European Journal Of Pharmaceutics And Biopharmaceutics[JOURNAL]
Sun
200 papers
In situ nasal gel loaded with Lactoferrin-Coated Brexpiprazole nanostructured lipid carriers for Schizophrenia: Cross-Species validation in Ketamine-Induced rat and zebrafish models.
Parmar J, Patel N, Patel A … +2 more , Desai N, Shah P
Eur J Pharm Biopharm · 2026 Jun · PMID 42242508 · Publisher ↗
Brexpiprazole (BXP), a third-generation antipsychotic, exhibits limited brain delivery following oral administration due to first-pass metabolism and blood-brain barrier constraints. To overcome these limitations, a Lact...
Brexpiprazole (BXP), a third-generation antipsychotic, exhibits limited brain delivery following oral administration due to first-pass metabolism and blood-brain barrier constraints. To overcome these limitations, a Lactoferrin (Lf)-functionalized BXP-loaded nanostructured lipid carrier (Lf-BXP-NLC) incorporated into a thermoresponsive in situ nasal gel was developed to enable sustained and receptor-mediated nose-to-brain transport. The optimized formulation demonstrated nanoscale particle size (<200 nm), narrow polydispersity, high entrapment efficiency (∼88%), and physiological gelation temperature (30-34 °C), with preserved physicochemical stability over 3 months. In vitro release and ex vivo permeation studies confirmed controlled drug release and enhanced mucosal transport. In vivo pharmacokinetic evaluation in rats revealed significantly improved brain exposure following intranasal administration, with approximately 1.9-fold higher AUC compared with drug suspension and 1.97-fold greater exposure relative to intravenous delivery. A rapid brain T (0.41 h) and direct transport percentage of ∼ 62% indicated dominant neuronal pathway involvement and reduced reliance on systemic circulation. Enhanced pharmacokinetics translated into pronounced pharmacodynamic benefits in ketamine-induced schizophrenia models, including significant attenuation of stereotypic behaviors, restoration of motor coordination, and near-normalization of neuromuscular performance. Cross-species validation in zebrafish further demonstrated substantial correction of anxiety-like behavior and cognitive impairment, reinforcing translational robustness. Importantly, no nasal ciliotoxicity was observed. Collectively, this multifunctional intranasal nanocarrier platform achieves rapid, sustained, and targeted brain delivery of BXP and offers a promising non-invasive strategy for precision neuropsychiatric therapy.
Shine bright, then fight: lectin-decorated gold nanostars for cancer theranostics.
Kolesnikova OA, Pushkarev AV, Nikitin MP … +2 more , Sizikov AA, Shipunova VO
Eur J Pharm Biopharm · 2026 May · PMID 42225226 · Publisher ↗
Targeted drug delivery, including nanoparticle-based methods, offers promise for addressing traditional oncology challenges, however, cancers like triple-negative breast cancer lack common targets such as HER2, progester...
Targeted drug delivery, including nanoparticle-based methods, offers promise for addressing traditional oncology challenges, however, cancers like triple-negative breast cancer lack common targets such as HER2, progesterone, and estrogen receptors. Developing targeted drugs based on non-classical receptor interactions is crucial for effective delivery across all tumor types. For example, altered glycosylation profiles in cancer cells can guide nanoparticles for chemo/photosensitizing treatments. Here we show that lectin-modified gold nanoparticles are effective agents for cancer theranostics. 70 nm gold nanostars, AuNS, possessing NIR-triggered photothermal properties were modified with a spectrum of phytolectins, allowing AuNS to interact with an altered glycosylation profile of cancer cells. Flow cytometry screening revealed that soybean agglutinin, SBA, is the best lectin for AuNS targeted delivery. In vitro toxicity studies demonstrated that 100% cell death was achieved for cells labeled with AuNS-SBA and irradiated with NIR light. In vivo studies confirmed that i.v.-administered fluorescent AuNS-SBA efficiently accumulated in BALB/c tumor allografts and generated a bright fluorescent signal in tumors. Moreover, after a single session of photothermal therapy, AuNS-SBA led to 100% tumor growth inhibition for large solid tumors (more than 200 mm) The obtained results demonstrate that lectin-decorated AuNS hold the potential to enhance targeted delivery and cancer theranostics.
Design of delayed-swellable spherical drug particles with taste-masking function for orally disintegrated (OD) tablet using mechanofusion coating and melt layering technique.
Niwa T, Kondo K, Makino H … +1 more , Itoh H
Eur J Pharm Biopharm · 2026 May · PMID 42217809 · Publisher ↗
Novel bitter-taste-masking microparticles for loading in orally disintegrating (OD) tablets have been developed using a mechanical powder processor. Swellable ordered-mixed drug particles (Swell-OM-spheres, SOS), in whic...
Novel bitter-taste-masking microparticles for loading in orally disintegrating (OD) tablets have been developed using a mechanical powder processor. Swellable ordered-mixed drug particles (Swell-OM-spheres, SOS), in which modified starch core particles are coated with pulverized drug crystals in an ordered mixture (OM) manner, were produced in our previous research. The authors have demonstrated that SOS particles had improved dissolution behavior of poorly water-soluble drugs due to their swellable function in the aqueous phase. Therefore, we aimed to design taste-masking fine particles by overcoating the functional excipients around SOS particles using the same equipment. In the first step, a gelling agent (Gel) was overcoated on the surface of SOS particles to form a swellable layer. In the second step, a waxy agent (Wx) was further coated on the surface of the resultant particles to form a water-insoluble layer. Thus, the coated particles with a four-layer structure (core/drug/Gel/Wx), named coated SOS (C-SOS) were prepared using a single equipment in a completely dry process without any water or solvent. The dissolution test revealed that C-SOS particles had a delayed booster release behavior. It is assumed that the outer insoluble layer of C-SOS particles would efficiently prevent the initial water penetration in aqueous medium, resulting in introducing a release lag time. Once water reaches the swellable gelling layer, the expansion of inner particles would burst the outer wax layer and begin rapid release of the drug, leading to sigmoidal release behavior with a short lag time. The present research realized the novel dry-powder coating technique for developing the microparticles with masked bitterness to be loaded in OD tablets.
Development of 3D-printed granisetron hydrogels with temperature-sensitive drug release.
Çetin C, Namli OC, Duman G … +2 more , Demir ZGT, Kuzhan O
Eur J Pharm Biopharm · 2026 May · PMID 42214768 · Publisher ↗
Chemotherapy-induced nausea and vomiting (CINV) significantly impair patient quality of life and often complicate oral drug administration. Granisetron hydrochloride, a selective 5-HT3 receptor antagonist, is clinically...
Chemotherapy-induced nausea and vomiting (CINV) significantly impair patient quality of life and often complicate oral drug administration. Granisetron hydrochloride, a selective 5-HT3 receptor antagonist, is clinically effective, but conventional oral and intravenous formulations present practical limitations. In this study, a temperature-responsive transdermal hydrogel system based on Pluronic F127 and sodium hyaluronate (HA) was developed and engineered using pressure-assisted microsyringe (PAM) 3D printing to achieve controlled in vitro drug release. Hydrogels containing different ratios of low- and high-molecular-weight HA were prepared and characterized. A lecithin-based dispersion was incorporated to improve drug solubilization and ensure homogeneous distribution within the aqueous matrix. The formulation containing predominantly high-molecular-weight HA exhibited the most favorable release profile in manually prepared samples. The optimized composition was subsequently fabricated via PAM 3D printing to standardize geometry and diffusion path length. The 3D-printed hydrogels demonstrated reproducible and temperature-dependent release behavior, reaching complete drug release within the experimental time frame at 37 °C. Kinetic analysis indicated a highly linear release profile within the investigated time window, consistent with diffusion-controlled release approximating zero-order behavior. These findings demonstrate that PAM 3D printing can serve as an engineering tool to regulate hydrogel architecture and improve release predictability. The developed system represents a structurally tunable and temperature-responsive platform for transdermal granisetron delivery.
Preclinical evaluation of Zr/Lu/Tb-labeled anti-CD228 monoclonal antibody for theranostics in skin cutaneous melanoma.
Hao X, Du H, Lin B … +7 more , Tang M, Zhang H, Wang D, Zhu Y, Long H, Liu H, Du X
Eur J Pharm Biopharm · 2026 Aug · PMID 42203156 · Publisher ↗
This study aimed to develop Zr/Lu/Tb-labeled anti-CD228 monoclonal antibody (42C10HZ11) for immuno-positron emission tomography/computed tomography (immuno-PET/CT) and radioimmunotherapy (RIT) in skin cutaneous melanoma...
This study aimed to develop Zr/Lu/Tb-labeled anti-CD228 monoclonal antibody (42C10HZ11) for immuno-positron emission tomography/computed tomography (immuno-PET/CT) and radioimmunotherapy (RIT) in skin cutaneous melanoma (SKCM). Anti-CD228 antibodies were conjugated with p-SCN-Bn-DFO or p-SCN-Bn-DOTA, followed by radiolabeling with Zr/Lu/Tb. The biological properties of the conjugates were assessed using radioligand cell binding, blocking, and internalization assays. Two cell line-derived xenograft preclinical models were established: CD228-high-expressing SK-MEL28 and CD228-low-expressing A375 models. Immuno-PET, biodistribution experiments, and RIT were performed. [Zr]Zr-DFO-CD228, [Lu]Lu-DOTA-CD228, and [Tb]Tb-DOTA-CD228 showed high radiochemical purity (>95%) and good in vitro stability. For immuno-PET/CT, the mean standardized uptake value of SK-MEL28 model tumors at 96 h post-injection was 4.24 ± 0.32 (n = 3), significantly higher than that in SK-MEL28 blocking group and A375 group (P < 0.001). Ex vivo biodistribution studies demonstrated that tumor dose uptake increased over time and remained at a high level, while non-target organs showed rapid clearance. Both 11.1 MBq [Lu]Lu-DOTA-CD228 and 11.1 MBq [Tb]Tb-DOTA-CD228 significantly inhibited tumor growth, prolonged survival, and showed low toxicity. Notably, [Tb]Tb-DOTA-CD228 demonstrated stronger anti-tumor efficacy than [Lu]Lu-DOTA-CD228. We demonstrated that immuno-PET/CT with [Zr]Zr-DFO-CD228 enables specific and precise non-invasive assessment of CD228 expression in SKCM models. [Tb]Tb-DOTA-CD228 inhibited tumor growth more potently than [Lu]Lu-DOTA-CD228 at the same administered activity, with preliminary mechanistic analyses suggesting that differential DNA damage, vascular responses, and immune modulation may account for the distinct anti-tumor effects of Tb and Lu, although further investigation is warranted. These findings provide preclinical evidence for CD228-targeted theranostics in SKCM.
QbD-based intranasal pH-sensitive Ibrutinib liposomes for glioblastoma management: in vitro, ex vivo, and in vivo pharmacokinetics and brain distribution assessment.
Sikder A, Naresh Katarpawar S, Kumar R … +9 more , Phatale V, Vambhurkar G, Pandey G, Wagh S, Sharma A, Amulya E, Khairnar P, Dikundwar AG, Srivastava S
Eur J Pharm Biopharm · 2026 Aug · PMID 42184887 · Publisher ↗
Ibrutinib (IBR), a potent Bruton's tyrosine kinase (BTK) inhibitor, has demonstrated promising anticancer potential; however, its poor solubility, limited bioavailability and restricted permeability across the blood-brai...
Ibrutinib (IBR), a potent Bruton's tyrosine kinase (BTK) inhibitor, has demonstrated promising anticancer potential; however, its poor solubility, limited bioavailability and restricted permeability across the blood-brain barrier (BBB) significantly constrain its therapeutic application in glioblastoma (GBM). For GBM therapy, overcoming the formidable BBB remains a major obstacle. In the current research, a pH-sensitive liposomal formulation encapsulating IBR (IBR-LIPO) was developed to facilitate direct nose-to-brain (N2B) delivery and enhance brain targeting. The optimized IBR-LIPO depicted a spherical morphology with a mean particle size below 200 nm, as confirmed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The optimized formulation depicted a zeta potential of -31.8 ± 0.95 indicating good stability. The formulation depicted an entrapment efficiency and drug loading of 85.46 ± 1.35% and 4.5 ± 0.34% respectively. The incorporation of cholesteryl hemisuccinate (CHS) conferred pH-responsive behavior, resulting in controlled yet initial-burst release profile in acidic conditions. Ex vivo nasal permeation and toxicity studies revealed a 2.54-fold enhancement in the nasal permeation with no signs of toxicity. In vitro evaluation using 2D and 3D cell culture revealed significantly improved cytotoxicity of IBR-LIPO compared to the free drug. In vivo pharmacokinetic analysis depicted enhanced brain delivery with a 2.30-fold enhancement in drug targeting efficiency (%DTE) and a 2.39-fold increase in direct transport percentage (%DTP) and a higher drug targeting index (DTI) over free IBR following intranasal (IN) administration. Collectively, these findings highlight IBR-LIPO as a promising nanocarrier for efficient N2B delivery and targeted GBM therapy.
Experimental and numerical investigation of container closure integrity in prefilled syringes at ultracold temperatures.
Tortora C, D'Avino G, Martino MD … +4 more , Moro A, Mardalizad A, Chillon A, Maffettone PL
Eur J Pharm Biopharm · 2026 Aug · PMID 42178034 · Publisher ↗
The increasing demand for deep-frozen pharmaceutical storage intensified by mRNA-based therapeutics poses new challenges for Container Closure Integrity (CCI) in prefilled syringe systems. This study presents a comprehen...
The increasing demand for deep-frozen pharmaceutical storage intensified by mRNA-based therapeutics poses new challenges for Container Closure Integrity (CCI) in prefilled syringe systems. This study presents a comprehensive investigation of CCI failure mechanisms at ultracold temperatures, combining micro-tensile characterization, advanced numerical modelling, and validation via a modified dye-ingress method. Results reveal that CCI failure consistently occurs below the rubber glass transition temperature, initiating with contact loss at the plunger ribs and progressing to complete leakage past the trimmed edge. These failures follow reproducible patterns confirmed by both experiments and simulations. The underlying mechanism arises from the interplay between thermal contraction, viscoplastic response, and loss of contact at the rubber-glass interface, with simulation results supporting plastic "freezing" of deformation as the dominant failure mode. The findings underscore the need to re-engineer elastomeric materials and sealing strategies for reliable performance under ultra-low temperature conditions and provide a predictive framework for future CCI assessment.
Cupuaçu (Theobroma grandiflorum) butter nanoparticles associated with oligosaccharides as cosmetic carriers for prebiotic effect: development, physicochemical characterization, and preclinical evaluation.
Riccio BVF, Debiasi BW, Silva IJD … +6 more , Tonani L, Chellegatti MADSC, Furtado NAJC, Kress MRVZ, Bentley MVBL, Gaspar LR
Eur J Pharm Biopharm · 2026 Aug · PMID 42178033 · Publisher ↗
The skin microbiota is essential for cutaneous homeostasis, and prebiotics may support it. Nanostructured systems, such as cupuaçu-derived nanoparticles, enhance the delivery and stability of cosmetic active substances,...
The skin microbiota is essential for cutaneous homeostasis, and prebiotics may support it. Nanostructured systems, such as cupuaçu-derived nanoparticles, enhance the delivery and stability of cosmetic active substances, but their role in modulating the skin microbiota remains unclear and requires targeted evaluation. In this study, lipid-polymeric hybrid nanoparticles based on cupuaçu (Theobroma grandiflorum) butter were developed as potential carriers for oligosaccharides. Three formulations were developed: cupuaçu butter (CB-NP), α-glucan oligosaccharide (AGO-CB-NP), and polydextrose nanoparticles (PD-CB-NP). They showed mean diameters of approximately 110 nm, low polydispersity index (PdI < 0.30), and moderately negative zeta potentials (around -16 mV). Rheology demonstrated pseudoplastic behavior. Structural characterization by X-ray diffraction (XRD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), and small-angle X-ray scattering (SAXS) indicated reduced crystallinity, chemical compatibility among the ingredients, and a hybrid core-shell organization, with a lipid-rich inner region and an outer layer likely associated with oligosaccharides. The formulations exhibited neither eye irritation nor phototoxicity potential in toxicological screening, conducted in accordance with OECD TG 491 and TG 432. In vitro prebiotic potential showed species-dependent responses: AGO-CB-NP stimulated the mutualist Staphylococcus epidermidis while inhibiting Malassezia furfur, whereas CB-NP inhibited Candida albicans growth. Moderate antioxidant activity (around 20% DPPH scavenging) was observed, and cupuaçu butter contained low levels of phenolic compounds (around 0.12 mg GAE g) and intermediate protection against UVA-induced reactive oxygen species. Among the tested formulations, AGO-CB-NP showed the most favorable profile. Overall, the results suggest a promising strategy for developing carriers for microbiome-oriented cosmetic formulations, encouraging further investigation in more complex biological systems, such as in clinical trials.
Hydrogels-based nasal sprays for nose-to-brain delivery: Formulation strategies, composite systems, and performance optimization.
Wang X, Huang W, Zhou Y … +1 more , Zhu K
Eur J Pharm Biopharm · 2026 Aug · PMID 42176871 · Publisher ↗
Nose-to-brain drug delivery has been extensively investigated for central nervous system therapy due to its ability to bypass the blood-brain barrier and reduce systemic exposure. Among available intranasal dosage forms,...
Nose-to-brain drug delivery has been extensively investigated for central nervous system therapy due to its ability to bypass the blood-brain barrier and reduce systemic exposure. Among available intranasal dosage forms, hydrogels-based nasal sprays have emerged as a promising platform due to their ability to prolong nasal residence and enable controlled drug release. This review, from the perspective of formulation-oriented design of hydrogel nasal sprays, focuses on composite systems, spray performance, and drug specific strategies in addition to material selection. Recent advances highlight the integration of nanocarriers within hydrogel matrices to achieve coordinated control of drug protection, release behavior, and mucosal retention, effectively addressing key challenges in nasal drug delivery. Meanwhile, key spray-related critical quality attributes, including viscosity, droplet size, and spray dynamics, are extensively reviewed with respect to their effects on nasal cavity deposition and nose-to-brain delivery efficiency. Finally drug specific formulation design is discussed as a central factor guiding strategies for small molecules, macromolecules, and oligonucleotide drugs. Overall, this review proposes a formulation-oriented and systems-level framework to guide the rational development and clinical translation of hydrogels-based nasal spray dosage forms for nose-to-brain drug delivery.
Tuning lipid monolayer behavior with soluble surfactants: A pathway to enhanced ultradeformable drug carriers.
Dopierała K, Przybylska A, Kustrzyńska K … +1 more , Michniak-Kohn B
Eur J Pharm Biopharm · 2026 Aug · PMID 42176870 · Publisher ↗
Transferosomes are ultradeformable lipid vesicles used to enhance transdermal drug delivery. Their key component is the edge activator, which modulates membrane fluidity and deformability. In this study, we propose an in...
Transferosomes are ultradeformable lipid vesicles used to enhance transdermal drug delivery. Their key component is the edge activator, which modulates membrane fluidity and deformability. In this study, we propose an integrated approach to evaluate the surfactants-Tween® 20, Tween® 60, Tween® 80 (Croda International), and sodium cholate (SC)-as edge activators in transferosomal formulations with 1,2-dioleoyl-3-trimethylammonium propane (DOTAP). Monolayer and bilayer investigations were combined to identify the most suitable surfactant. Among the investigated surfactants, SC exhibited the most favorable overall performance, leading to transferosomes with enhanced membrane fluidity and desirable viscoelastic properties. The results also revealed a strong influence of surfactant concentration on the interfacial behavior of the lipid bilayer, attributed to electrostatic interactions between SC and DOTAP. Atomic force microscopy confirmed increased vesicle deformability from 4.10 to 8.83 nm and reduced Young's modulus from 167.29 to 88.22 MPa for SC-containing systems compared to pure DOTAP. DLS measurements further demonstrated appropriate colloidal properties, with vesicle size of 216-345 nm. Within a simplified Quality by Design framework, SC emerged as the most promising edge activator, although adhesion-related parameters did not clearly indicate dominance of this formulation. Overall, the proposed integrated strategy provides a rational approach for the rational design of transferosomal formulations.
Supramolecular self-assemblies of H6/doxorubicin reverse P-gp-mediated multidrug resistance in breast cancer.
Sun Q, Wei Y, Sun B … +4 more , Jiang Q, Chen D, Bi Y, Chu Y
Eur J Pharm Biopharm · 2026 Aug · PMID 42173452 · Publisher ↗
Tumor multidrug resistance (MDR) remains a major cause of chemotherapy failure. Inhibiting the P-glycoprotein (P-gp)-mediated excessive efflux of chemotherapeutic drugs represent an effective strategy to overcome MDR. Co...
Tumor multidrug resistance (MDR) remains a major cause of chemotherapy failure. Inhibiting the P-glycoprotein (P-gp)-mediated excessive efflux of chemotherapeutic drugs represent an effective strategy to overcome MDR. Conventional P-gp inhibitors are limited in clinical use due to systemic toxicity and risks of normal tissue dysfunction. In this study, we constructed a self-assembled system based on H6, the α-hederagenin derivative with potent MDR reversal activity, and the chemotherapeutic agent doxorubicin (DOX). Guided by the CREKA peptide, this system specifically targets fibronectin in tumor tissues, thereby enhancing drug accumulation at the lesion site. The combination therapy of H6 and DOX exhibited a combination index (CI) of 0.16 (CI < 1), indicating strong synergistic effects. Both in vitro and in vivo experiments demonstrated that H6 interferes with ATP production and effectively inhibits P-gp efflux function. In a breast cancer MDR model, this strategy achieved a tumor inhibition rate of 81.7%, offering a promising approach to combat tumor MDR.
Local drug delivery for oral squamous cell carcinoma under oral cavity.
Ruslin M, Cao J, Ullah M … +8 more , Palungan J, Azizah W, Wa Ode RC, Mustopa AZ, Marlina E, Uchida S, Yoo JW, Hasan N
Eur J Pharm Biopharm · 2026 Aug · PMID 42173451 · Publisher ↗
Oral squamous cell carcinoma (OSCC) is a leading malignancy within head and neck cancers and is associated with substantial morbidity and mortality. Local drug delivery systems (LDDS) have emerged as an important strateg...
Oral squamous cell carcinoma (OSCC) is a leading malignancy within head and neck cancers and is associated with substantial morbidity and mortality. Local drug delivery systems (LDDS) have emerged as an important strategy to increase site-specific drug exposure at oral lesions while limiting systemic distribution and associated toxicity. However, therapeutic success in the oral cavity is constrained by stringent "hard constraints," including continuous salivary flow, enzymatic degradation, pH variability, and mechanical abrasion from chewing and tongue movement, which collectively reduce residence time and destabilize labile payloads. This review synthesizes major LDDS platforms for OSCC, including mucoadhesive films/patches, oral sprays, in situ gelling systems, and injectable hydrogels, and critically analyzes how platform performance is governed by interactions between payload properties (small molecules, biologics, nucleic acids), lesion characteristics (accessibility, geometry, margin control), and patient-centered factors. We highlight the need for decision-oriented frameworks that link clinical scenarios to platform selection and recommend standardized evaluation metrics for retention under salivary flow, resistance to mechanical stress, and biochemical stability in saliva-relevant conditions. Despite rapid progress in materials and delivery technologies, OSCC-specific optimization and translational testing remain limited. Future work should prioritize biocompatible, durable systems capable of maintaining predictable local exposure and controlled release under clinically relevant oral conditions, supported by rigorous preclinical validation and well-designed clinical studies to improve outcomes in OSCC.
A sea buckthorn seed oil nano-emulsion in the management of digital screen-induced ocular conditions.
Cheng M, Bi X, Zhao S … +9 more , Xiang R, Cai S, Zhao M, Wu T, Su Y, Ji M, Zhao J, Yin T, Zhang Y
Eur J Pharm Biopharm · 2026 Aug · PMID 42167615 · Publisher ↗
The widespread usage of digital devices has been associated with a significant increase in the incidence of various screen-related ocular diseases, particularly dry eye disease (DED), blue light (BL)-induced retinal dama...
The widespread usage of digital devices has been associated with a significant increase in the incidence of various screen-related ocular diseases, particularly dry eye disease (DED), blue light (BL)-induced retinal damage, and myopia progression. These conditions not only severely compromise visual function and quality of life but also pose a growing challenge to global public health systems. To move beyond the conventional approach of treating each disease separately, this work investigates a consolidated solution that leverages the multi-target properties of sea buckthorn seed oil (SBO) for synergistic treatment of multiple ocular conditions. A nano-lipid eye drop formulation loaded with sea buckthorn seed oil (SBO-NE) was developed to achieve synergistic therapeutic effects. The SBO-NE formulation exhibited excellent stability and ocular tolerability in rabbits. In vivo, SBO-NE exhibited multifaceted therapeutic potential in a DED model, including significant promotion of tear secretion, acceleration of corneal repair, and anti-inflammatory efficacy that exceeded that of Soothe® XP. Furthermore, superior protection against BL-induced retinal damage was demonstrated compared with oral lutein supplementation. In addition, SBO-NE treatment delayed myopia progression. Although less effective than atropine sulfate eye drops, SBO-NE elicited a significant delay without inducing the dry eye typically associated with atropine. In summary, these findings suggest that SBO-NE represents a promising multi-target therapeutic candidate with broad-spectrum efficacy across multiple ocular conditions associated with digital device exposure.
Polyvinyl alcohol-based hard capsules with enhanced mechanical strength and gas barrier properties by montmorillonite incorporation.
Ishihara-Furo C, Kobayashi-Koike A, Tahara K
Eur J Pharm Biopharm · 2026 Aug · PMID 42162850 · Publisher ↗
This study evaluated polyvinyl alcohol (PVA) as a novel shell material for hard capsules. PVA offers high-water solubility, low toxicity, and excellent oxygen- and water vapor barrier properties. However, under humid con...
This study evaluated polyvinyl alcohol (PVA) as a novel shell material for hard capsules. PVA offers high-water solubility, low toxicity, and excellent oxygen- and water vapor barrier properties. However, under humid conditions, PVA exhibits a pronounced loss of mechanical strength. To address this limitation, montmorillonite (MMT), a high aspect ratio filler, was incorporated into PVA, and the mechanical and barrier properties of films and hard capsule shells were evaluated. In unfilled PVA films, increasing relative humidity from 50% to 65% increased water uptake and reduced Young's modulus to approximately one-quarter of its original value. By contrast, PVA-MMT composite films containing 9-17 wt% MMT showed substantial improvement in mechanical performance under high humidity, with a 180% increase in Young's modulus at 9 wt% MMT, consistent with the Halpin-Tsai model. Oxygen- and water vapor permeability were reduced by 5-20-fold, indicating significant enhancement of gas barrier properties. Hard capsules prepared from PVA-MMT composites showed immediate-release dissolution comparable to commercial hypromellose capsules using acetaminophen. Overall, our findings demonstrate that MMT incorporation mitigates the humidity sensitivity of PVA, providing hard capsule shells with balanced mechanical strength and gas barrier properties suitable for pharmaceutical applications.
Radical scavenging reactivity of β-agonists: Mechanistic insights into the antioxidant behavior of salbutamol and tulobuterol.
Czaja K, Buczek A, Broda MA
Eur J Pharm Biopharm · 2026 Aug · PMID 42162849 · Publisher ↗
Salbutamol (SAL) and tulobuterol (TUL) are clinically used inhaled bronchodilators belonging to the class of β-adrenergic agonists. In addition to their bronchodilatory activity, increasing evidence suggests that drug mo...
Salbutamol (SAL) and tulobuterol (TUL) are clinically used inhaled bronchodilators belonging to the class of β-adrenergic agonists. In addition to their bronchodilatory activity, increasing evidence suggests that drug molecules administered to the respiratory tract may interact with reactive oxygen species (ROS) present in the oxidative microenvironment associated with airway inflammation. In this study, the intrinsic radical-scavenging properties of SAL and TUL were investigated using density functional theory calculations at the M06-2X/6-311 + G(d,p) level in the gas phase, as well as in water and methanol. Thermodynamic and kinetic parameters describing hydrogen atom transfer (HAT), single-electron transfer-proton transfer (SET-PT), and sequential proton loss-electron transfer (SPLET) mechanisms were evaluated toward the biologically relevant •OOH radical. Thermodynamic analysis indicates that benzylic C-H bonds in both molecules are more prone to homolytic cleavage than O-H groups, with particularly low bond dissociation enthalpies observed for salbutamol. However, kinetic modelling based on transition state theory with Wigner tunneling corrections identifies the phenolic O-H site of salbutamol as the most reactive position toward •OOH, exhibiting the lowest activation barrier and the highest rate constant. In tulobuterol, which lacks a phenolic group, HAT reactivity is governed by the benzylic C-H position but occurs with higher activation barriers. These results reveal a divergence between thermodynamic preference and kinetic control of radical scavenging and highlight the key role of phenolic functionality in determining the antioxidant behavior of β-agonists. From a biopharmaceutical perspective, these findings may contribute to a better understanding of the oxidative reactivity and stability of inhaled bronchodilators in pharmaceutical formulations and within the oxidative environment of the respiratory tract.
A multi-level characterization of TfR, Mfsd2a and LRP1 in a stem cell derived in vitro model of the blood-brain barrier.
König L, Khin M, Puris E … +3 more , Petralla S, Gericke B, Fricker G
Eur J Pharm Biopharm · 2026 Aug · PMID 42155641 · Publisher ↗
The blood-brain barrier (BBB) serves as a highly selective interface protecting the central nervous system (CNS) and shielding neural tissue from toxins in the bloodstream, yet its restrictive nature simultaneously poses...
The blood-brain barrier (BBB) serves as a highly selective interface protecting the central nervous system (CNS) and shielding neural tissue from toxins in the bloodstream, yet its restrictive nature simultaneously poses a significant challenge for therapeutic drug delivery for CNS-related diseases. Consequently, sophisticated in vitro models that accurately mirror the human BBB are essential for evaluating barrier characteristics and drug permeation. Here, we characterize the SBAD0201 hiPSC line differentiated towards a brain microvascular endothelial-like phenotype, that mimics essential characteristics of the human BBB. Our analysis focused on the absolute and relative protein quantification of the transport-relevant targets transferrin receptor (TfR), major facilitator superfamily domain-containing protein 2 transporter (Mfsd2a) and low-density lipoprotein receptor-related protein 1 receptor (LRP1). This study employs a comparative approach with the well-established hCMEC/D3 cell line, a widely used in vitro BBB model. The multi-layered validation, including qRT-PCR, western blot and immunofluorescence, reveals that SBAD0201-derived cells achieve a more mature phenotype. Notably, this model exhibits enhanced barrier integrity and an enriched repertoire of BBB-relevant receptors. These results underline the potential of the SBAD0201 platform as a robust and physiologically relevant tool for CNS research.
Structure-Permeability relationships of Vitamin-B-Based quaternary ammonium salts for oral drug development.
Olejniczak A, Freire MG, Niemczak M
Eur J Pharm Biopharm · 2026 Aug · PMID 42150676 · Publisher ↗
Effective oral drug delivery requires compounds with suitable solubility, permeability, and physicochemical properties to ensure efficient absorption in the gastrointestinal tract. This study evaluates vitamin-derived qu...
Effective oral drug delivery requires compounds with suitable solubility, permeability, and physicochemical properties to ensure efficient absorption in the gastrointestinal tract. This study evaluates vitamin-derived quaternary ammonium salts (QASs) based on nicotinamide, nicotinic acid, and p-aminobenzoic acid, together with their nonionic counterparts, as potential orally administrable molecules. In silico pharmacokinetic predictions identified nicotinate QASs as the most promising candidates, exhibiting favorable permeability, intestinal absorption, and solubility profiles. PAMPA experiments confirmed high passive permeability for all compounds, with 6-hour P values exceeding 1.1·10⁻⁶ cm·s⁻, and demonstrated that membrane transport depends strongly on alkyl chain length and counterion identity. Permeability decreased notably for derivatives with octyl chains, whereas nicotinate QASs displayed values comparable to diclofenac sodium, and the shortest-chain p-aminobenzoate and its nonionic analogue slightly surpassed the reference drug. Surface activity analysis revealed that reductions in solution surface tension significantly enhance membrane transport, overriding limitations associated with increased molecular size. Overall, the synergistic influence of alkyl chain length, anion selection, and surface activity underscores the potential of vitamin-derived QASs as tunable, multifunctional candidates for oral drug development.
Mechanistic enhancement of oral bioavailability through a coamorphous apremilast-aceclofenac systems: integrated LC-MS/MS Bioanalysis, in vivo pharmacokinetics, and PBPK modeling.
Khemchandani R, Pardhi E, Jadhav A … +9 more , Shaikh N, Bhale N, Pilli P, Pimpre K, Chandra Mouli HM, Doijad N, Mehra NK, Dikundwar AG, Samanthula G
Eur J Pharm Biopharm · 2026 Aug · PMID 42144121 · Publisher ↗
Poor aqueous solubility and dissolution-limited absorption remain major challenges in the oral delivery of apremilast (APR) and aceclofenac (ACF). In this study, coamorphous systems (CAMS) of APR-ACF were systematically...
Poor aqueous solubility and dissolution-limited absorption remain major challenges in the oral delivery of apremilast (APR) and aceclofenac (ACF). In this study, coamorphous systems (CAMS) of APR-ACF were systematically evaluated to enhance biopharmaceutical and pharmacokinetic performance using an integrated experimental-computational approach. Three CAMS with different stoichiometric ratios (AA11, AA12, and AA21) were prepared and assessed. Solid-state analysis confirmed the formation of single-phase homogeneous CAMS stabilized by intermolecular interactions. CAMS showed significant improvements in solubility and dissolution compared to crystalline and physical mixtures, with AA12 exhibiting the greatest enhancement. A fully validated LC-MS/MS method was developed for simultaneous quantification of APR and ACF in rat plasma. In vivo pharmacokinetic studies revealed formulation-dependent increases in systemic exposure. AA12 enhanced APR's AUC (∼2.6-fold) and C (∼1.5-fold) compared to crystalline drug, while ACF showed more moderate improvements (∼1.5-fold AUC, ∼1.3-fold C). T remained unchanged across formulations, indicating improved absorption extent. Physiologically based pharmacokinetic (PBPK) modeling incorporating the Advanced Compartmental Absorption and Transit (ACAT) framework, along with formulation-specific dissolution inputs, accurately predicted plasma concentration-time profiles and regional gastrointestinal absorption, confirming dissolution-driven absorption enhancement. This integrated in vitro-in vivo-in silico investigation establishes coamorphization as a validated strategy to overcome dissolution-limited absorption, identifying AA12 as the optimized CAMS for combined APR-ACF delivery.
The VitraCell: A new in vitro test setup for intravitreal dosage forms.
Reichel F, Auel T, Fischer B … +2 more , Klinken-Uth S, Seidlitz A
Eur J Pharm Biopharm · 2026 Aug · PMID 42144120 · Publisher ↗
The population is aging, which is accompanied by an increasing prevalence of ocular diseases that require novel intravitreal therapeutic options. Preclinical studies for new intravitreal therapies are typically conducted...
The population is aging, which is accompanied by an increasing prevalence of ocular diseases that require novel intravitreal therapeutic options. Preclinical studies for new intravitreal therapies are typically conducted in animals. Appropriate biorelevant in vitro models could replace, reduce and refine (3R) these in preclinical testing. Therefore, the VitraCell was developed as a new in vitro vitreous body model and adapted to certain physiological conditions. It consists of a central vitreous compartment filled with an optimized vitreous substitute composed of 0.22 % hyaluronic acid and 0.09 % agar. Two lateral chambers are connected to this central compartment, each representing a closed buffer circulation system with an associated buffer reservoir. The release, diffusion, and elimination characteristics of various active pharmaceutical ingredients and dosage forms, including implants containing triamcinolone acetonide and paracetamol, as well as a triamcinolone acetonide suspension, were investigated following simulated intravitreal injection. Distinct differences were identified, indicating the general suitability of the system. In addition, initial comparisons with in vivo literature data appear promising. Furthermore, sufficient stability of the vitreous substitute over a diffusion period of three weeks was demonstrated. In addition, comparative measurements were performed using compendial pharmacopeial methods, namely United States Pharmacopeia Apparatus 4 and 7. These methods exhibited markedly faster and probably physiologically less relevant release rates, further highlighting the suitability of the VitraCell, which therefore represents an additional step toward an optimized biorelevant in vitro test setup for intravitreal dosage forms.
The role of pharmaceutical formulation development in clinical trials of new medicinal products.
Owczarek B, Piasecka MM
Eur J Pharm Biopharm · 2026 Aug · PMID 42140451 · Publisher ↗
The discovery and development of new active pharmaceutical ingredients (APIs) is a complex and resource-intensive process characterized by high attrition rates and significant translational uncertainty. While advances in...
The discovery and development of new active pharmaceutical ingredients (APIs) is a complex and resource-intensive process characterized by high attrition rates and significant translational uncertainty. While advances in computational chemistry and AI have accelerated early-stage candidate identification, successful clinical translation depends not only on pharmacological activity but also on appropriate pharmaceutical formulation. This review examines the critical role of formulation development in bridging molecular discovery with clinical evaluation, emphasizing physicochemical characterization, enabling formulation strategies for poorly soluble compounds, and integration of mechanistic tools such as physiologically based pharmacokinetic (PBPK) and physiologically based biopharmaceutics modeling (PBBM). Particular attention is given to modified-release systems, amorphous solid dispersions, and long-acting injectable formulations, highlighting how formulation design directly influences systemic exposure, variability, and clinical reliability. Case studies of posaconazole and long-acting injectable aripiprazole demonstrate how rational reformulation and process optimization can significantly improve pharmacokinetic consistency and therapeutic performance while introducing technological and regulatory complexity. Emerging trends indicate a paradigm shift toward formulation-informed and model-integrated drug development, where AI, mechanistic modeling, and Quality by Design (QbD) principles are increasingly used to predict formulation performance and support clinical and regulatory decision-making. Integration of formulation science with predictive modeling and data-driven approaches enables earlier identification of translational risks, improves development efficiency, and enhances the probability of clinical success. Overall, formulation development should be regarded as a central determinant of clinical outcomes and regulatory success, rather than a downstream technical activity, supporting more predictive and efficient pharmaceutical development.
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