Pharmaceutics
·
2024
·Vol. 16
·期 1
·109
·
IF 4.9
Lili Wang,Zhuang Ding,Zhengping Wang,Yanna Zhao,Hengqian Wu,Qipeng Wei,Lingfeng Gao,Jun Han
Paxlovid®, a co-packaged medication comprised of separate tablets containing two active ingredients, nirmatrelvir (NRV) and ritonavir (RTV), exhibits good effectiveness against coronavirus disease 2019 (COVID-19). However, the size of the NRV/RTV tablets makes them difficult for some patients to swallow, especially the elderly and those with dysphagia. Therefore, an oral liquid formulation that can overcome this shortcoming and improve patient compliance is required. In this study, we developed a liquid formulation containing NRV and RTV by adopting strategies that used co-solvents and surfactants to enhance the solubility and inhibit possible recrystallization. The in vitro release results showed that NRV and RTV could be maintained at high concentrations in solution for a certain period in the investigated media. In vivo studies in rats showed that the oral bioavailability of NRV/RTV solution was significantly enhanced. Compared to Paxlovid®tablets, the AUC(0–t)of NRV and RTV increased by 6.1 and 3.8 times, respectively, while the Cmaxincreased by 5.5 times for both. Furthermore, the promoting effect of the absorption of RTV on the bioavailability of NRV was confirmed. Experiments with a beagle showed a similar trend. Stability studies were also conducted at 4 °C, 25 °C, and 40 °C for 90 days, indicating that the oral liquid formulation was physically and chemically stable. This study can be used as a valuable resource for developing and applying oral liquid NRV/RTV formulations in a clinical context.Keywords:nirmatrelvir;ritonavir;bioavailability;stability;liquid formulation
研究领域:
药剂学
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药物动力学
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药物开发
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PubMed
高影响因子
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
·
2022
·
IF 5.235
Song-Bo Kou,Kai-Li Zhou,Zhen-Yi Lin,Yan-Yue Lou,Bao-Li Wang,Jie-Hua Shi,Ying-Xin Liu
The binding behavior of ritonavir (RTV), a HIV/AIDS protease inhibitor, with ct-DNA was characterized through multiple testing technologies and theoretical calculation. The findings revealed that the RTV–DNA complex was formed through the noncovalent interaction mainly including conventional hydrogen bonds and carbon hydrogen bonds as well as hydrophobic interactions (pi–alkyl interactions). The stoichiometry and binding constant of the RTV–DNA complex were 1:1 and 1.87 × 103 M−1 at 298 K, respectively, indicating that RTV has moderate affinity with ct-DNA. The findings confirmed that RTV binds to the minor groove of DNA. The outcomes of CD experiments showed that the binding with RTV changed the conformation of DNA slightly. However, the conformation of RTV had obvious changes after binding to DNA, meaning that the flexibility of RTV molecule played an important role in stabilizing the RTV–DNA complex. Meanwhile, the results of DFT calculation revealed that the RTV and DNA interaction caused the changes in the frontier molecular orbitals, dipole moment and atomic charge distribution of RTV, altering the chemical properties of RTV when it bound to DNA. Communicated by Ramaswamy H. Sarma
研究领域:
生物化学
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药理学
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分子生物学
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高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2023
·
IF 3.4
Fenglun Zhao,Zheng Xiang,Junping Han,Jie Pan,Yuchen Qu,Kai Fan,Zhiqiang Wu,Delai Xu,Yunli Yu,Zhu Shen,Cunjin Su
In December 2021, the U.S. Food and Drug Administration (FDA) granted emergency authorization for Paxlovid® as an antiviral treatment for COVID-19. Paxlovid® is composed of two tablets, nirmatrelvir and ritonavir. Dose adjustment is necessary in cases of renal insufficiency. The aim of present study is to establish a LC–HRMS method for simultaneous determination of nirmatrelvir/ritonavir in human serum for therapeutic drug monitoring. Internal standard saquinavir was added in 25 μL human serum samples, and then the samples were precipitated with methanol. The analytes were separated by gradient elution on a C18 column, using a mobile phase of 0.1 % formic acid-water and methanol, at a flow rate of 0.4 mL/min. The injection volume was 2 μL, and the analysis time was 5 min. The determination of the analytes was performed by electrospray ionization in positive mode by full mass monitoring. The detected ions of nirmatrelvir, ritonavir and saquinavir were m/z 500.24792, 721.32004 and 671.39155, respectively. The linear concentration range for nirmatrelvir was 78.13–20000 ng mL −1 , for ritonavir was 15.63–4000 ng mL −1 (r 2 ＞0.9900). The accuracy ranged from 87.45 %∼104.63 %, and the intra-day and inter-day precision RSD was <15 %. The recovery of nirmatrelvir ranged from 98.72 %∼109.83 %, and that of ritonavir was 95.41∼112.36 %. The matrix effect of nirmatrelvir was 88.31∼97.73 %, and that of ritonavir was 85.17∼103.05 %. This method was used to measure the trough concentrations of nirmatrelvir/ritonavir in 17 patients. The trough concentration of nirmatrelvir was 1331.7–8352.5 ng/mL, and that of ritonavir was 53.4–1325.5 ng mL −1 , with large individual differences. The method is simple, sensitive, specific, and reproducible, and can be used for monitoring the blood concentration and pharmacokinetic study of nirmatrelvir/ritonavir in COVID-19 patients.
研究领域:
药理学
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分析化学
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临床医学
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PubMed
高影响因子
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
·
2020
·
IF 0
Bao-Li Wang,Kai-Li Zhou,Yan-Yue Lou,Dong-Qi Pan,Song-Bo Kou,Zhen-Yi Lin,Jie-Hua Shi
The binding affinity between ritonavir (RTV) and model transport protein, BSA was assessed through multi-spectroscopic approaches and computer simulation. The findings revealed RTV statically quenched the fluorescence of BSA and formed the 1:1 RTV-BSA complex with the binding constant (Kb) of 1.06 × 103 ∼ 5.08 × 103 M−1 under the studied temperatures (298 ∼ 310 K). During the interaction of RTV with BSA, the hydrogen bonds and van der Waals forces acted as predominant function while the hydrophobicity played an assistant function. Molecular modeling further verified the result obtained from the competitive binding experiments, RTV preferentially fit into in the sub-domain IIIA of BSA. The perturbation in the secondary structures of BSA upon acting with RTV was observed from IR results, whereas synchronous and 3D fluorescence spectral findings unraveled the slight change in the hydrophobicity surrounding Tyr and Trp residues.Communicated by Ramaswamy H. Sarma
研究领域:
生物化学
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药物化学
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分子生物学
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PubMed
MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Shuting Li,Binbin Liu,Ziqiao Chen,Xiao Ou,Haowei Rong,Ming Lu
Identification of a thermodynamically stable polymorph is an important step in the early stage of drug development. Ritonavir (RIT) is a well-known case where the most stable polymorph II emerged after being marketed, leading to a loss of $250 million. Herein, we report the findings that routine melt crystallization can reveal the late-appearing polymorph II of RIT at small supercooling, but the probability of nucleation is very low. The addition of 30–50% polyethylene glycol (PEG) promotes the crystallization of Form II as the only phase at low supercooling, making it easier to detect in polymorphism screening. During the course of our research, a new polymorph, denoted Form III, was unexpectedly discovered, crystallizing as the major phase from neat RIT melts. Single crystals of Form III were grown from melt microdroplets. Benefiting from the ability of synchrotron radiation to detect weak diffraction signals that cannot be accessible by a laboratory diffractometer, a reasonable structure of Form III was solved with slight disorder relative to thiazole groups (P1 space group and Z′ = 4). The thermodynamic stability ranking of the three true polymorphs is Form II > Form I > Form III, as opposed to the order of solubility. The capacity to efficiently reveal rich polymorphs, especially the kinetically hindered polymorph, and rapidly grow single crystals of a new phase for structure determination together highlights the necessity of incorporating melt crystallization into routine methods for pharmaceutical polymorphism screening.
研究领域:
药学
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材料科学
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晶体学
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PubMed
高影响因子
THERAPEUTIC DRUG MONITORING
·
2025
·
IF 2.4
Ma Zhiyuan,Bai Mengru,Shen Shuying,Zhou Junshan,Dong Rong,Zhang Jiangjun,Weng Yayun,Li Li,Li Yongchen,Liu Dan,Yan Wei,Lin Nengming,Xia Jianmei
Background: Nirmatrelvir/ritonavir is licensed for the treatment of mild-to-moderate coronavirus disease (COVID-19) in patients at an increased risk of progression to severe disease. However, data on the real-world plasma exposure to nirmatrelvir/ritonavir remain limited, particularly in Chinese patients. This study aimed to assess the nirmatrelvir/ritonavir trough concentration (C trough ) and identify its critical factors in hospitalized Chinese patients treated with nirmatrelvir/ritonavir 300 mg/100 mg twice daily over a 5-day course. Methods: A high-performance liquid chromatography-tandem mass spectrometry assay was developed and validated to measure the nirmatrelvir/ritonavir C trough . Correlation analyses were performed to identify the variables influencing nirmatrelvir/ritonavir C trough . Results: Among the 110 patients, 100% had plasma concentrations above the antiviral in vitro 90% effective concentration. The median C trough of nirmatrelvir was 4.55 mcg/mL (15.6× 90% effective concentration), ranging from 0.65 to 12.44 mcg/mL. Nirmatrelvir C trough in normal and mild renal impairment cohorts were comparable (4.09 ± 1.97 mcg/mL and 4.57 ± 2.21 mcg/mL) but significantly increased in the moderate renal impairment cohort (6.41 ± 2.31 mcg/mL). Sex, age, and obesity were not significantly associated with nirmatrelvir exposure. Conclusions: Nirmatrelvir C trough was high in Chinese patients with COVID-19, and therapeutic drug monitoring should not be routinely recommended, except in patients with renal impairment.
研究领域:
药理学
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传染病
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临床研究
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高影响因子
CARBOHYDRATE POLYMERS
·
2021
·
IF 9.381
Qingran Guan,Qisan Ma,Yanna Zhao,Xinxin Jiang,Huaizhen Zhang,Min Liu,Zhengping Wang,Jun Han
Amorphous solid dispersions (ASDs) are regarded as one of the most promising techniques for poorly-soluble active pharmaceutical ingredients (API). However, the thermodynamic instability of ASDs at supersaturated state makes them easy to recrystallize in aqueous media. In this study, ritonavir (RTV) was selected as a model drug for evaluating the solubility enhancement and recrystallization inhibition effect of various cellulose derivatives and the combinations of them with typical surfactants. Combination of HPMCAS-HF/SLS was filtrated for preparing ternary RTV solid dispersions (RTV SD) via solvent evaporation method. RTV SD exhibited enhanced dissolution manner, while the oral bioavailability of RTV SD was equivalent with the Reference Standard Norvir® but increased significantly compared to the ternary physical mixture. Thus, the ternary SD system might be promisingly employed as efficient drug delivery system for RTV, while the HPMCAS-HF/SLS combination could be recommended as effective excipient for fabricating steady solid dispersions loading poorly soluble API.
研究领域:
药剂学
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药物递送系统
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高影响因子
BMC Chemistry
·
2025
·Vol. 19
·期 1
·180
·
IF 4.6
Xiaoyu Yang,Wanling Lin,Yushang Zhao,Chaoyue Zhao,Fei Zhou,Dong Wang,Zhihong Yue,Lin Pei,Mei Jia,Bin Cao,Lin-Lin Cao,Hui Wang
“Xiannuoxin” (simnotrelvir/ritonavir) is a novel anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drug developed in China, which plays an antiviral role by inhibiting 3C-like protease (3CL pro ). At present, it has been put into clinical use, while a simple, accurate and sensitive detection method is urgently needed for the quantification of simnotrelvir/ritonavir in human serum and bronchoalveolar lavage fluid (BALF) to ensure safe and efficacious antiviral therapeutics. In this study, we developed a liquid chromatography tandem mass spectrophotometry (LC-MS/MS) method for the simultaneous determination of simnotrelvir, ritonavir and urea concentrations in human serum and BALF samples. Prior to LC-MS/MS analysis, a user-friendly, one-step pre-analytical process was conducted, followed by a rapid chromatographic run lasting 3 min. This was then succeeded by positive and negative electrospray ionization and detection using a triple quadrupole tandem mass spectrometer in the multiple reaction monitoring mode. Subsequently, the LC-MS/MS method underwent a comprehensive validation in aspects such as sensitivity (LoQs of 2.5 ng/mL, 0.1 ng/mL, and 1 μg/mL for simnotrelvir, ritonavir and urea), linearity, carryover, precision, trueness (recovery rates of simnotrelvir, ritonavir and urea were between 85 and 115%), matrix effect (within 85-115%) and stability (stable for 72 h at room temperature). The validation results demonstrated that this LC-MS/MS method was robust and reliable. Notably, we can use the urea dilution correction method to calculate the concentrations of simnotrelvir and ritonavir in epithelial lining fluid (ELF), which is of great significance for evaluating the effectiveness and safety of antiviral drug treatment.
研究领域:
药理学
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分析化学
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病毒学
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高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2023
·
IF 8.4
Xing Dai,Xiaohan Liu,Tao Xu,Chenjie Gu,Feiyu Zhao,Tao Jiang
Controlled aggregation of noble metal nanoparticles is incredibly crucial for obtaining reliable surface-enhanced Raman scattering (SERS) properties. Here, a rational agglomeration of large Ag nanowires (NWs) and small Ag nanocubes (NCs) was readily facilitated by simply utilizing the intrinsic viscosity of adhesive tape , leading to the generation of abundant electromagnetic “hotspots” around the numerous crossed nanotips and ultra-small nanogaps. After the molecular enrichment efficiency was further promoted by exploiting a hydrophilic-hydrophobic strategy, an ultra-low limit of detection as 8.8 × 10 −11 M was demonstrated for rhodamine 6 G. Benefiting from the high sensitivity of the SERS chip, its application in the determination of clinical sample containing mixed gefitinib and ritonavir was finally proved, facilitating impressive specificity and accuracy. Considering the simplicity and reliability, our strategy has great potentials to be applied in clinical blood drug identification and concentration monitoring.
研究领域:
纳米材料
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分析化学
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药物分析
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高影响因子
JOURNAL OF MEDICAL VIROLOGY
·
2026
·Vol. 98
·期 1
·e70777
·
IF 4.6
Lingzhu Zhao,Siduo Xu,Shouhan Yao,Zhiqiang Wei,Guohua Lou,Jinjin Qi,Haofeng Xu,Xueyu Wang,Zhenggang Yang,Min Zheng
The development of therapeutic strategies capable of achieving functional cure remains an unmet need in chronic hepatitis B management. Class A capsid assembly modulators (CAM-As) emerge as a promising treatment option. CAM-As not only directly disrupt the normal assembly of capsids, but some of which have also been reported to activate the innate immune response in animal models with unclear mechanisms. GLS4 is one of CAM-As with great potential. In this study, we investigate its capacity to activate immune response both in vitro and in vivo, as well as the underlying mechanisms involved. GLS4 activates the RIG-I-mediated interferon signaling pathway in both HBV-expressing hepatocellular carcinoma cell lines and HBV carrier mouse models, as indicated by RNA-seq. Besides, combination treatment with GLS4 and ritonavir elevates the frequencies of both peripheral blood IFNγ + NK cells and liver-resident IFNγ + CD8+ T cells in the pAAV/HBV1.2 hydrodynamic injection (HDI) model. In conclusion, our study reveals a previously unknown mechanism by which GLS4 activates the interferon signaling pathway in HBV-expressing hepatocytes. Furthermore, GLS4 partially restores innate and adaptive immunity in vivo. This signifies a potentially effective strategy for achieving a functional cure for HBV infection.
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高影响因子
PHARMAZIE
·
2021
·Vol. 76
·期 5
·195-201
·
IF 1.267
Dai Tianming,Wang Min,Wang Pengzhen,Dai Libing,Dai Renke,Meng Qingqi
The effects of eight oral anti-coronavirus drugs (lopinavir, ritonavir, chloroquine, darunavir, ribavirin, arbidol, favipiravir, oseltamivir) on the metabolism of four specific glycosides (polydatin, geniposide, quercitrin, glycyrrhizin) and on the activities of three major glycosidases
(β-glucosidase, α-rhamnosidase, β-glucuronidase) from gut microflora were explored in vitro and determined by LC-MS/MS. The metabolism of polydatin, geniposide, quercitrin and glycyrrhizin was significantly inhibited by one or several anti-coronavirus drugs of 100 μM
around 1 h and 4 h (P<0.05), among which darunavir could strongly reduce the production of genipin (70.6% reduction), quercitin (80.6% reduction) and glycyrrhetinic acid (37.9% reduction), which may cause a high risk of herb-drug interactions (HDI). Additionally, chloroquine reduced the
production of genipin and quercitin by more than 75% (P<0.05), whereas arbidol had no significant influence on the metabolism of polydatin, quercitrin and glycyrrhizin (P>0.05) so that its risk may be lower. The inhibition of darunavir on β-glucosidase was relatively strong (IC50
= 193±23 μM), and the inhibition became weaker on β-glucuronidase and α-rhamnosidase (IC50>500 μM). The consistency between gut microflora and glycosidase system indicated that the inhibition of darunavir on the activity of β-glucosidase and β-glucuronidase
may be the main reason for affecting the metabolism of geniposide, glycyrrhizin and polydatin in gut microflora. However, for the inhibition of darunavir and chloroquine on the metabolism of quercetrin, there was no correlation between gut microflora and α-rhamnosidase system. Assessing
the risk of HDI mediated by glycosidases in gut microflora may be conducive to the safety and efficacy of combining traditional herbal and Western medicine for the treatment of patients with Covid-19.
研究领域:
药理学
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微生物学
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生物化学
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高影响因子
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
·
2022
·
IF 3.318
Qing Shen,Huijuan Yang,Yunyan Li,Shiyan Li,Kang Chen,Honghai Wang,Haixing Wang,Jianfeng Ma
Yellow catfish ( Pelteobagrus fulvidraco ) is commonly contaminated by protease inhibitors because of the illegal use of antiviral drugs in aquaculture, so the determination of antiviral drugs is essential in food safety supervision. In this study, a novel sorbent, graphene and silica nanospheres composite (G/KCC-1), was synthesized for pipette-tip-based solid-phase extraction (PT-SPE) and purification of ritonavir, saquinavir, and indinavir in yellow catfish, followed by ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS) analysis. The wrinkly structure of G/KCC-1 with center-radial nanowrinkles enlarged the surface area and increased the capacity of absorbing the target analyte. With the proposed G/KCC-1 based PT-SPE UPLC-MS/MS method, the pH of sample solution, aspirating/dispensing cycles for extraction and elution were optimized to be 4.0, 25, and 10 respectively, and the eluting solvent was methanol/ammonia (95:5, v/v) with 0.02 M sodium chloride. This new method was further validated to be linear (correlation coefficient R 2 , 0.9993–0.9996), sensitive (limit of detection, LOD ≤ 0.8 ng mL −1 ), accurate (89.3–114.2%), and precise (relative standard deviation, RSD ≤ 6.23%). These results indicated that the proposed method is qualified in bioanalytical method validation and meets the requirements for detecting illegally used antiviral drugs in yellow catfish. The demonstrated G/KCC-1 based PT-SPE UPLC-MS/MS method is a potential analytical method in food and drug administration.
研究领域:
食品安全
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分析化学
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环境科学
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PubMed
高影响因子
危险品化学品经营许可证（带存储）