Pharmaceutical Research[JOURNAL]
Sun
200 papers
Leveraging Carnitine-functionalized Lipid Nanocarrier based Targeted Delivery of A1874 PROTAC for Glioblastoma.
Patel H, Chen X, Malik A … +4 more , Poonai KS, Chen ZS, Higuchi S, Patel K
Pharm Res · 2026 Jul · PMID 42387117 · Publisher ↗
PURPOSE: Glioblastoma(GBM) is highly aggressive and therapeutically refractory brain malignancy. Despite maximal intervention, patient prognosis remains dismal. A major obstacle in its management is the limited permeatio...
PURPOSE: Glioblastoma(GBM) is highly aggressive and therapeutically refractory brain malignancy. Despite maximal intervention, patient prognosis remains dismal. A major obstacle in its management is the limited permeation of therapeutic agents across the blood-brain barrier(BBB), further intensified by resistance to standard chemotherapy such as temozolomide(TMZ). Proteolysis-targeting chimeras(PROTACs), offer new opportunities by enabling selective degradation of oncogenic proteins. A1874, a heterobifunctional molecule, has demonstrated potent, selective degradation of oncogenic driver-BRD4 in pancreatic, breast, and colon cancer. BRD4 drives GBM cell proliferation, survival, and resistance to therapy; therefore, we investigated the therapeutic potential of A1874 in brain cancer. METHODS: Herein, we developed brain-targeted self-nanoemulsifying drug delivery system, termed PRONano, designed to enhance the targeted delivery of A1874. The system is functionalized with Palmitoyl-DL-carnitine chloride(PC) to facilitate transport across the BBB. Physicochemical characterization was performed to assess particle size. In-vitro cytotoxicity, qualitative and quantitative cellular uptake was analyzed. Mechanistic validation was conducted using western blot and qPCR, while 3D spheroid assay was employed to assess efficacy in tumor-mimicking microenvironment. RESULTS: PRONano exhibited nanoscale particle size and significantly enhanced intracellular uptake of A1874. Formulation exhibited enhanced cytotoxicity in temozolomide-sensitive and resistant GBM cells. Effective BRD4 protein degradation was identified in the Western blot. PRONano significantly inhibited 3-D spheroid tumor growth suggesting better penetration and efficacy in tumor-like microenvironment. CONCLUSIONS: PRONano is brain-targeted, rationally designed nanoformulation which can overcome major A1874 delivery constraints. This strategy augmented PROTAC delivery and therapeutic potential in GBM, supporting future preclinical development.
Impact of Febrile State on Vancomycin Clearance in Pediatric Patients: Insights From Population Pharmacokinetic Modeling.
Tanaka R, Sawaguchi A, Mizuno T … +10 more , Irie K, Ono H, Amano E, Goto H, Tashiro S, Tatsuta R, Yoshikawa N, Hirano N, Ihara K, Itoh H
Pharm Res · 2026 Jul · PMID 42387116 · Publisher ↗
OBJECTIVE: Augmented renal clearance is increasingly recognized in pediatric patients with febrile neutropenia (FN), leading to enhanced elimination of renally cleared antimicrobials including vancomycin (VCM). Although...
OBJECTIVE: Augmented renal clearance is increasingly recognized in pediatric patients with febrile neutropenia (FN), leading to enhanced elimination of renally cleared antimicrobials including vancomycin (VCM). Although fever‑associated hemodynamic changes may accelerate VCM clearance, their quantitative impact in the hospital-based general pediatric cohort remains unclear. The primary objective of this study was to quantify the effects of FN and infection-associated fever on VCM clearance in pediatric patients and to identify optimal dosing regimens across age and renal function strata. METHODS: This retrospective study included inpatients aged < 18 years receiving VCM with therapeutic drug monitoring. Population pharmacokinetic analysis was performed using a two‑compartment model with allometric scaling and maturation functions. Monte Carlo simulations were conducted to evaluate the probability of attaining a target area under the concentration-time curve (AUC) of 400-600 μg*h/mL across dosing regimens. RESULTS: A total of 129 patients and 214 VCM concentrations were analyzed. Estimated glomerular filtration rate and daily maximum body temperature (BT) ≥ 38°C were independently associated with increased VCM clearance. BT ≥ 38°C increased VCM clearance by 27%, and the final model showed robust predictive performance. Simulation analyses demonstrated that febrile patients required approximately 1.2-1.3‑fold higher daily VCM doses than those of afebrile patients across all age groups and renal function categories. CONCLUSION: Renal function and BT ≥ 38°C significantly increase VCM clearance in pediatric patients. Standard dosing may be insufficient in febrile patients, and higher initial doses should be considered. Incorporating body temperature and renal function into dosing decisions may improve target exposure attainment.
Sustained Intra-Articular Delivery of Triple Therapeutics Using a Phase-Transition Phospholipid-Based Gel for Effective Treatment of Gouty Arthritis.
Ma S, Yang J, Li A … +2 more , Lin Q, Gong T
Pharm Res · 2026 Jun · PMID 42380408 · Publisher ↗
PURPOSE: This study developed a coordinated-delivery phospholipid-based gel for therapeutics with distinct physicochemical properties to overcome the limitations of current monotherapies for gouty arthritis (GA), achievi...
PURPOSE: This study developed a coordinated-delivery phospholipid-based gel for therapeutics with distinct physicochemical properties to overcome the limitations of current monotherapies for gouty arthritis (GA), achieving synergistic therapeutic effects. METHODS: A phospholipid phase-transition gel (RMU-Gel) was prepared via a stirring method to co-encapsulate three agents with distinct physicochemical properties-resveratrol (Res), meloxicam (Melx), and uricase (URE). The study evaluated its in vitro release behavior, in vivo pharmacokinetics, the synergistic effects of Res and Melx, pharmacodynamics in a rat model of gouty arthritis, as well as the preliminary safety and biodegradability of the drug-loaded phospholipid gel. RESULTS: In vitro release results showed that RMU-Gel enabled a slow and prolonged release of the drugs in the release medium. The combination of resveratrol and meloxicam significantly enhanced anti-inflammatory and antioxidant responses. In the rat model, a single dose of RMU-Gel provided therapeutic effects lasting over 7 days, outperforming repeated injections of drug suspensions, with excellent safety and biodegradability. CONCLUSION: RMU-Gel offers a simple yet powerful platform for the coordinated co-delivery of physicochemically diverse agents. Specifically, the major breakthrough of this study is the successful co-encapsulation and sustained co-release of three therapeutics with markedly different physicochemical properties within a single phospholipid gel system, thereby preserving their multi-pathway therapeutic synergy. This provides a promising multifunctional strategy for efficient management of gouty arthritis.
Spray Dried Lysozyme Microspheres: Morphological Evolution and Enzymatic Activity Retention.
Li M, Yan S, Zhang S … +2 more , Chen XD, Wu WD
Pharm Res · 2026 Jun · PMID 42380407 · Publisher ↗
PURPOSE: Conventional spray drying often produces heterogeneous enzyme powders because of broad droplet size distributions and complex turbulent flow fields, limiting mechanistic understanding of particle formation and q...
PURPOSE: Conventional spray drying often produces heterogeneous enzyme powders because of broad droplet size distributions and complex turbulent flow fields, limiting mechanistic understanding of particle formation and quantitative structure-activity analysis. This study aimed to fabricate uniform lysozyme microspheres and clarify how formulation and drying conditions govern their microstructure and enzymatic activity. METHODS: A micro-fluidic jet spray dryer was used to prepare highly uniform pure lysozyme and excipient-containing lysozyme microspheres. The effects of carbohydrate excipients and drying temperature on particle morphology, secondary structure, surface composition, and enzymatic activity were systematically evaluated. RESULTS: Pure spray-dried lysozyme microspheres showed a highly uniform single-hole bowl-like morphology with smooth surfaces. However, drying-induced thermal and shear stresses reduced α-helix content and caused activity loss. Carbohydrate excipients altered the structural evolution pathways. Surface elemental analysis indicated lysozyme enrichment in most formulations, except those containing dextran T40. Mannitol crystallization induced phase separation, lysozyme unfolding, and inactivation. Trehalose preserved conformational stability through a hydrogen-bonded glassy matrix, whereas dextran T40 mainly suppressed lysozyme aggregation through steric hindrance. CONCLUSIONS: This work establishes a formulation properties/process-microstructure-enzymatic activity relationship in a uniform microsphere system, supporting the rational design of performance-predictable spray-dried enzyme powders.
Colloidal Stability of Amorphous Nanoparticles in Solution: Impact of Stabilizer.
Narula A, Nethercott MJ, Chakravarty P … +1 more , Li N
Pharm Res · 2026 Jun · PMID 42380406 · Publisher ↗
PURPOSE: Amorphous drug nanoparticles can enhance the oral bioavailability of poorly water-soluble drugs, but rapid particle growth limits their effectiveness and manufacturability. Therefore, the goal of this study was...
PURPOSE: Amorphous drug nanoparticles can enhance the oral bioavailability of poorly water-soluble drugs, but rapid particle growth limits their effectiveness and manufacturability. Therefore, the goal of this study was to evaluate how stabilizers influence the stability of amorphous drug nanoparticles in solution. METHODS: Six structurally diverse drugs with varying glass transition temperatures (T) were used as model drugs. Seven commonly used pharmaceutical excipients, including both polymers and surfactants, were tested as stabilizers. Particle growth was monitored using dynamic light scattering across different temperatures. Drug-polymer interactions were analyzed via differential scanning calorimetry and solid-state nuclear magnetic resonance spectroscopy. RESULTS: Partitioning stabilizers outperformed non-partitioning stabilizers, effectively stabilized nanoparticles at T > > wet T of the drug. In contrast, non-partitioning stabilizers showed performance dependent on both the wet Ts of the drug and the stabilizer. Strong ionic interactions between the stabilizer and the drug were found to be associated with better particle stability. CONCLUSIONS: The impact of excipients was dependent on their mechanism of action. HPMCAS was the most effective particle stabilizer among all excipients evaluated, possibly due to its ability to inhibit both Ostwald ripening and coalescence.
Impact of Mixing Approach and Bubble Formation on In Situ Forming Implant Properties.
Lin X, Eslami SM, Zhen Z … +10 more , Yuan H, Livingston EW, Aggarwal A, Atallah M, Beringhs AO, Li Q, Zhang Q, Bin Q, Wang Y, Lu X
Pharm Res · 2026 Jun · PMID 42380405 · Publisher ↗
PURPOSE: The commercial In situ forming implants (ISFIs) use either a dual-syringe system requiring pre-injection syringe mixing, or a pre-mixed ready-to-inject syringe. The purpose of this study is to comprehensively ev...
PURPOSE: The commercial In situ forming implants (ISFIs) use either a dual-syringe system requiring pre-injection syringe mixing, or a pre-mixed ready-to-inject syringe. The purpose of this study is to comprehensively evaluate the impact of these two mixing approaches on ISFIs' properties as well as in vitro performance. METHODS: Computed tomography (CT) imaging and scanning electron microscopy were used to access implant structure ad morphology. High-performance liquid chromatography was used for drug release determination. Gel permeation chromatography was used to evaluate polymer degradation. The CT contrast agent iohexol was used as a model compound and was fully dissolved in the matrix regardless of the mixing approach. RESULTS: Syringe-mixed ISFIs contained air bubbles, while ready-to-inject formulation displayed a more uniform polymer matrix without them. The introduction of air bubbles exhibited slower solvent NMP release, altered drug deposition, increased volume expansion, and enhanced initial degradation rate. CT imaging revealed that ready-to-inject formulation was more uniform, whereas syringe-mixed implants appeared to have more heterogenous cavity feature. CONCLUSIONS: The introduction of air bubbles through pre-injection mixing could potentially impact drug release and ISFI's performance. This study elucidates the comparison between two mixing techniques as a reference in the developmental process of future products.
Initial Exploration on the Application of the MoCMC Approach for Determining In Vitro Product Comparability.
Martinez MN, Longstaff DG
Pharm Res · 2026 Jun · PMID 42362986 · Publisher ↗
PURPOSE: To provide an initial assessment of the Matrix of Chemistry, Manufacturing and Control (MoCMC) approach for evaluating product physicochemical (Q3) similarity as part of the bioequivalence assessment of products...
PURPOSE: To provide an initial assessment of the Matrix of Chemistry, Manufacturing and Control (MoCMC) approach for evaluating product physicochemical (Q3) similarity as part of the bioequivalence assessment of products containing non-systemically absorbed drugs. METHODOLOGY: Each Q3 parameter was expressed as the radius of a polygon using a mathematical formula that converted each specified reference Q3 parameter mean to a value of "5". That formula was applied to the corresponding individual test and reference product Q3 parameters, and the areas of the resulting treatment polygons were determined. The ratio of product area/outer area [Matrix Comparability Index (MCI)] was calculated where each side of the outer polygon had a radius of "10". When generated across multiple lots per treatment, the MCI values were statistically compared. Both actual (from our previously published investigation) and hypothetical MCI values were used to characterize the performance of the MoCMC across a range of situations. RESULTS: The influence of any individual Q3 parameter decreased as the number of radii increased. The ability to identify statistically significant product differences decreased as variability of either test or reference MCI values increased. Nevertheless, by combining statistical analysis with a comparison of the spread of test and reference MCI values, the MoCMC identified product differences previously not detected by in vitro dissolution profiles alone. CONCLUSIONS: The MoCMC can serve as a tool for comparing products containing non-systemically absorbed drugs. However, statistical refinements are needed when applying this approach to an evaluation of product bioequivalence. The latter is under development.
Injectable in-situ Forming Lipid Liquid Crystal for Long-acting Fluocinolone Release in Posterior Ocular Therapy: In-vitro and In-vivo Evaluations.
Karimi M, Abrishami M, Farzadnia M … +2 more , Kamali H, Malaekeh-Nikouei B
Pharm Res · 2026 Jun · PMID 42343022 · Publisher ↗
OBJECTIVE: Intravitreal injection is a preferred route for targeted drug delivery to the posterior eye. However, commercial non-biodegradable polymeric implants for fluocinolone acetonide (FA) often necessitate surgical...
OBJECTIVE: Intravitreal injection is a preferred route for targeted drug delivery to the posterior eye. However, commercial non-biodegradable polymeric implants for fluocinolone acetonide (FA) often necessitate surgical removal after long-term release, reducing patient compliance and increase surgical risks. Biodegradable polymeric implants also typically exhibit an initial burst release. This study explores the development of an innovative biodegradable in-situ forming lipid liquid crystal (ISF-LLC) formulation for sustained FA delivery over two months via a single intravitreal injection without burst release. METHODS: The optimized formulation, developed using Design of Experiment software, comprised phosphatidylcholine and sorbitan monooleate (PC: SMO 30/70 w/w%) with N-methyl-2-pyrrolidone (NMP 30w/w%). RESULTS: The ISF-LLC formulation exhibited pseudoplastic behavior, excellent syringeability, stability, and a hexagonal crystalline structure. In-vivo pharmacokinetic analysis in rabbit vitreous humor revealed a slow, controlled release rate of 0.49 ± 0.01 μg/day over 60 days (within the clinical range 0.2-0.6 μg/day), with no burst release during the first 7 days (0.22 ± 0.01 μg/day). The vitreal half-life was 22.80 ± 0.51 days, and FA was undetectable systemically. Quantitative histopathology showed no significant differences in retinal thickness (203-209 μm vs. 203 ± 2 μm, p > 0.05) or inflammatory cell count (1-3 vs. 1.3 ± 0.6 cells/field, p > 0.05) between treated and control groups. No retinal damage or systemic toxicity was observed. CONCLUSIONS: The injectable biodegradable ISF-LLC formulation is a promising controlled-release, long-acting platform for intravitreal drug delivery, eliminating initial burst release and need for surgical removal, thereby improving patient outcomes in ocular therapy.
Utility of Relative Activity Factors to Determine Fraction Glucuronidation and Clearance of Icenticaftor in Humans.
Patel M, Shaikh S, Huth F … +1 more , Deshmukh S
Pharm Res · 2026 Jun · PMID 42343021 · Publisher ↗
PURPOSE: The purpose of this study is to quantify the contribution of individual UDP-glucuronosyl transferase (UGT) enzymes involved in the glucuronidation of icenticaftor, which is primarily glucuronidated in the human...
PURPOSE: The purpose of this study is to quantify the contribution of individual UDP-glucuronosyl transferase (UGT) enzymes involved in the glucuronidation of icenticaftor, which is primarily glucuronidated in the human liver to two distinct glucuronide metabolites that are ultimately excreted in the urine. METHODS: The formation of icenticaftor-glucuronide in recombinant UGT systems was scaled with relative activity factor (RAF) of involved UGT enzymes to determine the fraction glucuronidation in human liver. RESULTS: Scaling of the glucuronidation activity of UGT enzymes in recombinant UGT systems demonstrated that hepatic UGT1A9 contributed to about two-third of the overall icenticaftor glucuronidation while the remaining was accounted by UGT2B7. Moreover, the predicted UGT-mediated clearance of icenticaftor, upon scaling the intrinsic clearance (CL) with RAF, correlates well with that estimated in humans. CONCLUSION: Collectively, current data are indicative of the utility of activity-based scalars to predict fraction glucuronidation and clearance of icenticaftor in the clinic. UGT1A9 is identified as the major UGT enzyme in the glucuronidation of icenticaftor in human liver.
In-vitro Assessment of Immediate Release Rivaroxaban Coated Fixed Dose Combination Tablets with Extended Release Molnupiravir for the Management of Coagulopathy Associated with COVID.
Mohiuddin A, Mondal S, Dutta K … +1 more , Kaity S
Pharm Res · 2026 Jun · PMID 42337169 · Publisher ↗
PURPOSE: Coagulopathy associated with SARS-CoV-2 infection leads to the formation of abnormal blood clots even in tiny blood vessels, which can lead to severe life-threatening conditions like organ damage, heart attack,...
PURPOSE: Coagulopathy associated with SARS-CoV-2 infection leads to the formation of abnormal blood clots even in tiny blood vessels, which can lead to severe life-threatening conditions like organ damage, heart attack, and stroke. The objective of this study was to develop a solid oral fixed-dose combination (FDC) of molnupiravir (MPV) as an extended-release core (MPV-XR) with rivaroxaban (RIV) active coating for the management of viral infections with coagulopathy-related complications. While MPV-XR helps reduce viral infection along with daily pill burden, RIV simultaneously minimises coagulopathy-related complications. METHOD: We strategically selected the manufacturing process of RIV active coating on MPV-XR core tablets as an efficient, fast, and cost-effective method for large-scale formulation manufacturing. Both the MPV-XR core and the RIV-coated MPV-XR finished dosage form were characterised by various instrumental and pharmacopoeial studies. RESULTS: The composition of the P2 batch was found to be the optimum for the MPV-XR core tablet, and the RIV coating with 5% w/w solid content showed the best active-coated tablets with the minimum unit-to-unit content variation (AV, 5.5%). A scale-up batch was executed to evaluate the impact of batch magnification on product quality. CONCLUSION: FDC of MPV-XR with RIV coating was manufactured, and appropriate characterisation was performed. The scale-up batch samples also showed promising quality in terms of drug content and drug release. Thus, the novel formulation approach showed proven quality characteristics for specific use in coagulopathy associated with SARS-CoV-2 infection. However, detailed clinical study needs to be conducted before its large scale manufacturing and commercialization.
Women in Pharmaceutical Sciences: Progress, Possibility, and Lasting Impact.
Lavelle A
Pharm Res · 2026 Jun · PMID 42321584 · Publisher ↗
Abstract loading — click title to view on PubMed.
Meta-Analysis and Physiologically-Based Modeling of the Pharmacokinetics and Pharmacodynamics of Dexamethasone in Horses.
Yu R, Toutain PL, Ekstrand C … +1 more , Jusko WJ
Pharm Res · 2026 Jun · PMID 42321583 · Publisher ↗
PURPOSE: Dexamethasone (DEX) is widely used in equine practice for its potent anti-inflammatory effects and diverse studies have examined its pharmacology in horses. We integrated all available pharmacokinetic (PK) and p...
PURPOSE: Dexamethasone (DEX) is widely used in equine practice for its potent anti-inflammatory effects and diverse studies have examined its pharmacology in horses. We integrated all available pharmacokinetic (PK) and pharmacodynamic (PD) data from 12 studies to quantify DEX disposition and endocrine effects in horses. METHODS: DEX concentrations in blood, urine and synovial fluid, plus cortisol (CTS) and glucose (GLU) in plasma, following various administration routes (intravenous (IV), intramuscular (IM), intra-articular, oral) were available from original studies or digitized from literature. A minimal physiologically-based PK model and linked indirect response PD models were applied. RESULTS: The mean clearance of DEX was 344 mL/h/kg via hepatic metabolism (98%) and renal excretion (2%). Due to nonlinear tissue binding, DEX generally exhibited a prolonged terminal phase in plasma, maintaining concentrations above a designated plasma threshold of 5 pg/mL for 67 h following 0.05 mg/kg IV dose. Dosing input parameters of DEX varied markedly across dosing routes and prodrug formulations (alcohol, isonicotinate, phosphate), with bioavailability ranging 37 ~ 100%. Oral and pro-drug doses produced rapid absorption, except for IM DEX-isonicotinate that exhibited slow (flip-flop) availability. Adrenal suppression with an IC of 0.038 ng/mL and plasma GLU increases with an EC of 0.79 ng/mL were observed that commonly persisted for 2 ~ 4 days after single dose. CONCLUSIONS: This meta-analysis utilized a mechanistic and physiologically-based modeling framework to provide global perspectives that may promote the rational use of DEX in equine medicine and support evidence-based regulatory decisions.
Innovative Production of Diclofenac Sodium-Loaded Solid Lipid Nanoparticles by Membrane Nanoprecipitation: Evaluation of Encapsulation Efficiency and Photoprotection Ability.
Bazzarelli F, Ioele G, Chieffallo M … +4 more , Giorno L, Garofalo A, Fuoco A, Piacentini E
Pharm Res · 2026 Jun · PMID 42321582 · Publisher ↗
PURPOSE: The stability of diclofenac sodium (DS) in liquid formulation is influenced by environmental factors such as temperature, humidity and light. The encapsulation of this drug in solid lipid nanoparticles (SLNs) ca...
PURPOSE: The stability of diclofenac sodium (DS) in liquid formulation is influenced by environmental factors such as temperature, humidity and light. The encapsulation of this drug in solid lipid nanoparticles (SLNs) can offer a useful strategy to protect it from degradation. The present study shows the potential of membrane nanoprecipitation (MN) as a productive and advantageous method for the formulation of cocoa butter-based SLNs to improve the photostability of DS. METHODS: Conventional batch nanoprecipitation and MN were explored by varying the formulation parameters and process conditions to obtain SLNs. RESULTS: The MN produced SLNs with an average size of 421 ± 14 nm, a high encapsulation efficiency of 95 ± 3.2%, and a drug loading of 8.8 ± 0.2%, when an acetate buffer at pH 4.1 was used as the non-solvent phase. Chemical characterization of the proposed formulation was performed by DSC and FTIR analyses. The efficacy of SLNs in preserving DS stability was investigated under simulated sunlight exposure, demonstrating a residual drug concentration of 90% after 3.34 min with respect to the aqueous solution that showed the same concentration value after 0.072 min. CONCLUSIONS: Overall, MN represents a suitable and sustainable process for the continuous production of light-stable drug-loaded SLNs.
Force Distribution and Contact Mechanics in Mini-Tablet Compaction: A Discrete Element Method Study.
Najafian S, Tran TB, Chaudhuri B … +1 more , Hiew TN
Pharm Res · 2026 Jun · PMID 42315689 · Publisher ↗
PURPOSE: The purpose of this study was to investigate how powder fill weight, particle size, and particle size distribution influence force transmission and compaction behavior of powders during compaction within narrow...
PURPOSE: The purpose of this study was to investigate how powder fill weight, particle size, and particle size distribution influence force transmission and compaction behavior of powders during compaction within narrow die cavities. METHODS: Discrete element method simulations were used to model confined powder compaction. Monodisperse and polydisperse systems were analyzed by varying particle size, size distribution breadth, and fill weight. Compaction force-displacement behavior was examined together with particle-level normal, tangential, and cohesive forces, including their axial and radial spatial distributions. RESULTS: Particle size had a stronger influence on force heterogeneity than fill weight within the range examined, with larger particles generating higher and more heterogeneous contact forces. Force distributions were positively skewed, indicating load localization within force chains. Normal and tangential forces were highest near the die wall, reflecting strong confinement effects. While individual particle forces followed similar size-dependent trends across different size distributions, narrow distributions required higher compaction forces due to localized load-bearing structures, whereas wider distributions promoted more uniform force sharing and lower resistance to compaction. CONCLUSIONS: The results demonstrated that macroscopic compaction behavior was governed by the organization of force networks rather than particle-scale force magnitudes alone, highlighting the critical roles of particle size, polydispersity, and confinement effects in powder compaction.
Transdermal Ionic Liquid Gel of Erlotinib for Localized Breast Cancer Therapy.
Datta P, Katari O, Yadav V … +2 more , Dhake P, Jain S
Pharm Res · 2026 Jun · PMID 42310188 · Publisher ↗
OBJECTIVE: Breast cancer is the second most diagnosed and the fourth leading cause of death among affected women. Here, we have formulated erlotinib (ETB) ionogel to enhance the solubility and transdermal permeation of E...
OBJECTIVE: Breast cancer is the second most diagnosed and the fourth leading cause of death among affected women. Here, we have formulated erlotinib (ETB) ionogel to enhance the solubility and transdermal permeation of ETB post-topical application in breast cancer. The presence of the lymphatic network and mammary fat layers in the breast augments drug accumulation, thus evading the side effects of systemic chemotherapy and the invasive nature of current localized treatments. METHODS: Ionic liquid (IL) of choline geranate (CAGE) was synthesized via a salt metathesis reaction. ETB solubilized CAGE IL was subsequently transformed into an ionogel using Carbopol 980 NF and HPMC. RESULTS: The HPMC ETB ionogel showed 71.04% permeation within 24 h and 64.3% drug release in 48 h following the Makoid-Banaker model. FTIR and SEM analysis confirmed the deeper dermal distribution of ionogel with the ability to maintain skin integrity. The ETB IL achieved the highest cytotoxicity in different breast cancer cell lines. The AUC, C, and t of ETB ionogel increased by 1.19, 1.03, and 1.44-fold, respectively, than the ETB gel. The % tumor burden and tumor volume reductions were respectively calculated to be 2.4 and 2.3-fold lesser for ETB HPMC ionogel as compared to ETB HPMC gel. However, the % tumor growth inhibition increased by 1.2-folds for ionogel. CONCLUSIONS: The improved in vivo efficacy and lower TEWL value depicted the non-toxic and permeable nature of ETB HPMC ionogel due to greater occlusivity, thus proving its transdermal yet localised effect in treating breast cancer.
A Sulfonamide-Based Compound DRZ-V Enhances Wound Repair via Macrophage-Mediated Responses Associated with TIRAP-NF-κB Signaling.
Raja SR, Obukhov AG, Darwhekar GN … +7 more , Majmudar CY, Nair K, Behera SK, Bharti S, Yangdol R, Prajapati A, Baig MS
Pharm Res · 2026 Jun · PMID 42310187 · Publisher ↗
BACKGROUND: Macrophage polarization is a critical determinant of wound healing outcomes, regulating the transition from inflammation to tissue repair. Failure to shift from a pro-inflammatory M1 phenotype to a reparative...
BACKGROUND: Macrophage polarization is a critical determinant of wound healing outcomes, regulating the transition from inflammation to tissue repair. Failure to shift from a pro-inflammatory M1 phenotype to a reparative M2 phenotype contributes to chronic inflammation and delayed wound healing. Although the sulfonamide-based small molecule DRZ-V has shown anti-inflammatory properties, its role in macrophage functional reprogramming during wound repair has not been explored. This study investigated whether DRZ-V promotes macrophage phenotypic transition and enhances wound healing through modulation of TIRAP-mediated NF-κB signaling. METHODS: Wound healing activity was evaluated using a full-thickness excisional wound model in mice. Macrophage polarization and cytokine expression were analyzed in RAW 264.7 macrophages by quantitative real-time PCR. The influence of macrophage-conditioned media on fibroblast migration was assessed using an in vitro scratch assay. TIRAP phosphorylation and NF-κB p65 activation were examined by immunoblotting and immunofluorescence analyses. RESULTS: DRZ-V significantly accelerated wound closure in vivo. In macrophages, DRZ-V suppressed LPS-induced inflammatory responses by reducing pro-inflammatory cytokine expression while enhancing M2-associated markers, including Arg1, FIZZ1, and Ym1. DRZ-V also restored the expression of reparative mediators such as TGF-β and PDGF. Furthermore, conditioned media from DRZ-V-treated macrophages enhanced fibroblast migration, indicating indirect pro-reparative effects mediated through macrophage modulation. Mechanistically, these effects were associated with reduced TIRAP phosphorylation and attenuation of NF-κB activation. CONCLUSION: DRZ-V promotes wound repair by modulating macrophage-mediated inflammatory responses through inhibition of TIRAP-NF-κB signaling, highlighting its therapeutic potential for inflammatory and impaired wound healing conditions.
A Newly Designed Antibody-drug Conjugate Targeting B7-H3 Demonstrates Enhanced Therapeutic Efficacy Across a Spectrum of Cancers.
Qian J, Zhu X, Zhao X … +7 more , Zhu J, Wu Z, Zheng Q, Wang J, Yu F, Nie L, Weng Q
Pharm Res · 2026 Jun · PMID 42303884 · Publisher ↗
INTRODUCTION: The development of antibody-drug conjugates (ADCs) has accelerated due to their tumor-targeting precision. However, challenges in optimizing the target-linker-payload combination often lead to attrition fro...
INTRODUCTION: The development of antibody-drug conjugates (ADCs) has accelerated due to their tumor-targeting precision. However, challenges in optimizing the target-linker-payload combination often lead to attrition from safety or efficacy issues, highlighting the need for ADCs with an improved therapeutic index. This study presents a newly designed B7-H3-targeted ADC, BR112, and demonstrates its superior preclinical efficacy across multiple models. METHODS: BR112 comprises a humanized anti-B7-H3 antibody (112-59) conjugated to the microtubule inhibitor MMAE via a Pyridazinedione-valine-citrulline-p-aminobenzyl (PD-VC-PAB) linker with a drug-to-antibody ratio (DAR) of 4.15. The binding affinity and internalization profile of 112-59 were evaluated across multiple cell lines. In vitro cytotoxicity and in vivo antitumor efficacy were assessed in multiple cancer cell lines and three xenograft models. Pharmacokinetics of BR112 were analyzed in cynomolgus monkeys. RESULTS: The antibody 112-59 exhibited high binding affinity for human B7-H3 (Kd = 5.28 nM), with potent cell-binding (EC50 ≈ 1 nM) and superior internalization across multiple cancer cell lines, exceeding the performance of antibodies used in clinical-stage comparator ADCs (MGC018 and DS-7300). Consequently, BR112 demonstrated potent cytotoxicity in vitro, with IC50 values ranging from femtomolar to nanomolar. In vivo, BR112 induced complete tumor regression in xenograft models (HCC1954, HCC1806, Calu-6) at doses of 3-10 mg/kg, outperforming both MGC018 and DS-7300. Pharmacokinetic studies in cynomolgus monkeys showed dose-proportional exposure and minimal MMAE release, confirming linker stability. CONCLUSION: This study positions BR112 as a promising therapeutic candidate with enhanced efficacy and a stable pharmacokinetic profile for the treatment of B7-H3-expressing solid tumors.
Small Vesicles Big Impact: Exosomes in the Landscape of Women's Health.
Agrahari V, Modi D, Dave M … +1 more , Chablani L
Pharm Res · 2026 Jun · PMID 42271073 · Publisher ↗
Extracellular vesicles (EVs), particularly exosomes, are small membrane-bound vesicles that mediate intercellular communication by transferring bioactive molecules such as proteins, lipids, and nucleic acids. Increasing...
Extracellular vesicles (EVs), particularly exosomes, are small membrane-bound vesicles that mediate intercellular communication by transferring bioactive molecules such as proteins, lipids, and nucleic acids. Increasing evidence highlights their critical role in maintaining physiological homeostasis and in the pathogenesis of multiple diseases. In the context of women's health, exosomes have emerged as key regulators of reproductive function, endocrine signaling, immune modulation, and hormonal balance across the lifespan. This review provides an overview of exosome biogenesis, molecular composition, and functional properties, with a focus on their relevance to reproductive disorders, infectious diseases, hormonal imbalance, and menopause. We summarize recent advances demonstrating the utility of exosomes as biomarkers and diagnostic tools in conditions such as polycystic ovary syndrome (PCOS), gynecological cancers, and pregnancy-related complications. In addition, the role of placental and circulating exosomes in gestation, including their involvement in placenta-fetal communication, immune tolerance, and the pathophysiology of preeclampsia and the gestation phase, is also discussed. Furthermore, we discuss emerging evidence supporting exosome-based therapeutic roles for restoring ovarian function, modulating inflammation, and targeting tumor progression. Finally, we address current challenges in exosome isolation, characterization, and clinical translation, and outline future research directions required to harness exosome approaches to improve women's health outcomes.
Dead-Space Microdomains as Explicit Barriers to Extracellular Drug Transport in Alzheimer's Disease.
Charemis D, Lampropoulos D, Dimakopoulos Y … +2 more , Sivolapenko G, Hadjinicolaou M
Pharm Res · 2026 Jun · PMID 42265487 · Publisher ↗
OBJECTIVE: The impact of dead-space (DS) microdomains on cerebral drug penetration has been demonstrated experimentally; yet computational models typically capture their effects indirectly through effective tortuosity pa...
OBJECTIVE: The impact of dead-space (DS) microdomains on cerebral drug penetration has been demonstrated experimentally; yet computational models typically capture their effects indirectly through effective tortuosity parameters. Here, we develop an anatomically grounded framework that systematically evaluates pharmaceutical diffusion within the central nervous system (CNS). METHODS: A finite element (FE) model was developed with DS explicitly represented as impermeable obstructions in the extracellular space (ECS) - consistent with structural remodeling observed in Alzheimer's disease (AD). The model was calibrated by reproducing experimental diffusion timescales and subsequently applied to quantify the geometric contribution of DS to pharmaceutical transport. RESULTS: Transport hindrance exhibited a strong dependence on molecular size. Within a representative ECS unit, the arrival of the concentration contour at the venule was delayed by 11 s for Memantine, 14 s for Donepezil, and 80 s for Aducanumab. Spatial analyses revealed penetration delays that were not captured by domain-averaged uptake metrics. A Péclet number analysis confirmed that ECS transport for all three compounds remains diffusion-dominated under neurodegenerative conditions. CONCLUSIONS: The proposed framework provides a computationally efficient foundation for predictive multiphysics modeling in the human CNS and demonstrates how local ECS obstructions can lead to therapeutic hindrance in AD.
Long-Acting Antimalarial Drug Delivery Systems for Chemoprophylaxis: Formulation Strategies and Routes of Administration.
Kumar Y, Galave VB, Jindal AB
Pharm Res · 2026 Jun · PMID 42243601 · Publisher ↗
BACKGROUND: Malaria chemoprophylaxis generally requires prolonged and frequent administration of antimalarial drugs, which often results in poor patient adherence and reduced prophylactic effectiveness. OBJECTIVE: This r...
BACKGROUND: Malaria chemoprophylaxis generally requires prolonged and frequent administration of antimalarial drugs, which often results in poor patient adherence and reduced prophylactic effectiveness. OBJECTIVE: This review aims to summarize the advancements in long-acting drug delivery systems developed for antimalarial chemoprophylaxis and highlights recent clinical developments in this field. METHODS: Various formulation approaches reported in the literature for sustained antimalarial drug release were reviewed, including oral, parenteral, and topical long-acting delivery systems. Strategies such as gelatin capsules, solid drug nanoparticles, oil-based solutions, implants, polymeric nanorods, lipid-based depot systems, in situ-forming gels, microspheres, and microneedle-based delivery systems were evaluated. RESULTS: Long-acting antimalarial delivery systems have demonstrated significant potential in minimizing dosing frequency, improving patient adherence, and enhancing prophylactic effectiveness. Various formulation strategies have shown the ability to provide sustained drug release and prolonged protection against malaria. CONCLUSION: Long-acting drug delivery systems represent a promising strategy for improving malaria chemoprophylaxis by overcoming adherence-related challenges associated with conventional dosing regimens. Continued research and clinical advancements in sustained-release antimalarial formulations may significantly contribute to the development of effective antimalarial drug delivery systems for successful chemoprophylactic therapy.
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