Int J Pharm [JOURNAL]
Sun
200 papers
Dendrimeric liquid crystals actively modulate cavitation, skin transport pathways, and drug fate during low-frequency sonophoresis.
Petrilli R, Mazureki Campos P, Ribeiro TC … +2 more , Oliveira CLP, Lopez RFV
Int J Pharm · 2026 Jun · PMID 42323030 · Publisher ↗
This work presents the first exploration of dendrimeric liquid crystals (DLCs) as dual-function platforms for low-frequency ultrasound (LFU)-mediated skin delivery. We hypothesized that, beyond acting as drug reservoirs,...
This work presents the first exploration of dendrimeric liquid crystals (DLCs) as dual-function platforms for low-frequency ultrasound (LFU)-mediated skin delivery. We hypothesized that, beyond acting as drug reservoirs, DLCs could actively modulate cavitation, the formation of localized transport regions (LTRs), and the intradermal microenvironment governing drug partitioning after insonation. Tetrasulfonated zinc phthalocyanine (ZnPcS), a hydrophilic photosensitizer with poor intrinsic permeability, was selected as a model drug. NMR confirmed the supramolecular association between the PAMAM G2 dendrimer and a fluorinated acid. Polarized light microscopy and SAXS/WAXS demonstrated that when dispersed in a hydroxyethyl cellulose (HEC) hydrogel, DLCs formed stable and highly organized liquid crystalline domains. Drug incorporation and LFU exposure promoted additional rearrangements without disrupting matrix integrity, thereby supporting carrier robustness. Functionally, under LFU, DLC:HEC produced a complete rupture of the aluminum foil, whereas viscosity-matched HEC caused only partial damage, indicating stronger cavitation. This resulted in an approximately threefold expansion of the skin LTR surface coverage (24% vs. 7%). Despite this, DLCs strongly retained ZnPcS, passively releasing <5% of it; 1 min LFU increased the release by approximately fourfold. In the skin, during direct drug formulation insonation, DLC:HEC enhanced drug deposition in the stratum corneum by nearly one order of magnitude compared to HEC. After LFU pretreatment with drug-free DLC:HEC, DLC-associated domains likely persisted within the LTRs formed in the stratum corneum, establishing a shared microenvironment for subsequently applied formulations. Under these conditions, no statistically significant differences in ZnPcS skin distribution or receptor delivery were observed between the HEC and DLC-containing donors, indicating that transport was primarily governed by the preformed LFU-induced pathways and the interaction environment established within the modified stratum corneum. Overall, DLCs actively shape both pathway generation and drug fate in LFU-treated skin, providing a versatile strategy for balancing local retention and transdermal transport.
Construction of psoralen - loaded targeted polymeric nanoparticles for enhanced anti - triple negative breast cancer efficacy via modulation of tumor associated macrophages in vitro.
Liu F, Meng F, Cai T … +8 more , Asim MH, Wang H, Chen Z, Chen Y, Lin Y, Yang Z, Zhang R, Cai Y
Int J Pharm · 2026 Jun · PMID 42323029 · Publisher ↗
The progression of triple-negative breast cancer (TNBC) is highly dependent on its immunosuppressive tumor microenvironment, in which tumor-associated macrophages (TAMs) are a critical component. Consequently, targeting...
The progression of triple-negative breast cancer (TNBC) is highly dependent on its immunosuppressive tumor microenvironment, in which tumor-associated macrophages (TAMs) are a critical component. Consequently, targeting and reprogramming TAMs have emerged as promising therapeutic strategies. Psoralen (PSO), a natural furanocoumarin compound, exhibits anti-breast cancer activity and has the potential to modulate TAMs. However, its clinical application is hampered by poor water solubility and low targeting specificity. This study developed actively targeted nanoparticles loaded with PSO (designated MCSPP NPs), which consist of a mannosylated chitosan shell and a polymeric core. Systematic process optimization and characterization-including transmission electron microscopy, dynamic light scattering, Fourier-transform infrared spectroscopy, thermal analysis, X-ray diffraction, and in vitro release studies-confirmed the successful encapsulation of PSO in an amorphous state. The MCSPP NPs exhibited a double-layered quasi-spherical morphology with an average particle size of 285.53 ± 4.42 nm, a zeta potential of 24.31 ± 0.59 mV, and an encapsulation efficiency of 83.77%, along with favorable pH-responsive sustained-release properties. In vitro studies demonstrated that MCSPP NPs could be efficiently taken up by TNBC cells and M2-type macrophages via nonspecific endocytosis and mannose receptor-mediated active targeting, respectively. Consequently, MCSPP NPs induced more potent cell cycle arrest and apoptosis in tumor cells in the presence of M2 macrophages compared to treatment of tumor cells in monoculture. Further mechanistic investigation revealed that this synergistic effect was due to the reprogramming of M2-like TAMs, as evidenced by the downregulation of the M2 marker CD206 and a shift in cytokine secretion profile from immunosuppressive (IL-10 and TGF-β) to immunostimulatory (IL-12 and TNF-α). In vivo biodistribution assays in tumor-bearing mice confirmed that MCSPP NPs were able to accumulate and be retained at tumor sites, and this effect depended on their surface MAN modification. In summary, this study demonstrated that MCSPP NPs can inhibit TNBC through a synergistic "chemotherapy-immunomodulation" mechanism in vitro, highlighting the potential role of PSO in tumor immune microenvironment modulation.
Lipoplex as a useful tool for resensitization of methicillin-resistant Staphylococcus aureus to erythromycin via CRISPR-Cas technology.
Ates A, Onal M, Senyigit M … +3 more , Gundogdu G, Aytan F, Baspinar Y
Int J Pharm · 2026 Jun · PMID 42323028 · Publisher ↗
The global escalation of antimicrobial resistance (AMR) necessitates innovative therapeutic interventions. Methicillin-resistant Staphylococcus aureus (MRSA) remains a primary clinical threat due to its extensive resista...
The global escalation of antimicrobial resistance (AMR) necessitates innovative therapeutic interventions. Methicillin-resistant Staphylococcus aureus (MRSA) remains a primary clinical threat due to its extensive resistance profile. In this study, CRISPR-Cas9 technology was employed to target the ermA gene, which is responsible for erythromycin resistance in clinical MRSA isolates. A cationic liposome (Lip) composed of cholesterol, DOTAP, and DOPE was developed to deliver the pCasSA plasmid. Particle characterization revealed stable liposomes (Lips) (<200 nm, PDI < 0.3, ZP>+30 mV). pCasSA was loaded into the Lip, to form a lipoplex (Lpx), a complex of Lip and pCasSA, via electrostatic interactions. Cytotoxicity studies using mouse fibroblast L929 cells revealed that cell viabilities remained at approximately 93% and 83% following treatment with the highest concentration of Lip and Lpx formulations, respectively. Successful gene editing was confirmed via Sanger sequencing and RT-qPCR, showing a 75% reduction in ermA expression when Lpx wascombined with sonoporation. Phenotypic assays demonstrated a significant restoration of susceptibility. The minimum inhibitory concentration (MIC) of erythromycin decreased 8-fold (from 8 mg/L to 1 mg/L), and inhibition zones increased 2.5-fold (from 12 mm to 30 mm). These findings suggest that Lpx-mediated CRISPR-Cas9 delivery is a highly efficient strategy for antibiotic resensitization, potentially restoring the clinical utility of existing antimicrobials.
In vitro comparison of aerosol deposition by albuterol pMDI using corrugated tubing versus a commercial spacer.
He P, Konda R, Komalla V … +4 more , Reddel HK, Toelle BG, Ong HX, Traini D
Int J Pharm · 2026 Jun · PMID 42320738 · Publisher ↗
Commercial spacers are attachments used with pressurised metered dose inhalers (pMDI) which help improve lung delivery and reduce oropharyngeal deposition of the medication by slowing down the aerosol plume emitted from...
Commercial spacers are attachments used with pressurised metered dose inhalers (pMDI) which help improve lung delivery and reduce oropharyngeal deposition of the medication by slowing down the aerosol plume emitted from the device and retaining larger particles within the spacer. However, their cost may limit accessibility in resource constrained settings. Corrugated anaesthetic tubing has been used as a low-cost alternative spacer, though its aerosol performance has not been characterised. This study quantitatively compared in vitro aerosol deposition of albuterol (Ventolin®) delivered under three setups: with a 6'' corrugated tubing spacer, with a commercially available spacer device (E-Chamber La Grande) and without a spacer. Aerosol performance was evaluated using a Next Generation Impactor (NGI). Delivered dose (DD), fine particle dose (FPD), fine particle fraction (FPF), and mass median aerodynamic diameter (MMAD) parameters were assessed. Corrugated tubing produced significantly lower FPD at the 200 µg and 300 µg doses (corresponding to two and three actuations, respectively), indicating reduced delivery of respirable drug to the lungs and a potential reduction in clinical effectiveness. The commercial spacer generally demonstrated higher FPD than corrugated tubing and more uniform deposition patterns across the tested conditions. Spacer selection significantly influences aerosol delivery from pMDIs. While corrugated tubing represents a practical low-cost alternative, its reduced aerosol performance may compromise therapeutic efficacy. Commercial spacers remain the preferred option in practice, although performance depends on device configuration and test conditions. Further optimisation of affordable spacer designs is warranted for resource limited environments.
Mechanistic prediction of food-induced variability in drug release and pharmacokinetics using a dynamic gastrointestinal system and convolution-based modeling.
Qu W, Wu P, Yang S … +3 more , Liu T, Qi S, Chen XD
Int J Pharm · 2026 Jun · PMID 42320737 · Publisher ↗
Oral sustained-release (SR) formulations are widely used in clinical practice, yet reliable prediction of their in vivo performance remains challenging due to the dynamic and heterogeneous gastrointestinal (GI) environme...
Oral sustained-release (SR) formulations are widely used in clinical practice, yet reliable prediction of their in vivo performance remains challenging due to the dynamic and heterogeneous gastrointestinal (GI) environment. Here, a bioinspired dynamic human stomach-intestine system (DHSI-IV) was used to simulate physiologically relevant GI environments under different prandial states. Ibuprofen SR capsules were evaluated under fasted (water), milk, carbonated beverage, and high-fat meal conditions. The DHSI-IV reproduced pronounced prandial-dependent GI dynamics, with gastric half-emptying times ranging from 16.7 min (water) to 90.2 min (high-fat meal). These differences led to distinct dissolution behaviors, with cumulative release of 42.1 ± 1.5% (water), 33.15 ± 2.05% (carbonated beverage), 41.95 ± 3.35% (milk), and 44.35 ± 1.45% (high-fat meal). Coupling in vitro dissolution data with a simplified convolution-based pharmacokinetic (PK) back-calculation approach enabled prediction of systemic exposure. Predicted fasted-state PK parameters agreed with clinical data (T 4.0 ± 0.5 h vs. ∼ 4.5 h; C 12.5 ± 2.7 μg/mL vs. 13.88 ± 2.6 μg/mL). Under fed (high-fat meal) conditions, the model captured delayed absorption (T 5.5 ± 0.5 h vs. ∼ 6.0 h) and increased exposure (C 20.2 ± 2.3 μg/mL; AUC 153.7 ± 22.6 μg·h/mL). Overall, DHSI-IV provides a predictive platform for evaluating SR formulations under physiologically relevant GI conditions, supporting food-effect assessment and formulation optimization.
Biological barriers and mucus interactions in nanoparticle dry powder inhalation: overcoming the lung defense.
Hamishehkar H
Int J Pharm · 2026 Jun · PMID 42320736 · Publisher ↗
Nanoparticle-based dry powder inhaler (DPI) systems offer a promising platform for the treatment of chronic respiratory diseases by enabling localized delivery, controlled release, and reduced systemic side effects. Howe...
Nanoparticle-based dry powder inhaler (DPI) systems offer a promising platform for the treatment of chronic respiratory diseases by enabling localized delivery, controlled release, and reduced systemic side effects. However, their clinical translation is significantly limited by the lung's complex biological defense mechanisms. Following deposition, inhaled nanoparticles encounter sequential barriers, including the airway mucus layer, pulmonary surfactant interface, epithelial tight junctions, and macrophage-mediated immune clearance. These barriers collectively determine nanoparticle diffusion, retention, cellular uptake, or elimination. Airway mucus, structured by gel-forming mucins such as MUC5AC and MUC5B, forms a viscoelastic hydrogel network that restricts nanoparticle transport through steric hindrance and adhesive interactions. Disease-associated remodeling further increases mucus density and adhesiveness, exacerbating transport limitations. In the alveolar region, hydration-dependent redispersion and rapid adsorption of surfactant components reshape nanoparticle surface properties, influencing colloidal stability and immune recognition. Opsonization by surfactant proteins and recognition by alveolar macrophages often lead to accelerated clearance and inflammatory activation. Optimized nanoparticle design, particularly control of size, surface charge, hydrophilicity, and PEGylation, can enhance mucus penetration, minimize surfactant disruption, and partially evade immune uptake. Formulation strategies such as nano-in-micro architectures improve aerodynamic deposition while protecting nanoscale integrity. Excipients, particle porosity, and device formulation co-design further determine dispersion efficiency and reproducible lung delivery. This review integrates insights from pulmonary biology, immunology, and aerosol engineering to propose a biologically informed framework for DPI development. Addressing both aerodynamic performance and post-deposition biological interactions is essential for achieving sustained pulmonary residence, controlled immune engagement, and improved translational potential of inhaled nanomedicines.
Designing inhalable amorphous solid dispersions to mitigate crystallization risks in atropisomer development.
Disisto P, Bassanetti I, Fornasari L … +8 more , Balducci AG, Bussolati R, Betti M, Pecorari D, Castagnini F, Mileo V, Bacchi A, Marchiò L
Int J Pharm · 2026 Jun · PMID 42320735 · Publisher ↗
The development of inhalation formulations for CHF-6523, a selective PI3Kδ inhibitor, presents significant hurdles due to atropisomerism and a strong tendency to form amorphous solids, complicating the access to a suitab...
The development of inhalation formulations for CHF-6523, a selective PI3Kδ inhibitor, presents significant hurdles due to atropisomerism and a strong tendency to form amorphous solids, complicating the access to a suitable crystalline form of the pharmaceutically active isomer. NMR experiments and DFT calculations revealed a near-equilibrium distribution of two atropisomers (RS and SS, ≈55:45 in ethanol-d6/DO), and their low interconversion energy barriers of 86.5 and 87.1 kJ/mol. After a comprehensive salt screening, CHF-6523 monomaleate was the only crystalline solid obtained as a single diastereoisomer (RS). Concerns regarding the suitability of the maleate counterion for pulmonary administration prompted the exploration of amorphous solid dispersions (ASDs) using CHF-6523 xinafoate, identified as the most promising amorphous salt candidate. Three manufacturing techniques - blending, spray-drying and freeze-drying - were evaluated to preserve the amorphous phase, improve powder handling and ensure dissolution and aerosolization performance. Spray-dried powder provided the most favorable physicochemical profile, yielding particles with dv90 below 5 µm, a residual moisture of ∼ 6%, with water uptake below 1% and superior resistance to physical and chemical changes over 180 days. In vitro dissolution studies in simulated lung fluid showed that spray-dried and freeze-dried ASDs reached concentrations above 950 µg/mL within the first hour, outperforming the crystalline monomaleate and the free base (∼700-800 µg/mL at 4 h). Preliminary aerosol characterization confirmed the superior respirable fraction of the spray-dried ASD (∼73%), compared to blend (∼66%) and freeze-dried formulations (∼37%). This work demonstrates how atropisomer-related conformational dynamics can hinder crystalline form identification while guiding the development of stable amorphous formulations for inhalation therapies.
Microneedle technologies in emerging strategies for non-transdermal drug delivery.
Simões L, Mendes M, Sousa J … +2 more , Pais A, Vitorino C
Int J Pharm · 2026 Jun · PMID 42314781 · Publisher ↗
Microneedles (MNs) have been employed in skin drug delivery for over two decades. These platforms have been demonstrating the ability to penetrate restrictive tissue barriers in a minimally invasive manner, which signifi...
Microneedles (MNs) have been employed in skin drug delivery for over two decades. These platforms have been demonstrating the ability to penetrate restrictive tissue barriers in a minimally invasive manner, which significantly improved the efficiency of transdermal drug administration. More recently, MN technologies have emerged as a versatile platform for drug delivery beyond conventional transdermal applications. Advances in MN engineering have diversified MNs to include unique shapes, materials, and mechanical properties that can be tailored for tissue-specific applications, overcoming limitations of standard delivery methods. This review highlights recent progress in the use of MNs for targeted delivery to ocular, inner ear, gastrointestinal, vascular, buccal, and other internal tissues.
Programming nanozyme identity for precision catalytic medicine by tailoring the bio-nano interface.
Liu J, Wang Y, Xie Y … +7 more , Zhang C, Zhang J, Chen L, Zhao L, Li B, Yang H, Yong Y
Int J Pharm · 2026 Jun · PMID 42314780 · Publisher ↗
The clinical translation of nanozymes faces substantial challenges, as their therapeutic efficacy in vivo is often significantly diminished by multiple physiological barriers and complex bio-nano interfacial interactions...
The clinical translation of nanozymes faces substantial challenges, as their therapeutic efficacy in vivo is often significantly diminished by multiple physiological barriers and complex bio-nano interfacial interactions. To address these issues systematically, this review proposes an active "nanozyme identity programming" paradigm. Through rational design, this approach enables nanozymes to sequentially overcome biological barriers, thereby accelerating their clinical translation. We begin by systematically outlining the in vivo physiological roles and structural features of these barriers. We then examine how nanozymes can be functionally programmed at key hierarchical levels to acquire: (1) a "stealth identity" for prolonged circulation, (2) a "targeting identity" for precise lesion accumulation, and (3) a "microenvironment-responsive identity" for spatiotemporally controlled activation. Furthermore, we highlight the crucial roles of "bioinspired design" and artificial intelligence as powerful tools for integrating these functions and enabling the de novo design of intelligent nanozymes. Integrating this "identity programming" framework with the "nanozyme-interface-performance-application" research pipeline has shown great promise in developing advanced therapeutics for various pathological conditions, including inflammatory diseases, neurological disorders, cancers, and bacterial infections. Finally, we discuss the prospects, challenges, and opportunities of this paradigm in advancing nanozymes from functional materials toward precise nanomedicines and successful clinical translation.
Elucidating the role of TPGS in felodipine/PVPVA amorphous solid dispersions during water uptake: dissipative particle dynamics simulations using quantum chemistry-based interaction parameters.
Kobayashi C, Konami N, Ogura Y … +7 more , Okuwaki K, Higashi K, Inoue M, Yamashita T, Furuishi T, Fukuzawa K, Yonemochi E
Int J Pharm · 2026 Jun · PMID 42309202 · Publisher ↗
Amorphous solid dispersions (ASDs) are an effective formulation approach for improving the solubility of poorly water-soluble drugs. Nevertheless, their drug-release performance depends on the phase separation morphology...
Amorphous solid dispersions (ASDs) are an effective formulation approach for improving the solubility of poorly water-soluble drugs. Nevertheless, their drug-release performance depends on the phase separation morphology during the dissolution process. Although the addition of surfactants has been experimentally reported to improve the dissolution behavior of ASDs, experimental methods alone are insufficient to resolve the complex and heterogeneous intermolecular interactions between drugs and excipients in multicomponent systems at the molecular level. In this study, we used dissipative particle dynamics simulations, which efficiently analyze mesoscopic phenomena such as phase separation, to elucidate the mechanisms of drug aggregation, water uptake, and phase separation, and to discuss their potential implications for drug-release behavior. Interaction parameters (χ) were derived from quantum chemical calculations and used to parameterize the coarse-grained model. We compared binary ASDs composed of felodipine and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) with ternary ASDs that additionally contained the surfactant d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), focusing on the functional role of the surfactant. Results suggested that the balance between water uptake and drug aggregation may influence drug release behavior from ASDs, potentially through interfacial liquid-liquid phase separation (LLPS)-related organization. In particular, simulations of the ternary system containing TPGS showed reduced mesoscale drug aggregation through accelerated hydration, suppression of interfacial energy growth, and steric stabilization by TPGS molecules. These structural features may facilitate drug diffusion into the aqueous phase. These simulation-derived behaviors are consistent with previous experimental observations. Overall, this study provides a mechanistic, simulation-based framework for understanding phase separation behavior and its potential influence on drug release processes in ASDs, drug release processes in ASDs, thereby guiding formulation design, particularly for surfactant-containing systems.
Ionic liquid-coated Eudragit RS nanoparticles for topical delivery of honokiol to remodel the hair follicle microenvironment in androgenic alopecia.
Ezzeldeen Y, Swidan S, Teaima M … +1 more , El-Nabarawi M
Int J Pharm · 2026 Jun · PMID 42309201 · Publisher ↗
Androgenic alopecia (AGA) is a progressive hair loss condition caused by androgen-induced follicular miniaturization and hair growth signaling pathway impairment. Ineffective targeting of the pilosebaceous units and insu...
Androgenic alopecia (AGA) is a progressive hair loss condition caused by androgen-induced follicular miniaturization and hair growth signaling pathway impairment. Ineffective targeting of the pilosebaceous units and insufficient dermal retention limit the effectiveness of available topical therapies, emphasizing the need to explore more advanced treatment options. Honokiol (HK), a natural biphenolic compound, has proven to possess hair regeneration and anti-androgenic properties through modulation of key signaling pathways related to hair growth, specifically the activation of Wnt /β-catenin and suppression of transforming growth factor (TGF-β). However, its application is limited because of its poor bioavailability upon oral administration. The cutting-edge nanotechnology offers innovative tools for boosting drug effectiveness. Eudragit RS-based polymeric nanoparticles showed high efficacy for topical controlled release. In this study, HK-loaded Eudragit RS nanoparticles (HKE) were synthesized using the nanoprecipitation technique. A three-factor, three-level Box-Behnken Design optimized formulation parameters. To achieve enhanced follicular deposition, the optimized formula (HKE) was coated with choline geranate (CAGE), a green solvent that is known for its ability to enhance dermal penetration and drug deposition. Physicochemical characterization included morphology, particle dimensions (PS), surface charge (ZP), entrapment efficiency (EE), and in vitro release. HKE resulted in a mean PS of 63.88 nm, a strongly positive ZP (+41.05), high EE (87.5%), and sustained drug release. The ionic liquid coating reduced the ZP to +2.98 mV and increased PS to 91.58 nm, confirming surface modification. The synthesized coat was further validated with the TEM micrograph and FT-IR charts. In vivo evaluation demonstrated enhanced hair growth, accompanied with activation of the Wnt/β-catenin pathway and downregulation of the TGF-β, which was more pronounced with the coated nanoparticles. These findings suggested that the ionic liquid modified polymeric nanoparticles represent a promising scalable platform for the topical delivery of HK in AGA.
Targeting and traceability of DY635-functionalized lipids for cholesterol-free, hepatocyte-directed lipid nanoparticles.
Debbeler JP, Streiber M, Fraude-El Ghazi S … +6 more , Hiller H, Press AT, Schubert US, Bauer M, Gehring S, Traeger A
Int J Pharm · 2026 Jun · PMID 42309200 · Publisher ↗
This study presents the development and characterization of a targeted lipid nanoparticle (LNP) formulation for mRNA-based gene delivery based on the elimination of cholesterol and the subsequent introduction of targetin...
This study presents the development and characterization of a targeted lipid nanoparticle (LNP) formulation for mRNA-based gene delivery based on the elimination of cholesterol and the subsequent introduction of targeting moieties. Because the high cholesterol content of conventional LNPs and its interaction with apolipoprotein E (ApoE) result in predominant hepatic accumulation in vivo, the introduction of targeting moieties to achieve extrahepatic delivery remains challenging. Thus, an ethanol and cholesterol-free formulation strategy, called "blue" lipid nanoparticle (BLNP), was applied to (i) investigate the impact of cholesterol on expression profiles and (ii) to enable the incorporation of targeting ligands. In vivo expression distribution analyses revealed no sign of toxicity for both formulations and an altered expression profile of BLNPs compared to classical cholesterol-containing LNPs with predominant expression in the liver. The lipid 1,2-dioctadecanoyl-sn-glycero-3-phosphoethanolamine (DSPE) was further conjugated to the hepatocyte-targeting dye DY635 and, following purification and characterization, incorporated into BLNPs at concentrations up to 1.1%. Uptake and transfection studies demonstrated successful nanoparticle uptake after 30 min and gene expression in various cell lines, with almost doubled mRNA expression in human HuH7 hepatocytes at optimized conditions. Incorporation of DSPE-DY635 enabled fluorescent tracking by flow cytometry and confocal laser scanning microscopy (CLSM). Cellular uptake studies revealed efficient and traceable uptake into HuH7 cells within 60 min. Overall, the successful integration of a targeting lipid into a cholesterol-free LNP platform provides a flexible strategy for the modular introduction of alternative targeting ligands and the development of controlled, tissue-specific mRNA delivery systems.
Multiscale modeling unveils molecular mechanisms of deep eutectic solvent-anticancer drug interactions for rational formulation design.
Zhou S, Li T, Tong X … +7 more , Chen J, Zhou Y, Yi G, Wen X, Zeng H, Yang B, Liu J
Int J Pharm · 2026 Jun · PMID 42309199 · Publisher ↗
Deep eutectic solvents (DESs) represent a burgeoning class of versatile media with significant potential to enhance the solubility, stability, and bioavailability of poorly water-soluble antineoplastic active pharmaceuti...
Deep eutectic solvents (DESs) represent a burgeoning class of versatile media with significant potential to enhance the solubility, stability, and bioavailability of poorly water-soluble antineoplastic active pharmaceutical ingredients (AAPIs). However, the rational design of API-specific DES formulations remains impeded by an insufficient mechanistic understanding of the molecular-level interactions that govern API-DES compatibility. To address this critical gap, our study pioneers an integrated multi-scale computational strategy, synergizing free volume analysis, binding energy calculations, and hydrogen-bonding network quantification to unravel the supramolecular interplay between diverse DESs and a panel of clinically relevant AAPIs (including 5-FU, p-toluenesulfonamide (PTS), trigonelline, piperine, phloretin, nonivamide, curcumin, and erlotinib). We demonstrate that the free volume of DESs, formed from choline chloride or betaine with various hydrogen bond donors (HBDs), is dynamically altered upon AAPI incorporation, exhibiting either a "tightening" or "loosening" effect that correlates with dissolution enhancement or molecular stabilization. Interaction total energy (ΔE) profiles reveal strong dependencies on [HBA][HBD][AAPI] combinations, with glycerol-based DESs showing superior affinity for most AAPIs, while zwitterionic HBDs (e.g. glycine) form less stable complexes. The investigated [DES][AAPI] systems were classified into four ranks (I-IV) representing a descending gradient of predictive certainty and overall solubilization/stabilization potential. DESs such as [ChCl][PG], [ChCl][Glycerol], or [Betaine][Glycerol] appear more frequently in Classes I and IV than in Classes II and III. Given that Class I represents superior performance and Class IV represents high predictive uncertainty (rather than poor performance), the predominance of these DESs in Class I suggests a higher probability of favorable outcomes across diverse AAPIs.These insights provide a predictive framework for the rational design of DES systems tailored to specific APIs, enabling optimized solubility, stability, and controlled release in next-generation drug delivery applications.
Perspectives on chikungunya vaccinology: from traditional platforms to epitope-driven rational design.
Sagheer U, Deng L
Int J Pharm · 2026 Jun · PMID 42309198 · Publisher ↗
Chikungunya virus (CHIKV) is an arthritogenic alphavirus transmitted mainly by female Aedes aegypti and Aedes albopictus mosquitoes. It causes significant morbidity and persistent arthralgia, with its global spread drive...
Chikungunya virus (CHIKV) is an arthritogenic alphavirus transmitted mainly by female Aedes aegypti and Aedes albopictus mosquitoes. It causes significant morbidity and persistent arthralgia, with its global spread driven by Aedes vectors and viral lineage diversification. Vaccination remains the most cost-effective prevention strategy, but development is hindered by unpredictable outbreaks, undefined immune correlates of protection, and the variability of immunodominant epitopes. This review analyzes CHIKV's genomic and proteomic features, mechanisms of viral entry and transmission, immune evasion strategies, and host immune responses to inform vaccine design. It also critically assesses major vaccine platforms and their limitations. For example, the licensed vaccines Ixchiq (live-attenuated) and Vimkunya (virus-like particle) still facing limitations regarding safety in specific populations, durability of cross-protection, manufacturing complexity, and global accessibility. The review then highlights emerging epitope-based strategies informed by immunoinformatics, which have identified conserved viral epitopes to guide rational multi-epitope vaccine designs. These approaches may address limitations of conventional platforms by precisely targeting conserved protective epitopes, broadening human leukocyte antigen coverage, and reducing reactogenicity. While most epitope-based CHIKV vaccine candidates remain in computational or early preclinical stages, continued integration of immunoinformatics, structural vaccinology, and experimental validation could accelerate the development of safer and more broadly protective next-generation CHIKV vaccines.
Machine learning assisted in-line calibration models for near-infrared spectroscopy in dry granulation.
Zhang X, Pierce JA, Gonzalez M … +2 more , Nagy ZK, Reklaitis GV
Int J Pharm · 2026 Jun · PMID 42303189 · Publisher ↗
Dry granulation is a critical pharmaceutical manufacturing process employed for solid oral dosage forms. The process accommodates high throughput and variable particle properties. However, this makes controlling and moni...
Dry granulation is a critical pharmaceutical manufacturing process employed for solid oral dosage forms. The process accommodates high throughput and variable particle properties. However, this makes controlling and monitoring the process essential. Near-infrared (NIR) Spectroscopy is a widely used characterization tool in pharmaceutical manufacturing processes due to its fast and non-invasive nature. In this study, we developed an in-line NIR spectroscopy system with a specialized sampling device (SpiderWheel) for continuous granular flow monitoring. We compared nonlinear calibration techniques, including artificial neural networks (ANN), Bayesian neural networks via Monte Carlo Dropout (BNN-MCD), and least-squares support vector machines (LS-SVM), using partial least squares (PLS) regression as a linear baseline. Various spectral preprocessing methods were evaluated to improve model performance. The BNN-MCD model showed superior predictive accuracy for in-line measurements of granule size distribution (R = 0.993, RMSPE = 5.72%). It also accurately predicted other granular physical attributes, including porosity (R = 0.984), specific pore volume (R = 0.984), and envelope density (R = 0.980). Optimization with Savitzky-Golay filtering and standard scaling significantly improved nonlinear model performance. This study advances Process Analytical Technology (PAT) by developing accurate, machine learning assisted NIR spectroscopy calibration models for continuous pharmaceutical manufacturing. The proposed system enables precise and real-time characterization of granular properties, supporting Quality by Design (QbD) principles and reliable process monitoring.
Formulation and optimization of hydralazine hydrochloride-loaded mucoadhesive niosomes for sublingual hypertension management; in vitro characterization and in vivo pharmacodynamic evaluation.
Aboelezz DE, Sonbol IM, El-Zahaby SA … +2 more , El-Helaly SN, Abdelbary GA
Int J Pharm · 2026 Jun · PMID 42303188 · Publisher ↗
Hydralazine hydrochloride (HDR) is an effective antihypertensive drug with limited oral bioavailability due to extensive first-pass metabolism. This study aimed to develop and optimize a niosomal sublingual delivery syst...
Hydralazine hydrochloride (HDR) is an effective antihypertensive drug with limited oral bioavailability due to extensive first-pass metabolism. This study aimed to develop and optimize a niosomal sublingual delivery system to enhance HDR bioavailability and antihypertensive efficacy. HDR-loaded niosomes were prepared by thin-film hydration and optimized using a D-optimal factorial design by evaluating the effects of surfactant type, surfactant-to-cholesterol ratio, and dicetyl phosphate concentration on entrapment efficiency, particle size, and zeta potential. The optimized formulation was incorporated into fast-disintegrating sublingual films prepared using hydroxypropyl methylcellulose and polyvinyl alcohol. The developed niosomes had particle size in the range of 83.58 ± 5.204 and 645.8 ± 39.881 nm, with an in vitro drug release up to 99.728% ± 1.146 in 24 h. The ex vivo permeation across sheep sublingual mucosa showed enhanced outcomes in case of Tween 80, where it had higher HDR permeation compared to Brij 35 and Span 60 by 12 and 5 folds, respectively. In vivo pharmacodynamic studies in dexamethasone induced hypertensive rats demonstrated a faster onset and prolonged antihypertensive effect compared with a commercial oral tablet. The results confirmed that the mucoadhesive niosomal sublingual films represent a promising strategy for improving the bioavailability and therapeutic performance of hydralazine hydrochloride.
Fluorescence spectroscopy on smooth and rough solid pharmaceutical surfaces.
Helstrup R, Christensen NPA, Sørensen DH … +2 more , Rinnan Å, Grohganz H
Int J Pharm · 2026 Jun · PMID 42303187 · Publisher ↗
Fluorescence spectroscopy is an inherently sensitive and fast method that could be a powerful addition to existing process analytical technology (PAT) tools for non-destructive quantification of active pharmaceutical ing...
Fluorescence spectroscopy is an inherently sensitive and fast method that could be a powerful addition to existing process analytical technology (PAT) tools for non-destructive quantification of active pharmaceutical ingredients (API) in low-dose formulations. However, the fundamental physical factors influencing the fluorescence signal response remain poorly understood. In this study, bench-top solid state fluorescence spectroscopy was used to systematically examine the effects of API concentration, surface roughness, and compaction pressure on the fluorescence response of low-dose solid pharmaceutical samples. A solid formulation using tryptophan as a model fluorophore was prepared across a range of blend concentrations (0.10 - 0.50 % w/w), three compaction pressures, and three granule milling screen sizes. Clear and systematic distinctions in fluorescent signal were observed across API concentrations in powder blends, compacts, and granules. Compaction pressure induced systematic changes in fluorescent signal across both smooth and rough sample surfaces. Milling screen size showed no noticeable effect on the signal, whereas the granule particle size influenced the fluorescence response alongside changes in API concentration. Despite this influence of the particle size, a regression model showed promising concentration predictions upon cross-validation. These findings advance the fundamental understanding of fluorescence signal behaviour in solid pharmaceutical systems, supporting further development of fluorescence spectroscopy as a relevant technique for pharmaceutical challenges.
Development of rutin-loaded cerosomes for topical photoprotection and skin barrier modulation.
Vieira J, Júlio A, Hrdinová I … +7 more , Kováčik A, Vávrová K, Baby AR, Roque R, Saraiva N, Rosado C, Pereira-Leite C
Int J Pharm · 2026 Jun · PMID 42297314 · Publisher ↗
Xeroderma pigmentosum (XP) is a rare DNA-repair disorder associated with extreme photosensitivity, high skin cancer risk, progressive xerosis and barrier dysfunction. Current management relies largely on strict photoprot...
Xeroderma pigmentosum (XP) is a rare DNA-repair disorder associated with extreme photosensitivity, high skin cancer risk, progressive xerosis and barrier dysfunction. Current management relies largely on strict photoprotection, which does not address impaired hydration and epidermal barrier integrity. This work developed cerosomes (ceramide-containing vesicular systems) as multifunctional topical carriers combining barrier-replenishing ceramides with rutin as an antioxidant/photoprotective agent. Box-Behnken design was applied to optimize rutin-loaded cerosomes by evaluating phospholipid concentration, Tween®80:phospholipid ratio and ceramide concentration on the physicochemical properties. The optimized Tween® 80 formulation showed suitable attributes for topical delivery, with vesicle size <300 nm, polydispersity index <0.3, zeta potential <-30 mV, association efficiency >50% and loading capacity ∼0.8% but these were not maintained after 30 days at room-temperature. Surfactant substitution with Pluronic® F-127 or sodium deoxycholate improved storage stability up to 60 days, while rutin release was complete within 6 h and followed Fickian diffusion. In HaCaT keratinocytes, rutin-loaded cerosomes were cytocompatible up to 50-100 μM, while unloaded systems were more cytotoxic, suggesting a protective role of rutin. In vitro photoprotection assays showed that Pluronic®-stabilized cerosomes increased SPF to 40 vs 25 obtained with blank sunscreen, and improved photostability up to 60 min of simulated UV exposure. Barrier-related performance was supported by film-forming/occlusive effects, as well as modulation of water loss and theophylline permeation across artificial membranes and intact/damaged skin models. These findings support rutin-loaded cerosomes as a promising nanoplatform for combined photoprotection and barrier-oriented care in XP.
Functionalized smart surfaces to control the wound healing after glaucoma's surgery.
Machado M, Silva GA, Ferreira J … +2 more , Pinto LA, Ferreira Q
Int J Pharm · 2026 Jul · PMID 42297313 · Publisher ↗
Over the past decade, considerable attention has been directed toward the development of drug delivery systems capable of releasing therapeutic agents in a controlled and sustained manner over extended periods. Glaucoma,...
Over the past decade, considerable attention has been directed toward the development of drug delivery systems capable of releasing therapeutic agents in a controlled and sustained manner over extended periods. Glaucoma, one of the leading causes of irreversible blindness worldwide, is commonly managed with topical eye drops. However, this treatment strategy often suffers from poor patient compliance and limited efficacy. When pharmacological therapy is insufficient, surgical intervention becomes necessary. Among the available surgical options, implantation of drainage devices to divert aqueous humor is widely performed. Despite their functional performance, postoperative wound healing frequently induces an exaggerated fibroblast response that obstructs the drainage channel, resulting in bleb failure. Consequently, the long-term success rate of such procedures is reported to be approximately 70% at one year. To mitigate this challenge, strategies involving localized and time-controlled delivery of antifibrotic drugs have been investigated. In the present study, a nanostructured film was engineered to release precise doses of the antimetabolite 5-Fluorouracil (5-FU) at defined time intervals, aiming to modulate post-operative scarring. Previous work has demonstrated that encapsulation of 5-FU within β-Cyclodextrin (β-CD) cavities enhances drug solubility and reduces toxicity. Building on this concept, films were fabricated on quartz and poly(methyl methacrylate) (PMMA) substrates using the layer-by-layer (LBL) technique. Film growth and drug release kinetics were successfully monitored by ultraviolet-visible spectroscopy (UV-Vis), demonstrating that PMMA substrates enable a more sustained and prolonged drug release compared to quartz. In conclusion, these findings highlight the significant advantages of polymeric materials commonly used in biomedical devices and wound-contact applications for controlled drug delivery systems.
Nanorobotics at a crossroads: an overview of design, propulsion, and applications.
Abrunheiro M, Lourenço R, Sousa JJ … +3 more , Pais A, Mendes M, Vitorino C
Int J Pharm · 2026 Jun · PMID 42297312 · Publisher ↗
Nanobots are small nanoscale devices designed to perform highly specific tasks in precisely targeted areas, representing a promising approach in the diagnosis and treatment of various diseases. This review describes the...
Nanobots are small nanoscale devices designed to perform highly specific tasks in precisely targeted areas, representing a promising approach in the diagnosis and treatment of various diseases. This review describes the ideal characteristics and attributes of these systems, including their dimensions and the most commonly used materials. It also analyses the main propulsion mechanisms that enable their locomotion in biological environments, comparing them in terms of efficiency, biocompatibility, and therapeutic potential. Although these devices may have several therapeutic applications, the primary focus is on oncology, given their ability to deliver drugs directly to the tumor site, thereby minimizing chemotherapy-related side effects. Furthermore, the main challenges to their clinical application are discussed, particularly those related to propulsion systems, physiological barriers, and regulatory issues. In this context, relevant patents are presented to highlight the growing interest and technological advancements in clinical nanorobotics.
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