Pharmaceutical Research最新文献

Ocular inflammation is a major contributor to vision-threatening disorders, with phosphodiesterase 4 (PDE4), a key regulator of cAMP playing a central role in pro-inflammatory signaling. Although investigational PDE4 inhibitors like Rolipram (RP) show therapeutic promise, their systemic toxicity limits clinical application, underscoring the need for safer, targeted alternatives. Urolithin A (UA), a gut-derived metabolite of ellagic acid with emerging anti-inflammatory properties, was evaluated as a novel PDE4 inhibitor. Molecular docking revealed that UA binds with high affinity to the A-chain of PDE4A (-8.79 kcal/mol), forming unique π-π stacking and multiple hydrogen bonds. In contrast, RP binds preferentially to the B-chain with slightly lower affinity (-8.42 kcal/mol) and fewer stabilizing interactions. While both ligands engage similar catalytic residues, UA exhibited a more extensive binding profile, suggesting enhanced stability and specificity. In lipopolysaccharide (LPS)-stimulated human retinal pigment epithelial cells (ARPE-19), UA significantly inhibited PDE4A activity, elevated intracellular cAMP, and reduced key inflammatory mediators (NF-κB, IL-6, TNF-α), as demonstrated by immunofluorescence, ELISA, and gene expression analysis. These findings support UA's function as an anti-inflammatory agent by inhibiting PDE4A, highlighting its potential as a safer systemic or localized therapy for ocular inflammatory diseases.

Objective: Orodispersible films (ODF) blend the dose accuracy of solid dosage forms and the ease of administration of liquid dosage forms, hence offer many advantages. This study investigated the feasibility of two extrusion-based 3D printing techniques (pneumatic and syringe) to fabricate ODFs in a benchtop setting.

Methods: We fabricated fast-dissolving ODFs using pneumatic and syringe print heads and compared the variations in the process parameters, ease of fabrication, and characterized the properties of the final dosage forms. The variation in the printing parameters, drying time, drying temperature, and needle/nozzle types on the reproducibility and uniformity of the ODFs prepared from, these two printheads were studied. Feed materials for extrusion were selected based on rheological properties, printability, and reproducibility. An optimized ODF formulation composition was kept common and utilized for comparison.

Results: The ODFs from pneumatic and syringe-based extrusion printheads consistently created bulk batches with little to no significant variation. Syringe-based extrusion showed high precision with identical dimensions, whereas pneumatic extrusion showed quick fabrication. The ODFs produced by both methods were highly reproducible and showed excellent film properties such as mechanical strength, disintegration, and dissolution. The ODFs showed adequate mechanical strength (>0.72 N/mm²) for packaging and transport. The disintegration time was less than a minute, and quicker dissolution within 20 min.

Conclusion: Both pneumatic and syringe-based 3D printing technologies are deemed to be potentially viable alternatives for the fabrication of personalized dosage forms such as ODFs in pharmacy and clinical settings.

Extracorporeal membrane oxygenation (ECMO) is a life-saving cardiopulmonary bypass technology for critically ill patients. Patients treated with ECMO receive multiple drugs to treat critical illnesses, prevent infections, and maintain sedation. However, inaccurate dosing information of some of the administered drugs is a significant cause of ECMO related mortality. Hydrophobic drugs tend to adsorb on the surface of ECMO circuit components leading to suboptimal dosing and therapeutic failure. Modifying the drugs can be exploited as a strategy to reduce drug adsorption in ECMO circuits. Propofol (Diprivan®) is a widely used anesthetic in ECMO patients that is known to substantially adsorb to ECMO circuit components due to its hydrophobicity. The objective of this work was to evaluate the PEGylation of propofol as a strategy to reduce its adsorption to the ECMO circuit. Poly(ethylene glycol) (PEG) was covalently conjugated to propofol with varying PEG lengths, i.e., 3 monomers of PEG (PEG₃), 5 monomers of PEG (PEG₅) and 2 kDa molecular weight PEG (PEG_2kDa). The conjugates were synthesized, characterized, and compared for their water solubility, ability to spontaneously form micelles, and in reducing adsorption to hydrophobic materials in an in vitro ECMO mimic assay. Further, the conjugates were tested for their anesthetic activity in a C57BL/6 mouse model. We demonstrated that PEG₅-Propofol and PEG_2kDa-Propofol had improved water solubility and significantly reduced the adsorption of propofol. PEG₅-Propofol also demonstrated a similar anesthetic activity (520 ± 109 secs) to free propofol (485 ± 103 secs). Our results demonstrate that PEG₅-Propofol is a promising anesthetic for administration to patients on ECMO.

Purpose: Irisin, a hormone secreted by skeletal muscle during physical exercise, shows promise for health benefits. However, limited research on its characterization and formulation development has impeded its pharmaceutical development. This study aimed to develop fit-for-purpose subcutaneous formulations for irisin.

Methods: Irisin was expressed in E.coli and purified. The prepared irisin was characterized using orthogonal biophysical techniques, and its biological activity was assessed. Subcutaneous formulations were then developed by screening pH, excipients, and formats (lyophilized vs. aqueous), and the product stability profiles were investigated under various conditions.

Results: Irisin was successfully expressed in both soluble and refolded forms, and after purification, both forms displayed similar biophysical properties and induced adipocyte browning. Lyophilized formulations, incorporating phosphate buffer (pH 7), sucrose or trehalose, and polysorbate 80, preserved irisin's properties and bioactivity after lyophilization and could be rapidly reconstituted for subcutaneous administration. The formulations also remained stable at 40°C/75% RH for at least one month.

Conclusions: These findings lay a foundation for advancing irisin-based therapies for obesity and related diseases.

Introduction: The nonpsychoactive cannabinoid cannabidiol (CBD) has shown a wide range of pharmacological effects that are beneficial for wound healing. However, its local delivery is challenged by a very low aqueous solubility.

Methods: In this work, we synthesized hierarchical hydrogels made of the fructan hydrolyzed levan crosslinked with glycerol diglycidyl ether and loaded them with CBD nanoencapsulated within Pluronic^® F127 polymeric micelles (25% w/w payload).

Results: Hydrogels showed the typical porous structure (high resolution-scanning electron microscopy) and water uptake capacity up to ~ 1700%. The CBD release kinetics was studied in water (pH 6.8) and phosphate buffered saline (pH 7.4) under sink conditions, at 37°C. An initial burst release stage within the first 2 h of the assay was followed by a more sustained release stage over 72 h. As expected, hydrogels with a lower crosslinking density exhibited faster CBD release in both media. Release data fit the Korsmeyer-Peppas model with a combined mechanism involving diffusion and polymer chain relaxation together with the release of CBD-loaded polymeric micelles. The good compatibility of the hydrogels was initially confirmed in the monocyte-derived human macrophage cell line THP-1 over 72 h. Then, we showed > 70% viability of primary patient-derived gingival mesenchymal stem cells (GMSCs) exposed to hydrolyzed levan solutions, CBD-loaded polymeric micelle suspensions, and the CBD-loaded hydrogels for 28 days. Finally, we conducted preliminary differentiation studies of GMSCs cultured on non-loaded and CBD-loaded hydrolyzed levan hydrogels. Non-loaded hydrogels promote a transient increase in the secretion of the osteogenic marker alkaline phosphatase secretion that peaked at day 7 and declined thereafter, while CBD-loaded ones promote adipogenic differentiation.

Conclusion: Overall, results demonstrate the potential of levan hydrogels as platforms for local drug delivery applications.

The peritoneal cavity presents both unique challenges and promising opportunities for targeted therapy in malignancies like ovarian, gastric, pancreatic, and colorectal cancers. Intraperitoneal drug delivery offers significant pharmacokinetic advantages over intravenous administration by achieving high local drug concentrations and tumor-specific delivery potential while minimizing systemic toxicity. Despite these theoretical advantages, the clinical implementation of intraperitoneal therapy is limited by several barriers, including restricted tissue penetration, incomplete peritoneal coverage, rapid drug clearance, catheter-related complications, posttreatment peritoneal adhesions, and ascites-induced permeability dysregulation. This review highlights three advanced strategies developed to overcome these obstacles: (1) particulate-based delivery systems, such as nanoparticles to enhance tumor specificity through passive accumulation, active targeting and on-demand drug release in response to internal or external stimuli; (2) Sustained drug release hydrogels and (3) pressurized intraperitoneal aerosol chemotherapy. Despite promising preclinical and clinical advancements, successful translation requires systematic optimization of multiple parameters, such as ascites dynamics, tumor heterogeneity, and multidrug resistance. The integration of advanced delivery technologies with a comprehensive understanding of peritoneal physiology remains crucial for achieving safe and effective clinical applications.

Solid lipid nanoparticles (SLNs) have garnered significant interest for their safety and efficacy, especially following the success of COVID-19 mRNA vaccines. This study presents the synthesis and characterization of a novel stearic acid (SA)-gambogic acid (GA) conjugate, where GA, a xanthonoid, exhibits high affinity for the transferrin receptor (TfR) without competing with endogenous transferrin. The SA-GA conjugate was employed to formulate SLNs using a hot homogenization-ultrasonication-solvent evaporation technique for the peroral delivery of cyclosporine (CsA), paclitaxel (PTX), and urolithin-A (UA). Physicochemical properties, including particle size, zeta potential, drug loading, and entrapment efficiency, were assessed. Among the three tested compounds, UA exhibited the highest encapsulation efficiency at both 5% and 10% w/w loading, with particle sizes remaining under 250 nm. SA-GA SLNs demonstrated excellent stability in simulated gastric fluids, supporting their potential for oral administration. Cellular uptake studies using Coumarin-6 (C6) and drug-loaded SLNs indicated that UA achieved the highest uptake (~ 50%) in both FHS-74 (human small intestine) and HK2 (human kidney) cell lines. Further, in cisplatin-induced HK2 cell damage models, UA-loaded SA-GA SLNs significantly reduced inflammatory markers TLR4, NF-κB, and IL-1β. These results highlight UA-loaded SA-GA SLNs as a promising TfR-targeted oral delivery system for mitigating cisplatin-induced acute kidney injury (AKI) in cancer therapy.

Purpose: siRNA enables highly specific and targeted gene silencing, offering potential treatment for a range of diseases. Cytosolic access of siRNA is essential for efficacy; Current delivery systems generally use endosomal uptake pathways, leading to siRNA degradation due to inefficient escape. Guanidinium functionalized poly(oxanorbornene)imide (PONI) polymers facilitate direct cytosolic siRNA delivery with excellent gene knockdown efficacy in vitro and in vivo. The use of lyophilization to generate stable powders that retain excellent delivery and knockdown activity when reconstituted is demonstrated, providing a key tool for translation.

Methods: PONI-Guan polymers were mixed with siRNA to form PONI-Guan/siRNA polyplexes. The generated polyplexes were lyophilized and stored at varying temperature conditions for a total duration of 4 weeks. After reconstitution and delivery, cytosolic access of siRNA was assessed through confocal laser scanning microscopy. Knockdown efficacy was assessed in GFP expressing reporter deGFP HEK 293 T cell line using flow cytometry. Efficacy of reconstituted PONI-Guan/si_STAT3 in 4T1 breast cancer cells was evaluated by quantifying gene expression levels (qRT-PCR) and cell growth inhibition (Alamar blue assay). Delivery and therapeutic efficiency were compared between lyophilized and freshly made polyplexes.

Results: Lyophilized polyplexes retained critical functional features of freshly made polyplexes. Resuspended polyplexes facilitated effective cytosolic delivery siRNA and showed therapeutic relevance through the delivery of siRNA targeting STAT-3 gene in 4T1 cells with successful cell growth inhibition (~ 70%) and knockdown (~ 80%) of the gene.

Conclusion: Overall, this strategy signifies a highly transferrable and versatile method for effective storage of siRNA.

Background: Transdermal Drug Delivery Systems (TDDS) offer a non-invasive route for sustained systemic or localized drug delivery. By bypassing hepatic first-pass metabolism and improving bioavailability, TDDS enhances patient compliance, especially in the management of chronic diseases. Drug permeation across the skin is mediated through pathways involving the complex skin barrier, predominantly the stratum corneum, with efficacy influenced by both drug properties and skin physiology.

Methods: This review systematically integrates the fundamental mechanisms underlying TDDS, highlights cutting-edge technological advancements developed to overcome the skin barrier, and discusses their expanding clinical applications. The advanced technologies covered include permeation enhancers, vesicular systems (liposomes, transfersomes, ethosomes), microemulsions, microneedles (MNs), responsive systems (pH-, temperature-, enzyme-sensitive), and 3D printing.

Results: These innovative technologies effectively enhance drug flux, enable targeted delivery, and achieve spatiotemporal control of drug release. Clinically, FDA-approved TDDS formulations have been successfully applied to manage various conditions, including chronic pain (fentanyl, buprenorphine), neurological disorders (rotigotine, rivastigmine), cardiovascular diseases (nitroglycerin, clonidine), hormone replacement, and substance dependence (nicotine). Despite significant clinical value, TDDS still faces challenges such as limitations in delivering macromolecules, potential skin irritation, and inter-individual variability.

Conclusion: Future directions in TDDS research focus on integrating nanotechnology, AI-driven optimization, wearable sensors, and closed-loop smart systems. These integrations aim to achieve greater precision, personalization, and efficiency in transdermal drug delivery, providing valuable insights for future research and translational development.

Background: Jatyadi Taila (JT) is an Ayurvedic herbal formulation traditionally used for wound healing. However, its oily nature restricts clinical use due to greasy texture, slower absorption, occlusiveness, and application difficulties, resulting in poor patient compliance.

Objectives: To develop and optimize a JT containing nanoemulsion (JT-NE) and incorporate it into a Carbopol-based hydrogel for enhanced wound healing efficacy.

Methods: JT-NE was developed using a Quality by Design (QbD) approach and incorporated into a Carbopol-based hydrogel. The formulations were characterized for physicochemical properties, rheology, and morphology. In vitro fibroblast proliferation and migration assays, along with in vivo wound healing studies in full-thickness wound-bearing Wistar rats, were performed to evaluate therapeutic efficacy.

Results: The optimized JT-NE formulations exhibited a globule size range of 220-300 nm, polydispersity index (0.245-0.380), and zeta potential values of -25.94 ± 1.01 mV, 18.14 ± 1.20 mV, and -26.10 ± 1.25 mV. Hydrogels containing JT-NE demonstrated thixotropic behavior with an average viscosity of 88748 mPa, pH 4.5-5.5, a porous mesh-like morphology with entrapped JT-NE, and ~70% water loss within 4 h. In vitro, JT-NE significantly promoted fibroblast proliferation and migration. In vivo, the formulation enhanced wound closure, increased collagen biosynthesis, downregulated TNF-α, and upregulated KI-67 expression compared to untreated and JT treated groups.

Conclusion: The JT-NE hydrogel significantly improved the therapeutic efficacy of JT, offering a novel, patient-compliant delivery system for effective wound management.