Pharmaceutical Research[JOURNAL]
Sun
200 papers
An Innovative Multifaceted Approach to Enhance the Sensitivity of a Target Engagement ELISA.
Qiu N, Nitsche A, Beley I … +3 more , Maiolica A, Cunliffe J, De Gagné J
Pharm Res · 2026 Apr · PMID 41951864 · Full text
Target engagement (TE) assessments often come with bioanalytical challenges, particularly with low baseline level targets like cytokines and chemokines. Commercial immunoassay kits often cannot meet the requirements of s...
Target engagement (TE) assessments often come with bioanalytical challenges, particularly with low baseline level targets like cytokines and chemokines. Commercial immunoassay kits often cannot meet the requirements of sensitivity and drug interference. We present a novel methodology that significantly enhances the sensitivity of a conventional sandwich enzyme-linked immunosorbent assay (ELISA) for TE assessment. To increase sensitivity, various strategies were applied, including the combined use of U-bottomed assay plates and Intelligent Multifunctional Analytical Plates (IMAPlate™). Lowering volumes of enzyme substrate and stop solution in U-bottomed plate led to a concentrated color solution. The unique bottom-less "well" of the IMAPlate™ was utilized to measure the intensified color solution, resulting in a significantly magnified signal. The use of Pluronic F-127 detergent into the assay buffer system helped reduce assay background while improving sensitivity. The biotin labeling process of the detection antibody was optimized and combined with using poly horseradish-peroxidase (HRP)-streptavidin to further enhance sensitivity. To evaluate this approach, we developed a sandwich ELISA to quantify total (free and drug bound) serum human interleukin-13 (IL-13). A pair of non-competing for target binding antibodies was used. Due to IL-13's small size, steric hindrance was observed in the presence of NVS-0031 (anti-IL-13 mAb) and a saturation method to mitigate this interference was implemented. Despite an initial 40% sensitivity loss, we eventually improved sensitivity approximately 200-fold to achieve a limit of quantitation of 0.05 pg/mL. This methodology has been effectively employed in other ELISA-based bioanalytical assays that require heightened sensitivity (data not shown), demonstrating its wide-ranging applicability.
In vitro and ex vivo Pharmacological Profile of HY-022619, a Novel Intravenous P2Y Receptor Antagonist with Rapid-onset and Sustained Antiplatelet Activity.
Mo J, He EM, Zhao Y … +9 more , Shao L, Yue S, Xie Y, Wu S, He J, Zou Y, Chu Z, He G, Xu Y
Pharm Res · 2026 May · PMID 41951863 · Publisher ↗
PURPOSE: Patients with acute coronary syndrome (ACS) require rapid and potent antiplatelet therapy during percutaneous coronary intervention (PCI). Current first-line P2Y₁₂ inhibitors are limited by delayed efficacy or a...
PURPOSE: Patients with acute coronary syndrome (ACS) require rapid and potent antiplatelet therapy during percutaneous coronary intervention (PCI). Current first-line P2Y₁₂ inhibitors are limited by delayed efficacy or an ultrashort half-life. This study aims to characterize the metabolism and pharmacodynamics of HY-022619, a disodium phosphate ester salt of ticagrelor, to provide a theoretical basis for its clinical use in peri-PCI antithrombotic therapy. METHODS: The inhibitory activity of HY-022619 against the P2Y₁₂ receptor and ADP-induced platelet aggregation was evaluated in vitro. Molecular docking was performed to compare its receptor-binding mode with ticagrelor. Metabolic stability was assessed in whole blood, liver microsomes, and using recombinant enzymes. Pharmacodynamic profiles were investigated in rats and beagle dogs, with additional assessments of metabolic conversion and bleeding time in dogs. RESULTS: HY-022619 showed 22-fold greater P2Y₁₂ receptor inhibition and 15-fold stronger suppression of platelet aggregation than ticagrelor. Molecular docking revealed that enhanced activity was due to an additional salt bridge. HY-022619 remained stable in human and non-rodent whole blood (half-life > 60 min) and was primarily hydrolysed to ticagrelor in the liver by CES1 and CES2. In rats, intravenous administration produced rapid, dose-dependent platelet inhibition within 5 min. In dogs, HY-022619 acted rapidly with efficacy peaking at the end of infusion. It converted completely to ticagrelor within 5 min post-infusion, maintaining antiplatelet effects for 6 h, without significantly prolonging bleeding time compared to ticagrelor. CONCLUSION: HY-022619 demonstrates rapid, potent, and sustained antiplatelet effects, supporting its potential clinical application.
Regulatory Roles of Long Non-Coding RNAs in Methotrexate Pharmacology: Mechanistic and Translational Insights.
Guzmán-Martín CA, González-Moyotl NJ, Juárez-Vicuña Y … +11 more , Bojalil R, Martínez-Martínez LA, Arenas-Díaz AL, Martínez-Rosas M, Peña-Peña M, Vázquez-Toledo MA, Romero-Nava R, Jiménez-Ortega RF, Hidalgo-Bravo A, Velázquez-Cruz R, Sánchez-Muñoz F
Pharm Res · 2026 May · PMID 41946981 · Full text
BACKGROUND: Methotrexate (MTX) remains a cornerstone therapy in autoimmune diseases and oncology; however, substantial interindividual variability in efficacy and toxicity persists. While variability in MTX pharmacokinet...
BACKGROUND: Methotrexate (MTX) remains a cornerstone therapy in autoimmune diseases and oncology; however, substantial interindividual variability in efficacy and toxicity persists. While variability in MTX pharmacokinetics (PK) and pharmacodynamics (PD) has been linked to transporters, folate-cycle enzymes, and intracellular polyglutamate accumulation, the contribution of long non-coding RNAs (lncRNAs) as regulatory modifiers of these processes is not yet systematically defined. OBJECTIVE: To synthesize current evidence on lncRNA-mediated regulation of MTX response and to organize these interactions within a pharmacology-centered mechanistic framework. METHODS: A narrative, mechanism-oriented review was conducted integrating preclinical, translational, and computational studies evaluating lncRNA involvement in MTX-related pathways across immune-mediated diseases and cancer. RESULTS: lncRNAs were found to intersect with MTX pharmacology across four principal mechanistic nodes: (1) regulation of drug transport and intracellular retention (e.g., modulation of ABC transporters); (2) control of folate-axis targets and compensatory metabolic pathways (e.g., DHFR and TYMS regulation); (3) modulation of adenosine-mediated immunoregulation and NF-κB signaling, with lincRNA-p21 representing the most mechanistically supported example in rheumatoid arthritis; and (4) orchestration of stress-adaptive and survival pathways influencing antifolate resistance (e.g., PI3K-AKT-mTOR and apoptosis networks). However, most evidence derives from in vitro or computational studies, with limited integration of lncRNA perturbation and quantitative PK metrics such as intracellular MTX-polyglutamate levels. CONCLUSIONS: lncRNAs function as context-dependent modulators of MTX PK/PD processes rather than primary drug targets. Current evidence is heterogeneous, future studies integrating functional genomics, PK measurements, and prospective clinical validation are required to establish lncRNAs as predictive biomarkers or therapeutic targets in MTX precision pharmacology.
Development of a Novel Curcumin-Vanillic Acid Eutectic: Physicochemical Characterization, Antioxidant Activity, and Bioavailability Enhancement.
Pantwalawalkar J, Jadhav N, Nangare S
Pharm Res · 2026 May · PMID 41927965 · Publisher ↗
OBJECTIVE: Curcumin, a well-known phyto-nutraceutical with broad therapeutic potential, faces critical formulation challenges, including poor aqueous solubility, low dissolution rate, and limited tablettability, leading...
OBJECTIVE: Curcumin, a well-known phyto-nutraceutical with broad therapeutic potential, faces critical formulation challenges, including poor aqueous solubility, low dissolution rate, and limited tablettability, leading to poor oral bioavailability and reduced therapeutic efficacy. This study presents a novel curcumin-vanillic acid eutectic system designed to overcome these limitations through a sustainable and green formulation approach. METHODS: Vanillic acid, a natural phenolic compound with potent antioxidant properties, was selected as a coformer based on in silico analysis demonstrating structural compatibility and potential therapeutic synergy with curcumin. The eutectic mixture was prepared via solvent-free solid-state grinding and characterized using X-ray diffraction, differential scanning calorimetry, Fourier-transform infrared spectroscopy, and proton/carbon nuclear magnetic resonance. Physicochemical, tablettability, and antioxidant properties were subsequently evaluated. DoE software was used to optimize the eutectic-based tablet formulation, followed by its pharmacokinetic evaluation. RESULT: Spectroscopic results supported eutectic formation, showing modifications in the solid-state characteristics of curcumin accompanied by a lower melting point. These modifications yielded significant improvements in solubility (tenfold, eightfold, and 11-fold in water, buffer pH 1.2, and buffer pH 6.8) and tablettability relative to pure curcumin. The eutectic also exhibited enhanced antioxidant activity (p < 0.05), which may be attributed to the combined intrinsic antioxidant properties of the drug and coformer compared to pure curcumin. DoE-optimized eutectic tablets suggested an enhanced bioavailability of curcumin compared to conventional curcumin tablets; however, warranting confirmation in a larger sample size. CONCLUSION: Overall, the curcumin-vanillic acid eutectic represents a promising formulation approach for developing high-performance phyto-nutraceutical systems.
Whole-Body Pharmacokinetics of Lipid, mRNA and Translated Protein Following Intravenous Administration of Spike Protein Expressing mRNA-LNP in Mice.
Kumar M, Tiwari S, Rajwade A … +3 more , Kulkarni R, Patel A, Shah DK
Pharm Res · 2026 May · PMID 41927964 · Full text
AIM: Lipid nanoparticle (LNP)-encapsulated mRNAs (mRNA-LNPs) are being explored for various prophylactic and therapeutic applications. However, the relationship between the pharmacokinetics (PK) of lipid, mRNA, and expre...
AIM: Lipid nanoparticle (LNP)-encapsulated mRNAs (mRNA-LNPs) are being explored for various prophylactic and therapeutic applications. However, the relationship between the pharmacokinetics (PK) of lipid, mRNA, and expressed protein across tissues remains poorly understood. This study aimed to perform a biodistribution study to quantitatively assess this relationship. METHODS: Spike protein encoding mRNA was encapsulated in LNPs formulated with ALC-0315. mRNA-LNP was administered intravenously in mice. Biodistribution of ALC-0315, mRNA and expressed spike protein was determined in plasma and several tissues using LC-MS/MS, RT-qPCR and ELISA, respectively. Anti-spike protein IgM and IgG titers were also quantified using ELISA. RESULTS: ALC-0315 lipid was cleared rapidly from plasma but persists in tissue for several weeks post dosing, with highest uptake seen in liver and spleen, and the lowest in muscle and brain. Unlike lipid, the highest mRNA exposure was observed in spleen followed by liver. Spike protein expression was detected within minutes of dosing and peaked at 6 h. Maximum protein expression was observed in liver, followed by spleen, heart, kidney and lung. A robust humoral immune response was triggered against spike protein, with IgM titers detected as early as 24 h and IgG titers detected on day 7. CONCLUSION: The PK of lipid, mRNA, and protein components differ significantly. The plasma PK for all three analytes differed significantly from tissue PK. Synthetic ionizable lipid ALC-0315 persisted in tissues for several weeks post dosing. After intravenous dosing, mRNA-LNP was found to be rapidly taken up by the tissues, and protein expression detected within one hour in all tissues.
Factors Associated with Parental Vaccine Hesitancy in Childhood Immunization: Insights from a Cross-Sectional Survey in Southern Italy.
Barbieri MA, Cicala G, Molonia A … +6 more , Alibrandi A, Pallio G, La Fauci E, Ingrassia M, Irrera N, Benedetto L
Pharm Res · 2026 May · PMID 41927963 · Publisher ↗
INTRODUCTION: Parental vaccine hesitancy (VH) threatens childhood immunization and may improve vaccination coverage. This study aimed to investigate parental VH factors in childhood immunization in Southern Italy, focusi...
INTRODUCTION: Parental vaccine hesitancy (VH) threatens childhood immunization and may improve vaccination coverage. This study aimed to investigate parental VH factors in childhood immunization in Southern Italy, focusing on sociodemographic factors, adverse events following immunization (AEFIs), and participants perceptions of child vulnerability and health factors. METHODS: A cross-sectional electronic survey was conducted between September 2024 and January 2025 among parents/caregivers of children and adolescents in Sicily and Calabria. The survey included the Parent Attitudes about Childhood Vaccines Questionnaire (PACV-5), the Child Vulnerability Scale (CVS), and the Parent Health Locus of Control Scales (PHLoC). Multivariable logistic regression models were used to identify independent factors associated with VH reporting adjusted Odds Ratio (aOR) with corresponding 95% confidence intervals (CIs). RESULTS: In this facility-based sample, 44.5% screened positive for VH in childhood immunization. Prior vaccine refusal (aOR 3.56; 95% CI: 2.09-6.06), experiencing an AEFI after the last vaccination (aOR: 2.00; 95% CI: 1.09-3.67), including more than one AEFI (aOR: 1.88; 95% CI: 1.14-3.11), or changes in hesitancy following an AEFI (aOR 5.31; 95% CI: 2.60-10.90) were associated with higher VH. PHLoC Destiny (aOR 1.43; 95% CI: 1.21-1.69) and Divine (aOR 1.14; 95% CI: 1.01-1.30) were associated with higher VH, whereas PHLoC Professionals with lower VH (aOR 0.72; 95% CI: 0.60-0.86). CONCLUSION: Parental VH was associated with safety concerns and the influence of imponderable PHLoC factors, while trust in healthcare professionals was linked to lower VH, underscoring the need for targeted, empowerment-based communication strategies to improve vaccination confidence.
New Vistas for Withania somnifera in Signal Transduction of Inflammation and Aging.
Sharma E, Mehta D, Muthuraj P … +5 more , Panda S, Ajgaonkar S, Maniar D, Biju A, Nair S
Pharm Res · 2026 Apr · PMID 41927962 · Full text
Aging in humans is a multidimensional complexity featured by systematic chronic inflammation and further accompanied by organ dysfunction, gut dysbiosis, immune senescence, and age-related diseases. Chronic inflammation...
Aging in humans is a multidimensional complexity featured by systematic chronic inflammation and further accompanied by organ dysfunction, gut dysbiosis, immune senescence, and age-related diseases. Chronic inflammation in cells relates to secretory factors like the senescence-associated secretory phenotype which induces senescence in normal cells. Simultaneously, immune senescence is promoted by chronic inflammation, resulting in an impaired immune system unable to clear out senescent cells and inflammatory factors. Long term accumulation of elevated inflammatory factors in cells causes organ damage and leads to other age-related disorders. Eliminating inflammation could be a viable anti-aging strategy since it has been identified as an endogenous component in aging. Lately, products of natural origin have been gaining attention in combating age-related diseases and chronic inflammation. Various in vitro, in vivo, and clinical studies have well documented the role of Withania somnifera (WS) in alleviating inflammation and aging in cells by mediating several cellular signaling pathways. This review discusses the features and mechanisms of inflammation and aging (inflammaging) and the modulation of key associated pathways by WS, examining its role as a promising candidate for future strategies against inflammaging.
Melt-Extruded Paclitaxel Nanocrystal-Loaded Sutures for Sustained Local Drug Delivery.
Abdelhakk HM, Issa A, Shin CS … +1 more , Zhang F
Pharm Res · 2026 Apr · PMID 41927961 · Publisher ↗
PURPOSE: To develop biodegradable poly(lactic‑co‑glycolic acid) (PLGA) sutures loaded with paclitaxel (PTX) nanocrystals for sustained local drug delivery and to systematically evaluate their physicochemical, mechanical,...
PURPOSE: To develop biodegradable poly(lactic‑co‑glycolic acid) (PLGA) sutures loaded with paclitaxel (PTX) nanocrystals for sustained local drug delivery and to systematically evaluate their physicochemical, mechanical, and drug‑release properties. METHODS: PTX nanocrystals were prepared via wet media milling, yielding particles with a Z‑average size of 278.33 nm and a polydispersity index of 0.207. The nanocrystals were incorporated into PLGA sutures using a solvent‑free melt extrusion process followed by fiber drawing. Scanning electron microscopy was used to assess nanocrystal dispersion and fiber morphology, while wide‑angle X‑ray scattering evaluated PTX crystallinity and crystal orientation within the fibers. Mechanical properties were characterized by tensile testing. In vitro studies were conducted to assess fi ber shrinkage and PTX release behavior. RESULTS: Scanning electron microscopy confirmed homogeneous dispersion of PTX nanocrystals throughout the PLGA matrix, and wide‑angle X‑ray scattering demonstrated retention of PTX crystallinity with partial crystal orientation induced by fiber drawing. Molecular alignment of PLGA chains during stretching significantly enhanced mechanical performance, with stretched fibers exhibiting a tensile strength of 78.70 ± 11.50 MPa compared to 59.60 ± 2.50 MPa for unstretched polymer rods. Substantial fiber shrinkage was observed during in vitro studies; however, incorporation of PEG 8000 reduced shrinkage from 62% to 24%, but also reduced tensile strength to 40.33 ± 6.00 MPa. Drug‑release studies revealed a biphasic profile characterized by an initial lag phase followed by sustained PTX release, reaching approximately 60% cumulative release over 63 days. CONCLUSION: These findings support the feasibility of melt‑extruded, drug‑loaded PLGA sutures as a platform for sustained local drug delivery.
Surface Preparation and its Effect on Sticking.
Tsosie H, Thomas J, Strong J … +1 more , Zavaliangos A
Pharm Res · 2026 Apr · PMID 41927960 · Full text
PURPOSE: This study examined how controlled punch surface preparation and subsequent atmospheric aging influence adhesion between punch metal and formulation powder during tablet compaction. We aimed to clarify how the e...
PURPOSE: This study examined how controlled punch surface preparation and subsequent atmospheric aging influence adhesion between punch metal and formulation powder during tablet compaction. We aimed to clarify how the evolving surface state of S7 tool steel affects sticking for representative excipients and active pharmaceutical ingredients (APIs), and to establish a reproducible approach for surface state control in material-sparing sticking studies. METHODS: Removable S7 tool steel punch tips were mechanically polished, chemically cleaned, and rinsed to create a defined "as-cleaned" surface. Punches were aged at 55% RH for 10 min to 72 h. Sticking of mannitol, Starch 1500, acetylsalicylic acid (ASA), and ibuprofen (IBU) was quantified using a non-contact laser reflectivity sensor and measuring adhered mass after single compactions. Static contact angle measurements tracked surface evolution, and X-ray photoelectron spectroscopy (XPS) characterized chemical changes. RESULTS: Freshly cleaned punches showed strong adhesion for mannitol and starch. Starch lost its sticking tendency within minutes of aging, while mannitol remained adhesive until several hours of exposure. ASA and IBU exhibited moderate sticking that declined slightly with aging. Contact angle and XPS indicated rapid formation of a carbonaceous/oxide overlayer, reducing polar surface energy and altering adhesion pathways. CONCLUSIONS: Punch surface chemistry evolves quickly under ambient conditions, strongly impacting sticking behavior. Cleaning to testing time can alter adhesion outcomes within minutes, highlighting the need to standardize surface preparation and define the punch-surface state. This framework offers a practical basis for surface control in pharmaceutical compaction studies.
Correction: A Multi-Functional Tumor Theranostic Nanoplatform for MRI Guided Photothermal-Chemotherapy.
Shi J, Wang B, Chen Z … +4 more , Liu W, Pan J, Hou L, Zhang Z
Pharm Res · 2026 Apr · PMID 41888484 · Publisher ↗
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A Comprehensive Review of the Revolutionary Potential of Blockchain in Safe, Secure, and Sustainable Pharmaceutical Operations.
Faiyazuddin M, Moharir K, Gholap AD … +5 more , Christodoss PR, Choonara YE, Mnqiwu K, Sundaram G, Tahir M
Pharm Res · 2026 Apr · PMID 41888483 · Publisher ↗
BACKGROUND: Pharmaceutical research and industrial operations generate vast volumes of sensitive data across drug discovery, formulation development, manufacturing, and distribution, necessitating secure, transparent, an...
BACKGROUND: Pharmaceutical research and industrial operations generate vast volumes of sensitive data across drug discovery, formulation development, manufacturing, and distribution, necessitating secure, transparent, and reliable digital infrastructures. The global counterfeit drug market exceeds $200 billion annually, posing a significant threat to patient safety and public health. Blockchain Technology (BT) has demonstrated the potential to reduce counterfeit medicine circulation by approximately 40%, offering a transformative framework for pharmaceutical data governance. METHODS: A systematic literature review was performed using ScienceDirect, PubMed, IEEE Xplore, and SpringerLink databases to analyze peer-reviewed studies published between January 2017 and December 2024. Structured keyword strategies and predefined inclusion and exclusion criteria were employed to evaluate blockchain-driven pharmaceutical operations and their integration with Artificial Intelligence (AI) and the Internet of Things (IoT). RESULTS: The findings reveal that BT substantially improves data integrity, immutability, traceability, transparency, and security across pharmaceutical workflows. Integration with AI and IoT further enables real-time monitoring and predictive analytics, leading to 30-55% improvements in operational efficiency, 25-50% reductions in logistics and compliance-related costs, and significant enhancements in clinical trial data accuracy, pharmacovigilance reporting efficiency, intellectual property protection, and genomic data governance and counterfeit drug prevention. CONCLUSION: Blockchain-driven pharmaceutical ecosystems represent a paradigm shift in drug development, manufacturing, and distribution. Despite substantial benefits, challenges related to scalability, interoperability, data governance, and regulatory harmonization remain. Future research should prioritize the development of standardized frameworks, scalable architectures, and regulatory policies to accelerate industrial adoption and clinical translation.
Formation Mechanism of N-Despropyl Ropinirole in Ropinirole Hydrochloride Extended-Release Tablets: Nucleophilic Oxidation or Free Radical-Mediated Oxidation?
Wu K, Lin J, Liang X … +4 more , Wang P, Guo Q, Chen W, Li M
Pharm Res · 2026 Apr · PMID 41888482 · Publisher ↗
PURPOSE: To probe the formation mechanism of N-despropyl ropinirole, an oxidative degradant in ropinirole hydrochloride extended-release tablets. METHODS: Forced degradation studies were employed to investigate the mecha...
PURPOSE: To probe the formation mechanism of N-despropyl ropinirole, an oxidative degradant in ropinirole hydrochloride extended-release tablets. METHODS: Forced degradation studies were employed to investigate the mechanism by treating ropinirole API with HO and AIBN, respectively, and the samples analyzed by high resolution LC-QTOF-MS. Meanwhile, the samples from the forced degradation of the extended-release tablets were analyzed by GC-QTOF-MS. The proposed mechanism was supported by an HO isotope experiment. Lastly, API-excipient compatibility studies were conducted to evaluate the impact of the excipients on the formation of N-despropyl ropinirole. RESULTS: The growth trend of N-despropyl ropinirole in the accelerated stability study was similar to that observed in the forced degradation of ropinirole hydrochloride treated with AIBN, but vastly different from that observed in the forced degradation with HO. The forced degradation using isotope labelled HO showed that O was incorporated into propionaldehyde, the volatile co-degradant in the formation of N-despropyl ropinirole. The API-excipient compatibility studies indicated that N-despropyl ropinirole was formed gradually in the presence of CMC-Na and HPMC, respectively. CONCLUSIONS: Degradation of ropinirole in the ropinirole hydrochloride extended-release tablets is most likely to proceed via a free radical-mediated oxidative pathway, rather than a nucleophilic oxidative pathway. The forced degradation experiment using HO is consistent with the proposed free radical-mediated degradation mechanism. The source of the free radicals seems to originate from the two excipients, CMC-Na and HPMC. The results obtained in the current study would be quite beneficial for further improvement of the drug product in terms of controlling its major degradation pathway.
Hospital-Compounded Birabresib Capsules for NUT Carcinoma: A Quality- and Risk-Based CMC Strategy.
Annereau M, Legrand FX, Sánchez-Becerra MV … +8 more , Ramos S, Duperray F, Denis L, Sizun C, Durand S, Salomon V, Besse B, Do B
Pharm Res · 2026 May · PMID 41882454 · Full text
PURPOSE: NUT carcinoma is an ultra-rare and highly aggressive malignancy lacking authorised systemic therapies. Birabresib, a bromodomain and extra-terminal (BET) inhibitor, has shown preliminary clinical activity; howev...
PURPOSE: NUT carcinoma is an ultra-rare and highly aggressive malignancy lacking authorised systemic therapies. Birabresib, a bromodomain and extra-terminal (BET) inhibitor, has shown preliminary clinical activity; however, its development was discontinued and no GMP-grade active pharmaceutical ingredient or finished product is available. This work describes the hospital-based pharmaceutical development enabling authorised therapeutic use of birabresib in France. METHODS: Within the French ANSM temporary usage protocol (PUT), a quality- and risk-based Chemistry, Manufacturing and Controls (CMC) strategy inspired by ICH Q8-Q10 was implemented to convert a research-grade material into a qualified drug substance for compounding. An initial batch of birabresib dihydrate underwent comprehensive CMC-like characterisation, including purity, identity, structural confirmation, solid-state properties, residual solvents, and forced degradation to establish a primary chemical reference substance and a stability-indicating analytical method. RESULTS: The generated data supported acceptance criteria for subsequent batches and for 20-mg capsules compounded under Good Preparation Practice in a centralised hospital pharmacy. Finished product controls complied with pharmacopoeial and ICH requirements, and capsules were enrolled in a prospective stability programme under PUT-defined storage conditions. CONCLUSIONS: This risk-proportionate, CMC-oriented hospital framework enabled the first authorised therapeutic use of birabresib in NUT carcinoma and may be extended to other discontinued small molecules used in regulated access programmes for ultra-rare diseases.
Investigation into Clearance of Organic Compounds from Biomanufacturing Process Streams during Ultrafiltration/Diafiltration.
Dorival-García N, Mulligan A, Hayes R … +4 more , Felice C, Sexton A, Wang PP, Bones J
Pharm Res · 2026 Apr · PMID 41876941 · Full text
OBJECTIVE: Ultrafiltration and diafiltration (UF/DF) operations have been demonstrated to clear leachables from drug substance, however there is limited data available. Consequently, comprehensive and systematic characte...
OBJECTIVE: Ultrafiltration and diafiltration (UF/DF) operations have been demonstrated to clear leachables from drug substance, however there is limited data available. Consequently, comprehensive and systematic characterization of leachables clearance during UF/DF is required and essential. METHODS: To achieve this, the reduction capacity for 28 selected organic compounds spiked into 3 different proteins during UF/DF processes was investigated using liquid chromatography high-resolution mass spectrometry. Selection of compounds was based on their presence in representative biomanufacturing processes. RESULTS: Most compounds (24) showed clearance over 98% across the process for the 3 protein materials. The specific protein characteristics and process parameters for each protein had a minimal impact on clearance, with sieving coefficients essentially the same for each one of the 3 protein processes. The sieving coefficient is a parameter that characterizes clearance of compounds during UF/DF. Physicochemical properties of the compounds under study significantly influenced their clearance, with the octanol-water coefficient (Log P) being the most crucial factor. Compounds with Log P < 4 had sieving coefficients close to ideal clearance, and compounds with Log P > 7 showed lower but still significant clearance (> 93%). Other important parameters were established to be molecular weight, polarizability and solvent accessible surface area. Modelling tools based on Orthogonal Partial Least Squares (OPLS) regression were created to predict sieving coefficients. CONCLUSIONS: The present work has created a strong background to describe the ability of UF/DF to remove potential organic leachables. Application of these modelling approaches becomes critical to support product safety assessments. Demonstration of significant removal along UF/DF operations confirms risk reduction of leachables coming mostly from upstream stages.
Correction: Development of Alcohol-Resistant Extended-Release Formulations: Regulatory Considerations and Formulation Strategies.
Ji M, Swarnakar NK, Chalamuri SH … +2 more , Kathala K, Tiwari S
Pharm Res · 2026 Apr · PMID 41872647 · Publisher ↗
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Mechanistic Insights into pH-Responsive Drug Release and Antitumor Effects of an Albumin-Pirarubicin Conjugate.
Tsukigawa K, Imoto S, Imamura K … +8 more , Irie N, Nishi K, Tokuno M, Commey KL, Watanabe H, Maruyama T, Otagiri M, Yamasaki K
Pharm Res · 2026 May · PMID 41872646 · Publisher ↗
PURPOSE: This study provides mechanistic insight into the behavior of HSA-THP, a human serum albumin-pirarubicin conjugate linked via a pH-sensitive hydrazone bond. Building upon our previous synthesis, we aimed to eluci...
PURPOSE: This study provides mechanistic insight into the behavior of HSA-THP, a human serum albumin-pirarubicin conjugate linked via a pH-sensitive hydrazone bond. Building upon our previous synthesis, we aimed to elucidate its intracellular uptake, and pH-responsive drug release behavior under acidic intracellular and extracellular conditions in vitro, and to evaluate its in vivo pharmacological properties. METHODS: Intracellular uptake of HSA-THP was evaluated in colon 26 monolayer cultures using fluorescence imaging and HPLC. Cytotoxic effects were compared in 2D and 3D spheroid cultures. Tissue distribution and antitumor efficacy were assessed in tumor‑bearing mice, while systemic toxicity was evaluated in healthy mice following intravenous administration. RESULTS: Both intact HSA-THP and released THP were detected within tumor cells, with cleavage likely promoted by acidic intracellular compartments. The conjugate was also inferred to release THP under mildly acidic extracellular conditions, allowing dual-site drug liberation. In 3D spheroids, the cytotoxicity gap between HSA-THP and free THP seen in 2D cultures narrowed markedly, suggesting albumin-mediated tissue penetration and sustained intratumoral release. Pharmacokinetic analysis revealed prolonged plasma retention and preferential tumor accumulation, with higher levels of liberated THP in tumors but minimal amounts in normal tissues. This distribution pattern resulted in improved antitumor activity with reduced systemic toxicity. CONCLUSIONS: HSA-THP couples albumin's natural trafficking with pH-triggered dual-site drug release, providing mechanistic insight into how albumin conjugation influences drug distribution and activity. These findings establish a fundamental basis for the rational design of albumin-based macromolecular drug conjugates.
Development of a Dual-Isotope Imaging Technique for Simultaneous Quantification and Evaluation of Biodistribution of Antibodies Using "XCam-CdTe".
Nagayasu M, Katsuragawa M, Ozeki K … +6 more , Takeda S, Higashikawa K, Yagishita A, Ochiai A, Terao K, Takahashi T
Pharm Res · 2026 May · PMID 41872645 · Publisher ↗
PURPOSE: The tissue distribution of I- and In-labeled antibodies in a single animal remains challenging to assess simultaneously and sequentially using conventional methods. This study developed a method using "XCam-CdTe...
PURPOSE: The tissue distribution of I- and In-labeled antibodies in a single animal remains challenging to assess simultaneously and sequentially using conventional methods. This study developed a method using "XCam-CdTe" equipped with cadmium telluride double-sided strip detector to simultaneously administer I- and In-labeled antibodies and sequentially quantify their concentrations in tissues. METHODS: Following intravenous administration of I- and In-labeled anti-human interleukin-6 receptor (hIL-6R) antibodies to hIL-6R-Hepa1-6 tumor-bearing syngeneic mice, radioactivity concentrations in blood and tissues including tumors were simultaneously evaluated using XCam-CdTe for up to 72 h. After final imaging, tissues were collected for ex vivo radioactivity measurement using XCam-CdTe. RESULTS: The plasma concentration-time profiles of both labeled antibodies up to 72 h post-dose were consistent between radionuclides and comparable to typical antibodies. The I radioactivity concentration in tumor showed elimination patterns similar to plasma, while the In radioactivity concentration increased up to 72 h post-dose. In the neck region near the thyroid, the I radioactivity concentration increased over time, whereas the In was undetectable except at 1 h post-dose. Reasonable agreement was observed between in vivo and ex vivo measurements for tumors, although In imaging had limited sensitivity for low-activity regions in the neck. CONCLUSIONS: These results suggested that the XCam-CdTe measurement captured the typical pharmacokinetic characteristics of I- and In-labeled antibodies and that both I and In could be assessed simultaneously and over time in the same subject.
Optimizing the Vehicle for High Concentration Protein Suspensions.
Chung C, Schlesinger E
Pharm Res · 2026 Mar · PMID 41872644 · Publisher ↗
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Binding Kinetics Can Explain Linear and Nonlinear Pharmacokinetics of Dipeptidyl Peptidase-IV Inhibitors Within a Single Target-Mediated Framework.
Elalem A, Ette ME, Mager DE
Pharm Res · 2026 Apr · PMID 41851408 · Publisher ↗
INTRODUCTION: Dipeptidyl peptidase-IV inhibitors (DPP4i) are a class of small-molecule drugs for the treatment of patients with type 2 diabetes mellitus. Despite their common mechanism of action, the pharmacokinetics (PK...
INTRODUCTION: Dipeptidyl peptidase-IV inhibitors (DPP4i) are a class of small-molecule drugs for the treatment of patients with type 2 diabetes mellitus. Despite their common mechanism of action, the pharmacokinetics (PK) of DPP4i are varied, with some exhibiting nonlinear target-mediated drug disposition (TMDD). The purpose of this analysis is to test the hypothesis that differences in binding kinetics can explain the relative contribution of TMDD to the variable PK across six drugs in this class. METHODS: Mean PK profiles of six drugs at various dose levels were digitized from the literature, and noncompartmental analysis was performed to determine linearity. All data were analyzed simultaneously with a TMDD model using nonlinear mixed-effects modeling in Monolix. The percentage contribution of target-mediated clearance for each drug was calculated and compared with binding rate constants. RESULTS: A TMDD model with a peripheral compartment effectively captured the pharmacokinetics of all six drugs. The final model supported the hypothesis that the slower rate of dissociation (k) is responsible for the TMDD behavior in select drugs in this class and generated a shared set of system parameters to describe the PK of DPP4i. Population parameters were estimated with adequate precision. A single system-specific total receptor concentration was estimated (0.9 nM). CONCLUSION: A single TMDD model was established for all six DPP4i. The final model explains the behavior of the selected drugs despite their class binding specificity, and a nonlinear structural model was able to adequately capture the behavior of linear drugs when properly constrained.
Evaluation of Mass Spectrometry Compatible Reagents for Determining Small Molecule Loading in Poly(lactic acid) Nanoparticles.
Krug SA, Cottingham AL, Iwamoto M … +3 more , Fletcher S, Pearson RM, Kane MA
Pharm Res · 2026 Mar · PMID 41851407 · Publisher ↗
OBJECTIVE: The objective was to understand if sufficient base hydrolysis and subsequent small molecule quantitation within poly(lactic acid) nanoparticles (PLA-NPs) could be achieved using a mass spectrometry friendly vo...
OBJECTIVE: The objective was to understand if sufficient base hydrolysis and subsequent small molecule quantitation within poly(lactic acid) nanoparticles (PLA-NPs) could be achieved using a mass spectrometry friendly volatile base, such as ammonium hydroxide. Additionally, we sought to evaluate the impact of NP formulation parameters on drug loading as assessed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantitation. METHODS: A microfluidics approach was used to create a library of NPs by systematically varying flow rate ratio (FRR; 1 or 3) and surfactant composition (poly(vinyl alcohol) or poly(glutamic acid)). NPs were characterized using dynamic light scattering to determine their size, polydispersity index, and zeta potential. Several hydrophobic drugs (NRX204647 and 7C, RARγ agonists; SF-7-044, p38α modulator) were tested for NP encapsulation. Base-catalyzed hydrolysis of PLA-NPs using either sodium hydroxide or ammonium hydroxide was employed to release encapsulated drug, which was then quantified using LC-MS/MS. RESULTS: Comparison of sodium hydroxide- and ammonium hydroxide-mediated base hydrolysis of PLA-NPs demonstrated that ammonium hydroxide was as effective for releasing encapsulated hydrophobic drugs for LC-MS/MS-based quantitative analysis. NP formulation parameters (FRR and surfactant chemistry) and drug physicochemical properties influenced NP characteristics and drug loading. CONCLUSION: Using a mass spectrometry friendly base for release of hydrophobic drugs encapsulated within PLA-NP is effective, enabling a simplified quantitative method to evaluate drug loading.
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