JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2021
·
IF 3.981
Xiangjun Shi,Chao Wang,Qifeng Chen,Shuimei Shen,Shengjie Song,Xiyue Zhou
Ibrutinib(IBR) is an irreversible Bruton's tyrosine kinase inhibitor and has been classified as the Biopharmaceutical Classification System (BCS) class Ⅱ drug. The objective of the current study was to improve the physicochemical properties of IBR by co-crystallization. Based on ΔpKa analysis and structure analysis, we reported seven IBR pharmaceutical cocrystals with different structure types of co-formers such as hydroxy-2-naphthoic acids, mono-hydroxybenzoic acids, and aliphatic acids via the slurry method and ultrasonic method. The seven prepared cocrystals were characterized by powder X-ray diffraction(PXRD), differential scanning calorimetry(DSC), thermogravimetric analysis(TGA) and Fourier transform infrared spectroscopy(FT-IR). The solubility and accumulative dissolution of IBR cocrystals were explored. It was found that the solubility and dissolution were optimally increased up to 6.64 times and 1.85 times than that of IBR Form A, respectively. Moreover, all the IBR cocrystals maintained a stable cocrystal state after 90-d under 40 °C/75% RH condition and after 30-d under 60 °C/0% RH condition. According to the results analysis, there may be hydrogen bond(H-bond) and π-π stacking interactions in the IBR cocrystal system. The current study demonstrated that the co-crystallization of IBR with specific co-formers proposed a prospective technology and optional strategy to modify the physicochemical nature of IBR.
研究领域:
药学
·
化学
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DOI
高影响因子
SPECTROSCOPY LETTERS
·
2023
·
IF 1.7
Shao-Liang Jiang,Lu Hu,Song-Bo Kou,Li Li,Jie-Hua Shi
Ibrutinib, as an oral Bruton’s tyrosine kinase inhibitor, has highly potent, covalent irreversible, and other characteristics. In this work, the binding characteristics of ibrutinib with bovine serum albumin were investigated using multi-spectroscopic techniques and molecular simulations. The findings demonstrated that ibrutinib could quench the endogenous fluorescence of bovine serum albumin by static quenching mode, meanwhile bovine serum albumin could also quench the fluorescence of ibrutinib. In the binding process of ibrutinib with bovine serum albumin, ibrutinib caused a bathochromic shift in the absorption band of bovine serum albumin, further indicating that ibrutinib and bovine serum albumin formed a ground state ibrutinib and bovine serum albumin complex. It is confirmed that ibrutinib has a strong affinity to bovine serum albumin due to the binding constant of more 104 M−1. Experimental findings showed that ibrutinib resulted in the decrease in the hydrophobicity or the enhancement in the polarity of the surroundings around Tyr and Trp residues of bovine serum albumin and diminishing in α-helix and β-sheet content of bovine serum albumin. The findings from site-competition experiments confirmed that the binding site of ibrutinib onto bovine serum albumin was the same as that of ibuprofen, that is, ibrutinib bound to the site II' site of bovine serum albumin, which was verified by molecular docking. The findings from thermodynamic analysis revealed that ibrutinib spontaneously bound onto bovine serum albumin through an enthalpy-driven and the driving forces included hydrogen bonding and van der Waals forces being the dominating forces. The findings from molecular dynamics simulation confirmed that some residues such as ARG-208, ALA-209, ALA-212, LEU-326, and LYS-350 made major contributions in ibrutinib and bovine serum albumin complexation.
研究领域:
生物化学
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药物科学
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分子生物学
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DOI
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2021
·
IF 4.098
Yue-Yue Chang,Hai-Long Wu,Tong Wang,Huan Fang,Gao-Yan Tong,Yue Chen,Zhao-Yang Wang,Wei Chen,Ru-Qin Yu
In this study, a series of green, interference-free fluorimetric detection methods of the excitation-emission matrix coupled with the second-order calibration methods were proposed for the determination of ibrutinib and pralatrexate in various complicated biological fluids. The second-order advantage of the proposed method can overcome the problem of poor selectivity caused by the wide spectra of the fluorescence method. Even in the presence of uncalibrated interferences and severe peak overlap, the signal of pure substance and accurate quantitative results were still obtained. The average recoveries of the three methods were 94.5–104.9% for Alternating Trilinear Decomposition (ATLD) algorithm, 95.5–105.8% for Alternating Normalization Weighted Error (ANWE) algorithm and 94.4–105.7% for Parallel Factor Analysis (PARAFAC) algorithm, respectively. For ATLD, ANWE and PARAFAC, the relative standard deviations (RSD) were lower than 9.2%, 6.8% and 9.2%, and the RMSEPs were less than 8.1, 8.4 and 8.6 ng mL −1 , respectively. In addition, the elliptic joint confidence region (EJCR) was adopted to further prove the accuracy of the three methods. The results showed that the three methods can accurately be quantified without significant difference. Good figures of merit parameters were also obtained. Among them, the limit of detection (LOD) and limit of quantification (LOQ) of ibrutinib and pralatrexate were in the range of 0.11–0.76 ng mL −1 and 0.21–1.12 ng mL −1 , respectively, which were lower than the corresponding blood concentrations. These results indicate that the proposed method provides a promising, alternative and universal analysis strategy for clinical drug monitoring.
研究领域:
分析化学
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药物分析
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临床医学
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DOI
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2022
·
IF 5.062
Ping Song,Yuan Tian,Guizhou Hao,Lisa Xu,Yan Sun,Yong Sun
Ibrutinib is an anti-cancer drug, mainly used for treating B-cell malignancies. Because of its low water solubility and poor absorption in vivo , the bioavailability is extremely low, only 2.9%. In this study, a solid self-microemulsifying drug delivery system based on the lipid matrix was designed and prepared for ibrutinib. The composition of the self-microemulsion of ibrutinib includes oil phase Caprylic/Capric Triglyceride (Captex®335), surfactant Tween-80, and co-surfactant Diethylene glycol monoethyl ether (Transcutol HP). And the mesoporous silica SBA-15 was selected as an adsorbent to prepare solid powder preparations using the spray-drying method, which significantly improved its dispersibility and stability, and contributed to reducing the particle size and long-term preservation in gastric and intestinal fluids. The in vivo pharmacokinetic study of beagles showed that compared with commercial ibrutinib capsules , the relative oral bioavailability of ibrutinib capsules based on lipid matrix increased to 467.60%. In summary, the lipid-based solid preparation is a promising platform that can effectively improve the oral absorption of ibrutinib.
研究领域:
药剂学
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肿瘤学
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生物医学工程
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DOI
高影响因子
BIOORGANIC CHEMISTRY
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2021
·
IF 5.275
Sumei Ren,Xiaodong Wang,Jun Song,Guangyi Jin
A series of novel ibrutinib analogues was synthesized, and their proliferation inhibitory activities against various B lymphoma cell lines (DaudiB and Raji) and solid tumor cells (B16, CT26, HepG2 and 4T1) were evaluated. The most potent compound, YL7 , exhibited strong antiproliferative activity in all cell lines, and its IC 50 value in B16 cells was almost 9-fold better than that of ibrutinib. Mechanism of action studies showed that YL7 inhibited proliferation and migration and induced G1 cell cycle arrest, apoptosis and autophagy in B16 cells. Further assessment of in vivo antitumor efficacies demonstrated that YL7 significantly inhibited the growth of B16 melanoma. These preliminary studies suggest that it is reasonable to modify the structure of ibrutinib for antimelanoma treatment.
研究领域:
肿瘤学
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药物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
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IF 10
Mengna Sun,Tianyu Shi,Subiyinuer Tuerhong,Mengru Li,Qiaoli Wang,Changchang Lu,Lu Zou,Qinghua Zheng,Yingxin Wang,Juan Du,Rutian Li,Baorui Liu,Fanyan Meng
In situ vaccination is an attractive type of cancer immunotherapy, and methods of persistently dispersing immune agonists throughout the entire tumor are crucial for maximizing their therapeutic efficacy. Based on the probiotics usually used for dietary supplements, an immunomodulator-boosted Lactococcus lactis (IBL) strategy is developed to enhance the effectiveness of in situ vaccination with the immunomodulators. The intratumoral delivery of OX40 agonist and resiquimod-modified Lactococcus lactis (OR@Lac) facilitates local retention and persistent dispersion of immunomodulators, and dramatically modulates the key components of anti-tumor immune response. This novel vaccine activated dendritic cells and cytotoxic T lymphocytes in the tumor and tumor-draining lymph nodes, and ultimately significantly inhibited tumor growth and prolonged the survival rate of tumor-bearing mice. The combination of OR@Lac and ibrutinib, a myeloid-derived suppressor cell inhibitor, significantly alleviated or even completely inhibited tumor growth in tumor-bearing mice. In conclusion, IBL is a promising in situ tumor vaccine approach for clinical application and provides an inspiration for the delivery of other drugs.
研究领域:
肿瘤学
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免疫学
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微生物学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2019
·Vol. 34
·期 1
·e4703
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IF 1.748
Shuangshuang Sun,Dongfang Cheng,Shumeng Kong,Xiangping Li,Tongfang Li,Qinglong Yu,Lin Wang
Ibrutinib has an excellent effect in the treatment of mantle cell lymphoma so it has attracted much attention. A novel ibrutinib nanocrystalline was exploited in our study to improve the bioavailability. A fast and reliable UPLC–MS/MS method was established for the accurate quantification of ibrutinib in rat plasma. The chromatographic separation was achieved by an Agilent zorbax SB-C 18 rapid solution HD column (2.1 × 50 mm, 1.8 μm). The mobile phase consisted of deionized water (containing 10 m m ammonium acetate and 0.1% formic acid) and pure acetonitrile. Isocratic elution (water–acetonitrile 10:90, v/v) was adopted and the flow rate was 0.4 mL/min. Column temperature was set to 40°C. Vilazodone was used as the internal standard in this analytical method. Multiple reaction monitoring mode with positive electrospray ionization was selected to detect ibrutinib and vilazodone. Acetonitrile was used to precipitate protein to extract plasma samples. There was no endogenous interference for both ibrutinib and vilazodone and the linear range of this method was 1–2000 ng/mL. The recoveries were 98.4, 97.4 and 102.7% at low, medium and high concentrations. Accordingly, the matrix effect was 96.6, 111.1 and 99.6%. The pharmacokinetic difference between ibrutinib crude and a novel ibrutinib nanocrystalline in rats was investigated by this validated method successfully. The peak concentration and area under the concentration–time curve showed significant differences in gender and the bioavailability was improved after oral administration of ibrutinib nanocrystalline.
研究领域:
药物分析
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药理学
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生物医学工程
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DOI
高影响因子
Frontiers in Medicine
·
2025
·
IF 3
Yuhua Zhang,Yun Xiao,Yongjun Zhu,Lin Yan,Nan Cheng,Yongjie Wei,Yanling Zhang,Yanghua Tian,Wei Cao,Jianming Yang
Introduction: Ibrutinib, widely used in leukemia treatment, has been implicated in sensorineural hearing loss; however, its underlying mechanisms remain unclear.Methods: This study investigated the impact of ibrutinib on hearing using HEI-OC1 cells, cochlear explants and C57BL/6 J mice. We used RNA-sequences analysis to investigate the potential mechanisms of ibrutinib-induced ototoxicity. Mice received ibrutinib and auditory thresholds were assessed via auditory brainstem response testing; to assess the potential protective effects, we co-administered the caspase inhibitor Z-Val-Ala-Asp (OMe)-fluoromethylketone (Z-VAD-FMK) and monitored hearing.Results: Z-VAD-FMK mitigated ibrutinib-induced hearing loss by inhibiting apoptosis in auditory cells. Ibrutinib exposure resulted in cochlear hair cell (HC) damage and subsequent hearing loss by inhibiting the protein kinase B and G protein-coupled receptor 83 (GPR83) pathways. RNA sequencing suggested that GPR83 protects HCs by modulating autophagy. Z-VAD-FMK application and GPR83 overexpression attenuated ibrutinib-induced cochlear HC apoptosis and auditory decline.Conclusion: These findings confirm ibrutinib’s ototoxicity and highlight the protective role of GPR83 in ibrutinib-induced hearing loss, supporting future clinical investigations into Z-VAD-FMK and GPR83 as interventions for ibrutinib or other chemotherapeutic drug-induced ototoxicity.
研究领域:
耳科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2021
·
IF 4.219
Xiaoyu Wang,Zhe Wang,Xiaoyu Fan,Mingrui Yan,Lili Jiang,Yangliu Xia,Jun Cao,Yong Liu
Ibrutinib and acalabrutinib are two Bruton's tyrosine kinase (BTK) inhibitors which have gained Food and Drug Administration (FDA) approval for the treatment of various B cell malignancies. Herein, we investigated the effects of the two drugs on UDP-glucuronosyltransferase (UGT) activities to evaluate their potential risk for drug-drug interactions (DDIs) via UGT inhibition. Our data indicated that ibrutinib exerted broad inhibition on most of UGTs, including a potent competitive inhibition against UGT1A1 with a K i value of 0.90 ± 0.03 μM, a noncompetitive inhibition against UGT1A3 and UGT1A7 with K i values of 0.88 ± 0.03 μM and 2.52 ± 0.23 μM, respectively, while acalabrutinib only exhibited weak UGT inhibition towards all tested UGT isoforms. DDI risk prediction suggested that the inhibition against UGT1A1 and UGT1A3 by ibrutinib might bring a potential DDIs risk, while acalabrutinib was unlikely to trigger clinically significant UGT-mediated DDIs due to its weak effects. Our study raises an alarm bell about potential DDI risk associated with ibrutinib, however, the extrapolation from in vitro data to in vivo drug interactions should be taken with caution, and additional systemic study is needed.
研究领域:
药理学
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临床医学
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生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
·
2019
·
IF 3.197
Xiangjun Shi,Shengjie Song,Zejie Ding,Baibai Fan,Wan Huang,Tiantian Xu
At present, coamorphous systems have attracted increasing interest in the pharmaceutical field owing to their enhanced stabilities, increased solubilities, and improved bioavailabilities compared with those of their pure amorphous and crystalline counterparts. In this study, a novel coamorphous solid form of ibrutinib (IBT) and saccharin (SAC) (1:1 molar ratio) was prepared through rotary vacuum evaporation and then characterized. Differential scanning calorimetry and X-ray powder diffraction indicated the formation of the coamorphous IBT-SAC after rotary vacuum evaporation. Compared with amorphous IBT, coamorphous IBT-SAC exhibited enhanced stability owing to the intermolecular interaction between IBT and SAC. Moreover, the solubility and dissolution of the coamorphous IBT-SAC were increased up to 4.0-7.7 times and 4.3 times, respectively, compared with those of its crystalline Form A. In addition to the superior behaviors of coamorphous IBT-SAC in vitro , the in vivo bioavailability study revealed notable increases in the C max and area under the curve 0-t of the coamorphous form compared with those of its crystalline Form A. The current study demonstrates that the coamorphization of IBT and SAC presents a promising technology to overcome the limitations of solubility and stability that arise from IBT and can therefore contribute to a major improvement in the bioavailability of IBT.
研究领域:
药剂学
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药物化学
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DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 6.8
Xinyue Zhao,Naijie Wei,Ziyang Fang,Yingyan Xie,Xiaowen Yan,Qiuquan Wang
To address the low cytotoxicity and drug resistance issues of targeted covalent inhibitor (TCI) ibrutinib and severe side effects of chemotherapeutics doxorubicin (DOX), we developed a novel targeted covalently activated chemotherapy strategy. We designed and synthesized a targeted covalently activated chemotherapy drug, Ibt-DOX, which features a targeting ligand of ibrutinib, a DOX, an electrophilic warhead α-methylated acrylamide (α-MAA) and a self-immolative linker p-hydroxybenzyl alcohol. Upon specifically binding to BTK, Ibt-DOX inhibits the BTK-mediated BCR signaling, meanwhile releases DOX and induces immunogenic cell death (ICD), ultimately resulting in not only significantly enhanced targeted B-cell lymphoma cells death compared with ibrutinib, but also reduces the toxic side effects of DOX on BTK- cells. Our work offers a novel strategy through leveraging the synergistic effect of targeted covalent inhibition and the high cytotoxicity of chemotherapy drug, which will inspire the development of new targeted covalent chemotherapeutics for different cancers treatment.
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产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2019
·Vol. 9
·期 4
·2325-2331
·
IF 3.049
Yitong Chen,Baodi Ma,Songshuang Cao,Xiaomei Wu,Yi Xu
The production of (S)-N-boc-3-hydroxy piperidine (NBHP) via asymmetric bioreduction of 1-boc-3-piperidinone with reductase is impeded by the need for expensive coenzymes NAD(P)H. In order to regenerate the coenzyme in situ, the gene of alcohol dehydrogenase from Thermoanaerobacter brockii and glucose dehydrogenase from Bacillus subtilis were ligated into the multiple cloning sites of pRSFDuet-1 plasmid to construct the recombinant Escherichia BL21 (DE3) that co-expressing alcohol dehydrogenase and glucose dehydrogenase. Different culture conditions including the medium composition, inducer and pH etc were systematically investigated to improve the enzyme production. The enzyme activity was increased more than 11-fold under optimal culture condition, from 12.7 to 139.8 U L−1. In the further work, the asymmetric reduction of 1-boc-3-piperidinone by whole cells of recombinant E. coli was systematic optimized to increase the substrate concentration and reaction efficiency. At last, S-NBHP (>99% ee) was prepared at 500 mM substrate concentration without external addition of cofactors. The conversion of S-NBHP reached 96.2% within merely 3 h, corresponding a high space-time yield around 774 g L−1 d−1. All these results demonstrated the potential of recombinant E. coli BL21 (DE3) coupled expressing alcohol dehydrogenase and glucose dehydrogenase for efficient synthesis of S-NBHP.
研究领域:
生物技术
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药物化学
·
酶学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）