International Journal of Pharmaceutics最新文献

We have demonstrated the efficacy of a novel strategy for achieving the prolonged and sustained release of vancomycin as a prophylaxis against surgical site infection (SSI). This strategy uses hydrophobic ion pairing (HIP), joining vancomycin with counter ions and efficiently encapsulating the antibiotic in biodegradable polymer nanospheres. To complete the process, vancomycin-complexes were formed in an aqueous acidic medium, and then they were encapsulated in poly(lactic-co-glycolic) acid (PLGA), polylactic acid (PLA), and polycaprolactone (PCL) nanospheres via the double-emulsion solvent-evaporation method. Our results show that sulfate and sulfonate-based counter ions provide the most effective structure for vancomycin-HIP formation, achieving 95% complexation efficiency at a 1:2 molar ratio. Once formed, the vancomycin-dioctyl sodium sulfosuccinate (Van-DOSS) complex achieved a 3.7-fold increase in lipophilicity (LogP _{octanol/water}), which significantly improved encapsulation efficiency in comparison to unmodified vancomycin. Encapsulation efficiency increased by 2.7-fold in PLGA (64.7% ± 0.4%) and by 5.5-fold in PLA (46.7 ± 5.9%) and PCL (47.7 ± 6.9%). The Van-HIP nanospheres achieved an in-vitro release of vancomycin that was three-to-five times the minimum inhibitory concentration required for S. aureus over the critical 28-day window indicated for post-operative care after spine surgery. Consequently, these findings support a sustained-release option for antibiotic formulation to improve surgical outcomes.

Tablet mechanical strength is governed by both the intrinsic mechanical properties of the constituent materials and the applied compaction conditions. In this work, we investigated the relationships among tablet tensile strength, tablet brittleness, quantified by the tablet brittleness index, and powder plasticity, quantified by in-die mean yield pressure. Seven common excipients and twelve binary mixtures were selected to represent materials spanning a wide range of mechanical behaviors. For a given material, tablets become more brittle and weaker as porosity increases, following an exponential decay relationship. At a fixed tablet porosity, in-die mean yield pressure shows a positive correlation with tablet brittleness index that follows a power-law function. This relationship enables prediction of tablet brittleness index at a specified porosity directly from in-die mean yield pressure. Because in-die mean yield pressure can be readily obtained from in-die compression data using only small quantities of material, it offers an efficient means to estimate tablet brittleness early in development and provides valuable guidance for designing robust tablets.

Glatiramer acetate (GA) electrostatically complexes with cytosine-guanine oligodeoxynucleotides (CpG ODN), forming ∼100 nm cationic nanoparticles that localize this potent immunostimulant to the injection site. We previously reported GA-CpG nanoparticles retained the anti-tumor activity of CpG while mitigating systemic immune-related adverse events. Nonetheless, nanoparticulate systems like polypeptide-oligonucleotide complexes pose challenges with reproducible production, in-use stability, and storage stability, which must be solved before translation for clinical use. In this study, we systematically investigated a microfluidic mixing process to define reproducible production of GA-CpG nanoparticles. Dynamic light scattering measurements revealed significantly smaller and more uniform nanoparticles for microfluidic processing versus traditional mixing via pipette. We screened a range of buffer systems to determine the pH and ion types that could maintain colloidal stability and CpG potency. Buffer screening tests indicated that amino acid buffers, particularly glutamic acid, better maintained particle consistency than commonly used parenteral buffers. Finally, formulations of potential lyoprotectants and GA-CpG nanoparticles were developed. Freeze-thaw and freeze-drying experiments were conducted to assess the effects of buffers and lyoprotectants. Formulations with 5% HP-β-CD or trehalose yielded mean particle sizes of less than 127 nm and retained even after storage for 6 months at 40 °C/75% relative humidity. The work on electrostatic complexes reported here may provide valuable guidance to formulators aiming to optimize polypeptide-based oligonucleotide polyplex products for in-use or long-term stability.

The pH-mediated effect of drug ionization on solubility is well-described. However, pH can also indirectly influence solubility by altering the colloidal structures in human intestinal fluids. This study investigates the indirect pH effect on the apparent solubility of 13 uncharged drugs across a pH range of 4.5 to 7.5 in fed-state simulated intestinal fluids (SIF) composed of taurocholate and lecithin, with or without added lipids (monoolein and/or sodium oleate). A pronounced indirect pH effect on drug solubility was observed when oleate was present in the SIF, whereas monoolein had only a minor effect. Below pH 6.5, sodium oleate was converted to oleic acid, resulting in lipid droplet formation that enhanced lipophilic compound solubility in the total sample (lipid phase + micellar phase), while the micellar solubility remained similar to the reference SIF (without oleate). This resulted in an up to 50-fold increase of the ratio total/micellar drug solubility, which correlated well with drug lipophilicity or its combination with total polar surface area (R² ≈ 0.8). At higher pH, a lipid phase was not formed because the ionized sodium oleate partitioned in the micellar phase, where it significantly increased drug solubilization. These findings highlight the importance of considering indirect pH effects in solubility assessments by tuning simulated intestinal fluids composition to better reflect in vivo reality.

Continuous Direct Compression via Mini-Batch Blending (CDC via MBB) is gaining traction as an innovative manufacturing technology in the pharmaceutical industry. According to the Roche design, mini-batches (MBs) are sequentially fed and blended, remaining separate until they come into contact with one another in the hopper above the tablet press after the first diversion point. Material tracking is crucial for understanding how unexpected disturbances propagate through a CDC via MBB line. While tracking is straightforward for separate MBs, assessing the residence time distribution (RTD) in the tablet press becomes necessary after the first diversion point. In this study, a methodological framework is presented where a RTD was characterized experimentally using a tracer (tartaric acid) step change, transmission Raman spectroscopy and in-silico modelling using Discrete Element Method (DEM) simulations. The experimental results indicated intermixing between adjacent MBs. The RTD-based simulations enabled the quantification of intermixing, revealing that the produced tablet consisted of a blend of multiple MBs at any given time during the characterization of the tablet press. Further simulations based on the corroborated RTD enabled testing of the sampling and disturbance management strategies. The RTD models were used to compare conservative and smart material diversion strategies. It was established that the smart strategy significantly reduced the amount of non-conforming material after minor disturbances. Understanding the process dynamics based on the RTD characterization of the tablet press allows for the development of sampling and material diversion strategies during the CDC via MBB drug product process development. Insights from this work can be applied to other tablet press variants as discussed in Part 2 of this study.

Background: Lysosomes are markedly altered in tumor cells, exhibiting increased number and size, enhanced acidification, elevated cathepsin activity, and remodeled ion channel composition. These adaptations confer heightened degradative capacity and metabolic plasticity, supporting tumor survival, progression, and therapeutic resistance. Beyond their classical catabolic role, lysosomes function as central hubs for nutrient sensing, stress adaptation, and transcriptional regulation, making lysosomal integrity an emerging vulnerability in cancer therapy.

Aim: This review aims to elucidate the therapeutic potential of inducing lysosomal collapse as an anticancer strategy, with a particular focus on recent nanotherapeutic approaches designed to precisely disrupt lysosomal function.

Methods: This study systematically summarizes current knowledge on lysosomal structure and function in tumor cells and analyzes preclinical studies that exploit lysosomal destabilization for cancer treatment. Nanotherapeutic strategies targeting lysosomes are categorized according to their underlying mechanisms, including gas generation-mediated blasting, osmotic swelling, fiber-induced expansion, oxidative membrane damage, and direct phospholipid bilayer disruption. For each strategy, the design rationale, mechanistic basis, and representative experimental outcomes are critically evaluated.

Results: Accumulating evidence demonstrates that controlled lysosomal membrane permeabilization or rupture can effectively induce tumor cell death, reverse drug resistance, suppress metastasis, and alleviate immune evasion. Nanotherapeutic platforms enable spatially and temporally precise lysosomal disruption, enhancing antitumor efficacy while minimizing off-target toxicity. Comparative analysis reveals distinct advantages and limitations among different lysosome-targeting strategies, underscoring the importance of rational nanomaterial design.

Conclusions: These advances establish lysosomes as central regulators of tumor biology and promising therapeutic "death triggers". Lysosome-targeted nanotherapeutics represent a powerful and versatile approach for overcoming major barriers in cancer treatment, offering new opportunities for precise, effective, and mechanism-driven anticancer interventions.

A novel dry powder inhaler with a spiral channel featured mouthpiece (Swirling-DPI) is proposed in this work, designed to enhance drug particle deagglomeration and pulmonary delivery efficiency. Computational Fluid Dynamics (CFD) coupled with Discrete Particle Method (DPM) simulations are employed to systematically investigate the effects of spiral geometric parameters, such as pitch (5 mm-9 mm), channel inner diameter (3 mm-7 mm), and cross-section (trapezoidal and circular) on airflow dynamics and particle behavior. Results indicate that spiral geometric structures significantly alter flow fields and particle dynamics, and the impact effects of particles are optimized. The exit velocity of 200 µm carrier particles without drug effects in the 7 mm pitch Swirling-DPI is 2.44 times that of the Aerolizer, reducing the possibility of carrier particle entering the lungs and facilitating drug particle delivery. Compared with traditional Aerolizer, higher turbulent kinetic energy (TKE) is obtained in the Swirling-DPI with a pitch of 7 mm. The residence time of 200 µm carrier particles is increased by 43%, with higher impact energy, indicating enhanced potential for deagglomeration. The circular cross-section reduces flow resistance and the potential for particle retention, improving flow uniformity while maintaining high TKE levels. Comprehensive studies on particles and flow fields indicate that the spiral structure prolongs trajectories of large particles, increasing impact frequency. Comparative analysis confirms that Swirling-DPI is an effective strategy for optimizing drug aerodynamic properties and delivery efficacy, demonstrating excellent performance in promoting particle impact and enhancing turbulent kinetic energy.

Despite the recognized therapeutic potential of Rosmarinic Acid (RA), its clinical use remains limited due to poor water solubility, chemical instability, and rapid mucociliary clearance following intranasal administration. To address these limitations, two different nanocarriers: Solid Lipid Nanoparticles (SLNs) and oil-in-water nanoemulsions (O/W NEs) were designed, prepared and characterized, to improve the intranasal delivery and therapeutic efficacy of RA in allergic rhinitis. These nanosystems were optimized to encapsulate RA, enhancing its solubility and enabling controlled release. To prolong residence time at the nasal mucosa, chitosan was introduced in RA-based NEs as mucoadhesive polymer. A comprehensive physicochemical characterization was carried out, including evaluation of size, zeta potential, membrane fluidity, and structural organization. Stability was assessed under storage and physiologically conditions. In particular, Atomic Force Microscopy (AFM) and Small-Angle X-ray Scattering (SAXS) analyses were conducted to gain deeper insights into the formulations surface morphology and internal nanostructure. Obtained results confirmed the ability of both systems to protect RA from degradation and promote sustained release. Mucoadhesion studies demonstrated the interaction of the chitosan-coated NEs with mucin, increasing retention on the nasal mucosa. Among the two formulations, SLN-RA was selected for nasal spray development and extensively characterized, including resistance to nebulization, droplet size distribution, and microbiological and pharmacological studies, to evaluate its suitability for intranasal administration. The results confirmed that the SLN-based nasal spray maintained favorable physicochemical and mucoadhesive properties, ensuring efficient delivery to the upper respiratory tract. Biological assays revealed that encapsulated RA retained its antioxidant and anti-inflammatory properties, reducing the expression of inflammatory markers such as High Mobility Group Box 1 (HMGB1). Altogether, these findings suggest that SLNs represent the best and promising carrier for the non-invasive delivery of RA in the nasal cavity. Their integration into nasal spray formulations could offer an effective therapeutic strategy for allergic rhinitis and other inflammatory conditions of the upper respiratory tract.

Effective management of infected skin wounds remains a major clinical challenge, particularly as rising antibiotic resistance compromises conventional therapies. Antimicrobial peptides (AMPs) have emerged as promising alternatives, but their clinical translation is hindered by poor stability and potential toxicity. In this study, we report the rational design of a novel antimicrobial peptide, FR-20, a self-assembling derivative of the human cathelicidin LL-37, engineered for enhanced structural stability and antimicrobial efficacy. Using dynamic Schiff base cross-linking, we developed an injectable, self-healing chitosan hydrogel (CS/FR-20) loaded with FR-20. The hydrogel exhibited robust mechanical integrity, excellent injectability, and a porous microarchitecture, while maintaining strong cytocompatibility and hemocompatibility. CS/FR-20 demonstrated potent bactericidal activity against both Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). In a murine full-thickness wound infection model, it effectively eradicated bacteria, reduced inflammation, accelerated tissue regeneration, and showed no detectable systemic toxicity. These findings establish CS/FR-20 as a versatile, biocompatible platform for treating infected wounds, offering a clinically translatable strategy to overcome antibiotic resistance and promote effective wound healing.

Lipid-coated solid and mesoporous silica nanoparticles (LC-SiNPs and LC-MSNs) were developed as modular platform for the delivery of Toll-like receptor (TLR) agonists. In this study, the incorporation of the amphiphilic TLR4 agonist monophosphoryl lipid A (MPLA) into lipid bilayers of the newly developed platform was systematically optimized. Both core particle types -solid and mesoporous- provided a stable surface structure to enhance membrane stability. By varying cholesterol (15-45%) and anionic lipid (DPPG) (10-30%) content, we identified key composition parameters that influence TLR4 activation, membrane fluidity and particle-cell interactions. Solid-core MPLA-SiNPs showed enhanced immunostimulatory activity compared to unformulated MPLA when formulated with cholesterol levels increased to 45% and moderate DPPG fractions of 20%, while mesoporous MPLA-MSNs required higher DPPG content of 30% for comparable activation. To further refine performance, Bayesian optimization (BO) was applied, leading to a significant improvement in MPLA-SiNPs. The BO-optimized MPLA-SiNPs achieved an EC₅₀ value of 87 ng/mL, outperforming classical formulation strategies. This optimized EC₅₀ was 60 ng/mL lower than for the particles optimized using the classical One-Factor-At-a-Time approach and 280 ng/mL lower compared to unformulated MPLA. Macrophages as antigen-presenting cells carrying TLR4 receptors efficiently internalized and processed the particles. These findings underscore the importance of rational formulation design and demonstrate the potential of lipid-coated silica nanoparticles as modular vaccine carriers. This versatile and modular platform can in future be exploited for delivery of other TLR agonists and additionally be equipped with antigens.