Journal of pharmaceutical sciences最新文献

{"title":"Improving Viral-based Gene Delivery to Mammalian Cells through Simple Co-Incubation with Transportan Peptide In Vitro.","authors":"Nianwu Wang, Xiangxiang Hu, Hong-Bo Pang","doi":"10.1016/j.xphs.2025.103920","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103920","url":null,"abstract":"<p><p>Viral-based platforms, most notably lentivirus and adeno-associated virus (AAV), are widely used to deliver genetic materials into cells for various purposes. One of the challenges in their applications is poor cellular uptake efficiency, especially in difficult-to-transfect cell lines and primary cells. Current mainstream approaches to overcome this problem often require specialized instruments or cause unwanted damages to cell viability. As an alternative, we have developed technologies to improve cellular uptake of macromolecular payloads by simply mixing them with cell-penetrating peptides (co-administration). Our previous studies have shown that co-administration with Transportan (TP), a 27-amino-acid amphiphilic cell-penetrating peptide, could enhance the cellular uptake of nano-sized particles. Here, we set out to investigate whether TP has similar effect on viral-based gene delivery. Using GFP-expressing AAVs and lentivirus, we validated the ability of TP co-administration to increase their transfection in a number of cell lines with limited cytotoxicity. Then, we used one difficult-to-transfect cell lines and two primary cells: a macrophage cell line (Raw264.7), bone marrow-derived macrophages (BMDMs), and retinal pigment epithelium (RPE) cells. Similar effects were seen as well. Overall, we present here an easy approach to improve the efficiency of viral-based gene delivery and transfection, which may benefit various clinical applications.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103920"},"PeriodicalIF":3.8,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144731904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IN MEMORY OF PROFESSOR WILLIAM I. HIGUCHI (1931-2024).","authors":"Bradley D Anderson, Daniel J A Crommelin, James N Herron","doi":"10.1016/j.xphs.2025.103926","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103926","url":null,"abstract":"","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103926"},"PeriodicalIF":3.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144731905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitrosamine formation in lidocaine active pharmaceutical ingredients and drug products","authors":"Andrea Kalauz ,&nbsp;Sarolta Boglárka Szabó ,&nbsp;Adrienn Tóth-Malik ,&nbsp;Zsolt Kelemen ,&nbsp;Viola Horváth ,&nbsp;Imre Kapui","doi":"10.1016/j.xphs.2025.103921","DOIUrl":"10.1016/j.xphs.2025.103921","url":null,"abstract":"<div><div><em>N</em>-nitrosamine compounds have long been known for their carcinogenic properties, but they came into the focus of the pharmaceutical industry in 2018 when <em>N</em>-nitrosodimethylamine was detected in the active ingredient Valsartan. Since then, there has been a growing literature on the formation of <em>N</em>-nitrosamines in pharmaceutical products. In our study Lidocaine semi-solid and liquid pharmaceutical formulations were tested with a limit of 26.5–53.0 ppb <em>N</em>-nitrosodiethylamine (NDEA) and 100–200 ppb <em>N</em>-nitroso-desethyl lidocaine. It was found that the lidocaine active ingredient degrades to the secondary amine precursors of these nitrosamines at elevated temperatures and that the formation of nitrosamines is feasible in the drug products where the excipients contain trace amounts of nitrite. Nitrite was detected at ppb level in the excipients of the formulations, while diethylamine and desethyl lidocaine were detected at ppm level during the degradation of the active substance. The nitrosamine formation was investigated at their respective production temperatures (ointment: 70 °C/3 h; injection: 125 °C/15 min), and the NDEA and <em>N</em>-nitroso-desethyl lidocaine contents were measured by GC–MS and HPLC-MS. The formation of nitrosamines in the drug formulations was found to be not only time, temperature, and nitrite dependent but was also different in the base and salt form of the API and in the studied semi-solid and liquid pharmaceutical formulations. These experiments have proven to be a useful tool for predicting nitrosamine formation in lidocaine pharmaceutical formulations and can be used as a basis for making recommendations to reduce nitrosamine concentrations.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 9","pages":"Article 103921"},"PeriodicalIF":3.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144731906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Liquid Chromatography-Tandem Mass Spectrometry Method for Simultaneous Detection of Three Anti-HIV Drugs Tenofovir, Lamivudine, and Dolutegravir in Plasma.","authors":"Luqi Duan, Shreshtha Dash, Masa Eguchi, Rachele Delle Fratte, Zachary R Stephen, Rodney Jy Ho","doi":"10.1016/j.xphs.2025.103927","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103927","url":null,"abstract":"<p><p>Currently, the world health organization (WHO) recommends a fixed-dose combination therapy called TLD, composed of tenofovir, lamivudine, and dolutegravir (TLD) for human immunodeficiency virus (HIV) treatment. About 23 of 39 million people living with HIV/AIDS (PLWHA) are on a daily TLD pill. In this study, we successfully developed a simple, efficient, and sensitive method to extract and enable the simultaneous quantification of tenofovir, lamivudine, and dolutegravir in rats, non-human primates (NHP), and human plasma samples. The 3 HIV drugs in small volume, 100 µL plasma were extracted after protein precipitation, and all the analytes were quantified using a novel liquid chromatography-tandem mass spectrometry. The assay provided analysis of all three analytes in rat, NHP, and human plasma. This method was used to evaluate time-plasma drug concentrations in two NHPs (Macaca nemestrina). The reported bioanalytical method demonstrated high sensitivity, reproducibility, and robustness for quantifying the 3 HIV drugs with efficiency. Lower limit of quantification (LLOQ) for tenofovir (TFV), lamivudine (3TC) and dolutegravir (DTG) were between 0.3 - 2.6 ng/mL equivalent to 30 - 260 pg in 100 µL of rats, NHPs, or human plasma samples. This assay may be adapted for evaluating drug concentrations across multiple species to support preclinical, clinical, and translational studies for developing long-acting products.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103927"},"PeriodicalIF":3.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144731907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preparation and Evaluation of Stable Amorphous Flurbiprofen Complexes Using Two Different Cyclodextrins.","authors":"Hiroto Ito, Fumitoshi Hirayama, Daisuke Iohara","doi":"10.1016/j.xphs.2025.103922","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103922","url":null,"abstract":"<p><p>This study aimed to develop stable amorphous inclusion complexes of flurbiprofen (FP, used as a model drug) with two different cyclodextrins (CDs). Specifically, three-component amorphous systems were developed by co-grinding crystalline FP/β-CD complexes with either α- or γ-CD. Among these, the FP/β-CD/γ-CD system exhibited superior physical stability under accelerated humid conditions, whereas rapid crystallization occurred in binary amorphous FP/β-CD system. Notably, even a small amount of γ-CD (β-CD:γ-CD = 1:0.1) was sufficient to inhibit the crystallization of FP/β-CD complex, while α-CD and polyvinylpyrrolidone (PVP) were less effective. This stabilizing effect is likely attributed to the inherently low crystallization tendency of γ-CD. Crystallization inhibition was also observed in in vitro dissolution studies, where the amorphous FP/β-CD/γ-CD maintained a supersaturated state for a prolonged period compared to the amorphous FP/β-CD complex. In vivo absorption studies in rats revealed that the amorphous FP/β-CD/γ-CD significantly enhanced the oral absorption of FP, with 2.4-fold and 2.1-fold increases in C_max and AUC, respectively, compared to FP alone. Even a small amount of γ-CD was sufficient to influence the absorption kinetics of FP. These findings demonstrate the utility of γ-CD as an effective stabilizer for amorphous CD-based complexes and highlight the potential of combining two different CDs to improve both the physical stability and oral bioavailability of poorly water-soluble drugs capable of forming inclusion complexes.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103922"},"PeriodicalIF":3.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guiding and evaluating molecular modifications of aspirin for preferential COX-2 inhibition using machine learning","authors":"Qi Yang ,&nbsp;Guiyuan Pang ,&nbsp;Meiyu Huang ,&nbsp;Wenting Hu ,&nbsp;Chenglin Zhou ,&nbsp;Bin Wu ,&nbsp;Hongsheng Liu ,&nbsp;Lili Fan","doi":"10.1016/j.xphs.2025.103924","DOIUrl":"10.1016/j.xphs.2025.103924","url":null,"abstract":"<div><div>Aspirin is a classic non-steroidal anti-inflammatory drug (NSAID) that unfortunately carries an inherent risk of gastrointestinal side effects. This is due to its simultaneous action on both COX-1 and COX-2 enzymes, where the former is associated with adverse reactions and the latter with therapeutic effects. This study begins by constructing a compound database that acts on COX-1 and COX-2, followed by an analysis of the ligand-target binding differences from a macroscopic to microscopic perspective, using 12 types of ADME properties and the X-ray diffraction structures of aspirin-COX-1/2 complexes. Subsequently, we replaced the features with descriptors that describe the molecular topological structure to build predictive models for COX-1/2. Based on the binding differences, we used Chemdraw for real-time molecular modification of aspirin. Our findings suggest that increasing the molecular weight, topological polar surface area (TPSA), and partition coefficient (LogP) of the compound, while also making it more elongated, can enhance the preferential inhibition of COX-2 by aspirin. Therefore, we have modified the original aspirin by introducing carbon chains and hydroxyl groups. We designed 10 structurally modified versions of aspirin and used machine learning and molecular docking to verify their effects on the activity changes of two COX enzymes. The predictive results indicate that the modified aspirin has a stronger inhibitory effect on COX-2 and a weaker effect on COX-1. This provides a reference for the development of COX-2 selective inhibitors based on aspirin and also offers an innovative approach for computer-aided design to eliminate adverse drug reactions.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 9","pages":"Article 103924"},"PeriodicalIF":3.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular simulation of size-dependent crystal stability and water solubility of carbamazepine polymorphs: Guides to tailor drug formulation","authors":"Moritz Macht,&nbsp;Dirk Zahn","doi":"10.1016/j.xphs.2025.103923","DOIUrl":"10.1016/j.xphs.2025.103923","url":null,"abstract":"<div><div>While molecular simulations are by now well-established for predicting <em>bulk</em> crystal structures and their lattice energy, here we present an approach to predicting the stability of <em>finite</em> precipitates in different solvent scenarios. Mimicking carbamazepine formulation from apolar solution, we outline size-dependent energy profiles for crystallites of polymorphs I-III and amorphous particles, respectively. In particular, crystal nucleation barriers are computed as functions of supersaturation and contrasted to the size-dependent stability profiles of the competing polymorphs. On this basis, we argue that carbamazepine follows a two-step nucleation process starting from amorphous precipitates of spherical shape. These indeed reflect the thermodynamically preferred state of aggregates counting up to ∼100 carbamazepine molecules. In turn, larger aggregates experience thermodynamic driving to self-organization into crystalline arrangements. Crystallites of up to ∼1000 molecules showed an energetic preference of form II, whilst thermodynamic stability of form III applies to larger crystals. Tailoring critical nucleus size and energy from different degrees of supersaturation, our models suggest routes to promote nucleation of carbamazepine form II from apolar solution. In turn, immersing our series of crystallite/precipitate models in water, we re-evaluate size-dependent polymorph stability – and predict relative solubility in water. On this basis, boosts in relative solubility by 100 and 200 % are suggested for 50 and 25 nm scale spatial confinements (e.g. solid dispersion in polymer solutions), respectively.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 9","pages":"Article 103923"},"PeriodicalIF":3.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative population pharmacokinetic modeling of two BCMA-targeted and one CD19-targeted CAR-T therapies using full Bayesian inference with a student’s t-based M3 censoring approach for robust handling of outliers and BLQ data","authors":"Yiming Cheng,&nbsp;Hongxiang Hu,&nbsp;Ken Ogasawara,&nbsp;Yan Li","doi":"10.1016/j.xphs.2025.103925","DOIUrl":"10.1016/j.xphs.2025.103925","url":null,"abstract":"<div><h3>Background</h3><div>Chimeric antigen receptor (CAR) T-cell therapies represent a novel class of adoptive immunotherapies characterized by dynamic in vivo expansion, contraction, and long-term persistence. These unique kinetic properties distinguish CAR-T therapies from traditional small-molecule and biologic agents and pose significant challenges for pharmacometric modeling, particularly due to high interindividual variability, frequent outliers, and a large proportion of concentrations below the lower limit of quantification (BLQ).</div></div><div><h3>Objective</h3><div>In this study, we developed and applied an integrated Bayesian population pharmacokinetic (PopPK) modeling framework to evaluate and compare the cellular kinetics of three CAR-T therapies: liso-cel (CD19-targeted), and ide-cel and orva-cel (both BCMA-targeted).</div></div><div><h3>Method</h3><div>Four modeling strategies were examined, combining two residual error structures (normal vs. Student's t) with two censoring methods (M1 vs. M3). Full Bayesian inference was implemented using Markov Chain Monte Carlo (MCMC) methods in NONMEM®.</div></div><div><h3>Results and Conclusion</h3><div>Our results demonstrate that M3 censoring is essential for preserving information from BLQ data and that the Student’s t-distribution offers superior robustness to outlier contamination compared to conventional normal error models. The combined use of M3 censoring and Student’s t residuals yielded the most accurate and stable parameter estimates across all phases of the CAR-T kinetic profiles. Additionally, comparative modeling under a unified Bayesian platform revealed both shared and target-specific kinetic features among the three therapies, with BCMA-targeted products demonstrating faster expansion kinetics than the CD19-targeted product. Our findings support routine use of the Student’s t–M3 configuration under a Bayesian framework for CAR-T PopPK modeling.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 9","pages":"Article 103925"},"PeriodicalIF":3.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RISK BASED QUALIFICATION OF NON-MUTAGENIC IMPURITIES.","authors":"Naseem A Charoo, Syed Untoo, Mustafa Eltigani","doi":"10.1016/j.xphs.2025.103918","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103918","url":null,"abstract":"<p><p>The current approach to qualify NMIs (non-mutagenic impurities) exceeding the qualification threshold is to perform genotoxic, general toxicity and other specific studies in animals. Furthermore, these studies are rarely conducted on clean impurity samples. As a result, any toxicity identified in safety tests cannot be unambiguously attributed to the impurity alone, and hence the lack of impurity-specific safety data prevents results from being extrapolated to conditions such as increased impurity levels in the same drug product during shelf life. That is, animal safety tests would often need to be repeated in such cases. Moreover, NMIs are examined in animals at such a low level (despite being above the qualification threshold) that it is unlikely to detect a safety signal in these investigations, raising concerns about the design of these studies. Therefore, the current approach for qualification of impurities contradicts the 3Rs (Replacement, Reduction and Refinement) testing methodologies mandated by Directive 2010/63/EU on the protection of animals for scientific purposes, which applies to the regulatory testing of pharmaceutical compounds. We examine the integrated risk assessment approach for qualifying NMIs using non-animal methods while considering several variables that could influence the risk assessment process. We also discuss the benefits and present technological constraints in applying these alternate methodologies. The appropriately designed risk-based approach will eliminate unnecessary animal testing for qualification of impurities with low level of concern.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103918"},"PeriodicalIF":3.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically based pharmacokinetic coupled model of zonisamide to predict the exposure and dose exploration in maternal, fetal, and neonatal populations during pregnancy and postpartum","authors":"Yiming Li ,&nbsp;Zhiwei Liu ,&nbsp;Youjun Chen ,&nbsp;Wenhui Wang ,&nbsp;Tao Chen ,&nbsp;Saiya Li ,&nbsp;Yating Wu ,&nbsp;Haitang Xie","doi":"10.1016/j.xphs.2025.103912","DOIUrl":"10.1016/j.xphs.2025.103912","url":null,"abstract":"<div><div>Zonisamide (ZNS) is a second-generation antiepileptic drug. During pregnancy, ZNS clearance increases, leading to a decrease in drug concentration. Additionally, ZNS can be transferred to the fetus and neonate through the mother and breast milk, potentially posing risks to the fetus and neonate. Due to ethical constraints, clinical trials are difficult to conduct and data are limited. This study used PK-Sim® and MoBi® to develop a physiologically based pharmacokinetic (PBPK) coupled model predicting the exposure of ZNS in maternal, fetal, and neonatal populations during pregnancy and postpartum. The model was evaluated with clinical pharmacokinetic (PK) data, and dosage explorations were conducted. In the developed non-pregnant, pregnant, fetal, postpartum, and neonatal models, approximately 98.56 %, 95.24 %, and 100 % (fetal/postpartum/neonatal) of the observed concentrations fell within the 2-fold error range, respectively. For the first, second, and third trimesters, dose adjustments to 0.92, 1.17, and 1.5 times the baseline (the recommended maintenance dose of 300 mg QD) are the minimum effective doses (MED, exposure levels close to therapeutic drug monitoring minimum effective range of 10 µg/ml), while adjustments to 1.17, 1.5, and 1.92 times the baseline are normalized doses compared to baseline. Under the third trimester dosing regimen, postpartum dose adjustment to 1.17 times the baseline is the MED, while 1.58 times the baseline is normalized dose. Relative infant dose (RID) of neonates is 30–33 %. Immediate breastfeeding is not recommended for neonates postpartum. The ZNS PBPK coupled model was successfully developed, studying exposure in special populations during pregnancy and postpartum, and optimizing dosing regimens.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 9","pages":"Article 103912"},"PeriodicalIF":3.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}