Search Results (717)

Background/Objectives: Rebamipide is a gastroprotective agent with poor aqueous solubility and rapid gastrointestinal clearance, leading to reduced therapeutic efficiency. This study aimed to enhance the solubility, mucoadhesion, and sustained oral delivery of Rebamipide through the development of a deep eutectic mixture (DEM)-based bioadhesive controlled-release granule formulation. Methods: In silico hydrogen-bonding interactions between Rebamipide, malonic acid, and urea were analyzed using CCDC tools. A thermodynamically stable DEM (1:3:1) was prepared and incorporated into bioadhesive granules using chitosan and HPMC. Physicochemical characterization was conducted using FTIR, DSC, TGA, and PXRD. Solubility, in vitro dissolution, ex vivo mucoadhesion (sheep gastric mucosa), and in vivo gastric retention (BaSO₄-loaded granules in rats) were evaluated. Results: The optimized DEM significantly enhanced Rebamipide solubility (10.08 mg/mL vs. 0.045 mg/mL). Solid-state analyses confirmed hydrogen-bond formation and reduced crystallinity. DEM granules exhibited sustained drug release over 24 h (99.7 ± 0.8%) with improved dissolution efficiency compared to the marketed tablet (Mucosta®, 100 mg; T₅₀%: 5.03 h vs. 0.82 h). Kinetic modeling indicated non-Fickian anomalous transport (n = 0.47). The bioadhesive force of DEM granules (0.29 ± 0.02 N) was significantly higher than that of the pure drug and physical mixture. In vivo radiographic studies confirmed prolonged gastric retention. Conclusions: The DEM-based bioadhesive granule system effectively improves solubility, dissolution rate, mucoadhesion, and gastric retention of Rebamipide. This approach represents a promising platform for once-daily gastroretentive oral delivery, pending further pharmacokinetic evaluation. Full article

This review summarizes innovative co-formulation strategies for non-marketed dry powder inhalers (DPIs), enabling the simultaneous pulmonary delivery of multiple active pharmaceutical ingredients (APIs). Key approaches include co-amorphous systems (COAMS) and co-crystals, which combine two APIs into a single particle, improving aerodynamic properties, solubility, dissolution, and patient compliance while reducing manufacturing complexity. Core–shell microparticles, produced via spray drying, allow spatial separation and controlled release of APIs, minimizing drug–drug interactions and enabling tailored pharmacokinetics. Co-spray drying of dual APIs can yield particles with superior aerosolization and stability, though examples remain limited. Nanoparticle-based systems offer enhanced lung deposition and cellular uptake but face challenges in device compatibility, scalability, and regulatory approval. Each technology presents unique advantages and limitations regarding manufacturability, dose flexibility, and clinical translation. This review also highlights advances in in vitro toxicity testing, including air–liquid interface cultures, organoids, lung-on-chip models, and precision-cut lung slices, which are increasingly important as alternatives to animal studies. The importance of using an aerosol exposure system for the testing is highlighted. Ultimately, the choice of co-formulation platform should balance scientific innovation with practical considerations of manufacturing and regulatory requirements to maximize therapeutic benefit and commercial viability for future DPI combination products. Full article

Background: H007 is a novel selective AMP-activated protein kinase (AMPK) activator with demonstrated efficacy against hyperlipidemia; however, its oral bioavailability is limited by poor solubility and low intestinal permeability. This study aimed to develop a self-microemulsifying drug delivery system (SMEDDS) incorporating a H007–phospholipid complex (H007-PC) to improve both solubility and intestinal permeability. Methods: H007-PC-SME was prepared by integrating phospholipid complexes into an SMEDDS formulation. The formulation was optimized on the basis of emulsification efficiency, droplet size, and zeta potential, and was then evaluated for stability, in vitro drug release, and cellular uptake. Different H007 formulations were orally administered to golden hamsters to assess bioavailability, and a chylomicron flow blockade hamster model was used to evaluate lymphatic transport. Results: The optimized H007-PC-SME showed good stability, rapid self-emulsification, and improved drug solubility. Relative to ordinary H007 tablets, the relative bioavailability of H007-SME and H007-PC-SME was 376.65% and 464.62%, respectively, when calculated from M1 exposure, and 314.01% and 463.55%, respectively, when calculated from MP exposure. When evaluated in a cycloheximide model, H007-SME and H007-PC-SME increased the lymphatic transport fraction of M1 from approximately 0% to 22% and 54%, and that of MP from approximately 1% to 28% and 52% compared with ordinary H007 tablets. Conclusions: H007-PC-SME combines stable phospholipid complex formation with strong self-emulsification performance and effective drug dissolution. By overcoming the intrinsic limitations of the H007 active pharmaceutical ingredient and ordinary H007 tablets, this formulation improves membrane permeability and lymphatic transport, thereby enhancing oral bioavailability and therapeutic potential. The formulation shows good stability and acceptable in vitro biocompatibility under the tested conditions. The preparation process is straightforward, reproducible, and suitable for further pharmaceutical development. Full article

Background/Objectives: Enteric drug forms are developed to delay drug release to avoid drug degradation in the acidic environment of the stomach or to prevent irritation of the stomach mucosa. The bioavailability of posaconazole (POS) after oral administration depends on stomach pH and food intake. Delayed-release tablets and unmodified oral suspension are the POS formulations currently available on the market. The oral suspension formulation is characterized by highly variable bioavailability, which may significantly affect therapy effectiveness. Methods: In this study, multi-unit drug forms with delayed and sustained POS release were designed. Polymeric microparticles consisting of sodium alginate (ALG), methacrylic acid–ethyl acrylate copolymer (EUD), or both, were prepared using the spray-drying technique. The formulations that met the pharmacopoeia enteric release standards in the in vitro dissolution test were subjected to further in vitro evaluation via swelling and mucoadhesion assays, an antifungal activity test, attenuated total reflectance–Fourier transform infrared spectroscopy (ATR-FTIR), and thermal analysis. Results: It was shown that EUD formulations at concentrations of 5% and 6% provided enteric release, whereas ALG at 1.5% concentration exhibited a sustained, although not delayed, POS release profile. The optimal blended formulations (EAP15–EAP18), comprising 4% EUD with 1.5–2.0% ALG and either 1% or 4% POS, met the pharmacopoeia criteria for enteric dosage forms. Furthermore, these blends demonstrated the most favorable sustained-release profiles in the buffer phase, ranging from 2 to 3 h. The microparticles exhibited beneficial swelling and mucoadhesive properties, which are essential for prolonging contact with the intestinal mucosa; combined with antifungal properties. Conclusions: Obtained carrier may provide a promising preliminary basis for developing a multi-unit, sustained-release enteric dosage form for POS and future in vivo investigations. Full article

In this study, Paliperidone Palmitate (PP), a second-generation antipsychotic, commonly used for the treatment of schizophrenia, was encapsulated in bio-based non-isocyanate polyurethane (NIPU) nanoemulsions. NIPU was synthesized via an isocyanate-free polyaddition route, addressing safety and environmental concerns associated with conventional polyurethanes. The drug-loaded nanoparticles were produced utilizing oil-in-water (O/W) emulsions followed by solvent evaporation and lyophilization. NIPU concentrations of 0.3% and 0.5% w/v, as well as 0.5% w/v PVA were employed, while PP was incorporated at 0.2%, 0.5% and 1% w/v. The formulations were characterized by FTIR, DSC and XRD analyses, and the mechanical strength of neat sponges was evaluated. The nanoparticle formation and size were assessed by DLS and SEM analyses. The water contact angle, porosity measurements and aquatic and enzymatic hydrolysis were additionally performed. The resulting nanocarriers exhibited controlled particle size, increased drug-loading values, structural stability and biodegradability. Lastly, the in vitro dissolution studies revealed a system-specific burst release behavior, and a controlled and sustained overall drug-release profile for majority of the formulations, thereby indicating the potential of NIPU nanocarriers for drug delivery applications, particularly where sustained therapeutic effects are required. Full article

Children are often underserved by adult-oriented oral medicines, leading to off-label use and dosage-form manipulation that may compromise dosing accuracy. This review summarises recent advances in paediatric orodispersible tablets (ODTs), focusing on manufacturing technologies, superdisintegrants, taste masking, and in vitro disintegration testing. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance and a protocol registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (registration number INPLASY2025110022), we searched PubMed, EMBASE, MEDLINE, Scopus, and Google Scholar for experimental studies on paediatric-relevant ODT formulation and evaluation. Two reviewers screened studies and extracted data on manufacturing methods, excipients, disintegration/dissolution testing, and key outcomes. Risk of bias was assessed using a six-domain framework. Overall, 65 studies met the inclusion criteria for this review. Direct compression was the dominant method, with freeze-drying, sublimation, spray-drying, nanoparticle-in-tablet systems, and semi-solid extrusion/3D printing also reported. Crospovidone, croscarmellose sodium, and sodium starch glycolate were the most common superdisintegrants, while natural and co-processed disintegrants showed promise as cost-effective alternatives. Disintegration was usually assessed using pharmacopoeial methods, with some modified set-ups to better simulate oral conditions. Paediatric ODT development is advancing rapidly. Broader translation requires harmonised disintegration testing, age-stratified acceptability reporting, and GMP-ready workflows, alongside benchmarking of superdisintegrants and attention to dose flexibility, packaging, and affordability. Full article

Background/Objectives: This study aimed to develop bilayer tablets using hot-melt pneumatic extrusion (HMPE)-based 3D printing for the integrated treatment of allergic rhinitis and asthma. The formulation combined levocetirizine dihydrochloride (immediate release) and montelukast sodium (delayed release) within a single dosage form to provide a sequential-release formulation strategy relevant to the intended pharmacological roles of the two drugs. Distinct polymer matrices were selected for each drug layer to ensure mechanical robustness, stability, and appropriate release characteristics. Methods: The printed tablets were systematically characterized by mechanical testing, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and in vitro dissolution. Drug content uniformity was evaluated in accordance with USP <905>. Results: The tablets satisfied USP standards for content uniformity and exhibited sufficient mechanical strength for handling and packaging. DSC and PXRD analyses indicated amorphization of levocetirizine within the polymer matrix, while the amorphous state of the raw montelukast used in this study was retained after printing. In vitro dissolution tests demonstrated immediate release of levocetirizine in acidic medium (pH 1.2) and delayed release of montelukast at intestinal pH (6.8), thereby achieving the intended dual-phase release profile. Conclusions: These findings demonstrate the feasibility of fabricating an HMPE-based 3D-printed bilayer tablet integrating immediate-release levocetirizine and delayed-release montelukast, with reproducible dual-phase release and drug-specific solid-state and performance characteristics within a single oral dosage form. Full article

Background: This study aimed to investigate, from a scientific and formulation perspective, an oral semaglutide tablet incorporating sodium caprate (C10) as an intestinal absorption enhancer and to optimize its formulation performance using a Quality by Design (QbD)-based approach. Semaglutide—a peptide-based therapeutic—provides effective glycemic control and weight reduction; however, its extremely low oral bioavailability has limited administration to subcutaneous injection. Although various attempts have been made to improve peptide absorption, achieving consistent delivery through oral routes remains a significant challenge due to enzymatic degradation and poor membrane permeability. Methods: To overcome these limitations, an absorption enhancer (sodium caprate) was incorporated to enhance oral absorption, and a Quality by Design (QbD)-based approach was applied to systematically guide formulation development. Following the definition of the Quality Target Product Profile and critical quality attributes, risk assessments (Preliminary Hazard Analysis and Failure Mode and Effects Analysis) were conducted to identify key formulation factors. A design of experiments approach was then employed to determine the optimal tablet composition. Results: Consequently, the resulting formulation met all predefined quality criteria, including hardness, disintegration, friability, and content uniformity. In addition, the in vitro dissolution profile demonstrated a release pattern comparable to that of the reference product, with similarity factor values of 74.4, 74.7, and 71.3 at pH 1.2, 4.0, and 6.8, respectively. Conclusions: These findings indicate that the formulation can achieve consistent and reproducible quality performance as an oral semaglutide dosage form. The QbD-based formulation design strategy presented in this study provides a robust and broadly applicable approach for developing oral delivery systems for peptide drugs, including semaglutide, and ultimately provides useful formulation insight for future peptide-based oral delivery research. Full article

This study aimed to establish a more sensitive and reliable quantitative method for determining rafoxanide (RFX) in ovine plasma. The method was applied in an 84-day long-term comparative pharmacokinetic trial to evaluate the performance of a rafoxanide nanosuspension (RFX-NS) versus its conventional suspension (RFX-S) in sheep. Characterization of the two formulations revealed the following results: RFX-NS had an average particle size of 484.93 ± 43.11 nm, a uniform size distribution (PDI 0.06 ± 0.07), and a Zeta potential of −43.59 ± 0.67 mV, which were significantly superior to those of RFX-S (particle size 2379.67 ± 121.71 nm, PDI 0.93 ± 0.10, Zeta potential −38.10 ± 0.55 mV), demonstrating excellent physical stability. In vitro dissolution tests indicated a higher dissolution rate for RFX-NS (97.6% at 60 min). By integrating formulation characterization, in vitro dissolution assessment, and pharmacokinetic studies, this research provided a comprehensive analysis of the differences between the two formulations. Pharmacokinetic results showed that, compared to RFX-S, RFX-NS had a significantly reduced apparent volume of distribution (Vz/F: 856.02 ± 274.00 vs. 1404.17 ± 285.1 mL/kg, p < 0.01), a shorter elimination half-life (t_1/2: 4.05 ± 1.18 vs. 5.32 ± 0.94 days, p < 0.05), and a relative bioavailability of 128.98%. These findings suggest that RFX-NS is an improved novel formulation superior to the conventional suspension, as it enhances drug efficacy and efficiency by improving drug dissolution and absorption. Full article

Background: Nanostructured, rod-shaped microparticles represent a promising drug delivery platform for the pulmonary delivery and targeting of alveolar macrophages by exploiting the aerodynamic advantages of fiber-like geometries. These microrods feature a hierarchical architecture, designed for potential macromolecular payloads, and silica (SiO₂)-based systems have previously been shown to successfully deliver oligonucleotides in vitro. However, current microrod systems mainly rely on nanoparticulate SiO₂-based frameworks with limited biodegradability and lack a specific escape mechanism to the cytosol. Therefore, a nanostructured calcium phosphate (CaP) framework is proposed as a biodegradable and resorbable alternative, featuring pH-responsive dissolution under endolysosomal conditions. Methods and Results: This study presents the fabrication of nanostructured, rod-shaped calcium phosphate microparticles and discusses their suitability as a potential pulmonary drug delivery platform. The particles feature dissolution-driven disintegration in acidic and ion-rich environments relevant to phagolysosomes. In addition, the particles exhibited a favorable acute cytotoxicity profile in the murine alveolar macrophage cell line MH-S compared with their SiO₂-based counterparts. Comparative RNA-seq analysis of MH-S exposed to the particles indicates a mild transcriptomic response, while canonical signatures of classical or alternative macrophage activation programs were not observed, supporting a generally well-tolerated exposure profile of the carrier. Conclusions: Together, these findings establish key prerequisites for employing calcium phosphate microrods as a biodegradable pulmonary carrier platform in subsequent studies incorporating therapeutic cargos. Full article

Background/Objectives: Hot-melt injection molding (HMIM) was evaluated as a solvent-free process for the preparation of glibenclamide (GLB), a poorly soluble BCS Class II drug, glassy solutions with the objective of improving dissolution and bioavailability for diabetes. Methods: GLB was blended at a concentration of 10% w/w with PVP K25, PVP VA64, and Soluplus^® (SOL) matrices. The miscibility of the GLB–polymer systems (matrices) was calculated based on the Hansen solubility parameters and validated using differential scanning calorimetry (DSC) analysis. The HMIM extrudates were milled into granules and analysed for their solid-state properties (DSC, XRPD, FTIR, and SEM studies), and flow properties. The produced granules were compressed into immediate release tablets and assessed for in vitro performance, stability, and in vivo bioavailability using 20 healthy male Sprague Dawley rats. Results: Findings revealed the formation of single-phase glassy solutions, specifically for PVP VA64 and SOL, which also exhibited advantageous manufacturing and extrudate clarity. The glassy solution formulations showed considerably improved dissolution characteristics compared with the crystalline GLB and the commercial product. The glassy solution formulations displayed fast drug release for PVP K25 and PVP VA64, and biphasic drug release for SOL. Stability testing confirmed the capability of PVP VA64 and SOL to maintain GLB in a molecularly dispersed, amorphous state for 12 months. The in vivo assessment revealed an increase in relative bioavailability to 246.3% and 124.5% for the SOL and PVP VA64 formulations when compared to the commercial formulation. Conclusions: Overall, the findings demonstrate the potential of HMIM-processed glassy solutions, especially those prepared using SOL, as promising platforms for promoting oral delivery of the poorly soluble antidiabetic GLB. Full article

The present study investigates the co-crystallization process of rivaroxaban (RIV), a poorly water-soluble potent oral anticoagulant, with niacinamide (NIA), a highly soluble and pharmaceutically acceptable co-crystal former, in two different molar ratios (1:1 and 1:2). The aim was to enhance the physicochemical and biopharmaceutical properties of rivaroxaban such as dissolution rate and aqueous solubility, by forming stable co-crystals through a solvent evaporation technique. The resulting co-crystals (RIV-NIA, 1:1 co-crystallization compound, F1 and RIV-NIA, 1:2 co-crystallization compound, F3) were characterized using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), powder X-ray diffraction (XRD) and thermal analysis, which confirmed the formation of a new rivaroxaban–niacinamide co-crystalline phase. In vitro dissolution studies confirmed a significant enhancement in the dissolution rate of the two obtained co-crystals. These findings suggest that stoichiometric variation plays an important role in co-crystal performance and in improving solubility compared with the pure drug. Also, the obtained results suggest that niacinamide is an effective coformer for improving the dissolution and physicochemical properties of rivaroxaban. Full article

Background: The key parameters determining the bioavailability of an active pharmaceutical ingredient are its solubility/dissolution rate in physiological fluids and permeability across biological membranes. Highly accurate in vitro prediction of bioavailability is a key issue that typically arises during the development of new drug formulations and the improvement of existing ones. Objectives: The objective of the present work is to study the dissolution/release and permeation of olanzapine (OLZ) from two- and three-component solid dispersions (SDs) with sulfobutylether-β-cyclodextrin (SBE-β-CD) and several pharmaceutical adjuvants as solubilizing agents. Methods: Solid dispersions were prepared by mechanical grinding and characterized with X-ray Phase analysis (PXRD), Fourier Transform Infrared (FTIR) and Raman spectroscopy, Differential Scanning Calorimetry (DSC), and Scanning Electron Microscopy (SEM). Results: Raman spectroscopy was shown to be the best for revealing the interactions of OLZ with SBE-β-CD and γ-aminobutyric acid (GABA) in the three-component SD. The kinetic dependences of OLZ release and diffusion through the cellulose membrane were thoroughly described by quantitative parameters and classified according to the drug release mechanism. Significant improvement of release rate, OLZ concentration, and permeation with SDs compared to the pure OLZ was demonstrated. Conclusions: It was shown that the selected dispersions were stable when stored under normal conditions but underwent changes upon exposure to elevated temperature and humidity. The nature of these changes was determined by the properties of the components and their mutual interactions. Full article

Background/Objectives: Biorelevant in vitro dissolution testing is used increasingly to predict complex mechanisms in the gastrointestinal (GI) tract that determine oral bioavailability. However, the limited use of non-compendial systems is driven by the lack of widely accepted, standardized validation frameworks. This ongoing gap continues to restrict their adoption relative to United States Pharmacopeia (USP) apparatus. While the physiological relevance and biopredictive capabilities of the tiny-TIM and TIM-1 in vitro GI models have been demonstrated in previous studies, their inter-laboratory reproducibility has not been systematically established. Therefore, this international ring study evaluates the reproducibility of in vitro simulations of GI transit and absorption of paracetamol in fasted- and fed-state conditions in tiny-TIM and TIM-1. Methods: Three laboratories used TIM-1 and five used tiny-TIM to simulate oral administration of a 500 mg paracetamol solution to a healthy adult. Paracetamol solution was selected as a well-characterized and widely available BCS I compound to minimize formulation and solubility effects and focus on system performance, enabling the generation of a generic validation dataset for the reproducibility of TIM experiments. Results: Paracetamol bioaccessibility profiles were repeatable and reproducible (all pairwise f₂ > 50). Maximum differences in total bioaccessible paracetamol were 0.9% (TIM-1) and 2.8% (tiny-TIM) within laboratories and 3.4 and 5.9% between laboratories. Inter-lab variability at individual time points remained <4.0% (fasted) and 5.2% (fed). Both TIM models produced biopredictive metrics, correctly predicting no food effect on total paracetamol bioaccessibility and capturing delayed t_max. Gastric and intestinal environments showed repeatable pH, temperature, and GI transit characteristics, with fluctuations across transit stages that mirrored reported in vivo patterns. Conclusions: These results demonstrate that TIM systems can reproducibly simulate gastrointestinal conditions across laboratories and generate consistent measurements of drug product performance, despite the complexity of the dynamic processes involved. While this evaluation involving a single BCS I drug solution should not be directly extrapolated to experiments with poorly soluble compounds or different formulations, it supports the use of TIM systems as robust in vitro models in drug product development. This study provides a standardized, inter-laboratory, baseline performance dataset to support regulatory submissions incorporating TIM data and enable more confident interpretation of TIM experiments. Full article

This study aimed to develop a 100 mg immediate-release (IR) tablet containing dasatinib monohydrate, a tyrosine kinase inhibitor, using a Quality by Design (QbD) framework at laboratory scale. The development strategy focused on systematic identification and control of critical process parameters (CPPs) affecting tablet quality during wet granulation. Preformulation studies were conducted to evaluate key physicochemical properties of the active pharmaceutical ingredient (API), including solubility, particle size distribution, and crystallinity, which may influence dissolution behavior. A risk assessment approach based on preliminary hazard analysis (PHA) and failure mode and effects analysis (FMEA) was applied to identify high-risk process variables. Based on the risk assessment results, chopper speed during wet granulation and compression force during tableting were identified as critical process parameters. These factors were further investigated using a Design of Experiments (DoE) approach based on Define Custom Design (DCD) and response surface methodology (RSM) to evaluate their effects on critical quality attributes (CQAs), including dissolution performance, disintegration time, and tablet friability. Response surface analysis established a design space in which chopper speed ranged from approximately 2300–2500 rpm and compression force ranged from 11 to 13 kN, ensuring consistent tablet quality within the investigated operating range. The optimized process conditions produced tablets that satisfied predefined quality targets. Comparative dissolution studies demonstrated dissolution profiles comparable to the reference product across pH 1.2, 4.0, and 6.8 media, with similarity factor (f₂) values ranging from 51.18 to 85.23. The experimentally established design space demonstrated reproducible in vitro performance and physicochemical stability under accelerated storage conditions. Overall, this study demonstrates the practical application of a QbD-based development strategy integrating risk assessment and response surface optimization to improve process understanding and manufacturing robustness in wet granulation-based tablet production. Full article