Reliable prediction of active pharmaceutical ingredient (API) solubility in complex solvent systems remains challenging. Existing models often sacrifice generalizability for accuracy or have limited applicability due to...Reliable prediction of active pharmaceutical ingredient (API) solubility in complex solvent systems remains challenging. Existing models often sacrifice generalizability for accuracy or have limited applicability due to implementation complexity. The current study presents a practical, streamlined modeling framework requiring only temperature, solvent composition, and Hansen solubility parameters (HSPs) - information that is simple and readily accessible. These parameters serve as inputs for an effective and easy-to-apply model: the multilayer perceptron artificial neural network (MLPANN). Beyond optimizing the network architecture with a genetic algorithm (GA), model accuracy is further supported by six input scenarios designed to explore alternative HSP formulations and dimensional reduction strategies. To ensure generality, the MLPANN was trained on 496 experimental solubility values of acetaminophen, diazepam, ibuprofen, lorazepam, and naproxen in both neat and binary solvent systems, including water, ethanol, isopropanol, dioxane, NMP, and propylene glycol. Two scenarios, using the optimized networks, achieved R values exceeding 0.99 across training, validation, and testing subsets. Graphical validation-an important aspect often overlooked in previous studies-demonstrated excellent predictive performance for unseen testing data of acetaminophen in isopropanol-water and naproxen in ethanol-water mixtures.
Para-coumaric acid (P-CA), a plant-derived phenolic compound, exhibits potent antioxidant activity that counteracts oxidative stress, a key factor delaying wound repair. In this study, a novel biocompatible wound healing...Para-coumaric acid (P-CA), a plant-derived phenolic compound, exhibits potent antioxidant activity that counteracts oxidative stress, a key factor delaying wound repair. In this study, a novel biocompatible wound healing scaffold was developed by incorporating P-CA into a chitosan-based polymeric matrix using hot-melt extrusion (HME) combined with fused deposition modeling (FDM) 3D printing. Chitosan (CS), polyethylene oxide (PEO), and cryomilled polycaprolactone (PCL) were used to achieve optimal printability and mechanical strength. The physical mixtures were extruded (110 °C, 50 rpm, 2.5 mm die) and printed into scaffolds (20 × 20 × 1 mm, 80 % infill). The optimized formulation, PCL/CS/P-CA/PEO (35:20:10:35, %w/w), produced scaffolds with excellent dimensional accuracy and mechanical integrity. In-vitro drug release studies demonstrated a sustained release of P-CA over three days. Antibacterial testing against Escherichia coli (E.coli) showed no inhibition with PCL/PEO, while CS and P-CA provided moderate activity individually. Notably, their combination yielded the highest antibacterial effect, suggesting a synergistic effect. These results suggest that P-CA-loaded CS-based scaffolds can provide sustained drug delivery with enhanced antibacterial performance, offering promise for wound healing applications.
An apparatus was designed and constructed to simulate the effect of large intestinal motility on drug release measurement in vitro, the purpose being to evaluate the influence of implementing gut motility on release rate...An apparatus was designed and constructed to simulate the effect of large intestinal motility on drug release measurement in vitro, the purpose being to evaluate the influence of implementing gut motility on release rate from matrix tablets intended for controlled colonic delivery. The USP 1 dissolution apparatus was modified by replacing the basket with a bag holder and a mesh bag that contained the dosage form and adding polymer beads inside and outside of the bag in the dissolution vessel (Bag-Beads model). The motility index resulting from contractions of the gut wall was calculated from intraluminal pressure data measured in the large intestine of healthy volunteers with the SmartPill® ingestible telemetric capsule. It was possible to reproduce this motility index in the in vitro Bag-Beads model utilizing the SmartPill® by adjusting the number of beads of appropriate size and density and the rotation rate of the shaft holding the bag. Reproducibility of motility index and drug release measurement was established and a correlation between in vitro motility index and drug release rate was found for matrix tablets consisting of xyloglycan. This is a plant polysaccharide used as matrix former that was demonstrated previously to provide controlled colonic release by the action of bacterial enzymes. Drug release rate in the Bag-Beads model replicating the in vivo motility index was higher than release rate measured in the compendial USP 2 apparatus. This was true for different levels of bacterial xyloglucanase activity. It is concluded that this simulation of motility provides an indication of the effect of large intestinal dynamics on drug release. A comparison of the measured release rate with preclinical in vivo results is discussed, additional data is required, however, for an in vitro - in vivo correlation. The study highlights the potential to simulate the effect of contractile large intestinal activity for better in vitro prediction of drug release and the possibility to develop and optimize colonic targeting formulations under improved biorelevant testing conditions.
Craniofacial fractures present intricate geometries that require defect-matched scaffolds for effective regeneration. Advanced 3D printing enables the fabrication of anatomically tailored structures, making it a powerful...Craniofacial fractures present intricate geometries that require defect-matched scaffolds for effective regeneration. Advanced 3D printing enables the fabrication of anatomically tailored structures, making it a powerful tool in bone tissue engineering. In this study, a novel 3D-printed scaffold integrating polyvinyl alcohol (PVA), hyaluronic acid (HA), fucoidan (Fc), and merwinite (Mr) nanoparticles with recombinant VEGF was developed as a multifunctional platform, with the aim of promoting both osteogenesis and angiogenesis in complex craniofacial defects. The HA.Fc.VEGF.Mr scaffold exhibited a compressive strength of 3.19 ± 0.11 MPa and an elastic modulus of 21.75 ± 3.32 MPa, making it suitable for craniofacial bone repair. After 28 days of immersion in PBS, the scaffold showed a degradation rate of 50.6 ± 4.6 %, while VEGF release reached 95.1 ± 5.1 % in a sustained, linear pattern by day 11. Bioactivity was validated through apatite-like deposition in SBF immersion for 28 days, alongside measurable release of Ca, Si, and Mg ions. In vitro assessments demonstrated high cytocompatibility and enhanced osteogenic activity, confirmed by ALP levels, calcium deposition, and the upregulation of COL1, RUNX2, and osteocalcin. Angiogenic potential was further validated using the CAM assay, where the HA.Fc.VEGF.Mr scaffold exhibited superior neovascularization compared to other groups. These findings demonstrate the multifunctionality and regenerative potential of this scaffold for craniofacial bone repair.
The physiologically-based characteristics, the convenience of species extrapolation, and the capacity to integrate diverse in vivo mechanisms have contributed to the increasing employment of the physiologically based pha...The physiologically-based characteristics, the convenience of species extrapolation, and the capacity to integrate diverse in vivo mechanisms have contributed to the increasing employment of the physiologically based pharmacokinetic (PBPK) model in the pharmacokinetic and pharmacodynamic investigations of nanoparticles. However, due to the significant differences in in vivo mechanisms between nanoparticles and small molecule drugs, there are variations in the establishment of PBPK models, such as distribution mechanisms, clearance pathways, drug release, in vivo circulation pathways and indication. This review highlights the distinctions in PBPK modeling strategies between nanoparticles and small molecule drugs. It conducts a comprehensive analysis of current progress in PBPK models for nanoparticles, including model structure design, such as the setup of compartments and sub-compartments, blood circulation and lymphatic circulation, mononuclear phagocyte system, and tumor compartment; the in vivo mechanisms of nanoparticles, such as the permeability-limited mechanism, protein coronas, and drug release from nanoparticles; as well as parameter setting, including the tissue-to-plasma partition coefficient, permeability coefficient, clearance rate, and parameters related to the mononuclear phagocyte system. Ultimately, this review analyzes the validation methods and accuracy of the 61 PBPK models developed over the past two decades. In addition, several existing issues within the PBPK models for nanoparticles, along with their potential solutions, are proposed. It is anticipated that this review will be beneficial to researchers engaged in establishing PBPK models for studying the in vivo behavior of nanoparticles.
Intranasal delivery offers a non-invasive route for transporting drugs to the brain by bypassing the blood-brain barrier. However, the limited fluid volume in the nasal cavity restricts the solubilization of poorly water...Intranasal delivery offers a non-invasive route for transporting drugs to the brain by bypassing the blood-brain barrier. However, the limited fluid volume in the nasal cavity restricts the solubilization of poorly water-soluble drugs such as carbamazepine (CBZ). In this study, we developed an inclusion complex of CBZ with hydroxypropyl-β-cyclodextrin (HP-βCD) to enhance its solubility and facilitate nose-to-brain delivery. Phase solubility analysis and Job's plot confirmed the formation of a 1:1 complex. Powder formulations were prepared via freeze-drying and spray freeze-drying. The powders completely dissolved within 5 min and maintained their amorphous state during long-term storage. Intranasal administration of the CBZ/HP-βCD complex powders in rats resulted in significantly improved brain uptake compared with that of the CBZ bulk drug or physical mixtures. Notably, the brain-to-plasma ratio was higher for powder formulations than for liquids, suggesting enhanced direct transport to the brain. Regional brain distribution analysis revealed predominant accumulation in the olfactory bulb, likely because of its anatomical proximity and neural connections with the nasal cavity. Although this pattern is commonly observed during nose-to-brain delivery, it may limit drug access to deeper brain regions. Therefore, further optimization using targeted strategies or delivery enhancers is required. Overall, HP-βCD inclusion complexation represents a promising approach to improve solubility, stability, and brain delivery efficiency of poorly soluble CNS-active drugs following intranasal administration.
Macrophages can internalize liposomes and disrupt them to facilitate drug release in the body. However, the effect of targeting liposomes to macrophages on in vivo drug release remains unclear. In this study, we compared...Macrophages can internalize liposomes and disrupt them to facilitate drug release in the body. However, the effect of targeting liposomes to macrophages on in vivo drug release remains unclear. In this study, we compared the in vivo drug release from macrophage-targeting liposomes (modified with 1,2-distearoyl phosphatidylserine, PS) and PEGylated liposomes in 4 T1 breast tumor-bearing mice. The macrophage-targeting capability of PS-modified liposomes was confirmed by their significantly enhanced cellular uptake in macrophages compared to that of PEGylated liposomes. In vivo drug release studies showed that PS-modified liposomes exhibited higher drug release in various tissues than that of PEGylated liposomes, suggesting that macrophages facilitate the release of the drug from liposomes in the body. Despite a higher percentage of drug release in the tumor, the PS-modified liposomes did not improve antitumor activity compared to PEGylated liposomes due to their rapid clearance. These results suggest that targeting liposomes to macrophages can enhance in vivo drug release but fail to increase antitumor activity due to low tumor selectivity. Therefore, selectively targeting liposomes to tumor-associated macrophages is essential for boosting antitumor effects.
Histidine (His)-hydrochloride (HCl) is widely used in freeze-dried monoclonal antibody (mAb) formulations, but alternative buffers are required when chloride ions are undesirable. This study evaluates His-acetate (Ac) as...Histidine (His)-hydrochloride (HCl) is widely used in freeze-dried monoclonal antibody (mAb) formulations, but alternative buffers are required when chloride ions are undesirable. This study evaluates His-acetate (Ac) as a substitute and its impact on the stability of two model mAbs with distinct physicochemical properties- infliximab (mAb-1) and a humanized anti-ricin mAb (mAb-2). pH shifts during freeze-drying were compared among His-Ac, His-HCl, and sodium Ac buffers, confirming strong buffering capacity of His-Ac within pH 5.5-6.5. Conformational and colloidal stability assessments revealed that both mAbs displayed higher melting temperatures or favorable diffusion interaction parameters in His-Ac formulations. Moreover, mAb-2 exhibited a higher collapse temperature in His-Ac compared to His-HCl, indicating improved structural integrity or drying efficiency during primary drying. No significant differences were observed in aggregation onset temperature and glass transition temperature. Aggregation and chemical stability under stress conditions were evaluated by micro-flow imaging, size exclusion chromatography, and ion exchange chromatography. No notable changes in subvisible particle counts or monomer content occurred after freeze-drying. Overall, His-Ac demonstrated stability comparable to or better than His-HCl, supporting its use in freeze-dried mAb formulations.
Off-label use of medicines administered via enteral feeding tubes (EFT) can lead to dose inaccuracies, adverse effects and tube obstruction, compromising therapeutic outcomes. Thus, new manufacturing processes are requir...Off-label use of medicines administered via enteral feeding tubes (EFT) can lead to dose inaccuracies, adverse effects and tube obstruction, compromising therapeutic outcomes. Thus, new manufacturing processes are required to design medicines specifically for EFT administration. In this study, a 3D printing semi-solid extrusion (SSE) technique was employed to produce circular-shaped naproxen printlets (P-NPX) (18 × 18 × 2.6 mm, 30 % infill) for aqueous dispersion prior to EFT administration. Mesoporous silica nanoparticles (MSN) were used as NPX nanocarriers for development of printlets (P-NPX-MSN). Results show that MSN drug encapsulation enabled production of printlets with reproducible NPX content, without organic solvents; while providing better shape retention. Aqueous dispersion times were 806 ± 26 s for P-NPX and 813 ± 20 s for P-NPX-MSN. For both formulations, resulting dispersions were slightly acidic (pH ∼ 5), with viscosity of 1.3 cP and particle size distribution that ensured NPX administration without tube obstruction. Drug recovery was ∼ 100 % for both formulations after tube passage. Re-dispersed printlets had reduced vascular event compared to positive controls in Hen's Egg Test - Chorioallantoic Membrane (HET-CAM) assay (in vitro alternative model) and were classified as slight irritants. This study provides an innovative route for drugs presenting gastric irritation, advancing SSE 3D printing for personalised EFT medicines.
Despite significant advances in cancer treatment over the past five decades, survival outcomes for pancreatic cancer have remained largely unchanged. The effectiveness of chemotherapy as a treatment for pancreatic cancer...Despite significant advances in cancer treatment over the past five decades, survival outcomes for pancreatic cancer have remained largely unchanged. The effectiveness of chemotherapy as a treatment for pancreatic cancer is limited by the dense, protective tumour stroma, which impedes drug delivery. Ultrasound-targeted microbubble destruction (UTMD) has emerged as a promising strategy for enhancing the delivery of chemotherapy agents to solid tumours. In this study, we report the development and evaluation of a novel microbubble (MB) formulation, ST-001, which incorporates paclitaxel chemotherapy and a Rose Bengal sonosensitiser for targeted chemo-sonodynamic therapy of pancreatic cancer. The principle of UTMD using ST-001 was demonstrated in a murine model of pancreatic cancer, where B-mode ultrasound imaging was used to visualize MB accumulation within the tumour and its subsequent clearance following the application of therapeutic ultrasound. Preclinical efficacy studies demonstrated a significant survival advantage in ST-001 treated mice, which survived more than twice as long as those treated with standard Taxol, despite receiving only 14% of the paclitaxel dose. Additionally, a preclinical toxicology study in healthy mice demonstrated an excellent safety profile for ST-001, with no adverse effects observed in key hematological and blood biochemical markers, or in the histology of the spleen, liver, and kidneys.
Spinal cord injury (SCI) induces a cascade of secondary damage mechanisms, including oxidative stress, inflammation, and cell death, which severely impair neuronal recovery. In this study, N-acetylcysteine (NAC), a thiol...Spinal cord injury (SCI) induces a cascade of secondary damage mechanisms, including oxidative stress, inflammation, and cell death, which severely impair neuronal recovery. In this study, N-acetylcysteine (NAC), a thiol-based antioxidant with limited CNS bioavailability, was encapsulated in polycaprolactone (PCL) nanofibers using emulsion electrospinning. This approach allows localized and sustained drug delivery. Span 80 and Poloxamer 407 were used as surfactants to stabilize the emulsion and increase the hydrophilicity of the fibers. The resulting core/shell nanofibers (NAC-CSN) exhibited uniform morphology, improved wettability, and favorable mechanical properties, while supporting cell viability and migration in vitro. Sustained NAC release over several days was achieved, indicating diffusion-controlled delivery. In a rat model of SCI, NAC-CSN treatment attenuated oxidative and ferroptotic damage and promoted early neuroregeneration, which enabled measurable locomotor recovery. These findings suggest that NAC-CSN scaffolds offer an effective neuroprotective strategy against secondary SCI damage and, by enabling localized antioxidant delivery at the lesion site, represent a clinically applicable platform for future tissue engineering and translational therapies.
The existence of a storage capacity or reservoir function within human stratum corneum (HSC) for topically applied chemicals is well documented. However, the source of this reservoir remains ambiguous and may well depend...The existence of a storage capacity or reservoir function within human stratum corneum (HSC) for topically applied chemicals is well documented. However, the source of this reservoir remains ambiguous and may well depend on the chemical and the exposure conditions. We have investigated the role of reversible binding to keratin in contributing to this phenomenon by measuring the kinetics of uptake and desorption of solutes from isolated HSC, delipidized HSC, and silicone membrane from buffered aqueous solutions (pH 5.5) in vitro. A lipophilic permeant, geraniol, was studied for periods ranging from 24 to 168 h. Additional desorption data for testosterone and 1-propanol from isolated HSC were drawn from the literature. Results were compared with theoretical predictions for a homogeneous membrane with either no binding, equilibrium binding or slowly reversible binding. The theory includes a hitherto unpublished analysis of the short-time and long-time behavior of such systems. Calculations were also conducted for selected corticosteroids, the original stimuli for the HSC reservoir function concept. The HSC and delipidized HSC data for geraniol were most consistent with slowly reversible binding in the protein phase of the tissue. Almost complete desorption was achieved within 2-3 h of exposure to permeant-free buffer. Testosterone and 1-propanol data were consistent with this picture. Model-based calculations for corticosteroids, however, predict much longer retention times in the stratum corneum - up to two weeks - when extrapolated to the case of partially hydrated skin. We conclude that, while slowly reversible binding of many lipophilic permeants in the protein phase of the tissue is supported, the combination of very low diffusion rates in the lipid phase with strong equilibrium binding in the protein phase is a major contributor to HSC reservoir function for corticosteroids.
BACKGROUND: In recent years, significant efforts have been made to develop new dissolution methods capable of predicting the in vivo behavior of pharmaceutical formulations. This is essential for establishing valid in vi...BACKGROUND: In recent years, significant efforts have been made to develop new dissolution methods capable of predicting the in vivo behavior of pharmaceutical formulations. This is essential for establishing valid in vitro-in vivo correlations (IVIVCs) and biopredictive models. However, many of these methodologies involve sophisticated, costly, and complex devices designed to replicate human physiology. The objective of this study was to predict in vivo bioequivalence (BE) using a simplified dynamic dissolution methodology and to establish a physiologically based biopharmaceutics model (PBBM). METHODS: An oral fixed-dose combination of valsartan (VALS, BCS Class IV) and hydrochlorothiazide (HCTZ, BCS Class III) was used for the study. The reference product (Co-Diovan® Forte) and two generic formulations were evaluated using a dissolution approach. A two stage one compartment dissolution technique, known as the "dumping test," was applied to assess drug release profiles. The in vitro dissolution data obtained were incorporated into the PBBM, with two scaling factors-one for time and another for absorption-to enhance predictive accuracy. RESULTS: The "dumping test" successfully simulated the different dissolution behaviors of the formulations and explained the failure of bioequivalence in certain cases. The established IVIVC demonstrated both validity and biopredictive capability. The percentage prediction errors (% PEs) for the PBBM, after incorporating in vitro data and the scaling factors, remained within acceptable regulatory limits. CONCLUSIONS: The study demonstrated that a simple dynamic dissolution methodology can effectively predict in vivo bioequivalence and formulation performance. The application of the "dumping test" provided valuable insights into the dissolution characteristics of different formulations, highlighting its potential as a cost-effective and practical tool for biopredictive studies.
Evidence and data supporting the co-administration of intravenous medication (IVM) and parenteral nutrition solutions (PNS) is scarce. However, co-administration is often unavoidable practice in paediatric patients and p...Evidence and data supporting the co-administration of intravenous medication (IVM) and parenteral nutrition solutions (PNS) is scarce. However, co-administration is often unavoidable practice in paediatric patients and particularly neonates, where secured vascular access can be challenging. This is especially the case when multiple infusions must run simultaneously with limited intravenous access. Safe co-administration could offer a solution to challenges such as fluid restriction and provision of uninterrupted nutritional support The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) guidelines state that "the co-administration could be possible only if guided by supportive data on physicochemical compatibility and stability", which is neither available nor agreed internationally. This systematic review was conducted to address the deficit in compatibility data on commonly used IVMs and PNS in paediatrics and neonates.
The aversive taste of pharmaceutical formulations, especially bitterness, has been identified as a significant barrier to patient compliance. Taste masking technologies have emerged as significant approaches to improve t...The aversive taste of pharmaceutical formulations, especially bitterness, has been identified as a significant barrier to patient compliance. Taste masking technologies have emerged as significant approaches to improve the acceptability of orally administered drugs. These technologies have evolved from empirical methods to more systematic, precise, and intelligent solutions. Artificial intelligence (AI) advances have given rise to novel opportunities in taste prediction, excipient selection, and formulation optimization. This review critically examines the historical progression of taste masking technologies, elucidates the molecular and physiological basis of taste perception alongside interindividual variability, and compares conventional sensory and analytical techniques with emerging digital and biosensing platforms. Particular emphasis is placed on integrating AI into drug taste assessment, the development of masking strategies, and the control of manufacturing processes. Furthermore, the potential of AI-driven intelligent taste systems to enable precision masking, controlled release, and patient-specific palatability is discussed. This work outlines a conceptual and technological framework for next-generation taste optimization strategies, providing insights into developing smart, efficient, and personalized drug delivery systems.
Nanovesicles (NVs) derived from biological membranes offer promising opportunities in the realm of ultra-precise cancer therapy, with proven therapeutic efficacy and safety profiles. These biomimetic NVs possess a versat...Nanovesicles (NVs) derived from biological membranes offer promising opportunities in the realm of ultra-precise cancer therapy, with proven therapeutic efficacy and safety profiles. These biomimetic NVs possess a versatile liposome-like structure capable of accommodating hydrophilic and hydrophobic agents. NVs derived from a plethora of biological sources, including eukaryotic cells [erythrocytes, platelets, immune cells, cancer cells and mesenchymal stem cells (MSCs)], extracellular vesicles (EVs), and bacteria, successfully proved to enable the tumor-targeted delivery of a wide panoply of therapeutic molecules. These include chemotherapeutics, imaging agents, nucleic acids and immunoadjuvants, highlighting their potential as natural lipid-based drug delivery systems (DDSs) in cancer-oriented therapies. Clinical translation, however, encounters challenging issues that require further research and refinement. Safety, immunogenicity, scalability, stability, production protocols, quality control, and understanding biological processes remain crucial aspects for clinical implementation. This review offers a critical and comparative analysis of different membrane sources, underlines several NV applications in tumor-targeted therapies, and outlines future research directions and current limitations. Addressing these challenges is pivotal to harnessing the full potential of NVs derived from biological membranes for safe and effective clinical use.