Amphotericin B (AmB) remains the gold-standard antifungal agent, yet its clinical utility is severely limited by dose-dependent hemolytic and nephrotoxic side effects arising from its aggregation-prone nature and non-selective membrane binding. To address this challenge, we developed a polymer prodrug by conjugating AmB to oxidized chondroitin sulfate (CSox) via a Schiff-base linkage designed to be pH-labile, selected for CS's CD44-targeting capability, intrinsic anti-inflammatory activity, and favorable polyelectrolyte properties. The resulting CSox-AmB conjugate self-assembled into uniform micelles (141.60 ± 4.03 nm, zeta potential -25.47 ± 0.59 mV) with a drug loading of 7.07 ± 0.13%, maintaining AmB predominantly in its monomeric state (A348/A409 = 0.865 < 1). The prodrug exhibited sustained release (∼68% at 24 h) while preserving antifungal activity comparable to free AmB against Candida albicans. Concurrently, it attenuated mammalian cell cytotoxicity by 2.3- to 2.5-fold and markedly attenuated hemolytic activity in vitro (<1% at 25 μg·mL[-1]). This integrated design-conjugation enabling self-assembly, assembly enabling monomeric stabilization, and controlled release enabling efficacy with markedly reduced toxicity-positions CSox-AmB as a promising prodrug strategy that uncouples the antifungal activity of AmB from its inherent toxicities, warranting further in vivo evaluation toward clinical translation.

Tacrolimus is a potent calcineurin inhibitor suitable for the local treatment of oral mucosal immune-mediated diseases; however, no buccal formulation is currently available. The main objective of this work was to develop a mucoadhesive, semi-solid formulation containing tacrolimus that has adequate mucoadhesion salivation, and effective mucosal penetration with low systemic availability. A series of tacrolimus containing semisolid formulations based on chitosan, carbomer and hypromellose (HPMC) as mucoadhesive polymers were developed. Their rheologic behavior, pH value, macroscopic and microscopic properties as well as mucoadhesion and mucosal penetration were investigated. Lactate buffer was successfully used to stabilize chitosan against hydrolysis. It was shown that diols of different chain length, like 1,2-propanediol 1,2-pentanediol and 1,2-hexanediol improved mucosal penetration but reduced mucoadhesion due to gel matrix weakening. After 60 min in the mucoadhesion cell, mucosal tacrolimus amounts versus salivary wash-off for the diols were 0.78 ± 0.09 µg/cm[2] versus 0.47 ± 0.20% for 20% 1,2-propanediol, 1.99 ± 0.23 µg/cm[2] versus 14.26 ± 3.01% for 40% 1,2-propanediol, 3.56 ± 0.29 µg/cm[2] versus 25.04 ± 1.68% for 20% 1,2-pentanediol, and 3.66 ± 0.25 µg/cm[2] versus 28.13 ± 4.00% for 20% 1,2-hexanediol. A series of tacrolimus formulations with different degrees of mucoadhesion, salivary retention and penetration characteristics was successfully developed.

Drug repurposing combined with nanocarrier systems can accelerate cancer therapy development while reducing the time and cost of conventional drug discovery. We developed and optimised hyaluronic acid (HA)-chitosan (CH)-coated mesoporous silica nanoparticles (HA-CH-Prop-MSNPs) for delivery of the repurposed β-blocker propranolol. A two-stage D-optimal design optimised propranolol loading, then CH and HA coating, using particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency (EE). The formulation (0.2% low-molecular-weight CH, 0.07% HA, 2 mg/mL propranolol, 10 mg/mL mesoporous silica nanoparticles) exhibited a particle size of 200.5 nm, PDI of 0.495, zeta potential of -25.7 mV, and EE of 91.2%. HA-CH coating provided controlled release and shifted the mechanism from near-Fickian diffusion toward an increasing contribution from polymer relaxation-controlled transport. Propranolol release was significantly higher at tumour-mimicking pH 5.5 than at physiological pH 7.4 across all formulations. Compared with free propranolol, HA-CH-Prop-MSNPs reduced the IC50 against MCF-7 breast cancer cells 2.8-fold while maintaining negligible carrier cytotoxicity. Under accelerated storage conditions (40 °C/75% RH), the formulation remained stable for six months, with less than a 2% reduction in EE. These findings provide proof of concept that HA-CH-coated mesoporous silica nanoparticles enhance the in vitro anticancer activity of repurposed propranolol through encapsulation and controlled release, laying the foundation for future investigation of HA-mediated cellular targeting.

Poor aqueous solubility remains a major barrier in drug development, affecting approximately 40% of marketed drugs, up to 75% of drugs under development, and nearly 90% of new chemical entities. To overcome this limitation, solid modification of active pharmaceutical ingredients (APIs) emerged as a strategy to enhance drug physicochemical properties, particularly for Biopharmaceutics Classification System (BCS) II and IV drugs. This review systematically analyzes recent advancements in solid modification techniques, including salt formation, cocrystallization, polymorphs, solvate and hydrate forms, amorphous and co-amorphous systems, inclusion complexes, and nanocrystallization. A systematic literature search spanning 2020-2025 was conducted using PubMed and ScienceDirect databases, focusing on studies that improve the physicochemical properties of the APIs. By categorizing APIs, matrices, and methods of each study, this review shows the most frequently used techniques and their matrices, advantages, and limitations of each modification, providing insights for optimizing drug performance and future research in pharmaceutical development. Among the various approaches reviewed, cocrystals, amorphous systems, nanocrystals, and inclusion complexes emerged as the most frequently used techniques. Amorphous systems and inclusion complexes offer the highest median solubility enhancements by maximizing kinetic supersaturation or equilibrium solubility, respectively, while nanocrystals efficiently improve equilibrium solubility via particle size reduction, and cocrystals provide reliable, moderate gains with superior long-term thermodynamic stability.

Microneedle (MN) technology has emerged as a promising minimally invasive platform for transdermal drug delivery, enabling efficient transport of therapeutic agents across the stratum corneum while improving patient compliance. In recent years, natural biodegradable polymers have gained increasing attention in microneedle fabrication due to their biocompatibility, biodegradability, and functional versatility. This review provides a comprehensive overview of recent advances in natural polymer-based microneedle systems, including material selection, fabrication strategies, and mechanisms of controlled drug release. Importantly, beyond conventional descriptive analysis, this work introduces a rational design framework that systematically integrates therapeutic objectives, polymer properties, mechanical performance, and release kinetics to guide the development of optimized microneedle platforms. The review further addresses key translational challenges, including mechanical limitations, manufacturing scalability, stability concerns, and regulatory considerations. In addition, emerging trends such as stimuli-responsive systems, nanocarrier integration, and personalized drug delivery approaches are discussed. Notably, data-driven strategies, including artificial intelligence (AI) and machine learning, are highlighted as promising tools for predicting system performance, optimizing formulation parameters, and accelerating the development of next-generation microneedle-based drug delivery systems. Overall, this work shifts the paradigm from empirical formulation toward a predictive, engineering-driven design strategy, offering valuable insights to advance the clinical translation of smart microneedle technologies.

Nanostructured lipid carriers (NLCs) are diverse colloidal systems that enhance the solubility, stability, and bioavailability of bioactive compounds. Herein, we developed a co-loaded NLC encapsulating thymoquinone (TQ) and resveratrol (RV) to enhance prevention against globally emerging endocrine disruptor bisphenol S (BPS) induced cytotoxicity in NRK-52E cells. The formulation components were rationally optimised, achieving high encapsulation efficiencies for TQ (99.42% ± 0.08) and RV (98.60% ± 0.12), a particle size of 123.66 ± 6.32 nm, and a polydispersity index of 0.37 ± 0.04, indicating stable, homogeneous, quasi-spherical particles as observed in TEM. Interfacial encapsulation and reduced crystallinity observed by FTIR and XRD analyses, respectively, supported the formation of an imperfect core-shell structure. The drug-release profile indicated a diffusion-dominated, matrix-relaxation-assisted transport mechanism. In vitro assays demonstrated a strong cytoprotective effect of TQRV-NLCs at 0.01 μg/mL, comparable to 1 μg/mL free drugs, indicating a significant improvement in therapeutic efficacy. TQRV-NLCs markedly reduced BPS-induced oxidative stress, mitochondrial depolarisation, loss of cell migration, and loss of membrane integrity, while restoring membrane integrity, normalising cell cycle distribution, and preserving nuclear morphology in NRK-52E cells. In summary, this study provides proof of concept that TQRV-NLCs markedly enhance efficacy, confer superior cytoprotection, and offer preventive effects, presenting a promising strategy for renal protection against BPS.

Localized drug delivery systems provide an effective approach for achieving sustained drug release and prolonged drug retention at the target site while minimizing systemic exposure. In this study, physically crosslinked poly(vinyl alcohol)/tannic acid/quercetin (PVA/TA/Que) (PTQ) hydrogels were developed through hydrogen-bond-mediated self-assembly without chemical crosslinkers. The effect of TA concentration on hydrogel formation, structural properties, thermal stability, swelling, degradation, and release behavior was systematically investigated. Increasing TA concentration accelerated gelation, increased gel content, and produced denser hydrogel networks with lower porosity, reduced water uptake, slower degradation, and improved thermal stability. FT-IR and XRD analysis confirmed hydrogen-bond interactions between PVA and TA and reduced polymer crystallinity. PT50 exhibited the most favorable physicochemical properties and was selected for further evaluation. TA encapsulation efficiency exceeded 93%. In vitro studies demonstrated sustained and pH-responsive TA release, with only 27.39 ± 1.14% released over 312 h at pH 7.4, while Que showed a faster release profile. Hemocompatibility assays revealed hemolysis values below 2%, and hematological, biochemical, and histopathological analysis following subcutaneous implantation in rats showed no detectable systemic toxicity. Overall, the PTQ hydrogels demonstrated favorable physicochemical properties, controlled release behavior, excellent hemocompatibility, and good in vivo biosafety, indicating their potential for localized delivery of bioactive agents.

Posterior segment disorders remain challenging to manage due to limitations in ocular drug delivery. Although intravitreal triamcinolone acetonide (TA) is effective, it requires repeated administration, highlighting the need for sustained-release systems. This study aimed to develop in situ sustained-release formulations of TA using lipid liquid crystals (LLCs). Formulations were prepared with glyceryldioleate (GDO), phosphatidylcholine (PC), and N-methyl pyrrolidone (NMP) at PC:GDO ratios of 50:50, 40:60, and 60:40. A TA-hydroxypropyl-β-cyclodextrin (HPβCD) complex was also prepared. The formulations were characterized for rheological properties, morphology, degradation, and water uptake. In-vitro release was assessed in phosphate-buffered saline (pH 7.4), while in-vivo pharmacokinetics were evaluated in rabbits, comparing a selected LLC formulation with a TA suspension. The F5 formulation (40:60 PC: GDO) achieved sustained release of 35.4% over one month and exhibited superior stability, with 24.9% less degradation compared to F6, which showed undesirable drug crystallization. The TA-HPβCD complex demonstrated an even slower release (28%). F4 (50:50 PC: GDO) was selected as the optimized formulation, demonstrating the lowest water absorption and degradation with a consistent release profile. In-vivo studies confirmed that LLCs provided more controlled and prolonged release compared with conventional TA suspension. In conclusion, LLC-based TA formulations offer a promising strategy for sustained intravitreal drug delivery, with biodegradability, ease of preparation, and prolonged therapeutic levels.

The present work describes the development and optimization of a poly (lactide-co-glycolide) based sustained release injectable microsphere formulation of exenatide using a coacervation and in oil drying process. The internal phase composition, containing exenatide and stabilizer, was evaluated to identify critical parameters affecting stability, drug loading, particle morphology, and burst release of exenatide. Incorporation of chondroitin sulfate(0.5-2% w/w), formed stable uniform coacervates providing consistent particle size distribution, drug loading up to 4.7% w/w, initial burst (∼1.1%) and impurities, with 'shrunken' microsphere morphology. The secondary emulsification temperature of 2-8 °C produced smaller and more uniform particles. A gradient quenching process for hardening of microspheres using n-heptane: diethyl ether (1:9) to (10:0) provided low porosity and burst release relative to n-heptane alone. The drying and lyophilization conditions reduced residual solvent levels (<5000 ppm or below quantitation) and improved its wetting characteristics. The formulation remained stable for 24 months at 2-8 °C, with minimal loss of assay content. In vitro release showed controlled release for over one month. This translated into approximately 28 days of drug exposure in rat pharmacokinetic studies and sustained glycemic control for 28 days in a db/db mice, thus, correlating microsphere erosion, in vitro release, and in vivo outcomes. This study provides insight into the manufacturing process dynamics.

In this study, PEGylated liposomes (PEG-Lip) were combined with polysaccharides to sustain their oral absorption-enhancing effect. PEG-Lip was prepared by the thin-film hydration method and mixed with carrageenan (CGN), xanthan gum (XG), or locust bean gum (LBG). The prepared PEG-Lip had a particle size of ∼100 nm and a zeta potential of approximately -50 mV. The polysaccharide concentrations that did not inhibit PEG-Lip behavior were 0.5% for CGN and 0.25% for XG and XG-LBG mixtures. At 25 °C, the release of PEG-Lip from each polysaccharide was generally consistent with its diffusion within the polysaccharide. In the rheological evaluation, only XG3-LBG7, a 3:7 mixture of XG and LBG, exhibited gel-like behavior, whereas the other formulations functioned as viscosity modifiers. Oral administration in rats showed improved gastrointestinal retention compared with PEG-Lip alone. Furthermore, XG3-LBG7 provided the greatest improvement in the oral absorption of FITC-dextran (FD4). These findings suggest that optimizing both PEG-Lip release and the rheological properties of polysaccharides is important for improving oral absorption.

Soft gelatin capsules (softgels) are among the most commercially significant oral dosage forms, offering hermetic liquid and semi-solid encapsulation with superior bioavailability. Central to their manufacture is the rotary die encapsulation process, in which precision die rolls simultaneously form, fill, and seal capsules from two gelatin ribbons. Despite its critical role in determining seam integrity, leakage resistance, and efficiency, a comprehensive peer-reviewed analysis of die roll design classifications has not been published previously. This review analyses seven principal designs: single-step (uni-lip), double-step (bi-lip), D-Step Outer (DS-O), D-Step Inner (DS-I), triple-step (tri-lip), Max Offset Seal (MOS), and blasted surface. For each design, the mechanistic basis, application domain, advantages, limitations, and quality implications are examined. Special attention is given to the MOS architecture for trailing-edge seam asymmetry in suspension fills, the DS-I configuration for moisture-sensitive active pharmaceutical ingredients, and the glass bead-blasted surface for universal pinhole leakage mitigation. A global survey of encapsulation machine and die roll manufacturers-including Changsung, Technophar, Schaefer Technologies, United Pharmatek, Joysun, SEC Softgel, Hedagel, SKY Softgel, CapPlus Technologies, and AIPAK/SaintyCo-is presented (Table 2). Five comparative tables and six annotated figure placeholders cover die roll specifications, process parameters, service life, troubleshooting, and advantages versus limitations. Regulatory considerations under ICH Q8/Q9/Q10, FDA 21 CFR 314.70, and GCC/SFDA frameworks are discussed. Future directions include digital twin simulation, AI-assisted die design, and additive manufacturing tooling. This review serves as an authoritative reference for die roll selection, optimisation, troubleshooting, and regulatory lifecycle management.

The study aimed to develop and optimize chitosan-based mucoadhesive nanomicelles for intranasal delivery of lamotrigine (LTG), to enhance epilepsy treatment, bypass the blood-brain barrier, and potentially improve brain targeting. LTG-loaded nanomicelles were prepared using thin-film hydration and optimized using a central composite design, response surface methodology, and artificial neural networks. The formulation included D-ɑ-tocopheryl polyethylene glycol succinate, Poloxamer 407, chitosan, and glycerol. Critical quality attributes assessed were micelle size (MS), polydispersity index (PDI), Zeta potential (ZP), pH, LTG content, transmittance, in vitro mucoadhesion, LTG release, and 28-day stability. The MS, PDI, ZP, pH, and LTG content of the optimized mucoadhesive nanomicelles was 31.28 ± 0.34 nm, 0.487 ± 0.00, +31.37 ± 1.97 mV, 4.61 ± 0.01, and 2.89 ± 0.01 mg/mL, respectively. The transmittance was 98.50 ± 0.10%, and significant in vitro mucoadhesion, with reduced migration, was observed for mucin-containing gels. LTG release (96.94% at 6 h) followed the Higuchi diffusion model, with sufficient LTG released at 40 min to potentially reach the minimum effective concentration, based on in vitro release data alone. The formulation remained stable for 28 days at 4 °C and 25 °C. Chitosan-based mucoadhesive nanomicelles are a promising intranasal delivery system for LTG, with the potential for brain targeting, controlled LTG release, and improved epilepsy management.

Although therapeutic proteins are susceptible to visible light-induced photooxidation, the underlying mechanisms remain unclear because amino acid residues do not directly absorb light above 400 nm. To evaluate the role of light source characteristics, three monoclonal antibodies formulated in water were exposed to spectrally distinct fluorescent and light-emitting diode (LED) sources, eliminating excipient-related effects. Following exposure to visible light (400-800 nm), degradation was assessed by size-exclusion, Protein A, and ion-exchange chromatography, together with mass spectrometry. The LED spectrum displayed a pronounced emission at 451 nm and a broad band between 480 and 800 nm, whereas the fluorescent lamp exhibited prominent emissions at 436, 545, and 612 nm, with additional blue-light contributions overlapping antibody absorption. Both light sources induced dose- and antibody-dependent photodegradation, characterized by increased high molecular weight species, Fc-oxidation, acidic and basic charge variants, and methionine and tryptophan oxidation, without detectable fragmentation. Monomer content decreased by 1-4 %, Fc-oxidized variants increased by 5-20 %, and the ion-exchange main peak decreased by 2-8 %. LED-induced degradation was less pronounced than that induced by fluorescent light, reflecting reduced short-wavelength emission. These findings support photosensitizer-mediated oxidation at 400-450 nm and highlight the importance of controlling light exposure during bioprocessing.

Smoking cessation remains a therapeutic challenge, and limitations associated with conventional oral varenicline therapy may affect patient adherence. This study aimed to develop and characterize a dissolving microneedle patch co-loaded with varenicline and melatonin for transdermal delivery. Microneedle arrays were fabricated using polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), with Tween-80 incorporated to enhance the solubility of varenicline. The fabricated microneedles were evaluated for their mechanical and surface properties using nanoindentation, scratch testing, and atomic force microscopy. In vitro drug release and transdermal permeation studies were performed, while fluorescence imaging and histological analysis were used to assess microneedle insertion and skin integrity. The microneedles exhibited adequate hardness and flexibility, together with a uniform surface morphology, supporting effective penetration into the skin. Following 48 h of application, cumulative transdermal permeation of varenicline and melatonin reached 34.3% and 41.6%, respectively. The co-loaded microneedle formulation provided sustained release of both drugs over the study period. Histological evaluation confirmed the formation of discrete microchannels following microneedle insertion without significant disruption of the surrounding tissue. Overall, the findings demonstrate the feasibility of a varenicline-melatonin-loaded microneedle patch as a transdermal drug-delivery system for smoking cessation. Further investigation, including comparison with established commercial therapies and ex vivo dissolution and permeation studies, is warranted to establish its translational potential.

Atopic dermatitis (AD) features impaired skin barrier, elevated cutaneous pH, and Staphylococcus aureus overcolonization. Restoring acidic skin pH while suppressing microbial overgrowth represents a promising non-steroidal strategy. To develop a copper-based acidic hydrogel and evaluate its properties, antimicrobial activity, efficacy, and safety. A hydrogel with 0.115% copper ions was prepared from basic copper carbonate, acetic acid (6% w/w), and xanthan gum, formulated at a final pH of ∼3.2, and characterized by rheology and stability testing. Antimicrobial activity was evaluated by a quantitative carrier test against S. aureus, E. coli, and C. albicans. Efficacy was assessed in DNFB-induced AD-like BALB/c mice. Dermal safety was examined in a 14-day study in rabbits. The hydrogel showed gel-like behavior (G' > G″) with 94.6% structural recovery and remained stable over 23 months. It achieved >98% killing of all pathogens within 5 min and >99.6% within 10 min. In mice, treatment dose-dependently reduced ear swelling and dermatitis scores, attenuated epidermal hyperplasia, and decreased mast cell infiltration. In rabbits, only mild, reversible local irritation occurred, without systemic toxicity. This copper-based acidic hydrogel exhibits potent broad-spectrum antimicrobial activity, ameliorates AD-like lesions, and shows a favorable short-term dermal safety profile, supporting further development as a non-steroidal topical option for AD.