Pharmaceutical Research[JOURNAL]
Sun
200 papers
Effect of Molecular Size on Ocular Drug Distribution After Intravitreal Injection Using Computed Tomography and Mathematical Spatial Modeling.
Konishi K, Kimura S, Minematsu T … +3 more , Shinozaki A, Oishi M, Nagasaka Y
Pharm Res · 2025 Nov · PMID 41254320 · Publisher ↗
PURPOSE: Intravitreal injection is an administration route for ocular therapeutics of different molecular sizes, including antibodies, antisense oligonucleotides, and adeno-associated viruses. The purpose of this study w...
PURPOSE: Intravitreal injection is an administration route for ocular therapeutics of different molecular sizes, including antibodies, antisense oligonucleotides, and adeno-associated viruses. The purpose of this study was to identify the effect of molecular size on ocular drug distribution after intravitreal injection by computed tomography (CT) and to construct a mathematical model for clinical dosage and regimen optimization. METHODS: Contrast agents of different molecular sizes (ca. 1-110 nm) were intravitreally injected into rabbits and their distributions were visualized using CT. Subsequently, a computational spatial model of the rabbit eyeball with an intravitreal diffusion coefficient was constructed from CT images using the finite element method. The model was then extended to the human eyeball. RESULTS: CT images indicated that: 1) all contrast agents moved in the direction of gravity according to body position, and 2) intravitreal diffusivity decreased with increasing molecular size. The computational rabbit eyeball model successfully reproduced the CT images, and the intravitreal diffusion coefficient of each contrast agent was determined. Furthermore, simulation results with the human eyeball model suggested that maintaining the supine position after intravitreal injection provides better exposure at the macula, particularly for therapeutics with larger molecular size. CONCLUSIONS: Using computational spatial modeling based on CT images, we identified the effect of molecular size on ocular drug distribution after intravitreal injection in humans. These findings are expected to aid the establishment of appropriate times to maintain the supine position to ensure targeted exposure in accordance with modality size, as well as the estimation of optimal clinical doses.
Active Targeting of Colorectal Cancer Using Chemotherapy-Loaded Nanoparticles Functionalized with a Folate Receptor-α (FRα) Ligand, Pemetrexed.
Alnatour M, Sen R, Janardhanam LSL … +3 more , Anjum MM, Geary SM, Salem AK
Pharm Res · 2025 Dec · PMID 41254319 · Full text
PURPOSE: Colorectal cancer (CRC) is a leading cause of cancer mortality with current chemotherapeutic strategies often limited by systemic side effects and suboptimal tumor targeting. This study aimed to enhance the deli...
PURPOSE: Colorectal cancer (CRC) is a leading cause of cancer mortality with current chemotherapeutic strategies often limited by systemic side effects and suboptimal tumor targeting. This study aimed to enhance the delivery and efficacy of paclitaxel (PTX) for CRC therapy by engineering nanoparticles (NPs) actively targeted to the folate receptor-α (FRα) using pemetrexed, an FDA-approved antifolate with high FRα affinity. METHODS: A novel FRα-targeted polymer (PLGA-PEG-pemetrexed) was synthesized by ring-opening polymerization and used to prepare tumor-targeted nanoparticles (TTNPs). The physical characteristics of TTNPs and non-targeted NPs (NTNPs) were evaluated by dynamic light scattering and TEM. Cellular uptake was assessed in FRα-expressing CT26 colorectal cancer cells by flow cytometry and confocal imaging. Cytotoxicity was evaluated using PrestoBlue™ assays. In vivo tumor targeting and therapeutic efficacy were assessed in a syngeneic CT26 tumor-bearing BALB/c mouse model using IVIS imaging, tumor accumulation and growth measurements. RESULTS: The synthesized PLGA-PEG-pemetrexed formed uniform, negatively charged NPs with a hydrodynamic diameter of 140-170 nm. TTNPs demonstrated significantly enhanced uptake in FRα-expressing CT26 cells compared to NTNPs, which was abrogated by folic acid pre-treatment. In vitro, PTX-loaded TTNPs exhibited greater cytotoxicity against CT26 cells than free PTX. In vivo, TTNPs showed superior tumor accumulation compared to NTNPs, resulting in significantly greater tumor growth inhibition and increased intratumoral PTX concentrations. All treatments were well tolerated. CONCLUSION: Our results demonstrate that active targeting of chemotherapy-loaded NPs with a FRα ligand, pemetrexed, enhances tumor targeting and antitumor efficacy in a CRC model.
A Tale of Two Stressors in Biologic Drug Product Development: Shaking Mode and Primary Packaging.
Hejmady S, Taherian E, Nejadnik R
Pharm Res · 2026 Apr · PMID 41254318 · Full text
PURPOSE: Mechanical, interfacial, and shear stresses encountered during development, manufacturing and transportation of biologics can compromise monoclonal antibody (mAb) stability. However, most scale-down shaking mode...
PURPOSE: Mechanical, interfacial, and shear stresses encountered during development, manufacturing and transportation of biologics can compromise monoclonal antibody (mAb) stability. However, most scale-down shaking models often depend solely on orbital agitation and overlook the effect of the solid-liquid interface. To study this gap, stress conditions were applied to simulate early-stage product development and real-world transportation in this work. METHODOLOGY: Accordingly, the aggregation profiles of Cetuximab and Tocilizumab formulations, with and without polysorbate 80 (PS80), were systematically compared after applying horizontal and orbital shaking. Protein aggregation was assessed using orthogonal techniques such as size-exclusion chromatography, dynamic light scattering, flow imaging microscopy, ultraviolet-visible spectroscopy, and visual inspection. RESULTS: Horizontal shaking more effectively revealed Cetuximab's susceptibility to aggregation under mechanical and interfacial stress whereas orbital shaking conditions were not as discriminative. Furthermore, to explore the effect of vial surface chemistry on subsequent protein aggregation, Cetuximab was subjected to horizontal shaking stress using both untreated and silanized glass vials. Interestingly, hydrophobic silanized vials without surfactant resulted in increased Cetuximab aggregation compared to untreated vials. In contrast, Cetuximab with PS80 showed fewer aggregates in silanized vials than in glass vials. CONCLUSION: These results underscore the value of selecting right-for-purpose agitation models and highlight the need to explore the triple interface for improving stress screening in drug product development.
Next Generation 3D Printed Multipurpose Intravaginal Ring For Sustained Co-Delivery of Antiretroviral Drugs and A Contraceptive Hormone.
Dahl DK, Janusziewicz R, Shrivastava R … +4 more , Maturavongsadit P, Chan E, Montgomery SA, Benhabbour SR
Pharm Res · 2025 Dec · PMID 41225189 · Publisher ↗
OBJECTIVE: Globally, a significant overlap exists between females affected by HIV and HSV-2 infections, and who have an unmet need for contraception. Intravaginal rings (IVRs) have become widely accepted by women worldwi...
OBJECTIVE: Globally, a significant overlap exists between females affected by HIV and HSV-2 infections, and who have an unmet need for contraception. Intravaginal rings (IVRs) have become widely accepted by women worldwide for contraception and hormone replacement therapy and provide a promising platform as a multipurpose prevention technology (MPT). METHODS: Using state-of-the-art 3D printing process known as continuous liquid interface production (CLIP™), IVRs with an internal honeycomb (HC 2.53 mm) geometry were fabricated with a silicone-urethane resin. IVRs were loaded with a triple-drug combination of an anti-HIV drug (Dapivirine, DPV, 30 mg), an anti-herpes drug (Pritelivir, PTV, 20 mg) and a contraceptive hormone (Levonorgestrel, LNG, 2.0 mg) using a solvent swelling method in acetone. RESULTS: IVRs elicited zero-order release kinetics following an initial burst for all three APIs when formulated individually or in combination. Release rates were above benchmark therapeutic targets for DPV and LNG (200 µg/day DPV, 20 µg/day LNG). A series of accelerated stability studies demonstrated the physical integrity of IVRs after 6 months of storage at 40ºC/75%RH. DPV remained stable over 6 months, whereas PTV and LNG exhibited significant decrease in concentration after 3 months of storage with presence of degradation products detected by HPLC. Mouse size placebo rings (3 mm OD) elicited 100% cell viability in relevant cell lines and were well tolerated in vivo in mice. CONCLUSIONS: Collectively, these results demonstrate that this first-in-line 3D printed MPT IVR has potential to expand preventative choices for young women and girls against HIV, HSV, and unplanned pregnancy.
Exploration of 2-Mercaptoquinazolin-4(3H)-one Based N-Hydroxyheptanamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Anticancer Bioevaluation.
Thao LT, Kim HK, Ngoc HK … +7 more , Kang DH, Kim HY, Kang JS, Anh DT, Tung TT, Han SB, Nam NH
Pharm Res · 2025 Nov · PMID 41219568 · Publisher ↗
OBJECTIVE: Histone deacetylase (HDAC) inhibitors have emerged as promising cancer therapeutics by regulating gene expression, halting cell cycle progression, and inducing apoptosis. This study explores the structure-acti...
OBJECTIVE: Histone deacetylase (HDAC) inhibitors have emerged as promising cancer therapeutics by regulating gene expression, halting cell cycle progression, and inducing apoptosis. This study explores the structure-activity relationship of 2-mercaptoquinazolin-4(3H)-one derivatives as potential anticancer agents and HDAC inhibitors. METHODS: The library compounds were prepared via a three-step pathway by incorporating 2-mercaptoquinazoline and a hydroxamic acid moiety. The cytotoxicity of 27 synthesized hydroxamic acid derivatives was evaluated against SW620 (colon cancer), MDA-MB-231 (breast cancer), and MRC-5 (normal lung fibroblast) cell lines. Molecular docking studies on HDAC-isoforms for the 4a-i were also performed to identify the essential structural features that contribute to the biological activities. RESULTS: The results demonstrated that substituents at the N-3 position significantly influenced anticancer activity, with methyl-substituted derivatives (4a-i) exhibiting the highest cytotoxicity, followed by phenyl-substituted (7a-i) and benzyl-substituted (10a-i) compounds. Among the tested compounds, 4a (-H) and 4c (7-CH₃) showed as the most potent active compounds, with IC values of 4.24 ± 1.16 µM and 3.61 ± 0.32 µM against SW620 cells, and 2.93 ± 0.68 µM and 3.34 ± 0.32 µM against MDA-MB-231 cells, respectively. HDAC inhibition assays revealed that 4a-d and 4 g exhibited superior inhibitory activity compared to SAHA. Further investigation of 4a and 4c in SW620 cells showed that both compounds induced G2/M phase cell cycle arrest and promoted apoptosis, supporting their potential as promising HDAC inhibitors with anticancer properties. CONCLUSIONS: Among the most active compounds, 4a and 4c may serve as promising leads for the development of novel HDAC-targeted anticancer therapies.
Development and Optimization of Myricetin Loaded Inhalable Microsphere to Treat COPD.
Siddheshwar SS, Jagtap D, Mankar SD … +3 more , Ghorpade AC, Dighe SB, Bhawar S
Pharm Res · 2025 Nov · PMID 41219567 · Publisher ↗
OBJECTIVES: To develop and optimize myricetin-loaded inhalable microspheres using ionotropic gelation technique for sustained pulmonary delivery in Chronic Obstructive Pulmonary Disease (COPD) treatment. METHODS: Myricet...
OBJECTIVES: To develop and optimize myricetin-loaded inhalable microspheres using ionotropic gelation technique for sustained pulmonary delivery in Chronic Obstructive Pulmonary Disease (COPD) treatment. METHODS: Myricetin-loaded microspheres were prepared using varying concentrations of gellan gum and sodium alginate through a 3 full factorial design. Formulations were characterized for physicochemical properties, in vitro release, aerodynamic performance using twin impinger, and stability. The optimized formulation was evaluated for bronchodilatory activity using histamine-induced contraction of goat tracheal chain model and compared with theophylline anhydrous. RESULTS: The optimized formulation (DF4) exhibited spherical morphology with ideal particle size for pulmonary delivery (7.72 μm), high entrapment efficiency (72.84%), and negative zeta potential ensuring colloidal stability. This formulation demonstrated excellent aerodynamic properties (FPF 31.71%), sustained drug release over 12 h, and remarkable stability over 6 months under both accelerated and real-time storage conditions. The formulation showed significant bronchodilatory activity with 63.47% relaxation at 25 μg/ml, achieving approximately 80.8% efficacy compared to theophylline anhydrous. CONCLUSION: The optimized myricetin-loaded inhalable microspheres represent a promising pulmonary delivery system for COPD management, offering advantages of sustained drug release, improved lung deposition, and significant bronchodilatory effect. This formulation holds potential for reducing dosing frequency, enhancing patient compliance, and improving therapeutic outcomes in COPD patients, warranting further in vivo studies before clinical translation.
Silver Nanoclay Human Albumin Serum Composite Electrochemical Biosensor for Quantification of Zidovudine in Tablets.
Timakwe S, Matoetoe MC
Pharm Res · 2025 Nov · PMID 41219566 · Full text
OBJECTIVE: This work aims to develop an electrochemical biosensor for the analysis of zidovudine (ZDV) in commercial tablets. METHOD: The biosensor utilised silver nanoclay composites (AgNCs) together with drop-coated Hu...
OBJECTIVE: This work aims to develop an electrochemical biosensor for the analysis of zidovudine (ZDV) in commercial tablets. METHOD: The biosensor utilised silver nanoclay composites (AgNCs) together with drop-coated Human Serum Albumin (HSA) on a glassy carbon electrode (GCE/AgNCs/HSA). The electrochemical properties of the GCE/AgNCs/HSA were studied using cyclic voltammetry (CV) and analysed using the Randles-Sevcik equation. Procedurally, optimised differential pulse voltammetry (DPV) technique in 1 M PBS, pH 7.04, was used to determine analytical parameters of the methods, validation, and study of commercial tablets. RESULTS: The optimum procedural conditions used were -0.4 V to -1 V potential range, 0.0405 V step potential, 0.075 V modulation amplitude, 0.01 s modulation time, and 0.25 s interval time. GCE/AgNCs/HSA film's electrochemical properties obtained were a diffusion coefficient (D) of 1.55 × 10-11 cm2.s-1, a heterogeneous rate constant (Ks) of 3.40 × 10-6 cm.s-1, with two electrons. The calibration graph linear range was from 0.12 to 6.98 μM with a low limit of detection (LOD) of 0.3 μM, and 1.0 μM limit of quantification (LOQ). Method validation showed an acceptable %RSD for reproducibility and repeatability. The sensor was stable over 10 days and remained unaffected by the presence of the interferences studied. The commercial study of 300 mg commercial tablets was found to be 301.3 mg with 1.9% RSD, which is in agreement with the tablet's stated amount. CONCLUSION: The development of the GCE/AgNCs/HSA biosensor was successful and efficiently used to quantify ZDV in tablets.
Natural Powerhouse Duo: Hierarchical Levan Hydrogels with Nanoencapsulated Cannabidiol as Local Delivery Systems.
Solovyov D, Porfiryeva NN, Awad R … +6 more , Tornaci S, Davidovich-Pinhas M, Salms G, Dubnika A, Öner ET, Sosnik A
Pharm Res · 2025 Dec · PMID 41219565 · Full text
INTRODUCTION: The nonpsychoactive cannabinoid cannabidiol (CBD) has shown a wide range of pharmacological effects that are beneficial for wound healing. However, its local delivery is challenged by a very low aqueous sol...
INTRODUCTION: The nonpsychoactive cannabinoid cannabidiol (CBD) has shown a wide range of pharmacological effects that are beneficial for wound healing. However, its local delivery is challenged by a very low aqueous solubility. METHODS: In this work, we synthesized hierarchical hydrogels made of the fructan hydrolyzed levan crosslinked with glycerol diglycidyl ether and loaded them with CBD nanoencapsulated within PluronicF127 polymeric micelles (25% w/w payload). RESULTS: Hydrogels showed the typical porous structure (high resolution-scanning electron microscopy) and water uptake capacity up to ~ 1700%. The CBD release kinetics was studied in water (pH 6.8) and phosphate buffered saline (pH 7.4) under sink conditions, at 37°C. An initial burst release stage within the first 2 h of the assay was followed by a more sustained release stage over 72 h. As expected, hydrogels with a lower crosslinking density exhibited faster CBD release in both media. Release data fit the Korsmeyer-Peppas model with a combined mechanism involving diffusion and polymer chain relaxation together with the release of CBD-loaded polymeric micelles. The good compatibility of the hydrogels was initially confirmed in the monocyte-derived human macrophage cell line THP-1 over 72 h. Then, we showed > 70% viability of primary patient-derived gingival mesenchymal stem cells (GMSCs) exposed to hydrolyzed levan solutions, CBD-loaded polymeric micelle suspensions, and the CBD-loaded hydrogels for 28 days. Finally, we conducted preliminary differentiation studies of GMSCs cultured on non-loaded and CBD-loaded hydrolyzed levan hydrogels. Non-loaded hydrogels promote a transient increase in the secretion of the osteogenic marker alkaline phosphatase secretion that peaked at day 7 and declined thereafter, while CBD-loaded ones promote adipogenic differentiation. CONCLUSION: Overall, results demonstrate the potential of levan hydrogels as platforms for local drug delivery applications.
A Comprehensive Design-to-skin Pipeline to Fabricate Polymeric Microneedles Using Ultrahigh-resolution 3D Printing.
La Malfa F, van Hulst IA, Ossendorp F … +2 more , Staufer U, van der Maaden K
Pharm Res · 2025 Nov · PMID 41219564 · Full text
OBJECTIVE: Microneedle technologies have emerged as a promising approach to improve intradermal drug delivery. This study presents a comprehensive workflow for fabricating polymeric microneedle arrays utilising ultrahigh...
OBJECTIVE: Microneedle technologies have emerged as a promising approach to improve intradermal drug delivery. This study presents a comprehensive workflow for fabricating polymeric microneedle arrays utilising ultrahigh-resolution 3-dimensional (3D) printing and silicone mould fabrication. METHODS: In this work, an extensive toolbox with over 75 distinct microneedle designs was created and sequentially fabricated from acryl using our workflow based on ultrahigh-resolution 3D printing. RESULTS: The microneedle design parameters included obelisk and cone-like shapes, various lengths, base and tip diameters, and different densities. We systematically assessed the optimal design parameters for effective penetration of ex vivo human skin explants. CONCLUSION: Our workflow, combined with application in an ex vivo human skin model, allows systematic comparison of multiple microneedle design parameters for efficacy. This work demonstrates the potential of this systematic modelling and ultrahigh-resolution 3D printing approach to optimize microneedles for intradermal biomedical applications, including therapeutic cancer vaccination.
Retraction Note: MicroRNA-302 Replacement Therapy Sensitizes Breast Cancer Cells to Ionizing Radiation.
Liang Z, Ahn J, Guo D … +2 more , Votaw JR, Shim H
Pharm Res · 2025 Nov · PMID 41201704 · Publisher ↗
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Using Lung Regional Deposition Modeling as Model-Integrated Evidence for Locally Acting Orally Inhaled Drug Products.
Walenga RL, Chopski SG, Lee JH … +5 more , Wang F, Hu M, Babiskin AH, Fang L, Zhao L
Pharm Res · 2025 Nov · PMID 41199079 · Full text
Evaluation of drug delivery for locally acting orally inhaled drug products (OIDPs) is challenging because there are no routinely conducted studies that directly quantify drug concentration in specific regions of the hum...
Evaluation of drug delivery for locally acting orally inhaled drug products (OIDPs) is challenging because there are no routinely conducted studies that directly quantify drug concentration in specific regions of the human lungs. In vivo regional deposition studies are helpful for understanding region-specific drug delivery to the lungs but are limited by a variety of factors including small population samples, long study duration, and representation of results in two-dimensional rather than three-dimensional frameworks. Lung regional deposition modeling (RDM) can provide useful insights on region-specific drug delivery to the lungs for locally acting OIDPS because it can be used to understand many of the underlying physical processes that influence drug delivery, and it can be used to develop in vitro in vivo correlations. When RDM is combined with in vitro and/or in vivo data that serve as model validation comparators as well as sources for model parameter inputs, and model credibility is established, it may be considered model-integrated evidence (MIE) when it is used to facilitate generic locally acting OIDP development and approval and thereby improve accessibility of OIDPs.
Bionanoconjugates in Neurodegeneration: Peptide-Nanoparticle Alliances for Next-Generation Therapies.
Ranjitha VR, Kumar A, Kaalappa P
Pharm Res · 2025 Dec · PMID 41199078 · Publisher ↗
The convergence of peptides and nanoparticles through bionanoconjugation has emerged as a transformative strategy to address the persistent challenges in treating neurodegenerative disorders. Peptides, particularly short...
The convergence of peptides and nanoparticles through bionanoconjugation has emerged as a transformative strategy to address the persistent challenges in treating neurodegenerative disorders. Peptides, particularly short sequences (< 45 amino acids), offer unique advantages as protein mimetics, including structural flexibility, target specificity and blood-brain barrier permeability. Their clinical translation is hindered by rapid enzymatic degradation, short half-life, and poor bioavailability. Conjugation with nanoparticles, overcomes these limitations by enhancing stability, prolonging circulation, and enabling precise targeting. Peptide-nanoparticle conjugates, including TAT-functionalized gold nanoparticles and RGD-decorated polymeric systems, have shown significant improvements in blood brain barrier penetration. These advancements are associated with a reduction in amyloid-beta aggregation and the inhibition of tau hyperphosphorylation in preclinical models. These hybrids leverage peptides dual roles as therapeutic agents and drug carriers, often exploiting receptor-mediated transport for brain delivery. This review critically evaluates covalent and noncovalent conjugation strategies, such as carbodiimide chemistry, ligand exchange, and click reactions, highlighting their impact on structural stability and bioactivity. We further discuss advances in peptide classes, including cell-penetrating peptides, nuclear localization signals, targeting peptides and bioactive peptides, emphasizing their applications in mitigating oxidative stress, neuroinflammation, and protein misfolding in neurodegenerative disorders. Despite promising preclinical outcomes, challenges such as scalability, immunogenicity, and heterogeneous blood brain barrier models remain barriers to clinical translation. This review outlines a strategy for enhancing peptide-NP conjugates as future neurotherapeutics by integrating existing methodologies, therapeutic results, and challenges. This underscores the importance of collaborative efforts across various disciplines to bridge the gap between advancements in nanotechnology and their clinical applications.
Design and In Vitro Evaluation of Gambogic Acid-Conjugated Stearic Acid Solid Lipid Nanoparticles for Transferrin Receptor-Mediated Drug Delivery.
Ganugula R, Dinakar YH, Kurse A … +2 more , Kumar MNVR, Arora M
Pharm Res · 2025 Dec · PMID 41199077 · Publisher ↗
Solid lipid nanoparticles (SLNs) have garnered significant interest for their safety and efficacy, especially following the success of COVID-19 mRNA vaccines. This study presents the synthesis and characterization of a n...
Solid lipid nanoparticles (SLNs) have garnered significant interest for their safety and efficacy, especially following the success of COVID-19 mRNA vaccines. This study presents the synthesis and characterization of a novel stearic acid (SA)-gambogic acid (GA) conjugate, where GA, a xanthonoid, exhibits high affinity for the transferrin receptor (TfR) without competing with endogenous transferrin. The SA-GA conjugate was employed to formulate SLNs using a hot homogenization-ultrasonication-solvent evaporation technique for the peroral delivery of cyclosporine (CsA), paclitaxel (PTX), and urolithin-A (UA). Physicochemical properties, including particle size, zeta potential, drug loading, and entrapment efficiency, were assessed. Among the three tested compounds, UA exhibited the highest encapsulation efficiency at both 5% and 10% w/w loading, with particle sizes remaining under 250 nm. SA-GA SLNs demonstrated excellent stability in simulated gastric fluids, supporting their potential for oral administration. Cellular uptake studies using Coumarin-6 (C6) and drug-loaded SLNs indicated that UA achieved the highest uptake (~ 50%) in both FHS-74 (human small intestine) and HK2 (human kidney) cell lines. Further, in cisplatin-induced HK2 cell damage models, UA-loaded SA-GA SLNs significantly reduced inflammatory markers TLR4, NF-κB, and IL-1β. These results highlight UA-loaded SA-GA SLNs as a promising TfR-targeted oral delivery system for mitigating cisplatin-induced acute kidney injury (AKI) in cancer therapy.
Improving the CQAs and Lyophilization Process Efficiency of Freeze-dried Monoclonal Antibody Drug Products Using Controlled Ice Nucleation Technology.
Chen Y, Kleppe M, Sharma S … +3 more , Ingram S, Shameem M, Tang X
Pharm Res · 2025 Nov · PMID 41193929 · Publisher ↗
PURPOSE: The objective of this research was to explore the application of controlled ice nucleation (CN) technology to enhance the critical quality attributes (CQAs) and manufacturing efficiency of freeze-dried monoclona...
PURPOSE: The objective of this research was to explore the application of controlled ice nucleation (CN) technology to enhance the critical quality attributes (CQAs) and manufacturing efficiency of freeze-dried monoclonal antibody (mAb) drug products. The study aimed to address challenges associated with conventional freeze-drying process, such as low supercooling temperatures and inhomogeneous ice nucleation temperatures, and to evaluate whether CN could improve product quality, and the overall efficiency of the lyophilization process. METHODS: Various mAb drug products were manufactured using three different lyophilization methods during the freezing step, including conventional, annealing, and CN. The CQAs of the drug products were assessed, including residual moisture content, reconstitution time, product appearance, microscopic morphology, specific surface area, protein purity, charge variance, and sub-visible particulates. Comparative analyses were conducted to evaluate the impact of the CN on product quality and process efficiency. RESULTS: CN demonstrated significant improvements in product appearance, uniformity, reconstitution properties, and stability. It notably reduced the primary drying time, enhancing the overall efficiency of the freeze-drying process. Furthermore, the CN method produced lyophilized drug products with consistent cake appearance, improved quality, and enhanced stability, ensuring therapeutic efficacy and patient safety. CONCLUSIONS: CN technology represents a major advancement in pharmaceutical manufacturing. The implementation of CN has the potential to improve the CQAs of drug products, optimize the lyophilization process, reduce operational costs, and increase production throughput. These findings underscore the importance of adopting innovative technologies like CN to meet the growing demand for high-quality and efficient biopharmaceutical production.
Multifunctional Engineering of Exosomes for Precision Therapeutics: Strategies for Targeted Delivery, Barrier Evasion, and Clinical Translation.
Mendonca SR, Bangera PD, Keerikkadu M … +2 more , Tippavajhala VK, Rathnanand M
Pharm Res · 2025 Nov · PMID 41188685 · Full text
Exosomes (EXM), cell-secreted nanoscale vesicles, are now used as promising tools for therapeutic protein, nucleic acid, and small molecule delivery. However, various challenges, such as rapid immune system clearance, in...
Exosomes (EXM), cell-secreted nanoscale vesicles, are now used as promising tools for therapeutic protein, nucleic acid, and small molecule delivery. However, various challenges, such as rapid immune system clearance, ineffective cargo loading, and reduced targeting specificity, hold them back from being clinically translated. Recent breakthroughs in EXM engineering have made them excellent biomolecule delivery tools. This review critically explores state-of-the-art strategies to maximize cargo incorporation, reengineer EXM surfaces, and create synthetic EXM mimetics. We present important engineering methods, such as genetic manipulation to increase cargo encapsulation, functionalization with targeting ligands, and designing synthetic vesicle structures. We further discuss the therapeutic uses of engineered EXM for different applications, such as cancer treatment, gene therapy, and regenerative medicine, highlighting their potential to evade biological barriers like the blood-brain barrier. Challenges in manufacturing, quality control, and regulatory concerns of translating engineered EXM into clinical therapies are also discussed. We emphasized the upcoming trends that would facilitate improving EXM-based delivery platforms, such as the creation of multifunctional engineered EXM and the incorporation of artificial intelligence for tailored drug delivery. This review stresses the revolutionary value of EXM engineering in establishing next-generation targeted therapeutics, unveiling new fronts for precision medicine and personalized health.
Population Pharmacokinetics of Intravenous Levetiracetam in Neurosurgical Patients: Dosage Optimization Based on CrCl and Mannitol Use.
Fan J, Xu J, Chen X … +10 more , Deng P, Xue C, Huang S, Zhao H, Li T, Yang L, Yu Y, Qian J, Ma M, Tang L
Pharm Res · 2025 Nov · PMID 41188684 · Publisher ↗
OBJECTIVE: Conventional low-dose levetiracetam (LEV) for post-neurosurgical seizure prophylaxis often yields subtherapeutic serum levels. This study characterized the population pharmacokinetics (PPK) of intravenous LEV...
OBJECTIVE: Conventional low-dose levetiracetam (LEV) for post-neurosurgical seizure prophylaxis often yields subtherapeutic serum levels. This study characterized the population pharmacokinetics (PPK) of intravenous LEV to optimize dosing in neurosurgical patients. METHODS: We conducted a retrospective PPK analysis in 87 neurosurgical patients (131 concentrations). Nonlinear mixed-effects modeling was used. Monte Carlo simulations identified regimens achieving ≥ 90% probability of target attainment (PTA) for trough concentrations (C) of 12-46 μg/mL. RESULTS: LEV median daily dose was 15.4 (7.7-43.5) mg/kg. A median of 1.5 (1-6) concentration samples were collected per patient. The LEV concentrations was 9.11 (1.39-33.79) μg/mL. Importantly, 78 random concentrations and C of 10 patients were all subtherapeutic. Seizures occurred in 13 patients (14.9%); all responded to dose escalation/valproate. A one-compartment model described PK. Estimated clearance (CL) and volume of distribution were 3.73 L/h and 28.10 L, respectively. Covariate analysis identified CrCl and mannitol coadministration as significant CL determinants. Monte Carlo simulations indicated that without mannitol, 1 g q8h (0.5h infusion for CrCl at 20-89 mL/min; 4h infusion for CrCl at 90-129 mL/min) or 1.5 g q8h (0.5h infusion for CrCl at 130-180 mL/min) achieved > 90% PTA. With mannitol, higher doses were required: 1 g q8h (4h infusion, CrCl at 20-49 mL/min) or 1.5 g q8h (0.5h infusion for CrCl at 50-89 mL/min; 4h infusion for CrCl at 90-180 mL/min). CONCLUSION: Standard LEV prophylaxis dosing often yields inadequate exposure in neurosurgical patients. LEV clearance is influenced by CrCl and mannitol use, higher doses is required for patients with concurrent mannitol therapy.
Evaluation of Mannitol's Crystallization Impact on the Secondary Structure of Spray-Dried recombinant human Growth Hormone (rhGH) Formulations.
Peri RV, Anchan H, Jonnalagadda K … +1 more , Gupta P
Pharm Res · 2025 Nov · PMID 41184549 · Publisher ↗
OBJECTIVE: The development of protein formulations is grappled by the complexity of maintaining protein integrity during the arduous formulation process. While several excipients have been employed for the stabilization...
OBJECTIVE: The development of protein formulations is grappled by the complexity of maintaining protein integrity during the arduous formulation process. While several excipients have been employed for the stabilization of proteins, including the recombinant human growth hormone (rhGH), a precise process control is still paramount. This study aims to investigate the effect of mannitol polymorphism on the structural stability of rhGH in its spray-dried formulations. METHODS: rhGH was co-spray dried with mannitol at protein:mannitol ratios (1:0.5 to 1:6, w/w). Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) characterized mannitol crystallinity. Furthermore, circular dichroism (CD) spectroscopy measured secondary structure pre- and post-accelerated storage (40°C/75% RH, 4 weeks), and SDS-PAGE was leveraged to evaluate protein aggregation. RESULTS: Spray-dried powders exhibited spherical particles (1-5 µm) with surface indentations. PXRD reported high levels of mannitol crystallization with ratios of 1:0.5, 1:1.5, and 1:6, which was corroborated by the change in crystallization index using DSC. Parallelly, it corresponded to reductions in α-helix content ranging from 21.8 to 25%, after storage. In contrast, the 1:4 ratio predominantly demonstrated an 8.4% increase in α-helix content, indicating enhanced stability. SDS-PAGE confirmed greater aggregation in samples with higher mannitol crystallization, whereas the 1:4 formulation minimized aggregation. CONCLUSION: Mannitol crystallization strongly influences rhGH stability in spray-dried powders. An optimal protein:mannitol ratio of 1:4 helped maintain mannitol in the amorphous state, preserved secondary structure, and reduced aggregation during storage. These findings underscore excipient crystallization as a key determinant of protein stability and identify a stabilizing composition for spray-dried rhGH.
Pharmaceutical 3D Printing for Psychiatric Medications: Advanced Innovations in Taste Masking and Personalized Oral Drug Delivery.
H S P, G B KK, Naik P … +1 more , Goudanavar P
Pharm Res · 2025 Nov · PMID 41184548 · Publisher ↗
PURPOSE: This review aims to examine the impact of three-dimensional (3D) printing technologies on enhancing psychiatric pharmacotherapy through facilitating personalized and patient-centered drug delivery. This research...
PURPOSE: This review aims to examine the impact of three-dimensional (3D) printing technologies on enhancing psychiatric pharmacotherapy through facilitating personalized and patient-centered drug delivery. This research specifically addresses problems such as poor medication compliance, polypharmacy, and palatability issues, especially in pediatric and elderly populations. METHODS: A thorough review of the literature was conducted, focusing on novel advances in 3D printing techniques, including fused deposition modeling (FDM), semisolid extrusion (SSE), stereolithography, inkjet printing, binder jetting, and selective laser sintering (SLS). Selected research highlighted the application of such technologies in developing customized oral drug dosage forms. Emphasis was placed on the exploitation of polymers like Eudragit® E PO, flavor-masking excipients, and their combination with biosensor and artificial intelligence (AI) systems. Case studies were assessed to ascertain their relevance and innovation in the development of psychiatric medications. RESULTS: 3D printing allows the manufacture of tailored psychiatric drugs with greater dosing versatility, taste masking, and the ability to merge several active drug ingredients into a single pharmaceutical form. Patient-friendly dosage forms such as chew gummies and chocolate tablets demonstrated enhanced acceptability. Also, forthcoming technologies such as 4D printing and AI-driven biosensors yield intelligent, interactive drug release systems that are specific to individual physiological or behavioral inputs. CONCLUSIONS: 3D printing represents a paradigm-shifting advance in psychiatric care, offering solutions to long-standing treatment compliance and fixed-dose challenges. Although regulatory and scalability challenges persist, the intersection of pharmaceutical engineering, material science, and artificial intelligence creates an encouraging platform for the future of precision mental care therapies.
Drum Filling of Thin-Film Freeze-Dried Monoclonal Antibody Powder in UniDose Powder Nasal Spray System.
Sandoval MA, Jara MO, Henry T … +5 more , Giri BR, Wilcox D, Watts AB, Williams RO, Cui Z
Pharm Res · 2025 Dec · PMID 41184547 · Publisher ↗
PURPOSE: Intranasal delivery of monoclonal antibodies (mAb) offers an attractive approach for preventing or treating respiratory viral infections. Previously, we showed that thin-film freeze-dried powder (TFFD powder) of...
PURPOSE: Intranasal delivery of monoclonal antibodies (mAb) offers an attractive approach for preventing or treating respiratory viral infections. Previously, we showed that thin-film freeze-dried powder (TFFD powder) of AUG-3387, an anti-SARS-CoV-2 spike protein mAb, could be sprayed into the posterior nasal cavity region of a nasal cast model using Aptar's unidose powder (UDSp) nasal spray system. This work investigated the feasibility of filling TFFD mAb powders into the UDSp system using drum filling. METHODS: New TFFD AUG-3387 powders were prepared by including magnesium stearate and/or hydroxypropyl methylcellulose in them. The powders were comminuted and their flow properties measured. A selected powder was filled into UDSp systems using a Harro Höfliger Drum TT benchtop filler or a Quantos hand-held powder dispenser at target fill weights of 0.5 and 1.0 mg, and the performance of the filled systems was evaluated. RESULTS: The F8 TFFD AUG-3387 powder was selected for drum filling due to its 'passable' to 'excellent' flowability and its minimal sensitivity to controlled moisture exposure. Drum filling succeeded at both target fill weights, consistently compacting the powder into pucks without ejection failures. The average fill weight was 0.54 ± 0.09 mg for the 0.5 mg target and 1.11 ± 0.08 mg for the 1.0 mg target. The drum-filled UDSp systems performed similarly to the Quantos-filled systems in shot weight uniformity, emitted particle size, and deposition in a nasal cast, although differences were observed in certain spray characteristics. CONCLUSIONS: It is feasible to drum fill TFFD mAb powder at low fill weights.
Co-encapsulation of an AKT Inhibitor Enhances the Tumor-cell Selectivity of STING Agonists in Co-delivery Liposomes.
Ge Z, Zhang Q, Wang Y … +6 more , Miao L, Wang X, Fan N, Duan L, Li Y, Qi XJ
Pharm Res · 2025 Nov · PMID 41184546 · Publisher ↗
OBJECTIVE: The therapeutic potential of STING agonists in cancer immunotherapy is hindered by poor tumor selectivity, resulting in systemic inflammation. Conventional targeted delivery strategies rely on cell-surface mar...
OBJECTIVE: The therapeutic potential of STING agonists in cancer immunotherapy is hindered by poor tumor selectivity, resulting in systemic inflammation. Conventional targeted delivery strategies rely on cell-surface markers, which inadequately distinguish tumor from normal cells. Here, we propose an intracellular-protein-guided approach to achieve tumor selective STING activation. METHODS: Leveraging the elevated phosphorylated AKT (p-AKT) levels characteristic of tumor cells, we engineered a synergistic co-delivery liposomal platform to selectively enhance STING agonist activity within tumors. Hydroxypropyl-β-cyclodextrin (HPβCD) liposomes were used to co-encapsulate resveratrol (Res), a mild, natural STING agonist, and curcumin (Cur), an AKT inhibitor, enabling simultaneous tumor targeting and AKT inhibition-mediated amplification of STING signaling. RESULTS: The co-loaded HPβCD liposomes achieved potent, tumor-selective STING activation enhanced by AKT inhibition. In vitro, this system reduced tumor cell proliferation by > 60% compared to controls. In vivo, Cur pretreatment markedly amplified Res-induced STING signaling, eliciting robust adaptive immune responses, suppressing metastatic recurrence, and extending median survival from 35 to 85 days (p < 0.05) relative to monotherapy groups. CONCLUSIONS: This study demonstrates that combining AKT pathway inhibition with STING activation offers a powerful, tumor-selective immunotherapy approach. By leveraging intracellular biomarkers rather than surface antigens, the co-delivery liposomal system achieves potent immunomodulation with minimal off-target effects, highlighting its potential as a next-generation strategy for precision cancer immunotherapy.
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