Pharmaceutical Research最新文献

{"title":"Phytochemicals and their Nanoformulations for Overcoming Drug Resistance in Head and Neck Squamous Cell Carcinoma.","authors":"Zhai Pingping, Chen Nan, Tang Yong","doi":"10.1007/s11095-025-03836-0","DOIUrl":"10.1007/s11095-025-03836-0","url":null,"abstract":"<p><strong>Background: </strong>Drug resistance remains a significant challenge in the treatment of head and neck squamous cell carcinoma (HNSCC), leading to therapeutic failure and poor patient prognosis. Numerous mechanisms, including drug efflux pumps, altered tumor microenvironment (TME), and dysregulated cell death pathways, contribute to the development of resistance against conventional chemotherapeutic agents, immunotherapy, and targeted therapies. As resistance to traditional treatments continues to emerge, there is an urgent need for innovative therapeutic strategies to overcome these challenges. Phytochemicals are naturally occurring bioactive compounds and have demonstrated remarkable potential in targeting multiple resistance mechanisms simultaneously.</p><p><strong>Method: </strong>This review comprehensively overviews the current understanding of drug resistance mechanisms in HNSCC and explores innovative strategies utilizing phytochemicals and their nanoformulations to overcome these resistance mechanisms, with a particular focus on recent developments and future perspectives in this field.</p><p><strong>Results and discussion: </strong>Phytochemicals with anticancer properties include a wide range of herbal-derived molecules such as flavonoids, stilbenes, curcuminoids, alkaloids, traditional Chinese medicine, and others. These compounds can modulate ATP-binding cassette transporters, reverse epithelial-to-mesenchymal transition (EMT), target cancer stem cells (CSCs), and regulate various signaling pathways involved in drug resistance. The integration of phytochemicals into advanced nanoformulation systems has also shown a remarkable improvement in enhancing their bioavailability, stability, and targeted delivery to the TME, potentially improving their therapeutic efficacy. Furthermore, the combination of phytochemicals with conventional chemotherapeutic agents, targeted molecular therapy, and immune checkpoint inhibitors (ICIs) has exhibited synergistic effects, offering a promising approach to restoring drug sensitivity in resistant HNSCC cells.</p><p><strong>Conclusion: </strong>Phytochemicals and their nanoformulations may improve response of HNSCC to therapy by alleviating drug resistance.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"429-449"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542977","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 of a Melting Point Depression Method to Measure the Solubility of a Small-Molecule Drug in Poly-Lactic-co-Glycolic Acid (PLGA).","authors":"Coleman Johnson, Feng Zhang","doi":"10.1007/s11095-025-03840-4","DOIUrl":"10.1007/s11095-025-03840-4","url":null,"abstract":"<p><strong>Purpose: </strong>The solubility of a crystalline drug in a polymer is commonly determined by measuring melting point depression with differential scanning calorimetry (DSC). The accuracy of this measurement depends on rapid dissolution of the drug into the molten polymer during the DSC heating scan. A preferred method of accelerating this dissolution process is to preblend the drug and polymer by cryo-milling. However, cryo-milling may be unsuitable for water-sensitive drugs or polymers such as poly(lactic-co-glycolic acid) (PLGA). The purpose of this study was to develop a PLGA-specific melting point depression method that did not require a cryo-milling operation.</p><p><strong>Methods: </strong>A three-step DSC method was used to measure the solubility of a small-molecule drug, voriconazole, in amorphous PLGA (Resomer ® RG 502H). First, drug/PLGA powder mixtures of multiple drug loadings were melted and rapidly cooled to form glassy solid solutions. Second, these solid solutions were heated above their T_g until the drug crystallized. Third, these crystallized samples were slowly heated to measure melting point depression (i.e., solubility temperatures).</p><p><strong>Results: </strong>The crystallization procedure generated the desired drug polymorph and likely generated small, well-mixed crystalline drug particles, as the drug dissolved rapidly into the molten polymer during melting point depression scans. Drug/PLGA solubility temperatures were determined with confidence between 40 - 100% drug loading. The solubility curve was extrapolated to lower drug loadings using the Flory-Huggins model.</p><p><strong>Conclusion: </strong>This technique can assist product development of high-drug-loaded PLGA products, particularly those manufactured by melt extrusion.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"529-543"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573147","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":"Editorial Expression of Concern: Nano-Targeted Delivery of Toremifene, an Estrogen Receptor-α Blocker in Prostate Cancer.","authors":"Waseem Hariri, Thangirala Sudha, Dhruba J Bharali, Huadong Cui, Shaker A Mousa","doi":"10.1007/s11095-025-03847-x","DOIUrl":"10.1007/s11095-025-03847-x","url":null,"abstract":"","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"545"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634454","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":"Combined Treatment of Metformin and Resveratrol Promotes Myogenesis Through Increased Irisin Release in C2C12 Cells.","authors":"Eun Ji Seong, Yejin Kim, Zheng-Yuan Su, Hee-Taik Kang, Jong Hun Lee","doi":"10.1007/s11095-025-03834-2","DOIUrl":"10.1007/s11095-025-03834-2","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to investigate the additive effects of a combination of metformin and resveratrol on irisin expression in C2C12 cells.</p><p><strong>Methods: </strong>The study involved treating C2C12 cells with metformin and resveratrol, either alone or in combination, and analyzing their effects on myogenesis and irisin release. The activation of signaling pathways, including AMPK/SIRT1/PGC1α, as well as the relative mRNA and protein expression levels of MyoD, myogenin, and Myh were also assessed.</p><p><strong>Results: </strong>Combination treatment with metformin and resveratrol significantly increased MyoD, myogenin, Myh, and FNDC5 expression compared with the group treated with metformin alone. The increase in irisin production was associated with phosphorylation of AMPK and upregulation of PGC-1α and SIRT1, indicating activation of the AMPK/SIRT1/PGC-1α pathway. The mRNA and protein expression levels of MyoD, myogenin, and Myh were also significantly higher in the combination treatment group compared to the metformin alone group.</p><p><strong>Conclusion: </strong>The combination of metformin and resveratrol effectively increased irisin release through the AMPK/Sirt1/PGC-1α pathway, suggesting that this combination treatment could enhance myogenesis.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"419-428"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516316","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":"Clinical Evaluation of the Temperature Dependence of Subcutaneous Injection Experience in Healthy Volunteers.","authors":"Galen Shi, Hannie Shih, Jonathan Parker, Hemant Patel, Rhea Sirkar, Vivek Sree, David Collins","doi":"10.1007/s11095-025-03841-3","DOIUrl":"10.1007/s11095-025-03841-3","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the clinical effect of the warming step for subcutaneous (SC) injection on injection site pain (ISP).</p><p><strong>Methods: </strong>A single center, randomized, partially blinded, crossover study in 44 healthy participants was conducted. Participants self-injected with autoinjectors (1 mL) with either high pain (citrate/sodium chloride (NaCl)) or low pain (mannitol) formulations at refrigerated temperature or warmed to room temperature (RT) according to the instructions for use (IFU). The ISP was recorded using visual analog scale (VAS) and injection site reactions (ISRs) were captured using severity scores.</p><p><strong>Results: </strong>The average VAS scores were clinically different between high pain and low pain formulation but not affected by the warming step. While the average VAS was not affected by injectate temperature, some individual participants reported bidirectional VAS responses to injectate temperature. A post injection questionnaire showed that most participants were not bothered by the cold sensation of the injected solution. The clinical results are consistent with modeling that indicates rapid temperature equilibration of subcutaneously injected solutions.</p><p><strong>Conclusion: </strong>Formulation composition was the dominating factor contributing to ISP as compared to solution temperature due to transient thermal equilibrium of the injected solution in SC tissue. While injection temperature may be a lever for improving the injection experience for some patients, the warming step is unlikely to reduce ISP for most patients. Although this study was conducted with 1 mL injection of two representative formulations, this finding of lack of correlation between ISP and solution temperature is likely extrapolatable to most small volume (e.g., ≤ 2 mL) injections of subcutaneous formulations.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"475-484"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543029","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 Vitro-In Vivo Correlation Of Amorphous Solid Dispersion Enabled Itraconazole Tablets.","authors":"Ana L Coutinho, Asmita Adhikari, Samuel Krug, Maureen Kane, R Gary Hollenbeck, Stephen W Hoag, James E Polli","doi":"10.1007/s11095-025-03837-z","DOIUrl":"10.1007/s11095-025-03837-z","url":null,"abstract":"<p><strong>Purpose: </strong>There are scarce reports on in vitro-in vivo correlation (IVIVC) model development of immediate-release (IR) formulations, and few investigations of the impacts of formulation and process of spray-dried solid dispersions (SDD)-based tablets on human pharmacokinetics (PK), despite commercial product successes. The goal of this study was to investigate the formulation and process factors that impact bioavailability enhancement of IR itraconazole SDD tablets; and to develop an FDA level A IVIVC that would predict in vivo PK performance from in vitro dissolution testing.</p><p><strong>Methods: </strong>A direct, differential-equation-based IVIVC model approach was employed, using an oral solution for post-dissolution disposition and Fast-, Medium-, and Slow-release tablets.</p><p><strong>Results: </strong>The IVIVC met FDA internal predictability for level A IVIVC requirements. The in vitro dissolution employed USP simulated intestinal fluid (phosphate buffer), adjusted pH 6.4, and tablets were triturated into particles prior to their immersion into dissolution media to mimic the attenuated disintegration difference between Medium and Slow in vivo. Credibility assessment of the FDA level A IVIVC model was performed, including model verification and validation considerations in light of the question of interest, the context of use, and model risk.</p><p><strong>Conclusion: </strong>To our knowledge, this is the first and only study that successfully developed an FDA level A IVIVC of an amorphous solid dispersion, which assessed the impact of grades of the same polymer, disintegrant level, and dry granulation processing on the performance of SDD tablets in humans.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"485-502"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606028","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":"Enhanced Penetration and Retention of an Antibody in the Articular Cartilage Through Aggrecan Binding and Molecular Downsizing.","authors":"Yuki Noguchi, Maiko Hoshino, Masaru Muraoka, Garvita Gupta, Yang Sun, Naoka Hironiwa, Wenjie Tu, Eri Joyashiki, Kenta Haraya, Taichi Kuramochi, Tomoyuki Igawa","doi":"10.1007/s11095-025-03845-z","DOIUrl":"10.1007/s11095-025-03845-z","url":null,"abstract":"<p><strong>Purpose: </strong>Delivering immunogloblin G (IgG) to the articular cartilage is a challenge and presents an obstacle in developing therapeutic antibodies for articular diseases. In this study, we focused on binding to the aggrecan-a key component of the cartilage matrix as a proteoglycan-and molecular downsizing to enhance the penetration and retention of antibodies in the articular cartilage.</p><p><strong>Methods: </strong>The control IgG (143 kDa), anti-aggrecan IgG (141 kDa), F(ab')2 (93.0 kDa), and Fab (44.9 kDa) were intra-articularly injected into a rabbit joint, and the concentrations of each molecule in synovial fluid, articular cartilage, and plasma were monitored.</p><p><strong>Results: </strong>Each molecule exhibited a similar elimination profile in synovial fluid. However, compared to the control IgG, anti-aggrecan IgG showed increased exposure in cartilage. Moreover, anti-aggrecan F(ab')2 exhibited even higher concentrations in cartilage, while the anti-aggrecan Fab demonstrated the highest and most long-lasting concentration profile in cartilage. Fluorescence imaging of the ex vivo cartilage penetration further supported the superior transport of the anti-aggrecan Fab and F(ab')2 compared to the control IgG and the anti-aggrecan IgG.</p><p><strong>Conclusions: </strong>Our study demonstrates that binding to the cartilage matrix, in addition to molecular size, is important, and that their combination has a synergistic effect on the antibody exposure in the articular cartilage.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"503-510"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649785","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":"Advanced Manufacturing, Modeling And Analytical Tools In Injectable Products.","authors":"Howard Stamato, Maxwell Korang-Yeboah, Jyothi Rangineni, Xiaoming Xu, Robin Bogner","doi":"10.1007/s11095-025-03815-5","DOIUrl":"10.1007/s11095-025-03815-5","url":null,"abstract":"<p><p>Although great progress has been made in the effectiveness and availability of medicines, there is still more work to do assuring greater access and continuing to advance disease treatments. Recent advances in both the types of treatments that can be developed and the technology to produce, characterize, collect relevant data from, and deliver medicines to patients have accelerated in recent experience. The National Institute for Pharmaceutical Technology and Education assembled representatives from academia, industry, and health authorities to assess progress. This article gives a perspective on recent trends in advanced manufacturing of injectable pharmaceutical products and provides some insight from which pharmaceutical manufacturers may implement valuable improvements based on these technological advances.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"413-418"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516312","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":"Synthesis and Biological Evaluation of Novel Triazine Analogs as Rad6 Inhibitors.","authors":"Qian Lin, Ambikai Gajan, Ignatius Nguyen, Shiv Sharma, Pratima Nangia-Makker, Steven Firestine, Malathy P Shekhar","doi":"10.1007/s11095-025-03838-y","DOIUrl":"10.1007/s11095-025-03838-y","url":null,"abstract":"<p><p>Rad6 is an E2 ubiquitin-conjugating enzyme that plays critical roles in genome maintenance and proteostasis. Rad6 is frequently overexpressed in many cancers and promotes cancer development, progression, and chemotherapy resistance.</p><p><strong>Purpose: </strong>Given its role in cancer development and progression, Rad6 is an underexplored therapeutic target. Previous research identified compound SMI#9 as a small molecule inhibitor of Rad6. Despite its potency, SMI#9 has limited efficacy in vivo due to its limiting water solubility and the presence of a labile ester group.</p><p><strong>Methods: </strong>To address these limitations, we prepared a series of SMI#9 analogs in which the ester group was replaced with a secondary amine, and their effects on Rad6B-mediated ubiquitination of histone H2A were evaluated. In vivo interaction with Rad6 was assessed using cellular thermal shift assays. SMI#9 analog effects on cell survival and migration of triple negative and endocrine-resistant breast cancer, and melanoma cells were measured using MTT and Boyden chamber assays. Autophagy, mitochondrial function, and β-catenin localization were measured using CytoID, Mitotracker, and immunostaining, respectively. Cellular uptakes of analogs were determined by mass spectroscopy.</p><p><strong>Results: </strong>Analogs #4 and #6 inhibited H2A ubiquitination, induced autophagy and mitochondrial dysfunction, downregulated intracellular β-catenin, and inhibited proliferation. #6 targets Rad6 in vivo. #4 and #6 are chemically related, and #4 undergoes in vivo conversion to #6.</p><p><strong>Conclusions: </strong>#6 retains all the properties of SMI#9 but with lesser potency. However, its improved water solubility and metabolic stability allows for in vivo studies that were previously precluded due to the poor physicochemical properties of SMI#9.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"511-527"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531010","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":"Leveraging Model Master Files from a Technology Company Perspective: Facilitating Quantitative Medicine in Regulatory Frameworks.","authors":"Jan De Backer, James Clarke, Hosein Sadafi, William Ganley, Jessica Spires","doi":"10.1007/s11095-025-03833-3","DOIUrl":"https://doi.org/10.1007/s11095-025-03833-3","url":null,"abstract":"<p><p>Model Master Files (MMFs) offer a much needed approach to integrating computational modelling into drug development and regulatory frameworks, supporting the growth of quantitative medicine. By acting as confidential repositories for validated models, MMFs enable streamlined submissions, model reuse, and context-specific reviews while safeguarding intellectual property. For technology companies (such as software providers), MMFs provide a structured pathway to engage with the FDA, align innovations with regulatory standards, and expand the use of models across diverse applications. A challenge with the current framework is the need to provide the same validation and verification information to multiple drug companies each time the submit an application. With an MMF in place, drug companies can refer to this same document which the technology provider can add to over time. However, challenges persist, including limited direct interaction with the FDA outside (A)NDA submissions and the need for consistent model validation and version management. Addressing these issues through enhanced collaboration and clear guidelines will maximize the potential of MMFs, fostering broader adoption of modelling and simulation in drug development and advancing personalized medicine.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516319","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}