Journal of pharmaceutical sciences最新文献

{"title":"Single-cell transcriptional analysis of murine mesenteric lymph nodes following oral lyso-phosphatidylserine nanoparticle administration reveals cellular heterogeneity in tolerance features","authors":"Vincent Chak ,&nbsp;Edwin J. Ovalle ,&nbsp;Jonathan Bard ,&nbsp;Elizabeth A. Wohlfert ,&nbsp;Jason G. Kay ,&nbsp;Sathy Balu-Iyer","doi":"10.1016/j.xphs.2025.103919","DOIUrl":"10.1016/j.xphs.2025.103919","url":null,"abstract":"<div><div>Unwanted immune responses against self-proteins or exogenous therapeutic proteins can trigger autoimmune diseases or compromise the safety and efficacy of life-saving therapeutic biologics. To address this issue, we utilized the ability of phosphatidylserine (PS) to convert an immunogen into a tolerogen and rationally developed a LysoPS-containing tolerogenic nanoparticle platform to prevent and mitigate unwanted immune responses. We demonstrated that prophylactic oral treatment with LysoPS-containing proteins prevents unwanted immune responses by inducing tolerance. However, the biological processes and cellular communication involved in LysoPS-mediated oral tolerance remain unclear. Therefore, this study aimed to characterize immune cell interactions and the potential tolerogenic mechanism in mice treated with LysoPS using Single-cell RNA sequencing (scRNA-seq). Our data showed that LysoPS nanoparticles increased the expression of RNAs associated with tolerogenic features in B cells, T cells, and NK cells, primarily through TGF-β responses.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 9","pages":"Article 103919"},"PeriodicalIF":3.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718119","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":"A pharmaceutical industry survey results on exploring polysorbate alternatives in biological drug products: poloxamer and other surfactants","authors":"Seema Thakral ,&nbsp;Christine Levesque ,&nbsp;Kellye Cung ,&nbsp;Lin Li ,&nbsp;Ryan E Mould ,&nbsp;Ehab Moussa ,&nbsp;Jason Pinkstaff ,&nbsp;George Crotts ,&nbsp;Manceva Slobodanka ,&nbsp;Yogita Krishnamachari","doi":"10.1016/j.xphs.2025.103917","DOIUrl":"10.1016/j.xphs.2025.103917","url":null,"abstract":"<div><div>Polysorbates (specifically PS20 and PS80) are the most popular surfactants used in biological drug products because of their excellent stabilizing properties and well-recognized safety profile for parenteral administration. Due to concerns regarding compositional variability and stability of polysorbates, alternative surfactants are also being explored to stabilize biologics. Poloxamers are identified as potential surfactants and poloxamer 188 is already a constituent of 23 approved biological drug products. However, industry-wide position and understanding on use of alternative surfactants for biologics is not clearly reflected in literature. A confidential survey was conducted by IQ Consortium to understand (i) industry’s experience on the use of poloxamers for different biological modalities, (ii) the advantages and barriers/considerations associated with the use of poloxamers in biological products in comparison with polysorbates (iii) industry’s opinion on use of novel surfactants beyond polysorbates/poloxamer and use of multiple surfactants. The present report consolidates survey responses from 14 IQ Consortium member companies and the associated discussion. The availability of polysorbate alternatives in the formulator’s tool kit would be beneficial in the near future, and the report provides relevant information for this tool kit.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 9","pages":"Article 103917"},"PeriodicalIF":3.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707903","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":"Structural changes of cinnarizine-stabilizer core-shell nano- and micro-suspensions following freeze- and spray-drying determined from dynamic nuclear polarization enhanced NMR.","authors":"Saumya Badoni, Ran Wei, Maria Adobes Vidal, Jacob B Holmes, André Bitterlich, Jasmin Muminovic, Mauro Serratoni, Arnaud Grandeury, Lyndon Emsley","doi":"10.1016/j.xphs.2025.103915","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103915","url":null,"abstract":"<p><p>Developing potent drug molecules that are also highly soluble in aqueous media puts strong constraints on molecular design. As a result, there is intense interest today in developing drug formulation strategies that increase solubility. Specifically, nanosizing involves the reduction of the particle size of the active pharmaceutical ingredient (API) to the sub-micron range, which increases the surface area and dissolution rate. This strategy requires the addition of stabilizers, generally selected through extensive experimental screening, to maintain the desired physical properties over time. To better understand stabilization mechanisms and to develop better future formulations, atomic-level characterization of the particle structures is required in terms of both the size and spatial distribution of the components and the interactions. However, methods that can simultaneously provide this information are scarce. Here, using cinnarizine as a model for nanosuspensions, we show that by using DNP-enhanced NMR we can (i) detect and assign the API and the stabilizers present in formulations; (ii) observe atomic-level API-stabilizer interactions at natural isotopic abundance using two-dimensional ¹H-¹³C correlation NMR experiments; and (iii) determine the domain sizes and the hierarchical structure of the API-stabilizer particles on the nano-meter length scale, based on polarization build-up curves and steady-state enhancements. We then use this approach to evaluate how freeze-drying and spray drying processes, generally used to isolate the material in the solid state, impact the particle structure. More broadly, the results confirm the applicability of DNP-enhanced NMR methods to characterize pharmaceutical suspensions or slurries, and to follow changes upon further processing.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103915"},"PeriodicalIF":3.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707906","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":"Enhancing pharmacometric modeling with full Bayesian inference and Student’s t-Based M3 Censoring: A simulated population PK study on robust handling of outliers and censored data","authors":"Yiming Cheng,&nbsp;Yan Li","doi":"10.1016/j.xphs.2025.103916","DOIUrl":"10.1016/j.xphs.2025.103916","url":null,"abstract":"<div><div>Pharmacometric modeling and simulation, with population pharmacokinetic (PopPK) modeling as a key component, play a crucial role in characterizing drug disposition and variability, supporting dose optimization and regulatory decision-making. Traditional maximum likelihood estimation (MLE) methods, although efficient, are sensitive to outliers, particularly when datasets contain observations below the limit of quantification (BLQ). As clinical datasets become increasingly complex, more robust modeling approaches are needed. In this study, a simulation-based evaluation was conducted to compare four modeling strategies combining different residual error structures (normal vs. Student’s t) and censoring methods (M1 vs. M3). Two-compartment pharmacokinetic profiles were simulated for fifty subjects, incorporating varying degrees of outlier contamination and BLQ data. Full Bayesian inference using Markov Chain Monte Carlo (MCMC) methods was employed to estimate posterior distributions of PK parameters at both the population and individual levels. Notably, the combination of Student’s t-distributed residuals with M3 censoring (Student’s t_M3) consistently produced the most accurate and precise parameter estimates across all simulation scenarios, even under extreme outlier contamination and substantial BLQ presence. The combination of Student’s t-distributed residuals with M3 censoring within a Bayesian framework offers a robust and resilient strategy for PopPK modeling, effectively addressing both outlier contamination and data censoring challenges. These findings support the broader adoption of robust Bayesian modeling techniques in pharmacometric practice, particularly for complex and irregular clinical datasets such as cell and gene therapies.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 9","pages":"Article 103916"},"PeriodicalIF":3.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707905","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":"Development roadmap for subcutaneous delivery of high dose biologics - high concentration formulation, analytical comparability and patient preference considerations for large volume devices.","authors":"Indrajit Ghosh, Daniel Miranda, Tanmay A Kulkarni, Suyash Deodhar, Srinivas Tummala, Dilbir Bindra","doi":"10.1016/j.xphs.2025.103914","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103914","url":null,"abstract":"<p><p>High dose biologic drug products (DPs) have become a common trend for the treatment of chronic diseases across a wide range of therapeutic areas. While the expectation is to deliver these DPs via subcutaneous (SC) self-administration due to patient and healthcare provider preference, there are unique challenges that make the product development highly complex. Critical aspects that need to be considered while designing the development roadmap include high concentration formulation development, drug-device combination product design to deliver large volumes, assessment of pharmacokinetic (PK) bridging risk, user preferences, patient tolerability, etc. Such challenges can be overcome by robust formulation development strategies, analytical characterization to ensure product comparability, and well-designed patient preference and human factors studies to identify appropriate patient friendly delivery device technology. This review discusses novel formulation and processing technologies associated with patient tolerability and in-vitro/-vivo studies to minimize the risk of clinical bridging. The review also presents multiple case studies to understand user and patient preferences for defining the quality target product profile (QTPP) for selecting an appropriate device approach, dosing frequency, and overall development road map from first-in-human (FIH) to product launch. The opinions summarized in this review can be used as guidance for the development of high-dose biologic DPs.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103914"},"PeriodicalIF":3.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707904","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":"Scale-up and cGMP manufacturing of next-generation vaccine adjuvant saponin/MPLA nanoParticles (SMNP)","authors":"Sammaiah Pallerla ,&nbsp;Ivan S. Pires ,&nbsp;Mariane B. Melo ,&nbsp;DongSoo Yun ,&nbsp;Andreas Wagner ,&nbsp;Magdolna Budai ,&nbsp;Daniel Kumar ,&nbsp;Dietmar Katinger ,&nbsp;Eddy Sayeed ,&nbsp;Angela Lombardo ,&nbsp;Darrell J. Irvine","doi":"10.1016/j.xphs.2025.103913","DOIUrl":"10.1016/j.xphs.2025.103913","url":null,"abstract":"<div><div>Saponin/MPLA Nanoparticles (SMNP) is a novel vaccine adjuvant that exhibited excellent safety and potency in a range of preclinical models. Successful scale-up manufacturing under current Good Manufacturing Practices (cGMP) is vital for advancing the clinical development of this promising new adjuvant. Here we report studies transitioning from small-scale formulation to the production of clinical trial material (CTM) in accordance with cGMP. By optimizing the process, a 100-fold scale increase was achieved through closed-system dilution and diafiltration, ensuring both sterility and process efficiency. Analytical characterization confirmed that the SMNP produced under cGMP conditions maintained consistent particle size, morphology, and polydispersity compared to preclinical batches. Hemolysis testing validated safety by assessing QS-21-related activity. Stability studies, conducted in accordance with ICH (International Council for Harmonisation) guidelines, demonstrated both chemical and colloidal integrity during prolonged refrigeration, while also identifying potential degradation risks at frozen or elevated temperatures. This research emphasizes critical factors for ensuring reproducibility, managing raw material variability, and developing scalable, aseptic processes. These results provide a foundation for advancing SMNP-based adjuvants into early-phase clinical trials and subsequent commercial production.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 9","pages":"Article 103913"},"PeriodicalIF":3.7,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682758","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":"Dissolution improvement and solubility enhancement of two tumor-associated enzyme inhibitors via the formation of eutectic mixtures","authors":"Chenchen Wang,&nbsp;Xingyin Wang,&nbsp;Chaoyang Yin,&nbsp;Lanting Gao,&nbsp;Jie He,&nbsp;Guisen Zhang,&nbsp;Jian Zhang,&nbsp;Chao Hao,&nbsp;Tao Zhuang","doi":"10.1016/j.xphs.2025.103909","DOIUrl":"10.1016/j.xphs.2025.103909","url":null,"abstract":"<div><div>Eutectic mixtures have emerged as an effective means to improve the physicochemical properties of drugs for clinical applications. In this study, two tumor-associated enzyme inhibitors based eutectic mixtures, i.e., Imatinib (IMA) with Adenine Phosphate (AdPh) (IMA-AdPh EUT) and Olaparib (OLA) with AdPh (OLA-AdPh EUT), were designed and prepared via liquid-assisted grinding method. The binary phase diagrams, constructed from differential scanning calorimetry (DSC) results, demonstrated that the optimal molar ratios of IMA in IMA-AdPh EUT and OLA in OLA-AdPh EUT were 1:1 and 3:2, respectively. The eutectic mixtures were further verified by powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR). Equilibrium solubility studies and powder dissolution tests demonstrated that IMA or OLA in either eutectic mixture exhibited enhanced solubility and superior dissolution performance comparing to as single component or in the physical mixture. Consequently, IMA-AdPh EUT and OLA-AdPh EUT may provide a promising formulation strategy to improve solubility and dissolution performance of tumor-associated enzyme inhibitors.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 9","pages":"Article 103909"},"PeriodicalIF":3.7,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682757","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":"Assessing potential of precipitation inhibitors to prevent precipitation during dispersion and digestion of lipid-based formulations using in-line analytics.","authors":"Lotte Ejskjær, Kristof Kimpe, Hugo Bohets, Jan Bevernage, Brendan T Griffin, Patrick J O'Dwyer","doi":"10.1016/j.xphs.2025.103911","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103911","url":null,"abstract":"<p><p>A key risk to bio-enabling performance is that transient supersaturation is not maintained for a sufficient period during intestinal transit to ensure drug absorption. The incorporation of polymeric precipitation inhibitors offer promise to mitigate the risk precipitation. Lipid-based formulations (LBFs) are a bio-enabling formulation approach where there is a risk of drug precipitation upon dispersion in intestinal fluids and/or digestion of the formulation. This study evaluated the potential of a range of precipitation inhibitors (HPMC E5, HPMC AS LG, HPMC AS MG, PVP 30, PVP VA64, Poloxamer 188, Poloxamer 407, and Soluplus®) to maintain supersaturation of celecoxib and fenofibrate loaded Type IIIA and Type IV LBFs. In addition, the impact of incorporating the precipitation inhibitor within the LBF versus concomitant addition to the biorelevant media was also explored. Real-time precipitation upon dispersion and digestion of the formulations was measured using in-situ UV fibre optic probes. The addition of a precipitation inhibitor showed promising effects for maintaining supersaturation after dispersion of the Type IV LBF in biorelevant media at low drug loading i.e. 40% drug loading. However, at a higher drug loading of 80%, no inhibition of precipitation was evident. Certain precipitation inhibitors were effective only when pre-dissolved in FaSSIF, whereas others showed effectiveness only when incorporated directly within the LBF. For Type IIIa LBFs which undergo digestion, precipitation inhibitors were generally not effective at maintaining supersaturation using a dispersion-digestion setup. Results from standard solvent shift screening were useful for predicting the effectiveness of precipitation inhibitors in Type IV LBFs, but not in Type IIIa LBFs. Observations using in-line analytics suggest that in the majority of cases precipitation inhibitor offered limited capacity to improve the apparent drug concentration during dispersion and digestion of LBFs.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103911"},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675095","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":"Immersion probe Raman for pharmaceutical suspension testing in the manufacturing plant and laboratory: Flow considerations for quantitative applications","authors":"Gregory Doddridge,&nbsp;Jacquelyn North,&nbsp;Sankaran Anantharaman,&nbsp;Daniel A. Young,&nbsp;Zachary S. Breitbach,&nbsp;Yemin Liu","doi":"10.1016/j.xphs.2025.103910","DOIUrl":"10.1016/j.xphs.2025.103910","url":null,"abstract":"<div><div>Traditional analysis of pharmaceutical suspensions by liquid chromatography requires time, manual sample preparation, and solvents. In this work, we explored an alternative procedure for quantifying the active pharmaceutical ingredient (API) of liquid samples using a non-destructive method, back scattering Raman with an immersion probe, with no additional sample preparation in lab-based off-line and plant-based in-line settings. Coupling the Raman signal to compact high-performance liquid chromatography (HPLC) measurements was a useful way to monitor the suspension transfer and filling process during investigational studies. That process entailed a flowing, rather than static, suspension. Therefore, understanding the impact of a flowing suspension on the Raman signal of the API for quantitation was critical. To help address the lab-based and production-scale applications, we developed a theoretical framework for measuring flowing suspensions by Raman, created chemometric models for lab use, and experimentally investigated the impact of flowing versus static suspensions on back scatter Raman measurements.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 9","pages":"Article 103910"},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675042","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":"Fast-dissolving electrospun cellulose fiber-based matrices as modular oral dosage forms.","authors":"Mario A Cano-Vega, Héctor Lozano-Perez, Rodolfo Pinal, Meng Deng","doi":"10.1016/j.xphs.2025.103908","DOIUrl":"10.1016/j.xphs.2025.103908","url":null,"abstract":"<p><p>Fast-dissolving oral dosage forms are attractive systems for controlled delivery of poorly water-soluble drugs. This study introduces a novel modular oral dosage platform composed of fast-dissolving drug-loaded electrospun hydroxypropyl methylcellulose (HPMC)/ polyethylene oxide (PEO) fibers. Electrospun fibers were fabricated and optimized using two solvent systems, namely dichloromethane/ethanol and water/ethanol, and loaded with model compounds exhibiting different solubility profiles. Characterization by scanning electron microscopy, differential scanning calorimetry, and X-ray diffraction confirmed the formation of drug-loaded HPMC/PEO-based fibers with drug amorphization. Dissolution studies of as-fabricated fibers demonstrated rapid disintegration and efficient drug release from the fibers. An optimized fabrication process was further developed to form a proof-of-concept integrated bilayer module by enabling the precise deposition of drug-loaded electrospun fibers onto a solvent-cast non-drug-loaded HPMC-based film. The fibrous layer maintained its bead-free morphology, reduced crystallinity, and fast dissolution properties post-integration. Our findings highlight the potential of drug-loaded electrospun HPMC/PEO fibers as an advanced drug delivery system, supporting the development of next-generation modular oral dosage forms for controlled and customizable drug delivery.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103908"},"PeriodicalIF":3.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675041","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}