Search Results (222)

This study presents a practical and tunable 3D printing-based approach for manufacturing oral controlled-release bilayer tablets by modulating drug release solely through layer ratio control within a single dosage form. Theophylline-loaded filaments were prepared via hot-melt extrusion (HME) using Kollicoat^® IR or hydroxypropyl cellulose as polymer matrices. The mechanical properties of the manufactured filaments were evaluated and compared with commercial filaments to confirm their suitability for fused deposition modeling (FDM) printing. Physicochemical characterization using scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared spectroscopy indicated partial crystallinity and molecular dispersion of the drug within the polymer matrices. Using a dual-nozzle FDM 3D printer, five bilayer tablets composed of two drug-loaded filaments at different layer ratios were successfully fabricated without altering formulation composition or processing conditions. Drug release studies revealed distinct dissolution behaviors that were strongly dependent on the bilayer composition. Overall, this study demonstrates that controlled drug release can be effectively achieved through geometric modulation of bilayer structures using a combined HME–FDM 3D printing approach, providing a practical platform for personalized oral drug delivery without increasing formulation complexity. Full article

Background: Three-dimensional printing (3DP) is a promising technology for advancing pharmaceutical research by enabling the production of personalized drug products. However, its progress has been hindered by the conventional trial-and-error approach to excipient selection and optimization. Methods: In this study, the blend module was employed to determine the miscibility parameters—mixing energy (E_mix) and Flory–Huggins interaction parameter (χ) to find the right excipients and drug–excipient ratio and examine the incorporation of plasticizers and lipids to enhance printability. Furthermore, molecular dynamics (MD) simulations were employed to calculate the cohesive energy density (CED) for predicting the dissolution behavior of 3DP formulations. Results: Data from 51 formulations were analyzed, enabling correlation and experimental validation of the in silico predictions. The predicted miscibility values demonstrated a strong correlation with experimental printability results. Furthermore, using a miscibility parameter, it was possible to accurately forecast minor changes in the drug-to-excipient ratio, plasticizer/lipid concentration, and hot-melt extrusion (HME) temperature that affect printability. Hydrophilic carriers exhibited lower CED values corresponding to faster drug release. In contrast, more hydrophobic carriers revealed high CED values, indicating stronger drug entrapment and sustained release. Conclusions: The miscibility parameters and MD-simulated CED values provide a practical framework for early-stage, high-throughput excipient screening. Overall, in silico prediction offers a viable strategy for modeling the entire 3DP workflow, minimizing the need for trial-and-error experimentation, and thereby accelerating the clinical translation of 3DP drug delivery systems. Full article

Lycopene is a potent antioxidant carotenoid with significant health-promoting properties. However, its practical application is limited by poor water solubility. This study aimed to enhance lycopene dispersibility through the development of solid dispersions obtained by hot-melt extrusion (HME). Polymeric carriers composed of polyvinylpyrrolidone K30 (PVP K30), phosphatidylcholine, and xylitol were designed to achieve optimal processing conditions and thermal stability. Nine formulations containing 10–30% lycopene were prepared and characterized using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FT-IR), and dispersibility testing. TGA confirmed the thermal stability of lycopene at the extrusion temperature (150 °C). DSC and XRPD analyses indicated partial amorphization of lycopene in the extrudates, while FT-IR spectra revealed molecular interactions between lycopene and carrier components, particularly hydroxyl and carbonyl groups. Among the tested systems, the formulation containing PVP K30 and xylitol without phosphatidylcholine exhibited the highest dispersibility (1.0484 mg/mL after 3 h). Dispersibility decreased with increasing lycopene content. These findings demonstrate that HME is an effective technique for producing partially amorphous lycopene dispersions with improved dispersibility, and that polymer–polyol systems are particularly promising carriers for enhancing lycopene bioavailability. Full article

Background: Hereditary Multiple Exostoses (HME) is a rare autosomal dominant skeletal disorder resulting from loss-of-function variants in the EXT1, EXT2, or EXT3 genes. While malignant transformation into chondrosarcoma is well documented, the incidence and characterization of non-skeletal malignancies in HME remain poorly defined. Objective: We aimed to comprehensively review the literature for reported cases of non-skeletal malignancies in individuals with HME and evaluate a potential association with hematologic cancers, particularly in the pediatric population. Methods: An extensive literature search was conducted in the PubMed database up to August 2025 using search terms related to HME and malignancy. Eligible reports included case descriptions of non-skeletal cancers occurring in patients with confirmed or suspected HME. Extracted data included patient age, sex, cancer type, and available genetic or molecular findings. Results: Thirteen cases of non-skeletal malignancies associated with HME were identified. Fewer than half underwent molecular genetic testing. Six cases occurred in pediatric patients, four of which involved hematologic malignancies, three leukemias and one Burkitt lymphoma. In adults, malignancies affected a range of organ systems, including respiratory, gastrointestinal, nervous, and endocrine. A marked male predominance was observed (11 males vs. 2 females). Conclusions: Although a definitive causal relationship cannot be established, hematologic malignancies in pediatric HME patients appear to be disproportionately represented among reported cases. This finding highlights the need for further investigation through large-scale, population-based studies incorporating both clinical and genetic data. Full article

The principal challenge in the development of efficient porphyrin-based photosensitizers is the intrinsic aggregation-induced quenching effect, which significantly impairs the generation efficiency of singlet oxygen (¹O₂) in photodynamic therapy (PDT). This study addresses this limitation through a supramolecular approach grounded in host-guest chemistry. Partially methyl-substituted cucurbit[6]uril (HMeQ[6]) was selected as the macrocyclic host owing to its smaller portal size and larger outer diameter, features that facilitate both strong binding affinity and effective spatial isolation. A porphyrin derivative functionalized with two cationic arms (DPPY) was designed and synthesized as the guest molecule. The results derived from ¹H NMR titration and UV spectroscopy analyses demonstrate that, in aqueous solution, these components self-assemble via host-guest interactions to form a 2:1 stoichiometric supramolecular complex (DPPY@HMeQ[6]) with a binding constant of 2.11 × 10⁵ M⁻¹. TEM, AFM, and DLS analyses indicate that this complex further assembles into nanosheet structures with dimensions of approximately 100 nm. Spectroscopic analyses reveal that encapsulation by HMeQ[6] effectively inhibits π-π stacking aggregation of DPPY molecules, resulting in an approximate threefold increase in fluorescence intensity and an extension of fluorescence lifetime from 3.2 ns to 6.2 ns. Relative to free DPPY, the complex demonstrates a sixfold enhancement in ¹O₂ generation efficiency. Subsequently, 4T1 cells, derived from mouse triple-negative breast tumors, were selected as the experimental model. These cells exhibit high invasiveness and metastatic potential, thereby effectively recapitulating the pathological progression of human triple-negative breast cancer. In vitro cellular assays indicate efficient internalization of the complex by 4T1 cells, inducing a concentration-dependent increase in reactive oxygen species (ROS) and oxidative stress following light irradiation. The in vitro cytotoxicity of the supramolecular photosensitizer was assessed employing the CCK-8 assay and flow cytometry techniques. The half-maximal inhibitory concentration (IC₅₀) against cancer cells is 1.8 μM, with apoptosis rates reaching up to 65.3%, while exhibiting minimal dark toxicity. This study expands the potential applications of methyl-substituted cucurbiturils within functional supramolecular assemblies and proposes a viable approach for the development of efficient and activatable supramolecular photosensitizers. Full article

Background/Objectives: Fused deposition modeling (FDM) three-dimensional (3D) printing represents an emerging manufacturing platform for personalized oral dosage forms. Its success relies on developing robust drug-loaded filaments with consistent mechanical, thermal, and dissolution properties. This work aims to (i) develop and characterize ketoprofen-loaded filaments using hot-melt extrusion (HME) and (ii) utilize them to fabricate both immediate-release (IR) and sustained-release (SR) tablets via FDM 3D printing. Methods: Filaments were prepared using Kollicoat^® IR and hydroxypropyl methylcellulose (HPMC, 2600–5600 cP) as functional polymers. Sorbitol and sodium lauryl sulfate (SLS) were incorporated as plasticizer and surfactant, respectively. Filaments were evaluated for quality attributes, drug content, tensile strength, and physicochemical and surface characteristics using Scanning Electron Microscopy (SEM), Attenuated Total Reflection Fourier-transform infrared (ATR-FTIR), X-ray Diffraction (XRD), Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Optimized filaments were fed into an FDM 3D printer to fabricate ketoprofen tablets with varied geometries, shell numbers, and infill densities. Tablets were subjected to USP tests (weight variation, friability, hardness, disintegration, assay, content uniformity), dissolution profiling, and release kinetics modeling. Comparative dissolution studies with market Profenid^® and Bi-Profenid^® tablets were conducted. GastroPlus^® simulations were used for in vitro–in silico correlation. Results: Among the tested formulations, Kollicoat^® IR-based filaments with sorbitol and SLS (F6) demonstrated superior printability, characterized by consistent feeding, stable extrusion, and reliable formation of uniform structures for immediate-release applications. In contrast, HPMC-based filaments with sorbitol (F13) offered the most robust performance for SR formulations. Both exhibited uniform diameter, drug loading, and mechanical strength. IR tablets achieved >80% release within 30 min, while SR tablets prolonged release up to 12 h, following Higuchi and Korsmeyer–Peppas kinetics. All quality attributes complied with USP limits. Market products showed comparable dissolution, validating the approach. GastroPlus^® simulations predicted pharmacokinetic profiles consistent with reported data, supporting IVIVC. Conclusions: This integrated workflow establishes a robust strategy for producing IR and SR ketoprofen tablets from a single FDM platform. The results highlight the feasibility of point-of-care, personalized medicine using 3D printing technologies. Full article

Precise pore pressure prediction is highly essential for safe and effective drilling; however, the nonlinear and heterogeneous nature of the subsurface strata makes it extremely challenging. Conventional physics-based methods are not capable of handling this nonlinearity and variation. Recently, machine learning (ML) methods have been deployed by researchers to enhance prediction performance. These methods are often highly domain-specific and produce good results for the data they are trained for but struggle to generalize to unseen data. This study introduces a Hybrid Meta-Ensemble (HME), a meta model framework, as a novel data mining approach that applies ML methods and ensemble learning on well log data for pore pressure prediction. This proposed study first trains five baseline models including Convolutional Neural Network (CNN), Recurrent Neural Network (RNN), Deep Feedforward Neural Network (DFNN), Random Forest (RF), and Extreme Gradient Boost (XGBoost) to capture sequential and nonlinear relationships for pore pressure prediction. The stacked predictions are further improved through a meta learner that adaptively reweighs them according to subsurface heterogeneity, effectively strengthening the ability of ensembles to generalize across diverse geological settings. The experimentation is performed on well log data from four wells located in the Potwar Basin which is one of Pakistan’s principal oil- and gas-producing regions. The proposed Hybrid Meta-Ensemble (HME) has achieved an R² value of 0.93, outperforming the individual base models. Using the HME approach, the model effectively captures rock heterogeneity by learning optimal nonlinear interactions among the base models, leading to more accurate pressure predictions. Results show that integrating deep learning with robust meta learning substantially improves the accuracy of pore pressure prediction. Full article

Additive manufacturing can be regarded as a game-changing approach for paediatric drug development, as children have special drug-related requirements which are rarely met by conventional technologies. Traditional dosage forms have considerable drawbacks, among them dose, excipient safety, and taste issues, which can be resolved by using three-dimensional (3D) printing. Ease of swallowing and an appealing design are among the improvements brought forth by 3D printing techniques. Techniques that have been thoroughly researched in the paediatric field include hot-melt extrusion (HME) coupled with fused deposition modelling (FDM), direct powder extrusion (DPE) and semisolid extrusion (SSE) 3D printing. Selective Laser Sintering (SLS) 3D bioprinting and binder-jet (BJ) 3D printing are other less known but highly useful techniques. A number of studies focus on significant subjects for the paediatric medicine domain, such as the acceptability of the produced formulations, the size of tablets, the design, the concealment of bitter API flavour, and the stability of the dosage forms. The 3D-printed oral formulations are varied: conventional-sized tablets, miniaturised tablets, chewable tablets, and orodispersible films or tablets. Most of the drugs used in the presented studies are essential medicines for children, for which commercial products with flexible doses and age-appropriate characteristics are often lacking. The practical implications of currently published studies and future directions for paediatric pharmaceutical 3D printing are described. Although there is a substantial amount of technical and in vitro data as well as paediatric engagement work on this subject, its translation into clinical practice is still limited. The clinical efficacy of 3D-printed dosage forms has to be further researched, since only a few studies have targeted this aspect. Full article

Background/Objectives: This study aimed to develop a novel amorphous solid dispersion (ASD) platform using poly(2-ethyl-2-oxazoline) (PEtOx) for the solubility enhancement of poorly water-soluble drugs. Fenofibrate (FB), a Biopharmaceutics Classification System (BCS) Class II drug, was selected as the model drug. The novelty of this work lies in the formulation of dual-matrix systems by blending PEtOx of varying molecular weights (50 kDa, 200 kDa, 500 kDa) with solubility-enhancing polymers, Soluplus^® and Kollidon^® VA64, to investigate component compatibility, synergistic solubility enhancement, and the influence of PEtOx molecular weight on drug release. Methods: ASDs were prepared via hot-melt extrusion (HME) and characterized using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and Fourier transform–infrared spectroscopy (FTIR) to confirm FB amorphization and evaluate drug–polymer interactions. In vitro dissolution testing was performed to assess drug release performance, and stability studies were conducted at ambient conditions for one month to evaluate physical stability. Results: DSC, PXRD, and FTIR confirmed the successful amorphization of FB and good miscibility between PEtOx and the selected excipients. In vitro dissolution studies showed an 8–12-fold increase in FB release from ASDs compared to crystalline drug. Lower-molecular-weight PEtOx grades yielded faster release profiles, while binary blends with Soluplus^® or Kollidon^® VA64 enabled tailored drug release. Stability testing indicated that all formulations maintained their amorphous state over one month. Conclusions: PEtOx-based ASDs represent a versatile platform for enhancing the solubility and dissolution of poorly water-soluble drugs. By adjusting polymer molecular weight and combining with complementary excipients, release profiles can be optimized to achieve improved performance and stability. Full article

Cnidium officinale (CO) and Angelica gigas (AG) are traditional herbal medicines known for their bioactive compound ferulic acid (FA), which exerts skin-whitening, anti-inflammatory, antioxidant, and UV-protective effects. However, conventional extraction yields are limited and often require solvent-intensive processes. In this study, an eco-friendly hot-melt extrusion (HME) process was applied to enhance the FA content and extractability from CO and AG. Process optimization significantly improved particle morphology and reduced size, as confirmed by Fourier transform-infrared spectroscopy (FT-IR) and field emission-scanning electron microscopy (FE-SEM) analysis. Quantitative High-performance liquid chromatography (HPLC) analysis showed increased FA content in HME-treated extracts, which corresponded to enhanced biological efficacy. The HME extracts exhibited no cytotoxicity up to 500 µg/mL in B16F10 melanocytes and significantly inhibited α-melanocyte stimulating hormone (α-MSH)-induced melanin synthesis. In HaCaT keratinocytes, the HME group promoted superior wound closure at 24 and 48 h, indicating accelerated skin regeneration. These findings support HME as a sustainable and effective strategy for developing natural ingredient-based cosmetic formulations targeting hyperpigmentation and skin repair. Full article

Background/Objectives: Copovidone (polyvinylpyrrolidone-vinyl acetate copolymer, PVP/VA) is a widely used pharmaceutical excipient with various applications in drug formulation. In hot melt extrusion (HME), PVP/VA is an approved carrier material for the production of amorphous solid dispersions (ASDs) by embedding drugs on a molecular level. This study investigates the properties and processability of two copovidone grades—Plasdone™ S-630 (PS-630) and the novel Plasdone™ S-630 Ultra (PS-630U)—to assess their suitability as ASD carrier materials. Methods: The thermal and physicochemical characteristics of both polymers were evaluated, focusing on glass transition temperature and polymer melt rheology. The process performance in HME was investigated on small-scale as well as in production-scale extrusion. The two model drugs itraconazole and griseofulvin were used to examine drug dissolution and degradation during HME via in-line UV-vis spectroscopy. Results: When comparing both polymers, PS-630U offers various advantages due to the improved powder feeding behavior and reduced yellowing of extruded products while maintaining similar melt properties and drug compatibility compared to PS-630. Conclusions: These findings support the use of PS-630U as an optimized copovidone grade for ASD manufacturing, facilitating improved processing characteristics and best product qualities without the requirement of significant formulation adjustments. Full article

Background: The limited aqueous solubility of BCS Class II drugs, exemplified by itraconazole (ITR), continues to hinder their bioavailability and therapeutic performance following oral administration. The present study investigated the development of amorphous solid dispersions (ASDs) of ITR via continuous manufacturing technologies, such as hot melt extrusion (HME) and spray drying (SD), to improve drug release. Methods: Polymer selection was guided by Hansen solubility parameter (HSP) analysis, film casting, and molecular modeling, leading to the identification of aminoalkyl methacrylate copolymer type A (Eudragit^® EPO), polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus^®), and hypromellose acetate succinate HG (AQOAT^® AS-HG) as suitable carriers. ASDs were prepared at drug-to-polymer ratios of 1:1, 1:2, and 2:1. Comprehensive characterization was performed using ATR-FTIR, NMR, DSC, PXRD, SEM, PLM, and contact angle analysis. Results: HME demonstrated higher process efficiency, solvent-free operation, and superior dissolution enhancement compared to SD. Optimized HME-based ASDs were formulated into tablets. The ITR–Eudragit^® EPO formulation achieved 95.88% drug release within 2 h (Weibull model, R² > 0.99), while Soluplus^® and AQOAT^® AS-HG systems achieved complete release, best described by the Peppas–Sahlin model. Molecular modeling confirmed favorable drug–polymer interactions, correlating with the formation of stable complex and enhanced release performance. Conclusions: HME-based continuous manufacturing provides a scalable and robust strategy for improving the oral delivery of poorly water-soluble drugs. Integrating predictive modeling with experimental screening enables the rational design of ASD formulations with optimized dissolution behavior, offering potential for improved therapeutic outcomes in BCS Class II drug delivery. Full article

Background: Precision medicine refers to the formulation of personalized drug regimens according to the individual characteristics of patients to achieve optimal efficacy and minimize adverse reactions. Additive manufacturing (AM), also known as three-dimensional (3D) printing, has emerged as an optimal solution for precision drug delivery, enabling customizable and the fabrication of multifunctional structures with precise control over morphology and release behavior in pharmaceutics. However, the influence of 3D printing parameters on the printed tablets, especially regarding in vitro and in vivo performance, remains poorly understood, limiting the optimization of manufacturing processes for controlled-release profiles. Objective: To establish the fabrication process of 3D-printed controlled-release tablets via comprehensively understanding the printing parameters using fused deposition modeling (FDM) combined with hot-melt extrusion (HME) technologies. HPMC-AS/HPC-EF was used as the drug delivery matrix and carbamazepine (CBZ) was used as a model drug to investigate the in vitro drug delivery performance of the printed tablets. Methodology: Thermogravimetric analysis (TGA) was employed to assess the thermal compatibility of CBZ with HPMC-AS/HPC-EF excipients up to 230 °C, surpassing typical processing temperatures (160–200 °C). The formation of stable amorphous solid dispersions (ASDs) was validated using differential scanning calorimetry (DSC), hot-stage polarized light microscopy (PLM), and powder X-ray diffraction (PXRD). A 15-group full factorial design was then used to evaluate the effects of the fan speed (20–100%), platform temperature (40–80 °C), and printing speed (20–100 mm/s) on the tablet properties. Response surface modeling (RSM) with inverse square-root transformation was applied to analyze the dissolution kinetics, specifically t_50% (time for 50% drug release) and Q_4h (drug released at 4 h). Results: TGA confirmed the thermal compatibility of CBZ with HPMC-AS/HPC-EF, enabling stable ASD formation validated by DSC, PLM, and PXRD. The full factorial design revealed that printing speed was the dominant parameter governing dissolution behavior, with high speeds accelerating release and low speeds prolonging release through porosity-modulated diffusion control. RSM quadratic models showed optimal fits for t_50% (R² = 0.9936) and Q_4h (R² = 0.9019), highlighting the predictability of release kinetics via process parameter tuning. This work demonstrates the adaptability of polymer composite AM for tailoring drug release profiles, balancing mechanical integrity, release kinetics, and manufacturing scalability to advance multifunctional 3D-printed drug delivery devices in pharmaceutics. Full article

Background/Objectives: Hot-melt extrusion (HME) has gained prominence for the manufacture of sustained-release oral dosage forms, yet the application of wax-based matrices and their resilience to alcohol-induced dose dumping (AIDD) remains underexplored. This study aimed to develop and characterise wax-based sustained-release felodipine formulations, with a particular focus on excipient functionality and robustness against AIDD. Methods: Felodipine sustained-release formulations were prepared via HME using Syncrowax HGLC as a thermally processable wax matrix. Microcrystalline cellulose (MCC) and lactose monohydrate were incorporated as functional fillers and processing aids. The influence of wax content and filler type on mechanical properties, wettability, and drug release behaviour was systematically evaluated. Ethanol susceptibility testing was conducted under simulated co-ingestion conditions (4%, 20%, and 40% v/v ethanol) to assess AIDD risk. Results: MCC-containing tablets demonstrated superior sustained-release characteristics over 24 h, showing better wettability and disintegration. In contrast, tablets formulated with lactose monohydrate remained structurally intact during dissolution, overly restricting drug release. This limitation was effectively addressed through granulation, where reduced particle size significantly improved surface accessibility, with 0.5–1 mm granules achieving a satisfactory release profile. Ethanol susceptibility testing revealed divergent behaviours between the two filler systems. Unexpectedly, MCC-containing tablets showed suppressed drug release in ethanolic media, likely resulting from inhibitory effect of ethanol on filler swelling and disintegration. Conversely, formulations containing lactose monohydrate retained their release performance in up to 20% v/v ethanol, with only high concentrations (40% v/v) compromising matrix drug-retaining functionality and leading to remarkably increased drug release. Conclusions: This study highlights the pivotal role of excipient type and constitutional ratios in engineering wax-based sustained-release formulations. It further contributes to the understanding of AIDD risk through in vitro assessment and offers a rational design strategy for robust, alcohol-resistant oral delivery systems for felodipine. Full article

Background/Objectives: Hot-melt extrusion (HME) has become a key technology in pharmaceutical formulation, particularly for enhancing the solubility of poorly soluble Active Pharmaceutical Ingredients (APIs). While horizontal HME is widely adopted, vertical HME remains underexplored despite its potential benefits in footprint reduction, feeding efficiency, temperature control, and integration into continuous manufacturing. This study investigates vertical HME as an innovative approach in order to optimize drug polymer interactions and generate stable amorphous dispersions with controlled release behavior. Methods: Extrusion trials were conducted using a vertical hot-melt extruder developed by Rondol Industrie (Nancy, France). Acetylsalicylic acid (ASA) supplied by Seqens (Écully, France) was used as a model API and processed with Soluplus^® and Kollidon^® 12 PF (BASF, Ludwigshafen, Germany). Various process parameters (temperature, screw speed, screw profile) were explored. The extrudates were characterized by powder X-ray diffraction (PXRD) and small-angle X-ray scattering (SAXS) to evaluate crystallinity and microstructure. In vitro dissolution tests were performed under sink conditions using USP Apparatus II to assess drug release profiles. Results: Vertical HME enabled the formation of homogeneous amorphous solid dispersions. PXRD confirmed the absence of residual crystallinity, and SAXS revealed nanostructural changes in the polymer matrix influenced by drug loading and thermal input. In vitro dissolution demonstrated enhanced drug release rates compared to crystalline ASA, with good reproducibility. Conclusions: Vertical HME provides a compact, cleanable, and modular platform that supports the development of stable amorphous dispersions with controlled release. It represents a robust and versatile solution for pharmaceutical innovation, with strong potential for cost-efficient continuous manufacturing and industrial-scale adoption. Full article