Molecular Pharmaceutics最新文献

{"title":"Binding Interaction of Coumarin Derivative Daphnetin with Ovalbumin: Molecular Insights into the Complexation Process and Effects of Metal Ions and pH in the Binding and Antifibrillation Studies.","authors":"Sadia Nudrat, Bilash Maity, Sana Quraishi, Irungbam Karankumar, Kalpana Kumari, Madhurima Jana, Atanu Singha Roy","doi":"10.1021/acs.molpharmaceut.4c00675","DOIUrl":"10.1021/acs.molpharmaceut.4c00675","url":null,"abstract":"<p><p>This study investigates the interaction between daphnetin and ovalbumin (OVA) as well as its potential to inhibit OVA fibrillation using both spectroscopic and computational analysis. A moderate binding affinity of 1 × 10⁴ M^-1 was observed between OVA and daphnetin, with a static quenched mechanism identified during the fluorescence quenching processes. Metal ions' (Cu²⁺ and Zn²⁺) presence led to an increase in the binding affinities of daphnetin toward OVA, mirroring a similar trend observed with the pH variation. Synchronous and 3D fluorescence studies indicated an increase in the polarity of the microenvironment surrounding the Trp residues during binding. Interestingly, circular dichroism and Fourier transform infrared studies showed a significant change in the secondary structure of OVA upon binding with daphnetin. The efficacy of daphnetin in inhibiting protein fibrillation was confirmed through thioflavin T and Congo Red binding assays along with fluorescence microscopic imaging analysis. The thermodynamic assessment showed positive Δ<i>H</i>° [+(29.34 ± 1.526) kJ mol^-1] and Δ<i>S</i>° [+(181.726 ± 5.465) J mol^-1] values, indicating the presence of the hydrophobic forces, while negative Δ<i>G</i>° signifies spontaneous binding interactions. These experimental findings were further correlated with computational analysis, revealing daphnetin dynamics within the binding site of OVA.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905009","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":"Age-Specific ADME Gene Expression in Infant Intestinal Enteroids.","authors":"Eva J Streekstra, Tom Scheer-Weijers, Michael Bscheider, Sabine Fuerst-Recktenwald, Adrian Roth, Sven C D van Ijzendoorn, Sanne Botden, Willem de Boode, Martijn W J Stommel, Rick Greupink, Frans G M Russel, Evita van de Steeg, Saskia N de Wildt","doi":"10.1021/acs.molpharmaceut.4c00302","DOIUrl":"10.1021/acs.molpharmaceut.4c00302","url":null,"abstract":"<p><p>In childhood, developmental changes and environmental interactions highly affect orally dosed drug disposition across the age range. To optimize dosing regimens and ensure safe use of drugs in pediatric patients, understanding this age-dependent biology is necessary. In this proof-of-concept study, we aimed to culture age-specific enteroids from infant tissue which represent its original donor material, specifically for drug transport and metabolism. Enteroid lines from fresh infant tissues (<i>n</i> = 8, age range: 0.3-45 postnatal weeks) and adult tissues (<i>n</i> = 3) were established and expanded to 3D self-organizing enteroids. The gene expression of drug transporters P-gp (<i>ABCB1</i>), BCRP (<i>ABCG2</i>), MRP2 (<i>ABCC2</i>), and PEPT1 (<i>SLC15A1</i>) and drug metabolizing enzymes CYP3A4, CYP2C18, and UGT1A1 was determined with RT-qPCR in fresh tissue and its derivative differentiated enteroids. Expression levels of P-gp, BCRP, MRP2, and CYP3A4 were similar between tissues and enteroids. PEPT1 and CYP2C18 expression was lower in enteroids compared to that in the tissue. The expression of UGT1A1 in the tissue was lower than that in enteroids. The gene expression did not change with the enteroid passage number for all genes studied. Similar maturational patterns in tissues and enteroids were visually observed for P-gp, PEPT1, MRP2, CYP3A4, CYP2C18, and VIL1. In this explorative study, interpatient variability was high, likely due to the diverse patient characteristics of the sampled population (e.g., disease, age, and treatment). To summarize, maturational patterns of clinically relevant ADME genes in tissue were maintained in enteroids. These findings are an important step toward the potential use of pediatric enteroids in pediatric drug development, which in the future may lead to improved pediatric safety predictions during drug development. We reason that such an approach can contribute to a potential age-specific platform to study and predict drug exposure and intestinal safety in pediatrics.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905008","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":"Voices in <i>Molecular Pharmaceutics</i>: Meet Professor Xiang-Guo Li, an Expert in Radiopharmaceutical Chemistry and Positron Emission Tomography for Improved Imaging of Immunological Disorders and Brain Tumors.","authors":"Xiang-Guo Li","doi":"10.1021/acs.molpharmaceut.4c00865","DOIUrl":"10.1021/acs.molpharmaceut.4c00865","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970037","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":"Feasibility of Laboratory Equipment-Based Simulation Methods to Assess the Impact of Vehicle Transportation on Product Quality of mAb Dosing Solutions.","authors":"Kashappa Goud Desai, Cait Sofa, Ning Wang, Bivash Mandal, Brendan Blockus, Nathan Heacock, James D Colandene","doi":"10.1021/acs.molpharmaceut.4c00681","DOIUrl":"10.1021/acs.molpharmaceut.4c00681","url":null,"abstract":"<p><p>Therapeutic monoclonal antibody (mAb) products for intravenous (IV) administration generally require aseptic compounding with a commercially available diluent. When the administration site is located away from the preparation site, the prepared dosing solution may need to be transported in a vehicle. The impact of vehicle transportation on the product quality of mAbs needs to be evaluated to define safe handling and transportation conditions for dosing solutions. The design and execution of actual vehicle transportation studies require considerable resources and time. In this study, we systematically developed three different laboratory equipment-based methods that simulate vehicle transportation stresses: orbital shaker (OS), reciprocating shaker (RS), and vibration test system (VTS)-based simulation methods. We assessed their feasibility by comparing the impact on product quality caused by each simulated method with that caused by actual vehicle transportation. Without residual polysorbate 80 (PS80) in the mAb dosing solution, transportation via a cargo van led to a considerable increase in the subvisible particle counts and did not meet the compendial specifications for the light obscuration method. However, the presence of as low as 0.0004%w/v (4 ppm) PS80 in the dosing solution stabilized the mAb against vehicle transportation stresses and met the compendial specifications. Vehicle transportation of an IV bag with headspace resulted in negligible micro air bubbles and foaming in both PS80-free and PS80-containing mAb dosing solutions. These phenomena were found to be comparable to the VTS-based simulated method. However, the OS- and RS-based simulated methods formed significantly more micro air bubbles and foaming in an IV bag with headspace than either actual vehicle transportation or the VTS-based simulated method. Despite the higher interfacial stress (micro air bubbles and foaming) in the dosing solution created by the OS- and RS-based simulated methods, 0.0004%w/v (4 ppm) PS80 in the dosing solution was found to be sufficient to stabilize the mAb. The study shows that under appropriate simulated conditions, the OS-, RS-, and VTS-based simulated methods can be used as practical and meaningful models to assess the impact and risk of vehicle transportation on the quality of mAb dosing solutions.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981213","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":"Unraveling the Potential of Vitamin B₃-Derived Salts with a Salicylate Anion as Dermal Active Agents for Acne Treatment.","authors":"Adriana Olejniczak, Witold Stachowiak, Daniel Ziental, Jolanta Długaszewska, Tomasz Rzemieniecki, Marcin Wysokowski, Teofil Jesionowski, Michał Niemczak","doi":"10.1021/acs.molpharmaceut.4c00543","DOIUrl":"10.1021/acs.molpharmaceut.4c00543","url":null,"abstract":"<p><p>This study is focused on the utilization of naturally occurring salicylic acid and nicotinamide (vitamin B₃) in the development of novel sustainable Active Pharmaceutical Ingredients (APIs) with significant potential for treating acne vulgaris. The study highlights how the chemical structure of the cation significantly influences surface activity, lipophilicity, and solubility in aqueous media. Furthermore, the new ionic forms of APIs, the synthesis of which was assessed with <i>Green Chemistry</i> metrics, exhibited very good antibacterial properties against common pathogens that contribute to the development of acne, resulting in remarkable enhancement of biological activity ranging from 200 to as much as 2000 times when compared to salicylic acid alone. The molecular docking studies also revealed the excellent anti-inflammatory activity of <i>N</i>-alkylnicotinamide salicylates comparable to commonly used drugs (indomethacin, ibuprofen, and acetylsalicylic acid) and were even characterized by better IC₅₀ values than common anti-inflammatory drugs in some cases. The derivative, featuring a decyl substituent in the pyridinium ring of nicotinamide, exhibited efficacy against <i>Cutibacterium acnes</i> while displaying favorable water solubility and improved wettability on hydrophobic surfaces, marking it as particularly promising. To investigate the impact of the APIs on the biosphere, the EC₅₀ parameter was determined against a model representative of crustaceans─<i>Artemia franciscana</i>. The majority of compounds (with the exception of the salt containing the dodecyl substituent) could be classified as \"Relatively Harmless\" or \"Practically Nontoxic\", indicating their potential low environmental impact, which is essential in the context of modern drug development.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981214","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":"Albumin-Mediated Drug Uptake by Organic Anion Transporter 1/3 Is Real: Implications for the Prediction of Active Renal Secretion Clearance.","authors":"Shawn Pei Feng Tan, Annika Tillmann, Susan J Murby, Amin Rostami-Hodjegan, Daniel Scotcher, Aleksandra Galetin","doi":"10.1021/acs.molpharmaceut.4c00504","DOIUrl":"10.1021/acs.molpharmaceut.4c00504","url":null,"abstract":"<p><p>Modulation of the transport-mediated active uptake by human serum albumin (HSA) for highly protein-bound substrates has been reported and improved the <i>in vitro</i>-to-<i>in vivo</i> extrapolation (IVIVE) of hepatic clearance. However, evidence for the relevance of such a phenomenon in the case of renal transporters is sparse. In this study, transport of renal organic anion transporter 1 or 3 (OAT1/3) substrates into conditionally immortalized proximal tubular epithelial cells transduced with OAT1/3 was measured in the presence and absence of 1 and 4% HSA while keeping the unbound substrate concentration constant (based on measured fraction unbound, <i>f</i>_u,inc). In the presence of 4% HSA, the unbound intrinsic active uptake clearance (CL_int,u,active) of six highly protein-bound substrates increased substantially relative to the HSA-free control (3.5- to 122-fold for the OAT1 CL_int,u,active, and up to 28-fold for the OAT3 CL_int,u,active). The albumin-mediated uptake effect (fold increase in CL_int,u,active) was more pronounced with highly bound substrates compared to no effect seen for weakly protein-bound substrates adefovir (OAT1-specific) and oseltamivir carboxylate (OAT3-specific). The relationship between OAT1/3 CL_int,u,active and <i>f</i>_u,inc agreed with the facilitated-dissociation model; a relationship was established between the albumin-mediated fold change in CL_int,_u,active and <i>f</i>_u,inc for both the OAT1 and OAT3, with implications for IVIVE modeling. The relative activity factor and the relative expression factor based on global proteomic quantification of <i>in vitro</i> OAT1/3 expression were applied for IVIVE of renal clearance. The inclusion of HSA improved the bottom-up prediction of the level of OAT1/3-mediated secretion and renal clearance (CL_sec and CL_r), in contrast to the underprediction observed with the control (HSA-free) scenario. For the first time, this study confirmed the presence of the albumin-mediated uptake effect with renal OAT1/3 transporters; the extent of the effect was more pronounced for highly protein-bound substrates. We recommend the inclusion of HSA in routine <i>in vitro</i> OAT1/3 assays due to considerable improvements in the IVIVE of CL_sec and CL_r.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015565","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":"Exploring How Antibody Format Drives Clearance from the Brain.","authors":"Kelly Schwinghamer, Brian M Kopec, Ebehiremen Ayewoh, Xun Tao, Shraddha Sadekar, Alavattam Sreedhara, Robert F Kelley, Devin B Tesar, Teruna J Siahaan","doi":"10.1021/acs.molpharmaceut.4c00354","DOIUrl":"10.1021/acs.molpharmaceut.4c00354","url":null,"abstract":"<p><p>Monoclonal antibodies (mAbs) have high binding specificity and affinity, making them attractive for treating brain diseases. However, their effectiveness is limited by poor blood-brain barrier (BBB) penetration and rapid central nervous system (CNS) clearance. Our group identified blood-brain barrier modulator (BBBM) peptides that improved mAb penetration across the BBB into the brain. In this study, we investigated the pharmacokinetics of a mAb delivered to the brain using BBBMs after intravenous (IV) administration and explored the impact of antibody format (size, neonatal Fc receptor (FcRn) binding, hyaluronic acid binding) on brain clearance following direct injection into the central nervous system (CNS) via intracerebroventricular (ICV) injection. IRDye800CW-labeled antibodies were administered into C57BL/6 mice via ICV or IV injection, and organ concentrations were measured after various time points. When a mAb was coadministered with a BBBM peptide, the permeation of mAb across the BBB was increased compared to mAb alone at early time points; however, the mAb was cleared within 2 h from the brain. ICV experiments revealed that an antibody Fab fragment had a higher brain exposure than a mAb, and that a Fab fused to a hyaluronic acid binding domain (Fab-VG1) showed remarkable improvement in brain exposure. These findings suggest that BBBMs and antibody format optimization may be promising strategies for enhancing brain retention of therapeutic antibodies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141755724","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":"Preparation of Biomimetic Selenium-Baicalein Nanoparticles and Their Targeted Therapeutic Application in Nonsmall Cell Lung Cancer.","authors":"Huan Shi, Biaobiao Wang, Huilin Ma, Yunmei Li, Jiaqun Du, Bo Zhang, Yu Gao, Ying Liu, Chao Wu","doi":"10.1021/acs.molpharmaceut.4c00390","DOIUrl":"10.1021/acs.molpharmaceut.4c00390","url":null,"abstract":"<p><p>In this study, we prepared bionic selenium-baicalein nanoparticles (ACM-SSe-BE) for the targeted treatment of nonsmall cell lung cancer. Due to the coating of the A549 membrane, the system has homologous targeting capabilities, allowing for the preparation of target tumor cells. The borate ester bond between selenium nanoparticles (SSe) and baicalein (BE) is pH-sensitive and can break under acidic conditions in the tumor microenvironment to achieve the targeted release of BE at the tumor site. Moreover, SSe further enhances the antitumor effect of BE by increasing the production of ROS in tumor cells. Transmission electron microscopy (TEM) images and dynamic light scattering (DLS) showed that the ACM-SSe-BE had a particle size of approximately 155 ± 2 nm. FTIR verified the successful coupling of SSe and BE. In vitro release experiments indicated that the cumulative release of ACM-SSe-BE at pH 5.5 after 24 h was 69.39 ± 1.07%, which was less than the 20% release at pH 7.4, confirming the pH-sensitive release of BE in ACM-SSe-BE. Cell uptake experiments and in vivo imaging showed that ACM-SSe-BE had good targeting ability. The results of MTT, flow cytometry, Western blot, and cell immunofluorescence staining demonstrated that ACM-SSe-BE promoted A549 cell apoptosis and inhibited cell proliferation. The in vivo antitumor results were consistent with those of the cell experiments. These results clearly suggested that ACM-SSe-BE will be a promising bionic nanosystem for the treatment of nonsmall cell lung cancer.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896105","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":"First-Generation Radiolabeled Cyclic Peptides for Molecular Imaging of Platelet-Derived Growth Factor Receptor α.","authors":"Susan Pike, Melinda Wuest, Ana Lopez-Campistrous, Mi Yao Hu, Ratmir Derda, Frank Wuest, Todd McMullen","doi":"10.1021/acs.molpharmaceut.4c00549","DOIUrl":"10.1021/acs.molpharmaceut.4c00549","url":null,"abstract":"<p><p>Occult nodal spread and metastatic disease require longstanding imaging and biochemical assessments for thyroid cancer, a disease that has a propensity for diffuse, small-volume disease. We have developed a ⁶⁴Cu-labeled platelet-derived growth factor receptor α (PDGFRA) antibody for immuno-PET of PDGFRA in metastatic papillary thyroid cancer (PTC). The present work describes the discovery of small cyclic PDGFRA-targeting peptides, their binding features, and radiolabeling with positron emitter gallium-68 (⁶⁸Ga) for <i>in vitro and in vivo</i> characterization in thyroid cancer models. Phage-display technology with two separate libraries and seven different cell lines was used through three rounds of biopanning as well as flow cytometry and comparative analysis with recombinant protein to select specific peptide sequences. Phenotypic binding analysis was completed by using phosphorylation and cell migration assays. <i>In vitro</i> protein binding was analyzed with thermophoresis and flow cytometry using the fluorescent-labeled PDGFRA peptide. Peptide candidates were modified with the NOTA chelator for radiolabeling with ⁶⁸Ga. <i>In vitro</i> cell uptake was studied in various thyroid cancer cell lines. <i>In vivo</i> studies of ⁶⁸Ga-labeled peptides included metabolic stability and PET imaging. From the original library (10¹³ compounds), five different peptide groups were identified based on biopanning experiments with and without the α subunit of PDGFR, leading to ∼50 peptides. Subsequent phenotypic screening revealed two core peptide sequences (<b>CP16</b> and <b>CP18</b>) that demonstrated significant changes in the level of PDGFRA phosphorylation and cell migration. Alanine scan sublibraries were created from these two lead peptide sequences, and peptides were radiolabeled using ⁶⁸Ga-GaCl₃ at pH 4.5, resulting in RCP > 95% within 34-40 min, including SPE purification. Cyclic peptide <b>CP18.5</b> showed the strongest effects on cell migration, flow cytometry, and binding by visual interference color assay. ⁶⁸Ga-labeled PDGFRA-targeting peptides showed elevated cell and tumor uptake in models of thyroid cancer, with ^<b>68</b><b>Ga-NOTA-CP18.5</b> being the lead candidate. However, metabolic stability <i>in vivo</i> was compromised for ^<b>68</b><b>Ga-NOTA-CP18.5</b> vs ^<b>68</b><b>Ga-NOTA-CP18</b> but without impacting tumor uptake or clearance profiles. First-generation radiolabeled cyclic peptides have been developed as novel radiotracers, particularly ^<b>68</b><b>Ga-NOTA-CP18.5</b>, for the molecular imaging of PDGFRA in thyroid cancer.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994826","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":"Patient-Centric Long-Acting Injectable and Implantable Platforms─An Industrial Perspective.","authors":"Simone Alidori, Raju Subramanian, René Holm","doi":"10.1021/acs.molpharmaceut.4c00665","DOIUrl":"10.1021/acs.molpharmaceut.4c00665","url":null,"abstract":"<p><p>The increasing focus on patient centricity in the pharmaceutical industry over the past decade and the changing healthcare landscape, driven by factors such as increased access to information, social media, and evolving patient demands, has necessitated a shift toward greater connectivity and understanding of patients' unique treatment needs. One pharmaceutical technology that has supported these efforts is long acting injectables (LAIs), which lower the administration frequency for the patient's provided convenience, better compliance, and hence better therapeutical treatment for the patients. Furthermore, patients with conditions like the human immunodeficiency virus and schizophrenia have positively expressed the desire for less frequent dosing, such as that obtained through LAI formulations. In this work, a comprehensive analysis of marketed LAIs across therapeutic classes and technologies is conducted. The analysis demonstrated an increasing number of new LAIs being brought to the market, recently most as aqueous suspensions and one as a solution, but many other technology platforms were applied as well, in particular, polymeric microspheres and in situ forming gels. The analysis across the technologies provided an insight into to the physicochemical properties the compounds had per technology class as well as knowledge of the excipients typically used within the individual formulation technology. The principle behind the formulation technologies was discussed with respect to the release mechanism, manufacturing approaches, and the possibility of defining predictive in vitro release methods to obtain in vitro in vivo correlations with an industrial angle. The gaps in the field are still numerous, including better systematic formulation and manufacturing investigations to get a better understanding of potential innovations, but also development of new polymers could facilitate the development of additional compounds. The biggest and most important gaps, however, seem to be the development of predictive in vitro dissolution methods utilizing pharmacopoeia described equipment to enable their use for product development and later in the product cycle for quality-based purposes.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003010","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}