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
Effective diabetes management necessitates innovative strategies that simultaneously stimulate β-cell growth and prevent apoptosis. While sitagliptin is an established therapeutic, its clinical utility is often hampered by suboptimal oral bioavailability and a lack of site-specific delivery. This research details the development and in vitro assessment of Sita-Ex-Cs-SeNPs, a subcutaneous nanocarrier composed of sitagliptin-loaded chitosan-selenium nanoparticles conjugated with exenatide. The platform is engineered to leverage GLP-1 receptor affinity for pancreatic targeting and utilize selenium’s intrinsic antioxidant properties to achieve therapeutic synergy. We employed the ionotropic gelation technique to encapsulate sitagliptin and integrate exenatide and selenium into a unified, stable delivery system. The resulting nanoparticles exhibited a spherical architecture with an average diameter of 314.1 nm and a zeta potential of + 18.7 mV. We achieved a high encapsulation efficiency of 98
Glucagon-like peptide-1 agonists, especially Semaglutide (SMG), have revolutionized the management of diabetes and obesity, yet its clinical application is hindered by challenges in oral bioavailability and patient adherence to injectable formulations. Transdermal delivery offers a promising alternative, and this study explores dissolving microneedle (DMN) technology for SMG administration. PETOX is a water-soluble polymer utilized for the fabrication of dissolving microneedles and unique stabilization of SMG by incorporating L-arginine. Our study presents the first comprehensive investigation of L-arginine as an excipient in dissolving microneedles to enhance peptide integrity and stability. This study focuses on the development and characterization of DMN arrays formulated with a polymeric blend of hyaluronic acid, PETOX, and L-arginine, designed for the transdermal delivery of SMG. The SMG loaded microneedles (SMG-DMNs) exhibit robust mechanical strength (3.47 N/needle; fracture force), excellent Parafilm M® insertion (> 50
Metformin, a BCS Class III drug, is limited by poor intestinal permeability despite high solubility, affecting its bioavailability. This study aimed to enhance Metformin’s permeability via cocrystallization with functional coformers. L-Cysteine was selected based on ΔpKa criteria and presence of thiol (-SH) group, known to interact with epithelial tight junctions and enhancepermeability. Cocrystals were prepared using solvent evaporation at various drug-to-coformer ratios. 1:2 Metformin–Cysteine cocrystal showed improved dissolution and strong hydrogen bonding interactions confirmed by DSC and FTIR, with PXRD indicating new crystalline phases. In vitro dissolution rates of Metformin and its cocrystals were similar; however, ex vivo experiments demonstrated a 5.9 -fold increase in permeability with the Metformin–Cysteine cocrystal. In vivo pharmacokinetic studies in Wistar rats revealed a Tmax of 1 h, Cmax of 17.64 µg/mL, and AUC0–∞ of 118.86 µg h/mL, significantly higher than pure Metformin. These findings indicate that cocrystallization with L-Cysteine effectively enhances Metformin’s permeability and bioavailability. The thiol group in cysteine likely modulates intestinal barrier function, facilitating absorption. This study highlights the potential of functional coformers in overcoming permeability challenges in BCS Class III drugs and supports further development of Metformin–Cysteine cocrystals as improved oral formulations.
The urgent need for innovative cancer therapies has driven increasing interest in repurposing drugs originally developed for non-oncological diseases. Several FDA-approved and clinically investigated agents, including mesalamine, celecoxib, gliclazide, metformin, itraconazole, and doxycycline, have shown anticancer potential through diverse mechanisms. However, despite their therapeutic potential, many of these drugs suffer from limited tumor selectivity, suboptimal bioavailability, and off-target toxicity when used in oncology. Nanocarrier-based delivery systems offer a promising strategy to address these limitations by improving drug solubility, enhancing tumor accumulation, and enabling more selective delivery to cancer cells and the tumor microenvironment. In this context, nanocarriers not only serve as delivery vehicles but also provide opportunities for controlled release, combination therapy, and stimulus-responsive treatment strategies. This review summarizes recent progress in repurposing non-oncologic drugs for cancer therapy with a particular focus on nanocarrier-enabled delivery approaches. We discuss the molecular mechanisms underlying the anticancer activity of repurposed drugs, as well as their targeting of tumor cells, the tumor microenvironment, and cancer stem cells. In addition, we highlight advances in integrating these agents into nanocarrier platforms for combination therapy, photodynamic therapy, dual-drug delivery, and stimuli-responsive systems. Finally, we address translational challenges, including regulatory and intellectual property considerations, and discuss future perspectives involving artificial intelligence and personalized medicine to accelerate clinical implementation.
To improve the performance of pressurized metered dose inhalers (pMDIs) a better mechanistic understanding of early deposition within the device and upper airways is needed to move toward more efficient inhalation therapies. The present work aimed to address the longstanding gap between plume geometry (PG) measurements and pulmonary drug delivery by evaluating PG with the Plume Induction Port Evaluator (PIPE), a mass-based method that characterizes plume angles under flow and within a restricted geometry. Three Rhodamine B solution pMDI formulations containing 2.49, 9.99, and 19.99
The adsorption behavior of recombinant human growth hormone (r-hGH) on cationic (PS+, amidine) and anionic (PS−, sulfate) polystyrene surfaces was investigated under varying solution pH conditions (surface charge), ionic strengths (0.0075 M and 0.075 M), and solvent dielectric constants to elucidate the adsorption mechanism governed by physicochemical interactions. In addition, desorption upon dilution was also examined. The studies utilized 125I-labeled r-hGH and demonstrated that adsorption of r-hGH onto both PS⁺ and PS⁻ surfaces was influenced by solution conditions, ionic strength, and solvent dielectric constant. Marked electrostatic repulsion accompanied by decreased adsorption was observed on PS⁺ surfaces at pH 2.5 and on PS⁻ surfaces at pH 7.2. Adsorption was highest near the isoelectric point of r-hGH but decreased with increasing ionic strength. PS⁺ and PS⁻ surfaces showed significantly different adsorption profiles, resulting from the combined effects of hydrophobic and electrostatic interactions involving r-hGH, the change in r-hGH confirmation in solution, and the structural characteristics of the surface adsorbed protein. Studies were also carried out to assess the effect of the presence of proteins and surfactants at an ionic strength of 0.0075 M over a pH range of 2.5–7.2. Under conditions where both proteins inhibited adsorption, β-casein exhibited a greater inhibitory effect than BSA. Surfactants exhibited concentration dependent effects, with Tween 20 producing stronger inhibition than Pluronic F-68. Overall, these results demonstrate that r-hGH adsorption onto charged polystyrene surfaces is influenced by a complex interplay of charged interactions, hydrophobic effects, competitive adsorption, surfactant effects, and protein conformational stability.
Hesperetin and cannabidiol (CBD) are promising plant-derived bioactives whose oral performance is limited by poor aqueous solubility. To address the shared biopharmaceutical limitations of both compounds, amorphous PVP K30–phosphatidylcholine dispersions were prepared via hot-melt extrusion (HME). A Box–Behnken design (DoE) was applied to investigate the impact of (i) total API load (hesperetin:CBD mass ratio 1:1), (ii) phospholipid content in the carrier, and (iii) extrusion temperature on the solubility of both actives. The resulting extrudates were characterized by XRPD, DSC, and FT-IR/ATR. Solubility and dissolution profiles were evaluated in phosphate buffer (pH 6.8). In vitro passive permeability was assessed using PAMPA GIT model. DoE indicated that API load and phospholipid content were statistically significant factors for solubility of both hesperetin and CBD, whereas extrusion temperature was not significant within the studied range. XRPD confirmed amorphization for all formulations except F6, which contained a minor residual crystalline fraction of hesperetin. DSC revealed single glass-transition events, supporting good miscibility. The best-performing formulation (F7; 15
This study explored the feasibility of combining Raman spectroscopic imaging with data-driven modeling for estimating colchicine release from transdermal patches under in vitro conditions, aiming to reduce the operational complexity and long testing cycle of the conventional paddle-plate method. Ninety representative patch samples were prepared using a Box-Behnken design, with colchicine content, penetration enhancer content, and evaporation time as key variables. Surface Raman imaging data were collected, while reference release profiles were obtained by the paddle-plate method and fitted using the Weibull equation. Based on these data, three models-partial least squares regression, spectra-based convolutional neural network, and image-based convolutional neural network-were developed under curve-fitting-independent and curve-fitting-dependent strategies. Model performance was evaluated using R2, root mean square error, and similarity factors f1 and f2. The curve-fitting-independent strategy showed better predictive performance than the curve-fitting-dependent strategy, and all three models met the commonly used similarity criteria (f1 < 15 and f2 > 50). The lower performance of the curve-fitting-dependent strategy was mainly related to scale differences among the release-equation parameters. Green analysis further indicated that the proposed method reduced solvent consumption, waste generation, and energy use compared with conventional testing. Overall, Raman spectroscopic imaging combined with data-driven modeling provides a non-destructive, greener, and relatively rapid approach for in vitro release prediction and quality evaluation of transdermal patches.
Direct compression is a generally preferred for tablet manufacturing method. However, it demands excipients with balanced flowability, compressibility, and packing properties. Microcrystalline cellulose (MCC) and calcium sulphate (CaSO₄) have balancing functionalities but individual limitations. To develop and optimize a novel MCC–CaSO₄ co-processed excipient (MCCASUL) for direct compression application using the SeDeM Expert System. To determine critical material attributes (CMA),12 SeDeM parameters were used to categorised MCC and CaSO₄. Functional indices, Parametric Profile Index (IPP), and Good Compression Index (IGC) were also calculated. To overcome the compressibility deficiency of CaSO₄ the required proportion of MCC was determined using SeDeM dilution potential equation. Co-dispersion method was used to prepare 9 MCCASUL batch with varying MCC:CaSO₄ ratios and further evaluated using SeDeM indices. Further characterization by FTIR, DSC, SEM, Heckel, and Kawakita analyses were performed for the optimised batch. MCC was more compressible (ѱc = 7.00) than CaSO₄ (ѱc = 4.67). The theoretical amount of correction for MCC was 14.16
