Tofacitinib is a potent Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA); however, its clinical application is limited by inherent side effects, a short half-life, and the requirement for frequent dosing. In this study, poly(lactic-co-glycolic acid) (PLGA)-based injectable sustained-release tofacitinib microspheres with distinct in vitro release profiles (High, Medium, and Low) were fabricated via a microreactor-assisted technique. The microspheres were systematically characterized regarding their morphology, particle size, drug loading, encapsulation efficiency, and in vitro drug release. Cytotoxicity and anti-inflammatory activity were evaluated in RAW264.7 macrophage cells. Pharmacokinetic (PK) studies were performed in rats following intramuscular administration, and a preliminary in vitro-in vivo correlation (IVIVC) was established. The therapeutic efficacy of the microspheres was assessed using an adjuvant-induced arthritis (AIA) rat model. The prepared microspheres exhibited a uniform morphology with a mean particle size range of approximately 30-40 μm, encapsulation efficiency exceeding 80%, and sustained in vitro drug release lasting for more than 28 days. In vitro experiments demonstrated that the sustained-release formulations significantly reduced the secretion of interleukin-1β, interleukin-6, and tumor necrosis factor-α in RAW264.7 cells. Notably, the Low-release tofacitinib microspheres (Tofacitinib-Microspheres-Low) showed a more pronounced inhibitory effect at 72 h compared to 24 h (p < 0.001). PK studies revealed that the microspheres significantly prolonged systemic exposure to tofacitinib, with a markedly extended apparent half-life and increased area under the concentration-time curve relative to the conventional tofacitinib suspension. The IVIVC analysis has preliminarily established the predictability of in vivo drug behavior, with Level A IVIVC achieved for both the High- and Low-release formulations. In the AIA rat model, treatment with tofacitinib-loaded microspheres significantly reduced clinical arthritis scores, paw swelling, and inflammatory progression compared to the model group (p < 0.05), while maintaining normal hematological and biochemical parameters. In conclusion, high-molecular-weight 85/15 PLGA (90 kDa) is the optimal polymer grade for lab-scale single-dose injectable tofacitinib microspheres, enabling 42-day long-term anti-RA efficacy with mitigated acute peak drug-related toxicities. This microreactor-produced sustained-release injectable depot provides a mechanistic strategy to reduce administration frequency and improve safety of tofacitinib for RA management.
Press-coated tablets (PCTs) are a modern dosage form designed to circumvent the negative effects of liquid and heat exposure that may damage drug substances during common wet coating processes for tablets. However, the production process is complex and the mechanical properties of the formulations of the different compartments may lead to challenges regarding processability, distribution of properties, and mechanical stability of the PCTs. In this study, materials with markedly different deformation properties were combined to elucidate the stress distribution during press coating and to assess the effects of process parameters and core geometry on the final PCT properties. Thorough structural investigations of all PCT compartments and the in-die analyses of axial and radial stress were applied. The simplistic approach to unify effects on the core properties by relating the punch force only on the projection area of the core only applies to the recovered core diameter and fails for further parameters. It accordingly requires more consideration of the complex stress states. The radial stress analyses clarify the anisotropy within the compression process of PCTs. It explains the findings on the distributions of porosity across different coat compartments and on the compactibilities of the recovered core. Finally, the breaking pattern of PCTs were explained with structural findings and the deduction of acting residual stresses.
Developing directly-compressed formulations remains a resource-intensive task, requiring substantial experimental effort to characterise the compressibility and compactability of a formulation space. This study extends a global optimisation of mixture rules to a ternary formulation space (API-brittle filler-elastic filler) and investigates the potential for reducing experimental burden whilst maintaining the predictive accuracy of empirical compression and compaction models. Three grades each of paracetamol and ibuprofen, combined with a consistent placebo base, were used to evaluate the approach. The global optimisation outperformed the traditional line of best fit approach, achieving strong predictive performance for the Kawakita model (R2>0.94; RMSE<0.01) and more variable fits for the Ryshkewitch-Duckworth model (R2 = 0.93 - 0.95 and RMSE = 0.23 - 0.39 MPa for paracetamol; R2 = 0.70 - 0.83 and RMSE = 0.31 - 0.37 MPa for ibuprofen). The optimisations performance was found to improve when the training dataset considered only drug-loaded blends. The exploration of reducing experimental burden considered a Model-Based Design of Experiments (MBDoE) which was benchmarked against random experiment selection. Integrating MBDoE with optimised mixture rules reduced API consumption by over 30% across all formulations, with median savings of 75%-95% under Acceptable and Good performance thresholds. Savings decreased with increasing threshold stringency, with the greatest variability observed in ibuprofen formulations. The Kawakita model supported reductions across all threshold levels, whilst the Ryshkewitch-Duckworth model showed limited capacity beyond the Acceptable threshold. The MBDoE did not outperform the random selection of experiments, however the optimisation framework for populating empirical compression and compaction models offers a resource-efficient approach to predicting tablet porosity and tensile strength of ternary API loaded blends.
A comparative study was conducted into the fabrication of polycaprolactone (PCL)/carboxymethyl cellulose (CMC) and PCL/CMC-polyvinyl alcohol (PVA) core-shell nanofibres using co-axial electrospinning (ES) and pressurised gyration (PG). Ibuprofen and ibuprofen sodium were used as model drugs. The influence of solution composition and processing parameters on fibre morphology, internal structure, thermal properties, encapsulation efficiency, production rate, yield and drug-release behaviour was evaluated. Uniform nanofibres were obtained for most formulations by both methods, although occasional bead formation was observed in PG-fabricated PCL/CMC fibres. Scanning electron microscopy showed the PG fibres to have larger diameters than those obtained from ES, and transmission electron microscopy and confocal microscopy confirmed well-defined core-shell structures. ES achieved high production yields of 93-98% and good morphological control, whereas PG enabled much higher production rates (ca. 400 mg min-1 cf. 2-3 mg min-1 from ES), indicating scalability despite lower yield (around 50%). Drug-loading studies demonstrated encapsulation efficiencies of 54-109%, with ES giving markedly higher efficiencies than PG. Compared with monolithic fibres, core-shell fibres generally moderated early release, particularly in ES systems, while PG release behaviour was formulation-dependent. From these findings, it is clear that both ES and PG represent viable routes for producing PCL/CMC-based core-shell nanofibres. ES provides superior yield and structural control, while PG offers a significant advantage in production rate. These complementary characteristics, together with favourable drug-encapsulation and release performance, highlight the potential of PCL/CMC-based core-shell nanofibres as versatile and scalable platforms for biomedical drug-delivery applications.
Cancer is still one of the major causes of death globally, and the lack of specificity of current chemotherapeutic and imaging agents still remains to be a major issue in the therapy of cancer, which lead to the lack of efficacy and high systemic toxicity. Magnetic nanoparticles (MNPs) especially Superparamagnetic Iron Oxide Nanoparticles (SPION) and Ultrasmall Superparamagnetic Iron Oxide Nanoparticles (USPION) have shown potential as theranostic platforms due to their magnetic responsiveness, biocompatibility, and multiple functionalities. The advantages of iron oxide-based nanomaterials such as Fe3O4 (magnetite) and maghemite (γ-Fe2O3) are that multiple imaging, targeting, hyperthermia and drug delivery modalities can be integrated into a single material, allowing for improved antitumoral efficacy while reducing off-target toxicity. The recent progress in the synthesis, surface modification of magnetic nanoparticles with biocompatible polymers and targeting ligands, and their physicochemical characterization, for optimization of biological performance, is summarised. Special attention is given to the strategies for targeted and controlled delivery such as magnetic field guided localization, stimuli responsive drug release, ligand mediated targeting, and multifunctional nanocarrier design. Additionally, recent advances in magnetic resonance imaging (MRI), image-guided therapy, multimodal therapy and clinically relevant theranostic applications are critically discussed. Current challenges in translation are also discussed, such as scale-up, long-term safety, regulatory aspects and clinical translation. In conclusion, the magnetic nanoplatforms based on SPIONs and USPIONs are a very promising approach to precision oncology, combining diagnostic, therapeutic and monitoring functions in a single nanoplatform, which will facilitate the translation of magnetic nanomedicine toward personalized cancer treatment.
Non-melanoma skin cancer is one of the most frequent tumors, ranking as the fifth most common cancer. Photodynamic therapy is a noninvasive therapeutic option that involves the topical application of photosensitizers. In this context, curcumin, a polyphenolic compound extracted from Curcuma longa L., emerges as a safe alternative because of its potential phototoxic activity; however, it presents limitations such as poor skin penetration upon topical application and photodegradation. Among the promising strategies, the development of lipid nanoparticles, which are biocompatible and versatile systems, is noteworthy. In the present study, three curcumin lipid nanoparticles (LNPs) were developed and characterized, containing oleic acid, super refined castor oil, Phosal 50SA®, and Phosal 50PG® in PBS buffer, with 1.5% Poloxamer 407. The formation of these liquid crystalline phases was investigated. The LNPs exhibited mean particle sizes of 176 ± 6 nm(A1Cur), 169 ± 9 nm(C2Cur), 189 ± 19 nm(H3Cur), with corresponding PDIs of 0.133 ± 0.034; 0.226 ± 0.022 and 0.196 ± 0.009, and zeta potentials of -33 ± 1 mV; -26 ± 2 mV; -24 ± 2 mV for A1Cur, C2Cur and H3Cur, respectively. The encapsulation efficiency (EE%) was 89 ± 5% for A1Cur, 84 ± 6% for C2Cur, and 69 ± 6% for H3Cur, respectively. Small angle X-ray scattering (SAXS) revealed that only A1Cur exhibited a hexagonal liquid-crystalline phase morphology. In terms of in vitro skin penetration, A1Cur, C2Cur, and free curcumin exhibited transdermal effects, while H3Cur demonstrated greater topical potential. In ROS photogeneration assays, photoproduction was detected, particularly for LNP H3Cur. In vitro 24-hour cytotoxicity and phototoxicity against the A431 tumor cell line demonstrated that the cytotoxic and phototoxic effects were enhanced by the LNPs compared to free curcumin, especially for A1Cur. The liquid crystalline nanodispersions A1 and A1Cur were selected for incorporation into the dissolving microneedle systems, exhibiting good insertion capability and mechanical resistance to pressure. The LNPs demonstrated skin penetration potential and enhanced phototoxic and cytotoxic effects on a non-melanoma skin carcinoma cell line compared to free curcumin, highlighting the potential of these nanosystems as drug delivery vehicles for the treatment of non-melanoma cancer.
The importance of biologics has increased over the last few decades. Since proteins in liquid formulations tend to form protein particles in response to external stress factors, surfactants are added to prevent this. Currently, polysorbates (PSs) 20 and 80 are mainly used for this purpose. However, alternatives are being investigated, as PSs have stability issues, primarily due to oxidative or enzymatic degradation. The alternative that is discussed most frequently and already used in commercial biologics is poloxamer 188 (P188). However, this triblock copolymer, which consists of a polyoxypropylene block flanked by polyoxyethylene units, may also degrade through oxidative processes. Surprisingly, there are no direct comparative stability studies for PSs and P188. Therefore, the present study compared the oxidative degradation profiles of PS20 and PS80 with those of P188 in various relevant buffer systems. To this end, the formulations were subjected to stress in the form of 50 ppb (approximately 0.9 µM) of Fe2+ and light in the visible range, in line with their exposure during pharmaceutical production. Samples that received neither an iron spike nor light served as controls. The solutions contained 0.4 mg∙mL-1 PS20, PS80, or P188, respectively. The surfactants were formulated in either a 25 mM acetate, citrate, or histidine buffer solution (all pH 5.5) or in pure water. Significant differences were observed between these buffers, with greater effects at higher temperatures. The stability of the surfactant depended greatly on the buffer and the applied stress. All surfactants exhibited high rates of oxidative degradation when formulated in acetate buffer or pure water. PSs demonstrated the highest overall stability in citrate buffer, while P188 remained most stable in histidine, as well as in citrate buffer. However, both PSs exhibited instability in the presence of iron and light in histidine buffer, a phenomenon not observed in P188.
The development of long-acting injectable (LAI) formulations with precise control over drug release and high batch-to-batch reproducibility remains a major challenge, primarily due to limited control over particle formation dynamics and internal microstructure. Here, we integrate droplet microfluidics with newly synthesized poly(lactic acid)-poloxamer-poly(lactic acid) (PLA_PLU_PLA) triblock copolymers (having 0.05 to 0.2 wt% PLU) to engineer drug-loaded microparticles (MPs) with controlled interfacial assembly and phase behaviour. This approach enabled the reproducible fabrication of highly monodisperse MPs (coefficient of variation for MPs' size was below 10%) with tuneable size and morphology. MPs with diameters ranging from 34.8 ± 0.9 to 44.4 ± 1.6 μm were produced, while systematic variation of PLU content enabled precise modulation of surface architecture, producing golf-ball-like dimples and reduced porosity at higher and lower PLU content, respectively. This transition suggests PLU-dependent modulation of interfacial tension and phase segregation during solvent extraction, governing surface characteristics. Enzymatic degradation studies revealed a non-linear dependence on composition, with 0.1 wt% PLU MPs exhibiting the slowest degradation (10.7 ± 1.5% weight loss at 20 days), indicating a balance between hydrophilicity-driven water uptake and reduced matrix accessibility. Using paliperidone palmitate as a model active pharmaceutical ingredient, MPs with intermediate PLU content showed the most prolonged release profile (∼ 42% over 14 days), with phenomenological release modelling suggesting a balance between diffusional transport and matrix erosion governed by composition-dependent characteristic. Drug loading and encapsulation efficiency (11.8-16.5% and 68.0-88.0%, respectively) were composition-dependent, reflecting altered API-copolymer partitioning. Collectively, these findings establish the use of droplet microfluidics combined with rational PLA/PLU triblock copolymer design as a powerful and versatile platform for engineering next-generation depot formulations with tuneable MPs' morphology, degradation, and drug release performance.
Glipizide (GPZ), a biopharmaceutics classification system Class II antidiabetic drug with low aqueous solubility and a high melting point, presents challenges for fused deposition modeling (FDM) 3D printing due to the elevated processing temperatures commonly required. This study investigated low-temperature hot-melt extrusion (HME) and FDM 3D printing for the fabrication of personalized immediate-release GPZ tablets using vinylpyrrolidone-vinyl acetate copolymer (KVA64)-based filaments. GPZ-loaded filaments containing KVA64, mannitol (MAN), and triethyl citrate (TEC) were successfully prepared at 60 °C and printed at 90 °C. Among six formulations investigated, the filament composed of 12% w/w GPZ, 69% w/w KVA64, 10% w/w MAN, and 9% w/w TEC exhibited suitable flexibility, feedability, and moisture resistance. DSC, PXRD, and TGA findings were consistent with a partially amorphous GPZ dispersion containing residual crystalline domains, with no detectable thermal degradation under the processing conditions. A mixed-level factorial design was used to investigate the effects of infill pattern, number of shells, and layer thickness on GPZ release at 10 min. After Bonferroni adjustment for multiple comparisons, infill pattern, number of shells, and the infill pattern × layer thickness interaction remained statistically significant, whereas the main effect of layer thickness did not. Grid infill and fewer shells generally promoted faster drug release, while the effect of layer thickness depended on the infill architecture. Dose-adjusted tablets containing 5, 7.5, 10, and 15 mg GPZ were produced by modifying tablet thickness while maintaining a constant diameter. Thinner tablets exhibited faster dissolution because of their higher surface area-to-volume ratios. However, the 15 mg tablet did not meet the immediate-release dissolution criterion at 30 min, indicating that height-based scaling alone is insufficient for maintaining immediate-release performance at higher doses. These findings demonstrate the potential of low-temperature HME-FDM printing for personalized GPZ tablets while emphasizing the need to optimize both tablet geometry and internal architecture across the intended dose range.
The permeation enhancers (PEs) sodium salcaprozate (SNAC) and sodium decanoate (C10) are reported to enhance gastric and intestinal absorption of different macromolecules. While previous preclinical and clinical studies report effects of these PEs, no head-to-head comparison between their effect in different dosage forms administered by oral gavage in rats is reported. For that purpose, we developed mini-tablets containing octreotide and SNAC or C10 as the PE. The disintegration behavior of the mini-tablets was evaluated using biorelevant liquid volumes of 0.1-0.5 mL in different experimental setups. The efficacy of the PEs co-administered in solution and the in solid dosage form was compared in rats after oral gavage and subsequent assessment of the octreotide pharmacokinetics (PK). While the type of PE and the volume only slightly affected the disintegration time for the mini-tablets, significant differences were observed to depend on the exact experimental setup. Upon oral gavage, plasma octreotide concentrations were enhanced in presence of PE for both solution and mini-tablet formulations compared to control formulations without PEs, as reflected by the higher area under the plasma concentration curves (AUC). SNAC produced a significantly greater relative bioavailability than both the control and the C10-containing formulations. The relative bioavailability increased 2.0- and 9.4-fold for C10 and SNAC solutions, respectively. Notably, the mini-tablets both with and without PE showed higher numerical octreotide absorption than their solution counterparts and the mini-tablets resulted in a 1.6- and 1.8-fold increase for C10, and a 4.8- and 5.4-fold increase for SNAC in relative bioavailability after co-administering with low and high liquid volumes, respectively. In conclusion, the study shows that the PK profiles for octreotide are different after oral gavage administration of solutions compared to mini-tablets containing the PEs SNAC and C10 and that SNAC outperformed C10 as a permeation enhancer when administered by oral gavage.
Malaria remains a major global health burden, especially in children under the age of five. Pediatric treatment often requires tablet fragmentation for its dose adjustment according to body weight, which intensifies bitterness and may reduce treatment adherence. Complexation of bitter-tasting drugs with ion-exchange resins for taste masking is a promising strategy to improve palatability. Here, we evaluated whether a chloroquine-resin complex (CLQ-R) preserves the pharmacokinetic profile and antimalarial efficacy of chloroquine diphosphate (CLQ) while masking its bitter taste. CLQ-R was prepared at a 1:1 (w/w) drug-to-resin ratio using polacrilin potassium (Amberlite IRP88). The in vitro antimalarial activity of CLQ-R was assessed using Plasmodium falciparum 3D7 strain, and the parasite proliferation was determined by SYBR Green DNA-staining. CLQ plasma concentrations and mice biochemical parameters were evaluated following oral administration of CLQ or CLQ-R. The in vivo antimalarial activity was evaluated in P. berghei ANKA-infected C57BL/6 mice using the four-day suppressive and recrudescence tests, with parasitemia assessed by flow cytometry. Taste perception was determined by 48-hour two-bottle preference test. CLQ-R displayed similar plasma concentration and biochemical profiles to CLQ. CLQ-R was able to maintain a strong in vitro antimalarial activity with IC50 of 30 nM with minimal hemolytic activity and reduced in vivo parasitemia by > 95%. Notably, mice exhibited a 15.5% higher preference for CLQ-R, indicating improved palatability. These findings demonstrate that CLQ-R preserves CLQ pharmacological activity while masking its bitter taste, supporting its potential as a pediatric-friendly antimalarial formulation.
The effective management of acute postoperative pain remains challenging, primarily owing to the short half-life and rapid systemic clearance of anesthetics. Therefore, this study aims to report structural characterization, pharmacokinetic profiling, and enhanced analgesic efficacy of a bioresponsive lyotropic liquid crystal Quject® gel for long-acting ropivacaine delivery. A lipid system of lecithin, Span 20, and tocopherol acetate, was systematically optimized via ternary phase diagram to identify formulations that transition from sol-to-gel upon contact with biological fluids. Structural characterization using SAXS and cryo-TEM confirmed the formation of a stable reversed hexagonal phase (lattice constant a≈5.80 nm; characteristic Bragg peaks at q≈0.80, 1.38, and 1.60 nm⁻1 with 1:√3:√4 ratio). The dense nanochannels of the hexagonal depot restricted ropivacaine diffusion, resulting in a minimal initial burst (Day-0: 3.80%) and 43.66% cumulative drug release by Day-7, compared to near-complete release (≥95%) from lamellar controls over the same period. In vivo pharmacokinetic analysis in rats revealed a 7-fold increase in elimination half-life (t1/2: 5.98vs. 0.81-h) and a 4-fold reduction in peak plasma concentration (Cmax: 58.13 vs. 231.00 ng/mL) compared to those of ropivacaine HCl, substantially mitigating systemic toxicity risk. The tlast concentration extended to 42-h, encompassing the critical 48-h postoperative recovery period. Furthermore, the von Frey test in a rat incision model confirmed sustained analgesic efficacy for up to 72-h after a single subcutaneous administration compared to ropivacaine HCl (≤6-h). These findings establish a direct structure-pharmacokinetics-efficacy relationship within Quject® gel, offering scalable, biocompatible prolonged postoperative analgesia.
Punch sticking is a well-recognized and extensively studied challenge in pharmaceutical tablet manufacturing. However, the impact of solid-form impurities in formulations on sticking propensity has not been adequately investigated. Here, we examined the effect of solid-form impurities on the punch sticking behavior of two carbamazepine batches (CBZ-A and CBZ-B), obtained from different suppliers. CBZ-B contained a mixture of form III and CBZ dihydrate (CBZd), whereas CBZ-A consisted exclusively of form III. CBZ-B exhibited a substantially greater tendency to stick than CBZ-A. To further elucidate the factors influencing sticking, a design of experiments (DOE) approach was employed using CBZd to investigate the effect of particle size, compaction pressure, and active pharmaceutical ingredient (API) loading on sticking mass. The results show that sticking was exacerbated by smaller particle size, lower compaction pressure, and higher API loading. In addition, a significant interaction between particle size and API loading was identified, indicating that these variables jointly influence sticking propensity. These findings highlight the importance of controlling not only the solid-state phase purity of the API but also particle size, API loading, and compaction pressure to ensure robust tablet manufacturing.
Gastroretentive drug delivery systems aim to prolong gastric residence time, yet their in vivo performance is often inconsistent, largely due to insufficient consideration of mechanically driven gastric emptying. In particular, the role of antral peristalsis in the transport of solid oral dosage forms is underrepresented in current in vitro models. In this study, a next-generation in vitro antrum model was developed to simulate mechanically relevant conditions governing gastric emptying. The system is based on a flexible tubular compartment with mechanically induced peristaltic waves and allows controlled variation of key parameters, including wave velocity (3 mm/s), fluid volume (50-150 mL), inclination (0-40°), and occlusion as residual lumen diameter (1.6-25.6 mm). Using test objects with defined differences in size, density, and deformability, the model demonstrated that transport behavior is primarily governed by the interplay of geometric confinement, deformation, and contact mechanics. Rigid objects were transported once a critical lumen diameter threshold was reached, whereas highly deformable and entangled structures partially resisted peristaltic transport. Observed size-dependent transport behavior was consistent with in vivo findings from relevant literature. The model provides a simple and mechanistically relevant platform for early-stage screening of gastroretentive dosage forms and supports a mechanics-driven understanding of gastroretention.
Corneal neovascularization (CoNV) treatment via ocular drug delivery remains challenging because rapid ocular clearance and limited tissue penetration result in low bioavailability, reduced therapeutic efficacy, and the need for frequent administration. Although polymer-based delivery systems can provide sustained release, their clinical translation may be limited by low drug loading, suboptimal release kinetics, and potential toxicity associated with polymer degradation products. Here, we developed a carrier-free subconjunctival depot platform composed of pure regorafenib crystals, including microcrystals (∼5 µm) and nanocrystals (∼260 nm), to achieve sustained release through a dissolution/diffusion-controlled mechanism without the need for a polymer matrix. Both formulations maintained crystallinity and their initial particle size during 12 months of storage at 4 °C. Nanocrystals exhibited faster dissolution and clearance, whereas microcrystals provided prolonged local retention, maintaining detectable regorafenib levels through eight months after a single administration. In vivo imaging and histological analyses demonstrated the formation of dense monolithic depots within the subconjunctival space, supporting sustained release and local retention. In prophylactic CoNV models, nanocrystals enhanced tissue penetration and produced greater early inhibition of angiogenic sprouting than microcrystals (p < 0.05). In therapeutic models of established neovascularization, a single 2 mg subconjunctival injection of either formulation induced comparable and sustained regression of neovessels for up to eight months, with efficacy significantly greater than that of 0.5 mg bevacizumab administered at 2-month intervals (p < 0.01). In addition, the 1 mg microcrystal formulation reduced TNF-α, IL-1β, and VEGF expression relative to saline-treated controls and were associated with improved corneal epithelial healing compared with bevacizumab. Collectively, these findings demonstrate that carrier-free pure drug crystal depots can provide sustained ocular delivery for at least eight months following a single administration, while crystal size governs the balance between initial tissue exposure and long-term retention.
Although solid oral dosage forms are widely used in adult drug therapy, age-appropriate formulations for pediatric patients remain limited. The development of suitable dosage forms is challenged by specific requirements regarding excipient safety, tablet size, and dose flexibility, as well as the need to improve therapy adherence in the context of frequent dosing. This study aimed to develop a pediatric-appropriate extended-release matrix tablet based on lipid matrix formers, with particular attention to the use of safe excipients and the selection of excipients based on sustainability considerations. Lipid-based excipients, selected due to their natural origin and similarity to dietary fats, were investigated and compared with conventional matrix formers. A formulation screening approach was applied to identify promising candidates based on drug release after one hour, followed by further evaluation of manufacturability, tablet hardness, and extended-release performance. In addition, the influence of a physiological pH-gradient, bile salts, and long-term storage on drug release was assessed. The selected formulations showed good manufacturability, uniformity, and sustained drug release. Overall, several lipid-based matrix formulations suitable for pediatric use were identified, providing a promising basis for the development of solid oral extended-release dosage forms for children.
The incorporation of postbiotics into structurally optimized emulgels represents a promising strategy for the stabilization and topical delivery of microbial-derived bioactive compounds. In this study, a series of emulgels containing postbiotics from Lacticaseibacillus rhamnosus, Lactiplantibacillus plantarum, Lactobacillus acidophilus, and Lacticaseibacillus paracasei were formulated. Microscopic analysis and comprehensive physicochemical evaluations, including organoleptic assessment, enabled a detailed characterization of the semi-solid systems. The pH values were within the range commonly reported for topical formulations (below 5.5). Furthermore, stability tests demonstrated that the emulgels resist phase separation even under cyclically varying temperatures. Dynamic Light Scattering (DLS) measurements showed nano- to submicron particles (80-280 nm) with moderate polydispersity (0.20-0.42), confirming relatively homogeneous yet complex dispersions. Importantly, the postbiotics modified the internal organization without compromising colloidal stability. The application of postbiotic formulations on human skin ex vivo did not significantly alter transepidermal water loss (TEWL), with values remaining comparable before and after application, validating that the developed emulgels do not impair skin barrier integrity. The findings demonstrate the feasibility of incorporating microbial-derived postbiotic materials into emulgels and support their further investigation as components of delivery systems intended for cosmetic and skincare applications.
Moisture exposure can significantly affect the critical quality attributes of pharmaceutical tablets by altering their internal microstructure and micro-viscoelastic properties. In compressed granular materials, moisture-induced changes in chemical state, interparticle bonding, porosity, and residual stress distribution can alter both mechanical integrity and performance-related attributes. In this study, irreversible moisture-induced changes in tablet bulk, microstructural, and micro-viscoelastic properties were investigated and quantified using ultrasonics. As a result of uniform vapor diffusion into the samples (without direct liquid contact), moisture exposure increased tablet mass by approximately 8.3 ± 0.77%. Subsequently, the samples underwent a controlled dry-down phase during which ultrasonic waveforms were acquired using a custom-made rig in pitch-catch mode with paired pressure transducers. Waveforms acquired throughout the moisture cycle were analyzed in the temporal, spectral, and wave-dispersion domains to extract bulk- and microstructure-sensitive response metrics. It was observed that moisture exposure followed by controlled dry-down resulted in only minor residual geometric changes relative to the initial dry state, with diameter, thickness, and mass density showing average increases of approximately 0.97 ± 0.25%, 1.83 ± 0.13%, and 3.69 ± 0.49%, respectively. By contrast, substantial irreversible reductions were observed in pressure wave speed, group velocity, and apparent modulus of elasticity, by approximately 28.87%, 13.20%, and 47.34%, respectively. Equivalent axial residual stress remained approximately 3-4 times higher than equivalent radial residual stress after drying, indicating non-uniform recovery of deformation across directions. Overall, the findings demonstrate that the ultrasonic approach offers a sensitive, non-destructive means of detecting irreversible moisture-induced changes in tablet microstructure that are not captured by observable geometric recovery, highlighting its potential for quality assessment and monitoring applications.
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Histone deacetylase (HDAC) inhibitors such as vorinostat (VOR) eventuate cell cycle arrest and apoptosis by suppressing the HDAC activity, representing a promising class of anti-cancer agents. The clinical application of VOR in solid tumors (e.g., CRC) is hindered by rapid circulatory clearance, insufficient tumor distribution, and off-target cell delivery. To overcome these limitations, we constructed a targeted nanoformulation (T-NP.VOR) using the aminoethyl anisamide (AEAA)-functionalized, poly(ethylene glycol) (PEG)-decorated poly(lactic-co-glycolic acid) (PLGA) nano delivery carrier. In vitro, T‑NP.VOR significantly enhanced cellular uptake in CRC cells via Sigma‑1 receptor‑mediated uptake, leading to HDAC inhibition, cell cycle arrest, and apoptosis. In an orthotopic CRC mouse model, T‑NP.VOR markedly prolonged blood circulation and improved tumor distribution, resulting in significant tumor growth suppression and extended animal survival compared to free VOR and non‑targeted nanoformulation. Our findings confirm the PLGA-PEG-AEAA nanocarrier as a promising VOR delivery platform for CRC therapy.
Owing to the complexity of the tumor microenvironment, monotherapy often suffers from inherent limitations and fails to achieve satisfactory antitumor efficacy. Therefore, multimodal collaborative therapy has become a trend. In this study, CP@ZIF-PQ/Ce6 NPs, a ZIF-90-based multimodal nanosystem loaded with copper peroxide (CP) nanoparticles, the autophagy inhibitor primaquine phosphate (PQ) and the photosensitizer Ce6, were developed. This nanosystem enables the integration of photodynamic therapy (PDT), chemodynamic therapy (CDT), oxygen generation, and autophagy inhibition. Through the combined therapeutic effects of PDT/CDT/O2 generation/autophagy inhibition, CP@ZIF-PQ/Ce6 NPs enhance the production of reactive oxygen species(ROS), alleviate tumor hypoxia, and block the autophagy-mediated protective pathway in tumor cells. Moreover, the nanosystem exhibits dual pH- and ATP-responsive properties, allowing tumor microenvironment-triggered drug release. CP@ZIF-PQ/Ce6 NPs successfully integrate PDT, CDT, oxygen-generating therapy, and autophagy inhibition, demonstrating potent antitumor activity and favorable biocompatibility both in vitro and in vivo. This study provides an innovative strategy and experimental evidence for multimodal collaborative antitumor therapy to overcome the limitations of monotherapy imposed by the tumor microenvironment.