Pharmaceutical Research[JOURNAL]
Sun
200 papers
Correction: Preclinical Evaluation of AAV8-R338L Gene Therapy for Hemophilia: Efficacy, Pharmacokinetics, Distribution, Excretion and Toxicity in Mouse Models and Non-human Primates.
Dou D, Lu J, Li D … +4 more , He F, Zhu X, Zhang X, Chen X
Pharm Res · 2026 May · PMID 42209937 · Publisher ↗
Abstract loading — click title to view on PubMed.
From Crystal Structure to Dissolution Enhancement: Cocrystal Engineering of Resmetirom to Address Its Solubility Challenge.
Yang C, Zhu R, Zhang F … +4 more , Hu L, Zhu X, Liu X, Luo Y
Pharm Res · 2026 May · PMID 42209936 · Publisher ↗
PURPOSE: Resmetirom (RSM), the first FDA-approved drug for non‑cirrhotic steatohepatitis, suffers from poor aqueous solubility, limiting its oral bioavailability. This study aims to enhance the solubility of RSM through...
PURPOSE: Resmetirom (RSM), the first FDA-approved drug for non‑cirrhotic steatohepatitis, suffers from poor aqueous solubility, limiting its oral bioavailability. This study aims to enhance the solubility of RSM through cocrystal engineering guided by Hansen Solubility Parameters (HSP). METHODS: HSP as an initial miscibility filter combined with hydrogen-bond complementarity for cocrystal screening. Five novel cocrystals (Resmetirom-(S)-( +)-2-Amino-1-butanol (RSM‑S‑AB), Resmetirom-4-Aminopyridine (RSM‑AP), Resmetirom-Piperazine (RSM‑Pip), Resmetirom-Pyrimidine (RSM‑Pyr), Resmetirom-(R)-( +)-9-(2-Hydroxypropyl) adenine (RSM‑R‑HPA)) were obtained and characterized by PXRD, DSC, TGA, FT‑IR, and SCXRD. Hirshfeld surface analysis was employed to investigate intermolecular interactions. Equilibrium solubility and intrinsic dissolution rate (IDR) were measured in ultrapure water. RESULTS: All five cocrystals exhibited enhanced equilibrium solubility compared to pure RSM, with RSM‑S‑AB showing the greatest improvement (~ 30-fold). SCXRD revealed that the solubility enhancement stems from an extended hydrogen‑bonding network, a more open crystal packing, and additional polar groups introduced by the coformers. Lower melting points of all cocrystals further indicated reduced lattice energy. CONCLUSIONS: Cocrystal engineering guided by HSP and hydrogen‑bond complementarity successfully improved the aqueous solubility of RSM. The elucidated structure-solubility relationships provide a practical approach for optimizing the solid forms of poorly soluble drug candidates.
High-Dose Sunitinib Accelerates Triple-Negative Breast Cancer Metastasis by Modulating an Immunosuppressive Microenvironment: A Preclinical 4T1 Model Study.
Liu C, Xue J, Wang T … +4 more , Hou X, Chen D, Wang Y, Zhou T
Pharm Res · 2026 May · PMID 42204130 · Publisher ↗
BACKGROUND: Sunitinib (SUN), a multi-targeted anti-angiogenic tyrosine kinase inhibitor, could inhibit tumor growth and affect tumor microenvironment (TME). However, survival benefit for triple-negative breast cancer (TN...
BACKGROUND: Sunitinib (SUN), a multi-targeted anti-angiogenic tyrosine kinase inhibitor, could inhibit tumor growth and affect tumor microenvironment (TME). However, survival benefit for triple-negative breast cancer (TNBC) patients was limited and the drug resistance probably related to its pro-metastatic effect. The association between metastasis progression and SUN dosage, also the underlying mechanism still remains unclear. Herein, we illustrated the biphasic effect of SUN on metastasis attributed to divergent TME conditions modulated by different therapeutic SUN doses. METHODS: 4T1 murine TNBC cells and orthotopic allograft model were used. The effect of different doses of SUN on tumor progression was assessed on tumor-bearing mice. Mechanistically, scratch wound assay and Transwell were used to examine the motility of 4T1 cells in vitro. Flow cytometry, blood routine and combined drug evaluation were conducted to explore the TME-related pro-metastatic mechanism in vivo. RESULTS: Within therapeutic range, only high-dose SUN demonstrated pro-metastatic effect and have no benefit on prolonging the mice survival. Notably, it induced an immunosuppressive TME in multi-sites attenuating both innate and adaptive immune response rather than altering 4T1 cells motility. Consistent with the PD-L1 mediated T-cell inhibition in primary TME, co-administration of an anti-programmed death-1 (PD-1) monoclonal antibody reversed the high-dose SUN-induced increase in metastasis. CONCLUSIONS: Our data critically elaborated the impact of therapeutic dosage of SUN on tumor progression and treatment outcome. Our finding emphasized the biphasic effect under diverse SUN dosages and potentially informed optimized therapeutic regimens for TNBC patients.
Rational Design, Optimization and Bioinformatic Analysis of Anti-PD-L1 Peptide Conjugated Mocetinostat Prodrug Nanoparticles for Predictive Cancer Chemoimmunotherapeutic Efficacy.
Gayen S, Sanyal I, Roy S
Pharm Res · 2026 May · PMID 42204129 · Publisher ↗
OBJECTIVE: This study aimed to design and optimize anti-PD-L1 peptide-conjugated mocetinostat prodrug nanoparticles (PD-NPs) as a targeted chemoimmunotherapeutic strategy. METHOD: Rationale design and bioinformatic analy...
OBJECTIVE: This study aimed to design and optimize anti-PD-L1 peptide-conjugated mocetinostat prodrug nanoparticles (PD-NPs) as a targeted chemoimmunotherapeutic strategy. METHOD: Rationale design and bioinformatic analysis were performed to determine the binding affinity of PD-NPs with targeted proteins through molecular docking and molecular dynamic simulation. PD-NPs were synthesized by self-assembling EDC/NHS coupling reaction, characterized by different spectroscopical techniques. Enzyme-responsive drug release was assessed through in-vitro drug release study in presence and absence of cathepsin B, and quantified by HPLC and UV-visible spectroscopy. In-vitro studies were performed in A549, NCI-H1975 and NCI-H460 cells to assess HDAC activity, PD-1/PD-L1 binding affinity, intracellular cathepsin B levels, and immune activation. In-vivo toxicity study, hemolysis and pharmacokinetic study were performed to evaluate biological safety profile. Biodistribution, and histopathological evaluations were performed in B16-F10-induced lung tumor-bearing mice to assess therapeutic efficacy of PD-NPs. RESULT: The optimized zeta potential value was + 23.26 mV and Polydispersity Index (PDI) 0.21, indicating colloidal stability. TEM analysis demonstrated that PD-NPs has uniform spherical morphology. High drug loading efficiency was estimated to be 83.23 ± 2.5% which include 50.49% of anti-PD-L1 peptide and 32.74% of mocetinostat within the PD-NPs. CD spectroscopy, and DNA intercalation assay confirmed cathepsin B-triggered drug release. In-vitro studies demonstrated PD-NPs significantly exhibited HDAC enzymatic inhibition, PD-1/PD-L1 interaction blockade, and immune activation. In-vivo studies represented PD-NPs efficiently improving hemocompatibility, prolonging systemic circulation, enhancing tumor specific accumulation, and restoring typical architecture of lung tissues. CONCLUSION: PD-NPs showed remarkable structural stability, enzyme-responsive activation, and favorable biocompatibility, indicating their potential as a predictive cancer chemoimmunotherapy.
Physiological and Anatomical Alterations in Children with Liver Cirrhosis.
Elzinga FA, Lier S, Malik PRV … +6 more , Rottier BL, Akkerman OW, Verkade HJ, Bodewes F, Touw DJ, Mian P
Pharm Res · 2026 May · PMID 42174350 · Publisher ↗
OBJECTIVE: To evaluate physiological and anatomical changes in children with liver cirrhosis supporting the development of physiologically based pharmacokinetic (PBPK) models. METHODS: A literature review was conducted (...
OBJECTIVE: To evaluate physiological and anatomical changes in children with liver cirrhosis supporting the development of physiologically based pharmacokinetic (PBPK) models. METHODS: A literature review was conducted (December 2023-May 2024) using PubMed and Google Scholar to identify studies reporting physiological and anatomical parameters in children (< 18 years) with liver cirrhosis. Parameters were analyzed in relation to disease severity (Child-Pugh and/or MELD/PELD scores), stratified by age, and compared to adult data. This study examined parameters modified in adult liver cirrhosis PBPK models to assess if similar changes occur in children. RESULTS: Parameters such as albumin, α1-acid glycoprotein, glomerular filtration rate, functional liver mass, portal blood flow, hepatic arterial blood flow, renal blood flow, and cardiac index showed either comparable alterations or lacked sufficient pediatric data to confirm differences from adult data. Hematocrit was significantly lower in children aged 2 to < 6 years (P = 0.022), with up to 25% greater fractional decline compared to adults, possibly due to developmental and nutritional factors. CONCLUSION: While children with liver cirrhosis exhibit physiological trends similar to adults, hematocrit shows a clear age-specific difference. For other parameters, limited pediatric data prevents firm conclusions, highlighting the need for age-specific studies to improve PBPK models and guide pediatric drug therapy.
Effects of Normothermic Hepatic Ischemia-Reperfusion Injury on the Hepatic Disposition of Arachidonic Acid and Its Cytochrome P450-Generated Metabolites in Rats.
Edpuganti V, Mehvar R
Pharm Res · 2026 May · PMID 42174349 · Publisher ↗
PURPOSE: Cytochrome P450 (P450) metabolites of arachidonic acid (AA) are potential therapeutic targets in ischemia-reperfusion (IR) injury, yet their disposition and actions in hepatic IR are unknown. Cellular AA and its...
PURPOSE: Cytochrome P450 (P450) metabolites of arachidonic acid (AA) are potential therapeutic targets in ischemia-reperfusion (IR) injury, yet their disposition and actions in hepatic IR are unknown. Cellular AA and its P450 metabolites are primarily bound to lipid membranes, resulting in negligible free concentrations. This study investigates how hepatic IR injury impacts the disposition of free AA and its major P450 metabolites in rats. METHODS: Rats underwent 60 min of partial (70%) ischemia or sham surgery, followed by 5 min, 3 h, or 24 h of reperfusion. The effects of IR injury on free concentrations of AA and its major P450-generated metabolites in the liver were studied using LC-MS/MS. The activities of phospholipase A (PLA) enzymes, which release AA and its preformed metabolites from lipid membranes, were also measured in the liver and plasma. Additionally, in vitro rates of metabolite formation and the levels of major AA-metabolizing enzymes were assessed in microsomes. RESULTS: Hepatic IR injury significantly increased free liver concentrations of AA (sevenfold) and its metabolites (1.8-9.1-fold) only in the 5-min group. Similarly, PLA enzyme activity in the liver and plasma was higher only in this group. Conversely, liver IR injury caused a significant reduction or no change in the in vitro rate of AA metabolism to P450-mediated metabolites in the 5-min group. CONCLUSIONS: Liver IR injury rapidly increases liver concentrations of free P450-mediated metabolites of AA, likely due to IR-induced release of preformed metabolites and AA from lipid membranes, rather than an increase in P450 enzymatic activity.
Biomedical Large Language Models and Prompt Engineering for Causality Assessment of Individual Case Safety Reports in Pharmacovigilance.
Heckmann NS, Papoutsi DG, Barbieri MA … +5 more , Battini V, Mølgaard SN, Schmidt SØ, Melskens L, Sessa M
Pharm Res · 2026 May · PMID 42174348 · Publisher ↗
BACKGROUND: Biomedical Large Language Models (LLMs) combined with prompt engineering offer domain-specific reasoning, yet their application to individual-level causality assessment remains unexplored. This study evaluate...
BACKGROUND: Biomedical Large Language Models (LLMs) combined with prompt engineering offer domain-specific reasoning, yet their application to individual-level causality assessment remains unexplored. This study evaluated five combinations of biomedical LLMs, prompting strategies, and causality algorithms by comparing their agreement with two human expert evaluators. RESEARCH DESIGN AND METHODS: A total of 150 Individual Case Safety Reports (ICSRs) were analyzed: 140 reports from Food and Drug Administration Adverse Event Reporting System (FAERS), and 10 myocarditis/pericarditis ICSRs from Vaccine AERS (VAERS). Assessments were conducted using the Naranjo and WHO-UMC algorithms. Biomedical LLMs tested included TinyLlama 1.1B, Medicine LLaMA-3 8B, and MedLLaMA v20, combined with Chain-of-Thought (CoT) or Decomposition prompting. Agreement was measured using Gwet's Agreement Coefficient 1 (AC1) and percentage agreement, alongside performance metrics and qualitative error analysis. RESULTS: The Medicine LLaMA-3 8B-Naranjo-CoT combination achieved the highest agreement with human assessors for the final classification of causality (64%). Biomedical LLMs demonstrated low inter-rater agreement on critical items of causality assessment such as identification of listed AE, temporal plausibility, alternative causes, and objective evidence of AEs. Frequent model failures included irrelevant responses. CONCLUSIONS: Biomedical LLMs showed improved performance over general purpose models previously tested but remain suboptimal for reliable causality assessment of ICSRs.
Targeting VAMPs in Aging-Related Diseases: From Mechanisms to Pharmacotherapy.
Jia B, Dong H, Liu Y … +5 more , Liu X, Zhu X, Sun C, Zhang Q, Kang N
Pharm Res · 2026 May · PMID 42162535 · Publisher ↗
BACKGROUND: Vesicle-associated membrane proteins (VAMPs) are key regulators of membrane fusion, vesicular trafficking and intercellular communication. Structurally and functionally diverse, VAMPs participate in multiple...
BACKGROUND: Vesicle-associated membrane proteins (VAMPs) are key regulators of membrane fusion, vesicular trafficking and intercellular communication. Structurally and functionally diverse, VAMPs participate in multiple physiological processes, and their dysfunction facilitates the progression of various aging-related diseases. This review aims to systematically summarize the molecular mechanisms and therapeutic potential of VAMPs. METHODS: We summarize current evidence to clarify the functions of VAMPs in aging-related disorders, and elaborate their roles in vesicle dynamic events as well as the regulatory effects of post-translational modifications on VAMP activity. RESULTS: VAMPs are closely involved in neurodegenerative, metabolic, cardiovascular diseases and cancers. They modulate the whole process of vesicle circulation, and post-translational modifications dynamically regulate VAMP function. VAMP-targeting agents present promising prospects for disease intervention. CONCLUSION: Targeting VAMPs provides innovative therapeutic strategies to ameliorate aging-related pathological conditions.
Multiscale Dissolution Simulation of Particles from a Tablet in Dissolution Apparatus by Coupling Discrete Element with Lattice Boltzmann Methods.
Li Y, Hou P, Xing L … +2 more , Park K, Li T
Pharm Res · 2026 May · PMID 42162534 · Publisher ↗
PURPOSE: Dissolution kinetics of tablets is pivotal to therapeutic performance, quality assessment, and troubleshooting in manufacturing. We aimed to develop and validate a simulation framework to predict tablet dissolut...
PURPOSE: Dissolution kinetics of tablets is pivotal to therapeutic performance, quality assessment, and troubleshooting in manufacturing. We aimed to develop and validate a simulation framework to predict tablet dissolution kinetics under realistic hydrodynamic conditions, thereby supporting process development and quality control. METHODS: We modeled the dissolution of drug particles packed within a tablet by coupling the lattice Boltzmann method (LBM) for fluid flow and transport with the discrete element method (DEM) for particle mechanics in USP Apparatus II. The framework was first validated against experimental measurements of single‑particle dissolution, then scaled to bulk-particle (tablet‑level) simulations to assess model extensibility. RESULTS: The coupled LBM-DEM framework reproduced experimentally observed hydrodynamics and particle dynamics in a mechanically agitated dissolution device and scaled from single‑particle to tablet‑level simulations without sacrificing fidelity. CONCLUSIONS: This physics‑based framework enables the prediction of tablet dissolution under compendial hydrodynamic conditions and provides a foundation for incorporating additional particle‑mechanical phenomena (e.g., swelling and breakage) to fully model tablet disintegration and dissolution.
Reassessing and Updating Regulatory Standards on the Declaration of Storage Conditions in the Product Information of Medicinal Products: An Evidence-Based Proposal under EMA Guidance.
Pericão H, Cavaco H, Dias M … +24 more , Sarmento L, Magalhães M, Filipe B, Vieira H, Rita J, Gonçalves P, Vaz M, Coimbra B, Monteiro B, Gomes B, Josué C, Fuior E, Penso L, Ferreira M, Forjaz ML, Neves R, Azevedo S, Lopes C, Rosário S, Leal R, Erjavec P, Lima F, Loureiro R, Sanches-Fernandes GMM
Pharm Res · 2026 May · PMID 42162533 · Publisher ↗
PURPOSE: The European Medicines Agency (EMA) guideline Declaration of Storage Conditions in the Product Information of Medicinal Products (CPMP/QWP/609/96/Rev.2) was last revised in 2007. Since then, advances in stabilit...
PURPOSE: The European Medicines Agency (EMA) guideline Declaration of Storage Conditions in the Product Information of Medicinal Products (CPMP/QWP/609/96/Rev.2) was last revised in 2007. Since then, advances in stability science, increased climatic variability, and evolving regulatory expectations have highlighted limitations in the framework, particularly the use of vague descriptors such as "room temperature" or "no special storage conditions." This work reassesses the scientific and regulatory basis for storage statements, integrating current understanding of mean kinetic temperature (MKT), climate-related risks, and developments in ICH and WHO guidance, and proposes a harmonized revision (Rev.3). METHODS: A structured analysis of regulatory and scientific principles was conducted, incorporating MKT, climate-related risks, and developments in ICH and WHO guidance. These elements informed a revised framework and model storage statements, including a decision table linking stability outcomes to label statements. RESULTS: The proposed update introduces explicit temperature-based statements, strengthens the linkage between stability data and label wording, clarifies requirements for moisture- and light-sensitive products, expands guidance for sterile and reconstituted preparations, and provides contingency instructions for temperature excursions. A decision table mapping stability outcomes to label statements is included to support regulatory implementation. CONCLUSION: This revision provides an updated synthesis of EMA, ICH, and WHO requirements, translating regulatory principles into clear storage statements and contingency guidance. It offers a more precise framework reducing ambiguity, supports justification of storage conditions through stability data and MKT-informed risk assessment, aiming to improve understanding among patients and healthcare professionals, strengthening real-world product quality and contributing to future EMA guideline development. HIGHLIGHTS: Identifies scientific and regulatory limitations in current "no special storage conditions" terminology; Links ICH stability guidelines and climatic variability to precise storage statements; Proposes harmonised core label phrases for room temperature, fridge, and freezer; Introduces contingency labelling for climate-related and cold-chain excursions.
CFD study on deposition pattern of adult oropharyngeal drug particles with inhalation devices using realistic anatomical models under steady-state flow.
Ding Y, Wang S, Liu S … +2 more , Gong G, Tong Z
Pharm Res · 2026 May · PMID 42141173 · Publisher ↗
PURPOSE: With the rising burden of chronic respiratory diseases, inhalation therapy is essential for efficient drug delivery, yet oropharyngeal retention still limits effective lung deposition. Delivery efficiency depend...
PURPOSE: With the rising burden of chronic respiratory diseases, inhalation therapy is essential for efficient drug delivery, yet oropharyngeal retention still limits effective lung deposition. Delivery efficiency depends strongly on the inhaler type, the oropharyngeal geometry, and the relative positioning. This study aims to analyze these factors, particularly the angle of inhalation between the device and the airway. METHODS: Real adult mouth-throat models combined with Breezhaler® and Handihaler® devices were developed. Particle deposition under steady-state inhalation conditions was analyzed using the discrete phase modeling (DPM) method. RESULTS: The two devices exhibit distinct flow behaviors: Handihaler® produces higher resistance and stronger vortices, which increase oral deposition, whereas Breezhaler® maintains a more stable flow field. Oropharyngeal geometry, particularly tongue elevation, drives variations in deposition by enhancing turbulence. Significantly, the relative location and inhaler orientation angle are decisive determinants. A non-parallel incident angle significantly reduces aerodynamic resistance above the tongue and mitigates intense airflow impact, though it may cause localized vortex formation. The analysis indicates that higher values for the relative location factors (L and L) tend to correspond with lower deposition fractions and deposition densities in the mouth and throat. CONCLUSIONS: The Breezhaler® demonstrates lower simulated oropharyngeal deposition compared to the Handihaler® due to lower aerodynamic resistance and a more stable flow field within the evaluated models. Additionally, optimizing the relative location by modifying the inhalation angle could significantly reduce drug losses. These findings suggest that selecting the appropriate device type and controlling its orientation are critical for enhancing targeted pulmonary delivery.
NIPTE 2030: The Nation's Digital Trust Anchor for Pharma 5.0.
Hussain AS, Morris K, Gurvich VJ
Pharm Res · 2026 May · PMID 42141172 · Publisher ↗
As the National Institute for Pharmaceutical Technology and Education (NIPTE) marks its 20th anniversary, the pharmaceutical ecosystem faces a widening gap between regulatory "risk-to-quality" compliance and real-world "...
As the National Institute for Pharmaceutical Technology and Education (NIPTE) marks its 20th anniversary, the pharmaceutical ecosystem faces a widening gap between regulatory "risk-to-quality" compliance and real-world "risk-to-patient" outcomes. This Perspective offers a strategic roadmap for NIPTE to address the ontological fragmentation that treats drug products as legal descriptors rather than engineered systems. We suggest NIPTE is uniquely positioned to serve as the nation's "digital trust anchor" for Pharma 5.0-a human-centric evolution toward a patient-sovereign paradigm. By championing a five-layer CMC-GraphRAG architecture, NIPTE can lead the transition toward "Ontological Honesty" -defined here as the systematic grounding of AI reasoning in complete, mechanistically accurate representations of drug products and manufacturing processes as engineered systems. This choice allows NIPTE to elevate the patient's voice, transforming subjective experiences into mechanistically grounded Real-World Evidence (RWE). We illustrate these possibilities through the SMART-TDS pilot, which provides the scientific foundation-measured by the Semantic Precision Score (SPS) and Uncertainty Quantification (UQ)-necessary to support future industry-wide transitions toward dynamic, patient-centric quality assurance.
Formulation and Evaluation of Indomethacin Nanosuspensions Stabilized by Poly(2-oxazine) and Poly(2-oxazoline)-Based Polymers for Solubility Enhancement.
Espo E, Potdar D, Baas K … +13 more , Keßler L, Yang M, Bērziņš K, Kemell M, Kiiskinen T, Heinonen A, Kehrein J, Boyd BJ, Karttunen AP, Peltonen L, Luxenhofer R, Bunker A, Viitala T
Pharm Res · 2026 May · PMID 42141171 · Full text
OBJECTIVE: The challenges associated with poorly water-soluble drugs have been recognized for several decades. Poor aqueous solubility directly impairs the bioavailability of a drug, but this can be significantly improve...
OBJECTIVE: The challenges associated with poorly water-soluble drugs have been recognized for several decades. Poor aqueous solubility directly impairs the bioavailability of a drug, but this can be significantly improved using a nanosuspension (NS) formulation strategy. In general, there is high variability in stabilizers that function with different drugs, and it is often difficult to predict which stabilizer will yield a stable NS formulation. METHODS: In this study, poly(2-oxazine)- and poly(2-oxazoline)-based triblock copolymers (P1 and P2) were evaluated and benchmarked against commonly used stabilizers for the preparation of NS formulations, specifically hydroxypropyl methylcellulose and Pluronic F68. This study initiates the validation of P1 and P2 polymers for a new application, as these materials have not been previously studied as stabilizers in oral NS formulations. Indomethacin was selected as a poorly water-soluble model drug for NS preparation using a wet-ball milling technique. The stability of the resulting NSs was monitored over 28 days and their dissolution profiles were assessed under non-sink conditions. RESULTS: P1 and P2 demonstrated better particle size reduction, and stability properties compared to the traditional stabilizers. In particular, P1 presented a marked improvement in the dissolution profiles of indomethacin, significantly outperforming the other NS formulations and reference samples. Molecular dynamics simulations further revealed distinct differences in the interactions of P1 and P2 with the indomethacin crystal surface, supporting the experimental findings. CONCLUSIONS: Overall, our study highlights the potential of P1 as a promising stabilizer for nanosuspensions, providing mechanistic insights into polymer-drug compatibility, improved dissolution performance, and formulation stability.
Residual Content Impacts Critical Quality Attributes and Performance of Risperidone Microspheres.
Bhorkade S, Wan B, Pandey PK … +2 more , Dhruva S, Burgess D
Pharm Res · 2026 May · PMID 42141170 · Publisher ↗
PURPOSE: Poly (lactic-co-glycolic acid) (PLGA) microspheres are widely used long-acting injectable depots. However, their performance is highly sensitive to polymer material attributes that can influence microsphere stru...
PURPOSE: Poly (lactic-co-glycolic acid) (PLGA) microspheres are widely used long-acting injectable depots. However, their performance is highly sensitive to polymer material attributes that can influence microsphere structure, degradation, and drug release. While factors such as molecular weight and monomer ratio are well recognized, impact of residual species present in commercial PLGA has not been systematically evaluated. The novelty of the present study is the investigation of the effect of PLGA residual content on the physicochemical characteristics and in vitro performance of risperidone-loaded PLGA microspheres. METHODS: PLGA with varying amounts of residual content was obtained either through purification of a high-residual polymer by reprecipitation or by deliberately spiking PLGA with controlled quantities of monomeric residues (lactide or glycolide) or organic solvent. Risperidone was selected as the model drug, and microsphere formulations were prepared using PLGA with different amounts of residual content and compared with microspheres prepared using low residual PLGA. The microspheres were characterized for particle size, surface morphology, porosity, drug loading, polymer degradation kinetics, and in vitro drug release. RESULTS: Residual content was shown to significantly influence microsphere formation and performance. High solvent residue had a great impact on microsphere particle size, porosity, and drug loading, resulting in accelerated polymer degradation and drug release. A clear correlation was established between residual content, microsphere structure, degradation behavior, and release kinetics. CONCLUSIONS: These findings identify residual species as a critical material attribute of PLGA microspheres and highlight the importance of polymer purification and raw-material control to ensure consistent performance of microsphere formulations.
Mechanistic Insight into Formation and Release Enhancement of Sulindac-Amino Acid Small-Molecule Hydrogels.
Chen J, Sun H, Yue W … +7 more , Yue Z, Niu B, Li M, Lu X, Wang J, Liu X, Han J
Pharm Res · 2026 May · PMID 42129029 · Publisher ↗
PURPOSE: As research on gels continues to advance, pharmaceutical small-molecule hydrogels have attracted growing interest in formulation development. This study addressed two key questions: whether small-molecule hydrog...
PURPOSE: As research on gels continues to advance, pharmaceutical small-molecule hydrogels have attracted growing interest in formulation development. This study addressed two key questions: whether small-molecule hydrogels could function as an effective solubilization strategy and how to design such hydrogel systems. METHODS: Sulindac (SUL), a non-steroidal anti-inflammatory drug, is subject to significant limitations in clinical use owing to its low aqueous solubility. Herein, SUL-based small-molecule hydrogel systems were fabricated by simply mixing SUL with biocompatible amino acids in a small volume of deionized water. This study combined theoretical miscibility calculation, molecular dynamics simulation, and experimental verification (preparation, characterization, in vitro solubility and release assessments, etc.) to explore their formation and solubilization mechanisms. RESULTS: The formed SUL hydrogels with arginine (ARG) or lysine (LYS) exhibited characteristic three-dimensional network structures and excellent viscoelastic properties. Combined results from characterization analyses and molecular simulations revealed that hydrogel formation was promoted by three factors: favorable miscibility between SUL and ARG/LYS, a dissolution-aggregation equilibrium, and self-assembly driven by intermolecular interactions. Compared to pure SUL, the solubility of SUL in both hydrogels was enhanced more than 500-fold. Additionally, the novel SUL hydrogels demonstrated superior release kinetics and supersaturation capacity, characterized by rapid achievement of peak concentrations and sustained supersaturated release. These performances were attributed to the high-energy state of the hydrogels themselves and the complexation between SUL and ARG/LYS. CONCLUSIONS: This study presents a viable formulation approach for overcoming the poor water solubility of insoluble drugs through the design of small-molecule hydrogel formulations.
Immune Efficacy of a Vaccine Candidate Based on Binding Protein 26 (BP26) from Brucella melitensis Encapsulated in Niosome Nanoparticles Against Brucellosis.
Talebi K, Chiani M, Habibi M … +2 more , Samadi M, Asadi Karam MR
Pharm Res · 2026 May · PMID 42115561 · Publisher ↗
PURPOSE: Brucellosis is a common zoonosis, affecting animals and humans. Given the high prevalence of brucellosis, as well as the challenges associated with the animal vaccines, there is a need to develop effective vacci...
PURPOSE: Brucellosis is a common zoonosis, affecting animals and humans. Given the high prevalence of brucellosis, as well as the challenges associated with the animal vaccines, there is a need to develop effective vaccines against it. In this study, a Brucella vaccine candidate was developed based on niosome nanoparticles encapsulating BP26 protein from Brucella melitensis. METHODS: Cloning of amplified bp26 gene, cloning in pET28a-BL21 (DE3), and protein expression were done by optimized protocols. The properties of the synthesized niosome nanoparticles were evaluated using dynamic light scattering (DLS) and electron microscopy. Then, the entrapment efficacy, release profile, and effectiveness of BP26-encapsulated niosomes were assessed in vitro and in vivo. RESULTS: Analyses indicated BP26-encapsulated niosomes with an average size of 265.5 nm, entrapment efficacy of 95.4%, and release rate of 27.4%. The BP26 encapsulated in niosome maintained the humoral immune responses up to 110 days after the initial vaccination in mice. Mice immunized with free BP26 and those receiving BP26.niosome had significantly higher levels of both IgG1 (Th2) and IgG2a (Th1) compared to the controls. In addition, mice vaccinated with niosome encapsulating BP26 produced higher IFN-γ and IL-2 cytokines as Th1 response indicators compared to BP26 alone, demonstrating the tendency of niosomes to switch the responses toward cellular immunity. Niosomes encapsulating BP26 could significantly protect the mice against Brucella melitensis. CONCLUSIONS: Our results suggest BP26-encapsulating niosome as a potential vaccine candidate for combating B. melitensis. However, further investigations are needed to present BP26.niosome as a promising Brucella vaccine for clinical trials.
Computational Design and Biopharmaceutical Evaluation of a Chimeric Nanoparticle Vaccine for Targeted Delivery against BK Polyomavirus.
Zahmatkesh A, Faraji SN, Hosseini SY … +1 more , Yaghobi R
Pharm Res · 2026 May · PMID 42115560 · Publisher ↗
PURPOSE: To address the unmet need for a prophylactic therapy against BK polyomavirus (BKPV) in transplant recipients, this study employed a mechanism-based computational approach to design a multi-epitope chimeric nanop...
PURPOSE: To address the unmet need for a prophylactic therapy against BK polyomavirus (BKPV) in transplant recipients, this study employed a mechanism-based computational approach to design a multi-epitope chimeric nanoparticle (CNP) vaccine, predicting its biopharmaceutical and immunological profile. METHODS: A comprehensive computational biopharmaceutics pipeline was implemented. Conserved and immunodominant B-cell, helper T-lymphocyte (HTL), and cytotoxic T-lymphocyte (CTL) epitopes from all major BKPV proteins were identified using immunoinformatic tools. Epitopes were rigorously validated for antigenicity, safety, global population coverage, and cross-reactivity potential against JC polyomavirus. A multi-epitope construct, fused with immune-potentiating peptides, was designed and displayed on an Encapsulin nanocage via the SpyTag/SpyCatcher system to create a targeted delivery platform. RESULTS: Molecular docking and dynamics simulations demonstrated stable, high-affinity binding of the vaccine construct and the CNP with Toll-like receptors 2 and 4, predicting effective innate immune recognition. In silico immune simulation forecasted robust and durable humoral and cellular immune responses upon administration. CONCLUSIONS: This integrated computational study provides a mechanistic rationale for a novel CNP vaccine candidate against BKPV. The predicted stability, immunogenicity, and targeted delivery potential establish a strong foundation for subsequent in vitro and in vivo development, aligning with the translation of computational design into biopharmaceutical products.
Preparation of SP94-Modified Calcium Phosphate Lipid Nanoparticles Loaded with Bcl-2 siRNA and Doxorubicin and Their Targeted Therapeutic Effect on Hepatocellular Carcinoma.
Ma K, Yao J, Deng Y … +2 more , Lan T, Yan C
Pharm Res · 2026 May · PMID 42115559 · Publisher ↗
PURPOSE: To improve the targeted therapy of hepatocellular carcinoma (HCC), SP94-modified calcium phosphate lipid nanoparticles loaded with Bcl-2 siRNA and doxorubicin (SP94-LCP/DOX&Bcl-2 siRNA) were prepared. METHODS: S...
PURPOSE: To improve the targeted therapy of hepatocellular carcinoma (HCC), SP94-modified calcium phosphate lipid nanoparticles loaded with Bcl-2 siRNA and doxorubicin (SP94-LCP/DOX&Bcl-2 siRNA) were prepared. METHODS: SP94-LCP/DOX&Bcl-2 siRNA was fabricated via reversed-phase microemulsion. Its physicochemical properties (particle size, zeta potential, morphology), pharmaceutical performance (drug loading, encapsulation efficiency, stability, in vitro release), and in vitro activities (targeting, cytotoxicity, apoptosis, apoptosis-related proteins) were evaluated using HepG2 cells via cellular uptake, wound healing, Hoechst 33,258 staining, MTT, and Western blot assays. In vivo antitumor efficacy was tested in HepG2 xenograft nude mice. RESULTS: SP94-LCP/DOX&Bcl-2 siRNA had a mean diameter of 130 nm and a zeta potential of 20 mV, showing a spherical morphology with uniform distribution. The encapsulation efficiency of siRNA reached 92% and that of doxorubicin is 81%. It exhibited good stability and a significant sustained-release effect. SP94-LCP/DOX&Bcl-2 siRNA significantly reduced the IC₅₀ values of DOX + Bcl-2siRNA, and enhanced the uptake capacity of HepG2 cells for LCP. It remarkably inhibited the migration ability of HepG2 cells, concomitantly downregulating Bcl-2 and upregulating Bax expression, thereby facilitating apoptotic cell death. SP94-LCP/DOX&Bcl-2 siRNA could better inhibit tumor growth in mice and reduce the toxic and side effects on normal tissues of mice. CONCLUSIONS: In this study, SP94-LCP/DOX&Bcl-2 siRNA was successfully prepared. It exhibited remarkable targeting ability and antitumor activity, significantly enhancing the therapeutic effect of doxorubicin and siRNA on HCC. The construction of this drug delivery system provided a novel strategy for the clinical treatment of HCC.
Lateral Transport in Anisotropic Membrane during Permeation Study in Diffusion Cell.
Nimmansophon P, Li SK
Pharm Res · 2026 May · PMID 42115558 · Publisher ↗
PURPOSE: In membrane transport studies utilizing a diffusion cell such as In Vitro Permeation Test (IVPT), mass transport is not purely one-dimensional from the donor to the receptor. Lateral diffusion within the membran...
PURPOSE: In membrane transport studies utilizing a diffusion cell such as In Vitro Permeation Test (IVPT), mass transport is not purely one-dimensional from the donor to the receptor. Lateral diffusion within the membrane into the surrounding clamped region leads to edge effect-an increase in flux caused by lateral transport. In conventional skin permeation studies when the membrane is relatively thin compared to the diameter of the diffusion cell opening, edge effect is insignificant under the assumption of isotropic diffusion. However, biological membranes such as skin are not homogenous and diffusion within the membrane can be anisotropic (e.g., lateral diffusion can occur faster than transverse diffusion across the membrane). METHODS: This study evaluated the edge effect under these conditions using COMSOL Multiphysics simulations. RESULTS: The results indicated that the edge effect was evident but small for steady-state fluxes across a membrane (~ 4% to 10% flux increase) when the lateral diffusion coefficients were 10 to 30 times larger than the transverse diffusion coefficients, and the edge effect increased with increasing lateral diffusion coefficient and decreasing diffusion cell opening size. CONCLUSIONS: The findings suggested that edge effect should be considered when performing and interpreting IVPT data for membranes with either high anisotropy or small diffusion cell openings.
Lithocholic Acid-Derived Imidazolium Salts Suppress Breast Cancer Growth: In Vitro and In Vivo Evaluation.
Sawicka D, Sadowska A, Hryniewicka A … +4 more , Skonieczna B, Milewski R, Guzińska-Ustymowicz K, Car H
Pharm Res · 2026 May · PMID 42115557 · Publisher ↗
PURPOSE: A series of imidazolium salts (IMS), substituted with lithocholic acid (LA) and alkyl chains of varying lengths (LA-1 to LA-10), were evaluated for their cytotoxic effects against breast cancer (BC). METHODS: Th...
PURPOSE: A series of imidazolium salts (IMS), substituted with lithocholic acid (LA) and alkyl chains of varying lengths (LA-1 to LA-10), were evaluated for their cytotoxic effects against breast cancer (BC). METHODS: The cytotoxic potential of the tested salts was assessed in estrogen-dependent (MCF-7) and non-estrogen-dependent (MDA-MB-231) cell lines, as well as in the cardiomyocyte cell line H9C2. The study was also conducted in vivo using a MCF-7 mouse xenograft model. RESULTS: The cytotoxicity of IMS increased with the length of the aliphatic chain. A significant effect, compared with the reference drug, was observed for LA-7 and LA-8 (IC = 13.07-13.19 µg/ml) in MCF-7 cells and for LA-1-LA-8 (IC = 77.82-21.06 µg/mL) in MDA-MB-231 line. LA-8 and doxorubicin showed increased toxicity in MCF-7 cells, reducing HMGB1 concentration and DNA synthesis, while increasing apoptosis and the activation caspase 7 and 8. Most of the tested IMS exhibited significantly lower toxicity toward healthy H9C2 cardiomyocytes (IC = 52.09-105.40 µg/mL) compared with doxorubicin (IC = 51.71 µg/mL). In vivo studies demonstrated that LA-8 treatment significantly inhibited the growth of MCF-7 tumors. CONCLUSIONS: LA-based IMS demonstrate significant potential as chemotherapeutic agents for the treatment of breast cancer.
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