European Journal Of Pharmaceutics And Biopharmaceutics[JOURNAL]
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200 papers
Nose-to-Brain delivery of empagliflozin-loaded nanostructured lipid carriers incorporated In-situ gel: Biopharmaceutical evaluation for Alzheimer's disease.
Puranik K, Ranpise N, Khot S … +1 more , Negi P
Eur J Pharm Biopharm · 2026 Jun · PMID 42323146 · Publisher ↗
Alzheimer's therapy remains limited by poor drug targeting and multifactorial pathology. The therapeutic potential of SGLT-2 inhibitors like empagliflozin (EGZ) is constrained by poor brain bioavailability. Current study...
Alzheimer's therapy remains limited by poor drug targeting and multifactorial pathology. The therapeutic potential of SGLT-2 inhibitors like empagliflozin (EGZ) is constrained by poor brain bioavailability. Current study investigates the potential of EGZ-nanostructured lipid carrier (ENLC) for brain delivery via nasal route. The ENLC were prepared using hot melt emulsification technique followed by probe sonication and optimized using Box-Behnken design. ENLC were incorporated into poloxamer 407-chitosan in situ gel (ENPCG) to improve nasal retention, controlled release, and direct brain transport via olfactory and trigeminal uptake. ENPCG demonstrated a sustained drug release of 56.36 ± 3.37 % and enhanced nasal permeation. Nasal kinetics revealed high C (48.2 ± 1.42 µg/cm) relative to plain EGZ-suspension (15.9 ± 0.7 µg/cm) in goat nasal mucosa. ENPCG significantly improved cognitive memory in sporadic AD model, as confirmed by behavioural, biochemical, and histopathological assessments in Wistar rats. Pharmacokinetic study in Sprague Dawley rats revealed a 4.5-fold increase in AUC of intranasal ENPCG (30.56 ± 0.45 μg/mL*h) relative to intravenous ENLC (6.73 ± 0.15 μg/mL*h). ENPCG showed 95.31 ± 3.89 % drug targeting potential. Furthermore, a strong point-to-point ex vivo-in vivo correlation (R = 0.9952) was observed, suggesting a non-invasive potential of ENPCG for translating AD interventions.
Influence of counterion transfer on the physicochemical properties of fixed dose combinations containing bedaquiline and clofazimine.
Ngo HV, Daems S, Govaerts M … +2 more , Aguilar-Pérez C, den Mooter GV
Eur J Pharm Biopharm · 2026 Jun · PMID 42320764 · Publisher ↗
Fixed-dose combinations (FDCs) offer significant advantages in the treatment of multidrug-resistant tuberculosis (MDR-TB), including reduced pill burden, increased treatment adherence, minimization of resistance developm...
Fixed-dose combinations (FDCs) offer significant advantages in the treatment of multidrug-resistant tuberculosis (MDR-TB), including reduced pill burden, increased treatment adherence, minimization of resistance development, and decreased relapse rates. A critical prerequisite for developing FDCs in single-unit formulations is ensuring physicochemical compatibility between the combined drugs, particularly for ionizable compounds. Bedaquiline (BDQ) and clofazimine (CFZ) are weakly basic drugs and promising candidates for next-generation antituberculosis FDCs. BDQ fumarate (BDQF) is widely used in the commercial product due to its improved solubility and oral bioavailability. This study provides a comparative evaluation of binary systems containing BDQ or BDQF with CFZ at different molar ratios, including 1:1, 1:2, and 2:1. Through physicochemical characterization using Fourier transform - InfraRed (FTIR) spectroscopy, X-ray powder diffraction (XRPD), apparent solubility and dissolution studies, we demonstrate that BDQF undergoes counterion transfer with CFZ, leading to the formation of new salts of either CFZ or BDQ. These new salts significantly enhance the dissolution behavior of CFZ in the BDQF-CFZ binary systems, which cannot be seen in the BDQ-CFZ systems. On the other hand, the dissolution rate of BDQF was also decreased in specific drug ratios. More specifically, we found that the ratio of 2:1 can synergistically enhance the solubility of CFZ, maintain the equibilirum solubility and provide adequate dissolution of BDQF. The findings provide mechanistic insights of selecting suitable drug forms in optimizing FDC performance and designing optimal formulations for MDR-TB therapy.
Safety gaps in pediatric liquid antihypertensive compounding: a scoping review and regulatory-based safety assessment.
Fanhani FC, Alves LA, Marcondes Sari MH … +3 more , Matoso Mendes AE, Pontarolo R, Ferreira LM
Eur J Pharm Biopharm · 2026 Jun · PMID 42320763 · Publisher ↗
BACKGROUND: Extemporaneous liquid antihypertensive formulations are widely used in pediatrics but frequently lack detailed reporting of excipient safety data, particularly regarding age-specific physiological vulnerabili...
BACKGROUND: Extemporaneous liquid antihypertensive formulations are widely used in pediatrics but frequently lack detailed reporting of excipient safety data, particularly regarding age-specific physiological vulnerability and cumulative exposure. METHODS: A scoping review was conducted in accordance with PRISMA-ScR guidelines to map excipients used in pediatric extemporaneous antihypertensive liquid formulations. A regulatory-oriented assessment was applied, emphasizing age-appropriate safety considerations and exposure-based risk principles, including theoretical daily intake expressed as mg/kg/day. RESULTS: Forty-two studies were included. Reporting of excipient concentrations, age targets, and safety justifications was heterogeneous and often incomplete. Vehicles, co-solvents, preservatives, buffers, antioxidants, surfactants, and flavoring agents were identified, with selection typically driven by a focus on physicochemical stability rather than patient-centered criteria, such as age-appropriate excipient safety, dose flexibility, and acceptable volumes. Exposure-based considerations were addressed by a limited number of studies (n = 5). Exposure calculations based on typical pediatric dosing showed that concentrations considered acceptable in adult formulations may translate into clinically relevant toxicity risks in neonates and infants. Based on observed patterns, a conceptual risk stratification framework was developed to categorize excipients according to age-dependent toxicity, cumulative dose burden, and functional tolerability. CONCLUSIONS: The available literature on compounding antihypertensive formulations mainly emphasizes physicochemical performance, with less attention given to exposure-related safety parameters in pediatric patients. Integrating total daily excipient exposure metrics and structured justification for excipient selection may improve alignment with regulatory expectations and support safer, patient-centered compounding practices in pediatric clinical care.
Understanding drug diffusion and permeation in transdermal patches: A kinetic perspective.
Garg I, Verma M, Chaurasia U … +2 more , Negi T, Rawat S
Eur J Pharm Biopharm · 2026 Jun · PMID 42315040 · Publisher ↗
Transdermal drug delivery (TDD) offers a non-invasive method for systemic medication, bypassing first-pass metabolism and allowing controlled release. Transdermal patches (TPs) are among the most common TDD systems, with...
Transdermal drug delivery (TDD) offers a non-invasive method for systemic medication, bypassing first-pass metabolism and allowing controlled release. Transdermal patches (TPs) are among the most common TDD systems, with performance influenced by drug properties, skin physiology, polymer matrices, adhesives, permeation enhancers, and patch design. Different TP architectures including reservoir, matrix, adhesive-dispersion, and micro-reservoir systems, have unique release and permeation features. The stratum corneum remains the main barrier to drug transport, significantly affecting transdermal flux, lag time, and bioavailability. This review systematically examines the mathematical, kinetic, and dermatokinetic models used to describe drug release, skin permeation, and systemic absorption from TPs. Classical models, including zero-order, first-order, Higuchi, Korsmeyer-Peppas, Peppas-Sahlin, Weibull, Gompertz, Hixson-Crowell, Baker-Lonsdale, and Hopfenberg, are critically analyzed for their mechanistic basis and relevance. It distinguishes intrinsic drug release from skin permeation processes and highlights advances in reaction-diffusion modeling, physiologically based pharmacokinetic (PBPK) modeling, and in vitro-in vivo correlation (IVIVC). Emerging computational techniques like molecular docking, molecular dynamics, artificial intelligence, and machine learning are also explored to optimize transdermal formulation design and predict drug transport behaviors.
Mitochondria-targeted delivery of bromocriptine via cerium vanadate nanocarriers for Parkinson's disease.
Mishra K, Tiwari AK, K A … +12 more , Dadge SD, Rana R, Tripathi S, Verma P, Vale AM, Silva AA, Fiadeiro M, Sharma D, Bernardino L, Gayen JR, Singh S, Chourasia MK
Eur J Pharm Biopharm · 2026 Jun · PMID 42315039 · Publisher ↗
Parkinson's disease (PD) is a therapeutically challenging neurodegenerative disease marked by profound disruptions in mitochondrial-redox axis. Current therapeutic agents such as Bromocriptine mesylate (BM) exhibit neuro...
Parkinson's disease (PD) is a therapeutically challenging neurodegenerative disease marked by profound disruptions in mitochondrial-redox axis. Current therapeutic agents such as Bromocriptine mesylate (BM) exhibit neuroprotective potential, however their clinical benefit remains largely symptomatic as they do not address the underlying cause of neurodegeneration. Moreover, the therapeutic efficacy of BM is compromised due to its poor solubility, low bioavailability, and inadequate brain penetration. To overcome these biological barriers and provide mechanistic interventions, we report the first drug-loaded porous cerium vanadate nanoplatform (MT-BM-CNP), in which BM, as a model drug is encapsulated within cerium vanadate nanoparticles and surface-functionalized with L-methyl ester tryptophan-conjugated triphenylphosphonium for mitochondrial targeting. The intrinsic Ce/Ce and V/V redox-switching of cerium vanadate provides strong antioxidant buffering, while the triphenylphosphonium moiety facilitates selective mitochondrial delivery, a central locus of PD pathology. The MT-BM-CNP complex illustrates higher neuroprotective potential by integrating dopaminergic stimulation with intrinsic redox regulation, while exhibiting enhanced stability and sustained drug release. In the preclinical 6-hydroxydopamine PD models, the nanoformulation preserved nigral dopaminergic neurons, restored dopamine levels and significantly improved motor function, with preferential protection of neuronal somata over striatal axon terminals. This study introduces a novel drug-loading strategy using porous cerium vanadate nanoparticles and establishes MT-BM-CNP as a novel mitochondrial-redox axis targeted therapeutic system. This strategy is a significant advancement in nanotechnology-mediated neuroprotection for PD offering not only symptomatic relief but disease-modifying potential as well.
Design and validation of a poly-L-lysine dendrimer-based rapamycin delivery system for intracranial drug-coated balloons.
Huang J, Feng Y, Yao Y … +2 more , Cui H, Zhang Q
Eur J Pharm Biopharm · 2026 Jun · PMID 42315038 · Publisher ↗
Rapamycin can be used as a coating on balloon catheters but faces challenges such as poor tissue retention and significant drug loss during delivery. In this study, a third-generation poly-L-lysine (G3 PLL) dendrimer-bas...
Rapamycin can be used as a coating on balloon catheters but faces challenges such as poor tissue retention and significant drug loss during delivery. In this study, a third-generation poly-L-lysine (G3 PLL) dendrimer-based delivery system was developed for intracranial drug-coated balloons to modulate drug loading and local pharmacokinetic behavior. Using a rabbit carotid artery model, the residual drug on the balloon surface after expansion and rapamycin concentrations in vascular tissue and plasma were evaluated immediately and on days 1, 3, and 7. The results showed that the post-expansion residual drug rate on the balloon surface was 4.288 ± 0.788%, i.e., lower than that of conventional paclitaxel-coated balloons (15.8 ± 5.5%). The vascular tissue drug concentrations demonstrated a sustained release profile, starting at 719.134 ± 2.584 μg/g and remaining at 485.716 ± 3.164 μg/g on day 7. The peak plasma concentration (0.791 ± 0.018 μg/mL) was well below the known toxic threshold of 5 μg/mL. The proposed system enabled controlled intramural exposure while limiting systemic drug levels, reflecting modulation of drug disposition following transient balloon contact. In conclusion, these findings support the feasibility of a dendrimer-enabled formulation strategy for localized vascular drug delivery with favorable pharmacokinetic characteristics for intracranial arterial stenosis.
Moisture-responsive smart hydrogel for adaptive regulation of timolol delivery kinetics under variable wound exudate conditions.
Wiedemann Y, Pflumm S, Ludwigs S … +1 more , Lunter DJ
Eur J Pharm Biopharm · 2026 Jun · PMID 42309265 · Publisher ↗
Effective wound therapy requires systems that respond to dynamic moisture conditions while enabling controlled drug delivery. This work focuses on the application of a previously developed programmable, humidity responsi...
Effective wound therapy requires systems that respond to dynamic moisture conditions while enabling controlled drug delivery. This work focuses on the application of a previously developed programmable, humidity responsive hydrogel for exudate management in combination with targeted delivery of timolol, a β-adrenergic antagonist with emerging therapeutic relevance in wound healing. The influence of predefined hydrogel hydration and exudate levels on drug release and skin permeation across wounded and non-wounded skin was evaluated. The hydrated state of the hydrogel exhibited rapid diffusion-controlled drug release, whereas the conditioned hydrogel showed a biphasic swelling-controlled release behavior with initial polymer relaxation followed by predominantly diffusional transport. Higher exudate levels accelerated swelling and shifted the inflection point up to 2.7-fold earlier. Wounded skin showed rapid permeation, while non wounded skin exhibited pronounced lag phases and up to 77-fold lower permeation. The steady-state flux across wounded skin from the conditioned hydrogel was 1.7-fold lower compared to the hydrated hydrogel. The hydrogel exhibits a fluid handling capacity comparable to superabsorbent dressings while maintaining high moisture vapor transmission. Combining timolol with this smart and self-adjusting material paves the way for a novel category of personalized wound therapy adaptable to a broad range of wound states.
Modelling human skin morphology and simulating transdermal transport of 50 chemicals.
Tesfamarian M, Nägel A, Heisig M … +1 more , Wittum G
Eur J Pharm Biopharm · 2026 Jun · PMID 42276176 · Publisher ↗
A mathematical model was developed to investigate the transdermal transport of 50 chemicals across human skin. The model incorporates key skin properties and physicochemical parameters. Simulations were performed using e...
A mathematical model was developed to investigate the transdermal transport of 50 chemicals across human skin. The model incorporates key skin properties and physicochemical parameters. Simulations were performed using experimentally determined partition and diffusion coefficients for the different skin layers (Ellison et al., 2020). The simulation results were compared with experimental data for 13 chemicals. The predicted uptake dynamics were compared with temporal trends reported in experimental studies (Coderch et al., 2021; Hewitt et al., 2020; Deacon et al., 2024). A clear log P-dependent uptake behaviour was identified that enables a classification of the chemicals into three distinct groups. The simulation results demonstrate that the mesoscale diffusion model allows comparison of temporal uptake behaviour between chemicals.
Preferential nose-to-brain delivery of phenytoin via an intranasal phenytoin-arginine co-amorphous system.
Nagatomo T, Irino H, Kanbara Y … +5 more , Nagasawa K, Oikawa N, Uchiyama T, Suzuki N, Suzuki T
Eur J Pharm Biopharm · 2026 Jun · PMID 42264008 · Publisher ↗
This study aimed to design a co-amorphous (CA) formulation of poorly water-soluble phenytoin (PHT) to improve its brain delivery after intranasal administration. To screen a coformer required for novel CA system, PHT was...
This study aimed to design a co-amorphous (CA) formulation of poorly water-soluble phenytoin (PHT) to improve its brain delivery after intranasal administration. To screen a coformer required for novel CA system, PHT was ground with 20 amino acids at equimolar ratios, and L-arginine (ARG) was selected as a coformer for CA. Further investigation revealed that PHT and ARG at a molar ratio of 1:1 exhibited the highest glass transition temperature, suggesting superior amorphous stability, as well as high PHT loading of 59.2 %. In solubility studies using simulated nasal fluid, CA showed a maximum concentration of dissolved PHT immediately after the start of the test, which was 38-fold and 4-fold higher than that of PHT alone and physical mixture, respectively. Evaluation of the molecular state after CA dissolution by H NMR spectroscopy suggested the presence of ionic interactions between PHT and ARG. This enhancement was attributed to supersaturation induced by amorphization and ionization resulting from the addition of ARG. Following intranasal administration to mice, CA suspension showed a significant increase in the amount of PHT delivered to the brain and olfactory bulb (3.2- and 3.3-fold, respectively), compared with PHT alone, whereas no significant differences were observed in plasma exposure. These results suggest that CA formation improves the solubility of PHT and induces ionization, which may reduce membrane permeability, and thereby preferentially promote brain delivery via the nose-to-brain pathway without enhancing systemic exposure. These findings suggest that PHT-ARG CA system is an effective formulation strategy for achieving preferential intranasal delivery to the brain.
Exploring formulation options for extended release minitablets.
Bochmann E, Eugenia-Ilieva E, Heil S … +5 more , Katz JM, Koziolek M, Marmol AL, Sanzgiri Y, Westedt U
Eur J Pharm Biopharm · 2026 Jun · PMID 42264007 · Publisher ↗
Compared to conventional tablets, minitablets have several advantages, like acceptance for patients with swallowing difficulties (from pediatric to geriatric) and high flexibility in dosing. Despite these advantages, min...
Compared to conventional tablets, minitablets have several advantages, like acceptance for patients with swallowing difficulties (from pediatric to geriatric) and high flexibility in dosing. Despite these advantages, minitablets are challenging for extended release (ER) dosage forms. We explored different ER minitablet formulations for Compound A with the aim of maintaining drug plasma concentrations over 24 h. Compound A is a BCS class II drug with pH-dependent solubility and was available as monosodium monohydrate salt and its parent free acid form. To reduce pill burden, high drug load in the final drug product was in scope. Minitablets were manufactured by either wet or melt granulation. The formulation screening was based on compendial dissolution testing to enable sufficient throughput. Subsequently, the impact of certain physiological luminal pH on drug release was explored in a biorelevant test method (multi-stage dissolution test). We demonstrated that by combining the right API form, hydrophobic matrix formers as well as hydrophilic release components, minitablets that enable the extended release of Compound A over 24 h were feasible. A defined material-sparing pathway to adjust release profiles combined with targeted biorelevant drug release testing provides a novel approach to develop ER minitablets in a relatively short time.
Interactions between mRNA lipid nanoparticles and immune cells in fresh human whole blood.
Hak S, Rodà F, Molska A … +6 more , de Carlos Hernandez F, Wolowczyk C, Giambelluca M, Glomm WR, Borgos SE, Parot J
Eur J Pharm Biopharm · 2026 Jun · PMID 42264006 · Publisher ↗
Around 90 % of the drugs that enter clinical trials fail to reach the market. A main cause for this disturbing statistic is the poor correlation between drug performance in the clinic and in preclinical models of human (...
Around 90 % of the drugs that enter clinical trials fail to reach the market. A main cause for this disturbing statistic is the poor correlation between drug performance in the clinic and in preclinical models of human (patho)physiology. Especially for drugs with complex structure-function relationships, such as mRNA lipid nanoparticles (mRNA-LNPs), this is problematic due to their very high dependency on large-scale preclinical screening approaches in their development. mRNA-LNPs and other nanomedicines are often administered systemically where they interact with plasma proteins and circulating cells, which strongly affects therapeutic applications. Moreover, in various nanotherapeutic strategies, circulating immune cells may be therapeutic targets. Human whole blood is successfully used ex vivo to study human immunity, disease trajectories, and drug performance and side effects. To assess human blood's utility in mRNA-LNP development, we here screened for interactions between mRNA-LNPs and 5 immune cell types in human whole blood. We demonstrated that with only 6 blood donors and a systematically designed mRNA-LNP mini-library, it is possible to identify significant effects of different lipid ingredients on mRNA-LNP cellular uptake and cytokine induction. Our findings suggest that ex vivo use of human blood may become a valuable addition to the mRNA-LNP preclinical development pipeline.
Site-specific enrichment of highly sialylated N-glycans in an erythropoietin-hybrid Fc fusion protein.
Park J, Eom D, Park CS … +8 more , Moon C, Kim S, Lee S, Lee J, Shin J, Jo Y, Lee M, Kim HH
Eur J Pharm Biopharm · 2026 Jun · PMID 42264005 · Publisher ↗
Erythropoietin-hybrid Fc fusion protein (EPO-hyFc), comprising an EPO domain fused to a hybrid IgD-IgG4 Fc, is a next-generation erythropoiesis-stimulating agent with an approximately two-fold longer serum half-life than...
Erythropoietin-hybrid Fc fusion protein (EPO-hyFc), comprising an EPO domain fused to a hybrid IgD-IgG4 Fc, is a next-generation erythropoiesis-stimulating agent with an approximately two-fold longer serum half-life than darbepoetin alfa, a clinically established long-acting EPO formulation. Although sialylation at Asn-38 and Asn-83 is known to modulate serum stability and half-life, the site-specific N-glycosylation of EPO-hyFc has not been characterized. Here, we performed comprehensive N-glycan profiling using LC-MS/MS glycomics combined with nano-LC-MS/MS glycoproteomic analysis of Glu-C-digested peptides. In total, 23 N-glycans (15 sialylated and 8 neutral) were identified. Site-normalized quantification revealed that Asn-24 was mainly occupied by mono- and di-sialylated glycans (64.9%), whereas Asn-38 (76.9%) and Asn-83 (87.7%) were enriched in tri- and tetra-sialylated structures. The Fc site (Asn-261) contained mainly non-sialylated glycans (94.4%). The average number of sialic acids per N-glycan was 2.2, and the sialic acid-capping ratio was 90.9%, indicating extensive terminal sialylation across the EPO sites. These results provide the first site-specific characterization of N-glycosylation in EPO-hyFc and offer structural and quantitative insights for optimizing its stability, pharmacokinetics, and therapeutic efficacy.
Study on the improvement of bioavailability and hepatoprotective effect of silybin-7-eicosanedioate long-acting injection based on prodrug technology.
Zhou J, Wei R, Li B … +5 more , Guo B, Chen X, Kuang Y, Xu Y, Wu X
Eur J Pharm Biopharm · 2026 Jun · PMID 42264004 · Publisher ↗
Chronic hepatitis (CH) is a prevalent liver disease with poor clinical treatment efficacy due to the low bioavailability and short half-life of oral silybin (SLB) formulations [1]. This study employed a long-chain fatty...
Chronic hepatitis (CH) is a prevalent liver disease with poor clinical treatment efficacy due to the low bioavailability and short half-life of oral silybin (SLB) formulations [1]. This study employed a long-chain fatty acid prodrug strategy to synthesize four SLB prodrugs (SLB-7-DDDA, SLB-7-TDDA, SLB-7-HDDA, SLB-7-ODDA), among which SLB-7-ODDA was identified as the optimal candidate owing to its lowest degradation rate (purity > 95%). SLB-7-ODDA long-acting suspension injection (SLB-7-ODDA-LAIS) was prepared via wet ball milling, which showed uniform particle size distribution, excellent redispersibility, and sustained-release properties in vitro. In vivo studies conducted in rats revealed that SLB-7-ODDA-LAIS exhibited a relative bioavailability of 613.60% compared with marketed SLB capsules, along with significantly prolonged half-life. It also exerted significant hepatoprotective effects against CCl-induced CH by reducing serum transaminase levels, enhancing hepatic antioxidant capacity and alleviating liver fibrosis, and showed no significant muscle irritation. This formulation offers a novel long-acting therapeutic strategy for CH and a technical basis for enhancing the in vivo performance of low-bioavailability drugs.
Investigation of the intake process of different tablets by assessment of swallowability and palatability as well as measurement of deglutition parameters by electromyography and bioimpedance analysis.
Spittel S, Stegemann S, Seidl RO … +6 more , Wargenau M, Spitzhorn LS, Bosse HM, Kloft C, Hübl N, Klingmann V
Eur J Pharm Biopharm · 2026 Jun · PMID 42251919 · Publisher ↗
This study aimed to investigate the suitability and possible correlation of three different methods for evaluating the intake process of oral tablet formulations: (i) objective assessment of swallowability and palatabili...
This study aimed to investigate the suitability and possible correlation of three different methods for evaluating the intake process of oral tablet formulations: (i) objective assessment of swallowability and palatability (acceptability as composite endpoint), (ii) self-assessment of swallowability, palatability and anticipated swallowability by others, and (iii) specific measurement parameters for the oral and pharyngeal phase of swallowing derived from electromyography (EMG) and bioimpedance (BI) values. Therefore, 280 participants were stratified into 5 cohorts from 12 years up to ≥66 years. Following four placebo tablet formulations were tested: small round, large round, small oblong and large oblong. For all groups, acceptability (composite endpoint of swallowability and palatability) of the two smaller-sized formulations was 96.4 % each and thereby significantly higher than the acceptability of the large oblong tablet (81.1 %). Acceptability was lowest for the large round tablet (67.2 %). The subjective assessments of swallowability and palatability as well as anticipated swallowability by others showed a similar pattern. For most parameters, the EMG and BI values were significantly lower for the small tablet formulations compared to the larger tablet versions. All three methods for evaluating the tablet intake process were able to distinguish between smaller and larger formulations and thus present complementary approaches.
Promising advancements to the blue dye ingress test - Quantification of blister integrity by leakage rate.
Márton A, Benke J, Markus M … +3 more , Hoheisel W, Bartsch J, Thommes M
Eur J Pharm Biopharm · 2026 Jun · PMID 42250823 · Publisher ↗
The most common packaging type for solid dosage forms is the blister package. The critical quality attribute of blisters is the integrity, which is required to be tested. Hereby it is crucial to develop methodologies rep...
The most common packaging type for solid dosage forms is the blister package. The critical quality attribute of blisters is the integrity, which is required to be tested. Hereby it is crucial to develop methodologies representing an improvement compared to the current standard, the blue dye ingress test, regarding sensitivity limits and quantification. In this study, two analytical methods (optical emission spectroscopy and a helium mass spectrometry, which rely on a similar principle), were characterized. For the latter a sample preparation procedure was also developed for filling the blister packages with helium tracer gas. Leaky blister packages were prepared via laser drilling, and the leakage rate was measured. Quantification within the experimental space was found to be feasible using optical emission spectroscopy, and partially feasible using helium mass spectrometry. Furthermore, the repeatability was examined and the measurement results were verified with physical and empirical models describing the molecular flow. In conclusion, the two characterized methods represent promising competition to the established standard test due to quantification. Additionally, the procedures can serve as a sensitive reference method for development as well as production.
A charge-reversible hyaluronic acid prodrug nanoplatform for synergistically enhanced tumor-targeted doxorubicin delivery.
Yan Y, Shi J, Zheng Z … +2 more , Shi X, Zhao X
Eur J Pharm Biopharm · 2026 Jun · PMID 42250822 · Publisher ↗
Conventional nanocarriers often face challenges of insufficient tumor specificity and poor cellular internalization. To overcome these limitations, we developed an all-in-one prodrug nanoplatform based on hyaluronic acid...
Conventional nanocarriers often face challenges of insufficient tumor specificity and poor cellular internalization. To overcome these limitations, we developed an all-in-one prodrug nanoplatform based on hyaluronic acid (HA) that synergistically integrates active targeting, pH-responsive charge reversal, and controlled drug release. Doxorubicin (DOX) was covalently conjugated to oxidized HA via a pH-sensitive imine bond, while a charge-reversal polymer (PLL-DMMA) was grafted onto the HA backbone. This design enables CD44-mediated active targeting toward cancer cells. Crucially, the nanoplatform exhibits a smart charge-reversal characteristic: maintaining a negative surface charge (-32.8 mV) at physiological condition (pH 7.4) for extended circulation, while switching to positive (+16.5 mV) in the acidic tumor microenvironment (pH 6.5) to enhance cellular uptake. In vitro studies demonstrated significantly improved internalization in CD44-overexpressing MKN-45 cells compared to SNU-216 cells with low CD44 expression. The release profile showed high stability at pH 7.4 (<5% release in 5 days) and rapid drug release at endo/lysosomal pH (61.6% at pH 5.0). Cytotoxicity assays confirmed enhanced efficacy of the charge-reversed formulation, with lower IC values in both cell lines. This multifunctional prodrug nanoplatform represents a promising strategy for precision cancer chemotherapy through synergistic enhancement of tumor targeting and intracellular drug delivery.
Integrating artificial intelligence into drug delivery systems: Formulation development and current challenges.
Lucas I, Sousa J, Vitorino C
Eur J Pharm Biopharm · 2026 Jun · PMID 42242512 · Publisher ↗
Artificial intelligence (AI) is increasingly being explored as a supportive tool to address persistent challenges in drug delivery research, particularly those associated with formulation complexity, optimization efficie...
Artificial intelligence (AI) is increasingly being explored as a supportive tool to address persistent challenges in drug delivery research, particularly those associated with formulation complexity, optimization efficiency, and controlled drug release. While AI applications in drug discovery are well established, their role in drug delivery systems remains less structured and is primarily focused on supporting formulation design, optimization, and performance prediction within experimentally constrained environments. Conventional trial-and-error approaches are resource-intensive and often struggle to capture the multidimensional relationships between formulation variables, carrier properties, and biological performance. In this context, AI-driven methods offer opportunities to enhance data interpretation and guide formulation development in a more systematic and predictive manner. This review examines the application of AI across key stages of drug delivery development, including formulation design, nanocarrier optimization, and smart and controlled release systems. Machine learning (ML) and deep learning (DL) approaches applied to pre-formulation analysis, excipient selection, particle engineering, and release-profile optimization are discussed, highlighting their role as decision-support tools rather than autonomous systems. The integration of AI within Quality by Design (QbD) frameworks is also critically assessed, with particular attention to its potential to support the identification of critical formulation variables and design-space exploration. Despite these advances, translation into routine pharmaceutical practice remains limited by challenges related to data quality, experimental validation, model interpretability, and biological complexity. Overall, this review positions AI as a complementary and decision-support layer in drug delivery development and highlights the key barriers that must be addressed for its reliable, scalable, and regulatory-aligned implementation.
Impact of gastric mixing and water intake on postprandial pharmacokinetics of orally disintegrating tablets: A PBBM-based study.
Takahashi Y, Matsui K, Matsumura N … +1 more , Kambayashi A
Eur J Pharm Biopharm · 2026 Jun · PMID 42242511 · Publisher ↗
OBJECTIVE: Food intake substantially influences the oral absorption of many drugs, and the ability to quantitatively predict food effects in humans prior to clinical studies is critical for optimizing dosing regimens and...
OBJECTIVE: Food intake substantially influences the oral absorption of many drugs, and the ability to quantitatively predict food effects in humans prior to clinical studies is critical for optimizing dosing regimens and formulation design. Although various in silico approaches have been proposed to predict food effects on oral solid dosage forms, their predictive performance remains limited. Orally disintegrating tablets (ODTs), which can be administered without water, are known to exhibit characteristic postprandial absorption profiles that are inadequately captured by conventional models. This study aimed to develop a novel physiologically based biopharmaceutics model (PBBM) capable of quantitatively predicting the impact of postprandial water intake on drug absorption, using tolvaptan and rivaroxaban as model compounds Methods: To better represent the postprandial gastric environment, a novel model (Assumption 2) was developed in which the stomach was functionally divided into two compartments: the fundus and the antrum. For administration without water, the drug was assumed to remain in the fundus and transfer to the antrum after a defined lag time. In contrast, for administration with water, drug distribution between the fundus and antrum was assumed, accounting for the formation of a flow channel (Magenstraße). In addition, a mathematical description of drug-chyme mixing in the antrum was incorporated to reflect dissolution under high-viscosity conditions. RESULTS AND DISCUSSION: The conventional single-compartment gastric model (Assumption 1) substantially overestimated postprandial absorption rates. In contrast, the proposed compartment-divided model (Assumption 2) markedly improved the prediction of Tmax for both tolvaptan and rivaroxaban ODTs and successfully reproduced the characteristic postprandial absorption delay observed under water-free administration. These findings demonstrate that abandoning the conventional assumption of instantaneous homogeneous gastric mixing and explicitly accounting for administration-dependent (i.e., presence or absence of water intake) gastric distribution and drug entrapment within solid food substantially improves the prediction of postprandial pharmacokinetics. The remaining tendency toward slightly earlier predicted absorption, particularly for rivaroxaban, suggests that diffusion delays in ultra-high-viscosity environments generated by solid meals are not fully captured by parameters derived from liquid meal data. Overall, the proposed model structure is mechanistically valid, and further improvements in prediction accuracy are expected through the incorporation of parameters describing particle behavior in highly viscous gastric contents, informed by complementary in vitro and in vivo studies.
Stratum corneum lipid remodeling as a proposed mechanism for liposomal penetration enhancement.
Andersen NS, Ruiz GCM, Sørensen JA … +4 more , Ebbesen MF, Lunding A, Kuntshe J, Brewer JR
Eur J Pharm Biopharm · 2026 Jun · PMID 42242510 · Publisher ↗
The stratum corneum (SC) is the principal barrier to topical and transdermal delivery, yet how lipid-based formulations interact with the SC lipid matrix remains incompletely resolved. Here, we compared conventional leci...
The stratum corneum (SC) is the principal barrier to topical and transdermal delivery, yet how lipid-based formulations interact with the SC lipid matrix remains incompletely resolved. Here, we compared conventional lecithin/cholesterol liposomes, hexosomes, ultradeformable liposomes, and a surfactant-only micelle control in ex vivo human skin after 4 h Franz-cell exposure. Depth-resolved Laurdan generalized polarization (GP) imaging of cryosections was used to quantify formulation-induced changes in SC lipid organization, while DiD fluorescence and deuterated-lipid stimulated Raman scattering (SRS) provided orthogonal readouts of formulation-derived material within the tissue. Across formulations, GP decreased relative to matched controls, with the largest effects in the outer SC. Hexosomes produced larger outer-SC GP reductions than conventional liposomes (ΔGP ≈ 0.25-0.33 vs 0.14-0.18). In a separate donor-matched series, ultradeformable vesicles induced stronger SC remodeling than conventional liposomes, whereas Tween 20 micelles produced smaller effects. DiD and SRS signals were predominantly localized to the SC and decreased with depth, with SRS indicating a more surface-weighted distribution for rigid liposomes than for ultradeformable vesicles. Together, these findings identify formulation-dependent SC lipid remodeling, involving lipid redistribution and reduced local packing order, as a plausible mechanism by which lipid-based formulations may contribute to penetration enhancement reported in previous studies.
Lipoxin A4 (LXA) versus Nanolipoxin A4 (Nano-LXA) for osteosarcoma.
Gomes-da-Silva NC, Cavalcanti A, Alves G … +9 more , Meohas W, Facchetti B, Perini JA, Rebelo Alencar LM, Ricci-Junior E, Fechine PBA, Barja-Fidalgo TC, Rosas EC, Santos-Oliveira R
Eur J Pharm Biopharm · 2026 Jun · PMID 42242509 · Publisher ↗
Lipoxin A4 (LXA) is a specialized pro-resolving lipid mediator with reported antitumor and immunomodulatory activity, but its translation is limited by chemical lability and formulation constraints. Here, we evaluated fr...
Lipoxin A4 (LXA) is a specialized pro-resolving lipid mediator with reported antitumor and immunomodulatory activity, but its translation is limited by chemical lability and formulation constraints. Here, we evaluated free LXA ("Lipoxin") versus a Pluronic F-127 micellar nanoformulation ("Nanolipoxin") in a human osteosarcoma patient-derived xenograft (PDX) model and assessed In vivo biodistribution using Tc labeling. Nanolipoxin exhibited nanostructures with heterogeneous dimensions by SEM (mean length 65 nm; mean diameter 41 nm) and was stored at 2-8 °C to preserve stability. PDX-bearing NSG mice received intraperitoneal treatment (1 µg; n = 3/group) and were monitored for 15 days. Both Lipoxin and Nanolipoxin produced a modest inhibition of tumor growth versus saline, reaching statistical significance on day 9 (*P = 0.0319) and day 15 (**P = 0.0076), while no significant differences were detected between the two active treatments. No clinical toxicity was observed (clinical score 0; stable body weight). Serum biochemistry showed no ALT differences versus control and an AST decrease for both treatments; Nanolipoxin increased lipase relative to control (*P = 0.0334). Dynamic planar scintigraphy demonstrated preferential tumor retention of Tc-Nanolipoxin at 60 min (lesion 350.47 kBq), with moderate renal/hepatic uptake and low bladder signal. Collectively, these data support LXA-based strategies in osteosarcoma and demonstrate that nanoformulation provides tumor-localizing behavior while maintaining an acceptable short-term tolerability profile in this PDX setting.
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