Journal of Pharmaceutical Innovation最新文献

{"title":"Earthworm as a Sustainable Bioreactor: Biotransformed Nigella sativa Metabolites as Potential Dual Modulators of HDAC2 and BCL2 for HIV Latency: An Integrated Computational and Zebrafish Study","authors":"Kamardeen Shimar Mohamed Yasin,&nbsp;Arockiya Anita Margret,&nbsp;Chrisanne Freeman","doi":"10.1007/s12247-026-11075-y","DOIUrl":"10.1007/s12247-026-11075-y","url":null,"abstract":"<div><p>Earthworm-mediated biotransformation offers a sustainable strategy to enhance the biological potential of natural products through the generation of structurally modified bioactive metabolites. In this study, <i>Eisenia fetida</i> was employed as a living bioreactor to biotransform <i>Nigella sativa</i> (black cumin), and the resulting methanolic extracts were evaluated using integrated experimental and computational approaches. GC–MS profiling revealed distinct alterations in the metabolite composition of the black cumin-fed earthworm extract compared with the kitchen waste-fed control, indicating the formation of biotransformed metabolites. The biotransformed extract exhibited enhanced antioxidant, anti-inflammatory and erythrocyte membrane-stabilizing activities, together with selective antibacterial activity against <i>Staphylococcus aureus</i> and antifungal activity against <i>Aspergillus niger</i>. Zebrafish (<i>Danio rerio</i>) embryo toxicity assays demonstrated concentration-dependent developmental toxicity, with the bio-transformed extract exhibiting a higher median lethal concentration (LC₅₀ = 229.89 µg/mL) than the control extract (LC₅₀ = 147.10 µg/mL), indicating improved embryonic biocompatibility following earthworm-mediated biotransformation. Network pharmacology identified HDAC2 and BCL2 as key host proteins associated with HIV latency, epigenetic regulation and apoptosis. Molecular docking predicted favourable interactions of Benzoic acid, 3-formyl-2,4-dihydroxy-6-methyl-, methyl ester, identified as the prominent bio-transformed metabolite, exhibited favourable binding to HDAC2 (− 8.16 kcal mol⁻¹) and BCL2 (− 6.75 kcal mol⁻¹), supporting it as a putative as a dual-target candidate and provide a hypothesis for further experimental investigation, rather than demonstrating direct target modulation. Collectively, these findings indicate that earthworm-mediated biotransformation enhances both the biological activity and safety profile of <i>N. sativa</i>, highlighting the potential of earthworms as sustainable living bioreactors for generating novel metabolites with promising therapeutic applications in HIV latency and associated pathways. </p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":656,"journal":{"name":"Journal of Pharmaceutical Innovation","volume":"22 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149133391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Design of Novel mRNA and Multiepitope Subunit Vaccines for H10N5 Avian Influenza A virus","authors":"Hassan Ayaz,&nbsp;Ayesha Zahid,&nbsp;Adnan Zeb,&nbsp;Faisal Ahmad,&nbsp;Nazish Badar,&nbsp;Dalia M Alammari,&nbsp;Eid A. Alatawi,&nbsp;Sajjad Ahmad,&nbsp;Fahad M Alshabrmi,&nbsp;Taghreed N. Almanaa","doi":"10.1007/s12247-026-11081-0","DOIUrl":"10.1007/s12247-026-11081-0","url":null,"abstract":"<div><h3>Background</h3><p>Annually, influenza viruses cause a considerable number of deaths worldwide and are a primary cause of severe respiratory diseases. Finding novel immunogenic locations that might trigger a potent immune response is therefore crucial.</p><h3>Methods</h3><p>The present study utilized bioinformatics techniques to develop mRNA and multiepitope-based vaccines that specifically target the H10N5 Avian Influenza A virus. The epitopes of the hemagglutinin (HA) and neuraminidase (NA) proteins on T and B cells of this specific strain were identified using a variety of immunoinformatic techniques. The chosen HTL epitopes and their corresponding major histocompatibility complex (MHC) alleles were docked by using a molecular docking technique.</p><h3>Results</h3><p>A total of 6 linear B cell epitopes, 6 HTL epitopes, and 6 CTL epitopes were chosen for the structural design of preventive vaccines based on mRNA and multiepitope subunit. At physiological pH the developed vaccines demonstrated strong antigenicity, little toxicity, and non-allergenic qualities. The generated multiepitope subunit vaccine for Flu GC content and CAI value, which were determined to be 49.41% and 0.975%, respectively, were assessed using the codon optimization tool. The stable expression of the vaccine in the pET28aþ vector is confirmed by the GC content and CAI value. A significant degree of immune responses was found by in silico immunological simulation. The top ranked docking pose (HDOCK model 3) from ten models was subjected to 100 ns all-atom MD simulation in AMBER22 with the ff19SB force field in explicit OPC water. An average of 6.8 inter-chain hydrogen bonds, in addition to favourable short-range Coulomb (− 1,032 kJ/mol) and Lennard-Jones (− 436 kJ/mol) interaction energies, continued to maintain contact between the interfaces. Using molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) and molecular mechanics/generalized Born surface area (MM/GBSA) methods, the calculated free energies are ΔGbind of − 83.30 ± 29.20 and − 94.72 ± 29.41 kcal/mol, respectively, and the residues Lys381, Arg569, Lys396, Glu237, and Glu527 are identified as the leading contributors to the binding free energy. Thus, the constructed vaccine against avian influenza H10N5 A viral strain showed high potential.</p><h3>Conclusion</h3><p>The vaccine candidate demonstrated promising computational characteristics and requires experimental validation.</p></div>","PeriodicalId":656,"journal":{"name":"Journal of Pharmaceutical Innovation","volume":"22 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149133344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methotrexate Loaded Zinc Oxide/Indigo naturalis Nanocomposite Hydrogel Attenuates Imiquimod-induced Psoriasis Via Suppression of Inflammation, Regulation of Apoptosis, and Inhibition of NF-κB/MAPK Signaling Pathways","authors":"Xinxin Xu,&nbsp;Penghui Shi,&nbsp;Yingchao Wang,&nbsp;Hongmei Yan","doi":"10.1007/s12247-026-11037-4","DOIUrl":"10.1007/s12247-026-11037-4","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;Psoriasis is a multifactorial chronic inflammatory skin disorder driven by immune system dysregulation, uncontrolled keratinocyte proliferation, and the interconnected inflammatory signaling cascades activation, resulting in pathological skin remodeling and persistent epidermal inflammation. Although methotrexate (MTX) remains a first-line remedial agent for severe-to-moderate psoriasis, its long-term clinical use is limited by poor target specificity, systemic adverse effects, and frequent disease recurrence. Nanocomposite-based drug delivery systems have emerged as promising remedial strategies to increase localized drug delivery, ameliorate remedial efficacy, and decrease systemic toxicity.&lt;/p&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;p&gt;This research aimed to develop and characterize a methotrexate-loaded zinc oxide/Indigo naturalis-chitosan (MTX/ZnO/IN) nanocomposite hydrogel and assess its anti-psoriatic potential and underlying molecular mechanisms. The novelty of this study lies in the integration of MTX with ZnO and Indigo naturalis within a chitosan-based nanocomposite hydrogel, combined with comprehensive evaluation of preclinical, histopathological, inflammatory, apoptotic, and signaling responses.&lt;/p&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;The MTX/ZnO/IN nanocomposite hydrogel was characterized by FE-SEM, FT-IR, EDX, UV-Vis spectroscopy, and XRD analyses. The characterization outcomes confirmed the successful incorporation of MTX, ZnO, and IN within the hydrogel matrix, demonstrating the desired morphology, optical properties, chemical composition, and crystalline structure of the nanocomposite hydrogel. The anti-inflammatory activity of the MTX/ZnO/IN nanocomposite hydrogel was determined by quantifying the expression levels of key pro-inflammatory cytokines, including TNF-α, IL-1β, IL-17, and IFN-γ, using ELISA. In addition, the regulatory effects of the nanocomposite hydrogel on apoptosis-related proteins (Bcl-2 and Bax) and major components involved in the NF-κB and MAPK signaling pathways were assessed through Western blotting and qRT-PCR analyses. In addition, a psoriasis BALB/c mouse model was established to assess the in vivo remedial effect of MTX/ZnO/IN through evaluation of PASI scores, inflammatory biomarkers, histopathological alterations, and molecular signaling pathways.&lt;/p&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;Treatment with MTX/ZnO/IN significantly improved psoriasis-like skin lesions by decreasing PASI scores, epidermal hyperplasia, erythema, scaling, and inflammatory cell infiltration. The MTX/ZnO/IN nanocomposite hydrogel markedly suppressed the production of IL-1β, IL-17, TNF-α, and IFN-γ, downregulated the Cyr61 and ICAM-1 expression, restored the balance between apoptotic genes, and prevented activation of the MAPK and NF-κB signaling pathways. These outcomes reveal that MTX/ZnO/IN effectively suppresses inflammatory responses through regulation of apoptosis and inflammatory signaling cascades.&lt;/p&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;MTX/ZnO/IN nanocomposite hyd","PeriodicalId":656,"journal":{"name":"Journal of Pharmaceutical Innovation","volume":"22 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149133194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chrysin-Loaded Casein Nanoparticles Protect Against Sepsis-Associated Acute Kidney Injury via Activation of Nrf2/HO-1 and Suppression of TLR4/NF-κB Signaling","authors":"Shahad W. Kattan,&nbsp;Alhanouf I. Al-Harbi,&nbsp;Bian K. Almessiry,&nbsp;Hanadi Talal Ahmedah,&nbsp;Sara H. Mokhtar,&nbsp;Ekramy M. Elmorsy,&nbsp;Mona M. Elghareeb","doi":"10.1007/s12247-026-11079-8","DOIUrl":"10.1007/s12247-026-11079-8","url":null,"abstract":"<div><h3>Background</h3><p>Chrysin, a natural flavonoid with potent antioxidant and anti-inflammatory activities, is clinically limited by poor aqueous solubility and low oral bioavailability, necessitating advanced delivery strategies. Sepsis-induced acute kidney injury (AKI) remains a life-threatening condition with limited therapeutic interventions. This study aimed to develop and characterize a novel casein-based nanoparticulate delivery system (Chry-Cas-NPs) to enhance the oral bioavailability and therapeutic efficacy of chrysin.</p><h3>Methods</h3><p>Sixty male Sprague Dawley rats were randomly assigned to six groups, including controls, lipopolysaccharide (LPS)-exposed animals, and LPS-treated groups receiving crude chrysin (Chry) or Chry-Cas-NPs. The optimized nanoformulation was characterized for encapsulation efficiency, drug release, and physicochemical stability. Renal function, oxidative stress, inflammatory responses, iron accumulation, apoptosis, histopathology, and pharmacokinetic parameters were evaluated.</p><h3>Results</h3><p>The optimized nanoformulation demonstrated high encapsulation efficiency, controlled and sustained drug release, and excellent physicochemical stability, supporting its suitability as an oral nanocarrier system. LPS administration significantly impaired renal function, as evidenced by elevated serum urea, creatinine, uric acid, and kidney injury molecule-1. Oxidative stress was markedly increased, with suppression of Nrf2/HO-1 signaling, depletion of SOD, CAT, and GSH, and elevation of MDA and 8-hydroxy-2′-deoxyguanosine. Inflammatory injury was characterized by activation of TLR4/NF-κB signaling, upregulation of COX-2, and increased TNF-α, IL-6, IL-1β, nitric oxide, prostaglandin E2, and myeloperoxidase. LPS also induced renal iron accumulation and apoptosis, reflected by increased Bax, caspase-3, and caspase-8, with reduced Bcl-2 expression. Importantly, nanoencapsulation significantly enhanced systemic exposure of chrysin, demonstrating improved pharmacokinetic behavior compared to the free drug. Treatment with Chry-Cas-NPs significantly restored renal function, attenuated oxidative and inflammatory injury, reduced apoptosis, and preserved renal architecture, exhibiting superior therapeutic efficacy relative to crude chrysin due to improved bioavailability and sustained drug release. Mechanistically, the enhanced reno protective effect of Chry-Cas-NPs is attributed to efficient delivery and activation of Nrf2/HO-1 antioxidant pathways alongside suppression of TLR4/NF-κB-mediated inflammatory signaling.</p><h3>Conclusion</h3><p>Collectively, this study highlights casein-based nanoparticles as a promising, biocompatible oral delivery platform for poorly soluble flavonoids and supports their potential for translational development in the management of sepsis-associated AKI.</p></div>","PeriodicalId":656,"journal":{"name":"Journal of Pharmaceutical Innovation","volume":"22 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149133193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning–Based QSAR Screening of Natural Product and ZINC Libraries Uncovers Stable BACE-1 Inhibitors Validated by Gaussian Accelerated Molecular Dynamics (GaMD) Simulations","authors":"Waqar Ahmad,&nbsp;Xinyi Zhu,&nbsp;Shahin Shah Khan,&nbsp;Yi Bai,&nbsp;Pengfei Pei","doi":"10.1007/s12247-026-11068-x","DOIUrl":"10.1007/s12247-026-11068-x","url":null,"abstract":"<div><p>Beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) plays a central role in amyloid-β production and remains an important therapeutic target for Alzheimer’s disease. This study developed an integrated quantitative structure–activity relationship and molecular dynamics (QSAR–MD) framework to identify promising BACE-1 inhibitor candidates. From 15,642 initially retrieved bioactivity records, 5,245 remained after preprocessing, and 5,235 compounds with complete fingerprint data constituted the final QSAR dataset. Random Forest models based on twelve molecular fingerprint classes were benchmarked against AdaBoost, Gradient Boosting, and XGBoost using identical training and external-validation sets. CDK and CDK Extended fingerprints produced the highest validation performance (Q²CV = 0.78 ± 0.03; Q²EXT = 0.79 ± 0.01), while PubChem, MACCS, Klekota–Roth, and Substructure Count fingerprints yielded Q²EXT values of approximately 0.76–0.78. Model reliability was assessed using RMSE, MAE, Y-randomization, applicability-domain analysis, and SHAP interpretation. The selected CDK Extended RF model was applied to the ZINC and NPASS libraries, resulting in five prioritized candidates. Molecular docking indicated favorable interactions with key BACE-1 residues, including the catalytic dyad Asp32 and Asp228 and active-site residues Thr72 and Thr231. Analysis of 200 ns GaMD trajectories using RMSD, RMSF, radius of gyration, SASA, and PCA supported the overall structural stability of the complexes. MM/GBSA analysis identified NPC475168 as the most favorable candidate, with an estimated binding energy of − 64.84 kcal/mol. NPC313966, NPC252056, and NPC471858 also demonstrated favorable dynamic and energetic profiles relative to CNP520. Overall, NPC475168 emerged as the leading computational candidate, although experimental validation, selectivity profiling, and ADMET assessment remain necessary.</p></div>","PeriodicalId":656,"journal":{"name":"Journal of Pharmaceutical Innovation","volume":"22 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149133321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal Delivery of a Novel Pterostilbene-Phosphatidylcholine Nanosuspension (PTE-PL) Ameliorates Depression like Behavior in Chronic Mild Stress Rats","authors":"Sunita Bhise,&nbsp;Pratiksha Dudhbhate,&nbsp;Sagri Mane,&nbsp;Urmila Aswar","doi":"10.1007/s12247-026-11065-0","DOIUrl":"10.1007/s12247-026-11065-0","url":null,"abstract":"<div><h3>Purpose</h3><p>Pterostilbene (PTE), a natural stilbenoid, possesses potent anti-inflammatory and neuroprotective properties; however, its clinical translation is severely hindered by poor aqueous solubility (0.011 mg/mL), rapid metabolism, and limited oral bioavailability.</p><h3>Method</h3><p>To circumvent these barriers, we have developed an optimized intranasal nanosuspension (PTE-PL) of a pterostilbene-phosphatidylcholine complex (PTE-PC90H), designed for direct nose-to-brain delivery. The formulation was systematically optimized using a Box–Behnken experimental design to achieve ideal particle size and complexation efficiency. The formulation was further assessed for in vivo pharmacokinetic profiling, followed by its evaluation in chronic mild stress (CMS)-induced depression in rats.</p><h3>Results</h3><p>The optimized formulation, featuring a drug-to-lipid-to-surfactant ratio of 1:2:1, yielded a stable nanosuspension with a mean particle size of 241.43 ± 11.82 nm, a zeta potential of -21.98 ± 1.93 mV, and a complexation efficiency of 97.12 ± 1.71%. This formulation achieved a 5-fold increase in aqueous solubility and a 6-fold enhancement in trans-mucosal flux, across sheep nasal mucosa compared to plain PTE. The study revealed that intranasal (i.n.) PTE-PL reached peak plasma concentrations twice as fast as oral PTE, with a 12-fold increase in systemic bioavailability and an 80% improvement in brain targeting efficiency. In a CMS model in rats, intranasal PTE-PL (100 µg, i.n.) significantly reversed behavioral deficits (<i>p</i> &lt; 0.001), as measured by sucrose preference, locomotor activity, and forced swim tests. These behavioral improvements were underpinned by a robust biochemical response, including the restoration of monoamine and BDNF levels, enhancement of antioxidant defenses, and significant attenuation of cortisol, NLRP3, and NF-κB inflammatory pathways (<i>p</i> &lt; 0.001). Histopathological evaluation via Nissl staining confirmed neuroprotection of hippocampal neurons, while H&amp;E staining indicated no adverse nasal epithelial alterations.</p><h3>Conclusion</h3><p>This study demonstrated that the PTE-PL nanosuspension is a highly efficient, non-invasive, and neuroprotective delivery platform, offering a potential therapeutic strategy for the management of clinical depression.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":656,"journal":{"name":"Journal of Pharmaceutical Innovation","volume":"22 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149133324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analytical Box-Behnken Design Approach for Method Optimization and Validation for Concurrent Determination of Doxecitine and Doxribtimine by RP-HPLC in Bulk and Powder Dosage Form With Degradation Assessment","authors":"Anusha Gandi,&nbsp;Vasanthi Majji,&nbsp;Priyanka Paila,&nbsp;Srinivasa Rao Yarguntla","doi":"10.1007/s12247-026-11062-3","DOIUrl":"10.1007/s12247-026-11062-3","url":null,"abstract":"<div><h3>Purpose</h3><p>The goal of the present research was to create, refine, and validate a stability-indicating isocratic RP-HPLC technique based on AQbD for concurrent measurement of Doxecitine and Doxribtimine in pharmaceutical powder dosage form and bulk medications, with a AQbD approach utilizing a Box–Behnken Design was applied for chromatographic method optimization.</p><h3>Method</h3><p>Optimization was performed by selecting critical method variables like flow rate, the quantity of acetonitrile, and a volume of 0.1% perchloric acid as independent variables, while determining responses such as tailing factor along with retention time. Using mobile phase 0.1% acetonitrile and 30:70 % v/v perchloric acid with a 1.0 mL/min flow rate, a standard chromatographic differentiation was achieved on a X-Terra RP-18 column (250 × 4.6 mm, 5 µm, Waters) with detection at 249 nm and a runtime of 7 minutes. </p><h3>Result</h3><p>For Doxecitine and Doxribtimine, the retention times were determined to be roughly 2.52 and 4.73 minutes, respectively. With correlation values (r²) of 0.999 for the two analytes, the technique demonstrated outstanding linearity. According to ICH requirements, parameters such as system suitability, linearity, precision, specificity, accuracy, robustness, LOQ and LOD were determined to be within acceptable bounds. Studies on forced degradation verified the technique’s capability to indicate stability.</p><h3>Conclusion</h3><p>The established RP-HPLC technique based on AQbD provides a suitable approach for the simultaneous determination and stability testing of Doxecitine and Doxribtimine in pharmaceutical formulation, contributing significantly to the method optimization and regulatory compliance in pharmaceutical analysis.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":656,"journal":{"name":"Journal of Pharmaceutical Innovation","volume":"22 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149133322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"QbD-Assisted Development and Optimization of a Finerenone Nanosuspension for Enhanced Solubility","authors":"Ankit Mishra,&nbsp;Mitali Upadhyay,&nbsp;Meenakshi Patel","doi":"10.1007/s12247-026-11061-4","DOIUrl":"10.1007/s12247-026-11061-4","url":null,"abstract":"<div><h3>Purpose</h3><p>Finerenone (FN), a selective non-steroidal mineralocorticoid receptor antagonist used for the management of kidney disease, shows poor aqueous solubility and limited oral bioavailability. The present study aimed to develop and optimize a FN-nanosuspension using Quality by Design (QbD) approach to increase its solubility.</p><h3>Methods</h3><p>FN-nanosuspension was prepared using an antisolvent precipitation method followed by high-speed homogenization and lyophilisation. The QbD design was applied by describing the Quality Target Product Profile (QTPP), categorizing Critical Quality Attributes (CQAs), Critical Material Attributes (CMAs), and Critical Process Parameters (CPPs), and executing a risk assessment. JMP Pro 8 software was used to apply fractional factorial design for the screening of the variables and to identify the significant factors, followed by Box–Behnken Design (BBD) optimization. The prepared formulations were evaluated for particle size, PDI, zeta potential, saturation solubility, and drug content. The optimized formulation was characterized for solid-state properties (DSC, XRD, FTIR), morphology (SEM), residual solvent (GC), in vitro drug release, ex vivo intestinal permeability, and stability.</p><h3>Results</h3><p>The optimized FN-nanosuspension displayed a mean particle size of 276.6 ± 4.98 nm, acceptable zeta potential, with narrow PDI (&lt;0.3), indicating good physical stability. Saturation solubility was considerably improved compared to the pure drug. DSC, XRD, and FTIR studies confirmed the partial amorphization of the drug and no interaction between drug and excipient. The optimized nanosuspension demonstrated fast and enhanced in-vitro drug release (&gt;80% within 30 minutes) following Higuchi kinetics, along with a ~1.8-fold increase in drug diffusion by ex vivo study. Stability studies of the lyophilized formulation over six months showed no significant changes in particle size or aggregation.</p><h3>Conclusion</h3><p>The QbD-assisted development of FN-nanosuspension successfully enhanced solubility, dissolution rate, and intestinal permeability while ensuring formulation robustness and stability. The study highlights nanosuspension technology as an effective and scalable strategy to improve the oral performance of poorly soluble drugs such as FN.</p></div>","PeriodicalId":656,"journal":{"name":"Journal of Pharmaceutical Innovation","volume":"22 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149133363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Screening of Ziziphus Nummularia-Derived Phytochemicals: Molecular Docking & ADME Analysis For Rheumatoid Arthritis Therapy","authors":"Priyanka Kaundal,&nbsp;Anjoo Kamboj,&nbsp;Hitesh Malhotra,&nbsp;Sandhya Jaiswal","doi":"10.1007/s12247-026-11036-5","DOIUrl":"10.1007/s12247-026-11036-5","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Aim&lt;/h3&gt;&lt;p&gt;This study aimed to identify bioactive compounds for their potential as anti-arthritic drugs through virtual screening of phytochemicals from &lt;i&gt;Z. nummularia&lt;/i&gt; (ZN) to target human TLR-4, TNF-α, TCR, MMP-3 and COX-2 associated with rheumatoid arthritis.&lt;/p&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;Earlier studies suggest that ZN may have immunomodulatory effects, which could potentially be relevant in autoimmune forms of arthritis. The more rigorous scientific research is needed to establish the efficacy and safety of ZN specifically for arthritis treatment.&lt;/p&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;p&gt;In silico studies including Molecular docking and ADMET studies of 30 phytoconstituents obtained from ZN against selected protein target/receptors. Density Functional Theory (DFT) calculations were performed at the B3LYP/def2-SVP level to optimize molecular geometries and evaluate frontier molecular orbitals (HOMO–LUMO), electronic energy, and global reactivity descriptors of the selected phytoconstituents.&lt;/p&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;The bioactivity scores, ADME profiles, and molecular interactions were assessed using QikProp, Molinspiration, ADMETlab 2.0, ProTox-II, and GLIDE. Molecular docking was with target receptors TLR-4 (PDB ID: 4G8E), TNF-α (PDB ID: 1A8M), T-cell receptor (PDB ID: 2AXJ), MMP-3 (PDB ID: 1G49), and COX-2 (PDB ID: 1CX2). Binding mechanisms were investigated through molecular docking studies, while protein–ligand complex stability and flexibility were further assessed using Normal Mode Analysis (NMA) through the iMODS server&lt;b&gt;.&lt;/b&gt;&lt;/p&gt;&lt;h3&gt;Results and Conclusion&lt;/h3&gt;&lt;p&gt;Results showed that rutin-1CX2 and nummularogenin-4G8E complexes had the lowest energy scores of -9.9 kcal/mol. Nummularogenin-1G49 scored -9.8 kcal/mol, myricetin-3-O-galactoside-2AXJ scored -8.4 kcal/mol, and nummularogenin-1A8M scored -8.1 kcal/mol. These compounds exhibit drug-like properties, comply with Lipinski's rule of five, and interact with key catalytic residues, indicating their potential as anti-inflammatory drugs for rheumatoid arthritis. Both Nummularogenin and Rutin showed good binding profiles, with Nummularogenin exhibiting higher predicted affinity against several targets. Redocking the native COX-2 ligand was used to assess the docking protocol's dependability. This resulted in an RMSD of 1.278 Å, indicating an acceptable replication of the binding orientation seen in the experiment. For the purpose of comparing COX-2 binding, celecoxib was used as a reference inhibitor. Rutin and Nummularogenin underwent additional molecular dynamics (MD) simulation based on their good docking profiles, drug-like properties, and target interactions. Favourable RMSD, RMSF, Rg, and SASA profiles showed that both ligand–protein complexes had stable conformations during simulation. Overall, Nummularogenin was found to be a promising multi-target anti-inflammatory lead from &lt;i&gt;Z. nummularia&lt;/i&gt; by combined docking, validation, ADME, and MD simulation. Further biochemical, cellular, and","PeriodicalId":656,"journal":{"name":"Journal of Pharmaceutical Innovation","volume":"22 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149132903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-Silico Identification and Molecular Dynamics Characterization of FDA-Approved Drug Candidates Targeting MAO-B for Parkinson’s Disease Drug Repurposing","authors":"Atefeh Hemmat,&nbsp;Ali Doostmohammadi","doi":"10.1007/s12247-026-11072-1","DOIUrl":"10.1007/s12247-026-11072-1","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Parkinson’s disease (PD) is characterized by striatal dopamine depletion, a process exacerbated by upregulation of monoamine oxidase B (MAO-B), whose activity accelerates dopamine catabolism and contributes to oxidative stress. This computational study applied a knowledge-based virtual screening and drug-repurposing workflow to identify FDA-approved small molecules predicted to bind favourably to MAO-B. A curated library of 435 FDA-approved compounds with physicochemical properties compatible with blood–brain barrier permeation was screened by molecular docking against the crystal structure of human MAO-B (PDB ID: 6FW0). Rimacalib (-12.9 kcal/mol), apixaban (-12.0 kcal/mol), and roxadustat (-11.6 kcal/mol) achieved more favourable Vina docking scores than the reference inhibitor rasagiline (-9.1 kcal/mol) and were advanced to 100 ns all-atom molecular dynamics simulations. Analysis of backbone RMSD, residue RMSF, radius of gyration, solvent-accessible surface area, and principal component analysis characterized the global structural stability, flexibility, compactness, and conformational dynamics of the complexes, while hydrogen-bond occupancy analysis provided more direct evidence of sustained ligand engagement: apixaban and rimacalib maintained a persistent interaction with Thr195 for approximately 80% and over 70% of the simulation time, respectively, indicating stable positioning within the MAO-B binding pocket. MM/GBSA binding free energies ranked apixaban (-53.9 kcal/mol), rimacalib (-49.7 kcal/mol), roxadustat (-40.5 kcal/mol), and rasagiline (-20.3 kcal/mol); Phe103, Trp119, and Phe168 were identified as dominant aromatic hotspots. Beyond target engagement, apixaban and rimacalib were further prioritized based on their established clinical pharmacology, pharmacokinetic and predicted CNS-exposure profiles, and biological plausibility for PD, distinguishing them as candidates for genuine drug repurposing rather than docking-based hits alone. These findings highlight apixaban and rimacalib as predicted MAO-B-binding candidates warranting biochemical and pharmacological validation to establish their repurposing potential for PD.&lt;/p&gt;&lt;h3&gt;Graphical Abstract&lt;/h3&gt;&lt;div&gt;&lt;figure&gt;&lt;div&gt;&lt;div&gt;&lt;picture&gt;&lt;source&gt;&lt;img&gt;&lt;/source&gt;&lt;/picture&gt;&lt;/div&gt;&lt;div&gt;&lt;p&gt;Schematic representation of the computational drug repurposing pipeline for identifying potential Monoamine Oxidase B (MAO-B) inhibitors. The X-ray crystal structure of MAO-B (PDB ID: 6FW0) was obtained from the Protein Data Bank and prepared by removing water/heteroatoms and adding hydrogens to generate a ready-to-dock model. We retrieved FDA-approved compounds from DrugBank and filtered them (not withdrawn, 1.5 ≤ logP ≤ 3, MW &lt; 500 Da) to obtain 437 BBB-permeable candidates. Molecular docking identified the top five hits, followed by 100-ns molecular dynamics simulations evaluating RMSD, RMSF, Rg, SASA, hydrogen bonds, PCA, MM/GBSA, and FEL. The final selected candidates were Rimacalib, Apixaban, an","PeriodicalId":656,"journal":{"name":"Journal of Pharmaceutical Innovation","volume":"22 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149133287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}