Lipid-based nanocarriers have been intensively developed to achieve controlled drug delivery and maintain pharmacological stability, especially, for mRNA-based vaccines. Freeze-drying is commonly recognized as a key technique that allows nanoparticles to be converted into a dry form, stored under ambient conditions, and reconstituted at time of use. This study investigated the influence of reconstitution conditions of freeze-dried lipid nanoparticles (LNPs) stabilized with trehalose or trehalose/mannitol mixtures on disintegration and aggregation upon rehydration. Direct water pipetting and water vapor sorption methods were applied to reconstitute the freeze-dried specimens. When LNPs were reconstituted by the water pipetting, a slight decrease in particle size and a significant increase in particle number concentration were observed. On the other hand, when reconstituted by the pipetting subsequent to the water vapor sorption, slight increases in particle size and particle number concentration were observed. These results suggested that the water pipetting lead significant disintegration of LNPs whereas the water vapor sorption inhibited the particle damage and lead slight aggregation. However, when the duration of the water vapor sorption time was prolonged, the LNPs could be disintegrated due to the crystallization of trehalose. The addition of mannitol delayed the trehalose crystallization, and restricted the disintegration of LNPs upon rehydration. A practical suggestion based on this study would be to use a formulation of trehalose and mannitol mixture, allow it to absorb water vapor until the glass–rubber transition, and rehydrate before the crystallization of trehalose, which would be an appropriate reconstitution path to allow the LNP to be retained its original formation.
Pancreatic cancer (PC) is one of the most aggressive malignancies, with a very low 5-year survival rate due to late diagnosis, rapid metastasis, and resistance to conventional therapies. The pancreas’s deep anatomical location complicates early detection, and most patients present with advanced or metastatic disease, limiting surgical options. Current chemotherapy regimens often face challenges such as systemic toxicity, poor tumor penetration, and acquired chemoresistance. To overcome these limitations, poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) have emerged as a promising strategy for targeted drug delivery in PC treatment. PLGA NPs offer controlled drug release, enhanced bioavailability, and reduced off-target effects. Their surface can be functionalized with ligands to actively target PC cells, improving therapeutic efficacy while minimizing damage to healthy tissues. Additionally, PLGA NPs can encapsulate chemotherapeutics, siRNA, or immunomodulators, enabling combination therapy to combat drug resistance and tumor microenvironment barriers. Recent advances in nanomedicine highlight the potential of PLGA-based systems to enhance tumor accumulation, overcome stromal resistance, and improve therapy outcomes. This review discusses the current challenges in PC treatment, the role of PLGA NPs in targeted drug delivery, and future perspectives for clinical translation. Integrating PLGA NPs could revolutionize PC therapy, offering hope for improved survival and quality of life.
Urea is an effective therapeutic agent for the treatment of chronic hyponatremia; however, its high water solubility leads to rapid dissolution, limiting sustained therapeutic efficacy and patient compliance. This study aimed to develop and evaluate controlled-release urea delivery systems using biopolymer-based aerogel and xerogel matrices. Urea-loaded aerogel and xerogel composites were prepared from carboxymethyl cellulose (CMC) and surplus gelatin (GE), crosslinked with varying concentrations of glutaraldehyde (GA). The effects of the CMC:GE ratio and GA concentration on gelation behavior, swelling properties, and urea release kinetics were systematically investigated. Structural and thermal characteristics were analyzed using scanning electron microscopy (SEM), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). The CMC:GE ratio significantly influenced the structural and functional properties of the composites. Among the formulations studied, the aerogel with a CMC:GE ratio of 1:3 and 5
This study reports the development and multiscale evaluation of a nitrocellulose (Nc)-based in situ gel (ISG) system for localized delivery of moxifloxacin HCl (Mx) in periodontitis therapy. The formulations, composed of 15
Disintegrant performance in insoluble, poorly disintegrating matrices is strongly influenced by how the excipients are assembled at the granule level. This study investigated densified microcrystalline cellulose-starch (MCC-starch, 4:1) granular systems as direct compression disintegrants. In the screening stage, co-processed MCC-starch granules prepared by slugging at 10–190 MPa were incorporated into dibasic calcium phosphate (DCP) tablets at 10–15
Syringic acid (SA) demonstrates significant anti-inflammatory, antioxidant, and neuroprotective properties. Unfortunately, its clinical applicability is limited by low solubility and low bioavailability. SA-loaded emulsomes were developed to overcome these limitations. The emulsomes were prepared using thin-film hydration method and optimized by a Central Composite Design. Three independent variables were studied: the solid lipid-to-phosphatidylcholine ratio, drug amount, and solid lipid type (trilaurin or tripalmitin). The measured responses were entrapment efficiency (EE
Ulcerative colitis (UC) is fundamentally mediated by macrophage-driven immune dysregulation that amplifies mucosal inflammation. Andrographolide (AGD) has potent anti-inflammatory and antioxidant properties; however, AGD shows poor water solubility and bioavailability. To surmount these challenges, next-generation solid dispersion of AGD with soluplus and TPGS was engineered via the solvent evaporation method. Optimized SD8 demonstrated a 7.14-fold upsurge in solubility, 18.78 ± 0.98
Gastro-resistant oral dosage forms remain essential for protecting acid-labile active pharmaceutical ingredients, reducing gastric irritation, and enabling site-specific intestinal or colonic drug delivery. Although conventional enteric coatings are well established, their in vivo performance remains affected by gastric pH variability, food intake, alcohol exposure, gastric residence time, coating integrity, and interindividual differences in gastrointestinal transit. Advanced platforms, including ready-to-fill enteric capsules, hot-melt technologies, three-dimensional printing, electrospinning, micro- and nanocarriers, and pH-responsive hydrogels, have been proposed to overcome these limitations, but many remain at an experimental or early translational stage. This narrative review critically evaluates gastro-resistant oral formulations from technological, physiological, and regulatory perspectives. It compares established and emerging technologies with respect to release mechanisms, material requirements, processing constraints, acid-resistance performance, translational maturity, scalability, regulatory acceptability, and commercial feasibility. Recent advances, including rapid-release double-coating concepts and dual pH- and microbiota-triggered colonic delivery systems, are also discussed. Overall, the field is moving from simple gastric protection toward more predictive and functionally complex oral drug delivery platforms. Future progress will depend on biorelevant dissolution testing, stronger in vitro–in vivo correlations, quality-by-design approaches, process analytical technologies, greener manufacturing, and regulatory pathways capable of accommodating innovative materials and personalized oral therapeutics.
Acute lung injury (ALI) involves alveolar–capillary barrier disruption, inflammatory amplification, oxidative stress, and loss of alveolar architecture. This study developed pH-responsive chitosan-coated spanlastic nanovesicles as a pharmaceutical platform for lung-targeted delivery of Brilliant Blue G (BBG), a P2X7 receptor antagonist. BBG-loaded spanlastics were prepared by thin-film hydration and optimized using a 2³ factorial design assessing the effects of Span 60:BBG ratio, Span 60:edge activator ratio, and edge activator type on vesicle size, zeta potential, and entrapment efficiency. The optimized formulation was coated with chitosan to achieve surface cationization, enhance colloidal stability, support mucoadhesive interaction with lung tissue, and provide pH-responsive release. BBG-Ch-SPNs exhibited nanoscale size, positive zeta potential, high entrapment efficiency, acceptable hemocompatibility, and sustained drug release, with greater BBG liberation under acidic conditions relevant to inflamed lung microenvironments. Release kinetic analysis supported diffusion-controlled release with pH-dependent polymer relaxation, while stability testing confirmed preservation of vesicle size, surface charge, and drug entrapment over three months. In vivo, BBG-Ch-SPNs improved pulmonary retention and lung exposure compared with free BBG and uncoated spanlastics, demonstrating enhanced lung-targeting efficiency. Therapeutically, BBG-Ch-SPNs reduced BALF protein leakage, LDH activity, NOx levels, and leukocyte influx while preserving alveolar architecture and limiting septal thickening, edema, and inflammatory infiltration. These effects were accompanied by restored antioxidant defenses and suppression of P2X7R/NF-κB/NLRP3 inflammasome signaling. Overall, chitosan-coated spanlastics improved BBG formulation performance, pH-responsive delivery, pulmonary biodistribution, and therapeutic efficacy, supporting their potential as a targeted nanotherapeutic system for ALI.
This study presents a Quality by Design (QbD) strategy combined with Design of Experiments (DoE) to develop hybrid polymer–lipid hot-melt extruded (HME) formulations aimed at improving the dissolution rate and palatability of ibuprofen (IBU), a Biopharmaceutics Classification System (BCS) Class II drug with poor aqueous solubility. A fractional factorial design was applied to evaluate the influence of Eudragit EPO and Gelucire 48/16 (GLC) ratios on the preparation of IBU-loaded extrudates. Physicochemical characterisation of the micronised extrudates, using differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD), confirmed the formation of amorphous solid dispersions (98.0–99.8
Four-dimensional (4-D) printed constructs have recently become clinically relevant platforms for customized and precise drug delivery due to their bio-programmability, bio-responsiveness, and spatiotemporal transformative potential. The 4-DP bio-constructs are highly bio-interactive and dynamically evolving as per therapeutic requisite. In this review, we aim to provide a detailed discourse on the key mechanisms that drive 4-D transformations of a broad spectrum of materials-ranging from shape-memory (SM) systems, liquid crystalline elastomers (LCEs), self-healing and multi-responsive polymers, metamaterials, and select bio-derived materials. The review also summarizes various conventional and advanced additive manufacturing strategies that have been employed for 4-DP of various bio-constructs. Contemporary representatives of various 4-DP drug delivery devices such as smart hydrogels and scaffolds, implants, stents, prosthetics, microneedles, responsive biomedical devices, and dynamic organ- and tumor-on-chip platforms have also been highlighted. Characterization methodologies, preclinical considerations, translational challenges, and the evolving patent and industrial landscape have also been recapitulated. The review also intends to provide critical perspectives on the expanding horizons and translational glitches of 4-DP while elucidating the key bottlenecks to its commercial large-scale integration and clinical translation.
The goal of the present study is to optimize acetazolamide-loaded solid lipid nanoparticles (AZM-loaded SLNs) using central composite design (CCD) for prolonged ocular delivery. The emulsion solvent evaporation process was used to develop AZM-loaded SLNs. The optimal formulation parameters influencing particle size, entrapment efficiency, and percentage drug release were determined using a CCD, and the effects of these variables on the formulation were examined. Furthermore, the particle size, entrapment effectiveness, and in-vitro drug release were carried out, along with FTIR, XRD, DSC, SEM, and TEM, which were used to determine structural and physicochemical properties. The ex-vivo corneal permeability investigations were used to assess drug penetration, and in-vivo experiments in rabbit eyes were conducted to assess the impact on reducing intraocular pressure. Moreover, hemocompatibility, sterility, and eye irritation were also used to evaluate the formulation's safety features. The optimized AZM-loaded SLNs had a drug entrapment efficiency of 89.45
The increasing demand for oral liquid formulations (OLFs), highlights the need to optimize pharmacotherapy in pediatric and geriatric populations, where swallowing difficulties and dose individualization are critical. One such drug is bisoprolol, a highly selective β1-adrenergic receptor blocker widely used in the management of cardiovascular diseases, for which individualized dose titration is frequently required, particularly in pediatric and geriatric patients. Conventional solid dosage forms often lack the flexibility required, potentially compromising adherence and increasing the risk of medication errors. This study aimed to develop safe, stable, and palatable OLFs of bisoprolol fumarate suitable for individualized dosing. A Quality by Design (QbD)-oriented approach was employed to define the Quality Target Product Profile (QTPP) and identify Critical Quality Attributes (CQAs), including drug content, pH, and organoleptic properties. Two sets of formulations were prepared: sugar-free drops and syrups, each at two strengths (2.5 and 5.0 mg mL−1). Physical, chemical, and microbiological stability were assessed over 12 months under long-term (4 °C and 25 °C) and 6 months under accelerated conditions (40 °C), using a validated methodology. All formulations remained within predefined specifications, showing no significant degradation or physicochemical changes. Microbiological quality and palatability were maintained throughout the study. These findings demonstrate that the strategy based on QbD principles enables the development of robust, patient-centric OLFs, representing a reliable alternative to extemporaneous preparations and supporting safer, more flexible cardiovascular therapy.
Bilayer fixed-dose combination tablets are increasingly used to improve adherence and tailor drug-release profiles, but their development remains challenging because multiple interacting formulation and process variables strongly affect product performance. Quality by Design (QbD) offers a systematic framework to address these challenges, yet its implementation for bilayer tablets and associated analytical methods remains fragmented. In this review we map and critically analyze published applications of QbD to the formulation design, manufacturing process, and testing of bilayer tablets. Using the available literature and regulatory guidance, we summarize the rationale for bilayer formulations, the experimental designs employed, the RA tools used, and the main critical material attributes (CMAs), critical process parameters (CPPs), and critical quality attributes (CQAs) identified. Particular emphasis is placed on the use of design of experiments, process analytical technology, and multivariate data analysis to understand and control mechanical properties, interfacial adhesion, and drug-release behavior, as well as on the current status of analytical QbD for bilayer products. Overall, the evidence shows that QbD has improved control of drug release and interfacial strength and supported the scale-up of bilayer manufacturing, but prior risk analysis, robust control strategies, and Analytical Quality by Design (AQbD)-based dissolution and stability methods are still inconsistently implemented. The concepts and design principles summarized here are expected to support more rational, regulatory-aligned development of bilayer tablets and to guide future QbD applications in this field.
Antibody–Drug Conjugates (ADCs) have become well-established as an important class of oncology therapeutics with 15 FDA-approved ADCs for various cancer types and hundreds more ADCs in clinical development. This chapter highlights the unique regulatory considerations for the development of ADCs in oncology given their dual nature as biologics and small-molecule drugs. Topics covered include the organization of applications in eCTD format, meeting types with FDA, and key considerations for a successful regulatory application with a particular emphasis on the Chemistry, Manufacturing, and Controls (CMC)-related strategy. Regulatory pathways, such as Fast Track and Breakthrough Therapy, are discussed as options to expedite ADC development. In early development, both the antibody and the cytotoxic linker-payload must meet detailed CMC requirements to ensure patient safety. The transition from a Phase 1–enabling process to a validated, commercial-scale manufacturing process for a biologic involves a complex interplay of science, engineering, and regulatory compliance. This transition is often on the critical path, particularly as many novel biologic therapies receive Fast Track and/or Breakthrough Therapy Designation. This paper outlines the critical steps in process development and scale-up, highlighting common gaps encountered when moving from an early-stage process with limited manufacturing experience to a fully validated commercial process. By providing a comprehensive overview of the required regulatory deliverables and a roadmap for sequencing key workstreams, this paper aims to guide readers through the essential steps and potential pitfalls in advancing a biologic therapy from early clinical development to market launch.
The increasing biological complexity and heterogeneity of cancer have driven a shift in oncology drug discovery from single-target approaches toward system-level strategies capable of capturing multilayered disease regulation. Multi-omics technologies, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, and microbiomics, have emerged as powerful tools for elucidating cancer-driving mechanisms, identifying therapeutic targets, and enabling biomarker-guided drug development. This review examines how integrative multi-omics approaches support cancer drug discovery and therapeutic targeting, focusing on target identification, pathway elucidation, target validation, biomarker discovery, and therapeutic development. Genomics and transcriptomics facilitate the identification of driver alterations and dysregulated signaling pathways, whereas proteomics and metabolomics provide functional insights into protein activity, metabolic reprogramming, and treatment response. We further highlight the contributions of epigenomic and microbiomic profiling to biomarker discovery, therapeutic response prediction, and precision oncology. Given the complexity of multi-omics datasets, the review also explores the application of artificial intelligence (AI) and machine-learning methodologies for data integration, network modeling, biomarker discovery, and drug repurposing, including deep learning, Bayesian frameworks, graph-based models, and explainable AI approaches. Emerging computational frameworks and integration strategies that enable interpretation of heterogeneous molecular datasets and support therapeutic discovery are also discussed. Cancer-focused examples demonstrate how integrative multi-omics frameworks have enabled the identification of clinically relevant biomarkers, therapeutic targets, and rational combination therapies. Furthermore, the clinical translation of biomarker-driven precision oncology, exemplified by HER2-, EGFR-, and MSI-directed therapies, highlights the growing impact of omics-informed approaches on personalized cancer treatment. Overall, AI-enabled multi-omics approaches hold substantial promise for accelerating cancer drug discovery and precision oncology.
Rosacea is an inflammatory skin disorder that significantly impairs patients’ quality of life. Azelaic acid (AZA), a well-established keratolytic and anti-inflammatory agent; however, its clinical application is often limited by local adverse effects that reduce patient adherence. In this context, nanotechnology-based drug delivery systems, particularly polymeric nanocapsules, represent a promising strategy to improve physicochemical stability, reduce cutaneous irritation, and enable incorporation into semi-solid formulations with enhanced skin interaction. This study aimed to develop and characterize AZA-loaded polymeric nanocapsules incorporated into tragacanth gum–based hydrogels as a safe, effective, and patient-friendly therapeutic alternative for rosacea. The nanocapsules exhibited a uniform nanometric size (185.66 ± 2.08 nm), low polydispersity index (0.12 ± 0.02), slightly negative zeta potential (− 8.67 ± 0.26 mV), and a skin-compatible acidic pH (3.56 ± 0.16). Drug loading reached 0.53 mg/mL, with an encapsulation efficiency of 42.20
The U.S. FDA currently recommends avoiding carbomer grades that contain benzene and recommends benzene-free alternatives (USFDA. Guidance for Industry: reformulating drug products that contain carbomers manufactured with benzene. Center for Drug Evaluation and Research (CDER), Pharmaceutical Quality/CMC. Published in December 2023. Available at: https://www.fda.gov/media/175083/download ). This means that if a finished product is authorized with a carbomer grade containing benzene, it needs to be replaced with a non-benzene carbomer grade. Such an update would also require detailed comparative studies-covering structure, performance, stability, and biological equivalence-to confirm consistent product quality and effectiveness. The current study attempted to replace Carbomer 940 (C940) with Carbomer 980 (C980) in 0.75% Metronidazole Gel. The two carbomer grades were characterized as powders using multiple spectroscopic techniques. A method for analyzing carboxylic acid content was developed and validated, using light-scattering resonance technology to improve accuracy. The formulation prepared with C940 and C980 was characterized for rheology, in vitro release and permeation, and stability, along with the reference formulation. Powder characterization shows slight differences in the absorption spectra across NMR and FTIR studies, while NIR spectra are the same. Additionally, C980 has a slightly higher molecular weight, degree of polymerization, apparent viscosity, and carboxylic acid content, but a lower water loss. The formulations prepared with C940 and C980 are rheologically equivalent to the reference formulation as assessed by flow curves, yield stress, linear viscoelasticity, and creep. The in vitro release and permeation study also demonstrates that the formulations prepared with C940 and C980 exhibit performance equivalence to the innovator formulation under the tested conditions. Hence, replacing the benzene-grade carbomer with the corresponding non-benzene-grade carbomer does not significantly affect product performance relative to the reference product.
The U.S. FDA currently recommends avoiding carbomer grades that contain benzene and recommends benzene-free alternatives (USFDA. Guidance for Industry: reformulating drug products that contain carbomers manufactured with benzene. Center for Drug Evaluation and Research (CDER), Pharmaceutical Quality/CMC. Published in December 2023. Available at: https://www.fda.gov/media/175083/download ). This means that if a finished product is authorized with a carbomer grade containing benzene, it needs to be replaced with a non-benzene carbomer grade. Such an update would also require detailed comparative studies—covering structure, performance, stability, and biological equivalence—to confirm consistent product quality and effectiveness. The current study attempted to replace Carbomer 940 (C940) with Carbomer 980 (C980) in 0.75
