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[This corrects the article DOI: 10.1016/j.ijpx.2025.100469.].
[This corrects the article DOI: 10.1016/j.ijpx.2025.100415.].
[This corrects the article DOI: 10.1016/j.ijpx.2026.100485.].
[This corrects the article DOI: 10.1016/j.ijpx.2025.100438.].
Press-coated tablets (PCTs) are a modern dosage form designed to circumvent the negative effects of liquid and heat exposure that may damage drug substances during common wet coating processes for tablets. However, the production process is complex and the mechanical properties of the formulations of the different compartments may lead to challenges regarding processability, distribution of properties, and mechanical stability of the PCTs. In this study, materials with markedly different deformation properties were combined to elucidate the stress distribution during press coating and to assess the effects of process parameters and core geometry on the final PCT properties. Thorough structural investigations of all PCT compartments and the in-die analyses of axial and radial stress were applied. The simplistic approach to unify effects on the core properties by relating the punch force only on the projection area of the core only applies to the recovered core diameter and fails for further parameters. It accordingly requires more consideration of the complex stress states. The radial stress analyses clarify the anisotropy within the compression process of PCTs. It explains the findings on the distributions of porosity across different coat compartments and on the compactibilities of the recovered core. Finally, the breaking pattern of PCTs were explained with structural findings and the deduction of acting residual stresses.
Cytokine storm triggered by respiratory viral infection is the core pathogenic mechanism of severe pneumonia, and excessive activation of the NLRP3 inflammasome is a critical link in inducing this storm and subsequent lung tissue damage. This study targets the NLRP3 inflammasome to investigate the therapeutic effects, mechanisms of action, and targeted delivery advantages of folic acid-modified nanoparticles encapsulating Moringa A (MA NPs) for viral pneumonia. Utilizing techniques such as cellular experiments, mouse model validation, molecular docking, bio-layer interferometry (BLI), immunohistochemistry, immunofluorescence, and histopathology, this study systematically analyzed the effects of MA NPs on the NLRP3 inflammasome pathway, pyroptosis, macrophage polarization, and lung tissue injury, while also validating the targeting efficacy of the folic acid-modified nanodelivery system. The results showed that MA NPs significantly reduced the expression of NLRP3, ASC, Caspase-1, and GSDMD in H1N1 virus-infected cells, decreased the levels of pyroptosis-related cytokines, and MA was confirmed to be an NLRP3 inhibitor. In mouse models, MA NPs reduced the lung index, downregulated the expression of pro-inflammatory cytokines in lung tissue, and alleviated pathological and ultrastructural damage to lung tissue. Furthermore, MA NPs inhibited the excessive activation of the NLRP3 inflammasome and promoted the polarization of macrophages from the M1 phenotype to the M2 phenotype, thereby alleviating the pulmonary inflammatory microenvironment. Therefore, MA NPs can repair lung tissue damage by inhibiting excessive activation of the NLRP3 inflammasome and regulating macrophage polarization, and combined with the folic acid-targeted delivery system, achieve precision treatment for viral pneumonia. This provides a new approach and experimental basis for the synergistic intervention of viral pneumonia.
Pathogenic bacterial intracellular infection by Mycobacterium tuberculosis and Staphylococcus aureus is a major complication to treatment because of resistance to immune actions and the ability to withstand traditional antibiotics. Failure of existing therapies is usually due to inefficient intracellular penetration of drugs and inappropriate targeting of subcellular sites. We discuss the nanoparticle drug delivery systems (NDDSs) here that enhance intracellular delivery of antibiotics using customized carrier materials, targeted internalization processes and stimuli-responsive release of antibiotics. These systems enhance specificity of pathogen targeting and efficacy of drugs and overcome barriers of microenvironment. We also address translational challenges such as toxicity, heterogeneity of infection, scalability of manufacturing, and scanty clinical data. Future trends include versatile hybrid vehicles, combination with immunomodulators or gene-editing applications and AI-enhanced personalized nanomedicine. The potential to tackle pathogen-specific issues with nanotechnology advances can provide possible solutions to the treatment of persistent intracellular infections and antibiotic resistance, which are the prospects with NDDSs.
Magnetic resonance imaging was used to investigate gastric emptying and small-intestinal distribution of a manganese-labeled 10.6% glucose solution in a randomized crossover study in 12 healthy volunteers under fasted and postprandial conditions after ingestion of a solid light meal. Following the ingestion of 240 mL of the test solution (100 kcal), manganese contrast appeared rapidly in the small intestine and reached distal regions within approximately 20 min in 9 out of 12 subjects, irrespective of the prandial state. Contacted small-intestinal length and small-intestinal distribution increased continuously during the early phase and plateaued thereafter, closely paralleling gastric emptying of the solution. While absolute intestinal contact lengths were lower under postprandial conditions, normalized spreading showed comparable temporal profiles in fasted and fed states, indicating similar distribution mechanisms. Although distribution was slower than previously reported for water, the spatial extent of intestinal spreading was largely preserved in the caloric vehicle. These findings demonstrate that the Magenstrasse and Darmstrasse are not restricted to non-caloric liquids but also govern the rapid luminal distribution of substances dissolved in caloric solutions, largely independent of prandial state, with relevant implications for oral drug delivery and food-effect interpretation.
Potency is a critical specification for CAR-T cells and is typically determined by co-culture of CAR-T cells with target cell lines. However, cell line heterogeneity hampers standardization and can lead to analytical variation impacting potency test results. Further, both the assay and cell line maintenance are labor, time, and resource intensive. Here, we developed and validated a versatile, fully standardized, and GMP-compliant CAR-T cell potency assay. This assay utilizes antigen-loaded beads instead of target cell lines and was fully validated for CD19 and qualified for CD7 and HER2 CAR-T cells. Incubation of streptavidin beads with recombinant biotinylated antigen yielded a dose-dependent bead loading. Subsequent incubation of CAR-T cells with increasing amounts of antigen-loaded beads yielded a dose-dependent secretion of IFN-γ, whereas non-loaded or MOCK antigen-loaded beads did not significantly trigger IFN-γ secretion. Notably, as assessed for CD19 CAR-T cells, cryopreserved CAR-T cells yielded lower potency than fresh CAR-T cells and potency results correlated with the total amount of CAR-T cells in the test sample. Therefore, the assay was fully standardized using a fixed amount of 50 k CAR-T cells per test, a fixed amount of antigen loaded onto the beads (1 pg/bead), and a fixed amount of 500 k antigen-loaded beads. A quantitative and statistically substantiated potency threshold for batch release was established for fresh as well as cryopreserved CAR-T cell drug products This fully standardized assay protocol and validation strategy provides a facile potency assay for CAR-T cell drug products that can be implemented for essentially any antigen of interest.
A robust method to quantify the spatial distribution of active ingredients and their concentrations as a function of depth within the epidermis and dermis would be advantageous for both cosmetic and pharmaceutical products. Here, a cassette-based in vitro permeation test (IVPT) was performed (at a given site) under finite dose conditions with five physicochemically distinct substances (with a > 350,000-fold difference in lipophilicity) using human abdominal skin - both permeation and total deposition were determined. A total of eighteen skin discs (area = 2 cm2, 6 female donors, 3 samples per donor) were used for the IVPT. They were subsequently divided into three groups and distributed to L'Oréal Operator 1 (L1, n = 6), L'Oréal Operator 2 (L2, n = 6), and University of Geneva (UG, n = 6). The cutaneous biodistribution method was then used to determine the spatial distribution of the five substances at a high resolution from the stratum corneum down to the upper dermis. Twenty skin lamellae with a thickness of 20 μm were obtained from each disc and the amount of each substance in each lamella was quantified. A novel statistical analysis was employed to investigate the variability/reproducibility of the data generated intra-laboratory (L1 vs. L2) and inter-laboratory (L1 vs. UG and L2 vs. UG). The results demonstrated the absence of significant difference in the permeation, total deposition, and cutaneous biodistribution data obtained following the identical protocols at both the intra- and inter-laboratory level and confirmed the robustness of the cutaneous biodistribution method in understanding the disposition of topically applied substances in the skin.
The influence of co-administered water volume on the intragastric dissolution and the systemic exposure of drugs taken under fed conditions remains clinically relevant, particularly for drug substances with limited aqueous solubility. This secondary pharmacokinetic analysis, based on a previously published MRI study (n = 12) evaluated the effect of 50, 100, and 150 mL water on the salivary pharmacokinetics of 13C₃-caffeine (25 mg; high solubility, high permeability) and theobromine (50 mg; lower solubility, high permeability) administered in a hard gelatin capsule 30 min after a standardized meal. Saliva samples were collected over 119 min and quantified by LC-MS/MS. Both compounds appeared rapidly in saliva irrespective of the initial water volume, indicating that even 50 mL effectively triggered postprandial liquid emptying via the Magenstrasse. Wilcoxon Signed-Rank test of dose-normalized AUC0 - 119 min demonstrated no significant differences between both substances. Phase-specific analysis (0-59 min vs. 59-119 min) revealed a strong phase effect (p < 0.001) and a significant phase × substance interaction (p < 0.001), but no effect of initial fluid volume, reflecting a pronounced late exposure increase for theobromine after administration of an additional 240 mL water at 60 min. These findings indicate that small fluid volumes are sufficient to initiate rapid gastric transit of dissolved fractions under fed conditions. However, for less soluble compounds, undissolved fractions may persist intragastrically and contribute to delayed, biphasic absorption following subsequent fluid intake. Standardization of post-dose drinking behavior should therefore be considered in food-effect and bioavailability studies.
Chronic obstructive inflammatory respiratory diseases are among the most common non communicable respiratory diseases worldwide. Although inhaled corticosteroids are effective, inadequate inspiratory flow through an inhaler can still result in poor asthma and COPD control. The patient's inhalation pattern directly determines the Fine Particle Dose (FPD) delivered to the lungs. This study evaluates which internal resistance of the RS01 inhaler, (low, medium-low, medium, or medium-high resistance) provides the most consistent FPD, of controlled-release budesonide dry powder, across inspiratory profiles typical in asthmatic and COPD patients. Inspiratory profiles were defined by peak inspiratory flow rates (PIFR) from 30 to 100 L/min, inhaled volumes (Vi) from 1 to 5 L and times to inhale (Ti) from 1 to 5 s. They were generated using a Breath-Simulator (BRS300i) coupled to a Next Generation Impactor connected to Alberta Idealized Throat, for strong in vitro/in vivo correlations. The FPD was measured for each combination of PIFR, Vi, and Ti for the four different RS01 inhalers, using a central composite Design of Experiment setup. Results indicate that the medium-low and medium-high resistance RS01 inhalers provide the most stable FPD across the full range of inspiratory profiles. Among the both, the medium-low RS01 inhaler delivered the most stable drug amount. On the other hand, the FPD delivered with the low resistance and medium resistance RS01 inhalers was significantly influenced by PIFR. The applied approach may help to select more adequately a device for a developed dry powder formulation taking account of the patient's inspiratory profiles.
Cryptococcus neoformans is responsible for life-threatening infections with persistently high mortality despite current amphotericin B (AmB)-based treatments. Although liposomal AmB (AmBisome®) remains the standard of care, its complex composition and high production cost limit accessibility and the development of generic versions. Improving AmB efficacy therefore represents a priority. We previously demonstrated that PEG-15 hydroxystearate (PEG15HS) enhances the antifungal activity of AmB by modulating its aggregation state toward more active, less toxic species. Building on these findings, we aimed to develop a simple and scalable lipid-nanoparticle (LNP) formulation combining AmB and PEG15HS to potentiate AmB activity against C. neoformans. AmB-loaded LNPs were produced by the phase-inversion temperature method using a Labrafac™ WL1349/tributyrin (1:1, w/w) oil phase selected for optimal AmB solubility and colloidal stability. Two particle sizes (∼40 nm and ∼ 100 nm) were obtained by varying the surfactant-to-oil ratio. Formulations were characterized physicochemically and evaluated in vitro against clinical C. neoformans isolates by MIC determination and time-kill curve analysis. Cellular localization was investigated by confocal and transmission electron microscopy. Both AmB-LNP formulations markedly enhanced antifungal efficacy, reducing MICs up to 32-fold compared with liposomal AmB and demonstrating faster and more extensive fungicidal activity. Microscopy revealed that AmB-LNPs were internalized by C. neoformans, whereas blank LNPs remained extracellular, indicating that AmB may facilitate nanoparticle passage through the fungal cell wall and plasma membrane. PEG15HS-stabilized lipid nanoparticles substantially improve the antifungal performance of AmB, likely through controlled aggregation and enhanced interaction with fungal cells. This simplified, non-liposomal system offers a promising and more accessible alternative to AmBisome® for treating C. neoformans infections.
The treatment of malignant solid tumors still faces challenges including the high risk of surgical resection and the severe side effects of chemotherapy. Moreover, existing clinical strategies often fail to meet the treatment needs of patients with inoperable tumors. In this study, a safe and efficient nanofiber patch was designed via electrospinning for combined photothermal-chemotherapy of abdominal tumors. By loading copper sulfide nanoparticles and polydopamine, the patch achieved efficient photothermal effects under safe NIR II laser irradiation. Moreover, the patch exhibited pH/NIR dual-responsive drug release through polydopamine protonation and photothermally enhanced diffusion. With these superior properties, the implantable patch can non-invasively ablate solid tumors via photothermal therapy and eliminate residual cancer cells through controllable chemotherapy, while maintaining low systemic toxicity. Notably, this safe and effective therapeutic strategy exhibited significantly higher tumor apoptosis (68.6%) than the control of only chemotherapy patch (29.3%) or photothermal therapy patch (42.5%). The DPPCP patch + NIR group exhibited dramatically decreased signal intensity, demonstrating superior antitumor efficacy. Moreover, the DPPCP patch enabled 100% survival of nude mice over 90 days. In this work, the patch-mediated combined photothermal-chemotherapy strategy holds promise as an alternative to clinical surgical resection and postoperative chemotherapy, addressing the treatment needs of diverse cancer patients.
We investigated the microenvironmental pH (pHM)-modulating mechanism and intermolecular interaction of alkalizers and their impact on the aqueous stability, release profiles of drugs and alkalizers, pharmacokinetics, and intragastric pH variability in 46 healthy human subjects of lansoprazole (LAN), an acid-labile model drug. Preliminary screening of five alkalizers (CaCO3, MgO, NaHCO3, meglumine, and L-arginine) in LAN-loaded wet granules under simulated gastric fluid demonstrated that calcium carbonate (CaCO3) appeared to be the best stabilizing agent for LAN in a dose-dependent manner according to solution pH changes and drug contents. Immediate-release fixed-dose combination tablets (IFT) containing LAN and CaCO3 were prepared via a dual granulation process using a fluidized bed dryer (FBD) and/or a high shear mixer (HSM). Unlike the commercial enteric-coated granule-loaded Lanston® capsule, IFT released LAN and CaCO3 simultaneously, achieving over 90% drug release within 30 min while maintaining its aqueous stability in pH 1.2 gastric fluid via the acid-neutralizing capacity of simultaneously released CaCO3. The increased modulation of pHM and the intermolecular complex of LAN with calcium ions are crucial for stabilizing LAN under low pH conditions. The optimal IFT formulation demonstrated long-term stability for 3 years, maintaining drug content and dissolution rates while liberating impurities (<0.2%) within regulatory guidelines. IFT demonstrated bioequivalence with the commercial enteric-coated Lanston® capsule with decreased "time to reach the maximum plasma concentration" and displayed superior intragastric pH control, maintaining pH above 4 for a longer duration over 24 h in a cross-over design in 46 healthy human subjects. The current novel IFT containing acid-labile LAN and CaCO3 can be used to substitute current enteric-coated LAN tablets for the immediate release and rapid onset of LAN without chemical degradation in the gastric fluid.
Psoriasis is a prevalent inflammatory skin disorder exhibiting a rapidly increasing incidence. Curcumin (Cur) serves as an effective therapeutic agent for psoriasis and is commonly administered through the cutaneous route. Nevertheless, the poor skin permeability and retention of Cur restrict its therapeutic efficacy against psoriasis. In this study, we fabricated mussel adhesion protein (MAP)-modified Cur-loaded ethosomes (Cur-MAP-Es) aimed at enhancing both the permeation and retention of Cur within the skin for improved topical treatment of psoriasis. The average particle size of Cur-MAP-Es was 197.17 nm, and the encapsulation efficiency was 90.84%. The Cur-MAP-Es exhibited a spherical morphology, along with high elasticity, favorable stability, and a prolonged release pattern within 24 h. Additionally, the Cur-MAP-Es exhibited a 3.47-fold higher skin retention compared to the Cur-Es. Intradermal fluorescence distribution analysis indicated that most of the Cur in the Cur-MAP-Es was effectively retained in the epidermis after being delivered into the skin via vesicles. The interaction mechanisms of Cur-MAP-Es with the skin have revealed that Cur-MAP-Es can weaken the skin barrier, thereby facilitating enhanced permeability and drug retention. Furthermore, Cur-MAP-Es could significantly alleviate the inflammation in the mouse model of psoriasis. These results suggest that Cur-MAP-Es may serve as an effective strategy to enhance the topical delivery efficiency of Cur, thereby showing considerable potential in the management of psoriasis.
Efficient delivery of nucleic acid therapeutics by lipid nanoparticles (LNPs) depends on complex interaction between vectors and targets. Here, we propose a model wherein LNP tropism is orchestrated synergistically by the particle's surface charge and the target cell's endo/lysosomal vacuolar H+-ATPase (V-ATPase) activity. In vitro, neutral LNPs transfected Fed cells (cells in +FBS medium) with optimal V-ATPase activity more efficiently than -FBS cells, while positively-charged LNPs transfected -FBS cells (cells in -FBS medium) with reduced V-ATPase activity more efficiently than Fed cells. In vivo, this synergy was applicable to liver, versus lung tropism of neutral versus positively-charged LNPs respectively. In addition, pre-condition of the reticuloendothelial system (RES) with empty LNPs enhanced functional delivery to lung but not liver mediated by positively-charged LNPs. Pharmacological inhibition of V-ATPase activity reduced in vitro and in vivo delivery mediated by neutral LNPs. On the other hand, elevating V-ATPase activity via genetic knockdown of ATP6-V1H enhanced in vitro delivery mediated by negatively-charged LNPs. Moreover, we found that the major components of protein corona adsorbed to in vivo neutral LNPs and positively-charged LNPs were shared by each other, except that the latter contained higher levels of coagulation factors and hemoglobins. In summary, our findings uncover a synergistic interaction between LNPs and targets in vitro and in vivo orchestrated by surface charge of LNP and V-ATPase activity of target.
Acne vulgaris is a multifactorial inflammatory skin disorder in which the clinical utility of azelaic acid (AZA) is limited by poor aqueous solubility and inadequate skin permeation. This study developed AZA-loaded hyalubilosomes (AZA-HBs) integrated into dissolving PVA/PVP-chitosan microneedles (MNs) to improve dermal delivery and anti-acne efficacy. AZA-HBs formulations were developed using Design-Expert® software to study the effects of hyaluronic acid and bile salt amount, optimized via I-optimal design, and incorporated into dissolving MNs. The optimized AZA-HBs showed high entrapment efficiency (87.0 ± 0.55%), nanosized vesicles (170 ± 0.72 nm), narrow dispersity (PDI 0.33 ± 0.01), and good colloidal stability (zeta potential -29 ± 0.28 mV). The selected MN formulation exhibited excellent drug loading (95.3 ± 1.2%), strong mechanical performance with only (11.0 ± 1.0%) height reduction, and efficient insertion. The hybrid platform provided sustained AZA release, reaching (94-95%) over 48 h, and increased ex vivo skin permeation by (6.3-fold). It also improved cytocompatibility in HaCaT cells, whereas free AZA caused complete cell loss at the highest tested concentration. Moreover, the formulation enhanced antimicrobial potency (MICs of 6.25 μg/mL against S. epidermidis and 12.5 μg/mL against S. aureus) and eradicated (78%) of the biofilm. In vivo, AZA-HBs/MNs produced the strongest anti-acne effect, markedly reducing ear inflammation, suppressing TNF-α, IL-1β, IL-6, and TLR4, modulating Nrf2/HO-1/MYD88 signaling, and restoring normal histological and EGF immunohistochemical features. AZA-HBs-loaded dissolving PVA/PVP-chitosan microneedles offer sustained release, superior penetration, strong antimicrobial/antibiofilm activity, and significant anti-acne efficacy for topical AZA delivery.
18β-Glycyrrhetinic acid (18β-GA), the primary bioactive metabolite of glycyrrhizin (GL) derived from licorice root, exhibits anti-inflammatory, antioxidant, and antimicrobial activities, as well as excellent biocompatibility, making it a promising candidate for the treatment of dermatological disorders. However, its poor water solubility limits topical bioavailability. In this study, an Analytical Quality by Design (QbD) approach was established to develop and optimize nanocarriers loaded with 18β-GA, to improve skin penetration while providing sustained and controlled release. Ethosomes, glycerosomes, and glycethosomes were produced using an innovative and customized 3D-printed microfluidic chip, resulting in vesicles with controlled size, narrow polydispersity, high encapsulation efficiency, and high physicochemical stability through a reproducible and cost-effective process. A Design of Experiments (DoE) strategy was used to identify critical formulation parameters and develop a predictive mathematical model. The three optimized formulations were incorporated into an alginate hydrogel, exhibiting shear-thinning behavior, ideal for topical application. Ex vivo permeation studies revealed that the optimized nanocarriers modulate the skin delivery of 18β-GA, with formulation composition significantly influencing drug distribution profiles. The systems reduced rapid diffusion into the receptor phase and promoted controlled drug release, supporting localized delivery. Drug accumulation within the skin layers indicated that release from the formulation represents the rate-limiting step. The hydrogels exhibited prolonged drug release and improved skin contact, enabling sustained and uniform topical application. Process scalability was successfully achieved using a peristaltic pump, highlighting the robustness, low-cost nature, and industrial feasibility of the proposed microfluidic approach for controlled topical drug delivery.
Superficial tumors, including breast cancer, melanoma, and oral carcinoma, pose significant treatment challenges due to their anatomical location and the inherent limitations of conventional therapies, such as systemic toxicity and poor tumor specificity. Chemotherapy often leads to severe side effects, while photodynamic therapy (PDT) is hindered by the limited tissue penetration of both light and photosensitizers. To address these issues, we developed an innovative reactive oxygen species (ROS)-responsive drug delivery system based on a conjugate of tegafur (TF) and pheophorbide a (PPa) linked via a thioether bond. This prodrug (TF-TA-PPa) integrates chemotherapy and PDT into a single molecular entity, enabling synergistic anti-tumor effects. To enhance localized delivery and patient compliance, the conjugate was encapsulated into polymeric micelles and further incorporated into soluble microneedles (MNs) containing cell-penetrating peptides. The resulting TF-TA-PPa@PMN system enables painless transdermal administration, deep tumor penetration, and on-demand drug release triggered by near-infrared laser irradiation through ROS-mediated cleavage of the thioether linker. Comprehensive in vitro and in vivo evaluations demonstrated excellent biocompatibility, sustained drug release profiles, enhanced cellular uptake, and potent tumor suppression in a 4 T1 breast cancer model, achieving a remarkable tumor inhibition rate of 89.2% with minimal systemic toxicity. This integrated platform represents a promising strategy for the localized, combinatory treatment of superficial tumors with improved efficacy and reduced side effects.