically used for the treatment of schizophrenia and bipolar disorder. During a mechanism-based forced degradation study of lurasidone, two novel degradation products were observed under free radical-mediated oxidative (via AIBN) and solution photolytic conditions. The structures of the two novel degradants were identified through an approach combining HPLC, LC-MS n ( n = 1, 2), preparative HPLC purification and NMR spectroscopy. The degradant formed under the free radical-mediated condition is an oxidative degradant with half of the piperazine ring cleaved to form two formamides; a mechanism is proposed for the formation of the novel N , N ′-diformyl degradant, which should be readily applicable to other drugs that contain a piperazine moiety that is widely present in drug molecules. The degradant observed under the solution photolytic condition is identified as the photo-induced isomer of lurasidone with the benzisothiazole ring altered into a benzothiazole ring.
研究领域:
药物化学
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分析化学
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药理学
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DOI
高影响因子
AAPS PHARMSCITECH
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2023
·Vol. 24
·期 4
·1-11
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IF 3.3
Li Shuo,He Ying,Sun Dianjun,Wang Zhaomeng,Yu Jiang,Ye Jianying,He Zhonggui,Wang Yongjun
Latuda® is an oral tablet approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia. However, the clinical efficacy of Latuda® is compromised by patient noncompliance due to frequent daily administration, especially for patients experiencing severe schizophrenia, whose medication is often needed for several months to years. Hence, developing a long-acting injectable formulation of lurasidone is urgently needed. Herein, a poorly water-soluble lurasidone pamoate (LP) salt was synthesized via the facile ion pair-based salt formation technology. The solubility of LP was decreased by 233 folds compared with that of lurasidone hydrochloride (LH). Furthermore, suspensions of LH and LP with three different particle sizes, including 400 nm small-sized nanocrystals (SNCs), 4 μm medium-sized microcrystals (MMCs), and 15 μm large-sized microcrystals (LMCs) were prepared and characterized by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The in vitro release results showed that particle sizes had great effects on the sustained release of LH, where large-sized particles exhibited superior sustained release than the smaller ones. Besides, LP suspensions exhibited better sustained release than LH suspensions at the same size scale. Moreover, the pharmacokinetics showed that LP LMCs produced an extended in vivo intramuscularly injectable profile for up to 45 days, which was 10 days longer than that of the LH LMCs. Our findings demonstrated that particle size had appreciable impacts on drug sustained release and provided valuable knowledge for the rational design of optimized micronized suspensions for long-acting injectables. Graphical
研究领域:
药剂学
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药物传递
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药代动力学
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生物药剂学
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纳米技术
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DOI
高影响因子
Frontiers in Microbiology
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2025
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IF 4.5
Ting Cheng,Qingcui Xiao,Jing Cui,Shuangjie Dong,Yuqin Wu,Wenqiang Li,Xinya Yang,Lina Ma,Zhiyong Li,Peng Sun,Yinli Xie
Introduction Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes acute febrile illness with thrombocytopenia and a high mortality rate in humans. Currently, no specific antiviral agents have been approved for the prevention or treatment of SFTSV infection. The viral nucleoprotein (NP) is a critical component involved in viral RNA replication and transcription, representing a promising target for antiviral drug development. Methods We performed a structure-based virtual screening of the FDA-approved drug library using AutoDock Vina, aiming to identify potential inhibitors targeting the RNA-binding pocket of SFTSV NP. Promising candidates were further evaluated for antiviral activity in vitro. Results Among the screened compounds, lurasidone exhibited strong antiviral activity against SFTSV, with an IC 50 value of 4.552 μM and a selectivity index (SI) greater than 10, indicating favorable antiviral potency and low cytotoxicity. Mechanistic investigations suggest that lurasidone may exert its inhibitory effect by directly binding to the NP, thereby interfering with viral genome replication. Conclusion This study identifies lurasidone as a potential antiviral candidate targeting SFTSV NP and provides a theoretical basis for the repurposing of FDA-approved drugs against emerging viral infections. These findings offer new insights into therapeutic strategies for the treatment of SFTSV.
研究领域:
病毒学
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药物开发
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结构生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2024
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IF 5.3
Yutong Song,Yu Chen,Weili Heng,Enshi Hu,Yunyi Shi,Yuan Gao,Jianjun Zhang,Yuanfeng Wei,Shuai Qian
Coamorphous drug delivery systems have received increasing interest owing to their potential to improve the solubility, dissolution and bioavailability of poorly water-soluble drugs. However, the crystallization risk is one of major limitations in their application. It has been widely recognized that the coformer plays a vital role in physical stability of coamorphous formulation. Unfortunately, the screen of optimal coformer still adopts a trial-and-error method, which is time-consuming and expensive. Herein, a supramolecular synthon approach based on the interaction between functional groups, was exploited to design coamorphous systems (CMs) consisting of lurasidone hydrochloride (LH) and three coformers, saccharin (SAC), L-tryptophan (TRP), and L-cysteine hydrochloride (CYS). X-ray powder diffraction suggested the order of physical stability of the coamorphous systems was ranked as LH-CYS CM > LH-TRP CM > LH-SAC CM. The charge-assisted hydrogen bond between LH and coformer was confirmed by infrared spectroscopy and solid-state 13 C NMR. Moreover, structural, electronic, and molecular interaction information, especially hydrogen bonding interactions, were quantified by theoretical calculations, including miscibility calculations, molecular dynamics simulations and quantum chemical calculations. It was revealed that LH-CYS CM exhibited the best miscibility, strongest binding energy and strongest H-bond with partially covalent character, demonstrating the significant role of supramolecular synthon in stabilizing coamorphous formulations. Interestingly, LH-TRP CM, not LH-CYS CM, exhibited the lowest molecular mobility among three coamorphous systems, which was inconsistent with their physical stability. But from thermodynamic perspective, the order of configurational entropy and physical stability of coamorphous systems was completely consistent. We shed light on the comprehensive effects of molecular mobility and configurational entropy on physical stability of coamorphous systems. Importantly, the relationship between supramolecular synthon and kinetic/thermodynamic mechanisms was also discussed, and the positive correlation between configurational entropy and intermolecular interactions was proposed in this paper. Our findings demonstrated the great potential of supramolecular synthon in designing coamorphous systems with tailored physical stability, and further provided a deeper insight into the mechanisms of physical stability of coamorphous systems.
研究领域:
药学
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材料科学
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物理化学
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产品关联
DOI
PubMed
高影响因子
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