To mitigate the systemic toxicity associated with doxorubicin (DOX), this study aimed to develop DOX-loaded Binary Eutectic Thermoresponsive Lipid Nanoparticles (DOX-BEu TLN) using a simple binary eutectic blend of stearic acid (S.A) and lauric acid (L.A) for thermoresponsive drug delivery. DOX-BEu TLN were optimized using a Box–Behnken Design and prepared by a modified hot-melt encapsulation method. The physicochemical properties, including particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, morphology, drug release behavior, plasma stability, hemocompatibility, acute toxicity, histopathology, and anticancer activity against HepG2 and MCF-7 cells, were evaluated. The optimized DOX-BEu TLN exhibited a phase transition temperature of 41 °C and favorable physicochemical characteristics, including a particle size of 164.9–195.3 nm, PDI of 0.11–0.25, zeta potential ranging from − 13.8 to − 25.1 mV, and entrapment efficiency of 60.28–87.61
Cerebral ischemia treatment remains a clinical problem. According to studies, cerebral ischemia is primarily caused by the neurovascular unit, which serves as the main structural foundation. The new silver nanoparticles (AgNPs) green produced by Pinellia ternata are used in this work to treat cerebral ischemic stroke-reperfusion damage in rats. Several physicochemical methods, including ultraviolet–visible spectroscopy (UV-Vis), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), and energy-dispersive X-ray spectroscopy (EDX), were used to analyze the post-synthetically altered biogenic material in detail. Following transient middle cerebral artery occlusion and reperfusion, rats received oral administration of AgNPs@Pinellia ternata (10, 30, 90–270 µg/kg) once daily for 14 consecutive days. Behavioral, biochemical and histological assessments were subsequently performed to evaluate neuroprotective efficacy. The index of cell damage was measured by investigating infarct volume, learning and memory function, lactate dehydrogenase activity and serum malondialdehyde (MDA) level, and extravasation of cerebral parenchyma immunoglobulin G (IgG); treatment with AgNPs@Pinellia ternata significantly decreased the lactate dehydrogenase activity, infarct volume and serum MDA level, and IgG extravasation was significantly inhibited. Ischemic stroke-reperfusion injury-induced learning and memory impairments may be prevented by treatment with AgNPs@Pinellia ternata. It was demonstrated that treatment with AgNPs@Pinellia ternata protected rats against cerebral ischemic stroke-reperfusion injury.
Chronopharmacology considers the fact that diseases, drug response and toxicity are circadian rhythm-dependent. This creates the need for delivery systems capable of delivering multiple therapeutics at predetermined time points. In this review, we assess the feasibility of three-dimensional (3D)-printed multicompartmental microneedles (MCMNs) as programmable transdermal platforms for chronopharmacology-based polytherapy. Particular attention is paid to evidence on chronotherapeutic requirements, microneedle-mediated transdermal delivery, 3D-printing technologies, compartmental architecture, material choice and mechanisms controlling the temporal drug release. The focus is on layered, zoned, core-shell and reservoir architectures that spatially separate therapeutics and enable immediate, delayed, sustained, sequential or stimuli-responsive release. Reported printing resolutions are 50–100 μm for stereolithography, 5–10 μm for digital light processing and 100–200 μm for fused deposition modelling, which illustrate the technological capabilities. Compartmental designs have been demonstrated to have release windows of 0–30 min for rapid onset, 2–12 h for sustained delivery, and 24–72 h for prolonged release, providing a technological basis to synchronize drugs with distinct therapeutic windows. The review also correlates these capabilities with the chronotherapy applications reported for diseases like rheumatoid arthritis, hypertension, epilepsy and cancer. It also distinguishes well-established chronotherapeutic principles from the primarily preclinical evidence for MCMNs. The study also points out significant translational challenges such as drug diffusion between compartments, interface incompatibility, limits of printing resolution, standardisation in manufacturing, regulatory requirements and lack of clinical validation. To summarize, 3D-printed MCMNs represent a promising approach for integrating spatially organized polytherapy with programmable temporal drug release, which may enable personalized chronotherapeutic treatment.
The objective of this study was to develop and validate a stability-indicating RP-HPLC method for the estimation of triple combination of metformin (MET) sitagliptin (SITA), dapagliflozin, (DAPA) via AQbD framework using WAC guide and to provide insight into their synchronous acidic degradation kinetics. We identified risks using Ishikawa diagrams and Failure Mode and Effects Analysis (FMEA) and prioritized mobile phase composition, pH, and flow rate as High-Risk Critical Method Parameters (CMPs). A systematic optimization plan using a 26−3 fractional factorial screening design followed by a 17-run Box-Behnken Design was able to establish sufficient parts of an operable design region (MODR) for the method. An optimized isocratic separation was performed with a Shim-pack ODS-C18 column and using methanol: phosphate buffer (65:35 v/v, pH 5.5) system. The method enable baseline separation (Rs > 2.0) for 3 APIs and 6 degradation products in a single run (< 15 min). Validation according to ICH Q2 (R2) showed excellent linearity, and very high sensitivity. Kinetic modelling validated first order kinetics for acidic breakdown and SITA was determined to be the stability-limiting component (Activation Energy: 2.79 kcal/mol; t1/2: 229.21 min at 80 °C). The WAC analysis returned an impressive whiteness score of 87.2 per cent, comprising a complementary mix of assessment performance (101.5
The combination of duloxetine and olanzapine demonstrates safe usage in resistant depression, showing notable therapeutic benefits including improved anxiety, depression and cognitive function. For quality control and safe combination therapy, a rapid, precise and validated method for quantification is essential. A novel reverse phase high performance liquid chromatography method was developed and validated for simultaneous estimation of duloxetine and olanzapine, following ICHQ2(R2) guidelines. The separation used Shimadzu-shim pack C18 (5 μm, 250 mm× 4.6 mm) column, Phosphate buffer: acetonitrile: methanol (40:15:45
The present study investigates the preparation, characterization, and application of essential oil-loaded nanosponges formulated into a hydrogel system for sustained release and cancer therapeutics. Lemon essential oil (LEO) was encapsulated within nanosponges (NS), subsequently incorporated into a 1.5
The aim of the current research was to evaluate the impact of calcium chloride (CaCl₂) and polyethylene glycol 400 (PEG 400) as encapsulation enhancer on the loading of a BCS Class II drug into human plasma-derived exosomes. Exosomes were isolated using differential ultracentrifugation, dialysis, and lyophilization. Spironolactone (SP), a BCS Class II drug was encapsulated into exosomes via freeze-thaw method. The impact of PEG 400 and CaCl₂ -used as loading enhancers on drug encapsulation efficiency, carrier loading capacity, colloidal stability, in-vitro drug release kinetics and biocompatibility on human embryonic kidney (HEK 293) cell lines was evaluated. Sodium dodecyl sulfate polyacrylamide gel electrophoresis confirmed the presence of exosomal surface markers (CD9, CD63, and CD81). Scanning electron microscopy confirmed spherical morphology. Optimized PEG 400-based SP loaded exosomal formulation showed significantly higher encapsulation efficiency (94 ± 2.5
To evaluate the wound-healing efficacy of innovative combination therapies. This study investigates silver Nanoparticles (AgNPs) synthesized using Ageratina adenophora stem extract, in combination with chitosan (Cs) and the antibiotic doxycycline (Dox), in diabetic Wistar albino rats. In this study, (Cs/Dox/AgNPs) nanocomposites were characterized by UV–Vis spectroscopy, FTIR, SEM with EDS, Zeta potential, and DLS. The antimicrobial efficacy was tested against Gram-positive and Gram-negative bacteria as well as for their antifungal activity. In vitro cytotoxicity was assessed on 3T3 cells using the MTT assay, hemolytic potential was evaluated on human RBCs, and in vivo wound healing was studied in a diabetic rat model. The Cs/Dox/AgNPs exhibited surface plasmon resonance peaks at 365 nm and 270 nm. The nanocomposite exhibited potent antibacterial and antifungal activity. In vitro cytotoxicity on 3T3 cells and hemolytic assays on human RBCs indicated minimal toxicity. The combination therapy of Cs/Dox/AgNPs hydrogel showed significant in vitro wound healing potential with 92.40
Healing failure in chronic wounds reflects a self-reinforcing pathology of unresolved inflammation, oxidative damage, poor angiogenesis, and disordered matrix turnover, compounded by a wound bed that turns abnormally alkaline. Apigenin, a plant-derived flavonoid, counters several of these processes through antioxidant and anti-inflammatory activity, but its low aqueous solubility and weak bioavailability make topical use inefficient without a suitable carrier. To address this limitation, apigenin was incorporated into a pH-responsive poly(acrylic acid) hydrogel, in which pH-dependent swelling modulates drug release such that release increases under alkaline conditions. The principal contribution of this study is a delivery strategy that couples pH-triggered release to the alkalinity of the chronic wound bed, so that apigenin is liberated preferentially under the conditions that mark impaired healing. The gels were profiled for viscoelasticity, surface tack, and release across a pH range, and the released drug was tested on human umbilical vein endothelial cells (HUVECs) and adult human dermal fibroblasts (HDFa) for cytocompatibility and for effects on oxidative stress (ROS), inflammatory signalling (IL-6), matrix degradation (MMP-9), and endothelial network formation. Blank and drug-loaded gels were both cohesive and uniform and showed equivalent adhesion; the apigenin-loaded gel behaved as an elastic, shear-thinning solid (G′ above G″ from 0.5 to 30 Hz). Release tracked pH as intended, climbing from 8.73 ± 1.41
Carfilzomib-loaded liposomes were developed using a mixture of lipids comprising varying chain lengths, saturation levels, and transition temperatures. This study focused on developing a robust lyophilization process using the optimal cryoprotectant/processing condition to deliver a solid-state product without compromising its native attributes. For this, a suitable lipid blend, resulting in a desirable entrapment efficiency and particle size, was used to formulate liposomes using the quality-by-design approach to obtain a robust formulation. Further to stabilize colloidal liposomal dispersion and safeguard it from anticipated detrimental effects, it was subjected to lyophilization. This was optimized for the mixture of cryoprotectants and the process parameters (freezing rate and drying time) to obtain a time and energy-efficient lyophilization recipe. The obtained drug-loaded PEGylated lyophilized liposomes were assessed for various physicochemical attributes and were subjected to stability studies. The prototype liposomal formulation was found to have an entrapment efficiency of 97.58
To fabricate and characterize a dual-responsive nanogel composed of N-isopropylacrylamide and methacrylic acid (NIPAM-MAA) for the controlled delivery of fusidic acid (FA) against skin infections. NIPAM-MAA nanogels were synthesized by free radical polymerization and optimized based on swelling behavior and drug loading capacity. The optimized formulation (NMB-2) was characterized for particle size, polydispersity index, entrapment efficiency, drug loading, pH-responsive swelling, solid-state properties (FTIR, PXRD, DSC), and in vitro drug release kinetics. Release data were fitted to mathematical models to determine the transport mechanism. The optimized NMB-2 formulation achieved an entrapment efficiency of 68.50
Hepatitis C virus (HCV) remains a major global health burden, and resistance-associated substitutions in the NS5B RNA-dependent RNA polymerase (RdRp) limit the long-term efficacy of current direct-acting antivirals. Therefore, identification of novel inhibitors with improved stability and drug-like properties is urgently needed. A comprehensive multistage in silico strategy was implemented, integrating machine-learning–driven QSAR modeling with structure-based docking, long-timescale molecular dynamics simulations, MM-GBSA free-energy estimation, pharmacokinetic profiling, and hybrid QM/MM calculations. A curated dataset of 2,241 experimentally validated NS5B inhibitors was used to develop a support vector regression (SVR)-based QSAR model (5-fold CV R² = 0.8635; R²_train = 0.8619; R²_test = 0.8727; R²_external = 0.8654). The validated model screened 2,460 natural compounds, and the top-ranked candidates were docked against NS5B (PDB ID: 3G86), followed by 300 ns MD simulations and electronic-level interaction analysis. QSAR screening identified 342 compounds exceeding the µ + σ activity threshold. Docking analysis revealed several potential hits, among which HC2 showed favorable binding energy (− 10.0 kcal/mol) and key interactions with TRP397, VAL144, ARG394, GLU143, and HIS402. MD simulations confirmed structural stability, with consistent RMSD, RMSF, Rg, SASA, and hydrogen-bond profiles. MM-GBSA analysis indicated favorable binding free energy (− 18.80 ± 4.81 kcal/mol). QM/MM calculations indicated favorable ligand–protein interactions for HC2, with an interaction energy of − 13.61 kcal/mol. ADMET profiling indicated a generally favorable predicted profile, although some limitations were observed. HC2 emerged as a promising NS5B inhibitor candidate, demonstrating stable binding, favorable thermodynamics, and improved drug-like properties, warranting further experimental validation.
Hesperetin (HSP), a naturally occurring citrus flavanone with diverse antioxidant, anti-inflammatory, and pharmacological activities, has attracted considerable attention as a promising candidate for oral therapeutic delivery. However, its pharmaceutical applicability remains limited due to poor aqueous solubility, rapid metabolism, limited intestinal permeability, and low oral bioavailability. In the present study, chitosan-coated Eudragit® S100 nanoparticles were developed and optimized for colon-targeted delivery of HSP using a hybrid ionic gelation–solvent evaporation technique. Formulation optimization was performed using a 3² factorial response surface design by varying the Eudragit® S100:Chitosan ratio and Poloxamer-188 concentration. The developed nanoparticles were characterized for particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, morphology, crystallinity, in vitro drug release, and Ex vivo intestinal permeation behavior. The optimized formulation (F4) exhibited nanosized particles (195.4 ± 6.2 nm), a narrow size distribution, a favorable zeta potential (− 31.0 ± 2.0 mV), and a high entrapment efficiency (86.7 ± 2.6
Psoriasis is a chronic, immune-mediated inflammatory skin disorder for which topical therapy remains the cornerstone of treatment. However, the therapeutic efficacy of Symplocos racemosa, a promising herbal antipsoriatic agent, is limited by poor skin permeation from conventional topical formulations. Therefore, a Quality-by-Design optimized Symplocos racemosa extract-loaded transferosomal gel was developed to enhance dermal delivery and improve antipsoriatic efficacy. Symplocos racemosa extract-loaded transferosomes were fabricated by the thin-film hydration technique and optimized using a Box–Behnken design. The optimized nanovesicular formulation was characterized for physicochemical attributes, including vesicle size, entrapment efficiency, drug content and vesicular morphology, followed by incorporation into a gel base and evaluated for in vitro drug release, ex vivo, HaCaT keratinocyte cytocompatibility and in vivo antipsoriatic efficacy in Wistar rat model. The optimized transferosomal dispersion comprised nanosized vesicles (260.9 ± 2.6 nm) with high entrapment efficiency (81.22 ± 1.44
Predictive performance can identify a design-space candidate but cannot establish its quality claim. We developed a finite-sample procedure for a prespecified average out-of-specification (OOS) rate claim under a reference plan. Construction data ranked operating conditions and defined a finite nested candidate family. Independent calibration data provided exact one-sided tests for the full candidates. Holm’s procedure controlled the family-wise error rate (FWER) at 0.05. The case study compared Parteck M100 and M200 on a finite grid of 315 measured setpoints per grade. Partial least squares (PLS) and random forest (RF) scores were evaluated on matched splits. Exact hypergeometric tests conditioned on the known OOS labels among construction setpoints. Among target candidate masses 0.10, 0.55, and 1.00 under the reference plan, the largest supported candidate contained 174 M100 setpoints and 32 M200 setpoints at a tolerated average OOS rate of 0.15. Matched outcomes showed a grade-associated difference before score modeling. PLS and RF preserved the grade ordering of supported mass, although membership differed, especially for M200. In simulation, empirical FWER for the full-candidate Holm procedure remained below 0.05, whereas the unadjusted comparator reached 0.105. The fixed M200 candidate was retained in M100; the fixed M100 candidate was not retained in M200. The procedure supports an average OOS-rate claim for a candidate selected from a prespecified family under a stated reference plan. The procedure does not provide pointwise assurance. Candidate-family design, score-model choice, retention, and recertification must be interpreted separately.
Healthcare-associated infections from indwelling devices, exacerbated by antimicrobial resistance, demand innovative solutions beyond conventional antibiotic coatings. This study develops a novel antimicrobial nanocomposite (AgNP-DB) that additively (FICI = 0.75–0.80) combines green-synthesized silver nanoparticles (AgNPs) with domiphen bromide (DB) to overcome these limitations. Silver nanoparticles were sustainably synthesized using clove (Syzygium aromaticum) extract, which acted as both a reducing and a capping agent. The cationic DB was then efficiently loaded onto the anionic AgNPs via electrostatic interactions, as confirmed by a significant zeta potential shift from − 25.5 mV to -8.55 mV (indicating charge neutralization and limited colloidal stability, which is acceptable for the intended solid coating application) and characterized by UV-Vis, FTIR, and XRD. The resulting nanocomposite demonstrated a controlled, biphasic release profile, with an initial burst of 28.3
The pharmaceutical manufacturing industry faces significant challenges in integrating diverse data sources due to multi-generational equipment, varied technology stacks, and fragmented communication protocols. These challenges hinder scalability, increase technical effort, and limit the adoption of advanced analytics and AI-driven solutions. This paper introduces the Factory Integration Layer (FIL), a scalable, event-driven platform designed to bridge the gap between Information Technology (IT) and Operational Technology (OT) systems across globally distributed manufacturing sites. FIL leverages a hybrid edge-cloud architecture and a Unified Namespace (UNS) for standardized data organization, enabling seamless data integration and AI-driven innovation. The FIL platform is based on an event-driven, publish-subscribe architecture supported by messaging brokers such as MQTT and Kafka, ensuring asynchronous communication and decoupling between data producers and consumers. It incorporates centralized governance, semantic interoperability, and edge autonomy to address challenges such as equipment heterogeneity, semantic fragmentation, and cybersecurity risks. By implementing real-time data contextualization at the edge, persistent event storage in the cloud, and a centralized control plane, FIL delivers validated failover, disaster recovery, and horizontal scalability. The platform is designed to transform factory data into a shared enterprise asset, enabling a data-product marketplace paradigm with fine-grained access control and compliance. FIL provides the governed, contextualized, and low-latency data infrastructure required to enable enterprise analytics and AI applications across a global manufacturing footprint. This approach redefines factory data integration, turning it into a repeatable enabler of continuous improvement while addressing critical security and governance requirements.
Rising global cancer rates highlight the urgent need for better treatments, as conventional therapies often lack effectiveness, cause severe side effects, and fail to target cancer cells selectively. Plant-based coumarins like esculetin stand out as natural alternatives, showing stronger anticancer effects with fewer toxicities than synthetic drugs. By disrupting key signaling pathways that control cancer cell growth, survival, and programmed cell death, esculetin holds broad promise against multiple cancer types. This systematic meta-analysis synthesized quantitative data from 24 independent studies to evaluate the effects of esculetin on human cancer cell viability. A mixed-effects meta-regression model was fitted, with dose-group categories incorporated as moderators. The analysis revealed substantial heterogeneity (I² = 70.17
Local drug delivery systems have emerged as promising adjuncts to non-surgical periodontal therapy (NSPT) by enhancing drug bioavailability within periodontal pockets. This study aimed to formulate and evaluate a ginger essential oil (GEO) nano-emulgel and compare its clinical efficacy with glucosamine sulphate (GS) gel as adjuncts to NSPT. The primary objective of this work was to evaluate the effectiveness of the local application of Ginger essential oil (GEO) nano-emulgel versus Glucosamine sulphate (GS) gel on clinical parameters of periodontitis, including the plaque index (PI), mean sulcus bleeding index (MSBI), clinical attachment level (CAL), and probing depth (PD) in adjunct to non-surgical periodontal therapy. The secondary objective is to detect the effect of both gels on Receptor activator of nuclear factor kappa B ligand (RANKL) levels in the gingival crevicular fluid (GCF). GEO nano-emulgel and GS gel were formulated and characterized for physicochemical properties, rheology, and in vitro drug release. GEO nano-emulgel was further evaluated for particle size, polydispersity index, zeta potential, and morphology. A randomized controlled clinical trial was conducted on 30 patients with periodontitis allocated to either the GEO nano-emulgel or GS gel group (n = 15 each) following scaling and root surface debridement. Clinical periodontal parameters were assessed at baseline and after 3 months, while GCF RANKL levels were measured at baseline, 1 month, and 3 months using enzyme-linked immunosorbent assay. The optimized GEO nano-emulgel exhibited favorable physicochemical characteristics, sustained diffusion-controlled drug release, and pseudoplastic flow behavior. Both formulations significantly improved plaque index, mean sulcus bleeding index, probing depth, and clinical attachment level after treatment. No significant intergroup differences were observed in clinical parameters. However, GEO nano-emulgel achieved a significantly greater reduction in GCF RANKL levels than GS gel (p = 0.013). GEO nano-emulgel demonstrated promising adjunctive therapeutic potential for periodontitis by improving clinical outcomes and significantly reducing inflammatory RANKL levels compared with GS gel. Larger, long-term clinical trials are warranted to confirm these findings.
Pain is an unpleasant sensory experience and a leading cause of medical consultations. Researchers are constantly seeking effective pain relief with minimal side effects. In fact, effective topical formulations with rapid antinociceptive effects are critical for pain relief. The aim of this study was to prepare an effective topical gel with antinociceptive effects. Three different gel types (hydrogel, oleogel, and bigel) were prepared to deliver baclofen and frankincense oil topically for pain relief. The physicochemical properties of the gels were analyzed, and their in-vivo effectiveness was assessed using capsaicin as a positive control. Hydrogel was prepared using Carbomer 940 and Pluronic F-127 as gelling agents, while oleogel was prepared using beeswax and Pluronic F-127 as gelling agents. Bigel was prepared using a mixture of these ingredients at different concentrations. The concentrations of baclofen and frankincense oil were 2
