Elena Loi, Victoria Díaz-Tomé, Selene Cuello-Rodríguez, Maria Cristina Cardia, Víctor Álvarez-González, Joana Moreira, Francesco Lai, Francisco J Otero-Espinar
{"title":"Enhanced corneal permeation of diclofenac through an ophthalmic nanocrystal suspension.","authors":"Elena Loi, Victoria Díaz-Tomé, Selene Cuello-Rodríguez, Maria Cristina Cardia, Víctor Álvarez-González, Joana Moreira, Francesco Lai, Francisco J Otero-Espinar","doi":"10.1016/j.ijpharm.2025.126272","DOIUrl":"10.1016/j.ijpharm.2025.126272","url":null,"abstract":"<p><p>Diclofenac (DCF) is a non-steroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory and antipyretic effects, commonly used to treat painful and chronic inflammatory conditions linked to angiogenesis. It works by inhibiting cyclooxygenase (COX) enzymes and leukocyte migration, reducing prostaglandin synthesis and inflammation. Topically, DCF is used to manage ocular inflammation such as uveitis and keratitis, prevent cystoid macular edema post-surgery, and maintain mydriasis during operations. Clinical studies show it provides anti-inflammatory benefits comparable to dexamethasone but with a lower risk of increasing intraocular pressure. DCF may also help prevent posterior capsule opacification after cataract surgery. This study aimed to enhance DCF ocular delivery using nanocrystals. Stabilized with Poloxamer 188, the nanosuspensions produced monodisperse nanocrystals (∼450 nm) with a negative ζ-potential (-38 mV), significantly improving corneal permeation versus standard formulations. Ex vivo bovine cornea studies confirmed faster and more efficient drug penetration from the nanosuspension compared to a commercial solution. Safety was supported by BCOP, HET-CAM and cell viability assays, all showing no irritation. Corneal hydration remained stable, indicating low irritation potential. In summary, the developed nanosuspensions offer a promising strategy for improving DCF ocular delivery and therapeutic efficacy. Further clinical studies are needed to confirm long-term safety and effectiveness in humans.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126272"},"PeriodicalIF":5.2,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145292115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Optimizing cinnamophilin delivery via SNEDDS for enhanced anti-melanogenic activity: A comprehensive evaluation of skin safety, permeability, and tyrosinase inhibition.","authors":"Yu-Chen Chen, Yih-Fung Chen, Hsin-Ya Yu, Chia-Hsuan Lin, Wan-Yi Liu, Hsun-Shuo Chang, Yu-Tse Wu, Horng-Huey Ko","doi":"10.1016/j.ijpharm.2025.126260","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2025.126260","url":null,"abstract":"<p><p>Skin hyperpigmentation disorders, such as melasma and age spots, result from abnormal melanin overproduction and remain a significant dermatological concern. Tyrosinase, a key enzyme in melanogenesis, represents a critical target for depigmenting therapies. Cinnamophilin (CINN), a lignan isolated from Machilus species, exhibits strong antioxidant properties and potential tyrosinase inhibitory activity. However, its poor water solubility and limited skin permeability restrict its topical application. In this study, a self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the dermal delivery and efficacy of CINN. Molecular docking revealed the binding of CINN at the tyrosinase catalytic site through hydrogen bonding and π-π interactions, without direct coordination to catalytic copper ions. CINN also exhibited concentration-dependent tyrosinase inhibition in vitro, with an IC<sub>50</sub> value of 39.4 ± 0.1 μM. Enzyme kinetics indicated a mixed-type inhibition mechanism. The optimized CINN-loaded SNEDDS formulation exhibited a mean droplet size of 266.8 nm with a polydispersity index of 0.295 and enhanced skin permeability by approximately threefold in a PAMPA model. In α-MSH-stimulated B16F10 cells, CINN-loaded SNEDDS significantly reduced both melanin secretion and intracellular tyrosinase activity. These findings identify CINN as a natural tyrosinase inhibitor and demonstrate the potential of SNEDDS to improve its solubility, skin permeability, and anti-melanogenic efficacy for topical application.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126260"},"PeriodicalIF":5.2,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tingting Wu, Shuman Wang, Yajing Liu, Xiaoming Bai, Chen Shi
{"title":"Roles and mechanisms of cuproptosis for reversing cancer therapeutic resistance.","authors":"Tingting Wu, Shuman Wang, Yajing Liu, Xiaoming Bai, Chen Shi","doi":"10.1016/j.ijpharm.2025.126267","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2025.126267","url":null,"abstract":"<p><p>Cancer therapeutic resistance remains a major obstacle in clinical oncology, driven by multifaceted mechanisms including multidrug resistance, radioresistance, and immune evasion. Recent advances highlight cuproptosis, a novel copper-dependent programmed cell death modality, as a promising strategy to overcome these challenges. Cuproptosis is triggered by mitochondrial copper overload, leading to lipoylated protein aggregation, tricarboxylic acid cycle disruption, and proteotoxic stress. The regulatory mechanism of copper ions and cuproptosis on cancer offers a unique vulnerability for targeting therapy-resistant malignancies. This review summarized the mechanisms of copper ions, the discovery of cuproptosis, the commonly used copper ionophores and the potential of cuproptosis in overcoming therapeutic resistance, as well as the remaining challenges and future directions concerning cuproptosis. It will provide a novel therapeutic paradigm to overcome cancer therapeutic resistance.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126267"},"PeriodicalIF":5.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Omid Ferdowsizadeh, Ali Poorkhalil, Mohamad Pezeshki-Modaress, Hasan Farrokhzad
{"title":"Nanofibrous smart wound dressing based on pH-responsive methacrylates copolymers: A review.","authors":"Omid Ferdowsizadeh, Ali Poorkhalil, Mohamad Pezeshki-Modaress, Hasan Farrokhzad","doi":"10.1016/j.ijpharm.2025.126264","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2025.126264","url":null,"abstract":"<p><p>Electrospinning is a versatile and eco-friendly method for producing ultra-fine nanofibers from various polymers. Among them, Eudragit® (a family of methacrylate copolymers) has gained prominence due to its pH-responsive solubility and pharmaceutical-grade biocompatibility. Nanofibers derived from Eudragit not only enhance drug delivery and moisture retention but also offer smart functionalities for wound healing. Given the pivotal role of pH in regulating infection control, angiogenesis, enzyme activity, and tissue regeneration, pH-sensitive wound dressings can significantly accelerate healing, especially in chronic wounds with elevated alkalinity. This review provides a comprehensive examination of Eudragit based electrospun nanofibers for wound healing applications. It thoroughly assesses the solvent parameters influencing electrospinning efficiency and morphology, considering how different pH conditions in the wound microenvironment modulate fiber performance and drug release behavior. The central focus of this review is to integrate physicochemical insights with biological relevance, highlighting how pH-responsive nanofibers can be engineered to match wound pathophysiology. By consolidating recent research, this study aims to offer technical guidance for designing next-generation wound dressings with responsive capabilities. The findings serve as a roadmap for optimizing Eudragit electrospun systems tailored for targeted, phase-specific wound treatment.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126264"},"PeriodicalIF":5.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Artificial intelligence in the non-clinical laboratory: enhancing good laboratory and documentation practices.","authors":"Khadijah Zai, Anggoro Praja Mukti, Gabriella Sabeth Notty, Sukma Uswatun Niswah, Refliandi, Firman Oktivendra","doi":"10.1016/j.ijpharm.2025.126266","DOIUrl":"10.1016/j.ijpharm.2025.126266","url":null,"abstract":"<p><p>Non-clinical laboratories are under increasing regulatory pressure from agencies such as the FDA, EMA, and MHRA to ensure data integrity, traceability, and compliance with Good Laboratory Practice (GLP) and Good Documentation Practice (GDP). While Artificial Intelligence (AI) has been widely explored in clinical diagnostics and drug discovery, its application to non-clinical laboratories, particularly in relation to validation, regulatory alignment, and Technology Readiness Level (TRL), remains limited. This review critically examines how AI can strengthen GLP/GDP compliance through applications in anomaly detection, predictive modeling, computer vision, and natural language processing. Unlike existing reviews that emphasize technical algorithms, this work highlights regulatory dimensions, including risk-based validation protocols, integration with ICH guidelines (Q8-Q14), and compliance with frameworks such as FDA, EMA, and ALCOA + principles. The maturity of AI tools is assessed using TRL mapping, which differentiates between deployable applications, such as Random Forest models for predictive quality control and AI-enhanced Laboratory Information Management Systems (LIMS) for audit trail automation, and speculative, early-stage concepts, including NLP-driven audit documentation. Current barriers include limited interoperability with legacy systems, insufficient workforce training, and high infrastructure costs, particularly in low- and middle-income countries. To address these challenges, phased adoption strategies using open-source tools, cloud-based platforms, and human-in-the-loop oversight are proposed to ensure transparency and regulatory acceptability. By linking AI adoption with Pharma 4.0, Process Analytical Technology (PAT), and Quality by Design (QbD), this review provides a structured roadmap for regulators, practitioners, and technology developers. In doing so, it advances the discussion beyond technical feasibility to focus on compliance, scalability, and equitable access, ensuring that AI enhances rather than disrupts laboratory quality practices.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126266"},"PeriodicalIF":5.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Nano vesicular approaches for the treatment of skin cancer.","authors":"Shweta Singh, Ankur Vaidya, Navneet Verma","doi":"10.1016/j.ijpharm.2025.126265","DOIUrl":"10.1016/j.ijpharm.2025.126265","url":null,"abstract":"<p><p>Skin cancer is increasing as a global health issue, with rising cases particularly in Caucasian populations. It is the most common cause of decreased quality of life worldwide. There are an estimated 1.5 million new cases each year. The conventional chemotherapy treatment is challenging and often ineffective. These problems can be overcome by the use of lipid nanoparticles and may allow for early detection and monitoring of neoplastic changes, and determine the effectiveness of the treatment. The lipid nanoparticle is significant in delivery systems due to its non-invasive and targeted delivery system is based on the type of active drug. Due to its ability to penetrate deep into the layers of the skin, skin delivery systems are capable of delivering drugs to target cells in a protected manner. Research over the previous decade on carriers of active substances indicates that drugs can be delivered more accurately to the tumor site, resulting in higher therapeutic efficacy. This article describes the application of liposomes, niosomes, ethosomes, transethosomes, transferosomes, invasomes, metal nanoparticles, and polymer nanoparticles in existing therapies. This review aimed to examine the properties and applications of nano lipid carriers used in the treatment and prevention of numerous types of skin cancer.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126265"},"PeriodicalIF":5.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Semmal Syed Meerasa, Aqeel Ahmad, Amer Ali Khan, Shafiul Haque, Imran Saleem
{"title":"Endosomal escape and current obstacles in ionizable lipid nanoparticles mediated gene delivery: lessons from COVID-19 vaccines.","authors":"Semmal Syed Meerasa, Aqeel Ahmad, Amer Ali Khan, Shafiul Haque, Imran Saleem","doi":"10.1016/j.ijpharm.2025.126263","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2025.126263","url":null,"abstract":"<p><p>During last pandemic of COVID-19, two vaccines based on ionizable lipid nanoparticles (ILNP) were developed for COVID-19 prevention: Pfizer/BioNTech Vaccine (BNT162b2) and Moderna Vaccine (mRNA-1273). The observed efficacy of these two vaccine formulations catalyzed a global intensification of scientific inquiry into the therapeutic potential of these ionizable lipids, driving research efforts aimed at developing novel agents for a diverse range of pathologies. Successful ILNP-based delivery requires both selection of a suitable ionizable lipid and elucidation of its endosomal escape mechanism. This review focuses current knowledge on lipid diversity, emphasizing the structural and functional attributes of ionizable lipids essential for endosomal escape. A detailed analysis of COVID-19 vaccine lipid components, correlating their physicochemical properties with cellular and humoral immune responses, and exploring their implications for therapeutic innovation. Finally, we evaluate current challenges and future directions in ILNP-based therapy development.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126263"},"PeriodicalIF":5.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Impact of magnesium aluminometasilicates on rheological and compaction properties of moisture-sensitive excipients.","authors":"Pavlína Komínová, Petr Zámostný, Jan Henrik Finke","doi":"10.1016/j.ijpharm.2025.126258","DOIUrl":"10.1016/j.ijpharm.2025.126258","url":null,"abstract":"<p><p>Moisture is a critical external factor affecting the powder behaviour. This work focused on the effect of moisture on the rheological and compaction properties of two moisture-sensitive excipients, microcrystalline cellulose (MCC) and partially pregelatinized starch (PPS). Moreover, the impact of highly porous magnesium aluminometasilicates (MAS) admixed to the excipients was evaluated towards their moisture-controlling or property-improving qualities. The generally negative effects of moisture on rheological properties of pure excipients were positively influenced by MAS addition to achieve acceptable properties also under highest studied humidity (78 % RH). An almost twofold increase in the flow function coefficient value was observed with the addition of 25 w/w % of MAS to MCC and PPS. Increasing moisture leads to weaker tablets of pure MCC (40 % decrease of value) and, on the contrary, improves the tabletability of pure PPS with 54 % increase of tablet tensile strength under 78 % RH at compaction pressure of 250 MPa, respectively. Moisture also causes a decrease in tablet porosity, elastic recovery as well as plasticity factor (ratio between plastic and total deformation energy) for both excipients. The property improvement was proportional to the MAS content in the mixture of MCC-MAS. In PPS-MAS, the properties of PPS dominate the system more and higher MAS additions exhibited limited effect. However, all things considered, the addition of MAS could improve the processability and product quality by mostly predictable means of mixing rules and serve as a moisture-controlling additive. Moreover, these findings demonstrate a cost-effective strategy for mitigating humidity effects at the formulation level.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126258"},"PeriodicalIF":5.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Thermosensitive hydrogel containing liposomal nanoparticles of deferoxamine and curcumin: In vitro evaluation and diabetic wound healing effect in rats.","authors":"Neda Mostajeran, Hossein Kamali, Leila Arabi, Jebraeil Movaffagh, Hoda Alavizadeh, Vahideh Mohammadzadeh, Niloufar Rahiman, Mehdi Karimi Shahri, Mahmoud Reza Jaafari, Marzieh Mohammadi","doi":"10.1016/j.ijpharm.2025.126227","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2025.126227","url":null,"abstract":"<p><p>Diabetic wound as a serious complication of diabetes remains a major clinical challenge. Excessive chronic inflammation, recurrent infection and impaired angiogenesis are the main causes of the complex diabetic wound microstructure. Therefore, developing a multifunctional hydrogel-based wound dressing incorporating various modalities to restore the tissue function and accelerate the healing process could offer a promising strategy. To this goal, curcumin (CUR, as an anti-inflammatory agent) and deferoxamine (DFO, as an angiogenesis stimulant) were simultaneously loaded into liposomal nanoparticles and further incorporated into thermosensitive hydrogel made of PEG-PCL-PEG copolymer. Particle size, zeta potential, encapsulation efficiency (EE) and release pattern of liposomal nanoparticles were evaluated. Liposomal nanoparticles (DPPC/DPPGG/CUR/DEF: 80/10/10) incorporating DFO in the core and CUR in the shell were 160.5 ± 0.44 nm in size and negatively charged (-19.4 ± 0.21). EE for CUR and DFO were 88.37 % and 97.15 %, respectively. CUR release reached 14 % and DFO was released 100 % from liposomal formulation after 5 days. To determine the optimal concentration of curcumin and deferoxamine in induction of angiogenesis, chicken chorioallantoic membrane (CAM) test was conducted. The results indicated that liposomal formulation containing both curcumin (90 μM) and deferoxamine (100 μM) demonstrated the highest angiogenic effect. Afterwards, thermosensitive hydrogel (PEG-PCL-PEG) was synthesized. The finally optimized hydrogel was made of 30 % (Wt %) polymer solution of PCL:PEG (4:1 wt ratio). Thereafter, liposomal nanoparticles were incorporated into the hydrogel and the release pattern of curcumin and deferoxamine from liposome incorporated hydrogel was studied. Hydrogel to liposomal volume ratio was 70:30. The swelling ratio of the designed hydrogel reached 0.7 of its initial weight in 28 days. Moreover, stability study revealed that about 50 % of hydrogel's initial weight was degraded in 28 days. Rheology study showed that the synthesized hydrogel was pseudoplastic as the viscosity was decreased by increasing the shear rate. The release pattern of CUR and DFO from the liposome loaded hydrogel platform occurred in a gentler slope and more uniformly due to the hydrogel resistance although the final release rate was approximately the same as the liposomal formulation. In the final step, the effect of the developed hydrogel on an animal model of diabetic ulcer in rats was evaluated. Tissue morphology, collagen deposition, angiogenesis (CD31 and vimentin) were also evaluated. The results of histological studies showed that the hydrogel platform incorporating CUR-DEF coloaded liposomes performed better in terms of collagen deposition and re-epithelialization than other groups (hydrogel loaded with either liposomal CUR or liposomal DEF). Immunohistochemistry tests for CD31 and Vimentin in newly formed vessels also showed that angiogenesis occurred","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126227"},"PeriodicalIF":5.2,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}