Pharmaceutical Research[JOURNAL]
Sun
200 papers
Evaluation of Low-Field NMR as a PAT Technology for Upstream Bioprocess Monitoring.
Gerzon G, Fischer C, Pennestri M … +6 more , Hunter HN, Anklin C, Misra R, Wilson D, Sheng Y, Kirkitadze M
Pharm Res · 2026 Mar · PMID 41714542 · Publisher ↗
PURPOSE: This study aimed to evaluate the capacity of low-field nuclear magnetic resonance (LF NMR) as a standalone or orthogonal method for monitoring key parameters of interest for upstream cell culture fermentation in...
PURPOSE: This study aimed to evaluate the capacity of low-field nuclear magnetic resonance (LF NMR) as a standalone or orthogonal method for monitoring key parameters of interest for upstream cell culture fermentation in vaccine manufacturing. METHODS: Off-line near-infrared (NIR) and NMR measurements of fermentation samples from cells were acquired using the Matrix-F spectrometer with an Excalibur XP25 probe and the Fourier 80 LF NMR spectrometer respectively. Comparative analyses and multivariate modeling were employed against off-line reference and NIR models to characterize the process parameters of glucose, lactate and pH. Additional metabolites were identified and quantified using LF NMR signals. Indirect hard modeling was applied using LF NMR data to achieve relative quantification and visualization of metabolite concentrations. RESULTS: LF NMR was applied to quantify lactate, glucose and pH in the cell upstream fermentation media, showing good agreement and comparable measurements to off-line and NIR methods. Further analysis of the LF NMR spectra allowed identification and quantification of additional metabolites. The results demonstrate that LF NMR can provide complementary information to NIR and expand process understanding by revealing dynamic changes in parameters of interest during fermentation. CONCLUSIONS: This study demonstrates that LF NMR is a feasible and effective analytical tool for monitoring cell fermentation process during vaccine manufacturing. As a standalone or orthogonal method to NIR, LF NMR provides valuable insights to support real-time measurements for process control in vaccine manufacturing.
The Advanced Integrated Respiratory (AIR) Model: Comparative Analysis of Salbutamol Sulphate Deposition from pMDI, DPI, and Nebuliser Versus the NGI.
He P, Lam H, Chong D … +6 more , Cheng S, Spicer P, Young PM, Ledo L, Traini D, Ong HX
Pharm Res · 2026 Mar · PMID 41714541 · Full text
PURPOSE: In vitro respiratory models such as the Next Generation Impactor (NGI), remain the gold standard for aerodynamic particle size distribution (APSD) testing, however, they lack the anatomical complexity, limiting...
PURPOSE: In vitro respiratory models such as the Next Generation Impactor (NGI), remain the gold standard for aerodynamic particle size distribution (APSD) testing, however, they lack the anatomical complexity, limiting their ability to replicate in vivo deposition. To address this limitation, the Advanced Integrated Respiratory (AIR) model, a physiologically relevant benchtop system incorporating anatomically accurate silicone casts of the upper and lower airways, was used to assess deposition of salbutamol sulphate delivered via three clinically relevant platforms. METHODS: Salbutamol sulphate was delivered using a pressurised metered-dose inhaler (pMDI), a dry powder inhaler (DPI), and a jet nebuliser. Deposition profiles obtained in the AIR model were benchmarked against the NGI. RESULTS: Both systems showed consistent patterns for DPI and nebuliser aerosols, with highest deposition in the oropharyngeal and intrathoracic regions, respectively. In contrast, pMDI testing revealed important differences: the AIR model predicted markedly higher oropharyngeal retention and reduced intrathoracic delivery, aligning more closely with published in vivo scintigraphy studies than the NGI. CONCLUSION: These findings demonstrate that anatomically realistic models provide critical insights into deposition behaviour, particularly for propellant driven inhalers and underscore the value of integrating physiologically relevant platforms alongside conventional impactors in aerosol characterisation.
Continuous Microfluidic Manufacture of Nano-in-Microparticles Combining 3D-Printed Micromixers and Spray Drying.
Kara A, Ongoren B, Anaya BJ … +2 more , Lalatsa A, Serrano DR
Pharm Res · 2026 Mar · PMID 41714540 · Publisher ↗
PURPOSE: Conventional nanoparticle manufacturing techniques remain costly, labor-intensive, and difficult to scale, while also being subject to batch-to-batch variability. These limitations hinder their clinical translat...
PURPOSE: Conventional nanoparticle manufacturing techniques remain costly, labor-intensive, and difficult to scale, while also being subject to batch-to-batch variability. These limitations hinder their clinical translation, particularly in first-in-human trials. Emerging transformative technologies such as microfluidics and three-dimensional (3D) printing offer opportunities to develop agile, continuous, and scalable manufacturing processes. This study aims to demonstrate the feasibility of continuous microfluidic production of nanoparticles using customizable 3D-printed chips, integrated with atomization technologies, to generate solid nano-enabled controlled release therapies. METHODS: 3D-printed microfluidic chips were designed using computational fluid dynamics (CFD) to optimize flow characteristics. Nifedipine (NFD)-loaded nanoparticles were continuously manufactured with Eudragit L-100 and subsequently embedded into pullulan microparticles by spray-drying, yielding nano-in-microparticles (NIM). Particle size, encapsulation efficiency, solid-state properties, permeability, and release kinetics were assessed in ex vivo Franz cell studies across porcine intestinal membranes. RESULTS: Continuous microfluidic processing produced NFD-loaded nanoparticles with 95% encapsulation efficiency. Spray-drying yielded spherical pullulan-based NIMs of ~ 10 µm, which, upon rehydration, released NFD nanoparticles of ~ 100 nm. The nanoparticles retained their amorphous state and displayed a three-fold increase in intestinal permeability compared to free drug, accompanied by a three-fold reduction in lag time. Release studies demonstrated reduced burst release and a sustained zero-order release profile over 24 h, favorable for blood pressure maintenance therapy. CONCLUSIONS: The integration of 3D-printed microfluidic chip design with continuous manufacturing and spray-drying enables scalable production of solid nano-enabled therapies. The NFD-loaded NIMs demonstrated enhanced permeability and controlled release, supporting the potential of this platform for the clinical translation of nanomedicines.
Assessment of Vancomycin Penetration into Cerebrospinal Fluid in Patients with Ventriculitis Using a Physiologically Based Pharmacokinetic Approach.
Guimarães LMA, de Vasconcellos Nacif LO, de Lima Benzi JR … +5 more , de Oliveira Santos MT, Yamada C, Tuon FF, Telles JP, de Lima Moreira F
Pharm Res · 2026 Feb · PMID 41639518 · Full text
INTRODUCTION: Vancomycin is an antimicrobial agent for treating central nervous system (CNS) infections caused by Gram-positive bacteria. Due to practical and ethical reasons, it is difficult to evaluate vancomycin expos...
INTRODUCTION: Vancomycin is an antimicrobial agent for treating central nervous system (CNS) infections caused by Gram-positive bacteria. Due to practical and ethical reasons, it is difficult to evaluate vancomycin exposure in cerebrospinal fluid (CSF) and its relationship with therapeutic outcomes. Therefore, alternative methodologies are required. We developed a physiologically based pharmacokinetic (PBPK) model to characterize vancomycin exposure in plasma and CSF in patients with ventriculitis enrolled in a therapeutic drug monitoring program. METHODOLOGY: PBPK modeling and simulation were conducted using PK-Sim® version 11.3. A PBPK model was constructed to simulate vancomycin exposure in plasma and CSF. Physicochemical parameters of vancomycin were incorporated into a large molecule model, and tissue distribution was described using the Rodgers-Rowland model. RESULTS: The final PBPK model incorporated vancomycin's low brain permeability by adjusting the CSF-to-plasma partition coefficient to 0.17. Model validation was performed using data from 33 patients with ventriculitis under external ventricular drainage. The dosing regimen consisted of a 30 mg/kg loading dose followed by a continuous intravenous infusion of 60 mg/kg/day. Mean simulated vancomycin concentrations in plasma and CSF were 32 mg/L and 7.2 mg/L, respectively. The predicted CSF/plasma concentration ratio was 0.22, which closely matched the observed ratio of 0.17. CONCLUSION: Vancomycin penetration into the CNS is low and variable, highlighting the importance of therapeutic drug monitoring and individualized therapy in patients with ventriculitis. In the future, this model may facilitate the selection of optimal dosing regimens by simulating alternative dosing strategies and establishing PK/PD relationships for CNS infections.
Naringenin Loaded Hydrogel Supports Wound Repair in a Cell Model of Diabetic Skin.
Marwah MK, Hindalekar YS, Rana K … +9 more , Shokr H, Al Tahan MA, Sanchez-Aranguren L, Sarr M, Kainth R, Babaei P, Asif H, Ahmad S, Mahomed A
Pharm Res · 2026 Mar · PMID 41618075 · Full text
INTRODUCTION: Diabetic foot ulcers are a major complication of diabetes, driven by inflammation, oxidative stress, and poor vascular function. Naringenin, a citrus flavonoid, addresses these factors but has low solubilit...
INTRODUCTION: Diabetic foot ulcers are a major complication of diabetes, driven by inflammation, oxidative stress, and poor vascular function. Naringenin, a citrus flavonoid, addresses these factors but has low solubility and stability. We developed a Na-AMPS hydrogel dressing to enhance its delivery under diabetic-like conditions. METHODS: A Na-AMPS hydrogel containing 0.02%(w/w) naringenin was formulated and assessed for rheological and adhesive properties, drug release, and biological activity in HUVEC and HDFa cells. Cytotoxicity (XTT), reactive oxygen species (ROS), mitochondrial membrane potential (TMRM), cytokine levels (IL-6, IL-8, MMP-9, TGF-β), and wound closure (scratch assay) were measured. RESULTS/DISCUSSION: Naringenin modestly reduced the hydrogel elastic modulus (15,791.5 ± 1965 Pa at 30 Hz) without affecting adhesion. Release studies showed rapid drug release from solution but sustained release from hydrogels (17.88 ± 2.61% over 24 h). Under hyperglycaemic and pro-inflammatory conditions, naringenin significantly decreased ROS in HUVECs (41,030.58 ± 2737 to 31,778.74 ± 1822 AU; p < 0.001) and HDFa cells (38,188.13 ± 4593 to 29,950.94 ± 1426 AU; p < 0.05). Naringenin improved mitochondrial membrane potential in both cell types (p < 0.05-0.01) and attenuated pro-inflammatory cytokines. IL-6 decreased in HUVECs (39.40 ± 5.02 to 27.15 ± 3.10 pg/mL; p < 0.01) and HDFa cells (40.05 ± 2.23 to 16.41 ± 1.27 pg/mL; p < 0.0001). In HDFa's, MMP-9 was reduced (403.43 ± 18.70 to 195.33 ± 11.02 pg/mL; p < 0.0001), while in HUVECs, wound closure was enhanced. CONCLUSION: Naringenin-loaded Na-AMPS hydrogels demonstrated sustained release, suitable mechanical properties, and significant antioxidant, anti-inflammatory, and wound healing effects. These findings highlight their therapeutic potential for diabetic wounds treatment.
Penicillin Concentrations in Oropharyngeal and Frontal Sinus Tissue Following Intravenous Bolus and Continuous Infusion - An Experimental Porcine Study.
Hanberg P, Rasmussen HC, Bue M … +7 more , Stilling M, Jørgensen AR, Krogsgaard Petersen E, Lilleøre JG, Hvistendahl MA, Bille J, Klug TE
Pharm Res · 2026 Feb · PMID 41578093 · Full text
BACKGROUND AND PURPOSE: Studies have documented that continuous infusion is superior to bolus infusion in providing longer time with drug concentration above the minimal inhibitory concentration (T > MIC). This porcine s...
BACKGROUND AND PURPOSE: Studies have documented that continuous infusion is superior to bolus infusion in providing longer time with drug concentration above the minimal inhibitory concentration (T > MIC). This porcine study compared steady-state penicillin concentrations in oropharyngeal and frontal sinus tissues following intravenous bolus and continuous administration. EXPERIMENTAL APPROACH: Twelve pigs were randomized to receive either intravenous bolus (Group BI) or continuous (Group CI) infusion of penicillin (1.2 g). Doses were administered at 0, 6, and 12 h, with sampling from 12 to 18 h. Microdialysis was used for sampling in oropharyngeal and frontal sinus tissues, with simultaneous plasma sampling. The primary endpoints were T > MIC for two MIC targets (0.125 (low target) and 0.5 (high target) μg/mL) and attainment of ≥ 50%T > MIC treatment target. KEY RESULTS: No statistically significant differences were found between Group BI and CI for either MIC target. The ≥ 50%T > MIC target was achieved in all compartments except for the high MIC target in oropharyngeal tissue in Group CI (46%). although no statistical significance, T > MIC in oropharyngeal tissue tended to be longer in Group BI (low target: 98%; high target: 74%) compared with Group CI (low target: 68%; high target: 46%) (p = 0.07 and p = 0.19, respectively). CONCLUSION AND IMPLICATION: Penicillin bolus and continuous infusion resulted in comparable T > MIC in oropharyngeal and frontal sinus tissues. However, bolus infusion showed a higher likelihood of attaining ≥ 50%T > MIC in oropharyngeal tissue. These findings are specific to the porcine model and dosing regimens used and cannot be directly extrapolated to humans.
Lipid Nanoparticle Development in Practice: Challenges and Collective Insights.
Lu X, Ranjbar S, Zhang F … +11 more , Choonara Y, Pearson RM, Fetse J, He R, Mohamed E, Ranjan A, Hussain MD, Mohamed Kheir AHO, Yen CW, Salem AK, Mosharraf M
Pharm Res · 2026 Feb · PMID 41572106 · Publisher ↗
Lipid nanoparticles (LNPs) have emerged as a versatile delivery platform for improving pharmacokinetic performance, protecting nucleic acid cargo, and enabling tissue- and cell-specific targeting. Continued advancement o...
Lipid nanoparticles (LNPs) have emerged as a versatile delivery platform for improving pharmacokinetic performance, protecting nucleic acid cargo, and enabling tissue- and cell-specific targeting. Continued advancement of LNP-based therapeutics requires a deeper understanding of how raw material quality, formulation parameters, nanoparticle architecture, and biological context collectively influence clinical performance. In this Perspective, we discuss key challenges, practical insights, and lessons learned from ongoing LNP development efforts, with emphasis on characterization strategies, delivery specificity, scale-up considerations, long-term stability, and emerging applications of artificial intelligence. We highlight the importance of rational design principles, robust and reproducible manufacturing practices, comprehensive analytical characterization, and innovative approaches to support the next generation of LNP technologies.
Differences in mAb Galactosylation Caused by the Leaching of Manganese Ions from Different Bioreactors.
Liu X, Qin G, Mao J … +7 more , Li G, Tan C, Xu S, Wang P, Wang X, Lin Y, Xu D
Pharm Res · 2026 Mar · PMID 41572105 · Publisher ↗
BACKGROUND: Protein N-glycosylation is one of the critical quality attributes of monoclonal antibody (mAb). Evaluating its scalability and batch-to-batch consistency is essential for ensuring process robustness and produ...
BACKGROUND: Protein N-glycosylation is one of the critical quality attributes of monoclonal antibody (mAb). Evaluating its scalability and batch-to-batch consistency is essential for ensuring process robustness and product safety and efficacy. RESULTS: This study revealed that Project A exhibited significant scale differences in galactosylation ratio during process development and scale-up, with galactosylation levels in 2 L bioreactors being significantly greater than those in shake flasks and 200 L single-use bioreactors. We investigated the cause of this phenomenon and determined that the elevated galactosylation in 2 L bioreactor was due to the leaching of 0.05 μM to 0.06 μM manganese ions from the stainless-steel components in the 2 L glass bioreactor. These scale differences can be eliminated by adding 0.2 μM MnCl · 4HO. Second, for projects with lower galactosylation levels, this paper suggests the use of shake flasks instead of bioreactors to guide the process scale-up of mAb glycosylation, thereby reducing trial-and-error costs and the production costs associated with replacing glass bioreactors with single-use bioreactors. Notably, the scale differences in mAb galactosylation observed in Project A do not apply to Project B, which showed no scale effect, indicating that this phenomenon may be more applicable to cell lines that are more sensitive to metal ions. CONCLUSIONS: These findings demonstrate that metal ion leaching presents a substantial challenge to the process consistency of mAb. We have proposed a series of targeted and practical solutions to address the issue of "equipment and material leaching" during the production of mAb glycosylation amplification.
Enhanced Solubilization of Ketoprofen Using Triton X-100, Triton X-165, Brij C10, and Their Binary and Ternary Mixed Micelle Systems.
Agatić ZF, Lalić-Popović M, Todorović N … +3 more , Stjepanović A, Tepavčević V, Poša M
Pharm Res · 2026 Feb · PMID 41565935 · Publisher ↗
PURPOSE: This study investigates the thermodynamic behaviour and solubilization efficiency of micellar systems composed of Triton X-100, Triton X-165, and Brij C10, individually and in mixtures, using ketoprofen as a poo...
PURPOSE: This study investigates the thermodynamic behaviour and solubilization efficiency of micellar systems composed of Triton X-100, Triton X-165, and Brij C10, individually and in mixtures, using ketoprofen as a poorly water-soluble model drug (BCS class II). The aim was to clarify the relationship between micellar stability, molecular interactions, and drug solubilization. METHODS: Critical micelle concentrations (cmc) were determined by fluorescence spectroscopy with pyrene as a probe. Non-ideality of mixed micelles was analysed by Rubingh's model, Regular Solution Theory, and the Margules function. Thermodynamic parameters (g, s, h) were derived, and ketoprofen solubilization was quantified by HPLC as molar solubilization ratio (MSR) and excess solubilization parameters. RESULTS: Brij C10 exhibited the lowest cmc, reflecting strong hydrophobic contributions. Binary systems containing Brij C10 with Triton X-100 or X-165 showed pronounced synergism, indicated by negative β and gᴱ values. Triton-only systems behaved nearly ideally. Brij C10 alone provided the highest MSR, while binary Triton-Brij mixtures displayed partial antagonism in ΔMSR despite favourable thermodynamic stabilization. The ternary system was thermodynamically stable but less effective for ketoprofen solubilization due to packing constraints. CONCLUSIONS: Micellar stability and solubilization efficiency are not always correlated. Brij-rich micelles showed superior ketoprofen solubilization, whereas overly stabilized ternary systems limited drug loading. These findings highlight the need to balance stability and flexibility when designing micellar carriers for hydrophobic BCS class II drugs.
Potential Enhancement of Topical Drug Delivery Using Grapefruit-derived Nanoparticles Modified Using TAT Peptide.
Kanai R, Seki T, Yukimura T … +10 more , Komatsu S, Itakura S, Arce FJ, See GL, Kiba Y, Kitamura M, Kodama N, Inoue Y, Oshizaka T, Todo H
Pharm Res · 2026 Feb · PMID 41565934 · Publisher ↗
PURPOSE: Plant-derived nanoparticles (PdNPs) have garnered increasing attention as versatile tools for nucleic acid delivery, and they have been investigated for the transdermal delivery of encapsulated nucleic acids. Ho...
PURPOSE: Plant-derived nanoparticles (PdNPs) have garnered increasing attention as versatile tools for nucleic acid delivery, and they have been investigated for the transdermal delivery of encapsulated nucleic acids. However, not all PdNPs have high skin penetration enhancement ability. Surface modification of PdNPs with cell penetration peptides (CPPs) can enable skin penetration, with the Tat-peptide selected as a suitable CPP. In the present study, the feasibility of enhancing skin penetration was evaluated using grapefruit-derived nanoparticles (GNPs) modified with stearylated Tat-peptide (STR-Tat). METHODS: The surface modification of GNPs with STR-Tat was conducted using a simple mixing method of synthesized STR-Tat with GNPs. Changes in particle size and zeta-potential of STR-Tat-GNPs were measured. In addition, in vivo skin penetration experiments were conducted as well as investigating cellular uptake and cell toxicity to determine the effect of surface modification on the skin penetration ability of GNPs. RESULTS: A positive zeta potential was observed for STR-Tat-GNPs, whereas GNPs had a negative zeta potential. In addition, increased cellular uptake was confirmed for STR-Tat-GNPs without extensive cell toxicity. DiI-derived fluorescence was observed in hair follicles and at deeper sites of the dermis when DiI-labelled STR-Tat-GNPs were applied on mouse back skin in in vivo conditions. CONCLUSION: A simple mixing procedure of STR-Tat enhanced the skin penetration ability of a lipophilic dye initially associated with GNPs without cellular toxicity. Therefore, this approach may be applicable for providing plant-derived particles, which are expected to be an effective vehicle for nucleic acid delivery with high skin penetration ability.
In Silico Analysis of Potential Vaccine Antigens for the Treatment of Crimean-Congo Hemorrhagic Fever Virus (Cchfv).
Tülümen D, Aydemir E, Ayaz F
Pharm Res · 2026 Mar · PMID 41540299 · Full text
BACKGROUND: Crimean-Congo hemorrhagic fever virus (CCHFV), identified by the World Health Organization(WHO) as a potential epidemic threat, is a tick-borne Nairovirus primarily transmitted by Hyalomma marginatum species....
BACKGROUND: Crimean-Congo hemorrhagic fever virus (CCHFV), identified by the World Health Organization(WHO) as a potential epidemic threat, is a tick-borne Nairovirus primarily transmitted by Hyalomma marginatum species. Since its first detection in the 1940s, CCHFV has spread to multiple regions worldwide and remains a major public health concern due to its high fatality rate and expanding geographic distribution. The virus can be transmitted through tick bites or contact with infected individuals, and no licensed vaccine is currently available to prevent infection. METHODS: In this study, two CCHFV proteins, Q8JSZ3 (GP_CCHFI) and Q6TQR6 (L_CCHFI), were retrieved from public databases and analyzed using bioinformatic tools to explore their potential as vaccine candidates. RESULTS: The computational analyses revealed that both proteins possess non-toxic characteristics and show promise for future vaccine design. CONCLUSIONS: These findings provide a preliminary in-silico framework that may guide the development of effective vaccines against CCHFV.
Bench-to-Bedside Perspectives on Ocular Toxicity of Antibody-Drug Conjugates: Toxicology, Clinical Management and Molecule Optimization.
Zhang J, Li W, Li M … +11 more , Wu G, Ni Y, Du J, Xu G, Duan M, Yang Y, Yu X, Cui C, Liu C, Yu C, Wang L
Pharm Res · 2026 Feb · PMID 41540298 · Publisher ↗
OBJECTIVES: The present review aims to provide comprehensive bench-to-bedside insights into ADC-related ocular toxicity for drug designers, pharmaceutical manufacturers, toxicologists, and medical staff, thereby enhancin...
OBJECTIVES: The present review aims to provide comprehensive bench-to-bedside insights into ADC-related ocular toxicity for drug designers, pharmaceutical manufacturers, toxicologists, and medical staff, thereby enhancing the safety of ADC therapeutic applications. METHODS: The review comprehensively analyzes the recent progress in the pathological mechanisms of ADC-related ocular toxicity, evaluates existing non-clinical risk assessment strategies based on animal toxicological studies, and highlights future optimization directions. It also summarizes clinical adverse events to demonstrate the typical profile of ocular surface toxicity and provides clinical management strategies. RESULTS: ADC ocular toxicity primarily affects the ocular surface via on-target (antibody-mediated) and off-target (non-specific uptake) mechanisms. Key determinants include payload type (e.g., MMAF and DM4, which exhibit higher toxicity due to intracellular retention), linker properties (cleavable linkers mitigate off-target effects), and ADCs' physicochemical characteristics. Non-clinical models effectively predict corneal injury but poorly recapitulate conjunctival responses. Clinical management relies on early ophthalmic monitoring and dose adjustment, with 42.9%-100% of adverse events being reversible. CONCLUSION: This review offers valuable insights into ADC ocular toxicity, emphasizing the importance of early-stage selection and optimization of ADCs and their components to reduce ocular toxicity risks. It provides a reference for mitigating ADC-related ocular toxicity risks and facilitates the future development of ADCs with improved safety and efficacy.
Novel Cocrystal of Quercetagetin: In vitro and in vivo Insights into Biopharmaceutical Performance.
Suryawanshi S, Shaligram P, Gonnade RG … +1 more , Patil S
Pharm Res · 2026 Mar · PMID 41540297 · Publisher ↗
PURPOSE: Quercetagetin (QTGN) is a naturally occurring flavonol predominantly sourced from marigold flowers and possesses notable therapeutic potential, including antidiabetic, anticancer, antioxidant, anti-inflammatory,...
PURPOSE: Quercetagetin (QTGN) is a naturally occurring flavonol predominantly sourced from marigold flowers and possesses notable therapeutic potential, including antidiabetic, anticancer, antioxidant, anti-inflammatory, and antiviral properties. However, poor aqueous solubility and in turn bioavailability restrict therapeutic utility of QTGN. Crystal engineering is one of the approaches proven to be fruitful in resolving the solubility issues of many active pharmaceutical ingredients (APIs). METHOD: In the present work, a cocrystal of QTGN using betaine (BET) as coformer viz. Quercetagetin⋅betaine⋅ethanol (QTGN⋅BET⋅EtOH) was synthesized using the solvent evaporation method. It was further characterized using Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TGA), Powder X-ray diffraction (PXRD), and single crystal XRD (SCXRD). RESULT: FTIR studies confirmed hydrogen bonding between QTGN and BET. PXRD studies showed formation of new crystalline phase. The prepared cocrystal had stoichiometric ratio of 1:1:1 between QTGN, BET, and ethanol forming cocrystal ethanolate and shared robust hydroxyl⋯carboxylate supramolecular synthon as confirmed by TGA and SCXRD, respectively. Equilibrium solubility study and in vitro dissolution study showed a significant improvement (p < 0.0001) in aqueous solubility of QTGN upon its cocrystallization with BET. Furthermore, in vivo pharmacokinetic study revealed a 1.28-fold increase in bioavailability of QTGN when formulated as cocrystal solvate. The prepared cocrystal was found to be stable over a period of six months at 40°C and 75% RH when analyzed using PXRD studies. CONCLUSION: The current work represents a frontier in pharmaceutical formulation, providing a means to fully harness the therapeutic potential of QTGN using cocrystal approach.
From Blood Flow to Tumor Cell Internalization: A Multistage Computational Model of Nanoparticle Dynamics.
González-Garcinuño Á, Martin Del Valle E, Kenjeres S
Pharm Res · 2026 Feb · PMID 41540296 · Publisher ↗
BACKGROUND: Understanding the transport of nanoparticles within blood vessels and their distribution in tumor tissues is crucial for the successful implementation of nanotechnological strategies in clinical practice. Alt...
BACKGROUND: Understanding the transport of nanoparticles within blood vessels and their distribution in tumor tissues is crucial for the successful implementation of nanotechnological strategies in clinical practice. Although numerous studies have examined nanoparticle transport in blood flow, none have comprehensively investigated all the sequential steps a nanoparticle must undergo prior to internalization by target cells. METHODS: A computational framework was developed in COMSOL Multiphysics to simulate nanoparticle (NP) transport from systemic administration through to tumor cell internalization. The model integrates three coupled stages: (1) NP movement within a non-Newtonian blood flow; (2) trans-endothelial transport; and (3) NP motion within the tumor stroma, incorporating affinity forces to capture ligand-receptor interactions. The tumor geometry was reconstructed, including cancer cells and fibroblasts, to reproduce physiological porosity. Multiple case studies were conducted to evaluate the impact of particle density, injection velocity, and size on NP biodistribution. RESULTS: The computational model effectively simulates nanoparticle transport across all stages. Notably, it is the first model in the literature to incorporate the affinity of functionalized nanoparticles, which facilitates ligand-receptor interactions for targeted delivery. Simulation outcomes indicate that a low Stokes number is critical for ensuring a higher percentage of particles reach the end of the capillary network. Furthermore, surface modification of nanoparticles with ligands promotes more specific distribution within the stroma, reducing the percentage of nanoparticles that fail to reach target cells by approximately 50% CONCLUSIONS: A novel and comprehensive computational model has been developed to include the entire process of nanoparticle distribution following systemic administration, including specific recognition by cellular receptors.
Forecasting the Biological Effect of PEGylated-rHuEPO Candidates in Chronic Kidney Disease Patients using a Middle-out Translation Approach.
Reynaldo-Fernandez G, Rodriguez-Vera L, Amaro D … +6 more , Solozábal J, Duconge J, Mangas-Sanjuan V, Troconiz IF, Azeredo FJ, Vozmediano V
Pharm Res · 2026 Feb · PMID 41540295 · Publisher ↗
BACKGROUND: Anemia is a common and debilitating complication in patients with chronic kidney disease (CKD), often managed with erythropoiesis-stimulating agents. While PEGylation extends drug half-life, it may alter phar...
BACKGROUND: Anemia is a common and debilitating complication in patients with chronic kidney disease (CKD), often managed with erythropoiesis-stimulating agents. While PEGylation extends drug half-life, it may alter pharmacodynamics, requiring careful dose optimization. This study applies a middle-out translational pharmacokinetic/pharmacodynamic modeling approach, aligned with Model-Informed Drug Development principles, to evaluate two pegylated recombinant human erythropoietin candidates (PEG-EPO 32 kDa and PEG-EPO 40 kDa) and guide dose selection for CKD patients. METHODS: A semi-mechanistic pharmacokinetic/pharmacodynamic model developed in rabbits was extrapolated to humans using allometric scaling for pharmacokinetics and physiological adaptation for pharmacodynamics. The model was verified using intravenous data from Mircera®. Simulations were conducted in virtual CKD stage 4 and 5 populations to predict hemoglobin (Hb) trajectories over 90 days of dosing. Clinical thresholds were applied to assess efficacy and safety. RESULTS: Simulations with 0.6 µg/kg Q2W reproduced Mircera® profiles but showed higher proportions of patients exceeding Hb safety thresholds (> 11 g/dL in stage 4, > 9 g/dL in stage 5) for both PEG-EPOs. Dose reduction to 0.4 µg/kg Q2W aligned Hb responses with Mircera®, reducing the risk of excessive Hb elevation. CONCLUSIONS: Middle-out modeling successfully predicted clinical performance of PEG-EPO candidates and identified 0.4 µg/kg Q2W as optimal starting dose for clinical trials. PEG-EPO 32 kDa and 40 kDa emerges as a promising candidate for further development. This study exemplifies the value of MIDD in optimizing dose selection, enhancing translational relevance, and de-risking early clinical evaluation of long-acting erythropoiesis-stimulating agents in CKD.
Development of Alcohol-Resistant Extended-Release Formulations: Regulatory Considerations and Formulation Strategies.
Ji M, Swarnakar NK, Harish Chalamuri S … +2 more , Kathala K, Tiwari S
Pharm Res · 2025 Dec · PMID 41535409 · Publisher ↗
PURPOSE: This study was aimed to develop reservoir-type extended-release (ER) formulations resistant to alcohol-induced dose dumping (ADD) using polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP-90). METHODS: The ER...
PURPOSE: This study was aimed to develop reservoir-type extended-release (ER) formulations resistant to alcohol-induced dose dumping (ADD) using polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP-90). METHODS: The ER formulations were developed utilizing water-soluble and water-insoluble core diluents and binders, along with various PVAc with PVP-90 (3:1 w/w) coating levels. In vitro risk mitigation studies were conducted to understand the impact of alcohol on the properties of polymer compositions and their films, including viscosity, swelling, elasticity, and breaking force. The PVAc with PVP-90 (3:1) film exhibited minimal swelling and maintained better integrity in the presence of alcohol. RESULTS: The ER tablets incorporating water-soluble L-PVP in the core did not exhibit burst release in alcoholic media but showed compromised ADD resistance at lower coating levels. Increasing the concentration of PVP-90 in the core resulted in a slower disintegration rate, with concentrations exceeding 15% preventing full disintegration of tablets within 2 h in 0.1N HCl with 40% alcohol. The optimized formulation, containing 25% PVP-90 in the core and PVAc with PVP-90 coating, minimized ADD risk and maintained an ER release profile even after exposure to accelerated storage conditions (40°C/75% RH) for 3 months. CONCLUSION: The study highlights the importance of core and coating compositions in achieving ADD resistance. However, risk mitigation strategies including a new recommended dissolution method revealed that formulations meeting FDA guidelines could still exhibit dose dumping after just 2 h of alcohol exposure. This finding suggests the need to review regulatory standards for ADD resistance and harmonize requirements between agencies like EMA and US FDA to develop a relevant in vitro method for assessing ADD in modified release formulations.
Enabling Anti-inflammatory Activity through Hyaluronan-coated PLGA Nanoparticles Loaded with Carvacrol.
Salathia S, Agas D, Gigliobianco MR … +6 more , Boldrini L, Cappelli A, Casadidio C, Di Martino P, Sabbieti MG, Censi R
Pharm Res · 2026 Feb · PMID 41530587 · Full text
OBJECTIVE: Chronic inflammation is characterized by excessive cytokine production and macrophage infiltration, contributing to disease progression. This study aimed to enhance the therapeutic efficacy and local delivery...
OBJECTIVE: Chronic inflammation is characterized by excessive cytokine production and macrophage infiltration, contributing to disease progression. This study aimed to enhance the therapeutic efficacy and local delivery of carvacrol (CVL), a natural PPAR-γ activator with anti-inflammatory properties, through the development of a poly(lactic-co-glycolic) acid (PLGA)-based nanoparticle delivery system with hyaluronic acid (HA)-dependent macrophage targeting. METHODS: Poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles encapsulating CVL (CP NPs) were prepared and coated with 1.5% w/v hyaluronic acid (HA) to form CHP NPs for CD44 receptor-mediated targeting of pro-inflammatory macrophages. Physicochemical characterization, encapsulation efficiency, and drug release profile were evaluated. Cellular uptake and cytokine modulation were assessed in lipopolysaccharide-stimulated macrophages. RESULTS: CP NPs exhibited a size of 155 ± 3 nm and a zeta potential of -57.7 ± 1.3 mV, while HA coating yielded CHP NPs with a size of 225 ± 18 nm and a zeta potential of -25.5 ± 0.3 mV. Encapsulation efficiency and loading capacity reached 91 ± 5% and 26 ± 7%, respectively. HA coating enhanced nanoparticle internalization by 41% compared to uncoated NPs. A sustained release profile was achieved, with 50 ± 13% of CVL released over 21 days. In macrophages, CHP NPs increased anti-inflammatory cytokines IL-1ra (+ 258%), IL-4 (+ 260%), and IL-10 (+ 40%), while reducing pro-inflammatory cytokines IL-1α (-25%), IL-1β (-36%), and TNF-α (-36%) relative to untreated cells. CONCLUSIONS: HA-coated PLGA nanoparticles effectively delivered CVL, enhancing macrophage targeting and promoting an anti-inflammatory response. This platform offers a promising strategy for treating chronic inflammation-related diseases.
Efficacy of Inhalable Endolysin Cpl-1 Formulations in Combination with Gentamicin or Endolysin Pal in a Murine Lung Infection Model.
Wang Y, Stevens MT, Wang T … +4 more , Alreja AB, Nelson DC, Britton WJ, Chan HK
Pharm Res · 2026 Jan · PMID 41526528 · Full text
PURPOSE: Inhalable liquid formulation of endolysins represents a promising alternative to conventional antibiotics. Dry powder formulations offer improved stability for endolysin pulmonary delivery. This study aimed to e...
PURPOSE: Inhalable liquid formulation of endolysins represents a promising alternative to conventional antibiotics. Dry powder formulations offer improved stability for endolysin pulmonary delivery. This study aimed to evaluate the efficacy of an inhalable dry powder or liquid formulation of endolysin Cpl-1 alone and to compare it with liquid combinations of Cpl-1 with either gentamicin or endolysin Pal in a murine model of S. pneumoniae lung infection. METHODS: A dry powder formulation of Cpl-1 was produced via spray drying, while liquid formulations were prepared by dissolving Cpl-1, or in combination with gentamicin or endolysin Pal in liquid. The droplet size distribution of aerosolized formulations was also characterized. Mice were intratracheally infected with S. pneumoniae and treated with either powder or liquid formulations. The bacterial load in respiratory system was assessed 26 h post-infection. The stability and activity of Cpl-1 in BALF were also evaluated ex vivo. RESULTS: A single dose of Cpl-1 powder formulation or Cpl-1 liquid formulation (40 µg/mouse) reduced pulmonary bacterial load by approximately 1 log. Importantly, the combination of Cpl-1 and Pal in liquid form resulted in a synergistic 2.0 log reduction, significantly greater than either endolysin alone, while combining Cpl-1 with gentamicin did not enhance antibacterial activity. Ex vivo assays confirmed that Cpl-1 retained full enzymatic activity after incubation in BALF. CONCLUSION: This proof-of-principle study demonstrated that inhalable endolysin liquid and powder formulations could potentially be used to treat bacterial lung infections. Moreover, the combination of multiple endolysins could increase antimicrobial activity over endolysin monotherapy.
Ex vivo Tissue Provides Insight into Bleb Dynamics During Large-Volume Subcutaneous Injection.
Kim T, Artus P, Berat B … +2 more , Tang E, Bird J
Pharm Res · 2026 Feb · PMID 41514088 · Publisher ↗
PURPOSE: Large-volume subcutaneous injections can create visible protrusions called blebs, whose size and shape affect drug absorption and patient comfort. In vivo pig studies have documented how the bleb dimensions and...
PURPOSE: Large-volume subcutaneous injections can create visible protrusions called blebs, whose size and shape affect drug absorption and patient comfort. In vivo pig studies have documented how the bleb dimensions and tissue pressure vary with injection volume, flow rate, and fluid viscosities. However, its underlying mechanics remain unclear due to limited temporal and spatial measurements. This study evaluates whether ex vivo tissue can serve as an inexpensive and practical surrogate to study tissue deformation and uses this model to investigate the roles of fluid properties and vascular perfusion during large-volume injections. METHODS: We performed subcutaneous injections into store-bought pork belly tissue, replicating the injectate conditions from previous in vivo studies. Using a depth camera and pressure sensor, we continuously measure the bleb surface profile and in-line pressure. These measurements are converted into height, area, and tissue pressure at different injection volumes and are compared directly with previously published in vivo data. RESULTS: Bleb height and area increased monotonically with injected volume but were independent of viscosity and flow rate. Tissue pressure rose initially and then plateaued, even as bleb dimensions continued to grow. These trends closely mirrored in vivo findings. CONCLUSION: Ex vivo tissue mimics bleb shape and tissue pressures of in vivo subcutaneous injections, indicating that in vivo systemic factors are negligible over typical injection timescales. These results validate the use of ex vivo surrogates for studying bleb formation and challenge assumptions in current poroelastic models, which fail to capture the observed decoupling between tissue pressure and bleb growth.
Aerosol Delivery of Polyelectrolyte Surfactant-Antimicrobial Nanoparticles to the Lungs.
Varela Soler Y, Padilla-López AS, Rao S … +6 more , Calderon L, Mainelis G, Garbuzenko O, Minko T, Devore DI, Roth CM
Pharm Res · 2026 Feb · PMID 41514087 · Full text
BACKGROUND: Lung infections affect over 80% of adults with cystic fibrosis, with Pseudomonas aeruginosa being a leading pathogen. Although antibiotics are frequently nebulized as standard treatments, the physicochemical...
BACKGROUND: Lung infections affect over 80% of adults with cystic fibrosis, with Pseudomonas aeruginosa being a leading pathogen. Although antibiotics are frequently nebulized as standard treatments, the physicochemical environment of the diseased lung often limits their diffusion and overall effectiveness. Our previous studies showed polyelectrolyte surfactants (PS) to be a promising delivery system for cationic antimicrobials in vitro. This study seeks to expand that knowledge by evaluating their potential for nebulized delivery. METHODS: To achieve this, we evaluated their size and antimicrobial activity following nebulization; in vitro toxicity against epithelial cells and erythrocytes; and biodistribution and expression of inflammation markers following administration to healthy mice. RESULTS: The nanoparticle formulation exhibited a mucolytic effect on an artificial mucus model of cystic fibrosis mucus. Following nebulization, nanoparticles retained both their size and biological activity. Additionally, they displayed no observable toxicity in vitro against either human lung epithelial cells or erythrocytes; instead, epithelial cells treated with PS-based nanoparticles showed increased cell viability. Following administration of these formulations to mice via inhalation, over 70% of the recovered nanoparticles were retained in the lungs 24 h after treatment, with a small fraction being uniformly distributed to other tissues. A screen of key inflammatory cytokines revealed that inhalation treatment led to a slight increase of IL-6 in the liver and IL-18 in the spleen. These increases seem to be consistent with a minor inflammatory response. CONCLUSION: Overall, the results suggest that PS are a promising nanotechnology for the pulmonary delivery of cationic drugs.
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