Background/Objectives: Tablet development requires simultaneous optimization of multiple quality attributes under limited experimental budgets, yet formulation-property relationships are highly nonlinear in mixture systems. To support pre-formulation decision-making prior to extensive tablet prototyping, this study proposes an AI framework that organizes formulation and process data together with raw-material property records into a reusable database, and enriches conventional composition/process features with physically motivated mixture descriptors derived from raw-material properties and formulation/process settings. Methods: Mixture-level scalar descriptors are constructed by composition-weighted aggregation of material properties, and particle size distribution (PSD) is incorporated via a compact set of summary statistics computed from composition-weighted mixture PSDs. Three feature sets are compared: (i) Materials + Processes (MP), (ii) MP with scalar Descriptors (MPD), and (iii) MPD with PSD summaries (MPDD). Five target properties are modeled: hardness, disintegration time, flow function, cohesion, and thickness. We train and evaluate Random Forest, Extra Trees Regressor, Lasso, Partial Least Squares, Support Vector Regression, and a multi-branch neural network that processes the three feature blocks separately and concatenates them for prediction. For interpolation assessment, repeated Train/Dev/Test splitting (5:3:2) across multiple random seeds is used, and the effect of feature augmentation is quantified by paired RMSE improvements with bootstrap confidence intervals and paired Wilcoxon signed-rank tests. To assess robustness under practical formulation updates, rolling-origin time-series splits are employed and Applicability Domain indicators are computed to characterize out-of-distribution coverage. Results: Across interpolation evaluations, mixture-descriptor augmentation (MPD/MPDD) improves hardness and disintegration time in most settings, whereas gains for flow function are smaller and cohesion/thickness show mixed effects under limited sample sizes. Conclusions: Under extrapolation-oriented evaluation, the descriptors can improve hardness but may degrade disintegration-time prediction under covariate shift, emphasizing the need for careful descriptor selection and dimensionality control when deploying pre-formulation predictors.

Background/Objectives: Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that is critical for intestinal immune homeostasis. Despite its therapeutic potential, systemic delivery of IL-10 has failed in clinical trials for inflammatory bowel disease (IBD), largely due to its poor localization and short half-life. Methods: We present a proof-of-concept study demonstrating that hydrodynamic delivery of a naked plasmid bearing the human IL-10 gene to ex vivo human colonic segments from Crohn's disease patients results in localized IL-10 expression and modulation of inflammatory mediators. Results: Compared to venous administration, arterial delivery yielded significantly higher IL-10 mRNA and protein levels, as well as decreased IL-6 and TNF-α expression. Furthermore, nanoparticle tracing confirmed efficient tissue penetration via the arterial route. Conclusions: These findings establish arterial hydrodynamic delivery as a feasible, non-viral strategy for targeted gene therapy in IBD.

Background: Cancer patients are highly susceptible to microbial infections due to immune suppression, necessitating therapeutic strategies that integrate anticancer efficacy with effective antimicrobial intervention. Chalcone-derived nitrogen-fused heterocycles represent a promising platform for developing multi-target agents with relevance to antimicrobial drug delivery, particularly for localized infections. Methods: A series of chalcone-based pyrazoline-thiadiazole nitrogen-fused azole hybrids was synthesized via thiosemicarbohydrazide-functionalized intermediates and fully characterized. Antiproliferative activity was evaluated against MCF-7, HepG-2, HeLa, and HCT-116 cell lines, alongside selectivity toward WI-38 normal fibroblasts. Antibacterial, antibiofilm, and in vivo efficacy were assessed against methicillin-resistant Staphylococcus aureus (MRSA USA300) and Acinetobacter baumannii AB5057. Mechanistic investigations included cell-cycle analysis, apoptosis assays, ERK2, RIPK3, p53, BAX/Bcl-2 quantification, DNA gyrase inhibition, molecular docking, molecular dynamics simulations, and density functional theory calculations. Results: Compound 13 exhibited potent cytotoxicity, particularly against MCF-7 (IC50 = 3.87 ± 0.2 µM), outperforming doxorubicin (IC50 = 4.17 ± 0.2 µM), with high selectivity indices (SI = 10.7 for MCF-7). Mechanistically, compound 13 induced G2/M arrest (40.16% vs. 14.15% control), increased apoptosis to 32.89%, up-regulated ERK2 (3.17-fold), RIPK3 (11.97-fold), and p53 (3.54-fold), and markedly increased the BAX/Bcl-2 ratio (~42-fold). Compounds 7 and 13 displayed bactericidal activity against MRSA and A. baumannii (MIC/MBC = 10 mg/mL), potent antibiofilm effects, and significant in vivo efficacy in an MRSA skin infection model. Compound 13 reduced bacterial load by ~5 log units, outperforming vancomycin. DNA gyrase inhibition (IC50 = 17.10 ± 0.17 µM) and computational studies supported target engagement. Conclusions: Pyrazoline-thiadiazole-based nitrogen-fused azole hybrids, particularly compound 13, demonstrated quantifiable anticancer and antimicrobial efficacy with strong in vivo validation, supporting their potential as multi-target candidates relevant to antimicrobial drug delivery in infection-prone cancer patients.

Background/Objectives: Hot-melt injection molding (HMIM) was evaluated as a solvent-free process for the preparation of glibenclamide (GLB), a poorly soluble BCS Class II drug, glassy solutions with the objective of improving dissolution and bioavailability for diabetes. Methods: GLB was blended at a concentration of 10% w/w with PVP K25, PVP VA64, and Soluplus® (SOL) matrices. The miscibility of the GLB-polymer systems (matrices) was calculated based on the Hansen solubility parameters and validated using differential scanning calorimetry (DSC) analysis. The HMIM extrudates were milled into granules and analysed for their solid-state properties (DSC, XRPD, FTIR, and SEM studies), and flow properties. The produced granules were compressed into immediate release tablets and assessed for in vitro performance, stability, and in vivo bioavailability using 20 healthy male Sprague Dawley rats. Results: Findings revealed the formation of single-phase glassy solutions, specifically for PVP VA64 and SOL, which also exhibited advantageous manufacturing and extrudate clarity. The glassy solution formulations showed considerably improved dissolution characteristics compared with the crystalline GLB and the commercial product. The glassy solution formulations displayed fast drug release for PVP K25 and PVP VA64, and biphasic drug release for SOL. Stability testing confirmed the capability of PVP VA64 and SOL to maintain GLB in a molecularly dispersed, amorphous state for 12 months. The in vivo assessment revealed an increase in relative bioavailability to 246.3% and 124.5% for the SOL and PVP VA64 formulations when compared to the commercial formulation. Conclusions: Overall, the findings demonstrate the potential of HMIM-processed glassy solutions, especially those prepared using SOL, as promising platforms for promoting oral delivery of the poorly soluble antidiabetic GLB.

Objective: The objective is to investigate and optimize the β-cyclodextrin inclusion process for volatile oils in Ligusticum Chuanxiong-Vinegar cyperus rotundus based on Quality by Design (QbD) principles. Methods: First, ligustilide and α-cyperone were selected as inclusion process indicator components using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). Single-factor experiments were conducted to preselect the inclusion speed based on ligustilide and α-cyperone content as evaluation criteria. Subsequently, using the inclusion rates of ligustilide and α-cyperone as evaluation criteria, a factorial design was employed to investigate the inclusion temperature, inclusion time, and the volume ratio of β-cyclodextrin solution to essential oil, thereby optimizing the inclusion process parameters. Finally, the inclusion process parameters were validated, and the inclusion rates were determined. The obtained inclusion complexes were characterized by microscopic analysis, Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction analysis (XRD), and differential scanning calorimetry (DSC). Furthermore, phase dissolution studies and molecular docking were employed for confirmation. Results: The optimal process parameters were determined as follows: encapsulation speed of 300 rpm, β-cyclodextrin solution excess of 6, encapsulation time of 2.5~3 h, and encapsulation temperature of 30~35 °C. The encapsulation rates for ligustilide and α-cyperone in the resulting inclusion complex were 63.15~64.74% and 71.33~76.89%, respectively. Structural characterization confirmed the formation of the inclusion complex. Conclusions: This inclusion process is reliable and provides a reference for preparing β-cyclodextrin inclusion complexes of volatile oils in formulations containing the Chuanxiong-Vinegar cyperus rotundus drug pair.

Background: Trastuzumab is a blockbuster monoclonal antibody that has revolutionized the treatment of HER2-positive breast and gastric cancers. With the increasing availability of biosimilar monoclonal antibodies in clinical practice, independent verification of biosimilarity using products sampled from a real-world supply chain is important to assure clinicians and the patients to use these products confidently. Objective: The aim of this study is to assess the biosimilarity of AryoTrust, a trastuzumab biosimilar, in comparison with the reference product Herceptin. AryoTrust and Herceptin products were randomly withdrawn from Iraqi hospitals to reflect medicines administered in real clinical settings. Methods: AryoTrust and Herceptin were compared using an extensive set of orthogonal analytical techniques which included SDS-PAGE, ion-exchange chromatography, capillary isoelectric focusing, peptide mapping, N-glycan profiling, circular dichroism, differential scanning calorimetry, and surface plasmon resonance. In addition to these teste, functional comparability was also tested using an HER2-dependent cell-based proliferation inhibition bioassay. Results: The results showed that both products have highly comparable profiles in all assessed attributes. The analysis showed similar molecular integrity and purity, identical primary structure, comparable charge heterogeneity, similar isoelectric points (pI) of the main isoform, close glycosylation patterns (mainly, by core-fucosylated complex-type glycans), similar higher-order structural features, and thermal stability. The receptor binding studies exhibited comparable binding affinities with Fcγ receptors and FcRn. Finally, the cell-based bioassay revealed comparable dose-response curves with similar EC50 values and relative potency. Conclusions: The integrated analytical and functional data support the biosimilarity of AryoTrust to the reference product Herceptin, which has been marketed and used in Iraq. This study provides real-world scientific evidence supporting confidence in the quality and comparability of this trastuzumab biosimilar and reduces any doubt in the product and at the same time emphasizes the value of independent post-marketing biosimilarity assessments.

Background/Objectives: Blood loss is a major concern in elderly patients undergoing hip fracture surgery. Tranexamic acid (TXA) is used to improve bleeding outcomes; however, randomized clinical trials (RCTs) report mixed findings, with some studies finding no improvements. This meta-analysis was conducted to evaluate the effectiveness of intravenous TXA in patients with extracapsular proximal femur fractures undergoing surgery. Methods: A systematic literature review was performed to identify relevant RCTs. Evaluated outcomes were total blood loss (TBL), hidden blood loss (HBL), change in hemoglobin (Hb), change in hematocrit (Hct), risk for transfusion and number of transfused units per patient. Review Manager 5.3 was used. Results: Twenty-five RCTs were included. TXA administration was associated with significant reductions in TBL (MD = -255.59 mL, 95% CI -306.50 to -204.68) and HBL (MD = -219.28 mL, 95% CI -286.93 to -151.62) compared with control. Patients receiving TXA had significantly smaller changes in Hb (MD = 0.65 g/dL, 95% CI 0.39-0.90) and Hct (MD = 4.22%, 95% CI 2.04-6.40). TXA significantly reduced the risk of transfusion (RR = 0.55, 95% CI 0.43-0.70) and number of transfused units per patient (SMD = -0.66, 95% CI -1.15 to -0.17). Subgroup analyses showed consistent effects. Sensitivity analyses confirmed robustness of results, except for the significance in reducing the number of transfused units when studies with 'liberal' transfusion thresholds were excluded. Conclusions: These findings show statistically significant improvements in bleeding outcomes with the use of intravenous TXA in patients with extracapsular proximal femur fractures undergoing surgery. Further high-quality RCTs are needed to standardize TXA timing and dosing.

Wound healing is a dynamic and multifaceted biological process involving hemostasis, inflammation, proliferation, and tissue remodeling. Topical therapy is widely preferred for wound management due to its localized action and reduced systemic adverse effects. However, the effective delivery of therapeutic agents is often limited by the skin's barrier properties, the complex wound microenvironment, and the physicochemical characteristics of drugs. This review highlights the key physicochemical parameters governing topical drug delivery in wound therapy, including drug solubility, molecular size, lipophilicity, vesicle size distribution, surface charge, encapsulation efficiency, lipid composition, ethanol concentration, and vesicle deformability, which collectively influence drug permeation and retention at the wound site. Nanovesicular delivery systems have emerged as promising strategies to overcome these limitations. In particular, ultradeformable vesicles such as ethosomes, transferosomes, and transethosomes have demonstrated enhanced skin permeation and improved drug deposition in periwound tissue due to their flexible membrane structure and optimized physicochemical properties. This review systematically discusses the composition, preparation techniques, and critical formulation parameters of these vesicular systems that determine their stability, elasticity, and permeation performance. Furthermore, their applications in delivering anti-inflammatory drugs, antimicrobial agents, bioactive phytochemicals, and regenerative therapeutics for different wound types are examined. Widely used in vitro, ex vivo, and in vivo evaluation methods, including permeation studies and wound healing models such as excision, burn, infected, and diabetic wounds, are also summarized. Finally, the review outlines current challenges related to formulation standardization, physicochemical characterization, safety assessment, and large-scale production, while highlighting the future potential of ultradeformable vesicles as next-generation nanocarriers for advanced wound healing therapies.

Gadolinium nanoparticles (GdNPs) have gained increasing attention as multifunctional metal-based nanoplatforms that extend far beyond their traditional use as magnetic resonance imaging (MRI) contrast agents. Their specific magnetic properties, tunable physicochemical features, and tunable biocompatibilities with biocompatible coatings give them great potential as drug delivery and theranostic applications. They offer greater stability, lower systemic toxicity, and more surface modification options compared to molecular gadolinium chelates. The functionalized GdNPs not only show excellent properties as drug carriers for their specific indications but also serve as agents in various imaging modalities with superior therapeutic efficacy by means of radio sensitization and magnetically assisted delivery. Note too that GdNP-based formulations have demonstrated synergistic activity when administered with chemotherapeutic agents such as doxorubicin. GdNPs have demonstrated promising preclinical outcomes, and their clinical translation remains restricted due to a number of scale-up constraints, long-term safety challenges, pharmacokinetics, and regulatory problems. This review provides information on the use of GdNPs, their key physicochemical and magnetic properties, ligand engineering for targeted delivery, and biological mechanisms of their theranostic performance.

Background/Objectives: Upon systemic delivery, macrophages take up a significant portion of nanoparticles and may become saturated. The saturation of macrophages may pose risks to overall immune function and signaling pathways. While some information is available on the survival and functionality of macrophages upon saturation with nanoparticles, there is limited understanding of the molecular-level changes that can occur and their corresponding influences on macrophage phenotypes, gene expression, and immune signaling pathways. Methods: In this study, RAW 264.7 macrophages were saturated with silica nanoparticles (SNPs) of different sizes (50 and 100 nm), porosities (nonporous, mesoporous), densities (solid, mesoporous, and hollow), and surface compositions (hydrophobicity) at their maximum non-toxic concentrations. The saturated macrophages were evaluated for changes in gene expression and immune signaling pathways by RNA sequencing, weighted gene co-expression network analysis (WGCNA), and Hallmark and KEGG pathway analyses. Results: Our results show that in the range studied, the particle size did not have a significant effect on the gene expression profile. Porous SNPs of comparable sizes resulted in increased and unique changes in the gene expression profile compared to nonporous SNPs. Major immune signaling pathways, including TNF-alpha signaling via NF-κB pathways, mTORC1 signaling, and p53 pathways, were modulated in SNP-saturated macrophages. This modulation depended on the physicochemical properties of the particles. The Th1/Th2 multiplex immunoassay revealed that the uptake of SNPs increases the amount of the TNF-alpha cytokine compared to the nontreated controls, whereas no changes in IL-6 and IL-12p70 pro-inflammatory cytokines were observed. Conclusions: Our results demonstrate that physicochemical properties of SNPs, such as porosity, size, surface functionality, and density, influence the modulation of gene expression and macrophage immune signaling pathways. These results, along with others, can provide guidance on the selection of silica nanoparticles for the safe and effective systemic delivery of bioactive agents.