European Journal of Pharmaceutics and Biopharmaceutics最新文献

Self-assembling natural drug hydrogels have emerged as promising biomaterials for scalable and customizable drug delivery systems attributed to their inherent biocompatibility and biodegradability. Asiaticoside (AS), a bioactive compound derived from Centella asiatica (L.) Urb., is known for its antioxidant, antifibrotic, and anti-inflammatory properties, primarily accelerating wound healing through the promotion of collagen synthesis. However, its low water solubility leads to poor transdermal absorption and reduced bioavailability when applied topically. Panax notoginseng saponins (PNS), active compounds derived from the stems of Panax notoginseng (Burk.) F.H. Chen, exhibit amphiphilic and surfactant properties, rendering them effective stabilizers. Our research has demonstrated that the co-assembly of AS and PNS forms a hydrogel, termed AS&PNS hydrogel, which significantly enhances wound healing by reducing interleukin-6 (IL-6) levels and promoting the production of vascular endothelial growth factor (VEGF). Treatment with AS&PNS hydrogel also tended to normalize epidermal thickness and improve collagen fiber organization at the wound site. This novel hydrogel material presents a straightforward and effective approach to managing skin wounds.

Zerumbone (ZER), a compound derived from the rhizome of Zingiber Zerumbet (L.) Smith, has demonstrated anti-inflammatory properties but suffers from poor water solubility, limiting its clinical application. While ZER's effects on lung inflammation are known, its role in lung fibrosis remains unexplored. Herein, ZER was encapsulated in pH-sensitive liposomes formulated with oleic acid, dipalmitoylphosphatidylcholine, and cholesterol to enhance ZER solubility and delivery to the acidic environment of lung fibrosis. The liposomes were optimized using Box-Behnken design, resulting in an average diameter of 87.8 ± 3.5 nm, a polydispersity index of 0.16 ± 0.2, and a zeta potential of -24 ± 0.32 mV. ZER release from the carrier followed zero-order kinetics and showed higher release in acidic settings. Cascade impactor and HPLC analyses confirmed that ZER liposome powder produced by freeze-drying reached stage 7, indicating effective delivery to deep lung regions. The uptake of ZER liposomes was concentration and pH-dependent, being higher in acidic conditions and greater in MRC-5 cells compared to A549 cells. Notably, ZER liposomes reduced cell migration and downregulated fibrotic markers such as fibronectin, MMP-2, and α-SMA in MRC-5 and A549 cells. This study suggests that ZER liposomes hold promise for treating lung fibrosis and merit further investigation.

Aseptic filling of biopharmaceutical products requires a grade A cleanroom environment, preferably ensured by isolators in grade C surroundings. Isolators are decontaminated before the start of filling processes using vaporized hydrogen peroxide (VHP) and filling starts at pre-defined residual VHP levels (e.g., below 0.5 ppm) depending on product sensitivity towards VHP oxidation. Manufacturing equipment and consumables, including filling assemblies, are exposed to VHP during or after the decontamination cycle or after line interruptions. We studied the VHP uptake by tubing in a lab-scale model isolator to evaluate the impact of tubing properties including contact material, tubing dimensions, suppliers, and VHP exposure (concentration and exposure time). Quantifying the release of H₂O₂ from the tubing into solution using an Amplex Red Hydrogen Peroxide Assay, showed that H₂O₂ concentrations decreased linearly with an increase in wall thickness and increased with higher surface to volume ratio. We further conclude that thermoplastic elastomer and thermoplastic vulcanizate tubing did not show any measurable VHP uptake for the tested conditions, whereas significant VHP uptake occurred in different platinum cured silicone tubing depending on tubing material and supplier. We further verified the results in a GMP manufacturing isolator setting. Based on our findings, we recommend to evaluate VHP uptake of filling tubing used for fill-finish manufacturing in isolators, to reduce the risk of oxidation for active pharmaceutical ingredients or excipients.

Complete eradication of aggressive head and neck squamous cell carcinoma (HNSCC) still remains a major challenging problem due to numerous resistance properties of cancer stem cells (CSC) which is crucially responsible for tumor recurrence and metastasis. This challenge causes a high demand for the emergence of novel targeted treatment modalities for improved therapeutic efficacies. Phytochemicals derived from plants proves to be a wide reservoir of important drug candidates which have the potential to impede multiple aspects of malignant growth and progression. In the present study, we aimed to synthesize gold nanoparticles in a rapid and cost-effective manner by utilizing Madhuca indica flower extract and to evaluate its anticancer efficacy on head and neck cancer model via targeting cancer stemness and EMT. The phytochemicals present in the Madhuca indica flower extract acted as an effective reducing agent helping in the green synthesis of gold nanoparticles. The generated AuNPs were characterized by UV-Vis spectroscopy, XRD, FTIR, TEM, FE-SEM, DLS, EDX. Anti cancer potential of synthesized AuNPs were evaluated by in vitro and ex vivo HNSCC model. In vivo toxicity was assessed in Swiss albino mice model. The gold nanoparticles were characterized using UV-Vis spectroscopy which revealed unique wavelength maxima at 550 nm and its crystalline nature was confirmed by XRD. AuNPs were observed to be spherical in shape with the mean diameter of 20.34 ± 4.36 nm and zeta potential of nearly -50 mV. The FTIR spectral shift indicated the incorporation of various functional groups. MI-AuNP depicted strong anticancer attributes against HNSCC cell lines SCC154 and FaDu through significant inhibition of cancer stemness and EMT as evident from decreased tumor sphere forming efficiency and CD44+/CD24- subpopulation along with dose dependent downregulated expression of relevant CSC markers and EMT markers both in vitro and ex vivo HNSCC model. Additionally, no evidence of in vivo toxicity has been observed with MI-AuNP administration. In conclusion, this study reported for the first time that the MI-AuNP synthesized by novel green chemistry can efficiently prevent the self-renewal capability of HNSCC by targeting Cancer stemness. The scientific significance of this study lies in the fact that MI-AuNP might be a novel and potential therapeutic candidate against aggressive and metastatic HNSCC. The findings in this study unravels the way for developing a novel therapeutic candidate against aggressive and metastatic HNSCC with a much higher prognostic potential and significantly reduced off target toxicity.

Current analgesics on the market exhibit a short duration of action and induce the production of inflammatory factors in tissues damaged by surgical procedures. Inflammatory factor production can create acidic environments, limiting drug delivery. In this study, we developed a novel injectable formulation comprising bupivacaine multivesicular liposomes of high osmotic pressure (H-MVL) and meloxicam nanocrystals (MLX) in a thermosensitive gel (H-MVL/MLX@GEL) adapted to the microenvironment for long-term postoperative analgesia. To achieve formulation stability, H-MVL were prepared by regulating the osmotic pressure of the gel system. Moreover, the inclusion of MLX serves to not only attenuate local inflammatory factors, regulating the acidic microenvironment, but also to prolong the duration of action of meloxicam (MEL). The increased absorption of bupivacaine (BUP) and the prolongation of the half-life of BUP release in H-MVL/MLX@GEL were demonstrated through pharmacokinetic experiments. Sciatic nerve block models and hot plate analgesia tests demonstrated that H-MVL/MLX@GEL effectively alleviated pain for at least five days. The immunohistochemical results showed that the addition of MLX reduced the production of the local inflammatory factors interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), thereby improving the analgesic effect by regulating the local acidic environment and alleviating local irritation.

This study aimed to develop patches containing quercetin-loaded microcapsules and to evaluate their in vitro and in vivo safety and efficacy in preclinical surveys. A set of in vitro experiments evidenced the virucidal activity of quercetin against the HSV-1-KOS (sensitive to acyclovir) and HSV-1-AR (resistant to acyclovir) strains, with improved outcomes upon the first. The patches presented a homogeneous aspect, were easily handled, had a suitable bioadhesion, and possessed mechanical properties of soft and weak material, besides a pH compatible with human skin. The in vitro release profile of quercetin showed an initial burst release, followed by a controlled release rate, which was best described by Gompertz kinetics (R² of 0.93). Using quercetin-loaded patches for treating HSV-1-KOS-induced injuries was feasible since they were well tolerated in the in vivo skin irritation test and significantly decreased the injury scores until the fourth out of eight days of treatment in mice compared to acyclovir cream (50 mg/g). Altogether, the in vitro and in vivo antiviral assays indicate that this flavonol acts in the earlier stage of the infection, likely impairing the HSV-1 adsorption to the cell. The anti-inflammatory capacity of the quercetin-loaded patches was noteworthy as evidenced by histological analysis. These findings bring prospects for safer and more effective management of mucocutaneous HSV-1 injuries.

The aim of this study was to comprehensively characterize paliperidone palmitate (PP) long-acting suspension (Invega Sustenna®) through reverse engineering. We developed a series of analytical methods to assess critical quality attributes of four batches of Invega Sustenna®. The size distributions of the four batches of suspensions were measured using laser diffraction, and variations in the D50 and D90 parameters were observed. The morphology of suspension was determined through scanning electron microscope (SEM), which exhibited irregular granular shape across all batches. The size distributions determined by SEM images were similar to the laser diffraction results. Thermal characteristics were detected using differential scanning calorimetry (DSC) and crystalline properties were assessed by powder X-ray diffraction (PXRD), displaying consistency among the four batches in these two aspects. In vitro dissolution methods (sample separation and dialysis bag methods) were developed to evaluate the release behaviors of Invega Sustenna® and four lots showed a similar dissolution pattern. Furthermore, following a single-dose intramuscular administration to rats, two batches of Invega Sustenna® with the largest size differences demonstrated comparable plasma concentration-time profiles and pharmacokinetics parameters, indicative of one month long-acting release. In summary, we established a systematic quality characteristics assessment for Invega Sustenna®, including particle size distribution, particle morphology, thermal characteristics, crystalline properties, in vitro dissolution kinetics and in vivo pharmacokinetics. Our work will assist pharmaceutical companies and regulatory agencies in the development and regulatory assessment of novel or generic products of long-acting injectable suspension.

Prefilled syringes (PFS) are primary packaging materials that offer convenience and safety for subcutaneous injection of parenteral drug solutions. However, an increasingly common problem with the trend towards higher drug concentrations is the clogging of the needle during storage due to evaporative water loss and consequent solidification of the drug. In contrast to all previous studies on this topic, this work focuses on pharmacokinetically relevant aspects and investigates the effects of needle clogging on the spatial distribution of the injected drug in the tissue. X-ray computed tomography (XCT) (both tube-based and synchrotron-based) was used to visualize and analyze the spreading pattern and the fate of the injected liquid in porcine skin. By using controlled injection and force measurement the tissue distribution was correlated with the plunger force profile and the fluid dynamics of the jet. Studies of monoclonal antibody solution demonstrate that clogs, which are formed by evaporation of water and solidification of drug solution in the needle tip, usually dissolve in the flow of the liquid during injection. In the initial injection phase, the liquid jet starts to escape the needle only through a narrow channel in the clog. The resulting high dynamic pressure can alter the distribution of the liquid in the tissue, causing a long tail of liquid that penetrates deep into the fibrous network of the subcutaneous layer. However, the volume of this tail was calculated to be low relative to the overall volume of the injected drug solution (less than 2.4%) and is therefore unlikely to have a significant effect on the absorption kinetics of the injected drug. In addition, it was shown that if a clog were to enter the tissue, it would quickly dissolve.

Skin, as the primary interface with the external environment, is susceptible to damage, posing a formidable challenge for complete restoration in adult skin injuries. Wound healing remains a clinical challenge, necessitating advanced biomaterials to support cell proliferation, modulate inflammation, and combat infections. Among several options, hydrogel can be a capable contender for biological dressings. Here, we developed and evaluated a novel hydrogel composed of sodium alginate (SA) and carboxymethyl cellulose (CMC), enriched with decellularized extracellular matrix of amniotic membrane (dAM), using calcium chloride (CaCl₂) as a crosslinker. An incorporation of dAM imparted biomimetic qualities, as evidenced by SEM, showing a fibrous extracellular matrix-like structure. Rheological studies demonstrated the optimal viscosity of SA-CMC-dAM for cell proliferation and adhesion, overcoming limitations of SA and CMC alone. The hydrogel exhibited the highest moisture absorption (12.27±0.59 %) and enhanced hydrophilicity, as confirmed by the contact angle assay, ensuring suitability for wound applications. Biological assessments revealed superior fibroblast migration in scratch assays and significant anti-biofilm activity (∼70 % reduction in E. coli biofilms) alongside antimicrobial efficacy, supported by FDA/PI assays. The zebrafish embryo studies validated its biocompatibility (20 μg/ml) and demonstrated potent anti-inflammatory effects, with a marked reduction in neutrophil recruitment (∼25 %) in tail transection models compared to controls. These findings suggest that the SA-CMC-dAM hydrogel synergises structural, antibacterial, and anti-inflammatory properties, making it a promising candidate for wound healing applications. The biomimetic and multifunctional design provides a strong basis for further translational studies in mammalian systems.

The development of films, scaffolds, hydrogels, and other innovations based on biopolymers for the treatment of skin injuries is on the rise. Therefore, it is important to focus on their functionality, influence on human use, and environmental impact. This work investigates the antimicrobial capacity of gelatin films that incorporate O/W emulsions encapsulating bactericidal and healing active ingredients (EA). Their biocompatibility was evaluated in vitro in human skin keratinocyte and murine fibroblast cell cultures, as well as in vivo using the zebrafish model. Finally, its potential to heal wounds was assessed through a keratinocyte cell migration assay. The EA films exhibited antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus. The films were biocompatible with monolayer cultures, without affecting cell viability, metabolic activity, or membrane integrity. The films did not exhibit general toxicological effects in zebrafish nor specific organ toxicity in the heart, liver, or brain. Further, the EA films promoted keratinocyte migration in the wound healing assay. In conclusion, the films could be used as a potential treatment for various types of skin injuries, being safe for both potential human application and the environment after use and disposal.