Journal of Pharmaceutical Innovation最新文献

Myositis, a group of inflammatory myopathies characterized by muscle inflammation and progressive weakness, presents significant therapeutic challenges due to its complex and not fully understood pathophysiology. In this study, an innovative computational framework is proposed to investigate the molecular characteristics of drugs used in myositis treatment. Reverse degree-based topological indices, including the modified First Zagreb index, modified atom–bond connectivity index, and modified Randic index, are utilized to quantitatively describe molecular structures and capture their intrinsic properties. To enhance predictive accuracy and support pharmaceutical decision-making, advanced machine learning models, specifically Extreme Gradient Boosting (XGBoost) and Random Forest, are employed to model the relationships between topological descriptors and key physicochemical properties such as molar refractivity, molecular volume, and structural complexity. The obtained results demonstrate strong correlations, with coefficients ranging from 0.8 to 0.9, confirming the robustness of the proposed descriptors. Among the evaluated models, XGBoost demonstrated better fitting performance on the available dataset. However, given the limited sample size, these findings should be regarded as preliminary and require validation using larger datasets and independent evaluation strategies. This study contributes to pharmaceutical innovation by integrating graph-theoretical descriptors with state-of-the-art machine learning techniques to develop reliable predictive models for drug property estimation. The proposed approach offers a scalable and efficient tool for drug design optimization, supporting the advancement of precision medicine and facilitating future research in drug repurposing and therapeutic development for myositis and related disorders.

Purpose

Drug lag is a critical issue limiting South Korea’s pharmaceutical competitiveness and patient access, and it has been linked to delays in the Investigational New Drug (IND) review process. This study aimed to identify key barriers affecting IND review efficiency in South Korea by analyzing real-world industry experience and to propose concrete strategic actions to mitigate drug lag.

Methods

We employed an exploratory sequential mixed-methods design. First, we used grounded theory to identify problematic factors within the IND process through semi-structured interviews. We then applied the Analytic Hierarchy Process to evaluate these factors, followed by a quadrant analysis of importance and urgency to identify top-priority tasks.

Results

Three core categories (rationality and patient-centricity, professional review, and operational efficiency), were identified as key domains for enhancing IND efficiency. Rationality and patient-centricity emerged as the most important and urgent criterion, followed closely by professional review. Within rationality and patient-centricity, four sub-criteria placed in the first quadrant (highly important and highly urgent): integration of patient needs into evaluation, global regulatory harmonization, acceptance of scientific evidence for new modalities, and adoption of overseas regulatory standards. Two sub-criteria within professional review (expert team review and standardized review guidelines) were also pinpointed in the first quadrant. Although operational efficiency ranked lowest, simplified Korean translation requirements stood out as the most critical factor within this category.

Conclusion

Transitioning from focusing on procedural speed toward embracing regulatory flexibility to enhance scientific rationality and patient access is a viable pathway for mitigating drug lag in South Korea.

Purpose

To develop and optimize pregabalin-loaded thermosensitive in situ gel (PGB-loaded TS-in situ gel) for intranasal delivery to overcome PGB’s short half-life, frequent dosing, plasma-concentration fluctuations, and poor patient compliance. The study aimed to develop intranasal PGB-loaded TS-in situ gel to prolong residence time and reduce the dosing frequency by sustaining the therapeutic effects.

Methods

PGB-loaded TS-in situ gel was formulated using the cold technique and optimized through 3³ Box–Behnken design. It was characterized for morphology, viscosity, gel strength, gelation time, gelation temperature, and drug–polymer compatibility using X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FTIR). In-vitro drug release studies evaluated the release profile. Safety and tolerability were assessed through ex-vivo histopathology of sheep nasal mucosa and cell viability studies on rat nasal mucosa. In-vivo pharmacokinetics compared the intranasal formulation with oral PGB solution. Antiepileptic efficacy was evaluated using the 6-Hz psychomotor seizure model.

Results

The optimized formulation exhibited spherical morphology, viscosity before gelation (1220 cps), gel strength (29s), gelation time (36s), and gelation temperature of 33 °C. XRD, DSC, and FTIR confirmed molecular dispersion of PGB within the gel matrix. The formulation showed biphasic drug release, with approximately 99.82% release over 12 h. Histopathological and cell-viability studies demonstrated good nasal safety and tolerability. Pharmacokinetics showed enhanced intranasal absorption, with 1.66-fold higher Cmax, 4-fold higher Tmax, 3.35-fold higher MRT, and 5-fold higher AUC (0–∞) than the oral solution. In the 6-Hz psychomotor seizure model, the optimized formulation significantly reduced seizure characteristics associated with partial epilepsy.

Conclusion

The intranasal PGB-loaded TS-in situ gel provided sustained release, improved pharmacokinetic performance, and enhanced antiepileptic efficacy with nasal safety and tolerability, suggesting promising intranasal strategy for managing partial epileptic seizures. However, further clinical studies are required to confirm its efficacy and translational potential in humans.

Graphical Abstract

Purpose

Periodontitis requires localized therapy that controls infection while maintaining periodontal tissue compatibility. This study aimed to develop and optimize a doxycycline hydrochloride (Dox-HCl)-loaded hydrogel using a Design of Experiments approach.

Methods

A β-cyclodextrin (β-CD), sodium alginate (SA), and polyvinyl alcohol (PVA) hydrogel was optimized using a three-factor, three-level Box–Behnken design in JMP. The optimized F4 formulation was evaluated for physicochemical properties, syringeability, drug content, drug release, mucoadhesion, cytocompatibility, antimicrobial activity against Porphyromonas gingivalis, and CAM vascular responses.

Results

F4 showed a pH of ~ 6.8, shear-dependent viscosity, acceptable syringeability through a 25-gauge needle, and ~ 98.5% drug content. FTIR and DSC supported characterization of the Dox-HCl–excipient mixture, although final hydrogel compatibility and Dox-HCl/β-CD inclusion-complex formation were not definitively established. Approximately 94% drug release occurred within 240 min, following anomalous transport (Korsmeyer–Peppas n = 0.63). F4 showed concentration-dependent antimicrobial activity, with MIC and MBC values of 7.8 and 15.6 µg/mL, respectively. A 17 mm inhibition zone was observed against P. gingivalis, while L929 cell viability remained > 90%. HET-CAM analysis showed differences in selected vascular parameters between F4 and blank-hydrogel-treated CAMs.

Conclusion

F4 demonstrated favourable physicochemical properties with preliminary antimicrobial, cytocompatibility, release, mucoadhesive, and CAM responses, supporting its potential as a localized Dox-HCl delivery platform. Further studies addressing drug retention, periodontal-specific compatibility, polymicrobial biofilms, stability, vascular responses, and in vivo efficacy are required.

Introduction

Transmucosal drug delivery systems (TM-DDS) have transformed pharmaceutical sciences from 2020 to the present by utilising vascularised mucosal surfaces, including buccal, nasal, sublingual, vaginal, rectal, and ocular channels, thereby surmounting the restrictions associated with oral and parenteral administration. These needle-free platforms circumvent first-pass metabolism, resulting in significant enhancements in bioavailability, a swift therapeutic start, and improved patient compliance, particularly among paediatric and geriatric populations resistant to injections. This review emphasises that mucosal absorption occurs through paracellular channels and transcellular pathways across epithelial membranes, hindered by route-specific obstacles. The personalised treatments incorporate nanotechnology-integrated polymeric nanoparticles, liposomes, and dendrimers, enabling precise, controlled release and targeting the disease. The analysis illustrates that the clinical pipelines encompass endocrinology, cardiovascular disorders, oncology, and specific demographics, with market forecasts predicting buccal systems will attain USD 3.91 billion by 2027.

Methodology

This review aims to collect, analyse, and summarise information from already published research articles and reviews related to the transmucosal drug delivery system that were collected from various sources such as Google Scholar, PubMed, and ScienceDirect. Therefore, there is no need for ethical authorisation. The collective information was evaluated and synthesised to provide an overview of recent advances, challenges, and future perspectives in transmucosal drug delivery systems.

Conclusion

The TM-DDS demonstrates superior formulation stability, scalable production, less inter-patient variability, and compliance with FDA/EMA regulations. Emerging safer alternatives like intelligent biomaterials, personalised 3D printing, and enhanced pipelines promise accessible, patient-centred medicines that will improve efficacy, adherence, and global health outcomes in the future years.

Graphical Abstract

Purpose

Navayasa Churnam (NVC) is a traditional Ayurvedic polyherbal preparation that contains nine medicinal plants as well as elemental iron, commonly used for the treatment of variety of disease conditions including metabolic disorders. The present study aims to explore NVC's phytochemical composition and molecular processes underlying its potential antidiabetic effects.

Methods

This study evaluated NVC’s antidiabetic potential using an integrated techniques that included LC-Orbitrap HRMS/MS-based phyto-metabolomics, network pharmacology, molecular docking, in vitro, and in vivo validation.

Results

Untargeted LC-MS/MS profiling yielded a preliminary identification of 129 phytoconstituents spanning across flavonoids, alkaloids, phenolic acids, and terpenoids. NVC exhibited inhibitory effect towards α-glucosidase with an IC₅₀ value of 21.47 ± 1.55 µg/mL. NVC administration boosted glucose intake in HepG2 cells under hyperglycemic and lipotoxic circumstances compared to the disease control, with an effect similar to metformin. NVC therapy significantly reduced fasting blood glucose levels by approximately 62% in STZ-induced diabetic rats compared to disease control (p < 0.0001). NVC treatment increased hepatic GLUT4 levels from 6.5 to 8.5 ng/mg, suggesting partial restoration of GLUT4 expression (p < 0.05).

Conclusions

Network pharmacology identified 12 hub proteins involved in glucose metabolism, insulin signaling, and oxidative stress, and molecular docking demonstrated favorable interactions between NVC phytoconstituents and diabetes-related targets. Collectively, these findings provide quantified experimental and computational data supporting NVC formulation’s multi-targeted antidiabetic potential.

Graphical Abstract

Purpose

Rheumatoid arthritis is a chronic autoimmune disease requiring long-term therapy, often limited by systemic adverse effects and inadequate drug delivery to inflamed joints. This study aimed to develop and optimize a ferulic acid-loaded solid lipid nanoparticle hydrogel using a Quality-by-Design approach to improve topical anti-arthritic therapy.

Methods

Nanoparticles were prepared by hot-homogenization and optimized using a Box-Behnken design. The optimized nanoparticles were characterized by dynamic light scattering, zeta potential, scanning and transmission electron microscopy, followed by in-vitro evaluation and incorporation into a xanthan gum-based gel. The hydrogel was further assessed for physicochemical properties, stability, in-vitro drug release, ex-vivo skin permeation, dermal safety, anti-inflammatory activity using the carrageenan-induced paw edema model, and anti-arthritic efficacy in the complete Freund’s adjuvant-induced arthritis model.

Results

The optimized nanoparticles exhibited a favourable in-vitro safety profile with 95.6 ± 0.4% cell viability, significantly inhibited protein denaturation (74.3 ± 0.2%), and effectively suppressed COX-2 activity (IC₅₀ = 40.86 µg/ml). The hydrogel demonstrated desirable physicochemical properties, excellent stability, and sustained drug release, achieving 83.2 ± 0.3% cumulative drug release and 72.9 ± 0.4% ex-vivo skin permeation after 8 h. In vivo studies showed superior anti-inflammatory and anti-arthritic efficacy compared with the conventional gel, as evidenced by significant reductions in paw edema, preservation of body weight, and marked protection against cartilage and bone damage.

Conclusion

The Quality-by-Design optimized ferulic acid loaded solid lipid nanoparticles-based hydrogel is a promising topical drug delivery system for rheumatoid arthritis, offering sustained release, enhanced dermal permeation, and improved local therapeutic efficacy.

Graphical Abstract

Purpose

Colorectal cancer (CRC) is a heterogeneous and drug-resistant malignancy that urgently requires multi-target therapeutic agents. This study aimed to systematically elucidate the multi-target molecular mechanisms of calycosin-7-O-β-D-glucoside (CG), a bioactive flavonoid from Astragali radix, against CRC by integrating computational prediction, dynamic simulation, clinical bioinformatics validation, and in vitro experimental verification.

Methods

Network pharmacology was employed to predict CG targets and CRC-associated genes, with overlapping targets subjected to PPI network construction, GO/KEGG enrichment analyses, and core target screening. Molecular docking and 100‑ns molecular dynamics (MD) simulation were performed to evaluate binding affinity and complex stability. Multi‑database bioinformatics analyses (HPA, GEPIA, TIMER) validated clinical relevance, prognostic value, and immune infiltration correlations of core targets. In vitro assays, including CCK‑8, TUNEL, EdU, flow cytometry, colony formation, wound healing, Transwell invasion, tumorsphere formation, and Western blotting, were conducted in HCT116 and HT29 cells to confirm CG’s antitumor effects and mechanistic regulation.

Results

Network pharmacology identified 99 overlapping targets, with ten core targets and significant enrichment in the PI3K‑Akt signaling pathway. Molecular docking revealed strong binding affinities, and MD simulation confirmed long‑term stability of the CG–HSP90AA1 complex. Multi‑database analyses showed core target overexpression in CRC tissues, association with poor prognosis, and correlations with CD8⁺ T cells, Tregs, MDSCs, and neutrophils. In vitro, CG concentration‑dependently suppressed viability, induced apoptosis, inhibited proliferation, migration, invasion, and tumorsphere formation. Western blotting confirmed that CG reduced p‑PI3K/PI3K and p‑Akt/Akt ratios, decreased Bcl‑2/Bax, and activated cleaved caspase‑3, triggering the mitochondrial apoptotic pathway.

Conclusion

This study is the first to demonstrate that CG exerts anti‑CRC effects through multi‑target binding to HSP90AA1, TNF, and PTGS2, coordinately suppressing the PI3K‑Akt pathway and downstream apoptotic cascades, thereby inhibiting malignant phenotypes and cancer stem cell‑like properties. These findings establish a comprehensive “computational prediction → dynamic simulation → clinical association → experimental validation” paradigm and provide experimental evidence supporting CG as a promising adjuvant therapeutic candidate for CRC.

Purpose

Apomorphine hydrochloride (Apo HCl), a dopaminergic agonist used in advanced Parkinson’s disease, is limited by its short plasma half-life, oxidative instability, and need for frequent subcutaneous dosing. This study aimed to develop a sustained-release liposomal formulation of Apo HCl using a scalable manufacturing-oriented approach. Combining spray-drying-based lipid matrix formation with high-pressure homogenization offers a practical strategy for producing liposomal dispersions designed to protect Apo HCl and provide sustained subcutaneous drug release.

Methods

Apo HCl-loaded liposomes were prepared by spray drying, hydration and high-pressure homogenization. The effects of lipid composition, cholesterol content, and Apo HCl concentration were evaluated through physicochemical characterization, solid-state analysis, in vitro release, cytocompatibility, and short-term stability studies.

Results

The selected lead formulation showed a particle size of 112 nm, polydispersity index of 0.14, zeta potential of − 42 mV, and encapsulation efficiency of 99.2%. The liposomal formulation sustained Apo HCl release for up to 48 h, whereas the reference solution released rapidly within 1 h. Blank liposomes maintained L929 cell viability above 70% and showed favorable short-term refrigerated stability.

Conclusions

The selected lead Apo HCl liposomes represent a promising liposomal platform for sustained subcutaneous delivery and warrant further in vivo evaluation to confirm their pharmacokinetic performance and translational potential.

Summary

Apomorphine hydrochloride requires frequent administration due to its short duration of action, limiting patient convenience in Parkinson’s disease management. This study developed spray-drying-assisted liposomes for subcutaneous delivery. Lipid matrices were prepared by spray drying, hydrated under acidic and antioxidant-containing conditions, and processed by high-pressure homogenization. The selected lead formulation showed nanosized vesicles, low polydispersity, high encapsulation efficiency, negative zeta potential, and a gradual in vitro release profile within the 48 h study period. Stability and physicochemical characterization supported the suitability of the formulation approach. These findings indicate that Apo HCl liposomes may provide a promising platform for further in vivo evaluation.

Teaser

This study presents a spray-drying-assisted liposomal formulation designed to sustain apomorphine hydrochloride release and support further evaluation as a subcutaneous sustained-release delivery platform.

Purpose

This study aimed to generate and computationally prioritize lapatinib-inspired analogues with improved predicted EGFR kinase binding, conformational stability, pathway relevance, and developability in the context of breast cancer.

Methods

An artificial intelligence-assisted platform was used to generate 2,000 lapatinib analogues. The compounds were docked into the ATP-binding site of the human EGFR kinase domain co-crystallized with lapatinib (PDB ID: 1XKK), followed by Prime MM-GBSA rescoring of the top 20 candidates. Four prioritized analogues were subjected to 200 ns molecular dynamics simulations, including RMSD, RMSF, secondary-structure, interaction-persistence, ligand-flexibility, principal component, free-energy landscape, and dynamic cross-correlation analyses. Network pharmacology and GO/KEGG enrichment were used to identify breast cancer-associated targets and pathways. Drug-likeness, pharmacokinetic behaviour, and toxicity were predicted using QikProp, SwissADME, and ADMETlab 3.0.

Results

P407AM53379 showed the best docking score (-8.7), whereas P407AM21445 exhibited a favourable MM-GBSA estimate of -73.56 kcal/mol. P407AM63960 demonstrated the most balanced dynamic behaviour, with a mean protein Cα RMSD of approximately 1.42 Å, limited residue fluctuations, persistent interactions, compact conformational sampling, and a dominant low-energy basin. Network analysis linked the prioritized compounds with EGFR/ERBB, PI3K-AKT, MAPK, JAK-STAT, mTOR, and resistance-related pathways. However, predicted solubility, hERG, hepatotoxicity, genotoxicity, and molecular-size liabilities remained.

Conclusion

P407AM63960 emerged as the most dynamically balanced computationally prioritized EGFR-binding hypothesis among the comparable simulated systems. However, the structure-based analyses directly evaluated only the EGFR kinase domain. Chemical synthesis and experimental evaluation against both EGFR and HER2 are therefore required before dual-target activity, selectivity or therapeutic relevance can be established.