Search Results (2,122)

Currently, GLP-1RAs are peptide drugs, typically administered by injection due to insufficient absorption, and only one GLP-1RA, semaglutide, is available as an orally administered drug. To overcome the absorption challenges of oral peptides, this drug product contains the absorption enhancer SNAC. As the tablet is eroded in the stomach, SNAC neutralizes the acidic gastric environment, thereby protecting the semaglutide from enzymatic degradation. Then, SNAC fluidizes the stomach lipidic membrane to increase semaglutide transcellular permeability across the gastric epithelium. It is necessary to realize that the use of such a unique drug product, that relies solely on the stomach for absorption, is expected to be affected by the extreme gastric anatomy/physiology changes post-MBS. Hence, we analyzed the key mechanisms that may affect the bioavailability of oral semaglutide post-MBS. Several mechanisms appear to potentially reduce oral semaglutide absorption post-MBS, including decreased inner gastric surface area, decreased gastric contractility, and faster gastric emptying. Hence, the effectiveness of the complex formulation, that relies solely on the stomach for the SNAC activity and semaglutide absorption, may be severely hampered post-MBS; clinicians should be aware of the potential malabsorption of oral GLP-1RA post-MBS, and preferably consider subcutaneous therapy until specific pharmacokinetic/clinical data are available. Full article

Fractures are becoming a bigger and bigger global health problem, with an estimated 178 million new cases each year and 455 million people living with disabilities caused by fractures. Donor site morbidity, the risk of immune rejection, and limited functional integration all make current grafting techniques less effective. Biomaterials that come from nature, like collagen, gelatin, chitosan, alginate, hyaluronic acid (HA), and silk fibroin, have become promising scaffolds because they are bioactive, mimic the extracellular matrix (ECM), and can be broken down by enzymes. Crosslinking and composite reinforcement can greatly change how well they work. For example, collagen scaffolds that are highly crosslinked with glutaraldehyde keep up to 51.9% of their tensile strength after being exposed to enzymes, while non-crosslinked scaffolds only keep 12% of their strength. Chitosan–hydroxyapatite matrices, on the other hand, can reach compressive strengths of 2–12 MPa, which is close to the strength of cancellous bone. Additive manufacturing and 4D printing allow for precise control of structures and the ability to change their shape over time, which helps with vascularization and mechanical adaptation. Injectable and in situ-forming hydrogels show clinically important results, such as filling 85% of osteochondral defects in rabbits, improving left ventricular ejection fraction by up to 9% in large-animal cardiac models, and speeding up healing by 25–40% in chronic wounds. Even with these improvements, it is still hard to get batch consistency, a standardized way to test mechanical properties, and production that meets GMP (Good Manufacturing Practices) standards and can be scaled up. Full article

Kaurenoic acid (KA) is an ent-kaurane diterpenoid present in several medicinal plant species and has been reported to exhibit anti-inflammatory, cytotoxic, and analgesic activity in experimental models. Despite its pharmacological profile, the development of KA as a therapeutic agent has been hindered by its unfavorable physicochemical and biopharmaceutical properties. KA is highly lipophilic and poorly soluble in water, which limits its dissolution, systemic exposure, and oral bioavailability. These limitations are common among plant-derived bioactive compounds and pose significant challenges for clinical development. Lipid-based nanocarrier systems, particularly liposomal formulations, have therefore been investigated as potential delivery strategies for improving the biopharmaceutical performance of KA. Encapsulating KA within phospholipid bilayers can improve its apparent solubility, protect it from degradation, and modify its biodistribution compared to the free compound. In this review, we discuss the pharmacological mechanisms of KA, its physicochemical properties, and the biopharmaceutical barriers to its therapeutic development. We also critically evaluate published studies on nanocarrier-based formulations, focusing on encapsulation efficiency, particle size, release properties, and pharmacokinetics (PK). Additionally, regulatory and pharmaceutical considerations relevant to lipid-based delivery of KA are addressed. Available evidence supports lipid-based nanocarriers as a promising strategy to improve preclinical development and formulation performance of poorly soluble plant bioactives such as kaurenoic acid. Although KA-loaded nanocarriers demonstrate encouraging activity in preclinical models, comprehensive pharmacokinetic and safety evaluations remain necessary before clinical development can be realistically considered. 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

Polymer–drug conjugates (PDCs) represent an advanced drug delivery strategy designed to address critical limitations of conventional therapeutics, including poor water solubility, rapid systemic clearance, and off-target toxicity. By covalently linking therapeutic agents to polymeric carriers through rationally designed linkers, PDCs enable improved pharmacokinetic profiles, enhanced stability, and controlled drug release. This review provides a comprehensive overview of the key design principles governing PDC systems, with a particular focus on the role of biofunctional polymers. Essential parameters for polymer selection, including biocompatibility, biodegradability, molecular weight, and functional group availability, are discussed in relation to their influence on drug loading, release kinetics, and biological performance. In addition, both natural and synthetic polymers are evaluated for their ability to improve solubility, modulate biodistribution, and reduce systemic toxicity. An overview of stimuli-responsive PDCs is provided, including pH-, redox-, and temperature-sensitive systems, which enable site-specific and spatiotemporally controlled drug release in response to pathological microenvironments. We emphasize the special role of bioactive polymers such as poly-lysine, hyaluronic acid, chitosan, and gelatin for their intrinsic biological activity, including receptor-mediated targeting, antimicrobial activity, and synergistic therapeutic effects. These properties support the development of dual-active conjugates with enhanced specificity and efficacy. Overall, this review underscores the transition of polymers from passive carriers to active therapeutic components and outlines current challenges and future perspectives for the clinical translation of next-generation PDCs. Full article

Background: Global immunization programs continue to rely on needle-based injections despite persistent concerns regarding sharps disposal, accidental injuries, and the technical skill required for accurate intradermal administration. Needle-free jet injectors (NFJIs) are an alternative delivery method in which narrow, high-velocity liquid jets penetrate the skin without a needle. Contemporary designs, ranging from single-use disposable-syringe injectors to digitally controlled electromechanical devices, address historical safety issues and meet current WHO and FDA device expectations. Methods: Evidence from engineering analyses, preclinical modeling, and clinical trials was reviewed to characterize how jet velocity, nozzle structure, and formulation rheology influence skin penetration and drug dispersion. Published vaccine studies were examined for antibody responses, seroconversion, and reactogenicity compared with needle–syringe injection. Field vaccination campaign data from national campaigns and operational reports were evaluated to describe implementation steps, acceptability, and implementation constraints. Results: Published studies evaluating vaccines, including inactivated influenza, hepatitis B, typhoid, rabies, and measles, report antibody titers and seroconversion rates after NFJI administration that are comparable to those achieved with conventional intramuscular or intradermal needle injection. Needle-free delivery was associated with operational advantages in several immunization programs, including reduced sharps waste and improved vaccination rate during high-volume immunization campaigns. Local and systemic reactogenicity follows expected patterns, with slightly higher injection-site responses in some NFJI studies. Imaging and mechanical data confirm that jet performance depends on nozzle geometry and controlled pressure pulses. At the same time, formulation stability remains a critical determinant of successful jet-based vaccine administration, particularly for protein antigens, adjuvanted formulations, and emerging mRNA vaccines that may experience transient shear stress during high-velocity injection. Evidence from vaccination campaigns further indicates that needle-free jet injectors reduce sharps waste, simplify vaccine handling and administration procedures, and support rapid vaccine delivery in large-scale immunization programs. Conclusions: Needle-free jet injectors are a practical alternative to traditional needle-based injections for some vaccines. Their main benefits include enabling intradermal dose-sparing strategies, reducing reliance on sharps disposal methods, and enabling the efficient vaccination of large groups without compromising immunogenicity. Future research should define the physicochemical stability limits of biologic formulations subjected to jet injection and evaluate digitally controlled injectors capable of precise pressure modulation and adjustable delivery parameters. In addition, needle-free jet injection eliminates needle penetration and sharps handling, which may reduce needle-associated anxiety and improve vaccine acceptability among individuals with needle aversion. 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

Effective oral interventions for alcohol-induced metabolic stress and liver injury remain limited. Pre-absorptive gastrointestinal alcohol handling is gaining interest as a non-pharmacological strategy to reduce hepatic burden. In this study, we developed a formulation-integrated, food-compatible lyophilized recombinant whole-cell catalyst based on Escherichia coli Nissle 1917 engineered to express alcohol dehydrogenase and acetaldehyde dehydrogenase. Rather than focusing exclusively on strain-level genetic modification, the engineered cells were protected by lyophilization combined with a food-grade chitosan–alginate layer-by-layer coating, forming an artificial cell wall designed to enhance survivability during oral delivery. The formulation resisted simulated gastric acid, sodium taurocholate, and ethanol, retained enzymatic activity after storage, and demonstrated formulation stability. In alcohol-exposed mice, oral administration reduced blood ethanol and acetaldehyde levels, improved liver biochemical parameters, attenuated hepatic steatosis, and partially restored oxidative stress indicators. Integrated multi-omics analyses indicated coordinated gut-associated metabolic and inflammatory responses to alcohol and intervention, rather than a single dominant pathway. These findings provide hypothesis-generating evidence; causality remains to be established. Overall, this study demonstrates a proof-of-concept, food-compatible lyophilized recombinant whole-cell catalyst that integrates enzymatic function with formulation stability and gastrointestinal resilience, highlighting an applied, food-compatible microbial framework for exploring alcohol-related metabolic stress. 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

Agapanthus africanus (L.) Hoffmanns. is a medicinal plant traditionally used in South Africa for its promise as a source of bioactive compounds with anticancer properties. This study aimed to investigate the apoptotic effects of A. africanus fractions on cancer cell lines and to identify the bioactive phytochemical constituents using gas chromatography-mass spectrometry analysis. To test for cytotoxicity, MCF-7, A549, and HeLa cancer cells were treated with crude extract, n-hexane, n-butanol, dichloromethane, and aqueous fractions of A. africanus extracts at different concentrations (0.00–1000 µg/mL). Total apoptosis was quantified using Annexin V/PI staining. The 4′,6-diamidino-2-phenylindole was used to detect nuclear morphological changes and the Caspase-GLO 3/7 assay was employed to check the caspase activation in the cancer cells. Expression of apoptosis-related (caspase-3, bax, bcl-2) genes was evaluated using real time-polymerase chain reaction. The crude extract of A. africanus exhibited dose-dependent cytotoxicity against MCF-7, A549, and HeLa cells, with IC₅₀ values of 130 µg/mL, 380 µg/mL, and <125 µg/mL, respectively. Among the tested fractions, the n-butanol fraction showed cytotoxicity towards MCF-7 cells with an IC₅₀ value of <870 µg/mL. In contrast, n-hexane, dichloromethane and the aqueous fractions exhibited higher IC₅₀ values against cancer cells. Flow cytometry analysis, which was applied to quantify total apoptosis, revealed that the crude extract of A. africanus induced apoptosis by (~60%) compared to the n-butanol fraction, which exhibited a moderate apoptotic effect (~27%). DAPI nuclear staining showed nuclear shrinkage and chromatin condensation in the MCF-7 cell line, whereas in Caspase-GLO 3/7, the crude extract and n-butanol fraction resulted in significant luminescence, indicating activation of caspase-3/7. Caspase-3/7 analysis showed A. africanus treatments produced varying levels of apoptotic activation. The crude extract increased caspase activity by 2.9-fold, while the n-butanol fraction induced a 1.7-fold rise compared with untreated cells. GC-MS chromatograms detected and identified 16 compounds in the fractionated n-butanol and 23 compounds from the crude extract of A. africanus. The major compounds identified from the n-butanol fraction included n-hexadecanoic acid; α-tocopherol and 9,12,15-octadecatrienoic acid, while the GC–MS profile of the crude extract was dominated by 6,10,14-trimethylpentadecan-2-one; 1,3,5-Triphenylcyclohexane and phytol. The study indicates the pro-apoptotic potential of A. africanus, particularly in its crude form, supporting its ethnopharmacological use and suggesting its relevance as a candidate for anticancer drug discovery. Full article

Glycosaminoglycans (GAGs) and their degrading enzymes have extensive applications and biotechnology and medicine, and play a crucial role in the recycling of organic matter in oceans. In this study, a potential GAG utilization gene cluster was identified in the genome of a novel marine Bacteroidetes, Roseihalotalea indica gen. nov. sp. nov. TK19036^T, through sole carbon source cultivation and differential proteomic analysis. Multiple GAG-lyases within this locus were purified and characterized. RiPL8 comprises a functionally unknown N-terminal domain and a catalytic C-terminal domain, exhibiting specificity for degrading hyaluronic acid (HA). The activity of RiPL35 is sensitive to Ca²⁺ ion concentration with an optimum at 10 mM. RiPL38 is the first reported member of the PL38 family capable of degrading HA and chondroitin sulfate (CS). In summary, our study reveals Roseihalotalea indica gen. nov. sp. nov. TK19036^T harbors an unpredicted GAG degradation gene cluster, and the encoded GAG-lyases exhibit distinct substrate specificities compared to the host organism. Full article

Magnetic nanoparticles represent the next-generation drug delivery systems, enabling drug targeting to specific organs without adverse effects on the body and with a controlled release rate. Their strengths are represented by biocompatibility, low cost, and easy drug loading; some drawbacks are aggregation and poor stability in biological media. In the present work, we synthesized magnetic core–shell structures with a magnetite core coated with layered double hydroxides (LDHs) based on Mg²⁺ or Zn²⁺ and Al³⁺ ions and loaded with meloxicam, a poorly water-soluble anti-inflammatory drug. Several syntheses have been attempted to obtain iron oxides based on the only magnetite phase. The combined use of different characterization techniques allowed us to reveal that the best product, showing the crucial room temperature superparamagnetism and a good level of compositional uniformity, was obtained from co-precipitation in nitrogen flow. The next LDH coating was successful, even if the hybrids showed the occurrence of aggregation. The drug was mainly adsorbed onto the LDH surfaces, as shown by the X-ray diffraction and Infrared Spectroscopy techniques. The loaded meloxicam amount was low, but the subsequent release into simulated body fluid could be prolonged for 4 days. Our study provides a proof of concept about the importance of a thorough characterization of the nanocomposite hybrids and their possible use for tricky drugs, such as those of class II of the Biopharmaceutical Classification System. Full article

Background/Objectives: Tafamidis, a transthyretin kinetic stabilizer, increases circulating transthyretin levels in treated patients. While this effect is well documented, its underlying mechanism remains incompletely understood. This study aimed to evaluate the performance of physiologically based pharmacokinetic (PBPK) model performance and to calibrate a hypothesis-consistent quantitative systems pharmacology (QSP) model of tafamidis and transthyretin dynamics to explore mechanistic hypotheses underlying the clinically observed increase in circulating transthyretin and the associated dose–response relationship. The PBPK model constitutes the primary framework, while the coupled QSP component illustrates how tafamidis exposure predictions can be used to evaluate mechanistic hypotheses of TTR turnover. Methods: A PBPK–QSP model was constructed in Simcyp (V23) using LUA-based modules. The PBPK part was parameterized from the literature and validated against data from therapeutic single-dose, therapeutic multiple-dose, and supratherapeutic dose clinical studies. The QSP part of the model describes tafamidis–TTR binding kinetics, stabilization, and clearance of bound complexes. Simulations were performed in thirty virtual healthy male subjects aged 30–40 years, incorporating physiological variability in baseline TTR concentrations. Results: Mean predicted versus observed ratios of tafamidis AUC and $C_{max}$ values were within a 1.3-fold range across validation studies. The integrated model reproduced the clinically reported 33% increase in TTR concentration through a calibrated clearance-scaling factor. It supports the hypothesis that reduced clearance of tafamidis-bound TTR may explain the observed effect without modifying TTR synthesis. Dose-sensitivity simulations indicated that patients with low baseline TTR may achieve adequate stabilization at reduced doses, while those with higher baseline TTR concentration may require higher doses. Conclusions: The developed PBPK–QSP model not only reproduces tafamidis pharmacokinetics and TTR responses but also proposes a plausible mechanistic hypothesis consistent with clearance modulation of stabilized TTR contributing to the clinical effect. Full article

Background/Objectives: Recombinant adeno-associated virus (rAAV) has become a leading vector in gene therapy. However, manufacturing limitations may result in replication-competent AAV (rcAAV) contamination of clinical rAAV products, posing safety risks. Rigorous testing is therefore essential, and the use of accurately calibrated rcAAV reference standard materials is critical for ensuring assay stability and reliability. A disadvantage of the widely used Tissue Culture Infectious Dose 50 (TCID₅₀) assay is its high variability. This study introduces an optimized TCID₅₀ assay for the precise quantification of infectious rcAAV particles. Methods: We developed a TCID₅₀ assay tailored to rep2-based rcAAV, optimizing key aspects such as viral infection conditions, qPCR reaction systems, and standard curve preparation. We employed an innovative strategy to prepare the standard curve using serial dilutions of rcAAV in cell lysate, ensuring alignment with the test sample matrices. Results: The rcAAV-derived standard curve demonstrated exceptional linearity (R² > 0.99), sensitivity (LOQ ≈ 38 copies), and reproducibility, enabling robust endpoint qPCR analysis. The optimized assay significantly improved the precision of the TCID₅₀ assay, as an inter-assay coefficient of variation (CV) of 11.4% was achieved. Conclusions: This refined TCID₅₀ assay is a reliable method for calibrating infectious titers of rcAAV reference standard materials, thereby enabling the standardization of rcAAV testing. Full article

Background/Objectives: Cannabidiol is a non-psychoactive substance that possesses properties suitable for the treatment of several disorders related to the central nervous system. However, successful administration of cannabidiol remains challenging due to low and variable bioavailability and potential adverse effects. Intranasal delivery of cannabidiol may help overcome these limitations, but the pharmacokinetics of such administration has not been fully established. Methods: Starch-based cannabidiol-loaded nanoparticles were used as carriers and were administered to rats via the intranasal route. Cannabidiol levels in plasma and the brain were examined at different time points and compared to cannabidiol levels in plasma and the brain following intravenous administration of cannabidiol solution for injection. Pharmacokinetic parameters were calculated for each delivery route, and a pharmacokinetic model was fitted for the intranasal administration. Results: Intranasal administration resulted in a bioavailability of 47.9%. Systemic absorption accounted for 44% of the absorbed drug, while 56% was absorbed by direct brain entry. Intranasal administration resulted in rapid brain penetration with a brain t_max of 10 min and demonstrated a brain bioavailability of 28.5% compared to bioavailability after intravenous bolus injection of cannabidiol solution. Conclusions: Intranasal administration of cannabidiol-loaded nanoparticles was found to be effective for the delivery of cannabidiol to the brain with significantly lower systemic exposure compared to intravenous administration. A proposed pharmacokinetic model was found to be appropriate in describing and predicting the disposition pathways following intranasal administration, especially when designing drug delivery systems for brain targeting. Full article