Molecular Pharmaceutics最新文献

{"title":"Using Oscillation to Improve the Insertion Depth and Consistency of Hollow Microneedles for Transdermal Insulin Delivery with Mechanistic Insights.","authors":"Fiona Smith, Anna M Kotowska, Benjamin Fiedler, Edward Cerny, Karmen Cheung, Catrin S Rutland, Faz Chowdhury, Joel Segal, Frankie J Rawson, Maria Marlow","doi":"10.1021/acs.molpharmaceut.4c00942","DOIUrl":"10.1021/acs.molpharmaceut.4c00942","url":null,"abstract":"<p><p>Microneedles (MNs) offer the potential for discrete and painless transdermal drug delivery, yet poor insertion and dosing consistency have hindered their clinical translation. Specifically, hollow MNs are appropriate for the administration of liquid modalities, including insulin, which could prove to be beneficial for patients with type 1 diabetes mellitus. This work aimed to design and manufacture a hollow MN with an improved insertion and delivery profile suitable for insulin administration. <i>Ex vivo</i> insertion studies demonstrated that oscillation of MNs upon insertion into skin produced a favorable insertion profile, with reduced variation, compared to static MN insertion. Histological staining showed that this could be due to the repeated motion of the oscillating MN disrupting elastic fibers in the dermis. Additionally, permeation studies demonstrated that increased quantities of insulin were able to permeate the skin when oscillation was employed compared to static MN insertion. This study has shown that oscillation is a valuable tool in improving the transdermal delivery of insulin via a single hollow MN <i>in vitro</i>. Moving forward, <i>in vivo</i> studies should be completed to gain a fuller understanding of the benefits of the oscillation of MNs on transdermal drug delivery.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"316-329"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Polymers on the Kinetics of the Solid-State Phase Transition of Piracetam Polymorphs.","authors":"Fanfan Fan, Yi Lu, Shuyuan Xu, Minshan Guo, Ting Cai","doi":"10.1021/acs.molpharmaceut.4c01119","DOIUrl":"10.1021/acs.molpharmaceut.4c01119","url":null,"abstract":"<p><p>Metastable polymorphs of active pharmaceutical ingredients can occasionally be used to enhance bioavailability or make processing more convenient. However, the thermodynamic instability of metastable polymorphs poses a severe threat to the quality and performance of the drug products. In this study, we used hot-stage microscopy and powder X-ray diffraction to quantitatively analyze the kinetics of the solid-solid phase transition of piracetam (PCM) polymorphs in the absence and presence of several polymeric excipients. The Forms I and II of PCM are enantiotropically related polymorphs, and the transition point is 75 °C. We found that 1 wt % polymer can strongly affect the transformation rate of Form II to Form I of PCM above 75 °C. PVP K30 has the highest <i>T</i>_g and the strongest inhibitory effect on the transition, whereas PEG has the lowest <i>T</i>_g and the weakest effect on the transition. Below 75 °C, the addition of 1 wt % PEG can decrease the transformation rate from Form I to Form II of PCM by a few orders of magnitude, whereas no phase transition occurs in the presence of the other investigated polymers. The inhibitory effects of the same concentration of polymers on the kinetics of the solid-solid phase transition of piracetam polymorphs are considerably greater than those on the crystallization of PCM from the amorphous phase, especially at low temperatures. We propose that the low segmental mobility of polymers enriched between the crystalline phases can considerably inhibit the nucleation and growth of the stable form at the interface during the phase transition. Our findings deepen the current understanding of the mechanisms underlying the solid-state phase transition of polymorphic drugs in the presence of polymeric excipients, providing a promising formulation approach for stabilizing the metastable pharmaceutical polymorphs.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"509-519"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on \"Photodynamic Therapy Induced Mitochondrial Targeting Strategies for Cancer Treatment: Emerging Trends and Insights\".","authors":"David Kessel","doi":"10.1021/acs.molpharmaceut.4c00385","DOIUrl":"10.1021/acs.molpharmaceut.4c00385","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"583-584"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to \"Comment on 'Photodynamic Therapy Induced Mitochondrial Targeting Strategies for Cancer Treatment: Emerging Trends and Insights'\".","authors":"Vaibhavi Meghraj Desai, Mahima Choudhary, Rajdeep Chowdhury, Gautam Singhvi","doi":"10.1021/acs.molpharmaceut.4c01100","DOIUrl":"10.1021/acs.molpharmaceut.4c01100","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"585-587"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of HPMCAS Grade on the Release of Weakly Basic Drugs from Amorphous Solid Dispersions.","authors":"Pradnya Bapat, Lynne S Taylor","doi":"10.1021/acs.molpharmaceut.4c00986","DOIUrl":"10.1021/acs.molpharmaceut.4c00986","url":null,"abstract":"<p><p>Oppositely charged species can form electrostatic interactions in aqueous solution, and these may lead to reduced solubility of the interacting components. Herein, insoluble complex formation between the lipophilic weakly basic drugs, cinnarizine or loratadine, and the enteric polymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS), was studied and used to better understand drug and polymer release from their corresponding amorphous solid dispersions (ASDs). Surface area normalized release experiments were performed at various pH conditions for three different grades of HPMCAS, LF, MF and HF, as well as their ASDs. Both polymer and drug release rates were measured for the ASDs. Complexation tendency was evaluated by measuring the extent of polymer loss from the aqueous phase in the presence of the drug. Results showed that release from ASDs with HPMCAS-LF was less impacted by the presence of a cationic form of the drug than ASDs prepared with the HF grade. Furthermore, an increase in pH, leading to a reduction in the extent of ionized drug also led to an improvement in release rate. These observations provide a baseline to understand the role of drug-polymer electrostatic interactions on release from ASDs formulated with HPMCAS. Future studies should focus on adding complexity to media conditions by employing simulated intestinal fluids with solubilizing components.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"397-407"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Throughput Microarray Approaches for Predicting the Stability of Drug-Polymer Solid Dispersions.","authors":"Noha F Ghazi, Jonathan C Burley, Ian L Dryden, Clive J Roberts","doi":"10.1021/acs.molpharmaceut.4c00955","DOIUrl":"10.1021/acs.molpharmaceut.4c00955","url":null,"abstract":"<p><p>Amorphous solid dispersions (ASDs) offer a well-recognized strategy to improve the effective solubility and, hence, bioavailability of poorly soluble drugs. In this study, we developed an extensive library of a significant number of solid dispersion formulations using a library of chemically diverse drugs combined with a water-soluble polymer (polyvinylpyrrolidone vinyl acetate, PVPVA) at different loadings. These formulations were printed as microarrays of solid dispersion formulations, utilizing minimal material amounts (nanograms). They were subjected to a six-month stability study under accelerated conditions (40 °C and 75% relative humidity). Physical stability outcomes varied significantly among the different drug-polymer combinations, with stability ranging from immediate drug crystallization to several days of stability. The comprehensive data set obtained from this high-throughput screening was used to construct multiple linear regression models to correlate the stability of ASDs with the physicochemical properties of the used Active Pharmaceutical Ingredients (APIs). Our findings reveal that increased stability of ASDs is associated with a lower number of hydrogen bond acceptors alongside a higher overall count of heteroatoms and oxygen atoms in the drug molecules. This suggests that, while heteroatoms and oxygen are abundant, their role as hydrogen bond acceptors is limited due to their specific chemical environments, contributing to overall stability. Additionally, drugs with lower melting points formed more stable ASDs within the polymer matrix. This study, hence, highlights the importance of minimizing repulsive drug-polymer interactions to yield a physically stable ASD. The developed models, validated through Leave-One-Out Cross-Validation, demonstrated good predictability of stability trends. Hence, the high-throughput 2D inkjet printing technique that was used to manufacture the microarrays proved valuable for assessing drug-polymer crystallization onset risks and predicting stability outcomes. In conclusion, this study demonstrates a novel approach to solid dispersion formulation physical stability screening, enhancing efficiency, minimizing material requirements, and expanding the range of samples evaluated. Our findings provide insights into the critical physicochemical properties influencing ASD stability, offering a significant advancement in developing stable ASDs.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"343-362"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current State and New Horizons in Applications of Physiologically Based Biopharmaceutics Modeling (PBBM): A Workshop Report.","authors":"Christer Tannergren, Sumit Arora, Andrew Babiskin, Luiza Borges, Parnali Chatterjee, Yi-Hsien Cheng, André Dallmann, Anitha Govada, Tycho Heimbach, Martin Hingle, Sivacharan Kollipara, Evangelos Kotzagiorgis, Anders Lindahl, Claire Mackie, Maria Malamatari, Amitava Mitra, Rebecca Moody, Xavier Pepin, James Polli, Kimberly Raines, Gregory Rullo, Maitri Sanghavi, Rajesh Savkur, Rajendra Singh, Erik Sjögren, Sandra Suarez-Sharp, Sherin Thomas, Shereeni Veerasingham, Kevin Wei, Fang Wu, Yunming Xu, Miyoung Yoon, Bhagwant Rege","doi":"10.1021/acs.molpharmaceut.4c01148","DOIUrl":"10.1021/acs.molpharmaceut.4c01148","url":null,"abstract":"<p><p>This report summarizes the proceedings for Day 3 of the workshop titled \"<i>Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives</i>\". This day focused on the current and future drug product quality applications of PBBM from the innovator and generic industries as well as the regulatory agencies perspectives. The presentations, which included several case studies, covered the applications of PBBM in generic drug product development, applications of virtual bioequivalence trials to support formulation bridging and the utility of absorption modeling in clinical pharmacology assessments. In addition, recent progress in the prediction of colon absorption and <i>in vivo</i> performance of extended-release drug products was shared. The morning session was concluded by representatives from FDA, ANVISA, MHRA, Health Canada, EMA, and PMDA giving their perspectives on the application of PBBM in regulatory submissions. The afternoon breakout sessions focused on four parallel topics: 1) PBBM in generic drug product development; 2) virtual bioequivalence trials applications; 3) safe space and extrapolation; and 4) regional absorption and modified release PBBM applications. This allowed the participants to engage in in-depth discussions of best practices as well to identify key points of consideration to allow further progress on the applications of PBBM.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"5-27"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rationalizing mAb Candidate Screening Using a Single Holistic Developability Parameter.","authors":"Leon F Willis, Isabelle Trayton, Janet C Saunders, Maria G Brùque, William Davis Birch, David R Westhead, Katie Day, Nicholas J Bond, Paul W A Devine, Christopher Lloyd, Nikil Kapur, Sheena E Radford, Nicholas J Darton, David J Brockwell","doi":"10.1021/acs.molpharmaceut.4c00829","DOIUrl":"10.1021/acs.molpharmaceut.4c00829","url":null,"abstract":"<p><p>A framework for the rational selection of a minimal suite of nondegenerate developability assays (DAs) that maximize insight into candidate developability or storage stability is lacking. To address this, we subjected nine formulation:mAbs to 12 mechanistically distinct DAs together with measurement of their accelerated and long-term storage stability. We show that it is possible to identify a reduced set of key variables from this suite of DAs by using orthogonal statistical methods. We exemplify our approach by predicting the rank formulation:mAb degradation rate at 25 °C (determined over 6 months) using just five DAs that can be measured in less than 1 day, spanning a range of physicochemical features. Implementing such approaches focuses on resources, thus increasing sustainability and decreasing development costs.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"181-195"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxygen/Nitric Oxide Dual-Releasing Nanozyme for Augmenting TMZ-Mediated Apoptosis and Necrosis.","authors":"Jun Ma, Jingjing Qiu, Gus A Wright, Shiren Wang","doi":"10.1021/acs.molpharmaceut.4c00817","DOIUrl":"10.1021/acs.molpharmaceut.4c00817","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor, with a poor prognosis. Temozolomide (TMZ) represents the standard chemotherapy for GBM but has limited efficacy due to poor targeting and a hypoxic tumor microenvironment (TME). To address these challenges, we developed a dual-gas-releasing, cancer-cell-membrane-camouflaged nanoparticle to deliver TMZ. This nanoceria, camouflaged with a cancer cell membrane (CCM-CeO₂), targets explicitly GBM cells and accumulates in lysosomes, triggering the rapid release of TMZ. Additionally, CCM-CeO₂ could release oxygen (O₂) and nitric oxide (NO) in response to the TME. Synthesized using d-arginine, catalytic nanoceria could decompose excessive hydrogen peroxide (H₂O₂) in the TME to produce O₂, while d-arginine could nonenzymatically react with H₂O₂ to generate NO. CCM-CeO₂ could penetrate GBM spheroids to a depth of 148.3 ± 31 μm, with the O₂ and NO produced, reducing HIF-1α protein expression. When loaded with TMZ, CCM-CeO₂ could increase the intracellular ROS produced by TMZ, leading to lysosome membrane permeabilization and notably augmented apoptosis and necrosis in GBM cells. An in vitro antitumor assay using spheroids showed that CCM-CeO₂ reduced the IC₅₀ value of TMZ from 174.5 to 42.6 μg/mL, likely due to the catalase-like activity of nanoceria. These results suggest that alleviating hypoxia and increasing ROS produced by chemotherapeutics could be an effective therapeutic strategy for treating GBM.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"168-180"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning Models for Predicting Monoclonal Antibody Biophysical Properties from Molecular Dynamics Simulations and Deep Learning-Based Surface Descriptors.","authors":"I-En Wu, Lateefat Kalejaye, Pin-Kuang Lai","doi":"10.1021/acs.molpharmaceut.4c00804","DOIUrl":"10.1021/acs.molpharmaceut.4c00804","url":null,"abstract":"<p><p>Monoclonal antibodies (mAbs) have found extensive applications and development in treating various diseases. From the pharmaceutical industry's perspective, the journey from the design and development of mAbs to clinical testing and large-scale production is a highly time-consuming and resource-intensive process. During the research and development phase, assessing and optimizing the developability of mAbs is of paramount importance to ensure their success as candidates for therapeutic drugs. The critical factors influencing mAb development are their biophysical properties, such as aggregation propensity, solubility, and viscosity. This study utilized a data set comprising 12 biophysical properties of 137 antibodies from a previous study (Proc Natl Acad Sci USA. 114(5):944-949, 2017). We employed full-length antibody molecular dynamics simulations and machine learning techniques to predict experimental data for these 12 biophysical properties. Additionally, we utilized a newly developed deep learning model called DeepSP, which directly predicts the dynamical and structural properties of spatial aggregation propensity and spatial charge map in different antibody regions from sequences. Our research findings indicate that the machine learning models we developed outperform previous methods in predicting most biophysical properties. Furthermore, the DeepSP model yields similar predictive results compared to molecular dynamic simulations while significantly reducing computational time. The code and parameters are freely available at https://github.com/Lailabcode/AbDev. Also, the webapp, AbDev, for 12 biophysical properties prediction has been developed and provided at https://devpred.onrender.com/AbDev.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"142-153"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}