Pharmaceutical Research最新文献

Purpose: Quercetagetin (QTGN) is a naturally occurring flavonol predominantly sourced from marigold flowers and possesses notable therapeutic potential, including antidiabetic, anticancer, antioxidant, anti-inflammatory, and antiviral properties. However, poor aqueous solubility and in turn bioavailability restrict therapeutic utility of QTGN. Crystal engineering is one of the approaches proven to be fruitful in resolving the solubility issues of many active pharmaceutical ingredients (APIs).

Method: In the present work, a cocrystal of QTGN using betaine (BET) as coformer viz. Quercetagetin⋅betaine⋅ethanol (QTGN⋅BET⋅EtOH) was synthesized using the solvent evaporation method. It was further characterized using Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TGA), Powder X-ray diffraction (PXRD), and single crystal XRD (SCXRD).

Result: FTIR studies confirmed hydrogen bonding between QTGN and BET. PXRD studies showed formation of new crystalline phase. The prepared cocrystal had stoichiometric ratio of 1:1:1 between QTGN, BET, and ethanol forming cocrystal ethanolate and shared robust hydroxyl⋯carboxylate supramolecular synthon as confirmed by TGA and SCXRD, respectively. Equilibrium solubility study and in vitro dissolution study showed a significant improvement (p < 0.0001) in aqueous solubility of QTGN upon its cocrystallization with BET. Furthermore, in vivo pharmacokinetic study revealed a 1.28-fold increase in bioavailability of QTGN when formulated as cocrystal solvate. The prepared cocrystal was found to be stable over a period of six months at 40°C and 75% RH when analyzed using PXRD studies.

Conclusion: The current work represents a frontier in pharmaceutical formulation, providing a means to fully harness the therapeutic potential of QTGN using cocrystal approach.

Objectives: The present review aims to provide comprehensive bench-to-bedside insights into ADC-related ocular toxicity for drug designers, pharmaceutical manufacturers, toxicologists, and medical staff, thereby enhancing the safety of ADC therapeutic applications.

Methods: The review comprehensively analyzes the recent progress in the pathological mechanisms of ADC-related ocular toxicity, evaluates existing non-clinical risk assessment strategies based on animal toxicological studies, and highlights future optimization directions. It also summarizes clinical adverse events to demonstrate the typical profile of ocular surface toxicity and provides clinical management strategies.

Results: ADC ocular toxicity primarily affects the ocular surface via on-target (antibody-mediated) and off-target (non-specific uptake) mechanisms. Key determinants include payload type (e.g., MMAF and DM4, which exhibit higher toxicity due to intracellular retention), linker properties (cleavable linkers mitigate off-target effects), and ADCs' physicochemical characteristics. Non-clinical models effectively predict corneal injury but poorly recapitulate conjunctival responses. Clinical management relies on early ophthalmic monitoring and dose adjustment, with 42.9%-100% of adverse events being reversible.

Conclusion: This review offers valuable insights into ADC ocular toxicity, emphasizing the importance of early-stage selection and optimization of ADCs and their components to reduce ocular toxicity risks. It provides a reference for mitigating ADC-related ocular toxicity risks and facilitates the future development of ADCs with improved safety and efficacy.

Background: Crimean-Congo hemorrhagic fever virus (CCHFV), identified by the World Health Organization(WHO) as a potential epidemic threat, is a tick-borne Nairovirus primarily transmitted by Hyalomma marginatum species. Since its first detection in the 1940s, CCHFV has spread to multiple regions worldwide and remains a major public health concern due to its high fatality rate and expanding geographic distribution. The virus can be transmitted through tick bites or contact with infected individuals, and no licensed vaccine is currently available to prevent infection.

Methods: In this study, two CCHFV proteins, Q8JSZ3 (GP_CCHFI) and Q6TQR6 (L_CCHFI), were retrieved from public databases and analyzed using bioinformatic tools to explore their potential as vaccine candidates.

Results: The computational analyses revealed that both proteins possess non-toxic characteristics and show promise for future vaccine design.

Conclusions: These findings provide a preliminary in-silico framework that may guide the development of effective vaccines against CCHFV.

Objective: Chronic inflammation is characterized by excessive cytokine production and macrophage infiltration, contributing to disease progression. This study aimed to enhance the therapeutic efficacy and local delivery of carvacrol (CVL), a natural PPAR-γ activator with anti-inflammatory properties, through the development of a poly(lactic-co-glycolic) acid (PLGA)-based nanoparticle delivery system with hyaluronic acid (HA)-dependent macrophage targeting.

Methods: Poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles encapsulating CVL (CP NPs) were prepared and coated with 1.5% w/v hyaluronic acid (HA) to form CHP NPs for CD44 receptor-mediated targeting of pro-inflammatory macrophages. Physicochemical characterization, encapsulation efficiency, and drug release profile were evaluated. Cellular uptake and cytokine modulation were assessed in lipopolysaccharide-stimulated macrophages.

Results: CP NPs exhibited a size of 155 ± 3 nm and a zeta potential of -57.7 ± 1.3 mV, while HA coating yielded CHP NPs with a size of 225 ± 18 nm and a zeta potential of -25.5 ± 0.3 mV. Encapsulation efficiency and loading capacity reached 91 ± 5% and 26 ± 7%, respectively. HA coating enhanced nanoparticle internalization by 41% compared to uncoated NPs. A sustained release profile was achieved, with 50 ± 13% of CVL released over 21 days. In macrophages, CHP NPs increased anti-inflammatory cytokines IL-1ra (+ 258%), IL-4 (+ 260%), and IL-10 (+ 40%), while reducing pro-inflammatory cytokines IL-1α (-25%), IL-1β (-36%), and TNF-α (-36%) relative to untreated cells.

Conclusions: HA-coated PLGA nanoparticles effectively delivered CVL, enhancing macrophage targeting and promoting an anti-inflammatory response. This platform offers a promising strategy for treating chronic inflammation-related diseases.

Purpose: Large-volume subcutaneous injections can create visible protrusions called blebs, whose size and shape affect drug absorption and patient comfort. In vivo pig studies have documented how the bleb dimensions and tissue pressure vary with injection volume, flow rate, and fluid viscosities. However, its underlying mechanics remain unclear due to limited temporal and spatial measurements. This study evaluates whether ex vivo tissue can serve as an inexpensive and practical surrogate to study tissue deformation and uses this model to investigate the roles of fluid properties and vascular perfusion during large-volume injections.

Methods: We performed subcutaneous injections into store-bought pork belly tissue, replicating the injectate conditions from previous in vivo studies. Using a depth camera and pressure sensor, we continuously measure the bleb surface profile and in-line pressure. These measurements are converted into height, area, and tissue pressure at different injection volumes and are compared directly with previously published in vivo data.

Results: Bleb height and area increased monotonically with injected volume but were independent of viscosity and flow rate. Tissue pressure rose initially and then plateaued, even as bleb dimensions continued to grow. These trends closely mirrored in vivo findings.

Conclusion: Ex vivo tissue mimics bleb shape and tissue pressures of in vivo subcutaneous injections, indicating that in vivo systemic factors are negligible over typical injection timescales. These results validate the use of ex vivo surrogates for studying bleb formation and challenge assumptions in current poroelastic models, which fail to capture the observed decoupling between tissue pressure and bleb growth.

Background: Lung infections affect over 80% of adults with cystic fibrosis, with Pseudomonas aeruginosa being a leading pathogen. Although antibiotics are frequently nebulized as standard treatments, the physicochemical environment of the diseased lung often limits their diffusion and overall effectiveness. Our previous studies showed polyelectrolyte surfactants (PS) to be a promising delivery system for cationic antimicrobials in vitro. This study seeks to expand that knowledge by evaluating their potential for nebulized delivery.

Methods: To achieve this, we evaluated their size and antimicrobial activity following nebulization; in vitro toxicity against epithelial cells and erythrocytes; and biodistribution and expression of inflammation markers following administration to healthy mice.

Results: The nanoparticle formulation exhibited a mucolytic effect on an artificial mucus model of cystic fibrosis mucus. Following nebulization, nanoparticles retained both their size and biological activity. Additionally, they displayed no observable toxicity in vitro against either human lung epithelial cells or erythrocytes; instead, epithelial cells treated with PS-based nanoparticles showed increased cell viability. Following administration of these formulations to mice via inhalation, over 70% of the recovered nanoparticles were retained in the lungs 24 h after treatment, with a small fraction being uniformly distributed to other tissues. A screen of key inflammatory cytokines revealed that inhalation treatment led to a slight increase of IL-6 in the liver and IL-18 in the spleen. These increases seem to be consistent with a minor inflammatory response.

Conclusion: Overall, the results suggest that PS are a promising nanotechnology for the pulmonary delivery of cationic drugs.

Purpose: Accurate prediction of aerosol deposition in the extrathoracic airway is critical for designing inhaled therapies, yet many experimental and computational studies rely on geometries that are either simplified or subject-specific but not necessarily physiologically consistent with oral inhalation. This inconsistency can lead to varying estimates of drug delivery efficiency, particularly in the mouth-throat region where flow behavior and particle deposition are highly sensitive to physiological detail.

Methods: This study investigated the influence of airway geometry on aerosol drug delivery by quantifying the deposition of salbutamol sulfate across simplified and subject-specific extrathoracic models. An artificially opened mouth, derived from a closed mouth CT scan and a realistic oral inhalation geometry, were compared to a simplified airway model and the pharmaceutical standard model. All experiments were performed at an inhalation flow rate of 30 l min $_{}^{-1}$ using a metered dose inhaler (Ventolin $_{}^{\circledR }$ ).

Results: Each airway was segmented into 10 regions, from the device mouthpiece through the mouth-throat, larynx, and trachea, to the eight stages representing the lower airway. The artificial open mouth geometry produced the lowest ling deposition only 9% , while the realistic oral inhalation had lung deposition of 45%, more consistent with the simplified models.

Conclusions: Subject-specific airway models are not inherently more realistic than simplified models. When physiological features of oral inhalation-specifically soft palate elevation and a smaller mouth opening than a fully opened mouth-are not captured in the model geometry, simplified geometries based on oral inhalation conditions may more accurately represent true deposition patterns than subject-specific models derived from restful breathing CT scans.

Background: HER2-positive breast cancer is characterized by the absence of estrogen and progesterone receptors and the overexpression of the HER2 receptor. Existing targeted therapies, leads to side effects like cardiotoxicity, diarrhoea and suffer from poor penetration of the blood brain barrier. Zinc oxide nanoparticles have emerged as a promising drug delivery platform by improving biocompatibility, selective cytotoxicity via reactive oxygen species generation and facilitating effective penetration across biological barriers.

Objective: Our aim was to synthesize and characterize the Fulvestrant-zinc oxide nanoparticles, evaluate its efficacy in-vitro and ascertain its potential as a therapeutic agent for HER2-positive breast cancer.

Methods: Pharmacogenomics and gene enrichment process were applied to select target by following computational drug design strategy. Based on molecular docking, MMGBSA and molecular dynamics were undertaken to assess the stability. Subsequently, Fulvestrant-zinc oxide nanoparticles were synthesized and characterized using FT-IR, SEM and DSC techniques. In-vitro assessments involved MTT assays and AO/EtBr staining method.

Results: Computational results showed Fulvestrant superior HER2 binding, confirmed by molecular dynamics studies. In vitro studies revealed cytotoxicity and apoptosis.

Conclusion: This study highlights the Fulvestrant-zinc oxide nanoparticles as a promising therapeutic intervention for HER2-positive breast cancer. By undergoing computational approaches, Network analysis and pharmacogenomics.

Purpose: The intestinal absorption of compounds administered orally can be impacted by permeability, metabolism and uptake/efflux transport. This study aimed to characterize the EpiIntestinal duodenum microtissue developed from duodenum enterocytes and assess whether permeability, metabolism and transport could be simultaneously investigated in this model.

Methods: Healthy human primary duodenum enterocytes were cultured on a permeable support. Their ability to predict drug absorption was evaluated using a set of drugs with known human absorption. Intestinal drug-metabolizing enzymes and transporters were assessed by analyzing their protein expression and functional activities using specific probe substrates and inhibitors.

Results: The permeability (Papp) of the drug set showed a positive correlation with human % Fa. The expression and functional activities of P-gp, BCRP, MRPs (efflux ratio > 2), and PEPT1 were demonstrated in the microtissues. The functional activities of CYP3A4/5, CYP2C19, CYP2C8, UGT1A1 and SULT1B1 were also confirmed by the formations of probe substrate metabolites. In addition, the dominant effect of CYP3A4/5 over P-gp on the Papp of nicardipine was observed with a significant increase in permeability (Papp = 6.6 × 10^-6 cm/s) following the addition of elacridar and ketoconazole compared to the control Papp of 2.8 × 10^-6 cm/s and the Papp with elacridar at 3.7 × 10^-6 cm/s.

Conclusions: These findings suggest that the EpiIntestinal duodenum microtissue can effectively replicate the complex interplay of permeability, metabolism, and transport in the gut, thereby improving the prediction of oral drug absorption.

Background: Psoriasis is a chronic immune-mediated skin disorder marked by excessive keratinocyte proliferation, inflammation, and impaired barrier function, all of which limit effective topical drug delivery.

Objectives: To develop and optimize a tannic acid-loaded transfersomal gel to improve transdermal delivery, skin deposition, and therapeutic efficacy in psoriatic skin.

Methods: Transfersomes were prepared using the thin-film hydration method and optimized through a Box-Behnken design evaluating surfactant type, total lipid content, and phospholipid-to-surfactant ratio. The optimized vesicles were analyzed for particle size, PDI, zeta potential, and entrapment efficiency. Transfersomes were incorporated into a carbopol gel, and evaluated through rheological testing, in vitro release, ex vivo permeation studies, and in vivo antipsoriatic activity using an imiquimod-induced psoriasis mouse model.

Results: The optimized Span-80-based formulation showed a particle size of 205 nm, PDI 0.209, zeta potential -26.0 mV, and 84% entrapment efficiency. Gel incorporation provided suitable rheology and sustained release (63.7% over 24 h). Ex vivo studies revealed a flux of 4.99 μg/cm²/hr, a 2.74-fold improvement over conventional gel. In vivo, the transfersomal gel significantly reduced PASI scores from 10.8 ± 0.33 (disease control) to 4.5 ± 0.24. Histopathology confirmed decreased epidermal hyperplasia and inflammation.

Conclusions: The combination of ultradeformable transfersomes with tannic acid produced enhanced permeation, sustained release, and significant antipsoriatic effects. This optimized transfersomal gel demonstrates strong potential as an effective topical therapy for psoriasis.